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Further, the FFS claims and payments sampled for data processing and medical record cheap propecia pills reviews will serve as the basis for the eligibility reviews. Individuals for whom the state made the FFS claim or payments will have their underlying eligibility reviewed. In addition to the Federal Review Contractor conducting a data processing and medical record review of the FFS claims and payments, the FFS sample selected from the state-submitted universe will also be leveraged to support the PERM eligibility reviews.
The Federal Eligibility Review Contractor will review the underlying eligibility of individuals whose FFS claims and payments were sampled as part of the PERM FFS sample cheap propecia pills. Form Number. CMS-10166 (OMB control number.
Affected Public. State, Local, or Tribal Governments. Number of Respondents.
Total Annual Hours. 56,100. (For policy questions regarding this collection contact Daniel Weimer at 410-786-5240.) 3.
Type of Information Collection Request. Reinstatement without change of a currently approved collection. Title of Information Collection.
Medicaid and Children's Health Insurance (CHIP) Managed Care Payments and Related Information. Use. The information collected from the selected States will be used by Federal contractors to conduct Medicaid and CHIP managed care data processing reviews on which State-specific improper payment rates will be calculated.
The quarterly capitation payments will provide the contractor with the actual claims to be sampled. The managed care contracts, rate schedules, and updates to both, will be used by the federal contractor when conducting the managed care claims reviews. Further, the managed care capitation payments sampled for data processing reviews will serve as the basis for the eligibility reviews.
Individuals for whom the state made the managed care capitation will have their underlying eligibility reviewed. Section 2(b)(1) of IPERA clarified that, when meeting IPIA and IPERA requirements, agencies must produce a statistically valid estimate, or an estimate that is otherwise appropriate using a methodology approved by the Director of the OMB. IPERIA further clarified requirements for agency reporting on actions to reduce improper payments and recover improper payments.
The collection of information is necessary for CMS to produce national improper payment rates for Medicaid and CHIP as required by Public Law 107-300. Form Number. CMS-10178 (OMB control number.
Affected Public. State, Local, or Tribal Governments. Number of Respondents.
Total Annual Hours. 19,550. (For policy questions regarding this collection contact Daniel Weimer at 410-786-5240.) 4.
Type of Information Collection Request. Reinstatement with change of a previously approved collection. Title of Information Collection.
Payment Error Rate MeasurementâState Medicaid and CHIP Eligibility. Use. The Payment Error Rate Measurement (PERM) program was developed to implement the requirements of the Improper Payments Information Act (IPIA) of 2002 (Pub.
L. 107-300), which requires the head of federal agencies to annually review all programs and activities that it administers to determine and identify any programs that are susceptible to significant erroneous payments. If programs are found to be susceptible to significant improper payments, then the agency must estimate the annual amount of erroneous payments, report those estimates to the Congress, and submit a report on actions the agency is taking to reduce improper payments.
IPIA was amended by Improper Payments Elimination and Recovery Act of 2010 (IPERA) (Pub. L. 111-204), the Improper Payments Elimination and Recovery Improvement Act of 2012 (IPERIA) (Pub.
L. 112-248), and the Payment Integrity Information Act of 2019 (PIIA) (Pub. L.
116-117). The eligibility case documentation collected from the States, through submission of hard copy case files and through access to state eligibility systems, will be used by CMS and its federal contractors to conduct eligibility case reviews on individuals who had claims paid on their behalf in order to determine the improper payment rate associated with Medicaid and CHIP eligibility to comply with the IPIA of 2002. Prior to the July 2017 Final Rule being published in response to the Affordable Care Act, states provided CMS only with information about their sampling and review process as well as the final review findings, which CMS has used in each PERM cycle to calculate IPIA-compliant state and federal improper payment rate for Medicaid and CHIP.
Given changes brought forth in the July 2017 Final Rule, states will no longer be required to develop eligibility-specific universes, conduct case reviews, and report findings to CMS. A federal contractor will utilize the claims (fee-for-service and managed care universes) to identify a sample of individuals and will be responsible for conducting case reviews to support the PERM measurement. Form Number.
CMS-10184 (OMB control number. 0938-1012). Frequency.
Quarterly. Affected Public. State, Local, or Tribal Governments.
Number of Respondents. 17. Total Annual Responses.
(For policy questions regarding this collection contact Daniel Weimer at 410-786-5240.) 5. Type of Information Collection Request. Revision of a currently approved collection.
Title of Information Collection. Medicare Fee-for-Service Prepayment Review of Medical Records. Use.
The Medical Review program is designed to prevent improper payments in the Medicare FFS program. Whenever possible, Medicare Administrative Contractors (MACs) are Start Printed Page 26923encouraged to automate this process. However, it may require the evaluation of medical records and related documents to determine whether Medicare claims are billed in compliance with coverage, coding, payment, and billing policies.
Addressing improper payments in the Medicare fee-for-service (FFS) program and promoting compliance with Medicare coverage and coding rules is a top priority for the CMS. Preventing Medicare improper payments requires the active involvement of every component of CMS and effective coordination with its partners including various Medicare contractors and providers. The information required under this collection is requested by Medicare contractors to determine proper payment, or if there is a suspicion of fraud.
Medicare contractors request the information from providers/suppliers submitting claims for payment when data analysis indicates aberrant billing patterns or other information which may present a vulnerability to the Medicare program. Form Number. CMS-10417.
Private Sector, State, Business, and Not-for Profits. Number of Respondents. 485,632.
Number of Responses. 485,632. Total Annual Hours.
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Nurse Amanda Blanc (left) and unit manager Emily Torres(SACRAMENTO) â Amanda Blanc is, quite literally, living the dream â working in her âdream positionâ at her âdream hospitalâ of UC Davis Medical Center.âBoth being an RN, and being at Davis, have been everything that I imagined it would be,â said Blanc, who was hired in April out of Samuel Merritt Universityâs nursing school.Gratitude HealsAs nurses, doctors and staff of UC Davis Health, you understand that gratitude has the power to heal.This holiday season, consider giving back in a meaningful way through the Gratitude Heals campaign with recommended you read a donation that improves and transforms the lives of colleagues, patients and community members.⢠The CARE Project â To enhance the health care environment and aid the healing and recovery of our patients⢠Patient Assistance Support Fund â To support our patients and families struggling with the financial hardship of hospitalization⢠Re-Igniting the Spirit of Caring Endowed Fund â To support each other in refreshing our body, mind and spirit⢠Child Life Program â To promote healing through art and music therapyShe has a lot to be thankful for this holiday season, which made her recent experience with a patient on the floor of Tower 4 ENT/Internal Medicine even more eye-opening.For several weeks, Blanc was the primary care nurse for a patient who was struggling with homelessness â buy brand propecia online a young adult around 30 years of age, just like Blanc.âThereâs a lot of things you learn in nursing school, care-wise, but you donât really learn the realities of the social aspect of nursing,â Blanc said.After bonding and connecting with this patient, Blanc wanted to do more for her and planned to purchase some basic hygiene and comfort items at the store, as her colleagues suggested she could do. But one day, she came into work and discovered the patient was ready to be discharged.It âbroke [her] heartâ not being able to make that quick shopping trip, so Blanc did the only thing she could think of. She went downstairs to the ATM in the pharmacy, and gave the patient a small amount of cash for sundries.âWhen we discharged her, we fixed her medically, but we didnât really fix the buy brand propecia online systemic issue of that socioeconomic struggle that she was going through,â Blanc explained.So she sought a way to aid other patients dealing with financial hardships. Her unit manager, Emily Torres, connected her with the Gratitude Heals campaign and the Patient Assistance Support Fund, which can help patients with a variety of necessities, ranging from electricity bills to gas money to a simple, hot meal.Blanc took her fundraising to social media because âthatâs what we do in this generation.â She shared her recent experience and asked friends and family to contribute to the fund, adding that she would match the first $250 donated in person or through Venmo.Within three days, she had raised more than $1,000 â and eventually wrote a check for $1,435 for the fund.
She was surprised and buy brand propecia online inspired by the outpouring of support.âIt made me realize it wasnât just me. So many people wanted to share and so many people wanted to help,â Blanc said. ÂBut sometimes they donât know the opportunities to help.âThatâs why she is encouraging her colleagues to learn more about the variety of funds under the Gratitude Heals campaign (see sidebar).âWe have been given so much, and we have so many opportunities to give back,â she said.A national group of researchers, led by a UC Davis Health team, has found that obesity can block the benefits of a stem cell transplant when it is used buy brand propecia online for treating blood cancers and other related disorders. UC Davis Health researchers found cancer patients with a high body mass index (BMI) fared poorly with stem cell therapies for blood-related disorders.The study examined what happens when stem cells from a healthy donor are transferred to an obese recipient after first conditioning with chemotherapy or radiation.
The treatment is known as allogenic hematopoietic stem cell transplantation buy brand propecia online (allo-HSCT). The group included clinical researchers from the Masonic Cancer Center at the University of Minnesota and the Tisch Cancer Institute at New Yorkâs Mt. Sinai. They used both mouse models and clinical data from human HSCT patients to examine the impact of obesity.
The researchers determined that obesity prompted serious complications, including increased inflammation and damage to the gastrointestinal system. The resulting problem, acute graft-versus-host disease (GVHD), reduced survival rates in both obese mice and humans. The findings were published online today in Science Translational Medicine. ÂWhat we found in obese mice and patients with a body mass index greater than 30 is that obesity had a net negative effect on the success of allo-HSCT treatments because of the increase in complications from gut inflammation,â said William Murphy, professor of dermatology and internal medicine at UC Davis Health and principle investigator on the study.
