Planetary Health Diet Index and risk of total and cause-specific mortality in three prospective cohorts.

BACKGROUND: In 2019, the EAT-Lancet Commission proposed a healthy dietary pattern that, along with reductions in food waste and improved agricultural practices, could feed the increasing global population sustainably. We developed a Planetary Health Diet Index (PHDI) to quantify adherence to the EAT-Lancet reference diet. OBJECTIVES: We aimed to assess associations between PHDI and total and cause-specific mortality in 3 prospective cohorts of males and females in the United States. METHODS: We followed 66,692 females from the Nurses' Health Study (1986-2019), 92,438 females from the Nurses' Health Study II (1989-2019), and 47,274 males from the Health Professionals Follow-up Study (1986-2018) who were free of cancer, diabetes, and major cardiovascular diseases at baseline. The PHDI was calculated every 4 y using a semiquantitative food frequency questionnaire. Hazard ratios (HRs) were calculated using multivariable proportional-hazards models. RESULTS: During follow-up, we documented 31,330 deaths among females and 23,206 among males. When comparing the highest with the lowest quintile of PHDI, the pooled multivariable-adjusted HRs were 0.77 [95% confidence interval (CI): 0.75, 0.80] for all-cause mortality (P-trend < 0.0001). The PHDI was associated with lower risk of deaths from cardiovascular diseases (HR: 0.86; 95% CI: 0.81, 0.91), cancer (HR: 0.90; 95% CI: 0.85, 0.95), respiratory diseases (HR: 0.53; 95% CI: 0.48, 0.59), and neurodegenerative diseases (HR: 0.72; 95% CI: 0.67, 0.78). In females, but not males, the PHDI was also significantly associated with a lower risk of deaths from infectious diseases (HR: 0.62; 95% CI: 0.51, 0.76). PHDI scores were also associated inversely with greenhouse gas emissions and other environmental impacts. CONCLUSIONS: In 3 large United States-based prospective cohorts of males and females with up to 34 y of follow-up, a higher PHDI was associated with lower risk of total and cause-specific mortality and environment impacts.

Sedentary Behaviors, Light-Intensity Physical Activity, and Healthy Aging.

Importance: Sleep duration and moderate-to-vigorous physical activity (MVPA) are associated with healthy aging, but the associations of sedentary behaviors and light-intensity physical activity (LPA) with healthy aging are still unclear. Objective: To examine the independent association of sedentary behaviors and LPA with healthy aging, and to estimate the theoretical association of replacing sedentary behavior with LPA, MVPA, or sleep with healthy aging. Design, Setting, and Participants: In this cohort study using data from the Nurses' Health Study, participants aged 50 years or older and free of major chronic diseases in 1992 were prospectively followed up for 20 years. Data were analyzed from January to May 2022. Exposures: Three measures for sedentary behaviors (hours watching television, sitting at work, and other sitting at home) and 2 measures for LPA (hours of standing or walking around at home [LPA-Home] and at work [LPA-Work]). Main Outcomes and Measures: Healthy aging was defined as survival to at least age 70 years with maintenance of 4 health domains (ie, no major chronic diseases and no impairment in subjective memory, physical function, or mental health). The isotemporal substitution model was used to evaluate the potential impact on healthy aging of replacing 1 hour of 1 behavior with equivalent duration of another. Results: Among 45 176 participants (mean [SD] age, 59.2 [6.0] years), 3873 (8.6%) women achieved healthy aging. After adjustment for covariates including MVPA, each increment of 2 hours per day in sitting watching television was associated with a 12% (95% CI, 7%-17%) reduction in the odds of healthy aging. In contrast, each increase of 2 hours per day in LPA-Work was associated with a 6% (95% CI, 3%-9%) increase in the odds of healthy aging. Replacing 1 hour of sitting watching television with LPA-Home (OR, 1.08; 95% CI, 1.05-1.12), LPA-Work (OR, 1.10; 95% CI, 1.07-1.14), or MVPA (OR, 1.28; 95% CI, 1.23-1.34) was associated with increased odds of healthy aging. Among participants who slept 7 hours per day or less, replacing television time with sleep was also associated with increased odds of healthy aging. Conclusions and Relevance: In this cohort study, longer television watching time decreased odds of healthy aging, whereas LPA and MVPA increased odds of healthy aging and replacing sitting watching television with LPA or MVPA, or with sleep in those who slept 7 hours per day or less, was associated with increased odds of healthy aging, providing evidence for rearranging 24-hour behavior to promote overall health.

