Publications by Year: 2026

Ground level ozone (O3) concentrations have shown a persistent upward trend in urban megacities over the past decade, despite substantial reductions in primary pollutant emissions through regulatory and technological interventions. Unlike primary pollutants, O3 is produced via nonlinear photochemical reactions that are highly sensitive to meteorological and environmental conditions, posing challenges for control through traditional precursor-based strategies. Here, we present a comprehensive O3 prediction framework tailored to megacity environments that integrates meteorological variables, air pollutant concentrations, and traffic volume, using an eight-year, hourly dataset from 37 administrative districts in Seoul, South Korea. Eight machine learning algorithms were evaluated with rigorous hyperparameter tuning, identifying CatBoost as the most accurate model (R2 = 0.93). To address seasonal variability, separate models were developed for each season, reducing prediction errors and revealing distinct seasonal performance patterns. The winter model achieved the highest accuracy, with an R2 of 0.96 and the lowest RMSE, while the summer model showed relatively reduced performance, due to the complex and volatile nature of warm season photochemistry. Feature importance analysis indicated that temperature and NO2 were key predictors in spring and summer, whereas wind speed, CO and SO2 had greater influence in winter. These findings highlight the limitations of year-round static approaches and support the adoption of seasonally adaptive strategies that account for both meteorological and anthropogenic factors.

BACKGROUND: Fibrinogen is a critical coagulation factor that plays an essential role in thrombosis and is elevated in individuals with chronic inflammation.

OBJECTIVES: Here, we used fibrinogen as a representative quantitative measure of procoagulant risk and evaluated metabolites associated with fibrinogen levels using nontargeted plasma metabolomics profiling (Broad and Metabolon platforms).

METHODS: Our analysis included 10 533 individuals across 6 United States-based cohorts representing diverse population groups. The cross-sectional relationship between each of the 789 metabolites tested and plasma fibrinogen concentration was assessed after adjustment for relevant covariates, including age, cohort-reported sex, body mass index, and circulating lipoprotein levels.

RESULTS: Meta-analysis of per-cohort results revealed 270 metabolites significantly associated with fibrinogen levels (false discovery rate-adjusted P value < .05). Lipid species, such as glycerophospholipids, sphingolipids, and fatty acyls, were among the most significantly associated metabolites; some of these may capture effects of inflammation, as supported by sensitivity analyses adjusted for C-reactive protein. Significant associations between fibrinogen levels and serotonin, thyroxine, and sex hormone derivatives may capture endogenous influences on fibrinogen levels. Exogenous compounds and microbial cometabolites were significantly associated with fibrinogen, also implicating lifestyle and microbiome risk factors. Only a portion of fibrinogen-associated metabolites (30%) has been associated with cardiovascular disease outcomes in a prior study, suggesting that the associations discovered here may provide insights into vascular biology that case-control studies may not yet be powered to detect.

CONCLUSION: These findings contribute to the growing list of metabolite biomarkers that may influence coagulation and inflammation pathways and, thereby, vascular risk.

OBJECTIVE: Disordered eating behaviors may impact the gynecologic health of adolescents through effects on menstrual cycle function and body size; however, few studies have evaluated these associations. This study aimed to prospectively investigate the associations between individual disordered eating behaviors during adolescence and the risk of subsequent endometriosis diagnosis.

DESIGN: Prospective, longitudinal cohort (1996-2021).

SUBJECTS: Female participants (n = 11,773) from the Growing Up Today Study.

EXPOSURE: Frequency of binge eating, laxative use, and self-induced vomiting over the past year was self-reported on repeated questionnaires during follow-up.

MAIN OUTCOME MEASURES: Physician-diagnosed endometriosis was reported on repeated questionnaires during follow-up. Multivariable logistic regression models with generalized estimating equations were used to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs).

RESULTS: Over 25 years of follow-up, we identified 269 incident cases of endometriosis (2.3%), 190 of which were reported as laparoscopically confirmed. A total of 32% of girls reported ever binge eating, 14% reported self-induced vomiting to lose weight, and 9% reported ever using laxatives to lose weight. The odds of a laparoscopically-confirmed endometriosis diagnosis were more than three-fold higher (aOR = 3.07; 95% CI 1.74, 5.40) for girls who cumulatively reported self-induced vomiting more than monthly during follow-up, compared with girls who never reported self-induced vomiting. A similar effect estimate (aOR = 2.41; 95% CI 1.40, 4.12) was noted for girls who reported weekly or more frequent self-induced vomiting at least once during follow-up compared with girls who reported never vomiting. Cumulative exposure to binge eating during follow-up was not associated with diagnosis of laparoscopically-confirmed endometriosis; however, girls who reported the highest ever engagement in binge eating of weekly or more had 52% lower (aOR = 0.47; 95% CI 0.25, 0.90) odds of laparoscopically-confirmed endometriosis, compared with girls who reported less than weekly binge eating. Laxative use was not strongly associated with endometriosis diagnosis, although estimates were imprecise.