ÂOur findings suggest that obesity predisposes recipients to a âcytokine storm,â or severe inflammation, after the transplant that makes the GVHD worse.â Murphy and his colleagues observed that obesity markedly changed the gut microbiota (the âhealthy gutâ bacteria) in both the study mice and clinical subjects. Giving antibiotics to the obese mice could prevent some of the damage. ÂWe were surprised in this case that it was completely limited to acute GVHD of the gastrointestinal tract,â said Murphy. ÂUsually, other organs such as the liver, skin and lungs are affected.
We realized this could be due to a âleaky gutâ reported to occur in obesity that was made worse by prior conditioning used in HSCT. However, it is important to note that while some patterns were observed regarding the particular microbiota associated with the poor outcome, this is a very incomplete picture at this time, and more work is needed to determine exact mechanisms of action before extrapolating clinically.â While allo-HSCT has long been successful in treating blood cancers such leukemia, lymphoma and myelomas, it often involves high-intensity conditioning involving chemotherapy, radiation, or both. It is used to keep the body from rejecting the donated cells, but can cause major toxicities in the body. Unfortunately, it also can lead to GVHD, in which donor immune cells attack not only the cancer but the recipientâs organs as well.
The toxicity problem represents a major hurdle, not only for HSCT, but also when such approaches are applied in other types of cancer treatments known as immunotherapies. The researchers were surprised at how much obesity affected outcome, but only in the gut. In the preclinical mouse models, it was very rapid and serious. ÂThe severe immune responses we observed with GVHD and obesity parallel the effects we know about in other human immune responses involving a high body-mass index,â said Murphy.
ÂWhether itâs an acute viral like hair loss treatment, a life-threatening condition like sepsis, or even with some strong immunotherapy treatments, obesity can threaten what otherwise could be a good outcome due to the meta-inflammatory conditions it induces. Our results indicate that the altered microbiome may be a contributing factor and it is worth pursuing in further studies.â The study notes that despite the nationâs widespread obesity problem, its effect on various immune and disease processes remains poorly understood. There are likely multiple factors â such as the extent of fat deposits, how long obesity was present, the type of diet, and even the different types of conditioning used in HSCT â that need to be explored before the acute problems for obese patients undergoing specialized blood cancer treatments are more fully known. In addition to Murphy, other study authors included Lam T.
Khuat, Catherine T. Le, Chien-Chun Steven Pai, Robin R. Shields-Cutler, Shernan G. Holtan, Armin Rashidi, Sarah L.
Parker, Dan Knight, Jesus I. Luna, Cordelia Dunai, Ziming Wang, Ian R. Sturgill, Kevin Stoffel, Alexander A. Merleev, Shyam K.
More, Emanual Maverakis, Helen Raybould, Mingyi Chen, Robert J. Canter, Arta M. Monjazeb, Maneesh Dave, James L. M.
Ferrara, John E. Levine, Dan L. Longo, Mehrdad Abedi, and Bruce R. Blazar.
The study was funded by grants from the National Institutes of Health, UC Davis Comprehensive Cancer Center and the UC Davis Mouse Metabolic Phenotyping Center..
Nurse Amanda Blanc (left) and unit manager Emily Torres(SACRAMENTO) â Amanda Blanc is, quite literally, living the dream â working in her âdream positionâ at her âdream hospitalâ of UC Davis Medical Center.âBoth being an RN, and being at Davis, have been everything that I imagined it would be,â said Blanc, who was hired in April out of Samuel Merritt Universityâs nursing school.Gratitude HealsAs nurses, doctors and staff of UC Davis Health, you understand that gratitude has the power to heal.This holiday season, consider giving back in a meaningful way through the Gratitude Heals campaign with a donation that improves and transforms the lives of colleagues, patients and community members.⢠The CARE Project â To enhance the health care environment and aid the healing and recovery of our patients⢠Patient Assistance Support Fund â To support our patients and families struggling with the financial hardship of hospitalization⢠Re-Igniting the Spirit of Caring Endowed Fund â To support each other in refreshing our body, mind and spirit⢠Child Life Program â To promote healing through art and music therapyShe has a lot to be thankful for this holiday season, which made her recent experience with a patient Levitra best buy on the floor of Tower 4 ENT/Internal Medicine even more eye-opening.For several weeks, Blanc was the primary care nurse for a patient who was struggling with homelessness â a young adult around 30 years of age, cheap propecia pills just like Blanc.âThereâs a lot of things you learn in nursing school, care-wise, but you donât really learn the realities of the social aspect of nursing,â Blanc said.After bonding and connecting with this patient, Blanc wanted to do more for her and planned to purchase some basic hygiene and comfort items at the store, as her colleagues suggested she could do. But one day, she came into work and discovered the patient was ready to be discharged.It âbroke [her] heartâ not being able to make that quick shopping trip, so Blanc did the only thing she could think of. She went downstairs to the ATM in the pharmacy, and gave the patient a small amount of cash for sundries.âWhen we discharged her, we fixed her medically, but we didnât really fix the systemic issue of that socioeconomic struggle cheap propecia pills that she was going through,â Blanc explained.So she sought a way to aid other patients dealing with financial hardships. Her unit manager, Emily Torres, connected her with the Gratitude Heals campaign and the Patient Assistance Support Fund, which can help patients with a variety of necessities, ranging from electricity bills to gas money to a simple, hot meal.Blanc took her fundraising to social media because âthatâs what we do in this generation.â She shared her recent experience and asked friends and family to contribute to the fund, adding that she would match the first $250 donated in person or through Venmo.Within three days, she had raised more than $1,000 â and eventually wrote a check for $1,435 for the fund. She was surprised and cheap propecia pills inspired by the outpouring of support.âIt made me realize it wasnât just me.
So many people wanted to share and so many people wanted to help,â Blanc said. ÂBut sometimes they donât know the opportunities to help.âThatâs why she is encouraging her colleagues to learn more about the variety of funds under the Gratitude Heals campaign (see sidebar).âWe have been given so much, and we have so many opportunities to give back,â she said.A national group of researchers, led by a UC Davis Health team, has cheap propecia pills found that obesity can block the benefits of a stem cell transplant when it is used for treating blood cancers and other related disorders. UC Davis Health researchers found cancer patients with a high body mass index (BMI) fared poorly with stem cell therapies for blood-related disorders.The study examined what happens when stem cells from a healthy donor are transferred to an obese recipient after first conditioning with chemotherapy or radiation. The treatment cheap propecia pills is known as allogenic hematopoietic stem cell transplantation (allo-HSCT). The group included clinical researchers from the Masonic Cancer Center at the University of Minnesota and the Tisch Cancer Institute at New Yorkâs Mt.
Sinai. They used both mouse models and clinical data from human HSCT patients to examine the impact of obesity. The researchers determined that obesity prompted serious complications, including increased inflammation and damage to the gastrointestinal system. The resulting problem, acute graft-versus-host disease (GVHD), reduced survival rates in both obese mice and humans. The findings were published online today in Science Translational Medicine.
ÂWhat we found in obese mice and patients with a body mass index greater than 30 is that obesity had a net negative effect on the success of allo-HSCT treatments because of the increase in complications from gut inflammation,â said William Murphy, professor of dermatology and internal medicine at UC Davis Health and principle investigator on the study. ÂOur findings suggest that obesity predisposes recipients to a âcytokine storm,â or severe inflammation, after the transplant that makes the GVHD worse.â Murphy and his colleagues observed that obesity markedly changed the gut microbiota (the âhealthy gutâ bacteria) in both the study mice and clinical subjects. Giving antibiotics to the obese mice could prevent some of the damage. ÂWe were surprised in this case that it was completely limited to acute GVHD of the gastrointestinal tract,â said Murphy. ÂUsually, other organs such as the liver, skin and lungs are affected.
We realized this could be due to a âleaky gutâ reported to occur in obesity that was made worse by prior conditioning used in HSCT. However, it is important to note that while some patterns were observed regarding the particular microbiota associated with the poor outcome, this is a very incomplete picture at this time, and more work is needed to determine exact mechanisms of action before extrapolating clinically.â While allo-HSCT has long been successful in treating blood cancers such leukemia, lymphoma and myelomas, it often involves high-intensity conditioning involving chemotherapy, radiation, or both. It is used to keep the body from rejecting the donated cells, but can cause major toxicities in the body. Unfortunately, it also can lead to GVHD, in which donor immune cells attack not only the cancer but the recipientâs organs as well. The toxicity problem represents a major hurdle, not only for HSCT, but also when such approaches are applied in other types of cancer treatments known as immunotherapies.
The researchers were surprised at how much obesity affected outcome, but only in the gut. In the preclinical mouse models, it was very rapid and serious. ÂThe severe immune responses we observed with GVHD and obesity parallel the effects we know about in other human immune responses involving a high body-mass index,â said Murphy. ÂWhether itâs an acute viral like hair loss treatment, a life-threatening condition like sepsis, or even with some strong immunotherapy treatments, obesity can threaten what otherwise could be a good outcome due to the meta-inflammatory conditions it induces. Our results indicate that the altered microbiome may be a contributing factor and it is worth pursuing in further studies.â The study notes that despite the nationâs widespread obesity problem, its effect on various immune and disease processes remains poorly understood.
There are likely multiple factors â such as the extent of fat deposits, how long obesity was present, the type of diet, and even the different types of conditioning used in HSCT â that need to be explored before the acute problems for obese patients undergoing specialized blood cancer treatments are more fully known. In addition to Murphy, other study authors included Lam T. Khuat, Catherine T. Le, Chien-Chun Steven Pai, Robin R. Shields-Cutler, Shernan G.
Holtan, Armin Rashidi, Sarah L. Parker, Dan Knight, Jesus I. Luna, Cordelia Dunai, Ziming Wang, Ian R. Sturgill, Kevin Stoffel, Alexander A. Merleev, Shyam K.
More, Emanual Maverakis, Helen Raybould, Mingyi Chen, Robert J. Canter, Arta M. Monjazeb, Maneesh Dave, James L. M. Ferrara, John E.
