Background:Limitations in activities of daily living have widespread implications for the well-being of older adults. However, the relation between performance-based physical function and self-reported functional impairment is inconsistent. Methods:The cohort included 6,282 White women and 310 Black women aged 65 and older participating in the Study of Osteoporotic Fractures (SOF) from 1986 to 2010 who reported no limitations in any Instrumental Activities of Daily Living (IADL) at baseline. Approximately every two to six years, participants self-reported their physical limitations and trained interviewers assessed common measures of physical performance (i.e., usual gait speed, grip strength, and chair stand time). We used Cox proportional hazards models using age as the time scale to calculate hazard ratios between individual and summary measures of physical performance and incident IADL limitations. Results:Over follow-up, 4,193 White women and 118 Black women developed IADL impairment (IR = 451.34 and 361.52 per 10,000 person-years, respectfully). Usual gait speed was associated with IADL limitations in both race cohorts (slowest gait vs. fastest gait HR: 3.83, 95% CI: 3.41 - 4.31; HR: 2.59, 95% CI: 1.42 - 4.73). For every one-point increase in summary performance score, rate of IADL limitations was lower for both White women and Black women (HR: 0.79, 95% CI: 0.78-0.80; HR: 0.87, 95% CI: 0.81 - 0.94). Conclusion:In this longitudinal study, women with poorer performance in individual and summary measures of physical function had an increased rate of incident IADL limitations over follow-up compared to women with the best performance. These findings confirm previous research using cross-sectional data.

BACKGROUND:Opicinumab, a human monoclonal antibody against LINGO-1, is hypothesized to promote remyelination by enhancing the differentiation of oligodendrocyte progenitor cells. OBJECTIVE:The objective of the study is to investigate the efficacy and safety of opicinumab as an add-on therapy to anti-inflammatory disease-modifying therapies (DMTs) in participants with relapsing multiple sclerosis (RMS). METHODS:Participants with RMS aged 18-58 years, with disease duration up to 20 years, were randomized 1:1 to receive intravenous infusions of placebo or opicinumab every 4 weeks for 72 weeks. Primary endpoint was Overall Disability Response Score (ODRS) over 72 weeks. RESULTS:The study enrolled 263 participants. Adjusted mean difference (95% confidence interval (CI)) on ODRS was 0.15 (-0.05 to 0.35; p = 0.148) over 72 weeks, favoring opicinumab versus placebo. Numerically larger differences in favor of opicinumab were observed in participants aged ⩾ 40 years with Expanded Disability Status Scale ⩾ 3.0, with disease duration ⩾ 6 years, and receiving dimethyl fumarate as the background DMT. 85% participants in placebo group and 86% in opicinumab group had adverse events. CONCLUSION:Although the AFFINITY study did not show significant difference in mean ODRS between opicinumab and placebo groups, data from AFFINITY interpreted with the previous SYNERGY study may inform the design of future remyelination trials. CLINICALTRIALS:gov identifier:(NCT03222973).

Anti-amyloid beta monoclonal antibodies (anti-Aβ mAbs) have received approval from the US Food and Drug Administration for the treatment of patients with mild cognitive impairment or mild dementia due to Alzheimer's disease (collectively known as early AD) based on evidence from clinical trials. However, whether findings from these trials are generalizable to the real world is uncertain. We need reliable evidence on the real-world safety of these treatments to inform decision making for clinicians, patients, and caregivers. Using lecanemab as an exemplar, we outline the key considerations in designing and implementing an observational study on safety and utilization outcomes using established administrative healthcare claims data sources with the target trial emulation framework. The target trial emulation framework is a rigorous causal inference framework that minimizes common biases in observational studies. The approach proposed here can be applied to evaluation of additional mAbs as they become available. Highlights:Little is known about real-world safety of anti-amyloid beta monoclonal antibodies for early Alzheimer's disease.Existing real-world data can support studies of their safety and utilization outcomes.Target trial emulation can guide the design of these studies while minimizing bias.We provide key design and analytical considerations for future studies.

