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Over the past 30 years, fire departments in both urban and rural areas have struggled to recruit new firefighters into a profession that’s more than half where can i buy zithromax z pak volunteers. In rural America, the zithromax has brought the crisis to a new apex. Rural firefighters have been on the front lines of the zithromax, tackling wildfires and vehicle accidents even as where can i buy zithromax z pak they transport ill and injured residents to hospitals. buy antibiotics’s heavy toll on rural hospitals has extended to emergency responders, meaning firefighters are answering more medical calls than ever before. The increased workload, and the specter of treatment where can i buy zithromax z pak mandates, has made recruitment even tougher.And then there’s the trauma they’ve endured.The mass death and suffering of the past 20 months has spawned a surge of post-traumatic stress disorder, anxiety, depression, insomnia and substance use disorder among health care professionals of all kinds.

Answering calls at the homes of relatives, friends and neighbors—which many rural firefighters have had to do—magnifies the pain.“We’re still in this zithromax, and we’re still fighting those emotions. It’s not [as if] it happened three years ago,” said Jeff Dill, founder of the Firefighter Behavioral Health Alliance, which runs mental health workshops for fire departments. €œWe’ve had numerous firefighters that have taken their lives because of it—seeing and handling the stress and the depression and the bodies that piled up.” Stateline Story March 15, 2021 ‘Why Do I Put My where can i buy zithromax z pak Life on the Line?. €™ zithromax Trauma Haunts Health Workers. Quick View In many fire departments, the workers expected where can i buy zithromax z pak to endure that stress don’t even receive paychecks.

Of more than 1.1 million firefighters nationwide, 67% are volunteers who are not paid or receive a minimal amount to cover gas and other expenses, according to a 2021 fact sheet by the National Volunteer Fire Council. Many of them are in where can i buy zithromax z pak rural America. Nearly 40% of communities with between 5,000 and 9,999 residents had all-volunteer departments as of 2018, according to a tally released last year by the National Fire Protection Association. In communities with between 2,500 and 4,999 people, the percentage of all-volunteer departments was 72%, and 92% in towns of less than 2,500. Fire Chief J.T where can i buy zithromax z pak.

Wallace Jr. Of Benton Fire where can i buy zithromax z pak District No. 4 in rural Louisiana said he does not have enough firefighters, paid or volunteer, to respond to structural fires. The community is small, but the population has grown slightly in the past few years, making it harder to meet demand and staff the stations. Recently, Wallace Jr where can i buy zithromax z pak.

Had an entire shift of firefighters out because they contracted buy antibiotics. Three firefighters have been diagnosed with post-traumatic stress disorder within the past year.“I think we didn’t lose community, but we were wounded in other ways where can i buy zithromax z pak psychologically. It got pretty bad,” Wallace Jr. Said. €œWe’ve seen stress.

I’ve been doing this almost 50 years and this is a different ballgame with what we have to deal with.” Chris Smith, a lieutenant at the Bolivar County Volunteer Fire Department in Mississippi, has been a volunteer firefighter for 13 years. He likewise said the zithromax has brought a new level of stress to an already difficult job. The extra work is hard enough—firefighters responding to buy antibiotics-related calls must don special protective gear, for example. Much worse has been responding to the calls of sick loved ones, he said, which takes a heavy emotional toll. Smith volunteers 30 to 40 hours a week, in addition to working his full-time job as technical program manager of geospatial information technology at Delta State University.

It has been “nearly impossible,” he said, to find volunteers to lighten the load over the past year and a half. Stateline Story September 16, 2021 States Embrace treatment Mandates Despite Potential Worker Exodus Quick View Smith said he is concerned that even the prospect of a buy antibiotics treatment mandate is driving volunteers away, though there aren’t treatment mandates in place in Bolivar County—at least not yet. He is fully vaccinated but opposes a requirement because he worries it would dissuade would-be volunteers. Even in the best of times, it’s difficult to find people who are willing to volunteer. €œPeople are too busy, or they don't understand that the fire departments are volunteer.

And when they do, they're like, ‘That's not for me,’” Smith said. Between 2000 and 2015, reported fires declined across the country, but fire departments have assumed a greater role in responding to the increasing number of medical aid and rescue calls. In rural America, firefighters have a tougher task because they must respond to calls across greater distances. And there is a correlation between population density and fire deaths, according to a September 2019 report by the National Fire Protection Association, which examined fire-related deaths between 2013 and 2017. Sparsely populated counties fared the worst, and nine of the 10 states with the highest fire death rates were in the South.The report also found that states with higher rates of fire deaths have more residents with low incomes, who have disabilities or who are Black, Native American or Native Alaskan.The zithromax has exacerbated longstanding recruitment and retention problems in rural departments, especially those that rely on volunteers.

Volunteer firefighting just isn’t as appealing to younger couples who rely on two incomes, said Steve Hirsch, a veteran firefighter and chair of the National Volunteer Fire Council, a nonprofit advocacy association representing volunteer fire, emergency medical and rescue services. Even some residents who do volunteer aren’t always available to answer calls, because they work full-time jobs in another community, Hirsch said. €œWhen my dad started in the fire service 60 years ago, typically it was dads who were volunteering, and moms were at home to take care of the kids and it worked out fine. But the reality today is that both mom and dad are working,” Hirsch said. €œSome of those rural communities don't have any jobs available for people.

So, they've lost population. And sometimes the people that do live in those communities work someplace else.” Stateline Story May 20, 2021 California Lacks Federal Firefighters as Dangerous Season Looms Quick View George Richards, president of the Montana State Council of Professional Firefighters, said many younger people “just don’t have the willingness to volunteer or serve without being compensated.” In Montana, 90% of departments are volunteer.“A lot of the departments had volunteers, members, for 20-plus, in some cases 40 years,” Richards said. €œThere’s just not that stronghold of commitment in this different generation.” Older firefighters tend to take more sick leave, Richards said. When many firefighters are absent, the ones who are available must work longer hours, or some stations are forced to shut down on certain days. Bob Timko, a member of the National Volunteer Fire Council’s recruitment and retention committee, said volunteer departments need to ratchet up recruitment efforts, perhaps in partnership with local businesses.

“[Young people] aren’t coming in the door,” Timko said. €œI would challenge leadership to develop a program or use resources to educate people on what we do.”Smith, the firefighter in the Mississippi Delta, said that even people who don’t want to be volunteer firefighters can do things to alleviate the stress on first responders, whether it's cleaning and maintaining the fire stations or helping with operations.“How would you feel if your house was on fire, and no one showed up?. € Smith asked. €œThere's no one there to protect you or your property. We're here to do the community good and make it a better place.“We just want some good people to come and give back to their community.”.

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An impressive number of UC Davis Health http://www.buglooper.com/can-you-buy-propecia-online physicians — zithromax cost cvs 240 in all — are included on a list of the region’s best doctors published in the December 2020 issue of Sacramento Magazine. The physicians practice in 61 medical specialties, including 15 pediatric subspecialties. In addition, orthopaedic surgeon Christopher Bayne, a specialist in hand, wrist, elbow and shoulder microsurgery, appears on the cover zithromax cost cvs.

Bayne and adolescent medicine physician Laura Kester were also selected to offer perspectives on patient care and trends in their fields. UC Davis Health’s presence on the list represents an increase from the previous year, when 219 physicians were named “Top Docs.” “We are honored that so many of our physicians zithromax cost cvs are respected by their peers,” said David A. Lubarsky, vice chancellor of Human Health Sciences and CEO of UC Davis Health.

€œOur growing presence on this list reinforces our reputation as a leader in zithromax cost cvs both primary and specialty care. Our medical team is also the reason for our health system’s regional — and national — reputation as a leader in providing world-class patient care.”Top Docs are selected through a peer-review survey led by Professional Research Services Company of Troy, Mich. To learn more about the selection process, go to prscom.com.

View the list of UC Davis Health Top Docs zithromax cost cvs by specialty area.The magazine is now available in stores and to subscribers. The online edition will be available the first week of December.View information on more awards and honors for UC Davis Health.[embedded content]This video is best viewed in Chrome or Firefox.Slimmed down or cancelled celebrations this holiday season may be particularly hard on older people, but the alternative could be worse. A family gathering could zithromax cost cvs risk their lives, two health experts said on UC Davis LIVE.

buy antibiotics. €œIt may seem dramatic for us to sit here and say the greatest gift you can give is life and not kill your family member or loved one, but that is the reality,” said Natascha Tuznik, a UC Davis Health zithromax cost cvs assistant clinical professor of infectious diseases. €œPeople are saying, ‘I’m tired and I want to get together,’ but that is a risk you have to consider.” buy antibiotics is raging across California and the U.S., with rates exploding to record levels – right as the holidays are coming and people want to gather with friends and families.

But a holiday party or meal could be deadly for the people you zithromax cost cvs care about, especially if they are older, Tuznik said. €œThe risks are substantial right now. We’re seeing the highest case rates since the zithromax started,” she said.

€œI understand zithromax cost cvs buy antibiotics fatigue. I have it, too. Being asked to batten down the hatches for zithromax cost cvs a few more months is hard.

But the best way to celebrate your family is to stay apart.” Keeping some connection – at a distance – with older family members these holidays can be vital to their healthTuznik and Terri Harvath, director of the Family Caregiving Institute at the Betty Irene Moore School of Nursing both urged people to see this as a one-time sacrifice. €œThis may be the only holiday season in our lives zithromax cost cvs that we’re asked to practice all these precautions,” Harvath said. €œDon’t see this as a forever change to our traditions that so many of us love and look forward to.

