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Obesity is a complex metabolic disorder increasingly linked to alterations in the gut microbiome. While most research has focused on bacterial communities, the contribution of nonbacterial components including viruses, archaea, and eukaryotic microorganisms remains insufficiently characterized. Here, we performed a multicohort analysis to investigate the role of the nonbacterial gut microbiome in obesity across three independent human cohorts. Using compositional analyses adjusted for key covariates and network based approaches, we identified consistent multikingdom alterations associated with obesity. Individuals without obesity showed a reproducible enrichment of methanogenic archaea, particularly Methanobrevibacter smithii and Methanobrevibacter millerae, whereas individuals with obesity were characterized by increased abundance of bacteriophages from the class Caudoviricetes. In an elderly cohort, eukaryotic taxa such as Blastocystis spp. were additionally associated with the without obesity group. These patterns were largely consistent across cohorts and robust to sex stratification. Beyond taxonomic differences, ecological network analyses revealed substantial reorganization of microbial interactions in obesity. The identity and composition of hub taxa differed significantly between obesity and without obesity networks across all cohorts, indicating a shift in the taxa occupying central ecological roles. Notably, these differences were observed even when similar microbial kingdoms were represented, underscoring the importance of species-level resolution. Collectively, our findings demonstrate that obesity is associated with coordinated compositional and ecological alterations across the nonbacterial gut microbiome. This multikingdom perspective expands current understanding of microbiome dysbiosis in metabolic disease and highlights the archaeome and virome as potential contributors to host metabolic health.

Large language models (LLMs) show considerable potential for atrial fibrillation (AF) management, yet current clinical applications frequently remain suboptimal due to accuracy limitations. To address these limitations, this study developed PULSE (Potentiated User-friendly LLM-driven Search Engine), a novel knowledge-enhanced, domain-aware LLM agent specifically designed to improve AF patient self-management across the entire care continuum. The proposed framework integrates multimodal inputs, meticulously curated clinical knowledge bases, optimized prompt engineering, and retrieval-augmented generation within an agent-based architecture. Performance was rigorously evaluated against four leading base LLMs using response quality (clinical accuracy, content integrity, practical utility, and patient safety) and readability (clarity, conciseness, and empathy). Comprehensive clinical validation was subsequently conducted through blinded expert assessment of 75 real-world AF-related patient queries. The results demonstrated that PULSE improved clinical accuracy, content integrity, utility, and safety (P < 0.05) across all tested models. Furthermore, it substantially enhanced empathy and clarity while maintaining comparable conciseness. Overall, PULSE improves both the factual accuracy and readability of patient-facing medical outputs, highlighting the immense clinical potential of agent-driven LLM systems to advance chronic disease self-management and improve long-term patient outcomes.

Ectopic lipid accumulation in renal tubules induces lipotoxicity and contributes to the progression of diabetic kidney disease (DKD). Apolipoprotein J (ApoJ), a glucose-regulated, liver-derived molecular chaperone, is implicated in systemic metabolic homeostasis. This study aimed to investigate the pathophysiological role of ApoJ in the development of DKD. Spearman's r analysis was used to evaluate the association between circulating ApoJ concentrations and renal function in a cohort of 201 individuals with type 2 diabetes mellitus. The pathways were identified by proteomic analyses and subsequently validated using gain- and loss-of-function approaches in proximal tubular epithelial HK2 cells, tissue-specific ApoJ-knockout mice and additional mouse models of DKD. In individuals with type 2 diabetes, circulating ApoJ concentrations were positively associated with indices of renal dysfunction. In murine models of DKD, elevated renal ApoJ was accompanied by increased lipid accumulation and structural kidney injury. Mechanistic studies revealed that ApoJ inhibited FBW7-mediated ubiquitination of mammalian target of rapamycin (mTOR), thereby enhancing mTOR interaction with transcription factor EB (TFEB) in HK2 cells under conditions of nutrient excess, leading to lipid imbalance and renal fibrosis. Hepatocyte-specific deletion of ApoJ eliminated circulating ApoJ, prevented its accumulation in renal tubules and ameliorated diabetic kidney injury. Furthermore, pharmacological blockade with the ApoJ antagonist MK53 reactivated the TFEB-autophagy pathway, restored lipid homeostasis and reduced renal damage in diabetic mice. Our findings highlight a liver-to-kidney interorgan transfer of pathogenetic ApoJ in diabetic kidney injury and suggest that MK53 represents a potential therapeutic strategy for DKD.

