Structural and biochemical insights into the molecular mechanism of N-acetylglucosamine/N-Acetylmuramic acid kinase MurK from Clostridium acetobutylicum.

MurK is a MurNAc- and GlcNAc-specific amino sugar kinase, phosphorylates MurNAc and GlcNAc at the 6-hydroxyl group in an ATP-dependent manner, and contributes to the recovery of both amino sugars during the cell wall turnover in Clostridium acetobutylicum. Herein, we determined the crystal structures of MurK in complex with MurNAc, GlcNAc, and glucose, respectively. MurK represents the V-shaped fold, which is divided into a small N-terminal domain and a large C-terminal domain. The catalytic pocket is located within the deep cavity between the two domains of the MurK monomer. We mapped the significant enzyme-substrate interactions, identified key residues involved in the catalytic activity of MurK, and found that residues Asp77 and Arg78 from the ß4-α2-loop confer structural flexibilities to specifically accommodate GlcNAc and MurNAc, respectively. Moreover, structural comparison revealed that MurK adopts closed-active conformation induced by the N-acetyl moiety from GlcNAc/MurNAc, rather than closed-inactive conformation induced by glucose, to carry out its catalytic reaction. Taken together, our study provides structural and functional insights into the molecular mechanism of MurK for the phosphorylation of both MurNAc and GlcNAc, sugar substrate specificity, and conformational changes upon sugar substrate binding.

Characterizing Myasthenia Gravis Symptoms, Exacerbations, and Crises From Neurologist's Clinical Notes Using Natural Language Processing.

Background Myasthenia gravis (MG) is a rare, autoantibody neuromuscular disorder characterized by fatigable weakness. Real-world evidence based on administrative and structured datasets regarding MG may miss important details related to the clinical encounter. Examination of free-text clinical progress notes has the potential to illuminate aspects of MG care. Objective The primary objective was to examine and characterize neurologist progress notes in the care of individuals with MG regarding the prevalence of documentation of clinical subtypes, antibody status, symptomatology, and MG deteriorations, including exacerbations and crises. The secondary objectives were to categorize MG deteriorations into practical, objective states as well as examine potential sources of clinical inertia in MG care. Methods We performed a retrospective, cross-sectional analysis of de-identified neurologist clinical notes from 2017 to 2022. A qualitative analysis of physician descriptions of MG deteriorations and a discussion of risks in MG care (risk for adverse effects, risk for clinical decompensation, etc.) was performed. Results Of the 3,085 individuals with MG, clinical subtypes and antibody status identified included gMG (n = 400; 13.0%), ocular MG (n = 253; 8.2%), MG unspecified (2,432; 78.8%), seropositivity for acetylcholine receptor antibody (n = 441; 14.3%), and MuSK antibody (n = 29; 0.9%). The most common gMG manifestations were dysphagia (n = 712; 23.0%), dyspnea (n = 626; 20.3%), and dysarthria (n = 514; 16.7%). In MG crisis patients, documentation of difficulties with MG standard therapies was common (n = 62; 45.2%). The qualitative analysis of MG deterioration types includes symptom fluctuation, symptom worsening with treatment intensification, MG deterioration with rescue therapy, and MG crisis. Qualitative analysis of MG-related risks included the toxicity of new therapies and concern for worsening MG because of changing therapies. Conclusions This study of neurologist progress notes demonstrates the potential for real-world evidence generation in the care of individuals with MG. MG patients suffer fluctuating symptomatology and a spectrum of clinical deteriorations. Adverse effects of MG therapies are common, highlighting the need for effective, less toxic treatments.

Antibiotic Resistance of Helicobacter pylori in Mainland China: A Focus on Geographic Differences through Systematic Review and Meta-analysis.

