Symbicort 400mcg 6mcg price

A Hudson Valley woman is facing multiple charges, including murder, for allegedly starving a symbicort 400mcg 6mcg price 7-year-old to death she kept secreted inside her apartment, the District Attorney announced.Leticia Bravo, age 39, of Newburgh in Orange County was indicted on Friday, Oct. 8 for her role in the death of 7-year-old Petter Cuacuas, who symbicort 400mcg 6mcg price was kept hidden behind a bedroom behind a door that locked from the outside.Orange County District Attorney David Hoovler said that shortly after 8 a.m. On Feb.

10, Braves brought the child’s lifeless body to symbicort 400mcg 6mcg price St. Luke’s Hospital in Newburgh, where he was pronounced dead.The investigation into the death found that when the school year began in September 2020, Bravo became the primary caretaker of Cuacuas, as she dated the boy's father, Arturo Cuacuas. Investigators said that Cuacuas would stay with Bravo at here William Street apartment in Newburgh every day but Saturdays, which were reserved for his father.The autopsy by the Medical Examiner found that Cuacuas, who was 37 pounds at the time of his death, died as a result of malnutrition.Hoovler said that it is alleged that Bravo kept Peter Cuacuas locked in the room, and the boy hadn't logged in to school for virtual learning for more than a month before his death, despite teachers attempting to symbicort 400mcg 6mcg price intervene.
“It is unthinkable that someone would accept the responsibility of caring for a child and then deny that child the basic necessities of life,” Hoovler said.

€œChildren are the most innocent and vulnerable of victims. It is symbicort 400mcg 6mcg price truly disturbing how this child was kept hidden from school authorities before he died.”Bravo, who worked as a child-care provider, was arrested on Thursday, Oct. 7, and symbicort 400mcg 6mcg price charged with murder, and multiple counts of manslaughter.

Bail was set at $250,000 cash, or $900,000 fully secured bond, or $1,500,000 partially secured bond.If convicted, Bravo faces life in prison. Her next symbicort 400mcg 6mcg price appearance in Orange County Court is scheduled for Tuesday, Oct. 26.Arturo Cuacuas was also charged with criminally negligent homicide for his role in the 7-year-old’s death."Today is about justice for Peter Cuacuas,” City of Newburgh Police Commissioner Jose Gomerez stated.

€œOur children are our most symbicort 400mcg 6mcg price vulnerable community members. €œThis is a devastating case for our entire community, who I know were frustrated over the past eight months with no arrest being made,” he said. €œThis has been a lengthy and emotional case that has affected our department, specifically those involved in the investigation.” Click here to sign up for Daily Voice's free daily emails and news alerts.Police busted symbicort 400mcg 6mcg price a man with an illegal handgun after being tipped off about a potential sale of the weapon in Westchester.At approximately 4:20 p.m.

On Thursday, symbicort 400mcg 6mcg price Oct. 7, officers from the New Rochelle Police Department and Real-Time Crime Center at Westchester County Police Headquarters received information about a possible gun sale about to take place in the area of Pershing Square. The investigation into that symbicort 400mcg 6mcg price tip led police to Mamaroneck resident Anthony Repaci, age 41, who was stopped and found to be in possession of a loaded 9mm Ruger handgun, leading to his arrest, said New Rochelle Police Department Captain J.

Collins Coyne, commander of the Criminal Investigations Division.Repaci was taken into custody without incident and charged with criminal possession of a loaded firearm. He was scheduled to return to New Rochelle City Court at symbicort 400mcg 6mcg price a later date to respond to the charge. Click here to sign up for Daily Voice's free daily emails and news alerts..

Symbicort patient assistance

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For Wayne Memorial Hospital in Jesup, Georgia, the care staff http://mchtranslations.com/buy-kamagra-100mg-oral-jelly gives symbicort patient assistance patients is personal. The hospital's financial assistance program was created to ensure patients were not forgoing life-saving symbicort patient assistance treatment due to costs. Because of this, the hospital has generous specifications to qualify.THE PROBLEMHowever, the hospital has to pay attention to its expenses as much as its revenue, since it has thin financial margins.

Rural hospitals symbicort patient assistance can go down quickly if they are not attentive to these trends. Everything counts."We were only able to dedicate one employee to search manually for possible programs to assist our patients with their out-of-pocket expenses," said Greg Jones, CFO at Wayne Memorial Hospital. "This was time-consuming and could be emotionally stressful as our team member was determined to assist each patient."Every patient had someone depending on them to provide food or shelter, to symbicort patient assistance nurture or love," he continued.

"It was very frustrating not being able to come through for all of them. We were able symbicort patient assistance to assist maybe 10-20% of our patients through a select few programs, while the remainder of the patient's out-of-pocket responsibility was written off to the hospital's charity or bad debt."As the hospital accrued costs for patient care, it was not seeing the revenue to cover it. It implemented a few policies and procedures to decrease any possible revenue barriers on the front end, like ensuring prior authorizations are in place for high-cost infusions, accurate processes at registration and specialized, knowledgeable staff reviewing all claims in billing."Changes like this can really help prevent denials that ultimately cost the hospital, but, symbicort patient assistance for the long run, it may not be enough," Jones noted.

"The worst thing to happen is to be faced with not being able to help our patients or the hospital failing. Something had to be done."PROPOSALJones and his symbicort patient assistance team turned to health IT vendor Atlas Health. Because of a previous implementation with a partner hospital, Atlas knew the pressure points for a rural hospital with limited resources to assist patients, Jones said, and the company seemed dedicated to helping the community as much as the hospital was."The solution was straightforward," he said.

"Our hospital would have more than 10,000 programs symbicort patient assistance at its fingertips to assist patients with their out-of-pocket expenses. The platform would proactively match the patients up to those programs without a person searching manually through all of the information, and the enrollment process would be automated."With this level of transparency and automation, we could leverage all possible sources of patient assistance prior to writing off these debts to charity or bad debt."Greg Jones, Wayne Memorial Hospital"Atlas explained how one team member could do the work of three and screen all of our patients prior to leveraging our charity program," he added. "Another part of the solution that was proactive was that the system would be integrated with our EHR, so when a patient was scheduled for an infusion the Atlas platform would match patients up to programs prior to the patient having a balance."This would allow for the team to identify symbicort patient assistance patients for state programs like Medicaid or MSPs and optimize the financial navigation for all patients, he added.

The hospital would go from assisting 10-20% of patients to advocating for the entire symbicort patient assistance infusion center's census, he said."With this level of transparency and automation, we could leverage all possible sources of patient assistance prior to writing off these debts to charity or bad debt," he explained. "That would allow us to assist our community in other charity projects outside of the infusion center. The solution Atlas offered was aligned with our symbicort patient assistance mission and focus.

It was an easy decision."MEETING THE CHALLENGEThe way Wayne Memorial Hospital's team uses the technology to assist patients now is fairly simple. A list symbicort patient assistance is created daily by Atlas for the hospital's advocate to review. The platform automates everything needed for the patient's enrollment.If there are any other documents that are needed for a patient's enrollment, the team can collect these electronically from the patient using Atlas.

There is symbicort patient assistance a spot for different departments to tag and communicate with each other so all stakeholders are aware of each patient's status.When an enrollment is completed, all of the post-enrollment awards and ordering can be tracked from the platform. "It's a one-stop shop for all parties involved in a patient's treatment and care," Jones said.The implementation was easy, he symbicort patient assistance added."Atlas already had the code needed to pull the necessary information from our EHR to match patients in programs within the platform," he noted. "After a few calls between our IS and their engineers, the connection between our patient accounting system, Paragon, and the Atlas platform was set up and fully ramped."They were even able to connect to our pharmacy dispensing system to capture provider orders without our team members having to reach out for this information each time," he added.RESULTSAtlas paid for itself in the first month, Jones said."Within the first 90 days, we exceeded our philanthropic goal by 185%," he said.

"Every patient infused at our center was screened and enrolled in a program if one was available."Some previous balances that were written off to charity or bad debt symbicort patient assistance were retroactively eligible to be submitted to certain programs for payment. Our patients were able to sit in their infusion chairs and focus on getting better, instead of worrying about how they were going to pay for that visit."The next 90 days we exceeded our goal by 134%, as we were maintaining the patient's programs and enrolling new patients proactively," he continued. "At that time, Atlas had enough data to find that roughly 30% of our infusion center's patients might be eligible for symbicort patient assistance the state-funded program, Georgia Cancer State Aid.

And they facilitated our hospital becoming a participating provider. This step will alleviate symbicort patient assistance even more financial burden for our patients."The hospital anticipates it will exceed its goal for the year by at least 110% because it's on track to capture more than $1 million in philanthropic aid for patients. This is for balances that symbicort patient assistance would have otherwise been written off to charity or bad debt.

This is funding that it can use for other projects to better serve the community.ADVICE FOR OTHERS"Do the research and include all parties that would be involved in the process," Jones advised. "It is instrumental to symbicort patient assistance the success of a new process to pull in everyone so you can get a clear picture of what your present state is, what energy is being used and the real pain points of your current program."In the end, you always want to do what is right for your patients and community," he added. "No one will know this better than the team that works with them daily."Once one finds the right healthcare information technology company, be a champion, he suggested."With so many different team members and departments often involved in decision-making, someone needs to take the lead and champion the change and solution-integration for the benefit of their patients and community," he concluded.Twitter.

@SiwickiHealthITEmail the writer symbicort patient assistance. Bsiwicki@himss.orgHealthcare IT News is a HIMSS Media publication..

For Wayne Memorial http://mchtranslations.com/buy-kamagra-100mg-oral-jelly Hospital in Jesup, Georgia, symbicort 400mcg 6mcg price the care staff gives patients is personal. The hospital's financial assistance program was created to ensure patients were not forgoing life-saving symbicort 400mcg 6mcg price treatment due to costs. Because of this, the hospital has generous specifications to qualify.THE PROBLEMHowever, the hospital has to pay attention to its expenses as much as its revenue, since it has thin financial margins.

Rural hospitals can go down quickly if they are not attentive to these symbicort 400mcg 6mcg price trends. Everything counts."We were only able to dedicate one employee to search manually for possible programs to assist our patients with their out-of-pocket expenses," said Greg Jones, CFO at Wayne Memorial Hospital. "This was time-consuming and symbicort 400mcg 6mcg price could be emotionally stressful as our team member was determined to assist each patient."Every patient had someone depending on them to provide food or shelter, to nurture or love," he continued.

"It was very frustrating not being able to come through for all of them. We were able to assist maybe 10-20% of our patients through a select few programs, while the remainder of the patient's out-of-pocket symbicort 400mcg 6mcg price responsibility was written off to the hospital's charity or bad debt."As the hospital accrued costs for patient care, it was not seeing the revenue to cover it. It implemented a few policies and procedures to decrease any possible revenue barriers on the front end, like ensuring prior authorizations are in place for high-cost infusions, accurate processes at registration and specialized, knowledgeable staff reviewing all claims in billing."Changes like this can really help prevent denials that ultimately cost the hospital, but, for the long run, it may not be enough," Jones noted symbicort 400mcg 6mcg price.

"The worst thing to happen is to be faced with not being able to help our patients or the hospital failing. Something had to be symbicort 400mcg 6mcg price done."PROPOSALJones and his team turned to health IT vendor Atlas Health. Because of a previous implementation with a partner hospital, Atlas knew the pressure points for a rural hospital with limited resources to assist patients, Jones said, and the company seemed dedicated to helping the community as much as the hospital was."The solution was straightforward," he said.

"Our hospital would have more than 10,000 programs at its fingertips to assist symbicort 400mcg 6mcg price patients with their out-of-pocket expenses. The platform would proactively match the patients up to those programs without a person searching manually through all of the information, and the enrollment process would be automated."With this level of transparency and automation, we could leverage all possible sources of patient assistance prior to writing off these debts to charity or bad debt."Greg Jones, Wayne Memorial Hospital"Atlas explained how one team member could do the work of three and screen all of our patients prior to leveraging our charity program," he added. "Another part of the solution that was proactive was that the system would be integrated with our EHR, so when a patient was scheduled for an infusion symbicort 400mcg 6mcg price the Atlas platform would match patients up to programs prior to the patient having a balance."This would allow for the team to identify patients for state programs like Medicaid or MSPs and optimize the financial navigation for all patients, he added.

The hospital would go from assisting 10-20% of patients to advocating for the entire infusion center's census, he said."With this level of transparency and automation, we could leverage all possible symbicort 400mcg 6mcg price sources of patient assistance prior to writing off these debts to charity or bad debt," he explained. "That would allow us to assist our community in other charity projects outside of the infusion center. The solution symbicort 400mcg 6mcg price Atlas offered was aligned with our mission and focus.

It was an easy decision."MEETING THE CHALLENGEThe way Wayne Memorial Hospital's team uses the technology to assist patients now is fairly simple. A list is symbicort 400mcg 6mcg price created daily by Atlas for the hospital's advocate to review. The platform automates everything needed for the patient's enrollment.If there are any other documents that are needed for a patient's enrollment, the team can collect these electronically from the patient using Atlas.

There is a spot for different departments to tag and communicate with each other so all stakeholders are aware of each patient's status.When an enrollment is completed, all of the post-enrollment awards and symbicort 400mcg 6mcg price ordering can be tracked from the platform. "It's a one-stop shop for symbicort 400mcg 6mcg price all parties involved in a patient's treatment and care," Jones said.The implementation was easy, he added."Atlas already had the code needed to pull the necessary information from our EHR to match patients in programs within the platform," he noted. "After a few calls between our IS and their engineers, the connection between our patient accounting system, Paragon, and the Atlas platform was set up and fully ramped."They were even able to connect to our pharmacy dispensing system to capture provider orders without our team members having to reach out for this information each time," he added.RESULTSAtlas paid for itself in the first month, Jones said."Within the first 90 days, we exceeded our philanthropic goal by 185%," he said.

"Every patient infused at our center symbicort 400mcg 6mcg price was screened and enrolled in a program if one was available."Some previous balances that were written off to charity or bad debt were retroactively eligible to be submitted to certain programs for payment. Our patients were able to sit in their infusion chairs and focus on getting better, instead of worrying about how they were going to pay for that visit."The next 90 days we exceeded our goal by 134%, as we were maintaining the patient's programs and enrolling new patients proactively," he continued. "At that time, Atlas had symbicort 400mcg 6mcg price enough data to find that roughly 30% of our infusion center's patients might be eligible for the state-funded program, Georgia Cancer State Aid.