Instead, think about how we can modify those traditions, maybe in a virtual way.” Keep connected to older adultsChanging the celebrations, but keeping some version of them, may be most important to older adults, especially those who are more isolated. It can be just as important to the family zithromax cost cvs members who care for them. €œIt’s really important to be reaching out to these older adults and their caregivers,” Harvath said.

€œThe social isolation buy antibiotics has caused is a serious problem and zithromax cost cvs something we need to pay attention to. We know that social isolation is related to both physical and mental health problems.” For people who care for an older family member in their home, buy antibiotics restrictions have often meant lost resources from community organizations and lost help from other family or friends. €œUnfortunately, older adults zithromax cost cvs and their caregivers have borne a disproportionate burden of buy antibiotics,” Harvath said.

€œThey have higher rates of morbidity and mortality. They’ve also not been first in line for getting resources.” zithromax cost cvs She suggested doing whatever we can to keep a social connection to older family members and their caregivers through phone calls, virtual gatherings, packages and even going old school. €œSend cards and letters,” Harvath said.

€œRemember, your older family members have done that their whole lives.” Assessing the risk of a gatheringBoth Harvath and Tuznik start with this advice for any gathering with people outside your household. Don’t. But with older adults, the decision gets complicated.

On one hand, there may be only a few more opportunities to gather for them. On the other, they are most vulnerable to any exposure to buy antibiotics, which is spreading rapidly throughout the U.S. Population.

€œYou do have to weigh all the risks very carefully,” Harvath said. €œAfter every holiday, we’ve seen spikes in transmission, and all of those were during months when we could gather outdoors. The increased risk of being indoors (where there is much less air flow and it’s much harder to physically distance) is enormous.” Experts say take all precautions if you do visit older family members during the holidaysTo help decide if you’ll visit, the Gerontological Society of America has a survey tool that asks questions ranging from how rare is this opportunity to what is most important to you in making this decision.

How to stay safer if you do gather“People are calling it Zoomgiving,” Tuznik said. €œSome people are even making a place setting for their computer. If you want to be totally safe, virtual is the way.” The Centers for Disease Control and Prevention just released new guidelines that also warn about Thanksgiving and holiday gatherings.

€œIf you have to do it, there are at least some things you can do to stay safer,” she said. €œAnd make sure everybody is on board and everybody follows through. That’s really hard to do.

Will there be zero risk?. No. You will still all be at risk even if you follow everything to a T.” Her suggestions include.

Keep the gathering small. Maybe six people, maximum.Keep it outside, weather permitting.If you are inside, open doors and windows for more air flow.Bring your own food, utensils and even salad dressing. €œAs far as we know, there is no transmission related to food,” Tuznik said.

€œThe issue is congregating around the food.”Work to keep a physical distance – and remember when people drink, they forget or lose inhibitions.Wear masks whether you’re indoors or outside, when you’re not eating or drinking. €œMake sure they’re not loose and hanging,” she said.“Remember, no hugs, no kisses, just wave at everyone,” Tuznik said. €œIf there’s an uncle or aunt who says, ‘I’m not going to wear a mask and I’m not going to go along,’ then don’t have them at your house.

They’ll mess it up for everyone else.” Tuznik said even if everyone at the gathering has tested negative for buy antibiotics, it is still no guarantee that you’re risk free because tests are a snapshot of someone’s infectiousness at the moment. €œThe only way to be certain would be for everyone to quarantine for 14 days,” she said. Harvath said she is feeling what many others feel.

She misses her family. But she won’t see them this Thanksgiving. €œMy mom is staying home.

My daughter is not going to come. I’m not accepting any invitations,” she said. €œThe biggest gift we can give to family or friends is the reduction of exposure to something that can make them very sick or kill them.”.

An impressive linked here number of UC Davis Health physicians — 240 in all — are included on a list of the region’s best doctors published in the December 2020 issue of Sacramento Magazine where can i buy zithromax z pak. The physicians practice in 61 medical specialties, including 15 pediatric subspecialties. In addition, orthopaedic surgeon Christopher Bayne, a specialist in hand, where can i buy zithromax z pak wrist, elbow and shoulder microsurgery, appears on the cover.

Bayne and adolescent medicine physician Laura Kester were also selected to offer perspectives on patient care and trends in their fields. UC Davis Health’s presence on the list represents an increase from the previous year, where can i buy zithromax z pak when 219 physicians were named “Top Docs.” “We are honored that so many of our physicians are respected by their peers,” said David A. Lubarsky, vice chancellor of Human Health Sciences and CEO of UC Davis Health.

€œOur growing presence on this list reinforces our reputation as a where can i buy zithromax z pak leader in both primary and specialty care. Our medical team is also the reason for our health system’s regional — and national — reputation as a leader in providing world-class patient care.”Top Docs are selected through a peer-review survey led by Professional Research Services Company of Troy, Mich. To learn more about the selection process, go to prscom.com.

View the list of UC Davis Health Top Docs by specialty area.The magazine is now available where can i buy zithromax z pak in stores and to subscribers. The online edition will be available the first week of December.View information on more awards and honors for UC Davis Health.[embedded content]This video is best viewed in Chrome or Firefox.Slimmed down or cancelled celebrations this holiday season may be particularly hard on older people, but the alternative could be worse. A family gathering could risk their lives, two health where can i buy zithromax z pak experts said on UC Davis LIVE.

buy antibiotics. €œIt may seem dramatic for us to sit here and say the greatest gift you can give is life and not kill your family member or loved one, but that is the reality,” said Natascha Tuznik, a where can i buy zithromax z pak UC Davis Health assistant clinical professor of infectious diseases. €œPeople are saying, ‘I’m tired and I want to get together,’ but that is a risk you have to consider.” buy antibiotics is raging across California and the U.S., with rates exploding to record levels – right as the holidays are coming and people want to gather with friends and families.

But a holiday party or meal could be deadly for the people where can i buy zithromax z pak you care about, especially if they are older, Tuznik said. €œThe risks are substantial right now. We’re seeing the highest case rates since the zithromax started,” she said.

€œI understand where can i buy zithromax z pak buy antibiotics fatigue. I have it, too. Being asked to batten down the where can i buy zithromax z pak hatches for a few more months is hard.

But the best way to celebrate your family is to stay apart.” Keeping some connection – at a distance – with older family members these holidays can be vital to their healthTuznik and Terri Harvath, director of the Family Caregiving Institute at the Betty Irene Moore School of Nursing both urged people to see this as a one-time sacrifice. €œThis may be the only holiday season in our lives that we’re asked to practice all these precautions,” Harvath said where can i buy zithromax z pak. €œDon’t see this as a forever change to our traditions that so many of us love and look forward to.

Instead, think about how we can modify those traditions, maybe in a virtual way.” Keep connected to older adultsChanging the celebrations, but keeping some version of them, may be most important to older adults, especially those who are more isolated. It can be just as important to the family where can i buy zithromax z pak members who care for them. €œIt’s really important to be reaching out to these older adults and their caregivers,” Harvath said.

€œThe social isolation buy antibiotics has where can i buy zithromax z pak caused is a serious problem and something we need to pay attention to. We know that social isolation is related to both physical and mental health problems.” For people who care for an older family member in their home, buy antibiotics restrictions have often meant lost resources from community organizations and lost help from other family or friends. €œUnfortunately, older adults and their caregivers where can i buy zithromax z pak have borne a disproportionate burden of buy antibiotics,” Harvath said.

€œThey have higher rates of morbidity and mortality. They’ve also not been first in line for getting resources.” She suggested doing whatever we can to keep a social where can i buy zithromax z pak connection to older family members and their caregivers through phone calls, virtual gatherings, packages and even going old school. €œSend cards and letters,” Harvath said.

€œRemember, your older family members have done that their whole lives.” Assessing the risk of a gatheringBoth Harvath and Tuznik start with this advice for any gathering with people outside your household. Don’t. But with older adults, the decision gets complicated.

On one hand, there may be only a few more opportunities to gather for them. On the other, they are most vulnerable to any exposure to buy antibiotics, which is spreading rapidly throughout the U.S. Population.

€œYou do have to weigh all the risks very carefully,” Harvath said. €œAfter every holiday, we’ve seen spikes in transmission, and all of those were during months when we could gather outdoors. The increased risk of being indoors (where there is much less air flow and it’s much harder to physically distance) is enormous.” Experts say take all precautions if you do visit older family members during the holidaysTo help decide if you’ll visit, the Gerontological Society of America has a survey tool that asks questions ranging from how rare is this opportunity to what is most important to you in making this decision.

How to stay safer if you do gather“People are calling it Zoomgiving,” Tuznik said. €œSome people are even making a place setting for their computer. If you want to be totally safe, virtual is the way.” The Centers for Disease Control and Prevention just released new guidelines that also warn about Thanksgiving and holiday gatherings.

€œIf you have to do it, there are at least some things you can do to stay safer,” she said. €œAnd make sure everybody is on board and everybody follows through. That’s really hard to do.

Will there be zero risk?. No. You will still all be at risk even if you follow everything to a T.” Her suggestions include.

Keep the gathering small. Maybe six people, maximum.Keep it outside, weather permitting.If you are inside, open doors and windows for more air flow.Bring your own food, utensils and even salad dressing. €œAs far as we know, there is no transmission related to food,” Tuznik said.

