Publications

Neurofilament light chain (NfL) levels in circulation have been established as a sensitive biomarker of neuro-axonal damage across a range of neurodegenerative disorders. Elucidation of the genetic architecture of blood NfL levels could provide new insights into molecular mechanisms underlying neurodegenerative disorders. In this meta-analysis of genome-wide association studies (GWAS) of blood NfL levels from eleven cohorts of European ancestry, we identify two genome-wide significant loci at 16p12 (UMOD) and 17q24 (SLC39A11). We observe association of three loci at 1q43 (FMN2), 12q14, and 12q21 with blood NfL levels in the meta-analysis of African-American ancestry. In the trans-ethnic meta-analysis, we identify three additional genome-wide significant loci at 1p32 (FGGY), 6q14 (TBX18), and 4q21. In the post-GWAS analyses, we observe the association of higher NfL polygenic risk score with increased plasma levels of total-tau, Aβ-40, Aβ-42, and higher incidence of Alzheimer's disease in the Rotterdam Study. Furthermore, Mendelian randomization analysis results suggest that a lower kidney function could cause higher blood NfL levels. This study uncovers multiple genetic loci of blood NfL levels, highlighting the genes related to molecular mechanism of neurodegeneration.

The neurobiological mechanisms underlying the placebo phenomenon in patients with major depressive disorder (MDD) remain largely unknown. The progressive rise in rates of placebo responses within clinical trials over the past two decades may impede the detection of a true signal and thus present a major obstacle in new treatment development. Understanding the mechanisms would have several important implications, including (1) identifying biomarkers of placebo responders (thereby identifying those individuals who could benefit therapeutically from such interventions), (2) opening new avenues for manipulating such mechanisms to maximize symptom reduction, and (3) refining treatments with approaches that decrease (in clinical trials) or increase (in clinical practice) the placebo response. Here we investigated the research question: is the dopaminergic system one of the neurobiological underpinnings of the placebo response within MDD? Inspired by preclinical and clinical findings that have implicated dopamine in the occurrence, prediction, and expectation of reward, we hypothesized that dopaminergic activity in the mesolimbic system is a critical mediator of placebo response in MDD. To test this hypothesis, we designed a double-blind, placebo-controlled, sequential parallel comparison design clinical trial aimed at maximizing placebo antidepressant response. We integrated behavioral, imaging, and hemodynamic probes of mesocorticolimbic dopaminergic pathways within the context of manipulations of psychological constructs previously linked to placebo responses (e.g., expectation of improvement). The aim of this manuscript is to present the rationale of the study design and to demonstrate how a cross-modal methodology may be utilized to investigate the role of reward circuitry in placebo response in MDD.

BACKGROUND: Chronic kidney disease (CKD) increases morbidity and mortality in most vascular procedures. However, a binary classification of estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, which is often used in both modeling and clinical trials, may not be optimal for predicting clinical outcomes.

OBJECTIVE: Determine the optimal eGFR cutoff for use in risk stratification and prediction models.

METHODS: Vascular Quality Initiative (VQI) data for non-emergent, first-time OAR, EVAR, TEVAR, CEA, CAS, PVI, Supra- and infra-inguinal bypass were analyzed from to 2013-2023 and divided into cohorts based on eGFR (≥60, 45-59, 30-44, <30, and preoperative dialysis). χ2 and logistic regression were used to evaluate perioperative outcomes.

RESULTS: Compared to patients with eGFR ≥60, those with eGFR 45-59 had similar odds of mortality following all procedures, except TEVAR. Driven by this group, the combined cohort showed a slight increase in the odds of mortality for eGFR 45-59 (0.6% vs. 0.7%, aOR 1.16, P=0.002). Those in the 30-44 group demonstrated increased odds of mortality both overall and in the individual procedure groups (0.6% vs. 1.2%, aOR 1.78, P<0.001). The odds of mortality continued to increase with worsening eGFR. The overall rate of new permanent dialysis was low for all eGFR cohorts, with a 0.02% difference between those with eGFR >60 and those in the 45-59 cohort (0.04% vs. 0.06%; a OR 1.65, P<0.001). The odds of permanent dialysis likewise continued to increase with decreasing eGFR.

CONCLUSIONS: Rather than a binary eGFR cutoff of ≥60 and <60 to stratify patient risk, better risk stratification may be achieved by using five groups of ≥60, 45-59, 30-44, <30, and preoperative dialysis.

BACKGROUND: Type 2 diabetes mellitus and lower weight are both associated with osteoporotic fractures, but the roles of variability and trajectory are less clear.1 The associations of these factors among older adults with dysglycemia, who are at highest risk of fracture, with fracture risk and bone mineral density (BMD) remains uncertain.

