Experimental Evidence for the Role of Dynamics in pH-Dependent Enzymatic Activity.

Enzymatic activity is heavily influenced by pH, but the rationale for the dynamical mechanism of pH-dependent enzymatic activity has not been fully understood. In this work, combined neutron scattering techniques, including quasielastic neutron scattering (QENS) and small angle neutron scattering (SANS), are used to study the structural and dynamic changes of a model enzyme, xylanase, under different pH and temperature environments. The QENS results reveal that xylanase at optimal pH exhibits faster relaxational dynamics and a lower energy barrier between conformational substates. The SANS results demonstrate that pH affects both xylanase's stability and monodispersity. Our findings indicate that enzymes have optimized stability and function under their optimal pH conditions, with both structure and dynamics being affected. The current study offers valuable insights into enzymatic functionality mechanisms, allowing for broad industrial applications.

Formation Mechanisms, Interrelationships, and Effects of Cognitive Factors on Diet and Physical Activity During the Post-Bariatric Surgery Period: A Cross-Sectional Study Based on Compensatory Carry-Over Action Model.

Background: Diet and physical activity (PA) are pivotal behaviors for managing energy balance post-bariatric surgery. Given the need for dual behavioral management, understanding the interplay of cognitive factors influencing these behaviors is crucial. This study applied the compensatory carry-over action model (CCAM) to explore the impact of cognitive factors on behaviors and their subsequent effects on subjective health outcomes. Methods: This cross-sectional study was conducted among patients at the third month after bariatric surgery in China. Data on diet and PA status, behavioral cognitive factors (intention, self-efficacy, compensatory belief, transfer cognition), and subjective health outcomes (perceived stress, well-being, quality of life) were collected. Structural equation model (SEM) was employed to test hypotheses in CCAM and assess mediation relationships. Results: Analysis of data from 239 patients revealed the following: (1) Among antecedent cognitive factors, only compensatory belief significantly influenced diet (P<0.001). (2) Intention and self-efficacy directly correlated with their respective behaviors, while compensatory belief affected intention, and transfer cognition impacted self-efficacy (P<0.05), aligning with CCAM hypotheses. (3) PA demonstrated significant influence only on perceived stress (P=0.004), whereas diet significantly affected all subjective health outcomes (P<0.05). (4) Mediation analysis indicated intention partially mediated the relationship between compensatory belief and diet and fully mediated the relationship between compensatory belief and PA. Self-efficacy completely mediated the relationship between transfer cognition and diet and PA. Conclusion: Transfer cognition's carry-over effect did not directly influence behaviors among antecedent cognitions. Interventions should primarily target improving diet by mitigating compensatory belief. Moreover, diet exhibited a more pronounced impact on overall health compared to PA. Consequently, prioritizing dietary intervention over PA intervention is warranted based on the analysis of CCAM and the aim of promoting joint behaviors post-bariatric surgery.

In vitro interaction of naphthoquine with ivermectin, atovaquone, curcumin, and ketotifen in the asexual blood stage of Plasmodium falciparum 3D7.

Naphthoquine is a promising candidate for antimalarial combination therapy. Its combination with artemisinin has demonstrated excellent efficacy in clinical trials conducted across various malaria-endemic areas. A co-formulated combination of naphthoquine and azithromycin has also shown high clinical efficacy for malaria prophylaxis in Southeast Asia. Developing new combination therapies using naphthoquine will provide additional arsenal responses to the growing threat of artemisinin resistance. Furthermore, due to its long half-life, the possible interaction of naphthoquine with other drugs also needs attention. However, studies on its pharmacodynamic interactions with other drugs are still limited. In this study, the in vitro interactions of naphthoquine with ivermectin, atovaquone, curcumin, and ketotifen were evaluated in the asexual stage of Plasmodium falciparum 3D7. By using the combination index analysis and the SYBR Green I-based fluorescence assay, different interaction patterns of selected drugs with naphthoquine were revealed. Curcumin showed a slight but significant synergistic interaction with naphthoquine at lower effect levels, and no antagonism was observed across the full range of effect levels for all tested ratios. Atovaquone showed a potency decline when combined with naphthoquine. For ivermectin, a significant antagonism with naphthoquine was observed at a broad range of effect levels below 75% inhibition, although no significant interaction was observed at higher effect levels. Ketotifen interacted with naphthoquine similar to ivermectin, but significant antagonism was observed for only one tested ratio. These findings should be helpful to the development of new naphthoquine-based combination therapy and the clinically reasonable application of naphthoquine-containing therapies. IMPORTANCE: Pharmacodynamic interaction between antimalarials is not only crucial for the development of new antimalarial combination therapies but also important for the appropriate clinical use of antimalarials. The significant synergism between curcumin and naphthoquine observed in this study suggests the potential value for further development of new antimalarial combination therapy. The finding of a decline in atovaquone potency in the presence of naphthoquine alerts to a possible risk of treatment or prophylaxis failure for atovaquone-proguanil following naphthoquine-containing therapies. The observation of antagonism between naphthoquine and ivermectin raised a need for concern about the applicability of naphthoquine-containing therapy in malaria-endemic areas with ivermectin mass drug administration deployed. Considering the role of atovaquone-proguanil as a major alternative when first-line artemisinin-based combination therapy is ineffective and the wide implementation of ivermectin mass drug administration in malaria-endemic countries, the above findings will be important for the appropriate clinical application of antimalarials involving naphthoquine-containing therapies.

