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Abstract Context Diabetes mellitus (DM) is a systemic disease characterized by chronic hyperglycemia associated with inflammation and oxidative stress, and the lung may be a target organ of diabetic microvascular damage. Several studies have indicated a positive association between idiopathic pulmonary fibrosis (IPF) and diabetes with controversial findings. Objective Primary outcomes were to compare the prevalence of DM among individuals with IPF to non-IPF controls, and the prevalence of IPF among individuals with DM to non-DM controls. Methods Data sources include PubMed, EMBASE, and the Cochrane Library. Studies contained sufficient data to calculate the prevalence of DM among individuals with and without IPF, or the prevalence of IPF among individuals with and without DM. Two investigators independently identified eligible studies and extracted data. Pooled odds ratio (OR) with 95% CI was the summary effect measure. Results Eighteen studies including 26 410 623 individuals met the eligibility criteria, of whom 16 recruited people with IPF and 2 recruited people with DM. The OR of DM in IPF patients was 1.54 (95% CI, 1.30-1.84; P < .001) compared to that in non-IPF controls. However, compared with that in non-DM patients, the risk of IPF in DM patients was not found to be significantly reduced (OR: 0.89; 95% CI, 0.64-1.25; P = .497). Conclusion This meta-analysis suggests that people with IPF have 1.54 times increased odds of diabetes compared to non-IPF controls, while whether patients with DM have an increased risk of IPF is still controversial. Further large, prospective cohort studies investigating the prevalence of IPF in diabetic patients are warranted.

Up to 50% of adult patients with epilepsy experience comorbid depression or anxiety, complicating post-treatment recovery and requiring tailored outcome assessment. No core outcome set (COS) exists for this dual-diagnosis population, unlike broader epilepsy COSs or quality-of-life COSs for drug-resistant epilepsy, which do not prioritize mental health comorbidities. This protocol outlines the development of a standardized COS to evaluate post-treatment recovery in adults with epilepsy and comorbid depression or anxiety, using the International Classification of Functioning, Disability, and Health (ICF) framework to ensure a biopsychosocial perspective. This COS aims to enhance cross-study comparability and inform personalized care for this underserved group. This study will employ a three-phase process: (1) A systematic review of outcomes in epilepsy with comorbid depression or anxiety in adult patients, searching PubMed, Embase, and Cochrane Library per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, including outcomes such as seizure control, mood stability, cognitive function, social reintegration, and suicide-related outcomes; (2) Mapping outcomes to ICF domains (body functions, activities, participation) for comprehensive coverage; and (3) A three-round Delphi survey using a 9-point Likert scale to achieve consensus among an international panel of ≥60 stakeholders, including neurologists, psychiatrists, psychologists, patients, and caregivers, with ≥20% from low- and middle-income countries. Consensus requires ≥70% agreement on scores of 7-9 (critically important) and ≤15% on 1-3 (low importance). The COS will capture domains like seizure control, mood stability, cognitive function, and social reintegration. This COS will address a critical gap by standardizing outcome measurement for adults with epilepsy and mental health comorbidities, complementing broader COSs, such as the Epilepsy Outcome Set for Effectiveness Trials (EPSET), by focusing on mental health recovery, including suicide-related outcomes, and extending quality-of-life-focused sets, such as those using the Quality of Life in Epilepsy (QOLIE) scales, to include neurological and functional outcomes. The ICF-guided, patient-inclusive approach ensures global relevance. Potential limitations, including stakeholder bias, will be mitigated through diverse recruitment and robust consensus methods. This protocol leverages Delphi methodology and ICF principles to develop a novel COS for a complex dual-diagnosis population. By prioritizing mental health recovery in adults, including critical outcomes like suicide prevention, it offers a distinct tool to enhance research and clinical practice, with future validation planned to ensure applicability across settings. CRD42024576141.

[This corrects the article DOI: 10.1371/journal.pone.0330617.].

