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End of generic symbicort online for sale term report‘Brown. You may discuss your report with the head now. You should know, there are some issues.’ Many of you will have similar recollections of mid-July during their generic symbicort online for sale schooldays. The annual feedback lurking, snake-like in the reeds, freedom never granted until the teachers’ handwritten, often indecipherable words had been parentally decodified at home, my own Achilles’ heels art and English literature perennial causes of teachers’ deep sighs.

I acknowledge that the stick men figures of my primary school art failed to evolve into anything more than uncannily similar stick men figures over the course of my pre-teenage years, the point at which my metaphorical knotted sheets and I furnished an escape. Are we also, collectively, guilty of leaving our socks proverbially at ankle length in generic symbicort online for sale places?. Asthma. What are the priorities? generic symbicort online for sale.

We kick off with a blistering pair of editorials which eviscerate a common practice from opposite, but not necessarily, mutually exclusive angles. The first is by Ian Sinha and argues the case for the replacement of prednisolone with dexamethasone in acute asthma attacks. The ubiquitous prednisolone generic symbicort online for sale is, its detractors assert, known for its (gustatory, olfactory and visual) unpalatability. Once sampled, no child ever trusts pink medicine again – its emetogenic capacity and potential for non-compliance given the 3 day rather than 1 day course often cited as additional drawbacks.

Mark Levy and colleagues challenge the need for the abandonment of prednisolone largely based on the generic symbicort online for sale lack of hard evidence. This is where interpretation has to be disentangled from personal biases. Not easy and the reality is that even the most robust meta-analyses can’t always furnish us with ‘the answers’. I could, but won’t take sides on this (just now) as it would spoil your fun, but perhaps this is too close to call and, as long as the right children (school age) get some steroids (of one hue or generic symbicort online for sale another) early on and the wrong children (most preschoolers) don’t that might be a reasonable compromise.

There are other high-profile priorities like the use of high protracted courses of beta agonists and after discharge underuse of inhaled steroid-LABA combinations. I’m already looking forward to the next round generic symbicort online for sale of discussions. The UK (and we can shoegaze all we like) is a perennial ‘could do better’/end of year report C-performer. Not as bad as my F grade art, of course, but, how hard can it be to score at least a B grade?.

See pages 729 and 730Neonatal generic symbicort online for sale sepsis. New dataThough a great deal of credit is due for progress during the Millennium and early Sustainable Development goal eras, the data can’t disguise the areas where little changed. Until recently at least, perinatal mortality was one. A rule of generic symbicort online for sale thumb reminder.

In most low and middle income countries infant mortality accounts for about two thirds of all under 5 mortality. Of infant generic symbicort online for sale mortality, about two thirds is neonatal (first month) and, of neonatal, two thirds perinatal, deaths in the first week. Causes are consistent. Prematurity, asphyxia and sepsis, the dysregulated host immune response to to which neonates are exquisitely sensitive.

We like to generic symbicort online for sale think we have a ballpark idea of the burden of peri and neonatal death globally, but this ballpark is a very elastic one. Carolin Fleischmann and colleagues’ meticulous systematic review and meta-analysis brings some clarity, not only in overall sepsis load, but (and this is particularly useful in antibiotic selection) the early and late onset phenotypes. Of the total screened generic symbicort online for sale 26 studies published between 1979 and 2019 met the criteria (including a tight sepsis definition) were included accounting for 2.8 million live births and close to 30,000 sepsis. Random-effects MA estimated an incidence rate of 2,824/100,000 births with a case fatality of 17.6%.

Between 2009 and 2018, the incidence was markedly worse at 3,390. This isn’t a finding we can dismiss simply under the smokescreen of ascertainment bias and generic symbicort online for sale improvement of criteria. Take a look at the beta lactam, fourth generation cephalosporin, carbapenem and linezolid resistance patterns in other studies and one can only conclude this is not good news. See page 745Non-accidental injury generic symbicort online for sale.

More science. New dataThe TEN4 Bruise Clinical Decision Rule (BCDR) was first reported by Pierce in 2010. It was estimated that ‘bruising on the torso, ear, or neck for a generic symbicort online for sale child <48 months of age and bruising in any region for an infant <4 months of age, in the absence of a publicly witnessed injury' had a sensitivity of 97% and a specificity of 84% for predicting abuse. Using data from previous studies on patterns in day to day bruising, NAI and inherited bleeding disorders, Alison Kemp and colleagues refine the tool to test its ability to differentiate between bruise distribution phenotypes.

Applying TEN4 to to children under 4 generic symbicort online for sale years of age, with at least one bruise had an estimated sensitivity of 69% and specificity for abuse of 74%, figures that will ultimately inform how we report and a court interprets findings in an area where uncertainty is the rule. See page 774Can one afford to simply wait?. Other than the surgical approach having changed from scalpel to laparoscope, the individual and family experience of appendicitis as a package in terms of inpatient time, discomfort and cost has changed little in the recent past. For such a common entity, exploring new alternatives was always going to be necessary and the generic symbicort online for sale surgery vs antibiotic/expectant hypothesis is one such avenue.

The CONTRACT study, one of a series of randomised controlled trials tests the effectiveness of treating children with uncomplicated (for example, unperforated) appendicitis with parenteral antibiotics rather than surgery. Bold, but not unreasonable, given the objective equipoise and long experience of this approach in some countries. It is likely that the results of these RCTs will determine the route children take for years if not decades generic symbicort online for sale. The trial feasibility study undertaken by Nigel Hall and colleagues lent weight to.

Parents’ enthusiasm generic symbicort online for sale (50% enrolled after being approached). Acceptability of randomisation and patient and surgeon adherence to trial procedures. See page 764Ethics statementsPatient consent for publicationNot required.The anti inflammatory drugs symbicort has posed challenges for the delivery of healthcare for infants with disruption to 6-week health checks and health visitor services.1 An area of particular concern is late presentation to the hospital.2 However, current data do not offer an objective picture of how significant a problem this may be, with other reports showing low rates of delays in presentation.3 Infantile hypertrophic pyloric stenosis (IHPS) is a common, non-infective infantile condition with a predictable clinical course and therefore a good indicator condition to assess for delays in presentation. We aimed to assess generic symbicort online for sale whether infants with IHPS presented later during ‘lockdown’ compared with the same period the preceding year.Ten centres within the UK (England, Scotland and Northern Ireland) contributed data from babies with IHPS via a website (anti inflammatory drugsinchildren.co.uk) between 23 March 2020 and 31 May 2020 (the anti inflammatory drugs lockdown period) and between 23 March and 31 May 2019 (controls).

A total of 87 eligible infants were included, comprising 40 controls (46%) and 47 cases (54%). The demographic and baseline characteristics of the two groups were similar (table 1 and figure 1).View this table:Table 1 Characteristics of control (2019 patients) and lockdown (2020) patientsComparison between the age at presentation (A) and admission weight (B) of infants with IHPS in the control period generic symbicort online for sale (2019) and the lockdown period. No significant difference is seen between the two groups (age at admission p=0.64, admission weight p=0.84). IHPS, Infantile hypertrophic pyloric stenosis." data-icon-position data-hide-link-title="0">Figure 1 Comparison between the age at presentation (A) and admission weight (B) of infants with IHPS in the control period (2019) and the lockdown period.

No significant difference is seen between the two groups (age generic symbicort online for sale at admission p=0.64, admission weight p=0.84). IHPS, Infantile hypertrophic pyloric stenosis.Median age and weight at presentation in the control group were 31 days (24–41) and 3600 g (3190–4081), and those in the lockdown group were 34 days (26–41) and 3580 g (3120–4085). These differences were not statistically generic symbicort online for sale significant (p=0.64, p=0.84) (figure 1). The change in standardised weight loss was also comparable.

(table 2). Patients requirement for preoperative intensive care and serum biochemistry was also similar except the lockdown group had a statistically but not clinically significant higher serum potassium (4.16 vs 4.5 mmol/L, p=0.04) (table 2).View this table:Table 2 Comparison of the primary and secondary outcome measures for infants presenting during the lockdown and control periodsAs an indicator condition, we have some reassurance that infants with IHPS have not had a significantly delayed presentation due to the anti inflammatory drugs lockdown. A recent objective study looking at paediatric presentations to emergency departments found very low numbers of delayed presentations to the hospital, with minimal associated morbidity.3 4 Prompt, proactive changes to National Health Service 111 algorithms, guidance for parents by the Royal College of Paediatrics and Child Health5 and the rapid uptake of virtual general practice and health visitor consultations may have avoided morbidity. Further work, focusing on different types of conditions, or different subsections of society will help provide useful information relating to the impact of societal lockdown on healthcare-seeking behaviour in the UK and will enable more effective delivery of healthcare provision and public messaging in the event of further lockdowns.Ethics statementsPatient consent for publicationNot required..

Symbicort patent expiration us

There is a special program called Buy levitra with free samples the Low symbicort patent expiration us Income Subsidy (LIS) which helps with Medicare Part D cost sharing. LIS is also known as "Extra Help." The Social Security Administration administers LIS -- you don't apply through your Part D plan. See Medicare Rights Center chart on Extra Help Income and Asset Limits (listed amounts already deduct the $20/month income disregard)(they update it annually) Enrolling in Extra Help There are three basic ways to get into the LIS program. 1) by receiving Medicaid symbicort patent expiration us.

Medicaid recipients, including those who meet a spenddown, are "deemed" into LIS (automatically enrolled by SSA) and don't have to file a separate application for Extra Help. See more below about how receiving Medicaid just for one month can qualify you for Full Extra Help for up to 18 months. 2) by symbicort patent expiration us enrolling in a Medicare Savings Program. The Medicare Savings Program includes the Qualified Medicare Beneficiary (QMB) program, which covers beneficiaries up to 100% FPL.

Specified Low-Income Medicare Beneficiary (SLIMB), for those between 100-120%. And the symbicort patent expiration us Qualified Individual (QI-1) program, for individuals between 120-135% FPL. There are no resource tests in New York's Medicare Savings Program.) The New York State Department of Health posts the Medicare Savings Program income guidelines on their website. Just like Medicaid, Medicare Savings Program recipients are deemed into LIS and don't need to apply through SSA.

For more information see symbicort patent expiration us this article. 3) by applying for Extra Help through the Social Security Administration. The Extra Help income limits are 150% FPL and there is an asset test. SSA lists the income and resource limits for Extra Help on their website, where you can also file symbicort patent expiration us an application online and get more information about the program.

You can also find out information about Extra Help in many different languages. See Medicare Rights Center chart on Extra Help Income and Asset Limits - updated annually You can apply for Extra Help and MSP at the same time through SSA. SSA will forward your Extra Help application data to the New York State Department of Health, who will use that data symbicort patent expiration us to assess your eligibility for MSP. Individuals who apply for LIS through SSA and those who are deemed into LIS should receive written confirmation of their Extra Help status through SSA.

Of course, individuals who apply for LIS through SSA and are found ineligible are also entitled to a written notice and have appeal rights. Benefits of Extra Help 1) symbicort patent expiration us Assistance with Part D cost-sharing The Extra Help program provides a subsidy which covers most (but not all) of beneficiary’s cost sharing obligations. Extra Help beneficiaries do not have to worry about hitting the “donut hole” – the LIS subsidy continues to cover them through the donut hole and into catastrophic coverage. Full Extra Help.

LIS beneficiaries with incomes up to 135% FPL are generally eligible for "full" Extra Help -- meaning they pay no Part D deductible, no charge for monthly premiums up to the benchmark amount, and fixed, relatively low co-pays (between $1.30 and $8.95 for 2020 depending on the person's income level and the tier category of the drug symbicort patent expiration us. Medicaid beneficiaries in nursing homes, waiver programs, or managed long term care have $0 co-pays). Full Extra Help beneficiaries who hit the catastrophic coverage limit have $0 co-pays. See current symbicort patent expiration us co-pay levels here.

Partial Extra Help. Beneficiaries between 135%-150% FPL receive "partial" Extra Help, which limits the Part D deductible to $89 (2020 figure - click here for updated chart). Sets sliding scale symbicort patent expiration us fees for monthly premiums. And limits co-pays to 15%, until the beneficiary reaches the catastrophic coverage limit, at which point co-pays are limited to a $8.95 maximum (2020 or see current amount here) or 5% of the drug cost, whichever is greater.

2) Facilitated enrollment into a Part D plan Extra Help recipients who aren’t already enrolled in a Part D plan and don’t want to choose one on their own will be automatically enrolled into a benchmark plan by CMS. This facilitated symbicort patent expiration us enrollment ensures that Extra Help recipients have Part D coverage. However, the downside to facilitated enrollment is that the plan may not be the best “fit” for the beneficiary, if it doesn’t cover all his/her drugs, assesses a higher tier level for covered drugs than other comparable plans, and/or requires the beneficiary to go through administrative hoops like prior authorization, quantity limits and/or step therapy. Fortunately, Extra Help recipients can always enroll in a new plan … see #3 below.

3) Continuous special enrollment period Extra Help recipients have a continuous special enrollment period, meaning that they can switch plans at any symbicort patent expiration us time. They are not “locked into” the annual open enrollment period (October 15-December 7). NOTE. This changed symbicort patent expiration us in 2019.

Starting in 2019, those with Extra Help will no longer have a continuous enrollment period. Instead, Extra Help recipients will be eligible to enroll no more than once per quarter for each of the first three quarters of the year. 4) No late enrollment penalty Non LIS beneficiaries generally face a premium penalty (higher monthly premium) if they delayed their enrollment into Part D, meaning that they didn’t enroll when they were initially eligible and didn’t have “creditable coverage.” Extra Help recipients do not have to worry about this problem symbicort patent expiration us – the late enrollment penalty provision does not apply to LIS beneficiaries. 1) For “deemed” beneficiaries (Medicaid/Medicare Savings Program recipients).

Extra Help status lasts at least until the end of the current calendar year, even if the individual loses their Medicaid or Medicare Savings Program coverage during that year. Individuals who receive Medicaid or a Medicare Savings symbicort patent expiration us Program any month between July and December keep their LIS status for the remainder of that calendar year and the following year. Getting Medicaid coverage for even just a short period of time (ie, meeting a spenddown for just one month) can help ensure that the individual obtains Extra Help coverage for at least 6 months, and possibly as long as 18 months. TIP.

People with a high symbicort patent expiration us spend-down who want to receive Medicaid for just one month in order to get Extra Help for 6-18 months can use past medical bills to meet their spend-down for that one month. There are different rules for using past paid medical bills verses past unpaid medical bills. For information see Spend down training materials. Individuals who are losing their deemed status at the end of a calendar year because they are no longer receiving Medicaid or the Medicare Savings Program should be notified in advance symbicort patent expiration us by SSA, and given an opportunity to file an Extra Help application through SSA.

2) For “non-deemed” beneficiaries (those who filed their LIS applications through SSA) Non-deemed beneficiaries retain their LIS status until/unless SSA does a redetermination and finds the individual ineligible for Extra Help. There are no reporting requirements per se in the Extra Help program, but beneficiaries must respond to SSA’s redetermination request. What to do if the Part D plan doesn't know that someone has Extra Help Sometimes there are lengthy delays between the date that someone is approved for Medicaid or a Medicare Savings Program and when that information is formally conveyed to the Part D symbicort patent expiration us plan by CMS. As a practical matter, this often results in beneficiaries being charged co-pays, premiums and/or deductibles that they can't afford and shouldn't have to pay.

To protect LIS beneficiaries, CMS has a "Best Available Evidence" policy which requires plans to accept alternative forms of proof of someone's LIS status and adjust the person's cost-sharing obligation accordingly. LIS beneficiaries who are being charged improperly should be sure to contact their plan and provide proof of their LIS status symbicort patent expiration us. If the plan still won't recognize their LIS status, the person or their advocate should file a complaint with the CMS regional office. The federal regulations governing the Low Income Subsidy program can be found at 42 CFR Subpart P (sections 423.771 through 423.800).

Also, CMS provides detailed guidance on the symbicort patent expiration us LIS provisions in chapter 13 of its Medicare Prescription Drug Benefit Manual. This article was authored by the Empire Justice Center.Medicare Savings Programs (MSPs) pay for the monthly Medicare Part B premium for low-income Medicare beneficiaries and qualify enrollees for the "Extra Help" subsidy for Part D prescription drugs. There are three separate MSP programs, the Qualified Medicare Beneficiary (QMB) Program, the Specified Low Income Medicare Beneficiary (SLMB) Program and the Qualified Individual (QI) Program, each of which is discussed below. Those in QMB receive symbicort patent expiration us additional subsidies for Medicare costs.

See 2019 Fact Sheet on MSP in NYS by Medicare Rights Center ENGLISH SPANISH State law. N.Y. Soc. Serv.

L. § 367-a(3)(a), (b), and (d). 2020 Medicare 101 Basics for New York State - 1.5 hour webinar by Eric Hausman, sponsored by NYS Office of the Aging TOPICS COVERED IN THIS ARTICLE 1. No Asset Limit 1A.

Summary Chart of MSP Programs 2. Income Limits &. Rules and Household Size 3. The Three MSP Programs - What are they and how are they Different?.

4. FOUR Special Benefits of MSP Programs. Back Door to Extra Help with Part D MSPs Automatically Waive Late Enrollment Penalties for Part B - and allow enrollment in Part B year-round outside of the short Annual Enrollment Period No Medicaid Lien on Estate to Recover Payment of Expenses Paid by MSP Food Stamps/SNAP not reduced by Decreased Medical Expenses when Enroll in MSP - at least temporarily 5. Enrolling in an MSP - Automatic Enrollment &.

Applications for People who Have Medicare What is Application Process?. 6. Enrolling in an MSP for People age 65+ who Do Not Qualify for Free Medicare Part A - the "Part A Buy-In Program" 7. What Happens After MSP Approved - How Part B Premium is Paid 8 Special Rules for QMBs - How Medicare Cost-Sharing Works 1.

NO ASSET LIMIT!. Since April 1, 2008, none of the three MSP programs have resource limits in New York -- which means many Medicare beneficiaries who might not qualify for Medicaid because of excess resources can qualify for an MSP. 1.A. SUMMARY CHART OF MSP BENEFITS QMB SLIMB QI-1 Eligibility ASSET LIMIT NO LIMIT IN NEW YORK STATE INCOME LIMIT (2020) Single Couple Single Couple Single Couple $1,064 $1,437 $1,276 $1,724 $1,436 $1,940 Federal Poverty Level 100% FPL 100 – 120% FPL 120 – 135% FPL Benefits Pays Monthly Part B premium?.

