Publication
Theme Article
Comprehensive care addressing issues that are common in older people with MS, including polypharmacy and comorbidity, may improve quality of life, adherence, and overall health.
As age increases, the prevalence of comorbidities increases in the general population. In turn, this often leads to an increase in the number of medications administered. This phenomenon creates additional challenges in the management of neurodegenerative disorders such as multiple sclerosis (MS). Higher comorbidity burden is associated with longer diagnostic delays and greater disability at diagnosis. A higher burden of comorbidities in people with MS is associated with higher disability levels and accelerated disability progression. Responses to rehabilitation therapy may also be altered in terms of timing and sustainability of response. Conversely, a diagnosis of MS negatively affects the management and outcomes of some comorbidities, and treatment of certain comorbidities can worsen MS symptoms. Thus, comorbid conditions in people with MS have important implications with respect to MS-specific care and general health care throughout the life course of the disease. Comorbidities must be considered when developing plans of care. Similarly, polypharmacy is common in non-MS populations, even more so in MS populations, and can adversely affect quality of life and worsen underlying disability. In 2023, the Consortium of Multiple Sclerosis Centers needs assessment identified comorbidity and polypharmacy as a core topic relevant to the care of aging adults with MS, and an in-person meeting of experts in 2024 discussed the existing literature. This narrative review discusses how comorbid disease and polypharmacy affect people with MS, strategies to mitigate these negative risks, as well as areas where evidence is lacking and further study is needed to inform optimal treatment strategies for older adults with MS.
From the departments of Medicine and Community Health and Epidemiology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada (RAM); Nova Scotia Health, Halifax, Nova Scotia, Canada (RAM); Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Neurology, University of Colorado Anschutz School of Medicine, Aurora, CO (JB); UCHealth Yampa Valley Medical Center, Steamboat Springs, CO (PB); Department of Neurology, Georgetown University Medical Center, Washington, DC (JW); Department of Neurosciences, University of California San Diego, San Diego, CA (JSG); Department of Neurological Sciences, University of Nebraska, Omaha, NE (RStewart); Independence Care System, Brooklyn, NY (RStacom); private practice, Greensboro, NC (MDB); Departments of Internal Medicine and Geriatrics, University of Nebraska Medical Center, Omaha, NE (MTC); Ferkauf Graduate School of Psychology, Yeshiva University, Bronx, NY (FWF); Multiple Sclerosis Center, Holy Name Medical Center, Teaneck, NJ (FWF); Department of Neurology, University of Colorado Anschutz School of Medicine, Aurora, CO (JRC); Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD (SDN); Department of Neurology, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV (LHH); Division of MS/Neuroimmunology, The Ohio State University, Wexner Medical Center, Columbus, OH (YZ); Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada (SAM). Correspondence: Sarah A. Morrow, MD, MS, FRCPC, Foothills Medical Centre, 907 South Tower, 1409 29th St NW, Calgary AB, Canada T2N 2T9; email: sarah.morrow@albertahealthservices.ca.
The onset of multiple sclerosis (MS) typically occurs between the ages of 20 and 50 years. As the survival gap has decreased between people with and without MS over time,1 the median lifespan of people with MS has reached the mid-70s.2
This means that most people with MS will age with their disease. The aging process is associated with a decline in the effectiveness of repair and remyelination in the central nervous system, as well as chronic, systemic, low-grade inflammation.3
Aging is also strongly associated with a rising prevalence of comorbidity, at a time when the severity of physical disability and prevalence of cognitive impairment are also rising.4,5 As the peak age-specific prevalence of MS has risen and now exceeds 55 years,6 attention has shifted to the care of this population, offering the opportunity to envision new models of care to better identify and meet care needs.