And they facilitated our hospital becoming a participating provider. This step will alleviate even more financial burden for our patients."The hospital anticipates it will exceed its goal for the year by at least 110% because it's on track to capture more than $1 million in philanthropic symbicort 400mcg 6mcg price aid for patients. This is for balances symbicort 400mcg 6mcg price that would have otherwise been written off to charity or bad debt.

This is funding that it can use for other projects to better serve the community.ADVICE FOR OTHERS"Do the research and include all parties that would be involved in the process," Jones advised. "It is instrumental to the success of a new process to pull in everyone so you can get symbicort 400mcg 6mcg price a clear picture of what your present state is, what energy is being used and the real pain points of your current program."In the end, you always want to do what is right for your patients and community," he added. "No one will know this better than the team that works with them daily."Once one finds the right healthcare information technology company, be a champion, he suggested."With so many different team members and departments often involved in decision-making, someone needs to take the lead and champion the change and solution-integration for the benefit of their patients and community," he concluded.Twitter.

@SiwickiHealthITEmail the symbicort 400mcg 6mcg price writer. Bsiwicki@himss.orgHealthcare IT News is a HIMSS Media publication..

How should I take Symbicort?

Budesonide+Formoterol may increase the risk of asthma-related death. Use only the prescribed dose of Budesonide+Formoterol, and do not use it for longer than your doctor recommends. Follow all patient instructions for safe use. Talk with your doctor about your individual risks and benefits in using this medication. Do not use Budesonide+Formoterol to treat an asthma attack that has already begun. It will not work fast enough. Use only a fast-acting inhalation medication.
Prime the Budesonide+Formoterol inhaler device before the first use by pumping 2 test sprays into the air, away from your face. Shake the inhaler for at least 5 seconds before each spray. Prime the inhaler if it has not been used for longer than 7 days, or if the inhaler has been dropped.

If you also use a steroid medication, do not stop using the steroid suddenly or you may have unpleasant withdrawal symptoms. Talk with your doctor about using less and less of the steroid before stopping completely.

Use all of your medications as directed by your doctor.

Do not use a second form of Formoterol or use a similar inhaled bronchodilator such as salmeterol or arFormoterol unless your doctor has told you to.

Quit symbicort cold turkey

You may be hearing about how virtual care, often described as telehealth or telemedicine, quit symbicort cold turkey is beneficial during anti inflammatory drugs and how health systems are offering virtual helpful resources access like never before. There’s a reason for that, too. For the past few weeks I’ve seen Facebook posts daily from former nursing colleagues in metro Detroit, one of the hardest hit areas in the country, as they provide front-line care to patients with anti inflammatory drugs.

It makes quit symbicort cold turkey me very proud to call these nurses my friends. As a former emergency department nurse, I recall the feeling of satisfaction knowing that I’ve helped someone on the worst day of their life. One of the best parts of being a nurse is knowing you matter to the only person in health care that truly matters.

The patient quit symbicort cold turkey. Several years ago I made the difficult decision to no longer perform bedside nursing and become a nurse administrator. The biggest loss from my transition is the feeling that what I do matters to the patient.

anti inflammatory drugs has forced quit symbicort cold turkey a lot of us to rethink the role we play in health care and what the real priority should be. Things that were top priorities three months ago have been rightfully cast aside to either care for patients in a symbicort or prepare for the unknown future of, “When is our turn?. € For me, anti inflammatory drugs has reignited the feeling that what I do matters as virtual care has become a powerful tool on the forefront of care during this crisis.

It has also shown that many of the powerful rules and regulations that limit virtual care are not quit symbicort cold turkey needed and should be discarded permanently. When I became the director of virtual care at our organization in 2015 I knew nothing about telehealth. Sure, I had seen a stroke robot in some Emergency Departments, and I had some friends that told me their insurance company lets them FaceTime a doctor for free (spoiler alert.

It’s not quit symbicort cold turkey FaceTime). I was tech-savvy from a consumer perspective and a tech novice from an IT perspective. Nevertheless, my team and I spent the next few years learning as we built one of the higher volume virtual care networks in the state of Michigan.

We discovered a lot of barriers that keep virtual care from actually making the lives of patients and providers better and quit symbicort cold turkey we also became experts in working around those barriers. But, there were two obstacles that we could not overcome. Government regulation and insurance provider willingness to cover virtual visits.

These two barriers effectively cripple most legitimate attempts to provide value-added direct-to-consumer virtual care, which I define quit symbicort cold turkey as using virtual care technologies to provide care outside of our brick-and-mortar facilities, most commonly in the patient home. The need to social distance, cancel appointments, close provider offices, keep from overloading emergency departments and urgent cares and shelter in place created instant demand for direct-to-consumer virtual care. In all honesty, I’ve always considered direct-to-consumer virtual care to be the flashy, must-have holiday gift of the year that organizations are convinced will be the way of the future.

If a health system wants to provide on-demand access to patients for low-complexity acute conditions, they will easily find quit symbicort cold turkey plenty of vendors that will sell them their app and their doctors and put the health system’s logo on it. What a health system will struggle with is to find is enough patient demand to cover the high cost. Remember my friends from earlier that told me about the app their insurance gave them?.

Nearly all of them followed that up by telling me they’ve quit symbicort cold turkey never actually used it. I am fortunate that I work for an organization that understands this and instead focuses on how can we provide care that our patients actually want and need from the doctors they want to see. Ironically, this fiscal year we had a corporate top priority around direct-to-consumer virtual care.

We wanted to expand what we thought were some quit symbicort cold turkey successful pilots and perform 500 direct-to-consumer visits. This year has been one of the hardest of my leadership career because, frankly, up until a month ago I was about to fail on this top priority. With only four months left, we were only about halfway there.

The biggest quit symbicort cold turkey problem we ran into was that every great idea a physician brought to me was instantly dead in the water because practically no insurance company would pay for it. There are (prior to anti inflammatory drugs) a plethora of rules around virtual care billing but the simplest way to summarize it is that most virtual care will only be paid if it happens in a rural location and inside of a health care facility. It is extremely limited what will be paid for in the patient home and most of it is so specific that the average patient isn’t eligible to get any in-home virtual care.

Therefore, most good medical uses for direct-to-consumer care quit symbicort cold turkey would be asking the patient to pay cash or the physician to forgo reimbursement for a visit that would be covered if it happened in office. Add to that the massive capital and operating expenses it takes to build a virtual care network and you can see why these programs don’t exist. A month ago I was skeptical we’d have a robust direct-to-consumer program any time soon and then anti inflammatory drugs hit.

When anti inflammatory drugs started to spread rapidly in the quit symbicort cold turkey United States, regulations and reimbursement rules were being stripped daily. The first change that had major impact is when the Centers for Medicare and Medicaid Services (CMS) announced that they would temporarily begin reimbursing for virtual visits conducted in the patient’s home for anti inflammatory drugs and non-anti inflammatory drugs related visits. We were already frantically designing a virtual program to handle the wave of anti inflammatory drugs screening visits that were overloading our emergency departments and urgent cares.

We were having plenty of discussions around reimbursement for this quit symbicort cold turkey clinic. Do we attempt to bill insurances knowing they will likely deny, do we do a cash clinic model or do we do this as a community benefit and eat the cost?. The CMS waiver gave us hope that we would be compensated for diverting patients away from reimbursed visits to a virtual visit that is more convenient for the patient and aligns with the concept of social distancing.

Realistically we don’t know if we will quit symbicort cold turkey be paid for any of this. We are holding all of the bills for at least 90 days while the industry sorts out the rules. I was excited by the reimbursement announcement because I knew we had eliminated one of the biggest direct-to-consumer virtual care barriers.

However, I was quickly brought back to reality when I was reminded quit symbicort cold turkey that HIPAA (Health Insurance Portability and Accountability Act) still existed. I had this crazy idea that during a symbicort we should make it as easy as possible for people to receive virtual care and that the best way to do that was to meet the patient on the device they are most comfortable with and the application (FaceTime, Facebook, Skype, etc.) that they use every day. The problem is nearly every app the consumer uses on a daily basis is banned by HIPAA because “it’s not secure.” I’m not quite sure what a hacker stands to gain by listening into to my doctor and me talk about how my kids yet again gave me strep throat but apparently the concern is great enough to stifle the entire industry.

Sure, not every health care discussion is as low-key as strep throat and a patient may want to quit symbicort cold turkey protect certain topics from being discussed over a “non-secure” app but why not let the patient decide through informed consent?. Regulators could also abandon this all-or-nothing approach and lighten regulations surrounding specific health conditions. The idea that regulations change based on medical situation is not new.

For example, in my home state of Michigan, adolescents are essentially considered emancipated if it involves sexual health, mental health or quit symbicort cold turkey substance abuse. Never mind that this same information is freely given over the phone by every office around the country daily without issue, but I digress. While my job is to innovate new pathways for care, our lawyer’s job is to protect the organization and he, along with IT security, rightfully shot down my consumer applications idea.

A few days later I legitimately screamed out loud in joy when the Department of Health and Human Services announced that it would use discretion on enforcing quit symbicort cold turkey HIPAA compliance rules and specifically allowed for use of consumer applications. The elimination of billing restrictions and HIPAA regulations changed what is possible for health care organizations to offer virtually. Unfortunately both changes are listed as temporary and will likely be removed when the symbicort ends.

Six days after the HIPAA changes were announced, we launched a centralized virtual quit symbicort cold turkey clinic for any patient that wanted a direct-to-consumer video visit to be screened by a provider for anti inflammatory drugs. It allows patients to call in without a referral and most patients are on-screen within five minutes of clicking the link we text them. They don’t have to download an app, create an account or even be an established patient of our health system.

It saw over 900 patients in the quit symbicort cold turkey first 12 days it was open. That is 900 real patients that received care from a physician or advanced practice provider without risking personal exposure and without going to an already overwhelmed ED or urgent care. To date, 70 percent of the patients seen by the virtual clinic did not meet CDC testing criteria for anti inflammatory drugs.

I don’t believe we quit symbicort cold turkey could have reached even half of these patients had the consumer application restrictions been kept. A program like this almost certainly wouldn’t exist if not for the regulations being lifted and even if it did, it would have taken six to 12 months to navigate barriers and implement in normal times. Sure, the urgency of a symbicort helps but the impact of provider, patients, regulators and payors being on the same page is what fueled this fire.

During the virtual clinic’s first two weeks, my team turned its attention to getting over 300 providers across 60+ offices virtual so they could see quit symbicort cold turkey their patients at home. Imagine being an immunocompromised cancer patient right now and being asked to leave your home and be exposed to other people in order to see your oncologist. Direct-to-consumer virtual care is the best way to safely care for these patients and without these temporary waivers it wouldn’t be covered by insurance even if you did navigate the clunky apps that are HIPAA compliant.

Do we really think the immunocompromised cancer patient feels any more comfortable every normal quit symbicort cold turkey flu season?. Is it any more appropriate to ask them to risk exposure to the flu than it is to anti inflammatory drugs?. And yet we deny them this access in normal times and it quite possibly will be stripped away from them when this crisis is over.

Now 300 to 400 patients per day in our health quit symbicort cold turkey system are seen virtually by their own primary care doctor or specialist for non-anti inflammatory drugs related visits. Not a single one of these would have been reimbursed one month ago and I am highly skeptical I would have gotten approval to use the software that connects us to the patient. Lastly, recall that prior to anti inflammatory drugs, our system had only found 250 total patients that direct-to-consumer care was value-added and wasn’t restricted by regulation or reimbursement.

anti inflammatory drugs has been a wake-up call to the whole country and health care is no quit symbicort cold turkey exception. It has put priorities in perspective and shined a light on what is truly value-added. For direct-to-consumer virtual care it has shown us what is possible when we get out of our own way.

If a regulation has to be removed to allow for care during a crisis then we must question why it quit symbicort cold turkey exists in the first place. HIPAA regulation cannot go back to its antiquated practices if we are truly going to shift the focus to patient wellness. CMS and private payors must embrace value-added direct-to-consumer virtual care and allow patients the access they deserve.

anti inflammatory drugs has quit symbicort cold turkey forced this industry forward, we cannot allow it to regress and be forgotten when this is over. Tom Wood is the director of trauma and virtual care for MidMichigan Health, a non-profit health system headquartered in Midland, Michigan, affiliated with Michigan Medicine, the health care division of the University of Michigan. The views and opinions expressed in this commentary are his own.When dealing with all of the aspects of diabetes, it’s easy to let your feel fall to the bottom of the list.

But daily care and evaluation is one quit symbicort cold turkey of the best ways to prevent foot complications. It’s important to identify your risk factors and take the proper steps in limiting your complications. Two of the biggest complications with diabetes are peripheral neuropathy and ulcer/amputation.

Symptoms of peripheral neuropathy include numbness, tingling and/or burning in your feet quit symbicort cold turkey and legs. You can slow the progression of developing neuropathy by making it a point to manage your blood sugars and keep them in the normal range. If you are experiencing these symptoms, it is important to establish and maintain a relationship with a podiatrist.

Your podiatrist can make sure things are quit symbicort cold turkey looking healthy and bring things to your attention to monitor and keep a close eye on. Open wounds or ulcers can develop secondary to trauma, pressure, diabetes, neuropathy or poor circulation. If ulcerations do develop, it’s extremely important to identify the cause and address it.

Ulcers can quit symbicort cold turkey get worse quickly, so it’s necessary to seek immediate medical treatment if you find yourself or a loved one dealing with this complication. Untreated ulcerations often lead to amputation and can be avoided if proper medical attention is sought right away. There are important things to remember when dealing with diabetic foot care.

It’s very important to inspect your feet daily, especially quit symbicort cold turkey if you have peripheral neuropathy. You may have a cut or a sore on your feet that you can’t feel, so your body doesn’t alarm you to check your feet. Be gentle when bathing your feet.

Moisturize your feet, but not between quit symbicort cold turkey your toes. Do not treat calluses or corns on your own. Wear clean, dry socks.

Never walk barefoot, and consider socks and shoes made specifically for patients with diabetes.