Benefits from clinical guidelines often only exceed harms after 10 years (payoff time). Based on population norms, guidelines are often discontinued at 75 years of age, but survival likely differs for those with complex chronic disease. We compare estimates based on age alone versus the physiologically based Veterans Ageing Cohort Study-Charlson Comorbidity Index (VACS-CCI) among all patients in care, and among patients with diabetes or HIV. Estimates for patients in care within the US Veterans Health Administration (VHA) with a clinic visit in 2007-17 (followed thru 2021) were compared using C-statistics, Brier Scores, and calibration curves. "Physiological age" was defined as the chronological age at which median VACS-CCI matched US population survival estimates. Among those with 10-year follow-up, we compared percent correctly classified using age ≥75 years vs. VACS-CCI score of ≥42. Among 6.6 million (51.4% ≥ 65 years; 25.2% with diabetes; 0.5% with HIV) VACS-CCI improved discrimination over age (Overall C-statistic: 0.81 vs. 0.74; Brier Score 0.239 vs. 0.262). Among 65-year-old males-females, "physiological age" exceeded chronological age by 4.6-3.1 years overall; 8.6-7.8 years for diabetes; and 13.5-11.6 years for HIV. Compared to age ≥75 years, VACS-CCI improved correct classification of survival for 1 in 13.3 overall; 1 in 7.8 with diabetes; and 1 in 6.4 with HIV. Compared to chronological age alone, VACS-CCI offers an improved method to identify those likely to reach minimum payoff time, especially for those with complex chronic diseases. Use of clinical data to assess "physiological age" could improve healthcare value. This work was supported by National Institutes of Health NIAAA: P01 AA029545, U24 AA020794 and the Emory Center for AIDS Research (P30AI050409).

Trigeminal neuropathic pain (TNP) is a severe facial pain disorder whose pathogenesis is incompletely understood. We previously identified follistatin (FST) as a contributor to peripheral nerve injury-induced neuropathic pain through direct binding to the insulin-like growth factor-1 receptor (IGF1R) in the dorsal root ganglia. However, the regulatory mechanisms governing FST expression and its specific role in TNP remain unclear. Here, we report that FST is upregulated in trigeminal ganglion (TG) neurons following partial infraorbital nerve transection (pIONT), and that this process is regulated by the transcription factors ATF3 and SOX11. Genetic deletion or knockdown of Fst attenuated pIONT-induced TNP and reduced TG neuronal hyperexcitability. Intra-TG injection of FST promoted pain-like behaviors and activated ERK and AKT signaling in an IGF1R-dependent manner. In addition, FST decreased voltage-gated potassium (Kv) channel currents and enhanced neuronal excitability via IGF1R-ERK/AKT signaling. Notably, FST upregulated a cohort of genes, including Fst itself, Cyp26a1, and Ccl2, through the transcription factor Specificity Protein 1 (Sp1). Consistently, pIONT increased Sp1 phosphorylation, and pharmacological inhibition or knockdown of Sp1 alleviated mechanical allodynia, reduced the expression of Fst, Cyp26a1, and Ccl2, and decreased the excitability of TG neurons. Collectively, these results reveal a previously unknown mechanism by which FST activates IGF1R-ERK/AKT signaling to decrease Kv channel currents and promote Sp1-regulated gene expression, contributing to peripheral sensitization and TNP pathogenesis. Our data indicate that targeting the FST-IGF1R-ERK/AKT-Sp1 axis may represent a promising therapeutic strategy for TNP.

Occipital neuralgia (ON) is a refractory chronic headache disorder characterized by paroxysmal shooting or stabbing pain in the posterior scalp, innervated by occipital nerves that originate from C2 and C3 dorsal root ganglion (DRG) neurons. Limited access to human DRG samples has impeded the understanding of the cellular and molecular mechanisms and the development of effective treatments for ON. We innovatively employed percutaneous full-endoscopic C2 ganglionectomy and subsequently performed single-nucleus RNA-sequencing (snRNA-seq) on C2 DRG from both ON patients and healthy controls. Somatostatin-expressing (SST+) neurons were selectively downregulated in patients with ON. Behavioral studies demonstrated that ablation of SST+ neurons induced pain, while optogenetic or chemogenetic activation of these neurons alleviated acute and chronic pain in mice. Altogether, this study provides new insights into the mechanisms underlying ON, revealing potential therapeutic targets for pain management.