The Consortium of Multiple Sclerosis Centers (CMSC) is committed to ensuring that all people with MS, including older adults, receive optimal care, including by identifying unmet needs and developing sustainable, effective models of care. Therefore, a panel of clinicians with expertise in aging and MS distributed a needs assessment survey to CMSC members and attendees at the 2023 CMSC Annual Meeting. It identified 5 core topics relevant to the care of older adults with MS: the effects of comorbidity and polypharmacy, disease-modifying therapy (DMT) use and discontinuation in older adults, the interaction between aging and the MS disease process, the value of multidisciplinary care, and challenges in access to care. To explore these areas, a multidisciplinary panel of MS experts from the CMSC—including neurologists, nurse practitioners, psychologists, a geriatrician, a dietitian, a pharmacist, and a physical therapist—was convened in September 2023. Groups of panelists were assigned 1 of the 5 topics and tasked with addressing 3 guiding questions via a literature review: (1) What is currently known?; (2) What remains unknown?; and (3) What future directions should be prioritized for clinical care and research? Next, the findings were presented and discussed at an in-person meeting in June 2024, then summarized in a series of narrative reviews. Formal consensus methods were not adopted.
In this review, we focus on the topic of comorbidities and polypharmacy among older people with MS, emphasizing literature identified in a PubMed search, using a strategy based on a prior publication7 for comorbidity covering the period January 1, 2015, through December 31, 2024, a separate search of PubMed for polypharmacy covering the same period, as well as a search of the authors’ files. Article quality was not formally appraised, but clinical trials and meta-analyses were favored over single observational studies, and longitudinal studies were favored over cross-sectional studies.
Comorbidity, the total burden of illness other than the condition of interest (herein, MS), is well-recognized as common among people with MS,8 adversely affecting outcomes ranging from fatigue to disability progression to health care use. Comorbidity may encompass chronic or recurrent conditions, infections, as well as other time-limited conditions. Comorbidity is distinct from complications due to the primary disease, such as urinary tract infections arising due to neurogenic bladder, or symptoms such as fatigue. We acknowledge that these distinctions can be difficult to make at times. Polypharmacy is also common in MS.9,10 In other populations, as well as in people with MS, polypharmacy is closely related to comorbidity. Symptom management also affects polypharmacy.
In this review, we discuss what is known about the prevalence and consequences of comorbidity and polypharmacy in older people with MS, focusing on vascular and psychiatric comorbidities, which have a particularly high prevalence. Next, we discuss unmet needs and knowledge gaps and their implications for providing care for older people with MS. Finally, we identify areas that require future study.
A 2015 systematic review found that the most common comorbidities in people with MS were depression, anxiety disorders, hypertension, hyperlipidemia, irritable bowel syndrome, and chronic lung disease.8 The prevalence of many comorbid conditions, including hypertension, hyperlipidemia, diabetes, ischemic heart disease, cerebrovascular disease, and chronic lung disease, rises with age among people with MS. This was well-illustrated in a meta-analysis involving 17,926 participants from 14 clinical trials.11 Compared with people with MS aged 30 to 40 years, people with MS older than 50 years had a 3.5-fold higher prevalence of hyperlipidemia and diabetes and a 5- to 6-fold higher prevalence of hypertension, ischemic heart disease, and cerebrovascular disease. An analysis of the electronic health records of 122,660 people with MS in the US found that the prevalence of hypertension rose from 13.4% in those aged 30 to 34 years to 65.4% among those aged 70 to 74 years.12 Risk factors for vascular comorbidity among people with MS, apart from older age, include male sex, smoking, physical inactivity, lower socioeconomic status, and being a recent immigrant.13,14
In contrast to vascular comorbidities, the prevalence of psychiatric disorders, including anxiety and depression, tends to be more stable with aging among people with MS,15 similar to the general population. Smoking, lower levels of education and income, and being a recent immigrant are also associated with psychiatric comorbidity.13,15 However, male sex is associated with a lower risk of psychiatric comorbidity. Adverse childhood experiences16 and a higher genetic burden for depression or anxiety disorders are associated with increased risks of psychiatric disorders among people with MS.17,18
The incidence of many cancers also changes with age, an increasing concern in older people with MS, especially in those who may have been treated with immunosuppressive therapies. Few studies have reported age-specific incidence of cancer among people with MS. A 2021 study from Canada reported that among people with MS aged 31 to 39 years, the incidence of breast cancer per 100,000 person-years rose from a range of 35.3 to 48.3 to a range of 164.3 to 419.2.19 The incidence of colorectal cancer also rose steadily with age.19 Risks of breast and colorectal cancer were similar between people with and without MS. A 2024 study from France that covered the period 2012 to 2021 found that cancer risk overall was 1.2-fold higher in people with MS aged 55 to 64 years than those younger than 55 years, but was 11% lower among those 65 years and older.20
Association of Comorbidity With Outcomes
Comorbidity has several important effects on the outcomes of people with MS (Table) and implications for care throughout the life course of the disease.