The biodistribution of triamcinolone acetonide injections in severe keloids: an exploratory three-dimensional fluorescent cryomicrotome study.

Intralesional corticosteroid injections are a first-line treatment for keloids; yet clinical treatment results are highly variable and often suboptimal. Variation in triamcinolone acetonide (TAC) biodistribution may be an important reason for the variable effects of TAC treatment in keloids. In this exploratory study we investigated the biodistribution of TAC in keloids and normal skin using different drug delivery techniques. Fluorescent-labeled TAC suspension was administered into keloids and normal skin with a hypodermic needle and an electronic pneumatic jet injector. TAC biodistribution was represented by the fluorescent TAC volume and 3D biodistribution shape of TAC, using a 3D-Fluorescence-Imaging Cryomicrotome System. Twenty-one keloid and nine normal skin samples were analyzed. With needle injections, the mean fluorescent TAC volumes were 990 µl ± 479 in keloids and 872 µl ± 227 in normal skin. With the jet injector, the mean fluorescent TAC volumes were 401 µl ± 252 in keloids and 249 µl ± 67 in normal skin. 3D biodistribution shapes of TAC were highly variable in keloids and normal skin. In conclusion, TAC biodistribution in keloids is highly variable for both needle and jet injection. This may partly explain the variable treatment effects of intralesional TAC in keloids. Future research is needed to confirm this preliminary finding and to optimize drug delivery in keloids.

A simple light path modifying device to reduce scattering in front-face fluorescence spectra.

This technical note presents a device to diminish scattering signal in front-face fluorescence spectra while obtaining fluorescence signal. The beam path in a commercial fluorescence spectrometer was modified by two deflecting mirrors, leading reflections away from the sensor. This light path modifying (LPM) device was tested with two fluid and three solid substances, where the scattering-to-fluorescence ratio improved by a factor of 1.7 to 7.6. The spectra obtained with the LPM were much clearer, and distortion of the fluorescence peaks was avoided. Scans of quinine sulphate complied well with reference spectra.

Strain-specific gut microbial signatures in type 2 diabetes identified in a cross-cohort analysis of 8,117 metagenomes.

The association of gut microbial features with type 2 diabetes (T2D) has been inconsistent due in part to the complexity of this disease and variation in study design. Even in cases in which individual microbial species have been associated with T2D, mechanisms have been unable to be attributed to these associations based on specific microbial strains. We conducted a comprehensive study of the T2D microbiome, analyzing 8,117 shotgun metagenomes from 10 cohorts of individuals with T2D, prediabetes, and normoglycemic status in the United States, Europe, Israel and China. Dysbiosis in 19 phylogenetically diverse species was associated with T2D (false discovery rate < 0.10), for example, enriched Clostridium bolteae and depleted Butyrivibrio crossotus. These microorganisms also contributed to community-level functional changes potentially underlying T2D pathogenesis, for example, perturbations in glucose metabolism. Our study identifies within-species phylogenetic diversity for strains of 27 species that explain inter-individual differences in T2D risk, such as Eubacterium rectale. In some cases, these were explained by strain-specific gene carriage, including loci involved in various mechanisms of horizontal gene transfer and novel biological processes underlying metabolic risk, for example, quorum sensing. In summary, our study provides robust cross-cohort microbial signatures in a strain-resolved manner and offers new mechanistic insights into T2D.

Intraoperative characterization of cardiac tissue: the potential of light scattering spectroscopy.