BACKGROUND:Pregnant women are at high risk for developing severe illness related to COVID-19. We adapted the "COVID-19 infectiOn aNd medicineS In pregnancy" (CONSIGN) study protocol as part of an international collaboration to examine medication use patterns among pregnancies in the US. METHODS:We identified eligible women aged 12-55 years with documented live-birth deliveries in the Sentinel Distributed Database who had at least one qualifying diagnosis for COVID-19 or a positive-confirmed test for SARS-CoV-2, by trimester of COVID-19 infection. We conducted two sets of analyses comparing medication groups and COVID-19 treatment utilization in the 30 days prior to or after COVID-19 among pregnancies with COVID-19 to: (1) pregnancies without COVID-19 during 6 months prior to or during pregnancy; and (2) non-pregnancy episodes with COVID-19. RESULTS:From 2020 to 2022, we identified 52 355 pregnancies with COVID-19 matched to 52 355 pregnancies without COVID-19 (assigned same matched COVID-19 date), and 40 518 matched non-pregnancy episodes with COVID-19. Outpatient medication use in the 30 days prior to or after the COVID-19 date (or matched date) was quite low (< 15%) among pregnancies with and without COVID-19. Non-pregnancy episodes with COVID-19 had higher use of all medication groups in 30 days prior to COVID-19. However, in the 30 days post-COVID-19, anti-bacterials, anti-inflammatories such as NSAIDs, and analgesics were more common, and COVID-19-specific medications were less frequently used (< 1%) among pregnancies with COVID-19. Assessing COVID-19 severity, more pregnancies had a non-severe COVID-19 diagnosis than non-pregnancy episodes with COVID-19 (87.2% vs. 79.9%). CONCLUSIONS:In this retrospective evaluation, selected medication utilization was higher post-COVID-19 among pregnancies with COVID-19, compared to those without COVID-19 and to non-pregnancy episodes with COVID-19. However, the low use of COVID-19-specific medications underscores the need for a safety evaluation of therapies used for COVID-19 management in the pregnant population.

We conducted retrospective public health surveillance using data from 2006 to 2016 in 7 integrated delivery systems from the US Food and Drug Administration's Sentinel System. We identified pediatric hypertensive patients by clinical and claims-based definitions and compared demographics, baseline profiles, and follow-up time profiles. Among 3 757 803 pediatric patients aged 3 to 17 years, we identified 781 722 children and 551 246 teens with at least 3 blood pressure measurements over 36 months. Of these, 70 315 children (9%) and 47 928 teens (8.7%) met the clinical definition for hypertension, and 22 465 (2.8%) children and 60 952 (11%) of teens met the clinical definition for elevated, nonhypertensive blood pressure. Of the 3.7 million patients, we identified 3246 children and 7293 teens with any claim for hypertension (claims definition). Evidence of hypertension claims among those meeting our clinical definition was poor; 2.2% and 7.3% of clinically hypertensive children and teens had corresponding claims for hypertension. Baseline profiles for patients with claims-based hypertension suggest greater severity of disease compared with clinical patients. Claims-based patients had higher rates of all-cause mortality during follow-up. Pediatric hypertension in claims-based data sources is under-captured but may serve as a marker for greater disease severity. Investigators should understand coding practices when selecting real-world data sources for pediatric hypertension work.

Real-world studies in the USA report that 41–56

While many pregnant individuals use prescription medications, evidence supporting product safety during pregnancy is often inadequate. Existing electronic healthcare data sources provide large, diverse samples of health plan members to allow for the study of medical product utilization during pregnancy, as well as pregnancy, maternal, and infant outcomes. The Sentinel System is a national medical product surveillance system that includes administrative claims and electronic health record databases from large national and regional health insurers. In addition to these data sources, Sentinel develops and maintains a sizeable selection of analytic tools to facilitate epidemiologic analyses in a way that protects patient privacy and health system autonomy. In this article, we provide an overview of Sentinel System infrastructure, including the Mother-Infant Linkage Table, parameterizable analytic tools, and algorithms to estimate gestational age and identify pregnancy outcomes. We also describe past and future Sentinel work that contributes to our understanding of the way medical products are used and the safety of these products during pregnancy.