YES, and also Part A premium if did not have enough work quarters and meets citizenship requirement. See “Part A Buy-In” YES YES Pays Part A &. B deductibles &. Co-insurance YES - with limitations NO NO Retroactive to Filing of Application?.

Yes - Benefits begin the month after the month of the MSP application. 18 NYCRR §360-7.8(b)(5) Yes – Retroactive to 3rd month before month of application, if eligible in prior months Yes – may be retroactive to 3rd month before month of applica-tion, but only within the current calendar year. (No retro for January application). See GIS 07 MA 027.

Can Enroll in MSP and Medicaid at Same Time?. YES YES NO!. Must choose between QI-1 and Medicaid. Cannot have both, not even Medicaid with a spend-down.

2. INCOME LIMITS and RULES Each of the three MSP programs has different income eligibility requirements and provides different benefits. The income limits are tied to the Federal Poverty Level (FPL). 2019 FPL levels were released by NYS DOH in GIS 20 MA/02 - 2020 Federal Poverty Levels -- Attachment II and have been posted by Medicaid.gov and the National Council on Aging and are in the chart below.

NOTE. There is usually a lag in time of several weeks, or even months, from January 1st of each year until the new FPLs are release, and then before the new MSP income limits are officially implemented. During this lag period, local Medicaid offices should continue to use the previous year's FPLs AND count the person's Social Security benefit amount from the previous year - do NOT factor in the Social Security COLA (cost of living adjustment). Once the updated guidelines are released, districts will use the new FPLs and go ahead and factor in any COLA.

See 2019 Fact Sheet on MSP in NYS by Medicare Rights Center ENGLISH SPANISH Income is determined by the same methodology as is used for determining in eligibility for SSI The rules for counting income for SSI-related (Aged 65+, Blind, or Disabled) Medicaid recipients, borrowed from the SSI program, apply to the MSP program, except for the new rules about counting household size for married couples. N.Y. Soc. Serv.

L. 367-a(3)(c)(2), NYS DOH 2000-ADM-7, 89-ADM-7 p.7. Gross income is counted, although there are certain types of income that are disregarded. The most common income disregards, also known as deductions, include.

(a) The first $20 of your &. Your spouse's monthly income, earned or unearned ($20 per couple max). (b) SSI EARNED INCOME DISREGARDS. * The first $65 of monthly wages of you and your spouse, * One-half of the remaining monthly wages (after the $65 is deducted).

* Other work incentives including PASS plans, impairment related work expenses (IRWEs), blind work expenses, etc. For information on these deductions, see The Medicaid Buy-In for Working People with Disabilities (MBI-WPD) and other guides in this article -- though written for the MBI-WPD, the work incentives apply to all Medicaid programs, including MSP, for people age 65+, disabled or blind. (c) monthly cost of any health insurance premiums but NOT the Part B premium, since Medicaid will now pay this premium (may deduct Medigap supplemental policies, vision, dental, or long term care insurance premiums, and the Part D premium but only to the extent the premium exceeds the Extra Help benchmark amount) (d) Food stamps not counted. You can get a more comprehensive listing of the SSI-related income disregards on the Medicaid income disregards chart.

As for all benefit programs based on financial need, it is usually advantageous to be considered a larger household, because the income limit is higher. The above chart shows that Households of TWO have a higher income limit than households of ONE. The MSP programs use the same rules as Medicaid does for the Disabled, Aged and Blind (DAB) which are borrowed from the SSI program for Medicaid recipients in the “SSI-related category.” Under these rules, a household can be only ONE or TWO. 18 NYCRR 360-4.2.

See DAB Household Size Chart. Married persons can sometimes be ONE or TWO depending on arcane rules, which can force a Medicare beneficiary to be limited to the income limit for ONE person even though his spouse who is under 65 and not disabled has no income, and is supported by the client applying for an MSP. EXAMPLE. Bob's Social Security is $1300/month.

He is age 67 and has Medicare. His wife, Nancy, is age 62 and is not disabled and does not work. Under the old rule, Bob was not eligible for an MSP because his income was above the Income limit for One, even though it was well under the Couple limit. In 2010, NYS DOH modified its rules so that all married individuals will be considered a household size of TWO.

DOH GIS 10 MA 10 Medicare Savings Program Household Size, June 4, 2010. This rule for household size is an exception to the rule applying SSI budgeting rules to the MSP program. Under these rules, Bob is now eligible for an MSP. When is One Better than Two?.

Of course, there may be couples where the non-applying spouse's income is too high, and disqualifies the applying spouse from an MSP. In such cases, "spousal refusal" may be used SSL 366.3(a). (Link is to NYC HRA form, can be adapted for other counties). 3.

The Three Medicare Savings Programs - what are they and how are they different?. 1. Qualified Medicare Beneficiary (QMB). The QMB program provides the most comprehensive benefits.

Available to those with incomes at or below 100% of the Federal Poverty Level (FPL), the QMB program covers virtually all Medicare cost-sharing obligations. Part B premiums, Part A premiums, if there are any, and any and all deductibles and co-insurance. QMB coverage is not retroactive. The program’s benefits will begin the month after the month in which your client is found eligible.

** See special rules about cost-sharing for QMBs below - updated with new CMS directive issued January 2012 ** See NYC HRA QMB Recertification form ** Even if you do not have Part A automatically, because you did not have enough wages, you may be able to enroll in the Part A Buy-In Program, in which people eligible for QMB who do not otherwise have Medicare Part A may enroll, with Medicaid paying the Part A premium (Materials by the Medicare Rights Center). 2. Specifiedl Low-Income Medicare Beneficiary (SLMB). For those with incomes between 100% and 120% FPL, the SLMB program will cover Part B premiums only.

SLMB is retroactive, however, providing coverage for three months prior to the month of application, as long as your client was eligible during those months. 3. Qualified Individual (QI-1). For those with incomes between 120% and 135% FPL, and not receiving Medicaid, the QI-1 program will cover Medicare Part B premiums only.

QI-1 is also retroactive, providing coverage for three months prior to the month of application, as long as your client was eligible during those months. However, QI-1 retroactive coverage can only be provided within the current calendar year. (GIS 07 MA 027) So if you apply in January, you get no retroactive coverage. Q-I-1 recipients would be eligible for Medicaid with a spend-down, but if they want the Part B premium paid, they must choose between enrolling in QI-1 or Medicaid.

They cannot be in both. It is their choice. DOH MRG p. 19.

In contrast, one may receive Medicaid and either QMB or SLIMB. 4. Four Special Benefits of MSPs (in addition to NO ASSET TEST). Benefit 1.

Back Door to Medicare Part D "Extra Help" or Low Income Subsidy -- All MSP recipients are automatically enrolled in Extra Help, the subsidy that makes Part D affordable. They have no Part D deductible or doughnut hole, the premium is subsidized, and they pay very low copayments. Once they are enrolled in Extra Help by virtue of enrollment in an MSP, they retain Extra Help for the entire calendar year, even if they lose MSP eligibility during that year. The "Full" Extra Help subsidy has the same income limit as QI-1 - 135% FPL.

However, many people may be eligible for QI-1 but not Extra Help because QI-1 and the other MSPs have no asset limit. People applying to the Social Security Administration for Extra Help might be rejected for this reason. Recent (2009-10) changes to federal law called "MIPPA" requires the Social Security Administration (SSA) to share eligibility data with NYSDOH on all persons who apply for Extra Help/ the Low Income Subsidy. Data sent to NYSDOH from SSA will enable NYSDOH to open MSP cases on many clients.

The effective date of the MSP application must be the same date as the Extra Help application. Signatures will not be required from clients. In cases where the SSA data is incomplete, NYSDOH will forward what is collected to the local district for completion of an MSP application. The State implementing procedures are in DOH 2010 ADM-03.

Also see CMS "Dear State Medicaid Director" letter dated Feb. 18, 2010 Benefit 2. MSPs Automatically Waive Late Enrollment Penalties for Part B Generally one must enroll in Part B within the strict enrollment periods after turning age 65 or after 24 months of Social Security Disability. An exception is if you or your spouse are still working and insured under an employer sponsored group health plan, or if you have End Stage Renal Disease, and other factors, see this from Medicare Rights Center.

If you fail to enroll within those short periods, you might have to pay higher Part B premiums for life as a Late Enrollment Penalty (LEP). Also, you may only enroll in Part B during the Annual Enrollment Period from January 1 - March 31st each year, with Part B not effective until the following July. Enrollment in an MSP automatically eliminates such penalties... For life..

Even if one later ceases to be eligible for the MSP. AND enrolling in an MSP will automatically result in becoming enrolled in Part B if you didn't already have it and only had Part A. See Medicare Rights Center flyer. Benefit 3.

No Medicaid Lien on Estate to Recover MSP Benefits Paid Generally speaking, states may place liens on the Estates of deceased Medicaid recipients to recover the cost of Medicaid services that were provided after the recipient reached the age of 55. Since 2002, states have not been allowed to recover the cost of Medicare premiums paid under MSPs. In 2010, Congress expanded protection for MSP benefits. Beginning on January 1, 2010, states may not place liens on the Estates of Medicaid recipients who died after January 1, 2010 to recover costs for co-insurance paid under the QMB MSP program for services rendered after January 1, 2010.

The federal government made this change in order to eliminate barriers to enrollment in MSPs. See NYS DOH GIS 10-MA-008 - Medicare Savings Program Changes in Estate Recovery The GIS clarifies that a client who receives both QMB and full Medicaid is exempt from estate recovery for these Medicare cost-sharing expenses. Benefit 4. SNAP (Food Stamp) benefits not reduced despite increased income from MSP - at least temporarily Many people receive both SNAP (Food Stamp) benefits and MSP.

Income for purposes of SNAP/Food Stamps is reduced by a deduction for medical expenses, which includes payment of the Part B premium. Since approval for an MSP means that the client no longer pays for the Part B premium, his/her SNAP/Food Stamps income goes up, so their SNAP/Food Stamps go down. Here are some protections. Do these individuals have to report to their SNAP worker that their out of pocket medical costs have decreased?.

And will the household see a reduction in their SNAP benefits, since the decrease in medical expenses will increase their countable income?. The good news is that MSP households do NOT have to report the decrease in their medical expenses to the SNAP/Food Stamp office until their next SNAP/Food Stamp recertification. Even if they do report the change, or the local district finds out because the same worker is handling both the MSP and SNAP case, there should be no reduction in the household’s benefit until the next recertification. New York’s SNAP policy per administrative directive 02 ADM-07 is to “freeze” the deduction for medical expenses between certification periods.

Increases in medical expenses can be budgeted at the household’s request, but NYS never decreases a household’s medical expense deduction until the next recertification. Most elderly and disabled households have 24-month SNAP certification periods. Eventually, though, the decrease in medical expenses will need to be reported when the household recertifies for SNAP, and the household should expect to see a decrease in their monthly SNAP benefit. It is really important to stress that the loss in SNAP benefits is NOT dollar for dollar.

A $100 decrease in out of pocket medical expenses would translate roughly into a $30 drop in SNAP benefits. See more info on SNAP/Food Stamp benefits by the Empire Justice Center, and on the State OTDA website. Some clients will be automatically enrolled in an MSP by the New York State Department of Health (NYSDOH) shortly after attaining eligibility for Medicare. Others need to apply.

The 2010 "MIPPA" law introduced some improvements to increase MSP enrollment. See 3rd bullet below. Also, some people who had Medicaid through the Affordable Care Act before they became eligible for Medicare have special procedures to have their Part B premium paid before they enroll in an MSP. See below.

WHO IS AUTOMATICALLY ENROLLED IN AN MSP. Clients receiving even $1.00 of Supplemental Security Income should be automatically enrolled into a Medicare Savings Program (most often QMB) under New York State’s Medicare Savings Program Buy-in Agreement with the federal government once they become eligible for Medicare. They should receive Medicare Parts A and B. Clients who are already eligible for Medicare when they apply for Medicaid should be automatically assessed for MSP eligibility when they apply for Medicaid.

(NYS DOH 2000-ADM-7 and GIS 05 MA 033). Clients who apply to the Social Security Administration for Extra Help, but are rejected, should be contacted &. Enrolled into an MSP by the Medicaid program directly under new MIPPA procedures that require data sharing. Strategy TIP.

Since the Extra Help filing date will be assigned to the MSP application, it may help the client to apply online for Extra Help with the SSA, even knowing that this application will be rejected because of excess assets or other reason. SSA processes these requests quickly, and it will be routed to the State for MSP processing. Since MSP applications take a while, at least the filing date will be retroactive. Note.

The above strategy does not work as well for QMB, because the effective date of QMB is the month after the month of application. As a result, the retroactive effective date of Extra Help will be the month after the failed Extra Help application for those with QMB rather than SLMB/QI-1. Applying for MSP Directly with Local Medicaid Program. Those who do not have Medicaid already must apply for an MSP through their local social services district.

(See more in Section D. Below re those who already have Medicaid through the Affordable Care Act before they became eligible for Medicare. If you are applying for MSP only (not also Medicaid), you can use the simplified MSP application form (theDOH-4328(Rev. 8/2017-- English) (2017 Spanish version not yet available).

Either application form can be mailed in -- there is no interview requirement anymore for MSP or Medicaid. See 10 ADM-04. Applicants will need to submit proof of income, a copy of their Medicare card (front &. Back), and proof of residency/address.

See the application form for other instructions. One who is only eligible for QI-1 because of higher income may ONLY apply for an MSP, not for Medicaid too. One may not receive Medicaid and QI-1 at the same time. If someone only eligible for QI-1 wants Medicaid, s/he may enroll in and deposit excess income into a pooled Supplemental Needs Trust, to bring her countable income down to the Medicaid level, which also qualifies him or her for SLIMB or QMB instead of QI-1.

Advocates in NYC can sign up for a half-day "Deputization Training" conducted by the Medicare Rights Center, at which you'll be trained and authorized to complete an MSP application and to submit it via the Medicare Rights Center, which submits it to HRA without the client having to apply in person. Enrolling in an MSP if you already have Medicaid, but just become eligible for Medicare Those who, prior to becoming enrolled in Medicare, had Medicaid through Affordable Care Act are eligible to have their Part B premiums paid by Medicaid (or the cost reimbursed) during the time it takes for them to transition to a Medicare Savings Program. In 2018, DOH clarified that reimbursement of the Part B premium will be made regardless of whether the individual is still in a Medicaid managed care (MMC) plan. GIS 18 MA/001 Medicaid Managed Care Transition for Enrollees Gaining Medicare ( PDF) provides, "Due to efforts to transition individuals who gain Medicare eligibility and who require LTSS, individuals may not be disenrolled from MMC upon receipt of Medicare.

To facilitate the transition and not disadvantage the recipient, the Medicaid program is approving reimbursement of Part B premiums for enrollees in MMC." The procedure for getting the Part B premium paid is different for those whose Medicaid was administered by the NYS of Health Exchange (Marketplace), as opposed to their local social services district. The procedure is also different for those who obtain Medicare because they turn 65, as opposed to obtaining Medicare based on disability. Either way, Medicaid recipients who transition onto Medicare should be automatically evaluated for MSP eligibility at their next Medicaid recertification. NYS DOH 2000-ADM-7 Individuals can also affirmatively ask to be enrolled in MSP in between recertification periods.

IF CLIENT HAD MEDICAID ON THE MARKETPLACE (NYS of Health Exchange) before obtaining Medicare. IF they obtain Medicare because they turn age 65, they will receive a letter from their local district asking them to "renew" Medicaid through their local district. See 2014 LCM-02. Now, their Medicaid income limit will be lower than the MAGI limits ($842/ mo reduced from $1387/month) and they now will have an asset test.

For this reason, some individuals may lose full Medicaid eligibility when they begin receiving Medicare. People over age 65 who obtain Medicare do NOT keep "Marketplace Medicaid" for 12 months (continuous eligibility) See GIS 15 MA/022 - Continuous Coverage for MAGI Individuals. Since MSP has NO ASSET limit. Some individuals may be enrolled in the MSP even if they lose Medicaid, or if they now have a Medicaid spend-down.

If a Medicare/Medicaid recipient reports income that exceeds the Medicaid level, districts must evaluate the person’s eligibility for MSP. 08 OHIP/ADM-4 ​If you became eligible for Medicare based on disability and you are UNDER AGE 65, you are entitled to keep MAGI Medicaid for 12 months from the month it was last authorized, even if you now have income normally above the MAGI limit, and even though you now have Medicare. This is called Continuous Eligibility. EXAMPLE.

Sam, age 60, was last authorized for Medicaid on the Marketplace in June 2016. He became enrolled in Medicare based on disability in August 2016, and started receiving Social Security in the same month (he won a hearing approving Social Security disability benefits retroactively, after first being denied disability). Even though his Social Security is too high, he can keep Medicaid for 12 months beginning June 2016. Sam has to pay for his Part B premium - it is deducted from his Social Security check.

He may call the Marketplace and request a refund. This will continue until the end of his 12 months of continues MAGI Medicaid eligibility. He will be reimbursed regardless of whether he is in a Medicaid managed care plan. See GIS 18 MA/001 Medicaid Managed Care Transition for Enrollees Gaining Medicare (PDF) When that ends, he will renew Medicaid and apply for MSP with his local district.

Individuals who are eligible for Medicaid with a spenddown can opt whether or not to receive MSP. (Medicaid Reference Guide (MRG) p. 19). Obtaining MSP may increase their spenddown.

MIPPA - Outreach by Social Security Administration -- Under MIPPA, the SSA sends a form letter to people who may be eligible for a Medicare Savings Program or Extra Help (Low Income Subsidy - LIS) that they may apply. The letters are. · Beneficiary has Extra Help (LIS), but not MSP · Beneficiary has no Extra Help (LIS) or MSP 6. Enrolling in MSP for People Age 65+ who do Not have Free Medicare Part A - the "Part A Buy-In Program" Seniors WITHOUT MEDICARE PART A or B -- They may be able to enroll in the Part A Buy-In program, in which people eligible for QMB who are age 65+ who do not otherwise have Medicare Part A may enroll in Part A, with Medicaid paying the Part A premium.