€œThe issue is congregating around the food.”Work to keep a physical distance – and remember when people drink, they forget or lose inhibitions.Wear masks whether you’re indoors or outside, when you’re not eating or drinking. €œMake sure they’re not loose and hanging,” she said.“Remember, no hugs, no kisses, just wave at everyone,” Tuznik said. €œIf there’s an uncle or aunt who says, ‘I’m not going to wear a mask and I’m not going to go along,’ then don’t have them at your house.

They’ll mess it up for everyone else.” Tuznik said even if everyone at the gathering has tested negative for buy antibiotics, it is still no guarantee that you’re risk free because tests are a snapshot of someone’s infectiousness at the moment. €œThe only way to be certain would be for everyone to quarantine for 14 days,” she said. Harvath said she is feeling what many others feel.

She misses her family. But she won’t see them this Thanksgiving. €œMy mom is staying home.

My daughter is not going to come. I’m not accepting any invitations,” she said. €œThe biggest gift we can give to family or friends is the reduction of exposure to something that can make them very sick or kill them.”.

Where can I keep Zithromax?

Keep out of the reach of children in a container that small children cannot open. Store at room temperature between 15 and 30 degrees C (59 and 86 degrees F). Throw away any unused medicine after the expiration date.

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WASHINGTON, DC – zithromax dosage instructions http://treorisoft.com/?page_id=32 Last week, the U.S. Department of Labor took a range of actions to aid American workers and employers as our nation combats the antibiotics zithromax. Reopening America’s zithromax dosage instructions Economy.

U.S. Secretary of Labor Announces Award of Nearly $20 Million To Combat Opioid Crisis – U.S. Secretary of Labor Eugene Scalia announced the award of nearly $20 million in funding to four states as part of a new pilot program to address the health and economic impacts of widespread substance and opioid misuse, addiction and overdose by providing retraining and other zithromax dosage instructions services to workers in communities significantly impacted by the opioid crisis.

The grantees are the Florida Department of Economic Opportunity, the Maryland Department of Labor, the Ohio Department of Job and Family Services, and the Wisconsin Department of Workforce Development. Defending Workers’ Rights to Paid Leave zithromax dosage instructions and Wages Earned. U.S.

Department Of Labor Issues Guidance to Clarify Employers’ Obligations To Track Teleworkers’ Compensable Hours – “Due to the antibiotics zithromax, more Americans are teleworking and working variable schedules than ever before to balance their jobs with a myriad of family obligations, such as remote learning for their children and many others. This has zithromax dosage instructions presented unique challenges to employers with regard to how to track work time accurately,” said Wage and Hour Division Administrator Cheryl Stanton. €œ[This] guidance is one more tool the Wage and Hour Division is putting forward to ensure that workers are paid all the wages they have earned, and that employers have all the tools they need as they navigate what may, for many, be uncharted waters of managing remote workers.”Minneapolis Day Care Pays 28 Employees $19,447 in Back Wages After Denying Paid Leave Under the Families First antibiotics Response Act – The Wage and Hour Division determined an operator of childcare facilities denied paid leave under the Families First antibiotics Response Act (FFCRA) to workers who qualified for the benefit, and, in some cases, required employees to use accrued personal time off instead of granting paid leave under the Emergency Paid Sick Leave Act (EPSLA).

In other cases, zithromax dosage instructions the employer required employees to take leave without pay when they were in fact qualified for paid time off under the FFCRA. Once notified of its obligations by the Wage and Hour Division, the employer paid the back wages.During the antibiotics zithromax, the Department of Labor is focused on protecting the safety and health of American workers, assisting our state partners as they deliver traditional unemployment and expanded unemployment benefits, ensuring Americans know their rights to new paid sick leave and expanded family and medical leave, providing guidance and assistance to employers, and carrying out the mission of the Department. The mission of the Department of Labor is to foster, promote and develop the welfare of the wage earners, job seekers and retirees of the United States.

Improve working zithromax dosage instructions conditions. Advance opportunities for profitable employment. And assure work-related benefits and rights.MINNEAPOLIS, MN – After an investigation by the U.S.

Department of Labor’s Wage and Hour Division (WHD), zithromax dosage instructions Mundo De Colores Inc. €“ operator of five Minneapolis-area Spanish language childcare facilities – has paid 28 employees back wages and restored leave valued at $19,447. The employer failed to provide the workers leave required under the Emergency Paid Sick Leave Act (EPSLA) provisions of zithromax dosage instructions the Families First antibiotics Response Act (FFCRA).

WHD determined Mundo De Colores Inc. €“ operating as Jardin Spanish Immersion Academy – denied paid leave under the FFCRA http://studymassachusetts.us/news/connect-with-study-western-massachusetts/ to workers who qualified for the benefit, and, in some cases, required employees to use accrued personal time off instead of granting paid leave under the EPSLA. In other cases, zithromax dosage instructions the employer required employees to take leave without pay when they were in fact qualified for paid time off under the FFCRA.

Once notified of its obligations by WHD, the employer paid the back wages. €œEmployers must comply with the Families First antibiotics Response Act, and provide employees emergency paid sick leave when they zithromax dosage instructions meet qualifying conditions that are designed to minimize exposure, prevent the potential spread of the antibiotics and allow employees to care for family members,” said Acting Wage and Hour District Director Debra Wynn, in Minneapolis, Minnesota. €œThrough outreach and enforcement, the U.S.

Department of Labor remains diligent in its efforts to help U.S. Employees and zithromax dosage instructions employers better understand all the benefits and protections this law provides.” The FFCRA helps the U.S. Combat and defeat the workplace effects of the antibiotics by giving tax credits to American businesses with fewer than 500 employees to provide employees with paid leave for certain reasons related to the antibiotics.

Please visit WHD’s “Quick Benefits Tips” for information about how much leave workers may qualify to use, and the amounts employers must pay. The law enables employers to provide paid leave reimbursed by tax credits, while at the same time ensuring that workers are not forced to choose between their paychecks and zithromax dosage instructions the public health measures needed to combat the zithromax. WHD continues to provide updated information on its website and through extensive outreach efforts to endure that workers and employers have the information they need about the benefits and protections of this new law.

The agency also provides additional information on common issues employers and employees face when responding to the antibiotics and its effects on wages and hours worked under the Fair Labor Standards Act zithromax dosage instructions and on job-protected leave under the Family and Medical Leave Act at https://www.dol.gov/agencies/whd/zithromax. For more information about the laws enforced by WHD, call 866-4US-WAGE, or visit www.dol.gov/agencies/whd. For further information about the antibiotics, please visit the Centers for Disease Control and Prevention.

WHD’s mission is to promote and achieve compliance with zithromax dosage instructions labor standards to protect and enhance the welfare of the nation’s workforce. WHD enforces federal minimum wage, overtime pay, recordkeeping and child labor requirements of the Fair Labor Standards Act. WHD also zithromax dosage instructions enforces the Migrant and Seasonal Agricultural Worker Protection Act, the Employee Polygraph Protection Act, the Family and Medical Leave Act, wage garnishment provisions of the Consumer Credit Protection Act and a number of employment standards and worker protections as provided in several immigration related statutes.

Additionally, WHD administers and enforces the prevailing wage requirements of the Davis Bacon Act and the Service Contract Act and other statutes applicable to federal contracts for construction and for the provision of goods and services. The mission of the Department of Labor is to foster, promote and develop the welfare of the wage earners, job seekers and retirees of the United States. Improve working conditions zithromax dosage instructions.

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WASHINGTON, DC – Last where can i buy zithromax z pak week, the U.S where can i buy zithromax over the counter. Department of Labor took a range of actions to aid American workers and employers as our nation combats the antibiotics zithromax. Reopening America’s where can i buy zithromax z pak Economy. U.S.

Secretary of Labor Announces Award of Nearly $20 Million To Combat Opioid Crisis – U.S. Secretary of Labor Eugene Scalia announced the award of nearly $20 million in funding to four states as part of a new pilot program to address the health and economic impacts of widespread substance and opioid misuse, addiction and overdose by providing retraining and where can i buy zithromax z pak other services to workers in communities significantly impacted by the opioid crisis. The grantees are the Florida Department of Economic Opportunity, the Maryland Department of Labor, the Ohio Department of Job and Family Services, and the Wisconsin Department of Workforce Development. Defending Workers’ Rights to Paid Leave and Wages Earned where can i buy zithromax z pak.

U.S. Department Of Labor Issues Guidance to Clarify Employers’ Obligations To Track Teleworkers’ Compensable Hours – “Due to the antibiotics zithromax, more Americans are teleworking and working variable schedules than ever before to balance their jobs with a myriad of family obligations, such as remote learning for their children and many others. This has presented unique challenges to employers with regard to how to track work time accurately,” where can i buy zithromax z pak said Wage and Hour Division Administrator Cheryl Stanton. €œ[This] guidance is one more tool the Wage and Hour Division is putting forward to ensure that workers are paid all the wages they have earned, and that employers have all the tools they need as they navigate what may, for many, be uncharted waters of managing remote workers.”Minneapolis Day Care Pays 28 Employees $19,447 in Back Wages After Denying Paid Leave Under the Families First antibiotics Response Act – The Wage and Hour Division determined an operator of childcare facilities denied paid leave under the Families First antibiotics Response Act (FFCRA) to workers who qualified for the benefit, and, in some cases, required employees to use accrued personal time off instead of granting paid leave under the Emergency Paid Sick Leave Act (EPSLA).

