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Latest erectile dysfunction News By Steven Reinberg HealthDay ReporterMONDAY, where can i buy viagra Nov https://www.msamentoring.com/online-viagra-cost/. 29, 2021 (HealthDay News) A heart condition, myocarditis, has been found in a number of U.S. College athletes who have had erectile dysfunction treatment, a new study where can i buy viagra finds.

Myocarditis has also been linked in some young people to the erectile dysfunction treatment. But the odds are far greater that this inflammation of the heart muscle will occur in those who get erectile dysfunction treatment itself, experts said. "We're still learning about how the viagra attacks the heart," said lead where can i buy viagra researcher Dr.

Jean Jeudy, a professor of radiology at the University of Maryland School of Medicine. "Myocarditis is part of the body's reaction to fighting the , but it's also in response to the viagra trying to attack the heart." Myocarditis is usually caused by a viral or bacterial . It can where can i buy viagra affect the heart's rhythm and ability to pump.

It can also cause lasting scarring of the heart muscle, Jeudy's team noted. The risk for myocarditis among people with erectile dysfunction treatment is 16 times higher than among those without the , according to the U.S. Centers for Disease Control and where can i buy viagra Prevention.

Jeudy and his colleagues said that myocarditis has been linked to up to 20% of sudden deaths in young athletes. Concern had been raised that myocarditis can occur after being vaccinated for erectile dysfunction treatment, especially among young males like those in this study. According to the CDC, however, there are approximately 50 cases of myocarditis for where can i buy viagra every 1 million young men vaccinated, far below the risk of myocarditis from erectile dysfunction treatment itself.

Based on its data, the CDC says the benefit from the treatment far outweighs the risk of getting myocarditis. "We know that erectile dysfunction treatment can affect the heart, and we know there's no reason to risk the potential for the kind of long-term effects of erectile dysfunction treatment," Jeudy said. "So getting vaccinated is probably where can i buy viagra the No.

1 thing to think about," he stressed. For this study, Jeudy's team took advantage of the Big Ten Athletic Conference's ability to get data on the frequency of myocarditis in student athletes recovering from erectile dysfunction treatment. The conference required all athletes who had erectile dysfunction treatment to where can i buy viagra get a series of heart tests before returning to play.

Tests included cardiac MRIs, echocardiograms, ECGs and blood tests. Jeudy reviewed the results of nearly 1,600 cardiac MRIs from 13 participating universities. Thirty-seven of where can i buy viagra these athletes (2.3%) had myocarditis related to erectile dysfunction treatment.

What was surprising, however, was that few had symptoms. Twenty of these patients with erectile dysfunction treatment myocarditis (54%) had no cardiac symptoms or heart abnormalities seen on other tests. Only MRIs found the where can i buy viagra problem.

For some of the athletes studied, myocarditis was limited and went away within a month, but others continued to show abnormalities on MRIs, Jeudy said. MRIs are expensive, and most patients hospitalized for erectile dysfunction treatment don't get them, so it's likely that many cases of myocarditis go undiagnosed, he said. The long-term consequence of myocarditis among those infected with erectile dysfunction treatment will where can i buy viagra only become clear over time, Jeudy said.

He noted that persistent inflammation or heart scarring can increase the risk of an irregular heartbeat known as arrhythmia. When can athletes resume play?. "At the very least, this athlete is going to be out for six where can i buy viagra months, with evaluation, making sure that they have a gradual return to play," Jeudy said.

"It's largely connected with symptoms. If there are signs of decreased function or underlying arrhythmia, that would be a concern for that particular athlete." The findings were released Monday at the annual where can i buy viagra meeting of the Radiological Society of North America. Findings presented at medical meetings are considered preliminary until published in a peer-reviewed journal.

Dr. Marc Siegel, a clinical professor of medicine at NYU Langone Medical Center in New where can i buy viagra York City, said erectile dysfunction treatment can affect many parts of the body. "It's a viagra that sets off a lot of alarms around the body, inflammatory alarms that go off," said Siegel, who was not involved with the study.

"Those inflammatory alarms occur in organs where the viagra isn't even present," he said. "It's the body where can i buy viagra fighting back against the viagra systemically. We're seeing it in the brain.

We're seeing it in the heart. We're seeing it where can i buy viagra in the lungs. It's a multi-system organ risk of inflammation." Siegel said the best way to prevent getting erectile dysfunction treatment and its complications is to get vaccinated.

"This study is yet another motivation to get vaccinated before you ever get erectile dysfunction treatment," he said. More information For more on erectile dysfunction treatment, where can i buy viagra see the U.S. Centers for Disease Control and Prevention.

SOURCES. Jean Jeudy, where can i buy viagra MD, professor, radiology, University of Maryland School of Medicine, Baltimore. Marc Siegel, MD, clinical professor, medicine, NYU Langone Medical Center, New York City.

Presentation, Radiological Society of North America, Nov. 29, 2021 where can i buy viagra Copyright © 2021 HealthDay. All rights reserved.Latest Neurology News By Alan Mozes HealthDay ReporterMONDAY, Nov.

29, 2021 (HealthDay News) Repetitive head hits are common in football, and they're also linked to debilitating brain injuries. But rendering a where can i buy viagra definitive diagnosis typically means waiting for autopsy results after the player has died. Now, a new study suggests that brain scans can reliably spot troubling signs of sports-inflicted neurological damage while a person is still alive.

The research also showed that more brain lesions show up on the scans the longer football players have engaged in the sport. "A routine [MRI] scan might be able to capture where can i buy viagra long-term harm to the brain in people who have been exposed to repetitive hits to the head, like those from American football and other contact sports," concluded study author Michael Alosco. Alosco is co-director of the Alzheimer's Disease Research Center Clinical Core with Boston University's School of Medicine.

He and his colleagues explained that what such MRIs are looking for are bright spots on the brain known as "white matter hyperintensities." "They literally appear as bright white spots," said Alosco. "Anyone can see where can i buy viagra them. And they signal injury to the white matter of the brain." Outside the context of contact sports, such spots typically are a sign of aging, he noted, "and it is common to see them in people who are older than 65." Among the elderly, heart disease is often the root cause, Alosco said, because when the heart fails to deliver enough blood to the brain, the resulting oxygen deficit ends up injuring the person's small blood vessels and white matter.

"However, these hyperintensities can have many causes, and research also links them with progressive brain diseases like Alzheimer's disease," he added. So, he and his team set out to see whether the same bright spots might be linked where can i buy viagra to repetitive hits to the head among athletes involved in contact sports. In all, the study focused on 67 football players, along with eight others who were either soccer players, boxers or military veterans.

On average, the football players had 12 years of play under their belts (including 16 professionals and 11 where can i buy viagra semi-professionals). By the time the study got underway, all the athletes had already died (at an average age of 67). And all had donated their brains for research into head injuries.

But all had also undergone brain scans while alive (at an average age where can i buy viagra of 62). When Alosco and his colleagues reanalyzed those scans, they found that the longer a football player had played the sport, the more bright spots he had while alive. In addition, for every additional "unit" of white matter spots, the risk for having serious small vessel disease and general white matter damage in the brain doubled.

Each additional unit of such markers was also linked to a tripling of the presence of a specific protein ("tau") that has long been linked to both Alzheimer's disease and a neurodegenerative disease called chronic traumatic encephalopathy (CTE) where can i buy viagra. In fact, autopsies confirmed that roughly seven in 10 of the athletes in the study had CTE, a precursor for dementia. And family members of the athletes in the study further confirmed that roughly two-thirds suffered from dementia.

The findings were where can i buy viagra published online Nov. 24 in the journal Neurology. Alosco said the results are "exciting," given that they offer "a very practical way to study brain harm" in real time, rather than after the fact.

But a more sobering assessment where can i buy viagra was offered by Dr. Robert Glatter, an emergency medicine physician at Lenox Hill Hospital in New York City and a former sideline physician for the New York Jets. The study "adds to the argument to ban tackle football altogether," he said.

"The implications where can i buy viagra of the study are quite clear. Repetitive head and body impacts over time — whether concussive or subconcussive — increase the risk for developing brain injury, indicating a long-term or cumulative effect," Glatter said. QUESTION The abbreviated term ADHD denotes the condition commonly known as.

See Answer And the problem is that, despite some effort to reduce risk, "playing contact football is inherently dangerous and unpredictable at best," raising the risk of CTE, where can i buy viagra cognitive impairment and neurodegenerative diseases like Alzheimer's and Parkinson's. Still, another expert cautioned against overinterpreting the results until more research is completed. The study only looked at athletes who had already developed brain injuries, noted Dr.

Julie Schneider, associate director of the Alzheimer's Disease Center at Rush University Medical Center, in Chicago where can i buy viagra. And that, she said, makes it impossible to conclude that the bright spots in question actually predict such injuries. What's now needed, said Schneider, are "studies starting with players prior to having symptoms." That will be the only way to "figure out the sequence of brain changes, and their relationship with dementia during life." More information There's more on the link between football and brain injuries at NYU Grossman School of Medicine.

SOURCES. Michael Alosco, PhD, associate professor, neurology, and co-director, Alzheimer's Disease Research Center Clinical Core, and investigator, CTE Center, department of neurology, Boston University School of Medicine. Julie A.

Schneider, MD, MS, professor of pathology and neurological sciences, and associate director, Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago. Robert Glatter, MD, emergency medicine physician, Lenox Hill Hospital, New York City, and former sideline physician, New York Jets. Neurology, Nov.

24, 2021, online Copyright © 2021 HealthDay. All rights reserved. From Brain and Nervous System Resources Featured Centers Health Solutions From Our Sponsors.

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We are social epidemiologists and community advocates focused on addressing social determinants of health mixing cialis and viagra inequities. While we appreciate O’Neill et al’s effort to link multiple provincial-level administrative data sets to examine homicide victimisation by immigration status in Ontario, Canada, we have concerns about the framing and interpretation of findings and their potential impact on immigrants and refugees.1FRAMING AND APPROACHWhile O’Neill et al’s data and sample size are strengths, the attention to the context of being an immigrant to Canada, theoretical framework and motivation for examining immigrants in relation to homicide victimisation are not fully developed. O’Neill et mixing cialis and viagra al do not acknowledge having done any community engagement which is critical and ethical2 given the long history of exclusion, exploitation, racism and discrimination, and the current global climate of increasing criminalisation of migrants.

Meaningful community engagement offers important context. Helps shape the research purpose, mixing cialis and viagra questions, approach, interpretation and recommendations. And can reduce the potential for harm.Though criminalisation of migration under security pretexts is an infringement of international law,3 and contradicts evidence that immigration is related to a reduction in crime,4 many high-income countries, including Canada, are framing harmful immigration policy (eg, restricting entry, detaining immigrants) as an urgent need to protect against threats of safety and security,4 5 disproportionately targeting racialised and Muslim immigrants and refugees.

Within this policy context, along with political rhetoric to generate support for it, hate crimes are at mixing cialis and viagra record highs in Canada, with approximately 85% of these crimes motivated by racism and ethnic or religious discrimination.6Not only does this paper fail to consider this context, the statements that immigrant communities are ‘predisposed to violence’ without evidence to support this claim. The conflation of perpetrating and dying by homicide, by alternating between the use of ‘homicide’ and ‘homicide victimisation’. And the suggestion that ‘cultural views on gender’ increase risk of violence and homicide victimisation against immigrant women, are particularly mixing cialis and viagra harmful.RESULTS AND INTERPRETATIONThe authors’ emphasis on the increased risk of homicide victimisation of female and male refugees compared to long-term residents is misleading given that these results are not statistically significant.

The authors argue that the findings are important regardless of significance, because of large effect sizes. But for many researchers, effect sizes of 1.31 and 1.23, respectively, would be considered small to medium and would lead to a much more cautious interpretation.The authors’ interpretation that non-refugee immigrants have a lower risk of homicide victimisation because Canada’s immigration policies select for highly educated mixing cialis and viagra and healthy immigrants reflects problems with the theory informing this research, since homicide victimisation is not within the control of an individual. Social epidemiology was founded on the need to theorise political, economic and cultural context over and above individual characteristics.7 A concerning omission is that there is no mention of the potential for hate crimes6 to be at least partially responsible for homicide victimisation among refugees and immigrants.

Additionally, in the text, it is left unclear how a refugee’s history of ‘violence, trauma and mixing cialis and viagra torture’ and ‘depression and psychosocial illness’ are linked to homicide victimisation. Such unsupported statements omit essential consideration that Canadian neighbourhoods are heterogeneous combinations of refugees, non-refugees and long-term residents and that violence occurs within a social context which includes racism, xenophobia and Islamophobia.8With the study’s low counts of homicide victimisations among refugees (31 among females and 89 among males over 20 years), 90% of all homicide victimisations in the same time period occurring among long-term residents (table 1 of paper), and no clear data pointing to specific factors to intervene upon, we argue that this potential in excess homicide victimisation does not warrant targeted homicide prevention strategies, as the authors suggest. Broader prevention strategies targeting the entire population (eg, a national ban on handguns and assault weapons,9 10 implementing Canada’s Anti-Racism Strategy8) may be more beneficial in reducing mixing cialis and viagra homicide victimisation.POTENTIAL IMPACTWe are concerned that the paper’s framing, approach and interpretation could negatively impact immigrant and refugee communities targeted by significant racism, anti-immigrant sentiment and Islamophobia at policy, practice, community and individual levels.6 11 Community engagement from the start, and comprehensive multi-level, multistage social determinants of immigrant health framework,11 could have prevented misinterpretations of the findings and this potential for harm.

It could have also shifted the approach from a deficit- to an asset-based one that recognises the leadership and impacts of women who founded groups such as Mothers for Peace12 and Mending a Crack in the Sky.13 These groups combat the stigmatisation of mothers and families that have lost children to violence. Support mothers and families experiencing mixing cialis and viagra ongoing trauma due to violence. And advocate for policy and programme change to reduce poverty, violence and homicide for all people in Canada, a more inclusive public health approach.We thank Wanigaratne and Mawani et al for taking the time to write this Commentary,1 which we have read with great interest.

We agree that the framing and interpretation of findings about immigrant and mixing cialis and viagra refugee communities is of great importance and appreciate the opportunity to provide clarification. We would first like to acknowledge the valuable expertise of the authors as well as their strong relationships and vital advocacy work within communities.The primary aim of our study was to provide descriptive epidemiology of homicide in Ontario.2 Very few population-level descriptive studies have been published characterising homicides, particularly regarding trends in homicide victimisation between and across population subgroups. Our study team includes epidemiologists, professional and academics who work at the intersection of public health and violence, experience with implementing violence prevention programmes in marginalised populations around the world and expertise in working with large linked health administrative data.The linked health and administrative databases we used help fill the data gap with respect to understanding the victims of violence, including but not limited to refugee status.3 This aim is consistent with other descriptive database studies published about health and health system outcomes mixing cialis and viagra among immigrant and refugee populations in Ontario.4–11 The motivation for this study was to provide descriptive data that can be used by communities and researchers to better understand the distribution of health outcomes across populations.

Our study found differences in risk of homicide across several social and economic indicators, including lower socioeconomic ….

We are social epidemiologists and community advocates focused on addressing social determinants of health inequities where can i buy viagra http://www.ec-neuhof-strasbourg.ac-strasbourg.fr/wp/?p=6183. While we appreciate O’Neill et al’s effort to link multiple provincial-level administrative data sets to examine homicide victimisation by immigration status in Ontario, Canada, we have concerns about the framing and interpretation of findings and their potential impact on immigrants and refugees.1FRAMING AND APPROACHWhile O’Neill et al’s data and sample size are strengths, the attention to the context of being an immigrant to Canada, theoretical framework and motivation for examining immigrants in relation to homicide victimisation are not fully developed. O’Neill et al do not acknowledge having done any community engagement which is critical and ethical2 given the long history of exclusion, exploitation, racism and discrimination, and the current global where can i buy viagra climate of increasing criminalisation of migrants. Meaningful community engagement offers important context.

Helps shape the research purpose, where can i buy viagra questions, approach, interpretation and recommendations. And can reduce the potential for harm.Though criminalisation of migration under security pretexts is an infringement of international law,3 and contradicts evidence that immigration is related to a reduction in crime,4 many high-income countries, including Canada, are framing harmful immigration policy (eg, restricting entry, detaining immigrants) as an urgent need to protect against threats of safety and security,4 5 disproportionately targeting racialised and Muslim immigrants and refugees. Within this policy context, along with political rhetoric to generate support for it, hate crimes are at record highs in Canada, with approximately 85% of these crimes motivated where can i buy viagra by racism and ethnic or religious discrimination.6Not only does this paper fail to consider this context, the statements that immigrant communities are ‘predisposed to violence’ without evidence to support this claim. The conflation of perpetrating and dying by homicide, by alternating between the use of ‘homicide’ and ‘homicide victimisation’.

And the suggestion that ‘cultural views on gender’ increase risk of violence and homicide victimisation against immigrant women, are particularly harmful.RESULTS AND INTERPRETATIONThe authors’ emphasis on the increased risk of homicide victimisation of female and male refugees where can i buy viagra compared to long-term residents is misleading given that these results are not statistically significant. The authors argue that the findings are important regardless of significance, because of large effect sizes. But for many researchers, effect sizes of 1.31 and 1.23, respectively, would be considered small to medium and would lead where can i buy viagra to a much more cautious interpretation.The authors’ interpretation that non-refugee immigrants have a lower risk of homicide victimisation because Canada’s immigration policies select for highly educated and healthy immigrants reflects problems with the theory informing this research, since homicide victimisation is not within the control of an individual. Social epidemiology was founded on the need to theorise political, economic and cultural context over and above individual characteristics.7 A concerning omission is that there is no mention of the potential for hate crimes6 to be at how to get viagra least partially responsible for homicide victimisation among refugees and immigrants.

Additionally, in the where can i buy viagra text, it is left unclear how a refugee’s history of ‘violence, trauma and torture’ and ‘depression and psychosocial illness’ are linked to homicide victimisation. Such unsupported statements omit essential consideration that Canadian neighbourhoods are heterogeneous combinations of refugees, non-refugees and long-term residents and that violence occurs within a social context which includes racism, xenophobia and Islamophobia.8With the study’s low counts of homicide victimisations among refugees (31 among females and 89 among males over 20 years), 90% of all homicide victimisations in the same time period occurring among long-term residents (table 1 of paper), and no clear data pointing to specific factors to intervene upon, we argue that this potential in excess homicide victimisation does not warrant targeted homicide prevention strategies, as the authors suggest. Broader prevention strategies targeting the where can i buy viagra entire population (eg, a national ban on handguns and assault weapons,9 10 implementing Canada’s Anti-Racism Strategy8) may be more beneficial in reducing homicide victimisation.POTENTIAL IMPACTWe are concerned that the paper’s framing, approach and interpretation could negatively impact immigrant and refugee communities targeted by significant racism, anti-immigrant sentiment and Islamophobia at policy, practice, community and individual levels.6 11 Community engagement from the start, and comprehensive multi-level, multistage social determinants of immigrant health framework,11 could have prevented misinterpretations of the findings and this potential for harm. It could have also shifted the approach from a deficit- to an asset-based one that recognises the leadership and impacts of women who founded groups such as Mothers for Peace12 and Mending a Crack in the Sky.13 These groups combat the stigmatisation of mothers and families that have lost children to violence.

Support mothers and families experiencing ongoing trauma due to violence where can i buy viagra. And advocate for policy and programme change to reduce poverty, violence and homicide for all people in Canada, a more inclusive public health approach.We thank Wanigaratne and Mawani et al for taking the time to write this Commentary,1 which we have read with great interest. We agree that the framing and interpretation of findings about immigrant and refugee communities is where can i buy viagra of great importance and appreciate the opportunity to provide clarification. We would first like to acknowledge the valuable expertise of the authors as well as their strong relationships and vital advocacy work within communities.The primary aim of our study was to provide descriptive epidemiology of homicide in Ontario.2 Very few population-level descriptive studies have been published characterising homicides, particularly regarding trends in homicide victimisation between and across population subgroups.

Our study team includes epidemiologists, professional and academics who work at the intersection of public health and violence, experience with implementing violence where can i buy viagra prevention programmes in marginalised populations around the world and expertise in working with large linked health administrative data.The linked health and administrative databases we used help fill the data gap with respect to understanding the victims of violence, including but not limited to refugee status.3 This aim is consistent with other descriptive database studies published about health and health system outcomes among immigrant and refugee populations in Ontario.4–11 The motivation for this study was to provide descriptive data that can be used by communities and researchers to better understand the distribution of health outcomes across populations. Our study found differences in risk of homicide across several social and economic indicators, including lower socioeconomic ….

What may interact with Viagra?

Do not take Viagra with any of the following:

• cisapride
• methscopolamine nitrate
• nitrates like amyl nitrite, isosorbide dinitrate, isosorbide mononitrate, nitroglycerin
• nitroprusside
• other sildenafil products (Revatio)

Viagra may also interact with the following:

• certain drugs for high blood pressure
• certain drugs for the treatment of HIV or AIDS
• certain drugs used for fungal or yeast s, like fluconazole, itraconazole, ketoconazole, and voriconazole
• cimetidine
• erythromycin
• rifampin

This list may not describe all possible interactions. Give your health care providers a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

Viagra online purchase

To the viagra online purchase Editor. Ivermectin is approved viagra online purchase by the Food and Drug Administration as an oral treatment for intestinal strongyloidiasis and onchocerciasis and as a topical treatment for pediculosis and rosacea. It is also used as a treatment viagra online purchase for parasites in pets and livestock.

Ivermectin may decrease severe acute respiratory syndrome erectile dysfunction 2 (erectile dysfunction) replication in vitro,1,2 but randomized, controlled trials have shown no clinical benefit in the prevention or treatment of erectile dysfunction disease 2019 (erectile dysfunction treatment).3 Veterinary use of ivermectin has increased, and the number of prescriptions for use by humans in the United States is 24 times as high as the number before the viagra. Moreover, the number of such prescriptions in viagra online purchase August 2021 was 4 times as high as the number in July 2021.3,4 The Oregon Poison Center is a telephone consultative center staffed by specialty-trained nurses, pharmacists, and physicians who provide treatment advice for the public and comprehensive treatment consultation for health care workers caring for patients in Oregon, Alaska, and Guam. The center has recently received viagra online purchase an increasing number of calls regarding ivermectin exposure related to erectile dysfunction treatment.

The rate of calls regarding ivermectin had been 0.25 calls per month in 2020 and had increased to 0.86 calls per month from January through July 2021. In August 2021, the center viagra online purchase received 21 calls. Monthly total viagra online purchase call volumes for all poison exposures were stable throughout 2020 and 2021.

Of the 21 persons who called in August, 11 were men, and most were older than 60 years of age (median age, 64. Range, 20 to viagra online purchase 81). Approximately half viagra online purchase (11 persons) were reported to have used ivermectin to prevent erectile dysfunction treatment, and the remaining persons had been using the drug to treat erectile dysfunction treatment symptoms.

Three persons had received prescriptions from physicians or veterinarians, and 17 had purchased veterinary formulations. The source of ivermectin for the remaining person viagra online purchase was not confirmed. Symptoms had developed in most persons viagra online purchase within 2 hours after a large, single, first-time dose.

In 6 persons, symptoms had developed gradually after several days to weeks of repeated doses taken every other day viagra online purchase or twice weekly. One person had also been taking vitamin D to treat or prevent erectile dysfunction treatment. Reported doses ingested by the persons viagra online purchase who had been using veterinary products ranged from 6.8 mg to 125 mg of 1.87% paste and 20 to 50 mg of the 1% solution.

The dose of the human-use tablets was 21 mg per viagra online purchase dose twice weekly for prevention. Six of the 21 persons were hospitalized for toxic effects from ivermectin use. All 6 reported preventive use, including the 3 viagra online purchase who had obtained the drug by prescription.

Four received care in an intensive care unit, and none died viagra online purchase. Symptoms were gastrointestinal distress in 4 persons, confusion in 3, ataxia and weakness in 2, hypotension in 2, and seizures in 1. Of the persons who were not admitted to a hospital, viagra online purchase most had gastrointestinal distress, dizziness, confusion, vision symptoms, or rash.

These cases illustrate the potential toxic effects of ivermectin, including severe episodes of confusion, ataxia, seizures, and hypotension, and the viagra online purchase increasing frequency of inappropriate use. There is insufficient evidence to support the use of ivermectin to treat or prevent erectile dysfunction treatment,3 and improper use, as well as the possible occurrence of medication interactions,5 may result in serious side effects requiring hospitalization. Courtney Temple, M.D.Ruby Hoang, D.O.Robert G viagra online purchase.

Hendrickson, M.D.Oregon viagra online purchase Health and Science University, Portland, OR Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. This letter viagra online purchase was published on October 20, 2021, at NEJM.org.5 References1. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM.

The FDA-approved drug ivermectin inhibits the replication of erectile dysfunction in viagra online purchase vitro. Antiviral Res viagra online purchase 2020;178:104787-104787.2. Lehrer S, Rheinstein PH.

Ivermectin docks viagra online purchase to the erectile dysfunction spike receptor-binding domain attached to ACE2. In Vivo viagra online purchase 2020;34:3023-3026.3. Centers for Disease Control and Prevention.

Rapid increase in ivermectin prescriptions and reports of severe illness associated with viagra online purchase use of products containing ivermectin to prevent or treat erectile dysfunction treatment. CDC Health viagra online purchase Alert Network no. CDCHAN-00449.

August 26, 2021 (https://emergency.cdc.gov/han/2021/han00449.asp).Google Scholar4 viagra online purchase. Lind JN, Lovegrove MC, Geller viagra online purchase AI, Uyeki TM, Datta SD, Budnitz DS. Increase in outpatient ivermectin dispensing in viagra online purchase the US during the erectile dysfunction treatment viagra.