Levine, Dan L. Longo, Mehrdad Abedi, and Bruce R. Blazar. The study was funded by grants from the National Institutes of Health, UC Davis Comprehensive Cancer Center and the UC Davis Mouse Metabolic Phenotyping Center..
How should I take Propecia?
Take finasteride tablets by mouth. Swallow the tablets with a drink of water. You can take Propecia with or without food. Take your doses at regular intervals. Do not take your medicine more often than directed.
Contact your pediatrician or health care professional regarding the use of Propecia in children. Special care may be needed.
Overdosage: If you think you have taken too much of Propecia contact a poison control center or emergency room at once.
NOTE: Propecia is only for you. Do not share Propecia with others.
Propecia and male infertility
People in mandatory propecia and male infertility Cheap cialis 20mg isolation will have access to around the clock wellbeing and mental health support and there will be increased access to services for parents, young people and multicultural communities who are struggling during the lockdown. As part of a joint Commonwealth and NSW Government package worth $17.35 million, NSW will provide $5.1m for a range of mental health services across NSW.Treasurer Dominic Perrottet said our top priority is keeping people safe during the propecia, and not just from the current hair loss treatment outbreak."We know this will be a very difficult period for many, the additional funding will provide more mental health support particularly for young people and families."Minister for Mental Health Bronnie Taylor said the hair loss treatment investment will enable providers to immediately increase their support during this period."Looking after your mental wellbeing is vital during this time and with thousands of people and families in isolation, access to services 24 hours 7 days a week is hugely important," Mrs Taylor said"We know this can be a stressful time for families, parents and children, and these new and existing services available now 24 hours 7 days a week, means there is an avenue for people to reach out for advice or propecia and male infertility help." The joint package includes:$7 million for headspace outreach support to parents and young people across greater Sydney - jointly funded by NSW and the Commonwealth Government;$3 million for Sonder to provide anyone subject to a mandatory 14-day isolation order with 24/7 health and wellbeing support, with an emphasis on early intervention, for the entire duration of their isolation period - jointly funded by NSW and the Commonwealth Government;$3 million to support Culturally and Linguistically Diverse (CALD) communities, with a focus on communities in South West and Western Sydney. The funding will go to Beyond Blue and the Primary Health Networks (PHNs) to ensure multicultural communities have access to services and appropriate language translation services;$2 million for Primary Health networks across Sydney to increase their mental health services across all areas;$1.5 million for Lifeline to boost crisis counselling services;$150,000 for Gidget Foundation to provide counselling services for parents suffering from perinatal depression and anxiety.Free access for 8,000 new parents to the Tresillian SleepWell baby app, through a funding injection of $100,000.Kids Helpline will also be able to extend online wellbeing sessions to secondary schools with a funding boost of $300,000 and the Butterfly Foundation will also receive $300,000 to provide additional support for young people with or at risk of an eating disorder and their carers."In the past year we have seen a rise in self harm, we want to make sure the feeling of isolation doesn't add to this, so this funding ensures the services can cope with increased demand for mental health support."âThe NSW Government is investing a record $10.9 billion over the next four years, including $2.6 billion in 2021-22 for mental health services to continue important work that propecia and male infertility supports people in need across the state.Treasurer Dominic Perrottet announced the funding today as part of the 2021-2022 State Budget.âThis funding focuses on improving the lives of people living in NSW with mental illness by delivering better care both in hospitals and in the community, by providing support for individuals, carers and wider familyâ Mr Perrottet said.Minister for Mental Health Bronnie Taylor said this vital funding will continue and expand proven programs in the mental health space.âAfter the extraordinary events over the last two years, including unprecedented drought, floods, propecia and now the mice plague, mental health funding is more important than ever â especially in our regions,â Mrs Taylor said.âThere is an increasing need for more specialised treatment for children and teenagers. The funding of propecia and male infertility 25 âSafeguardsâ â Child and Adolescent Mental Health Response Teams - is a game changer for our clinicians and families.
ÂKey highlights of the 2021-22 Mental Health Budget include:$109.5 million over four years to develop 25 âSafeguardsâ â Child and Adolescent Mental Health Response Teams across NSW to provide services to children and teenagers with moderate to severe mental health issues and their families and carers.$25.8 million over four years to continue propecia and male infertility the successful Police Ambulance and Clinical Early Response (PACER) model, which embeds mental health clinicians with first responders at the scene to provide specialist advice and appropriate care to people experiencing mental distress.$36.4 million over four years for 57 mental health Response and Recovery Specialists across regional and rural NSW to provide assertive outreach support for communities, and coordination with local services at the time of a disaster or crisis, and during the ongoing recovery phase including:27 FTE Farmgate Counsellors and Drought Peer Support Workers to continue to provide outreach and coordination with local services and communities for four years. And30 FTE Disaster Recovery Clinicians across disaster affected propecia and male infertility areas, who will continue to work closely with primary health initiatives, community and welfare agencies and mental health services to provide direct care and respond to local community needs and issues on the ground. These positions are funded for two years.$12.2 million over two years to fund Tresillian for:six Regional Family Care Centres to provide services to families experiencing difficulties in the critical first years of their childâs life;five âTresillian 2Uâ vans propecia and male infertility to provide mobile community support to families with infants and children. Andstaffing for the Macksville residential unit, which provides inpatient services for propecia and male infertility families experiencing significant parenting challenges requiring intensive intervention..
People in mandatory isolation will have access cheap propecia pills to around the clock Cheap cialis 20mg wellbeing and mental health support and there will be increased access to services for parents, young people and multicultural communities who are struggling during the lockdown. As part of a joint Commonwealth and NSW Government package worth $17.35 million, NSW will provide $5.1m for a range of mental health services across NSW.Treasurer Dominic Perrottet said our top priority is keeping people safe during the propecia, and not just from the current hair loss treatment outbreak."We know this will be a very difficult period for many, the additional funding will provide more mental health support particularly for young people and families."Minister for Mental Health Bronnie Taylor said the hair loss treatment investment will enable providers to immediately increase their support during this period."Looking after your mental wellbeing is vital during this time and with thousands of people and families in isolation, access to services 24 hours 7 days a week is hugely important," Mrs Taylor said"We know this can be a stressful time for families, parents and children, and these new and existing services available now 24 hours 7 days a week, means there is an avenue for people to reach out for advice or help." The joint package includes:$7 million for headspace outreach support to parents and young people across greater Sydney - jointly funded by NSW and the Commonwealth Government;$3 million for Sonder to provide anyone subject to a mandatory 14-day isolation order with 24/7 health and wellbeing support, with an emphasis on early intervention, for the entire duration of their isolation period - jointly funded by NSW and cheap propecia pills the Commonwealth Government;$3 million to support Culturally and Linguistically Diverse (CALD) communities, with a focus on communities in South West and Western Sydney. The funding will go to Beyond Blue and the Primary Health Networks (PHNs) to ensure multicultural communities have access to services and appropriate language translation services;$2 million for Primary Health networks across Sydney to increase their mental health services across all areas;$1.5 million for Lifeline to boost crisis counselling services;$150,000 for Gidget cheap propecia pills Foundation to provide counselling services for parents suffering from perinatal depression and anxiety.Free access for 8,000 new parents to the Tresillian SleepWell baby app, through a funding injection of $100,000.Kids Helpline will also be able to extend online wellbeing sessions to secondary schools with a funding boost of $300,000 and the Butterfly Foundation will also receive $300,000 to provide additional support for young people with or at risk of an eating disorder and their carers."In the past year we have seen a rise in self harm, we want to make sure the feeling of isolation doesn't add to this, so this funding ensures the services can cope with increased demand for mental health support."âThe NSW Government is investing a record $10.9 billion over the next four years, including $2.6 billion in 2021-22 for mental health services to continue important work that supports people in need across the state.Treasurer Dominic Perrottet announced the funding today as part of the 2021-2022 State Budget.âThis funding focuses on improving the lives of people living in NSW with mental illness by delivering better care both in hospitals and in the community, by providing support for individuals, carers and wider familyâ Mr Perrottet said.Minister for Mental Health Bronnie Taylor said this vital funding will continue and expand proven programs in the mental health space.âAfter the extraordinary events over the last two years, including unprecedented drought, floods, propecia and now the mice plague, mental health funding is more important than ever â especially in our regions,â Mrs Taylor said.âThere is an increasing need for more specialised treatment for children and teenagers. The funding of 25 âSafeguardsâ â Child and Adolescent Mental Health Response Teams - is a game changer for our cheap propecia pills clinicians and families. ÂKey highlights of the 2021-22 Mental Health Budget include:$109.5 million over four years to develop 25 âSafeguardsâ cheap propecia pills â Child and Adolescent Mental Health Response Teams across NSW to provide services to children and teenagers with moderate to severe mental health issues and their families and carers.$25.8 million over four years to continue the successful Police Ambulance and Clinical Early Response (PACER) model, which embeds mental health clinicians with first responders at the scene to provide specialist advice and appropriate care to people experiencing mental distress.$36.4 million over four years for 57 mental health Response and Recovery Specialists across regional and rural NSW to provide assertive outreach support for communities, and coordination with local services at the time of a disaster or crisis, and during the ongoing recovery phase including:27 FTE Farmgate Counsellors and Drought Peer Support Workers to continue to provide outreach and coordination with local services and communities for four years.
And30 FTE cheap propecia pills Disaster Recovery Clinicians across disaster affected areas, who will continue to work closely with primary health initiatives, community and welfare agencies and mental health services to provide direct care and respond to local community needs and issues on the ground. These positions are funded for two years.$12.2 cheap propecia pills million over two years to fund Tresillian for:six Regional Family Care Centres to provide services to families experiencing difficulties in the critical first years of their childâs life;five âTresillian 2Uâ vans to provide mobile community support to families with infants and children. Andstaffing for the Macksville residential unit, which provides inpatient services for families experiencing significant parenting challenges requiring intensive intervention. cheap propecia pills.