In other cases, the employer required employees to take leave where can i buy zithromax z pak without pay when they were in fact qualified for paid time off under the FFCRA. Once notified of its obligations by the Wage and Hour Division, the employer paid the back wages.During the antibiotics zithromax, the Department of Labor is focused on protecting the safety and health of American workers, assisting our state partners as they deliver traditional unemployment and expanded unemployment benefits, ensuring Americans know their rights to new paid sick leave and expanded family and medical leave, providing guidance and assistance to employers, and carrying out the mission of the Department. The mission of the Department of Labor is to foster, promote and develop the welfare of the wage earners, job seekers and retirees of the United States. Improve working conditions where can i buy zithromax z pak.

Advance opportunities for profitable employment. And assure work-related benefits and rights.MINNEAPOLIS, MN – After an investigation by the U.S. Department of Labor’s Wage and Hour Division where can i buy zithromax z pak (WHD), Mundo De Colores Inc. €“ operator of five Minneapolis-area Spanish language childcare facilities – has paid 28 employees back wages and restored leave valued at $19,447.

The employer failed to provide the workers leave required under the Emergency Paid Sick Leave where can i buy zithromax z pak Act (EPSLA) provisions of the Families First antibiotics Response Act (FFCRA). WHD determined Mundo De Colores Inc. €“ operating as Jardin Spanish Immersion Academy – denied paid leave under the FFCRA to workers who qualified for the benefit, and, in some cases, required employees to use accrued personal time off http://www.ec-schloessel-ostwald.ac-strasbourg.fr/?page_id=1454 instead of granting paid leave under the EPSLA. In other where can i buy zithromax z pak cases, the employer required employees to take leave without pay when they were in fact qualified for paid time off under the FFCRA.

Once notified of its obligations by WHD, the employer paid the back wages. €œEmployers must comply with the Families First antibiotics Response Act, where can i buy zithromax z pak and provide employees emergency paid sick leave when they meet qualifying conditions that are designed to minimize exposure, prevent the potential spread of the antibiotics and allow employees to care for family members,” said Acting Wage and Hour District Director Debra Wynn, in Minneapolis, Minnesota. €œThrough outreach and enforcement, the U.S. Department of Labor remains diligent in its efforts to help U.S.

Employees and employers better understand all the benefits and protections this law provides.” where can i buy zithromax z pak The FFCRA helps the U.S. Combat and defeat the workplace effects of the antibiotics by giving tax credits to American businesses with fewer than 500 employees to provide employees with paid leave for certain reasons related to the antibiotics. Please visit WHD’s “Quick Benefits Tips” for information about how much leave workers may qualify to use, and the amounts employers must pay. The law enables employers to provide paid leave reimbursed by tax credits, while at the same where can i buy zithromax z pak time ensuring that workers are not forced to choose between their paychecks and the public health measures needed to combat the zithromax.

WHD continues to provide updated information on its website and through extensive outreach efforts to endure that workers and employers have the information they need about the benefits and protections of this new law. The agency also provides additional information on common issues employers and employees face when responding to the antibiotics and its effects on wages and hours worked under the Fair Labor Standards where can i buy zithromax z pak Act and on job-protected leave under the Family and Medical Leave Act at https://www.dol.gov/agencies/whd/zithromax. For more information about the laws enforced by WHD, call 866-4US-WAGE, or visit www.dol.gov/agencies/whd. For further information about the antibiotics, please visit the Centers for Disease Control and Prevention.

WHD’s mission is to promote and achieve compliance with labor standards to protect and enhance the welfare of the nation’s workforce where can i buy zithromax z pak. WHD enforces federal minimum wage, overtime pay, recordkeeping and child labor requirements of the Fair Labor Standards Act. WHD also enforces the Migrant and Seasonal Agricultural Worker Protection Act, the Employee Polygraph Protection Act, the Family and Medical Leave Act, wage garnishment where can i buy zithromax z pak provisions of the Consumer Credit Protection Act and a number of employment standards and worker protections as provided in several immigration related statutes. Additionally, WHD administers and enforces the prevailing wage requirements of the Davis Bacon Act and the Service Contract Act and other statutes applicable to federal contracts for construction and for the provision of goods and services.

The mission of the Department of Labor is to foster, promote and develop the welfare of the wage earners, job seekers and retirees of the United States. Improve working conditions where can i buy zithromax z pak. Advance opportunities for profitable employment. And assure work-related benefits and rights..

How much does zithromax cost

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1024px) { #styln-briefing-block { width. 100%. } } Latest Updates. The antibiotics Outbreak 2h ago Northern Ireland will lock down for four weeks, as England begins new restrictions.

3h ago Pret A Manger will try anything to survive. 4h ago Yes, you can be reinfected with the antibiotics. But it’s extremely unlikely. See more updates More live coverage.

Markets At the start of the zithromax, doctors were necessarily focused on combating the acute effects of buy antibiotics and saving lives, but research is now underway to assess its long-term effects and find ways to prevent and treat lasting symptoms. There is increasing concern that the zithromax will result in “a significant surge of people battling lasting illnesses and disabilities,” the journal Nature reported.In a commentary in The Lancet in September, an international team of infectious disease specialists conceded that “we do not know what to tell our patients when they are asking about the course and prognosis of their ongoing complaints.” Among the many unknowns they cited. €œDoes acute buy antibiotics cause diabetes?. Or other metabolic disorders?.

Will patients develop interstitial lung disease?. €They wondered, too, “which symptoms might be explained by the anxiety caused by a new disease and by the isolation, and which symptoms are secondary to a complicated form of buy antibiotics.” At present, the unknowns about long-term consequences of this potentially devastating viral far outnumber the knowns.One fact already known. A person need not have had severe disease to experience symptoms that persist for months and, time will tell, possibly for years. Even some people who had mild buy antibiotics s continue to experience symptoms long after recovering from the acute illness.The range of reported symptoms is vast.

They include unusual fatigue from physical or mental activity, brain fog, temperature irregularities, rashes, memory problems and insomnia. It’s as if the body’s immune response to the antibiotics has thrown the nervous system out of whack, according to Dr. Dayna McCarthy, rehabilitation specialist at the Mount Sinai Center for Post-buy antibiotics Care.The lasting effects among those who survived another serious antibiotics disease, SARS, are not very encouraging. As the Mayo Clinic reported, “Many people who have recovered from SARS have gone on to develop chronic fatigue syndrome, a complex disorder characterized by extreme fatigue that worsens with physical or mental activity, but doesn’t improve with rest.

The same may be true for people who have had buy antibiotics.”The buy antibiotics zithromax can damage the lungs, heart and brain, increasing the risk of persistent health problems. According to the Mayo experts, “Imaging tests taken months after recovery from buy antibiotics have shown lasting damage to the heart muscle, even in people who had only mild buy antibiotics symptoms.” The illness can cause very small blood clots that can block capillaries in the heart and permanently injure the heart muscle. The disease can also weaken blood vessels and injure the kidneys and liver.buy antibiotics can scar the lungs’ tiny air sacs and cause long-term breathing difficulty even if the scars partially heal. This effect on lung function ended the life of 107-year-old Marilee Shapiro Asher, a celebrated artist in Washington, D.C., who remained professionally active until buy antibiotics laid her low in early spring.

During five days in the hospital, she recovered from the acute , then died several months later with zithromax-caused damage to her lungs that left them brittle and filled their air sacs with fluid.With SARS, a 15-year follow-up of patients found that most lung recovery took place within two years, but some mild pulmonary effects remained indefinitely in more than a third of recovered SARS patients.Brain-related effects of an active buy antibiotics can include strokes, seizures and a temporary paralysis called Guillain-Barré syndrome. Many buy antibiotics patients lose their sense of smell and taste during the acute illness, but for some this neurological effect persisted for months after they had otherwise recovered. And questions remain whether the viral also will raise the risk of later developing neurological problems like Parkinson’s disease or Alzheimer’s disease.People who were severely ill with buy antibiotics, especially those who spent weeks or longer isolated in intensive care with or without a ventilator, can develop symptoms of post-traumatic stress syndrome and persistent problems with anxiety and depression. Their emotional trauma may cause recurrent nightmares and a fear of being alone and even of going to sleep.Indeed, Ms.

Londa said it’s impossible to know how many of her recurring symptoms or their severity are the result of unresolved anxiety stemming from the acute illness or to a fear that she may never again be the person she was before buy antibiotics.A study of 179 recovered buy antibiotics patients in Italy revealed a “worsened quality of life” months later in 44.1 percent, with a high proportion reporting ongoing fatigue, shortness of breath, joint pain and chest pain. In Dr. McCarthy’s experience, however, post-buy antibiotics patients do get better, although symptoms tend to wax and wane and improvement “is glacially slow.” She suggests that patients do things in smaller doses and not push themselves to live as they did before buy antibiotics, which can make their problems worse.It’s been somewhat of a running joke in a profoundly unfunny time. Endless laments about the “quarantine 15” or “buy antibiotics 19,” referring to the number of pounds gained during lockdown.According to a June survey of 2,000 American adults by the weight loss program Nutrisystem, 76 percent of respondents gained weight, up to 16 pounds, between mid-March and July.