A cross-sectional analysis. J Gen Intern viagra online purchase Med 2021;36:2909-2911.5. Edwards G viagra online purchase.

Ivermectin. Does P-glycoprotein play a viagra online purchase role in neurotoxicity?. Filaria J 2003;2:Suppl 1:S8-S8.To the Editor viagra online purchase.

Pregnant women with erectile dysfunction disease 2019 (erectile dysfunction treatment) are at increased risk for adverse outcomes, and erectile dysfunction treatment vaccination is recommended during pregnancy.1,2 However, safety data on erectile dysfunction treatment vaccination during pregnancy remain limited.3,4 We performed a case–control study with data from Norwegian registries on first-trimester pregnancies, erectile dysfunction treatment vaccination, background characteristics, and underlying health conditions (Supplementary Methods and Tables S1 through S3 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). We identified all women who were registered between February 15 and August 15, 2021, as having had a miscarriage before 14 weeks of gestation (case patients) and those with a primary care–based confirmation of ongoing pregnancy in the first trimester viagra online purchase (controls). In Norway, although vaccination during the first trimester is not recommended except in women with viagra online purchase underlying risk conditions, women not yet aware that they were pregnant may still be vaccinated in the first trimester.

We estimated odds ratios with 95% confidence intervals for erectile dysfunction treatment vaccination within 5-week and 3-week windows before a miscarriage or ongoing pregnancy, adjusting for women’s age, country of birth, marital status, educational level, household income, number of children, employment in a health care profession, underlying risk conditions for erectile dysfunction treatment, previous test positive for severe acute respiratory syndrome erectile dysfunction 2, and calendar month. Table 1 viagra online purchase. Table 1 viagra online purchase.

Odds Ratios for erectile dysfunction treatment viagra online purchase Vaccination in a 5-Week or 3-Week Window before Miscarriage or Confirmation of an Ongoing Pregnancy. Among 13,956 women with ongoing pregnancies (of whom 5.5% were vaccinated) and 4521 women with miscarriages (of whom 5.1% were vaccinated), the median number of days between vaccination and miscarriage or confirmation of ongoing pregnancy was 19 (Fig. S2).

Among women with miscarriages, the adjusted odds ratios for erectile dysfunction treatment vaccination were 0.91 (95% confidence interval [CI], 0.75 to 1.10) for vaccination in the previous 3 weeks and 0.81 (95% CI, 0.69 to 0.95) for vaccination in the previous 5 weeks (Table 1). The results were similar in an analysis that included all available treatment types (Table S5), in an analysis stratified according to the number of doses received (one or two) (Table S6), and in sensitivity analyses limited to health care personnel (for whom vaccination was routinely recommended other than in the first trimester) or women with at least 8 weeks of follow-up after confirmed pregnancy (to exclude subsequent pregnancy loss) (Table S7). A limitation of our report is that the registry lacks information on gestational age at the time of early pregnancy registration, and thus we could not match case patients and controls according to gestational age.

However, most recognized miscarriages are known to occur between pregnancy weeks 6 and 10,5 a period that is similar to the gestational ages at which women in Norway consult a physician to confirm pregnancy (Fig. S1). Also, only approximately 40% of women in Norway have a primary care appointment to confirm pregnancy, but the characteristics of these women appear to be similar to those of women who do not have a registered pregnancy confirmation (Table S4).

We cannot address associations between vaccination and miscarriages that were not clinically recognized. Although adjustment for potential confounders had minimal effect on our results, the registry does not include information on lifestyle and other factors that might confound our findings (see Supplementary Appendix). Our study found no evidence of an increased risk for early pregnancy loss after erectile dysfunction treatment vaccination and adds to the findings from other reports supporting erectile dysfunction treatment vaccination during pregnancy.3,4 Maria C.

Magnus, Ph.D.HÃ¥kon K. Gjessing, Ph.D.Helena N. Eide, M.D.Norwegian Institute of Public Health, Oslo, Norway [email protected]Allen J.

Wilcox, M.D., Ph.D.National Institute of Environmental Health Sciences, Durham, NCDeshayne B. Fell, Ph.D.School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, CanadaSiri E. HÃ¥berg, M.D., Ph.D.Norwegian Institute of Public Health, Oslo, Norway Supported in part by the Research Council of Norway (project number, 324312) and through its Centers of Excellence funding scheme (project number, 262700) and by NordForsk (project number, 105545).

Dr. Magnus has received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant agreement number, 947684). The funders had no role in the completion of the research project, the writing of the manuscript for publication, or the decision to submit the manuscript for publication.

Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. This letter was published on October 20, 2021, at NEJM.org.5 References1. Centers for Disease Control and Prevention.

erectile dysfunction treatments while pregnant or breastfeeding. August 11, 2021 (https://www.cdc.gov/erectile dysfunction/2019-ncov/treatments/recommendations/pregnancy.html).Google Scholar2. National Health Service.

Pregnancy, breastfeeding, fertility and erectile dysfunction (erectile dysfunction treatment) vaccination. September 2, 2021 (https://www.nhs.uk/conditions/erectile dysfunction-erectile dysfunction treatment/erectile dysfunction-vaccination/pregnancy-breastfeeding-fertility-and-erectile dysfunction-erectile dysfunction treatment-vaccination/).Google Scholar3. Zauche LH, Wallace B, Smoots AN, et al.

Receipt of mRNA erectile dysfunction treatments and risk of spontaneous abortion. N Engl J Med 2021;385:1533-1535.4. Kharbanda EO, Haapala J, DeSilva M, et al.

Spontaneous abortion following erectile dysfunction treatment vaccination during pregnancy. JAMA 2021 September 8 (Epub ahead of print).5. Mukherjee S, Velez Edwards DR, Baird DD, Savitz DA, Hartmann KE.

Risk of miscarriage among black women and white women in a U.S. Prospective cohort study. Am J Epidemiol 2013;177:1271-1278.10.1056/NEJMc2114466-t1Table 1.

Odds Ratios for erectile dysfunction treatment Vaccination in a 5-Week or 3-Week Window before Miscarriage or Confirmation of an Ongoing Pregnancy. Vaccination Status5-Week Exposure Window3-Week Exposure WindowOngoing PregnanciesMiscarriagesUnadjusted Odds Ratio (95% CI)Adjusted Odds Ratio (95% CI)*Ongoing PregnanciesMiscarriagesUnadjusted Odds Ratio (95% CI)Adjusted Odds Ratio (95% CI)*numbernumberAmong all womenUnvaccinated13,1844,290ReferenceReference13,5074,375ReferenceReferenceVaccinated7722310.92 (0.79–1.07)0.81 (0.69–0.95)4491461.00 (0.83–1.21)0.91 (0.75–1.10)Among health care personnelUnvaccinated2,419756ReferenceReference2,533788ReferenceReferenceVaccinated261750.92 (0.70–1.20)0.93 (0.70–1.22)147430.94 (0.66–1.33)0.92 (0.64–1.32)To the Editor. We recently reported treatment effectiveness for the BNT162b2 treatment (Pfizer–BioNTech) and the ChAdOx1 nCoV-19 treatment (AstraZeneca) against and hospitalization caused by the B.1.617.2 (delta) variant of severe acute respiratory syndrome erectile dysfunction 2 (erectile dysfunction) in Scotland.1 At that time, the number of deaths was too small to allow estimation of treatment effectiveness against death from with the delta variant.

We used a Scotland-wide surveillance platform (Early viagra Evaluation and Enhanced Surveillance of erectile dysfunction treatment [EAVE II]) that includes individual-level linked data on vaccination, testing, viral sequencing, primary care, hospital admissions, and mortality among 5.4 million people (approximately 99% of the Scottish population).2,3 We conducted a cohort study and used Cox regression to estimate treatment effectiveness against death from delta variant from April 1 to August 16, 2021, among adults 18 years of age or older, who were followed up to September 27, 2021.3 Our methods and findings are summarized below, with additional details provided in the Supplementary Appendix, available with the full text of this letter at NEJM.org. The EAVE II protocol is also available at NEJM.org. At the date of swab testing, persons were defined as being unvaccinated or vaccinated with either one or two treatment doses.4 Cases of erectile dysfunction were defined by a positive result on reverse-transcriptase–polymerase-chain-reaction (RT-PCR) testing.

Testing was performed with the TaqPath erectile dysfunction treatment Combo Kit (Thermo Fisher Scientific). True S gene “dropout” (indicating the presence of an S gene mutation not found in the delta variant) was defined as a negative result for the S gene and cycle threshold (Ct) values of less than 30 for the OR and N genes. Positivity for the S gene was defined as Ct values of less than 30 for the S gene and valid Ct values for the OR and N genes.1 Death from erectile dysfunction disease 2019 (erectile dysfunction treatment) was defined as a death for which erectile dysfunction treatment was recorded on the death certificate or death that occurred within 28 days after a positive RT-PCR test.1,4 Hazard ratios were adjusted for age, sex, socioeconomic status, and number of relevant coexisting conditions.5 treatment effectiveness was estimated as 1 minus the hazard ratio.

A total of 1,563,818 adults underwent testing in the community. Our mortality analysis was based on 114,706 adults who tested positive for erectile dysfunction. Sequencing data showed that 99.5% of S-positive s were caused by the delta variant and that 98.8% of delta variant s were S-positive (Fig.

S1 and Table S1 in the Supplementary Appendix). Among adults who tested positive, those who were unvaccinated tended to be much younger, to have fewer coexisting conditions, and to have a lower socioeconomic status and were more likely to be men than those who were vaccinated. These differences tended to be especially pronounced in comparison with those who received the ChAdOx1 nCoV-19 treatment (Table S2).

Table 1. Table 1. treatment Effectiveness in Preventing Death from erectile dysfunction treatment, Stratified According to Age Group, Vaccination Status, and treatment (All Community Cases from April 1 to August 16, 2021, with Follow-up Conducted until September 27, 2021).

Overall, 201 deaths from erectile dysfunction treatment were caused by erectile dysfunction that had been tested and found to be S-positive or S-negative (Table 1). Among persons 18 to 39 years of age who had s for which data on S gene status were available, no deaths occurred among those who were fully vaccinated, as compared with 17 deaths among those who were unvaccinated. Among those who were 40 to 59 years of age, treatment effectiveness against death from erectile dysfunction treatment was 88% (95% confidence interval [CI], 76 to 93) for ChAdOx1 nCoV-19 and 95% (95% CI, 79 to 99) for BNT162b2.

treatment effectiveness was 90% (95% CI, 84 to 94) and 87% (95% CI, 77 to 93), respectively, among those 60 years of age or older. Overall, treatment effectiveness against death from the delta variant 14 or more days after the second treatment dose was 90% (95% CI, 83 to 94) for BNT162b2 and 91% (95% CI, 86 to 94) for ChAdOx1 nCoV-19 (Table S3). A limitation of this study is the fact that it was based on an analysis of community samples.

In addition, 1.8% of samples did not yield S gene categorization because of missing data in the Ct fields. In summary, we found that the BNT162b2 and ChAdOx1 nCoV-19 treatments offered substantial protection against death from erectile dysfunction treatment caused by the delta variant. Aziz Sheikh, M.D.University of Edinburgh, Edinburgh, United Kingdom [email protected]Chris Robertson, Ph.D.University of Strathclyde, Glasgow, United KingdomBob Taylor, Ph.D.Public Health Scotland, Glasgow, United Kingdom Supported by a grant (MR/R008345/1) from the Medical Research Council.

A grant (MC_PC_19004) from BREATHE–The Health Data Research Hub for Respiratory Health, funded through the U.K. Research and Innovation Industrial Strategy Challenge Fund and delivered through Health Data Research UK. Public Health Scotland.

And the Scottish Government Director General for Health and Social Care. Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. This letter was published on October 20, 2021, and updated on October 25, 2021, at NEJM.org.The data used to undertake this analysis are not publicly available because they are based on deidentified national clinical records.

These data are available, subject to approval by the NHS Scotland Public Benefit and Privacy Panel, by application through the Scotland National Safe Haven. The R code used to perform this analysis is available from https://github.com/EAVE-II.5 References1. Sheikh A, McMenamin J, Taylor B, Robertson C.

erectile dysfunction delta VOC in Scotland. Demographics, risk of hospital admission, and treatment effectiveness. Lancet 2021;397:2461-2462.2.

Simpson CR, Robertson C, Vasileiou E, et al. Early viagra Evaluation and Enhanced Surveillance of erectile dysfunction treatment (EAVE II). Protocol for an observational study using linked Scottish national data.

BMJ Open 2020;10(6):e039097-e039097.3. Mulholland RH, Vasileiou E, Simpson CR, et al. Cohort profile.

Early viagra Evaluation and Enhanced Surveillance of erectile dysfunction treatment (EAVE II) database. Int J Epidemiol 2021;50:1064-1074.4. Vasileiou E, Simpson CR, Shi T, et al.

Interim findings from first-dose mass erectile dysfunction treatment vaccination roll-out and erectile dysfunction treatment hospital admissions in Scotland. A national prospective cohort study. Lancet 2021;397:1646-1657.5.

Clift AK, Coupland CAC, Keogh RH, et al. Living risk prediction algorithm (Qerectile dysfunction treatment) for risk of hospital admission and mortality from erectile dysfunction 19 in adults. National derivation and validation cohort study.

BMJ 2020;371:m3731-m3731.10.1056/NEJMc2113864-t1Table 1. treatment Effectiveness in Preventing Death from erectile dysfunction treatment, Stratified According to Age Group, Vaccination Status, and treatment (All Community Cases from April 1 to August 16, 2021, with Follow-up Conducted until September 27, 2021).* Age Group, Vaccination Status, and treatmentPerson-Years of Follow-upNo. Of PersonsNo.

Of DeathsRate per 100 Person-YearsAdjusted Hazard Ratio (95% CI)†18 to 39 Years of AgeUnvaccinated8669.535,449170.20—One treatment dose 0–27 days before testChAdOx1 nCoV-1956.615000.00—BNT162b22338.410,53510.04—One treatment dose ≥28 days before test or two doses with second dose 0–13 days before testChAdOx1 nCoV-19463.01,79300.00—BNT162b21706.310,16710.06—Two treatment doses with second dose ≥14 days before testChAdOx1 nCoV-19767.74,14000.00—BNT162b2567.33,04000.00—40 to 59 Years of AgeUnvaccinated1230.34,803332.68ReferenceOne treatment dose 0–27 days before testChAdOx1 nCoV-19453.81,49720.440.24 (0.06–1.01)BNT162b286.928600.000.00 (0.00–∞)One treatment dose ≥28 days before test or two doses with second dose 0–13 days before testChAdOx1 nCoV-191865.27,94520.110.04 (0.01–0.15)BNT162b2477.92,02200.000.00 (0.00–∞)Two treatment doses with second dose ≥14 days before testChAdOx1 nCoV-191707.49,587160.940.12 (0.07–0.24)BNT162b2629.83,31820.320.05 (0.01–0.21)≥60 Years of AgeUnvaccinated81.43802429.49ReferenceOne treatment dose 0–27 days before testChAdOx1 nCoV-1919.14600.000.00 (0.00–∞)BNT162b20.2100.000.00 (0.00–∞)One treatment dose ≥28 days before test or two doses with second dose 0–13 days before testChAdOx1 nCoV-19213.969220.930.03 (0.01–0.14)BNT162b269.819045.730.25 (0.09–0.74)Two treatment doses with second dose ≥14 days before testChAdOx1 nCoV-19973.85,262737.500.10 (0.06–0.16)BNT162b2351.01,952246.840.13 (0.07–0.23)To the Editor. The B.1.617.2 (delta) variant of severe acute respiratory syndrome erectile dysfunction 2 (erectile dysfunction) has emerged as the dominant strain circulating in many regions worldwide. The BNT162b2 mRNA treatment against erectile dysfunction disease 2019 (erectile dysfunction treatment) was found to be effective in preventing with the delta variant in a recent observational study,1 but other reports have suggested reduced treatment effectiveness against this variant.2,3 On May 10, 2021, the U.S.

Food and Drug Administration approved the emergency use of BNT162b2 in adolescents 12 years of age or older on the basis of a clinical trial that had been conducted before the delta variant had become prevalent in the United States.4 Additional evidence was needed regarding the effectiveness of the BNT162b2 treatment among adolescents, particularly against the delta variant. We sought to estimate the treatment effectiveness of BNT162b2 against the delta variant among vaccinated adolescents for whom an unvaccinated match was found. We used data from Clalit Health Services, the largest health care organization in Israel, to conduct an observational cohort study involving adolescents between the ages of 12 and 18 years who had no prior erectile dysfunction noted in their electronic medical record and who had been vaccinated between June 8 and September 14, 2021.

According to the sequencing of samples obtained from infected persons that was performed by the Israeli Ministry of Health during this period, the delta variant was responsible for more than 95% of new s in the general population in Israel. We used the same methods that were used in our previous studies of treatment effectiveness, which were conducted in the same health care organization using the same database.5 (See the Methods section in the Supplementary Appendix, available with the full text of this letter at NEJM.org.) treatment effectiveness was defined as 1 minus the risk ratio, which was estimated over several follow-up periods for documented erectile dysfunction and symptomatic erectile dysfunction treatment. More severe outcomes related to erectile dysfunction treatment are rare in this age group.

Table 1. Table 1. Effectiveness of BNT162b2 treatment among Adolescents.

Of 184,905 vaccinated adolescents, 130,464 met the eligibility requirements, and 94,354 of these treatment recipients were successfully matched with 94,354 unvaccinated controls (Fig. S1 and the Methods section in the Supplementary Appendix). The eligible population was similar to the matched population with respect to several demographic and clinical characteristics (Tables S1 and S2).

The frequency of polymerase-chain-reaction testing for erectile dysfunction was similar in the vaccinated and unvaccinated populations (9.4 and 9.9 tests per 100 persons per week, respectively). The median follow-up was 27 days after baseline, which was defined as the administration of the first dose among the treatment recipients. Kaplan–Meier curves for erectile dysfunction in both the vaccinated and unvaccinated groups were similar during the initial days, after which the incidence began to rise more slowly in the vaccinated group (Table 1 and Fig.

S2). The estimated treatment effectiveness against documented erectile dysfunction was 59% (95% confidence interval [CI], 52 to 65) on days 14 through 20 after the first dose, 66% (95% CI, 59 to 72) on days 21 to 27 after the first dose, and 90% (95% CI, 88 to 92) on days 7 to 21 after the second dose. The estimated treatment effectiveness against symptomatic erectile dysfunction treatment was 57% (95% CI, 39 to 71) on days 14 to 20 after the first dose, 82% (95% CI, 73 to 91) on days 21 to 27 after the first dose, and 93% (95% CI, 88 to 97) on days 7 to 21 after the second dose.

In a recent randomized trial involving 1983 vaccinated adolescents between the ages of 12 and 15 years with no history of erectile dysfunction , investigators estimated that the treatment effectiveness of two doses of BNT162b2 was 100% (95% CI, 75 to 100) against symptomatic by non-delta variants.4 The present observational study provides substantially more precise estimates of treatment effectiveness among adolescents between the ages of 12 and 18 years for both documented and symptomatic disease in a setting in which the delta variant was predominant. Our estimates of the effectiveness of two doses of the BNT162b2 treatment against the delta variant among adolescents are similar to estimates of effectiveness against the alpha variant in the general population with the use of the same study design5 and are similar to the estimate of 88% (95% CI, 85 to 90) against the delta variant in the general population in an observational study that used a different design.1 Our results show that the BNT162b2 mRNA treatment was highly effective in the first few weeks after vaccination against both documented and symptomatic erectile dysfunction treatment with the delta variant among adolescents between the ages of 12 and 18 years. Ben Y.

Reis, Ph.D.Boston Children’s Hospital, Boston, MANoam Barda, M.D.Michael Leshchinsky, M.S.Eldad Kepten, Ph.D.Clalit Research Institute, Tel Aviv, IsraelMiguel A. Hernán, M.D.Marc Lipsitch, D.Phil.Harvard T.H. Chan School of Public Health, Boston, MANoa Dagan, M.D.Ran D.

Balicer, M.D.Clalit Research Institute, Tel Aviv, Israel [email protected] Supported by the Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute. Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. This letter was published on October 20, 2021, at NEJM.org.

Drs. Reis and Barda and Drs. Dagan and Balicer contributed equally to this letter.

5 References1. Lopez Bernal J, Andrews N, Gower C, et al. Effectiveness of erectile dysfunction treatments against the B.1.617.2 (Delta) variant.

N Engl J Med 2021;385:585-594.2. Puranik A, Lenehan PJ, Silvert E, et al. Comparison of two highly-effective mRNA treatments for erectile dysfunction treatment during periods of Alpha and Delta variant prevalence.

August 21, 2021 (https://www.medrxiv.org/content/10.1101/2021.08.06.21261707v3). Preprint.Google Scholar3. Herlihy R, Bamberg W, Burakoff A, et al.

Rapid increase in circulation of the erectile dysfunction B.1.617.2 (Delta) variant — Mesa County, Colorado, April–June 2021. MMWR Morb Mortal Wkly Rep 2021;70:1084-1087.4. Frenck RW Jr, Klein NP, Kitchin N, et al.

Safety, immunogenicity, and efficacy of the BNT162b2 erectile dysfunction treatment in adolescents. N Engl J Med 2021;385:239-250.5. Dagan N, Barda N, Kepten E, et al.

BNT162b2 mRNA erectile dysfunction treatment in a nationwide mass vaccination setting. N Engl J Med 2021;384:1412-1423.10.1056/NEJMc2114290-t1Table 1. Effectiveness of BNT162b2 treatment among Adolescents.* Time PeriodDocumented erectile dysfunction Symptomatic erectile dysfunction treatmentUnvaccinatedGroupVaccinatedGrouptreatment Effectiveness(95% CI)Risk Difference(95% CI)UnvaccinatedGroupVaccinatedGrouptreatment Effectiveness(95% CI)Risk Difference(95% CI)events (no.

At risk)%no. Of events/100,000 personsevents (no. At risk)%no.

Of events/100,000 personsDays 14–20 after first dose463(69,408)192(69,609)59(52–65)436.5(363.1–510.2)95(70,203)41(70,227)57(39–71)86.1(49.0–123.7)Days 21–27 after first dose400(56,997)137(57,358)66(59–72)514.7(423.1–590.6)84(57,803)15(57,878)82(73–91)133.0(101.1–169.4)Days 7–21 after second dose818(46,384)79(46,815)90(88–92)2032.7(1866.3–2184.6)151(47,194)11(47,303)93(88–97)379.6(317.0–451.3)Cases of Myocarditis Table 1. Table 1. Reported Myocarditis Cases, According to Timing of First or Second treatment Dose.

Table 2. Table 2. Classification of Myocarditis Cases Reported to the Ministry of Health.

Among 9,289,765 Israeli residents who were included during the surveillance period, 5,442,696 received a first treatment dose and 5,125,635 received two doses (Table 1 and Fig. S2). A total of 304 cases of myocarditis (as defined by the ICD-9 codes for myocarditis) were reported to the Ministry of Health (Table 2).

These cases were diagnosed in 196 persons who had received two doses of the treatment. 151 persons within 21 days after the first dose and 30 days after the second dose and 45 persons in the period after 21 days and 30 days, respectively. (Persons in whom myocarditis developed 22 days or more after the first dose of treatment or more than 30 days after the second dose were considered to have myocarditis that was not in temporal proximity to the treatment.) After a detailed review of the case histories, we ruled out 21 cases because of reasonable alternative diagnoses.

Thus, the diagnosis of myocarditis was affirmed for 283 cases. These cases included 142 among vaccinated persons within 21 days after the first dose and 30 days after the second dose, 40 among vaccinated persons not in proximity to vaccination, and 101 among unvaccinated persons. Among the unvaccinated persons, 29 cases of myocarditis were diagnosed in those with confirmed erectile dysfunction treatment and 72 in those without a confirmed diagnosis.

Of the 142 persons in whom myocarditis developed within 21 days after the first dose of treatment or within 30 days after the second dose, 136 received a diagnosis of definite or probable myocarditis, 1 received a diagnosis of possible myocarditis, and 5 had insufficient data. Classification of cases according to the definition of myocarditis used by the CDC 4-6 is provided in Table S1. Endomyocardial biopsy samples that were obtained from 2 persons showed foci of endointerstitial edema and neutrophils, along with mononuclear-cell infiates (monocytes or macrophages and lymphocytes) with no giant cells.

No other patients underwent endomyocardial biopsy. The clinical features of myocarditis after vaccination are provided in Table S3. In the 136 cases of definite or probable myocarditis, the clinical presentation in 129 was generally mild, with resolution of myocarditis in most cases, as judged by clinical symptoms and inflammatory markers and troponin elevation, electrocardiographic and echocardiographic normalization, and a relatively short length of hospital stay.

However, one person with fulminant myocarditis died. The ejection fraction was normal or mildly reduced in most persons and severely reduced in 4 persons. Magnetic resonance imaging that was performed in 48 persons showed findings that were consistent with myocarditis on the basis of at least one positive T2-based sequence and one positive T1-based sequence (including T2-weighted images, T1 and T2 parametric mapping, and late gadolinium enhancement).

Follow-up data regarding the status of cases after hospital discharge and consistent measures of cardiac function were not available. Figure 1. Figure 1.

Timing and Distribution of Myocarditis after Receipt of the BNT162b2 treatment. Shown is the timing of the diagnosis of myocarditis among recipients of the first dose of treatment (Panel A) and the second dose (Panel B), according to sex, and the distribution of cases among recipients according to both age and sex after the first dose (Panel C) and after the second dose (Panel D). Cases of myocarditis were reported within 21 days after the first dose and within 30 days after the second dose.The peak number of cases with proximity to vaccination occurred in February and March 2021.

