Faculty Bibliography

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.

BACKGROUND AND OBJECTIVES/OBJECTIVE:While reductions in optical coherence tomography (OCT) pRNFL and ganglion cell-inner plexiform layer thicknesses have been shown to be associated with brain atrophy in adult-onset MS (AOMS) cohorts, the relationship between OCT and brain MRI measures is less established in pediatric-onset MS (POMS). Our aim was to examine the associations of OCT measures with volumetric MRI in a cohort of patients with POMS to determine whether OCT measures reflect CNS neurodegeneration in this patient population, as is seen in AOMS cohorts. METHODS:This was a cross-sectional study with retrospective ascertainment of patients with POMS evaluated at a single center with expertise in POMS and neuro-ophthalmology. As part of routine clinical care, patients with POMS are evaluated by a POMS expert and undergo volumetric brain MRI, including whole-brain (WB), subregional, and gray matter (GM) volume analyses. Patients with POMS are routinely referred to neuro-ophthalmology for evaluation that includes high-contrast visual acuity, color vision testing, and OCT. Generalized estimating equation (GEE) models, accounting for within-patient, intereye correlations (both eyes of each patient were included), MS disease duration, and disease-modifying therapy efficacy, were used to determine the relationship between visual pathway structure and function and volumetric MRI measures. RESULTS:= 0.015, respectively). DISCUSSION/CONCLUSIONS:Our results demonstrate that changes in visual pathway structures are associated with reductions in overall brain volume and GM volumes, as well as greater lesion and black hole burden. Collectively, our results emphasize the importance of visual assessment in POMS and suggest that OCT reflects overall CNS neurodegeneration in this cohort.

OBJECTIVE:This study examines the differential predictive value of baseline characteristics of clients being treated for an alcohol problem with respect to the development of an Opioid Use Disorder (OUD) or Opioid Overdose (OD) within 1 year, between 1 and 4 years, and beyond 4 years after treatment. METHOD/METHODS:A cohort of 87,172 patients treated for an alcohol use problem within state treatment centers was examined. We extracted the first OUD/OD diagnosis event within 1 year, between 1-4 years, and more than four years of the patient's first OASAS admission. We calculated odds ratios for all predictors and control variables with respect to OUD/OD events and compared the predictive values of these variables for the different periods. RESULTS:Both sociodemographic and clinical factors were predictive of an OUD/OD overall and in most specific follow-up periods. Sociodemographic factors were more strongly associated with OUD/OD during follow-ups beyond 4 years, perhaps due to the increasing availability of opioids over time. Mental health and alcohol use severity factors were more strongly associated with OUD in the 1 year and 1-4 year periods, suggesting a rapid progression to OUD/OD. CONCLUSIONS:Both sociodemographic and clinical factors were predictive of a diagnosis of OUD/OD within a brief period of time, however they were only predictive of approximately 40% of those who would develop OUD/OD within any specific time period. These findings highlight the need for a more formal assessment of opioid use at treatment entry, and for the implementation of harm reduction measures throughout treatment.

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.

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:There is paucity of data on long-term functional and cognitive outcomes after COVID-19 compared to COVID-negative controls. METHODS:We conducted an observational cohort study of patients ≥ 1 year after COVID-19 compared to contemporaneous COVID-19 negative controls (SARS-CoV-2 nucleocapsid IgG negative with no history of COVID-19). Functional (modified Rankin Scale [mRS], Barthel Index), cognitive (telephone MoCA [t-MoCA]), and patient-reported neuropsychiatric symptoms were compared between groups using multivariable logistic regression analysis. In a subgroup of COVID-19 patients who were followed longitudinally, trajectories of recovery were assessed using the paired samples Sign test. RESULTS:Of 145 participants, N = 115 COVID-19 patients (median age 62, 51 % female, 33 % hospitalized for COVID-19, median 2.9 years from index infection), and N = 30 non-COVID-19 controls (median age 75, 70 % female) were enrolled. Neuropsychiatric symptoms were reported in 76 % of COVID-19 patients versus 7 % of controls (aOR 15.0, 95 %CI 3.09-72.47, P < 0.001). Abnormal mRS> 0 occurred in 42 % of COVID-19 patients compared to 11 % of controls (P = 0.002). However, this difference was not significant after adjusting for age, sex, COVID-19 hospitalization and history of mood disorder (aOR 2.10, 95 %CI 0.52-8.51). Rates of abnormal t-MoCA≤ 18 (40 % of COVID-19 versus 41 % of controls, P = 1.00) and Barthel scores< 100 (19 % of COVID-19 versus 14 % in controls, P = 0.785) were similar. Among N = 26 COVID-19 patients with repeated measures, mRS significantly improved between 6-months to 3-years post-COVID (+1.3 points, p = 0.004), while no changes were observed in t-MoCA or Barthel. CONCLUSIONS:Three years after COVID-19, neuropsychiatric symptoms were significantly more frequent compared to controls, however no differences in functional or cognitive status were detected.