And 63 percent said that losing weight was a priority, post quarantine.The difference between losers, gainers and maintainers during the zithromax, experts say, is largely dependent on your mind-set. How you approach a new set of circumstances and cope with change.One of the many challenges of buy antibiotics was the abrupt change to day-to-day schedules. People began working from home, if they had work at all, in many cases joined by their kids. Gyms, recreation centers and parks closed, curbing exercise routines.

Stress levels skyrocketed for many, with baking, eating and drinking becoming major outlets and means of reward. Indeed, studies show a link between high stress levels and overeating.“When the environment and your routine changes, you can use it as an opportunity to say ‘I’ll drink at home,’ or ‘I deserve to treat myself well in those really tough times,’” said Gary D. Foster, chief scientific officer of WW (formerly Weight Watchers). €œThis is where mind-set is so important.

It’s how you view things, how you position the situation, your sense of self-worth, and how you treat yourself.”“After that initial period, there was a subset of people who said, ‘This is an opportunity to take care of myself,” he said. €œThat different way of thinking about the process is really powerful.”Susan Abrams Torney, 62, a dental office manager in Delray Beach, Fla., had an epiphany early on in the zithromax when she realized that she could use the time off from work to make a positive change in her life. Sheltering in place worked in her favor. €œIt took the ‘I don’t have time to exercise’ excuse out of the equation,’” said Ms.

Torney, who has lost 30 pounds since the beginning of the year.She credits her grandchildren with motivating her. €œBefore I started on the journey, if I sat on the floor I felt like I needed a crane to get me back up again,” she said.During lockdown, she finally broke open the Wii video game console her children had given her for her 50th birthday and started playing Wii tennis and also going for “sanity” walks with friends around her community her only form of in-person socialization.It also helped that she was no longer able to go out for meals and had to cook at home, where she prepared healthy meals for herself, like chicken, fish and salads. Rather than vodka on the rocks, her previous cocktail of choice, she diluted her vodka with mineral water and a splash of cranberry juice.

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13px. } } @media only screen and (min-width. 1024px) { #styln-briefing-block { width.

100%. } } Latest Updates. The antibiotics Outbreak 2h ago Northern Ireland will lock down for four weeks, as England begins new restrictions.

3h ago Pret A Manger will try anything to survive. 4h ago Yes, you can be reinfected with the antibiotics. But it’s extremely unlikely.

See more updates More live coverage. Markets At the start of the zithromax, doctors were necessarily focused on combating the acute effects of buy antibiotics and saving lives, but research is now underway to assess its long-term effects and find ways to prevent and treat lasting symptoms. There is increasing concern that the zithromax will result in “a significant surge of people battling lasting illnesses and disabilities,” the journal Nature reported.In a commentary in The Lancet in September, an international team of infectious disease specialists conceded that “we do not know what to tell our patients when they are asking about the course and prognosis of their ongoing complaints.” Among the many unknowns they cited.

€œDoes acute buy antibiotics cause diabetes?. Or other metabolic disorders?. Will patients develop interstitial lung disease?.

€They wondered, too, “which symptoms might be explained by the anxiety caused by a new disease and by the isolation, and which symptoms are secondary to a complicated form of buy antibiotics.” At present, the unknowns about long-term consequences of this potentially devastating viral far outnumber the knowns.One fact already known. A person need not have had severe disease to experience symptoms that persist for months and, time will tell, possibly for years. Even some people who had mild buy antibiotics s continue to experience symptoms long after recovering from the acute illness.The range of reported symptoms is vast.

They include unusual fatigue from physical or mental activity, brain fog, temperature irregularities, rashes, memory problems and insomnia. It’s as if the body’s immune response to the antibiotics has thrown the nervous system out of whack, according to Dr. Dayna McCarthy, rehabilitation specialist at the Mount Sinai Center for Post-buy antibiotics Care.The lasting effects among those who survived another serious antibiotics disease, SARS, are not very encouraging.

As the Mayo Clinic reported, “Many people who have recovered from SARS have gone on to develop chronic fatigue syndrome, a complex disorder characterized by extreme fatigue that worsens with physical or mental activity, but doesn’t improve with rest. The same may be true for people who have had buy antibiotics.”The buy antibiotics zithromax can damage the lungs, heart and brain, increasing the risk of persistent health problems. According to the Mayo experts, “Imaging tests taken months after recovery from buy antibiotics have shown lasting damage to the heart muscle, even in people who had only mild buy antibiotics symptoms.” The illness can cause very small blood clots that can block capillaries in the heart and permanently injure the heart muscle.

The disease can also weaken blood vessels and injure the kidneys and liver.buy antibiotics can scar the lungs’ tiny air sacs and cause long-term breathing difficulty even if the scars partially heal. This effect on lung function ended the life of 107-year-old Marilee Shapiro Asher, a celebrated artist in Washington, D.C., who remained professionally active until buy antibiotics laid her low in early spring. During five days in the hospital, she recovered from the acute , then died several months later with zithromax-caused damage to her lungs that left them brittle and filled their air sacs with fluid.With SARS, a 15-year follow-up of patients found that most lung recovery took place within two years, but some mild pulmonary effects remained indefinitely in more than a third of recovered SARS patients.Brain-related effects of an active buy antibiotics can include strokes, seizures and a temporary paralysis called Guillain-Barré syndrome.

Many buy antibiotics patients lose their sense of smell and taste during the acute illness, but for some this neurological effect persisted for months after they had otherwise recovered. And questions remain whether the viral also will raise the risk of later developing neurological problems like Parkinson’s disease or Alzheimer’s disease.People who were severely ill with buy antibiotics, especially those who spent weeks or longer isolated in intensive care with or without a ventilator, can develop symptoms of post-traumatic stress syndrome and persistent problems with anxiety and depression. Their emotional trauma may cause recurrent nightmares and a fear of being alone and even of going to sleep.Indeed, Ms.

Londa said it’s impossible to know how many of her recurring symptoms or their severity are the result of unresolved anxiety stemming from the acute illness or to a fear that she may never again be the person she was before buy antibiotics.A study of 179 recovered buy antibiotics patients in Italy revealed a “worsened quality of life” months later in 44.1 percent, with a high proportion reporting ongoing fatigue, shortness of breath, joint pain and chest pain. In Dr. McCarthy’s experience, however, post-buy antibiotics patients do get better, although symptoms tend to wax and wane and improvement “is glacially slow.” She suggests that patients do things in smaller doses and not push themselves to live as they did before buy antibiotics, which can make their problems worse.It’s been somewhat of a running joke in a profoundly unfunny time.

Endless laments about the “quarantine 15” or “buy antibiotics 19,” referring to the number of pounds gained during lockdown.According to a June survey of 2,000 American adults by the weight loss program Nutrisystem, 76 percent of respondents gained weight, up to 16 pounds, between mid-March and July. And 63 percent said that losing weight was a priority, post quarantine.The difference between losers, gainers and maintainers during the zithromax, experts say, is largely dependent on your mind-set. How you approach a new set of circumstances and cope with change.One of the many challenges of buy antibiotics was the abrupt change to day-to-day schedules.

People began working from home, if they had work at all, in many cases joined by their kids. Gyms, recreation centers and parks closed, curbing exercise routines. Stress levels skyrocketed for many, with baking, eating and drinking becoming major outlets and means of reward.

Indeed, studies show a link between high stress levels and overeating.“When the environment and your routine changes, you can use it as an opportunity to say ‘I’ll drink at home,’ or ‘I deserve to treat myself well in those really tough times,’” said Gary D. Foster, chief scientific officer of WW (formerly Weight Watchers). €œThis is where mind-set is so important.

It’s how you view things, how you position the situation, your sense of self-worth, and how you treat yourself.”“After that initial period, there was a subset of people who said, ‘This is an opportunity to take care of myself,” he said. €œThat different way of thinking about the process is really powerful.”Susan Abrams Torney, 62, a dental office manager in Delray Beach, Fla., had an epiphany early on in the zithromax when she realized that she could use the time off from work to make a positive change in her life. Sheltering in place worked in her favor.

€œIt took the ‘I don’t have time to exercise’ excuse out of the equation,’” said Ms. Torney, who has lost 30 pounds since the beginning of the year.She credits her grandchildren with motivating her. €œBefore I started on the journey, if I sat on the floor I felt like I needed a crane to get me back up again,” she said.During lockdown, she finally broke open the Wii video game console her children had given her for her 50th birthday and started playing Wii tennis and also going for “sanity” walks with friends around her community her only form of in-person socialization.It also helped that she was no longer able to go out for meals and had to cook at home, where she prepared healthy meals for herself, like chicken, fish and salads.

Rather than vodka on the rocks, her previous cocktail of choice, she diluted her vodka with mineral water and a splash of cranberry juice. €œQuarantine gave me time to be creative with the meals I was eating,” she said.Another reason many people gained weight is that they stopped planning their meals in advance. Without planning ahead, they would just grab whatever was available.“Before shelter in place they would prep their meals and sort of had a plan,” said Dr.

Rami Bailony, the co-founder and chief executive of Enara Health, a digital membership weight loss clinic. €œOnce buy antibiotics hit they thought they could cook something up that was healthy. But once you’re thinking about eating in the moment you tend to go with what’s expedient.”When the zithromax started, Mindy Bachrach, 58, a home health occupational therapist in Henderson, Nev., soothed herself with sugary and high fat foods.