The associations with vaccination status, age, and sex are provided in Table 1 and Figure 1. Of 136 persons with definite or probable myocarditis, 19 presented after the first dose of treatment and 117 after the second dose. In the 21 days after the first dose, 19 persons with myocarditis were hospitalized, and hospital admission dates were approximately equally distributed over time.

A total of 95 of 117 persons (81%) who presented after the second dose were hospitalized within 7 days after vaccination. Among 95 persons for whom data regarding age and sex were available, 86 (91%) were male and 72 (76%) were under the age of 30 years. Comparison of Risks According to First or Second Dose Table 3.

Table 3. Risk of Myocarditis within 21 Days after the First or Second Dose of treatment, According to Age and Sex. A comparison of risks over equal time periods of 21 days after the first and second doses according to age and sex is provided in Table 3.

Cases were clustered during the first few days after the second dose of treatment, according to visual inspection of the data (Figure 1B and 1D). The overall risk difference between the first and second doses was 1.76 per 100,000 persons (95% confidence interval [CI], 1.33 to 2.19). The overall risk difference was 3.19 (95% CI, 2.37 to 4.02) among male recipients and 0.39 (95% CI, 0.10 to 0.68) among female recipients.

The highest difference was observed among male recipients between the ages of 16 and 19 years. 13.73 per 100,000 persons (95% CI, 8.11 to 19.46). In this age group, the percent attributable risk to the second dose was 91%.

The difference in the risk among female recipients between the first and second doses in the same age group was 1.00 per 100,000 persons (95% CI, −0.63 to 2.72). Repeating these analyses with a shorter follow-up of 7 days owing to the presence of a cluster that was noted after the second treatment dose disclosed similar differences in male recipients between the ages of 16 and 19 years (risk difference, 13.62 per 100,000 persons. 95% CI, 8.31 to 19.03).

These findings pointed to the first week after the second treatment dose as the main risk window. Observed versus Expected Incidence Table 4. Table 4.

Standardized Incidence Ratios for 151 Cases of Myocarditis, According to treatment Dose, Age, and Sex. Table 4 shows the standardized incidence ratios for myocarditis according to treatment dose, age group, and sex, as projected from the incidence during the previagra period from 2017 through 2019. Myocarditis after the second dose of treatment had a standardized incidence ratio of 5.34 (95% CI, 4.48 to 6.40), which was driven mostly by the diagnosis of myocarditis in younger male recipients.

Among boys and men, the standardized incidence ratio was 13.60 (95% CI, 9.30 to 19.20) for those 16 to 19 years of age, 8.53 (95% CI, 5.57 to 12.50) for those 20 to 24 years, 6.96 (95% CI, 4.25 to 10.75) for those 25 to 29 years, and 2.90 (95% CI, 1.98 to 4.09) for those 30 years of age or older. These substantially increased findings were not observed after the first dose. A sensitivity analysis showed that for male recipients between the ages of 16 and 24 years who had received a second treatment dose, the observed standardized incidence ratios would have required overreporting of myocarditis by a factor of 4 to 5 on the assumption that the true incidence would not have differed from the expected incidence (Table S4).

Rate Ratio between Vaccinated and Unvaccinated Persons Table 5. Table 5. Rate Ratios for a Diagnosis of Myocarditis within 30 Days after the Second Dose of treatment, as Compared with Unvaccinated Persons (January 11 to May 31, 2021).

Within 30 days after receipt of the second treatment dose in the general population, the rate ratio for the comparison of the incidence of myocarditis between vaccinated and unvaccinated persons was 2.35 (95% CI, 1.10 to 5.02) according to the Brighton Collaboration classification of definite and probable cases and after adjustment for age and sex. This result was driven mainly by the findings for males in younger age groups, with a rate ratio of 8.96 (95% CI, 4.50 to 17.83) for those between the ages of 16 and 19 years, 6.13 (95% CI, 3.16 to 11.88) for those 20 to 24 years, and 3.58 (95% CI, 1.82 to 7.01) for those 25 to 29 years (Table 5). When follow-up was restricted to 7 days after the second treatment dose, the analysis results for male recipients between the ages of 16 and 19 years were even stronger than the findings within 30 days (rate ratio, 31.90.

95% CI, 15.88 to 64.08). Concordance of our findings with the Bradford Hill causality criteria is shown in Table S5..

To the Editor where can i buy viagra. Ivermectin is where can i buy viagra approved by the Food and Drug Administration as an oral treatment for intestinal strongyloidiasis and onchocerciasis and as a topical treatment for pediculosis and rosacea. It is also used as a treatment for where can i buy viagra parasites in pets and livestock. Ivermectin may decrease severe acute respiratory syndrome erectile dysfunction 2 (erectile dysfunction) replication in vitro,1,2 but randomized, controlled trials have shown no clinical benefit in the prevention or treatment of erectile dysfunction disease 2019 (erectile dysfunction treatment).3 Veterinary use of ivermectin has increased, and the number of prescriptions for use by humans in the United States is 24 times as high as the number before the viagra. Moreover, the number of such prescriptions in August 2021 was 4 times as high as the number in July 2021.3,4 The Oregon Poison Center is a telephone consultative center staffed by specialty-trained nurses, pharmacists, and physicians who where can i buy viagra provide treatment advice for the public and comprehensive treatment consultation for health care workers caring for patients in Oregon, Alaska, and Guam.

The center where can i buy viagra has recently received an increasing number of calls regarding ivermectin exposure related to erectile dysfunction treatment. The rate of calls regarding ivermectin had been 0.25 calls per month in 2020 and had increased to 0.86 calls per month from January through July 2021. In August 2021, the center received 21 calls where can i buy viagra. Monthly total call volumes where can i buy viagra for all poison exposures were stable throughout 2020 and 2021. Of the 21 persons who called in August, 11 were men, and most were older than 60 years of age (median age, 64.

Range, 20 where can i buy viagra to 81). Approximately half (11 persons) were reported to have used ivermectin where can i buy viagra to prevent erectile dysfunction treatment, and the remaining persons had been using the drug to treat erectile dysfunction treatment symptoms. Three persons had received prescriptions from physicians or veterinarians, and 17 had purchased veterinary formulations. The source where can i buy viagra of ivermectin for the remaining person was not confirmed. Symptoms had where can i buy viagra developed in most persons within 2 hours after a large, single, first-time dose.

In 6 persons, symptoms had developed gradually after several days to weeks of where can i buy viagra repeated doses taken every other day or twice weekly. One person had also been taking vitamin D to treat or prevent erectile dysfunction treatment. Reported doses ingested by the persons who had where can i buy viagra been using veterinary products ranged from 6.8 mg to 125 mg of 1.87% paste and 20 to 50 mg of the 1% solution. The dose of the where can i buy viagra human-use tablets was 21 mg per dose twice weekly for prevention. Six of the 21 persons were hospitalized for toxic effects from ivermectin use.

All 6 reported preventive use, including the 3 who had obtained where can i buy viagra the drug by prescription. Four received care in an where can i buy viagra intensive care unit, and none died. Symptoms were gastrointestinal distress in 4 persons, confusion in 3, ataxia and weakness in 2, hypotension in 2, and seizures in 1. Of the persons who were not admitted to a hospital, most where can i buy viagra had gastrointestinal distress, dizziness, confusion, vision symptoms, or rash. These cases illustrate the potential toxic effects of ivermectin, including severe episodes of confusion, ataxia, seizures, and hypotension, and the increasing frequency where can i buy viagra of inappropriate use.

There is insufficient evidence to support the use of ivermectin to treat or prevent erectile dysfunction treatment,3 and improper use, as well as the possible occurrence of medication interactions,5 may result in serious side effects requiring hospitalization. Courtney Temple, M.D.Ruby where can i buy viagra Hoang, D.O.Robert G. Hendrickson, M.D.Oregon Health and Science University, Portland, OR Disclosure forms provided by the where can i buy viagra authors are available with the full text of this letter at NEJM.org. This letter was published on where can i buy viagra October 20, 2021, at NEJM.org.5 References1. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM.

The FDA-approved drug ivermectin inhibits where can i buy viagra the replication of erectile dysfunction in vitro. Antiviral Res where can i buy viagra 2020;178:104787-104787.2. Lehrer S, Rheinstein PH. Ivermectin docks to the erectile dysfunction spike receptor-binding domain where can i buy viagra attached to ACE2. In Vivo 2020;34:3023-3026.3 where can i buy viagra.

Centers for Disease Control and Prevention. Rapid increase in ivermectin prescriptions and reports of severe illness associated with use of products containing ivermectin where can i buy viagra to prevent or treat erectile dysfunction treatment. CDC Health Alert Network where can i buy viagra no. CDCHAN-00449. August 26, where can i buy viagra 2021 (https://emergency.cdc.gov/han/2021/han00449.asp).Google Scholar4.

Lind JN, Lovegrove MC, where can i buy viagra Geller AI, Uyeki TM, Datta SD, Budnitz DS. Increase in outpatient ivermectin dispensing in the US during where can i buy viagra the erectile dysfunction treatment viagra. A cross-sectional analysis. J Gen Intern Med 2021;36:2909-2911.5 where can i buy viagra. Edwards G where can i buy viagra.

Ivermectin. Does P-glycoprotein play where can i buy viagra a role in neurotoxicity?. Filaria J 2003;2:Suppl where can i buy viagra 1:S8-S8.To the Editor. Pregnant women with erectile dysfunction disease 2019 (erectile dysfunction treatment) are at increased risk for adverse outcomes, and erectile dysfunction treatment vaccination is recommended during pregnancy.1,2 However, safety data on erectile dysfunction treatment vaccination during pregnancy remain limited.3,4 We performed a case–control study with data from Norwegian registries on first-trimester pregnancies, erectile dysfunction treatment vaccination, background characteristics, and underlying health conditions (Supplementary Methods and Tables S1 through S3 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). We identified all women who were registered between February 15 and August 15, 2021, as having had a miscarriage before 14 weeks of gestation (case patients) and those with a primary care–based confirmation of ongoing pregnancy in the first trimester where can i buy viagra (controls).

In Norway, although vaccination during the first trimester is not recommended except in women with where can i buy viagra underlying risk conditions, women not yet aware that they were pregnant may still be vaccinated in the first trimester. We estimated odds ratios with 95% confidence intervals for erectile dysfunction treatment vaccination within 5-week and 3-week windows before a miscarriage or ongoing pregnancy, adjusting for women’s age, country of birth, marital status, educational level, household income, number of children, employment in a health care profession, underlying risk conditions for erectile dysfunction treatment, previous test positive for severe acute respiratory syndrome erectile dysfunction 2, and calendar month. Table 1 where can i buy viagra. Table 1 where can i buy viagra. Odds Ratios for erectile dysfunction treatment Vaccination in a 5-Week or 3-Week Window where can i buy viagra before Miscarriage or Confirmation of an Ongoing Pregnancy.

Among 13,956 women with ongoing pregnancies (of whom 5.5% were vaccinated) and 4521 women with miscarriages (of whom 5.1% were vaccinated), the median number of days between vaccination and miscarriage or confirmation of ongoing pregnancy was 19 (Fig. S2). Among women with miscarriages, the adjusted odds ratios for erectile dysfunction treatment vaccination were 0.91 (95% confidence interval [CI], 0.75 to 1.10) for vaccination in the previous 3 weeks and 0.81 (95% CI, 0.69 to 0.95) for vaccination in the previous 5 weeks (Table 1). The results were similar in an analysis that included all available treatment types (Table S5), in an analysis stratified according to the number of doses received (one or two) (Table S6), and in sensitivity analyses limited to health care personnel (for whom vaccination was routinely recommended other than in the first trimester) or women with at least 8 weeks of follow-up after confirmed pregnancy (to exclude subsequent pregnancy loss) (Table S7). A limitation of our report is that the registry lacks information on gestational age at the time of early pregnancy registration, and thus we could not match case patients and controls according to gestational age.

However, most recognized miscarriages are known to occur between pregnancy weeks 6 and 10,5 a period that is similar to the gestational ages at which women in Norway consult a physician to confirm pregnancy (Fig. S1). Also, only approximately 40% of women in Norway have a primary care appointment to confirm pregnancy, but the characteristics of these women appear to be similar to those of women who do not have a registered pregnancy confirmation (Table S4). We cannot address associations between vaccination and miscarriages that were not clinically recognized. Although adjustment for potential confounders had minimal effect on our results, the registry does not include information on lifestyle and other factors that might confound our findings (see Supplementary Appendix).

Our study found no evidence of an increased risk for early pregnancy loss after erectile dysfunction treatment vaccination and adds to the findings from other reports supporting erectile dysfunction treatment vaccination during pregnancy.3,4 Maria C. Magnus, Ph.D.HÃ¥kon K. Gjessing, Ph.D.Helena N. Eide, M.D.Norwegian Institute of Public Health, Oslo, Norway [email protected]Allen J. Wilcox, M.D., Ph.D.National Institute of Environmental Health Sciences, Durham, NCDeshayne B.

Fell, Ph.D.School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, CanadaSiri E. Håberg, M.D., Ph.D.Norwegian Institute of Public Health, Oslo, Norway Supported in part by the Research Council of Norway (project number, 324312) and through its Centers of Excellence funding scheme (project number, 262700) and by NordForsk (project number, 105545). Dr. Magnus has received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant agreement number, 947684). The funders had no role in the completion of the research project, the writing of the manuscript for publication, or the decision to submit the manuscript for publication.

Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. This letter was published on October 20, 2021, at NEJM.org.5 References1. Centers for Disease Control and Prevention. erectile dysfunction treatments while pregnant or breastfeeding. August 11, 2021 (https://www.cdc.gov/erectile dysfunction/2019-ncov/treatments/recommendations/pregnancy.html).Google Scholar2.

National Health Service. Pregnancy, breastfeeding, fertility and erectile dysfunction (erectile dysfunction treatment) vaccination. September 2, 2021 (https://www.nhs.uk/conditions/erectile dysfunction-erectile dysfunction treatment/erectile dysfunction-vaccination/pregnancy-breastfeeding-fertility-and-erectile dysfunction-erectile dysfunction treatment-vaccination/).Google Scholar3. Zauche LH, Wallace B, Smoots AN, et al. Receipt of mRNA erectile dysfunction treatments and risk of spontaneous abortion.

N Engl J Med 2021;385:1533-1535.4. Kharbanda EO, Haapala J, DeSilva M, et al. Spontaneous abortion following erectile dysfunction treatment vaccination during pregnancy. JAMA 2021 September 8 (Epub ahead of print).5. Mukherjee S, Velez Edwards DR, Baird DD, Savitz DA, Hartmann KE.

Risk of miscarriage among black women and white women in a U.S. Prospective cohort study. Am J Epidemiol 2013;177:1271-1278.10.1056/NEJMc2114466-t1Table 1. Odds Ratios for erectile dysfunction treatment Vaccination in a 5-Week or 3-Week Window before Miscarriage or Confirmation of an Ongoing Pregnancy. Vaccination Status5-Week Exposure Window3-Week Exposure WindowOngoing PregnanciesMiscarriagesUnadjusted Odds Ratio (95% CI)Adjusted Odds Ratio (95% CI)*Ongoing PregnanciesMiscarriagesUnadjusted Odds Ratio (95% CI)Adjusted Odds Ratio (95% CI)*numbernumberAmong all womenUnvaccinated13,1844,290ReferenceReference13,5074,375ReferenceReferenceVaccinated7722310.92 (0.79–1.07)0.81 (0.69–0.95)4491461.00 (0.83–1.21)0.91 (0.75–1.10)Among health care personnelUnvaccinated2,419756ReferenceReference2,533788ReferenceReferenceVaccinated261750.92 (0.70–1.20)0.93 (0.70–1.22)147430.94 (0.66–1.33)0.92 (0.64–1.32)To the Editor.

We recently reported treatment effectiveness for the BNT162b2 treatment (Pfizer–BioNTech) and the ChAdOx1 nCoV-19 treatment (AstraZeneca) against and hospitalization caused by the B.1.617.2 (delta) variant of severe acute respiratory syndrome erectile dysfunction 2 (erectile dysfunction) in Scotland.1 At that time, the number of deaths was too small to allow estimation of treatment effectiveness against death from with the delta variant. We used a Scotland-wide surveillance platform (Early viagra Evaluation and Enhanced Surveillance of erectile dysfunction treatment [EAVE II]) that includes individual-level linked data on vaccination, testing, viral sequencing, primary care, hospital admissions, and mortality among 5.4 million people (approximately 99% of the Scottish population).2,3 We conducted a cohort study and used Cox regression to estimate treatment effectiveness against death from delta variant from April 1 to August 16, 2021, among adults 18 years of age or older, who were followed up to September 27, 2021.3 Our methods and findings are summarized below, with additional details provided in the Supplementary Appendix, available with the full text of this letter at NEJM.org. The EAVE II protocol is also available at NEJM.org. At the date of swab testing, persons were defined as being unvaccinated or vaccinated with either one or two treatment doses.4 Cases of erectile dysfunction were defined by a positive result on reverse-transcriptase–polymerase-chain-reaction (RT-PCR) testing. Testing was performed with the TaqPath erectile dysfunction treatment Combo Kit (Thermo Fisher Scientific).

True S gene “dropout” (indicating the presence of an S gene mutation not found in the delta variant) was defined as a negative result for the S gene and cycle threshold (Ct) values of less than 30 for the OR and N genes. Positivity for the S gene was defined as Ct values of less than 30 for the S gene and valid Ct values for the OR and N genes.1 Death from erectile dysfunction disease 2019 (erectile dysfunction treatment) was defined as a death for which erectile dysfunction treatment was recorded on the death certificate or death that occurred within 28 days after a positive RT-PCR test.1,4 Hazard ratios were adjusted for age, sex, socioeconomic status, and number of relevant coexisting conditions.5 treatment effectiveness was estimated as 1 minus the hazard ratio. A total of 1,563,818 adults underwent testing in the community. Our mortality analysis was based on 114,706 adults who tested positive for erectile dysfunction. Sequencing data showed that 99.5% of S-positive s were caused by the delta variant and that 98.8% of delta variant s were S-positive (Fig.

S1 and Table S1 in the Supplementary Appendix). Among adults who tested positive, those who were unvaccinated tended to be much younger, to have fewer coexisting conditions, and to have a lower socioeconomic status and were more likely to be men than those who were vaccinated. These differences tended to be especially pronounced in comparison with those who received the ChAdOx1 nCoV-19 treatment (Table S2). Table 1. Table 1.

treatment Effectiveness in Preventing Death from erectile dysfunction treatment, Stratified According to Age Group, Vaccination Status, and treatment (All Community Cases from April 1 to August 16, 2021, with Follow-up Conducted until September 27, 2021). Overall, 201 deaths from erectile dysfunction treatment were caused by erectile dysfunction that had been tested and found to be S-positive or S-negative (Table 1). Among persons 18 to 39 years of age who had s for which data on S gene status were available, no deaths occurred among those who were fully vaccinated, as compared with 17 deaths among those who were unvaccinated. Among those who were 40 to 59 years of age, treatment effectiveness against death from erectile dysfunction treatment was 88% (95% confidence interval [CI], 76 to 93) for ChAdOx1 nCoV-19 and 95% (95% CI, 79 to 99) for BNT162b2. treatment effectiveness was 90% (95% CI, 84 to 94) and 87% (95% CI, 77 to 93), respectively, among those 60 years of age or older.

Overall, treatment effectiveness against death from the delta variant 14 or more days after the second treatment dose was 90% (95% CI, 83 to 94) for BNT162b2 and 91% (95% CI, 86 to 94) for ChAdOx1 nCoV-19 (Table S3). A limitation of this study is the fact that it was based on an analysis of community samples. In addition, 1.8% of samples did not yield S gene categorization because of missing data in the Ct fields. In summary, we found that the BNT162b2 and ChAdOx1 nCoV-19 treatments offered substantial protection against death from erectile dysfunction treatment caused by the delta variant. Aziz Sheikh, M.D.University of Edinburgh, Edinburgh, United Kingdom [email protected]Chris Robertson, Ph.D.University of Strathclyde, Glasgow, United KingdomBob Taylor, Ph.D.Public Health Scotland, Glasgow, United Kingdom Supported by a grant (MR/R008345/1) from the Medical Research Council.

A grant (MC_PC_19004) from BREATHE–The Health Data Research Hub for Respiratory Health, funded through the U.K. Research and Innovation Industrial Strategy Challenge Fund and delivered through Health Data Research UK. Public Health Scotland. And the Scottish Government Director General for Health and Social Care. Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

This letter was published on October 20, 2021, and updated on October 25, 2021, at NEJM.org.The data used to undertake this analysis are not publicly available because they are based on deidentified national clinical records. These data are available, subject to approval by the NHS Scotland Public Benefit and Privacy Panel, by application through the Scotland National Safe Haven. The R code used to perform this analysis is available from https://github.com/EAVE-II.5 References1. Sheikh A, McMenamin J, Taylor B, Robertson C. erectile dysfunction delta VOC in Scotland.

Demographics, risk of hospital admission, and treatment effectiveness. Lancet 2021;397:2461-2462.2. Simpson CR, Robertson C, Vasileiou E, et al. Early viagra Evaluation and Enhanced Surveillance of erectile dysfunction treatment (EAVE II). Protocol for an observational study using linked Scottish national data.

BMJ Open 2020;10(6):e039097-e039097.3. Mulholland RH, Vasileiou E, Simpson CR, et al. Cohort profile. Early viagra Evaluation and Enhanced Surveillance of erectile dysfunction treatment (EAVE II) database. Int J Epidemiol 2021;50:1064-1074.4.

Vasileiou E, Simpson CR, Shi T, et al. Interim findings from first-dose mass erectile dysfunction treatment vaccination roll-out and erectile dysfunction treatment hospital admissions in Scotland. A national prospective cohort study. Lancet 2021;397:1646-1657.5. Clift AK, Coupland CAC, Keogh RH, et al.

Living risk prediction algorithm (Qerectile dysfunction treatment) for risk of hospital admission and mortality from erectile dysfunction 19 in adults. National derivation and validation cohort study. BMJ 2020;371:m3731-m3731.10.1056/NEJMc2113864-t1Table 1. treatment Effectiveness in Preventing Death from erectile dysfunction treatment, Stratified According to Age Group, Vaccination Status, and treatment (All Community Cases from April 1 to August 16, 2021, with Follow-up Conducted until September 27, 2021).* Age Group, Vaccination Status, and treatmentPerson-Years of Follow-upNo. Of PersonsNo.

Of DeathsRate per 100 Person-YearsAdjusted Hazard Ratio (95% CI)†18 to 39 Years of AgeUnvaccinated8669.535,449170.20—One treatment dose 0–27 days before testChAdOx1 nCoV-1956.615000.00—BNT162b22338.410,53510.04—One treatment dose ≥28 days before test or two doses with second dose 0–13 days before testChAdOx1 nCoV-19463.01,79300.00—BNT162b21706.310,16710.06—Two treatment doses with second dose ≥14 days before testChAdOx1 nCoV-19767.74,14000.00—BNT162b2567.33,04000.00—40 to 59 Years of AgeUnvaccinated1230.34,803332.68ReferenceOne treatment dose 0–27 days before testChAdOx1 nCoV-19453.81,49720.440.24 (0.06–1.01)BNT162b286.928600.000.00 (0.00–∞)One treatment dose ≥28 days before test or two doses with second dose 0–13 days before testChAdOx1 nCoV-191865.27,94520.110.04 (0.01–0.15)BNT162b2477.92,02200.000.00 (0.00–∞)Two treatment doses with second dose ≥14 days before testChAdOx1 nCoV-191707.49,587160.940.12 (0.07–0.24)BNT162b2629.83,31820.320.05 (0.01–0.21)≥60 Years of AgeUnvaccinated81.43802429.49ReferenceOne treatment dose 0–27 days before testChAdOx1 nCoV-1919.14600.000.00 (0.00–∞)BNT162b20.2100.000.00 (0.00–∞)One treatment dose ≥28 days before test or two doses with second dose 0–13 days before testChAdOx1 nCoV-19213.969220.930.03 (0.01–0.14)BNT162b269.819045.730.25 (0.09–0.74)Two treatment doses with second dose ≥14 days before testChAdOx1 nCoV-19973.85,262737.500.10 (0.06–0.16)BNT162b2351.01,952246.840.13 (0.07–0.23)To the Editor. The B.1.617.2 (delta) variant of severe acute respiratory syndrome erectile dysfunction 2 (erectile dysfunction) has emerged as the dominant strain circulating in many regions worldwide. The BNT162b2 mRNA treatment against erectile dysfunction disease 2019 (erectile dysfunction treatment) was found to be effective in preventing with the delta variant in a recent observational study,1 but other reports have suggested reduced treatment effectiveness against this variant.2,3 On May 10, 2021, the U.S. Food and Drug Administration approved the emergency use of BNT162b2 in adolescents 12 years of age or older on the basis of a clinical trial that had been conducted before the delta variant had become prevalent in the United States.4 Additional evidence was needed regarding the effectiveness of the BNT162b2 treatment among adolescents, particularly against the delta variant. We sought to estimate the treatment effectiveness of BNT162b2 against the delta variant among vaccinated adolescents for whom an unvaccinated match was found.

We used data from Clalit Health Services, the largest health care organization in Israel, to conduct an observational cohort study involving adolescents between the ages of 12 and 18 years who had no prior erectile dysfunction noted in their electronic medical record and who had been vaccinated between June 8 and September 14, 2021. According to the sequencing of samples obtained from infected persons that was performed by the Israeli Ministry of Health during this period, the delta variant was responsible for more than 95% of new s in the general population in Israel. We used the same methods that were used in our previous studies of treatment effectiveness, which were conducted in the same health care organization using the same database.5 (See the Methods section in the Supplementary Appendix, available with the full text of this letter at NEJM.org.) treatment effectiveness was defined as 1 minus the risk ratio, which was estimated over several follow-up periods for documented erectile dysfunction and symptomatic erectile dysfunction treatment. More severe outcomes related to erectile dysfunction treatment are rare in this age group. Table 1.