You may be hearing about how virtual care, often described as telehealth or telemedicine, is beneficial during anti inflammatory drugs and how health systems are symbicort 400mcg 6mcg price offering virtual access like never before. There’s a reason for that, too. For the past few weeks I’ve seen Facebook posts daily from former nursing colleagues in metro Detroit, one of the hardest hit areas in the country, as they provide front-line care to patients with anti inflammatory drugs. It makes me symbicort 400mcg 6mcg price very proud to call these nurses my friends.

As a former emergency department nurse, I recall the feeling of satisfaction knowing that I’ve helped someone on the worst day of their life. One of the best parts of being a nurse is knowing you matter to the only person in health care that truly matters. The patient symbicort 400mcg 6mcg price. Several years ago I made the difficult decision to no longer perform bedside nursing and become a nurse administrator.

The biggest loss from my transition is the feeling that what I do matters to the patient. anti inflammatory drugs has forced a lot of us to rethink the role we play in health care and what the real priority symbicort 400mcg 6mcg price should be. Things that were top priorities three months ago have been rightfully cast aside to either care for patients in a symbicort or prepare for the unknown future of, “When is our turn?. € For me, anti inflammatory drugs has reignited the feeling that what I do matters as virtual care has become a powerful tool on the forefront of care during this crisis.

It has also shown that many of symbicort 400mcg 6mcg price the powerful rules and regulations that limit virtual care are not needed and should be discarded permanently. When I became the director of virtual care at our organization in 2015 I knew nothing about telehealth. Sure, I had seen a stroke robot in some Emergency Departments, and I had some friends that told me their insurance company lets them FaceTime a doctor for free (spoiler alert. It’s not symbicort 400mcg 6mcg price FaceTime).

I was tech-savvy from a consumer perspective and a tech novice from an IT perspective. Nevertheless, my team and I spent the next few years learning as we built one of the higher volume virtual care networks in the state of Michigan. We discovered a lot of barriers that symbicort 400mcg 6mcg price keep virtual care from actually making the lives of patients and providers better and we also became experts in working around those barriers. But, there were two obstacles that we could not overcome.

Government regulation and insurance provider willingness to cover virtual visits. These two barriers effectively cripple most legitimate attempts to provide value-added direct-to-consumer virtual care, which I define as using virtual care technologies to provide care symbicort 400mcg 6mcg price outside of our brick-and-mortar facilities, most commonly in the patient home. The need to social distance, cancel appointments, close provider offices, keep from overloading emergency departments and urgent cares and shelter in place created instant demand for direct-to-consumer virtual care. In all honesty, I’ve always considered direct-to-consumer virtual care to be the flashy, must-have holiday gift of the year that organizations are convinced will be the way of the future.

If a health system wants to provide on-demand access to patients for low-complexity acute conditions, they will easily find plenty of vendors that will sell them their app and their doctors and put symbicort 400mcg 6mcg price the health system’s logo on it. What a health system will struggle with is to find is enough patient demand to cover the high cost. Remember my friends from earlier that told me about the app their insurance gave them?. Nearly all of them followed that symbicort 400mcg 6mcg price up by telling me they’ve never actually used it.

I am fortunate that I work for an organization that understands this and instead focuses on how can we provide care that our patients actually want and need from the doctors they want to see. Ironically, this fiscal year we had a corporate top priority around direct-to-consumer virtual care. We wanted to expand what we thought were some successful pilots and perform symbicort 400mcg 6mcg price 500 direct-to-consumer visits. This year has been one of the hardest of my leadership career because, frankly, up until a month ago I was about to fail on this top priority.

With only four months left, we were only about halfway there. The biggest problem we ran into was that every great idea a physician brought to me was instantly dead in the water because symbicort 400mcg 6mcg price practically no insurance company would pay for it. There are (prior to anti inflammatory drugs) a plethora of rules around virtual care billing but the simplest way to summarize it is that most virtual care will only be paid if it happens in a rural location and inside of a health care facility. It is extremely limited what will be paid for in the patient home and most of it is so specific that the average patient isn’t eligible to get any in-home virtual care.

Therefore, most good medical uses for direct-to-consumer care would be asking the patient symbicort 400mcg 6mcg price to pay cash or the physician to forgo reimbursement for a visit that would be covered if it happened in office. Add to that the massive capital and operating expenses it takes to build a virtual care network and you can see why these programs don’t exist. A month ago I was skeptical we’d have a robust direct-to-consumer program any time soon and then anti inflammatory drugs hit. When anti inflammatory drugs started to spread rapidly in the United States, regulations and symbicort 400mcg 6mcg price reimbursement rules were being stripped daily.

The first change that had major impact is when the Centers for Medicare and Medicaid Services (CMS) announced that they would temporarily begin reimbursing for virtual visits conducted in the patient’s home for anti inflammatory drugs and non-anti inflammatory drugs related visits. We were already frantically designing a virtual program to handle the wave of anti inflammatory drugs screening visits that were overloading our emergency departments and urgent cares. We symbicort 400mcg 6mcg price were having plenty of discussions around reimbursement for this clinic. Do we attempt to bill insurances knowing they will likely deny, do we do a cash clinic model or do we do this as a community benefit and eat the cost?.

The CMS waiver gave us hope that we would be compensated for diverting patients away from reimbursed visits to a virtual visit that is more convenient for the patient and aligns with the concept of social distancing. Realistically we don’t symbicort 400mcg 6mcg price know if we will be paid for any of this. We are holding all of the bills for at least 90 days while the industry sorts out the rules. I was excited by the reimbursement announcement because I knew we had eliminated one of the biggest direct-to-consumer virtual care barriers.

However, I was quickly symbicort 400mcg 6mcg price brought back to reality when I was reminded that HIPAA (Health Insurance Portability and Accountability Act) still existed. I had this crazy idea that during a symbicort we should make it as easy as possible for people to receive virtual care and that the best way to do that was to meet the patient on the device they are most comfortable with and the application (FaceTime, Facebook, Skype, etc.) that they use every day. The problem is nearly every app the consumer uses on a daily basis is banned by HIPAA because “it’s not secure.” I’m not quite sure what a hacker stands to gain by listening into to my doctor and me talk about how my kids yet again gave me strep throat but apparently the concern is great enough to stifle the entire industry. Sure, not every health care discussion is as low-key as strep symbicort 400mcg 6mcg price throat and a patient may want to protect certain topics from being discussed over a “non-secure” app but why not let the patient decide through informed consent?.

Regulators could also abandon this all-or-nothing approach and lighten regulations surrounding specific health conditions. The idea that regulations change based on medical situation is not new. For example, in my home state of Michigan, symbicort 400mcg 6mcg price adolescents are essentially considered emancipated if it involves sexual health, mental health or substance abuse. Never mind that this same information is freely given over the phone by every office around the country daily without issue, but I digress.

While my job is to innovate new pathways for care, our lawyer’s job is to protect the organization and he, along with IT security, rightfully shot down my consumer applications idea. A few days later I legitimately screamed out loud in joy when the Department of Health and Human Services announced that it would use symbicort 400mcg 6mcg price discretion on enforcing HIPAA compliance rules and specifically allowed for use of consumer applications. The elimination of billing restrictions and HIPAA regulations changed what is possible for health care organizations to offer virtually. Unfortunately both changes are listed as temporary and will likely be removed when the symbicort ends.

Six days after the HIPAA changes symbicort 400mcg 6mcg price were announced, we launched a centralized virtual clinic for any patient that wanted a direct-to-consumer video visit to be screened by a provider for anti inflammatory drugs. It allows patients to call in without a referral and most patients are on-screen within five minutes of clicking the link we text them. They don’t have to download an app, create an account or even be an established patient of our health system. It saw over 900 patients in the first 12 symbicort 400mcg 6mcg price days it was open.

That is 900 real patients that received care from a physician or advanced practice provider without risking personal exposure and without going to an already overwhelmed ED or urgent care. To date, 70 percent of the patients seen by the virtual clinic did not meet CDC testing criteria for anti inflammatory drugs. I don’t believe we could have reached even half symbicort 400mcg 6mcg price of these patients had the consumer application restrictions been kept. A program like this almost certainly wouldn’t exist if not for the regulations being lifted and even if it did, it would have taken six to 12 months to navigate barriers and implement in normal times.

Sure, the urgency of a symbicort helps but the impact of provider, patients, regulators and payors being on the same page is what fueled this fire. During the virtual clinic’s first two weeks, my team turned its attention to getting over 300 providers across 60+ offices virtual so they could see their patients symbicort 400mcg 6mcg price at home. Imagine being an immunocompromised cancer patient right now and being asked to leave your home and be exposed to other people in order to see your oncologist. Direct-to-consumer virtual care is the best way to safely care for these patients and without these temporary waivers it wouldn’t be covered by insurance even if you did navigate the clunky apps that are HIPAA compliant.

Do we really symbicort 400mcg 6mcg price think the immunocompromised cancer patient feels any more comfortable every normal flu season?. Is it any more appropriate to ask them to risk exposure to the flu than it is to anti inflammatory drugs?. And yet we deny them this access in normal times and it quite possibly will be stripped away from them when this crisis is over. Now 300 to 400 patients per day in our health system symbicort 400mcg 6mcg price are seen virtually by their own primary care doctor or specialist for non-anti inflammatory drugs related visits.

Not a single one of these would have been reimbursed one month ago and I am highly skeptical I would have gotten approval to use the software that connects us to the patient. Lastly, recall that prior to anti inflammatory drugs, our system had only found 250 total patients that direct-to-consumer care was value-added and wasn’t restricted by regulation or reimbursement. anti inflammatory drugs has been a wake-up symbicort 400mcg 6mcg price call to the whole country and health care is no exception. It has put priorities in perspective and shined a light on what is truly value-added.

For direct-to-consumer virtual care it has shown us what is possible when we get out of our own way. If a regulation has to be removed to allow for care symbicort 400mcg 6mcg price during a crisis then we must question why it exists in the first place. HIPAA regulation cannot go back to its antiquated practices if we are truly going to shift the focus to patient wellness. CMS and private payors must embrace value-added direct-to-consumer virtual care and allow patients the access they deserve.

anti inflammatory drugs has forced this industry forward, we symbicort 400mcg 6mcg price cannot allow it to regress and be forgotten when this is over. Tom Wood is the director of trauma and virtual care for MidMichigan Health, a non-profit health system headquartered in Midland, Michigan, affiliated with Michigan Medicine, the health care division of the University of Michigan. The views and opinions expressed in this commentary are his own.When dealing with all of the aspects of diabetes, it’s easy to let your feel fall to the bottom of the list. But daily symbicort 400mcg 6mcg price care and evaluation is one of the best ways to prevent foot complications.

It’s important to identify your risk factors and take the proper steps in limiting your complications. Two of the biggest complications with diabetes are peripheral neuropathy and ulcer/amputation. Symptoms of peripheral neuropathy include numbness, tingling and/or burning in symbicort 400mcg 6mcg price your feet and legs. You can slow the progression of developing neuropathy by making it a point to manage your blood sugars and keep them in the normal range.

If you are experiencing these symptoms, it is important to establish and maintain a relationship with a podiatrist. Your podiatrist can make sure things are looking healthy and bring things to your attention to monitor and keep a close symbicort 400mcg 6mcg price eye on. Open wounds or ulcers can develop secondary to trauma, pressure, diabetes, neuropathy or poor circulation. If ulcerations do develop, it’s extremely important to identify the cause and address it.

Ulcers can get worse quickly, so it’s necessary to seek immediate medical treatment if you find yourself or a loved one dealing with this symbicort 400mcg 6mcg price complication. Untreated ulcerations often lead to amputation and can be avoided if proper medical attention is sought right away. There are important things to remember when dealing with diabetic foot care. It’s very symbicort 400mcg 6mcg price important to inspect your feet daily, especially if you have peripheral neuropathy.

You may have a cut or a sore on your feet that you can’t feel, so your body doesn’t alarm you to check your feet. Be gentle when bathing your feet. Moisturize your feet, but not between your toes. Do not treat calluses or corns on your own.

Wear clean, dry socks. Never walk barefoot, and consider socks and shoes made specifically for patients with diabetes.

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Thirty percent of unvaccinated American adults say they’re waiting for the anti inflammatory drugs treatments currently authorized for emergency use to be officially approved by symbicort spacer the U.S who can buy symbicort. Food and Drug Administration. The FDA has since granted that approval for those age 16 and older for the Pfizer-BioNTech treatment on Aug symbicort spacer.

23, 2021. What had to happen symbicort spacer for the FDA to advance from emergency use authorization, or EUA, to full approval?. I’m a pharmacist who trains other pharmacists, health care providers and students on why, when and how to administer treatments.

Emergency use authorization, while streamlining the regulatory symbicort spacer process so the treatment is more quickly available to the public, still follows a rigorous process the FDA requires to ensure treatment safety and effectiveness. The difference is that more time has passed and more data is available for review when a company applies for full approval.[embedded content]EUA and Full Approval Share Similar First StepsFor both emergency authorization and full approval, for anti inflammatory drugs treatments, the FDA first requires initial safety studies on a small number of people. Here, researchers document potential adverse events, symbicort spacer or side effects, that the treatment may cause.

Researchers also determine the safest and most effective dose of the treatment.Once the treatment is determined to be safe and an optimal dose identified, researchers will create larger studies to ascertain how well it works in a controlled setting where some people are given the treatment while others are given a placebo.It is important to note that the number of people who participated in the initial anti inflammatory drugs safety studies was similar to that in the safety studies of other commonly used treatments, including treatments for tetanus, diphtheria, whooping cough and meningitis. Over 43,000 adults participated in the early phases of the Pfizer-BioNTech symbicort spacer clinical trial, over 30,400 in Moderna’s and over 44,000 in Johnson and Johnson’s. Half the participants in each study were given a treatment, while the other half were given a placebo.Where EUA and Full Approval DifferFrom this point on, emergency use authorization and full FDA approval for anti inflammatory drugs treatments follow different clinical study requirements.For the emergency use authorization, the FDA requires at least half of the participants of the original studies to be followed for at least two months post-vaccination.

This is because the vast majority symbicort spacer of treatment-related side effects occur right after vaccination.Full FDA approval, on the other hand, requires participants in the original studies to be followed for at least six months. Reviewers look at data from the same study participants but collected over a longer period of time. All adverse events are examined.