Diagnosis
Higher comorbidity burden at diagnosis is associated with longer diagnostic delays and greater disability at diagnosis, after adjusting for age and other potential confounding factors.21 The older the age at initial presentation, the higher the rate of misdiagnosis of MS.22 This is a particular concern given reports that the age of symptom onset in MS has shifted to later ages in recent decades.23 Conditions most often misdiagnosed as MS include age-related vascular changes, hypertension, and migraine.24,25 Conversely, another study found that those with comorbid degenerative spine disease, cerebrovascular disease, psychiatric disorders, or ophthalmologic disorders other than optic neuritis were initially misdiagnosed as not having MS.26 Thus, additional caution is warranted when considering the diagnosis of MS in older adults with the presence of comorbidity, as recently recommended by the revised diagnostic criteria for MS.27
Relapses, Disability Progression, and Mortality
After diagnosis, vascular comorbidity is associated with higher relapse rates, faster disability progression, greater brain atrophy, and increased mortality.28-31 Findings regarding the association of dyslipidemia with relapses have been mixed, with some studies showing increased relapse rates and others showing no association.32-3 A recent meta-analysis of 17 clinical trials found hat dyslipidemia was not associated with an increased relapse rate29 but was associated with worsening disability. Moreover, as the number of cardiometabolic comorbidities rose, the risk of any disease activity, including relapses, new lesions, or disability progression, rose 21%. Other observational studies also suggest the burden of cardiovascular risk is associated with worse outcomes. In a retrospective cohort study, each 1-point increase in the Framingham Risk Score was associated with a 31% elevated relapse rate and 20% elevated rate of requiring an assistive device to walk.35 Although these longitudinal studies support a possible causal effect of vascular comorbidity on outcomes, reverse causality and unmeasured confounding cannot be excluded. Limited cross-sectional work suggests that vascular comorbidity is also associated with lower cognitive performance in people with MS, including slower processing speed.36-39 Among people with MS 55 years and older, higher diastolic blood pressure was associated with lower verbal memory after controlling for age, and with lower visual memory.40
Psychiatric comorbidity is also associated with elevated relapse rates, accelerated progression of physical and cognitive impairments, lower health-related quality of life, reduced participation in social roles, and mortality.29,41,42 The meta-analysis of 17 clinical trials found depression was associated with a 21% increased rate of relapses and a 29% increased rate of disability worsening.29 A Canadian study in which one-third of participants with MS had a mood or anxiety disorder found that the presence of such a disorder was associated with faster disability progression.43 The effect was stronger in women and not statistically significant in men. Subsequently, a retrospective cohort study in Sweden found that depression was associated with an increased rate of sustained Expanded Disability Status Scale scores of 3.0, 4.0, and 6.0.44 Recent work using a polygenic score for depression as an instrument variable suggests the effects of depression on disability are not due to reverse causality, but rather independent,substantially strengthening causal inference.45
In cross-sectional studies, psychiatric comorbidity, including diagnoses of depression and anxiety disorders, as well as elevated symptoms of depression and anxiety, is associated with lower cognitive performance among people with MS, including reaction time, processing speed, and verbal memory.46-49 Longitudinal studies suggest that depression, rather than anxiety, is most associated with changes in cognition over time, although findings have been mixed.41,50,51 In older adults with long-standing MS, undertreated depression is associated with lower levels of physical activity, lower diet quality, less community participation, and lower health-related quality of life.52 Depression and MS have synergistic effects on mortality, with 2 studies, 1 in Canada and 1 from the United Kingdom, showing attributable proportions of 13% to 14%.53,54 This implies that preventing or effectively treating depression could have a substantial benefit in reducing mortality.
Imaging Outcomes
Cross-sectional studies suggest that vascular comorbidity is associated with lower brain volumes.55 One such study found that people with MS with 2 or more comorbidities, including diabetes, hypertension, and dyslipidemia, had lower brain parenchymal fractions, gray matter fractions, and cortical and deep gray matter volumes when compared with people with MS with no comorbidities.55 Longitudinal studies, which should provide more definitive evidence, have produced inconsistent findings.30,31,56,57 In addition, the average age of study participants was less than 50 years in all these studies, making it difficult to determine whether these findings may generalize to older people with MS.