Met343Val mutation disrupts the shuttling of Trp380 leading to a low-activity conformer of activated protein C and causes thrombosis.

BACKGROUND: Protein C (PC) pathway serves as a major defense mechanism against thrombosis by the activation of PC through the thrombin-thrombomodulin (TM) complex and subsequent inactivation of the activated factor V (FVa) and factor VIII (FVIIIa) with the assistance of protein S, thereby contributing to hemostatic balance. We identified two unrelated patients who suffered from recurrent thrombosis and carried the same heterozygous mutation c.1153A>G, p. Met343Val (M343V) in PROC gene. This mutation had not been previously reported. OBJECTIVES: To explore the molecular basis underlying the anticoagulant defect in patients carrying the M343V mutation in PROC. METHODS: We expressed PC-M343V variant in mammalian cells and characterized its properties through coagulation assays. RESULTS: Our findings demonstrated that while activation of mutant zymogen by thrombin-TM was slightly affected, cleavage of chromogenic substrate by APC-M343V was significantly impaired. However, Ca2+ increased the cleavage efficiency by approximately 50%. Additionally, there was a severe reduction in affinity between APC-M343V and Na+. Furthermore, the inhibitory ability of APC-M343V towards FVa was markedly impaired. Structural and simulation analyses suggested that Val343 might disrupt the potential hydrogen bonds with Trp380 and cause Trp380 to orient closer to His211, potentially interfering with substrate binding and destabilizing the catalytic triad of APC. CONCLUSION: The M343V mutation in patients adversely affects the reactivity and/or folding of the active site as well as the binding of the physiological substrate to the protease, resulting in impaired protein C anticoagulant activity, ultimately leading to thrombosis.

Establishment of in-hospital nutrition support program for middle-aged and elderly patients with acute decompendated heart failure.

OBJECTIVE: To construct a nutrition support program for middle-aged and elderly patients with acute decompensated heart failure (ADHF) during hospitalization. METHODS: Based on the JBI Evidence-Based Health Care Model as the theoretical framework, the best evidence was extracted through literature analysis and a preliminary nutrition support plan for middle-aged and elderly ADHF patients during hospitalization was formed. Two rounds of expert opinion consultation were conducted using the Delphi method. The indicators were modified, supplemented and reduced according to the expert's scoring and feedback, and the expert scoring was calculated. RESULTS: The response rates of the experts in the two rounds of consultation were 86.7% and 100%, respectively, and the coefficient of variation (CV) for each round was between 0.00% and 29.67% (all < 0.25). In the first round of expert consultation, 4 items were modified, 3 items were deleted, and 3 items were added. In the second round of the expert consultation, one item was deleted and one item was modified. Through two rounds of expert consultation, expert consensus was reached and a nutrition support plan for ADHF patients was finally formed, including 4 first-level indicators, 7 s-level indicators, and 24 third-level indicators. CONCLUSION: The nutrition support program constructed in this study for middle-aged and elderly ADHF patients during hospitalization is authoritative, scientific and practical, and provides a theoretical basis for clinical development of nutrition support program for middle-aged and elderly ADHF patients during hospitalization.

Cumulative remnant cholesterol burden increases the risk of cardiovascular disease among young adults.