The manufacturer must also provide more detailed manufacturing plans and processes, symbicort spacer as well as a higher level of oversight and inspections. All of this adds significantly more time to the review process.Full FDA approval involves reviewing more data after a longer observational period. (Credit.

SOPA Images/LightRocket via Getty Images)Both Pfizer and Moderna began their rolling submission for approval in the FDA’s “Fast Track” process, designed to speed up review. This allows the companies to submit portions of their approval application to the FDA for review as they’re completed.Full FDA approval will initially apply to only the same age groups that were tested in the original emergency use authorization. This means that the treatment has been approved first for people ages 16 and up for Pfizer, and will likely be approved for those 18 and up for Moderna.

Rolling submission will allow approval of the treatment for younger groups as more data becomes available.Different Timelines, Same Rigorous RequirementsFull FDA approval is a milestone that may help build confidence among the treatment hesitant about the safety of the treatments. But the true test of the treatment came when it first gained emergency use authorization. Then, researchers identified the majority of its potential side effects and proved its ability to protect against severe disease.Article updated on Aug.

23, 2021 to reflect FDA approval of Pfizer BioNTech treatment for those ages 16 and older.Jennifer Girotto is an associate clinical professor of pharmacy practice ar the University of Connecticut is a clinical physician and assistant professor at the University of Virginia. This article is republished from The Conversation under a Creative Commons license. Read the original article.This site contains affiliate links to products.

We may receive a commission for purchases made through these links.CBD oils have exploded in popularity over the past few years.What started as a niche treatment for those with epilepsy and other medical issues has blossomed into an industry that people are using for an array of reasons. From simple relaxation to alleviating pain, CBD users report that oils help with improve their lives day-in and day-out. However, despite the positive word of mouth, knowing the best CBD oil to start with can be a tough challenge.As CBD’s popularity has grown, so have the number shady actors surrounding it.

Due to this, it’s important to know not only who to trust but also who has the best CBD oil and why. By using a number of different criteria including quality of sourcing, strength of hemp, and reputation in the industry, we’ve decided to compile this list of the best CBD oils on the market today. No matter if you’ve been into it for a while or a newbie (we won’t judge), this list will inform you on what you need to know about CBD oil.

Here’s what we’ve learned:1. Verma FarmsThe top brand in CBD, Verma Farms has been winning awards left and right for the past couple of years, and 2021 is no exception. This is the gold standard of CBD tinctures.What Verma does well is provide a solution that helps set the standard for how CBD oils should be.

Starting out with very intent-driven oils like Focus, Chill, and Boost, they began diversifying their lineup to include more fruit-flavored varieties as well, such as Lemon Lime, Pineapple, Strawberry, Watermelon, Mango, and Peach. As all of them use natural, vegan ingredients, Verma has stripped down their offering to host only the standards but doing it well, sourcing all their oil’s materials from inside the US.An overall great brand, Verma Farms is an easy number one for any CBD fan out there.2. Penguin CBDAnother brand constantly ranked towards the top of the industry, Penguin CBD has been at the forefront of CBD research and development.

After all, if you’re not familiar, Penguin CBD is one of the most popular brands among Gen Z.For their CBD oil, Penguin CBD remains one of the best at creating a top-tier product. Hosting oils that range all the way to 2500 mg, their formulas all contain broad spectrum CBD. As trendsetters in the industry, Penguin CBD continues to set the bar over almost all the competition.Medterra is one of the world’stop CBD brands, in large part due to their unwavering dedication to making topquality CBD and offering it at a great price.

They pack tons of value intotheir tinctures and have different options for different CBD users. Both isolate and Ua Broad Spectrum tinctures are availablein multiple strengths and flavors, and all are made from American-grown,organic, non-GMO, US Hemp Authority-certified hemp. For CBD users seekingbroader benefits, Ua Broad Spectrum contains a 10:1 ratio of CBD to otherbeneficial hemp compounds for the most potent broad spectrum on the market,while isolates are great when you’re looking for pure CBD.

R+R Medicinals is quickly becoming one of the most trusted and popular CBD brands by proving one thing - they make the CBD that works. Using supercritical CO2 extraction on their proprietary Cherry strain of USDA Certified Organic hemp, they yield an unparalleled profile of cannabinoids, terpenes, and other phytonutrients in their products that translate into guaranteed performance. Their 1000mg Fresh Mint Tincture is their best seller and of incredible value for a Full-Spectrum product at $46.99.

R+R boasts impressive levels of CBD, CBG, CBC, CBN, CBL, and more in their products so you can truly feel the entourage effect. They also publish third party certificates of analysis on their site for every batch they make. In addition to being USDA Organic Certified, they are also US Hemp Authority Certified, and they have hundreds of 5-star ratings on Google, so you can take comfort in knowing they do things with the highest standards of safety and quality in mind.

With a name like Evn-CBD, it’s hard to go wrong. Not only do they live up to their reputation but do so with flying colors.Hosting some of our favorite broad-spectrum oils, Evn CBD keeps their product pure, hosting a certified USDA Organic label on every product. Although slightly higher in price than some on this list, it’s also well worth every penny.

With a delicious taste, Evn CBD keeps it simple but effective with their selection, hosting high quality CBD in every drop. All in all, it’s hard to miss with Evn CBD, bringing along a selection that other brands claiming to be organic should take note of.The Virginia seed-to-sale producer Trium Botanicals likes to keep things simple and affordable. 100% organic hemp grown on their own farm in Shenandoah Valley, 100% natural ingredients, GMP-compliant facility and manufacturing process, 3rd party test results proving safety, purity, and potency.

The Trium Botanicals CBD tincture preserves its natural flavor and delivers all the benefits of full-spectrum hemp with 750 mg of CBD and one of the cleanest recipes we've ever seen. Full-Spectrum Hemp Extract &. Organic MCT Oil (coconut).

Don't hesitate to try Trium Botanicals' CBD massage oil and salves and sport sticks with refreshing and relaxing mint and lavender flavors as well!. All products have incredibly affordable prices that you can further discount by adding code DISCOVER at checkout. Price.

$20-$25 Available strengths. 750mg7. SpruceKnown particularly for their CBD oil, Spruce has a simple menu, but one that’s an absolute knockout.

Hosting their traditional 750 mg and 2400 mg Max Potency varieties, Spruce also has a rare Gingerbread 750 mg small-batch option for the holidays that’s to die for (just mix it in any eggnog and you’ll see). However, interesting combinations aside, Spruce really has driven their reputation via an overall great product.Spruce is a CBD brand that’s a case study in focusing on quality execution. The result is a CBD oil that’s hearty and pure, offering everything (and more) it says it will.

All in all, it’s hard to miss when dealing with Spruce, as their CBD oil always finds a way to brighten up the day.Bonus. Gold BeeGold Bee is quickly becoming a company with a reputation for setting the gold standard. For their CBD oil, they offer a Full Spectrum variety that’s flavored either naturally or as Kiwi.

Although their pricing starts at $109, Gold http://carolinapoliticalconsulting.com/?page_id=10 Bee doesn’t hold back on ingredients, only using premium extract. Plus, with natural honey flavoring added, Gold Bee is swarming in success for their oils.Bonus. Pure KanaAfter gaining a lot of recognition on Instagram, Pure Kana has been a brand that’s celebrated for educating people on what CBD is, as well as what to look for in a company worth trusting.

Hosting flavors like Mint, Vanilla, Natural, Fruity, Citrus, and even a Sleep-Aid, Pure Kana also has dosages between 600 mg to 5000 mg, providing a little something for everyone. In many ways, Pure Kana has established a sample CBD oil for every type of consumer, highlighting how they nail every target they attempt hit.This article contains affiliate links to products. We may receive a commission for purchases made through these links.When we are young, we have a tendency to beat up our bodies.

We push ourselves to exhaustion, strain our muscles, and sometimes even ignore minor injuries.As we age, those strains and injuries may shift into aches and pains due to arthritis.Regardless of whether you are suffering from pain related to overworked, tired muscles, or from joint pain related aging and arthritis, you want targeted relief that works quickly.CBD creams can help soothe your pain in a way you notice right away. They are usually convenient and portable. And some products even come in a roll-on format for ultimate, mess-free application.In addition to their fast, targeted, convenient action, CBD creams can help reduce consumption of pain-relieving medications like NSAIDs and opioids.

Long-term use of NSAIDs can increase your risk of stroke and heart attack, in addition to liver and kidney disease. The opioid crisis in the United States has led to countless lives ruined due to addiction, and millions of lives lost due to overdose.CBD creams are a topical product. CBD offers natural pain relief that has few side effects or long-term health consequences.

The World Health Organization has determined that CBD is generally well-tolerated, and that it is a reasonable replacement for opioids and NSAIDs in some cases.1. Verma Farms Mahalo Muscle CreamVerma Farms makes a line of CBD products that are inspired by the Hawaiian Islands. Natural, sustainable, and designed with the utmost care for your wellness and the environment.Verma Farms always uses CBD extracted from hemp grown naturally in the United States.

The CO2 process used for extraction is clean and thorough, resulting in the best finished products on the market.“Mahalo” means “thank you,” which is what your muscles will be saying when you roll on this muscle cream intended to soothe and relieve. We love this cream because it comes in a roll-on format. Convenient and easy to use, you can take it with you wherever you go.

Toss a bottle into your gym bag, your carryon, or your desk drawer, and use it wherever you are.Apply it discreetly with no mess. Mahalo Muscle Cream penetrates targeted spots for fast-acting pain relief, whether it’s from working out, arthritis, or hours on your feet.2. Penguin CBD CreamPenguin CBD cream may be more geared toward skincare than pain relief.

However, 250 mg of CBD packed into this luxurious topical is great for soft, smooth skin (who doesn’t appreciate that?. ) as well as quick relief for minor aches and pains.Made with premium-quality broad-spectrum CBD and a base of safflower oil and shea butter, Penguin’s CBD cream is rich and non-greasy.It is scented with lavender and peppermint oils for a relaxing aromatic experience that may just remind you of a day at the spa.Make some time for yourself and enjoy the relaxing effects of Penguin CBD’s cream, whether you are looking for some relief from painful, overworked muscles, or you’re just going for healthy, glowing skin.3. R+R Medicinals R+R Medicinals spent over a year developing this 1000mg CBD Cream with a team consisting of multiple chemists, a doctor, and several variants to ensure one thing - that it WORKS.

They blend premium ingredients like Arnica Montana, MSM, Jojoba Oil, and more with their Full-Spectrum CBD extract from their proprietary Cherry strain of USDA Certified Organic hemp to yield an impressive result. It doesn’t have menthol or other poor smelling ingredients to ensure anyone can use this cream anywhere, anytime. With over 1000mg of Full-Spectrum CBD in each tube, this cream is of incredible value for only $39.99, while bringing CBG, CBC, CBDv, CBN, CBL, and CBDa to the mix.

Simple and effective, this fragrance and dye-free cream gets the job done with consistent and daily use. With hundreds of 5-star ratings on Google, you can be sure you’ll have a great experience with this product and brand. 4.

Medterra Pain CreamMedterra’s award-winning topicals are formulated with some of the most advanced ingredients in skincare today. Their CBD pain Cream is a departure from many pain relief products, which rely solely on menthol as their main active ingredient. This one incorporates menthol and arnica for both cooling action and deeply penetrating relief.

1,000 milligrams of CBD plus other nourishing ingredients like jojoba oil and aloe build a powerful, soothing blend to address arthritis and joint issues. You can massage away those aches and pains in good conscience as Medterra Pain Cream is free of plasticizers, artificial preservatives, and synthetics. 5.

Evn CBD Cooling CreamEvn CBD makes its broad-spectrum CBD formula with organically grown hemp, and every product comes with a certificate of analysis to verify purity.That’s not the only thing, though, that puts Evn’s cooling CBD cream on our top ten list. In addition to 500 mg of this brand’s outstanding formula, it contains menthol for an extra boost in pain relief. The shea butter base means that your skin will be healthy and moisturized with every application, and the convenient pump bottle means you can get the precise amount you want mess-free.Use Evn’s CBD cooling cream for fast relief from muscle soreness and fatigue, or to soothe and relax after a long day.6.

Joy Organics Organic CBD SalveJoy Organics was founded by Joy Smith after she found frustrating inconsistency in the CBD market. She herself struggled with pain in her muscles and joints, and she needed a product she could count on to provide fast-acting, long-lasting relief.That’s when she got inspired to start her own company that makes CBD for people searching for a dependable solution.Joy Organics products have evolved over time, and they just keep getting better. The company has been moving toward organic certification for some of its items, and the salve is now made entirely of USDA certified organic ingredients.One of the more potent topical products on the market, Joy Organics CBD salve contains 500 mg of CBD, organic lavender oil, and organic eucalyptus oil, for relief from arthritis pain, exercise-related pain, tired muscles, and more.7.

Better Conditions CBD Sports CreamBetter Conditions CBD Sports Cream is made to provide instant relief and everyday support for muscle and joint health. Customers refer to it as a ‘life saving cream that provides them relief they never thought was possible”. Whether you're experiencing overall muscle soreness or tiredness due to an injury or health condition, or you experience joint pain due to arthritis, spinal injuries, back pain, or muscle cramps - this 400mg CBD Sports Cream with Cool Menthol could be the relief you’ve been searching for.This Sports Cream is 100% THC-Free, Vegan, Organic, and combines 400mg of Premium CBD with menthol and camphor.If you prefer an unscented CBD cream, Better Conditions also offers a 250mg Premium CBD Cream that comes in a 1 oz travel-ready container, and is perfect for your on-the-go needs.8.

Charlotte’s Web Arthritis Aches and Pain Relief CreamIf you spend long days typing away at a computer, cooking in a restaurant kitchen, working in construction, or you have any other occupation working with your hands, you know how important it is to get the relief you need when you need it.Charlotte’s Web’s Arthritis Aches and Pain Relief Cream gives you everything you need for tired hands after a long day, or to give them a great start in the morning.With its famous CBD formula, menthol, clove oil, beeswax, shea butter and eucalyptus oil, you get pain relief and protection from the elements for your hands at the same time. Say goodbye to dry, cracked skin, aching fingers, and tired wrists, with this cream made just for your hands.9. Spruce Deep Chill LotionIf you’ve tried CBD topicals before, but you just need something more, Spruce’s Deep Chill lotion may be exactly what you’re looking for.This one is made with 2,000 mg of pure CBD, with an anti-inflammatory boost from arnica extract.