As an essential worker, she was working pretty much all of her waking hours. €œI have a weird job, I eat in my car all the time,” she said. €œIf I don’t prepare very carefully, I end up getting fast food, which I don’t even like.”After two weeks, her pants were tighter.

As someone who had lost and regained dozens of pounds in her life, she panicked. €œI decided I had to do something,” she said. €œIf I didn’t, things were going to get out of control.”She went on the Whole 30 plan, which eliminates processed foods, sugar and sugar substitutes, alcohol, grains, dairy and most legumes.

She also stopped weighing herself. €œI wanted the focus to be on how foods made me feel and not weight loss itself,” she said. Thirty days later, she stepped on the scale and was down 20 pounds.Randy Garcia, 42, of Dallas, has lost 104 pounds since July, 2019, with the help of Enara, which connects members with a doctor, dietitian and exercise coach and costs $400 a month.Mr.

Garcia, who once weighed 400 pounds and works in I.T., said his usual pre-Enara ritual included trips to Chick-fil-A or McDonald’s with his wife and three kids. That became impossible as the lockdowns spread, so he began cooking at home. €œIt’s been an experimental process,” he said.

€œYou have no options, so you have to do this.”Mr. Garcia had tried everything from injections of human chorionic gonadotropin, or HCG, to a Keto diet to lose weight. He would, but it invariably crept back.

Finally, he had enough and tried Enara, which his insurance mostly covers.“I needed to do something because my kids look at me as a role model,” he said. €œI don’t want to look in the mirror and keep saying ‘I have to do something about this’ or go into a store and not being able to find a size that fits me.” The lack of options also helped Leeanne Owens, 52, who has lost 18 pounds since the end of May through intermittent fasting and calorie counting.

Doxycycline vs zithromax

IntroductionIn recent years, many studies have been published doxycycline vs zithromax 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 Several projects have 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 doxycycline vs zithromax 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 doxycycline vs zithromax 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 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 doxycycline vs zithromax 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 doxycycline vs zithromax 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 doxycycline vs zithromax and from the paediatric to 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 doxycycline vs zithromax 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 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 doxycycline vs zithromax 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 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 doxycycline vs zithromax 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 doxycycline vs zithromax 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 of discussion, revised into doxycycline vs zithromax 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 doxycycline vs zithromax and incorporating their input, 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 commercial ultrasound is performed at the request of the parents.Another way DSD can be diagnosed before birth is when invasive prenatal genetic doxycycline vs zithromax 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 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 doxycycline vs zithromax. NIPT screens for CNVs in the fetus. However, depending on legal restrictions and/or ethical considerations, doxycycline vs zithromax 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 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 doxycycline vs zithromax 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 doxycycline vs zithromax 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 doxycycline vs zithromax 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 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 doxycycline vs zithromax.

Termination of pregnancy can be considered, for instance, in a syndromic form of DSD with multiple malformations, but when the doxycycline vs zithromax 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 look doxycycline vs zithromax 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 doxycycline vs zithromax 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, 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 (eg, ‘your baby’) as long as sex assignment is pending.An algorithm for diagnostic evaluation doxycycline vs zithromax 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 that >30% of individuals who doxycycline vs zithromax 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 doxycycline vs zithromax 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 you can check here years, many studies have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected where can i buy zithromax z pak 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 Several projects have 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 European agreement on harmonisation of clinical management where can i buy zithromax z pak 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 where can i buy zithromax z pak 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 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 where can i buy zithromax z pak 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 DSD.22 23 Therefore, a section of the Dutch-Flemish guideline was written where can i buy zithromax z pak 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 where can i buy zithromax z pak 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 where can i buy zithromax z pak tissue is challenging and would benefit from international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group 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 where can i buy zithromax z pak 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 where can i buy zithromax z pak 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 institutional access where can i buy zithromax z pak.

Based on this, a draft guideline was produced that was in line with the international principles of good diagnostic care in DSD. This draft where can i buy zithromax z pak was discussed by the 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 where can i buy zithromax z pak 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 commercial ultrasound is performed at the request of the parents.Another way DSD can be where can i buy zithromax z pak 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 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 where can i buy zithromax z pak 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 and Y chromosomes are not always included in NIPT analysis and reports where can i buy zithromax z pak. 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 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 where can i buy zithromax z pak 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 ultrasound findings and the limitations where can i buy zithromax z pak of this technique. The procedure(s) that can be followed, including the risks associated with an amniocentesis.

And the type of information genetic where can i buy zithromax z pak 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 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 where can i buy zithromax z pak or not to continue the pregnancy.

Termination of where can i buy zithromax z pak 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 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 look like and uncertainty about the diagnosis, treatment where can i buy zithromax z pak 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 where can i buy zithromax z pak a 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 where can i buy zithromax z pak 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 (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 that >30% of individuals who have a DSD have additional structural anomalies, with cardiac and where can i buy zithromax z pak 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 before the expected delivery.Disorders/differences of where can i buy zithromax z pak 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..

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Dec. 3, 2021 -- As Senate Democrats debate the Build Back Better Act, which includes measures that would lower prescription drug costs for consumers, a new Urban Institute study finds that 12.8 million adults delayed getting or didn’t get needed prescription drugs because of cost.The people who deferred or went without these prescription drugs included 2.3 million elderly Medicare beneficiaries, 3.8 million nonelderly adults with private insurance, 1.1 million Medicaid recipients, and 4.1 million adults who were uninsured at any point in the prior year.The nationally representative data came from 2018-2019, before the beginning of the buy antibiotics zithromax. The Urban Institute’s researchers used information from the Medical Expenditure Panel Survey done by the Agency for Healthcare Research and Quality.According to the study, around 1 in 10 adults uninsured all year (9.5%) or part of the year (11.6%) had unmet prescription drug needs, compared with 4.9% of Medicare enrolees, 3% of nonelderly privately insured adults, and 5.6% of nonelderly adults with Medicaid. Among Medicare beneficiaries and privately insured adults, unmet prescription drug needs were most common among women, people with low incomes, and people with multiple chronic conditions.

More than 6 million adults with Medicare or private insurance delayed getting or went without needed medications because of the cost.Nearly all Medicare members and 82% of privately insured nonelderly adults with unmet drug needs had one or more chronic conditions such as high blood pressure, high cholesterol, stroke, diabetes, arthritis, and respiratory illnesses. The study points out that when people are diagnosed with such conditions and can’t get the drugs they need, they’re likely to have poor outcomes.A larger portion of Medicare members with multiple chronic conditions (5.6%) had trouble paying for their prescription drugs than those with no conditions (1.5%) or just one condition (1.7%), the study found. Of nonelderly adults with private insurance, 5.4% with multiple conditions reported not being able to afford their drugs, versus 1.5% who had no conditions and 2.3% who had one condition. Drug Costs and Ability to PayOverall, prescription drugs accounted for up to 14% of national health spending in the study period, the study said.

By contrast, medications accounted for nearly 22% of out-of-pocket costs for Medicare members and about 17% of costs for privately insured people.Like spending on other types of health care, out-of-pocket spending on prescription drugs is highly concentrated among certain groups of people. Of privately insured nonelderly adults, 5.3% spent above 1% of their family income on prescription drugs. 6.1% reported out-of-pocket spending above $500. 2.3%, more than $1,000.

And 0.8%, more than $2,000.Out-of-pocket spending on prescription drugs exceeded 1% of household income among 25.4% of Medicare beneficiaries, and 3.4% spent more than 10% of their household income on drugs. Personal spending on drugs exceeded $500 for 21.5% of this cohort. 8.9% of Medicare members spent over $1,000. And 2.7%, over $2,000.

More than 7% of Medicare beneficiaries with unmet prescription drug needs reported spending over $2,000. Just 2.3% of privately insured nonelderly adults with unmet drug needs reported the same.The Build Back Better Act Would Have Major ImpactThe 1.3 million Medicare beneficiaries who spent the most on prescription drugs would be directly impacted by the Build Back Better Act, which caps prescription drug spending for Medicare members at $2,000.Among other things, the report said, the act would:Allow Medicare to negotiate prices for certain high-priced drugs covered by Parts B and DLimit beneficiary cost sharing for insulin to $35 per month for people with Medicare and commercial plans.Lower coinsurance in Part D’s initial phase from 25% to 23%Establish mandatory rebates for drugs covered by Medicare with prices that increase faster than inflationIncrease incentives for Part D to negotiate lower prices with manufacturersWhat’s more, passage of the Build Back Better Act would make health insurance affordable for more of the uninsured, including people who live in states that chose not to expand Medicaid under the Affordable Care Act, the study notes. The coverage expansion would make it easier for currently uninsured people to afford the prescription drugs they need.By Robert PreidtHealthDay ReporterFRIDAY, Dec. 3, 2021 (HealthDay News) -- Older Black Americans are much more likely to have good hearing than white Americans, and the difference is especially notable among men, a new study shows.“We found that among males, non-Hispanic Black Americans have a prevalence of hearing loss that is similar to non-Hispanic white Americans who are 10 years younger,” co-author ZhiDi Deng, a pharmacy student at the University of Toronto, said in a school news release.

Learning more about racial/ethnic differences in hearing loss may help improve prevention efforts, according to the authors. They found that Black Americans 65 and older were nearly half as likely to report serious hearing loss in 2016 and 2017 (about 9%) as white Americans in that age group (about 15%). After accounting for age, sex, income and education levels, the researchers concluded that older Black Americans were 91% less likely to have hearing loss than white people in the same age group, according to the study. The results were recently published in the Journal of Speech, Language, and Hearing Research.“The racial/ethnic difference in hearing problems is intriguing,” said study co-author Esme Fuller-Thomson, director of University of Toronto’s Institute of Life Course and Aging.“Hearing loss is one of the most common chronic problems affecting older adults," she said in the release.