See Step-by-Step Guide by the Medicare Rights Center). This guide explains the various steps in "conditionally enrolling" in Part A at the SSA office, which must be done before applying for QMB at the Medicaid office, which will then pay the Part A premium. See also GIS 04 MA/013. In June, 2018, the SSA revised the POMS manual procedures for the Part A Buy-In to to address inconsistencies and confusion in SSA field offices and help smooth the path for QMB enrollment.

The procedures are in the POMS Section HI 00801.140 "Premium-Free Part A Enrollments for Qualified Medicare BenefiIaries." It includes important clarifications, such as. SSA Field Offices should explain the QMB program and conditional enrollment process if an individual lacks premium-free Part A and appears to meet QMB requirements. SSA field offices can add notes to the “Remarks” section of the application and provide a screen shot to the individual so the individual can provide proof of conditional Part A enrollment when applying for QMB through the state Medicaid program. Beneficiaries are allowed to complete the conditional application even if they owe Medicare premiums.

In Part A Buy-in states like NYS, SSA should process conditional applications on a rolling basis (without regard to enrollment periods), even if the application coincides with the General Enrollment Period.

LIS is also known http://isiwa.com/buy-levitra-with-free-samples/ as "Extra Help." The Social Security Administration administers LIS -- you don't apply through your generic symbicort online for sale Part D plan. See Medicare Rights Center chart on Extra Help Income and Asset Limits (listed amounts already deduct the $20/month income disregard)(they update it annually) Enrolling in Extra Help There are three basic ways to get into the LIS program. 1) by receiving Medicaid.

Medicaid recipients, including those who meet a spenddown, are generic symbicort online for sale "deemed" into LIS (automatically enrolled by SSA) and don't have to file a separate application for Extra Help. See more below about how receiving Medicaid just for one month can qualify you for Full Extra Help for up to 18 months. 2) by enrolling in a Medicare Savings Program.

The Medicare Savings Program includes the Qualified Medicare Beneficiary (QMB) program, which generic symbicort online for sale covers beneficiaries up to 100% FPL. Specified Low-Income Medicare Beneficiary (SLIMB), for those between 100-120%. And the Qualified Individual (QI-1) program, for individuals between 120-135% FPL.

There are no resource tests in New York's Medicare Savings Program.) The New York State Department of Health posts generic symbicort online for sale the Medicare Savings Program income guidelines on their website. Just like Medicaid, Medicare Savings Program recipients are deemed into LIS and don't need to apply through SSA. For more information see this article.

3) by generic symbicort online for sale applying for Extra Help through the Social Security Administration. The Extra Help income limits are 150% FPL and there is an asset test. SSA lists the income and resource limits for Extra Help on their website, where you can also file an application online and get more information about the program.

You can also find out generic symbicort online for sale information about Extra Help in many different languages. See Medicare Rights Center chart on Extra Help Income and Asset Limits - updated annually You can apply for Extra Help and MSP at the same time through SSA. SSA will forward your Extra Help application data to the New York State Department of Health, who will use that data to assess your eligibility for MSP.

Individuals who apply for LIS through SSA and those who are deemed into LIS should receive written confirmation generic symbicort online for sale of their Extra Help status through SSA. Of course, individuals who apply for LIS through SSA and are found ineligible are also entitled to a written notice and have appeal rights. Benefits of Extra Help 1) Assistance with Part D cost-sharing The Extra Help program provides a subsidy which covers most (but not all) of beneficiary’s cost sharing obligations.

Extra Help beneficiaries do not generic symbicort online for sale have to worry about hitting the “donut hole” – the LIS subsidy continues to cover them through the donut hole and into catastrophic coverage. Full Extra Help. LIS beneficiaries with incomes up to 135% FPL are generally eligible for "full" Extra Help -- meaning they pay no Part D deductible, no charge for monthly premiums up to the benchmark amount, and fixed, relatively low co-pays (between $1.30 and $8.95 for 2020 depending on the person's income level and the tier category of the drug.

Medicaid beneficiaries in nursing homes, waiver programs, or generic symbicort online for sale managed long term care have $0 co-pays). Full Extra Help beneficiaries who hit the catastrophic coverage limit have $0 co-pays. See current co-pay levels here.

Partial generic symbicort online for sale Extra Help. Beneficiaries between 135%-150% FPL receive "partial" Extra Help, which limits the Part D deductible to $89 (2020 figure - click here for updated chart). Sets sliding scale fees for monthly premiums.

And limits generic symbicort online for sale co-pays to 15%, until the beneficiary reaches the catastrophic coverage limit, at which point co-pays are limited to a $8.95 maximum (2020 or see current amount here) or 5% of the drug cost, whichever is greater. 2) Facilitated enrollment into a Part D plan Extra Help recipients who aren’t already enrolled in a Part D plan and don’t want to choose one on their own will be automatically enrolled into a benchmark plan by CMS. This facilitated enrollment ensures that Extra Help recipients have Part D coverage.

However, the downside to facilitated enrollment is that the plan may not be the best “fit” for the beneficiary, generic symbicort online for sale if it doesn’t cover all his/her drugs, assesses a higher tier level for covered drugs than other comparable plans, and/or requires the beneficiary to go through administrative hoops like prior authorization, quantity limits and/or step therapy. Fortunately, Extra Help recipients can always enroll in a new plan … see #3 below. 3) Continuous special enrollment period Extra Help recipients have a continuous special enrollment period, meaning that they can switch plans at any time.

They are not “locked into” the annual open enrollment period generic symbicort online for sale (October 15-December 7). NOTE. This changed in 2019.

Starting in 2019, those with generic symbicort online for sale Extra Help will no longer have a continuous enrollment period. Instead, Extra Help recipients will be eligible to enroll no more than once per quarter for each of the first three quarters of the year. 4) No late enrollment penalty Non LIS beneficiaries generally face a premium penalty (higher monthly premium) if they delayed their enrollment into Part D, meaning that they didn’t enroll when they were initially eligible and didn’t have “creditable coverage.” Extra Help recipients do not have to worry about this problem – the late enrollment penalty provision does not apply to LIS beneficiaries.

1) For “deemed” beneficiaries (Medicaid/Medicare Savings generic symbicort online for sale Program recipients). Extra Help status lasts at least until the end of the current calendar year, even if the individual loses their Medicaid or Medicare Savings Program coverage during that year. Individuals who receive Medicaid or a Medicare Savings Program any month between July and December keep their LIS status for the remainder of that calendar year and the following year.

Getting Medicaid coverage for even just a short period of time (ie, meeting generic symbicort online for sale a spenddown for just one month) can help ensure that the individual obtains Extra Help coverage for at least 6 months, and possibly as long as 18 months. TIP. People with a high spend-down who want to receive Medicaid for just one month in order to get Extra Help for 6-18 months can use past medical bills to meet their spend-down for that one month.

There are different rules for generic symbicort online for sale using past paid medical bills verses past unpaid medical bills. For information see Spend down training materials. Individuals who are losing their deemed status at the end of a calendar year because they are no longer receiving Medicaid or the Medicare Savings Program should be notified in advance by SSA, and given an opportunity to file an Extra Help application through SSA.

2) generic symbicort online for sale For “non-deemed” beneficiaries (those who filed their LIS applications through SSA) Non-deemed beneficiaries retain their LIS status until/unless SSA does a redetermination and finds the individual ineligible for Extra Help. There are no reporting requirements per se in the Extra Help program, but beneficiaries must respond to SSA’s redetermination request. What to do if the Part D plan doesn't know that someone has Extra Help Sometimes there are lengthy delays between the date that someone is approved for Medicaid or a Medicare Savings Program and when that information is formally conveyed to the Part D plan by CMS.

As a practical matter, this often results in beneficiaries being charged co-pays, premiums generic symbicort online for sale and/or deductibles that they can't afford and shouldn't have to pay. To protect LIS beneficiaries, CMS has a "Best Available Evidence" policy which requires plans to accept alternative forms of proof of someone's LIS status and adjust the person's cost-sharing obligation accordingly. LIS beneficiaries who are being charged improperly should be sure to contact their plan and provide proof of their LIS status.

If the generic symbicort online for sale plan still won't recognize their LIS status, the person or their advocate should file a complaint with the CMS regional office. The federal regulations governing the Low Income Subsidy program can be found at 42 CFR Subpart P (sections 423.771 through 423.800). Also, CMS provides detailed guidance on the LIS provisions in chapter 13 of its Medicare Prescription Drug Benefit Manual.

This article was authored by the Empire Justice Center.Medicare Savings Programs (MSPs) pay for the monthly Medicare Part B premium for low-income Medicare beneficiaries and qualify enrollees for generic symbicort online for sale the "Extra Help" subsidy for Part D prescription drugs. There are three separate MSP programs, the Qualified Medicare Beneficiary (QMB) Program, the Specified Low Income Medicare Beneficiary (SLMB) Program and the Qualified Individual (QI) Program, each of which is discussed below. Those in QMB receive additional subsidies for Medicare costs.

See 2019 Fact Sheet on MSP in generic symbicort online for sale NYS by Medicare Rights Center ENGLISH SPANISH State law. N.Y. Soc.

2020 Medicare 101 Basics for New York State - 1.5 hour webinar by Eric Hausman, sponsored by NYS Office of the Aging TOPICS COVERED IN THIS ARTICLE 1. No Asset Limit 1A. Summary Chart of MSP Programs 2.

Income Limits &. Rules and Household Size 3. The Three MSP Programs - What are they and how are they Different?.

4. FOUR Special Benefits of MSP Programs. Back Door to Extra Help with Part D MSPs Automatically Waive Late Enrollment Penalties for Part B - and allow enrollment in Part B year-round outside of the short Annual Enrollment Period No Medicaid Lien on Estate to Recover Payment of Expenses Paid by MSP Food Stamps/SNAP not reduced by Decreased Medical Expenses when Enroll in MSP - at least temporarily 5.

Enrolling in an MSP - Automatic Enrollment &. Applications for People who Have Medicare What is Application Process?. 6.

Enrolling in an MSP for People age 65+ who Do Not Qualify for Free Medicare Part A - the "Part A Buy-In Program" 7. What Happens After MSP Approved - How Part B Premium is Paid 8 Special Rules for QMBs - How Medicare Cost-Sharing Works 1. NO ASSET LIMIT!.

Since April 1, 2008, none of the three MSP programs have resource limits in New York -- which means many Medicare beneficiaries who might not qualify for Medicaid because of excess resources can qualify for an MSP. 1.A. SUMMARY CHART OF MSP BENEFITS QMB SLIMB QI-1 Eligibility ASSET LIMIT NO LIMIT IN NEW YORK STATE INCOME LIMIT (2020) Single Couple Single Couple Single Couple $1,064 $1,437 $1,276 $1,724 $1,436 $1,940 Federal Poverty Level 100% FPL 100 – 120% FPL 120 – 135% FPL Benefits Pays Monthly Part B premium?.

YES, and also Part A premium if did not have enough work quarters and meets citizenship requirement. See “Part A Buy-In” YES YES Pays Part A &. B deductibles &.

Co-insurance YES - with limitations NO NO Retroactive to Filing of Application?. Yes - Benefits begin the month after the month of the MSP application. 18 NYCRR §360-7.8(b)(5) Yes – Retroactive to 3rd month before month of application, if eligible in prior months Yes – may be retroactive to 3rd month before month of applica-tion, but only within the current calendar year.

(No retro for January application). See GIS 07 MA 027. Can Enroll in MSP and Medicaid at Same Time?.

YES YES NO!. Must choose between QI-1 and Medicaid. Cannot have both, not even Medicaid with a spend-down.

2. INCOME LIMITS and RULES Each of the three MSP programs has different income eligibility requirements and provides different benefits. The income limits are tied to the Federal Poverty Level (FPL).

2019 FPL levels were released by NYS DOH in GIS 20 MA/02 - 2020 Federal Poverty Levels -- Attachment II and have been posted by Medicaid.gov and the National Council on Aging and are in the chart below. NOTE. There is usually a lag in time of several weeks, or even months, from January 1st of each year until the new FPLs are release, and then before the new MSP income limits are officially implemented.

During this lag period, local Medicaid offices should continue to use the previous year's FPLs AND count the person's Social Security benefit amount from the previous year - do NOT factor in the Social Security COLA (cost of living adjustment). Once the updated guidelines are released, districts will use the new FPLs and go ahead and factor in any COLA. See 2019 Fact Sheet on MSP in NYS by Medicare Rights Center ENGLISH SPANISH Income is determined by the same methodology as is used for determining in eligibility for SSI The rules for counting income for SSI-related (Aged 65+, Blind, or Disabled) Medicaid recipients, borrowed from the SSI program, apply to the MSP program, except for the new rules about counting household size for married couples.

L. 367-a(3)(c)(2), NYS DOH 2000-ADM-7, 89-ADM-7 p.7. Gross income is counted, although there are certain types of income that are disregarded.

The most common income disregards, also known as deductions, include. (a) The first $20 of your &. Your spouse's monthly income, earned or unearned ($20 per couple max).

(b) SSI EARNED INCOME DISREGARDS. * The first $65 of monthly wages of you and your spouse, * One-half of the remaining monthly wages (after the $65 is deducted). * Other work incentives including PASS plans, impairment related work expenses (IRWEs), blind work expenses, etc.

For information on these deductions, see The Medicaid Buy-In for Working People with Disabilities (MBI-WPD) and other guides in this article -- though written for the MBI-WPD, the work incentives apply to all Medicaid programs, including MSP, for people age 65+, disabled or blind. (c) monthly cost of any health insurance premiums but NOT the Part B premium, since Medicaid will now pay this premium (may deduct Medigap supplemental policies, vision, dental, or long term care insurance premiums, and the Part D premium but only to the extent the premium exceeds the Extra Help benchmark amount) (d) Food stamps not counted. You can get a more comprehensive listing of the SSI-related income disregards on the Medicaid income disregards chart.

As for all benefit programs based on financial need, it is usually advantageous to be considered a larger household, because the income limit is higher. The above chart shows that Households of TWO have a higher income limit than households of ONE. The MSP programs use the same rules as Medicaid does for the Disabled, Aged and Blind (DAB) which are borrowed from the SSI program for Medicaid recipients in the “SSI-related category.” Under these rules, a household can be only ONE or TWO.

18 NYCRR 360-4.2. See DAB Household Size Chart. Married persons can sometimes be ONE or TWO depending on arcane rules, which can force a Medicare beneficiary to be limited to the income limit for ONE person even though his spouse who is under 65 and not disabled has no income, and is supported by the client applying for an MSP.

EXAMPLE. Bob's Social Security is $1300/month. He is age 67 and has Medicare.

His wife, Nancy, is age 62 and is not disabled and does not work. Under the old rule, Bob was not eligible for an MSP because his income was above the Income limit for One, even though it was well under the Couple limit. In 2010, NYS DOH modified its rules so that all married individuals will be considered a household size of TWO.

DOH GIS 10 MA 10 Medicare Savings Program Household Size, June 4, 2010. This rule for household size is an exception to the rule applying SSI budgeting rules to the MSP program. Under these rules, Bob is now eligible for an MSP.

When is One Better than Two?. Of course, there may be couples where the non-applying spouse's income is too high, and disqualifies the applying spouse from an MSP. In such cases, "spousal refusal" may be used SSL 366.3(a).

(Link is to NYC HRA form, can be adapted for other counties). 3. The Three Medicare Savings Programs - what are they and how are they different?.

1. Qualified Medicare Beneficiary (QMB). The QMB program provides the most comprehensive benefits.

Available to those with incomes at or below 100% of the Federal Poverty Level (FPL), the QMB program covers virtually all Medicare cost-sharing obligations. Part B premiums, Part A premiums, if there are any, and any and all deductibles and co-insurance. QMB coverage is not retroactive.

The program’s benefits will begin the month after the month in which your client is found eligible. ** See special rules about cost-sharing for QMBs below - updated with new CMS directive issued January 2012 ** See NYC HRA QMB Recertification form ** Even if you do not have Part A automatically, because you did not have enough wages, you may be able to enroll in the Part A Buy-In Program, in which people eligible for QMB who do not otherwise have Medicare Part A may enroll, with Medicaid paying the Part A premium (Materials by the Medicare Rights Center). 2.

Specifiedl Low-Income Medicare Beneficiary (SLMB). For those with incomes between 100% and 120% FPL, the SLMB program will cover Part B premiums only. SLMB is retroactive, however, providing coverage for three months prior to the month of application, as long as your client was eligible during those months.

3. Qualified Individual (QI-1). For those with incomes between 120% and 135% FPL, and not receiving Medicaid, the QI-1 program will cover Medicare Part B premiums only.

QI-1 is also retroactive, providing coverage for three months prior to the month of application, as long as your client was eligible during those months. However, QI-1 retroactive coverage can only be provided within the current calendar year. (GIS 07 MA 027) So if you apply in January, you get no retroactive coverage.

Q-I-1 recipients would be eligible for Medicaid with a spend-down, but if they want the Part B premium paid, they must choose between enrolling in QI-1 or Medicaid. They cannot be in both. It is their choice.

DOH MRG p. 19. In contrast, one may receive Medicaid and either QMB or SLIMB.

4. Four Special Benefits of MSPs (in addition to NO ASSET TEST). Benefit 1.

Back Door to Medicare Part D "Extra Help" or Low Income Subsidy -- All MSP recipients are automatically enrolled in Extra Help, the subsidy that makes Part D affordable. They have no Part D deductible or doughnut hole, the premium is subsidized, and they pay very low copayments. Once they are enrolled in Extra Help by virtue of enrollment in an MSP, they retain Extra Help for the entire calendar year, even if they lose MSP eligibility during that year.

The "Full" Extra Help subsidy has the same income limit as QI-1 - 135% FPL. However, many people may be eligible for QI-1 but not Extra Help because QI-1 and the other MSPs have no asset limit. People applying to the Social Security Administration for Extra Help might be rejected for this reason.

Recent (2009-10) changes to federal law called "MIPPA" requires the Social Security Administration (SSA) to share eligibility data with NYSDOH on all persons who apply for Extra Help/ the Low Income Subsidy. Data sent to NYSDOH from SSA will enable NYSDOH to open MSP cases on many clients. The effective date of the MSP application must be the same date as the Extra Help application.