Menthol and camphor create a penetrating cooling effect, while coconut oil, shea butter, and rosemary soothe and relax.Spruce warns that anyone who is regularly tested for THC may want to steer clear of its products. They are all made with a full-spectrum formula that falls within the federally legal limit. However, THC may still show up on drug tests at this concentration.If you want to give this product a try, you’ll have to act fast.

It is made in small batches and regularly sells out.10. Elixinol Sports GelCosmetics (including lotions, creams, and other topicals) have a reputation for being made with ingredients tested on animals and ingredients that may have a questionable safety profile. Elixinol, however, offers conscientiously made products that are vegan, cruelty-free, and contain no synthetic colors or fragrances.

The company is US Hemp Authority-certified for its conscientious farming and extraction methods. And it is a product partner with Realm of Caring — a company dedicated to doing research and providing education for individuals or families who can benefit from CBD.This sports gel comes in an easy-to-use pump. It contains 1,000 mg of THC-free broad-spectrum CBD, anti-inflammatory arnica extract, warming capsaicin, and camphor.

It is formulated to go on smooth, feel great, absorb quickly, and leave no trace of greasy residue. Bonus. Cornbread Hemp CBD Lotion + MentholCornbread is a relative newcomer to the CBD market, but its products are getting attention for their superior quality and the care that goes into making them right off the bat.Its CBD is made with a whole-flower extract, meaning no leaves and stems are used.

This creates a potent, robust full-spectrum formula that is pungent but not bitter. It is USDA certified as organic, it isn’t tested on animals, and it is free of parabens.The CBD Lotion + Menthol contains just enough menthol to provide soothing relief, without knocking you down with scent.It is creamy and pleasant to use, but it is thin so that it goes on smooth, absorbs quickly, and finishes non-greasy.Bonus. Bluebird Botanicals Hemp CBD Essential LotionWe love Bluebird Botanicals products because of their premium quality, but also because of the way this brand shows that it cares.Bluebird Botanicals is B Corporation certified, which means it has been evaluated and certified by an independent agency on its treatment of employees, environmental conscientiousness, and the way it contributes to the community at large.The CBD lotion moisturizes and soothes.

It is Leaping Bunny certified, meaning it is completely cruelty-free, and it is made with all vegan ingredients.One of the best things about all of Bluebird’s topicals (other than its outstanding effectiveness and smooth creaminess) is the fact that its containers are completely eco-friendly, plant-based, and biodegradable. Tips for Getting the Most Out of Your CBD CreamSometimes you just need to soothe your aching, sore muscles on the fly, and you don’t have time to do more than simply roll on your cream and get on with your day.If you are looking for relief in the office or on the plane, there isn’t much you can do in order to enhance effectiveness. Make sure you are applying to clean skin.

If there are cooling or warming botanicals, covering the portion of skin where you applied the CBD can help intensify effects.If, however, you are at home and have the time to give your sore muscles and aching joints a little extra attention, you can do the following things to increase absorption and support the effects of your CBD cream. Do everything listed here, or just a few:● Take a warm/hot shower or bath. This helps relax your muscles ahead of application, and it opens up your pores for faster absorption.● Take time out to let the effects set in.

Applying CBD cream right before bed can give you relief for a better night’s sleep, and you get to relax the whole time your CBD cream is acting on your body.● Consider trying a CBD tincture, CBD gummies, or CBD pills to help boost the effects of your cream. Ingestible forms of CBD help with general, overall pain and inflammation, while cream focuses on one specific area.● Make sure to check with a doctor if your pain persists or gets worse. CBD is intended to help treat minor aches and pains, but chronic problems may point to disease that needs medical attention..

Thirty percent of unvaccinated American adults say they’re waiting for the anti inflammatory drugs treatments currently authorized for emergency use symbicort 400mcg 6mcg price to be officially approved by the U.S. Food and Drug Administration. The FDA has since granted that approval for those symbicort 400mcg 6mcg price age 16 and older for the Pfizer-BioNTech treatment on Aug.

23, 2021. What had to happen for the FDA to advance from emergency use authorization, or EUA, to full symbicort 400mcg 6mcg price approval?. I’m a pharmacist who trains other pharmacists, health care providers and students on why, when and how to administer treatments.

Emergency use authorization, while streamlining the symbicort 400mcg 6mcg price regulatory process so the treatment is more quickly available to the public, still follows a rigorous process the FDA requires to ensure treatment safety and effectiveness. The difference is that more time has passed and more data is available for review when a company applies for full approval.[embedded content]EUA and Full Approval Share Similar First StepsFor both emergency authorization and full approval, for anti inflammatory drugs treatments, the FDA first requires initial safety studies on a small number of people. Here, researchers document potential adverse events, symbicort 400mcg 6mcg price or side effects, that the treatment may cause.

Researchers also determine the safest and most effective dose of the treatment.Once the treatment is determined to be safe and an optimal dose identified, researchers will create larger studies to ascertain how well it works in a controlled setting where some people are given the treatment while others are given a placebo.It is important to note that the number of people who participated in the initial anti inflammatory drugs safety studies was similar to that in the safety studies of other commonly used treatments, including treatments for tetanus, diphtheria, whooping cough and meningitis. Over 43,000 symbicort 400mcg 6mcg price adults participated in the early phases of the Pfizer-BioNTech clinical trial, over 30,400 in Moderna’s and over 44,000 in Johnson and Johnson’s. Half the participants in each study were given a treatment, while the other half were given a placebo.Where EUA and Full Approval DifferFrom this point on, emergency use authorization and full FDA approval for anti inflammatory drugs treatments follow different clinical study requirements.For the emergency use authorization, the FDA requires at least half of the participants of the original studies to be followed for at least two months post-vaccination.

This is because the vast majority of treatment-related side effects occur right after vaccination.Full symbicort 400mcg 6mcg price FDA approval, on the other hand, requires participants in the original studies to be followed for at least six months. Reviewers look at data from the same study participants but collected over a longer period of time. All adverse events are examined.

The manufacturer must also provide more detailed manufacturing plans and processes, as well as symbicort 400mcg 6mcg price a higher level of oversight and inspections. All of this adds significantly more time to the review process.Full FDA approval involves reviewing more data after a longer observational period. (Credit.

SOPA Images/LightRocket via Getty Images)Both Pfizer and Moderna began their rolling submission for approval in the FDA’s “Fast Track” process, designed to speed up review. This allows the companies to submit portions of their approval application to the FDA for review as they’re completed.Full FDA approval will initially apply to only the same age groups that were tested in the original emergency use authorization. This means that the treatment has been approved first for people ages 16 and up for Pfizer, and will likely be approved for those 18 and up for Moderna.

Rolling submission will allow approval of the treatment for younger groups as more data becomes available.Different Timelines, Same Rigorous RequirementsFull FDA approval is a milestone that may help build confidence among the treatment hesitant about the safety of the treatments. But the true test of the treatment came when it first gained emergency use authorization. Then, researchers identified the majority of its potential side effects and proved its ability to protect against severe disease.Article updated on Aug.

23, 2021 to reflect FDA approval of Pfizer BioNTech treatment for those ages 16 and older.Jennifer Girotto is an associate clinical professor of pharmacy practice ar the University of Connecticut is a clinical physician and assistant professor at the University of Virginia. This article is republished from The Conversation under a Creative Commons license. Read the original article.This site contains affiliate links to products.

We may receive a commission for purchases made through these links.CBD oils have exploded in popularity over the past few years.What started as a niche treatment for those with epilepsy and other medical issues has blossomed into an industry that people are using for an array of reasons. From simple relaxation to alleviating pain, CBD users report that oils help with improve their lives day-in and day-out. However, despite the positive word of mouth, knowing the best CBD oil to start with can be a tough challenge.As CBD’s popularity has grown, so have the number shady actors surrounding it.

Due to this, it’s important to know not only who to trust but also who has the best CBD oil and why. By using a number of different criteria including quality of sourcing, strength of hemp, and reputation in the industry, we’ve decided to compile this list of the best CBD oils on the market today. No matter if you’ve been into it for a while or a newbie (we won’t judge), this list will inform you on what you need to know about CBD oil.

Here’s what we’ve learned:1. Verma FarmsThe top brand in CBD, Verma Farms has been winning awards left and right for the past couple of years, and 2021 is no exception. This is the gold standard of CBD tinctures.What Verma does well is provide a solution that helps set the standard for how CBD oils should be.

Starting out with very intent-driven oils like Focus, Chill, and Boost, they began diversifying their lineup to include more fruit-flavored varieties as well, such as Lemon Lime, Pineapple, Strawberry, Watermelon, Mango, and Peach. As all of them use natural, vegan ingredients, Verma has stripped down their offering to host only the standards but doing it well, sourcing all their oil’s materials from inside the US.An overall great brand, Verma Farms is an easy number one for any CBD fan out there.2. Penguin CBDAnother brand constantly ranked towards the top of the industry, Penguin CBD has been at the forefront of CBD research and development.

After all, if you’re not familiar, Penguin CBD is one of the most popular brands among Gen Z.For their CBD oil, Penguin CBD remains one of the best at creating a top-tier product. Hosting oils that range all the way to 2500 mg, their formulas all contain broad spectrum CBD. As trendsetters in the industry, Penguin CBD continues to set the bar over almost all the competition.Medterra is one of the world’stop CBD brands, in large part due to their unwavering dedication to making topquality CBD and offering it at a great price.

They pack tons of value intotheir tinctures and have different options for different CBD users. Both isolate and Ua Broad Spectrum tinctures are availablein multiple strengths and flavors, and all are made from American-grown,organic, non-GMO, US Hemp Authority-certified hemp. For CBD users seekingbroader benefits, Ua Broad Spectrum contains a 10:1 ratio of CBD to otherbeneficial hemp compounds for the most potent broad spectrum on the market,while isolates are great when you’re looking for pure CBD.

R+R Medicinals is quickly becoming one of the most trusted and popular CBD brands by proving one thing - they make the CBD that works. Using supercritical CO2 extraction on their proprietary Cherry strain of USDA Certified Organic hemp, they yield an unparalleled profile of cannabinoids, terpenes, and other phytonutrients in their products that translate into guaranteed performance. Their 1000mg Fresh Mint Tincture is their best seller and of incredible value for a Full-Spectrum product at $46.99.

R+R boasts impressive levels of CBD, CBG, CBC, CBN, CBL, and more in their products so you can truly feel the entourage effect. They also publish third party certificates of analysis on their site for every batch they make. In addition to being USDA Organic Certified, they are also US Hemp Authority Certified, and they have hundreds of 5-star ratings on Google, so you can take comfort in knowing they do things with the highest standards of safety and quality in mind.

With a name like Evn-CBD, it’s hard to go wrong. Not only do they live up to their reputation but do so with flying colors.Hosting some of our favorite broad-spectrum oils, Evn CBD keeps their product pure, hosting a certified USDA Organic label on every product. Although slightly higher in price than some on this list, it’s also well worth every penny.

With a delicious taste, Evn CBD keeps it simple but effective with their selection, hosting high quality CBD in every drop. All in all, it’s hard to miss with Evn CBD, bringing along a selection that other brands claiming to be organic should take note of.The Virginia seed-to-sale producer Trium Botanicals likes to keep things simple and affordable. 100% organic hemp grown on their own farm in Shenandoah Valley, 100% natural ingredients, GMP-compliant facility and manufacturing process, 3rd party test results proving safety, purity, and potency.

The Trium Botanicals CBD tincture preserves its natural flavor and delivers all the benefits of full-spectrum hemp with 750 mg of CBD and one of the cleanest recipes we've ever seen. Full-Spectrum Hemp Extract &. Organic MCT Oil (coconut).

Don't hesitate to try Trium Botanicals' CBD massage oil and salves and sport sticks with refreshing and relaxing mint and lavender flavors as well!. All products have incredibly affordable prices that you can further discount by adding code DISCOVER at checkout. Price.

$20-$25 Available strengths. 750mg7. SpruceKnown particularly for their CBD oil, Spruce has a simple menu, but one that’s an absolute knockout.

Hosting their traditional 750 mg and 2400 mg Max Potency varieties, Spruce also has a rare Gingerbread 750 mg small-batch option for the holidays that’s to die for (just mix it in any eggnog and you’ll see). However, interesting combinations aside, Spruce really has driven their reputation via an overall great product.Spruce is a CBD brand that’s a case study in focusing on quality execution. The result is a CBD oil that’s hearty and pure, offering everything (and more) it says it will.

All in all, it’s hard to miss when dealing with Spruce, as their CBD oil always finds a way to brighten up the day.Bonus. Gold BeeGold Bee is quickly becoming a company with a reputation for setting the gold standard. For their CBD oil, they offer a Full Spectrum variety that’s flavored either naturally or as Kiwi.

Although their pricing starts at $109, Gold Bee doesn’t hold back on ingredients, only using premium extract. Plus, with natural honey flavoring added, Gold Bee is swarming in success for their oils.Bonus. Pure KanaAfter gaining a lot of recognition on Instagram, Pure Kana has been a brand that’s celebrated for educating people on what CBD is, as well as what to look for in a company worth trusting.

Hosting flavors like Mint, Vanilla, Natural, Fruity, Citrus, and even a Sleep-Aid, Pure Kana also has dosages between 600 mg to 5000 mg, providing a little something for everyone. In many ways, Pure Kana has established a sample CBD oil for every type of consumer, highlighting how they nail every target they attempt hit.This article contains affiliate links to products. We may receive a commission for purchases made through these links.When we are young, we have a tendency to beat up our bodies.

We push ourselves to exhaustion, strain our muscles, and sometimes even ignore minor injuries.As we age, those strains and injuries may shift into aches and pains due to arthritis.Regardless of whether you are suffering from pain related to overworked, tired muscles, or from joint pain related aging and arthritis, you want targeted relief that works quickly.CBD creams can help soothe your pain in a way you notice right away. They are usually convenient and portable. And some products even come in a roll-on format for ultimate, mess-free application.In addition to their fast, targeted, convenient action, CBD creams can help reduce consumption of pain-relieving medications like NSAIDs and opioids.

