Abstract Background and aims Although the CHAIN trial showed neutral overall effects of FYTF-919 on ICH, treatment responses appeared to vary across patient profiles. We aimed to characterise treatment-effect heterogeneity and identify potential subgroups that derive benefit from FYTF-919. Methods CHAIN was a prospective, randomised, double-blinded, placebo-controlled trial at 26 hospitals in China. Adults with acute moderate-to-severe ICH were randomly assigned to FYTF-919 or placebo for 28 days. The primary outcome was uw-mRS at 90 days. Baseline characteristics were assessed for effect modification using causal forest and non-linear regression, and further evaluated in categorised subgroups analyses with interaction terms added. This trial is registered at ClinicalTrials.gov, NCT05066620. Results Between Nov 24, 2021 and Dec 28, 2023, 1619 participants with available 90-day uw-mRS were included (801 FYTF-919; 818 placebo). Hematoma volume, age and time to randomisation were the strongest contributors to treatment-effect heterogeneity. Non-linear interaction was observed for hematoma volume (p=0·008). Patients with moderate hematoma (16-56mL) showed more favourable 90-day uw-mRS with FYTF-919 (difference 0·07, 95%CI 0·02 to 0·11), whereas no benefit was observed among small or large hematoma. Treatment effects also differed by time to randomisation (<15h vs. ≥15h, p=0·029 for interaction), with more favourable outcomes among participants randomised later. No heterogeneity was observed for other characteristics including age, GCS and hematoma location. Conclusions Treatment effects of FYTF-919 in acute ICH varied across hematoma volume and timing of randomisation. These findings suggest potential benefit in selected subgroups and warrant validation in future trials. Conflict of interest Weiyi Zhong, Dou Wang, Liling Zeng, Jianwen Guo, Craig Anderson, Lili Song: nothing to disclose Figure 1 - belongs to Results Figure 2 - belongs to Results

Hyperuricemia (HUA) is a major risk factor for gout and multiple metabolic disorders. Although serum uric acid (UA) is the gold standard for HUA diagnosis, it fails to reflect early metabolic disturbances and shows limited predictive value for asymptomatic HUA. This study sought to elucidate the pathological mechanisms underlying HUA and identify novel diagnostic biomarkers beyond UA. This study enrolled 195 patients with HUA and 98 healthy controls. Global metabolomics and proteomics profiling were performed to characterize molecular alterations underlying HUA. Based on the biological relevance of the shared dysregulated pathways, a pathway correlation network was constructed to elucidate the pathological mechanisms driving HUA initiation and progression. Furthermore, diagnostic biomarkers for HUA were identified using machine learning algorithms, and were validated with an external cohort. HUA patients exhibited distinct metabolic and proteomic profiles compared with healthy controls. Integrated multi-omics pathway analysis revealed that peroxisome proliferators-activated receptor signaling pathway, arachidonic acid metabolism, purine metabolism, pyrimidine metabolism and sphingolipid signaling pathway were significantly dysregulated in HUA. Among them, arachidonic acid metabolism was identified as a hub pathway involved in HUA progression. Furthermore, a metabolite panel consisting of cysteine-S-sulfate, glycerophosphocholine and 4-hydroxyphenylpyruvic acid was screened by machine learning and validated in an independent cohort, which showed slightly higher diagnostic performance for HUA than UA. This study reveals the core metabolic and protein regulatory networks of HUA, and identifies a novel serum metabolite panel for the diagnosis of HUA. These findings provide new insights for improved clinical diagnosis and management.