CONCLUSION: We observed that females with a greater frequency of self-induced vomiting were more likely to be diagnosed with endometriosis during follow-up, whereas girls with a history of frequent binge eating had a lower likelihood of endometriosis diagnosis. We found no association between laxative use and endometriosis.

BACKGROUND: Pregnancy is a major modifier of vitamin D metabolism, which is suggested to serve an immunomodulatory role, support placental function, and aid fetal development. However, little is known about local tissue concentrations of vitamin D metabolites following supplementation during gestation.

OBJECTIVES: We aimed to quantify intracellular concentrations of 25-hydroxyvitamin D3 (25[OH]D) and the bioactive 1,25-dihydroxyvitamin D3 (1,25[OH]2D) across tissues following vitamin D supplementation and to determine how this distribution is altered during gestation in mice.

METHODS: Forty nulliparous female C57BL/6 (wild-type) mice were fed a semipurified diet supplemented with either a normal (1000 IU/kg) or high-dose (6000 IU/kg) vitamin D3 (cholecalciferol) for 4 wk. Thirty females were mated with 10 diet-matched C57BL/6 males, whereas 10 females served as nonpregnant controls. Maternal serum, lung, liver, kidney, and placental tissue and fetal samples were collected at gestational day 18.5. Concentrations of 25(OH)D and 1,25(OH)2D were measured using high-pressure liquid chromatography and tandem mass spectrometry and compared between groups using t tests in R (R Foundation for Statistical Computing).

RESULTS: High-dose vitamin D supplementation increased serum 25(OH)D (calcidiol) across all groups, with a clear dose response. Serum 1,25(OH)2D (calcitriol) concentrations were substantially increased in pregnant compared with nonpregnant females (mean difference: 74 pg/mL for control dose, P < 0.05 and 65 pg/mL for high dose, P = 0.1). Tissue analysis revealed the lungs as important targets of 25(OH)D accumulation, with significantly higher concentrations than liver tissue in nonpregnant (mean difference: 27 ng/g, P < 0.05) mice. Pregnancy induced notable shifts in vitamin D metabolite distribution, including reduced serum 25(OH)D concentrations and enhanced renal conversion to serum 1,25(OH)2D. Despite high placental accumulation of 25(OH)D, fetal 25(OH)D concentrations were significantly lower in the high-dose group (mean difference: -2.6 ng/g, P < 0.05), suggesting a protective saturation mechanism. High-dose vitamin D supplementation was well tolerated without any adverse gestational events.

CONCLUSIONS: Our findings suggest that pregnancy results in a redistribution of vitamin D metabolites in tissues, with the kidneys and placenta playing central roles. This distribution is responsive to prenatal vitamin D supplementation; however, under supraphysiological maternal dosing, fetal 25(OH)D uptake may be decreased.

Bipolar disorder (BP) and schizophrenia (SZ) share overlapping yet distinct structural brain alterations. Clarifying these differences is essential for improving diagnosis and prognosis. We hypothesized that cortical and subcortical alterations would differ between BP and SZ across illness stages and that these changes would relate to clinical severity. We examined cortical thickness and subcortical volumes using T1-weighted MRI in 438 participants recruited at McLean Hospital: 122 BP, 155 SZ, and 155 healthy controls (HC). Patient groups included both first-episode (FE-BP, FE-SZ) and chronic (CH-BP, CH-SZ) stages. BP patients demonstrated widespread cortical thinning, particularly in frontal, parietal, and temporal regions, with greater reductions in CH-BP. In CH-SZ, thinning was more circumscribed, affecting the precentral, superior frontal, and inferior parietal cortices. Subcortically, FE-BP showed corpus callosum (CC) volume loss, with further reductions in CH-BP, while CH-SZ exhibited central CC thinning. Ventricular enlargement was observed in CH-BP, FE-SZ, and CH-SZ, with marked left lateral ventricle expansion in CH-BP and CH-SZ. FE-BP also showed reduced caudate and amygdala volumes, with similar trends in chronic stages. Clinically, PANSS negative scores were consistently higher in SZ than BP, whereas positive symptoms did not differ. Cortical and subcortical alterations correlated with disease duration and PANSS scores, linking brain changes to symptom burden. BP exhibited larger morphometric effect sizes than SZ, despite greater negative symptom severity in SZ. This dissociation suggests that structural alterations do not necessarily parallel clinical severity, underscoring the importance of integrating neuroimaging and clinical measures to refine disease trajectories and diagnostic boundaries.