Long-term use of NSAIDs can increase your risk of stroke and heart attack, in addition to liver and kidney disease. The opioid crisis in the United States has led to countless lives ruined due to addiction, and millions of lives lost due to overdose.CBD creams are a topical product. CBD offers natural pain relief that has few side effects or long-term health consequences.

The World Health Organization has determined that CBD is generally well-tolerated, and that it is a reasonable replacement for opioids and NSAIDs in some cases.1. Verma Farms Mahalo Muscle CreamVerma Farms makes a line of CBD products that are inspired by the Hawaiian Islands. Natural, sustainable, and designed with the utmost care for your wellness and the environment.Verma Farms always uses CBD extracted from hemp grown naturally in the United States.

The CO2 process used for extraction is clean and thorough, resulting in the best finished products on the market.“Mahalo” means “thank you,” which is what your muscles will be saying when you roll on this muscle cream intended to soothe and relieve. We love this cream because it comes in a roll-on format. Convenient and easy to use, you can take it with you wherever you go.

Toss a bottle into your gym bag, your carryon, or your desk drawer, and use it wherever you are.Apply it discreetly with no mess. Mahalo Muscle Cream penetrates targeted spots for fast-acting pain relief, whether it’s from working out, arthritis, or hours on your feet.2. Penguin CBD CreamPenguin CBD cream may be more geared toward skincare than pain relief.

However, 250 mg of CBD packed into this luxurious topical is great for soft, smooth skin (who doesn’t appreciate that?. ) as well as quick relief for minor aches and pains.Made with premium-quality broad-spectrum CBD and a base of safflower oil and shea butter, Penguin’s CBD cream is rich and non-greasy.It is scented with lavender and peppermint oils for a relaxing aromatic experience that may just remind you of a day at the spa.Make some time for yourself and enjoy the relaxing effects of Penguin CBD’s cream, whether you are looking for some relief from painful, overworked muscles, or you’re just going for healthy, glowing skin.3. R+R Medicinals R+R Medicinals spent over a year developing this 1000mg CBD Cream with a team consisting of multiple chemists, a doctor, and several variants to ensure one thing - that it WORKS.

They blend premium ingredients like Arnica Montana, MSM, Jojoba Oil, and more with their Full-Spectrum CBD extract from their proprietary Cherry strain of USDA Certified Organic hemp to yield an impressive result. It doesn’t have menthol or other poor smelling ingredients to ensure anyone can use this cream anywhere, anytime. With over 1000mg of Full-Spectrum CBD in each tube, this cream is of incredible value for only $39.99, while bringing CBG, CBC, CBDv, CBN, CBL, and CBDa to the mix.

Simple and effective, this fragrance and dye-free cream gets the job done with consistent and daily use. With hundreds of 5-star ratings on Google, you can be sure you’ll have a great experience with this product and brand. 4.

Medterra Pain CreamMedterra’s award-winning topicals are formulated with some of the most advanced ingredients in skincare today. Their CBD pain Cream is a departure from many pain relief products, which rely solely on menthol as their main active ingredient. This one incorporates menthol and arnica for both cooling action and deeply penetrating relief.

1,000 milligrams of CBD plus other nourishing ingredients like jojoba oil and aloe build a powerful, soothing blend to address arthritis and joint issues. You can massage away those aches and pains in good conscience as Medterra Pain Cream is free of plasticizers, artificial preservatives, and synthetics. 5.

Evn CBD Cooling CreamEvn CBD makes its broad-spectrum CBD formula with organically grown hemp, and every product comes with a certificate of analysis to verify purity.That’s not the only thing, though, that puts Evn’s cooling CBD cream on our top ten list. In addition to 500 mg of this brand’s outstanding formula, it contains menthol for an extra boost in pain relief. The shea butter base means that your skin will be healthy and moisturized with every application, and the convenient pump bottle means you can get the precise amount you want mess-free.Use Evn’s CBD cooling cream for fast relief from muscle soreness and fatigue, or to soothe and relax after a long day.6.

Joy Organics Organic CBD SalveJoy Organics was founded by Joy Smith after she found frustrating inconsistency in the CBD market. She herself struggled with pain in her muscles and joints, and she needed a product she could count on to provide fast-acting, long-lasting relief.That’s when she got inspired to start her own company that makes CBD for people searching for a dependable solution.Joy Organics products have evolved over time, and they just keep getting better. The company has been moving toward organic certification for some of its items, and the salve is now made entirely of USDA certified organic ingredients.One of the more potent topical products on the market, Joy Organics CBD salve contains 500 mg of CBD, organic lavender oil, and organic eucalyptus oil, for relief from arthritis pain, exercise-related pain, tired muscles, and more.7.

Better Conditions CBD Sports CreamBetter Conditions CBD Sports Cream is made to provide instant relief and everyday support for muscle and joint health. Customers refer to it as a ‘life saving cream that provides them relief they never thought was possible”. Whether you're experiencing overall muscle soreness or tiredness due to an injury or health condition, or you experience joint pain due to arthritis, spinal injuries, back pain, or muscle cramps - this 400mg CBD Sports Cream with Cool Menthol could be the relief you’ve been searching for.This Sports Cream is 100% THC-Free, Vegan, Organic, and combines 400mg of Premium CBD with menthol and camphor.If you prefer an unscented CBD cream, Better Conditions also offers a 250mg Premium CBD Cream that comes in a 1 oz travel-ready container, and is perfect for your on-the-go needs.8.

Charlotte’s Web Arthritis Aches and Pain Relief CreamIf you spend long days typing away at a computer, cooking in a restaurant kitchen, working in construction, or you have any other occupation working with your hands, you know how important it is to get the relief you need when you need it.Charlotte’s Web’s Arthritis Aches and Pain Relief Cream gives you everything you need for tired hands after a long day, or to give them a great start in the morning.With its famous CBD formula, menthol, clove oil, beeswax, shea butter and eucalyptus oil, you get pain relief and protection from the elements for your hands at the same time. Say goodbye to dry, cracked skin, aching fingers, and tired wrists, with this cream made just for your hands.9. Spruce Deep Chill LotionIf you’ve tried CBD topicals before, but you just need something more, Spruce’s Deep Chill lotion may be exactly what you’re looking for.This one is made with 2,000 mg of pure CBD, with an anti-inflammatory boost from arnica extract.

Menthol and camphor create a penetrating cooling effect, while coconut oil, shea butter, and rosemary soothe and relax.Spruce warns that anyone who is regularly tested for THC may want to steer clear of its products. They are all made with a full-spectrum formula that falls within the federally legal limit. However, THC may still show up on drug tests at this concentration.If you want to give this product a try, you’ll have to act fast.

It is made in small batches and regularly sells out.10. Elixinol Sports GelCosmetics (including lotions, creams, and other topicals) have a reputation for being made with ingredients tested on animals and ingredients that may have a questionable safety profile. Elixinol, however, offers conscientiously made products that are vegan, cruelty-free, and contain no synthetic colors or fragrances.

The company is US Hemp Authority-certified for its conscientious farming and extraction methods. And it is a product partner with Realm of Caring — a company dedicated to doing research and providing education for individuals or families who can benefit from CBD.This sports gel comes in an easy-to-use pump. It contains 1,000 mg of THC-free broad-spectrum CBD, anti-inflammatory arnica extract, warming capsaicin, and camphor.

It is formulated to go on smooth, feel great, absorb quickly, and leave no trace of greasy residue. Bonus. Cornbread Hemp CBD Lotion + MentholCornbread is a relative newcomer to the CBD market, but its products are getting attention for their superior quality and the care that goes into making them right off the bat.Its CBD is made with a whole-flower extract, meaning no leaves and stems are used.

This creates a potent, robust full-spectrum formula that is pungent but not bitter. It is USDA certified as organic, it isn’t tested on animals, and it is free of parabens.The CBD Lotion + Menthol contains just enough menthol to provide soothing relief, without knocking you down with scent.It is creamy and pleasant to use, but it is thin so that it goes on smooth, absorbs quickly, and finishes non-greasy.Bonus. Bluebird Botanicals Hemp CBD Essential LotionWe love Bluebird Botanicals products because of their premium quality, but also because of the way this brand shows that it cares.Bluebird Botanicals is B Corporation certified, which means it has been evaluated and certified by an independent agency on its treatment of employees, environmental conscientiousness, and the way it contributes to the community at large.The CBD lotion moisturizes and soothes.

It is Leaping Bunny certified, meaning it is completely cruelty-free, and it is made with all vegan ingredients.One of the best things about all of Bluebird’s topicals (other than its outstanding effectiveness and smooth creaminess) is the fact that its containers are completely eco-friendly, plant-based, and biodegradable. Tips for Getting the Most Out of Your CBD CreamSometimes you just need to soothe your aching, sore muscles on the fly, and you don’t have time to do more than simply roll on your cream and get on with your day.If you are looking for relief in the office or on the plane, there isn’t much you can do in order to enhance effectiveness. Make sure you are applying to clean skin.

If there are cooling or warming botanicals, covering the portion of skin where you applied the CBD can help intensify effects.If, however, you are at home and have the time to give your sore muscles and aching joints a little extra attention, you can do the following things to increase absorption and support the effects of your CBD cream. Do everything listed here, or just a few:● Take a warm/hot shower or bath. This helps relax your muscles ahead of application, and it opens up your pores for faster absorption.● Take time out to let the effects set in.

Applying CBD cream right before bed can give you relief for a better night’s sleep, and you get to relax the whole time your CBD cream is acting on your body.● Consider trying a CBD tincture, CBD gummies, or CBD pills to help boost the effects of your cream. Ingestible forms of CBD help with general, overall pain and inflammation, while cream focuses on one specific area.● Make sure to check with a doctor if your pain persists or gets worse. CBD is intended to help treat minor aches and pains, but chronic problems may point to disease that needs medical attention..

Symbicort inhaler price uk

IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected to have a disorder/difference of sex development (DSD).1–13 Based on these studies, it has become clear that symbicort inhaler price uk services Buy real zithromax online and institutions still differ in the composition of the multidisciplinary teams that provide care for patients who have a DSD.11 14 Several projects have now worked to resolve this variability in care. The European Cooperation in Science and Technology (EU COST) action BM1303 ‘A systematic elucidation of differences of sex development’ has been a platform to achieve European agreement on harmonisation of clinical management and laboratory practices.15–17 Another such initiative involved an update of the 2006 DSD consensus document by an international group of professionals and patient representatives.18 These initiatives symbicort inhaler price uk 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 symbicort inhaler price uk 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 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 symbicort inhaler price uk 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 symbicort inhaler price uk and/or their parents about atypical sex development and why this may warrant referral to a specialised team may be challenging, especially for professionals with limited experience in DSD.22 23 Therefore, a section of the Dutch-Flemish guideline was written 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 symbicort inhaler price uk adult team requires optimal communication between the specialists involved.

Application of NGS-based techniques may lead to a higher diagnostic yield, providing a molecular genetic diagnosis in previously unsolved cases.16 We address the timing of this testing and the problems associated with this technique such as the interpretation of variants of unknown clinical significance (VUS). Similarly, histopathological interpretation and classification of removed gonadal tissue is challenging symbicort inhaler price uk and would benefit from international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group was formed with all members responsible for updating the literature for a specific part of the guideline. Literature search in PubMed was not systematic, but rather intended to be broad in order to cover all areas and follow expert opinions. This approach is more in line with the Clinical Practice Advisory Document method described by Burke et al24 for guidelines involving genetic practice because it is often troublesome to substantiate such guidelines with sufficient evidence due to the symbicort inhaler price uk 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 symbicort inhaler price uk 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 symbicort inhaler price uk 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 symbicort inhaler price uk 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 to the paediatric and genetic associations for symbicort inhaler price uk 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 symbicort inhaler price uk DSD can be diagnosed before birth is when invasive prenatal genetic testing carried out for a different reason, for example, due to suspicion of other structural anomalies, reveals a discrepancy between the genotypic sex and the phenotypic sex seen by ultrasound. In certified laboratories, the possibility of a sample switch is extremely low but should be ruled out immediately.

More often, the discrepancy will be due to sex-chromosome mosaicism or a true form of DSD.A situation now occurring with increasing frequency is a discrepancy between the genotypic sex revealed by non-invasive prenatal testing (NIPT), which is now symbicort inhaler price uk 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 symbicort inhaler price uk in NIPT analysis and reports. If the X and Y chromosomes are included, it is important to realise that the presence of a Y-chromosome does not necessarily imply male fetal development. At the time that NIPT is performed (usually 11–13 weeks), genital development cannot be reliably appreciated by ultrasound, symbicort inhaler price uk so any discrepancy or atypical aspect of the genitalia will only be noticed later in pregnancy and should prompt further evaluation.Counselling and diagnosticsIf a DSD is suspected, first-line sonographers and obstetricians should refer the couple to their colleague prenatal specialists working with or in a DSD team.

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

The clinical geneticist should be experienced in prenatal 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 symbicort inhaler price uk 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 symbicort inhaler price uk as an apparently isolated condition, expecting parents may also consider termination of pregnancy, which, although considered controversial by some, is legal in Belgium and the Netherlands. The psychologist of the DSD team can support parents during and after pregnancy and help them cope with feelings of uncertainty and eventual considerations of a termination of pregnancy, as well as with practical issues, for example, how to inform others. The stress of not knowing exactly what the child’s genitalia will look like symbicort inhaler price uk and uncertainty about the diagnosis, treatment and prognosis cannot be avoided completely. Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images.

