Crohn's disease (CD) is a complex inflammatory bowel disease resulting from an interplay of genetic, microbial, and environmental factors. Cell-type-specific contributions to CD etiology and genetic risk are incompletely understood. Here we built a comprehensive atlas of cell-type- resolved chromatin accessibility comprising 557,310 candidate cis-regulatory elements (cCREs) in terminal ileum and ascending colon from patients with active and inactive CD and healthy controls. Using this atlas, we identified cell-type-, anatomic location-, and context-specific cCREs and characterized the regulatory programs underlying inflammatory responses in the intestinal mucosa of CD patients. Genetic variants that disrupt binding motifs of cell-type-specific transcription factors significantly affected chromatin accessibility in specific mucosal cell types. We found that CD heritability is primarily enriched in immune cell types. However, using fine- mapped non-coding CD variants we identified 29 variants located within cCREs several of which were accessible in epithelial and stromal cells implicating cell types from additional lineages in mediating CD risk in some loci. Our atlas provides a comprehensive resource to study gene regulatory effects in CD and health, and highlights the cellular complexity underlying CD risk.
Human ADA2 deficiency (DADA2) is an inborn error of immunity with a broad clinical phenotype which encompasses vasculopathy including livedo racemosa and lacunar strokes, as well as hemato-immunological features. Diagnosis is based on the combination of decreased serum ADA2 activity and the identification of biallelic deleterious alleles in the ADA2 gene. DADA2 carriers harbor a single pathogenic variant in ADA2 and are mostly considered healthy and asymptomatic. However, some DADA2 carriers present a phenotype compatible with DADA2. Here, we report ten patients from seven kindreds presenting with a phenotype indicative of DADA2, in whom only a single pathogenic variant (p.G47R, p.G47V, p.R169Q, p.H424N) was identified. To test whether being heterozygote for specific variants could explain the patients' phenotype, we investigated the effect of the ADA2 missense variants p.G47A, p.G47R, p.G47V, p.G47W, p.R169Q, p.E328K, p.T360A, p.N370K, p.H424N and p.Y453C on ADA2 protein expression, secretion and enzymatic activity. Functional studies indicate that they exert a dominant negative effect on ADA2 enzymatic activity, dimerization and/or secretion. At the molecular level, heterozygosity for these variants mimics what is observed in DADA2. We conclude that humans with heterozygous dominant negative missense variants in ADA2 are at risk of DADA2.
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Background: Monitoring and treating diarrheal illness often rely on individuals seeking care at hospitals or clinics. Cases that seek care through pharmacies and community health workers (CHW) are frequently excluded from disease burden estimates, which are used to allocate mitigation resources. Studies on care seeking behavior can help identify these gaps but typically focus on children under five, even though diarrheal diseases like cholera and Enterotoxigenic E. coli affect all age groups. This study aimed to estimate the proportion of individuals seeking care for themselves or their children with diarrhea, considering different age groups, case definitions, and study settings.
Methods and findings: We conducted a systematic review of population-based primary research studies published during 2000-2024 that examined care-seeking behavior for diarrhea. We included 166 studies from 62 countries. Hospitals and clinics were the most common source of care sought outside the home, with CHW and health posts rarely reported. Using a random-effects meta-analysis, we found substantial heterogeneity in care seeking between studies from low- and middle- income countries (I 2 = 99.3) and estimated that the proportion of diarrhea cases seeking care at a hospital or clinic was 32.8% on average (95% Confidence Interval (CI) 28.1% to 37.9%; prediction interval 3.3% to 87.5%). Although there were trends toward higher care-seeking for children compared to adults, substantial variation existed between studies, and the differences were not significant. We estimated that the adjusted odds of seeking care at a hospital or clinic were significantly higher for severe diarrhea and cholera compared to general diarrhea (Odds Ratio 3.43; 95% CI 1.71 to 6.88).
Conclusions: Our findings confirm that passive surveillance through hospitals and clinics may substantially undercount the number of people with diarrhea, particularly those with milder symptoms, although this proportion varied widely. Additionally, our findings underscore the importance of including care seeking questions across all age groups in future studies, as we cannot assume lower care seeking for adults across all settings. Our study was limited by fewer data on care- seeking from health posts, traditional healers, and CHW compared to hospitals and clinics, highlighting a need for further research on these sources of care.