Significance: Damage to the cardiac conduction system remains one of the most significant risks associated with surgical interventions to correct congenital heart disease. This work demonstrates how light-scattering spectroscopy (LSS) can be used to non-destructively characterize cardiac tissue regions. Aim: To present an approach for associating tissue composition information with location-specific LSS data and further evaluate an LSS and machine learning system as a method for non-destructive tissue characterization. Approach: A custom LSS probe was used to gather spectral data from locations across 14 excised human pediatric nodal tissue samples (8 sinus nodes, 6 atrioventricular nodes). The LSS spectra were used to train linear and neural-network-based regressor models to predict tissue composition characteristics derived from the 3D models. Results: Nodal tissue region nuclear densities were reported. A linear model trained to regress nuclear density from spectra achieved a prediction r-squared of 0.64 and a concordance correlation coefficient of 0.78. Conclusions: These methods build on previous studies suggesting that LSS measurements combined with machine learning signal processing can provide clinically relevant cardiac tissue composition.

Real-World Experience With Avacopan in Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis.

Introduction: Postmarketing data on outcomes of avacopan use in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) are lacking. Methods: We performed a multicenter retrospective analysis of 92 patients with newly diagnosed or relapsing AAV who received therapy with avacopan. The coprimary outcome measures were clinical remission at 26 and 52 weeks. We use descriptive statistics and univariate logistic regression to assess outcomes and predictors of remission, respectively. Results: Of the 92 patients, 23% (n = 21) had a baseline estimated glomerular filtration rate (eGFR) < 15 ml/min per 1.73 m2 and 10% on kidney replacement therapy at baseline. Among those with kidney involvement, mean (SD) enrollment eGFR was 33 (27) ml/min per 1.73 m2 with a mean (SD) change of +12 (25) and +20 (23) ml/min per 1.73 m2 at weeks 26 and 52, respectively. In addition to avacopan, 47% of patients received combination therapy of rituximab and low-dose cyclophosphamide, and 14% of patients received plasma exchange (PLEX). After induction, the median (interquartile range [IQR]) time to start avacopan was 3.6 (2.1-7.7) weeks, and the median time to discontinue prednisone after starting avacopan was 5.6 (3.3-9.5) weeks. Clinical remission was achieved in 90% of patients at week 26 and 84% of patients at week 52. Of the patients, 20% stopped avacopan due to adverse events, with the most common being elevated serum aminotransferases (4.3%). Conclusion: A high rate of remission and an acceptable safety profile were observed with the use of avacopan in the treatment of AAV in this postmarketing analysis, including the populations excluded from the ADVOCATE trial.

Altered proteome profiles related to visceral adiposity may mediate the favorable effect of green Mediterranean diet: the DIRECT-PLUS trial.

OBJECTIVE: The objective of this study was to explore the effects of a green Mediterranean (green-MED) diet, which is high in dietary polyphenols and green plant-based protein and low in red/processed meat, on cardiovascular disease and inflammation-related circulating proteins and their associations with cardiometabolic risk parameters. METHODS: In the 18-month weight loss trial Dietary Intervention Randomized Controlled Trial Polyphenols Unprocessed Study (DIRECT-PLUS), 294 participants with abdominal obesity were randomized to basic healthy dietary guidelines, Mediterranean (MED), or green-MED diets. Both isocaloric MED diet groups consumed walnuts (28 g/day), and the green-MED diet group also consumed green tea (3-4 cups/day) and green shakes (Mankai plant shake, 500 mL/day) and avoided red/processed meat. Proteome panels were measured at three time points using Olink CVDII. RESULTS: At baseline, a dominant protein cluster was significantly related to higher phenotypic cardiometabolic risk parameters, with the strongest associations attributed to magnetic resonance imaging-assessed visceral adiposity (false discovery rate of 5%). Overall, after 6 months of intervention, both the MED and green-MED diets induced improvements in cardiovascular disease and proinflammatory risk proteins (p < 0.05, vs. healthy dietary guidelines), with the green-MED diet leading to more pronounced beneficial changes, largely driven by dominant proinflammatory proteins (IL-1 receptor antagonist protein, IL-16, IL-18, thrombospondin-2, leptin, prostasin, galectin-9, and fibroblast growth factor 21; adjusted for age, sex, and weight loss; p < 0.05). After 18 months, proteomics cluster changes presented the strongest correlations with visceral adiposity reduction. CONCLUSIONS: Proteomics clusters may enhance our understanding of the favorable effect of a green-MED diet that is enriched with polyphenols and low in red/processed meat on visceral adiposity and cardiometabolic risk.

Consumption of Olive Oil and Diet Quality and Risk of Dementia-Related Death.

