Publications

BACKGROUND: Prospective associations between total and groups of ultra-processed foods (UPF) and cardiovascular disease (CVD) remained to be characterised. Our aim was to assess the association of total and group-specific UPF intakes with CVD, coronary heart disease (CHD), and stroke in three large prospective cohorts of US adults. Additionally, we conducted a systematic review and meta-analyses on the existing evidence on the associations of total UPF intake with these outcomes.

METHODS: UPF intake was assessed through food frequency questionnaires in the Nurses' Health Study (NHS; n = 75,735), Nurses' Health Study II (NHSII; n = 90,813), and Health Professionals Follow-Up Study (HPFS; n = 40,409). Cox regression estimated cohort-specific associations of total and group-specific UPF intake with risk of CVD (cases = 16,800), CHD (cases = 10,401), and stroke (cases = 6758), subsequently pooled through fixed-effect models. Random-effects meta-analyses pooled existing prospective findings on the UPF-CVD association identified on Medline and Embase up to April 5, 2024, without language restrictions. Risk of bias was assessed with the Newcastle-Ottawa Scale, funnel plots, and Egger's tests, and meta-evidence was evaluated using NutriGrade.

FINDINGS: The baseline mean (SD) age was 50.8 years (7.2) for the NHS, 36.7 years (4.6) for the NHSII, and 53.4 years (9.6) for the HPFS. The proportion of participants of White race was 97.7% in the NHS, 96.4% in the NHSII, and 94.9% in the HPFS. Among the three cohorts, multivariable-adjusted hazard ratios [HRs (95% CIs)] for CVD, CHD, and stroke for the highest (vs. lowest) total UPF intake quintile were 1.11 (1.06-1.16), 1.16 (1.09-1.24), and 1.04 (0.96-1.12), respectively. UPF groups demonstrated divergent associations. Sugar-/artificially-sweetened drinks and processed meats were associated with higher CVD risk, whereas inverse associations were observed for bread/cold cereals, yoghurt/dairy desserts, and savoury snacks. Meta-analysing 22 prospective studies showed that total UPF intake at the highest category (vs. lowest) was associated with 17% (11%-24%), 23% (12%-34%), and 9% (3%-15%) higher CVD, CHD, and stroke risk. Meta-evidence quality was high for CHD, moderate for CVD, and low for stroke.

INTERPRETATION: Total UPF intake was adversely associated with CVD and CHD risk in US adults, corroborated by prospective studies from multiple countries, also suggesting a small excess stroke risk. Nutritional advice for cardiovascular health should consider differential consequences of group-specific UPF. Replication is needed in racially/ethnically-diverse populations.

FUNDING: National Institutes of Health (NIH) grants supported the NHS, NHSII, and HPFS.

IMPORTANCE: Limited access to healthy foods, resulting from residence in neighborhoods with low food access, is a public health concern. The contribution of this exposure in early life to child obesity remains uncertain.

OBJECTIVE: To examine associations of neighborhood food access during pregnancy or early childhood with child body mass index (BMI) and obesity risk.

DESIGN, SETTING, AND PARTICIPANTS: Data from cohorts participating in the US nationwide Environmental Influences on Child Health Outcomes consortium between January 1, 1994, and March 31, 2023, were used. Participant inclusion required a geocoded residential address in pregnancy (mean 32.4 gestational weeks) or early childhood (mean 4.3 years) and information on child BMI.

EXPOSURES: Residence in low-income, low-food access neighborhoods, defined as low-income neighborhoods where the nearest supermarket is more than 0.5 miles for urban areas or more than 10 miles for rural areas.

MAIN OUTCOMES AND MEASURES: BMI z score, obesity (age- and sex-specific BMI ≥95th percentile), and severe obesity (age- and sex-specific BMI ≥120% of the 95th percentile) from age 0 to 15 years.

RESULTS: Of 28 359 children (55 cohorts; 14 657 [51.7%] male and 13 702 [48.3%] female; 590 [2.2%] American Indian, Alaska Native, Native Hawaiian, or Other Pacific Islander; 1430 [5.4%] Asian; 4034 [15.3%] Black; 17 730 [67.2%] White; and 2592 [9.8%] other [unspecified] or more than 1 race; 5754 [20.9%] Hispanic and 21 838 [79.1%] non-Hispanic) with neighborhood food access data, 23.2% resided in low-income, low-food access neighborhoods in pregnancy and 24.4% in early childhood. After adjusting for individual sociodemographic characteristics, residence in low-income, low-food access (vs non-low-income, low-food access) neighborhoods in pregnancy was associated with higher BMI z scores at ages 5 years (β, 0.07; 95% CI, 0.03-0.11), 10 years (β, 0.11; 95% CI, 0.06-0.17), and 15 years (β, 0.16; 95% CI, 0.07-0.24); higher obesity risk at 5 years (risk ratio [RR], 1.37; 95% CI, 1.21-1.55), 10 years (RR, 1.71; 95% CI, 1.37-2.12), and 15 years (RR, 2.08; 95% CI, 1.53-2.83); and higher severe obesity risk at 5 years (RR, 1.21; 95% CI, 0.95-1.53), 10 years (RR, 1.54; 95% CI, 1.20-1.99), and 15 years (RR, 1.92; 95% CI, 1.32-2.80). Findings were similar for residence in low-income, low-food access neighborhoods in early childhood. These associations were robust to alternative definitions of low income and low food access and additional adjustment for prenatal characteristics associated with child obesity.