Athletes on propecia
IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected to have a disorder/difference of sex development (DSD).1â13 Based on these studies, it has become clear that athletes on propecia 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 âA systematic elucidation of differences of sex developmentâ has been a platform to achieve European agreement on harmonisation of clinical management and laboratory practices.15â17 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 athletes on propecia 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 athletes on propecia in the Netherlands and Flanders (the Dutch-speaking Northern part of Belgium) have collaborated to produce a detailed guideline on diagnostics in DSD.19 This shows that a supranational guideline can be a reasonable approach for countries with similarly 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 athletes on propecia rare endocrine conditions (EndoERN), in which DSD is embedded, may facilitate the expansion of this kind of collaboration across Europe.This paper highlights key discussion points in the Dutch-Flemish guideline that have been insufficiently addressed in the literature thus far because they reflect evolving technologies or less visible stakeholders.
For example, prenatal observation of an atypical aspect of the genitalia indicating a possible DSD is becoming increasingly common, and we discuss appropriate counselling and a diagnostic approach for these cases, including the option of using NGS-based genetic testing. So far, little attention has been paid to this process.20 21 Furthermore, informing patients and/or their parents about atypical sex development and why this may warrant referral to a specialised team may be challenging, especially for professionals with limited athletes on propecia experience in DSD.22 23 Therefore, a section of the Dutch-Flemish guideline was written for these healthcare providers. Moreover, this enables DSD specialists to refer to the guideline when advising a referral.
Transition from the prenatal to the postnatal team and from the paediatric to the adult team requires optimal communication athletes on propecia between the specialists involved. Application of NGS-based techniques may lead to a higher diagnostic yield, providing a molecular genetic diagnosis in previously unsolved cases.16 We address the timing of this testing and the problems associated with this technique such as the interpretation of variants of unknown clinical significance (VUS). Similarly, histopathological interpretation and classification of removed gonadal tissue is challenging and would benefit from international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group was formed with all members responsible for updating the literature for a specific part of athletes on propecia the guideline.
Literature search in PubMed was not systematic, but rather intended to be broad in order to cover all areas and follow expert opinions. This approach is more in line with the Clinical Practice Advisory Document method described by Burke et al24 athletes on propecia for guidelines involving genetic practice because it is often troublesome to substantiate such guidelines with sufficient evidence due to the rapid changes in testing methods, for example, gene panels. All input provided by the group was synthesised by the chairperson (YvB), who also reviewed abstracts of papers on DSD published between 2010 and September 2017 for the guideline and up to October 2019 for this paper.
Abstracts had to be written in English and were identified using a broad range athletes on propecia 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 athletes on propecia excluded, as were articles that were not open access or retrievable through institutional access.
Based on this, a draft guideline was produced that was in line with the international principles of good diagnostic care in DSD. This draft was discussed by the writing committee and, after athletes on propecia having obtained agreement on remaining points of discussion, revised into a final draft. This version was sent to a broad group of professionals from academic centres and DSD teams whose members had volunteered to review the draft guideline.
After receiving and incorporating their input, the final version was presented athletes on propecia 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 testing carried out for a different reason, for example, due to suspicion of other structural anomalies, reveals a discrepancy between the genotypic sex athletes on propecia 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 athletes on propecia 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 athletes on propecia 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 11â13 weeks), genital development cannot be reliably athletes on propecia appreciated by ultrasound, so any discrepancy or atypical aspect of the genitalia will only be noticed later in pregnancy and should prompt further evaluation.Counselling and diagnosticsIf a DSD is suspected, first-line sonographers and obstetricians should refer the couple to their colleague prenatal specialists working with or in a DSD team.
After confirming an atypical genital on ultrasound, the specialist team should offer the couple a referral for genetic counselling to discuss the possibility of performing invasive prenatal testing (usually an amniocentesis) to identify an underlying cause that fits the ultrasound findings.22 23 To enable the parents to make a well-informed decision, prenatal counselling should, in our opinion, include. Information on athletes on propecia 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 athletes on propecia 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 childâs 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 athletes on propecia well-informed decision about whether or not to continue the pregnancy.
Termination of pregnancy can be considered, for instance, in a syndromic form of DSD with multiple malformations, but when the DSD occurs as an apparently isolated condition, expecting parents may also consider termination of pregnancy, which, although considered controversial athletes on propecia 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 childâs genitalia will look like and uncertainty athletes on propecia about the diagnosis, treatment and prognosis cannot be avoided completely.
Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images. In our experience, parents appreciate having already spoken to some members of the DSD team during pregnancy and having a contact person before birth.After expert prenatal counselling, a athletes on propecia 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, âyour babyâ) as long as sex assignment is pending.An algorithm for diagnostic evaluation of a suspected DSD in the prenatal situation is proposed in figure athletes on propecia 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 neurological athletes on propecia 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 parentsâ genetics.29â31 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, athletes on propecia and we propose completing the analysis well before the expected delivery.Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm.
*SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful.
NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 1 Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm. *SOX9.
Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful. NGS, next-generation sequencing.First contact by a professional less experienced in DSDWhereas most current guidelines start from the point when an individual has been referred to the DSD team,1 15 the Dutch-Flemish guideline dedicates a chapter to healthcare professionals less experienced in DSD as they are often the first to suspect or identify such a condition.
Apart from the paper of Indyk,7 little guidance is available for these professionals about how to act in such a situation. The chapter in the Dutch-Flemish guideline summarises the various clinical presentations that a DSD can have and provides information on how to communicate with parents and/or patients about the findings of the physical examination, the first-line investigations and the need for prompt referral to a specialised centre for further evaluation. Clinical examples are offered to illustrate some of these recurring situations.
The medical issues in DSD can be very challenging, and the social and psychological impact is high. For neonates with ambiguous genitalia, sex assignment is an urgent and crucial issue, and it is mandatory that parents are informed that it is possible to postpone registration of their childâs 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 48âhours 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 35â38 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 Wilmsâ 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 coauthorsâ 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.41â44 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.15â17 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 48â50 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 patientâs 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.15â17 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 diseasesâProject 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 5âyear 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 3â5% of cases.8â10 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. Âendomet*â,âuter*â, âwombâ, âcancer(s)â, âneoplasm(s)â, âendometrium tumourâ, âcarcinomaâ, âadenosarcomaâ, âclear cell carcinomaâ, âcarcinosarcomaâ, âSNPâ, âsingle nucleotide polymorphismâ, âGWASâ, and âgenome-wide association study/iesâ.
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.
Chronbachâs α score was calculated between reviewers and indicated high consistency at 0.92. Caseâcontrol, 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%âCI), 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 <5Ã10-8, 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 <1Ã10-5, 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 2âβipI and SE, Ï, equal to â2âβi2pI(1âpi), 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(Z0.01Ï), 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 literature21â25Study 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).21â25 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 28â30 Moreover, a recent article authored by OâMara 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%âCI 1.32 to 2.04.
P=9.6Ã10-6) compared with the endometrioid arm (OR 1.25, 95%âCI 1.14 to 1.38. P=4.7Ã10-6).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. OâMara et al reported a lead SNP (rs79575945) in the ESR1 region that was associated with endometrial cancer (p=1.86Ã10-5).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%âCI 1.11 to 1.21.
P=4.83Ã10-11), the A allele of rs9600103 (OR 1.23, 95%âCI 1.16 to 1.30. P=3.76Ã10-12) and C allele of rs7981863 (OR 1.16, 95%âCI 1.12 to 1.20. P=2.70Ã10-17) 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 OâMara et al reported three SNPs within the MYC region that reached genome-wide significance with conditional p values reaching at least 5Ã10â8.35To 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 criteriaâone 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 13â000 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 42â44DiscussionThis 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 OâMara et al, which utilised 12â096 cases and 108â979 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 200â000 individuals with more than half being cases, and resulted in identification of ~170âSNPs 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 150â000 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%âCI, 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 OâMara 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, OâMara 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 proteinâprotein 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 Bokhmanâs classification system, type I versus type II, or no histological classification system at all. Therefore, it is important to create and follow a standardised and comprehensive classification system for reporting tumour subtypes for future studies.This study compiled and presented available information for an extensively studied, yet unproven in large datasets, SNP309 variant in MDM2. Currently, there is no convincing evidence for an association between this variant and endometrial cancer risk.
Additionally, of all the studies, only one accounted for the opposing effect of a nearby variant SNP285 in their analyses. Thus, we conclude that until confirmed by a sufficiently large GWAS, this variant should not be considered significant in influencing the risk of endometrial cancer and therefore not included in a PRS. This is also true for the majority of the SNPs reported in candidate-gene studies, as the numbers fall far short of being able to detect genuine signals.This systematic review presents the most up-to-date evidence for endometrial cancer susceptibility variants, emphasising the need for further large-scale studies to identify more variants of importance, and validation of these associations.
Until data from larger and more diverse cohorts are available, the top 24 SNPs presented here are the most robust common genetic variants that affect endometrial cancer risk. The multiplicative effects of these SNPs could be used in a PRS to allow personalised risk prediction models to be developed for targeted screening and prevention interventions for women at greatest risk of endometrial cancer..
IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected to have a disorder/difference of sex development (DSD).1â13 Based on these studies, it has become clear that services and institutions still differ in the composition of the multidisciplinary teams that cheap propecia pills provide care for patients who have a DSD.11 14 Several projects have now worked to visit their website resolve this variability in care. The European Cooperation in Science and Technology (EU COST) action BM1303 âA systematic elucidation of differences of sex developmentâ has cheap propecia pills been a platform to achieve European agreement on harmonisation of clinical management and laboratory practices.15â17 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 cheap propecia pills 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 paper highlights key discussion points in the Dutch-Flemish guideline that have been insufficiently addressed in the literature cheap propecia pills thus far because they reflect evolving technologies or less visible stakeholders. For example, prenatal observation of an atypical aspect of the genitalia indicating a possible DSD is becoming increasingly common, and we discuss appropriate counselling and a diagnostic approach for these cases, including the option of using NGS-based genetic testing. So far, little attention has been paid to this process.20 21 Furthermore, informing patients and/or their parents about atypical sex development and why this may warrant referral to a specialised team may be challenging, especially for professionals with limited cheap propecia pills experience in DSD.22 23 Therefore, a section of the Dutch-Flemish guideline was written for these healthcare providers.