Abstract Background and aims In acute intracerebral hemorrhage (ICH), treatment effect heterogeneity may be missed by conventional hypothesis-driven subgroup analyses. We used an agentic AI copilot as a knowledge-discovery framework to identify potential treatment-effect heterogeneity of FYTF-919 in acute ICH. Methods We conducted a secondary analysis of the CHAIN prospective, randomized, double-blind, placebo-controlled trial (N=1642). The primary outcome was 180-day functional status (mRS 0-2 versus 3-6). Eighty-nine baseline demographic, clinical, and imaging variables were analyzed using the Evolutionary Multi-Agent Collaboration (EMAC) framework for subgroup discovery. EMAC employs a multi-agent system where a Data Agent screens variables for clinical validity, a Miner Agent generates and evolves candidate subgroup rules, and a Summary Agent scores each rule by treatment effect, statistical significance, subgroup size, and LLM-assessed clinical plausibility. This agent-driven cycle iteratively refines subgroup definitions toward clinically meaningful and statistically robust rules. Top-ranked subgroups were validated using multivariable logistic regression models to estimate adjusted odds ratios (aORs) with 95% confidence intervals across five drug and surgical treatment modules. Results The EMAC-assisted framework identified interpretable patient profiles showing significant treatment-effect heterogeneity in all five modules (adjusted p<0.05). The strongest effect was observed in surgery-versus-no-surgery among drug-treated patients (aOR=4.55). Modules evaluating drug benefit showed consistent treatment-effect signals (aOR=2.80). Hematoma volume emerged as recurrent feature identifying patients with greatest relative treatment benefit. Conclusions An agentic AI copilot provides a structured and scalable approach for exploratory identification of treatment subgroups in ICH clinical trials. This approach may support hypothesis generation and inform future optimized trial designs for FYTF-919. Conflict of interest Figure 1 - belongs to Methods Figure 2 - belongs to Results

BACKGROUND:The human gut microbiota exhibits significant diversity across populations, influenced by factors such as geography, diet, and lifestyle, particularly between the Han Chinese and non-Chinese populations. While previous studies have predominantly focused on the taxonomic abundance of the gut microbiome, the impact of single nucleotide polymorphisms (SNPs) in driving population-specific differences remains largely underexplored. RESULTS:In this study, we systematically investigated gut microbial differences between the Han Chinese and non-Chinese populations using the Human Gut Microbiome Reference Genome Catalog (HGMRGC). We observed geography was the primary driver of microbial variation of abundance and SNPs. We identified 689 population-specific genome clusters from the Collinsella genus with functional differences in carbohydrate utilization and 108 species exhibiting distinct prevalence related to vitamin biosynthesis, antibiotic resistance, and carbohydrate metabolism. Beta diversity analysis highlighted significant inter-population differences in both microbial abundance and SNPs, while alpha diversity analysis revealed that non-Chinese populations exhibited higher diversity in microbial abundance, and Han Chinese populations displayed greater diversity in SNPs. CONCLUSIONS:This study offers a comprehensive analysis of gut microbial differences between Han Chinese and non-Chinese populations, highlighting the profound influence of population-specific traits on microbial diversity and function. We also provide a comprehensive human gut microbial reference genome catalog, with a particular focus on the Han Chinese population, laying a foundation for future research on gut microbiota genomic variations.

Abstract Background and aims Spontaneous intracerebral hemorrhage is a dynamic, multi-stage condition with marked heterogeneity in hematoma volume and location and clinical time windows, motivating adaptive trial strategies. Using CHAIN as an illustrative case, we assessed whether a Bayesian adaptive enrichment design could lead to conclusions different from a conventional fixed design by identifying and prioritizing potential responder subgroups. Methods We fitted separate models for subgroup and overall treatment effects, using a Gaussian likelihood for the standardized outcome. Under limited effective sample sizes and potentially time-varying effects, we compared scenarios with 2 vs 3 interim looks, stopping thresholds of 20% vs 30%, and three alternative resampling strategies. Six pre-specified variables were tested one at a time as enrichment targets, and one extra exploratory subgroup was derived from literature review and expert input. Results A total of 72 sets of results were generated. Enrichment was triggered in all scenarios. In the 12 scenarios of Location, lobar was enriched and ultimately obtained positive results, including early effective cessation. All other scenarios obtained negative results. In 80.6% (58/72) of scenarios, the adaptive enrichment design produced outcomes different from the original result. As one scenario, under the 25/50/75% three-look design (20% stopping threshold; full-period resampling), the exploratory volume-strata analysis, enrichment favored the 15–50 mL subgroup, at the third interim analysis estimated 0.06 (95% CrI 0.02–0.10), indicating a positive signal. Conclusions Bayesian adaptive enrichment can support timely identification of clinically plausible responder subgroups in ICH and may lead to different trial decisions, but depends critically on prespecified, evidence-grounded enrichment targets. Conflict of interest All authors declare that they have no conflicts of interest.