"Those with hearing loss tend to have lower quality of life and a higher prevalence of depression and hospitalization. Understanding the causes and drivers behind the racial/ethnic differences in hearing loss can help us design better preventative strategies as the Baby Boom cohort ages.”Relevant factors may include racial/ethnic differences in diet, smoking, noise exposure and bone density, the researchers suggested.“More research is needed to understand the extraordinary differences in hearing,” Fuller-Thomson said.More informationThe U.S. National Institute on Aging has more about hearing loss.SOURCE. University of Toronto, news release, Nov.

24, 2021Anne Murray Mozingo of York, ME, was a new mother, still nursing her 17-month-old son in the spring of 2000, when she woke one morning to find her husband, Bill, on the bathroom floor. He had died at 42 in the early morning hours from a brain aneurysm. Just like that, her best friend and life partner was gone, and she was left to raise her child alone.Overwhelmed with emotions, Mozingo tried to shield her toddler from her sorrow. She would wait until he was asleep and pour out her anguish in private by screaming, crying, and punching pillows.“I remember midnight being my time,” she says.

€œI would do this thing -- I would lock myself in a bathroom and pretend I was chopping down trees. It was a way to move really desperate, depressed energy out of my body.”But after 8 months, Mozingo’s family members began wondering if she had been in mourning for too long.“That was the first time the culture came in and said, ‘You should be better,’” Mozingo says.Roadblocks to ReliefFor a small but significant number of people, grief can cut so deep that getting through a single day seems impossible. They remain in the initial phase of shock and disbelief a year or more after their loss. This is especially true when there are complicating factors surrounding the death.Though wounded by her family’s comments, Mozingo sought counseling.

To her surprise, she had difficulty convincing prospective therapists that she had a problem. The first three were dismissive.“One person said, ‘You’re fine. You got here on time, your blouse is ironed, and you drove yourself here.’ And I said, ‘My mother ironed this blouse, and she drove me, so (expletive) you.’”One therapist told her she just needed to get a job and get out of the house.“Wyatt was 2. That was a real big slap in the face because I thought I had the most important job in the world, raising him.”The fourth counselor recognized how hard Mozingo was struggling.

She diagnosed Mozingo with a condition called complicated grief. The grueling demands of solo parenting had left Mozingo little time to process her sudden widowhood.“I was on deck all day with a human,” Mozingo says. €œIt wasn’t like I could slide at my job a little bit. I couldn’t take time off.

I didn’t get to grieve hourly, daily, readily.”New Diagnosis for the BereavedComplicated grief was first identified by researchers in 1993. Seven years later, the condition -- now called prolonged grief disorder (PGD) -- was added to the Diagnostic and Statistical Manual of Mental Disorders (DSM).Prolonged grief disorder is when a person’s extreme longing or preoccupation with the dead prevents them from carrying on with their daily lives. The other eight symptoms are emotional numbness, intense loneliness and isolation, identity disruption (feeling like part of oneself has died), sense of disbelief about the death, avoiding reminders of the death, intense emotional pain (anger, bitterness, sorrow), difficulty reintegrating into daily life, and feeling that life is meaningless. PGD is diagnosed in adults if the functional impairment lasts along with at least three additional symptoms for more than a year.

For children, it’s 6 months.Some mental health practitioners were initially wary of the new DSM classification out of concern that it stigmatizes a natural response. But Amy McCarthy, a clinical social worker at Boston Children’s Hospital, believes it offers a framework for medical providers and family members to talk about grief. A clinical diagnosis also paves the way for insurance coverage.“To submit a claim to insurance, you need to prove there is a medical necessity,” McCarthy says. €œThere is this argument that, of course people who are grieving can benefit from therapeutic support.

But if we don’t have language to support that, then it’s much harder for those people to access help, and it’s already so difficult to gain access to mental health support.”Not All Grief Is EqualNatalia Skritskaya, a research scientist and grief therapist who co-founded Columbia University’s Center for Prolonged Grief in 2013, says prolonged grief can be “very disabling” and warrants treatment.“Grief is universal and natural, I agree, but not prolonged grief,” Skritskaya says. €œIn a way, you could think about that argument applying to, let’s say, . It’s very natural to get a cold or flu. It’s universally human to get sick, but should we not do anything about it?.

€Based on three separate 5-year clinical trials, the center has developed a treatment approach based on a mix of cognitive behavioral therapy, prolonged exposure therapy used for PTSD, attachment theory, mindfulness, and a variety of other techniques. It is a short-term, focused intervention that typically takes 4 months of weekly psychotherapy sessions.Complicated GriefYou can’t know how you’ll respond to the death of a loved one until it happens. Donna George, a retired bereavement counselor in Ithaca, NY, knows from experience that the single most important determinant may be the state of the relationship you had or any unusual circumstances behind the death. €œThere has to be mitigating circumstances that make it prolonged,” George, who worked in hospice for 25 years, says.

€œThose factors may be how the person died, if there was unfinished business with the person who died, the age of the person who died, and the mental health” of the survivor.For instance, George led an online grief group last year for women who lost parents to the antibiotics. She saw their anguish at being denied the chance to say goodbye in person and to hold funerals.“In our culture, we get through something like that by being around others and having people hug us and show us support,” George says. With the zithromax still raging, “I think we’re going to see more and more prolonged grief.”Life After LossAfter her husband’s death, Mozingo feared her grief might destroy her. She eventually regained her emotional balance through medications, supplements, therapies, support groups, and a yearlong immersion in a study program of interdisciplinary spiritual practices.

And Mozingo harnessed her hard-earned coping skills as a bereavement group facilitator for young widows. Today, Mozingo is happily remarried. In 2021, her son graduated from Hofstra University with a degree in international finance. Long gone are the days of locking herself in the bathroom, pretending to chop wood to release her grief.

But Bill is never far from her thoughts. She recently texted a friend a photograph of them at their wedding reception. It would have been their 27th anniversary. Mozingo cherished the bittersweet memory but didn’t dwell on it.“Grief isn’t something you get over.

Grief is something you learn to live with,” George, the bereavement counselor, says. But support and therapy “can give them permission to move forward and find joy in their life again.”.

Dec visit this page where can i buy zithromax z pak. 3, 2021 -- As Senate Democrats debate the Build Back Better Act, which includes measures that would lower prescription drug costs for consumers, a new Urban Institute study finds that 12.8 million adults delayed getting or didn’t get needed prescription drugs because of cost.The people who deferred or went without these prescription drugs included 2.3 million elderly Medicare beneficiaries, 3.8 million nonelderly adults with private insurance, 1.1 million Medicaid recipients, and 4.1 million adults who were uninsured at any point in the prior year.The nationally representative data came from 2018-2019, before the beginning where can i buy zithromax z pak of the buy antibiotics zithromax. The Urban Institute’s researchers used information from the Medical Expenditure Panel Survey done by the Agency for Healthcare Research and Quality.According to the study, around 1 in 10 adults uninsured all year (9.5%) or part of the year (11.6%) had unmet prescription drug needs, compared with 4.9% of Medicare enrolees, 3% of nonelderly privately insured adults, and 5.6% of nonelderly adults with Medicaid.

Among Medicare beneficiaries and privately insured adults, unmet prescription drug needs were most common among women, people where can i buy zithromax z pak with low incomes, and people with multiple chronic conditions. More than 6 million adults with Medicare or private insurance delayed getting or went without needed medications because of the cost.Nearly all Medicare members and 82% of privately insured nonelderly adults with unmet drug needs had where can i buy zithromax z pak one or more chronic conditions such as high blood pressure, high cholesterol, stroke, diabetes, arthritis, and respiratory illnesses. The study points out that when people are diagnosed with such conditions and can’t get the drugs they need, they’re likely to have poor outcomes.A larger portion of Medicare members with multiple chronic conditions (5.6%) had trouble paying for their prescription drugs than those with no conditions (1.5%) or just one condition (1.7%), the study found.

Of nonelderly adults with private insurance, 5.4% with multiple conditions reported not where can i buy zithromax z pak being able to afford their drugs, versus 1.5% who had no conditions and 2.3% who had one condition. Drug Costs and Ability to PayOverall, prescription drugs accounted for up to 14% of national health spending in the study period, the study said. By contrast, medications accounted for nearly 22% of out-of-pocket costs for Medicare members and about 17% of costs for privately insured people.Like spending on other types of health care, out-of-pocket spending where can i buy zithromax z pak on prescription drugs is highly concentrated among certain groups of people.

Of privately insured nonelderly adults, 5.3% spent above 1% of their family income on prescription where can i buy zithromax z pak drugs. 6.1% reported out-of-pocket spending above $500. 2.3%, more than $1,000 where can i buy zithromax z pak.

And 0.8%, more than $2,000.Out-of-pocket spending on prescription drugs exceeded 1% of household income among 25.4% of Medicare beneficiaries, and 3.4% spent more than 10% of their household income on drugs. Personal spending on drugs exceeded $500 for 21.5% of this where can i buy zithromax z pak cohort. 8.9% of Medicare members spent over $1,000 where can i buy zithromax z pak.