Importance: Age-standardized dementia mortality rates are on the rise. Whether long-term consumption of olive oil and diet quality are associated with dementia-related death is unknown. Objective: To examine the association of olive oil intake with the subsequent risk of dementia-related death and assess the joint association with diet quality and substitution for other fats. Design, Setting, and Participants: This prospective cohort study examined data from the Nurses' Health Study (NHS; 1990-2018) and Health Professionals Follow-Up Study (HPFS; 1990-2018). The population included women from the NHS and men from the HPFS who were free of cardiovascular disease and cancer at baseline. Data were analyzed from May 2022 to July 2023. Exposures: Olive oil intake was assessed every 4 years using a food frequency questionnaire and categorized as (1) never or less than once per month, (2) greater than 0 to less than or equal to 4.5 g/d, (3) greater than 4.5 g/d to less than or equal to 7 g/d, and (4) greater than 7 g/d. Diet quality was based on the Alternative Healthy Eating Index and Mediterranean Diet score. Main Outcome and Measure: Dementia death was ascertained from death records. Multivariable Cox proportional hazards regressions were used to estimate hazard ratios (HRs) and 95% CIs adjusted for confounders including genetic, sociodemographic, and lifestyle factors. Results: Of 92 383 participants, 60 582 (65.6%) were women and the mean (SD) age was 56.4 (8.0) years. During 28 years of follow-up (2 183 095 person-years), 4751 dementia-related deaths occurred. Individuals who were homozygous for the apolipoprotein ε4 (APOE ε4) allele were 5 to 9 times more likely to die with dementia. Consuming at least 7 g/d of olive oil was associated with a 28% lower risk of dementia-related death (adjusted pooled HR, 0.72 [95% CI, 0.64-0.81]) compared with never or rarely consuming olive oil (P for trend < .001); results were consistent after further adjustment for APOE ε4. No interaction by diet quality scores was found. In modeled substitution analyses, replacing 5 g/d of margarine and mayonnaise with the equivalent amount of olive oil was associated with an 8% (95% CI, 4%-12%) to 14% (95% CI, 7%-20%) lower risk of dementia mortality. Substitutions for other vegetable oils or butter were not significant. Conclusions and Relevance: In US adults, higher olive oil intake was associated with a lower risk of dementia-related mortality, irrespective of diet quality. Beyond heart health, the findings extend the current dietary recommendations of choosing olive oil and other vegetable oils for cognitive-related health.

Discovery and validation of plasma, saliva and multi-fluid plasma-saliva metabolomic scores predicting insulin resistance and diabetes progression or regression among Puerto Rican adults.

AIMS/HYPOTHESIS: Many studies have examined the relationship between plasma metabolites and type 2 diabetes progression, but few have explored saliva and multi-fluid metabolites. METHODS: We used LC/MS to measure plasma (n=1051) and saliva (n=635) metabolites among Puerto Rican adults from the San Juan Overweight Adults Longitudinal Study. We used elastic net regression to identify plasma, saliva and multi-fluid plasma-saliva metabolomic scores predicting baseline HOMA-IR in a training set (n=509) and validated these scores in a testing set (n=340). We used multivariable Cox proportional hazards models to estimate HRs for the association of baseline metabolomic scores predicting insulin resistance with incident type 2 diabetes (n=54) and prediabetes (characterised by impaired glucose tolerance, impaired fasting glucose and/or high HbA1c) (n=130) at 3 years, along with regression from prediabetes to normoglycaemia (n=122), adjusting for traditional diabetes-related risk factors. RESULTS: Plasma, saliva and multi-fluid plasma-saliva metabolomic scores predicting insulin resistance included highly weighted metabolites from fructose, tyrosine, lipid and amino acid metabolism. Each SD increase in the plasma (HR 1.99 [95% CI 1.18, 3.38]; p=0.01) and multi-fluid (1.80 [1.06, 3.07]; p=0.03) metabolomic scores was associated with higher risk of type 2 diabetes. The saliva metabolomic score was associated with incident prediabetes (1.48 [1.17, 1.86]; p=0.001). All three metabolomic scores were significantly associated with lower likelihood of regressing from prediabetes to normoglycaemia in models adjusting for adiposity (HRs 0.72 for plasma, 0.78 for saliva and 0.72 for multi-fluid), but associations were attenuated when adjusting for lipid and glycaemic measures. CONCLUSIONS/INTERPRETATION: The plasma metabolomic score predicting insulin resistance was more strongly associated with incident type 2 diabetes than the saliva metabolomic score. Only the saliva metabolomic score was associated with incident prediabetes.