CONCLUSIONS: Residence in low-income, low-food access neighborhoods in early life was associated with higher subsequent child BMI and higher risk of obesity and severe obesity. We encourage future studies to examine whether investments in neighborhood resources to improve food access in early life would prevent child obesity.

INTRODUCTION: Older adults are at high risk of adverse health outcomes in the post-emergency department (ED) discharge period. Prior work has shown that discharged older adults have variable understanding of their discharge instructions which may contribute to these outcomes. To identify discharge comprehension gaps amenable to future interventions, we utilize meta-analysis to determine patient comprehension across five domains of discharge instructions: diagnosis, medications, self-care, routine follow-up, and return precautions.

METHODS: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, two reviewers sourced evidence from databases including Medline (PubMed), EMBASE, Web of Science, CINAHL, and Google Scholar (for gray literature). Publications or preprints appearing before April 2024 were included if they focused on geriatric ED discharge instructions and reported a proportion of patients with comprehension of at least one of five predefined discharge components. Meta-analysis of eligible studies for each component was executed using random-effects modeling to describe the proportion of geriatric ED cases understanding the discharge instructions; where appropriate we calculated pooled estimates, reported as percentages with 95% confidence interval (CI).

RESULTS: Of initial records returned (N = 2898), exclusions based on title or abstract assessment left 51 studies for full-text review; of these, seven constituted the study set. Acceptable heterogeneity and absence of indication of publication bias supported pooled estimates for proportions comprehending instructions on medications (41%, 95% CI 31%-50%, I2 = 43%), self-care (81%, 95% CI 76%-85%, I2 = 43%), and routine follow-up (76%, 95% CI 72%-79%, I2 = 25%). Key findings included marked heterogeneity with respect to comprehending two discharge parameters: diagnosis (I2 = 73%) and return precautions (I2 = 95%).

CONCLUSIONS: Older patients discharged from the ED had greater comprehension of self-care and follow-up instructions than about their medications. These findings suggest that medication instructions may be a priority domain for future interventions.

IMPORTANCE: Chronic back pain (CBP) is a leading cause of disability. Placebo treatments often provide as much pain relief as bona fide treatments, such as steroid injections. Open-label (honestly prescribed) placebos (OLPs) may relieve CBP without deception, but OLP mechanisms remain poorly understood.

OBJECTIVE: To investigate the long-term efficacy and neurobiological mechanisms of OLP for CBP.

DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial of CBP with longitudinal functional magnetic resonance imaging (MRI) comparing OLP with usual care, with 1-year follow-up, was conducted in a university research setting and a community orthopedic clinic. Participants were individuals aged 21 to 70 years with CBP. The trial was conducted from November 2017 to August 2018, with 1-year follow-up completed by November 2019. Data analysis was performed from April 2020 to May 2024. The primary analysis was conducted on an intention-to-treat sample.

INTERVENTIONS: Participants randomized to OLP received a 1-time subcutaneous lumbar saline injection presented as placebo accompanied by information about the power of placebo to relieve pain, alongside their ongoing care. Usual care participants continued their ongoing care.

MAIN OUTCOMES AND MEASURES: The primary outcome was pain intensity (0-10, with 0 indicating no pain and 10 the most intense) at 1 month posttreatment. Secondary outcomes included pain interference, depression, anxiety, anger, and sleep quality. Functional MRI was performed before and after treatment during evoked and spontaneous back pain.

RESULTS: A total of 101 adults (52 [51.4%] females; mean [SD] age, 40.4 [15.4] years) with moderate severity CBP (mean [SD], 4.10 [1.25] intensity; duration, 9.7 [8.5] years) were enrolled. Compared with usual care, OLP reduced CBP intensity posttreatment (relative reduction, 0.61; Hedges g = 0.45; 95% CI, -0.89 to 0.04; P = .02). Through 1-year follow-up, pain relief did not persist, although significant benefits were observed for depression, anger, anxiety, and sleep disruption (Hedges g = 0.3-0.5; all P < .03). Brain responses to evoked back pain for OLP vs usual care increased in rostral anterior cingulate and ventromedial prefrontal cortex and decreased in somatomotor cortices and thalamus. During spontaneous pain, functional connectivity analyses identified OLP vs usual care increases in ventromedial prefrontal cortex connectivity to the rostral ventral medulla, a pain-modulatory brainstem nucleus. No adverse effects of treatment were reported by participants.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of OLP vs usual care, a single nondeceptive placebo injection reduced CBP intensity for 1 month posttreatment and provided benefits lasting for at least 1 year posttreatment. Brain mechanisms of OLP in a clinical population overlap with those of deceptive placebos in healthy volunteers, including engagement of prefrontal-brainstem pain modulatory pathways.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03294148.

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.