Chronic pain caused by peripheral nerve injury involves altered spinal pain transduction, where enhanced excitatory and/or reduced inhibitory pathways can drive pain. The cellular transcriptional changes that sustain entrenched neuropathic pain remain poorly understood. Here we use single-nucleus and spatial transcriptomic approaches in male mice to investigate spinal cellular and molecular programs associated with entrenched and treated neuropathic pain. We show that nerve injury leads to broad upregulation of synaptic and excitatory pathways in dorsal neuronal and glial populations. We confirm that these core populations are conserved in the human spinal cord, and show that an effective pain therapy dampens neuropathic transcriptional programs. These data identify spinal cell populations and pathways associated with neuropathic pain states and therapeutic reversal.

Alterations in the BRCA1 DNA repair associated (BRCA1) and BRCA2 DNA repair associated (BRCA2), two key DNA repair genes, are strongly linked to adult-onset malignancies and play a significant role in tumor development. Although BRCA1 and BRCA2 are firmly recognized as hereditary cancer risk genes in adult populations, their role in central nervous system (CNS) tumor susceptibility in younger patients is still debated. We analyzed 367 pediatric, adolescent, and young adult (AYA) patients with primary CNS tumors. Tumors were classified according to the WHO Classification of Tumors of the CNS, fifth edition. All patients underwent clinical exome sequencing, including BRCA1 and BRCA2. Rare germline BRCA1/2 variants were identified in 17 of 367 patients (4.6%). Among them, 5 patients (1.4% of the overall cohort) carried pathogenic or likely pathogenic variants, whereas 12 patients (3.3%) carried variants of uncertain significance (VUSs). Our findings are consistent with emerging evidence suggesting that monoallelic pathogenic BRCA1/2 variants may act as low-penetrance susceptibility factors in pediatric and AYA CNS tumors rather than as primary oncogenic drivers. Interpretation is limited by cohort heterogeneity, lack of a noncancer control group, and absence of systematic somatic analyses to assess biallelic inactivation or homologous recombination deficiency. Nevertheless, these data support the inclusion of BRCA genes in germline testing panels for pediatric and AYA CNS tumors, with relevant implications for genetic counseling and long-term surveillance.

Glypican-3 (GPC3) is highly expressed in hepatocellular carcinoma (HCC), making it an attractive target for chimeric antigen receptor (CAR) T cell therapy; however, this approach has previously shown limited clinical efficacy, potentially owing to high levels of transforming growth factor-β (TGFβ) in the tumour microenvironment1-4. We therefore engineered CAR T cells with a dominant-negative TGFβ receptor II, which showed enhanced antitumour activity in preclinical studies5. Here we report findings from a first-in-human trial evaluating the safety and efficacy of C-CAR031 in patients with advanced, treatment-refractory HCC ( NCT05155189 ). Thirty-six patients received CAR T infusions at four dose levels (from 0.75 × 106 to 4.0 × 106 cells per kg). Cytokine release syndrome was reported in 34 patients, of which two cases were grade 3. Nine patients had non-haematological adverse events of grade 3 or higher. Tumour regression was observed in 32 patients, with a median best tumour reduction from baseline of 41.6% (range: 3.4-94.4%) in target lesions. The objective response rate was 44.4%, and the median duration of response was 4.4 months (95% confidence interval: 2.9-7.4). Median progression-free survival and overall survival were 4.2 months (95% confidence interval: 2.9-4.8) and 14.2 months (95% confidence interval: 10.1 to not evaluable), respectively. High-throughput analyses of tumour samples and functional validation suggested that GPC3 antigen loss and increased TGFβ levels may contribute to C-CAR031 resistance. Collectively, these results indicate that C-CAR031 has a manageable safety profile and encouraging antitumour activity in heavily pretreated patients with advanced HCC.