24-h urinary sodium and potassium excretions, plasma metabolomic profiles, and cardiometabolic biomarkers in the United States adults: a cross-sectional study.

BACKGROUND: High-sodium and low-potassium intakes are associated with a higher risk of hypertension and cardiovascular disease, but there are limited data on the circulating metabolomics profiles of 24-h urinary sodium and potassium excretions in free-living individuals. OBJECTIVES: We aimed to characterize the metabolomics signatures of a high-sodium and low-potassium diet in a cross-sectional study. METHODS: In 1028 healthy older adults from the Women's and Men's Lifestyle Validation Studies, we investigated the association of habitual sodium and potassium intakes measured by 2 to 4 24-h urine samples with plasma metabolites (quantified using liquid chromatography-tandem mass spectrometry) and metabolomic pathways. Our primary exposures were energy-adjusted 24-h urinary sodium excretion, potassium excretion, and sodium-to-potassium ratio, calculated based on energy expenditure derived from the doubly labeled water method. We then assessed the partial correlations of their metabolomics scores, derived from elastic net regressions, with cardiometabolic biomarkers. RESULTS: Higher sodium excretion was associated with 38 metabolites including higher piperine, phosphatidylethanolamine, and C5:1 carnitine. In pathway analysis, higher sodium excretion was associated with enhanced biotin and propanoate metabolism and enhanced degradation of lysine and branched-chain amino acids (BCAAs). Metabolites associated with higher potassium and lower sodium-to-potassium ratio included quinic acid and proline-betaine. After adjusting for confounding factors, the metabolomics score for sodium-to-potassium ratio positively correlated with fasting insulin (Spearman's rank correlation coefficient ρ = 0.27), C-peptide (ρ = 0.30), and triglyceride (ρ = 0.46), and negatively with adiponectin (ρ = -0.40), and high-density lipoprotein cholesterol (ρ = -0.42). CONCLUSIONS: We discovered metabolites and metabolomics pathways associated with a high-sodium diet, including metabolites related to biotin, propanoate, lysine, and BCAA pathways. The metabolomics signature for a higher sodium low-potassium diet is associated with multiple components of elevated cardiometabolic risk.

Calibration of citrus intake assessed by food frequency questionnaires using urinary proline betaine in an observational study setting.

BACKGROUND: Whether observational study can be employed to establish calibration equations for self-reported dietary intake using food biomarkers is unknown. OBJECTIVES: This study aims to demonstrate the feasibility of obtaining calibration equations based on food biomarkers and 7-d diet records (7DDRs) to correct measurement errors of food frequency questionnaires (FFQs) in an observational study setting. METHODS: The study population consisted of 669 males and 749 females from the Women's and Men's Lifestyle Validation Studies. In the training set, the biomarker-predicted intake derived by regressing 7DDR-assessed intake on urinary proline betaine concentration was regressed on the FFQ-assessed intake to obtain the calibration equations. The regression coefficients were applied to the test set to calculate the calibrated FFQ intake. We examined total citrus as well as individual citrus fruits/beverages. RESULTS: Urinary proline betaine was moderately correlated with orange juice intake (Pearson correlation [r] = 0.53 for 7DDR and 0.48 for FFQ) but only weakly correlated with intakes of orange (r = 0.12 for 7DDR and 0.15 for FFQ) and grapefruit (r = 0.14 for 7DDR and 0.09 for FFQ). The FFQ-assessed citrus intake was systematically higher than the 7DDR-assessed intake, and after calibrations, the mean calibrated FFQ measurements were almost identical to 7DDR assessments. In the test set, the mean intake levels from 7DDRs, FFQs, and calibrated FFQs were 62.5, 75.3, and 63.2 g/d for total citrus; 41.6, 42.5, and 41.9 g/d for orange juice; 11.8, 24.3, and 12.3 g/d for oranges; and 8.3, 9.3, and 8.6 g/d for grapefruit, respectively. We observed larger differences between calibrated FFQ and 7DDR assessments at the extreme ends of intake, although, on average, good agreements were observed for all citrus except grapefruit. CONCLUSIONS: Our 2-step calibration approach has the potential to be adapted to correct systematic measurement error for other foods/nutrients with established food biomarkers in a cost effective way.

