Faculty Bibliography

INTRODUCTION/BACKGROUND:Sleep disturbances are common in older people with cognitive impairment, potentially contributing to negative outcomes. A core outcome set (COS) is required to reduce heterogeneity in clinical trials and promote the development of high-quality evidence to support clinical management. METHODS:A multi-stage mixed methods study was conducted in accordance with The Core Outcome Set Standards for Development. RESULTS:A systematic review identified 287 sleep outcomes from previous clinical trials. Qualitative interviews ensured the COS was informed by what matters most to people with cognitive impairment and their caregivers. A modified Delphi process identified nine outcomes for the COS: total sleep time, sleep onset latency, wakefulness after sleep onset, number of night-time awakenings, sleep efficiency, and measures of sleep quality, daytime sleepiness, cognition, and mood. DISCUSSION/CONCLUSIONS:This COS will support researchers to produce more reliable and coherent trial data to guide the management of sleep disturbances in people with neurodegenerative cognitive impairment. HIGHLIGHTS/CONCLUSIONS:Evidence is lacking regarding the treatment of sleep disturbances in people with cognitive impairment. Heterogeneity of reported outcomes in clinical trials limits data synthesis. A qualitative analysis established what matters most to people with cognitive impairment and their caregivers when determining treatment effectiveness. A Delphi panel of experts agreed upon a core outcome set. This core outcome set will improve the reliability and comparability of data from future trials.

PURPOSE/OBJECTIVE:As differences in imaging patterns may indicate unnecessary care, this study examined differences in repeat imaging rates between imaging studies interpreted by a nonphysician practitioner (NPP) versus a radiologist. METHODS:This multiyear (2013-2022) retrospective study evaluated imaging performed on Medicare fee-for-service beneficiaries using a CMS Research Identifiable File. Imaging studies, grouped by anatomic region and modality (eg, shoulder radiography [XR]) with ≥30 repeat studies within 90 days for both NPP-interpreted and radiologist-interpreted index studies, were included. Logistic regression was used to assess the likelihood of repeat imaging within 90 days for NPP-interpreted versus radiologist-interpreted index studies, adjusted for patient gender, age, race or ethnicity, comorbidities, urbanicity, and community income. RESULTS:There were 1,397,002 imaging studies that met the selection criteria. Of these, repeat imaging occurred for 12.5%. Unadjusted repeat imaging rates were higher for NPP-interpreted versus radiologist-interpreted imaging for XR (20.4% versus 14.6%), ultrasound (11.6% versus 4.5%), and MR (8.8% versus 3.8%). Adjusted for covariates, the odds ratio (OR) for repeat imaging was higher for NPP-interpreted versus radiologist-interpreted imaging: 1.35 (95% confidence interval [CI]: 1.33-1.37) for XR, 2.41 (95% CI: 2.21-2.63) for ultrasound, and 2.56 (95% CI: 1.81-3.64) for MR. By anatomic region-modality, these ORs ranged from 1.39 (95% CI: 1.34-1.44) for shoulder XR to 3.40 (95% CI: 2.80-4.14) for abdominal ultrasound, but was not significantly different for knee XR (OR: 1.01, 95% CI: 0.99-1.04). CONCLUSION/CONCLUSIONS:Among Medicare beneficiaries, imaging studies are more likely to be repeated when interpreted by a NPP than when interpreted by a radiologist. Potential excess reimaging has implications for unnecessary care.

OBJECTIVE:Personalized approaches to ischemic stroke diagnosis are needed. We determine differences in proteomic signatures of incident embolic (EIS) and thrombotic stroke (TIS) by age and resultant pathways using large-scale proteomics. METHODS:Participants in the Atherosclerosis Risk in Communities Study (ARIC) from visit 2 (V2, 1990-1992) until 2020 without prevalent stroke with available SomaScan data (4,955 protein targets) at V2 (mid-life, n = 10,929), and then again at visit 5 (V5, 2011-2013, n = 4,463) were included. Covariate adjusted Cox hazard models determined the association between proteins, and adjudicated incident EIS or TIS from V2 to V5 and from V5 to 2020. RESULTS:Among 10,929 participants (56% female, 23% Black, follow-up ~20 years), 20 proteins measured in mid-life were associated with either EIS (n = 168) or TIS (n = 459) in mid-life, and 4 measured in late-life were associated with late-life stroke (73 EIS and 124 TIS events) at the Bonferroni threshold p < 1E-5. In mid-life, N-terminal pro-B-type natriuretic peptide (NPPB) was significantly associated with EIS, but not TIS (p-difference = 9.14E-7). Nineteen mid-life proteins were strongly associated with TIS; 7 strongly associated with TIS and only nominally (p < 0.05) with EIS and the remaining 12 with TIS only. In late-life, NPPB, serine protease inhibitor Kazal-type 4, oligodendrocyte-myelin-glycoprotein, and neurocan-core protein were significantly associated with EIS, but not TIS. Ingenuity Pathway Analysis tools implicated cancer for EIS-associated proteins, whereas TIS pathways reflected cell-structure and atherogenesis. INTERPRETATION/CONCLUSIONS:We identified plasma proteins associated with risk of EIS versus TIS reflecting distinct stroke mechanisms: cardiac dysfunction protein in EIS (eg, NPPB) and inflammation dysregulation in TIS (eg, interleukins). ANN NEUROL 2025.