ETHNOPHARMACOLOGICAL RELEVANCE:In Traditional Chinese Medicine (TCM), dampness is a pathogenic factor arising from impaired production and transportation of bodily fluids. While Fuling Zexie decoction (FLZXD) has demonstrated therapeutic efficacy in dampness constitution (DC) treatment, the material basis underlying its constitutional modulatory effects remains unclear. AIM OF THE STUDY:This study proposes objective indicators for the differentiation and therapeutic evaluation of DC and elucidates the material basis of FLZXD in DC treatment. MATERIALS AND METHODS:Serum exosome proteomic profiling was conducted across two independent cohorts to identify DC-related indicators and assess the therapeutic efficacy of FLZXD in DC-associated hyperlipidemia (DC-hyperlipidemia). The bioactive compounds of FLZXD were prioritized through a comprehensive analysis of patent documentation and network pharmacology, with subsequent validation of DC-related targets using enzyme-linked immunosorbent assay (ELISA). RESULTS:Proteomic analysis of serum exosomes revealed signatures that differentiate individuals with a balanced constitution (BC) from those with DC. The differentially expressed proteins (DEPs) were enriched predominantly in pathways related to the complement cascade and cardiovascular diseases. FLZXD demonstrated therapeutic efficacy against DC-hyperlipidemia, as evidenced by the reversal of DEPs expression following treatment, which was supported by the patentable findings and network pharmacology analysis. Through experimental validation and pharmacological evidence, the active herbs of FLZXD (Fuling, Zexie and Baizhu, collectively referred to as FZB) were identified, and a total of 73 putative therapeutic targets involved in the dampness-resolving effects of FZB were revealed. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment further confirmed that FLZXD exerts its anti-dampness effects primarily through regulation of the complement and coagulation cascades. Among eight candidate indicators specifically associated with DC, four proteins were validated via ELISA, indicating potential utility for the differentiation of DC. The sensitivity (%), specificity (%), fold change (FC), p-value, and area under the curve (AUC) for each indicator were as follows: apolipoprotein B-100 (APOB) (100.00, 80.00, 0.63, 0.0051, 0.94), complement factor H-related protein 1 (CFHR1) (90.00, 100.00, 0.55, 0.0001, 0.98), alpha-1-acid glycoprotein 1 (ORM1) (100.00, 80.00, 0.71, 0.0043, 0.92), and pigment epithelium-derived factor (SERPINF1) (90.00, 70.00, 0.66, 0.0002, 0.87). CONCLUSIONS:The integrative approach, combining proteomic profiling, network pharmacology analysis, and clinical validation, establishes an integrative approach for research on TCM constitutions. This approach provides (1) molecular insights into the differentiation of DC, (2) a foundation for mechanism-based, targeted therapeutic strategies, and (3) enhanced patient stratification to support personalized treatment approaches.

Objective:To identify the predictors of 3-month outcomes in Chinese patients with intracerebral hemorrhage (ICH) receiving conservative management. Methods:From October 2013 to May 2016, a total of 5,589 individuals with ICH were screened as part of the CRRICH study (Clinical re-evaluation of removing blood stasis therapy in treating acute intracerebral hemorrhage). Of these, 319 patients were ultimately enrolled. This study constitutes a post analysis of the CRRICH study. Potential predictors of poor outcomes following spontaneous ICH, initially identified through univariate analysis, were further evaluated using an unconditional multiple logistic regression model. Poor outcomes were defined as a modified Rankin scale score > 2 at 90 days post-ICH. Results:Of the 319 patients (mean age 62.46 ± 0.71 years; male/female ratio 1.8:1), 89 (27.9%) had poor 3-month outcomes. Multivariable analysis showed increased odds of poor outcomes with older age (odds ratio [OR] 1.05; 95% confidence interval [CI] 1.02-1.08; p < 0.001), right hemispheric hemorrhage (OR 2.41; 95% CI 1.26-4.60; p = 0.008), intraventricular hemorrhage (OR 3.70; 95% CI 1.80-7.61; p < 0.001), and a higher National Institutes of Health Stroke Scale score (NIHSS) (OR 1.21; 95% CI 1.14-1.29; p < 0.001). Conversely, higher body mass index (BMI) (OR 0.88; 95% CI 0.77-0.99; p = 0.015) and shorter symptom-to-admission time (OR 0.77; 95% CI 0.62-0.97; p = 0.025) were associated with reduced odds of poor outcomes. Conclusion:In conservatively treated ICH patients, right hemispheric involvement, ventricular hemorrhage, older age, and higher NIHSS score increased poor outcome risks at 3 months, while higher BMI and early admission reduced risks, aiding clinical prognosis prediction.