BACKGROUND: Empirical treatment needs to be supported by regional data, but knowledge of interregional differences is currently lacking in China. This study aimed to summarize and map the primary and secondary antibiotic resistance of H. pylori in different regions of mainland China. METHODS: PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure and Wanfang databases were systematically reviewed for studies published between January 1st, 2000 and July 15th, 2023. Data related to primary and secondary H. pylori antibiotic resistance rates were included. Random-effects models were used to synthesize the pooled resistance rates. RESULTS: Ultimately, 74 studies were included in the final analysis. Sixteen provinces reported resistance data. The overall resistance rates of H. pylori in mainland China were 30.72% (95% CI 27.53%-33.99%) to clarithromycin, 70.14% (95% CI 29.53%-37.46%) to metronidazole, and 32.98% (95% CI 28.73%-37.37%) to levofloxacin; for amoxicillin, tetracycline, and furazolidone, the rates were 2.41% (95% CI 1.43%-3.60%), 2.53% (95% CI 1.19%-4.28%) and 1.54% (95% CI 0.28%-3.62%), respectively. Spatial and temporal differences were observed. The resistance rates increased after treatment failure, however, secondary resistance to amoxicillin, tetracycline, and furazolidone were still low across the vast majority of study regions. CONCLUSION: Surveillance of the updated prevalence of antibiotic resistance of H. pylori for different regions is warranted, which should factor into clinical decision making and guideline recommendations.

Evaluation of low volume sampling devices for a pharmacodynamic biomarker analysis: Challenges and solutions.

Low volume sampling technologies have gained popularity as they are minimally invasive, reduce patient burden, enhance population diversity, and have the potential to facilitate decentralized clinical trials. Herein, we validated a Gyrolab assay to measure soluble Mucosal Addressin Cell Adhesion Molecule 1 (sMAdCAM-1) in dried blood samples collected using two low volume sampling devices, Mitra and Tasso-M20. This validated assay was implemented in a proof-of-concept study to compare three low volume sampling devices (Mitra, Tasso-M20 and TassoOne Plus) with serum collected via venipuncture from healthy volunteers receiving etrolizumab. We observed significantly higher concentration of sMAdCAM-1 in dried blood samples collected using Mitra and Tasso-M20 compared to serum in some paired samples, which was attributed to interference from the dried blood extraction buffer. To mitigate this interference, samples required substantial dilution into the appropriate buffer, which negatively impacted the detectability of sMAdCAM-1 with the Gyrolab assay. By employing the Quanterix single molecule array (Simoa), known for its superior assay sensitivity, the interference was minimized in the diluted samples. Both liquid blood collected in TassoOne Plus and dried blood collected using Mitra and Tasso-M20 demonstrated great concordance with serum for sMAdCAM-1 measurement. However, a bias was observed in Mitra dried blood samples, presumably due to the different sample collection sites in comparison with venipuncture and Tasso devices. Our study highlights the potential of low volume sampling technologies for biomarker analysis, and underscores the importance of understanding the challenges and limitations of these technologies before integrating them into clinical studies.

Artificial Intelligence-Generated Patient Education Materials for Helicobacter pylori Infection: A Comparative Analysis.

BACKGROUND: Patient education contributes to improve public awareness of Helicobacter pylori. Large language models (LLMs) offer opportunities to revolutionize patient education transformatively. This study aimed to assess the quality of patient educational materials (PEMs) generated by LLMs and compared with physician sourced. MATERIALS AND METHODS: Unified instruction about composing a PEM about H. pylori at a sixth-grade reading level in both English and Chinese were given to physician and five LLMs (Bing Copilot, Claude 3 Opus, Gemini Pro, ChatGPT-4, and ERNIE Bot 4.0). The assessments of the completeness and comprehensibility of the Chinese PEMs were conducted by five gastroenterologists and 50 patients according to three-point Likert scale. Gastroenterologists were asked to evaluate both English and Chinese PEMs and determine the accuracy and safety. The accuracy was assessed by six-point Likert scale. The minimum acceptable scores were 4, 2, and 2 for accuracy, completeness, and comprehensibility, respectively. The Flesch-Kincaid and Simple Measure of Gobbledygook scoring systems were employed as readability assessment tools. RESULTS: Accuracy and comprehensibility were acceptable for English PEMs of all sources, while completence was not satisfactory. Physician-sourced PEM had the highest accuracy mean score of 5.60 and LLM-generated English PEMs ranged from 4.00 to 5.40. The completeness score was comparable between physician-sourced PEM and LLM-generated PEMs in English. Chinese PEMs from LLMs proned to have lower score in accuracy and completeness assessment than English PEMs. The mean score for completeness of five LLM-generated Chinese PEMs was 1.82-2.70 in patients' perspective, which was higher than gastroenterologists' assessment. Comprehensibility was satisfactory for all PEMs. No PEM met the recommended sixth-grade reading level. CONCLUSION: LLMs have potential in assisting patient education. The accuracy and comprehensibility of LLM-generated PEMs were acceptable, but further optimization on improving completeness and accounting for a variety of linguistic contexts are essential for enhancing the feasibility.