BACKGROUND: Previous studies have shown that remnant cholesterol (RC) was associated with cardiovascular disease (CVD) among middle-aged or older adults. However, lack of evidence on long-term exposures to RC and their role in CVD risk among young adults. We thus aimed to explore the association between cumulative RC burden and CVD in young adults. METHODS: We enrolled participants younger than 45 years free of CVD history in the Kailuan Study who completed the first three health examinations from 2006 to 2010. Cumulative RC burden included cumulative RC burden score, time-weighted cumulative RC, exposure duration of high RC, and time course of RC accumulation. The outcome was the incidence of CVD. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) between cumulative RC burden and CVD risk. RESULTS: A total of 15,219 participants were included (73.70% male, median age 39.13 years). During a median follow-up duration of 8.71 years (interquartile range: 8.4-9.15 years), 502 individuals developed CVD. After adjustment for traditional cardiovascular risk factors, highest risk of CVD was observed in participants with the highest cumulative RC burden score (HR, 1.66; 95% CI, 1.29-2.12), the highest quartile time-weighted cumulative RC (HR,1.50; 95% CI, 1.15-1.96), the longest exposure duration of high RC (HR, 1.71; 95% CI, 1.21-2.42), and those with cumulative RC burden and positive slope (HR, 1.79; 95% CI, 1.35-2.36). CONCLUSIONS: Cumulative RC burden increased the risk of CVD among young adults, suggesting that maintaining low RC levels throughout young adulthood may minimize CVD risk.

Long-term survival outcomes and immune checkpoint inhibitor retreatment in patients with advanced cervical cancer treated with camrelizumab plus apatinib in the phase II CLAP study.

BACKGROUND: Camrelizumab plus apatinib have demonstrated robust antitumor activity and safety in patients with advanced cervical cancer (CLAP study; NCT03816553). We herein present the updated long-term results of the CLAP study and explore potential biomarkers for survival. The outcomes of patients who underwent immune checkpoint inhibitor (ICI) retreatment were also reported. METHODS: In this phase II trial, eligible patients received camrelizumab 200 mg intravenously every two weeks and apatinib 250 mg orally once daily in 4-week cycles for up to two years. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. RESULTS: Between January 21 and August 1, 2019, a total of 45 patients were enrolled. Data were analyzed as of July 31, 2023, representing > 48 months since treatment initiation for all patients. Nine (20.0%) patients completed the 2-year study. The median duration of response (DOR) was 16.6 months, and 45.0% of patients achieved a DOR of ≥ 24 months. The 12-month progression-free survival (PFS) rate was 40.7% (95% confidence interval [CI], 25.2-55.6), with an 18-month PFS rate of 37.8% (95% CI, 22.7-52.8). The median overall survival (OS) was 20.3 months (95% CI, 9.3-36.9), and the 24-month OS rate was 47.8% (95% CI, 31.7-62.3). Age > 50 years, programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 1 (versus [vs.] < 1), CPS ≥ 10 (vs. < 1), high tumor mutational burden, and PIK3CA mutations were associated with improved PFS (hazard ratio [HR] < 1) and longer OS (HR < 1). Eight patients who initially responded in the CLAP trial but later experienced disease progression were retreated with ICIs. Among them, 2 (25.0%) achieved a partial response, while 5 (62.5%) had stable disease. Notably, four patients who received retreatment with ICIs survived for more than 45 months. No new safety signals were identified in the present study. CONCLUSION: Long-term survival follow-up data demonstrated that camrelizumab plus apatinib has robust, sustained, and durable efficacy in patients with advanced cervical cancer who progress after first-line platinum-based chemotherapy. No new safety signals were noted with long-term treatment.

The short-chain fatty acid propionate prevents ox-LDL-induced coronary microvascular dysfunction by alleviating endoplasmic reticulum stress in HCMECs.