BACKGROUND:Stroke-associated pneumonia (SAP) represents a major complication and cause of death in patients suffering from intracerebral haemorrhage (ICH). It's urgent to develop more effective therapeutic strategies. Tongfu Xingshen capsule (TFXS) is a traditional Chinese medicine that has been utilised in clinical studies for the treatment of ICH and SAP, but the underlying mechanisms remain to be fully elucidated. PURPOSE:This study aims to explore the therapeutic effects and mechanisms of TFXS on SAP using an aspiration-induced Klebsiella pneumoniae infection-complicating ICH rat model and an intratracheal injection of lipopolysaccharide (LPS)-induced acute lung injury-complicating ICH rat model. METHODS:The chemical components of TFXS are characterised using ULPLC-Q Exactive-Orbitrap-MS. The therapeutic effects of TFXS are evaluated through neurological scoring, histopathology analysis, magnetic resonance imaging, immunofluorescence, Alcian blue-nuclear fast red staining, myeloperoxidase activity assessment, leukocyte counting, and ELISA. To investigate the underlying mechanisms, faecal microbiota transplantation, 16S rRNA sequencing, untargeted metabolomics, and Spearman correlation analyses are performed. RESULTS:A total of 60 compounds are identified in TFXS. Pharmacological analysis reveals that TFXS significantly mitigates neurological deficits, enhances haematoma absorption, attenuates brain damage and neuroinflammation, and improves pneumonia and pulmonary injury by reducing the infiltration of leukocytes and lymphocytes, as well as suppressing the infiltration and overactivation of neutrophils. TFXS also alleviates intestinal lesions and barrier damage by increasing acidic mucins and the expression of the tight junction protein zonula occludens-1 (ZO-1). Mechanistically, TFXS ameliorates pneumonia and pulmonary injury in a gut microbiota-dependent manner. It reverses sphingolipid metabolism disorders and ceramide accumulation by modulating SAP-induced gut microbiota dysbiosis and enhancing the abundance of probiotics, including Lactobacillus, Allobaculum and Enterococcus. CONCLUSION:TFXS exerts anti-inflammatory and protective effects on the brain, lung, and gut by alleviating gut microbiota dysbiosis and sphingolipid metabolism disorders. These findings highlight TFXS as a promising therapeutic candidate for the treatment of SAP.

Recently,the burden of stroke in China is currently increasing,and the clinical evidences have emerged in the field of integrative medicine for stroke.To standardize the prevention and treatment of integrative medicine for stroke,twelve research questions were identified after evaluating the necessity of updating guideline and selecting research questions,which were based on "Evidence-based Practice Guideline on Integrative Medicine for Stroke 2019".The guideline project was set up to China Association of Chinese Medicine as "Clinical Practice Guideline for the Prevention and Treatment of Stroke with Integrated Traditional Chinese and Western Medicin".Eighteen recommendations regarding integrative medicine for ischaemic stroke,haemorrhagic stroke,and complications of stroke were proposed following the latest clinical practice guidelines,systematic retrieval and objective evaluation of clinical evidence,experience of clinical experts of Chinese and Western medicine,discussion in working group,and solicited opinion.This guideline provided scientific and specific guidance for medical practitioners at all levels,and promoted the standardized application of integrative medicine for stroke,to reduce the death,recurrence and disability of stroke.