Table 1. Effectiveness of BNT162b2 treatment among Adolescents. Of 184,905 vaccinated adolescents, 130,464 met the eligibility requirements, and 94,354 of these treatment recipients were successfully matched with 94,354 unvaccinated controls (Fig. S1 and the Methods section in the Supplementary Appendix). The eligible population was similar to the matched population with respect to several demographic and clinical characteristics (Tables S1 and S2).

The frequency of polymerase-chain-reaction testing for erectile dysfunction was similar in the vaccinated and unvaccinated populations (9.4 and 9.9 tests per 100 persons per week, respectively). The median follow-up was 27 days after baseline, which was defined as the administration of the first dose among the treatment recipients. Kaplan–Meier curves for erectile dysfunction in both the vaccinated and unvaccinated groups were similar during the initial days, after which the incidence began to rise more slowly in the vaccinated group (Table 1 and Fig. S2). The estimated treatment effectiveness against documented erectile dysfunction was 59% (95% confidence interval [CI], 52 to 65) on days 14 through 20 after the first dose, 66% (95% CI, 59 to 72) on days 21 to 27 after the first dose, and 90% (95% CI, 88 to 92) on days 7 to 21 after the second dose.

The estimated treatment effectiveness against symptomatic erectile dysfunction treatment was 57% (95% CI, 39 to 71) on days 14 to 20 after the first dose, 82% (95% CI, 73 to 91) on days 21 to 27 after the first dose, and 93% (95% CI, 88 to 97) on days 7 to 21 after the second dose. In a recent randomized trial involving 1983 vaccinated adolescents between the ages of 12 and 15 years with no history of erectile dysfunction , investigators estimated that the treatment effectiveness of two doses of BNT162b2 was 100% (95% CI, 75 to 100) against symptomatic by non-delta variants.4 The present observational study provides substantially more precise estimates of treatment effectiveness among adolescents between the ages of 12 and 18 years for both documented and symptomatic disease in a setting in which the delta variant was predominant. Our estimates of the effectiveness of two doses of the BNT162b2 treatment against the delta variant among adolescents are similar to estimates of effectiveness against the alpha variant in the general population with the use of the same study design5 and are similar to the estimate of 88% (95% CI, 85 to 90) against the delta variant in the general population in an observational study that used a different design.1 Our results show that the BNT162b2 mRNA treatment was highly effective in the first few weeks after vaccination against both documented and symptomatic erectile dysfunction treatment with the delta variant among adolescents between the ages of 12 and 18 years. Ben Y. Reis, Ph.D.Boston Children’s Hospital, Boston, MANoam Barda, M.D.Michael Leshchinsky, M.S.Eldad Kepten, Ph.D.Clalit Research Institute, Tel Aviv, IsraelMiguel A.

Hernán, M.D.Marc Lipsitch, D.Phil.Harvard T.H. Chan School of Public Health, Boston, MANoa Dagan, M.D.Ran D. Balicer, M.D.Clalit Research Institute, Tel Aviv, Israel [email protected] Supported by the Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute. Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. This letter was published on October 20, 2021, at NEJM.org.

Drs. Reis and Barda and Drs. Dagan and Balicer contributed equally to this letter. 5 References1. Lopez Bernal J, Andrews N, Gower C, et al.

Effectiveness of erectile dysfunction treatments against the B.1.617.2 (Delta) variant. N Engl J Med 2021;385:585-594.2. Puranik A, Lenehan PJ, Silvert E, et al. Comparison of two highly-effective mRNA treatments for erectile dysfunction treatment during periods of Alpha and Delta variant prevalence. August 21, 2021 (https://www.medrxiv.org/content/10.1101/2021.08.06.21261707v3).

Preprint.Google Scholar3. Herlihy R, Bamberg W, Burakoff A, et al. Rapid increase in circulation of the erectile dysfunction B.1.617.2 (Delta) variant — Mesa County, Colorado, April–June 2021. MMWR Morb Mortal Wkly Rep 2021;70:1084-1087.4. Frenck RW Jr, Klein NP, Kitchin N, et al.

Safety, immunogenicity, and efficacy of the BNT162b2 erectile dysfunction treatment in adolescents. N Engl J Med 2021;385:239-250.5. Dagan N, Barda N, Kepten E, et al. BNT162b2 mRNA erectile dysfunction treatment in a nationwide mass vaccination setting. N Engl J Med 2021;384:1412-1423.10.1056/NEJMc2114290-t1Table 1.

Effectiveness of BNT162b2 treatment among Adolescents.* Time PeriodDocumented erectile dysfunction Symptomatic erectile dysfunction treatmentUnvaccinatedGroupVaccinatedGrouptreatment Effectiveness(95% CI)Risk Difference(95% CI)UnvaccinatedGroupVaccinatedGrouptreatment Effectiveness(95% CI)Risk Difference(95% CI)events (no. At risk)%no. Of events/100,000 personsevents (no. At risk)%no. Of events/100,000 personsDays 14–20 after first dose463(69,408)192(69,609)59(52–65)436.5(363.1–510.2)95(70,203)41(70,227)57(39–71)86.1(49.0–123.7)Days 21–27 after first dose400(56,997)137(57,358)66(59–72)514.7(423.1–590.6)84(57,803)15(57,878)82(73–91)133.0(101.1–169.4)Days 7–21 after second dose818(46,384)79(46,815)90(88–92)2032.7(1866.3–2184.6)151(47,194)11(47,303)93(88–97)379.6(317.0–451.3)Cases of Myocarditis Table 1.

Table 1. Reported Myocarditis Cases, According to Timing of First or Second treatment Dose. Table 2. Table 2. Classification of Myocarditis Cases Reported to the Ministry of Health.

Among 9,289,765 Israeli residents who were included during the surveillance period, 5,442,696 received a first treatment dose and 5,125,635 received two doses (Table 1 and Fig. S2). A total of 304 cases of myocarditis (as defined by the ICD-9 codes for myocarditis) were reported to the Ministry of Health (Table 2). These cases were diagnosed in 196 persons who had received two doses of the treatment. 151 persons within 21 days after the first dose and 30 days after the second dose and 45 persons in the period after 21 days and 30 days, respectively.

(Persons in whom myocarditis developed 22 days or more after the first dose of treatment or more than 30 days after the second dose were considered to have myocarditis that was not in temporal proximity to the treatment.) After a detailed review of the case histories, we ruled out 21 cases because of reasonable alternative diagnoses. Thus, the diagnosis of myocarditis was affirmed for 283 cases. These cases included 142 among vaccinated persons within 21 days after the first dose and 30 days after the second dose, 40 among vaccinated persons not in proximity to vaccination, and 101 among unvaccinated persons. Among the unvaccinated persons, 29 cases of myocarditis were diagnosed in those with confirmed erectile dysfunction treatment and 72 in those without a confirmed diagnosis. Of the 142 persons in whom myocarditis developed within 21 days after the first dose of treatment or within 30 days after the second dose, 136 received a diagnosis of definite or probable myocarditis, 1 received a diagnosis of possible myocarditis, and 5 had insufficient data.

Classification of cases according to the definition of myocarditis used by the CDC 4-6 is provided in Table S1. Endomyocardial biopsy samples that were obtained from 2 persons showed foci of endointerstitial edema and neutrophils, along with mononuclear-cell infiates (monocytes or macrophages and lymphocytes) with no giant cells. No other patients underwent endomyocardial biopsy. The clinical features of myocarditis after vaccination are provided in Table S3. In the 136 cases of definite or probable myocarditis, the clinical presentation in 129 was generally mild, with resolution of myocarditis in most cases, as judged by clinical symptoms and inflammatory markers and troponin elevation, electrocardiographic and echocardiographic normalization, and a relatively short length of hospital stay.

However, one person with fulminant myocarditis died. The ejection fraction was normal or mildly reduced in most persons and severely reduced in 4 persons. Magnetic resonance imaging that was performed in 48 persons showed findings that were consistent with myocarditis on the basis of at least one positive T2-based sequence and one positive T1-based sequence (including T2-weighted images, T1 and T2 parametric mapping, and late gadolinium enhancement). Follow-up data regarding the status of cases after hospital discharge and consistent measures of cardiac function were not available. Figure 1.

Figure 1. Timing and Distribution of Myocarditis after Receipt of the BNT162b2 treatment. Shown is the timing of the diagnosis of myocarditis among recipients of the first dose of treatment (Panel A) and the second dose (Panel B), according to sex, and the distribution of cases among recipients according to both age and sex after the first dose (Panel C) and after the second dose (Panel D). Cases of myocarditis were reported within 21 days after the first dose and within 30 days after the second dose.The peak number of cases with proximity to vaccination occurred in February and March 2021. The associations with vaccination status, age, and sex are provided in Table 1 and Figure 1.

Of 136 persons with definite or probable myocarditis, 19 presented after the first dose of treatment and 117 after the second dose. In the 21 days after the first dose, 19 persons with myocarditis were hospitalized, and hospital admission dates were approximately equally distributed over time. A total of 95 of 117 persons (81%) who presented after the second dose were hospitalized within 7 days after vaccination. Among 95 persons for whom data regarding age and sex were available, 86 (91%) were male and 72 (76%) were under the age of 30 years. Comparison of Risks According to First or Second Dose Table 3.

Table 3. Risk of Myocarditis within 21 Days after the First or Second Dose of treatment, According to Age and Sex. A comparison of risks over equal time periods of 21 days after the first and second doses according to age and sex is provided in Table 3. Cases were clustered during the first few days after the second dose of treatment, according to visual inspection of the data (Figure 1B and 1D). The overall risk difference between the first and second doses was 1.76 per 100,000 persons (95% confidence interval [CI], 1.33 to 2.19).

The overall risk difference was 3.19 (95% CI, 2.37 to 4.02) among male recipients and 0.39 (95% CI, 0.10 to 0.68) among female recipients. The highest difference was observed among male recipients between the ages of 16 and 19 years. 13.73 per 100,000 persons (95% CI, 8.11 to 19.46). In this age group, the percent attributable risk to the second dose was 91%. The difference in the risk among female recipients between the first and second doses in the same age group was 1.00 per 100,000 persons (95% CI, −0.63 to 2.72).

Repeating these analyses with a shorter follow-up of 7 days owing to the presence of a cluster that was noted after the second treatment dose disclosed similar differences in male recipients between the ages of 16 and 19 years (risk difference, 13.62 per 100,000 persons. 95% CI, 8.31 to 19.03). These findings pointed to the first week after the second treatment dose as the main risk window. Observed versus Expected Incidence Table 4. Table 4.

Standardized Incidence Ratios for 151 Cases of Myocarditis, According to treatment Dose, Age, and Sex. Table 4 shows the standardized incidence ratios for myocarditis according to treatment dose, age group, and sex, as projected from the incidence during the previagra period from 2017 through 2019. Myocarditis after the second dose of treatment had a standardized incidence ratio of 5.34 (95% CI, 4.48 to 6.40), which was driven mostly by the diagnosis of myocarditis in younger male recipients. Among boys and men, the standardized incidence ratio was 13.60 (95% CI, 9.30 to 19.20) for those 16 to 19 years of age, 8.53 (95% CI, 5.57 to 12.50) for those 20 to 24 years, 6.96 (95% CI, 4.25 to 10.75) for those 25 to 29 years, and 2.90 (95% CI, 1.98 to 4.09) for those 30 years of age or older. These substantially increased findings were not observed after the first dose.

A sensitivity analysis showed that for male recipients between the ages of 16 and 24 years who had received a second treatment dose, the observed standardized incidence ratios would have required overreporting of myocarditis by a factor of 4 to 5 on the assumption that the true incidence would not have differed from the expected incidence (Table S4). Rate Ratio between Vaccinated and Unvaccinated Persons Table 5. Table 5. Rate Ratios for a Diagnosis of Myocarditis within 30 Days after the Second Dose of treatment, as Compared with Unvaccinated Persons (January 11 to May 31, 2021). Within 30 days after receipt of the second treatment dose in the general population, the rate ratio for the comparison of the incidence of myocarditis between vaccinated and unvaccinated persons was 2.35 (95% CI, 1.10 to 5.02) according to the Brighton Collaboration classification of definite and probable cases and after adjustment for age and sex.

This result was driven mainly by the findings for males in younger age groups, with a rate ratio of 8.96 (95% CI, 4.50 to 17.83) for those between the ages of 16 and 19 years, 6.13 (95% CI, 3.16 to 11.88) for those 20 to 24 years, and 3.58 (95% CI, 1.82 to 7.01) for those 25 to 29 years (Table 5). When follow-up was restricted to 7 days after the second treatment dose, the analysis results for male recipients between the ages of 16 and 19 years were even stronger than the findings within 30 days (rate ratio, 31.90. 95% CI, 15.88 to 64.08). Concordance of our findings with the Bradford Hill causality criteria is shown in Table S5..

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High efficacy viagra without a doctor prescription canada of high dose intravenous ceftriaxone against extragenital gonorrhoeaCeftriaxone monotherapy is well established for treating Neisseria gonorrhoeae (NG) urethritis, but international viagra online data are limited for pharyngeal and rectal s. This prospective single-centre study was conducted in Japan in 2017–2020 among HIV-negative men who have sex with men (MSM) who underwent routine STI screening, including nucleic acid amplification tests (NAATs) for rectal and pharyngeal NG every 3 months.1 Among 320 cases of extragenital gonorrhoea (all asymptomatic), 208 received only ceftriaxone viagra without a doctor prescription canada (single 1 g intravenous dose) and 112 received additional treatment with doxycycline (100 mg two times a day for 7 days) or azithromycin (single 1 g dose) for concomitant STIs (predominantly, Chlamydia trachomatis (CT)). There was no difference in NG cure rates between the two groups (98.1% vs 95.5%) or by site.

Data are needed for other ceftriaxone dosing strategies and in areas where ceftriaxone resistance is a major concern.Published viagra without a doctor prescription canada in STI—The Editor’s Choice. Neisseria gonorrhoeae is associated with poor pregnancy and birth outcomesThis systematic review and meta-analysis compiled data from 30 studies that reported NG testing during pregnancy and compared pregnancy and birth outcomes between women with and without NG.2 Results indicated that NG s during pregnancy nearly doubled the risk of viagra without a doctor prescription canada preterm birth (summary adjusted OR 1.90. 95% CI 1.14 to 3.19).

The effect was more pronounced viagra without a doctor prescription canada in low-income and middle-income countries than in high-income countries. Additionally, results suggested that NG may be associated with premature rupture of membranes, perinatal mortality, low birth weight and ophthalmia neonatorum, although estimates in most studies did not sufficiently control viagra without a doctor prescription canada for confounders. The findings identify NG s as risk factor for poor pregnancy outcomes.Inadvertent HPV vaccination during or peripregnancy is not associated with adverse outcomesHuman papillomaviagra (HPV) vaccination is not recommended in pregnancy due to lack of safety data.

However, a pregnancy test is not required prior to viagra without a doctor prescription canada vaccination. This multisite cohort study collated data from 445 women who received the nonavalent HPV treatment during pregnancy and 496 that received the treatment peripregnancy (within 42 days before last menstrual period (LMP)).3 Pregnancy and neonatal outcomes in these groups were compared with those of 552 distal (16–22 weeks pre-LMP) exposures to the quadrivalent or nonavalent HPV treatment. Compared with viagra without a doctor prescription canada distal-exposures, during-pregnancy or peripregnancy, exposures were not associated with spontaneous abortion, preterm birth or small-for-gestational-age births.

Birth defects viagra without a doctor prescription canada were rare in all groups. The findings inform counselling for women who inadvertently receive the nonavalent (and possibly quadrivalent) HPV treatment during pregnancy. Data are viagra without a doctor prescription canada needed for the bivalent HPV treatment.Has the time come for point-of-care STI testing?.

Point-of-care (POC) STI testing has been proposed as a strategy to both improve treatment viagra without a doctor prescription canada rates and optimise antibiotic stewardship. This study investigated the performance of the Visby Medical Sexual Health Test, a POC PCR-based NAAT for rapid (30 m) detection of CT, NG and Trichomonas vaginalis (TV).4 The analysis used self-collected vaginal samples from 1535 women who attended 10 clinics in seven US states over an 11-month period. Results were compared with viagra without a doctor prescription canada those of clinician-collected samples tested using gold-standard laboratory-based NAATs.

Specificity and sensitivity of the POC test were 98.3% and 97.4% for CT, 97.4% and 99.4% for NG and 99.2% and 96.9% for TV. These results highlight the potential utility of easy-to-use POC NAATs in clinical practice.Point of care HIV-1 RNA testing facilitates the same-day confirmation of HIV and leads to rapid viral suppression when followed by immediate antiretroviral treatmentMSM with primary HIV (PHI) and those with established but undiagnosed can be an important source viagra without a doctor prescription canada of onward transmission. This study from Amsterdam evaluated a strategy viagra without a doctor prescription canada comprising.

(i) an online media campaign to increase awareness about PHI among MSM and promote self-referral for testing, (ii) qualitative POC HIV-1 RNA testing for same-day confirmation of and delivery of results and (iii) immediate referral of newly diagnosed men to a treatment centre to initiate antiretroviral therapy (ART within 24 hours.5 Time to viral suppression was only 55 days for MSM who benefitted from the strategy and shorter than previous strategies that deferred ART initiation and/or did not employ HIV-1 RNA POC testing. The approach proved feasible in Amsterdam and should be investigated in other settings.Pre-exposure prophylaxis, HIV incidence and risk behaviour among MSM viagra without a doctor prescription canada in West AfricaThis prospective cohort study investigated the use of pre-exposure prophylaxis (PrEP) among MSM in Côte D’Ivoire, Mali, Togo and Burkina Faso as an extension of CohMSM, a prevention study that did not include PrEP.6 Participants were free to choose between daily or event-driven PrEP, change between the two and stop and restart PrEP. Among 598 MSM followed for 743.6 person years, HIV incidence was 2.3 per 100 person-years (95% CI 1.3 viagra without a doctor prescription canada to 3.7) and lower than in CohMSM (adjusted incidence rate ratio 0.21.

95% CI 0.12 to 0.36). There was no evidence of an increase in risk behaviour since reports of condomless anal sex and prevalence viagra without a doctor prescription canada of STIs remained stable, whereas the number of male sexual partners and of sex acts with casual male partners decreased. PrEP is an effective prevention tool for MSM in West Africa.Ethics statementsPatient consent for publicationNot required..

High efficacy where can i buy viagra of high dose go intravenous ceftriaxone against extragenital gonorrhoeaCeftriaxone monotherapy is well established for treating Neisseria gonorrhoeae (NG) urethritis, but data are limited for pharyngeal and rectal s. This prospective single-centre study was conducted in Japan in 2017–2020 among HIV-negative men who have where can i buy viagra sex with men (MSM) who underwent routine STI screening, including nucleic acid amplification tests (NAATs) for rectal and pharyngeal NG every 3 months.1 Among 320 cases of extragenital gonorrhoea (all asymptomatic), 208 received only ceftriaxone (single 1 g intravenous dose) and 112 received additional treatment with doxycycline (100 mg two times a day for 7 days) or azithromycin (single 1 g dose) for concomitant STIs (predominantly, Chlamydia trachomatis (CT)). There was no difference in NG cure rates between the two groups (98.1% vs 95.5%) or by site.

Data are needed where can i buy viagra for other ceftriaxone dosing strategies and in areas where ceftriaxone resistance is a major concern.Published in STI—The Editor’s Choice. Neisseria gonorrhoeae is associated with poor pregnancy and birth outcomesThis systematic review and meta-analysis compiled data from 30 studies that reported NG testing during pregnancy and compared pregnancy and birth outcomes between women with and without NG.2 Results indicated that NG s during pregnancy nearly doubled the risk where can i buy viagra of preterm birth (summary adjusted OR 1.90. 95% CI 1.14 to 3.19).

The effect where can i buy viagra was more pronounced in low-income and middle-income countries than in high-income countries. Additionally, results suggested that NG where can i buy viagra may be associated with premature rupture of membranes, perinatal mortality, low birth weight and ophthalmia neonatorum, although estimates in most studies did not sufficiently control for confounders. The findings identify NG s as risk factor for poor pregnancy outcomes.Inadvertent HPV vaccination during or peripregnancy is not associated with adverse outcomesHuman papillomaviagra (HPV) vaccination is not recommended in pregnancy due to lack of safety data.

However, a pregnancy test is not where can i buy viagra required prior to vaccination. This multisite cohort study collated data from 445 women who received the nonavalent HPV treatment during pregnancy and 496 that received the treatment peripregnancy (within 42 days before last menstrual period (LMP)).3 Pregnancy and neonatal outcomes in these groups were compared with those of 552 distal (16–22 weeks pre-LMP) exposures to the quadrivalent or nonavalent HPV treatment. Compared with distal-exposures, during-pregnancy or peripregnancy, exposures were not associated with spontaneous abortion, preterm birth or small-for-gestational-age births where can i buy viagra.

Birth defects where can i buy viagra were rare in all groups. The findings inform counselling for women who inadvertently receive the nonavalent (and possibly quadrivalent) HPV treatment during pregnancy. Data are needed for the bivalent HPV treatment.Has the time come for where can i buy viagra point-of-care STI testing?.

Point-of-care (POC) STI testing has been proposed as a strategy to both improve treatment rates and optimise where can i buy viagra antibiotic stewardship. This study investigated the performance of the Visby Medical Sexual Health Test, a POC PCR-based NAAT for rapid (30 m) detection of CT, NG and Trichomonas vaginalis (TV).4 The analysis used self-collected vaginal samples from 1535 women who attended 10 clinics in seven US states over an 11-month period. Results were compared where can i buy viagra with those of clinician-collected samples tested using gold-standard laboratory-based NAATs.

Specificity and sensitivity of the POC test were 98.3% and 97.4% for CT, 97.4% and 99.4% for NG and 99.2% and 96.9% for TV. These results highlight the potential utility of easy-to-use POC NAATs in clinical practice.Point of care HIV-1 RNA testing facilitates the same-day confirmation of HIV and leads to rapid viral suppression when followed by immediate antiretroviral treatmentMSM with primary HIV (PHI) and those with established but undiagnosed can be an important source of onward where can i buy viagra transmission. This study from Amsterdam evaluated a strategy where can i buy viagra comprising.

(i) an online media campaign to increase awareness about PHI among MSM and promote self-referral for testing, (ii) qualitative POC HIV-1 RNA testing for same-day confirmation of and delivery of results and (iii) immediate referral of newly diagnosed men to a treatment centre to initiate antiretroviral therapy (ART within 24 hours.5 Time to viral suppression was only 55 days for MSM who benefitted from the strategy and shorter than previous strategies that deferred ART initiation and/or did not employ HIV-1 RNA POC testing. The approach proved feasible in Amsterdam and should be investigated in other settings.Pre-exposure prophylaxis, HIV incidence and risk behaviour among MSM in West AfricaThis prospective cohort study where can i buy viagra investigated the use of pre-exposure prophylaxis (PrEP) among MSM in Côte D’Ivoire, Mali, Togo and Burkina Faso as an extension of CohMSM, a prevention study that did not include PrEP.6 Participants were free to choose between daily or event-driven PrEP, change between the two and stop and restart PrEP. Among 598 MSM followed for 743.6 person years, HIV incidence was 2.3 per 100 person-years (95% CI 1.3 where can i buy viagra to 3.7) and lower than in CohMSM (adjusted incidence rate ratio 0.21.

95% CI 0.12 to 0.36). There was no evidence of an increase in risk behaviour since reports of condomless anal sex and prevalence of STIs remained stable, whereas the number of male where can i buy viagra sexual partners and of sex acts with casual male partners decreased. PrEP is an effective prevention tool for MSM in West Africa.Ethics statementsPatient consent for publicationNot required..

Viagra mechanism of action

IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected to have a disorder/difference of sex development (DSD).1–13 Based on these studies, it has become clear that services and institutions still who can buy viagra online differ in the composition of the multidisciplinary teams that provide care for viagra mechanism of action patients who have a DSD.11 14 Several projects have now worked to resolve this variability in care. The European Cooperation in Science and Technology (EU COST) action BM1303 ‘A systematic viagra mechanism of action elucidation of differences of sex development’ has been a platform to achieve European agreement on harmonisation of clinical management and laboratory practices.15–17 Another such initiative involved an update of the 2006 DSD consensus document by an international group of professionals and patient representatives.18 These initiatives have highlighted how cultural and financial aspects and the availability of resources differ significantly between countries and societies, a situation that hampers supranational agreement on common diagnostic protocols. As only a few national guidelines have been published in international journals, comparison of these guidelines is difficult even though such a comparison is necessary to capture the differences and initiate actions to overcome them. Nonetheless, four DSD (expert) centres located in the Netherlands and Flanders (the Dutch-speaking Northern part of viagra mechanism of action Belgium) have collaborated to produce a detailed guideline on diagnostics in DSD.19 This shows that a supranational guideline can be a reasonable approach for countries with similarly structured healthcare systems and similar resources. Within the guideline there is agreement that optimisation of expertise and care can be achieved through centralisation, for example, by limiting analysis of next-generation sequencing (NGS)-based diagnostic panels to only a few centres and by centralising pathological review of gonadal tissues.