Clinical, neuroimaging and genomics evidence have increasingly underscored a degree of overlap between autism and attention-deficit/hyperactivity disorder (ADHD). This study explores the specific contribution of their core symptoms to shared biology in a sample of N=166 verbal children (6-12 years) with rigorously-established primary diagnoses of either autism or ADHD (without autism). We investigated the associations between inter-individual differences in clinician-based dimensional measures of autism and ADHD symptoms and whole-brain low motion intrinsic functional connectivity (iFC). Additionally, we explored their linked gene expression patterns in silico . Whole-brain multivariate distance matrix regression revealed a transdiagnostic association between autism severity and iFC of two nodes: the middle frontal gyrus of the frontoparietal network and posterior cingulate cortex of the default mode network. Across children, the greater the iFC between these nodes, the more severe the autism symptoms, even after controlling for ADHD symptoms. Results from segregation analyses were consistent with primary findings, underscoring the significance of internetwork iFC interactions for autism symptom severity across diagnoses. No statistically significant brain-behavior relationships were observed for ADHD symptoms. Genetic enrichment analyses of the iFC maps associated with autism symptoms implicated genes known to: (i) have greater rate of variance in autism and ADHD, and (ii) be involved in neuron projection, suggesting shared genetic mechanisms for this specific brain-clinical phenotype. Overall, these findings underscore the relevance of transdiagnostic dimensional approaches in linking clinically-defined phenomena to shared presentations at the macroscale circuit- and genomic-levels among children with diagnoses of autism and ADHD.
Background: The associations of PM 2.5 mass and various adverse health outcomes have been widely investigated. However, fewer studies focused on the potential health impacts of PM 2.5 components, especially for dementia and Alzheimer's diseases (AD).
Methods: We constructed a nationwide population-based open cohort study among Medicare beneficiaries aged 65 or older during 2000-2018. This dataset was linked with the predicted levels of 15 PM 2.5 components, including 5 major mass contributors (EC, OC, NH 4 + , NO 3 - , SO 4 2- ) and 10 trace elements (Br, Ca, Cu, Fe, K, Ni, Pb, Si, V, Zn) across contiguous US territory. Data were aggregated by ZIP code, calendar year and individual level demographics. Two mixture analysis methods, weighted quantile sum regression (WQS) and quantile g-computation (qgcomp), were used with quasi-Poisson models to analyze the health effects of the total mixture of PM 2.5 components on dementia and AD, as well as the relative contribution of individual components.
Results: Exposure to PM 2.5 components over the previous 5 years was significantly associated with increased risks of both dementia and AD, with stronger associations observed for AD. SO 4 2- , OC, Cu were identified with large contributions to the combined positive association of the mixture from both WQS and qgcomp models.
Conclusion: We found positive associations between the 15 PM 2.5 components and the incidence of dementia and AD. Our findings suggest that reducing PM 2.5 emissions from traffic and fossil fuel combustion could help mitigate the growing burden of dementia and Alzheimer's disease.
Medication-refractory focal epilepsy poses a significant challenge, with approximately 30% of patients ineligible for surgery due to the involvement of eloquent cortex in the epileptogenic network. For such patients with limited surgical options, electrical neuromodulation represents a promising alternative therapy. In this study, we investigate the potential of non-invasive temporal interference (TI) electrical stimulation to reduce epileptic biomarkers in patients with epilepsy by comparing intracerebral recordings obtained before, during, and after TI stimulation, and to those recorded during low and high kHz frequency (HF) sham stimulation. Thirteen patients with symptoms of mesiotemporal epilepsy (MTLE) and implanted with stereoelectroencephalography (sEEG) depth electrodes received TI stimulation with an amplitude modulation (AM) frequency of 130Hz (Δf), where the AM was delivered with lower frequency kHz carriers (1kHz + 1.13kHz), or higher frequency carriers (9kHz + 9.13kHz), targeting the hippocampus - a common epileptic focus and consequently stimulation target in MTLE. Our results show that TI stimulation yields a statistically significant decrease in interictal epileptiform discharges (IEDs) and pathological high-frequency oscillations (HFOs) - specifically Fast-ripples (FR) -, where the suppression is apparent in the hippocampal focus and propagation from the focus is reduced brain-wide. HF sham stimulation at 1kHz frequency also impacted the IED rate in the cortex, but without reaching the hippocampal focus. The HF sham effect diminished with increasing frequencies (2, 5, and 9kHz, respectively), specifically as a function of depth into the cortex. This depth dependence was not observed with the TI, independent of the employed carrier frequency (low or high kHz). Our findings underscore the possible application of TI in epilepsy, as an additional non-invasive brain stimulation tool, potentially offering opportunities to assess brain region responses to electrical neuromodulation before committing to a deep brain stimulation (DBS) or responsive neurostimulation (RNS) implant. Our results further demonstrate distinct biophysical differences between kHz and focal AM stimulation.