Introduction:Long-term SARS-CoV-2-IgG antibody durability after natural infection remains a critical determinant of long-term protection. However, the factors that affect long-term IgG antibody durability are not fully understood. Methods:This study delves into the clinical and host genetic factors influencing the level of long-term anti-SARS-CoV-2-receptor-binding domain IgG (RBD-IgG) antibodies after natural infection during the first wave of the COVID-19 pandemic (17 January to 24 June 2020). The cohort, comprising 572 COVID-19 patients from Wuhan, China, had no exposure to COVID-19 vaccines, variants, or antiviral treatments, enabling a focused analysis of the virus's direct impact. Results:We found that the rate of RBD-IgG seropositivity 6 months after infection remained high (94.58%). Through a generalized linear model and mediation analysis, older age, independent of disease severity, was found to be a key independent factor associated with higher post-infection RBD-IgG titers. Hypothesis-generating analyses through a genome-wide association study revealed that rs117929853 (p = 3.6 × 10-8), a variant located upstream of the xanthine dehydrogenase gene (XDH), was significantly associated with RBD-IgG persistence, suggesting a potential mechanistic link between XDH polymorphisms and sustained humoral immunity. Conclusion:The study underscores the significant role of age and genetic factors in the pathogenesis of sustained humoral immunity, which requires further validation.

Shi Zheng (SZ, syndrome of dampness) is a major syndrome type in traditional Chinese Medicine (TCM), the ambiguity of its pathomechanism and the lack of blood diagnostic indicators have limited the understanding of the development of SZ. To explore the pathological mechanism of SZ and establish a symptom-centered diagnosis and treatment model. We recruited 250 participants, including healthy individuals and patients diagnosed with SZ. Serum metabolomics and proteomics analyses were performed to screen common pathways. Along with the biological significance of common pathways, a common pathway-symptom correlation diagram was constructed to elucidate the pathological mechanism underlying the occurrence and development of SZ. The enrichment score and correlations with SZ main symptom was used to screen the key common pathways. The key common pathways related to differential metabolites and proteins were used to establish a multi-index diagnostic model and protein therapy target group. Joint metabolomics and proteomics analyses revealed 18 common pathways associated with symptoms. Six key pathways, such as pathogenic Escherichia coli infection, rheumatoid arthritis, PPAR signaling pathway, bile secretion, GnRH signaling pathway, and fat digestion and absorption were correlated with the main symptoms of SZ. These symptoms included greasy/thick/slippery tongue coating, heavy head, heavy body, heavy limbs, heavy joints, greasy hair, sticky mouth, sticky stool, and damp scrotum. Moreover, seven differential metabolites related to the key pathways were identified: LysoPA (20:3(5Z,8Z,11Z)/0:0), prostaglandin E2, leukotriene B4, lithocholate 3-O-glucuronide, 3-hydroxyquinine, lithocholic acid glycine conjugate, and PA(18:0/22:6(5Z,8E,10Z,13Z,15E,19Z)-2OH(7S, 17S)), and the combined diagnostic value of the seven indicators was the highest (discovery cohort: AUC = 0.90; validation cohort: AUC = 0.99). There were 23 differential proteins related to the key pathways, and six protein targets were identified, including RHOA, TNFSF13, PRKCD, APOA2, ATP1A1, and FABP1. The combined analysis of metabolomics and proteomics established a symptom-centered diagnosis and treatment model of Shi Zheng.

Ischemic stroke is a common chronic disease worldwide and is correlated with a high disability rate. Sarcopenia is considered a key factor in the disablement process. Limited evidence of sarcopenia in acute ischemic stroke is available. The aim of this study was to investigate the effect of sarcopenia on the prognosis of patients with acute ischemic stroke. A prospective cohort study was conducted and included patients who were diagnosed with acute ischemic stroke between August 2020 and May 2021. A modified Poisson regression was applied to determine the relative risk (RR) for the change in modified Rankin Scale (mRS) score and allow adjustment for confounders. The modified Poisson regression was used to identify associations between sarcopenia, and multiple linear regression analyses were used to assess the effect of sarcopenia on the Barthel Index (BI) and stroke-specific quality of life (SSQOL). The generalized linear mixed model was used to investigate the effect of sarcopenia on prognosis at 1, 3 and 6 months. Cox regression proportional risk model was used to analyze the effect of sarcopenia on readmission in patients with acute ischemic stroke. The prevalence of sarcopenia was 39.83

