Publications by Year: 2026

Microbial community analysis typically involves determining which microbial features are associated with properties such as environmental or health phenotypes. This task is impeded by data characteristics, including sparsity (technical or biological) and compositionality. Here we introduce MaAsLin 3 (microbiome multivariable associations with linear models) to simultaneously identify both abundance and prevalence relationships in microbiome studies with modern, potentially complex designs. MaAsLin 3 can newly account for compositionality either experimentally (for example, quantitative PCR or spike-ins) or computationally, and it expands the range of testable biological hypotheses and covariate types. On a variety of synthetic and real datasets, MaAsLin 3 outperformed state-of-the-art differential abundance methods, and when applied to the Inflammatory Bowel Disease Multi-omics Database, MaAsLin 3 corroborated previously reported associations, identifying 77% with feature prevalence rather than abundance. In summary, MaAsLin 3 enables researchers to identify microbiome associations more accurately and specifically, especially in complex datasets.

Obstructive sleep apnea (OSA) is associated with obesity and cardiovascular risk. The SURMOUNT-OSA master protocol comprised two, 52-week, randomized, double-blind, placebo-controlled phase 3 studies (study 1 and study 2) and demonstrated a significant reduction of a number of cardiometabolic risk measures in participants with OSA and obesity following treatment with tirzepatide. Here we report prespecified analysis of cardiometabolic risk measures in SURMOUNT-OSA. Post hoc analyses include changes in a homeostatic model assessment for insulin resistance and mediation analysis to determine the proportion of observed changes attributable to reductions in body weight, apnea-hypopnea index and sleep apnea-specific hypoxic burden. In both study 1 and study 2 of SURMOUNT-OSA, tirzepatide treatment was associated with greater alleviation of cardiometabolic risk factors than placebo. Independent mediation effect of changes in OSA metrics was observed on high-sensitivity C-reactive protein, homeostatic model assessment for insulin resistance and triglycerides. The combination of changes in weight and OSA metrics, as well as weight alone, had a significant mediation effect on systolic blood pressure, but there was no significant mediation effect of weight or OSA metrics observed on diastolic blood pressure. Based on the mediation analysis, treating both sleep-disordered breathing and obesity is likely required to optimize the treatment effect on cardiometabolic benefits for patients with moderate-to-severe OSA and obesity. The ClinicalTrials.gov registration number for this study is NCT05412004 .

MRI studies in bipolar disorder (BD) have yielded inconsistent findings, partly due to the varied use of psychotropic medications. This study utilised a mega-analysis approach, accounting for concurrent medication status (syndrome-based and Neuroscience-based Nomenclature (NbN) classifications), in order to assess the association of medication status with subcortical brain volumes in BD. Data from 2,664 BD patients and 4,065 controls (CN) were pooled from 34 research groups as part of the ENIGMA Bipolar Disorder Working Group. Standardized ENIGMA protocols were used to measure subcortical brain volumes. Linear-mixed-effects regression evaluated the association between psychotropic medications and subcortical volumes, and moderation analyses explored interactions. Medication-free patients (n = 410) showed mild ventricular enlargement (d = 0.07) and increased putamen volume (d = 0.06) compared to CN. Patients taking psychotropic medications exhibited smaller subcortical volumes (d = -0.06 to -0.11) and larger ventricles (d = 0.11 to 0.19). Use of antiepileptic and antipsychotic medications was associated with smaller hippocampal and thalamic volumes (d = -0.07 to -0.14), while NbN classification indicated that the categories of 'valproate' and 'dopamine and other monoamine receptor antagonists' are key variables when considering volume differences between BD and CN. Concurrent lithium use weakened the negative association between antiepileptic use and hippocampal volume (β = 0.19, q = 0.038) in patients. Medication status is associated with altered subcortical brain volumes in BD. The NbN classification provides a useful framework for future studies, emphasizing the need for comprehensive longitudinal research to further unravel complex clinical-pharmacological-neurobiological interactions in BD.

AIMS/HYPOTHESIS: Metformin, a mainstay of treatment for type 2 diabetes, can cause vitamin B12 deficiency. Clinical risk factors have been identified but genetic factors remain undiscovered. Our objective was to identify and validate genetic predisposing factors and establish clinical utility.