RATIONALE/BACKGROUND:Abrupt air quality improvements have followed the closure or dramatic emission control of large air pollution sources. These "natural experiments" provide ideal opportunities to assess the real-world health benefits of air quality improvements. The shutdown of the Shenango coking plant, a significant fossil-fuel pollution source located on an island in the Ohio River near Pittsburgh, PA, presented such an opportunity to test for changes in respiratory health in the local community following the closure. OBJECTIVES/OBJECTIVE:To identify and quantify the immediate and/or longer-term changes in respiratory hospitalizations and emergency department (ED) visits among the population residing near the Shenango coke plant at the time of its closure. METHODS:We acquired data for respiratory hospitalizations and ED visit counts by residents living in zip codes surrounding the plant, as well as at comparison control sites, three years before and after the shutdown date. The immediate and longer-term changes of respiratory health outcomes were tested with an interrupted time series model, and compared with external control sites and internal control outcomes. MEASUREMENTS AND MAIN RESULTS/RESULTS:We found the closure of the Shenango plant was associated with an immediate 20.5% (95% CI: 12.8%-27.6%) decrease for weekly respiratory ED visits, and an immediate 41.2% (95% CI: 14.4%-59.9%) decrease in pediatric asthma ED visits, followed by an additional 4% per month longer-term downward trend. Longer-term reductions, as compared to pre-closure trends, were also observed for chronic obstructive pulmonary disease hospitalizations. CONCLUSIONS:Our study provides strong confirmation that reductions in fossil-fuel-related air pollution produce both short and longer-term respiratory health benefits. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

BACKGROUND:Carnobacterium maltaromaticum and Faecalibacterium prausnitzii induce de novo gut synthesis of vitamin D to inhibit colorectal carcinogenesis in mice. Magnesium (Mg) treatment increases circulating vitamin D and Mg homeostasis is dependent on TRPM7 genotype. OBJECTIVE:We hypothesize that Mg treatment increases gut C. maltaromaticum and F. prausnitzii and the effect differs by TRPM7 polymorphism. METHODS:The Personalized Prevention of Colorectal Cancer Trial is a double-blind, precision-based randomized controlled trial with 240 participants randomized by both treatment and TRPM7 genotype. Stool, rectal swabs, and rectal mucosa were collected. RESULTS:Of 239 participants that completed the trial, 226 with valid microbiome data were analyzed (treatment n=112, placebo n=114). The interaction between treatment and TRPM7 genotype was only significant for C. maltaromaticum (p=0.001) and F. prausnitzii (p=0.02) in rectal swabs. In a stratified analysis by TRPM7 genotype without the missense variant, Mg treatment compared to placebo significantly increased abundance of C. maltaromaticum (0.217±0.615 (23.01%) compared to -0.065±0.588 (-6.30%); P=0.006) and F. prausnitzii (0.105±0.817 (2.13%) compared to -0.095±0.856 (-1.92%); P =0.04) in rectal swabs. The effect on C. maltaromaticum remained after multiple comparisons (Q=0.05 for C. maltaromaticum across all sample types and genotypes). In those with the TRPM7 missense variant, Mg decreased C. maltaromaticum, but not F. prausnitzii, compared to placebo in rectal swabs (-0.065±0.511 (-6.54%) compared to 0.133±0.503 (13.30%); adjusted P=0.04). The effect did not remain after FDR correction. Mg treatment's effect on C. maltaromaticum in rectal swabs primarily appeared in females, and the treatment-genotype interaction remained significant. CONCLUSION/CONCLUSIONS:In individuals with adequate TRPM7 function, Mg supplementation increases abundance of C. maltaromaticum and F. prausnitzii. CLINICAL TRIAL REGISTRY/BACKGROUND:This trial was registered on ClinicalTrials.gov as NCT04229992 (https://clinicaltrials.gov/study/NCT04229992?term=NCT04229992&rank=1). The parent study is registered as NCT03265483, and another relevant study is registered as NCT01105169.