BACKGROUND:Fuzheng Jiedu granules (FZJD) is widely used for COVID-19 in China, with early studies indicating reduced mortality in severe cases. However, with emerging variants and shifted treatment focus on preventing severity and relieving symptoms, high-level clinical evidence, especially for high-risk patients, remains lacking. METHODS:A randomized controlled trial (ChiCTR2200058181 ) was performed to assess FZJD's efficacy and safety in high-risk adults with non-severe COVID-19. The primary outcome was the proportion of progression to severe COVID-19 after enrollment, with secondary outcomes focusing on the time to resolution of main symptoms. RESULTS:From November 2021 to July 2022, 231 eligible patients were randomized to receive either 15 g of FZJD (n = 119) or placebo (n = 112) thrice daily for 14 days. Patients receiving FZJD (1/101, 1.0 % [95 % CI, 0.0 %, 5.4 %]) had a numerically lower progression proportion to severe COVID-19 than those receiving placebo (2/95, 2.1 % [95 % CI, 0.3 %, 7.4 %]), although with a non-significant difference of -1.1 % (95 % CI, -7.4 %, 6.2 %; p = 0.545) after adjusted by center. FZJD use was associated with significantly shorter time to sustained disappearance of cough (median days, 10.0 vs. 12.0, HR, 1.46 [1.03, 2.07], p = 0.022), fever (median days, 6.0 vs. 7.0, HR, 1.69 [1.03, 2.76], p = 0.031), and chest distress (median days, 7.0 vs. 11.0, HR, 3.28 [1.23, 8.73], p = 0.031). Patients experience comparable adverse events in the two groups (2.7 % in FZJD vs. 1.9 % in placebo). CONCLUSION:Among high-risk COVID-19 patients, FZJD showed obvious symptom improvements and numerically lower disease progression than placebo, without additional adverse events.

Ferroptosis is a new type of controlled cell death. It is distinguished by its reliance on iron and the production of lipid peroxidation. The role of ferroptosis in stroke has attracted a lot of attention recently. The purpose of this review is to clarify the connection between ferroptosis and stroke and to investigate the potential contribution of natural products to the clinical management of stroke and the discovery of novel medications. In this review, we summarize in detail the mechanism of ferroptosis after stroke, especially the relevant targets of ferroptosis after stroke. Furthermore, we summarize the natural products and herbal medicine currently employed in ferroptosis along with their mechanisms of action, highlighting the potential and challenges of clinical translation. We included 55 articles and classified them. After systematic screening, We think that ginkgolide B, kellerin, loureirin C, quercetin, icariside II, salvianolic acid A, berberine, Dl-3-n-butylphthalide is an effective candidate drug for the treatment of stroke.

The human gut microbiota exhibits significant diversity across populations, influenced by factors such as geography, diet, and lifestyle, particularly between the Han Chinese and non-Chinese populations. While previous studies have predominantly focused on the taxonomic abundance of the gut microbiome, the impact of single nucleotide polymorphisms (SNPs) in driving population-specific differences remains largely underexplored. In this study, we systematically investigated gut microbial differences between the Han Chinese and non-Chinese populations using the Human Gut Microbiome Reference Genome Catalog (HGMRGC). HGMRGC includes 271,480 non-redundant genomes from 5,785 prokaryotic species, which was generated by metagenomic sequencing data from 9,320 publicly available samples across 22 countries and 3,584 newly sequenced samples from Han Chinese individuals across 29 provinces and regions in China. We observed geography was the primary driver of microbial variation of abundance and SNPs. We identified 625 novel population-specific genome clusters from HGMRGC with functional differences in carbohydrate utilization and 126 species exhibiting distinct prevalence related to vitamin biosynthesis, antibiotic resistance, and carbohydrate metabolism. Beta diversity analysis highlighted significant inter-population differences in both microbial abundance and SNPs, while alpha diversity analysis revealed that non-Chinese populations exhibited higher diversity in microbial abundance, and Han Chinese populations displayed greater diversity in SNPs. These results provide valuable insights into population-specific microbial diversity, laying the groundwork for future research on its functional and health implications. ### Competing Interest Statement Lijuan Han is an employee of Kangmeihuada GeneTech Co., Ltd (KMHD). Dmitry A. Rodionov and Andrei L. Osterman are cofounders of Phenobiome Inc., a company pursuing development of computational tools for predictive phenotype profiling of microbial communities. The remaining authors declare no competing interests.