International networks such as viagra mechanism of action the European Reference Network for rare endocrine conditions (EndoERN), in which DSD is embedded, may facilitate the expansion of this kind of collaboration across Europe.This paper highlights key discussion points in the Dutch-Flemish guideline that have been insufficiently addressed in the literature thus far because they reflect evolving technologies or less visible stakeholders. For example, prenatal observation of an atypical aspect of the genitalia indicating a possible DSD is becoming increasingly common, and we discuss appropriate counselling and a diagnostic approach for these cases, including the option of using NGS-based genetic testing. So far, little attention has been paid to this process.20 21 Furthermore, informing patients and/or their parents about atypical sex development and why this may warrant referral to a specialised team may be challenging, especially for professionals with limited experience in viagra mechanism of action DSD.22 23 Therefore, a section of the Dutch-Flemish guideline was written for these healthcare providers. Moreover, this enables DSD specialists to refer to the guideline when advising a referral. Transition from the prenatal to the postnatal team and from the paediatric to viagra mechanism of action the adult team requires optimal communication between the specialists involved.

Application of NGS-based techniques may lead to a higher diagnostic yield, providing a molecular genetic diagnosis in previously unsolved cases.16 We address the timing of this testing and the problems associated with this technique such as the interpretation of variants of unknown clinical significance (VUS). Similarly, histopathological interpretation and classification of removed gonadal tissue is challenging and would benefit from international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group was formed viagra mechanism of action with all members responsible for updating the literature for a specific part of the guideline. Literature search in PubMed was not systematic, but rather intended to be broad in order to cover all areas and follow expert opinions. This approach is more in line with the Clinical Practice Advisory Document method described by Burke viagra mechanism of action et al24 for guidelines involving genetic practice because it is often troublesome to substantiate such guidelines with sufficient evidence due to the rapid changes in testing methods, for example, gene panels. All input provided by the group was synthesised by the chairperson (YvB), who also reviewed abstracts of papers on DSD published between 2010 and September 2017 for the guideline and up to October 2019 for this paper.

Abstracts had to be written in English and were identified using viagra mechanism of action a broad range of Medical Subject Headings terms (eg, DSD, genetic, review, diagnosis, diagnostics, 46,XX DSD, 46,XY DSD, guideline, multidisciplinary care). Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports viagra mechanism of action were excluded, as were articles that were not open access or retrievable through institutional access. Based on this, a draft guideline was produced that was in line with the international principles of good diagnostic care in DSD. This draft was discussed by the writing committee and, after having obtained agreement on remaining points viagra mechanism of action of discussion, revised into a final draft.

This version was sent to a broad group of professionals from academic centres and DSD teams whose members had volunteered to review the draft guideline. After receiving and incorporating their input, viagra mechanism of action the final version was presented to the paediatric and genetic associations for approval. After approval by the members of the paediatric (NVK), clinical genetic (VKGN) and genetic laboratory (VKGL) associations, the guideline was published on their respective websites.19 Although Turner syndrome and Klinefelter syndrome are considered to be part of the DSD spectrum, they are not extensively discussed in this diagnostic guideline as guidelines dedicated to these syndromes already exist.25 26 However, some individuals with Turner syndrome or Klinefelter syndrome may present with ambiguous or atypical genitalia and may therefore initially follow the DSD diagnostic process.Guideline highlightsPrenatal settingPresentationThe most frequent prenatal presentation of a DSD condition is atypical genitalia found on prenatal ultrasound as an isolated finding or in combination with other structural anomalies. This usually occurs after the 20-week routine medical ultrasound for screening of congenital anomalies, but may also occur earlier, for example, when a viagra mechanism of action commercial ultrasound is performed at the request of the parents.Another way DSD can be diagnosed before birth is when invasive prenatal genetic testing carried out for a different reason, for example, due to suspicion of other structural anomalies, reveals a discrepancy between the genotypic sex and the phenotypic sex seen by ultrasound. In certified laboratories, the possibility of a sample switch is extremely low but should be ruled out immediately.

More often, the viagra mechanism of action discrepancy will be due to sex-chromosome mosaicism or a true form of DSD.A situation now occurring with increasing frequency is a discrepancy between the genotypic sex revealed by non-invasive prenatal testing (NIPT), which is now available to high-risk pregnant women in the Netherlands and to all pregnant women in Belgium, and later ultrasound findings. NIPT screens for CNVs in the fetus. However, depending on legal restrictions viagra mechanism of action and/or ethical considerations, the X and Y chromosomes are not always included in NIPT analysis and reports. If the X and Y chromosomes are included, it is important to realise that the presence of a Y-chromosome does not necessarily imply male fetal development. At the time that NIPT is performed (usually 11–13 weeks), genital development cannot be reliably appreciated by ultrasound, so any discrepancy or atypical aspect of the genitalia viagra mechanism of action will only be noticed later in pregnancy and should prompt further evaluation.Counselling and diagnosticsIf a DSD is suspected, first-line sonographers and obstetricians should refer the couple to their colleague prenatal specialists working with or in a DSD team.

After confirming an atypical genital on ultrasound, the specialist team should offer the couple a referral for genetic counselling to discuss the possibility of performing invasive prenatal testing (usually an amniocentesis) to identify an underlying cause that fits the ultrasound findings.22 23 To enable the parents to make a well-informed decision, prenatal counselling should, in our opinion, include. Information on viagra mechanism of action the ultrasound findings and the limitations of this technique. The procedure(s) that can be followed, including the risks associated with an amniocentesis. And the type of information genetic testing can and viagra mechanism of action cannot provide. Knowing which information has been provided and what words have been used by the prenatal specialist is very helpful for those involved in postnatal care.It is important that parents understand that the biological sex of a baby is determined by a complex interplay of chromosomes, genes and hormones, and thus that assessment of the presence or absence of a Y-chromosome alone is insufficient to assign the sex of their unborn child or, as in any unborn child, say anything about the child’s future gender identity.Expecting parents can be counselled by the clinical geneticist and the psychologist from the DSD team, although other DSD specialists can also be involved.

The clinical viagra mechanism of action geneticist should be experienced in prenatal counselling and well informed about the diagnostic possibilities given the limited time span in which test results need to be available to allow parents to make a well-informed decision about whether or not to continue the pregnancy. Termination of pregnancy can be considered, for instance, in a syndromic form of DSD with multiple malformations, but when the DSD occurs as an apparently isolated condition, expecting parents may also consider termination of pregnancy, which, although considered controversial by some, is legal in viagra mechanism of action Belgium and the Netherlands. The psychologist of the DSD team can support parents during and after pregnancy and help them cope with feelings of uncertainty and eventual considerations of a termination of pregnancy, as well as with practical issues, for example, how to inform others. The stress viagra mechanism of action of not knowing exactly what the child’s genitalia will look like and uncertainty about the diagnosis, treatment and prognosis cannot be avoided completely. Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images.

In our experience, parents appreciate having already spoken to some members of the DSD team during pregnancy and having a viagra mechanism of action contact person before birth.After expert prenatal counselling, a significant number of pregnant couples decline prenatal testing (personal experience IALG, MK, ABD, YvB, MC and HC-vdG). At birth, umbilical cord blood is a good source for (molecular) karyotyping and storage of DNA and can be obtained by the obstetrician, midwife or neonatologist. The terminology used in communication with parents should be carefully chosen,22 23 and midwives and staff of neonatal and delivery units should be clearly instructed to use gender-neutral and non-stigmatising vocabulary viagra mechanism of action (eg, ‘your baby’) as long as sex assignment is pending.An algorithm for diagnostic evaluation of a suspected DSD in the prenatal situation is proposed in figure 1. When couples opt for invasive prenatal diagnosis, the genetic analysis usually involves an (SNP)-array. It was recently viagra mechanism of action estimated that >30% of individuals who have a DSD have additional structural anomalies, with cardiac and neurological anomalies and fetal growth restriction being particularly common.27 28 If additional anomalies are seen, the geneticist can consider specific gene defects that may underlie a known genetic syndrome or carry out NGS.

NGS-based techniques have also now made their appearance in prenatal diagnosis of congenital anomalies.29 30 Panels using these techniques can be specific for genes involved in DSD, or be larger panels covering multiple congenital anomalies, and are usually employed with trio-analysis to compare variants identified in the child with the parents’ genetics.29–31 Finding a genetic cause before delivery can help reduce parental stress in the neonatal period and speed up decisions regarding gender assignment. In such cases there is no tight time limit, and we viagra mechanism of action propose completing the analysis well before the expected delivery.Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!.

Conventional karyotyping can be useful. NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 1 Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!.

Conventional karyotyping can be useful. NGS, next-generation sequencing.First contact by a professional less experienced in DSDWhereas most current guidelines start from the point when an individual has been referred to the DSD team,1 15 the Dutch-Flemish guideline dedicates a chapter to healthcare professionals less experienced in DSD as they are often the first to suspect or identify such a condition. Apart from the paper of Indyk,7 little guidance is available for these professionals about how to act in such a situation. The chapter in the Dutch-Flemish guideline summarises the various clinical presentations that a DSD can have and provides information on how to communicate with parents and/or patients about the findings of the physical examination, the first-line investigations and the need for prompt referral to a specialised centre for further evaluation. Clinical examples are offered to illustrate some of these recurring situations.

The medical issues in DSD can be very challenging, and the social and psychological impact is high. For neonates with ambiguous genitalia, sex assignment is an urgent and crucial issue, and it is mandatory that parents are informed that it is possible to postpone registration of their child’s sex. In cases where sex assignment has already taken place, the message that the development of the gonads or genitalia is still atypical is complicated and distressing for patients and parents or carers. A list of contact details for DSD centres and patient organisations in the Netherlands and Flanders is attached to the Dutch-Flemish guideline. Publishing such a list, either in guidelines or online, can help healthcare professionals find the nearest centres for consultations and provide patients and patient organisations with an overview of the centres where expertise is available.Timing and place of genetic testing using NGS-based gene panelsThe diagnostic workup that is proposed for 46,XX and 46,XY DSD is shown in figures 2 and 3, respectively.

Even with the rapidly expanding molecular possibilities, a (family) history and a physical examination remain the essential first steps in the diagnostic process. Biochemical and hormonal screening aim at investigating serum electrolytes, renal function and the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes. Ultrasound screening of kidneys and internal genitalia, as well as establishing genotypic sex, should be accomplished within 48 hours and complete the baseline diagnostic work-up of a child born with ambiguous genitalia.1 16 32 3346,XX disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. NGS, next-generation sequencing.

CAH, Congenital adrenal hyperplasia. AMH, Anti-Müllerian Hormone." data-icon-position data-hide-link-title="0">Figure 2 46,XX disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. NGS, next-generation sequencing. CAH, Congenital adrenal hyperplasia.

AMH, Anti-Müllerian Hormone.46,XY disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. * SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful.

NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 3 46,XY disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful.

NGS, next-generation sequencing.Very recently, a European position paper has been published focusing on the genetic workup of DSD.16 It highlights the limitations and drawbacks of NGS-based tests, which include the chance of missing subtle structural variants such as CNVs and mosaicism and the fact that NGS cannot detect methylation defects or other epigenetic changes.16 28 31 Targeted DNA analysis is preferred in cases where hormonal investigations suggest a block in steroidogenesis (eg, 11-β-hydroxylase deficiency, 21-hydroxylase deficiency), or in the context of a specific clinical constellation such as the often coincidental finding of Müllerian structures in a boy with normal external genitalia or cryptorchidism, that is, persistent Müllerian duct syndrome.33 34 Alternative tests should also be considered depending on the available information. Sometimes, a simple mouth swab for FISH analysis can detect mosaic XY/X in a male with hypospadias or asymmetric gonadal development or in a female with little or no Turner syndrome stigmata and a normal male molecular karyotyping profile or peripheral blood karyotype. Such targeted testing avoids incidental findings and is cheaper and faster than analysis of a large NGS-based panel, although the cost difference is rapidly declining.However, due to the genetic and phenotypic heterogeneity of DSD conditions, the most cost-effective next steps in the majority of cases are whole exome sequencing followed by panel analysis of genes involved in genital development and function or trio-analysis of a large gene panel (such as a Mendeliome).16 35–38 Pretest genetic counselling involves discussing what kind of information will be reported to patients or parents and the chance of detecting VUS, and the small risk of incidental findings when analysing a DSD panel should be mentioned. Laboratories also differ in what class of variants they report.39 In our experience, the fear of incidental findings is a major reason why some parents refrain from genetic testing.Timing of the DSD gene panel analysis is also important. While some patients or parents prefer that all diagnostic procedures be performed as soon as possible, others need time to reflect on the complex information related to more extensive genetic testing and on its possible consequences.

If parents or patients do not consent to panel-based genetic testing, analysis of specific genes, such as WT1, should be considered when appropriate in view of the clinical consequences if a mutation is present (eg, clinical surveillance of renal function and screening for Wilms’ tumour in the case of WT1 mutations). Genes that are more frequently involved in DSD (eg, SRY, NR5A1) and that match the specific clinical and hormonal features in a given patient could also be considered for sequencing. Targeted gene analysis may also be preferred in centres located in countries that do not have the resources or technical requirements to perform NGS panel-based genetic testing. Alternatively, participation by these centres in international collaborative networks may allow them to outsource the molecular genetic workup abroad.Gene panels differ between centres and are regularly updated based on scientific progress. A comparison of DSD gene panels used in recent studies can be found at https://www.nature.com/articles/s41574-018-0010-8%23Sec46.15 The panels currently used at the coauthors’ institutions can be found on their respective websites.

Given the pace of change, it is important to regularly consider repeating analysis in patients with an unexplained DSD, for example, when they transition into adult care or when they move from one centre to another. This also applies to patients in whom a clinical diagnosis has never been genetically confirmed. Confusion may arise when the diagnosis cannot be confirmed or when a mutation is identified in a different gene, for example, NR5A1 in someone with a clinical diagnosis of CAIS that has other consequences for relatives. Hence, new genetic counselling should always accompany new diagnostic endeavours.Class 3 variants and histopathological examinationsThe rapidly evolving diagnostic possibilities raise new questions. What do laboratories report?.

How should we deal with the frequent findings of mainly unique VUS or class 3 variants (ACMG recommendation) in the many different DSD-related genes in the diagnostic setting?. Reporting VUS can be a source of uncertainty for parents, but not reporting these variants precludes further investigations to determine their possible pathogenicity. It can also be difficult to prove variant pathogenicity, both on gene-level and variant-level.39 Moreover, given the gonad-specific expression of some genes and the variable phenotypic spectrum and reduced penetrance, segregation analysis is not always informative. A class 3 variant that does not fit the clinical presentation may be unrelated to the observed phenotype, but it could also represent a newly emerging phenotype. This was recently demonstrated by the identification of the NR5A1 mutation, R92W, in individuals with 46,XX testicular and ovotesticular DSD.40 This gene had previously been associated with 46,XY DSD.

In diagnostic laboratories, there is usually no capacity or expertise to conduct large-scale functional studies to determine pathogenicity of these unique class 3 VUS in the different genes involved in DSD. Functional validation of variants identified in novel genes may be more attractive in a research context. However, for individual families with VUS in well-established DSD genes such as AR or HSD17B3, functional analysis may provide a confirmed diagnosis that implies for relatives the option of undergoing their own DNA analysis and estimating the genetic risk of their own future offspring. This makes genetic follow-up important in these cases and demonstrates the usefulness of international databases and networks and the centralisation of functional studies of genetic variants in order to reduce costs and maximise expertise.The same is true for histopathological description, germ-cell tumour risk assessment in specific forms of DSD and classification of gonadal samples. Germ-cell tumour risk is related to the type of DSD (among other factors), but it is impossible to make risk estimates in individual cases.41–44 Gonadectomy may be indicated in cases with high-risk dysgenetic abdominal gonads that cannot be brought into a stable superficial (ie, inguinal, labioscrotal) position that allows clinical or radiological surveillance, or to avoid virilisation due to 5-alpha reductase deficiency in a 46,XY girl with a stable female gender identity.45 Pathological examination of DSD gonads requires specific expertise.

For example, the differentiation between benign germ cell abnormalities, such as delayed maturation and (pre)malignant development of germ cells, is crucial for clinical management but can be very troublesome.46 Centralised pathological examination of gonadal biopsy and gonadectomy samples in one centre, or a restricted number of centres, on a national scale can help to overcome the problem of non-uniform classification and has proven feasible in the Netherlands and Belgium. We therefore believe that uniform assessment and classification of gonadal differentiation patterns should also be addressed in guidelines on DSD management.International databases of gonadal tissues are crucial for learning more about the risk of malignancy in different forms of DSD, but they are only reliable if uniform criteria for histological classification are strictly applied.46 These criteria could be incorporated in many existing networks such as the I-DSD consortium, the Disorders of Sex Development Translational Research Network, the European Reference Network on Urogenital Diseases (eUROGEN), the EndoERN and COST actions.15–17 47Communication at the transition from paediatric to adult carePaediatric and adult teams need to collaborate closely to facilitate a well-organised transition from paediatric to adult specialist care.15 48–50 Both teams need to exchange information optimally and should consider transition as a longitudinal process rather than a fixed moment in time. Age-appropriate information is key at all ages, and an overview of topics to be discussed at each stage is described by Cools et al.15 Table 1 shows an example of how transition can be organised.View this table:Table 1 Example of transition table as used in the DSD clinic of the Erasmus Medical CenterPsychological support and the continued provision of information remains important for individuals with a DSD at all ages.15 22 In addition to the information given by the DSD team members, families and patients can benefit from resources such as support groups and information available on the internet.47 Information available online should be checked for accuracy and completeness when referring patients and parents to internet sites.Recommendations for future actionsMost guidelines and articles on the diagnosis and management of DSD are aimed at specialists and are only published in specialist journals or on websites for endocrinologists, urologists or geneticists. Yet there is a need for guidelines directed towards first-line and second-line healthcare workers that summarise the recommendations about the first crucial steps in the management of DSD. These should be published in widely available general medical journals and online, along with a national list of DSD centres.

Furthermore, DSD (expert) centres should provide continuous education to all those who may be involved in the identification of individuals with a DSD in order to enable these healthcare professionals to recognise atypical genitalia, to promptly refer individuals who have a DSD and to inform the patient and parents about this and subsequent diagnostic procedures.As DSD continues to be a rare condition, it will take time to evaluate the effects of having such a guideline on the preparedness of first-line and second-line healthcare workers to recognise DSD conditions. One way to evaluate this might be the development and use of questionnaires asking patients, carers and families and referring physicians how satisfied they were with the initial medical consultation and referral and what could be improved. A helpful addition to existing international databases that collect information on genetic variations would be a list of centres that offer suitable functional studies for certain genes, ideally covering the most frequently mutated genes (at minimum).Patient organisations can also play an important role in informing patients about newly available diagnostic or therapeutic strategies and options, and their influence and specific role has now been recognised and discussed in several publications.17 47 However, it should be kept in mind that these organisations do not represent all patients, as a substantial number of patients and parents are not member of such an organisation.Professionals have to provide optimal medical care based on well-established evidence, or at least on broad consensus. Yet not everything can be regulated by recommendations and guidelines. Options, ideas and wishes should be openly discussed between professionals, patients and families within their confidential relationship.

This will enable highly individualised holistic care tailored to the patient’s needs and expectations. Once they are well-informed of all available options, parents and/or patients can choose what they consider the optimal care for their children or themselves.15 16ConclusionThe Dutch-Flemish guideline uniquely addresses some topics that are under-represented in the literature, thus adding some key aspects to those addressed in recent consensus papers and guidelines.15–17 33 47As more children with a DSD are now being identified prenatally, and the literature on prenatal diagnosis of DSD remains scarce,20 21 we propose a prenatal diagnostic algorithm and emphasise the importance of having a prenatal specialist involved in or collaborating with DSD (expert) centres.We also stress that good communication between all involved parties is essential. Professionals should be well informed about protocols and communication. Collaboration between centres is necessary to optimise aspects of care such as uniform interpretation of gonadal pathology and functional testing of class 3 variants found by genetic testing. Guidelines can provide a framework within which individualised patient care should be discussed with all stakeholders.AcknowledgmentsThe authors would like to thank the colleagues of the DSD teams for their input in and critical reading of the Dutch-Flemish guideline.

Amsterdam University Center (AMC and VU), Maastricht University Medical Center, Erasmus Medical Center Rotterdam, Radboud University Medical Center Nijmegen, University Medical Center Groningen, University Medical Center Utrecht, Ghent University Hospital. The authors would like to thank Kate McIntyre for editing the revised manuscript and Tom de Vries Lentsch for providing the figures as a PDF. Three of the authors of this publication are members of the European Reference Network for rare endocrine diseases—Project ID 739543.IntroductionEndometrial cancer is the most common gynaecological malignancy in the developed world.1 Its incidence has risen over the last two decades as a consequence of the ageing population, fewer hysterectomies for benign disease and the obesity epidemic. In the USA, it is estimated that women have a 1 in 35 lifetime risk of endometrial cancer, and in contrast to cancers of most other sites, cancer-specific mortality has risen by approximately 2% every year since 2008 related to the rapidly rising incidence.2Endometrial cancer has traditionally been classified into type I and type II based on morphology.3 The more common subtype, type I, is mostly comprised of endometrioid tumours and is oestrogen-driven, arises from a hyperplastic endometrium, presents at an early stage and has an excellent 5 year survival rate.4 By contrast, type II includes non-endometrioid tumours, specifically serous, carcinosarcoma and clear cell subtypes, which are biologically aggressive tumours with a poor prognosis that are often diagnosed at an advanced stage.5 Recent efforts have focused on a molecular classification system for more accurate categorisation of endometrial tumours into four groups with distinct prognostic profiles.6 7The majority of endometrial cancers arise through the interplay of familial, genetic and lifestyle factors. Two inherited cancer predisposition syndromes, Lynch syndrome and the much rarer Cowden syndrome, substantially increase the lifetime risk of endometrial cancer, but these only account for around 3–5% of cases.8–10 Having first or second degree relative(s) with endometrial or colorectal cancer increases endometrial cancer risk, although a large European twin study failed to demonstrate a strong heritable link.11 The authors failed to show that there was greater concordance in monozygotic than dizygotic twins, but the study was based on relatively small numbers of endometrial cancers.

Lu and colleagues reported an association between common single nucleotide polymorphisms (SNPs) and endometrial cancer risk, revealing the potential role of SNPs in explaining part of the risk in both the familial and general populations.12 Thus far, many SNPs have been reported to modify susceptibility to endometrial cancer. However, much of this work predated genome wide association studies and is of variable quality. Understanding genetic predisposition to endometrial cancer could facilitate personalised risk assessment with a view to targeted prevention and screening interventions.13 This emerged as the most important unanswered research question in endometrial cancer according to patients, carers and healthcare professionals in our recently completed James Lind Womb Cancer Alliance Priority Setting Partnership.14 It would be particularly useful for non-endometrioid endometrial cancers, for which advancing age is so far the only predictor.15We therefore conducted a comprehensive systematic review of the literature to provide an overview of the relationship between SNPs and endometrial cancer risk. We compiled a list of the most robust endometrial cancer-associated SNPs. We assessed the applicability of this panel of SNPs with a theoretical polygenic risk score (PRS) calculation.

We also critically appraised the meta-analyses investigating the most frequently reported SNPs in MDM2. Finally, we described all SNPs reported within genes and pathways that are likely involved in endometrial carcinogenesis and metastasis.MethodsOur systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) collaboration 2009 recommendations. The registered protocol is available through PROSPERO (CRD42018091907).16Search strategyWe searched Embase, MEDLINE and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases via the Healthcare Databases Advanced Search (HDAS) platform, from 2007 to 2018, to identify studies reporting associations between polymorphisms and endometrial cancer risk. Key words including MeSH (Medical Subject Heading) terms and free-text words were searched in both titles and abstracts. The following terms were used.

€œendomet*”,“uter*”, “womb”, “cancer(s)”, “neoplasm(s)”, “endometrium tumour”, “carcinoma”, “adenosarcoma”, “clear cell carcinoma”, “carcinosarcoma”, “SNP”, “single nucleotide polymorphism”, “GWAS”, and “genome-wide association study/ies”. No other restrictions were applied. The search was repeated with time restrictions between 2018 and June 2019 to capture any recent publications.Eligibility criteriaStudies were selected for full-text evaluation if they were primary articles investigating a relationship between endometrial cancer and SNPs. Study outcome was either the increased or decreased risk of endometrial cancer relative to controls reported as an odds ratio (OR) with corresponding 95% confidence intervals (95% CIs).Study selectionThree independent reviewers screened all articles uploaded to a screening spreadsheet developed by Helena VonVille.17 Disagreements were resolved by discussion. Chronbach’s α score was calculated between reviewers and indicated high consistency at 0.92.

Case–control, prospective and retrospective studies, genome-wide association studies (GWAS), and both discovery and validation studies were selected for full-text evaluation. Non-English articles, editorials, conference abstracts and proceedings, letters and correspondence, case reports and review articles were excluded.Candidate-gene studies with at least 100 women and GWAS with at least 1000 women in the case arm were selected to ensure reliability of the results, as explained by Spencer et al.18 To construct a panel of up to 30 SNPs with the strongest evidence of association, those with the strongest p values were selected. For the purpose of an SNP panel, articles utilising broad European or multi-ethnic cohorts were selected. Where overlapping populations were identified, the most comprehensive study was included.Data extraction and synthesisFor each study, the following data were extracted. SNP ID, nearby gene(s)/chromosome location, OR (95% CI), p value, minor or effect allele frequency (MAF/EAF), EA (effect allele) and OA (other allele), adjustment, ethnicity and ancestry, number of cases and controls, endometrial cancer type, and study type including discovery or validation study and meta-analysis.

