Pragmatic nationwide master observational trial based on genomic alterations in advanced solid tumors: KOrean Precision Medicine Networking Group Study of MOlecular profiling guided therapy based on genomic alterations in advanced Solid tumors (KOSMOS)-II study protocol KCSG AL-22-09.

BACKGROUND: Next-generation sequencing (NGS) has been introduced to many Korean institutions to support molecular diagnostics in cancer since 2017, when it became eligible for reimbursement by the National Health Insurance Service. However, the uptake of molecularly guided treatment (MGT) based on NGS results has been limited because of stringent regulations regarding prescriptions outside of approved indications, a lack of clinical trial opportunities, and limited access to molecular tumor boards (MTB) at most institutions. The KOSMOS-II study was designed to demonstrate the feasibility and effectiveness of MGT, informed by MTBs, using a nationwide precision medicine platform. METHODS: The KOSMOS-II trial is a large-scale nationwide master observational study. It involves a framework for screening patients with metastatic solid tumors for actionable genetic alterations based on local NGS testing. It recommends MGT through a remote and centralized MTB meeting held biweekly. MGT can include one of the following options: Tier 1, the therapeutic use of investigational drugs targeting genetic alterations such as ALK, EGFR, ERBB2, BRAF, FH, ROS1, and RET, or those with high tumor mutational burden; Tier 2, comprising drugs with approved indications or those permitted for treatment outside of the indications approved by the Health Insurance Review and Assessment Service of Korea; Tier 3, involving clinical trials matching the genetic alterations recommended by the MTB. Given the anticipated proportion of patients receiving MGT in the range of 50% ± 3.25%, this study aims to enroll 1,000 patients. Patients must have progressed to one or more lines of therapy and undergone NGS before enrollment. DISCUSSION: This pragmatic master protocol provides a mass-screening platform for rare genetic alterations and high-quality real-world data. Collateral clinical trials, translational studies, and clinico-genomic databases will contribute to generating evidence for drug repositioning and the development of new biomarkers. TRIAL REGISTRATION: NCT05525858.

Novel point-of-care cytokine biomarker lateral flow test for the screening for sexually transmitted infections and bacterial vaginosis: study protocol of a multicentre multidisciplinary prospective observational clinical study to evaluate the performance and feasibility of the Genital InFlammation Test (GIFT).

INTRODUCTION: A prototype lateral flow device detecting cytokine biomarkers interleukin (IL)-1α and IL-1ß has been developed as a point-of-care test-called the Genital InFlammation Test (GIFT)-for detecting genital inflammation associated with sexually transmitted infections (STIs) and/or bacterial vaginosis (BV) in women. In this paper, we describe the rationale and design for studies that will be conducted in South Africa, Zimbabwe and Madagascar to evaluate the performance of GIFT and how it could be integrated into routine care. METHODS AND ANALYSIS: We will conduct a prospective, multidisciplinary, multicentre, cross-sectional and observational clinical study comprising two distinct components: a biomedical ('diagnostic study') and a qualitative, modelling and economic ('an integration into care study') part. The diagnostic study aims to evaluate GIFT's performance in identifying asymptomatic women with discharge-causing STIs (Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), Trichomonas vaginalis (TV) and Mycoplasma genitalium (MG)) and BV. Study participants will be recruited from women attending research sites and family planning services. Several vaginal swabs will be collected for the evaluation of cytokine concentrations (ELISA), STIs (nucleic acid amplification tests), BV (Nugent score) and vaginal microbiome characteristics (16S rRNA gene sequencing). The first collected vaginal swab will be used for the GIFT assay which will be performed in parallel by a healthcare worker in the clinic near the participant, and by a technician in the laboratory. The integration into care study aims to explore how GIFT could be integrated into routine care. Four activities will be conducted: user experiences and/or perceptions of the GIFT device involving qualitative focus group discussions and in-depth interviews with key stakeholders; discrete choice experiments; development of a decision tree classification algorithm; and economic evaluation of defined management algorithms. ETHICS AND DISSEMINATION: Findings will be reported to participants, collaborators and local government for the three sites, presented at national and international conferences, and disseminated in peer-reviewed publications.The protocol and all study documents such as informed consent forms were reviewed and approved by the University of Cape Town Human Research Ethics Committee (HREC reference 366/2022), Medical Research Council of Zimbabwe (MRCZ/A/2966), Comité d'Ethique pour la Recherche Biomédicale de Madagascar (N° 143 MNSAP/SG/AMM/CERBM) and the London School of Hygiene and Tropical Medicine ethics committee (LSHTM reference 28046).Before the start, this study was submitted to the Clinicaltrials.gov public registry (NCT05723484). TRIAL REGISTRATION NUMBER: NCT05723484.

