Macrophage Migration Inhibitory Factor Mediates PAR-Induced Bladder Pain.

INTRODUCTION: Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine, is constitutively expressed in urothelial cells that also express protease-activated receptors (PAR). Urothelial PAR1 receptors were shown to mediate bladder inflammation. We showed that PAR1 and PAR4 activator, thrombin, also mediates urothelial MIF release. We hypothesized that stimulation of urothelial PAR1 or PAR4 receptors elicits release of urothelial MIF that acts on MIF receptors in the urothelium to mediate bladder inflammation and pain. Thus, we examined the effect of activation of specific bladder PAR receptors on MIF release, bladder pain, micturition and histological changes. METHODS: MIF release was measured in vitro after exposing immortalized human urothelial cells (UROtsa) to PAR1 or PAR4 activating peptides (AP). Female C57BL/6 mice received intravesical PAR1- or PAR4-AP for one hour to determine: 1) bladder MIF release in vivo within one hour; 2) abdominal hypersensitivity (allodynia) to von Frey filament stimulation 24 hours after treatment; 3) micturition parameters 24 hours after treatment; 4) histological changes in the bladder as a result of treatment; 5) changes in expression of bladder MIF and MIF receptors using real-time RT-PCR; 6) changes in urothelial MIF and MIF receptor, CXCR4, protein levels using quantitative immunofluorescence; 7) effect of MIF or CXCR4 antagonism. RESULTS: PAR1- or PAR4-AP triggered MIF release from both human urothelial cells in vitro and mouse urothelium in vivo. Twenty-four hours after intravesical PAR1- or PAR4-AP, we observed abdominal hypersensitivity in mice without changes in micturition or bladder histology. PAR4-AP was more effective and also increased expression of bladder MIF and urothelium MIF receptor, CXCR4. Bladder CXCR4 localized to the urothelium. Antagonizing MIF with ISO-1 eliminated PAR4- and reduced PAR1-induced hypersensitivity, while antagonizing CXCR4 with AMD3100 only partially prevented PAR4-induced hypersensitivity. CONCLUSIONS: Bladder PAR activation elicits urothelial MIF release and urothelial MIF receptor signaling at least partly through CXCR4 to result in abdominal hypersensitivity without overt bladder inflammation. PAR-induced bladder pain may represent an interesting pre-clinical model of Interstitial Cystitis/Painful Bladder Syndrome (IC/PBS) where pain occurs without apparent bladder injury or pathology. MIF is potentially a novel therapeutic target for bladder pain in IC/PBS patients

Macrophage Migration Inhibitory Factor Mediates Protease-Activated Receptor 4-Induced Bladder Pain Through Urothelial High Mobility Group Box 1

Macrophage migration inhibitory factor (MIF) mediates pain although the mechanisms are not well understood. Urothelial activation of protease activated receptor 4 (PAR4) results in urothelial MIF release, urothelial high mobility group box 1 (HMGB1) release and bladder pain in mice without bladder inflammation. All three effects are prevented by MIF inhibition while intravesical disulfide HMGB1 alone can induce bladder pain. This study utilizes genetic MIF deletion to determine whether MIF mediates PAR4-induced bladder pain and is upstream of HMGB1-induced bladder pain. Wild type (C57/BL6) and MIF knockout (KO) mice were treated with intravesical PAR4 activating peptide or disulfide HMGB1 and tested for abdominal mechanical hypersensitivity at baseline (before treatment) and 24 h after injection. Micturition parameters and bladder histology were examined after behavioral test. Real-time PCR and western blotting measured HMGB1 mRNA and protein levels in the bladders of naïve wild type and MIF KO mice, while immunofluorescence measured HMGB1 protein levels in the urothelium of both strains. Intravesical PAR4 activation resulted in abdominal mechanical hypersensitivity in wild-type mice but not MIF KO mice. Intravesical disulfide HMGB1 induced abdominal mechanical hypersensitivity in both strains. Neither treatment resulted in significant changes in micturition or bladder histology in either strain. HMGB1 mRNA and protein levels were higher in MIF KO mouse bladders and the urothelium of MIF KO bladder had greater immunostaining than the wild-type strain. MIF is a pivotal molecule mediating PAR4-induced bladder pain and regulating urothelial HMGB1 production and release to elicit bladder pain

Precision mapping of COVID-19 vulnerable locales by epidemiological and socioeconomic risk factors, developed using South Korean data

COVID-19 has severely impacted socioeconomically disadvantaged populations. To support pandemic control strategies, geographically weighted negative binomial regression (GWNBR) mapped COVID-19 risk related to epidemiological and socioeconomic risk factors using South Korean incidence data (January 20, 2020 to July 1, 2020). We constructed COVID-19-specific socioeconomic and epidemiological themes using established social theoretical frameworks and created composite indexes through principal component analysis. The risk of COVID-19 increased with higher area morbidity, risky health behaviours, crowding, and population mobility, and with lower social distancing, healthcare access, and education. Falling COVID-19 risks and spatial shifts over three consecutive time periods reflected effective public health interventions. This study provides a globally replicable methodological framework and precision mapping for COVID-19 and future pandemics