BACKGROUND:Health equity is receiving increased attention in medical education. However, guidance is often lacking on how to integrate health equity into routine medical education. Journal club presents an opportunity to deepen medical educators' and learners' understanding of health equity principles and use it as a lens through which to critically appraise the literature. AIM/OBJECTIVE:We present a health equity framework, iteratively co-created by faculty and learners, that can be applied in a journal club setting. SETTING/METHODS:Academic medical center in New York City, USA. PARTICIPANTS/METHODS:Faculty, residency program directors, medical students, and residents. PROGRAM DESCRIPTION/METHODS:Authors developed the health equity journal club framework during a medical student selective course. Learner and faculty applied the framework to journal club articles; their feedback informed revisions. Framework domains included authorship, ethics, methodology, language, peer review, and references. PROGRAM EVALUATION/RESULTS:Learner evaluations were overall positive, and 86% (n = 13) of responding residency program directors (n = 15) across 15 departments who were surveyed plan to use the framework moving forward. DISCUSSION/CONCLUSIONS:A health equity journal club framework applied to critical appraisal of the literature may facilitate health equity as a routine part of medical education. Co-creating the framework proved vital to inclusion of learner voices.

BACKGROUND:Studies examining the association of chronic kidney disease (CKD) with cancer risk have demonstrated conflicting results. METHODS:This was an individual participant data meta-analysis including 54 international cohorts contributing to the CKD Prognosis Consortium. Included cohorts had data on albuminuria [urine albumin-to-creatinine ratio (ACR)], estimated glomerular filtration rate (eGFR), overall and site-specific cancer incidence, and established risk factors for cancer. Included participants were aged 18 years or older, without previous cancer or kidney failure. RESULTS:Among 1,319,308 individuals, the incidence rate of overall cancer was 17.3 per 1000 person-years. Higher ACR was positively associated with cancer risk [adjusted hazard ratio 1.08 (95% CI 1.06-1.10) per 8-fold increase in ACR]. No association of eGFR with overall cancer risk was seen. For site-specific cancers, lower eGFR was associated with urological cancer and multiple myeloma, whereas higher ACR was associated with many cancer types (kidney, head/neck, colorectal, liver, pancreas, bile duct, stomach, larynx, lung, hemolymphatic, leukaemia, and multiple myeloma). Results were similar in a 1-year landmark analysis. DISCUSSION/CONCLUSIONS:Albuminuria, but not necessarily eGFR, was independently associated with the subsequent risk of cancer. Our results warrant an investigation into mechanisms that explain the link between albuminuria and cancer.

AIMS/OBJECTIVE:To evaluate a previously proposed type 2 diabetes staging schema by examining the decline in oral beta-cell compensation and the increase in diabetes risk. METHODS:We analyzed 1,235 participants (43-85 years) from one ELSA-Brasil center. We defined stages as previously proposed: stage 1, isolated 1-h PG ≥155 mg/dL; stage 2, also having prediabetes/intermediate hyperglycemia (preDM/IH) defined by the American Diabetes Association (ADA); and stage 3, diabetes. We made additional evaluations defining IH based on the World Health Organization (WHO)/International Expert Committee (IEC) criteria. We estimated beta-cell compensation with the insulin secretion-sensitivity index-2 (ISSI-2). RESULTS:ISSI-2 declined (p < 0.001) across stages. After 5.29 (0.44) years (n = 850), the adjusted diabetes incidence increased from stage 0 (normoglycemia) to stage 1 (RR = 2.64;1.12,6.22) and stage 2 (RR = 5.94;2.83,12.44), considering WHO/IEC criteria. With the ADA criteria, RRs were larger but not progressive. Adding 1-h PG testing doubled the detection of unknown diabetes. A strategy combining FPG with 1-h PG performed just as well as using all four tests. CONCLUSIONS:Staging captured progressive deterioration to type 2 diabetes. Adding 1-h PG improved current and future case detection, which represents a major advance in diabetes prevention. However, refinements in staging will require further evaluation of tests and their thresholds.