Comparison of the Prevention of Esophageal Stricture Between Oral Prednisolone Alone and Oral Prednisolone Combined with Nasogastric Tube in Superficial Esophageal Cancer After Endoscopic Submucosal Dissection.

BACKGROUND/AIMS:  There is a lack of effective and safe methods for preventing esophageal stricture after large endoscopic submucosal dissection (ESD) in patients with superficial esophageal cancer. We aimed to compare the effectiveness of oral prednisolone alone versus a combination of oral prednisolone and nasogastric tube in preventing esophageal stricture following extensive ESD. MATERIALS AND METHODS:  We retrospectively gathered clinical data from a single center on patients with early esophageal cancer who underwent ESD. Patients were categorized into 2 groups: the steroid group (receiving only oral prednisolone) and the steroid+nasogastric tube retention (NGT) group. We analyzed the incidence of esophageal stricture and identified risk factors for its development. RESULTS:  The study included 79 patients, with 30 in the steroid group and 49 in the steroid+NGT group. The incidence of stricture was significantly higher in the steroid group (9/30, 30.0%) compared to the steroid+NGT group (3/49, 6.1%) (P = .004). Notably, we observed a significant difference in the stricture rates between the 2 groups, particularly in patients with a complete circumferential defect (100% and 16.7%) (P = .015). Multivariate logistic regression analysis revealed that a full circumferential defect of the esophageal mucosa (OR 12.501; 95% CI 1.907, 81.047; P = .008), invasion depth beyond the lamina propria (OR 5.635; 95% CI 1.039, 30.559; P = .045), and the absence of NGT retention (OR 12.896; 95% CI 2.099, 79.219; P = .006) were independent risk factors predicting the development of a stricture. CONCLUSION:  The combination of steroids with NGT retention is more effective than using oral steroids alone in preventing esophageal stricture after extensive ESD.

Main focus of parents of children with attention deficit hyperactivity disorder and the effectiveness of early clinical screening.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a common mental and behavioral disorder among children. AIM: To explore the focus of attention deficit hyperactivity disorder parents and the effectiveness of early clinical screening. METHODS: This study found that the main directions of parents seeking medical help were short attention time for children under 7 years old (16.6%) and poor academic performance for children over 7 years old (12.1%). We employed a two-stage experiment to diagnose ADHD. Among the 5683 children evaluated from 2018 to 2021, 360 met the DSM-5 criteria. Those diagnosed with ADHD underwent assessments for letter, number, and figure attention. Following the exclusion of ADHD-H diagnoses, the detection rate rose to 96.0%, with 310 out of 323 cases identified. RESULTS: This study yielded insights into the primary concerns of parents regarding their children's symptoms and validated the efficacy of a straightforward diagnostic test, offering valuable guidance for directing ADHD treatment, facilitating early detection, and enabling timely intervention. Our research delved into the predominant worries of parents across various age groups. Furthermore, we showcased the precision of the simple exclusion experiment in discerning between ADHD-I and ADHD-C in children. CONCLUSION: Our study will help diagnose and guide future treatment directions for ADHD.

Early warning of atrial fibrillation using deep learning.