PURPOSE:The US Food and Drug Administration's Sentinel Innovation Center aimed to establish a query-ready, quality-checked distributed data network containing electronic health records (EHRs) linked with insurance claims data for at least 10 million individuals to expand the utility of real-world data for regulatory decision-making. METHODS:In this report, we describe the resulting network, the Real-World Evidence Data Enterprise (RWE-DE), including data from two commercial EHR-claims linked assets collectively termed the Commercial Network covering 21 million lives, and four academic partner institutions collectively termed the Development Network covering 4.5 million lives. RESULTS:We discuss provenance and completeness of the data converted in the Sentinel Common Data Model (SCDM), describe patient populations, and report on EHR-claims linkage characterization for all contributing data sources. Further, we introduce a standardized process to store free-text notes in the Development Network for efficient retrieval as needed. CONCLUSIONS:Finally, we outline typical use cases for the RWE-DE where it can broaden the reach of the types of questions that can be addressed by the Sentinel system.

PURPOSE:Immediate-release forms of generic mixed amphetamine salts (MAS) have been the subject of passive surveillance reports signaling lack of effectiveness. We examined switching patterns that might suggest whether long-term users of specific MAS are more likely to switch away or switch back after use of the MAS of interest in the FDA's Sentinel Distributed Database. METHODS:We required at least 60-day continuous supply of selected MAS grouped by Abbreviated New Drug Application (ANDA) to describe patterns of switching away from and to generics approved under the ANDAs of interest among individuals ages 15-64 years with attention deficit hyperactivity disorder or narcolepsy during 2013-2019. RESULTS:We observed the greatest number of treatment episodes for ANDA 040422 (n = 525 771), followed by ANDA 202424 (n = 181 693), ANDA 040439 (n = 62 363), ANDA 040440 (n = 21 143), and ANDA 040480 (n = 8792). Of those with switches away from their original ANDA, episodes initiated on generic products under ANDA 040422 (48.6%) and ANDA 202424 (43.0%) were most likely to switch back, while those initiated on generic product under ANDA 040480 were least likely (24.1%). Of those episodes with switches to a generic under an ANDA of interest, about one-third (range 27.1% to 37.0%) switched back to the same product. These switches back had a median time to switch of about 30 days. CONCLUSIONS:These descriptive analyses, although subject to limitations, did not suggest increased switching away or switching back after use of the generics of interest. Continued post-marketing surveillance is warranted.

BACKGROUND:Montelukast prescribing information includes a Boxed Warning issued in March 2020 regarding neuropsychiatric adverse events. A previous Sentinel System study of asthma patients from 2000 to 2015 did not demonstrate an increased risk of intentional self-harm measured using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, with montelukast compared to inhaled corticosteroids (ICS). METHODS:Using a new user cohort study design, we examined intentional self-harm events in patients aged 10 years and older who were incident users of either montelukast or ICS as monotherapy, with a diagnosis of asthma, between October 1, 2015, to June 30, 2022, in the Sentinel System. We measured intentional self-harm using ICD-10-CM codes, which may have better accuracy for capturing suicide attempts than ICD-9-CM codes. We used inverse probability of treatment weighting to balance baseline covariates. We performed subgroup analyses by age group, sex, psychiatric history, and pre/post Boxed Warning era and conducted sensitivity analyses varying type of care setting of the outcome and exposure episode gaps. RESULTS:Among 752,230 and 724,855 patients in the montelukast and ICS exposure groups respectively, we found no association between montelukast use and self-harm compared to ICS use [Hazard Ratio (95% Confidence Interval): 0.96 (0.85, 1.08)]. This finding was consistent across all subgroups, and sensitivity analyses. CONCLUSION:Our results cannot exclude other neuropsychiatric idiosyncratic reactions to montelukast. Compared to the previous Sentinel study, this study identified about double the rate of self-harm events, suggesting a greater sensitivity of ICD-10 codes for measuring self-harm than ICD-9.