Multidrug resistance and invasive metastasis constitute pivotal clinical bottlenecks that severely compromise curative outcomes of malignant tumors. Conventional chemotherapy and immunotherapy frequently fail to achieve satisfactory efficacy due to drug resistance barriers and tumor immune escape. Herein, a hyaluronic acid‑cinnamaldehyde Schiff base micelle nanoplatform loading quaternary ammonium‑modified carbon dots (HACA@QASCDs) is rationally constructed, which achieves targeted killing of drug‑resistant tumor cells, remodeling of immunosuppressive microenvironments, and inhibition of distant metastasis via a sequential cascade of irreversible membrane perforation, mitochondria‑dependent apoptosis, and immunogenic cell death (ICD). HACA@QASCDs actively accumulate in drug‑resistant CT26 (DR‑CT26) cells through HA‑CD44 recognition and enable pH‑triggered QASCDs release in acidic tumor microenvironments. The liberated QASCDs elicit irreversible membrane perforation, leading to lactate dehydrogenase leakage, disrupted calcium homeostasis, mitochondrial depolarization, and subsequent intrinsic apoptosis. Such membrane damage simultaneously ignites ICD, and the released damage‑associated molecular patterns effectively drive dendritic cell maturation and M2‑to‑M1 macrophage polarization. In vivo evaluations in bilateral syngeneic tumor models reveal that HACA@QASCDs alone yields 54.2% primary tumor inhibition and 28.6% distant tumor inhibition. Upon combination with αPD‑L1, the distant tumor inhibition rate is markedly elevated to 68.7%. By integrating membrane perforation‑mediated direct cytotoxicity and ICD‑evoked immune activation, HACA@QASCDs offers a highly potent and clinically translatable synergistic strategy to surmount tumor multidrug resistance and block invasive metastasis.

Borderline personality disorder (BPD) is a severe mental health condition influenced by environmental risk factors (for example, interpersonal trauma) and genetic factors. We conducted the largest genome-wide association study (GWAS) meta-analysis of BPD so far, with a discovery sample of 12,339 cases and 1,041,717 controls, and a replication study of 685 cases and 107,750 controls (all participants of European ancestry). We identified 11 independent associated genomic loci and 9 risk genes in gene-based analyses. We observed a single-nucleotide polymorphism heritability of 17.3% and derived polygenic scores (PGS) that predicted 4.6% of the phenotypic variance in BPD on the liability scale. BPD showed the strongest positive genetic correlations with GWAS of post-traumatic stress disorder, depression, attention deficit hyperactivity disorder, antisocial behavior, and measures of suicide and self-harm. Phenome-wide analyses in Vanderbilt University Medical Center Biobank and UK Biobank using BPD-PGS confirmed these associations and also identified associations with other medical conditions, including obstructive pulmonary disease and diabetes. These analyses highlight BPD as a polygenic disorder, with the genetic risk showing substantial overlap with psychiatric and physical health conditions.

Cue-induced craving is a core driver of addiction and relapse, and its significant heterogeneity represents a major barrier to precision intervention. Currently, there remains a lack of objective, quantifiable, and individualized neurobiological biomarkers. Here, we employed task-based electroencephalography (EEG) to capture the dynamic neural signatures underlying cue-induced craving in patients with heroin use disorder (HUD) and developed an individualized functional connectivity (FC)-based prediction model. We identified β-band power envelope connectivity (PEC) as a reliable biomarker capable of estimating subjective craving severity at the individual level. Notably, even after FC reconfiguration induced by intermittent theta burst stimulation (iTBS) over the left dorsolateral prefrontal cortex (L-DLPFC) or precuneus (PCu), the PEC-based framework's prediction of immediate craving levels following these perturbed states remained effective. Crucially, baseline β-band PEC demonstrated strong prognostic value for improvements in craving scores (L-DLPFC-iTBS: r = 0.856, P < 0.001; PCu-iTBS: r = 0.675, P = 0.008). This individualized predictive model was further validated in an independent dot-probe task dataset, demonstrating its generalizability across distinct cue-induced craving paradigms. Together, our study demonstrates that EEG FC features predict individual cue-induced craving levels and intervention outcomes, facilitating the advancement of digital biomarker-driven precision medicine.

This scoping review summarizes the progress of reinforcement learning (RL) in clinical decision-making for sepsis at the intersection of medicine and artificial intelligence (AI). All 72 included studies were retrospective, with the majority using the Medical Information Mart for Intensive Care (MIMIC) database (58 studies [80.6%]), and relatively few employing private datasets (10 studies [13.9%]). Study designs varied widely, especially in state representation, action space, reward definition, and choice of algorithms. Most research focused on vasopressor and intravenous fluid management, while fewer studies addressed antibiotics, corticosteroids, mechanical ventilation, heparin, or vasopressin. Although many studies reported RL-derived policies that outperformed clinicians, the reliability and validity of the evaluation methods remain uncertain. Future research should emphasize clinically guided design of states, actions, and rewards, develop rigorous and widely accepted evaluation tools, and explore a broader range of sepsis treatment strategies. Ultimately, advancing interpretability, generalizability, and safety will be critical to effectively integrating RL into routine clinical practice.