Atrial fibrillation (AF), the most prevalent cardiac rhythm disorder, significantly increases hospitalization and health risks. Reverting from AF to sinus rhythm (SR) often requires intensive interventions. This study presents a deep-learning model capable of predicting the transition from SR to AF on average 30.8 min before the onset appears, with an accuracy of 83% and an F1 score of 85% on the test data. This performance was obtained from R-to-R interval signals, which can be accessible from wearable technology. Our model, entitled Warning of Atrial Fibrillation (WARN), consists of a deep convolutional neural network trained and validated on 24-h Holter electrocardiogram data from 280 patients, with 70 additional patients used for testing and further evaluation on 33 patients from two external centers. The low computational cost of WARN makes it ideal for integration into wearable technology, allowing for continuous heart monitoring and early AF detection, which can potentially reduce emergency interventions and improve patient outcomes.

Management of patient with Fusobacterim nucletum related pleural empyema: intrapleural antibiotic therapy can be considered for salvage therapy.

Pleural empyema can lead to significant morbidity and mortality despite chest drainage and antibiotic treatment, necessitating novel and minimally invasive interventions. Fusobacterium nucleatum is an obligate anaerobe found in the human oral and gut microbiota. Advances in sequencing and puncture techniques have made it common to detect anaerobic bacteria in empyema cases. In this report, we describe the case of a 65-year-old man with hypertension who presented with a left-sided encapsulated pleural effusion. Initial fluid analysis using metagenomic next-generation sequencing (mNGS) revealed the presence of Fusobacterium nucleatum and Aspergillus chevalieri. Unfortunately, the patient experienced worsening pleural effusion despite drainage and antimicrobial therapy. Ultimately, successful treatment was achieved through intrapleural metronidazole therapy in conjunction with systemic antibiotics. The present case showed that intrapleural antibiotic therapy is a promising measure for pleural empyema.

TNF compromises intestinal bile-acid tolerance dictating colitis progression and limited infliximab response.

The intestine constantly encounters and adapts to the external environment shaped by diverse dietary nutrients. However, whether and how gut adaptability to dietary challenges is compromised in ulcerative colitis is incompletely understood. Here, we show that a transient high-fat diet exacerbates colitis owing to inflammation-compromised bile acid tolerance. Mechanistically, excessive tumor necrosis factor (TNF) produced at the onset of colitis interferes with bile-acid detoxification through the receptor-interacting serine/threonine-protein kinase 1/extracellular signal-regulated kinase pathway in intestinal epithelial cells, leading to bile acid overload in the endoplasmic reticulum and consequent apoptosis. In line with the synergy of bile acids and TNF in promoting gut epithelial damage, high intestinal bile acids correlate with poor infliximab response, and bile acid clearance improves infliximab efficacy in experimental colitis. This study identifies bile acids as an "opportunistic pathogenic factor" in the gut that would represent a promising target and stratification criterion for ulcerative colitis prevention/therapy.

The role of triglyceride-glucose index in the differential diagnosis of atherosclerotic stroke and cardiogenic stroke.

OBJECTIVE: This study aims to investigate the role of the triglyceride glucose (TyG) index in differentiating cardiogenic stroke (CE) from large atherosclerotic stroke (LAA). METHOD: In this retrospective study, patients with acute ischemic stroke were recruited from the First Affiliated Hospital of Soochow University, Lianyungang Second People's Hospital and Lianyungang First People's Hospital. Their general data, medical history and laboratory indicators were collected and TyG index was calculated. Groups were classified by the TyG index quartile to compare the differences between groups. Logistic regression was utilized to assess the relationship between the TyG index and LAA. The receiver operating characteristic curve (ROC) curve was used to evaluate the diagnostic efficiency of the TyG index in differentiating LAA from CE. RESULT: The study recruited 1149 patients. After adjusting for several identified risk factors, groups TyG-Q2, TyG-Q3, and TyG-Q4 had a higher risk of developing LAA compared to group TyG-Q1(odds ratio (OR) = 1.63,95% confidence interval (CI) = 1.11-2.39, OR = 1.72,95%CI = 1.16-2.55, OR = 2.06,95%CI = 1.36-3.09). TyG has certain diagnostic value in distinguishing LAA from CE(AUC = 0.595, 95%CI0.566-0.623;P<0.001). CONCLUSION: Summarily, the TyG index has slight significance in the identification of LAA and CE; it is particularly a marker for their preliminary identification.