METHODS: We followed 775 men and 1080 women from the Cardiovascular Health Study (mean age 77.4 years) with abnormal oral glucose tolerance testing in 1989-1990. We measured their weights yearly through 1994-1995 and derived intra-individual mean weight, weight slope, and weight variability. We also used growth mixture modelling to derive four latent body-mass index trajectories over time. We used Cox proportional hazards models to calculate hazard ratios (HR) and 95% confidence intervals (CI) for subsequent hip fracture through 2015 and linear regression models to estimate cross-sectional associations with bone mineral density (BMD) of the hip.

RESULTS: Each 10 kg higher mean weight was associated with a lower risk of subsequent hip fracture overall (HR 0.81; CI 0.70-0.94) and among women (HR 0.76; CI 0.64-0.91) and with higher BMD (P-value <0.001). Higher weight variability was directly associated with incident hip fracture among women (HR 1.18; CI: 1.03-1.35). Compared with a stable trajectory, a "progressive overweight" trajectory was associated with lower risk of hip fracture (HR 0.66; CI: 0.44-0.99). An uncommon trajectory of "accelerating obesity" was associated with higher BMD.

CONCLUSIONS: Among older adults with dysglycemia at high risk for fracture, lower mean weight is associated with higher fracture risk, but variability and trajectory may also contribute. These results highlight the complex effects of weight in older age.

BACKGROUND: Preliminary evidence suggests that Qigong (QG), a mind-body therapy, may help address symptoms of multiple sclerosis (MS), but the heterogeneity of QG content and delivery may affect its feasibility, acceptability, and efficacy.

OBJECTIVE: To survey researchers, clinicians, and QG instructors with experience working with people with MS to identify key components of MS-specific QG guidelines and protocols.

METHODS: We conducted an online survey to identify QG forms and movements considered helpful for MS, reasons for selection, characteristics of effective learning environments, and recommended dosage and frequency of practice. Quantitative data were analyzed using summary statistics. Qualitative data were analyzed using reflexive thematic analysis.

RESULTS: Forty-seven experts, including QG instructors, clinicians, and QG and MS researchers, completed the survey. Respondents had a mean (SD) of 20 (11) years of QG teaching experience, 26 (12) years of clinical practice, 24 (9) years of QG research experience, 13 (5) years of MS research experience, and worked with at least 3 (2) people with MS. Approximately 125 QG forms/movements were recommended. Some forms were specifically recommended to address MS symptoms (e.g., emotional regulation, balance and coordination, muscle strength and flexibility, immune regulation, and circulation). Some respondents felt that any QG form could be beneficial if basic principles were met (e.g., intentional movement, posture, focused awareness, rhythmic breathing/movement, and a relaxed mind and body). Instructor qualities included the ability to convey information clearly, being caring and compassionate, proficient in QG, and having basic knowledge of MS. To promote confidence in learning QG, recommendations included having simple, easy-to-learn movements with modifications based on physical ability. We provide a sample protocol based on these recommendations.

CONCLUSIONS: This study provides expert guidance for developing a QG protocol for an MS population, including content and delivery recommendations.

BACKGROUND: High rates of physical inactivity persist in the United States, with higher rates among non-Hispanic Black adults than among their White peers. However, a comparison of physical activity engagement across nativity among Black adults in the United States has yet to be fully documented. The purpose of this cross-sectional study was to examine physical activity engagement rates among African immigrant and Afro-Caribbean immigrant adults compared with native-born African American adults using data from the 2010 to 2018 National Health Interview Survey.

METHODS: Using data from the 2010 to 2018 National Health Interview Survey, we used generalized linear models to compare levels of physical activity (meeting the moderate-to-vigorous physical activity [MVPA] recommendations) by ethnic subgroups of Black adults, sequentially adjusting for sociodemographic and health-related risk factors.

RESULTS: Data from 38,037 adults (58.8% female, 21% college/graduate degree, and 41.4% with obesity) were included. Only 41.9% of all participants met the MVPA recommendations. In the fully adjusted models across the 9 years, higher levels of MVPA were seen among African Americans (42%) than among African immigrants (38%) and Afro-Caribbean immigrants (41%). Compared with African Americans, African immigrants were less likely to engage in physical activity that met the MVPA guidelines (prevalence ratio: 0.90; 95% confidence interval: 0.85, 0.96), whereas there were no differences in meeting the guidelines between Afro-Caribbean immigrants (prevalence ratio: 0.96; 95% confidence interval:0.90, 1.02) and African Americans.

CONCLUSION: Culturally tailored interventions addressing socioenvironmental barriers and facilitators of physical activity may have important impacts on physical activity promotion and long-term disease burden among Black adults across nativity.