Integrating clinical knowledge into AI remains challenging despite numerous medical guidelines and vocabularies. Medical codes, central to healthcare systems, often reflect operational patterns shaped by geographic factors, national policies, insurance frameworks, and physician practices rather than the precise representation of clinical knowledge. This disconnect hampers AI in representing clinical relationships, raising concerns about bias, transparency, and generalizability. Here, we developed a resource of 67,124 clinical vocabulary embeddings derived from a clinical knowledge graph tailored to electronic health record vocabularies, spanning over 1.3 million edges. Using graph transformer neural networks, we generated clinical vocabulary embeddings that provide a new representation of clinical knowledge by unifying seven medical vocabularies. These embeddings were validated through a phenotype risk score analysis involving 4.57 million patients from Clalit Healthcare Services, effectively stratifying individuals based on survival outcomes. Inter-institutional panels of clinicians evaluated the embeddings for alignment with clinical knowledge across 90 diseases and 3,000 clinical codes, confirming their robustness and transferability. This resource addresses gaps in integrating clinical vocabularies into AI models and training datasets, paving the way for knowledge-grounded population and patient-level models.
Context: 47,XXY/Klinefelter syndrome (XXY) is associated with impaired testicular function and differences in physical growth, metabolism, and neurodevelopment. Clinical features of XXY may be attributable to inadequate testosterone during the mini-puberty period of infancy.
Objective: We tested the hypothesis that exogenous testosterone treatment positively effects short-term physical, hormonal, and neurodevelopmental outcomes in infants with XXY.
Design: Double-blind randomized controlled trial, 2017-2021.
Setting: US tertiary care pediatric hospital.
Patients: Infants 30-90 days of age with prenatally identified, non-mosaic 47,XXY (n=71).
Intervention: Testosterone cypionate 25mg intramuscular injections every 4 weeks for 3 doses.
Main outcome measures: The a priori primary outcomes were change in percent fat mass (%FM) z-scores and change in the total composite percentile on Alberta Infant Motor Scales (AIMS) assessment from baseline to 12 weeks.
Results: The between group difference in change in %FM z-scores was -0.57 [95% CI -1.1, - 0.06], p=0.03), secondary to greater increases in lean mass in the testosterone-treated group (1.5±0.4 kg vs 1.2±0.4, p=0.001). Testosterone suppressed gonadotropins and inhibin B (p<0.001 for all). In contrast, there were no significant group differences in short term motor, cognitive, or language outcomes (p>0.15 for all).
Conclusions: In this double-blind randomized controlled trial in infants with XXY, testosterone injections resulted in physical effects attributable to systemic androgen exposure; however, there was no impact on neurodevelopmental outcomes and the hypothalamic-pituitary-gonadal axis was suppressed. These results do not support routine testosterone treatment in infants with XXY, however long term follow up on physical health, neurodevelopment and testicular function is needed.
Transcriptome-wide association studies (TWAS) are commonly used to prioritize causal genes underlying associations found in genome-wide association studies (GWAS) and have been extended to identify causal genes through multivariable TWAS methods. However, recent studies have shown that widespread infinitesimal effects due to polygenicity can impair the performance of these methods. In this report, we introduce a multivariable TWAS method named Tissue-Gene pairs, direct causal Variants, and Infinitesimal effects selector (TGVIS) to identify tissue-specific causal genes and direct causal variants while accounting for infinitesimal effects. In simulations, TGVIS maintains an accurate prioritization of causal gene-tissue pairs and variants and demonstrates comparable or superior power to existing approaches, regardless of the presence of infinitesimal effects. In the real data analysis of GWAS summary data of 45 cardiometabolic traits and expression/splicing quantitative trait loci (eQTL/sQTL) from 31 tissues, TGVIS is able to improve causal gene prioritization and identifies novel genes that were missed by conventional TWAS.
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