Soluble Fibrinogen-Like Protein 2 Downregulation and Th17/Treg Imbalance in a Taurocholate-Induced Murine Experimental Model of Severe Acute Pancreatitis.

BACKGROUND: Severe acute pancreatitis (SAP) is associated with tremendous systemic inflammation, T-helper 17 (Th17) cells, and regulatory T (Treg) cells play an essential role in the inflammatory responses. Meanwhile, soluble fibrinogen-like protein 2 (Sfgl2) is a critical immunosuppressive effector cytokine of Treg cells and modulates immune responses. However, the impact of SAP induction on Sfgl2 expression and the role of Sfgl2 in immunomodulation under SAP conditions are largely unknown. METHODS: A taurocholate-induced mouse SAP model was established. The ratios of CD4+CD25+Foxp3+ Treg cells or CD4+IL-17+ Th17 cells in blood and pancreatic tissues as well as surface expression of CD80, CD86, and major histocompatibility complex class II (MHC-II) were determined by flow cytometry. Gene mRNA expression was determined by qPCR. Serum amylase and soluble factors were quantitated by commercial kits. Bone marrow-derived dendritic cells (DCs) were generated, and NF-κB/p65 translocation was measured by immunofluorescence staining. RESULTS: SAP induction in mice decreased the Th17/Treg ratio in the pancreatic tissue and increased the Th17/Treg ratio in the peripheral blood. In addition, SAP was associated with a reduced level of Sfgl2 in the pancreatic tissue and blood: higher levels of serum IL-17, IL-2, IFN-α, and TNF-α, and lower levels of serum IL-4 and IL-10. Furthermore, the SAP-induced reduction in Sfgl2 expression was accompanied by dysregulated maturation of bone marrow-derived DCs. CONCLUSIONS: SAP causes reduced Sfgl2 expression and Th17/Treg imbalance, thus providing critical insights for the development of Sfgl2- and Th17/Treg balance-targeted immunotherapies for patients with SAP.

Two doses of fosaprepitant included prophylactic treatment for the three-day cisplatin-based chemotherapy induced nausea and vomiting.

PURPOSE: Neurokinin 1 receptor antagonists included prophylactic treatment was recommended for patients who receive one-day cisplatin chemotherapy. It is unclear whether the prolonged administration of fosaprepitant is effective for three-day cisplatin-based chemotherapy induced nausea and vomiting (CINV). We aim to explore the prophylactic antiemetic efficacy and safety of two doses of fosaprepitant included regimen in the patients receiving multiple-day cisplatin chemotherapy. METHODS: This randomized, parallel-group, open-labelled study was conducted in nine hospitals between February 2021 and February 2023. Patients diagnosed as lung cancer and chemotherapy naive were screened. Eligible participants were scheduled to be treated with highly emetogenic chemotherapy regimen which including three days of cisplatin. Then they were randomly divided into the experimental group (two doses of fosaprepitant, Group 2DF) and the control group (one dose of fosaprepitant, Group C). The primary endpoints included the safety and the average none CINV days (NCDs). This study was registered on the website of chictr.org.cn, number ChiCTR2100042665. RESULTS: Overall, 204 participants were randomly assigned, and 198 patients were analyzed. No statistical difference in adverse events was found between the two groups. All treatment-related adverse effects for fosaprepitant observed were of grade 1-2. The average NCDs of Group 2DF was significantly more than Group C (18.21 ± 3.40 days vs 16.14 ± 5.20 days, P = 0.001). Furthermore, the better life function score was achieved in Group 2DF according to FLIE questionnaire. CONCLUSION: The administration of two-dose fosaprepitant was safe and more effective than one dose in protecting patients from CINV induced by three-day cisplatin included chemotherapy.

Clarifying varied Helicobacter pylori eradication therapies: A comprehensive review.