Overall, a large body of evidence supports an adverse effect of comorbidity across a broad range of outcomes in MS, although the mechanisms underlying these effects remain unknown. Nonetheless, the breadth of impacts suggests that attention to preventing/treating comorbidity should be a routine aspect of MS care.
Comorbidity and Influences on Treatment of MS
Disease-Modifying Therapy
Although understudied in people with MS, comorbidity may impact the effectiveness, safety, and tolerability of DMTs, including pharmacologic and nonpharmacologic therapies. Comorbidity may also constitute a contraindication for therapy, and some DMTs may increase the risk of comorbidity development. In a Canadian study during the era of predominantly injectable DMT use, the likelihood of initiating therapy was lower with each additional comorbidity.58 Among treatment-naive individuals who initiate DMTs, comorbidity is associated with a 42% increased rate of treatment switches due to tolerability concerns.59 In a population-based retrospective cohort study, the presence of any comorbid psychiatric disorder was associated with a 22% higher rate of discontinuing DMTs.60 In another retrospective cohort study, a higher Framingham Risk Score was associated with an elevated risk of DMT escalation.35
Several DMTs confer an increased risk of developing comorbidity.61 For example, fingolimod, teriflunomide, and alemtuzumab are associated with an increased incidence of hypertension. Fingolimod and teriflunomide are associated with an increased incidence of hyperlipidemia, and natalizumab is associated with an increased incidence of cerebrovascular disease.61 Alemtuzumab is associated with an increased risk of autoimmune disease, including thyroid disorders. DMT use may also increase the risk for cancer, particularly in individuals 62 years and older.62 Some comorbidities confer contraindications to DMT use, and this is a bigger challenge among older people with MS who have a higher burden of comorbidity. Ischemic heart disease, for example, is a contraindication to the use of fingolimod, and active cancer is a contraindication to immuosuppressive DMTs. Comorbidity may also influence decisions to stop or de-escalate treatment, as it may affect relative risks and benefits of DMTs in older people with MS; this is discussed in more detail in a companion article. Thus, comorbidity status should be reviewed and updated routinely to inform decisions regarding DMTs.
What Is Known
MS adversely affects the management and outcomes of some comorbidities. For example, people with MS who experience acute myocardial infarctions are 39% less likely to undergo cardiac catheterization, 32% less likely to get revascularized, less likely to get all the recommended pharmacotherapy, and have lower survival than people without MS.67 Women with MS who develop breast cancer68 and people who develop colorectal cancer have lower survival rates that are not accounted for by disability status.69 In contrast, following the diagnosis of MS, patients' diabetes and hypertension appear to be well-managed.70 Yet cardiovascular risk prediction tools that guide vascular management perform poorly in people with MS,71 such that vascular risk is underestimated and appropriate interventions, such as statin initiation, may not be offered.
In contrast, many of the screening tools for depression and anxiety disorders developed for general and medical populations perform adequately in people with MS.72 Moreover, study data show the use of only 1 or 2 questions to identify depression or anxiety appears to work well.73,74 Pharmacologic and psychotherapeutic interventions are effective for managing depression in people with MS.75,76
What Is Not Known, and Future Research Questions
Persistent gaps in knowledge have limited the provision of specific management recommendations in clinical practice, including those related to education, identifying and managing comorbidity, and organization of care. A first step is to ensure that all providers caring for people with MS are aware of the high prevalence of comorbidity and its potential contributions to suboptimal outcomes. MS care teams can play an important role in educating other providers. Second, we need to know whether comorbidity influences the correct attribution of new or worsened symptoms to a relapse or a pseudorelapse. Third, we need to determine how often people with MS should undergo screening or assessment for common comorbidities. Should screening for diabetes, hypertension, and hyperlipidemia in older people with MS occur more often than in the general population? How should screening and risk assessment tools be adapted for people with MS? Fourth, how should management of comorbidity differ in people with MS from those without MS? Although this has not been explicitly evaluated, some recommendations can be made based on our understanding of the adverse effects of therapies used for comorbidity and symptoms of MS. For example, diuretics used to manage hypertension may worsen the symptoms of neurogenic bladder. β-blockers may worsen fatigue. Therapies with anticholinergic effects may adversely affect cognition and fatigue. All medications used to manage comorbidity should be reviewed against the American Geriatrics Society Beers Criteria77 to avoid therapies that may be inappropriate for older adults. Fifth, does effective management or prevention of comorbidity improve outcomes in people with MS? Finally, what is the optimal model of care for addressing comorbidity management in older people with MS? There is a lack of consensus as to which provider on the care team is responsible for identifying and managing comorbidities and how this can be coordinated/integrated with MS care.