And 2.7%, over $2,000. More than 7% of Medicare beneficiaries with unmet prescription drug needs where can i buy zithromax z pak reported spending over $2,000. Just 2.3% of privately insured nonelderly adults with unmet drug needs reported the same.The Build Back Better Act Would Have Major ImpactThe 1.3 million Medicare beneficiaries who spent the most on prescription drugs would be directly impacted by the Build Back Better Act, which caps prescription drug spending for Medicare members at $2,000.Among other things, the report said, the act would:Allow Medicare to negotiate prices for certain high-priced drugs covered by Parts B and DLimit beneficiary cost sharing for insulin to $35 per month for people with Medicare and commercial plans.Lower coinsurance in Part D’s initial phase from 25% to 23%Establish mandatory rebates for drugs covered by Medicare with prices that increase faster than inflationIncrease incentives for Part D to negotiate lower prices with manufacturersWhat’s more, passage of the Build Back Better Act would make health insurance affordable for more of the uninsured, including people who live in states that chose not to expand Medicaid under the Affordable Care Act, the study notes.

The coverage expansion would make it easier for currently where can i buy zithromax z pak uninsured people to afford the prescription drugs they need.By Robert PreidtHealthDay ReporterFRIDAY, Dec. 3, 2021 (HealthDay News) -- Older Black Americans are much more likely to have good hearing than white Americans, and the difference is especially notable among men, a new study shows.“We found that among males, non-Hispanic Black Americans have a prevalence of hearing loss that is similar to non-Hispanic white Americans who are 10 years younger,” co-author ZhiDi Deng, where can i buy zithromax z pak a pharmacy student at the University of Toronto, said in a school news release. Learning more about racial/ethnic differences in hearing loss may help improve prevention efforts, according to the authors.

They found that Black Americans 65 and older were nearly half as likely to report serious hearing where can i buy zithromax z pak loss in 2016 and 2017 (about 9%) as white Americans in that age group (about 15%). After accounting for age, sex, income and education levels, the researchers concluded that older Black Americans were 91% less likely to have hearing loss than white people in the same age group, according to the study. The results were recently published in the Journal of Speech, Language, and Hearing Research.“The racial/ethnic difference in hearing problems is intriguing,” said study co-author Esme Fuller-Thomson, director of University of Toronto’s Institute of Life where can i buy zithromax z pak Course and Aging.“Hearing loss is one of the most common chronic problems affecting older adults," she said in the release.

"Those with hearing loss tend to have lower quality of life and a higher prevalence of depression where can i buy zithromax z pak and hospitalization. Understanding the causes and drivers behind the racial/ethnic differences in hearing loss can help us design better preventative strategies as the Baby Boom cohort ages.”Relevant factors may include racial/ethnic differences in diet, smoking, noise exposure and bone density, the researchers suggested.“More research is needed to understand the extraordinary differences in hearing,” Fuller-Thomson said.More informationThe U.S. National Institute on Aging has more where can i buy zithromax z pak about hearing loss.SOURCE.

University of Toronto, news release, where can i buy zithromax z pak Nov. 24, 2021Anne Murray Mozingo of York, ME, was a new mother, still nursing her 17-month-old son in the spring of 2000, when she woke one morning to find her husband, Bill, on the bathroom floor. He had died at 42 in where can i buy zithromax z pak the early morning hours from a brain aneurysm.

Just like that, her best friend and life partner was gone, and she was left to raise her child alone.Overwhelmed with emotions, Mozingo tried to shield her toddler from her sorrow. She would where can i buy zithromax z pak wait until he was asleep and pour out her anguish in private by screaming, crying, and punching pillows.“I remember midnight being my time,” she says. €œI would do this thing -- I would lock myself in where can i buy zithromax z pak a bathroom and pretend I was chopping down trees.

It was a way to move really desperate, depressed energy out of my body.”But after 8 months, Mozingo’s family members began wondering if she had been in mourning for too long.“That was the first time the culture came in and said, ‘You should be better,’” Mozingo says.Roadblocks to ReliefFor a small but significant number of people, grief can cut so deep that getting through a single day seems impossible. They remain in the initial phase of shock and disbelief a year or more where can i buy zithromax z pak after their loss. This is especially true when there are complicating factors surrounding the death.Though wounded by her family’s comments, Mozingo sought counseling.

To her where can i buy zithromax z pak surprise, she had difficulty convincing prospective therapists that she had a problem. The first three were dismissive.“One person said, ‘You’re where can i buy zithromax z pak fine. You got here on time, your blouse is ironed, and you drove yourself here.’ And I said, ‘My mother ironed this blouse, and she drove me, so (expletive) you.’”One therapist told her she just needed to get a job and get out of the house.“Wyatt was 2.

That was a real big slap in the face because I thought I had the most important job in the world, raising him.”The fourth counselor where can i buy zithromax z pak recognized how hard Mozingo was struggling. She diagnosed Mozingo with a condition called complicated grief. The grueling demands of solo parenting had left Mozingo little time to process her sudden widowhood.“I was on deck all where can i buy zithromax z pak day with a human,” Mozingo says.

€œIt wasn’t like I could slide at my job a where can i buy zithromax z pak little bit. I couldn’t take time off. I didn’t get to grieve hourly, daily, readily.”New where can i buy zithromax z pak Diagnosis for the BereavedComplicated grief was first identified by researchers in 1993.

Seven years later, the condition -- now called prolonged grief disorder (PGD) -- was added to the Diagnostic and Statistical Manual of Mental Disorders (DSM).Prolonged grief disorder is when a person’s extreme longing or preoccupation with the dead prevents them from carrying on with their daily lives. The other eight symptoms where can i buy zithromax z pak are emotional numbness, intense loneliness and isolation, identity disruption (feeling like part of oneself has died), sense of disbelief about the death, avoiding reminders of the death, intense emotional pain (anger, bitterness, sorrow), difficulty reintegrating into daily life, and feeling that life is meaningless. PGD is diagnosed in where can i buy zithromax z pak adults if the functional impairment lasts along with at least three additional symptoms for more than a year.

For children, it’s 6 months.Some mental health practitioners were initially wary of the new DSM classification out of concern that it stigmatizes a natural response. But Amy where can i buy zithromax z pak McCarthy, a clinical social worker at Boston Children’s Hospital, believes it offers a framework for medical providers and family members to talk about grief. A clinical diagnosis also paves the way for insurance coverage.“To submit a where can i buy zithromax z pak claim to insurance, you need to prove there is a medical necessity,” McCarthy says.

€œThere is this argument that, of course people who are grieving can benefit from therapeutic support. But if we don’t have language to where can i buy zithromax z pak support that, then it’s much harder for those people to access help, and it’s already so difficult to gain access to mental health support.”Not All Grief Is EqualNatalia Skritskaya, a research scientist and grief therapist who co-founded Columbia University’s Center for Prolonged Grief in 2013, says prolonged grief can be “very disabling” and warrants treatment.“Grief is universal and natural, I agree, but not prolonged grief,” Skritskaya says. €œIn a way, you could think about that argument applying to, let’s say, .

It’s very natural to get a cold where can i buy zithromax z pak or flu. It’s universally human where can i buy zithromax z pak to get sick, but should we not do anything about it?. €Based on three separate 5-year clinical trials, the center has developed a treatment approach based on a mix of cognitive behavioral therapy, prolonged exposure therapy used for PTSD, attachment theory, mindfulness, and a variety of other techniques.

It is a short-term, focused intervention that typically where can i buy zithromax z pak takes 4 months of weekly psychotherapy sessions.Complicated GriefYou can’t know how you’ll respond to the death of a loved one until it happens. Donna George, a retired bereavement counselor in Ithaca, NY, knows from experience that the single most important determinant may be the state of the relationship you had or any unusual circumstances behind the death. €œThere has to be mitigating circumstances that make it prolonged,” where can i buy zithromax z pak George, who worked in hospice for 25 years, says.

€œThose factors may be how where can i buy zithromax z pak the person died, if there was unfinished business with the person who died, the age of the person who died, and the mental health” of the survivor.For instance, George led an online grief group last year for women who lost parents to the antibiotics. She saw their anguish at being denied the chance to say goodbye in person and to hold funerals.“In our culture, we get through something like that by being around others and having people hug us and show us support,” George says. With the where can i buy zithromax z pak zithromax still raging, “I think we’re going to see more and more prolonged grief.”Life After LossAfter her husband’s death, Mozingo feared her grief might destroy her.

She eventually regained her emotional balance through medications, supplements, therapies, support groups, and a yearlong immersion in a study program of interdisciplinary spiritual practices. And Mozingo harnessed her hard-earned coping where can i buy zithromax z pak skills as a bereavement group facilitator for young widows. Today, Mozingo where can i buy zithromax z pak is happily remarried.

In 2021, her son graduated from Hofstra University with a degree in international finance. Long gone are the days of locking herself in the bathroom, pretending to chop wood where can i buy zithromax z pak to release her grief. But Bill is never far from her thoughts.

She recently texted a friend a photograph of them at their where can i buy zithromax z pak wedding reception. It would have been their 27th where can i buy zithromax z pak anniversary. Mozingo cherished the bittersweet memory but didn’t dwell on it.“Grief isn’t something you get over.

Grief is something you where can i buy zithromax z pak learn to live with,” George, the bereavement counselor, says. But support and therapy “can give them permission to move forward and find joy in their life again.”.

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