Current global variations exist in Helicobacter pylori (H. pylori) eradication regimens. Triple therapy (TT), bismuth quadruple therapy (BQT), and high-dose dual therapy (HDDT) currently represent the predominant regimens. These regimens diverge in terms of treatment duration, the utilization of susceptibility testing, acid-inhibiting drug administration, and patient education. We conducted a comprehensive systematic literature review on these H. pylori treatment regimens. Our review aims to provide standardized treatment recommendations for H. pylori, reducing the risk of amalgamating findings from diverse eradication regimens. Recent research suggests that the optimal treatment duration for TT and BQT may be 14 and 10 days, respectively. Selecting the appropriate treatment duration for HDDT should rely on regional research evidence, and 14 days may be the optimal duration. The incorporation of susceptibility testing in TT is of paramount importance. In the case of BQT, the absence of susceptibility testing may be considered as an option, contingent upon cost and availability, and should be determined based on local antibiotic resistance patterns and the efficacy of empirical regimens. The type and dosage of acid-inhibiting drug would affect the efficacy of these regimens. Acid-inhibiting drugs should be selected and applied reasonably according to the population and therapies. Adequate patient education plays a pivotal role in the eradication of H. pylori. In regions with accessible local research evidence, the 10-day empirical BQT regimen may be considered a preferred choice for H. pylori eradication.

Bibliometric Analyses of the Research Trends of Female Pelvic Organ Prolapse.

INTRODUCTION AND HYPOTHESIS: The study was aimed at systematically analyzing the research status and trends of pelvic organ prolapse (POP) using bibliometrics. METHODS: We retrieved documents published between 1975 and 2022 from the Web of Science Core Collection (WoSCC) database, and manually selected them for bibliometric analyses of country, institution, journal, highly locally cited documents and research trends based on co-citation clustering and keywords using the R Bibliometricx package and CiteSpace software. RESULTS: A total of 5,703 publications were included. Although the number of annual publications on POP increased, the trend of annual publication reached an obvious plateau in the first half of the 2010s. The USA, China, the UK, the University of Michigan, the University of Pittsburgh, and the University of Sydney were the top three countries and institutions with the most publications respectively. International Urogynecology Journal, American Journal of Obstetrics and Gynecology, and Obstetrics and Gynecology were the journals with the most extensive academic influence on the field of POP research. The international cooperation was lacking and the highly cited documents focused on high-level, evidence-based studies. Epidemiological studies and surgical treatment have achieved a plateau or decline. Recent studies have focused on conservative treatment, physical therapy, and minimally invasive surgery. In addition to evidence-based medicine studies, tissue engineering is the future direction of POP. CONCLUSIONS: This study used bibliometric analyses to provide insights into the status and potential research directions of POP. More high-quality, evidence-based medicine studies and in-depth tissue engineering research should be propelled forward.

Advancements and trends in exosome research in lung cancer from a bibliometric analysis (2004-2023).

Background: Lung cancer, characterized by its high morbidity and lethality, necessitates thorough research to enhance our understanding of its pathogenesis and discover novel therapeutic approaches. Recent studies increasingly demonstrate that lung cancer cells can modulate the tumor microenvironment, promoting tumor growth, and metastasis through the release of exosomes. Exosomes are small vesicles secreted by cells and contain a variety of bioactive molecules such as proteins, nucleic acids, and metabolites. This paper presents a comprehensive review of exosome research in lung cancer and its progress through bibliometric analysis. Methods: Publications related to exosomes in lung cancer patients were systematically searched on the Web of Science Core Collection (WoSCC) database. Bibliometric analysis was performed using VOSviwers, CiteSpace, and the R package "Bibliometrics". Publications were quantitatively analyzed using Microsoft Office Excel 2019. The language of publication was restricted to "English" and the search strategy employed TS=(exosomes or exosomes or exosomes) and TS=(lung cancer). The search period commenced on January 1, 2004, and concluded on November 12, 2023, at noon. The selected literature types included Articles and Reviews. Results: The study encompassed 1699 papers from 521 journals across 71 countries and 2105 institutions. Analysis revealed a consistent upward trend in lung cancer exosome research over the years, with a notable surge in recent times. This surge indicates a growing interest and depth of inquiry into lung cancer exosomes. Major research institutions in China and the United States, including Nanjing Medical University, Shanghai Jiao Tong University, Chinese Academy Of Sciences, and Utmd Anderson Cancer Center, emerged as crucial research hubs. The annual publication count in this field witnessed a continuous rise, particularly in recent years. Key terms such as lung cancer, non-small cell lung cancer (NSCLC), microvesicles, intercellular communication, exosomal miRNAs, and oncology dominated the research landscape. Fields like cell biology, biochemistry, biotechnology, and oncology exhibited close relation with this research. Clotilde Théry emerged as the most cited author in the field, underlining her significant contributions. These results demonstrate the broad impact of exosome research in lung cancer, with key terms covering not only disease-specific aspects such as lung cancer and NSCLC but also basic biological concepts like microvesicles and intercellular communication. Explorations into exosomal microRNAs and oncology have opened new avenues for lung cancer exosome research. In summary, lung cancer exosome research is poised to continue receiving attention, potentially leading to breakthroughs in treatment and prevention. Conclusion: Publications on lung cancer exosomes show a rising trend year by year, with China and the United States ranking first and second in terms of the number of publications. However, there is insufficient academic learning cooperation and exchanges between the two sides, and Chinese universities account for a large proportion of research institutions in this field. Jing Li is the most productive author, Clotilde Théry is the most co-cited author, and Cancers is the journal with the highest number of publications. The current focus in the field of lung cancer exosomes is on biomarkers, liquid biopsies, immunotherapy, and tumor microenvironment.