Coronary microvascular dysfunction (CMD) is a critical pathogenesis of cardiovascular diseases. Lower endothelial nitric oxide synthase (eNOS) phosphorylation leads to reduced endothelium-derived relaxing factor nitric oxide (NO) generation, causing and accelerating CMD. Endoplasmic reticulum stress (ER stress) has been shown to reduce NO production in umbilical vein endothelial cells. Oxidized low-density lipoprotein (ox-LDL) damages endothelial cell function. However, the relationship between ox-LDL and coronary microcirculation has yet to be assessed. Short-chain fatty acid (SCFA), a fermentation product of the gut microbiome, could improve endothelial-dependent vasodilation in human adipose arterioles, but the effect of SCFA on coronary microcirculation is unclear. In this study, we found ox-LDL stimulated expression of ER chaperone GRP78. Further, we activated downstream PERK/eIF2a, IRE1/JNK, and ATF6 signaling pathways, decreasing eNOS phosphorylation and NO production in human cardiac microvascular endothelial. Furthermore, SCFA-propionate can inhibit ox-LDL-induced eNOS phosphorylation reduction and raise NO production; the mechanism is related to the inhibition of ER stress and downstream signaling pathways PERK/eIF2a, IRE1/JNK, and ATF6. In summary, we demonstrate that ox-LDL induced CMD by activating ER stress, propionate can effectively counteract the adverse effects of ox-LDL and protect coronary microcirculation function via inhibiting ER stress.

Upgraded and Light-Up Biosensing Platform: Entropy-Driven Catalysis Circuit Manipulates the Configuration Transformation of Novel DNA Silver Nanoclusters on the Graphene Oxide Surface.

To tackle the predicament of the traditional turn-off mechanism, exploring an activated turn-on system remains an intriguing and crucial objective in biosensing fields. Herein, a dark DNA Ag nanocluster (NC) with hairpin-structured DNA containing a six-base cytosine loop (6C loop) as a template is atypically synthesized. Intriguingly, the dark DNA Ag NCs can be lit to display strong red-emission nanoclusters. Building upon these exciting findings, an unprecedented and upgraded turn-on biosensing system [entropy-driven catalysis circuit (EDCC)-Ag NCs/graphene oxide (GO)] has been created, which employs an EDCC to precisely manipulate the conformational transition of DNA Ag NCs on the GO surface from adsorption to desorption. Benefiting from the effective quenching of GO and signal amplification capability of the EDCC, the newly developed EDCC-Ag NCs/GO biosensing system displays a high signal-to-background (S/B) ratio (26-fold) and sensitivity (limit of detection as low as 0.4 pM). Meanwhile, it has good specificity, excellent stability, and reliability in both buffer and biological samples. To the best of our knowledge, it is the first example that adopts an EDCC to precisely modulate the configuration transformation of DNA Ag NCs on the GO surface to obtain a biosensor with low background, strong fluorescence, high contrast, and sensitivity. This exciting finding may provide a new route to fabricate a novel turn-on biosensor based on hairpin-templated DNA Ag NCs in the optical imaging and bioanalytical fields.

Supportive Care Needs of Patients With Temporary Ostomy in Enhanced Recovery After Surgery: A Mixed-Methods Study.

BACKGROUND: Enhanced recovery after surgery (ERAS), a global surgical quality improvement initiative, reduces the length of stay in the hospital. Temporary stoma care for rectal cancer is complex, and patients require prolonged care services to adjust to the stoma. The shorter stay durations in the new model challenge the conventional care pathways and create new patient needs. PURPOSE: This study was designed to explore the supportive care needs of patients under the new surgical model to provide a reference for the design of ERAS nursing care plans. METHODS: A convergent parallel mixed-methods design was used in this study. Patients with temporary stomas for rectal cancer were recruited using a convenience sampling method in gastrointestinal surgery wards and wound & stoma clinics in two public tertiary care hospitals in China. Standardized questionnaires were administered to 140 patients to collect quantitative data, and semistructured interviews were conducted individually with 13 patients to collect qualitative data. The questionnaire data were analyzed using descriptive statistics, and the interview data were analyzed using thematic analysis. RESULTS: "Health system and information needs" and "care and support needs" were identified in both the qualitative and quantitative analyses as the most significant unmet needs of the participants. In addition, the qualitative analysis identified receiving focused stoma care instructions and easily understandable information as essential to fulfilling health system and information needs. Care and support needs included access to continued postdischarge services and attention from medical professionals. CONCLUSION/IMPLICATIONS FOR PRACTICE: The participants in this study experienced a variety of unmet supportive care needs under the ERAS protocol, with gaps particularly notable in two categories: "health system and information needs" and "care and support needs." Increased perioperative care and shorter hospital stays under the ERAS protocol reduce opportunities for patients to receive targeted instruction and shift much of the ostomy education and care workload out of the hospital, requiring greater attention from clinical nurses to ensure quality of care.