Objective: To assess long-term safety and effectiveness of delayed-release dimethyl fumarate (DMF) in patients with relapsing forms of multiple sclerosis (MS) in clinical practice. Background: DMF has demonstrated a favorable benefit–risk profile in patients with relapsing forms of MS in clinical trials and real-world studies. To provide information on long-term exposure in clinical practice, the ESTEEM study (NCT02047097) was conducted. Design/Methods: In this ongoing study, patients treated with DMF were recruited from ~380 sites. The primary objective was to assess the incidence and type of serious adverse events (SAEs) and AEs leading to discontinuation. Secondary objectives included assessment of DMF effectiveness on annualized relapse rate (ARR) and patient-reported outcomes (PROs). Results: As of April 2021, 5251 patients had received >1 dose of DMF. Mean (SD) age of patients at enrollment was 40.1 (11.2) years; 74.0% were female. Patients received DMF for a mean (SD) duration of 30.4 (20.4) months. Primary reasons for discontinuation were AEs (1066/5251; 20.3%), of which the most common were gastrointestinal AEs (442/1066; 41.5%), and efficacy reasons (439/5251, 8.4%). Of 5251 patients, 173 (3.3%) patients discontinued due to lymphopenia. SAEs were reported in 326 (6.2%) patients, most commonly infections and infestations (n=86; 1.6%). No PML was reported. Adjusted ARR (95% CI) remained low, ranging from 0.16 (0.14–0.17) after Year 1 to 0.05 (0.04–0.08) after Year 5. Mean scores for measures of physical and psychological impact, fatigue, overall health outcomes, and work productivity and activity impairment remained stable at 5.5 years compared with baseline. Conclusions: In this interim analysis, DMF demonstrated a safety profile in real-world clinical practice consistent with the known profile of DMF. Similarly, relapse rates were low and both ARR and PROs remained stable over time. This indicates a sustained effectiveness for patients who remain on DMF treatment for up to 5 years. Disclosure: Dr. Pandey has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS. Dr. Pandey has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi Genzyme. Dr. Pandey has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech . Dr. Pandey has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for BMS. Dr. Pandey has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen . Dr. Pandey has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Alexion. Dr. Pandey has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Genentech . Dr. Pandey has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Horizon Therapeutics . The institution of Dr. Pandey has received research support from NIH. The institution of Dr. Pandey has received research support from CMSC. Kathryn Giles has stock in Synderdisc. The institution of Kathryn Giles has received research support from Biogen. Dr. Balashov has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. Dr. Macdonell has nothing to disclose. Jorg Windsheimer has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck, Biogen,BMS,Janssen,Roche,Hexal. Jorg Windsheimer has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen,Teva,BMS. Mikel Martinez has nothing to disclose. Dr. Bozin has received personal compensation for serving as an employee of Biogen. Dr. Bozin has received personal compensation for serving as an employee of Arvelle Therapeutics. Dr. Bozin has stock in Biogen. Xiaotong Jiang has nothing to disclose. Dr. Lyons has received personal compensation for serving as an employee of Biogen. Dr. Lyons has received stock or an ownership interest from Biogen. Oksana Mokliatchouk has received personal compensation for serving as an employee of Biogen. Oksana Mokliatchouk has received stock or an ownership interest from Biogen. Dr. Okai has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alexion. Dr. Okai has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. Dr. Okai has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS. Dr. Okai has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for EMD Serono. Dr. Okai has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech. Dr. Okai has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Okai has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi Genzyme. Dr. Okai has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Alexion. Dr. Okai has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Biogen. Dr. Okai has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for EMD SERONO . Dr. Okai has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Sanofi Genzyme .

In Escherichia coli, the cytosolic chaperone SecB is responsible for the selective entry of a subset of precursor proteins into the Sec pathway. In vitro, SecB binds to a variety of unfolded substrates without apparent sequence specificity, but not native proteins. Selectivity has therefore been suggested to occur by kinetic partitioning of substrates between protein folding and SecB association. Evidence for kinetic partitioning is based on earlier observations that SecB blocks the refolding of the precursor form of maltose-binding protein (preMBP)5 and slow-folding maltose-binding protein (MBP) mutants, but not faster-folding mature wild-type MBP. In order to quantitatively validate the kinetic partitioning model, we have independently measured each of the rate constants involved in the interaction of SecB with refolding preMBP (a physiological substrate of SecB) and mature MBP. The measured rate constants correctly predict substrate folding kinetics over a wide range of SecB, MBP, and preMBP concentrations. Analysis of the data reveals that, for many substrates, kinetic partitioning is unlikely to be responsible for SecB-mediated protein export. Instead, the ability of SecB-bound substrates to continue folding while bound to SecB and their ability to interact with other components of the secretory machinery such as SecA may be key opposing determinants that inhibit and promote protein export, respectively.