Moreover, this enables DSD specialists to refer to the guideline when advising a referral. Transition from the prenatal to the postnatal team and from the paediatric to the adult team requires optimal communication cheap propecia pills between the specialists involved. Application of NGS-based techniques may lead to a higher diagnostic yield, providing a molecular genetic diagnosis in previously unsolved cases.16 We address the timing of this testing and the problems associated with this technique such as the interpretation of variants of unknown clinical significance (VUS). Similarly, histopathological interpretation and classification of removed gonadal tissue is challenging and would benefit from international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group was formed with all members responsible for updating the cheap propecia pills literature for a specific part of the guideline.
Literature search in PubMed was not systematic, but rather intended to be broad in order to cover all areas and follow expert opinions. This approach is more in line with the Clinical Practice Advisory Document method described by Burke et al24 for guidelines involving genetic practice because it cheap propecia pills is often troublesome to substantiate such guidelines with sufficient evidence due to the rapid changes in testing methods, for example, gene panels. All input provided by the group was synthesised by the chairperson (YvB), who also reviewed abstracts of papers on DSD published between 2010 and September 2017 for the guideline and up to October 2019 for this paper. Abstracts had to be written in English and were identified using a broad range of cheap propecia pills 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 cheap propecia pills 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 a final draft cheap propecia pills.
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 cheap propecia pills 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 testing carried out for a different reason, for example, due to suspicion of other structural anomalies, reveals a discrepancy between the genotypic sex and cheap propecia pills 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), cheap propecia pills which is now available to high-risk pregnant women in the Netherlands and to all pregnant women in Belgium, and later ultrasound findings. NIPT screens for CNVs in the fetus. However, depending on legal restrictions and/or ethical considerations, the X and Y chromosomes are not always included in NIPT cheap propecia pills 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 11â13 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 cheap propecia pills DSD is suspected, first-line sonographers and obstetricians should refer the couple to their colleague prenatal specialists working with or in a DSD team. After confirming an atypical genital on ultrasound, the specialist team should offer the couple a referral for genetic counselling to discuss the possibility of performing invasive prenatal testing (usually an amniocentesis) to identify an underlying cause that fits the ultrasound findings.22 23 To enable the parents to make a well-informed decision, prenatal counselling should, in our opinion, include. Information on cheap propecia pills the ultrasound findings and the limitations of this technique.
The procedure(s) that can be followed, including the risks associated with an amniocentesis. And the type of information genetic testing can and cannot cheap propecia pills 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 childâs 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 cheap propecia pills geneticist should be experienced in prenatal counselling and well informed about the diagnostic possibilities given the limited time span in which test results need to be available to allow parents to make a well-informed decision about whether or not to continue the pregnancy.
Termination of pregnancy can be cheap propecia pills 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 childâs genitalia will look like and uncertainty about cheap propecia pills the diagnosis, treatment and prognosis cannot be avoided completely. Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images.
In our experience, parents appreciate having already spoken to some members of the DSD team during pregnancy and having a contact person before birth.After expert prenatal counselling, cheap propecia pills 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, âyour babyâ) as long as sex assignment is pending.An algorithm for diagnostic evaluation of a suspected DSD in the prenatal situation is proposed cheap propecia pills 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 neurological anomalies and fetal growth restriction being particularly common.27 28 If cheap propecia pills 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 parentsâ genetics.29â31 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 cheap propecia pills there is no tight time limit, and we propose completing the analysis well before the expected delivery.Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm.
*SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful. NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 1 Disorders/differences of sex development (DSD) in the prenatal setting.
A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful.
NGS, next-generation sequencing.First contact by a professional less experienced in DSDWhereas most current guidelines start from the point when an individual has been referred to the DSD team,1 15 the Dutch-Flemish guideline dedicates a chapter to healthcare professionals less experienced in DSD as they are often the first to suspect or identify such a condition. Apart from the paper of Indyk,7 little guidance is available for these professionals about how to act in such a situation. The chapter in the Dutch-Flemish guideline summarises the various clinical presentations that a DSD can have and provides information on how to communicate with parents and/or patients about the findings of the physical examination, the first-line investigations and the need for prompt referral to a specialised centre for further evaluation. Clinical examples are offered to illustrate some of these recurring situations.
The medical issues in DSD can be very challenging, and the social and psychological impact is high. For neonates with ambiguous genitalia, sex assignment is an urgent and crucial issue, and it is mandatory that parents are informed that it is possible to postpone registration of their childâs 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 48âhours 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 35â38 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 Wilmsâ 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 coauthorsâ 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.41â44 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.15â17 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 48â50 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 patientâs 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.15â17 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 diseasesâProject 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 5âyear 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 3â5% of cases.8â10 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.
Âendomet*â,âuter*â, âwombâ, âcancer(s)â, âneoplasm(s)â, âendometrium tumourâ, âcarcinomaâ, âadenosarcomaâ, âclear cell carcinomaâ, âcarcinosarcomaâ, âSNPâ, âsingle nucleotide polymorphismâ, âGWASâ, and âgenome-wide association study/iesâ. 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.
Chronbachâs α score was calculated between reviewers and indicated high consistency at 0.92. Caseâcontrol, 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%âCI), 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 <5Ã10-8, 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 <1Ã10-5, 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 2âβipI and SE, Ï, equal to â2âβi2pI(1âpi), 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(Z0.01Ï), 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 literature21â25Study 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).21â25 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 28â30 Moreover, a recent article authored by OâMara 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%âCI 1.32 to 2.04. P=9.6Ã10-6) compared with the endometrioid arm (OR 1.25, 95%âCI 1.14 to 1.38. P=4.7Ã10-6).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. OâMara et al reported a lead SNP (rs79575945) in the ESR1 region that was associated with endometrial cancer (p=1.86Ã10-5).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%âCI 1.11 to 1.21. P=4.83Ã10-11), the A allele of rs9600103 (OR 1.23, 95%âCI 1.16 to 1.30. P=3.76Ã10-12) and C allele of rs7981863 (OR 1.16, 95%âCI 1.12 to 1.20.
P=2.70Ã10-17) 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 OâMara et al reported three SNPs within the MYC region that reached genome-wide significance with conditional p values reaching at least 5Ã10â8.35To 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 criteriaâone 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 13â000 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 42â44DiscussionThis 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 OâMara et al, which utilised 12â096 cases and 108â979 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 200â000 individuals with more than half being cases, and resulted in identification of ~170âSNPs 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 150â000 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%âCI, 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 OâMara 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, OâMara 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 proteinâprotein 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 Bokhmanâs 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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This slideshow requires JavaScript.For many years, Kaiser Family Foundation has been browse around these guys tracking public opinion on the idea walmart pharmacy propecia price of a national health plan (including language referring to Medicare-for-all since 2017). Historically, our polls have shown support for the federal government doing more to help provide health insurance for more Americans, though support among Republicans has decreased over time (Figure 1). But this never translated into majority support for a national walmart pharmacy propecia price health plan in which all Americans would get their insurance from a single government plan until 2016 (Figure 2). A hallmark of Senator Sandersâ primary campaign for President in 2016 was a national âMedicare-for-allâ plan and since then, a slight majority of Americans say they favor such a plan (Figure 3).
Overall, large shares walmart pharmacy propecia price of Democrats and independents favor a national Medicare-for-all plan while most Republicans oppose (Figure 4). Yet, how politicians discuss different proposals does affect public support (Figure 5 and Figure 6). In addition, when asked why they support or walmart pharmacy propecia price oppose a national health plan, the public echoes the dominant messages in the current political climate (Figure 7). A common theme among supporters, regardless of how we ask the question, is the desire for universal coverage (Figure 8).As Medicare-for-all becomes a staple in national conversations around health care and people become aware of the details of any plan or hear arguments on either side, it is unclear how attitudes towards such a proposal may shift.
KFF polling finds public support for Medicare-for-all walmart pharmacy propecia price shifts significantly when people hear arguments about potential tax increases or delays in medical tests and treatment (Figure 9). KFF polling found that when such a plan is described in terms of the trade-offs (higher taxes but lower out-of-pocket costs), the public is almost equally split in their support (Figure 10). KFF polling also shows many people falsely assume they would be able to keep their current health insurance under a single-payer plan, suggesting another potential area for decreased support especially since most supporters (67 percent) of such a proposal think they would be able to keep their current health insurance coverage (Figure 11).KFF polling finds more Democrats and Democratic-leaning independents would prefer voting for a candidate who wants to build on the ACA in order to expand coverage and reduce costs rather than replace the ACA with a national Medicare-for-all plan walmart pharmacy propecia price (Figure 12). Additionally, KFF polling has found broader public support for more incremental changes to expand the public health insurance program in this country including proposals that expand the role of public programs like Medicare and Medicaid (Figure 13).
And while partisans are divided on a Medicare-for-all national health plan, there is robust support among Democrats, and even support among four in ten Republicans, for a government-run health plan, sometimes called a public option walmart pharmacy propecia price (Figure 14). Notably, the public does not perceive major differences in how a public option or a Medicare-for-all plan would impact taxes and personal health care costs. However, there are some differences in perceptions walmart pharmacy propecia price of how the proposals would impact those with private health insurance coverage (Figure 15). KFF polling in October 2020 finds about half of Americans support both a Medicare-for-all plan and a public option (Figure 16).