Validating the Role of Chatgpt in Automatic Systematic Reviews and Meta-Analysis: a Case Study Focusing on Mortality Benefits of Glucagon-Like Peptide-1 Receptor Agonists

Background Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) play a crucial role in managing type 2 diabetes mellitus (T2DM) and obesity, providing benefits such as glycemic control, weight loss, and cardiovascular protection. Evaluating the impact of GLP-1 RAs on all-cause mortality and cardiovascular mortality is vital for understanding their broader health benefits. This study aims to leverage AI tools, specifically ChatGPT, to enhance the efficiency and accuracy of systematic reviews and meta-analyses, thus addressing methodological limitations and heterogeneities seen in traditional approaches. Objective To determine the effect of GLP-1 receptor agonists on all-cause and cardiovascular mortality in patients with type 2 diabetes and obesity through a comprehensive systematic review and meta-analysis, utilizing AI for improved methodological efficiency. Eligibility Criteria • Inclusion Criteria: o Placebo-controlled randomized controlled trials (RCTs). o Studies reporting mortality outcomes (all-cause and cardiovascular). o Studies involving adult participants receiving GLP-1 RAs. • Exclusion Criteria: o Studies with active comparators instead of placebo controls. o Post hoc analyses and duplicate publications. o Studies not reporting relevant mortality data. Search Strategy • A comprehensive literature search will be conducted using PubMed and Embase databases. • Search terms will include specific GLP-1 RAs (e.g., exenatide, liraglutide, semaglutide) and synonyms for mortality outcomes. • AI tools (ChatGPT) will be employed to generate and refine search strings, validated by human reviewers to ensure accuracy and comprehensiveness. • Example Search Strings: PubMed: ("Exenatide"[MeSH Terms] OR "Exenatide"[Title/Abstract] OR "Liraglutide"[MeSH Terms] OR "Liraglutide"[Title/Abstract] OR "semaglutide"[Title/Abstract] OR "dulaglutide"[Title/Abstract] OR "albiglutide"[Title/Abstract] OR "lixisenatide"[Title/Abstract]) AND ("Mortality"[MeSH Terms] OR "mortalit*"[Title/Abstract] OR "death"[MeSH Terms] OR "death*"[Title/Abstract] OR "survival"[MeSH Terms] OR "survival"[Title/Abstract]) Embase: ('exenatide'/exp OR 'exenatide' OR 'liraglutide'/exp OR 'liraglutide' OR 'semaglutide' OR 'dulaglutide' OR 'albiglutide' OR 'lixisenatide') AND ('mortality'/exp OR mortalit* OR 'death'/exp OR death* OR 'survival'/exp OR survival) Screening and Data Extraction • Screening Process: o Two human reviewers will perform screening. A third reviewer will run the screening process using ChatGPT. o Blinding will be maintained across the entire screening process. • Data Extraction: o ChatGPT assists in extracting key data points from eligible studies, including study design, participant demographics, intervention details, and mortality outcomes. o Data extraction tables are reviewed and confirmed by human reviewers. Risk of Bias Assessment • The risk of bias will be evaluated using the Cochrane Collaboration's RoB 2.0 tool. • ChatGPT will initially perform the risk of bias assessment, providing detailed justifications for each decision, which will be reviewed by two independent experts for accuracy. Data Synthesis and Analysis • Statistical Analysis: o Meta-analysis will be conducted by an expert, using fixed-effects and random-effects models to calculate pooled hazard ratios (HRs) for all-cause and cardiovascular mortality. o Heterogeneity will be assessed using the I² statistic. • Sensitivity and Publication Bias Analysis: o Sensitivity analysis will be performed by omitting each study sequentially to assess the robustness of the results. o Publication bias will be evaluated using Egger's test and funnel plots. • AI-Execute Meta-Analysis o A custom GPT will be trained to generate the code to preform the meta-analysis in R. o The process will be run by a blinded reviewer and the results will be compared to the human executed meta-analysis 9. AI Methodology • AI Integration: o AI tools (ChatGPT) will be integrated into various stages of the systematic review process, including search strategy development, study screening, data extraction, risk of bias assessment, and meta-analysis. • Validation and Oversight: o Human reviewers will validate all AI-generated outputs to ensure accuracy and reliability. o Comparisons between AI-generated and human-conducted meta-analysis results will be performed to assess concordance. 10. Ethical Considerations • As this study involves the synthesis of published data, no ethical approval is required. 11. Dissemination Plans • The findings will be disseminated through publication in a peer-reviewed journal. 12. Funding • No specific funding was received for this study. 13. Conflicts of Interest • The authors declare no conflicts of interest related to this study. 14. Contact Information • Principal Investigator: Lefteris Teperikidis, Clinical Research Unit, Special Unit for Biomedical Research and Education (SUBRE), School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece. • Email: [email protected]

Data for: PARP inhibition blocks alcohol-induced neurodegeneration and neuroinflammatory cytosolic phospholipase A2 elevations

Data for: PARP inhibition blocks alcohol-induced neurodegeneration and neuroinflammatory cytosolic phospholipase A2 elevation

MIF mediates PAR-induced bladder pain

<p>Data files used to generate figures and analyses.</p