Measuring Physical Functioning Using Wearable Sensors in Parkinson Disease and Chronic Obstructive Pulmonary Disease (the Accuracy of Digital Assessment of Performance Trial Study): Protocol for a Prospective Observational Study.

BACKGROUND: Physical capacity and physical activity are important aspects of physical functioning and quality of life in people with a chronic disease such as Parkinson disease (PD) or chronic obstructive pulmonary disease (COPD). Both physical capacity and physical activity are currently measured in the clinic using standardized questionnaires and tests, such as the 6-minute walk test (6MWT) and the Timed Up and Go test (TUG). However, relying only on in-clinic tests is suboptimal since they offer limited information on how a person functions in daily life and how functioning fluctuates throughout the day. Wearable sensor technology may offer a solution that enables us to better understand true physical functioning in daily life. OBJECTIVE: We aim to study whether device-assisted versions of 6MWT and TUG, such that the tests can be performed independently at home using a smartwatch, is a valid and reliable way to measure the performance compared to a supervised, in-clinic test. METHODS: This is a decentralized, prospective, observational study including 100 people with PD and 100 with COPD. The inclusion criteria are broad: age ≥18 years, able to walk independently, and no co-occurrence of PD and COPD. Participants are followed for 15 weeks with 4 in-clinic visits, once every 5 weeks. Outcomes include several walking tests, cognitive tests, and disease-specific questionnaires accompanied by data collection using wearable devices (the Verily Study Watch and Modus StepWatch). Additionally, during the last 10 weeks of this study, participants will follow an aerobic exercise training program aiming to increase physical capacity, creating the opportunity to study the responsiveness of the remote 6MWT. RESULTS: In total, 89 people with PD and 65 people with COPD were included in this study. Data analysis will start in April 2024. CONCLUSIONS: The results of this study will provide information on the measurement properties of the device-assisted 6MWT and TUG in the clinic and at home. When reliable and valid, this can contribute to a better understanding of a person's physical capacity in real life, which makes it possible to personalize treatment options. TRIAL REGISTRATION: ClinicalTrials.gov NCT05756075; https://clinicaltrials.gov/study/NCT05756075. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/55452.

Comprehensive observational study evaluating the enduring effectiveness of 4CMenB, the meningococcal B vaccine against gonococcal infections in the Northern Territory and South Australia, Australia: study protocol.

INTRODUCTION: The effectiveness of antibiotics for treating gonococcal infections is compromised due to escalating antibiotic resistance; and the development of an effective gonococcal vaccine has been challenging. Emerging evidence suggests that the licensed meningococcal B (MenB) vaccine, 4CMenB is effective against gonococcal infections due to cross-reacting antibodies and 95% genetic homology between the two bacteria, Neisseria meningitidis and Neisseria gonorrhoeae, that cause the diseases. This project aims to undertake epidemiological and genomic surveillance to evaluate the long-term protection of the 4CMenB vaccine against gonococcal infections in the Northern Territory (NT) and South Australia (SA), and to determine the potential benefit of a booster vaccine doses to provide longer-term protection against gonococcal infections. METHODS AND ANALYSES: This observational study will provide long-term evaluation results of the effectiveness of the 4CMenB vaccine against gonococcal infections at 4-7 years post 4CMenB programme implementation. Routine notifiable disease notifications will be the basis for assessing the impact of the vaccine on gonococcal infections. Pathology laboratories will provide data on the number and percentage of N. gonorrhoeae positive tests relative to all tests administered and will coordinate molecular sequencing for isolates. Genome sequencing results will be provided by SA Pathology and Territory Pathology/New South Wales Health Pathology, and linked with notification data by SA Health and NT Health. There are limitations in observational studies including the potential for confounding. Confounders will be analysed separately for each outcome/comparison. ETHICS AND DISSEMINATION: The protocol and all study documents have been reviewed and approved by the SA Department for Health and Well-being Human Research Ethics Committee (HREC/2022/HRE00308), and the evaluation will commence in the NT on receipt of approval from the NT Health and Menzies School of Health Research Human Research Ethics Committee. Results will be published in peer-reviewed journals and presented at scientific meetings and public forums.