Despite the critical role of α-amylase assessment in diagnosing postoperative pancreatic fistula, conventional intermittent testing suffers from inherent delays, overburdened clinical laboratories, and color interference from pigmented drainage fluids. To address these limitations, we present an electrochemical biosensor enabling potential bedside continuous monitoring of α-amylase activity in abdominal drainage fluids from high-risk patients. The system integrates chronoamperometry with a glucose oxidase-functionalized cellulose fiber membrane, a carbon screen-printed electrode, and a microfluidic channel, facilitating continuous, color-immune detection in flowing clinical samples. The sensor exhibited a bilinear range of 100-10000 U/L with a detection limit of 34.7 U/L. To ensure reproducibility, single-point calibration and on-site reconstruction methods were employed to minimize batch-to-batch variability. Finally, preliminary validation using complex, dynamic-flow clinical drainage samples demonstrated reasonable agreement with hospital-reported values, indicating potential clinical utility, though larger cohort studies are warranted to fully establish accuracy and reliability. Overall, this proof-of-concept study demonstrates quantitative α-amylase detection in raw drainage fluid under dynamic flow conditions, representing a step toward continuous monitoring and clinical translation, pending further optimization.

Alzheimer's Disease (AD) is a complex neurodegenerative disorder, with women comprising nearly two-thirds of individuals with AD. However, sex-specific heterogeneity in AD progression remains insufficiently understood. A data-driven approach is needed to characterise such heterogeneity from longitudinal electronic health records (EHRs). We developed a deep learning-based framework to uncover sex-specific AD sub-phenotypes using longitudinal EHRs from OneFlorida+ Clinical Research Consortium. We constructed temporal representations of these EHRs and employed an autoencoder architecture to generate latent embeddings, followed by clustering to derive sex-specific sub-phenotypes with associated progression patterns. We also performed statistical and survival analyses to unravel the characteristics of our identified sub-phenotypes. From 1665 individuals with AD (961 females, 704 males), we identified five major sex-specific sub-phenotypes of AD with distinct progression pathways and comorbidity patterns. Female-dominant sub-phenotypes presented later AD onset, longer disease duration, and enrichment of respiratory and neurological disorders. Male-dominant sub-phenotypes exhibited earlier onset, shorter duration, and higher prevalence of endocrine and metabolic conditions. Survival analysis showed significant differences in time to AD onset across sub-phenotypes. Our findings revealed distinct disease trajectories and comorbidity patterns between male- and female-dominant subgroups with AD. This study provides insight into sex-specific AD progression and demonstrates a data-driven framework for characterising disease heterogeneity using longitudinal EHRs. This study was supported by grants from the Florida Department of Health, the Centers for Disease Control and Prevention, the National Institute of Environmental Health Sciences, and the NIHNational Center for Advancing Translational Sciences.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide. It is associated with the ongoing degeneration of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies that contain α-synuclein. These pathological changes lead to abnormalities of motor symptoms (tremor, rigidity, bradykinesia) and non-motor symptoms (cognitive decline, sleep abnormalities, psychiatric abnormalities). The pathogenesis of PD is complex and multifactorial, involving interconnected mechanisms such as oxidative stress, mitochondrial dysfunction, neuroinflammation, impaired autophagy, ferroptosis, and genetic factors. To develop effective therapeutic interventions, these pathways need to be understood. Current treatments, such as levodopa and deep-brain stimulation (DBS), are symptom-based and do not break disease progression. Thus, considerable research efforts have been geared towards finding disease-modifying therapeutic strategies. Natural bioactive compounds, gene-based therapies, stem cell-based therapies, and nanotechnology-assisted drug delivery systems are promising alternatives as suggested by recent advances. Antioxidant compounds like curcumin, resveratrol, and epigallocatechin gallate (EGCG) show promising antioxidant and neuroprotective effects, and nanomedicine provides boosted delivery to the brain and targeted drug distribution. In future clinical applications, these new strategies could help to more effectively and permanently manage PD.