BackgroundA stable and reproducible experimental bacterial pneumonia model postintracerebral hemorrhage (ICH) is necessary to help investigating the pathogenesis and novel treatments of Stroke-associated pneumonia (SAP).AimTo establish a Gram-negative bacterial pneumonia-complicating ICH rat model and an acute lung injury (ALI)-complicating ICH rat model.MethodsWe established two standardized models of post-ICH pneumonia by nasal inoculation with Klebsiella pneumoniae (Kp) or intratracheal inoculation with lipopolysaccharide (LPS). Survival and neurological scores were monitored. Magnetic resonance imaging was performed to evaluate hematoma volume. Abdominal aortic blood was collected for leukocyte counting, serum was isolated to determine concentrations of S100β and proinflammatory cytokines using ELISAs. Histopathological changes of brain, lung and gut were assessed using hematoxylin−eosin staining. Lung was isolated for immunofluorescence staining for myeloperoxidase (MPO). Bronchoalveolar lavage fluid was collected for leukocyte counting, and supernatant was prepared to measure MPO activity. Ileum was isolated for immunofluorescence staining for tight junction proteins ZO-1 and γδ TCRs/IL-17A and for Alcian blue–nuclear fast red staining of acidic mucins. Feces were collected, 16S rRNA sequencing, untargeted metabolomics and Spearman’s correlation analyses were performed to explore changes of gut microbiota, metabolites and their interactions.ResultsIn Kp-induced bacterial pneumonia-complicating ICH rats, we demonstrated that Kp challenge caused more severe neurological deficits, brain damage, neuroinflammation, and aggravated pneumonia and lung injury. Disruptions of the intestinal structure and gut barrier and the reductions of the protective intestinal IL-17A-producing γδT cells were also observed. Kp challenge exacerbated the gut microbiota dysbiosis and fecal metabolic profile disorders, which were characterized by abnormal sphingolipid metabolism especially elevated ceramide levels; increased levels of neurotoxic quinolinic acid and an upregulation of tryptophan (Trp)–serotonin–melatonin pathway. Spearman’s correlation analyses further revealed that the reduction or depletion of some beneficial bacteria, such as Allobaculum and Faecalitalea, and the blooming of some opportunistic pathogens, such as Turicibacter, Dietzia, Corynebacterium and Clostridium_sensu_stricto_1 in Kp-induced SAP rats were associated with the disordered sphingolipid and Trp metabolism. Using an LPS-induced ALI complicating ICH model, we also characterized SAP-induced brain, lung and gut histopathology injuries; peripheral immune disorders and intense pulmonary inflammatory responses.ConclusionsThese two models may be highly useful for investigating the pathogenesis and screening and optimizing potential treatments for SAP. Moreover, the differential genera and sphingolipid or Trp metabolites identified above seem to be promising therapeutic targets.