Engineering of molecularly imprinted cavity within 3D covalent organic frameworks: An innovation for enhanced extraction and removal of microcystins.

The scarcity of selective adsorbents for efficient extraction and removal of microcystins (MCs) from complex samples greatly limits the precise detection and effective control of MCs. Three-dimensional covalent organic frameworks (3D COFs), characterized by their large specific surface areas and highly ordered rigid structure, are promising candidates, but suffer from lack of specific recognition. Herein, we design to engineer molecularly imprinted cavities within 3D COFs via molecularly imprinted technology, creating a novel adsorbent with exceptional selectivity, kinetics and capacity for the efficient extraction and removal of MCs. As proof-of-concept, a new CC bond-containing 3D COF, designated JNU-7, is designed and prepared for copolymerization with methacrylic acid, the pseudo template L-arginine and ethylene dimethacrylate to yield the JNU-7 based molecularly imprinted polymer (JNU-7-MIP). The JNU-7-MIP exhibits a great adsorption capacity (156 mg g-1) for L-arginine. Subsequently, the JNU-7-MIP based solid-phase extraction coupled with high performance liquid chromatography-mass spectrometry achieves low detection limit of 0.008 ng mL-1, wide linear range of 0.025-100 ng mL-1, high enrichment factor of 186, rapid extraction of 10 min, and good recoveries of 92.4%-106.5% for MC-LR. Moreover, the JNU-7-MIP can rapidly remove the MC-LR from 1 mg L-1 to levels (0.26-0.35 µg L-1) lower than the WHO recommended limit for drinking water (1 µg L-1). This work reveals the considerable potential of 3D COF based MIPs as promising adsorbents for the extraction and removal of contaminants in complex real samples.

FGFR inhibition blocks NF-ĸB-dependent glucose metabolism and confers metabolic vulnerabilities in cholangiocarcinoma.

Genomic alterations that activate Fibroblast Growth Factor Receptor 2 (FGFR2) are common in intrahepatic cholangiocarcinoma (ICC) and confer sensitivity to FGFR inhibition. However, the depth and duration of response is often limited. Here, we conduct integrative transcriptomics, metabolomics, and phosphoproteomics analysis of patient-derived models to define pathways downstream of oncogenic FGFR2 signaling that fuel ICC growth and to uncover compensatory mechanisms associated with pathway inhibition. We find that FGFR2-mediated activation of Nuclear factor-κB (NF-κB) maintains a highly glycolytic phenotype. Conversely, FGFR inhibition blocks glucose uptake and glycolysis while inciting adaptive changes, including switching fuel source utilization favoring fatty acid oxidation and increasing mitochondrial fusion and autophagy. Accordingly, FGFR inhibitor efficacy is potentiated by combined mitochondrial targeting, an effect enhanced in xenograft models by intermittent fasting. Thus, we show that oncogenic FGFR2 signaling drives NF-κB-dependent glycolysis in ICC and that metabolic reprogramming in response to FGFR inhibition confers new targetable vulnerabilities.

Comparison of the Global Leadership Initiative on Malnutrition and the Patient-Generated Subjective Global Assessment for diagnosing malnutrition in patients undergoing surgery for hepatobiliary and pancreatic malignancies.

OBJECTIVE: to analyse the differences in malnutrition assessment between the Global Leadership Initiative on Malnutrition (GLIM) criteria and the Patient-Generated Subjective Global Assessment (PG-SGA) among patients with hepatobiliary and pancreatic malignancies. METHOD: this study was a cross-sectional study and included 126 hospitalised patients who underwent surgery for hepatobiliary and pancreatic malignancies between November 1, 2019 and August 1, 2020. The patients' clinical data were collected, and malnutrition assessments were completed using the different nutritional assessment tools. The consistency of both tools was analysed using Cohen's kappa coefficient. RESULTS: the prevalence of malnutrition showed a difference in diagnosis results between the GLIM criteria (36.51 %) and the PG-SGA (55.56 %). The two methods had moderate consistency (kappa = 0.590, p < 0.01). The sensitivity of a malnutrition diagnosis using a combination of GLIM and PG-SGA was 65.7 % (53.3 % and 76.4 %, respectively), and specificity was 100 % (92 % and 100 %, respectively). When malnutrition was evaluated using only PG-SGA, sensitivity was 88.9 % (95 % confidence interval (CI) 63.9 % to 98.1 %), whereas when only the GLIM score was used for malnutrition evaluation, sensitivity was 98.2 % (95 % CI, 92.8 % to 99.7 %). In addition, the PG-SGA score and the GLIM score had significant correlations. CONCLUSION: GLIM performed better than PG-SGA in the correlation analysis of nutritional indicators. GLIM is more suitable for patients with hepatobiliary and pancreatic malignancies than PG-SGA.