BACKGROUND: Killed whole-cell oral cholera vaccines can be used to prevent cholera but require multiple doses and have limited efficacy in young children. PanChol is a single-dose, live-attenuated, oral cholera vaccine derived from a current seventh pandemic Vibrio cholerae O1 strain. It co-expresses Inaba and Ogawa antigens, over-expresses the non-toxic cholera toxin B subunit, and is designed to minimise reactogenicity and be incapable of toxigenic reversion. We aimed to assess safety and immunogenicity of PanChol in a first-in-human trial.

METHODS: This phase 1a trial was conducted at the Brigham and Women's Hospital (Boston, MA, USA) and involved an open-label fixed dose-escalation module, followed by a randomised, double-blind, placebo-controlled dose-expansion module. Eligible participants were healthy adults aged 18-55 years without a previous V cholerae infection or cholera vaccination or a history of gastrointestinal disorders. In the open-label dose-escalation phase, eligible participants were enrolled into one of five cohorts receiving one dose of oral 106-1010 colony-forming units (CFU) of PanChol. A dose de-escalation (104 CFU and 105 CFU) module was added after protocol amendment. In the subsequent randomised, double-blind module, participants were randomly assigned (7:7:4) to one of two dosing groups of one oral dose of PanChol (2 × 107 CFU or 2 × 108 CFU) or one oral dose of placebo (matching diluent). The list of assignments was generated from a custom program written by the statistician using blocked random assignments with a hidden block size (two blocks of 18). The co-primary outcomes were safety, including solicited, unsolicited, and serious adverse events following a single-dose of PanChol, and seroconversion (four-fold rise in titre over baseline) of vibriocidal titres to both Inaba and Ogawa V cholerae at 14 days post-vaccination (day 15). Safety was assessed in all participants who received the study product, and immunogenicity was assessed in all vaccine recipients who had samples available past day 7. Stool shedding of PanChol organisms was assessed as a secondary outcome in all participants. This trial is registered with ClinicalTrials.gov, NCT05657782, and is ongoing.

FINDINGS: Between Dec 13, 2022, and Feb 7, 2025, 57 healthy adults were enrolled, including 15 in the dose-escalation module (three in each group), six in the dose de-escalation module (three in each group), and 36 in the dose-expansion module (14 assigned to 107 CFU PanChol, 14 to 108 CFU PanChol, and eight to placebo); all participants received the allocated intervention. 27 (47%) of 57 participants were male, 30 (53%) were female, and the median age was 30·6 years (IQR 25·1-45·1); the majority were White (35 [61%]) and not Hispanic or Latino (51 [89%]). 34 (69%) of 49 PanChol recipients reported at least one solicited adverse event, compared with three (38%) of eight placebo recipients. Most solicited adverse events in PanChol recipients were mild and transient. The most common solicited adverse event was diarrhoea, reported in 19 (39%) of 49 PanChol recipients (15 mild and four moderate) and in three (38%) of eight recipients of placebo (one severe and two mild). In the dose-escalation and dose de-escalation modules, 18 (86%) of 21 participants had 39 unsolicited adverse events. In the randomised module, at least one unsolicited adverse event occurred in ten (71%) of 14 participants given 107 CFU, in 12 (86%) of 14 participants given 108 CFU, and in seven (88%) of eight placebo recipients. Most unsolicited adverse events were mild and only four were higher than grade 2, all of which were deemed unrelated to vaccination. One unsolicited adverse event was deemed related to vaccination (mild gassy sensation on day 3 in a 107 CFU recipient). Shedding was detected in no placebo recipients, in one (33%) of three recipients of 104 CFU PanChol, and in 44 (96%) of 46 recipients of at least 105 CFU (two recipients of 108 CFU did not shed PanChol). All 45 vaccinees given at least 105 CFU PanChol who had samples available past day 7 seroconverted vibriocidal antibodies to both serotypes.