For risk estimates, a preference towards most adjusted results was applied. For candidate-gene studies, a standard p value of<0.05 was applied and for GWAS a p value of <5×10-8, indicating genome-wide significance, was accepted as statistically significant. However, due to the limited number of SNPs with p values reaching genome-wide significance, this threshold was then lowered to <1×10-5, allowing for marginally significant SNPs to be included. As shown by Mavaddat et al, for breast cancer, SNPs that fall below genome-wide significance may still be useful for generating a PRS and improving the models.19We estimated the potential value of a PRS based on the most significant SNPs by comparing the predicted risk for a woman with a risk score in the top 1% of the distribution to the mean predicted risk. Per-allele ORs and MAFs were taken from the publications and standard errors (SEs) for the lnORs were derived from published 95% CIs.

The PRS was assumed to have a Normal distribution, with mean 2∑βipI and SE, σ, equal to √2∑βi2pI(1−pi), according to the binomial distribution, where the summation is over all SNPs in the risk score. Hence the relative risk (RR) comparing the top 1% of the distribution to the mean is given by exp(Z0.01σ), where Z is the inverse of the standard normal cumulative distribution.ResultsThe flow chart of study selection is illustrated in figure 1. In total, 453 text articles were evaluated and, of those, 149 articles met our inclusion criteria. One study was excluded from table 1, for having an Asian-only population, as this would make it harder to compare with the rest of the results which were all either multi-ethnic or Caucasian cohorts, as stated in our inclusion criteria for the SNP panel.20 Any SNPs without 95% CIs were also excluded from any downstream analysis. Additionally, SNPs in linkage disequilibrium (r2 >0.2) with each other were examined, and of those in linkage disequilibrium, the SNP with strongest association was reported.

Per allele ORs were used unless stated otherwise.View this table:Table 1 List of top SNPs most likely to contribute to endometrial cancer risk identified through systematic review of recent literature21–25Study selection flow diagram. *Reasons. Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study. Adapted from.

Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PRISMA Statement. PLoS Med 6(6). E1000097.

Doi:10.1371/journal.pmed1000097." data-icon-position data-hide-link-title="0">Figure 1 Study selection flow diagram. *Reasons. Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study. Adapted from.

Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PRISMA Statement. PLoS Med 6(6). E1000097.

Doi:10.1371/journal.pmed1000097.Top SNPs associated with endometrial cancer riskFollowing careful interpretation of the data, 24 independent SNPs with the lowest p values that showed the strongest association with endometrial cancer were obtained (table 1).21–25 These SNPs are located in or around genes coding for transcription factors, cell growth and apoptosis regulators, and enzymes involved in the steroidogenesis pathway. All the SNPs presented here were reported on the basis of a GWAS or in one case, an exome-wide association study, and hence no SNPs from candidate-gene studies made it to the list. This is partly due to the nature of larger GWAS providing more comprehensive and powered results as opposed to candidate gene studies. Additionally, a vast majority of SNPs reported by candidate-gene studies were later refuted by large-scale GWAS such as in the case of TERT and MDM2 variants.26 27 The exception to this is the CYP19 gene, where candidate-gene studies reported an association between variants in this gene with endometrial cancer in both Asian and broad European populations, and this association was more recently confirmed by large-scale GWAS.21 28–30 Moreover, a recent article authored by O’Mara and colleagues reviewed the GWAS that identified most of the currently known SNPs associated with endometrial cancer.31Most of the studies represented in table 1 are GWAS and the majority of these involved broad European populations. Those having a multi-ethnic cohort also consisted primarily of broad European populations.

Only four of the variants in table 1 are located in coding regions of a gene, or in regulatory flanking regions around the gene. Thus, most of these variants would not be expected to cause any functional effects on the gene or the resulting protein. An eQTL search using GTEx Portal showed that some of the SNPs are significantly associated (p<0.05) with modified transcription levels of the respective genes in various tissues such as prostate (rs11263761), thyroid (rs9668337), pituitary (rs2747716), breast mammary (rs882380) and testicular (rs2498794) tissue, as summarised in table 2.View this table:Table 2 List of eQTL hits for the selected panel of SNPsThe only variant for which there was an indication of a specific association with non-endometrioid endometrial cancer was rs148261157 near the BCL11A gene. The A allele of this SNP had a moderately higher association in the non-endometrioid arm (OR 1.64, 95% CI 1.32 to 2.04. P=9.6×10-6) compared with the endometrioid arm (OR 1.25, 95% CI 1.14 to 1.38.

P=4.7×10-6).21Oestrogen receptors α and β encoded by ESR1 and ESR2, respectively, have been extensively studied due to the assumed role of oestrogens in the development of endometrial cancer. O’Mara et al reported a lead SNP (rs79575945) in the ESR1 region that was associated with endometrial cancer (p=1.86×10-5).24 However, this SNP did not reach genome-wide significance in a more recent larger GWAS.21 No statistically significant associations have been reported between endometrial cancer and SNPs in the ESR2 gene region.AKT is an oncogene linked to endometrial carcinogenesis. It is involved in the PI3K/AKT/mTOR pro-proliferative signalling pathway to inactivate apoptosis and allow cell survival. The A allele of rs2494737 and G allele of rs2498796 were reported to be associated with increased and decreased risk of endometrial cancer in 2016, respectively.22 30 However, this association was not replicated in a larger GWAS in 2018.21 Nevertheless, given the previous strong indications, and biological basis that could explain endometrial carcinogenesis, we decided to include an AKT1 variant (rs2498794) in our results.PTEN is a multi-functional tumour suppressor gene that regulates the AKT/PKB signalling pathway and is commonly mutated in many cancers including endometrial cancer.32 Loss-of-function germline mutations in PTEN are responsible for Cowden syndrome, which exerts a lifetime risk of endometrial cancer of up to 28%.9 Lacey and colleagues studied SNPs in the PTEN gene region. However, none showed significant differences in frequency between 447 endometrial cancer cases and 439 controls of European ancestry.33KRAS mutations are known to be present in endometrial cancer.

These can be activated by high levels of KLF5 (transcriptional activator). Three SNPs have been identified in or around KLF5 that are associated with endometrial cancer. The G allele of rs11841589 (OR 1.15, 95% CI 1.11 to 1.21. P=4.83×10-11), the A allele of rs9600103 (OR 1.23, 95% CI 1.16 to 1.30. P=3.76×10-12) and C allele of rs7981863 (OR 1.16, 95% CI 1.12 to 1.20.

P=2.70×10-17) have all been found to be associated with an increased likelihood of endometrial cancer in large European cohorts.21 30 34 It is worth noting that these SNPs are not independent, and hence they quite possibly tag the same causal variant.The MYC family of proto-oncogenes encode transcription factors that regulate cell proliferation, which can contribute to cancer development if dysregulated. The recent GWAS by O’Mara et al reported three SNPs within the MYC region that reached genome-wide significance with conditional p values reaching at least 5×10–8.35To test the utility of these SNPs as predictive markers, we devised a theoretical PRS calculation using the log ORs and EAFs per SNP from the published data. The results were very encouraging with an RR of 3.16 for the top 1% versus the mean, using all the top SNPs presented in table 1 and 2.09 when using only the SNPs that reached genome-wide significance (including AKT1).Controversy surrounding MDM2 variant SNP309MDM2 negatively regulates tumour suppressor gene TP53, and as such, has been extensively studied in relation to its potential role in predisposition to endometrial cancer. Our search identified six original studies of the association between MDM2 SNP rs2279744 (also referred to as SNP309) and endometrial cancer, all of which found a statistically significant increased risk per copy of the G allele. Two more original studies were identified through our full-text evaluation.

However, these were not included here as they did not meet our inclusion criteria—one due to small sample size, the other due to studying rs2279744 status dependent on another SNP.36 37 Even so, the two studies were described in multiple meta-analyses that are listed in table 3. Different permutations of these eight original studies appear in at least eight published meta-analyses. However, even the largest meta-analysis contained <2000 cases (table 3)38View this table:Table 3 Characteristics of studies that examined MDM2 SNP rs2279744In comparison, a GWAS including nearly 13 000 cases found no evidence of an association with OR and corresponding 95% CI of 1.00 (0.97 to 1.03) and a p value of 0.93 (personal communication).21 Nevertheless, we cannot completely rule out a role for MDM2 variants in endometrial cancer predisposition as the candidate-gene studies reported larger effects in Asians, whereas the GWAS primarily contained participants of European ancestry. There is also some suggestion that the SNP309 variant is in linkage disequilibrium with another variant, SNP285, which confers an opposite effect.It is worth noting that the SNP285C/SNP309G haplotype frequency was observed in up to 8% of Europeans, thus requiring correction for the confounding effect of SNP285C in European studies.39 However, aside from one study conducted by Knappskog et al, no other study including the meta-analyses corrected for the confounding effect of SNP285.40 Among the studies presented in table 3, Knappskog et al (2012) reported that after correcting for SNP285, the OR for association of this haplotype with endometrial cancer was much lower, though still significant. Unfortunately, the meta-analyses which synthesised Knappskog et al (2012), as part of their analysis, did not correct for SNP285C in the European-based studies they included.38 41 42 It is also concerning that two meta-analyses using the same primary articles failed to report the same result, in two instances.38 42–44DiscussionThis article represents the most comprehensive systematic review to date, regarding critical appraisal of the available evidence of common low-penetrance variants implicated in predisposition to endometrial cancer.

We have identified the most robust SNPs in the context of endometrial cancer risk. Of those, only 19 were significant at genome-wide level and a further five were considered marginally significant. The largest GWAS conducted in this field was the discovery- and meta-GWAS by O’Mara et al, which utilised 12 096 cases and 108 979 controls.21 Despite the inclusion of all published GWAS and around 5000 newly genotyped cases, the total number did not reach anywhere near what is currently available for other common cancers such as breast cancer. For instance, BCAC (Breast Cancer Association Consortium) stands at well over 200 000 individuals with more than half being cases, and resulted in identification of ~170 SNPs in relation to breast cancer.19 45 A total of 313 SNPs including imputations were then used to derive a PRS for breast cancer.19 Therefore, further efforts should be directed to recruit more patients, with deep phenotypic clinical data to allow for relevant adjustments and subgroup analyses to be conducted for better precision.A recent pre-print study by Zhang and colleagues examined the polygenicity and potential for SNP-based risk prediction for 14 common cancers, including endometrial cancer, using available summary-level data from European-ancestry datasets.46 They estimated that there are just over 1000 independent endometrial cancer susceptibility SNPs, and that a PRS comprising all such SNPs would have an area under the receiver-operator curve of 0.64, similar to that predicted for ovarian cancer, but lower than that for the other cancers in the study. The modelling in the paper suggests that an endometrial cancer GWAS double the size of the current largest study would be able to identify susceptibility SNPs together explaining 40% of the genetic variance, but that in order to explain 75% of the genetic variance it would be necessary to have a GWAS comprising close to 150 000 cases and controls, far in excess of what is currently feasible.We found that the literature consists mainly of candidate-gene studies with small sample sizes, meta-analyses reporting conflicting results despite using the same set of primary articles, and multiple reports of significant SNPs that have not been validated by any larger GWAS.

The candidate-gene studies were indeed the most useful and cheaper technique available until the mid to late 2000s. However, a lack of reproducibility (particularly due to population stratification and reporting bias), uncertainty of reported associations, and considerably high false discovery rates make these studies much less appropriate in the post-GWAS era. Unlike the candidate-gene approach, GWAS do not require prior knowledge, selection of genes or SNPs, and provide vast amounts of data. Furthermore, both the genotyping process and data analysis phases have become cheaper, the latter particularly due to faster and open-access pre-phasing and imputation tools being made available.It is clear from table 1 that some SNPs were reported with wide 95% CI, which can be directly attributed to small sample sizes particularly when restricting the cases to non-endometrioid histology only, low EAF or poor imputation quality. Thus, these should be interpreted with caution.

Additionally, most of the SNPs reported by candidate-gene studies were not detected by the largest GWAS to date conducted by O’Mara et al.21 However, this does not necessarily mean that the possibility of those SNPs being relevant should be completely dismissed. Moreover, meta-analyses were attempted for other variants. However, these showed no statistically significant association and many presented with high heterogeneity between the respective studies (data not shown). Furthermore, as many studies utilised the same set of cases and/or controls, conducting a meta-analysis was not possible for a good number of SNPs. It is therefore unequivocal that the literature is crowded with numerous small candidate-gene studies and conflicting data.

This makes it particularly hard to detect novel SNPs and conduct meaningful meta-analyses.We found convincing evidence for 19 variants that indicated the strongest association with endometrial cancer, as shown in table 1. The associations between endometrial cancer and variants in or around HNF1B, CYP19A1, SOX4, MYC, KLF and EIF2AK found in earlier GWAS were then replicated in the latest and largest GWAS. These SNPs showed promising potential in a theoretical PRS we devised based on published data. Using all 24 or genome-wide significant SNPs only, women with a PRS in the top 1% of the distribution would be predicted to have a risk of endometrial cancer 3.16 and 2.09 times higher than the mean risk, respectively.However, the importance of these variants and relevance of the proximate genes in a functional or biological context is challenging to evaluate. Long distance promoter regulation by enhancers may disguise the genuine target gene.

In addition, enhancers often do not loop to the nearest gene, further complicating the relevance of nearby gene(s) to a GWAS hit. In order to elucidate biologically relevant candidate target genes in endometrial cancer, O’Mara et al looked into promoter-associated chromatin looping using a modern HiChIP approach.47 The authors utilised normal and tumoural endometrial cell lines for this analysis which showed significant enrichment for endometrial cancer heritability, with 103 candidate target genes identified across the 13 risk loci identified by the largest ECAC GWAS. Notable genes identified here were CDKN2A and WT1, and their antisense counterparts. The former was reported to be nearby of rs1679014 and the latter of rs10835920, as shown in table 1. Moreover, of the 36 candidate target genes, 17 were found to be downregulated while 19 were upregulated in endometrial tumours.The authors also investigated overlap between the 13 endometrial cancer risk loci and top eQTL variants for each target gene.47 In whole blood, of the two particular lead SNPs, rs8822380 at 17q21.32 was a top eQTL for SNX11 and HOXB2, whereas rs937213 at 15q15.1 was a top eQTL for SRP14.

In endometrial tumour, rs7579014 at 2p16.1 was found to be a top eQTL for BCL11A. This is particularly interesting because BCL11A was the only nearby/candidate gene that had a GWAS association reported in both endometrioid and non-endometrioid subtypes. The study looked at protein–protein interactions between endometrial cancer drivers and candidate target gene products. Significant interactions were observed with TP53 (most significant), AKT, PTEN, ESR1 and KRAS, among others. Finally, when 103 target candidate genes and 387 proteins were combined together, 462 pathways were found to be significantly enriched.

Many of these are related to gene regulation, cancer, obesity, insulinaemia and oestrogen exposure. This study clearly showed a potential biological relevance for some of the SNPs reported by ECAC GWAS in 2018.Most of the larger included studies used cohorts primarily composed of women of broad European descent. Hence, there are negligible data available for other ethnicities, particularly African women. This is compounded by the lack of reference genotype data available for comparative analysis, making it harder for research to be conducted in ethnicities other than Europeans. This poses a problem for developing risk prediction models that are equally valuable and predictive across populations.

Thus, our results also are of limited applicability to non-European populations.Furthermore, considering that non-endometrioid cases comprise a small proportion (~20%) of all endometrial cancer cases, much larger cohort sizes are needed to detect any genuine signals for non-endometrioid tumours. Most of the evaluated studies looked at either overall/mixed endometrial cancer subtypes or endometrioid histology, and those that looked at variant associations with non-endometrioid histology were unlikely to have enough power to detect any signal with statistical significance. This is particularly concerning because non-endometrioid subtypes are biologically aggressive tumours with a much poorer prognosis that contribute disproportionately to mortality from endometrial cancer. It is particularly important that attempts to improve early detection and prevention of endometrial cancer focus primarily on improving outcomes from these subtypes. It is also worth noting that, despite the current shift towards a molecular classification of endometrial cancer, most studies used the overarching classical Bokhman’s classification system, type I versus type II, or no histological classification system at all.

Therefore, it is important to create and follow a standardised and comprehensive classification system for reporting tumour subtypes for future studies.This study compiled and presented available information for an extensively studied, yet unproven in large datasets, SNP309 variant in MDM2. Currently, there is no convincing evidence for an association between this variant and endometrial cancer risk. Additionally, of all the studies, only one accounted for the opposing effect of a nearby variant SNP285 in their analyses. Thus, we conclude that until confirmed by a sufficiently large GWAS, this variant should not be considered significant in influencing the risk of endometrial cancer and therefore not included in a PRS. This is also true for the majority of the SNPs reported in candidate-gene studies, as the numbers fall far short of being able to detect genuine signals.This systematic review presents the most up-to-date evidence for endometrial cancer susceptibility variants, emphasising the need for further large-scale studies to identify more variants of importance, and validation of these associations.

Until data from larger and more diverse cohorts are available, the top 24 SNPs presented here are the most robust common genetic variants that affect endometrial cancer risk. The multiplicative effects of these SNPs could be used in a PRS to allow personalised risk prediction models to be developed for targeted screening and prevention interventions for women at greatest risk of endometrial cancer..

IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected to have a disorder/difference of sex development (DSD).1–13 Based on these studies, it has become clear that services and institutions still differ in the composition of the multidisciplinary teams that provide care for patients who have a DSD.11 14 http://holmeswestern.com/ Several projects have where can i buy viagra now worked to resolve this variability in care. The European Cooperation in Science and Technology (EU COST) action BM1303 ‘A systematic elucidation of differences of sex development’ has been a platform to achieve where can i buy viagra European agreement on harmonisation of clinical management and laboratory practices.15–17 Another such initiative involved an update of the 2006 DSD consensus document by an international group of professionals and patient representatives.18 These initiatives have highlighted how cultural and financial aspects and the availability of resources differ significantly between countries and societies, a situation that hampers supranational agreement on common diagnostic protocols. As only a few national guidelines have been published in international journals, comparison of these guidelines is difficult even though such a comparison is necessary to capture the differences and initiate actions to overcome them.

Nonetheless, four DSD (expert) centres located in the Netherlands and Flanders (the Dutch-speaking Northern part of Belgium) have collaborated to produce a detailed guideline on diagnostics in DSD.19 This shows that a supranational guideline can be a reasonable approach for countries with similarly where can i buy viagra structured healthcare systems and similar resources. Within the guideline there is agreement that optimisation of expertise and care can be achieved through centralisation, for example, by limiting analysis of next-generation sequencing (NGS)-based diagnostic panels to only a few centres and by centralising pathological review of gonadal tissues. International networks such as the European Reference Network for rare endocrine conditions (EndoERN), in which DSD is embedded, may facilitate the expansion of this kind of collaboration across Europe.This paper highlights key discussion points in the Dutch-Flemish guideline that where can i buy viagra have been insufficiently addressed in the literature thus far because they reflect evolving technologies or less visible stakeholders.

For example, prenatal observation of an atypical aspect of the genitalia indicating a possible DSD is becoming increasingly common, and we discuss appropriate counselling and a diagnostic approach for these cases, including the option of using NGS-based genetic testing. So far, little attention has been paid to this process.20 21 Furthermore, informing patients and/or their parents about atypical sex development and why this may warrant referral to where can i buy viagra a specialised team may be challenging, especially for professionals with limited experience in DSD.22 23 Therefore, a section of the Dutch-Flemish guideline was written for these healthcare providers. Moreover, this enables DSD specialists to refer to the guideline when advising a referral.

Transition from the prenatal to the postnatal team and from the paediatric to the adult team requires optimal where can i buy viagra communication between the specialists involved. Application of NGS-based techniques may lead to a higher diagnostic yield, providing a molecular genetic diagnosis in previously unsolved cases.16 We address the timing of this testing and the problems associated with this technique such as the interpretation of variants of unknown clinical significance (VUS). Similarly, histopathological interpretation and classification of removed gonadal tissue is challenging and would benefit from international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group where can i buy viagra was formed with all members responsible for updating the literature for a specific part of the guideline.

Literature search in PubMed was not systematic, but rather intended to be broad in order to cover all areas and follow expert opinions. This approach is more in line with the Clinical Practice Advisory Document method described by Burke et al24 for guidelines involving genetic practice because it is often troublesome to where can i buy viagra substantiate such guidelines with sufficient evidence due to the rapid changes in testing methods, for example, gene panels. All input provided by the group was synthesised by the chairperson (YvB), who also reviewed abstracts of papers on DSD published between 2010 and September 2017 for the guideline and up to October 2019 for this paper.

Abstracts had where can i buy viagra to be written in English and were identified using a broad range of Medical Subject Headings terms (eg, DSD, genetic, review, diagnosis, diagnostics, 46,XX DSD, 46,XY DSD, guideline, multidisciplinary care). Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports were excluded, as were articles that were not open access or retrievable through where can i buy viagra institutional access.

Based on this, a draft guideline was produced that was in line with the international principles of good diagnostic care in DSD. This draft was discussed by the where can i buy viagra writing committee and, after having obtained agreement on remaining points of discussion, revised into a final draft. This version was sent to a broad group of professionals from academic centres and DSD teams whose members had volunteered to review the draft guideline.

After receiving and incorporating their input, the final version was presented where can i buy viagra to the paediatric and genetic associations for approval. After approval by the members of the paediatric (NVK), clinical genetic (VKGN) and genetic laboratory (VKGL) associations, the guideline was published on their respective websites.19 Although Turner syndrome and Klinefelter syndrome are considered to be part of the DSD spectrum, they are not extensively discussed in this diagnostic guideline as guidelines dedicated to these syndromes already exist.25 26 However, some individuals with Turner syndrome or Klinefelter syndrome may present with ambiguous or atypical genitalia and may therefore initially follow the DSD diagnostic process.Guideline highlightsPrenatal settingPresentationThe most frequent prenatal presentation of a DSD condition is atypical genitalia found on prenatal ultrasound as an isolated finding or in combination with other structural anomalies. This usually occurs after the 20-week routine medical ultrasound for screening of congenital anomalies, but may also occur earlier, for where can i buy viagra example, when a commercial ultrasound is performed at the request of the parents.Another way DSD can be diagnosed before birth is when invasive prenatal genetic testing carried out for a different reason, for example, due to suspicion of other structural anomalies, reveals a discrepancy between the genotypic sex and the phenotypic sex seen by ultrasound.

In certified laboratories, the possibility of a sample switch is extremely low but should be ruled out immediately. More often, the discrepancy will be due to where can i buy viagra sex-chromosome mosaicism or a true form of DSD.A situation now occurring with increasing frequency is a discrepancy between the genotypic sex revealed by non-invasive prenatal testing (NIPT), which is now available to high-risk pregnant women in the Netherlands and to all pregnant women in Belgium, and later ultrasound findings. NIPT screens for CNVs in the fetus.

However, depending on legal restrictions and/or ethical considerations, the X where can i buy viagra and Y chromosomes are not always included in NIPT analysis and reports. If the X and Y chromosomes are included, it is important to realise that the presence of a Y-chromosome does not necessarily imply male fetal development. At the where can i buy viagra time that NIPT is performed (usually 11–13 weeks), genital development cannot be reliably appreciated by ultrasound, so any discrepancy or atypical aspect of the genitalia will only be noticed later in pregnancy and should prompt further evaluation.Counselling and diagnosticsIf a DSD is suspected, first-line sonographers and obstetricians should refer the couple to their colleague prenatal specialists working with or in a DSD team.

After confirming an atypical genital on ultrasound, the specialist team should offer the couple a referral for genetic counselling to discuss the possibility of performing invasive prenatal testing (usually an amniocentesis) to identify an underlying cause that fits the ultrasound findings.22 23 To enable the parents to make a well-informed decision, prenatal counselling should, in our opinion, include. Information on the where can i buy viagra ultrasound findings and the limitations of this technique. The procedure(s) that can be followed, including the risks associated with an amniocentesis.

And the type of where can i buy viagra information genetic testing can and cannot provide. Knowing which information has been provided and what words have been used by the prenatal specialist is very helpful for those involved in postnatal care.It is important that parents understand that the biological sex of a baby is determined by a complex interplay of chromosomes, genes and hormones, and thus that assessment of the presence or absence of a Y-chromosome alone is insufficient to assign the sex of their unborn child or, as in any unborn child, say anything about the child’s future gender identity.Expecting parents can be counselled by the clinical geneticist and the psychologist from the DSD team, although other DSD specialists can also be involved. The clinical geneticist should be experienced in prenatal where can i buy viagra counselling and well informed about the diagnostic possibilities given the limited time span in which test results need to be available to allow parents to make a well-informed decision about whether or not to continue the pregnancy.

Termination of pregnancy can be considered, for instance, in a syndromic form where can i buy viagra of DSD with multiple malformations, but when the DSD occurs as an apparently isolated condition, expecting parents may also consider termination of pregnancy, which, although considered controversial by some, is legal in Belgium and the Netherlands. The psychologist of the DSD team can support parents during and after pregnancy and help them cope with feelings of uncertainty and eventual considerations of a termination of pregnancy, as well as with practical issues, for example, how to inform others. The stress of not knowing exactly what the child’s genitalia will where can i buy viagra look like and uncertainty about the diagnosis, treatment and prognosis cannot be avoided completely.

Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images. In our experience, parents appreciate having already spoken to some members of the DSD team during pregnancy and having a contact person before birth.After expert prenatal counselling, a significant number of pregnant couples decline prenatal testing (personal experience IALG, MK, ABD, YvB, where can i buy viagra MC and HC-vdG). At birth, umbilical cord blood is a good source for (molecular) karyotyping and storage of DNA and can be obtained by the obstetrician, midwife or neonatologist.