Patients with obesity who are admitted to an ICU bring specific challenges for rehabilitation during and after critical illness. This narrative review explores impact of differences in body compositions and pathophysiology on outcomes to summarise interprofessional, patient-centred rehabilitation strategies across the trajectory of recovery. The interprofessional expert panel reviewed major trials and guidelines, integrating their clinical expertise with the current evidence. Three distinct phenotypes potentially influence outcomes for survivors. Whilst patients with preserved muscle mass may have a survival advantage, the phenotypes characterised by ectopic visceral fat or sarcopenia are frequently complicated by multimorbidity and polypharmacy, likely increasing the risk of adverse effects such as suboptimal sedation, prolonged ventilation and immobilisation, malnutrition, and impaired recovery. Targeted respiratory interventions, including secretion-clearance techniques and appropriate patient positioning to prevent atelectasis, reduce the work of breathing. Optimisation of communication and swallowing function is an essential component for facilitating safe oral intake and promoting active patient participation in rehabilitation. Concurrently, targeted nutrition strategies combined with early, targeted, progressive mobilisation might mitigate ICU acquired weakness and support functional recovery. The availability of appropriate weight‑based equipment is fundamental to ensuring safe mobilisation for both patients and healthcare professionals. Interprofessional collaboration is central to optimising outcomes and should extend beyond the ICU to structured post-ICU follow-up to address persistent, worsening, or newly emerging health impairments. Early rehabilitation in critically ill patients with obesity should integrate physiological, logistical, and psychosocial considerations to support equitable and functional recovery.

The heart transplant allocation system is evolving in response to increasing demand for donor organs, technological advances, and changes in medical decision-making. In this evolving landscape, the historical focus of allocating donor hearts to the "sickest patients first" principle may warrant periodic reassessment and thoughtful safeguards to ensure responsible stewardship and fairness. It is important to note that ethical considerations are central to frontline transplantation cardiologists and cardiothoracic surgeons, who must balance their role in advocating for their individual patients while aligning with allocation policies designed to benefit all recipients equitably. The goals of this scientific statement are (1) to raise awareness of ethical principles in heart transplantation, (2) to review ethical implications of the past and current allocation systems, and (3) to encourage clinicians and stakeholders to address ethical issues that will provide the foundation for future allocation systems.

Clinical practice guidelines (CPGs) are intended to improve health and reduce disease burden, yet their global status and their association with disease burden remain unknown. This longitudinal ecological study analyzes the quantity and quality of CPGs and explores their associations with disease burden. From 1995 to 2023, 10,657 CPGs were published, with the number of CPGs in 2023 being 5.15 times the number of CPGs in 1995. Europe contributed 40.2% of all CPGs, while CPGs from Africa accounted for only 0.8% of and showed minimal growth. Treatment CPGs contributed the most (45.0%), while diagnosis CPGs showed the fastest growth. Prevention CPGs (8.4%) and nursing CPGs (5.3%) and rehabilitation CPGs were less common, with rehabilitation CPGs showing the slowest growth. The 3-year update rate of CPG is 23.8%. Quality assessment of 1633 CPGs using AGREE II revealed substantial variation across domains. Overall 37.8% CPGs achieved scores above 70% per domain, while the "applicability" domain had the lowest median score (36%). Cross-region CPGs and CPGs for neoplasms exhibited the highest AGREE II scores, with the median score exceeding 70% in 3/6 domains. In contrast, CPGs from Asia and CPGs for cardiovascular diseases did not exceed the 70% threshold in any domain. Neither the quantity nor the quality of CPGs was significantly associated with disease burden at the national level. In conclusion, this study reveals that the quantity of CPGs has increased over the past three decades, although geographic and thematic differences remain. Future opportunities for CPG development include improving the AGREE II scores and focusing on less represented areas including rehabilitation, nursing and prevention.