Polypharmacy refers to the concurrent use of 5 to 9 medications, while hyperpolypharmacy refers to the concurrent use of 10 or more medications.78 In 2017 to 2018, 17% of adults in the general US population experienced polypharmacy overall, which rose to 37% among adults 65 years and older.79 The prevalence of polypharmacy is relatively high among people with MS, ranging from 13% to 90%, depending on the study.80-82 In the only population-based study, relying on administrative health claims from British Columbia, Canada, 28% of 14,227 people with MS met the criteria for polypharmacy.10 Antidepressants, antiseizure medication, peptic ulcer medications, lipid therapies, and centrally acting muscle relaxants were the drug classes that most often contributed to polypharmacy.10 Antidepressants and other medications with strong anticholinergic effects can adversely affect cognition in older adults over time, including in people with MS.83 Older people with MS are more likely than those without MS to use benzodiazepines and
nonbenzodiazepine/hypnotic drugs (eszopiclone; zolpidem) to treat insomnia and anxiety, even in the absence of psychiatric comorbidity.84 These medications should be avoided in older people with MS due to the potential risk for harm, such as risk of falls and cognitive impairment.
In cross-sectional studies, older people with MS who have more comorbidities, greater disability, and increased cognitive impairment are more likely to experience polypharmacy.80,81,85Men and women have similar risks of polypharmacy.86 In the Canadian study discussed above, 29.0% (1738/5995) of people with MS between 50 and 64 years of age, and 43.7% (1540/3525) of people with MS 65 years and older experienced polypharmacy. Although only 19.4% (1955/10067) of people with MS who had no comorbidities experienced polypharmacy, this rose to 46.8% (491/1050) among those with 2 comorbidities, and to 65.8% (406/617) among those with 3 or more comorbidities. In a
cross-sectional analysis, polypharmacy is associated with lower health-related quality of life, as measured by the Multiple Sclerosis Quality of Life Inventory-54.87
Although longitudinal studies examining the association of polypharmacy with outcomes in people with MS are lacking, observations in populations 65 years and older who do not have MS suggest that polypharmacy is associated with an increased risk of drug interactions and adverse drug events, as well as increased mortality rates, and these effects are increased in frail vs nonfrail individuals.88 In older adults, a complex bidirectional relationship exists between polypharmacy and frailty, where each may worsen the other; although this has not been demonstrated in MS, it is plausible and suggests that efforts to address polypharmacy are important.89
Reducing Inappropriate Polypharmacy, and How the Pharmacist Can Help
What Is Known
It is well known that polypharmacy can lead to an increased risk of adverse events as well as nonadherence.9 Thus, it is imperative that clinicians treating people with MS with comorbidities consider strategies to minimize polypharmacy. The first consideration is their medical profile when prescribing medications. Although diuretics are used to manage hypertension, in people with MS, they may worsen symptoms of neurogenic bladder. Making conscientious decisions regarding any prescribed medication will help minimize future polypharmacy. Second, periodically addressing medications to ensure they are still appropriate and required, still have benefit, or are not duplicate therapies will help reduce polypharmacy. An important aspect of this evaluation is considering age-related effects on hepatic and renal function that may alter the risk-benefit balance of therapy by influencing the rates of drug metabolism or excretion,90,91 as well as changes in the volume of distribution of lipid-soluble drugs.92 For example, impaired renal function is a contraindication to the use of dalfampridine. Gabapentin, pregabalin, and cladribine can be used, although dose reduction is needed (note that hepatic impairment will require dose adjustment or discontinuation). Antibiotics may also require dose modification. Finally, simplifying medication regimens, such as switching from twice-daily to once-daily dosing, will also reduce medication burden and improve adherence.