Intestinal constipation is a substantive global health concern, significantly impairing patient quality of life. An emerging view is that the gut microbiota plays a critical role in intestinal function, and probiotics could offer therapeutic benefits. This study aims to consolidate evidence from randomized controlled trials (RCTs) that assess the effectiveness of probiotics in modulating microbiota and ameliorating symptoms of constipation. We will execute a systematic evidence search across Medline (via PubMed), Embase, Cochrane CENTRAL, Web of Science, Scopus, and CINAHL, employing explicit search terms and further reference exploration. Two independent reviewers will ensure study selection and data integrity while assessing methodological quality via the Cochrane Collaboration's Risk of Bias-2 tool. Our primary goal is to outline changes in microbiota composition, with secondary outcomes addressing symptom relief and stool characteristics. Meta-analyses will adopt a random-effects model to quantify the effects of interventions, supplemented by subgroup analyses and publication bias assessments to fortify the rigor of our findings. This study endeavors to provide a rigorous, synthesized overview of the probiotics interventions evidence for modulating gut microbiota in individuals with intestinal constipation. The insights derived could inform clinical guidelines, nurture the creation of novel constipation management strategies, and direct future research in this field. As this study aggregates and analyzes existing data without direct human subject involvement, no ethical approval is required. We will disseminate the study's findings through scientific forums and seek publication in well-regarded, peer-reviewed journals. OSF registration number: 10.17605/OSF.IO/MEAHT.

Anal fistula is the natural evolution of perianal abscess and one of the most common perianal diseases for adults. For complex fistula, it is still very challenging for anorectal surgeons to manage. With the introduction of laser technique in surgery, it is becoming more and more widely used for the treatment of cryptoglandular anal fistula. During the past decade, numerous studies have reported the clinical effectiveness and postoperative outcomes of different forms of laser treatment for anal fistula. However, as these studies were varied in terms of baseline characteristics, the evidence for the true clinical effectiveness of laser treatment for anal fistula need further critical appraisal. Therefore, the purpose of this study is to evaluate the outcomes of surgical laser therapy for cryptoglandular anal fistula stratified by laser type and Parks' classification through a synthesis of quantitative and qualitative evidence. This study will be carried out with adherence to the Cochrane Handbook. We will search PubMed, Cochrane Library, and Embase until June, 2022 to identify all relevant interventional and observational studies examining the effects of laser therapy on the clinical outcomes for cryptoglandular anal fistula. Data extraction from eligible studies will be performed independently by two unblinded authors using standardized extraction forms. Risk of bias assessment for each study will be conducted using Cochrane tool for randomized controlled trials (RCTs) and the Newcastle-Ottawa scale (NOS) tool for observational studies. The DerSimonian-Laird random-effects model will be used to calculate the pooled estimates. Heterogeneity will be examined by subgroup analysis stratified by laser type and Parks' classification and other study characteristics. Potential publication bias will be assessed by funnel plot symmetrical and Egger's regression tests. The synthesis of quantitative and qualitative evidence of this systemic review will yield updated and comprehensive evidence of laser treatment on specific outcomes, which can provide anorectal surgeons with high level evidence-based recommendations to improve patient care and clinical outcomes. OSF registration number: DOI 10.17605/OSF.IO/36ADW.

Background As key mediators of antitumor immunity, CD8 + tumor-infiltrating lymphocytes present antigens and initiate robust immune responses against cancer cells. When stratified by location, CD8 + T lymphocytes were counted and classified as intratumoral, stromal, or total CD8 + tumor-infiltrating lymphocytes. Despite their crucial role, the impact, especially the specific type of CD8 + T lymphocytes on breast cancer prognosis remains controversial. This meta-analysis synthesized evidence to delineate the relationship between CD8 + tumor-infiltrating lymphocytes density of different counting methods and breast cancer patient outcomes. Methods PubMed, Embase, and the Cochrane Library were systemically searched from inception through January 2024 for studies evaluating the prognostic significance of CD8 + tumor-infiltrating lymphocytes in breast cancer. The primary endpoint was disease-free survival (DFS), and the second endpoints were overall survival (OS), breast cancer-specific survival (BCSS), and recurrence-free survival (RFS). Results Thirty-four studies encompassing 23,626 breast cancer patients were included. Pooled hazard ratios (HRs) indicated a significant association of high CD8 + TIL presence with improved DFS (HR = 0.63; 95% CI = 0.54–0.73), OS (HR = 0.72; 95% CI = 0.65–0.79), BCSS (HR = 0.67; 95% CI = 0.58–0.78), and RFS (HR = 0.53; 95% CI = 0.38–0.73). Stratification by TIL location (intratumoral [iCD8], stromal [sCD8], or total [tCD8]) did not significantly impact DFS or OS. Conclusion High CD8 + TIL density in breast cancer patients is correlated with a favorable prognosis, irrespective of the location of CD8 + tumor-infiltrating lymphocytes. These findings affirm the prognostic utility of CD8 + TIL assessment and may guide future immunotherapeutic strategies.