BackgroundThe association of prediabetes and diabetes on health-related quality of life (HRQoL) remains inconclusive in current epidemiological research. In this investigation, we administered 5-level EuroQoL-5 dimension version (EQ-5D-5L) to systematically assess HRQoL across glycemic strata (diabetes, prediabetes, and normal glycemic levels) in Guangzhou, and to offer baseline data that can be easily compared to other regions in China or across countries.MethodThis investigation utilized baseline cross-sectional data extracted from a three-year prospective cohort study conducted at the Health Management Center of Guangzhou 11th People’s Hospital. Propensity score matching was implemented at a 1:1:4 ratio to balance participants across diabetes, prediabetes, and normal glycemic group. HRQoL outcomes, operationalized through EQ-Index and EQ visual analog scale (EQ-VAS) measurements, were compared across groups using one-way ANOVA or Wilcoxon rank-sum tests. Multivariate linear regression was constructed to adjust for potential confounders, followed by subgroup analyses stratified by sex, age categories, body mass index (BMI) classifications, and hypertension comorbidity status.ResultsA total of 18,605 participants were included in the study. After propensity score matching, 533 participants allocated to the prediabetes group, 533 to the diabetes group, and 2064 to the normal glycemic group. Intergroup comparisons demonstrated significantly lower EQ-VAS scores in the diabetes group (79.11) compared to both prediabetes (80.67) and normal glycemic group (81.65). Similarly, the diabetes group exhibited the lowest EQ-Index scores (0.968) relative to prediabetes (0.972) and normal glycemic group (0.972). Multivariate linear regression adjusted with sex, age, BMI, etc. revealed a 2.139-point reduction in EQ-VAS scores for the diabetes group versus normal glycemic group (95% CI: -3.748, -0.530; P=0.009). Subgroup analyses identified particularly compromised HRQoL in diabetes and prediabetes populations among female participants, individuals with obesity, and those aged ≥60 years.DiscussionPrediabetes and diabetes mellitus are associated with diminished HRQoL compared to normal glycemic levels, with a more pronounced negative associations observed among female populations, older adults, and individuals with obesity. These findings emphasize the clinical necessity for implementing targeted interventions to optimize HRQoL outcomes in these high-risk subgroups, which aligns with the fundamental objectives of contemporary diabetes management frameworks.Clinical trial registrationClinicalTrials.gov ID: NCT05315895.

INTRODUCTION:The traditional Chinese medicine herbal compound FYTF-919 (Zhong Feng Xing Nao prescription) may improve outcome from acute intracerebral hemorrhage by reducing brain edema, hematoma absorption, and enhancement of the immune system. We outline the statistical analysis plan (SAP) for the Chinese Herbal medicine in Acute INtracerebral hemorrhage (CHAIN) study. CHAIN is a multicenter, prospective, randomized, double-blind, placebo-controlled trial being undertaken at 20-30 hospitals in China. After the completion of eligibility checks, patients are randomly allocated to FYTF-919 (100 mL per day, oral) or matching placebo over 28 days. A sample size of 1,504 patients is estimated to provide 90% power (α 0.05) for a 0.06 absolute improvement in the primary outcome of utility-weighted modified Rankin scale scores at 90 days, analyzed by general linear regression. METHODS:The SAP was developed by the study statistician, principal investigators, international experts, and the study project manager. The plan provides details for analyzing baseline characteristics, patient management, and outcomes. It includes provisions for covariate adjustments, subgroup analysis, the handling missing data, and in the conduct of sensitivity analyses. DISCUSSION:A predefined SAP was established for CHAIN, facilitating transparent and verifiable analysis. The CHAIN SAP was prospectively developed with a focus on maintaining high-quality standards of internal validity to minimize potential analysis biases.

Intracerebral hemorrhage (ICH) could trigger inflammatory responses. However, the specific role of inflammatory proteins in the pathological mechanism, complications, and prognosis of ICH remains unclear. In this study, we investigated the expression of 92 plasma inflammation-related proteins in patients with ICH (n = 55) and healthy controls (n = 20) using an Olink inflammation panel and discussed the relation to the severity of stroke, clinical complications, 30-day mortality, and 90-day outcomes. Our result showed that six proteins were upregulated in ICH patients compared with healthy controls, while seventy-four proteins were downregulated. In patients with ICH, seven proteins were increased in the severe stroke group compared with the moderate stroke group. In terms of complications, two proteins were downregulated in patients with pneumonia, while nine proteins were upregulated in patients with sepsis. Compared with the survival group, three proteins were upregulated, and one protein was downregulated in the death group. Compared with the good outcome group, eight proteins were upregulated, and four proteins were downregulated in the poor outcome group. In summary, an in-depth exploration of the differential inflammatory factors in the early stages of ICH could deepen our understanding of the pathogenesis of ICH, predict patient prognosis, and explore new treatment strategies.