Droplet Hi-C for Fast and Scalable Profiling of Chromatin Architecture in Single Cells.

Comprehensive analysis of chromatin architecture is crucial for understanding the gene regulatory programs during development and in disease pathogenesis, yet current methods often inadequately address the unique challenges presented by analysis of heterogeneous tissue samples. Here, we introduce Droplet Hi-C, which employs a commercial microfluidic device for high-throughput, single-cell chromatin conformation profiling in droplets. Using Droplet Hi-C, we mapped the chromatin architecture at single-cell resolution from the mouse cortex and analyzed gene regulatory programs in major cortical cell types. Additionally, we used this technique to detect copy number variation (CNV), structural variations (SVs) and extrachromosomal DNA (ecDNA) in cancer cells, revealing clonal dynamics and other oncogenic events during treatment. We further refined this technique to allow for joint profiling of chromatin architecture and transcriptome in single cells, facilitating a more comprehensive exploration of the links between chromatin architecture and gene expression in both normal tissues and tumors. Thus, Droplet Hi-C not only addresses critical gaps in chromatin analysis of heterogeneous tissues but also emerges as a versatile tool enhancing our understanding of gene regulation in health and disease.

On-farm harvest timing effects on alfalfa weevil across the Intermountain West region of the United States.

Alfalfa (Medicago sativa L.) is an economically important commodity in the Intermountain Western United States. A major concern for alfalfa producers in this region is the alfalfa weevil (Hypera postica Gyllenhal). Insecticide resistance development coupled with regulatory changes in pesticide use has resulted in renewed interest by producers in non-chemical control methods such as cultural control. One such cultural control method is early harvest, which consists of producers timing their harvests early in the season to decrease alfalfa weevil damage. This method is thought to be effective by exposing weevil larvae to adverse conditions before significant damage occurs. Still, early harvest can be difficult to employ because recommendations are often vague. To better understand how early harvest impacts both alfalfa weevils and their natural enemies and how producers are using this method across the Intermountain Western United States, we conducted a study in alfalfa production fields in Colorado, Montana, and Wyoming over three growing seasons. We determined that the timing of the initial alfalfa harvest spanned more than 1 month across fields, and alfalfa plant stage at harvest ranged from late vegetative to early bloom. Harvest was more impactful on reducing alfalfa weevil densities the earlier it was implemented. Removing windrows in a timely manner is likely useful to further decrease alfalfa weevil densities. Harvest timing was not associated with parasitism rates of alfalfa weevil, but higher parasitism rates were associated with lower post-harvest alfalfa weevil densities. This work has increased our understanding of early harvest in an on-farm setting and to improve recommendations for producers across the Intermountain Western United States.

Use of melatonin supplements and risk of type 2 diabetes and cardiovascular diseases in the USA: insights from three prospective cohort studies.