Although several previous studies have examined the association between the platelet to lymphocyte ratio (PLR) and acute appendicitis (AA), findings have been controversial. We aimed to systematically assess the available evidence to elucidate the overall relationship between the PLR and AA. Pubmed and Embase databases were searched for all available published literature before August, 2019 by two independent investigators for observational studies reporting the association between the PLR and AA. Random effects models were applied for all meta-analyses. Pooled standardized mean difference (SMD) and 95% confidence interval (CI) were calculated as effect estimates. Eleven articles met the inclusion criteria and included in this study. Meta-analysis showed that the level of PLR in the AA group was significantly higher than that in the control group (SMD: 1.19, 95% CI: 0.75 to 1.62, P<0.001). A series of subgroup analyses were conducted to investigate the heterogeneity, showing a significant increase in PLV levels in adults with age ≥30 years (SMD: 1.46, 95% CI: 0.89 to 2.02),compared to those in adult <30 years(SMD: 0.58, 95% CI: 0.12 to 1.04) or in children (SMD: 1.03, 95% CI: 0.51 to 1.56). Compared to non-AA controls, a significant increased PLR level was also observed in non-perforated AA (SMD: 1.23, 95% CI: 0.88 to 1.59) and in AA patients during pregnancy (SMD: 0.70, 95% CI: 0.36 to 1.04), while not in perforated AA (SMD: 2.28, 95% CI: -1.72 to 6.28). A significant increase in PLR level is found in patients with AA, indicating that PLR is a promising biomarker for AA. PLR provides a convenient option for emergency department to quickly screen for clinically or radiologically confirmed AA awaiting appendectomy, especially for pregnant women suspected of having AA. More high-quality evidence is needed to further confirm the diagnostic accuracy of PLR for AA.

Delayed wound healing (DWH) following anal fistula surgery is a common complication that prolongs recovery, increases patient morbidity, and imposes significant healthcare costs. Potential risk factors such as diabetes, smoking, fistula complexity, and surgical techniques have been suggested in individual studies, yet no comprehensive synthesis exists to guide clinical practice. This study aims to identify and evaluate risk factors associated with DWH after anal fistula surgery by combining existing evidence and grading the evidence. This study will follow the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines. We will search PubMed, Embase, Cochrane Library, Web of Science, and grey literature databases from inception to March 2025, with no language restrictions. Observational studies (cohort and case-control) reporting risk factors for DWH, defined as incomplete healing beyond 6-12 weeks post-surgery, will be included. Two independent reviewers will screen titles/abstracts, perform full-text reviews, extract data regarding study design, sample size, risk factors and outcomes, and assess risk of bias using the Newcastle-Ottawa Scale (NOS). Primary outcomes will include odds ratios (OR) or relative risks (RR) for factors such as comorbidities, lifestyle factors, and operative approaches. A random-effects meta-analysis will pool effect estimates if heterogeneity (I² < 50%) permits; otherwise, a narrative synthesis will be conducted. Subgroup analyses will explore differences by study design and patient characteristics, with publication bias assessed using funnel plots and Egger's test. The certainty of evidence will be evaluated with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. This study's strengths include its comprehensive search strategy and rigorous methodology, providing a robust synthesis of risk factors. Clinically, identifying modifiable risk factors could enhance preoperative optimization and postoperative care, reducing delayed healing rates. Future studies should standardize definitions of delayed healing and explore under-investigated factors like wound care techniques or microbiome influences to refine risk prediction models. PROSPERO CRD420251013602.