Signatures will not be required from clients. In cases where the SSA data is incomplete, NYSDOH will forward what is collected to the local district for completion of an MSP application. The State implementing procedures are in DOH 2010 ADM-03.

Also see CMS "Dear State Medicaid Director" letter dated Feb. 18, 2010 Benefit 2. MSPs Automatically Waive Late Enrollment Penalties for Part B Generally one must enroll in Part B within the strict enrollment periods after turning age 65 or after 24 months of Social Security Disability.

An exception is if you or your spouse are still working and insured under an employer sponsored group health plan, or if you have End Stage Renal Disease, and other factors, see this from Medicare Rights Center. If you fail to enroll within those short periods, you might have to pay higher Part B premiums for life as a Late Enrollment Penalty (LEP). Also, you may only enroll in Part B during the Annual Enrollment Period from January 1 - March 31st each year, with Part B not effective until the following July.

Enrollment in an MSP automatically eliminates such penalties... For life.. Even if one later ceases to be eligible for the MSP.

AND enrolling in an MSP will automatically result in becoming enrolled in Part B if you didn't already have it and only had Part A. See Medicare Rights Center flyer. Benefit 3.

No Medicaid Lien on Estate to Recover MSP Benefits Paid Generally speaking, states may place liens on the Estates of deceased Medicaid recipients to recover the cost of Medicaid services that were provided after the recipient reached the age of 55. Since 2002, states have not been allowed to recover the cost of Medicare premiums paid under MSPs. In 2010, Congress expanded protection for MSP benefits.

Beginning on January 1, 2010, states may not place liens on the Estates of Medicaid recipients who died after January 1, 2010 to recover costs for co-insurance paid under the QMB MSP program for services rendered after January 1, 2010. The federal government made this change in order to eliminate barriers to enrollment in MSPs. See NYS DOH GIS 10-MA-008 - Medicare Savings Program Changes in Estate Recovery The GIS clarifies that a client who receives both QMB and full Medicaid is exempt from estate recovery for these Medicare cost-sharing expenses.

Benefit 4. SNAP (Food Stamp) benefits not reduced despite increased income from MSP - at least temporarily Many people receive both SNAP (Food Stamp) benefits and MSP. Income for purposes of SNAP/Food Stamps is reduced by a deduction for medical expenses, which includes payment of the Part B premium.

Since approval for an MSP means that the client no longer pays for the Part B premium, his/her SNAP/Food Stamps income goes up, so their SNAP/Food Stamps go down. Here are some protections. Do these individuals have to report to their SNAP worker that their out of pocket medical costs have decreased?.

And will the household see a reduction in their SNAP benefits, since the decrease in medical expenses will increase their countable income?. The good news is that MSP households do NOT have to report the decrease in their medical expenses to the SNAP/Food Stamp office until their next SNAP/Food Stamp recertification. Even if they do report the change, or the local district finds out because the same worker is handling both the MSP and SNAP case, there should be no reduction in the household’s benefit until the next recertification.

New York’s SNAP policy per administrative directive 02 ADM-07 is to “freeze” the deduction for medical expenses between certification periods. Increases in medical expenses can be budgeted at the household’s request, but NYS never decreases a household’s medical expense deduction until the next recertification. Most elderly and disabled households have 24-month SNAP certification periods.

Eventually, though, the decrease in medical expenses will need to be reported when the household recertifies for SNAP, and the household should expect to see a decrease in their monthly SNAP benefit. It is really important to stress that the loss in SNAP benefits is NOT dollar for dollar. A $100 decrease in out of pocket medical expenses would translate roughly into a $30 drop in SNAP benefits.

See more info on SNAP/Food Stamp benefits by the Empire Justice Center, and on the State OTDA website. Some clients will be automatically enrolled in an MSP by the New York State Department of Health (NYSDOH) shortly after attaining eligibility for Medicare. Others need to apply.

The 2010 "MIPPA" law introduced some improvements to increase MSP enrollment. See 3rd bullet below. Also, some people who had Medicaid through the Affordable Care Act before they became eligible for Medicare have special procedures to have their Part B premium paid before they enroll in an MSP.

See below. WHO IS AUTOMATICALLY ENROLLED IN AN MSP. Clients receiving even $1.00 of Supplemental Security Income should be automatically enrolled into a Medicare Savings Program (most often QMB) under New York State’s Medicare Savings Program Buy-in Agreement with the federal government once they become eligible for Medicare.

They should receive Medicare Parts A and B. Clients who are already eligible for Medicare when they apply for Medicaid should be automatically assessed for MSP eligibility when they apply for Medicaid. (NYS DOH 2000-ADM-7 and GIS 05 MA 033).

Clients who apply to the Social Security Administration for Extra Help, but are rejected, should be contacted &. Enrolled into an MSP by the Medicaid program directly under new MIPPA procedures that require data sharing. Strategy TIP.

Since the Extra Help filing date will be assigned to the MSP application, it may help the client to apply online for Extra Help with the SSA, even knowing that this application will be rejected because of excess assets or other reason. SSA processes these requests quickly, and it will be routed to the State for MSP processing. Since MSP applications take a while, at least the filing date will be retroactive.

Note. The above strategy does not work as well for QMB, because the effective date of QMB is the month after the month of application. As a result, the retroactive effective date of Extra Help will be the month after the failed Extra Help application for those with QMB rather than SLMB/QI-1.

Applying for MSP Directly with Local Medicaid Program. Those who do not have Medicaid already must apply for an MSP through their local social services district. (See more in Section D.

Below re those who already have Medicaid through the Affordable Care Act before they became eligible for Medicare. If you are applying for MSP only (not also Medicaid), you can use the simplified MSP application form (theDOH-4328(Rev. 8/2017-- English) (2017 Spanish version not yet available).

Either application form can be mailed in -- there is no interview requirement anymore for MSP or Medicaid. See 10 ADM-04. Applicants will need to submit proof of income, a copy of their Medicare card (front &.

Back), and proof of residency/address. See the application form for other instructions. One who is only eligible for QI-1 because of higher income may ONLY apply for an MSP, not for Medicaid too.

One may not receive Medicaid and QI-1 at the same time. If someone only eligible for QI-1 wants Medicaid, s/he may enroll in and deposit excess income into a pooled Supplemental Needs Trust, to bring her countable income down to the Medicaid level, which also qualifies him or her for SLIMB or QMB instead of QI-1. Advocates in NYC can sign up for a half-day "Deputization Training" conducted by the Medicare Rights Center, at which you'll be trained and authorized to complete an MSP application and to submit it via the Medicare Rights Center, which submits it to HRA without the client having to apply in person.

Enrolling in an MSP if you already have Medicaid, but just become eligible for Medicare Those who, prior to becoming enrolled in Medicare, had Medicaid through Affordable Care Act are eligible to have their Part B premiums paid by Medicaid (or the cost reimbursed) during the time it takes for them to transition to a Medicare Savings Program. In 2018, DOH clarified that reimbursement of the Part B premium will be made regardless of whether the individual is still in a Medicaid managed care (MMC) plan. GIS 18 MA/001 Medicaid Managed Care Transition for Enrollees Gaining Medicare ( PDF) provides, "Due to efforts to transition individuals who gain Medicare eligibility and who require LTSS, individuals may not be disenrolled from MMC upon receipt of Medicare.

To facilitate the transition and not disadvantage the recipient, the Medicaid program is approving reimbursement of Part B premiums for enrollees in MMC." The procedure for getting the Part B premium paid is different for those whose Medicaid was administered by the NYS of Health Exchange (Marketplace), as opposed to their local social services district. The procedure is also different for those who obtain Medicare because they turn 65, as opposed to obtaining Medicare based on disability. Either way, Medicaid recipients who transition onto Medicare should be automatically evaluated for MSP eligibility at their next Medicaid recertification.

NYS DOH 2000-ADM-7 Individuals can also affirmatively ask to be enrolled in MSP in between recertification periods. IF CLIENT HAD MEDICAID ON THE MARKETPLACE (NYS of Health Exchange) before obtaining Medicare. IF they obtain Medicare because they turn age 65, they will receive a letter from their local district asking them to "renew" Medicaid through their local district.

See 2014 LCM-02. Now, their Medicaid income limit will be lower than the MAGI limits ($842/ mo reduced from $1387/month) and they now will have an asset test. For this reason, some individuals may lose full Medicaid eligibility when they begin receiving Medicare.

People over age 65 who obtain Medicare do NOT keep "Marketplace Medicaid" for 12 months (continuous eligibility) See GIS 15 MA/022 - Continuous Coverage for MAGI Individuals. Since MSP has NO ASSET limit. Some individuals may be enrolled in the MSP even if they lose Medicaid, or if they now have a Medicaid spend-down.

If a Medicare/Medicaid recipient reports income that exceeds the Medicaid level, districts must evaluate the person’s eligibility for MSP. 08 OHIP/ADM-4 ​If you became eligible for Medicare based on disability and you are UNDER AGE 65, you are entitled to keep MAGI Medicaid for 12 months from the month it was last authorized, even if you now have income normally above the MAGI limit, and even though you now have Medicare. This is called Continuous Eligibility.

EXAMPLE. Sam, age 60, was last authorized for Medicaid on the Marketplace in June 2016. He became enrolled in Medicare based on disability in August 2016, and started receiving Social Security in the same month (he won a hearing approving Social Security disability benefits retroactively, after first being denied disability).

Even though his Social Security is too high, he can keep Medicaid for 12 months beginning June 2016. Sam has to pay for his Part B premium - it is deducted from his Social Security check. He may call the Marketplace and request a refund.

This will continue until the end of his 12 months of continues MAGI Medicaid eligibility. He will be reimbursed regardless of whether he is in a Medicaid managed care plan. See GIS 18 MA/001 Medicaid Managed Care Transition for Enrollees Gaining Medicare (PDF) When that ends, he will renew Medicaid and apply for MSP with his local district.

Individuals who are eligible for Medicaid with a spenddown can opt whether or not to receive MSP. (Medicaid Reference Guide (MRG) p. 19).

Obtaining MSP may increase their spenddown. MIPPA - Outreach by Social Security Administration -- Under MIPPA, the SSA sends a form letter to people who may be eligible for a Medicare Savings Program or Extra Help (Low Income Subsidy - LIS) that they may apply. The letters are.

· Beneficiary has Extra Help (LIS), but not MSP · Beneficiary has no Extra Help (LIS) or MSP 6. Enrolling in MSP for People Age 65+ who do Not have Free Medicare Part A - the "Part A Buy-In Program" Seniors WITHOUT MEDICARE PART A or B -- They may be able to enroll in the Part A Buy-In program, in which people eligible for QMB who are age 65+ who do not otherwise have Medicare Part A may enroll in Part A, with Medicaid paying the Part A premium. See Step-by-Step Guide by the Medicare Rights Center).

This guide explains the various steps in "conditionally enrolling" in Part A at the SSA office, which must be done before applying for QMB at the Medicaid office, which will then pay the Part A premium. See also GIS 04 MA/013. In June, 2018, the SSA revised the POMS manual procedures for the Part A Buy-In to to address inconsistencies and confusion in SSA field offices and help smooth the path for QMB enrollment.

The procedures are in the POMS Section HI 00801.140 "Premium-Free Part A Enrollments for Qualified Medicare BenefiIaries." It includes important clarifications, such as. SSA Field Offices should explain the QMB program and conditional enrollment process if an individual lacks premium-free Part A and appears to meet QMB requirements. SSA field offices can add notes to the “Remarks” section of the application and provide a screen shot to the individual so the individual can provide proof of conditional Part A enrollment when applying for QMB through the state Medicaid program.

Beneficiaries are allowed to complete the conditional application even if they owe Medicare premiums. In Part A Buy-in states like NYS, SSA should process conditional applications on a rolling basis (without regard to enrollment periods), even if the application coincides with the General Enrollment Period. (The General Enrollment Period is from Jan 1 to March 31st every year, in which anyone eligible may enroll in Medicare Part A or Part B to be effective on July 1st).

Common side effects

• headache;
• nausea, vomiting, diarrhea, upset stomach;
• back pain;
• stuffy nose;
• muscle or joint pain; or
• changes in your voice.

Astrazeneca symbicort inhaler

AdvertisementContinue reading the main storySupported byContinue reading the main storyPhys EdHow Weight Training May Help With Weight ControlPeople who regularly do muscle-strengthening exercises are about 20 to 30 percent less likely to become obese over time than people who do not.Credit...Neil Hall/EPA, via ShutterstockJuly 7, 2021Lifting weights a few times a week might astrazeneca symbicort inhaler help us stave off obesity, according to an interesting new study of resistance exercise Kamagra jelly for sale and body fat. It shows that people who regularly complete muscle-strengthening exercises of any kind are about 20 to 30 percent less likely to become obese over time than people who do not, whether they also work out aerobically or not.The findings indicate that weight training could be more consequential for weight control than many of us might expect, and a little lifting now may keep us lighter, later.The incidence of obesity in America astrazeneca symbicort inhaler is rising, with about 40 percent of adults currently meeting the standard criteria for obesity. That number is expected to increase to more than 50 percent by the end of this decade.Unfortunately, few of us will drop any added pounds, long term, once we gain them. Most people who shed more than about astrazeneca symbicort inhaler 5 percent of their body weight regain it within five years.The most effective way to deal with obesity, then, is probably to prevent it. And regular exercise can help in that regard.

Many studies astrazeneca symbicort inhaler show that people who often walk, jog, cycle, swim or otherwise work out aerobically tend to gain less weight with age than sedentary people and are at lower risk of becoming obese.But far less has been known about whether weight training likewise influences weight. Some past research hints that resistance training helps people retain muscle mass while people are trying to lose weight astrazeneca symbicort inhaler. But whether it might also check long-term weight gain and avert obesity has not been clear.So, for the new study, which was published in June in PLOS Medicine, researchers at Iowa State University in Ames, Iowa, and other institutions, decided to look into the relationship, if any, between weights and waistlines. They began by turning to the large and useful database compiled for the Aerobics Center Longitudinal Study, a famous undertaking that had tracked the medical, health and fitness status of tens of thousands of patients who visited the astrazeneca symbicort inhaler Cooper Clinic in Dallas between 1987 and 2005. The men and women had gone through extensive testing during repeated visits to the clinic over the years.Now, the Iowa researchers pulled the records for almost 12,000 of the participants, most of them middle-aged.

None of them were obese, based on their B.M.I., when they astrazeneca symbicort inhaler first joined the Aerobics Center study. (B.M.I., or body mass index, indirectly estimates body fat, based on your height astrazeneca symbicort inhaler and weight. You can check yours online here.)These particular men and women had completed the typical array of health and fitness measurements during their visits to the clinic and also filled out an exercise questionnaire that asked, among other issues, about weight training. Did they ever astrazeneca symbicort inhaler engage in “muscle-strengthening exercises,” it inquired, and if so, how often and for how many minutes each week?. The researchers then began crosschecking, comparing people’s weights and other measurements from one clinic visit to the next.

Based on B.M.I., about 7 percent of astrazeneca symbicort inhaler the men and women had become obese within about six years of their first visit to the clinic.But B.M.I. Is a loose approximation of body composition and not always an accurate measure of obesity. So the researchers also checked changes to people’s waist circumferences astrazeneca symbicort inhaler and their body-fat percentage to determine if they had become obese. By the yardsticks of a waist circumference greater than 40 inches for men and 35 for women, or a body-fat percentage above 25 percent for men and 30 percent for women, as many as 19 percent of participants developed obesity over the years.Weight lifting, however, changed astrazeneca symbicort inhaler those outcomes, the researchers found, substantially lowering the risk that someone would become obese, by any measure. Men and women who reported strengthening their muscles a few times a week, for a weekly total of one to two hours, were about 20 percent less likely to become obese over the years, based on B.M.I., and about 30 percent less likely, based on waist circumference or body-fat percentage.The benefits remained when the researchers controlled for age, sex, smoking, general health and aerobic exercise.

People who worked astrazeneca symbicort inhaler out aerobically and lifted weights were much less likely to become obese. But so were those who lifted almost exclusively and reported little, if any, aerobic exercise.The results suggest that “you can get a lot of benefit from even a little” weight training, says Angelique Brellenthin, a professor of kinesiology at Iowa State, who led the new study.Of course, the study was observational and does not prove that resistance training prevents weight gain, only that they are linked. It also did not consider people’s diets, genetics or health attitudes, any of which could affect obesity astrazeneca symbicort inhaler risk.Perhaps most important, it does not tell us how muscle strengthening influences weight, although it is likely that resistance training builds and maintains muscle mass, Dr. Brellenthin says astrazeneca symbicort inhaler. A metabolically active tissue, muscle burns calories and slightly increases our metabolic rate.

Interestingly, the desirable astrazeneca symbicort inhaler effect of adding muscle mass may also explain why fewer lifters avoided obesity when the researchers used B.M.I. As a measure. B.M.I. Does not differentiate muscle from fat, Dr. Brellenthin points out.

If you add muscle with weight training, your B.M.I. Can rise.Still, the primary message of the study is that some weight training likely helps, over time, with weight control. €œSo, my advice would be to fit in a few body weight exercises before or after your usual daily walk,” Dr. Brellenthin suggests. Or join a gym or an online class.

Or try one of Well’s easy, at-home resistance-training routines, like the 7-Minute Standing Workout.AdvertisementContinue reading the main storyAdvertisementContinue reading the main storySupported byContinue reading the main storyWhat to Look for in a Physical TherapistNot all P.T.s are created equal. Find a professional who values evidence over anecdote.In some instances, exercise during physical therapy is even as effective as surgery.Credit...Getty ImagesJuly 6, 2021There’s been a quiet revolution taking place in the field of physical therapy. In the early 2000s, you could go to five different physical therapists for an injury and receive five different treatment plans. Some would have advised targeted exercises to strengthen muscles or classic treatments, like heat and cold packs.Others might have relied on “voodoo treatments” like uasound, lasers and electrotherapy, despite the fact that experts weren’t really sure how — or even if — they worked. Today, many of those techniques have been set aside as the science has slowly accumulated that they don’t accelerate healing.