BACKGROUND: Use of melatonin supplements has been increasing substantially in both children and adults in the USA; however, their long-term cardiometabolic effects remain unclear. We aimed to assess the associations between regular use of melatonin supplements and the risk of developing type 2 diabetes or cardiovascular disease in adults. METHODS: In this study, we included individuals from three US cohorts: the Nurses' Health Study (women only), the Health Professionals Follow-up Study (men only), and the Nurses' Health Study II (women only). Women aged 25-55 years and men aged 45-75 years at baseline, who had no diagnosis of cancer at baseline, and who responded to the question about melatonin supplement use (yes or no) were included. We excluded baseline prevalent cardiovascular disease and baseline prevalent type 2 diabetes for the main analyses. The main outcomes were cardiovascular disease and type 2 diabetes incidence. In secondary analyses, we stratified by duration of rotating night shift work in the Nurses' Health Study and Nurses' Health Study II to examine whether the associations with melatonin supplement use differed by rotating night shift work. FINDINGS: For the cardiovascular disease analysis, we included 67 202 women from the Nurses' Health Study (follow-up 1998-2019, mean age at baseline: 63·6 years [SD 7·1]), 26 629 men from the Health Professionals Follow-up Study (1998-2020, 62·9 years [8·8], and 65 241 women from the Nurses' Health Study II (2003-19, 48·2 years [4·7]). Follow-up for incident type 2 diabetes was from 1998 to June 30, 2021, for the Nurses' Health Study; 2003 to Jan 31, 2023, for the Nurses' Health Study II; and from 1998 to Jan 31, 2020, for the Health Professionals' Follow-up Study. Melatonin supplement use in the study cohorts doubled over recent decades from less than 2% in 1998-2007 to 4% or higher in 2014-15 (4·0% in men and 5·3% in women). We documented 16 917 incident cardiovascular disease events during 2 609 068 person-years of follow-up and 12 730 incident cases of type 2 diabetes during 2 701 830 person-years of follow-up. In a pooled analysis of the three cohorts, comparing users with non-users of melatonin supplements, the pooled multivariable-adjusted hazard ratios were 0·94 (95% CI 0·83-1·06, p=0·32) for cardiovascular disease and 0·98 (0·86-1·12, p=0·80) for type 2 diabetes. In secondary analyses, melatonin supplement use appeared to attenuate the positive association between long-term shift work (>5 years) and risk of cardiovascular disease (pinteraction=0·013) among the female nurses. INTERPRETATION: With up to 23 years of follow-up of three large prospective cohorts of middle-aged and older men and women, self-reported melatonin supplement use was not associated with risk of type 2 diabetes or cardiovascular disease. Further research is warranted to assess if melatonin supplement use could mitigate the potential risks of type 2 diabetes and cardiovascular disease associated with rotating night shift work. FUNDING: US National Institutes of Health.

Integration of Computational Pipeline to Streamline Efficacious Drug Nomination and Biomarker Discovery in Glioblastoma.

Glioblastoma multiforme (GBM) is the deadliest, most heterogeneous, and most common brain cancer in adults. Not only is there an urgent need to identify efficacious therapeutics, but there is also a great need to pair these therapeutics with biomarkers that can help tailor treatment to the right patient populations. We built patient drug response models by integrating patient tumor transcriptome data with high-throughput cell line drug screening data as well as Bayesian networks to infer relationships between patient gene expression and drug response. Through these discovery pipelines, we identified agents of interest for GBM to be effective across five independent patient cohorts and in a mouse avatar model: among them are a number of MEK inhibitors (MEKis). We also predicted phosphoglycerate dehydrogenase enzyme (PHGDH) gene expression levels to be causally associated with MEKi efficacy, where knockdown of this gene increased tumor sensitivity to MEKi and overexpression led to MEKi resistance. Overall, our work demonstrated the power of integrating computational approaches. In doing so, we quickly nominated several drugs with varying known mechanisms of action that can efficaciously target GBM. By simultaneously identifying biomarkers with these drugs, we also provide tools to select the right patient populations for subsequent evaluation.

Adherence to Healthy and Unhealthy Plant-Based Diets and the Risk of Gout.