Global declines in sperm quality urgently demand the identification of modifiable environmental risk factors. Dibromoacetic acid (DBA), a prevalent yet unregulated drinking water disinfection byproduct, is a suspected reproductive toxicant, but population evidence and clear mechanisms are lacking. By integrating epidemiology, network toxicology, and mechanistic validation, we first identified a significant negative association between urinary DBA (100% detection rate) and sperm concentration/count in 282 men. Histone-to-protamine replacement constitutes a critical step in sperm chromatin remodeling. In follow-up mechanistic experiments, we further verified that disruption of this process acted as a novel, central mechanism by which DBA triggered spermatogenic impairment in experimental models. Mechanistically, DBA activated the USF1-PIWIL1 axis to induce a specific piR-rno-9885 that post-transcriptionally suppressed Tnp1. Concurrently, it inhibited the chromatin remodelers CHD4/5. This dual-pathway synergy (piRNA-mediated Tnp1 suppression and CHD4/5 inhibition) compromised chromatin condensation. Moreover, DBA exposure perturbed hormonal homeostasis and triggered testicular inflammation, further disturbing the spermatogenic microenvironment. Collectively, our epidemiological data reveal an adverse human exposure association, while animal and cellular mechanistic assays validate DBA as a reproductive toxicant with a defined molecular mode of action. More broadly, our integrated approach establishes a translatable paradigm that bridges population-level association identification with in-depth mechanistic insight. This paradigm offers an actionable framework for drinking water monitoring, risk assessment, and regulation of DBA and analogous unregulated disinfection byproducts.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex, multifactorial condition. To achieve truly personalized therapy for MASLD, it will be essential to stratify patients based on clinical and biochemical data by identifying subgroups with distinct disease mechanisms and prognostic trajectories. This study conducted unbiased clustering analysis of 349 MASLD patients based on clinical variables. Multi-omics analyses that included spatial transcriptomics, single-cell RNA sequencing (scRNA-seq), and immunohistochemistry were subsequently applied to characterize the biological features of high-risk subgroups. Among the four identified MASLD subgroups, one cluster showed a higher 5-year cumulative incidence of liver-related events (LRE) (24.0%; 95% CI, 14.8%-37.4%), with excess risk persisting after adjustment for advanced fibrosis. This high-risk subgroup was characterized by an immune-driven disease phenotype with excessive IgA expression. Multivariable analysis identified elevated IgA (≥ 318 mg/dL) as an independent predictor of LRE (hazard ratio = 3.17, 95% CI 1.27-7.91; P = 0.01), a finding validated in an independent vibration-controlled transient elastography cohort (n = 287) as well as an external multicenter validation cohort (n = 272). Spatial transcriptomics and scRNA-seq analyses demonstrated portal enrichment of IgA-expressing B-lineage cells, with IGHA1-high regions showing activation of pathways related to B-cell receptor signaling, extracellular matrix remodeling, and vascular remodeling. Intestinal immunohistochemistry and circulating EndoCAb IgG levels supported a link between increased gut permeability and coordinated systemic and intrahepatic IgA-associated immune activation. A data-driven clustering strategy identified a novel MASLD subtype characterized by enhanced IgA-mediated immune activation along the gut-liver axis as a key determinant of disease progression. This IgA-based stratification improves risk assessment and enables mechanism-based therapeutic targeting in high-risk MASLD patients. This study identified a high-risk MASLD subgroup characterized by elevated IgA levels and increased incidence of liver-related events, independent of fibrosis severity. These findings highlight the relevance of immune dysregulation, particularly IgA-associated responses, in MASLD progression.

Co-occurring acne and rosacea is challenging. A digital standardized skin care regimen (SSCG) may be associated with better real-world outcomes, but the clinical-barrier temporal sequence remains unclear. To evaluate associations between SSCG participation and outcomes, the clinical-barrier temporal sequence, transepidermal water loss (TEWL) mediation, and communication frequency. Single-center retrospective cohort with verified dual diagnosis. All patients received doxycycline plus azelaic acid; propensity score matching yielded 282 pairs. Primary outcome was IGA 0/1 at week 12. Cross-lagged, mediation, and E-value analyses were used. SSCG participation was associated with higher IGA 0/1 (54.6% vs 34.4%; RR = 1.59, 95%CI:1.31-1.92), lower relapse (18.8% vs 34.0%), and greater DLQI MCID attainment (91.1% vs 71.3%). Week-6 IGA predicted week-12 TEWL reduction; the reverse path was nonsignificant. TEWL mediated 12.4% of the estimated association. Communication frequency showed no dose-response. Retrospective design, bundled intervention, possible self-selection and cost-related bias, chart-based adherence assessment, and unrecorded exposome and contraceptive changes. In this cohort, SSCG participation was associated with higher clearance and lower relapse. Findings are associative and hypothesis-generating.