You may still find them in some offices, however, as the field has struggled with a lack of uniformity and a lingering reputation for pseudoscience, leaving patients unsure whom to trust.Take uasound, for instance. The technique has been used in physical therapy since the 1950s to treat everything from back pain to ankle sprains using high-frequency sound waves to speed the healing process. As early as the 1990s, uasound’s efficacy started to be debunked, with few studies showing any clinical benefit, but it’s taken over 20 years for the technique to finally fall out of favor with practitioners.“There’s very little, if any, evidence that uasound does anything at all,” said Bruce Greenfield, a professor in the department of rehabilitation medicine at Emory University. €œBut P.T.s are using it, and they’re charging for it, and they’re getting reimbursed for it — basically for a technique that’s not effective. Is that fraud?.

I don’t know.”Over the last 15 years, leaders in the physical therapy field have worked to shed this reputation, improving standards and consistency. They’ve developed systems to diagnose and classify injuries and turned to scientific research to create evidence-backed treatment guidelines. €œThat’s how you change the face of the profession,” said David Wert, an associate professor of physical therapy at the University of Pittsburgh. €œUsing evidence and applying interventions for folks that are meaningful.”A Shift From Passive to Active TreatmentOriginally, physical therapy was largely based on the use of treatments like heat and ice to ease people’s pain and aid healing. Practitioners have also been quick to adopt technologies like laser therapy, which purportedly travels through skin and cells to increase energy production in mitochondria (the powerhouse of the cell) to accelerate recovery.

But a treatment’s effect on a cell in a petri dish doesn’t necessarily translate to a patient in the clinic. The most recent — and some say most definitive — study on the technique shows no benefit over a placebo.Over the past two decades, studies and meta-analyses (like the one conducted on uasound) have revealed that these types of passive treatments, where patients lie down on a table and have a therapy performed on them, actually do very little. And in some cases, they can even slow down recovery.For example, ice has long been used to reduce swelling after an injury by constricting blood vessels in the area, which prevents blood and inflammatory cells from reaching the damaged tissue. But those blood and inflammatory cells are also a necessary part of the healing process, and restricting them with a cold pack or ice bath can delay or even prevent recovery.When compared head-to-head, active exercise-based therapies are both less expensive and more effective than passive ones. In some instances, exercise is even as effective as surgery.

In one study of 350 patients who had meniscal tears, there was no difference after six months between the patients who’d had surgery and those who’d used active physical therapy. Other research is currently exploring whether the same might be true for partial rotator cuff tears.Instead, what’s emerged from decades of research as a clear winner — whether it’s used to treat low back pain or frozen shoulder or knee ligament injuries — is good old-fashioned exercise.“We have gotten quite a bit more evidence for the effectiveness of exercise in both facilitating recovery and also protecting people from different kinds of injuries or diseases,” said James Gordon, chair of the division of biokinesiology and physical therapy at the University of Southern California. Marilyn Moffat, a professor of physical therapy at New York University, agreed, saying that for every type of patient seen by physical therapists, “whether it’s patients with cardiovascular disease, whether it’s patients with diabetes, whether it’s patients with orthopedic problems or fibromyalgia or neuromuscular disorders or falls or frailty or obesity, the literature out there in terms of exercise interventions is so strong for every single one.”Changing the Field, SlowlyThese days, most physical therapists recognize that treatments should consist of exercises that improve strength and flexibility, as well as ergonomic adjustments to people’s work or workout routines to prevent future injuries. However, some practitioners argue that passive treatments still have their place and they are still taught in physical therapy doctorate programs.James Irrgang, chair of the physical therapy department at the University of Pittsburgh, said he wasn’t surprised there is still a gap between what evidence shows is effective and what some clinical practices do. Across medicine, it traditionally takes 17 years for research to make its way to the clinic.

As a result, Dr. Irrgang said that much of the emphasis in physical therapy now is on implementation. €œHow do we get the clinicians to adhere to the best available evidence?. €He hopes the answer is through education. In 2006, Dr.

Irrgang — who at the time was the president of the Academy of Orthopaedic Physical Therapy — helped develop guidelines in the form of a report card for diagnostic and treatment techniques commonly used by physical therapists, based on the best scientific evidence.Some techniques, like doing exercises to increase quadriceps strength after an A.C.L. Tear, get an A. Others, like using electrotherapy to improve heel pain for plantar fasciitis, get a D.What to Look for in a Physical TherapistSo how can you tell if your P.T. Is relying on the best science?. During your first visit, the physical therapist will evaluate your symptoms, level of pain, how you move and your limitations for range of motion, strength and balance.

That will become the basis of a diagnosis. This is not a medical diagnosis. The physical therapist wants to know what is limiting the function of, say, your knee, via muscle weakness or joint stiffness.Dr. Moffat said that this initial appointment is a good time to decide whether you want to work with the physical therapist. €œThe most important thing is what the therapist does with their initial exam,” she said.

€œDo they really take the time initially to examine what’s going on and then determine what’s most appropriate for that patient?. €After the evaluation, the treatment they recommend should be evidence-based, drawing from the clinical practice guidelines, but it should also be tailored to your individual limitations and goals. It should also be active, incorporating strengthening and stretching exercises.It’s important for the physical therapist to be empathetic and honest about what your course of treatment will entail, because the process can be painful. Whether or not you like your practitioner can also make a big difference in how you see the outcome. According to one meta-analysis, patients consistently rated their physical therapists based on how much they liked them as people, not on whether or not they got better.And if you find yourself in a clinic where passive therapies like heat packs or uasound seem to be the main approach to treatment, “Find another place to go,” Dr.

Gordon said. Those treatments may be useful for temporarily reducing pain or inflammation, “but they are not therapeutic in and of themselves. They are adjuncts to treatment.”This approach to physical therapy may not use lasers or cryocompression pants or whatever the hot new toy is, and it requires work on the patient’s part, but it does work.“I think we are improving what we do, but I think it’s an evolution,” said Dr. Gordon, who’s been practicing physical therapy for over 40 years. Incremental, evidence-based advances are “having an impact, but it’s not sexy.

It’s not a new robotic thing. It’s hard to put it on the seven o’clock news. But it is truly a revolution in health care.”Dana Smith is a health and science writer based in Durham, N.C. Her work has appeared in The Atlantic, The Guardian, Scientific American, STAT and more.AdvertisementContinue reading the main story.

AdvertisementContinue reading the main storySupported byContinue reading the main storyPhys EdHow Weight Training May Help With Weight ControlPeople who regularly do muscle-strengthening exercises are about 20 to 30 percent less likely to become obese over time than people who do not.Credit...Neil Hall/EPA, via ShutterstockJuly 7, 2021Lifting weights a few times a week might help us stave off obesity, according to an interesting navigate to this website new study of resistance exercise generic symbicort online for sale and body fat. It shows that people who regularly complete muscle-strengthening exercises of any kind are about 20 to 30 percent less likely to become obese over time than people who do not, whether they also work out aerobically or not.The findings indicate that weight generic symbicort online for sale training could be more consequential for weight control than many of us might expect, and a little lifting now may keep us lighter, later.The incidence of obesity in America is rising, with about 40 percent of adults currently meeting the standard criteria for obesity. That number is expected to increase to more than 50 percent by the end of this decade.Unfortunately, few of us will drop any added pounds, long term, once we gain them.

Most people who shed more than about 5 percent of their body weight regain generic symbicort online for sale it within five years.The most effective way to deal with obesity, then, is probably to prevent it. And regular exercise can help in that regard. Many studies show that people who often walk, jog, cycle, swim or otherwise work out aerobically tend to gain less weight with age than sedentary people and are at lower risk of becoming obese.But far less generic symbicort online for sale has been known about whether weight training likewise influences weight.

Some past research hints generic symbicort online for sale that resistance training helps people retain muscle mass while people are trying to lose weight. But whether it might also check long-term weight gain and avert obesity has not been clear.So, for the new study, which was published in June in PLOS Medicine, researchers at Iowa State University in Ames, Iowa, and other institutions, decided to look into the relationship, if any, between weights and waistlines. They began by turning to the large and useful database generic symbicort online for sale compiled for the Aerobics Center Longitudinal Study, a famous undertaking that had tracked the medical, health and fitness status of tens of thousands of patients who visited the Cooper Clinic in Dallas between 1987 and 2005.

The men and women had gone through extensive testing during repeated visits to the clinic over the years.Now, the Iowa researchers pulled the records for almost 12,000 of the participants, most of them middle-aged. None of them were obese, based on their B.M.I., when they first generic symbicort online for sale joined the Aerobics Center study. (B.M.I., or body mass index, generic symbicort online for sale indirectly estimates body fat, based on your height and weight.

You can check yours online here.)These particular men and women had completed the typical array of health and fitness measurements during their visits to the clinic and also filled out an exercise questionnaire that asked, among other issues, about weight training. Did they ever engage in generic symbicort online for sale “muscle-strengthening exercises,” it inquired, and if so, how often and for how many minutes each week?. The researchers then began crosschecking, comparing people’s weights and other measurements from one clinic visit to the next.

Based on B.M.I., about 7 percent of the men and women had become obese within about six years of generic symbicort online for sale their first visit to the clinic.But B.M.I. Is a loose approximation of body composition and not always an accurate measure of obesity. So the researchers also checked changes to people’s waist circumferences and their body-fat percentage to determine generic symbicort online for sale if they had become obese.

By the yardsticks of a waist circumference greater than 40 inches for men and 35 for women, or a body-fat percentage above 25 percent for men and 30 percent for women, as many as 19 percent of participants developed obesity over the years.Weight generic symbicort online for sale lifting, however, changed those outcomes, the researchers found, substantially lowering the risk that someone would become obese, by any measure. Men and women who reported strengthening their muscles a few times a week, for a weekly total of one to two hours, were about 20 percent less likely to become obese over the years, based on B.M.I., and about 30 percent less likely, based on waist circumference or body-fat percentage.The benefits remained when the researchers controlled for age, sex, smoking, general health and aerobic exercise. People who worked out aerobically and lifted weights were much generic symbicort online for sale less likely to become obese.

But so were those who lifted almost exclusively and reported little, if any, aerobic exercise.The results suggest that “you can get a lot of benefit from even a little” weight training, says Angelique Brellenthin, a professor of kinesiology at Iowa State, who led the new study.Of course, the study was observational and does not prove that resistance training prevents weight gain, only that they are linked. It also did not consider people’s diets, genetics or health attitudes, any generic symbicort online for sale of which could affect obesity risk.Perhaps most important, it does not tell us how muscle strengthening influences weight, although it is likely that resistance training builds and maintains muscle mass, Dr. Brellenthin says generic symbicort online for sale.

A metabolically active tissue, muscle burns calories and slightly increases our metabolic rate. Interestingly, the desirable effect of adding muscle mass may also explain generic symbicort online for sale why fewer lifters avoided obesity when the researchers used B.M.I. As a measure.

B.M.I. Does not differentiate muscle from fat, Dr. Brellenthin points out.

If you add muscle with weight training, your B.M.I. Can rise.Still, the primary message of the study is that some weight training likely helps, over time, with weight control. €œSo, my advice would be to fit in a few body weight exercises before or after your usual daily walk,” Dr.

Brellenthin suggests. Or join a gym or an online class. Or try one of Well’s easy, at-home resistance-training routines, like the 7-Minute Standing Workout.AdvertisementContinue reading the main storyAdvertisementContinue reading the main storySupported byContinue reading the main storyWhat to Look for in a Physical TherapistNot all P.T.s are created equal.

Find a professional who values evidence over anecdote.In some instances, exercise during physical therapy is even as effective as surgery.Credit...Getty ImagesJuly 6, 2021There’s been a quiet revolution taking place in the field of physical therapy. In the early 2000s, you could go to five different physical therapists for an injury and receive five different treatment plans. Some would have advised targeted exercises to strengthen muscles or classic treatments, like heat and cold packs.Others might have relied on “voodoo treatments” like uasound, lasers and electrotherapy, despite the fact that experts weren’t really sure how — or even if — they worked.

Today, many of those techniques have been set aside as the science has slowly accumulated that they don’t accelerate healing. You may still find them in some offices, however, as the field has struggled with a lack of uniformity and a lingering reputation for pseudoscience, leaving patients unsure whom to trust.Take uasound, for instance. The technique has been used in physical therapy since the 1950s to treat everything from back pain to ankle sprains using high-frequency sound waves to speed the healing process.

As early as the 1990s, uasound’s efficacy started to be debunked, with few studies showing any clinical benefit, but it’s taken over 20 years for the technique to finally fall out of favor with practitioners.“There’s very little, if any, evidence that uasound does anything at all,” said Bruce Greenfield, a professor in the department of rehabilitation medicine at Emory University. €œBut P.T.s are using it, and they’re charging for it, and they’re getting reimbursed for it — basically for a technique that’s not effective. Is that fraud?.

I don’t know.”Over the last 15 years, leaders in the physical therapy field have worked to shed this reputation, improving standards and consistency. They’ve developed systems to diagnose and classify injuries and turned to scientific research to create evidence-backed treatment guidelines. €œThat’s how you change the face of the profession,” said David Wert, an associate professor of physical therapy at the University of Pittsburgh.

€œUsing evidence and applying interventions for folks that are meaningful.”A Shift From Passive to Active TreatmentOriginally, physical therapy was largely based on the use of treatments like heat and ice to ease people’s pain and aid healing. Practitioners have also been quick to adopt technologies like laser therapy, which purportedly travels through skin and cells to increase energy production in mitochondria (the powerhouse of the cell) to accelerate recovery. But a treatment’s effect on a cell in a petri dish doesn’t necessarily translate to a patient in the clinic.

The most recent — and some say most definitive — study on the technique shows no benefit over a placebo.Over the past two decades, studies and meta-analyses (like the one conducted on uasound) have revealed that these types of passive treatments, where patients lie down on a table and have a therapy performed on them, actually do very little. And in some cases, they can even slow down recovery.For example, ice has long been used to reduce swelling after an injury by constricting blood vessels in the area, which prevents blood and inflammatory cells from reaching the damaged tissue. But those blood and inflammatory cells are also a necessary part of the healing process, and restricting them with a cold pack or ice bath can delay or even prevent recovery.When compared head-to-head, active exercise-based therapies are both less expensive and more effective than passive ones.

In some instances, exercise is even as effective as surgery. In one study of 350 patients who had meniscal tears, there was no difference after six months between the patients who’d had surgery and those who’d used active physical therapy. Other research is currently exploring whether the same might be true for partial rotator cuff tears.Instead, what’s emerged from decades of research as a clear winner — whether it’s used to treat low back pain or frozen shoulder or knee ligament injuries — is good old-fashioned exercise.“We have gotten quite a bit more evidence for the effectiveness of exercise in both facilitating recovery and also protecting people from different kinds of injuries or diseases,” said James Gordon, chair of the division of biokinesiology and physical therapy at the University of Southern California.

Marilyn Moffat, a professor of physical therapy at New York University, agreed, saying that for every type of patient seen by physical therapists, “whether it’s patients with cardiovascular disease, whether it’s patients with diabetes, whether it’s patients with orthopedic problems or fibromyalgia or neuromuscular disorders or falls or frailty or obesity, the literature out there in terms of exercise interventions is so strong for every single one.”Changing the Field, SlowlyThese days, most physical therapists recognize that treatments should consist of exercises that improve strength and flexibility, as well as ergonomic adjustments to people’s work or workout routines to prevent future injuries. However, some practitioners argue that passive treatments still have their place and they are still taught in physical therapy doctorate programs.James Irrgang, chair of the physical therapy department at the University of Pittsburgh, said he wasn’t surprised there is still a gap between what evidence shows is effective and what some clinical practices do. Across medicine, it traditionally takes 17 years for research to make its way to the clinic.

As a result, Dr. Irrgang said that much of the emphasis in physical therapy now is on implementation. €œHow do we get the clinicians to adhere to the best available evidence?.

€He hopes the answer is through education. In 2006, Dr. Irrgang — who at the time was the president of the Academy of Orthopaedic Physical Therapy — helped develop guidelines in the form of a report card for diagnostic and treatment techniques commonly used by physical therapists, based on the best scientific evidence.Some techniques, like doing exercises to increase quadriceps strength after an A.C.L.

Tear, get an A. Others, like using electrotherapy to improve heel pain for plantar fasciitis, get a D.What to Look for in a Physical TherapistSo how can you tell if your P.T. Is relying on the best science?.

During your first visit, the physical therapist will evaluate your symptoms, level of pain, how you move and your limitations for range of motion, strength and balance. That will become the basis of a diagnosis. This is not a medical diagnosis.

The physical therapist wants to know what is limiting the function of, say, your knee, via muscle weakness or joint stiffness.Dr. Moffat said that this initial appointment is a good time to decide whether you want to work with the physical therapist. €œThe most important thing is what the therapist does with their initial exam,” she said.

€œDo they really take the time initially to examine what’s going on and then determine what’s most appropriate for that patient?. €After the evaluation, the treatment they recommend should be evidence-based, drawing from the clinical practice guidelines, but it should also be tailored to your individual limitations and goals. It should also be active, incorporating strengthening and stretching exercises.It’s important for the physical therapist to be empathetic and honest about what your course of treatment will entail, because the process can be painful.

Whether or not you like your practitioner can also make a big difference in how you see the outcome. According to one meta-analysis, patients consistently rated their physical therapists based on how much they liked them as people, not on whether or not they got better.And if you find yourself in a clinic where passive therapies like heat packs or uasound seem to be the main approach to treatment, “Find another place to go,” Dr. Gordon said.

Those treatments may be useful for temporarily reducing pain or inflammation, “but they are not therapeutic in and of themselves. They are adjuncts to treatment.”This approach to physical therapy may not use lasers or cryocompression pants or whatever the hot new toy is, and it requires work on the patient’s part, but it does work.“I think we are improving what we do, but I think it’s an evolution,” said Dr. Gordon, who’s been practicing physical therapy for over 40 years.

Incremental, evidence-based advances are “having an impact, but it’s not sexy. It’s not a new robotic thing. It’s hard to put it on the seven o’clock news.

But it is truly a revolution in health care.”Dana Smith is a health and science writer based in Durham, N.C. Her work has appeared in The Atlantic, The Guardian, Scientific American, STAT and more.AdvertisementContinue reading the main story.