The two-directional prospective association between inflammatory bowel disease and neurodegenerative disorders: a systematic review and meta-analysis based on longitudinal studies.

Objective: Previous studies reported possible connections between inflammatory bowel disease (IBD) and several neurodegenerative disorders. However, the comprehensive relationships between IBD and various neurodegenerative disorders were not summarized. We executed a meta-analysis of longitudinal studies to provide an estimate of the strength of the two-directional prospective association between IBD and neurodegenerative disorders. Methods: We accomplished a thorough bibliographic search of PubMed, Web of Science, Embase, PsycINFO, and Cochrane Library databases until June 2023 to locate relevant longitudinal studies. The extracted data were then analyzed via meta-analysis using either a fixed or random effects model. Results: The final analysis encompassed 27 studies. Individuals with IBD faced an increased risk of developing four neurodegenerative disorders than the general public, namely, Alzheimer's disease (hazard ratio[HR] = 1.35, 95% confidence interval [CI]: 1.03-1.77, P=0.031), dementia (HR =1.24, 95% CI: 1.13-1.36, P<0.001), multiple sclerosis (HR =2.07, 95% CI:1.42-3.02, P<0.001) and Parkinson's disease (HR =1.23, 95% CI:1.10-1.38, P<0.001). Two articles reported an increased incidence of amyotrophic lateral sclerosis or multiple system atrophy in IBD patients. Three studies investigated the prospective association between multiple sclerosis and IBD, revealing an elevated risk of the latter in patients with the former. (HR=1.87, 95% CI:1.66-2.10, P<0.001). Interpretation: These findings verified the two-directional relationship between the brain-gut axis, specifically demonstrating a heightened risk of various neurodegenerative diseases among IBD patients. It may be profitable to prepare screening strategies for IBD patients to find neurodegenerative diseases during the long-term course of treatment for IBD with a view to potential earlier diagnosis and treatment of neurodegenerative diseases, reducing public health and social burden. Systematic Review Registration: PROSPERO (CRD42023437553).

A Phase 1a Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7303509, an Anti-TGFß3 Antibody, in Healthy Volunteers.