Maternal smoking, consumption of alcohol, and caffeinated beverages during pregnancy and the risk of childhood brain tumors: a meta-analysis of observational studies.

BACKGROUND: We conducted this meta-analysis to investigate the potential association between maternal smoking, alcohol and caffeinated beverages consumption during pregnancy and the risk of childhood brain tumors (CBTs). METHODS: A thorough search was carried out on PubMed, Embase, Web of Science, Cochrane Library, and China National Knowledge Internet to identify pertinent articles. Fixed or random effects model was applied to meta-analyze the data. RESULTS: The results suggested a borderline statistically significant increased risk of CBTs associated with maternal smoking during pregnancy (OR 1.04, 95% CI 0.99-1.09). We found that passive smoking (OR 1.12, 95% CI 1.03-1.20), rather than active smoking (OR 1.00, 95% CI 0.93-1.07), led to an increased risk of CBTs. The results suggested a higher risk in 0-1 year old children (OR 1.21, 95% CI 0.94-1.56), followed by 0-4 years old children (OR 1.12, 95% CI 0.97-1.28) and 5-9 years old children (OR 1.11, 95% CI 0.95-1.29). This meta-analysis found no significant association between maternal alcohol consumption during pregnancy and CBTs risk (OR 1.00, 95% CI 0.80-1.24). An increased risk of CBTs was found to be associated with maternal consumption of caffeinated beverages (OR 1.16, 95% CI 1.07-1.26) during pregnancy, especially coffee (OR 1.18, 95% CI 1.00-1.38). CONCLUSIONS: Maternal passive smoking, consumption of caffeinated beverages during pregnancy should be considered as risk factors for CBTs, especially glioma. More prospective cohort studies are warranted to provide a higher level of evidence.

Do efficacy results obtained from randomized controlled trials translate to effectiveness data from observational studies for relapsing-remitting multiple sclerosis?

BACKGROUND: Randomized controlled trials are considered the gold standard in regulatory decision making, as observational studies are known to have important methodological limitations. However, real-world evidence may be helpful in specific situations. This review investigates how the effect estimates obtained from randomized controlled trials compare to those obtained from observational studies, using drug therapy for relapsing-remitting multiple sclerosis as an example. STUDY DESIGN AND SETTING: A systematic review of randomized controlled trials and observational studies was conducted. The primary outcome was the annualized relapse rate. Using (network) meta-analysis together with posterior predictive distributions, the drug-specific rate ratios from the network of randomized controlled trials were compared with those from the network of observational studies. RESULTS: Effect estimates from 26 observational studies showed greater magnitudes and were less precise compared to estimates obtained from 21 randomized controlled trials. Twenty of the 28 treatment comparisons between designs had similar rate ratios. Seven inconsistencies in observed rate ratios could be attributed to two specific disease-modifying therapies. CONCLUSION: In this case study, estimates from observational studies predominantly agreed with estimates from randomized controlled trials given their posterior predictive distributions. Multiple observational studies together may therefore supplement additional pivotal randomized controlled trials in relapsing-remitting multiple sclerosis, for instance facilitating the extrapolation of trial results to the broader patient population.

Bronchial Valves for Persistent Air Leak: A Systematic Review and Meta-analysis.

BACKGROUND: Patients with persistent air leak (PAL) pose a therapeutic challenge to physicians, with prolonged hospital stays and high morbidity. There is little evidence on the efficacy and safety of bronchial valves (BV) for PAL. METHODS: We systematically searched the PubMed and Embase databases to identify studies evaluating the efficacy and safety of BV for PAL. We calculated the success rate (complete resolution of air leak or removal of intercostal chest drain after bronchial valve placement and requiring no further procedures) of BV for PAL in individual studies. We pooled the data using a random-effects model and examined the factors influencing the success rate using multivariable meta-regression. RESULTS: We analyzed 28 observational studies (2472 participants). The pooled success rate of bronchial valves in PAL was 82% (95% confidence intervals, 75 to 88; 95% prediction intervals, 64 to 92). We found a higher success rate in studies using intrabronchial valves versus endobronchial valves (84% vs. 72%) and in studies with more than 50 subjects (93% vs. 77%). However, none of the factors influenced the success rate of multivariable meta-regression. The overall complication rate was 9.1% (48/527). Granulation tissue was the most common complication reported followed by valve migration or expectoration and hypoxemia. CONCLUSION: Bronchial valves are an effective and safe option for treating PAL. However, the analysis is limited by the availability of only observational data.