INTERPRETATION: A single oral dose of PanChol was safe and well tolerated at all doses and induced 100% vibriocidal seroconversion over a 100 000-fold dose range. These findings support the progression of PanChol into later phase clinical trials, including studies in endemic settings and in children.

FUNDING: Wellcome Trust.

HIV-associated neurocognitive disorder (HAND) remains a significant complication in people living with HIV, with inflammation playing a central role in its pathogenesis. Understanding how the brain's immune network responds to lentiviral infection is therefore critical. We show that acute simian immunodeficiency virus (SIV) infection elicits a robust resident brain immune response in control animals, marked by enhanced microglial ramification. In contrast, animals pretreated with anti-interleukin (IL)-15 antibodies (αIL-15) before SIVmac239X infection display reduced neuroinflammation without altering brain viral burden. Peripheral IL-15 blockade decreases brain-infiltrating T lymphocytes, alters their spatial dynamics, suppresses proinflammatory cytokine (IL-6) expression in microglia, and increases anti-inflammatory cytokine (TGF-β) expression in brain macrophages. Transcriptomic profiling reveals a global reduction in inflammatory signaling and an upregulation of genes associated with M1 macrophage pathways. Together, these findings demonstrate that peripheral IL-15 modulation attenuates neuroinflammation during acute lentiviral infection and highlight IL-15 as a potential therapeutic target for neuroinflammatory conditions of the brain.

Translation of foundation models from benchmarks to clinical impact has been slow, revealing a fundamental limitation: correlation-based predictions from models trained on observational data miss causal pathways that determine disease course and treatment response. Hybrid models combining deep learning with representations of biological mechanisms will enable causal reasoning and provide mechanistic understanding required for disease intervention.

This analysis assessed differences in influenza vaccine effectiveness (VE) and severe in-hospital outcomes between U.S. male and female adults hospitalized with laboratory-confirmed influenza in a multi-center network during 2022-2024. Compared with men, women hospitalized with influenza were less likely to smoke (21.5 % vs 25.3 %, P = 0.02), to have COPD (21.9 % vs 22.7 %, P < 0.001), and to be admitted to an intensive care unit once hospitalized (17.3 % vs 20.7 %, P = 0.04). Influenza VE (95 % confidence interval [CI]) was significantly higher in women aged ≥50 years compared with men aged ≥50 years (48.5 % [39.2 %-56.4 %] vs 26.2 % [13.0 %-37.5 %]). VE was slightly lower in women aged 18-49 years compared with women ≥50 years (46.2 % [95 % CI: 24.2 %-61.8 % vs 61.3 % [41.0 %-74.6 %]) but significantly lower in men aged ≥50 years compared with men aged 18-49 years (61.3 % [41.0 %-74.6 %] vs 26.2 % [13.0 %-37.5 %]). Disaggregation of sex should be considered in future influenza VE studies.

OBJECTIVE: Assessing the localization accuracy of electric and magnetic source imaging (ESI/MSI) for deep brain sources using a 3D-printed head phantom.

METHODS: We developed a realistic pediatric head phantom preserving brain, skull, and scalp properties with implanted sources in clinically relevant deep brain locations. Localization accuracy of ESI/MSI was assessed across varying noise levels using dipole fitting and dynamic statistical parametric mapping (dSPM).

RESULTS: The phantom generated realistic MEG and EEG data resembling actual epilepsy patient recordings. MSI showed superior accuracy to ESI for the deep tangential insular source (dipole: ∼17 vs. ∼33 mm; dSPM: ∼24 vs. ∼32 mm). While ESI-ECD localized some radial sources well (e.g. ∼9 mm for brainstem), its dSPM struggled to localize deep sources (e.g. insula and amygdala). Both modalities found the radial thalamus source most challenging to localize.

CONCLUSIONS: MSI outperformed ESI for localizing deep tangential sources; yet, both techniques struggled to localize deep radial sources. For point-like sources, dipole fitting delivered the highest accuracy (∼9 mm, ESI for brainstem), whereas averaged dSPM was superior for sources with distributed-source behavior (∼13 mm, MSI for orbital gyrus).

SIGNIFICANCE: 3D Printed realistic head phantoms can aid assessing the accuracy of ESI/MSI and selecting appropriate methods for different clinical scenarios.