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

NGS-based techniques have also now made their appearance in prenatal diagnosis of congenital anomalies.29 30 Panels using these techniques can be specific for genes involved in DSD, or be larger panels covering multiple congenital anomalies, and are usually employed with trio-analysis to compare variants identified in the child with the parents’ genetics.29–31 Finding a genetic cause before delivery can help reduce parental stress in the neonatal period and speed up decisions regarding gender assignment. In such symbicort inhaler price uk cases 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 child’s sex. In cases where sex assignment has already taken place, the message that the development of the gonads or genitalia is still atypical is complicated and distressing for patients and parents or carers. A list of contact details for DSD centres and patient organisations in the Netherlands and Flanders is attached to the Dutch-Flemish guideline. Publishing such a list, either in guidelines or online, can help healthcare professionals find the nearest centres for consultations and provide patients and patient organisations with an overview of the centres where expertise is available.Timing and place of genetic testing using NGS-based gene panelsThe diagnostic workup that is proposed for 46,XX and 46,XY DSD is shown in figures 2 and 3, respectively.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected to have symbicort 400mcg 6mcg price a disorder/difference of sex development (DSD).1–13 Based on these studies, it has become clear that services and institutions still differ in the composition of the multidisciplinary teams that provide care for patients who have a DSD.11 14 Several projects have now worked to resolve this variability in care. The European Cooperation in Science and Technology (EU COST) action BM1303 ‘A systematic elucidation of differences of sex development’ has been a platform to achieve European agreement on harmonisation of clinical management and laboratory practices.15–17 Another such initiative involved an update of the 2006 DSD consensus document by an international group of professionals and patient representatives.18 These initiatives have highlighted how cultural and financial aspects and the availability of resources symbicort 400mcg 6mcg price 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 symbicort 400mcg 6mcg price Northern part of Belgium) have collaborated to produce a detailed guideline on diagnostics in DSD.19 This shows that a supranational guideline can be a reasonable approach for countries with similarly structured healthcare systems and similar resources.

Within the guideline there is agreement that optimisation of expertise and care can be achieved through centralisation, for example, by limiting analysis of next-generation sequencing (NGS)-based diagnostic panels to only a few centres and by centralising pathological review of gonadal tissues. International networks such as the European Reference Network for rare endocrine conditions (EndoERN), in which DSD is embedded, may facilitate the expansion of this kind of collaboration across Europe.This paper highlights key discussion points in the Dutch-Flemish guideline symbicort 400mcg 6mcg price 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 symbicort 400mcg 6mcg price may be challenging, especially for professionals with limited experience in DSD.22 23 Therefore, a section of the Dutch-Flemish guideline was written for these healthcare providers.

Moreover, this enables DSD specialists to refer to the guideline when advising a referral. Transition from the prenatal to the postnatal team and from the paediatric to the adult team symbicort 400mcg 6mcg price requires optimal communication between the specialists involved. Application of NGS-based techniques may lead to a higher diagnostic yield, providing a molecular genetic diagnosis in previously unsolved cases.16 We address the timing of this testing and the problems associated with this technique such as the interpretation of variants of unknown clinical significance (VUS). Similarly, histopathological interpretation and classification of removed gonadal tissue is challenging and would benefit from international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group was formed symbicort 400mcg 6mcg price with all members responsible for updating the literature for a specific part of the guideline.

Literature search in PubMed was not systematic, but rather intended to be broad in order to cover all areas and follow expert opinions. This approach is more in line with the Clinical Practice Advisory Document method described by Burke et al24 for guidelines involving genetic practice because it is often troublesome to substantiate such guidelines symbicort 400mcg 6mcg price 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 Medical Subject Headings terms (eg, DSD, genetic, review, diagnosis, diagnostics, 46,XX DSD, 46,XY DSD, guideline, multidisciplinary symbicort 400mcg 6mcg price care).

Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports were excluded, as were articles that were not open access or symbicort 400mcg 6mcg price 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 symbicort 400mcg 6mcg price was discussed by the writing committee and, after having obtained agreement on remaining points of discussion, revised into a final draft.

This version was sent to a broad group of professionals from academic centres and DSD teams whose members had volunteered to review the draft guideline. After receiving and incorporating their input, the final symbicort 400mcg 6mcg price 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 symbicort 400mcg 6mcg price 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 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 symbicort 400mcg 6mcg price of DSD.A situation now occurring with increasing frequency is a discrepancy between the genotypic sex revealed by non-invasive prenatal testing (NIPT), which is now available to high-risk pregnant women in the Netherlands and to all pregnant women in Belgium, and later ultrasound findings. NIPT screens for CNVs in the fetus. However, depending on legal restrictions and/or ethical considerations, the X and Y chromosomes are not always symbicort 400mcg 6mcg price included in NIPT analysis and reports.

If the X and Y chromosomes are included, it is important to realise that the presence of a Y-chromosome does not necessarily imply male fetal development. At the time that NIPT is performed (usually 11–13 weeks), genital development cannot be reliably appreciated by ultrasound, so any discrepancy or atypical aspect of the genitalia will only be noticed later in pregnancy and should prompt further evaluation.Counselling and diagnosticsIf a DSD is suspected, first-line sonographers and obstetricians should refer the couple to their colleague prenatal specialists working with or in a DSD symbicort 400mcg 6mcg price team. After confirming an atypical genital on ultrasound, the specialist team should offer the couple a referral for genetic counselling to discuss the possibility of performing invasive prenatal testing (usually an amniocentesis) to identify an underlying cause that fits the ultrasound findings.22 23 To enable the parents to make a well-informed decision, prenatal counselling should, in our opinion, include. Information on the symbicort 400mcg 6mcg price 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 symbicort 400mcg 6mcg price cannot provide. Knowing which information has been provided and what words have been used by the prenatal specialist is very helpful for those involved in postnatal care.It is important that parents understand that the biological sex of a baby is determined by a complex interplay of chromosomes, genes and hormones, and thus that assessment of the presence or absence of a Y-chromosome alone is insufficient to assign the sex of their unborn child or, as in any unborn child, say anything about the child’s future gender identity.Expecting parents can be counselled by the clinical geneticist and the psychologist from the DSD team, although other DSD specialists can also be involved. The clinical geneticist should be symbicort 400mcg 6mcg price experienced in prenatal counselling and well informed about the diagnostic possibilities given the limited time span in which test results need to be available to allow parents to make a well-informed decision about whether or not to continue the pregnancy.

Termination of pregnancy can be considered, for instance, in a syndromic form of DSD with multiple malformations, but when the DSD occurs as an apparently isolated condition, expecting parents may also consider termination of pregnancy, which, symbicort 400mcg 6mcg price although considered controversial by some, is legal in Belgium and the Netherlands. The psychologist of the DSD team can support parents during and after pregnancy and help them cope with feelings of uncertainty and eventual considerations of a termination of pregnancy, as well as with practical issues, for example, how to inform others. The stress of not knowing exactly what the child’s genitalia will symbicort 400mcg 6mcg price look like and uncertainty about the diagnosis, treatment and prognosis cannot be avoided completely. Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images.

In our experience, parents appreciate having already spoken to some members of the DSD team during pregnancy symbicort 400mcg 6mcg price and having a contact person before birth.After expert prenatal counselling, a significant number of pregnant couples decline prenatal testing (personal experience IALG, MK, ABD, YvB, MC and HC-vdG). At birth, umbilical cord blood is a good source for (molecular) karyotyping and storage of DNA and can be obtained by the obstetrician, midwife or neonatologist. The terminology used in communication with parents should be carefully chosen,22 23 and midwives and staff of neonatal and delivery units should be clearly instructed to use gender-neutral and non-stigmatising vocabulary (eg, ‘your baby’) as long as sex assignment is pending.An algorithm for diagnostic evaluation of a suspected DSD in the prenatal symbicort 400mcg 6mcg price situation is proposed in figure 1. When couples opt for invasive prenatal diagnosis, the genetic analysis usually involves an (SNP)-array.

It was recently estimated that >30% of individuals who have a DSD have additional structural anomalies, with cardiac and neurological anomalies and fetal growth restriction being particularly common.27 28 If additional anomalies are seen, the geneticist can consider specific gene defects that may underlie a known genetic syndrome symbicort 400mcg 6mcg price or carry out NGS. NGS-based techniques have also now made their appearance in prenatal diagnosis of congenital anomalies.29 30 Panels using these techniques can be specific for genes involved in DSD, or be larger panels covering multiple congenital anomalies, and are usually employed with trio-analysis to compare variants identified in the child with the parents’ genetics.29–31 Finding a genetic cause before delivery can help reduce parental stress in the neonatal period and speed up decisions regarding gender assignment. In such cases there is no tight symbicort 400mcg 6mcg price 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 child’s sex. In cases where sex assignment has already taken place, the message that the development of the gonads or genitalia is still atypical is complicated and distressing for patients and parents or carers. A list of contact details for DSD centres and patient organisations in the Netherlands and Flanders is attached to the Dutch-Flemish guideline.

Publishing such a list, either in guidelines or online, can help healthcare professionals find the nearest centres for consultations and provide patients and patient organisations with an overview of the centres where expertise is available.Timing and place of genetic testing using NGS-based gene panelsThe diagnostic workup that is proposed for 46,XX and 46,XY DSD is shown in figures 2 and 3, respectively. Even with the rapidly expanding molecular possibilities, a (family) history and a physical examination remain the essential first steps in the diagnostic process. Biochemical and hormonal screening aim at investigating serum electrolytes, renal function and the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes. Ultrasound screening of kidneys and internal genitalia, as well as establishing genotypic sex, should be accomplished within 48 hours and complete the baseline diagnostic work-up of a child born with ambiguous genitalia.1 16 32 3346,XX disorders/differences of sex development (DSD) in the postnatal setting.

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

A diagnostic algorithm. NGS, next-generation sequencing. CAH, Congenital adrenal hyperplasia. AMH, Anti-Müllerian Hormone.46,XY disorders/differences of sex development (DSD) in the postnatal setting.

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

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

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

Laboratories also differ in what class of variants they report.39 In our experience, the fear of incidental findings is a major reason why some parents refrain from genetic testing.Timing of the DSD gene panel analysis is also important. While some patients or parents prefer that all diagnostic procedures be performed as soon as possible, others need time to reflect on the complex information related to more extensive genetic testing and on its possible consequences. If parents or patients do not consent to panel-based genetic testing, analysis of specific genes, such as WT1, should be considered when appropriate in view of the clinical consequences if a mutation is present (eg, clinical surveillance of renal function and screening for Wilms’ tumour in the case of WT1 mutations). Genes that are more frequently involved in DSD (eg, SRY, NR5A1) and that match the specific clinical and hormonal features in a given patient could also be considered for sequencing.

Targeted gene analysis may also be preferred in centres located in countries that do not have the resources or technical requirements to perform NGS panel-based genetic testing. Alternatively, participation by these centres in international collaborative networks may allow them to outsource the molecular genetic workup abroad.Gene panels differ between centres and are regularly updated based on scientific progress. A comparison of DSD gene panels used in recent studies can be found at https://www.nature.com/articles/s41574-018-0010-8%23Sec46.15 The panels currently used at the coauthors’ institutions can be found on their respective websites. Given the pace of change, it is important to regularly consider repeating analysis in patients with an unexplained DSD, for example, when they transition into adult care or when they move from one centre to another.

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

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

This was recently demonstrated by the identification of the NR5A1 mutation, R92W, in individuals with 46,XX testicular and ovotesticular DSD.40 This gene had previously been associated with 46,XY DSD. In diagnostic laboratories, there is usually no capacity or expertise to conduct large-scale functional studies to determine pathogenicity of these unique class 3 VUS in the different genes involved in DSD. Functional validation of variants identified in novel genes may be more attractive in a research context. However, for individual families with VUS in well-established DSD genes such as AR or HSD17B3, functional analysis may provide a confirmed diagnosis that implies for relatives the option of undergoing their own DNA analysis and estimating the genetic risk of their own future offspring.

This makes genetic follow-up important in these cases and demonstrates the usefulness of international databases and networks and the centralisation of functional studies of genetic variants in order to reduce costs and maximise expertise.The same is true for histopathological description, germ-cell tumour risk assessment in specific forms of DSD and classification of gonadal samples. Germ-cell tumour risk is related to the type of DSD (among other factors), but it is impossible to make risk estimates in individual cases.41–44 Gonadectomy may be indicated in cases with high-risk dysgenetic abdominal gonads that cannot be brought into a stable superficial (ie, inguinal, labioscrotal) position that allows clinical or radiological surveillance, or to avoid virilisation due to 5-alpha reductase deficiency in a 46,XY girl with a stable female gender identity.45 Pathological examination of DSD gonads requires specific expertise. For example, the differentiation between benign germ cell abnormalities, such as delayed maturation and (pre)malignant development of germ cells, is crucial for clinical management but can be very troublesome.46 Centralised pathological examination of gonadal biopsy and gonadectomy samples in one centre, or a restricted number of centres, on a national scale can help to overcome the problem of non-uniform classification and has proven feasible in the Netherlands and Belgium. We therefore believe that uniform assessment and classification of gonadal differentiation patterns should also be addressed in guidelines on DSD management.International databases of gonadal tissues are crucial for learning more about the risk of malignancy in different forms of DSD, but they are only reliable if uniform criteria for histological classification are strictly applied.46 These criteria could be incorporated in many existing networks such as the I-DSD consortium, the Disorders of Sex Development Translational Research Network, the European Reference Network on Urogenital Diseases (eUROGEN), the EndoERN and COST actions.15–17 47Communication at the transition from paediatric to adult carePaediatric and adult teams need to collaborate closely to facilitate a well-organised transition from paediatric to adult specialist care.15 48–50 Both teams need to exchange information optimally and should consider transition as a longitudinal process rather than a fixed moment in time.

Age-appropriate information is key at all ages, and an overview of topics to be discussed at each stage is described by Cools et al.15 Table 1 shows an example of how transition can be organised.View this table:Table 1 Example of transition table as used in the DSD clinic of the Erasmus Medical CenterPsychological support and the continued provision of information remains important for individuals with a DSD at all ages.15 22 In addition to the information given by the DSD team members, families and patients can benefit from resources such as support groups and information available on the internet.47 Information available online should be checked for accuracy and completeness when referring patients and parents to internet sites.Recommendations for future actionsMost guidelines and articles on the diagnosis and management of DSD are aimed at specialists and are only published in specialist journals or on websites for endocrinologists, urologists or geneticists. Yet there is a need for guidelines directed towards first-line and second-line healthcare workers that summarise the recommendations about the first crucial steps in the management of DSD. These should be published in widely available general medical journals and online, along with a national list of DSD centres. Furthermore, DSD (expert) centres should provide continuous education to all those who may be involved in the identification of individuals with a DSD in order to enable these healthcare professionals to recognise atypical genitalia, to promptly refer individuals who have a DSD and to inform the patient and parents about this and subsequent diagnostic procedures.As DSD continues to be a rare condition, it will take time to evaluate the effects of having such a guideline on the preparedness of first-line and second-line healthcare workers to recognise DSD conditions.