Children face an urgent threat in the form of hazards posed by plastics in the environment. Despite robust and rapidly accumulating evidence on the effects of plastic on children's health, plastic presents a paradox for child health providers: while plastic is a vehicle for so many interventions, robust evidence from laboratory and human studies show that chemicals used to produce plastics contribute to chronic conditions in multiple organ systems and disrupt hormone function, and exposure to plastic-derived toxins is associated with adverse birth outcomes, metabolic conditions, neurodevelopmental disease and disability, and reproductive conditions. Evidence-based, safe, simple, and low-cost steps exist for child health providers in primary care to help families limit children's exposure to plastic-derived toxins. Health-care providers also have a crucial opportunity to protect the health and wellbeing of future generations of children by supporting local and global campaigns for governments, industries, and the general public to reduce the accumulation of plastics in the environment and minimise the use of plastics within health-care systems.

BACKGROUND:We previously reported that individuals with the Transient receptor potential melastatin 7 (TRPM7) GA/AA genotype and consumed diets high in Ca:Mg ratio had an increased risk of colorectal polyps. OBJECTIVE:The aim was to identify if the gut microbiota plays a role in the association of TRPM7 genotype, Ca:Mg intake ratio and risk of colorectal polyps. METHODS:We analyzed the gut microbiota of 240 participants in a double-blind 2x2 factorial (TRPM7 genotype and Ca:Mg intake ratios) randomized trial by sequencing the stool, rectal swab, and rectal mucosa tissue samples of each participant. RESULTS:The gut microbiota of participants with the GA genotype significantly differed from those with the GG genotype in all three sample types, with an altered abundance of Prevotella and Bacteroides in swab samples. Prevotella in rectal mucosa and Bacteroides in swab were associated with an increased risk of metachronous colorectal polyps. Optimizing high diet Ca:Mg ratios to 2.3 through Mg supplementation resulted in a reduced abundance of Prevotella in rectal swabs and Bacteroides in stool samples. We identified multiple microbes in all three sample types linked to the risk of metachronous colorectal polyps. CONCLUSIONS:Our findings indicate that the gut microbiota in stool, rectal swab and mucosa are associated with the risk of metachronous colorectal polyps, and diet changes could modify the abundance of TRPM7-related microbes. CLINICAL TRIAL REGISTRATION/BACKGROUND:The study was registered as NCT01105169 at ClinicalTrials.gov: https://clinicaltrials.gov/study/NCT01105169.

BACKGROUND:Early life is a critical period for brain development, laying the foundation for cognitive reserve. However, it remains unclear how various aspects of early life independently contribute to dementia risk, and whether these associations are modified by APOE ε4 genotype. PARTICIPANTS AND SETTING/METHODS:We used data from the U.S. Health and Retirement Study (HRS), a nationally representative cohort of older adults, followed from 2006 to 2020. Our sample included 8678 community-dwelling, dementia-free participants aged ≥ 60 and < 90 at baseline with data on APOE genotype and retrospective early life conditions. METHODS:Dementia incidence was classified using the validated Langa-Weir algorithm. Early life risk domains included financial capital, social capital, human capital, adversity, and health conditions. Cause-specific Cox proportional hazards models assessed the associations between these domains and incident dementia, adjusting for demographics and adulthood risk factors. To examine effect modification by genetic risk, we created 4-category group variables combining APOE ε4 status and early life risk. RESULTS:Deficits in financial, social, and human capital, as well as poor childhood health, were each associated with a 12%-46% increased dementia risk, independently of APOE ε4 status. After further adjusting for adulthood risk factors, low social and human capital remained significant predictors (16% and 21% increased risk, respectively). APOE ε4 was associated with an 83%-86% increased risk across all models. In effect modification analyses, early life disadvantage was associated with dementia only among non-carriers of APOE ε4, whereas ε4 carriers had elevated dementia risk regardless of early life conditions. CONCLUSIONS:Inadequate childhood resources may have enduring impacts on dementia risk among individuals without the APOE ε4 allele. Genetic predisposition via APOE ε4 overwhelms the influence of early life disadvantage. These findings underscore the need for dementia prevention strategies that jointly consider genetic vulnerability and early life conditions.