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October 26, 2020 (Edmonton, Alberta) — Pharmacy Brands Canada is pleased to announce an exciting new sygma symbicort partnership with Canada Health Infoway (Infoway) to launch PrescribeIT®, Canada’s only national not-for-profit electronic prescribing service. This innovative e-prescribing platform will soon be offered in our mettra Pharmacy, Value Drug Mart, Apple Drugs, Peoples Pharmacy and Rxellence independent community pharmacies across Western sygma symbicort Canada. PrescribeIT® enables physicians and other prescribers to send prescriptions and renewal requests electronically to a patient’s preferred pharmacy, resulting in more efficient patient care, enhanced safety, and greater accuracy when filling prescriptions.In partnership with Infoway and collaboration with provincial ministries, Pharmacy Brands Canada plans to roll out the PrescribeIT® service to independent pharmacy banner locations across Western Canada over the next 12 months."We are excited to partner with Infoway to introduce this e-prescription service to our independently owned community pharmacy banner members, their pharmacy teams, patients, allied health partners and communities," said Pauwlina Cyca, Director of Pharmacy Services, Pharmacy Brands Canada.

"The PrescribeIT® platform completes the circle of care, and ensures continuity for each patient, every prescription and every pharmacy."“Infoway is excited about this new partnership sygma symbicort with Pharmacy Brands Canada,” said Jamie Bruce, Executive Vice President, Infoway. €œPrescribeIT® provides safer and more effective medication management and protects patients’ personal health information from being sold or used for commercial activities. It’s an important step in helping Canadians experience better health outcomes.”PrescribeIT® is a free service offered by health care prescribers sygma symbicort and pharmacies.

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Infoway is an independent, not-for-profit organization funded by the federal government. Visit www.infoway-inforoute.ca.About PrescribeIT®Canada Health Infoway is sygma symbicort working with Health Canada, the provinces and territories, and industry stakeholders to develop, operate and maintain the national e-prescribing service known as PrescribeIT®. PrescribeIT® will serve all Canadians, pharmacies and prescribers and provide safer and more effective medication management by enabling sygma symbicort prescribers to transmit a prescription electronically between a prescriber’s electronic medical record (EMR) and the pharmacy management system (PMS) of a patient’s pharmacy of choice.

PrescribeIT® will protect Canadians’ personal health information from being sold or used for commercial activities. Visit www.PrescribeIT.ca.-30-Media InquiriesInquiries about PrescribeIT® Tania EnsorSenior Director, Marketing, Stakeholder Relations and Reputation sygma symbicort Management, PrescribeIT®Canada Health Infoway416.707.6285Email UsFollow @PrescribeIT_CAInquiries about Pharmacy Brands CanadaSarah MacDonaldDirector, MarketingPharmacy Brands CanadaThis email address is being protected from spambots. You need JavaScript enabled to view it.October 20, 2020 (TORONTO) — Canada Health Infoway (Infoway) and Aware MD are pleased to announce that they have reached an agreement that will give more Canadians access to e-prescribing.

PrescribeIT® is Infoway’s national e-prescribing service that enables prescribers and pharmacists to electronically create, receive, renew and cancel prescriptions, while improving overall patient care through secure clinician sygma symbicort messaging.Under the agreement, Aware MD will integrate its Cerebrum™ electronic medical record (EMR) with PrescribeIT’s solution infrastructure, with targeted completion by the second half of 2021. The specialists who use the Cerebrum™ solution will be able to send prescriptions electronically from their EMR to the patient’s pharmacy of choice, and pharmacies will be able to request prescription renewals electronically from the patient’s specialist. Aware MD provides services sygma symbicort to 400 cardiologists and radiologists in 104 clinics across Ontario, who in turn provide care to more than two million patients.“This partnership with Infoway is very important for us because it will benefit the medical specialists who use our EMR solution and, more importantly, it will benefit the patients they care for,” said Anatoly Langer, MD, MSc, FRCPC, FACC, President of Aware MD.

€œThe days of hand written and faxed prescriptions are in the past, and PrescribeIT® is a step forward sygma symbicort for all parties involved — physicians, pharmacists and patients.”“We are excited to work with Aware MD to make PrescribeIT® available to the specialists across Ontario who use the Cerebrum™ EMR solution,” said Jamie Bruce, Executive Vice President, Infoway. €œBy eliminating the use of paper and faxed prescriptions, PrescribeIT® makes prescribing safer, more secure, easier and more convenient, resulting in better health outcomes for Canadians.”About Aware MDAware MD Inc. Is a Canadian company located in Toronto that has been in business sygma symbicort since 2003.

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Infoway is an independent, not-for-profit organization funded by sygma symbicort the federal government. Visit www.infoway-inforoute.ca.About PrescribeIT®Canada Health Infoway is working with Health Canada, the provinces and territories, and industry stakeholders to develop, operate and maintain the national e-prescribing service sygma symbicort known as PrescribeIT®. PrescribeIT® will serve all Canadians, pharmacies and prescribers and provide safer and more effective medication management by enabling prescribers to transmit a prescription electronically between a prescriber’s electronic medical record (EMR) and the pharmacy management system (PMS) of a patient’s pharmacy of choice.

PrescribeIT® will protect Canadians’ sygma symbicort personal health information from being sold or used for commercial activities. Visit www.PrescribeIT.ca.-30-Media InquiriesInquiries about PrescribeIT® Tania EnsorSenior Director, Marketing, Stakeholder Relations and Reputation Management, PrescribeIT®Canada Health Infoway416.707.6285Email UsFollow @PrescribeIT_CA.

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Aware MD provides services to 400 cardiologists and radiologists in 104 clinics across Ontario, who in turn provide care to more than two million patients.“This partnership with Infoway is very important for us because it will benefit generic symbicort online for sale the medical specialists who use our EMR solution and, more importantly, it will benefit the patients they care for,” said Anatoly Langer, MD, MSc, FRCPC, FACC, President of Aware MD. €œThe days of hand written and faxed prescriptions are in the past, and PrescribeIT® is a step forward for all parties involved — physicians, pharmacists and patients.”“We are excited to work with Aware MD to make PrescribeIT® available to the specialists across Ontario who use the Cerebrum™ EMR generic symbicort online for sale solution,” said Jamie Bruce, Executive Vice President, Infoway. €œBy eliminating the use of paper and faxed prescriptions, PrescribeIT® makes prescribing safer, more secure, easier and more convenient, resulting in better health outcomes for Canadians.”About Aware MDAware MD Inc. Is a Canadian company located in Toronto that has been in business since generic symbicort online for sale 2003.

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Visit www.awaremd.com.About Canada Health InfowayInfoway helps to improve the health of Canadians by working with partners to accelerate the development, generic symbicort online for sale adoption and effective use of digital health across Canada. Through our investments, we help deliver better quality and access to care and more efficient delivery of health services for patients and clinicians. Infoway is an independent, not-for-profit organization funded by generic symbicort online for sale the federal government. Visit www.infoway-inforoute.ca.About PrescribeIT®Canada Health Infoway is working with Health Canada, the provinces and territories, and industry stakeholders to develop, operate and maintain the generic symbicort online for sale national e-prescribing service known as PrescribeIT®.

PrescribeIT® will serve all Canadians, pharmacies and prescribers and provide safer and more effective medication management by enabling prescribers to transmit a prescription electronically between a prescriber’s electronic medical record (EMR) and the pharmacy management system (PMS) of a patient’s pharmacy of choice. PrescribeIT® will protect Canadians’ personal health information from being sold or used generic symbicort online for sale for commercial activities. Visit www.PrescribeIT.ca.-30-Media InquiriesInquiries about PrescribeIT® Tania EnsorSenior Director, Marketing, Stakeholder Relations and Reputation Management, PrescribeIT®Canada Health Infoway416.707.6285Email UsFollow @PrescribeIT_CA.

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AbstractIntroduction. We report a very rare case of familial breast cancer and diffuse gastric cancer, with germline pathogenic variants in both BRCA1 and CDH1 genes. To the best of our knowledge, this is the first report of such an association.Family description. The proband is a woman diagnosed with breast cancer at the age of 52 years.

She requested genetic counselling in 2012, at the age of 91 years, because of a history of breast cancer in her daughter, her sister, her niece and her paternal grandmother and was therefore concerned about her relatives. Her sister and maternal aunt also had gastric cancer. She was tested for several genes associated with hereditary breast cancer.Results. A large deletion of BRCA1 from exons 1 to 7 and two CDH1 pathogenic cis variants were identified.Conclusion.

This complex situation is challenging for genetic counselling and management of at-risk individuals.cancer. Breastcancer. Gastricclinical geneticsgenetic screening/counsellingmolecular geneticsIntroductionGLI-Kruppel family member 3 (GLI3) encodes for a zinc finger transcription factor which plays a key role in the sonic hedgehog (SHH) signalling pathway essential in both limb and craniofacial development.1 2 In hand development, SHH is expressed in the zone of polarising activity (ZPA) on the posterior side of the handplate. The ZPA expresses SHH, creating a gradient of SHH from the posterior to the anterior side of the handplate.

In the presence of SHH, full length GLI3-protein is produced (GLI3A), whereas absence of SHH causes cleavage of GLI3 into its repressor form (GLI3R).3 4 Abnormal expression of this SHH/GLI3R gradient can cause both preaxial and postaxial polydactyly.2Concordantly, pathogenic DNA variants in the GLI3 gene are known to cause multiple syndromes with craniofacial and limb involvement, such as. Acrocallosal syndrome5 (OMIM. 200990), Greig cephalopolysyndactyly syndrome6 (OMIM. 175700) and Pallister-Hall syndrome7 (OMIM.

146510). Also, in non-syndromic polydactyly, such as preaxial polydactyly-type 4 (PPD4, OMIM. 174700),8 pathogenic variants in GLI3 have been described. Out of these diseases, Pallister-Hall syndrome is the most distinct entity, defined by the presence of central polydactyly and hypothalamic hamartoma.9 The other GLI3 syndromes are defined by the presence of preaxial and/or postaxial polydactyly of the hand and feet with or without syndactyly (Greig syndrome, PPD4).

Also, various mild craniofacial features such as hypertelorism and macrocephaly can occur. Pallister-Hall syndrome is caused by truncating variants in the middle third of the GLI3 gene.10–12 The truncation of GLI3 causes an overexpression of GLI3R, which is believed to be the key difference between Pallister-Hall and the GLI3-mediated polydactyly syndromes.9 11 Although multiple attempts have been made, the clinical and genetic distinction between the GLI3-mediated polydactyly syndromes is less evident. This has for example led to the introduction of subGreig and the formulation of an Oro-facial-digital overlap syndrome.10 Other authors, suggested that we should not regard these diseases as separate entities, but as a spectrum of GLI3-mediated polydactyly syndromes.13Although phenotype/genotype correlation of the different syndromes has been cumbersome, clinical and animal studies do provide evidence that distinct regions within the gene, could be related to the individual anomalies contributing to these syndromes. First, case studies show isolated preaxial polydactyly is caused by both truncating and non-truncating variants throughout the GLI3 gene, whereas in isolated postaxial polydactyly cases truncating variants at the C-terminal side of the gene are observed.12 14 These results suggest two different groups of variants for preaxial and postaxial polydactyly.

Second, recent animal studies suggest that posterior malformations in GLI3-mediated polydactyly syndromes are likely related to a dosage effect of GLI3R rather than due to the influence of an altered GLI3A expression.15Past attempts for phenotype/genotype correlation in GLI3-mediated polydactyly syndromes have directly related the diagnosed syndrome to the observed genotype.10–12 16 Focusing on individual hand phenotypes, such as preaxial and postaxial polydactyly and syndactyly might be more reliable because it prevents misclassification due to inconsistent use of syndrome definition. Subsequently, latent class analysis (LCA) provides the possibility to relate a group of observed variables to a set of latent, or unmeasured, parameters and thereby identifying different subgroups in the obtained dataset.17 As a result, LCA allows us to group different phenotypes within the GLI3-mediated polydactyly syndromes and relate the most important predictors of the grouped phenotypes to the observed GLI3 variants.The aim of our study was to further investigate the correlation of the individual phenotypes to the genotypes observed in GLI3-mediated polydactyly syndromes, using LCA. Cases were obtained by both literature review and the inclusion of local clinical cases. Subsequently, we identified two subclasses of limb anomalies that relate to the underlying GLI3 variant.

We provide evidence for two different phenotypic and genotypic groups with predominantly preaxial and postaxial hand and feet anomalies, and we specify those cases with a higher risk for corpus callosum anomalies.MethodsLiterature reviewThe Human Gene Mutation Database (HGMD Professional 2019) was reviewed to identify known pathogenic variants in GLI3 and corresponding phenotypes.18 All references were obtained and cases were included when they were diagnosed with either Greig or subGreig syndrome or PPD4.10–12 Pallister-Hall syndrome and acrocallosal syndrome were excluded because both are regarded distinct syndromes and rather defined by the presence of the non-hand anomalies, than the presence of preaxial or postaxial polydactyly.13 19 Isolated preaxial or postaxial polydactyly were excluded for two reasons. The phenotype/genotype correlations are better understood and both anomalies can occur sporadically which could introduce falsely assumed pathogenic GLI3 variants in the analysis. Additionally, cases were excluded when case-specific phenotypic or genotypic information was not reported or if these two could not be related to each other. Families with a combined phenotypic description, not reducible to individual family members, were included as one case in the analysis.Clinical casesThe Sophia Children’s Hospital Database was reviewed for cases with a GLI3 variant.

Within this population, the same inclusion criteria for the phenotype were valid. Relatives of the index patients were also contacted for participation in this study, when they showed comparable hand, foot, or craniofacial malformations or when a GLI3 variant was identified. Phenotypes of the hand, foot and craniofacial anomalies of the patients treated in the Sophia Children's Hospital were collected using patient documentation. Family members were identified and if possible, clinically verified.

Alternatively, family members were contacted to verify their phenotypes. If no verification was possible, cases were excluded.PhenotypesThe phenotypes of both literature cases and local cases were extracted in a similar fashion. The most frequently reported limb and craniofacial phenotypes were dichotomised. The dichotomised hand and foot phenotypes were preaxial polydactyly, postaxial polydactyly and syndactyly.

Broad halluces or thumbs were commonly reported by authors and were dichotomised as a presentation of preaxial polydactyly. The extracted dichotomised craniofacial phenotypes were hypertelorism, macrocephaly and corpus callosum agenesis. All other phenotypes were registered, but not dichotomised.Pathogenic GLI3 variantsAll GLI3 variants were extracted and checked using Alamut Visual V.2.14. If indicated, variants were renamed according to standard Human Genome Variation Society nomenclature.20 Variants were grouped in either missense, frameshift, nonsense or splice site variants.

In the group of frameshift variants, a subgroup with possible splice site effect were identified for subgroup analysis when indicated. Similarly, nonsense variants prone for nonsense mediated decay (NMD) and nonsense variants with experimentally confirmed NMD were identified.21 Deletions of multiple exons, CNVs and translocations were excluded for analysis. A full list of included mutations is available in the online supplementary materials.Supplemental materialThe location of the variant was compared with five known structural domains of the GLI3 gene. (1) repressor domain, (2) zinc finger domain, (3) cleavage site, (4) activator domain, which we defined as a concatenation of the separately identified transactivation zones, the CBP binding domain and the mediator binding domain (MBD) and (5) the MID1 interaction region domain.1 6 22–24 The boundaries of each of the domains were based on available literature (figure 1, exact locations available in the online supplementary materials).

The boundaries used by different authors did vary, therefore a consensus was made.In this figure the posterior probability of an anterior phenotype is plotted against the location of the variant, stratified for the type of mutation that was observed. For better overview, only variants with a location effect were displayed. The full figure, including all variant types, can be found in the online supplementary figure 1. Each mutation is depicted as a dot, the size of the dot represents the number of observations for that variant.

If multiple observations were made, the mean posterior odds and IQR are plotted. For the nonsense variants, variants that were predicted to produce nonsense mediated decay, are depicted using a triangle. Again, the size indicates the number of observations." data-icon-position data-hide-link-title="0">Figure 1 In this figure the posterior probability of an anterior phenotype is plotted against the location of the variant, stratified for the type of mutation that was observed. For better overview, only variants with a location effect were displayed.

The full figure, including all variant types, can be found in the online supplementary figure 1. Each mutation is depicted as a dot, the size of the dot represents the number of observations for that variant. If multiple observations were made, the mean posterior odds and IQR are plotted. For the nonsense variants, variants that were predicted to produce nonsense mediated decay, are depicted using a triangle.

Again, the size indicates the number of observations.Supplemental materialLatent class analysisTo cluster phenotypes and relate those to the genotypes of the patients, an explorative analysis was done using LCA in R (R V.3.6.1 for Mac. Polytomous variable LCA, poLCA V.1.4.1.). We used our LCA to detect the number of phenotypic subgroups in the dataset and subsequently predict a class membership for each case in the dataset based on the posterior probabilities.In order to make a reliable prediction, only phenotypes that were sufficiently reported and/or ruled out were feasible for LCA, limiting the analysis to preaxial polydactyly, postaxial polydactyly and syndactyly of the hands and feet. Only full cases were included.

To determine the optimal number of classes, we fitted a series of models ranging from a one-class to a six-class model. The optimal number of classes was based on the conditional Akaike information criterion (cAIC), the non adjusted and the sample-size adjusted Bayesian information criterion (BIC and aBIC) and the obtained entropy.25 The explorative LCA produces both posterior probabilities per case for both classes and predicted class membership. Using the predicted class membership, the phenotypic features per class were determined in a univariate analysis (χ2, SPSS V.25). Using the posterior probabilities on latent class (LC) membership, a scatter plot was created using the location of the variant on the x-axis and the probability of class membership on the y-axis for each of the types of variants (Tibco Spotfire V.7.14).

Using these scatter plots, variants that give similar phenotypes were clustered.Genotype/phenotype correlationBecause an LC has no clinical value, the correlation between genotypes and phenotypes was investigated using the predictor phenotypes and the clustered phenotypes. First, those phenotypes that contribute most to LC membership were identified. Second those phenotypes were directly related to the different types of variants (missense, nonsense, frameshift, splice site) and their clustered locations. Quantification of the relation was performed using a univariate analysis using a χ2 test.