Importance: Plant-based diets are increasing in popularity due, in part, to their health benefits for selected cardiometabolic diseases as well as favorable environmental impact. Little is known about how such a diet is related to gout risk. Objective: To examine associations between adherence to a plant-based diet (including healthy and unhealthy versions of this diet), as well as its 18 individual food groups, and incident gout. Design, Setting, and Participants: This prospective cohort study used data from population-based cohorts of US men and women enrolled in the Health Professionals Follow-Up Study (1986-2012) and Nurses' Health Study (1984-2010). Participants were men and women free of gout at baseline. Statistical analyses were performed over March 2020 to August 2023. Exposures: An overall plant-based diet index (PDI), as well as healthy (hPDI) and unhealthy (uPDI) versions of this index that emphasize healthy and less healthy plant-based foods, respectively. These diet indices were comprised of 18 food groups, assessed using a validated semiquantitative food frequency questionnaire. Main Outcomes and Measures: Incident cases of gout that were confirmed with a supplementary questionnaire to meet the preliminary American College of Rheumatology survey criteria for gout. Cox proportional hazards regression models were used to evaluate multivariable-adjusted associations of all 3 PDIs with incident gout using quintiles (Q) of adherence. Results: Among a total of 122 679 participants (mean [SD] age, 53.8 [9.8] years among 43 703 men; mean [SD] age, 50.9 [7.2] years among 78 976 women) over 2 704 899 person-years of follow-up, 2709 participants experienced incident gout. The overall PDI was not significantly associated with gout in either cohort (Q5 vs Q1 pooled hazard ratio [HR], 1.02 [95% CI, 0.89-1.17]; P for trend = .63). In the pooled analysis, hPDI was significantly inversely associated with risk of gout (Q5 vs Q1 HR, 0.79 [95% CI, 0.69-0.91]; P for trend = .002), while the uPDI was positively associated with risk of gout (Q5 vs Q1 HR, 1.17 [95% CI, 1.03-1.33]; P for trend = .02), particularly in women (Q5 vs Q1 HR, 1.31 [95% CI, 1.05-1.62]; P for trend = .01). In analysis of individual food groups, higher intakes of certain healthy plant foods, such as whole grains (pooled HR per 1 serving/d, 0.93 [95% CI, 0.89-0.97]) and tea and coffee (pooled HR per 1 serving/d, 0.95 [95% CI, 0.92-0.97]), as well as dairy (pooled HR per 1 serving/d, 0.86 [95% CI, 0.82-0.90]), were independently associated with a lower risk of gout, while selected unhealthy plant foods, such as fruit juice (pooled HR per 1 serving/d, 1.06 [95% CI, 1.00-1.13]) and sugar-sweetened beverages (pooled HR per 1 serving/d, 1.16 [95% CI, 1.07-1.26]) were associated with increased risk of gout. Conclusions and Relevance: The findings of this prospective cohort study of PDIs and gout support current dietary recommendations to increase consumption of healthy plant foods while lowering intake of unhealthy plant foods to mitigate gout risk.

Four-dimensional computed tomography as first-line imaging in primary hyperparathyroidism, a retrospective comparison to conventional imaging in a predominantly single adenoma population.

BACKGROUND: To determine the use of four-dimensional CT as first-line imaging compared to the traditional combination of ultrasound and [99mTc]Tc-Sestamibi SPECT. MATERIALS AND METHODS: Retrospective review of preoperative imaging in patients with primary hyperparathyroidism, who underwent parathyroidectomy between 2012 and 2021. In one group, the combination ultrasound and [99mTc]Tc-Sestamibi SPECT was used as first-line imaging (n = 54), in the other group four-dimensional CT was the first-line imaging modality (n = 51). Sensitivity and positive predictive value were calculated on patient, lateralisation and localisation level. The need for additional imaging was also assessed for both groups. RESULTS: Four-dimensional CT had a significantly higher sensitivity compared to the combination of ultrasound/[99mTc]Tc-Sestamibi SPECT on patient and localisation level (70.6% vs. 51.9%, p = 0.049 and 60.8% vs. 35.2%, p = 0.009 respectively). Sensitivity for lateralisation also appeared higher, but did not reach significance (62.7% vs. 44.4%, p = 0.060). Positive predictive value was not significantly higher for four-dimensional CT compared to ultrasound and [99mTc]Tc-Sestamibi SPECT (88.9% vs. 85.7% for lateralisation and 86.1% vs. 67.9% for localisation respectively). Additional imaging was required in 14 patients with four-dimensional CT as first-line imaging (27.4%) consisting of 2 ultrasound/[99mTc]Tc-Sestamibi SPECT and 13 [18F]fluorocholine PET/CT, compared to 24 patients with ultrasound/[99mTc]Tc-Sestamibi SPECT as first-line imaging (44.4%), requiring 22 four-dimensional CT and 9 [18F]fluorocholine PET/CT. CONCLUSIONS: Four-dimensional CT as the sole first-line parathyroid imaging modality had higher sensitivity than the combination of ultrasound and [99mTc]Tc-Sestamibi SPECT, therefore requiring fewer additional procedures. Although the most costly, [18F]fluorocholine PET/CT was the most effective technique to localise parathyroid adenoma in case all other imaging was negative.