METHODS: Individuals with metformin-induced vitamin B12 deficiency (n=487) and metformin-tolerant control individuals (n=6686) were identified in UK Biobank. Genome-wide association analysis was undertaken using logistic regression. Replication was undertaken in three cohorts: a Scottish cohort; the Diabetes Prevention Program Outcomes Study (DPPOS); and a separate cohort from Liverpool. In the Liverpool cohort, plasma metformin levels were also measured.

RESULTS: Analysis identified a genome-wide significant non-synonymous SNP in the cubilin gene (CUBN, rs1801222/p.S253F) associated with metformin-induced vitamin B12 deficiency (additive model; adjusted p=1.86×10-10; OR 1.56 [95% CI 1.36, 1.79] for AG vs GG genotype; OR 2.43 [95% CI 1.85, 3.20] for AA vs GG genotype), which was replicated in both the Scottish and the DPPOS cohorts. Vitamin B12 deficiency occurred in 0.84-1.20% of non-metformin-exposed individuals regardless of rs1801222 genotype. However, a large interaction with metformin use was observed, with vitamin B12 deficiency occurring at 6.02% in GG, 7.96% in GA and 12.84% in AA genotype groups. When followed up from metformin initiation, 10% with the AA genotype were vitamin B12 deficient by 11 years vs 21 years for 10% of the GG group.

CONCLUSIONS/INTERPRETATION: The observed genetic association suggests that the rs180122 genotype should be considered a significant risk factor for metformin-induced vitamin B12 deficiency. While clinical monitoring of serum vitamin B12 levels in patients on metformin is inconsistently done, this finding highlights the potential clinical utility of targeted monitoring for certain subsets of individuals, including those genetically at high risk.

BACKGROUND: In Bangladesh, more than a quarter of drinking water tubewells are contaminated with arsenic above the national standard (50 µg/l), while nearly half exceed the World Health Organization guideline (10 µg/l). Among other negative health consequences, arsenic is a suspected environmental risk factor for neural tube defects (NTDs), including spina bifida. Maternal folate status protects against NTDs, though recent evidence suggests arsenic attenuates folate’s protective effects. Arsenic is methylated prior to excretion with methyl groups produced in one-carbon metabolism, for which folate is a cofactor. We thus hypothesized that DNA methylation (DNAme) may provide insight into the interactions between arsenic, maternal folate levels, and offspring spina bifida.

METHODS: Here we analyzed leukocyte DNAme using the Illumina MethylationEPIC v2.0 array in 374 women from Bangladesh, 246 with a previous spina-bifida affected birth and 128 controls. Chronic arsenic exposure was evaluated in maternal toenail; fasting plasma folate was measured at blood draw. Linear models evaluated DNAme associated with offspring spina bifida, arsenic, folate, and their interaction terms.

RESULTS: Maternal DNAme was associated with spina bifida at 71 CpGs, arsenic at 6 CpGs, and folate at 33 CpGs (all FDR < 0.05). The spina bifida*arsenic and arsenic*folate interactions were associated with 11 and 28 CpGs, respectively, while spina bifida*folate returned no significant associations. We observed lower DNAme in mothers of spina bifida cases at significant loci, including in developmental genes such as HOXB3 and HOXB4. Arsenic’s influence on DNAme was more pronounced in individuals with low folate.

CONCLUSIONS: Our work suggests that postnatal maternal leukocyte DNAme is associated with offspring spina bifida status and is modified by arsenic exposure but not plasma folate.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12940-025-01254-8.

Aging of the blood system impacts systemic health and can be traced to hematopoietic stem cells (HSCs). Despite multiple reports on human HSC aging, a unified map detailing their molecular age-related changes is lacking. We developed a consensus map of gene expression in HSCs by integrating seven single-cell datasets. This map reveals previously unappreciated heterogeneity within the HSC population. It also links inflammatory pathway activation (TNF/NFκB, AP-1) and quiescence within a single gene expression program. This program dominates an inflammatory HSC subpopulation that increases with age, highlighting a potential target for further experimental studies and anti-aging interventions.

OBJECTIVES: Both mental health conditions, such as depression, anxiety, and post-traumatic stress disorder (PTSD), and cardiovascular disease (CVD) events are increased in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We assessed associations and interactions between mental health conditions, RA and/or SLE (RA/SLE), and CVD risk.