Because of our selection criteria, meaning patients at least have two phenotypes, a multivariate using a logistic regression analysis was used to detect the most significant predictors in the overall phenotype (SPSS V.25). Finally, we explored the relation of the clustered genotypes to the presence of corpus callosum agenesis, a rare malformation in GLI3-mediated polydactyly syndromes which cannot be readily diagnosed without additional imaging.ResultsWe included 251 patients from the literature and 46 local patients,10–12 16 21 26–43 in total 297 patients from 155 different families with 127 different GLI3 variants, 32 of which were large deletions, CNVs or translocations. In six local cases, the exact variant could not be retrieved by status research.The distribution of the most frequently observed phenotypes and variants are presented in table 1. Other recurring phenotypes included developmental delay (n=22), broad nasal root (n=23), frontal bossing or prominent forehead (n=16) and craniosynostosis (n=13), camptodactyly (n=8) and a broad first interdigital webspace of the foot (n=6).View this table:Table 1 Baseline phenotypes and genotypes of selected populationThe LCA model was fitted using the six defined hand/foot phenotypes.

Model fit indices for the LCA are displayed in table 2. Based on the BIC, a two-class model has the best fit for our data. The four-class model does show a gain in entropy, however with a higher BIC and loss of df. Therefore, based on the majority of performance statistics and the interpretability of the model, a two-class model was chosen.

Table 3 displays the distribution of phenotypes and genotypes over the two classes.View this table:Table 2 Model fit indices for the one-class through six-class model evaluated in our LCAView this table:Table 3 Distribution of phenotypes and genotypes in the two latent classes (LC)Table 1 depicts the baseline phenotypes and genotypes in the obtained population. Note incomplete data especially in the cranium phenotypes. In total 259 valid genotypes were present. In total, 289 cases had complete data for all hand and foot phenotypes (preaxial polydactyly, postaxial polydactyly and syndactyly) and thus were available for LCA.

Combined, for phenotype/genotype correlation 258 cases were available with complete genotypes and complete hand and foot phenotypes.Table 2 depicts the model fit indices for all models that have been fitted to our data.Table 3 depicts the distribution of phenotypes and genotypes over the two assigned LCs. Hand and foot phenotypes were used as input for the LCA, thus are all complete cases. Malformation of the cranium and genotypes do have missing cases. Note that for the LCA, full case description was required, resulting in eight cases due to incomplete phenotypes.

Out of these eight, one also had a genotype that thus needed to be excluded. Missingness of genotypic data was higher in LC2, mostly due to CNVs (table 1).In 54/60 cases, a missense variant produced a posterior phenotype. Likewise, splice site variants show the same phenotype in 23/24 cases (table 3). For both frameshift and nonsense variants, this relation is not significant (52 anterior vs 54 posterior and 26 anterior vs 42 posterior, respectively).

Therefore, only for nonsense and frameshift variants the location of the variant was plotted against the probability for LC2 membership in figure 1. A full scatterplot of all variants is available in online supplementary figure 1.Figure 1 reveals a pattern for these nonsense and frameshift variants that reveals that variants at the C-terminal of the gene predict anterior phenotypes. When relating the domains of the GLI3 protein to the observed phenotype, we observe that the majority of patients with a nonsense or frameshift variant in the repressor domain, the zinc finger domain or the cleavage site had a high probability of an LC2/anterior phenotype. This group contains all variants that are either experimentally determined to be subject to NMD (triangle marker in figure 1) or predicted to be subject to NMD (diamond marker in figure 1).

Frameshift and nonsense variants in the activator domain result in high probability for an LC1/posterior phenotype. These variants will be further referred to as truncating variants in the activator domain.The univariate relation of the individual phenotypes to these two groups of variants are estimated and presented in table 4. In our multivariate analysis, postaxial polydactyly of the foot and hand are the strongest predictors (Beta. 2.548, p<0001 and Beta.

1.47, p=0.013, respectively) for patients to have a truncating variant in the activator domain. Moreover, the effect sizes of preaxial polydactyly of the hand and feet (Beta. ˆ’0.797, p=0123 and −1.772, p=0.001) reveals that especially postaxial polydactyly of the foot is the dominant predictor for the genetic substrate of the observed anomalies.View this table:Table 4 Univariate and multivariate analysis of the phenotype/genotype correlationTable 4 shows exploration of the individual phenotypes on the genotype, both univariate and multivariate. The multivariate analysis corrects for the presence of multiple phenotypes in the underlying population.Although the craniofacial anomalies could not be included in the LCA, the relation between the observed anomalies and the identified genetic substrates can be studied.

The prevalence of hypertelorism was equally distributed over the two groups of variants (47/135 vs 21/47 respectively, p<0.229). However for corpus callosum agenesis and macrocephaly, there was a higher prevalence in patients with a truncating variant in the activator domain (3/75 vs 11/41, p<0.001. OR. 8.8, p<0.001) and 42/123 vs 24/48, p<0.05).

Noteworthy is the fact that 11/14 cases with corpus callosum agenesis in the dataset had a truncating variant in the activator domain.DiscussionIn this report, we present new insights into the correlation between the phenotype and the genotype in patients with GLI3-mediated polydactyly syndromes. We illustrate that there are two LCs of patients, best predicted by postaxial polydactyly of the hand and foot for LC1, and the preaxial polydactyly of the hand and foot and syndactyly of the foot for LC2. Patients with postaxial phenotypes have a higher risk of having a truncating variant in the activator domain of the GLI3 gene which is also related to a higher risk of corpus callosum agenesis. These results suggest a functional difference between truncating variants on the N-terminal and the C-terminal side of the GLI3 cleavage site.Previous attempts of phenotype to genotype correlation have not yet provided the clinical confirmation of these assumed mechanisms in the pathophysiology of GLI3-mediated polydactyly syndromes.

Johnston et al have successfully determined the Pallister-Hall region in which truncating variants produce a Pallister-Hall phenotype rather than Greig syndrome.11 However, in their latest population study, subtypes of both syndromes were included to explain the full spectrum of observed malformations. In 2015, Demurger et al reported the higher incidence of corpus callosum agenesis in the Greig syndrome population with truncating mutations in the activator domain.12 Al-Qattan in his review summarises the concept of a spectrum of anomalies dependent on haplo-insufficiency (through different mechanisms) and repressor overexpression.13 However, he bases this theory mainly on reviewed experimental data. Our report is the first to provide an extensive clinical review of cases that substantiate the phenotypic difference between the two groups that could fit the suggested mechanisms. We agree with Al-Qattan et al that a variation of anomalies can be observed given any pathogenic variant in the GLI3 gene, but overall two dominant phenotypes are present.

A population with predominantly preaxial anomalies and one with postaxial anomalies. The presence of preaxial or postaxial polydactyly and syndactyly is not mutually exclusive for one of these two subclasses. Meaning that preaxial polydactyly can co-occur with postaxial polydactyly. However, truncating mutations in the activator domain produce a postaxial phenotype, as can be derived from the risk in table 4.

The higher risk of corpus callosum agenesis in this population shows that differentiating between a preaxial phenotype and a postaxial phenotype, instead of between the different GLI3-mediated polydactyly syndromes, might be more relevant regarding diagnostics for corpus callosum agenesis.We chose to use LCA as an exploratory tool only in our population for two reasons. First of all, LCA can be useful to identify subgroups, but there is no ‘true’ model or number of subgroups you can detect. The best fitting model can only be estimated based on the available measures and approximates the true subgroups that might be present. Second, LC membership assignment is a statistical procedure based on the posterior probability, with concordant errors of the estimation, rather than a clinical value that can be measured or evaluated.

Therefore, we decided to use our LCA only in an exploratory tool, and perform our statistics using the actual phenotypes that predict LC membership and the associated genotypes. Overall, this method worked well to differentiate the two subgroups present in our dataset. However, outliers were observed. A qualitative analysis of these outliers is available in the online supplementary data.The genetic substrate for the two phenotypic clusters can be discussed based on multiple experiments.

Overall, we hypothesise two genetic clusters. One that is due to haploinsufficiency and one that is due to abnormal truncation of the activator. The hypothesised cluster of variants that produce haploinsufficiency is mainly based on the experimental data that confirms NMD in two variants and the NMD prediction of other nonsense variants in Alamut. For the frameshift variants, it is also likely that the cleavage of the zinc finger domain results in functional haploinsufficiency either because of a lack of signalling domains or similarly due to NMD.

Missense variants could cause haploinsufficiency through the suggested mechanism by Krauss et al who have illustrated that missense variants in the MID1 domain hamper the functional interaction with the MID1-α4-PP2A complex, leading to a subcellular location of GLI3.24 The observed missense variants in our study exceed the region to which Krauss et al have limited the MID-1 interaction domain. An alternative theory is suggested by Zhou et al who have shown that missense variants in the MBD can cause deficiency in the signalling of GLI3A, functionally implicating a relative overexpression of GLI3R.22 However, GLI3R overexpression would likely produce a posterior phenotype, as determined by Hill et al in their fixed homo and hemizygous GLI3R models.15 Therefore, our hypothesis is that all included missense variants have a similar pathogenesis which is more likely in concordance with the mechanism introduced by Krauss et al. To our knowledge, no splice site variants have been functionally described in literature. However, it is noted that the 15 and last exon encompasses the entire activator domain, thus any splice site mutation is by definition located on the 5′ side of the activator.

Based on the phenotype, we would suggest that these variants fail to produce a functional protein. We hypothesise that the truncating variants of the activator domain lead to overexpression of GLI3R in SHH rich areas. In normal development, the presence of SHH prevents the processing of full length GLI34 into GLI3R, thus producing the full length activator. In patients with a truncating variant of the activator domain of GLI3, thus these variants likely have the largest effect in SHH rich areas, such as the ZPA located at the posterior side of the hand/footplate.

Moreover, the lack of posterior anomalies in the GLI3∆699/- mouse model (hemizygous fixed repressor model) compared with the GLI3∆699/∆699 mouse model (homozygous fixed repressor model), suggesting a dosage effect of GLI3R to be responsible for posterior hand anomalies.15 These findings are supported by Lewandowski et al, who show that the majority of the target genes in GLI signalling are regulated by GLI3R rather than GLI3A.44 Together, these findings suggest a role for the location and type of variant in GLI3-mediated syndromes.Interestingly, the difference between Pallister-Hall syndrome and GLI3-mediated polydactyly syndromes has also been attributed to the GLI3R overexpression. However, the difference in phenotype observed in the cases with a truncating variant in the activator domain and Pallister-Hall syndrome suggest different functional consequences. When studying figure 1, it is noted that the included truncating variants on the 3′ side of the cleavage site seldomly affect the CBP binding region, which could provide an explanation for the observed differences. This binding region is included in the Pallister-Hall region as defined by Johnston et al and is necessary for the downstream signalling with GLI1.10 11 23 45 Interestingly, recent reports show that pathogenic variants in GLI1 can produce phenotypes concordant with Ellis von Krefeld syndrome, which includes overlapping features with Pallister-Hall syndrome.46 The four truncating variants observed in this study that do affect the CBP but did not result in a Pallister-Hall phenotype are conflicting with this theory.

Krauss et al postulate an alternative hypothesis, they state that the MID1-α4-PP2A complex, which is essential for GLI3A signalling, could also be the reason for overlapping features of Opitz syndrome, caused by variants in MID1, and Pallister-Hall syndrome. Further analysis is required to fully appreciate the functional differences between truncating mutations that cause Pallister-Hall syndrome and those that result in GLI3-mediated polydactyly syndromes.For the clinical evaluation of patients with GLI3-mediated polydactyly syndromes, intracranial anomalies are likely the most important to predict based on the variant. Unfortunately, the presence of corpus callosum agenesis was not routinely investigated or reported thus this feature could not be used as an indicator phenotype for LC membership. Interestingly when using only hand and foot phenotypes, we did notice a higher prevalence of corpus callosum agenesis in patients with posterior phenotypes.

The suggested relation between truncating mutations in the activator domain causing these posterior phenotypes and corpus callosum agenesis was statistically confirmed (OR. 8.8, p<0.001). Functionally this relation could be caused by the GLI3-MED12 interaction at the MBD. Pathogenic DNA variants in MED12 can cause Opitz-Kaveggia syndrome, a syndrome in which presentation includes corpus callosum agenesis, broad halluces and thumbs.47In conclusion, there are two distinct phenotypes within the GLI3-mediated polydactyly population.

Patients with more posteriorly and more anteriorly oriented hand anomalies. Furthermore, this difference is related to the observed variant in GLI3. We hypothesise that variants that cause haploinsufficiency produce anterior anomalies of the hand, whereas variants with abnormal truncation of the activator domain have more posterior anomalies. Furthermore, patients that have a variant that produces abnormal truncation of the activator domain, have a greater risk for corpus callosum agenesis.

Thus, we advocate to differentiate preaxial or postaxial oriented GLI3 phenotypes to explain the pathophysiology as well as to get a risk assessment for corpus callosum agenesis.Data availability statementData are available upon reasonable request.Ethics statementsPatient consent for publicationNot required.Ethics approvalThe research protocol was approved by the local ethics board of the Erasmus MC University Medical Center (MEC 2015-679)..

AbstractIntroduction. We report a very rare case of familial breast cancer and diffuse gastric cancer, with germline pathogenic variants in both BRCA1 and CDH1 genes. To the best of our knowledge, this is the first report of such an association.Family description. The proband is a woman diagnosed with breast cancer at the age of 52 years. She requested genetic counselling in 2012, at the age of 91 years, because of a history of breast cancer in her daughter, her sister, her niece and her paternal grandmother and was therefore concerned about her relatives.

Her sister and maternal aunt also had gastric cancer. She was tested for several genes associated with hereditary breast cancer.Results. A large deletion of BRCA1 from exons 1 to 7 and two CDH1 pathogenic cis variants were identified.Conclusion. This complex situation is challenging for genetic counselling and management of at-risk individuals.cancer. Breastcancer.

Gastricclinical geneticsgenetic screening/counsellingmolecular geneticsIntroductionGLI-Kruppel family member 3 (GLI3) encodes for a zinc finger transcription factor which plays a key role in the sonic hedgehog (SHH) signalling pathway essential in both limb and craniofacial development.1 2 In hand development, SHH is expressed in the zone of polarising activity (ZPA) on the posterior side of the handplate. The ZPA expresses SHH, creating a gradient of SHH from the posterior to the anterior side of the handplate. In the presence of SHH, full length GLI3-protein is produced (GLI3A), whereas absence of SHH causes cleavage of GLI3 into its repressor form (GLI3R).3 4 Abnormal expression of this SHH/GLI3R gradient can cause both preaxial and postaxial polydactyly.2Concordantly, pathogenic DNA variants in the GLI3 gene are known to cause multiple syndromes with craniofacial and limb involvement, such as. Acrocallosal syndrome5 (OMIM. 200990), Greig cephalopolysyndactyly syndrome6 (OMIM.

175700) and Pallister-Hall syndrome7 (OMIM. 146510). Also, in non-syndromic polydactyly, such as preaxial polydactyly-type 4 (PPD4, OMIM. 174700),8 pathogenic variants in GLI3 have been described. Out of these diseases, Pallister-Hall syndrome is the most distinct entity, defined by the presence of central polydactyly and hypothalamic hamartoma.9 The other GLI3 syndromes are defined by the presence of preaxial and/or postaxial polydactyly of the hand and feet with or without syndactyly (Greig syndrome, PPD4).

Also, various mild craniofacial features such as hypertelorism and macrocephaly can occur. Pallister-Hall syndrome is caused by truncating variants in the middle third of the GLI3 gene.10–12 The truncation of GLI3 causes an overexpression of GLI3R, which is believed to be the key difference between Pallister-Hall and the GLI3-mediated polydactyly syndromes.9 11 Although multiple attempts have been made, the clinical and genetic distinction between the GLI3-mediated polydactyly syndromes is less evident. This has for example led to the introduction of subGreig and the formulation of an Oro-facial-digital overlap syndrome.10 Other authors, suggested that we should not regard these diseases as separate entities, but as a spectrum of GLI3-mediated polydactyly syndromes.13Although phenotype/genotype correlation of the different syndromes has been cumbersome, clinical and animal studies do provide evidence that distinct regions within the gene, could be related to the individual anomalies contributing to these syndromes. First, case studies show isolated preaxial polydactyly is caused by both truncating and non-truncating variants throughout the GLI3 gene, whereas in isolated postaxial polydactyly cases truncating variants at the C-terminal side of the gene are observed.12 14 These results suggest two different groups of variants for preaxial and postaxial polydactyly. Second, recent animal studies suggest that posterior malformations in GLI3-mediated polydactyly syndromes are likely related to a dosage effect of GLI3R rather than due to the influence of an altered GLI3A expression.15Past attempts for phenotype/genotype correlation in GLI3-mediated polydactyly syndromes have directly related the diagnosed syndrome to the observed genotype.10–12 16 Focusing on individual hand phenotypes, such as preaxial and postaxial polydactyly and syndactyly might be more reliable because it prevents misclassification due to inconsistent use of syndrome definition.

Subsequently, latent class analysis (LCA) provides the possibility to relate a group of observed variables to a set of latent, or unmeasured, parameters and thereby identifying different subgroups in the obtained dataset.17 As a result, LCA allows us to group different phenotypes within the GLI3-mediated polydactyly syndromes and relate the most important predictors of the grouped phenotypes to the observed GLI3 variants.The aim of our study was to further investigate the correlation of the individual phenotypes to the genotypes observed in GLI3-mediated polydactyly syndromes, using LCA. Cases were obtained by both literature review and the inclusion of local clinical cases. Subsequently, we identified two subclasses of limb anomalies that relate to the underlying GLI3 variant. We provide evidence for two different phenotypic and genotypic groups with predominantly preaxial and postaxial hand and feet anomalies, and we specify those cases with a higher risk for corpus callosum anomalies.MethodsLiterature reviewThe Human Gene Mutation Database (HGMD Professional 2019) was reviewed to identify known pathogenic variants in GLI3 and corresponding phenotypes.18 All references were obtained and cases were included when they were diagnosed with either Greig or subGreig syndrome or PPD4.10–12 Pallister-Hall syndrome and acrocallosal syndrome were excluded because both are regarded distinct syndromes and rather defined by the presence of the non-hand anomalies, than the presence of preaxial or postaxial polydactyly.13 19 Isolated preaxial or postaxial polydactyly were excluded for two reasons. The phenotype/genotype correlations are better understood and both anomalies can occur sporadically which could introduce falsely assumed pathogenic GLI3 variants in the analysis.