Scandinavian electronic health-care registers provide a unique setting to investigate potential unidentified side effects of drugs. We analysed the association between prescription drugs dispensed in Norway and Sweden and the short-term risk of developing pulmonary embolism. A total of 12,104 pulmonary embolism cases were identified from patient- and cause-of-death registries in Norway (2004-2014) and 36,088 in Sweden (2005-2014). A case-crossover design was used to compare individual drugs dispensed 1-30 days before the date of pulmonary embolism diagnosis with dispensation in a 61-90 day time-window, while controlling for the receipt of other drugs. A BOLASSO approach was used to select drugs that were associated with short-term risk of pulmonary embolism. Thirty-eight drugs were associated with pulmonary embolism in the combined analysis of the Norwegian and Swedish data. Drugs associated with increased risk of pulmonary embolism included certain proton-pump inhibitors, antibiotics, antithrombotics, vasodilators, furosemide, anti-varicose medications, corticosteroids, immunostimulants (pegfilgrastim), opioids, analgesics, anxiolytics, antidepressants, antiprotozoals, and drugs for cough and colds. Mineral supplements, hydrochlorothiazide and potassium-sparing agents, beta-blockers, angiotensin 2 receptor blockers, statins, and methotrexate were associated with lower risk. Most associations persisted, and several additional drugs were associated, with pulmonary embolism when using a longer time window of 90 days instead of 30 days. These results provide exploratory, pharmacopeia-wide evidence of medications that may increase or decrease the risk of pulmonary embolism. Some of these findings were expected based on the drugs' indications, while others are novel and require further study as potentially modifiable precipitants of pulmonary embolism.

BACKGROUND: Persons with multiple chronic conditions face complex medical regimens and clinicians may not focus on what matters most to these patients who vary widely in their health priorities. Patient Priorities Care is a facilitator-led process designed to identify patients' priorities and align decision-making and care, but the need for a facilitator has limited its widespread adoption.

OBJECTIVE: The aims of this study are to design and test mechanisms for patients to complete a self-directed process for identifying priorities and providing their priorities to clinicians.

METHODS: The study involved patients of at least 65 years of age at 2 family medicine practices with 5 physicians each. We first tested 2 versions of an interactive website and asked patients to bring their results to their visit. We then tested an Epic previsit questionnaire derived from the website's questions and included standard previsit materials. We completed postintervention phone interviews and an online survey with participating patients and collected informal feedback and conducted a focus group with participating physicians.

RESULTS: In the test of the first website version, 17.3% (35/202) of invited patients went to the website, 11.4% (23/202) completed all of the questions, 2.5% (5/202) brought results to their visits, and the median session time was 43.0 (IQR 28.0) minutes. Patients expressed confusion about bringing results to the visit. After clarifying that issue in the second version, 15.1% (32/212) of patients went to the website, 14.6% (31/212) completed the questions, 1.9% (4/212) brought results to the visit, and the median session time was 35.0 (IQR 35.0) minutes. In the test of the Epic questionnaire, 26.4% (198/750) of patients completed the questionnaire before at least 1 visit, and the median completion time was 14.0 (IQR 23.0) minutes. The 8 main questions were answered 62.9% (129/205) to 95.6% (196/205) of the time. Patients who completed questionnaires were younger than those who did not (72.3 vs 76.1 years) and were more likely to complete at least 1 of their other assigned questionnaires (99.5%, 197/198) than those who did not (10.3%, 57/552). A total of 140 of 198 (70.7%) patients responded to a survey, and 86 remembered completing the questionnaire; 78 (90.7%) did not remember having difficulty answering the questions and 57 (68.7%) agreed or somewhat agreed that it helped them and their clinicians to understand their priorities. Doctors noted that the sickest patients did not complete the questionnaire and that the discussion provided a good segue into end-of-life care.

CONCLUSIONS: Embedding questionnaires assaying patient priorities into patient portals holds promise for expanding access to priorities-concordant care.

Preoperative risk biomarkers for delirium may aid in identifying high-risk patients and developing intervention therapies, which would minimize the health and economic burden of postoperative delirium. Previous studies have typically used single omics approaches to identify such biomarkers. Preoperative cerebrospinal fluid (CSF) from the Healthier Postoperative Recovery study of adults ≥ 63 years old undergoing elective major orthopedic surgery was used in a matched pair delirium case-no delirium control design. We performed metabolomics and lipidomics, which were combined with our previously reported proteomics results on the same samples. Differential expression, clustering, classification, and systems biology analyses were applied to individual and combined omics datasets. Probabilistic graph models were used to identify an integrated multi-omics interaction network, which included clusters of heterogeneous omics interactions among lipids, metabolites, and proteins. The combined multi-omics signature of 25 molecules attained an AUC of 0.96 [95% CI: 0.85-1.00], showing improvement over individual omics-based classification. We conclude that multi-omics integration of preoperative CSF identifies potential risk markers for delirium and generates new insights into the complex pathways associated with delirium. With future validation, this hypotheses-generating study may serve to build robust biomarkers for delirium and improve our understanding of its pathophysiology.