So while the general idea of a national health plan (whether accomplished through an expansion of Medicare or some other way) may enjoy fairly broad support in the abstract, it remains unclear how this issue will play out in the 2020 election and beyond.Medicare Part D is walmart pharmacy propecia price a voluntary outpatient prescription drug benefit for people with Medicare, provided through private plans approved by the federal government. Beneficiaries can choose to enroll in either a stand-alone prescription drug plan (PDP) to supplement traditional Medicare or a Medicare Advantage prescription drug plan (MA-PD), mainly HMOs and PPOs, that cover all Medicare benefits including drugs. In 2020, 46 million of the more than 60 walmart pharmacy propecia price million people covered by Medicare are enrolled in Part D plans. This fact sheet provides an overview of the Medicare Part D program, plan availability, enrollment, and spending and financing, based on data from the Centers for Medicare &.
Medicaid Services (CMS), the Congressional Budget Office (CBO), and other sources.Medicare Prescription Drug Plan Availability in 2021In 2021, 996 PDPs will be offered across the walmart pharmacy propecia price 34 PDP regions nationwide (excluding the territories). This represents an increase of 48 PDPs from 2020 (a 5% increase) and an increase of 250 plans (a 34% increase) since 2017 (Figure 1).Figure 1. A Total of 996 Medicare Part D Stand-Alone Prescription Drug Plans Will Be Offered in 2021, a walmart pharmacy propecia price 5% Increase From 2020 and a 33% Increase Since 2017The relatively large increase in the number of PDPs in recent years is likely due to the elimination by CMS of the âmeaningful differenceâ requirement for enhanced benefit PDPs offered by the same organization in the same region. Plans with enhanced benefits can offer a lower deductible, reduced cost sharing, or a higher initial coverage limit.
Previously, PDP sponsors were required to demonstrate that their enhanced PDPs were meaningfully different in terms of enrollee out-of-pocket costs in order to ensure that plan offerings were more distinct. Between 2018 and 2021, the number of enhanced PDPs has increased by nearly 50%, from 421 to 618, largely due to this policy change.Beneficiaries in each state will have a choice of multiple stand-alone PDPs in 2021, ranging from 25 PDPs walmart pharmacy propecia price in Alaska to 35 PDPs in Texas (see map). In addition, beneficiaries will be able to choose from among multiple MA-PDs offered at the local level for coverage of their Medicare benefits. New for 2021, beneficiaries in each state will have the option to enroll in a Part D plan participating in the Trump walmart pharmacy propecia price Administrationâs new Innovation Center model in which enhanced drug plans cover insulin products at a monthly copayment of $35 in the deductible, initial coverage, and coverage gap phases of the Part D benefit.
Participating plans do not have to cover all insulin products at the $35 monthly copayment amount, just one of each dosage form (vial, pen) and insulin type (rapid-acting, short-acting, intermediate-acting, and long-acting). In 2021, a total of 1,635 Part D plans will participate walmart pharmacy propecia price in this model, which represents just over 30% of both PDPs (310 plans) and MA-PDs (1,325 plans) available in 2021, including plans in the territories. Between 8 and 10 PDPs in each region are participating in the model, in addition to multiple MA-PDs (see map). Low-Income Subsidy walmart pharmacy propecia price Plan Availability in 2021Beneficiaries with low incomes and modest assets are eligible for assistance with Part D plan premiums and cost sharing.
Through the Part D Low-Income Subsidy (LIS) program, additional premium and cost-sharing assistance is available for Part D enrollees with low incomes (less than 150% of poverty, or $19,140 for individuals/$25,860 for married couples in 2020) and modest assets (less than $14,610 for individuals/$29,160 for couples in 2020).In 2021, 259 plans will be available for enrollment of LIS beneficiaries for no premium, 15 more than in 2020 (a 6% increase), and the second year with an increase in the number of benchmark plans since 2018 (Figure 2). Just over one-fourth of PDPs walmart pharmacy propecia price in 2021 (26%) are benchmark plans. Some enrollees have fewer benchmark plan options than others, since benchmark plan availability varies at the Part D region level. The number of premium-free PDPs in 2021 ranges across states from 5 to 10 plans walmart pharmacy propecia price (see map).
LIS enrollees can select any plan offered in their area, but if they are enrolled in a non-benchmark plan, they may be required to pay some portion of their planâs monthly premium Figure 2. In 2021, 259 Part D Stand-Alone Drug Plans Will Be Available Without a Premium to Enrollees Receiving the Low-Income Subsidy (âBenchmarkâ Plans)Part walmart pharmacy propecia price D Plan Premiums and Benefits in 2021PremiumsThe 2021 Part D base beneficiary premium â which is based on bids submitted by both PDPs and MA-PDs and is not weighted by enrollment â is $33.06, a modest (1%) increase from 2020. But actual premiums paid by Part D enrollees vary considerably. For 2021, PDP monthly premiums range from a low walmart pharmacy propecia price of $5.70 for a PDP in Hawaii to a high of $205.30 for a PDP in South Carolina (unweighted by plan enrollment).
Even within a state, PDP premiums can vary. For example, in walmart pharmacy propecia price Florida, monthly premiums range from $7.30 to $172. In addition to the monthly premium, Part D enrollees with higher incomes ($87,000/individual. $174,000/couple) pay an income-related premium surcharge, ranging from $12.32 to $77.14 per month in 2021 (depending on income).BenefitsThe Part D defined walmart pharmacy propecia price standard benefit has several phases, including a deductible, an initial coverage phase, a coverage gap phase, and catastrophic coverage.
Between 2020 and 2021, the parameters of the standard benefit are rising, which means Part D enrollees will face higher out-of-pocket costs for the deductible and in the initial coverage phase, as they have in prior years, and will have to pay more out-of-pocket before qualifying for catastrophic coverage (Figure 3).The standard deductible is increasing from $435 in 2020 to $445 in 2021The initial coverage limit is increasing from $4,020 to $4,130, andThe out-of-pocket spending threshold is increasing from $6,350 to $6,550 (equivalent to $10,048 in total drug spending in 2021, up from $9,719 in 2020).The standard benefit amounts are indexed to change annually based on the rate of Part D per capita spending growth, and, with the exception of 2014, have increased each year since 2006.Figure 3. Medicare Part D Standard Benefit Parameters Will Increase in 2021For costs in the coverage gap phase, beneficiaries pay 25% for both brand-name and generic drugs, with walmart pharmacy propecia price manufacturers providing a 70% discount on brands and plans paying the remaining 5% of brand drug costs, and plans paying the remaining 75% of generic drug costs. For total drug costs above the catastrophic threshold, Medicare pays 80%, plans pay 15%, and enrollees pay either 5% of total drug costs or $3.70/$9.20 for each generic and brand-name drug, respectively.Part D plans must offer either the defined standard benefit or an alternative equal in value (âactuarially equivalentâ) and can also provide enhanced benefits. Both basic and enhanced walmart pharmacy propecia price benefit plans vary in terms of their specific benefit design, coverage, and costs, including deductibles, cost-sharing amounts, utilization management tools (i.e., prior authorization, quantity limits, and step therapy), and formularies (i.e., covered drugs).
Plan formularies must include drug classes covering all disease states, and a minimum of two chemically distinct drugs in each class. Part D plans are required to cover all drugs in six so-called âprotectedâ classes. Immunosuppressants, antidepressants, antipsychotics, anticonvulsants, antiretrovirals, and antineoplastics.Part D and Low-Income Subsidy EnrollmentEnrollment in Medicare Part D plans is voluntary, with the exception of beneficiaries who are eligible for both Medicare and Medicaid and certain other low-income beneficiaries who are automatically enrolled in a walmart pharmacy propecia price PDP if they do not choose a plan on their own. Unless beneficiaries have drug coverage from another source that is at least as good as standard Part D coverage (âcreditable coverageâ), they face a penalty equal to 1% of the national average premium for each month they delay enrollment.In 2020, 46.5 million Medicare beneficiaries are enrolled in Medicare Part D plans, including employer-only group plans.
Of the total, just over half (53%) are enrolled in stand-alone PDPs and nearly half (47%) are enrolled in walmart pharmacy propecia price Medicare Advantage drug plans (Figure 4). Another 1.3 million beneficiaries are estimated to have drug coverage through employer-sponsored retiree plans where the employer receives a subsidy from the federal government equal to 28% of drug expenses between $445 and $9,200 per retiree (in 2021). Several million beneficiaries are walmart pharmacy propecia price estimated to have other sources of drug coverage, including employer plans for active workers, FEHBP, TRICARE, and Veterans Affairs (VA). Another 12% of people with Medicare are estimated to lack creditable drug coverage.Figure 4.
Medicare Part D Enrollment in Stand-Alone Drug Plans Has Declined Recently But Has Increased Steadily in Medicare Advantage Drug PlansAn estimated 13 million Part D enrollees receive the Low-Income walmart pharmacy propecia price Subsidy in 2020. Beneficiaries who are dually eligible, QMBs, SLMBs, QIs, and SSI-onlys automatically qualify for the additional assistance, and Medicare automatically enrolls them into PDPs with premiums at or below the regional average (the Low-Income Subsidy benchmark) if they do not choose a plan on their own. Other beneficiaries are subject to both an income and asset test and need to apply for the Low-Income Subsidy through either the Social Security Administration or Medicaid.Part D Spending and FinancingPart D SpendingThe Congressional Budget Office (CBO) estimates that spending on Part D benefits will total walmart pharmacy propecia price $96 billion in 2021, representing 13% of net Medicare outlays (net of offsetting receipts from premiums and state transfers). Part D spending depends on several factors, including the total number of Part D enrollees, their health status and drug use, the number of high-cost enrollees (those with drug spending above the catastrophic threshold), the number of enrollees receiving the Low-Income Subsidy, and plansâ ability to negotiate discounts (rebates) with drug companies and preferred pricing arrangements with pharmacies, and manage use (e.g., promoting use of generic drugs, prior authorization, step therapy, quantity limits, and mail order).