Montelukast prescribing information includes a Boxed Warning issued in March 2020 for neuropsychiatric adverse events. A previous study in the Sentinel System in patients with asthma from 2000 to 2015 showed no increased risk of intentional self-harm (ISH) measured using the ICD-9 Clinical Modification (ICD-9-CM) codes in patients dispensed montelukast vs inhaled corticosteroids (ICS). We examined ISH events following montelukast or ICS use using ICD-10-CM codes, which may have better accuracy than ICD-9-CM for capturing suicide attempts. This study compared the incidence rate and time to ISH events among new users of montelukast or ICS aged 10 years and older, with a diagnosis of asthma, in the Sentinel System from October 1, 2015, to June 30, 2022. Inverse probability of treatment weighting (IPTW) was used to balance baseline covariates; subgroup analyses by age group, sex, psychiatric history, and pre/post–Boxed Warning era; and sensitivity analyses varying the care setting and exposure episode gaps were conducted. There were 752,230 and 724,855 patients identified in the montelukast and ICS exposure groups, respectively, after weighting. A higher rate of ISH (incidence rate [IR] per 1000 person-years [95% CI]: 5.3 [4.8, 5.8]) was seen in the 10 to 24 years age group compared to the 25 years and older age group (IR [95% CI]: 2.0 [1.9, 2.2]), and females recorded more ISH events (IR [95% CI]: 3.2 [3.0, 3.4]) compared to males (IR [95% CI]: 2.0 [1.8, 2.3]). We found no association between montelukast use and ISH compared to ICS use overall (hazard ratio [HR] [95% CI]: 0.96 [0.85, 1.08]), or in the 10- to 24-year-old age group (HR [95% Cl]: 1.01 [0.85, 1.20]). Subgroup and sensitivity analyses showed similar null findings. ISH was roughly 7-fold more frequent in patients with a psychiatric history compared to patients with no psychiatric history. ISH rates were approximately double those observed in the previous study using ICD-9 coding. Although no association between montelukast use and ISH was observed, these results do not exclude less common idiosyncratic reactions to montelukast. ICD-10 codes for self-harm events appeared to have greater sensitivity than ICD-9 codes.

These results suggest that proper coverage of nodal basins, when indicated by expert guidelines, could improve distant metastasis. ENI analysis of previous prospective CRT studies for esophageal cancer could validate these findings.

BackgroundProgressive multifocal leukoencephalopathy (PML), an important identified risk for natalizumab, has been described for standard interval dosing (SID; dosing interval every-4-weeks). Information on PML with natalizumab extended interval dosing (EID; dosing interval >every-4-weeks) in the US and the rest of the world (ROW) is limited.Research design and methodsA retrospective analysis of patient demographics, risk factors, clinical characteristics, and clinical outcomes was conducted on confirmed natalizumab EID and SID PML cases evaluated from Biogen pharmacovigilance systems.ResultsOf 857 confirmed natalizumab PML cases, EID and SID accounted for 7.5% and 92.5%, respectively (US: 12.9% and 87.1%; ROW: 5.4% and 94.6%). PML risk factors included anti-JCV index > 1.5 (US: EID, 56.7% and SID, 12.8%; ROW: EID, 44.1% and SID, 21.0%), mean duration of natalizumab treatment (US: 90.0 and 70.2 months; ROW: 54.1 and 49.8 months), and prior immunosuppressive therapy (US: 20.0% and 21.7%; ROW:11.8% and 18.0%). In the EID and SID groups, 68.8% and 76.0% of patients, respectively, were alive at up to 2 years after diagnosis.ConclusionsThis analysis provides insights on PML in patients receiving natalizumab that extend current knowledge, particularly regarding PML in patients receiving natalizumab EID, which can be built upon in the future.

Multiple sclerosis (MS) clinical trials have included low numbers of patients from racial and ethnic minority populations; therefore, it is uncertain whether differences exist in response to disease-modifying therapies. We evaluated the real-world safety and effectiveness of dimethyl fumarate (DMF) treatment over 5 years in four patient cohorts: Black, non-Black, Hispanic, and non-Hispanic people with relapsing–remitting MS. ESTEEM is an ongoing, 5-year, multinational, prospective study evaluating the long-term safety and effectiveness of DMF in people with MS. The analysis included patients newly prescribed DMF in routine practice at 393 sites globally. Overall, 5251 patients were analyzed (220 Black, 5031 non-Black; 105 Hispanic, 5146 non-Hispanic). Median (min−max) months of follow-up was 32 (0–72) for Black, 29 (1–77) for Hispanic, and 41 (0–85) for both the non-Black and non-Hispanic populations. In total, 39 (18