Osteoporosis and diabetes mellitus (DM) are both prevalent chronic conditions associated with significant morbidity, particularly in aging populations. Patients with DM are at increased risk of developing osteoporosis due to complex pathophysiological interactions between glucose metabolism and bone health. Although pharmacological interventions have been used to prevent and manage osteoporosis in individuals with DM, variability in reported outcomes across studies hinders evidence synthesis and meta-analyses. A standardized Core Outcome Set (COS) is required to harmonize outcome reporting in clinical trials, improving comparability and clinical relevance. This paper outlines the protocol for developing a COS for pharmacological interventions targeting osteoporosis among patients with DM. The development of the COS will follow a five-phase approach. Phase 1 involves a systematic review to identify key outcomes in clinical trials of osteoporosis pharmacotherapy in diabetic populations. Phase 2 consists of a modified Delphi process involving international experts in endocrinology, bone metabolism, and diabetes care, as well as patients and public representatives. This will be followed by Phase 3, where consensus meetings will be held to finalize the essential outcomes for inclusion. Phase 4 will focus on identifying appropriate outcome measurement tools based on a systematic review and additional consensus-building meetings. Finally, Phase 5 will involve dissemination and implementation activities to ensure broad adoption of the COS in future research and clinical trials. Patient and Public Involvement (PPI) will be integrated throughout all phases of the project to ensure the relevance of selected outcomes. The resulting COS will provide a standardized framework for reporting outcomes in pharmacological intervention studies of osteoporosis in patients with DM. By facilitating meta-analyses and data pooling, this COS will improve the comparability of clinical trials, enhance research efficiency, and reduce outcome reporting bias. Ultimately, the COS will support better clinical decision-making, fostering the development of targeted and effective therapies for osteoporosis in the context of diabetes.

High horseshoe-shaped anal fistula (HHAF) is a complicated and challenging condition that presents considerable obstacles in treatment. We are presently investigating a novel surgical technique involving a combination of multi-incision and tube-dragging therapy, and laser closure (MITD-LaC) for the management of HHAF. Due to the current scarcity of rigorous evidence evaluating this approach, it is essential to perform a well-designed randomized controlled trial to compare the effectiveness of this new method with incision and thread-drawing therapy. This trial is a prospective, randomized, controlled and interventional study. After preliminary screening of qualified outpatients, a total of 64 adult patients will be enrolled in the trial and randomly allocated to either the MITD-LaC group or the control group (n = 32 per group). These patients will receive either MITD-LaC or incision and thread-drawing therapy. The design aims to allow for a robust comparison between the two treatment modalities. The primary endpoint is the wound healing time, while secondary endpoints include postoperative anal pain at 1, 3, and 5 days (measured with visual analogue scale), fecal incontinence score within 30 days after operation (measured with Cleveland Clinic Florida incontinence score), and the occurrence of postoperative complications within 1 month after surgery, and quality of life up to six months postoperatively (evaluated by The Quality of Life in patients with Anal Fistula Questionnaire Score). This study represents the first randomized controlled trial evaluating the short-term outcomes of MITD-LaC, thereby aiming to contribute high-quality evidence to guide clinical practice. Moreover, this trial incorporates comprehensive outcome measures assessing both subjective and objective dimensions. Because of this multidimensional assessment, MITD-LaC offers a promising potential for broader application in the treatment of HHAF. Consequently, obtaining more definitive and authoritative evidence through scientifically rigorous clinical trials is of utmost importance in further validating this treatment approach. We have submitted the clinical study protocol to the Ethics Committee, and it has been approved under ethical approval number 2021-1036-111-01. The results of the trial will be disseminated through peer-reviewed academic journals and presentations at professional conferences. ChiCTR2100053556.