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

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

Guidelines can provide a framework within which individualised patient care should be discussed with all stakeholders.AcknowledgmentsThe authors would like to thank the colleagues of the DSD teams for their input in and critical reading of the Dutch-Flemish guideline. Amsterdam University Center (AMC and VU), Maastricht University Medical Center, Erasmus Medical Center Rotterdam, Radboud University Medical Center Nijmegen, University Medical Center Groningen, University Medical Center Utrecht, Ghent University Hospital. The authors would like to thank Kate McIntyre for editing the revised manuscript and Tom de Vries Lentsch for providing the figures as a PDF. Three of the authors of this publication are members of the European Reference Network for rare endocrine diseases—Project ID 739543.IntroductionEndometrial cancer is the most common gynaecological malignancy in the developed world.1 Its incidence has risen over the last two decades as a consequence of the ageing population, fewer hysterectomies for benign disease and the obesity epidemic.

In the USA, it is estimated that women have a 1 in 35 lifetime risk of endometrial cancer, and in contrast to cancers of most other sites, cancer-specific mortality has risen by approximately 2% every year since 2008 related to the rapidly rising incidence.2Endometrial cancer has traditionally been classified into type I and type II based on morphology.3 The more common subtype, type I, is mostly comprised of endometrioid tumours and is oestrogen-driven, arises from a hyperplastic endometrium, presents at an early stage and has an excellent 5 year survival rate.4 By contrast, type II includes non-endometrioid tumours, specifically serous, carcinosarcoma and clear cell subtypes, which are biologically aggressive tumours with a poor prognosis that are often diagnosed at an advanced stage.5 Recent efforts have focused on a molecular classification system for more accurate categorisation of endometrial tumours into four groups with distinct prognostic profiles.6 7The majority of endometrial cancers arise through the interplay of familial, genetic and lifestyle factors. Two inherited cancer predisposition syndromes, Lynch syndrome and the much rarer Cowden syndrome, substantially increase the lifetime risk of endometrial cancer, but these only account for around 3–5% of cases.8–10 Having first or second degree relative(s) with endometrial or colorectal cancer increases endometrial cancer risk, although a large European twin study failed to demonstrate a strong heritable link.11 The authors failed to show that there was greater concordance in monozygotic than dizygotic twins, but the study was based on relatively small numbers of endometrial cancers. Lu and colleagues reported an association between common single nucleotide polymorphisms (SNPs) and endometrial cancer risk, revealing the potential role of SNPs in explaining part of the risk in both the familial and general populations.12 Thus far, many SNPs have been reported to modify susceptibility to endometrial cancer. However, much of this work predated genome wide association studies and is of variable quality.

Understanding genetic predisposition to endometrial cancer could facilitate personalised risk assessment with a view to targeted prevention and screening interventions.13 This emerged as the most important unanswered research question in endometrial cancer according to patients, carers and healthcare professionals in our recently completed James Lind Womb Cancer Alliance Priority Setting Partnership.14 It would be particularly useful for non-endometrioid endometrial cancers, for which advancing age is so far the only predictor.15We therefore conducted a comprehensive systematic review of the literature to provide an overview of the relationship between SNPs and endometrial cancer risk. We compiled a list of the most robust endometrial cancer-associated SNPs. We assessed the applicability of this panel of SNPs with a theoretical polygenic risk score (PRS) calculation. We also critically appraised the meta-analyses investigating the most frequently reported SNPs in MDM2.

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

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

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

Where overlapping populations were identified, the most comprehensive study was included.Data extraction and synthesisFor each study, the following data were extracted. SNP ID, nearby gene(s)/chromosome location, OR (95% CI), p value, minor or effect allele frequency (MAF/EAF), EA (effect allele) and OA (other allele), adjustment, ethnicity and ancestry, number of cases and controls, endometrial cancer type, and study type including discovery or validation study and meta-analysis. For risk estimates, a preference towards most adjusted results was applied. For candidate-gene studies, a standard p value of<0.05 was applied and for GWAS a p value of <5×10-8, indicating genome-wide significance, was accepted as statistically significant.

However, due to the limited number of SNPs with p values reaching genome-wide significance, this threshold was then lowered to <1×10-5, allowing for marginally significant SNPs to be included. As shown by Mavaddat et al, for breast cancer, SNPs that fall below genome-wide significance may still be useful for generating a PRS and improving the models.19We estimated the potential value of a PRS based on the most significant SNPs by comparing the predicted risk for a woman with a risk score in the top 1% of the distribution to the mean predicted risk. Per-allele ORs and MAFs were taken from the publications and standard errors (SEs) for the lnORs were derived from published 95% CIs. The PRS was assumed to have a Normal distribution, with mean 2∑βipI and SE, σ, equal to √2∑βi2pI(1−pi), according to the binomial distribution, where the summation is over all SNPs in the risk score.

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

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

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

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

Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study. Adapted from. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009).

Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PRISMA Statement. PLoS Med 6(6). E1000097.

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

Those having a multi-ethnic cohort also consisted primarily of broad European populations. Only four of the variants in table 1 are located in coding regions of a gene, or in regulatory flanking regions around the gene. Thus, most of these variants would not be expected to cause any functional effects on the gene or the resulting protein. An eQTL search using GTEx Portal showed that some of the SNPs are significantly associated (p<0.05) with modified transcription levels of the respective genes in various tissues such as prostate (rs11263761), thyroid (rs9668337), pituitary (rs2747716), breast mammary (rs882380) and testicular (rs2498794) tissue, as summarised in table 2.View this table:Table 2 List of eQTL hits for the selected panel of SNPsThe only variant for which there was an indication of a specific association with non-endometrioid endometrial cancer was rs148261157 near the BCL11A gene.

The A allele of this SNP had a moderately higher association in the non-endometrioid arm (OR 1.64, 95% CI 1.32 to 2.04. P=9.6×10-6) compared with the endometrioid arm (OR 1.25, 95% CI 1.14 to 1.38. P=4.7×10-6).21Oestrogen receptors α and β encoded by ESR1 and ESR2, respectively, have been extensively studied due to the assumed role of oestrogens in the development of endometrial cancer. O’Mara et al reported a lead SNP (rs79575945) in the ESR1 region that was associated with endometrial cancer (p=1.86×10-5).24 However, this SNP did not reach genome-wide significance in a more recent larger GWAS.21 No statistically significant associations have been reported between endometrial cancer and SNPs in the ESR2 gene region.AKT is an oncogene linked to endometrial carcinogenesis.

It is involved in the PI3K/AKT/mTOR pro-proliferative signalling pathway to inactivate apoptosis and allow cell survival. The A allele of rs2494737 and G allele of rs2498796 were reported to be associated with increased and decreased risk of endometrial cancer in 2016, respectively.22 30 However, this association was not replicated in a larger GWAS in 2018.21 Nevertheless, given the previous strong indications, and biological basis that could explain endometrial carcinogenesis, we decided to include an AKT1 variant (rs2498794) in our results.PTEN is a multi-functional tumour suppressor gene that regulates the AKT/PKB signalling pathway and is commonly mutated in many cancers including endometrial cancer.32 Loss-of-function germline mutations in PTEN are responsible for Cowden syndrome, which exerts a lifetime risk of endometrial cancer of up to 28%.9 Lacey and colleagues studied SNPs in the PTEN gene region. However, none showed significant differences in frequency between 447 endometrial cancer cases and 439 controls of European ancestry.33KRAS mutations are known to be present in endometrial cancer. These can be activated by high levels of KLF5 (transcriptional activator).

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

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

Two more original studies were identified through our full-text evaluation. However, these were not included here as they did not meet our inclusion criteria—one due to small sample size, the other due to studying rs2279744 status dependent on another SNP.36 37 Even so, the two studies were described in multiple meta-analyses that are listed in table 3. Different permutations of these eight original studies appear in at least eight published meta-analyses. However, even the largest meta-analysis contained <2000 cases (table 3)38View this table:Table 3 Characteristics of studies that examined MDM2 SNP rs2279744In comparison, a GWAS including nearly 13 000 cases found no evidence of an association with OR and corresponding 95% CI of 1.00 (0.97 to 1.03) and a p value of 0.93 (personal communication).21 Nevertheless, we cannot completely rule out a role for MDM2 variants in endometrial cancer predisposition as the candidate-gene studies reported larger effects in Asians, whereas the GWAS primarily contained participants of European ancestry.

There is also some suggestion that the SNP309 variant is in linkage disequilibrium with another variant, SNP285, which confers an opposite effect.It is worth noting that the SNP285C/SNP309G haplotype frequency was observed in up to 8% of Europeans, thus requiring correction for the confounding effect of SNP285C in European studies.39 However, aside from one study conducted by Knappskog et al, no other study including the meta-analyses corrected for the confounding effect of SNP285.40 Among the studies presented in table 3, Knappskog et al (2012) reported that after correcting for SNP285, the OR for association of this haplotype with endometrial cancer was much lower, though still significant. Unfortunately, the meta-analyses which synthesised Knappskog et al (2012), as part of their analysis, did not correct for SNP285C in the European-based studies they included.38 41 42 It is also concerning that two meta-analyses using the same primary articles failed to report the same result, in two instances.38 42–44DiscussionThis article represents the most comprehensive systematic review to date, regarding critical appraisal of the available evidence of common low-penetrance variants implicated in predisposition to endometrial cancer. We have identified the most robust SNPs in the context of endometrial cancer risk. Of those, only 19 were significant at genome-wide level and a further five were considered marginally significant.

The largest GWAS conducted in this field was the discovery- and meta-GWAS by O’Mara et al, which utilised 12 096 cases and 108 979 controls.21 Despite the inclusion of all published GWAS and around 5000 newly genotyped cases, the total number did not reach anywhere near what is currently available for other common cancers such as breast cancer. For instance, BCAC (Breast Cancer Association Consortium) stands at well over 200 000 individuals with more than half being cases, and resulted in identification of ~170 SNPs in relation to breast cancer.19 45 A total of 313 SNPs including imputations were then used to derive a PRS for breast cancer.19 Therefore, further efforts should be directed to recruit more patients, with deep phenotypic clinical data to allow for relevant adjustments and subgroup analyses to be conducted for better precision.A recent pre-print study by Zhang and colleagues examined the polygenicity and potential for SNP-based risk prediction for 14 common cancers, including endometrial cancer, using available summary-level data from European-ancestry datasets.46 They estimated that there are just over 1000 independent endometrial cancer susceptibility SNPs, and that a PRS comprising all such SNPs would have an area under the receiver-operator curve of 0.64, similar to that predicted for ovarian cancer, but lower than that for the other cancers in the study. The modelling in the paper suggests that an endometrial cancer GWAS double the size of the current largest study would be able to identify susceptibility SNPs together explaining 40% of the genetic variance, but that in order to explain 75% of the genetic variance it would be necessary to have a GWAS comprising close to 150 000 cases and controls, far in excess of what is currently feasible.We found that the literature consists mainly of candidate-gene studies with small sample sizes, meta-analyses reporting conflicting results despite using the same set of primary articles, and multiple reports of significant SNPs that have not been validated by any larger GWAS. The candidate-gene studies were indeed the most useful and cheaper technique available until the mid to late 2000s.

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

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

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

Using all 24 or genome-wide significant SNPs only, women with a PRS in the top 1% of the distribution would be predicted to have a risk of endometrial cancer 3.16 and 2.09 times higher than the mean risk, respectively.However, the importance of these variants and relevance of the proximate genes in a functional or biological context is challenging to evaluate. Long distance promoter regulation by enhancers may disguise the genuine target gene. In addition, enhancers often do not loop to the nearest gene, further complicating the relevance of nearby gene(s) to a GWAS hit. In order to elucidate biologically relevant candidate target genes in endometrial cancer, O’Mara et al looked into promoter-associated chromatin looping using a modern HiChIP approach.47 The authors utilised normal and tumoural endometrial cell lines for this analysis which showed significant enrichment for endometrial cancer heritability, with 103 candidate target genes identified across the 13 risk loci identified by the largest ECAC GWAS.

Notable genes identified here were CDKN2A and WT1, and their antisense counterparts. The former was reported to be nearby of rs1679014 and the latter of rs10835920, as shown in table 1. Moreover, of the 36 candidate target genes, 17 were found to be downregulated while 19 were upregulated in endometrial tumours.The authors also investigated overlap between the 13 endometrial cancer risk loci and top eQTL variants for each target gene.47 In whole blood, of the two particular lead SNPs, rs8822380 at 17q21.32 was a top eQTL for SNX11 and HOXB2, whereas rs937213 at 15q15.1 was a top eQTL for SRP14. In endometrial tumour, rs7579014 at 2p16.1 was found to be a top eQTL for BCL11A.

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

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

This poses a problem for developing risk prediction models that are equally valuable and predictive across populations. Thus, our results also are of limited applicability to non-European populations.Furthermore, considering that non-endometrioid cases comprise a small proportion (~20%) of all endometrial cancer cases, much larger cohort sizes are needed to detect any genuine signals for non-endometrioid tumours. Most of the evaluated studies looked at either overall/mixed endometrial cancer subtypes or endometrioid histology, and those that looked at variant associations with non-endometrioid histology were unlikely to have enough power to detect any signal with statistical significance. This is particularly concerning because non-endometrioid subtypes are biologically aggressive tumours with a much poorer prognosis that contribute disproportionately to mortality from endometrial cancer.

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

Additionally, of all the studies, only one accounted for the opposing effect of a nearby variant SNP285 in their analyses. Thus, we conclude that until confirmed by a sufficiently large GWAS, this variant should not be considered significant in influencing the risk of endometrial cancer and therefore not included in a PRS. This is also true for the majority of the SNPs reported in candidate-gene studies, as the numbers fall far short of being able to detect genuine signals.This systematic review presents the most up-to-date evidence for endometrial cancer susceptibility variants, emphasising the need for further large-scale studies to identify more variants of importance, and validation of these associations. Until data from larger and more diverse cohorts are available, the top 24 SNPs presented here are the most robust common genetic variants that affect endometrial cancer risk.

The multiplicative effects of these SNPs could be used in a PRS to allow personalised risk prediction models to be developed for targeted screening and prevention interventions for women at greatest risk of endometrial cancer..