TET2-STAT3-CXCL5 nexus promotes neutrophil lipid transfer to fuel lung adeno-to-squamous transition.

Phenotypic plasticity is a rising cancer hallmark, and lung adeno-to-squamous transition (AST) triggered by LKB1 inactivation is significantly associated with drug resistance. Mechanistic insights into AST are urgently needed to identify therapeutic vulnerability in LKB1-deficient lung cancer. Here, we find that ten-eleven translocation (TET)-mediated DNA demethylation is elevated during AST in KrasLSL-G12D/+; Lkb1L/L (KL) mice, and knockout of individual Tet genes reveals that Tet2 is required for squamous transition. TET2 promotes neutrophil infiltration through STAT3-mediated CXCL5 expression. Targeting the STAT3-CXCL5 nexus effectively inhibits squamous transition through reducing neutrophil infiltration. Interestingly, tumor-infiltrating neutrophils are laden with triglycerides and can transfer the lipid to tumor cells to promote cell proliferation and squamous transition. Pharmacological inhibition of macropinocytosis dramatically inhibits neutrophil-to-cancer cell lipid transfer and blocks squamous transition. These data uncover an epigenetic mechanism orchestrating phenotypic plasticity through regulating immune microenvironment and metabolic communication, and identify therapeutic strategies to inhibit AST.

Self-validating photothermal and electrochemical dual-mode sensing based on Hg2+ etching Ti3C2 MXene.

Mercury ions can cause serious damage to the ecological environment, and it is necessary to develop reliable and elegant mercury ion sensors. In this protocol, a label-free photothermal/electrochemical dual-mode strategy for Hg2+ is proposed based on delaminated Ti3C2 MXene nanosheets (DL-Ti3C2 MXene). Hg2+ exists in water in the form of HgCl2, Hg(OH)2, and HgClOH, and the electron-rich elements O and Cl can specifically bind to the positively charged DL-Ti3C2 MXene at the edge, and further oxidation-reduction reaction occurs to obtain TiO2/C and Hg2Cl2. In view of the reduction activity and the performance of photothermal conversion of DL-Ti3C2 MXene itself, the electrochemical and photothermal responses decrease with the increase of the logarithm of Hg2+ concentration. The corresponding linear ranges are 50 pmol L-1-500 nmol L-1 and 1 nmol L-1-50 µmol L-1, and their detection limits calculated at 3 S/N are 17.2 pmol L-1 and 0.43 nmol L-1, respectively. DL-Ti3C2 MXene has the characteristics of a wide range of raw materials, low cost, and easy preparation. In addition, the design takes full advantage of the properties of the material itself, avoids the complex assembly and detection process of conventional sensors, and enables high selectivity and sensitivity for mercury detection. In particular, the dual-mode sensing endows self-confirmation of mercury ion detection results, thereby improving the reliability of the sensor.

Rehabilitation with brain-computer interface and upper limb motor function in ischemic stroke: A randomized controlled trial.

BACKGROUND: Upper limb motor dysfunction is a major problem in the rehabilitation of patients with stroke. Brain-computer interface (BCI) is a kind of communication system that converts the "ideas" in the brain into instructions and has been used in stroke rehabilitation. This study aimed to investigate the efficacy and safety of BCI in rehabilitation training on upper limb motor function among patients with ischemic stroke. METHODS: This was an investigator-initiated, multicenter, randomized, open-label, blank-controlled clinical trial with blinded outcome assessment conducted at 17 centers in China. Patients were assigned in a 1:1 ratio to the BCI group or the control group based on traditional rehabilitation training. The primary efficacy outcome is the difference in improvement of the Fugl-Meyer Assessment upper extremity (FMA-UE) score between two groups at month 1 after randomization. The safety outcomes were any adverse events within 3 months. FINDINGS: A total of 296 patients with ischemic stroke were enrolled and randomly allocated to the BCI group (n = 150) and the control group (n = 146). The primary efficacy outcomes of FMA-UE score change from baseline to 1 month were 13.17 (95% confidence interval [CI], 11.56-14.79) in the BCI group and 9.83 (95% CI, 8.19-11.47) in the control group (mean difference between groups was 3.35; 95% CI, 1.05-5.65; p = 0.0045). Adverse events occurred in 33 patients (22.00%) in the BCI group and in 31 patients (21.23%) in the control group. CONCLUSIONS: BCI rehabilitation training can further improve upper limb motor function based on traditional rehabilitation training in patients with ischemic stroke. This study was registered at ClinicalTrials.gov: NCT04387474. FUNDING: This work was supported by the National Key R&D Program of China (2018YFC1312903), the National Key Research and Development Program of China (2022YFC3600600), the Training Fund for Open Projects at Clinical Institutes and Departments of Capital Medical University (CCMU2022ZKYXZ009), the Beijing Natural Science Foundation Haidian original innovation joint fund (L222123), the Fund for Young Talents of Beijing Medical Management Center (QML20230505), and the high-level public health talents (xuekegugan-02-47).