METHOD: Patients with RA/SLE in All of Us Research Program were matched 1:20 to patients without either. We calculated hazard ratios (HR, 95% confidence intervals) for associations of baseline depression, anxiety, or PTSD with incident CVD, adjusting for socioeconomic and comorbid factors, repeating for RA and SLE separately. We tested for interactions between RA/ SLE and mental health conditions influencing CVD risk.

RESULTS: Among 5,543 patients with RA/SLE, matched to 110,860 patients without RA/SLE, 31.7% vs. 15.2% had mental health conditions. Matching factor-adjusted CVD event HR was the highest among those with RA/SLE and mental health conditions vs. those with neither (2.91, 2.52-3.36). After full adjustment, this decreased to 1.59 (1.37-1.85). While similar associations were observed for RA and SLE, higher risks were among patients with mental health conditions and SLE (2.08, 1.60-2.71) vs. RA (1.41, 1.17-1.70). No statistical interactions between mental health conditions and RA/SLE influencing CVD risks were detected.

CONCLUSIONS: In this large US cohort, patients with RA/SLE and mental health conditions had the highest CVD risks compared to those with either condition or none. Strategies are needed to address mental health conditions that contribute to excess CVD risk for patients with RA/SLE. Key points • Patients with RA/SLE and mental health conditions had the highest CVD incidence, compared to those with either RA/SLE or any of the mental health conditions alone. • Adjustment for sociodemographic factors and comorbidities attenuated this relative CVD risk. • No significant interactions were found between RA/SLE and mental health conditions influencing observed CVD risks.

BACKGROUND: Pelvic and groin lymphoceles and lymphatic leaks remain challenging postsurgical complications. Ethiodized-oil (lipiodol) lymphangiography has been increasingly utilized as a combined diagnostic and therapeutic modality, but published experience with lipiodol-only management in this setting is limited. While transnodal glue embolization is well established, evidence on its long-term outcomes and safety profile remains sparse, with particular concerns regarding the potential risk of lymphedema. These gaps highlight the need for further evaluation of lymphangiography alone as a minimally invasive treatment option.

MATERIALS AND METHODS: This retrospective study included patients who underwent lymphangiography between January 2019 and March 2023 for persistent symptomatic pelvic lymphoceles or groin lymphatic leaks. Imaging findings, drain output, prior interventions, and clinical outcomes were reviewed. Technical success was defined as adequate visualization of the targeted lymphatic vessels. Clinical success was defined as resolution or minimal residual leak without need for further treatment.

RESULTS: Ten patients (5 males, median age, 69 years) underwent lymphangiography for pelvic lymphoceles (n = 7) or groin lymphatic leaks (n = 3). The median interval from surgery to INL was 67.5 days (range, 12-108). Three patients had previously undergone surgical interventions, and four patients had undergone sclerotherapy without clinical improvement before INL was performed. Technical success was achieved in all patients (100%) with identification of lymphatic leak in all patients. Clinical success was achieved in 7 patients (70%) following lymphangiography alone, with a median time to resolution of 5.5 days (range, 5-12 days) and no immediate adverse events.

CONCLUSIONS: Lymphangiography using ethiodized oil contrast is a safe, and potentially effective minimally invasive treatment for pelvic and groin lymphatic leaks. These findings support a stepwise management approach, using lymphangiography as a first-line intervention before escalating to intranodal glue embolization.

Bacterial biofilms, prevalent in human infections, present a major barrier to effective antibacterial therapy due to limited drug permeability and resistance. Here we introduce a 'trick-bacteria-with-bacteria' strategy that employs bacteria modified via calcium chloride treatment and antibiotic loading, followed by ultraviolet inactivation. These modified bacteria integrate selectively into biofilms of the same species, enabling targeted intra-biofilm drug release triggered by local pH and hydrogen peroxide. Species-specific integration is essential, as mismatched strains exhibit spatial segregation due to differences in surface adhesins and protein profiles. The strategy is effective against polymicrobial biofilms and demonstrated efficacy in treating biofilms formed by Staphylococcus aureus, Escherichia coli and Candida albicans. It also reinvigorates biofilm-associated macrophages by inducing the release of biofilm-derived l-arginine, enhancing immune responses. In vivo studies using subcutaneous and bone implant infection models showed stronger biofilm eradication and longer-term immunity in animals treated with modified bacteria compared with those treated with antibiotics, including resistance to re-infection. This approach could be adapted to modify infection-related bacteria from patients for personalized intra-biofilm drug delivery.