Additionally, cases were excluded when case-specific phenotypic or genotypic information was not reported or if these two could not be related to each other. Families with a combined phenotypic description, not reducible to individual family members, were included as one case in the analysis.Clinical casesThe Sophia Children’s Hospital Database was reviewed for cases with a GLI3 variant. Within this population, the same inclusion criteria for the phenotype were valid. Relatives of the index patients were also contacted for participation in this study, when they showed comparable hand, foot, or craniofacial malformations or when a GLI3 variant was identified. Phenotypes of the hand, foot and craniofacial anomalies of the patients treated in the Sophia Children's Hospital were collected using patient documentation.

Family members were identified and if possible, clinically verified. Alternatively, family members were contacted to verify their phenotypes. If no verification was possible, cases were excluded.PhenotypesThe phenotypes of both literature cases and local cases were extracted in a similar fashion. The most frequently reported limb and craniofacial phenotypes were dichotomised. The dichotomised hand and foot phenotypes were preaxial polydactyly, postaxial polydactyly and syndactyly.

Broad halluces or thumbs were commonly reported by authors and were dichotomised as a presentation of preaxial polydactyly. The extracted dichotomised craniofacial phenotypes were hypertelorism, macrocephaly and corpus callosum agenesis. All other phenotypes were registered, but not dichotomised.Pathogenic GLI3 variantsAll GLI3 variants were extracted and checked using Alamut Visual V.2.14. If indicated, variants were renamed according to standard Human Genome Variation Society nomenclature.20 Variants were grouped in either missense, frameshift, nonsense or splice site variants. In the group of frameshift variants, a subgroup with possible splice site effect were identified for subgroup analysis when indicated.

Similarly, nonsense variants prone for nonsense mediated decay (NMD) and nonsense variants with experimentally confirmed NMD were identified.21 Deletions of multiple exons, CNVs and translocations were excluded for analysis. A full list of included mutations is available in the online supplementary materials.Supplemental materialThe location of the variant was compared with five known structural domains of the GLI3 gene. (1) repressor domain, (2) zinc finger domain, (3) cleavage site, (4) activator domain, which we defined as a concatenation of the separately identified transactivation zones, the CBP binding domain and the mediator binding domain (MBD) and (5) the MID1 interaction region domain.1 6 22–24 The boundaries of each of the domains were based on available literature (figure 1, exact locations available in the online supplementary materials). The boundaries used by different authors did vary, therefore a consensus was made.In this figure the posterior probability of an anterior phenotype is plotted against the location of the variant, stratified for the type of mutation that was observed. For better overview, only variants with a location effect were displayed.

The full figure, including all variant types, can be found in the online supplementary figure 1. Each mutation is depicted as a dot, the size of the dot represents the number of observations for that variant. If multiple observations were made, the mean posterior odds and IQR are plotted. For the nonsense variants, variants that were predicted to produce nonsense mediated decay, are depicted using a triangle. Again, the size indicates the number of observations." data-icon-position data-hide-link-title="0">Figure 1 In this figure the posterior probability of an anterior phenotype is plotted against the location of the variant, stratified for the type of mutation that was observed.

For better overview, only variants with a location effect were displayed. The full figure, including all variant types, can be found in the online supplementary figure 1. Each mutation is depicted as a dot, the size of the dot represents the number of observations for that variant. If multiple observations were made, the mean posterior odds and IQR are plotted. For the nonsense variants, variants that were predicted to produce nonsense mediated decay, are depicted using a triangle.

Again, the size indicates the number of observations.Supplemental materialLatent class analysisTo cluster phenotypes and relate those to the genotypes of the patients, an explorative analysis was done using LCA in R (R V.3.6.1 for Mac. Polytomous variable LCA, poLCA V.1.4.1.). We used our LCA to detect the number of phenotypic subgroups in the dataset and subsequently predict a class membership for each case in the dataset based on the posterior probabilities.In order to make a reliable prediction, only phenotypes that were sufficiently reported and/or ruled out were feasible for LCA, limiting the analysis to preaxial polydactyly, postaxial polydactyly and syndactyly of the hands and feet. Only full cases were included. To determine the optimal number of classes, we fitted a series of models ranging from a one-class to a six-class model.

The optimal number of classes was based on the conditional Akaike information criterion (cAIC), the non adjusted and the sample-size adjusted Bayesian information criterion (BIC and aBIC) and the obtained entropy.25 The explorative LCA produces both posterior probabilities per case for both classes and predicted class membership. Using the predicted class membership, the phenotypic features per class were determined in a univariate analysis (χ2, SPSS V.25). Using the posterior probabilities on latent class (LC) membership, a scatter plot was created using the location of the variant on the x-axis and the probability of class membership on the y-axis for each of the types of variants (Tibco Spotfire V.7.14). Using these scatter plots, variants that give similar phenotypes were clustered.Genotype/phenotype correlationBecause an LC has no clinical value, the correlation between genotypes and phenotypes was investigated using the predictor phenotypes and the clustered phenotypes. First, those phenotypes that contribute most to LC membership were identified.

Second those phenotypes were directly related to the different types of variants (missense, nonsense, frameshift, splice site) and their clustered locations. Quantification of the relation was performed using a univariate analysis using a χ2 test. Because of our selection criteria, meaning patients at least have two phenotypes, a multivariate using a logistic regression analysis was used to detect the most significant predictors in the overall phenotype (SPSS V.25). Finally, we explored the relation of the clustered genotypes to the presence of corpus callosum agenesis, a rare malformation in GLI3-mediated polydactyly syndromes which cannot be readily diagnosed without additional imaging.ResultsWe included 251 patients from the literature and 46 local patients,10–12 16 21 26–43 in total 297 patients from 155 different families with 127 different GLI3 variants, 32 of which were large deletions, CNVs or translocations. In six local cases, the exact variant could not be retrieved by status research.The distribution of the most frequently observed phenotypes and variants are presented in table 1.

Other recurring phenotypes included developmental delay (n=22), broad nasal root (n=23), frontal bossing or prominent forehead (n=16) and craniosynostosis (n=13), camptodactyly (n=8) and a broad first interdigital webspace of the foot (n=6).View this table:Table 1 Baseline phenotypes and genotypes of selected populationThe LCA model was fitted using the six defined hand/foot phenotypes. Model fit indices for the LCA are displayed in table 2. Based on the BIC, a two-class model has the best fit for our data. The four-class model does show a gain in entropy, however with a higher BIC and loss of df. Therefore, based on the majority of performance statistics and the interpretability of the model, a two-class model was chosen.

Table 3 displays the distribution of phenotypes and genotypes over the two classes.View this table:Table 2 Model fit indices for the one-class through six-class model evaluated in our LCAView this table:Table 3 Distribution of phenotypes and genotypes in the two latent classes (LC)Table 1 depicts the baseline phenotypes and genotypes in the obtained population. Note incomplete data especially in the cranium phenotypes. In total 259 valid genotypes were present. In total, 289 cases had complete data for all hand and foot phenotypes (preaxial polydactyly, postaxial polydactyly and syndactyly) and thus were available for LCA. Combined, for phenotype/genotype correlation 258 cases were available with complete genotypes and complete hand and foot phenotypes.Table 2 depicts the model fit indices for all models that have been fitted to our data.Table 3 depicts the distribution of phenotypes and genotypes over the two assigned LCs.

Hand and foot phenotypes were used as input for the LCA, thus are all complete cases. Malformation of the cranium and genotypes do have missing cases. Note that for the LCA, full case description was required, resulting in eight cases due to incomplete phenotypes. Out of these eight, one also had a genotype that thus needed to be excluded. Missingness of genotypic data was higher in LC2, mostly due to CNVs (table 1).In 54/60 cases, a missense variant produced a posterior phenotype.

Likewise, splice site variants show the same phenotype in 23/24 cases (table 3). For both frameshift and nonsense variants, this relation is not significant (52 anterior vs 54 posterior and 26 anterior vs 42 posterior, respectively). Therefore, only for nonsense and frameshift variants the location of the variant was plotted against the probability for LC2 membership in figure 1. A full scatterplot of all variants is available in online supplementary figure 1.Figure 1 reveals a pattern for these nonsense and frameshift variants that reveals that variants at the C-terminal of the gene predict anterior phenotypes. When relating the domains of the GLI3 protein to the observed phenotype, we observe that the majority of patients with a nonsense or frameshift variant in the repressor domain, the zinc finger domain or the cleavage site had a high probability of an LC2/anterior phenotype.

This group contains all variants that are either experimentally determined to be subject to NMD (triangle marker in figure 1) or predicted to be subject to NMD (diamond marker in figure 1). Frameshift and nonsense variants in the activator domain result in high probability for an LC1/posterior phenotype. These variants will be further referred to as truncating variants in the activator domain.The univariate relation of the individual phenotypes to these two groups of variants are estimated and presented in table 4. In our multivariate analysis, postaxial polydactyly of the foot and hand are the strongest predictors (Beta. 2.548, p<0001 and Beta.

1.47, p=0.013, respectively) for patients to have a truncating variant in the activator domain. Moreover, the effect sizes of preaxial polydactyly of the hand and feet (Beta. ˆ’0.797, p=0123 and −1.772, p=0.001) reveals that especially postaxial polydactyly of the foot is the dominant predictor for the genetic substrate of the observed anomalies.View this table:Table 4 Univariate and multivariate analysis of the phenotype/genotype correlationTable 4 shows exploration of the individual phenotypes on the genotype, both univariate and multivariate. The multivariate analysis corrects for the presence of multiple phenotypes in the underlying population.Although the craniofacial anomalies could not be included in the LCA, the relation between the observed anomalies and the identified genetic substrates can be studied. The prevalence of hypertelorism was equally distributed over the two groups of variants (47/135 vs 21/47 respectively, p<0.229).

However for corpus callosum agenesis and macrocephaly, there was a higher prevalence in patients with a truncating variant in the activator domain (3/75 vs 11/41, p<0.001. OR. 8.8, p<0.001) and 42/123 vs 24/48, p<0.05). Noteworthy is the fact that 11/14 cases with corpus callosum agenesis in the dataset had a truncating variant in the activator domain.DiscussionIn this report, we present new insights into the correlation between the phenotype and the genotype in patients with GLI3-mediated polydactyly syndromes. We illustrate that there are two LCs of patients, best predicted by postaxial polydactyly of the hand and foot for LC1, and the preaxial polydactyly of the hand and foot and syndactyly of the foot for LC2.

Patients with postaxial phenotypes have a higher risk of having a truncating variant in the activator domain of the GLI3 gene which is also related to a higher risk of corpus callosum agenesis. These results suggest a functional difference between truncating variants on the N-terminal and the C-terminal side of the GLI3 cleavage site.Previous attempts of phenotype to genotype correlation have not yet provided the clinical confirmation of these assumed mechanisms in the pathophysiology of GLI3-mediated polydactyly syndromes. Johnston et al have successfully determined the Pallister-Hall region in which truncating variants produce a Pallister-Hall phenotype rather than Greig syndrome.11 However, in their latest population study, subtypes of both syndromes were included to explain the full spectrum of observed malformations. In 2015, Demurger et al reported the higher incidence of corpus callosum agenesis in the Greig syndrome population with truncating mutations in the activator domain.12 Al-Qattan in his review summarises the concept of a spectrum of anomalies dependent on haplo-insufficiency (through different mechanisms) and repressor overexpression.13 However, he bases this theory mainly on reviewed experimental data. Our report is the first to provide an extensive clinical review of cases that substantiate the phenotypic difference between the two groups that could fit the suggested mechanisms.

We agree with Al-Qattan et al that a variation of anomalies can be observed given any pathogenic variant in the GLI3 gene, but overall two dominant phenotypes are present. A population with predominantly preaxial anomalies and one with postaxial anomalies. The presence of preaxial or postaxial polydactyly and syndactyly is not mutually exclusive for one of these two subclasses. Meaning that preaxial polydactyly can co-occur with postaxial polydactyly. However, truncating mutations in the activator domain produce a postaxial phenotype, as can be derived from the risk in table 4.

The higher risk of corpus callosum agenesis in this population shows that differentiating between a preaxial phenotype and a postaxial phenotype, instead of between the different GLI3-mediated polydactyly syndromes, might be more relevant regarding diagnostics for corpus callosum agenesis.We chose to use LCA as an exploratory tool only in our population for two reasons. First of all, LCA can be useful to identify subgroups, but there is no ‘true’ model or number of subgroups you can detect. The best fitting model can only be estimated based on the available measures and approximates the true subgroups that might be present. Second, LC membership assignment is a statistical procedure based on the posterior probability, with concordant errors of the estimation, rather than a clinical value that can be measured or evaluated. Therefore, we decided to use our LCA only in an exploratory tool, and perform our statistics using the actual phenotypes that predict LC membership and the associated genotypes.

Overall, this method worked well to differentiate the two subgroups present in our dataset. However, outliers were observed. A qualitative analysis of these outliers is available in the online supplementary data.The genetic substrate for the two phenotypic clusters can be discussed based on multiple experiments. Overall, we hypothesise two genetic clusters. One that is due to haploinsufficiency and one that is due to abnormal truncation of the activator.

The hypothesised cluster of variants that produce haploinsufficiency is mainly based on the experimental data that confirms NMD in two variants and the NMD prediction of other nonsense variants in Alamut. For the frameshift variants, it is also likely that the cleavage of the zinc finger domain results in functional haploinsufficiency either because of a lack of signalling domains or similarly due to NMD. Missense variants could cause haploinsufficiency through the suggested mechanism by Krauss et al who have illustrated that missense variants in the MID1 domain hamper the functional interaction with the MID1-α4-PP2A complex, leading to a subcellular location of GLI3.24 The observed missense variants in our study exceed the region to which Krauss et al have limited the MID-1 interaction domain. An alternative theory is suggested by Zhou et al who have shown that missense variants in the MBD can cause deficiency in the signalling of GLI3A, functionally implicating a relative overexpression of GLI3R.22 However, GLI3R overexpression would likely produce a posterior phenotype, as determined by Hill et al in their fixed homo and hemizygous GLI3R models.15 Therefore, our hypothesis is that all included missense variants have a similar pathogenesis which is more likely in concordance with the mechanism introduced by Krauss et al. To our knowledge, no splice site variants have been functionally described in literature.

However, it is noted that the 15 and last exon encompasses the entire activator domain, thus any splice site mutation is by definition located on the 5′ side of the activator. Based on the phenotype, we would suggest that these variants fail to produce a functional protein. We hypothesise that the truncating variants of the activator domain lead to overexpression of GLI3R in SHH rich areas. In normal development, the presence of SHH prevents the processing of full length GLI34 into GLI3R, thus producing the full length activator. In patients with a truncating variant of the activator domain of GLI3, thus these variants likely have the largest effect in SHH rich areas, such as the ZPA located at the posterior side of the hand/footplate.

Moreover, the lack of posterior anomalies in the GLI3∆699/- mouse model (hemizygous fixed repressor model) compared with the GLI3∆699/∆699 mouse model (homozygous fixed repressor model), suggesting a dosage effect of GLI3R to be responsible for posterior hand anomalies.15 These findings are supported by Lewandowski et al, who show that the majority of the target genes in GLI signalling are regulated by GLI3R rather than GLI3A.44 Together, these findings suggest a role for the location and type of variant in GLI3-mediated syndromes.Interestingly, the difference between Pallister-Hall syndrome and GLI3-mediated polydactyly syndromes has also been attributed to the GLI3R overexpression. However, the difference in phenotype observed in the cases with a truncating variant in the activator domain and Pallister-Hall syndrome suggest different functional consequences. When studying figure 1, it is noted that the included truncating variants on the 3′ side of the cleavage site seldomly affect the CBP binding region, which could provide an explanation for the observed differences. This binding region is included in the Pallister-Hall region as defined by Johnston et al and is necessary for the downstream signalling with GLI1.10 11 23 45 Interestingly, recent reports show that pathogenic variants in GLI1 can produce phenotypes concordant with Ellis von Krefeld syndrome, which includes overlapping features with Pallister-Hall syndrome.46 The four truncating variants observed in this study that do affect the CBP but did not result in a Pallister-Hall phenotype are conflicting with this theory. Krauss et al postulate an alternative hypothesis, they state that the MID1-α4-PP2A complex, which is essential for GLI3A signalling, could also be the reason for overlapping features of Opitz syndrome, caused by variants in MID1, and Pallister-Hall syndrome.

Further analysis is required to fully appreciate the functional differences between truncating mutations that cause Pallister-Hall syndrome and those that result in GLI3-mediated polydactyly syndromes.For the clinical evaluation of patients with GLI3-mediated polydactyly syndromes, intracranial anomalies are likely the most important to predict based on the variant. Unfortunately, the presence of corpus callosum agenesis was not routinely investigated or reported thus this feature could not be used as an indicator phenotype for LC membership. Interestingly when using only hand and foot phenotypes, we did notice a higher prevalence of corpus callosum agenesis in patients with posterior phenotypes. The suggested relation between truncating mutations in the activator domain causing these posterior phenotypes and corpus callosum agenesis was statistically confirmed (OR. 8.8, p<0.001).

Functionally this relation could be caused by the GLI3-MED12 interaction at the MBD. Pathogenic DNA variants in MED12 can cause Opitz-Kaveggia syndrome, a syndrome in which presentation includes corpus callosum agenesis, broad halluces and thumbs.47In conclusion, there are two distinct phenotypes within the GLI3-mediated polydactyly population. Patients with more posteriorly and more anteriorly oriented hand anomalies. Furthermore, this difference is related to the observed variant in GLI3. We hypothesise that variants that cause haploinsufficiency produce anterior anomalies of the hand, whereas variants with abnormal truncation of the activator domain have more posterior anomalies.

Furthermore, patients that have a variant that produces abnormal truncation of the activator domain, have a greater risk for corpus callosum agenesis. Thus, we advocate to differentiate preaxial or postaxial oriented GLI3 phenotypes to explain the pathophysiology as well as to get a risk assessment for corpus callosum agenesis.Data availability statementData are available upon reasonable request.Ethics statementsPatient consent for publicationNot required.Ethics approvalThe research protocol was approved by the local ethics board of the Erasmus MC University Medical Center (MEC 2015-679)..