Elevated gut microbiota metabolite bile acids confer protective effects on clinical prognosis in ischemic stroke patients.

Background: There is evidence of an association between the gut microbiota and progression of stroke. However, the relationship between gut microbial metabolites, specifically bile acids (BAs), and post-ischemic stroke disability and poor functional outcomes remains unexplored. Methods: Patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA) in the Third China National Stroke Registry were grouped according to total bile acid (TBA) quartile on admission. Association of TBA with disability and poor functional outcomes were evaluated using logistic regression models and restricted cubic splines. Results: Data for 9,536 patients were included. After adjusting for confounders, the risks of disability and poor functional outcomes were significantly lower in the highest TBA quartile than in the lowest TBA quartile at the 3-month follow-up, with respective odds ratios (ORs) of 0.65 (95% confidence interval [CI] 0.55-0.78; p < 0.001) and 0.66 (95% CI 0.55-0.78, p < 0.001). Each standard deviation increase in the TBA level reduced the risks of disability and poor functioning outcomes by 10% (adjusted ORs 0.9 [95% CI 0.83-0.98; p = 0.01] and 0.9 [95% CI 0.83-0.97; p < 0.001], respectively). This association remained similar at the 1-year follow-up. After stratification by TOAST subtype, the risk of disability or a poor functional outcome in patients with the large-artery atherosclerosis or "other" subtype was significantly lower in the highest quartile than in the lowest quartile (p < 0.05). Conclusion: Serum TBA is an independent risk factor for disability and poor functional outcomes after AIS or TIA, and exerts a protective effects on brain.

A retrospective cohort study of neoadjuvant chemoradiotherapy combined with immune checkpoint inhibitors in locally advanced rectal cancer.

INTRODUCTION: This study aimed to investigate the safety and efficacy of neoadjuvant chemoradiotherapy combined with immune checkpoint inhibitors (ICIs) in patients with locally advanced rectal cancer (LARC). Patients diagnosed with LARC and treated with programmed cell death protein-1 (PD-1) inhibitors were recruited. METHODS: Four different treatment strategies were employed in this study: plan A [long-course radiotherapy + PD-1 inhibitor/capecitabine + PD-1 inhibitor/XELOX+ total mesorectal excision (TME)], plan B (long-course radiotherapy + capecitabine + PD-1 inhibitor/XELOX + TME), plan C (short-course radiotherapy + PD-1 inhibitor/XELOX + TME), and plan D (PD-1 inhibitor/XELOX + short-course radiotherapy + TME). The basic information about patients, pathological indicators, adverse events, and efficacy indexes of treatment plans were analyzed. RESULTS: 96.8 % of patients were mismatch repair proficient (pMMR) and only 2 patients belonged to mismatch repair deficient (dMMR). The 2 patients with dMMR showed a pathological complete response (pCR) rate of 100 %, while the pCR rate of pMMR patients was 43.3 %. The overall tumor descending rate reached 79 %, and the anus-retained rate was 88.7 % in all LARC patients. Plan A exhibited the highest pCR rate of 60 %, and plan C had the highest tumor descending rate and anal preservation rate. Radiation enteritis was the most common adverse event in LARC patients after neoadjuvant therapy, and its incidence was the highest in Plan A. CONCLUSION: Neoadjuvant chemoradiotherapy combined with ICIs demonstrated favorable efficacy and safety in treating LARC patients.