The terminology used in communication with parents should be carefully chosen,22 23 and midwives and staff of where can i buy viagra neonatal and delivery units should be clearly instructed to use gender-neutral and non-stigmatising vocabulary (eg, ‘your baby’) as long as sex assignment is pending.An algorithm for diagnostic evaluation of a suspected DSD in the prenatal situation is proposed in figure 1. When couples opt for invasive prenatal diagnosis, the genetic analysis usually involves an (SNP)-array. It was recently estimated where can i buy viagra that >30% of individuals who have a DSD have additional structural anomalies, with cardiac and neurological anomalies and fetal growth restriction being particularly common.27 28 If additional anomalies are seen, the geneticist can consider specific gene defects that may underlie a known genetic syndrome or carry out NGS.

NGS-based techniques have also now made their appearance in prenatal diagnosis of congenital anomalies.29 30 Panels using these techniques can be specific for genes involved in DSD, or be larger panels covering multiple congenital anomalies, and are usually employed with trio-analysis to compare variants identified in the child with the parents’ genetics.29–31 Finding a genetic cause before delivery can help reduce parental stress in the neonatal period and speed up decisions regarding gender assignment. In such cases there is no tight time limit, and we propose completing the analysis well where can i buy viagra before the expected delivery.Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm.

*SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful.

NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 1 Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm. *SOX9.

Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful. NGS, next-generation sequencing.First contact by a professional less experienced in DSDWhereas most current guidelines start from the point when an individual has been referred to the DSD team,1 15 the Dutch-Flemish guideline dedicates a chapter to healthcare professionals less experienced in DSD as they are often the first to suspect or identify such a condition.

Apart from the paper of Indyk,7 little guidance is available for these professionals about how to act in such a situation. The chapter in the Dutch-Flemish guideline summarises the various clinical presentations that a DSD can have and provides information on how to communicate with parents and/or patients about the findings of the physical examination, the first-line investigations and the need for prompt referral to a specialised centre for further evaluation. Clinical examples are offered to illustrate some of these recurring situations.

The medical issues in DSD can be very challenging, and the social and psychological impact is high. For neonates with ambiguous genitalia, sex assignment is an urgent and crucial issue, and it is mandatory that parents are informed that it is possible to postpone registration of their child’s sex. In cases where sex assignment has already taken place, the message that the development of the gonads or genitalia is still atypical is complicated and distressing for patients and parents or carers.

A list of contact details for DSD centres and patient organisations in the Netherlands and Flanders is attached to the Dutch-Flemish guideline. Publishing such a list, either in guidelines or online, can help healthcare professionals find the nearest centres for consultations and provide patients and patient organisations with an overview of the centres where expertise is available.Timing and place of genetic testing using NGS-based gene panelsThe diagnostic workup that is proposed for 46,XX and 46,XY DSD is shown in figures 2 and 3, respectively. Even with the rapidly expanding molecular possibilities, a (family) history and a physical examination remain the essential first steps in the diagnostic process.

Biochemical and hormonal screening aim at investigating serum electrolytes, renal function and the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes. Ultrasound screening of kidneys and internal genitalia, as well as establishing genotypic sex, should be accomplished within 48 hours and complete the baseline diagnostic work-up of a child born with ambiguous genitalia.1 16 32 3346,XX disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm.

NGS, next-generation sequencing. CAH, Congenital adrenal hyperplasia. AMH, Anti-Müllerian Hormone." data-icon-position data-hide-link-title="0">Figure 2 46,XX disorders/differences of sex development (DSD) in the postnatal setting.

A diagnostic algorithm. NGS, next-generation sequencing. CAH, Congenital adrenal hyperplasia.

AMH, Anti-Müllerian Hormone.46,XY disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. * SOX9.

Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful. NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 3 46,XY disorders/differences of sex development (DSD) in the postnatal setting.

A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!.

Conventional karyotyping can be useful. NGS, next-generation sequencing.Very recently, a European position paper has been published focusing on the genetic workup of DSD.16 It highlights the limitations and drawbacks of NGS-based tests, which include the chance of missing subtle structural variants such as CNVs and mosaicism and the fact that NGS cannot detect methylation defects or other epigenetic changes.16 28 31 Targeted DNA analysis is preferred in cases where hormonal investigations suggest a block in steroidogenesis (eg, 11-β-hydroxylase deficiency, 21-hydroxylase deficiency), or in the context of a specific clinical constellation such as the often coincidental finding of Müllerian structures in a boy with normal external genitalia or cryptorchidism, that is, persistent Müllerian duct syndrome.33 34 Alternative tests should also be considered depending on the available information. Sometimes, a simple mouth swab for FISH analysis can detect mosaic XY/X in a male with hypospadias or asymmetric gonadal development or in a female with little or no Turner syndrome stigmata and a normal male molecular karyotyping profile or peripheral blood karyotype.

Such targeted testing avoids incidental findings and is cheaper and faster than analysis of a large NGS-based panel, although the cost difference is rapidly declining.However, due to the genetic and phenotypic heterogeneity of DSD conditions, the most cost-effective next steps in the majority of cases are whole exome sequencing followed by panel analysis of genes involved in genital development and function or trio-analysis of a large gene panel (such as a Mendeliome).16 35–38 Pretest genetic counselling involves discussing what kind of information will be reported to patients or parents and the chance of detecting VUS, and the small risk of incidental findings when analysing a DSD panel should be mentioned. Laboratories also differ in what class of variants they report.39 In our experience, the fear of incidental findings is a major reason why some parents refrain from genetic testing.Timing of the DSD gene panel analysis is also important. While some patients or parents prefer that all diagnostic procedures be performed as soon as possible, others need time to reflect on the complex information related to more extensive genetic testing and on its possible consequences.

If parents or patients do not consent to panel-based genetic testing, analysis of specific genes, such as WT1, should be considered when appropriate in view of the clinical consequences if a mutation is present (eg, clinical surveillance of renal function and screening for Wilms’ tumour in the case of WT1 mutations). Genes that are more frequently involved in DSD (eg, SRY, NR5A1) and that match the specific clinical and hormonal features in a given patient could also be considered for sequencing. Targeted gene analysis may also be preferred in centres located in countries that do not have the resources or technical requirements to perform NGS panel-based genetic testing.

Alternatively, participation by these centres in international collaborative networks may allow them to outsource the molecular genetic workup abroad.Gene panels differ between centres and are regularly updated based on scientific progress. A comparison of DSD gene panels used in recent studies can be found at https://www.nature.com/articles/s41574-018-0010-8%23Sec46.15 The panels currently used at the coauthors’ institutions can be found on their respective websites. Given the pace of change, it is important to regularly consider repeating analysis in patients with an unexplained DSD, for example, when they transition into adult care or when they move from one centre to another.

This also applies to patients in whom a clinical diagnosis has never been genetically confirmed. Confusion may arise when the diagnosis cannot be confirmed or when a mutation is identified in a different gene, for example, NR5A1 in someone with a clinical diagnosis of CAIS that has other consequences for relatives. Hence, new genetic counselling should always accompany new diagnostic endeavours.Class 3 variants and histopathological examinationsThe rapidly evolving diagnostic possibilities raise new questions.

What do laboratories report?. How should we deal with the frequent findings of mainly unique VUS or class 3 variants (ACMG recommendation) in the many different DSD-related genes in the diagnostic setting?. Reporting VUS can be a source of uncertainty for parents, but not reporting these variants precludes further investigations to determine their possible pathogenicity.

It can also be difficult to prove variant pathogenicity, both on gene-level and variant-level.39 Moreover, given the gonad-specific expression of some genes and the variable phenotypic spectrum and reduced penetrance, segregation analysis is not always informative. A class 3 variant that does not fit the clinical presentation may be unrelated to the observed phenotype, but it could also represent a newly emerging phenotype. This was recently demonstrated by the identification of the NR5A1 mutation, R92W, in individuals with 46,XX testicular and ovotesticular DSD.40 This gene had previously been associated with 46,XY DSD.

In diagnostic laboratories, there is usually no capacity or expertise to conduct large-scale functional studies to determine pathogenicity of these unique class 3 VUS in the different genes involved in DSD. Functional validation of variants identified in novel genes may be more attractive in a research context. However, for individual families with VUS in well-established DSD genes such as AR or HSD17B3, functional analysis may provide a confirmed diagnosis that implies for relatives the option of undergoing their own DNA analysis and estimating the genetic risk of their own future offspring.

This makes genetic follow-up important in these cases and demonstrates the usefulness of international databases and networks and the centralisation of functional studies of genetic variants in order to reduce costs and maximise expertise.The same is true for histopathological description, germ-cell tumour risk assessment in specific forms of DSD and classification of gonadal samples. Germ-cell tumour risk is related to the type of DSD (among other factors), but it is impossible to make risk estimates in individual cases.41–44 Gonadectomy may be indicated in cases with high-risk dysgenetic abdominal gonads that cannot be brought into a stable superficial (ie, inguinal, labioscrotal) position that allows clinical or radiological surveillance, or to avoid virilisation due to 5-alpha reductase deficiency in a 46,XY girl with a stable female gender identity.45 Pathological examination of DSD gonads requires specific expertise. For example, the differentiation between benign germ cell abnormalities, such as delayed maturation and (pre)malignant development of germ cells, is crucial for clinical management but can be very troublesome.46 Centralised pathological examination of gonadal biopsy and gonadectomy samples in one centre, or a restricted number of centres, on a national scale can help to overcome the problem of non-uniform classification and has proven feasible in the Netherlands and Belgium.

We therefore believe that uniform assessment and classification of gonadal differentiation patterns should also be addressed in guidelines on DSD management.International databases of gonadal tissues are crucial for learning more about the risk of malignancy in different forms of DSD, but they are only reliable if uniform criteria for histological classification are strictly applied.46 These criteria could be incorporated in many existing networks such as the I-DSD consortium, the Disorders of Sex Development Translational Research Network, the European Reference Network on Urogenital Diseases (eUROGEN), the EndoERN and COST actions.15–17 47Communication at the transition from paediatric to adult carePaediatric and adult teams need to collaborate closely to facilitate a well-organised transition from paediatric to adult specialist care.15 48–50 Both teams need to exchange information optimally and should consider transition as a longitudinal process rather than a fixed moment in time. Age-appropriate information is key at all ages, and an overview of topics to be discussed at each stage is described by Cools et al.15 Table 1 shows an example of how transition can be organised.View this table:Table 1 Example of transition table as used in the DSD clinic of the Erasmus Medical CenterPsychological support and the continued provision of information remains important for individuals with a DSD at all ages.15 22 In addition to the information given by the DSD team members, families and patients can benefit from resources such as support groups and information available on the internet.47 Information available online should be checked for accuracy and completeness when referring patients and parents to internet sites.Recommendations for future actionsMost guidelines and articles on the diagnosis and management of DSD are aimed at specialists and are only published in specialist journals or on websites for endocrinologists, urologists or geneticists. Yet there is a need for guidelines directed towards first-line and second-line healthcare workers that summarise the recommendations about the first crucial steps in the management of DSD.

These should be published in widely available general medical journals and online, along with a national list of DSD centres. Furthermore, DSD (expert) centres should provide continuous education to all those who may be involved in the identification of individuals with a DSD in order to enable these healthcare professionals to recognise atypical genitalia, to promptly refer individuals who have a DSD and to inform the patient and parents about this and subsequent diagnostic procedures.As DSD continues to be a rare condition, it will take time to evaluate the effects of having such a guideline on the preparedness of first-line and second-line healthcare workers to recognise DSD conditions. One way to evaluate this might be the development and use of questionnaires asking patients, carers and families and referring physicians how satisfied they were with the initial medical consultation and referral and what could be improved.

A helpful addition to existing international databases that collect information on genetic variations would be a list of centres that offer suitable functional studies for certain genes, ideally covering the most frequently mutated genes (at minimum).Patient organisations can also play an important role in informing patients about newly available diagnostic or therapeutic strategies and options, and their influence and specific role has now been recognised and discussed in several publications.17 47 However, it should be kept in mind that these organisations do not represent all patients, as a substantial number of patients and parents are not member of such an organisation.Professionals have to provide optimal medical care based on well-established evidence, or at least on broad consensus. Yet not everything can be regulated by recommendations and guidelines. Options, ideas and wishes should be openly discussed between professionals, patients and families within their confidential relationship.

This will enable highly individualised holistic care tailored to the patient’s needs and expectations. Once they are well-informed of all available options, parents and/or patients can choose what they consider the optimal care for their children or themselves.15 16ConclusionThe Dutch-Flemish guideline uniquely addresses some topics that are under-represented in the literature, thus adding some key aspects to those addressed in recent consensus papers and guidelines.15–17 33 47As more children with a DSD are now being identified prenatally, and the literature on prenatal diagnosis of DSD remains scarce,20 21 we propose a prenatal diagnostic algorithm and emphasise the importance of having a prenatal specialist involved in or collaborating with DSD (expert) centres.We also stress that good communication between all involved parties is essential. Professionals should be well informed about protocols and communication.

Collaboration between centres is necessary to optimise aspects of care such as uniform interpretation of gonadal pathology and functional testing of class 3 variants found by genetic testing. Guidelines can provide a framework within which individualised patient care should be discussed with all stakeholders.AcknowledgmentsThe authors would like to thank the colleagues of the DSD teams for their input in and critical reading of the Dutch-Flemish guideline. Amsterdam University Center (AMC and VU), Maastricht University Medical Center, Erasmus Medical Center Rotterdam, Radboud University Medical Center Nijmegen, University Medical Center Groningen, University Medical Center Utrecht, Ghent University Hospital.

The authors would like to thank Kate McIntyre for editing the revised manuscript and Tom de Vries Lentsch for providing the figures as a PDF. Three of the authors of this publication are members of the European Reference Network for rare endocrine diseases—Project ID 739543.IntroductionEndometrial cancer is the most common gynaecological malignancy in the developed world.1 Its incidence has risen over the last two decades as a consequence of the ageing population, fewer hysterectomies for benign disease and the obesity epidemic. In the USA, it is estimated that women have a 1 in 35 lifetime risk of endometrial cancer, and http://www.ec-dannenberger-souffelweyersheim.site.ac-strasbourg.fr/?tribe_venue=centre-culturel in contrast to cancers of most other sites, cancer-specific mortality has risen by approximately 2% every year since 2008 related to the rapidly rising incidence.2Endometrial cancer has traditionally been classified into type I and type II based on morphology.3 The more common subtype, type I, is mostly comprised of endometrioid tumours and is oestrogen-driven, arises from a hyperplastic endometrium, presents at an early stage and has an excellent 5 year survival rate.4 By contrast, type II includes non-endometrioid tumours, specifically serous, carcinosarcoma and clear cell subtypes, which are biologically aggressive tumours with a poor prognosis that are often diagnosed at an advanced stage.5 Recent efforts have focused on a molecular classification system for more accurate categorisation of endometrial tumours into four groups with distinct prognostic profiles.6 7The majority of endometrial cancers arise through the interplay of familial, genetic and lifestyle factors.

Two inherited cancer predisposition syndromes, Lynch syndrome and the much rarer Cowden syndrome, substantially increase the lifetime risk of endometrial cancer, but these only account for around 3–5% of cases.8–10 Having first or second degree relative(s) with endometrial or colorectal cancer increases endometrial cancer risk, although a large European twin study failed to demonstrate a strong heritable link.11 The authors failed to show that there was greater concordance in monozygotic than dizygotic twins, but the study was based on relatively small numbers of endometrial cancers. Lu and colleagues reported an association between common single nucleotide polymorphisms (SNPs) and endometrial cancer risk, revealing the potential role of SNPs in explaining part of the risk in both the familial and general populations.12 Thus far, many SNPs have been reported to modify susceptibility to endometrial cancer. However, much of this work predated genome wide association studies and is of variable quality.

Understanding genetic predisposition to endometrial cancer could facilitate personalised risk assessment with a view to targeted prevention and screening interventions.13 This emerged as the most important unanswered research question in endometrial cancer according to patients, carers and healthcare professionals in our recently completed James Lind Womb Cancer Alliance Priority Setting Partnership.14 It would be particularly useful for non-endometrioid endometrial cancers, for which advancing age is so far the only predictor.15We therefore conducted a comprehensive systematic review of the literature to provide an overview of the relationship between SNPs and endometrial cancer risk. We compiled a list of the most robust endometrial cancer-associated SNPs. We assessed the applicability of this panel of SNPs with a theoretical polygenic risk score (PRS) calculation.

We also critically appraised the meta-analyses investigating the most frequently reported SNPs in MDM2. Finally, we described all SNPs reported within genes and pathways that are likely involved in endometrial carcinogenesis and metastasis.MethodsOur systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) collaboration 2009 recommendations. The registered protocol is available through PROSPERO (CRD42018091907).16Search strategyWe searched Embase, MEDLINE and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases via the Healthcare Databases Advanced Search (HDAS) platform, from 2007 to 2018, to identify studies reporting associations between polymorphisms and endometrial cancer risk.

Key words including MeSH (Medical Subject Heading) terms and free-text words were searched in both titles and abstracts. The following terms were used. €œendomet*”,“uter*”, “womb”, “cancer(s)”, “neoplasm(s)”, “endometrium tumour”, “carcinoma”, “adenosarcoma”, “clear cell carcinoma”, “carcinosarcoma”, “SNP”, “single nucleotide polymorphism”, “GWAS”, and “genome-wide association study/ies”.

No other restrictions were applied. The search was repeated with time restrictions between 2018 and June 2019 to capture any recent publications.Eligibility criteriaStudies were selected for full-text evaluation if they were primary articles investigating a relationship between endometrial cancer and SNPs. Study outcome was either the increased or decreased risk of endometrial cancer relative to controls reported as an odds ratio (OR) with corresponding 95% confidence intervals (95% CIs).Study selectionThree independent reviewers screened all articles uploaded to a screening spreadsheet developed by Helena VonVille.17 Disagreements were resolved by discussion.

Chronbach’s α score was calculated between reviewers and indicated high consistency at 0.92. Case–control, prospective and retrospective studies, genome-wide association studies (GWAS), and both discovery and validation studies were selected for full-text evaluation. Non-English articles, editorials, conference abstracts and proceedings, letters and correspondence, case reports and review articles were excluded.Candidate-gene studies with at least 100 women and GWAS with at least 1000 women in the case arm were selected to ensure reliability of the results, as explained by Spencer et al.18 To construct a panel of up to 30 SNPs with the strongest evidence of association, those with the strongest p values were selected.

For the purpose of an SNP panel, articles utilising broad European or multi-ethnic cohorts were selected. Where overlapping populations were identified, the most comprehensive study was included.Data extraction and synthesisFor each study, the following data were extracted. SNP ID, nearby gene(s)/chromosome location, OR (95% CI), p value, minor or effect allele frequency (MAF/EAF), EA (effect allele) and OA (other allele), adjustment, ethnicity and ancestry, number of cases and controls, endometrial cancer type, and study type including discovery or validation study and meta-analysis.

For risk estimates, a preference towards most adjusted results was applied. For candidate-gene studies, a standard p value of<0.05 was applied and for GWAS a p value of <5×10-8, indicating genome-wide significance, was accepted as statistically significant. However, due to the limited number of SNPs with p values reaching genome-wide significance, this threshold was then lowered to <1×10-5, allowing for marginally significant SNPs to be included.

As shown by Mavaddat et al, for breast cancer, SNPs that fall below genome-wide significance may still be useful for generating a PRS and improving the models.19We estimated the potential value of a PRS based on the most significant SNPs by comparing the predicted risk for a woman with a risk score in the top 1% of the distribution to the mean predicted risk. Per-allele ORs and MAFs were taken from the publications and standard errors (SEs) for the lnORs were derived from published 95% CIs. The PRS was assumed to have a Normal distribution, with mean 2∑βipI and SE, σ, equal to √2∑βi2pI(1−pi), according to the binomial distribution, where the summation is over all SNPs in the risk score.

Hence the relative risk (RR) comparing the top 1% of the distribution to the mean is given by exp(Z0.01σ), where Z is the inverse of the standard normal cumulative distribution.ResultsThe flow chart of study selection is illustrated in figure 1. In total, 453 text articles were evaluated and, of those, 149 articles met our inclusion criteria. One study was excluded from table 1, for having an Asian-only population, as this would make it harder to compare with the rest of the results which were all either multi-ethnic or Caucasian cohorts, as stated in our inclusion criteria for the SNP panel.20 Any SNPs without 95% CIs were also excluded from any downstream analysis.

Additionally, SNPs in linkage disequilibrium (r2 >0.2) with each other were examined, and of those in linkage disequilibrium, the SNP with strongest association was reported. Per allele ORs were used unless stated otherwise.View this table:Table 1 List of top SNPs most likely to contribute to endometrial cancer risk identified through systematic review of recent literature21–25Study selection flow diagram. *Reasons.

Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study. Adapted from.

Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PRISMA Statement.

PLoS Med 6(6). E1000097. Doi:10.1371/journal.pmed1000097." data-icon-position data-hide-link-title="0">Figure 1 Study selection flow diagram.

*Reasons. Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study.

Adapted from. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

The PRISMA Statement. PLoS Med 6(6). E1000097.

Doi:10.1371/journal.pmed1000097.Top SNPs associated with endometrial cancer riskFollowing careful interpretation of the data, 24 independent SNPs with the lowest p values that showed the strongest association with endometrial cancer were obtained (table 1).21–25 These SNPs are located in or around genes coding for transcription factors, cell growth and apoptosis regulators, and enzymes involved in the steroidogenesis pathway. All the SNPs presented here were reported on the basis of a GWAS or in one case, an exome-wide association study, and hence no SNPs from candidate-gene studies made it to the list. This is partly due to the nature of larger GWAS providing more comprehensive and powered results as opposed to candidate gene studies.

Additionally, a vast majority of SNPs reported by candidate-gene studies were later refuted by large-scale GWAS such as in the case of TERT and MDM2 variants.26 27 The exception to this is the CYP19 gene, where candidate-gene studies reported an association between variants in this gene with endometrial cancer in both Asian and broad European populations, and this association was more recently confirmed by large-scale GWAS.21 28–30 Moreover, a recent article authored by O’Mara and colleagues reviewed the GWAS that identified most of the currently known SNPs associated with endometrial cancer.31Most of the studies represented in table 1 are GWAS and the majority of these involved broad European populations. Those having a multi-ethnic cohort also consisted primarily of broad European populations. Only four of the variants in table 1 are located in coding regions of a gene, or in regulatory flanking regions around the gene.

Thus, most of these variants would not be expected to cause any functional effects on the gene or the resulting protein. An eQTL search using GTEx Portal showed that some of the SNPs are significantly associated (p<0.05) with modified transcription levels of the respective genes in various tissues such as prostate (rs11263761), thyroid (rs9668337), pituitary (rs2747716), breast mammary (rs882380) and testicular (rs2498794) tissue, as summarised in table 2.View this table:Table 2 List of eQTL hits for the selected panel of SNPsThe only variant for which there was an indication of a specific association with non-endometrioid endometrial cancer was rs148261157 near the BCL11A gene. The A allele of this SNP had a moderately higher association in the non-endometrioid arm (OR 1.64, 95% CI 1.32 to 2.04.

P=9.6×10-6) compared with the endometrioid arm (OR 1.25, 95% CI 1.14 to 1.38. P=4.7×10-6).21Oestrogen receptors α and β encoded by ESR1 and ESR2, respectively, have been extensively studied due to the assumed role of oestrogens in the development of endometrial cancer. O’Mara et al reported a lead SNP (rs79575945) in the ESR1 region that was associated with endometrial cancer (p=1.86×10-5).24 However, this SNP did not reach genome-wide significance in a more recent larger GWAS.21 No statistically significant associations have been reported between endometrial cancer and SNPs in the ESR2 gene region.AKT is an oncogene linked to endometrial carcinogenesis.

It is involved in the PI3K/AKT/mTOR pro-proliferative signalling pathway to inactivate apoptosis and allow cell survival. The A allele of rs2494737 and G allele of rs2498796 were reported to be associated with increased and decreased risk of endometrial cancer in 2016, respectively.22 30 However, this association was not replicated in a larger GWAS in 2018.21 Nevertheless, given the previous strong indications, and biological basis that could explain endometrial carcinogenesis, we decided to include an AKT1 variant (rs2498794) in our results.PTEN is a multi-functional tumour suppressor gene that regulates the AKT/PKB signalling pathway and is commonly mutated in many cancers including endometrial cancer.32 Loss-of-function germline mutations in PTEN are responsible for Cowden syndrome, which exerts a lifetime risk of endometrial cancer of up to 28%.9 Lacey and colleagues studied SNPs in the PTEN gene region. However, none showed significant differences in frequency between 447 endometrial cancer cases and 439 controls of European ancestry.33KRAS mutations are known to be present in endometrial cancer.

These can be activated by high levels of KLF5 (transcriptional activator). Three SNPs have been identified in or around KLF5 that are associated with endometrial cancer. The G allele of rs11841589 (OR 1.15, 95% CI 1.11 to 1.21.

P=4.83×10-11), the A allele of rs9600103 (OR 1.23, 95% CI 1.16 to 1.30. P=3.76×10-12) and C allele of rs7981863 (OR 1.16, 95% CI 1.12 to 1.20. P=2.70×10-17) have all been found to be associated with an increased likelihood of endometrial cancer in large European cohorts.21 30 34 It is worth noting that these SNPs are not independent, and hence they quite possibly tag the same causal variant.The MYC family of proto-oncogenes encode transcription factors that regulate cell proliferation, which can contribute to cancer development if dysregulated.

The recent GWAS by O’Mara et al reported three SNPs within the MYC region that reached genome-wide significance with conditional p values reaching at least 5×10–8.35To test the utility of these SNPs as predictive markers, we devised a theoretical PRS calculation using the log ORs and EAFs per SNP from the published data. The results were very encouraging with an RR of 3.16 for the top 1% versus the mean, using all the top SNPs presented in table 1 and 2.09 when using only the SNPs that reached genome-wide significance (including AKT1).Controversy surrounding MDM2 variant SNP309MDM2 negatively regulates tumour suppressor gene TP53, and as such, has been extensively studied in relation to its potential role in predisposition to endometrial cancer. Our search identified six original studies of the association between MDM2 SNP rs2279744 (also referred to as SNP309) and endometrial cancer, all of which found a statistically significant increased risk per copy of the G allele.