INTRODUCTION: Transforming growth factor beta (TGFß) cytokines (TGFß1, TGFß2, and TGFß3) play critical roles in tissue fibrosis. However, treatment with systemic pan-TGFß inhibitors have demonstrated unacceptable toxicities. In this study, we evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of RO7303509, a high-affinity, TGFß3-specific, humanized immunoglobulin G1 monoclonal antibody, in healthy adult volunteers (HVs). METHODS: This phase 1a, randomized, double-blind trial included six cohorts for evaluation, with each cohort receiving single doses of placebo or RO7303509, administered intravenously (IV; 50 mg, 150 mg, 240 mg) or subcutaneously (SC; 240 mg, 675 mg, 1200 mg). The frequency and severity of adverse events (AEs) and RO7303509 serum concentrations were monitored throughout the study. We also measured serum periostin and cartilage oligomeric matrix protein (COMP) by immunoassay and developed a population pharmacokinetics model to characterize RO7303509 serum concentrations. RESULTS: The study enrolled 49 HVs, with a median age of 39 (range 18-73) years. Ten (27.8%) RO7303509-treated subjects reported 24 AEs, and six (30.8%) placebo-treated subjects reported six AEs. The most frequent AEs related to the study drug were injection site reactions and infusion-related reactions. Maximum serum concentrations (Cmax) and area under the concentration-time curve from time 0 to infinity (AUC0-inf) values for RO7303509 appeared to increase dose-proportionally across all doses tested. Serum concentrations across cohorts were best characterized by a two-compartment model plus a depot compartment with first-order SC absorption kinetics. No subjects tested positive for anti-drug antibodies (ADAs) at baseline; one subject (2.8%; 50 mg IV) tested positive for ADAs at a single time point (day 15). No clear pharmacodynamic effects were observed for periostin or COMP upon TGFß3 inhibition. CONCLUSION: RO7303509 was well tolerated at single SC doses up to 1200 mg in HVs with favorable pharmacokinetic data that appeared to increase dose-proportionally. TGFß3-specific inhibition may be suitable for development as a chronic antifibrotic therapy. TRIAL REGISTRATION: ISRCTN13175485.

Evaluation of Patient-Centric Sample Collection Technologies for Pharmacokinetic Assessment of Large and Small Molecules.

Low-volume sampling devices offer the promise of lower discomfort and greater convenience for patients, potentially reducing patient burden and enabling decentralized clinical trials. In this study, we determined whether low-volume sampling devices produce pharmacokinetic (PK) data comparable to conventional venipuncture for a diverse set of monoclonal antibodies (mAbs) and small molecules. We adopted an open-label, non-randomized, parallel-group, single-site study design, with four cohorts of 10 healthy subjects per arm. The study drugs, doses, and routes of administration included: crenezumab (15 mg/kg, intravenous infusion), etrolizumab (210 mg, subcutaneous), GDC-X (oral), and hydroxychloroquine (HCQ, 200 mg, oral). Samples were collected after administration of a single dose of each drug using conventional venipuncture and three low-volume capillary devices: TassoOne Plus for liquid blood, Tasso-M20 for dry blood, both applied to the arm, and Neoteryx Mitra® for dry blood obtained from fingertips. Serum/plasma concentrations from venipuncture and TassoOne Plus samples overlapped and PK parameters were comparable for all drugs, except HCQ. After applying a baseline hematocrit value, the dry blood concentrations and PK parameters for the two monoclonal antibodies were comparable to those obtained from venipuncture. For the two small molecules, two bridging strategies were evaluated for converting dry blood concentrations to equivalent plasma concentrations. A baseline hematocrit correction and/or linear regression-based correction was effective for GDC-X, but not for HCQ. Additionally, the study evaluated the bioanalytical data quality and comparability from the various collection methods, as well as patient preference for the devices.

Pyramidal and parvalbumin neurons modulate the process of electroacupuncture stimulation for stroke rehabilitation.

Electroacupuncture (EA) stimulation has been shown to be beneficial in stroke rehabilitation; however, little is known about the neurological mechanism by which this peripheral stimulation approach treats for stroke. This study showed that both pyramidal and parvalbumin (PV) neuronal activity increased in the contralesional primary motor cortex forelimb motor area (M1FL) after ischemic stroke induced by focal unilateral occlusion in the M1FL. EA stimulation reduced pyramidal neuronal activity and increased PV neuronal activity. These results were obtained by a combination of fiber photometry recordings, in vivo and in vitro electrophysiological recordings, and immunofluorescence. Moreover, EA was found to regulate the expression/function of N-methyl-D-aspartate receptors (NMDARs) altered by stroke pathology. In summary, our findings suggest that EA could restore disturbed neuronal activity through the regulation of the activity of pyramidal and PV neurons. Furthermore, NMDARs we shown to play an important role in EA-mediated improvements in sensorimotor ability during stroke rehabilitation.