The increasing incidence of jellyfish stings from expanding global marine activities necessitates painless therapeutic strategies with real-time treatment assessment capabilities. Here, we present a bioinspired core-shell photonic crystal microneedle (PCMN) patch that addresses this need through dual functionality of both therapeutic delivery and optically transduced monitoring. This device is fabricated by coating hyaluronic acid (HA) shells onto non-close-packed PCMN cores, which are functionalized with chlorpheniramine, while the HA shells incorporate lidocaine as a pain management payload. Upon skin insertion, the patch achieves distinct release profiles of lidocaine (from the shell) and chlorpheniramine (from the core), which are consistent with a structure-dependent release mechanism, addressing the distinct temporal requirements of jellyfish envenomation. Critically, this drug release process is accompanied by measurable shifts in the reflection spectrum, enabling real-time and quantifiable optical monitoring of the release process. The quantitative assessment of drug release can be achieved through the position of the reflection peak in an in vitro agarose-phantom model, allowing direct calibration of treatment progress with simple and portable devices. In a murine model of jellyfish sting envenomation, the PCMN@HA platform demonstrated partially attenuated systemic envenomation within 7 h. This work establishes a theranostic platform that integrates a biomimetic device design with optical signal readout, with potential applications extending to other dermatological conditions requiring temporally controlled pharmacotherapy.

High-pressure processing (HPP) is a promising non-thermal technology for enhancing the bioactivity of polyphenolic compounds. This study investigated the impact of varying HPP conditions (100-600 MPa, 2-10 min) on the antioxidant capacity, resveratrol content, and inhibitory effects against α-glucosidase, cholesterol esterase, and pancreatic lipase. Resveratrol treated with 200-300 MPa for 2 min exhibited significantly higher antioxidant activities (DPPH, ABTS, FRAP, CUPRAC, and DMPD) and enzyme inhibition effects, correlating with increased resveratrol content. Principal component analysis and heatmap visualisation confirmed a strong association between antioxidant performance and enzyme inhibition. These findings suggest that moderate HPP enhances the functional properties of resveratrol, offering a feasible strategy for developing functional foods targeting metabolic disorders. However, further in vivo validation and mechanistic studies are warranted. This study highlights HPP's potential as a clean-label approach to optimising the health benefits of dietary polyphenols.

Brown adipose tissue (BAT) regulates systemic metabolism beyond thermogenesis, yet the circulating mediators through which BAT communicates with other organs remain less explored. Here, we performed comprehensive serum metabolomics and lipidomics in BAT-ablated mice and human cohorts with varying BAT activity to delineate how BAT activity shapes the circulating metabolome. By integrating datasets across serum, tissues, extracellular fluids, and conditioned media, we assembled BAT-linked circulating molecular signatures. The analyses support a critical role for BAT in the clearance of circulating branched-chain amino acids and triglycerides. We also identified a cold-inducible metabolite, 3-hydroxystearic acid (3-OHSA), produced primarily by BAT and released into circulation. 3-OHSA serves as a circulating readout of cold-activated BAT and acts on the liver to reduce mitochondrial membrane potential and reactive oxygen species production, thereby limiting oxidative stress. This work provides a framework for identifying BAT-derived mediators and uncovers a BAT-liver axis that coordinates adaptation to metabolic stress.

1,4-Dichlorobenzene (1,4-DCB), a widely used household insect repellent and fungicide, has been epidemiologically linked to ulcerative colitis, yet its potential mechanisms remain poorly understood. In this study, juvenile male mice developed colonic inflammation following exposure to 1,4-DCB at doses of 0.03-3 mg/kg/day, a range corresponding to the human estimated daily intake (EDI) and relevant internal exposure levels in adolescents. This was evidenced by increased fecal moisture (by 12.22%-18.21%) and colon weight (17.57%-38.33%), shortened colon length (13.51%-24.88%), crypt expansion, and connective tissue hyperplasia. 1,4-DCB exposure upregulated the colonic expression of regenerating family member 3 gamma (Reg3γ), a key antimicrobial peptide that targets Gram-positive bacteria. This upregulation was accompanied by gut microbiota dysbiosis, elevated colonic levels of lipopolysaccharide (LPS) and pro-inflammatory cytokines, as well as decreased levels of tight junction proteins. Microbiota depletion alleviated these colitis symptoms induced by 1,4-DCB. In human colonic cells, we further validated LPS-induced inflammation and impaired permeability as well as identified vitamin D receptor (VDR) as a potential primary molecular target for 1,4-DCB. Overall, this study provides the first evidence that environmentally relevant levels of 1,4-DCB induce colonic inflammation through the VDR-Reg3γ-gut microbiota axis. These findings highlight the potential colonic health risk posed by this prevalent indoor pollutant.