One useful tool when addressing polypharmacy is the American Geriatrics Society Beers Criteria.77 It was developed for older adults to identify possible inappropriate medication use. Several of the medications on the Beers List place older adults at high fall risk, which can be an additive risk to people with MS.
Pharmacists play a crucial role in addressing polypharmacy; clinical pharmacy specialists are becoming an integral part of the MS multidisciplinary team. In addition to in-depth knowledge of the mechanism of action, drug-drug interactions, and titration scheduling, pharmacists can assist with access to medications and drug information counseling. Pharmacists are a resource for medication education for the entire health care team.
What Is Not Known, and Future Research Questions
As people with MS live longer, they will inevitably develop comorbidities and experience polypharmacy. More studies that focus specifically on older people with MS and common MS medications are needed, especially regarding DMTs and symptomatic treatments commonly prescribed for people with MS. As noted previously, most studies on this topic involve non-MS populations; however, over 45% of people with MS in the US are older than 55 years,6 leaving a significant knowledge gap when considering their unique treatment considerations. Specifically, use of DMTs in older people with MS must involve careful consideration of the risk vs benefit of their long-term use, adverse effects, and immunosuppression and immune response to vaccines. Finally, the interaction or impact of DMTs on comorbidities and/or medications for these comorbidities must be addressed.
Currently, there are no guidelines or best-practice recommendations that identify which people with MS will most likely benefit from deprescribing. Further, it is not well established who should be responsible for identifying any medication issues and/or managing these comorbidities with polypharmacy in mind. Models that can integrate these important issues into coordinated MS care will inevitably lead to better overall care and outcomes for people with MS.
Comorbidity is common in older people with MS and can adversely affect health outcomes, as well as management of MS. Conversely, MS may affect comorbidity management and increase the risk of polypharmacy. Both issues require consistent attention by clinicians caring for older people with MS.
Acknowledgments: The authors would like to thank the Consortium of MS Centers for supporting the creation and distribution of these recommendations and for funding the in-person meeting.
Disclosures: Ruth Ann Marrie, MD, PhD, receives research funding from the Arthritis Society, the Canadian Institutes of Health Research, Children’s Hospital Research Institute of Manitoba, Consortium of Multiple Sclerosis Centers, Crohn’s and Colitis Canada, Manitoba Medical Service Foundation, MS Canada, National Multiple Sclerosis Society, Pfizer Foundation, Public Health Agency of Canada, and the US Department of Defense. She is a coinvestigator on studies receiving funding from Biogen and Roche Canada, and holds the Gillian Hope Multiple Sclerosis Clinical Research Chair (Dalhousie University). Jacquelyn Bainbridge, PharmD, has served on advisory boards for EMD Serono, Novartis, and TG Therapeutics. Jeff Wilken, PhD, has been a speaker for Biogen, EMD Serono, and Sanofi; a paid consultant for Bayer and Sanofi; and has received research funding from Biogen and Sanofi. Renee Stewart, APRN-DNP, has served on a Genentech advisory board. Rachael Stacom, NP-BC, MSCN, has served on advisory boards for Genentech and TG Therapeutics. Frederick W. Foley, PhD, has served on advisory boards for Bayer and Biogen; has been a paid consultant for Biogen; and has been a speaker for EMD Serono and Sanofi. John R. Corboy, MD, MA, has received compensation as the medical director of the Rocky Mountain MS Center and associate editor of the Annals of Neurology. He has received research support from EMD Serono, the National Institutes of Health via the Immune Tolerance Network, and the National Multiple Sclerosis Society. Le H. Hua, MD, has received personal fees for speaking, consulting, and advisory board activities from Alexion, EMD Serono, Genentech, Genzyme, Horizon, Novartis, and TG Therapeutics, and has had research support paid to her institution from Genentech outside the submitted work. Authors Patty Bobryk, MHS, PT, MSCS, ATP; Jennifer S. Graves, MD, PhD, MAS; Mona D. Bostick, RDN, LDN, MSCS; Maureen T. Choman, MD; Scott D. Newsome, DO; Yinan Zhang, MD; and Sarah A. Morrow, MD, MS, FRCPC, have declared no relevant disclosures.
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