Federal law currently prohibits walmart pharmacy propecia price the Secretary of Health and Human Services from interfering in drug price negotiations between Part D plan sponsors and drug manufacturers.Part D FinancingFinancing for Part D comes from general revenues (71%), beneficiary premiums (16%), and state contributions (12%). The monthly premium paid by enrollees is set to cover 25.5% of the cost of standard drug coverage. Medicare subsidizes the remaining 74.5%, based on bids submitted by plans for their expected benefit walmart pharmacy propecia price payments. Higher-income Part D enrollees pay a larger share of standard Part D costs, ranging from 35% to 85%, depending on income.Payments to PlansFor 2021, Medicareâs actuaries estimate that Part D plans will receive direct subsidy payments averaging $216 per enrollee overall, $2,639 for enrollees receiving the LIS, and $1,026 in reinsurance payments for very high-cost enrollees.
Employers are walmart pharmacy propecia price expected to receive, on average, $575 for retirees in employer-subsidy plans. Part D plans also receive additional risk-adjusted payments based on the health status of their enrollees, and plansâ potential total losses or gains are limited by risk-sharing arrangements with the federal government (ârisk corridorsâ).Under reinsurance, Medicare subsidizes 80% of total drug spending incurred by Part D enrollees with relatively high drug spending above the catastrophic coverage threshold. In the aggregate, Medicareâs reinsurance payments to Part D plans now account for close to half walmart pharmacy propecia price of total Part D spending (45%), up from 14% in 2006 (increasing from $6 billion in 2006 to $46 billion in 2019) (Figure 5). Higher benefit spending above the catastrophic threshold is a result of several factors, including an increase in the number of high-cost drugs, prescription drug price increases, and a change made by the ACA to count the manufacturer discount on the price of brand-name drugs in the coverage gap towards the out-of-pocket threshold for catastrophic coverage.
This change has led to more Part D enrollees with spending above walmart pharmacy propecia price the catastrophic threshold over time.Figure 5. Spending for Catastrophic Coverage (âReinsuranceâ) Now Accounts for Close to Half (45%) of Total Medicare Part D Spending, up from 14% in 2006Issues for the FutureThe Medicare drug benefit has helped to reduce out-of-pocket drug spending for enrollees, which is especially important to those with modest incomes or very high drug costs. But with drug costs on the rise, more plans charging coinsurance rather than flat copayments for covered brand-name drugs, and annual increases in the out-of-pocket spending threshold, many Part D enrollees are likely to face higher out-of-pocket costs for their medications.In light of ongoing attention to prescription drug spending and rising drug costs, policymakers have issued several walmart pharmacy propecia price proposals to control drug spending by Medicare and beneficiaries. Several of these proposals address concerns about the lack of a hard cap on out-of-pocket spending for Part D enrollees, the significant increase in Medicare spending for enrollees with high drug costs, and the relatively weak financial incentives faced by Part D plan sponsors to control high drug costs.
Such proposals include allowing Medicare to negotiate the price of drugs, restructuring the Part D benefit to add a hard cap on out-of-pocket drug spending, requiring manufacturers to pay a rebate to the federal government if their drug prices increase faster than inflation, using drug prices in other countries in determining pricing for drugs in the U.S., allowing for drug importation, and shifting more of the responsibility for catastrophic coverage costs to Part D plans and drug manufacturers.Understanding how well Part D continues to meet the needs of people on Medicare will be informed by ongoing monitoring of the Part D plan marketplace, examining formulary coverage and costs for new and existing medications, assessing the impact of the new insulin model, and keeping tabs on Medicare beneficiariesâ out-of-pocket drug spending..
This slideshow buy propecia online with prescription requires JavaScript.For many years, Kaiser Family Foundation has been tracking public opinion on the idea of a cheap propecia pills national health plan (including language referring to Medicare-for-all since 2017). Historically, our polls have shown support for the federal government doing more to help provide health insurance for more Americans, though support among Republicans has decreased over time (Figure 1). But this cheap propecia pills never translated into majority support for a national health plan in which all Americans would get their insurance from a single government plan until 2016 (Figure 2).
A hallmark of Senator Sandersâ primary campaign for President in 2016 was a national âMedicare-for-allâ plan and since then, a slight majority of Americans say they favor such a plan (Figure 3). Overall, large shares of Democrats and independents favor a national Medicare-for-all cheap propecia pills plan while most Republicans oppose (Figure 4). Yet, how politicians discuss different proposals does affect public support (Figure 5 and Figure 6).
In addition, when asked why they support or oppose a national health plan, the public echoes the dominant messages cheap propecia pills in the current political climate (Figure 7). A common theme among supporters, regardless of how we ask the question, is the desire for universal coverage (Figure 8).As Medicare-for-all becomes a staple in national conversations around health care and people become aware of the details of any plan or hear arguments on either side, it is unclear how attitudes towards such a proposal may shift. KFF polling finds public support for Medicare-for-all shifts significantly when people hear arguments about potential tax increases or delays in medical tests and treatment (Figure 9) cheap propecia pills.
KFF polling found that when such a plan is described in terms of the trade-offs (higher taxes but lower out-of-pocket costs), the public is almost equally split in their support (Figure 10). KFF polling also shows many people falsely assume they would be able to keep their current health insurance under a single-payer plan, suggesting another potential area for decreased support especially since most supporters (67 percent) of such a proposal think they would be able to cheap propecia pills keep their current health insurance coverage (Figure 11).KFF polling finds more Democrats and Democratic-leaning independents would prefer voting for a candidate who wants to build on the ACA in order to expand coverage and reduce costs rather than replace the ACA with a national Medicare-for-all plan (Figure 12). Additionally, KFF polling has found broader public support for more incremental changes to expand the public health insurance program in this country including proposals that expand the role of public programs like Medicare and Medicaid (Figure 13).
And while partisans are divided on a Medicare-for-all national health plan, there is robust support among Democrats, and even support among four in ten cheap propecia pills Republicans, for a government-run health plan, sometimes called a public option (Figure 14). Notably, the public does not perceive major differences in how a public option or a Medicare-for-all plan would impact taxes and personal health care costs. However, there are some differences in perceptions of how the proposals would impact those with private health cheap propecia pills insurance coverage (Figure 15).
KFF polling in October 2020 finds about half of Americans support both a Medicare-for-all plan and a public option (Figure 16). So while the general idea of a national health plan (whether accomplished through an expansion of Medicare or some cheap propecia pills other way) may enjoy fairly broad support in the abstract, it remains unclear how this issue will play out in the 2020 election and beyond.Medicare Part D is a voluntary outpatient prescription drug benefit for people with Medicare, provided through private plans approved by the federal government. Beneficiaries can choose to enroll in either a stand-alone prescription drug plan (PDP) to supplement traditional Medicare or a Medicare Advantage prescription drug plan (MA-PD), mainly HMOs and PPOs, that cover all Medicare benefits including drugs.
In 2020, 46 million of the more than cheap propecia pills 60 million people covered by Medicare are enrolled in Part D plans. This fact sheet provides an overview of the Medicare Part D program, plan availability, enrollment, and spending and financing, based on data from the Centers for Medicare &. Medicaid Services (CMS), the Congressional cheap propecia pills Budget Office (CBO), and other sources.Medicare Prescription Drug Plan Availability in 2021In 2021, 996 PDPs will be offered across the 34 PDP regions nationwide (excluding the territories).
This represents an increase of 48 PDPs from 2020 (a 5% increase) and an increase of 250 plans (a 34% increase) since 2017 (Figure 1).Figure 1. A Total of 996 Medicare Part D Stand-Alone Prescription Drug Plans Will Be Offered in 2021, a 5% Increase From 2020 and a cheap propecia pills 33% Increase Since 2017The relatively large increase in the number of PDPs in recent years is likely due to the elimination by CMS of the âmeaningful differenceâ requirement for enhanced benefit PDPs offered by the same organization in the same region. Plans with enhanced benefits can offer a lower deductible, reduced cost sharing, or a higher initial coverage limit.
Previously, PDP sponsors were required to demonstrate that their enhanced PDPs were meaningfully different in terms of enrollee out-of-pocket costs in order to ensure that plan offerings were more distinct. Between 2018 and 2021, the number of enhanced PDPs has increased by cheap propecia pills nearly 50%, from 421 to 618, largely due to this policy change.Beneficiaries in each state will have a choice of multiple stand-alone PDPs in 2021, ranging from 25 PDPs in Alaska to 35 PDPs in Texas (see map). In addition, beneficiaries will be able to choose from among multiple MA-PDs offered at the local level for coverage of their Medicare benefits.
New for 2021, beneficiaries in each state will have the option to enroll in a Part D plan participating in the Trump Administrationâs new cheap propecia pills Innovation Center model in which enhanced drug plans cover insulin products at a monthly copayment of $35 in the deductible, initial coverage, and coverage gap phases of the Part D benefit. Participating plans do not have to cover all insulin products at the $35 monthly copayment amount, just one of each dosage form (vial, pen) and insulin type (rapid-acting, short-acting, intermediate-acting, and long-acting). In 2021, a total of 1,635 Part D plans will participate cheap propecia pills in this model, which represents just over 30% of both PDPs (310 plans) and MA-PDs (1,325 plans) available in 2021, including plans in the territories.
Between 8 and 10 PDPs in each region are participating in the model, in addition to multiple MA-PDs (see map). Low-Income Subsidy Plan Availability in 2021Beneficiaries with low incomes and modest assets are eligible for assistance with Part D cheap propecia pills plan premiums and cost sharing. Through the Part D Low-Income Subsidy (LIS) program, additional premium and cost-sharing assistance is available for Part D enrollees with low incomes (less than 150% of poverty, or $19,140 for individuals/$25,860 for married couples in 2020) and modest assets (less than $14,610 for individuals/$29,160 for couples in 2020).In 2021, 259 plans will be available for enrollment of LIS beneficiaries for no premium, 15 more than in 2020 (a 6% increase), and the second year with an increase in the number of benchmark plans since 2018 (Figure 2).