Two more original studies were identified through our full-text evaluation. However, these were not included here as they did not meet our inclusion criteria—one due to small sample size, the other due to studying rs2279744 status dependent on another SNP.36 37 Even so, the two studies were described in multiple meta-analyses that are listed in table 3. Different permutations of these eight original studies appear in at least eight published meta-analyses.

However, even the largest meta-analysis contained <2000 cases (table 3)38View this table:Table 3 Characteristics of studies that examined MDM2 SNP rs2279744In comparison, a GWAS including nearly 13 000 cases found no evidence of an association with OR and corresponding 95% CI of 1.00 (0.97 to 1.03) and a p value of 0.93 (personal communication).21 Nevertheless, we cannot completely rule out a role for MDM2 variants in endometrial cancer predisposition as the candidate-gene studies reported larger effects in Asians, whereas the GWAS primarily contained participants of European ancestry. There is also some suggestion that the SNP309 variant is in linkage disequilibrium with another variant, SNP285, which confers an opposite effect.It is worth noting that the SNP285C/SNP309G haplotype frequency was observed in up to 8% of Europeans, thus requiring correction for the confounding effect of SNP285C in European studies.39 However, aside from one study conducted by Knappskog et al, no other study including the meta-analyses corrected for the confounding effect of SNP285.40 Among the studies presented in table 3, Knappskog et al (2012) reported that after correcting for SNP285, the OR for association of this haplotype with endometrial cancer was much lower, though still significant. Unfortunately, the meta-analyses which synthesised Knappskog et al (2012), as part of their analysis, did not correct for SNP285C in the European-based studies they included.38 41 42 It is also concerning that two meta-analyses using the same primary articles failed to report the same result, in two instances.38 42–44DiscussionThis article represents the most comprehensive systematic review to date, regarding critical appraisal of the available evidence of common low-penetrance variants implicated in predisposition to endometrial cancer.

We have identified the most robust SNPs in the context of endometrial cancer risk. Of those, only 19 were significant at genome-wide level and a further five were considered marginally significant. The largest GWAS conducted in this field was the discovery- and meta-GWAS by O’Mara et al, which utilised 12 096 cases and 108 979 controls.21 Despite the inclusion of all published GWAS and around 5000 newly genotyped cases, the total number did not reach anywhere near what is currently available for other common cancers such as breast cancer.

For instance, BCAC (Breast Cancer Association Consortium) stands at well over 200 000 individuals with more than half being cases, and resulted in identification of ~170 SNPs in relation to breast cancer.19 45 A total of 313 SNPs including imputations were then used to derive a PRS for breast cancer.19 Therefore, further efforts should be directed to recruit more patients, with deep phenotypic clinical data to allow for relevant adjustments and subgroup analyses to be conducted for better precision.A recent pre-print study by Zhang and colleagues examined the polygenicity and potential for SNP-based risk prediction for 14 common cancers, including endometrial cancer, using available summary-level data from European-ancestry datasets.46 They estimated that there are just over 1000 independent endometrial cancer susceptibility SNPs, and that a PRS comprising all such SNPs would have an area under the receiver-operator curve of 0.64, similar to that predicted for ovarian cancer, but lower than that for the other cancers in the study. The modelling in the paper suggests that an endometrial cancer GWAS double the size of the current largest study would be able to identify susceptibility SNPs together explaining 40% of the genetic variance, but that in order to explain 75% of the genetic variance it would be necessary to have a GWAS comprising close to 150 000 cases and controls, far in excess of what is currently feasible.We found that the literature consists mainly of candidate-gene studies with small sample sizes, meta-analyses reporting conflicting results despite using the same set of primary articles, and multiple reports of significant SNPs that have not been validated by any larger GWAS. The candidate-gene studies were indeed the most useful and cheaper technique available until the mid to late 2000s.

However, a lack of reproducibility (particularly due to population stratification and reporting bias), uncertainty of reported associations, and considerably high false discovery rates make these studies much less appropriate in the post-GWAS era. Unlike the candidate-gene approach, GWAS do not require prior knowledge, selection of genes or SNPs, and provide vast amounts of data. Furthermore, both the genotyping process and data analysis phases have become cheaper, the latter particularly due to faster and open-access pre-phasing and imputation tools being made available.It is clear from table 1 that some SNPs were reported with wide 95% CI, which can be directly attributed to small sample sizes particularly when restricting the cases to non-endometrioid histology only, low EAF or poor imputation quality.

Thus, these should be interpreted with caution. Additionally, most of the SNPs reported by candidate-gene studies were not detected by the largest GWAS to date conducted by O’Mara et al.21 However, this does not necessarily mean that the possibility of those SNPs being relevant should be completely dismissed. Moreover, meta-analyses were attempted for other variants.

However, these showed no statistically significant association and many presented with high heterogeneity between the respective studies (data not shown). Furthermore, as many studies utilised the same set of cases and/or controls, conducting a meta-analysis was not possible for a good number of SNPs. It is therefore unequivocal that the literature is crowded with numerous small candidate-gene studies and conflicting data.

This makes it particularly hard to detect novel SNPs and conduct meaningful meta-analyses.We found convincing evidence for 19 variants that indicated the strongest association with endometrial cancer, as shown in table 1. The associations between endometrial cancer and variants in or around HNF1B, CYP19A1, SOX4, MYC, KLF and EIF2AK found in earlier GWAS were then replicated in the latest and largest GWAS. These SNPs showed promising potential in a theoretical PRS we devised based on published data.

Using all 24 or genome-wide significant SNPs only, women with a PRS in the top 1% of the distribution would be predicted to have a risk of endometrial cancer 3.16 and 2.09 times higher than the mean risk, respectively.However, the importance of these variants and relevance of the proximate genes in a functional or biological context is challenging to evaluate. Long distance promoter regulation by enhancers may disguise the genuine target gene. In addition, enhancers often do not loop to the nearest gene, further complicating the relevance of nearby gene(s) to a GWAS hit.

In order to elucidate biologically relevant candidate target genes in endometrial cancer, O’Mara et al looked into promoter-associated chromatin looping using a modern HiChIP approach.47 The authors utilised normal and tumoural endometrial cell lines for this analysis which showed significant enrichment for endometrial cancer heritability, with 103 candidate target genes identified across the 13 risk loci identified by the largest ECAC GWAS. Notable genes identified here were CDKN2A and WT1, and their antisense counterparts. The former was reported to be nearby of rs1679014 and the latter of rs10835920, as shown in table 1.

Moreover, of the 36 candidate target genes, 17 were found to be downregulated while 19 were upregulated in endometrial tumours.The authors also investigated overlap between the 13 endometrial cancer risk loci and top eQTL variants for each target gene.47 In whole blood, of the two particular lead SNPs, rs8822380 at 17q21.32 was a top eQTL for SNX11 and HOXB2, whereas rs937213 at 15q15.1 was a top eQTL for SRP14. In endometrial tumour, rs7579014 at 2p16.1 was found to be a top eQTL for BCL11A. This is particularly interesting because BCL11A was the only nearby/candidate gene that had a GWAS association reported in both endometrioid and non-endometrioid subtypes.

The study looked at protein–protein interactions between endometrial cancer drivers and candidate target gene products. Significant interactions were observed with TP53 (most significant), AKT, PTEN, ESR1 and KRAS, among others. Finally, when 103 target candidate genes and 387 proteins were combined together, 462 pathways were found to be significantly enriched.

Many of these are related to gene regulation, cancer, obesity, insulinaemia and oestrogen exposure. This study clearly showed a potential biological relevance for some of the SNPs reported by ECAC GWAS in 2018.Most of the larger included studies used cohorts primarily composed of women of broad European descent. Hence, there are negligible data available for other ethnicities, particularly African women.

This is compounded by the lack of reference genotype data available for comparative analysis, making it harder for research to be conducted in ethnicities other than Europeans. This poses a problem for developing risk prediction models that are equally valuable and predictive across populations. Thus, our results also are of limited applicability to non-European populations.Furthermore, considering that non-endometrioid cases comprise a small proportion (~20%) of all endometrial cancer cases, much larger cohort sizes are needed to detect any genuine signals for non-endometrioid tumours.

Most of the evaluated studies looked at either overall/mixed endometrial cancer subtypes or endometrioid histology, and those that looked at variant associations with non-endometrioid histology were unlikely to have enough power to detect any signal with statistical significance. This is particularly concerning because non-endometrioid subtypes are biologically aggressive tumours with a much poorer prognosis that contribute disproportionately to mortality from endometrial cancer. It is particularly important that attempts to improve early detection and prevention of endometrial cancer focus primarily on improving outcomes from these subtypes.

It is also worth noting that, despite the current shift towards a molecular classification of endometrial cancer, most studies used the overarching classical Bokhman’s classification system, type I versus type II, or no histological classification system at all. Therefore, it is important to create and follow a standardised and comprehensive classification system for reporting tumour subtypes for future studies.This study compiled and presented available information for an extensively studied, yet unproven in large datasets, SNP309 variant in MDM2. Currently, there is no convincing evidence for an association between this variant and endometrial cancer risk.

Additionally, of all the studies, only one accounted for the opposing effect of a nearby variant SNP285 in their analyses. Thus, we conclude that until confirmed by a sufficiently large GWAS, this variant should not be considered significant in influencing the risk of endometrial cancer and therefore not included in a PRS. This is also true for the majority of the SNPs reported in candidate-gene studies, as the numbers fall far short of being able to detect genuine signals.This systematic review presents the most up-to-date evidence for endometrial cancer susceptibility variants, emphasising the need for further large-scale studies to identify more variants of importance, and validation of these associations.

Until data from larger and more diverse cohorts are available, the top 24 SNPs presented here are the most robust common genetic variants that affect endometrial cancer risk. The multiplicative effects of these SNPs could be used in a PRS to allow personalised risk prediction models to be developed for targeted screening and prevention interventions for women at greatest risk of endometrial cancer..

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CMS has generic viagra canada implemented the demonstration in Illinois, Ohio, North Carolina, Florida, and Texas with the option to expand to other states in the Palmetto/JM jurisdiction. Under this demonstration, CMS offers choices for providers to demonstrate their compliance with CMS' home health policies. Providers in the demonstration states may participate in either 100 percent pre-claim review or 100 percent postpayment review. These providers will generic viagra canada continue to be subject to a review method until the HHA reaches the target affirmation or claim approval rate.

Once a HHA reaches the target pre-claim review affirmation or post-payment review claim approval rate, it may choose to be relieved from claim reviews, except for a spot check of their claims to ensure continued compliance. Providers who do not wish to participate in either 100 percent pre-claim or postpayment reviews have the option to furnish home health services and submit the associated claim for payment without undergoing such reviews. However, they will receive a 25 percent payment reduction generic viagra canada on all claims submitted for home health services and may be eligible for review by the Recovery Audit Contractors. The information required under this collection is required by Medicare contractors to determine proper payment or if there is a suspicion of fraud.

Under the pre-claim review option, the HHA sends the pre-claim review request along with all required documentation to the Medicare contractor for review prior to submitting the final claim for payment. If a claim is submitted without a pre-claim review decision one file, the generic viagra canada Medicare contractor will request the information from the HHA to determine if payment is appropriate. For the postpayment review option, the Medicare contractor will also request the information from the HHA provider who submitted the claim for payment from the Medicare program to determine if payment was appropriate. Form Number.

CMS-10599 (OMB generic viagra canada control number. 0938-1311). Frequency. Frequently, until the HHA reaches the target affirmation or claim generic viagra canada approval threshold and then occasionally.

Affected Public. Private Sector (Business or other for-profits and Not-for-profits). Number of Respondents generic viagra canada. 3,631.

Number of Responses. 1,467,243. Total Annual Hours. 744,5143.

(For questions regarding this collection contact Jennifer McMullen (410)786-7635.) 2. Type of Information Collection Request. Revision of a currently approved collection. Title of Information Collection.

Continuation of Data Collection to Support QHP Certification and other Financial Management and Exchange Operations. Use. As directed by the rule Establishment of Exchanges and Qualified Health Plans. Exchange Standards for Employers (77 FR 18310) (Exchange rule), each Exchange is responsible for the certification and offering of Qualified Health Plans (QHPs).

To offer insurance through an Exchange, a health insurance issuer must have its health plans certified as QHPs by the Exchange. A QHP must meet certain necessary minimum certification standards, such as network adequacy, inclusion of Essential Community Providers (ECPs), and non-discrimination. The Exchange is responsible for ensuring that QHPs meet these minimum certification standards as described in the Exchange rule under 45 CFR 155 and 156, based on the Patient Protection and Affordable Care Act (PPACA), as well as other standards determined by the Exchange. Issuers can offer individual and small group market plans outside of the Exchanges that are not QHPs.

Form Number. CMS-10433 (OMB control number. 0938-1187). Frequency.

Annually. Affected Public. Private sector, State, Local, or Tribal Governments, Business or other for-profits. Number of Respondents.

2,925. Number of Responses. 2,925. Total Annual Hours.

71,660. (For questions regarding this collection, contact Nicole Levesque at (617) 565-3138). 3. Type of Information Collection Request.

Extension of a currently approved collection. Title of Information Collection. Notice of Rescission of Coverage and Disclosure Requirements for Patient Protection under the Affordable Care Act. Use.

Sections 2712 and 2719A of the Public Health Service Act (PHS Act), as added by the Affordable Care Act, contain rescission notice, and patient protection disclosure requirements that are subject to the Paperwork Reduction Act of 1995. The No Surprises Act, enacted as part of the Consolidated Appropriations Act, 2021, amended section 2719A of the PHS Act to sunset when the new emergency services protections under the No Surprises Act take effect. The provisions of section 2719A of the PHS Act will no longer apply with respect to plan years beginning on or after January 1, 2022. The No Surprises Act re-codified the patient protections related to choice of health care professional under section 2719A of the PHS Act in newly added section 9822 of the Internal Revenue Code, section 722 of the Employee Retirement Income Security Act, and section 2799A-7 of the PHS Act and extended the applicability of these provisions to grandfathered health plans for plan years beginning on or after January 1, 2022.

The rescission notice will be used by health plans to provide advance notice to certain individuals that their coverage may be rescinded as a result of fraud or intentional misrepresentation of material fact. The patient protection notification will be used by health plans to inform certain individuals of their right to choose a primary care provider or pediatrician and to use obstetrical/gynecological services without prior authorization. The related provisions are finalized in the 2015 final regulations titled “Final Rules under the Affordable Care Act for Grandfathered Plans, Preexisting Condition Exclusions, Start Printed Page 67475 Lifetime and Annual Limits, Rescissions, Dependent Coverage, Appeals, and Patient Protections” (80 FR 72192, November 18, 2015) and 2021 interim final regulations titled “Requirements Related to Surprise Billing. Part I” (86 FR 36872, July 13, 2021).

The 2015 final regulations also require that, if State law prohibits balance billing, or a plan or issuer is contractually responsible for any amounts balanced billed by an out-of-network emergency services provider, a plan or issuer must provide a participant, beneficiary or enrollee adequate and prominent notice of their lack of financial responsibility with respect to amounts balanced billed in order to prevent inadvertent payment by the individual. Plans and issuers will not be required to provide this notice for plan years beginning on or after January 1, 2022. Form Number. CMS-10330 (OMB control number.

0938-1094). Frequency. On Occasion. Affected Public.

State, Local, or Tribal Governments, Private Sector. Number of Respondents. 2,277. Total Annual Responses.

15,752. Total Annual Hours. 814. (For policy questions regarding this collection, contact Usree Bandyopadhyay at (410) 786-6650.) 4.

Type of Information Collection Request. Extension of a currently approved collection. Title of Information Collection. Requirements Related to Surprise Billing.

Qualifying Payment Amount, Notice and Consent, Disclosure on Patient Protections Against Balance Billing, and State Law Opt-in. Use. On December 27, 2020, the Consolidated Appropriations Act, 2021 (Pub. L.

116-260), which included the No Surprises Act, was signed into law. The No Surprises Act provides federal protections against surprise billing and limits out-of-network cost sharing under many of the circumstances in which surprise medical bills arise most frequently. The 2021 interim final regulations “Requirements Related to Surprise Billing. Part I” (86 FR 36872, 2021 interim final regulations) issued by the Departments of Health and Human Services, the Department of Labor, the Department of Treasury, and the Office of Personnel Management, implement provisions of the No Surprises Act that apply to group health plans, health insurance issuers offering group or individual health insurance coverage, and carriers in the Federal Employees Health Benefits (FEHB) Program that provide protections against balance billing and out-of-network cost sharing with respect to emergency services, non-emergency services furnished by nonparticipating providers at certain participating health care facilities, and air ambulance services furnished by nonparticipating providers of air ambulance services.

The 2021 interim final regulations prohibit nonparticipating providers, emergency facilities, and providers of air ambulance services from balance billing participants, beneficiaries, and enrollees in certain situations unless they satisfy certain notice and consent requirements. The No Surprises Act and the 2021 interim final regulations require group health plans and issuers of health insurance coverage to provide information about qualifying payment amounts to nonparticipating providers and facilities and to provide disclosures on patient protections against balance billing to participants, beneficiaries and enrollees.

CMS, Office of Strategic Operations where can i buy viagra and http://ld2technologies.in/how-to-get-amoxil-without-a-doctor/ Regulatory Affairs, Division of Regulations Development, Attention. Document Identifier/OMB Control Number. ___, Room C4-26-05, 7500 Security Boulevard, Baltimore, Maryland 21244-1850. To obtain copies of a supporting statement and any related forms for where can i buy viagra the proposed collection(s) summarized in this notice, you may make your request using one of following.

1. Access CMS' website address at website address at https://www.cms.gov/​Regulations-and-Guidance/​Legislation/​PaperworkReductionActof1995/​PRA-Listing.html. Start Further where can i buy viagra Info William N. Parham at (410) 786-4669.

End Further Info End Preamble Start Supplemental Information Contents This notice sets out a summary of the use and burden associated with the following information collections. More detailed where can i buy viagra information can be found in each collection's supporting statement and associated materials (see ADDRESSES ). CMS-10599 Review Choice Demonstration for Home Health Services CMS-10433 Continuation of Data Collection to Support QHP Certification and other Financial Management and Exchange Operations CMS-10330 Notice of Rescission of Coverage and Disclosure Requirements for Patient Protection under the Affordable Care Act CMS-10780 Requirements Related to Surprise Billing. Qualifying Payment Amount, Notice and Consent, and Disclosure on Patient Protections Against Balance Billing, and State Law Opt-in Under the PRA (44 U.S.C.

3501-3520), federal agencies must where can i buy viagra obtain approval from the Office of Management and Budget (OMB) for each collection of information they conduct or sponsor. The term “collection of information” is defined in 44 U.S.C. 3502(3) and 5 CFR 1320.3(c) and includes agency requests or requirements that members of the public submit reports, keep records, or provide information to a third party. Section 3506(c)(2)(A) of the PRA requires federal agencies to publish a Start Printed Page 67474 60-day notice in the Federal where can i buy viagra Register concerning each proposed collection of information, including each proposed extension or reinstatement of an existing collection of information, before submitting the collection to OMB for approval.

To comply with this requirement, CMS is publishing this notice. Information Collection 1. Type of Information Collection where can i buy viagra Request. Revision of a currently approved collection.

Title of Information Collection. Review Choice Demonstration for Home Health where can i buy viagra Services. Use. Section 402(a)(1)(J) of the Social Security Amendments of 1967 (42 U.S.C.

1395b-1(a)(1)(J)) authorizes the Secretary to “develop or demonstrate improved methods for the investigation and prosecution of fraud in the provision of care or services under the health programs established by the Social Security Act (the Act).” Pursuant to this authority, the where can i buy viagra CMS seeks to develop and implement a Medicare demonstration project, which CMS believes will help assist in developing improved procedures for the identification, investigation, and prosecution of Medicare fraud occurring among Home Health Agencies (HHA) providing services to Medicare beneficiaries. This revised demonstration helps assist in developing improved procedures for the identification, investigation, and prosecution of potential Medicare fraud. The demonstration helps make sure that payments for home health services are appropriate through either pre-claim or postpayment review, thereby working towards the prevention and identification of potential fraud, waste, and abuse. The protection of where can i buy viagra Medicare Trust Funds from improper payments.

And the reduction of Medicare appeals. CMS has implemented the demonstration in Illinois, Ohio, North Carolina, Florida, and Texas with the option to expand to other states in the Palmetto/JM jurisdiction. Under this demonstration, CMS offers choices for providers to where can i buy viagra demonstrate their compliance with CMS' home health policies. Providers in the demonstration states may participate in either 100 percent pre-claim review or 100 percent postpayment review.

These providers will continue to be subject to a review method until the HHA reaches the target affirmation or claim approval rate. Once a HHA reaches the target pre-claim review affirmation or post-payment review claim approval rate, it may choose to be relieved from claim reviews, except for a spot check of their claims to where can i buy viagra ensure continued compliance. Providers who do not wish to participate in either 100 percent pre-claim or postpayment reviews have the option to furnish home health services and submit the associated claim for payment without undergoing such reviews. However, they will receive a 25 percent payment reduction on all claims submitted for home health services and may be eligible for review by the Recovery Audit Contractors.

The information required under this collection is required by Medicare contractors to determine proper payment or if there is a suspicion of fraud where can i buy viagra. Under the pre-claim review option, the HHA sends the pre-claim review request along with all required documentation to the Medicare contractor for review prior to submitting the final claim for payment. If a claim is submitted without a pre-claim review decision one file, the Medicare contractor will request the information from the HHA to determine if payment is appropriate. For the postpayment review option, the Medicare contractor will also request the information from the HHA provider who submitted the claim for payment from the where can i buy viagra Medicare program to determine if payment was appropriate.

Form Number. CMS-10599 (OMB control number. 0938-1311). Frequency.

Frequently, until the HHA reaches the target affirmation or claim approval threshold and then occasionally. Affected Public. Private Sector (Business or other for-profits and Not-for-profits). Number of Respondents.

3,631. Number of Responses. 1,467,243. Total Annual Hours.

744,5143. (For questions regarding this collection contact Jennifer McMullen (410)786-7635.) 2. Type of Information Collection Request. Revision of a currently approved collection.

Title of Information Collection. Continuation of Data Collection to Support QHP Certification and other Financial Management and Exchange Operations. Use. As directed by the rule Establishment of Exchanges and Qualified Health Plans.

Exchange Standards for Employers (77 FR 18310) (Exchange rule), each Exchange is responsible for the certification and offering of Qualified Health Plans (QHPs). To offer insurance through an Exchange, a health insurance issuer must have its health plans certified as QHPs by the Exchange. A QHP must meet certain necessary minimum certification standards, such as network adequacy, inclusion of Essential Community Providers (ECPs), and non-discrimination. The Exchange is responsible for ensuring that QHPs meet these minimum certification standards as described in the Exchange rule under 45 CFR 155 and 156, based on the Patient Protection and Affordable Care Act (PPACA), as well as other standards determined by the Exchange.

Issuers can offer individual and small group market plans outside of the Exchanges that are not QHPs. Form Number. CMS-10433 (OMB control number. 0938-1187).

Frequency. Annually. Affected Public. Private sector, State, Local, or Tribal Governments, Business or other for-profits.

Number of Respondents. 2,925. Number of Responses. 2,925.

Total Annual Hours. 71,660. (For questions regarding this collection, contact Nicole Levesque at (617) 565-3138). 3.

Type of Information Collection Request. Extension of a currently approved collection. Title of Information Collection. Notice of Rescission of Coverage and Disclosure Requirements for Patient Protection under the Affordable Care Act.

Use. Sections 2712 and 2719A of the Public Health Service Act (PHS Act), as added by the Affordable Care Act, contain rescission notice, and patient protection disclosure requirements that are subject to the Paperwork Reduction Act of 1995. The No Surprises Act, enacted as part of the Consolidated Appropriations Act, 2021, amended section 2719A of the PHS Act to sunset when the new emergency services protections under the No Surprises Act take effect. The provisions of section 2719A of the PHS Act will no longer apply with respect to plan years beginning on or after January 1, 2022.

The No Surprises Act re-codified the patient protections related to choice of health care professional under section 2719A of the PHS Act in newly added section 9822 of the Internal Revenue Code, section 722 of the Employee Retirement Income Security Act, and section 2799A-7 of the PHS Act and extended the applicability of these provisions to grandfathered health plans for plan years beginning on or after January 1, 2022. The rescission notice will be used by health plans to provide advance notice to certain individuals that their coverage may be rescinded as a result of fraud or intentional misrepresentation of material fact. The patient protection notification will be used by health plans to inform certain individuals of their right to choose a primary care provider or pediatrician and to use obstetrical/gynecological services without prior authorization. The related provisions are finalized in the 2015 final regulations titled “Final Rules under the Affordable Care Act for Grandfathered Plans, Preexisting Condition Exclusions, Start Printed Page 67475 Lifetime and Annual Limits, Rescissions, Dependent Coverage, Appeals, and Patient Protections” (80 FR 72192, November 18, 2015) and 2021 interim final regulations titled “Requirements Related to Surprise Billing.

Part I” (86 FR 36872, July 13, 2021). The 2015 final regulations also require that, if State law prohibits balance billing, or a plan or issuer is contractually responsible for any amounts balanced billed by an out-of-network emergency services provider, a plan or issuer must provide a participant, beneficiary or enrollee adequate and prominent notice of their lack of financial responsibility with respect to amounts balanced billed in order to prevent inadvertent payment by the individual.