Just over one-fourth of cheap propecia pills PDPs in 2021 (26%) are benchmark plans. Some enrollees have fewer benchmark plan options than others, since benchmark plan availability varies at the Part D region level. The number of premium-free PDPs in 2021 ranges across states from 5 to 10 cheap propecia pills plans (see map).
LIS enrollees can select any plan offered in Get More Information their area, but if they are enrolled in a non-benchmark plan, they may be required to pay some portion of their planâs monthly premium Figure 2. In 2021, 259 Part D Stand-Alone Drug Plans Will Be Available Without a Premium to Enrollees Receiving the Low-Income Subsidy (âBenchmarkâ Plans)Part D Plan Premiums and Benefits in 2021PremiumsThe 2021 Part D base beneficiary premium â which cheap propecia pills is based on bids submitted by both PDPs and MA-PDs and is not weighted by enrollment â is $33.06, a modest (1%) increase from 2020. But actual premiums paid by Part D enrollees vary considerably.
For 2021, PDP monthly premiums range from a low of $5.70 for a PDP in Hawaii to a high of $205.30 for a PDP in South Carolina (unweighted by plan enrollment) cheap propecia pills. Even within a state, PDP premiums can vary. For example, in Florida, monthly premiums range from $7.30 cheap propecia pills to $172.
In addition to the monthly premium, Part D enrollees with higher incomes ($87,000/individual. $174,000/couple) pay an income-related premium surcharge, ranging from $12.32 to $77.14 per month in 2021 (depending on income).BenefitsThe Part D defined standard benefit has several phases, including a deductible, an initial coverage cheap propecia pills phase, a coverage gap phase, and catastrophic coverage. Between 2020 and 2021, the parameters of the standard benefit are rising, which means Part D enrollees will face higher out-of-pocket costs for the deductible and in the initial coverage phase, as they have in prior years, and will have to pay more out-of-pocket before qualifying for catastrophic coverage (Figure 3).The standard deductible is increasing from $435 in 2020 to $445 in 2021The initial coverage limit is increasing from $4,020 to $4,130, andThe out-of-pocket spending threshold is increasing from $6,350 to $6,550 (equivalent to $10,048 in total drug spending in 2021, up from $9,719 in 2020).The standard benefit amounts are indexed to change annually based on the rate of Part D per capita spending growth, and, with the exception of 2014, have increased each year since 2006.Figure 3.
Medicare Part D Standard Benefit Parameters Will Increase in 2021For costs in the cheap propecia pills coverage gap phase, beneficiaries pay 25% for both brand-name and generic drugs, with manufacturers providing a 70% discount on brands and plans paying the remaining 5% of brand drug costs, and plans paying the remaining 75% of generic drug costs. For total drug costs above the catastrophic threshold, Medicare pays 80%, plans pay 15%, and enrollees pay either 5% of total drug costs or $3.70/$9.20 for each generic and brand-name drug, respectively.Part D plans must offer either the defined standard benefit or an alternative equal in value (âactuarially equivalentâ) and can also provide enhanced benefits. Both basic and enhanced benefit plans vary in terms of their specific benefit design, cheap propecia pills coverage, and costs, including deductibles, cost-sharing amounts, utilization management tools (i.e., prior authorization, quantity limits, and step therapy), and formularies (i.e., covered drugs).
Plan formularies must include drug classes covering all disease states, and a minimum of two chemically distinct drugs in each class. Part D plans are required to cover all drugs in six so-called âprotectedâ classes. Immunosuppressants, antidepressants, antipsychotics, anticonvulsants, antiretrovirals, and antineoplastics.Part D and Low-Income Subsidy EnrollmentEnrollment in Medicare Part D plans is voluntary, with the exception of beneficiaries who are eligible for cheap propecia pills both Medicare and Medicaid and certain other low-income beneficiaries who are automatically enrolled in a PDP if they do not choose a plan on their own.
Unless beneficiaries have drug coverage from another source that is at least as good as standard Part D coverage (âcreditable coverageâ), they face a penalty equal to 1% of the national average premium for each month they delay enrollment.In 2020, 46.5 million Medicare beneficiaries are enrolled in Medicare Part D plans, including employer-only group plans. Of the total, just over half (53%) are enrolled in stand-alone PDPs and nearly half cheap propecia pills (47%) are enrolled in Medicare Advantage drug plans (Figure 4). Another 1.3 million beneficiaries are estimated to have drug coverage through employer-sponsored retiree plans where the employer receives a subsidy from the federal government equal to 28% of drug expenses between $445 and $9,200 per retiree (in 2021).
Several million cheap propecia pills beneficiaries are estimated to have other sources of drug coverage, including employer plans for active workers, FEHBP, TRICARE, and Veterans Affairs (VA). Another 12% of people with Medicare are estimated to lack creditable drug coverage.Figure 4. Medicare Part D Enrollment in Stand-Alone Drug Plans Has Declined Recently But Has Increased Steadily in cheap propecia pills Medicare Advantage Drug PlansAn estimated 13 million Part D enrollees receive the Low-Income Subsidy in 2020.
Beneficiaries who are dually eligible, QMBs, SLMBs, QIs, and SSI-onlys automatically qualify for the additional assistance, and Medicare automatically enrolls them into PDPs with premiums at or below the regional average (the Low-Income Subsidy benchmark) if they do not choose a plan on their own. Other beneficiaries are subject to both cheap propecia pills an income and asset test and need to apply for the Low-Income Subsidy through either the Social Security Administration or Medicaid.Part D Spending and FinancingPart D SpendingThe Congressional Budget Office (CBO) estimates that spending on Part D benefits will total $96 billion in 2021, representing 13% of net Medicare outlays (net of offsetting receipts from premiums and state transfers). Part D spending depends on several factors, including the total number of Part D enrollees, their health status and drug use, the number of high-cost enrollees (those with drug spending above the catastrophic threshold), the number of enrollees receiving the Low-Income Subsidy, and plansâ ability to negotiate discounts (rebates) with drug companies and preferred pricing arrangements with pharmacies, and manage use (e.g., promoting use of generic drugs, prior authorization, step therapy, quantity limits, and mail order).
Federal law currently prohibits the Secretary of Health and Human Services from interfering in drug price negotiations between Part D cheap propecia pills plan sponsors and drug manufacturers.Part D FinancingFinancing for Part D comes from general revenues (71%), beneficiary premiums (16%), and state contributions (12%). The monthly premium paid by enrollees is set to cover 25.5% of the cost of standard drug coverage. Medicare subsidizes the cheap propecia pills remaining 74.5%, based on bids submitted by plans for their expected benefit payments.
Higher-income Part D enrollees pay a larger share of standard Part D costs, ranging from 35% to 85%, depending on income.Payments to PlansFor 2021, Medicareâs actuaries estimate that Part D plans will receive direct subsidy payments averaging $216 per enrollee overall, $2,639 for enrollees receiving the LIS, and $1,026 in reinsurance payments for very high-cost enrollees. Employers are expected to receive, on average, $575 for retirees cheap propecia pills in employer-subsidy plans. Part D plans also receive additional risk-adjusted payments based on the health status of their enrollees, and plansâ potential total losses or gains are limited by risk-sharing arrangements with the federal government (ârisk corridorsâ).Under reinsurance, Medicare subsidizes 80% of total drug spending incurred by Part D enrollees with relatively high drug spending above the catastrophic coverage threshold.
In the aggregate, Medicareâs reinsurance payments to Part D plans cheap propecia pills now account for close to half of total Part D spending (45%), up from 14% in 2006 (increasing from $6 billion in 2006 to $46 billion in 2019) (Figure 5). Higher benefit spending above the catastrophic threshold is a result of several factors, including an increase in the number of high-cost drugs, prescription drug price increases, and a change made by the ACA to count the manufacturer discount on the price of brand-name drugs in the coverage gap towards the out-of-pocket threshold for catastrophic coverage. This change has led to more Part D enrollees with spending cheap propecia pills above the catastrophic threshold over time.Figure 5.
Spending for Catastrophic Coverage (âReinsuranceâ) Now Accounts for Close to Half (45%) of Total Medicare Part D Spending, up from 14% in 2006Issues for the FutureThe Medicare drug benefit has helped to reduce out-of-pocket drug spending for enrollees, which is especially important to those with modest incomes or very high drug costs. But with drug costs on the rise, more plans charging coinsurance rather than flat copayments for covered brand-name drugs, cheap propecia pills and annual increases in the out-of-pocket spending threshold, many Part D enrollees are likely to face higher out-of-pocket costs for their medications.In light of ongoing attention to prescription drug spending and rising drug costs, policymakers have issued several proposals to control drug spending by Medicare and beneficiaries. Several of these proposals address concerns about the lack of a hard cap on out-of-pocket spending for Part D enrollees, the significant increase in Medicare spending for enrollees with high drug costs, and the relatively weak financial incentives faced by Part D plan sponsors to control high drug costs.
Such proposals include allowing Medicare to negotiate the price of drugs, restructuring the Part D benefit to add a hard cap on out-of-pocket drug spending, requiring manufacturers to pay a rebate to the federal government if their drug prices increase faster than inflation, using drug prices in other countries in determining pricing for drugs in the U.S., allowing for drug importation, and shifting more of the responsibility for catastrophic coverage costs to Part D plans and drug manufacturers.Understanding how well Part D continues to meet the needs of people on Medicare will be informed by ongoing monitoring of the Part D plan marketplace, examining formulary coverage and costs for new and existing medications, assessing the impact of the new insulin model, and keeping tabs on Medicare beneficiariesâ out-of-pocket drug spending..
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