Biases and limitations in observational studies of Long COVID prevalence and risk factors: A rapid systematic umbrella review.

BACKGROUND: Observational studies form the foundation of Long COVID knowledge, however combining data from Long COVID observational studies has multiple methodological challenges. This umbrella review synthesizes estimates of Long COVID prevalence and risk factors as well as biases and limitations in the primary and review literatures. METHODS AND FINDINGS: A systematic literature search was conducted using multiple electronic databases (PubMed, EMBASE, LitCOVID) from Jan 1, 2019 until June 9, 2023. Eligible studies were systematic reviews including adult populations assessed for at least one Long COVID symptom four weeks or more after SARS-CoV-2 infection. Overall and subgroup prevalence and risk factors as well as risk of bias (ROB) assessments were extracted and descriptively analyzed. The protocol was registered with PROSPERO (CRD42023434323). Fourteen reviews of 5-196 primary studies were included: 8 reported on Long COVID prevalence, 5 on risk/protective factors, and 1 on both. Prevalence of at least 1 Long COVID symptom ranged from 21% (IQR: 8.9%-35%) to 74.5% (95% CI: 55.6%-78.0%). Risk factor reviews found significant associations between vaccination status, sex, acute COVID-19 severity, and comorbidities. Both prevalence and risk factor reviews frequently identified selection and ascertainment biases. Using the AMSTAR 2 criteria, the quality of included reviews, particularly the prevalence reviews, were concerning for the adequacy of ROB assessments and justifications for conducting meta-analysis. CONCLUSION: A high level of heterogeneity render the interpretation of pooled prevalence estimates of Long COVID challenging, further hampered by the lack of robust critical appraisals in the included reviews. Risk factor reviews were of higher quality overall and suggested consistent associations between Long COVID risk and patient characteristics.

The landscape of real-world evidence of rituximab utilization and clinical outcomes in patients with cancer, rheumatoid arthritis, and multiple sclerosis: A scoping review.

BACKGROUND: Rituximab (RTX) is an anti-CD20 monoclonal antibody that is used to treat various conditions in cancer, rheumatoid arthritis (RA), and multiple sclerosis (MS). Although RTX has been used in the United States for almost 3 decades, questions remain regarding its real-world utilization and effectiveness. OBJECTIVE: To describe the state of observational research and real-world evidence evaluating RTX in oncology, RA, and off-label use in MS. METHODS: A broad search was conducted in MEDLINE, Embase, and CINAHL covering the period of January 2010 to June 2022. Two reviewers independently screened all identified records for each disease category (cancer, RA, MS) beginning with title review, followed by abstract, and full-text review to identify relevant publications to include in the final analysis. Data were extracted and summarized for each disease based on overall trends, similarities, and differences across included studies and stratified by disease state. RESULTS: A total of 260 studies met eligibility criteria, with 79 studies for the RA cohort, 144 for cancer, and 37 for MS. Across all disease cohorts, most studies (n = 189; 72.7%) were retrospective. 171 (65.8%) studies used hospital or electronic health record data as their data source and 65 (23.2%) used registry databases. Most studies (n = 153; 58.8%) assessed the effectiveness of RTX measured by disease-specific endpoints, followed by safety (n = 60; 23.1%), treatment patterns (n = 32; 12.3%), and descriptive analyses assessing treatment adherence and economic burden of disease (n = 16; 6.2%). Although safety was not the primary outcome for most studies, the majority of studies across all disease states still reported some form of safety measure. Conclusive statements on RTX's benefit varied across disease states, with MS having the most (n = 30; 81.1%) studies suggesting the drug's positive benefit. There were limited studies assessing RTX use, associated economic burden, and biosimilar switching. CONCLUSIONS: The findings underscore the need for health care providers to better understand the treatment landscape and utilization of RTX, particularly in terms of patient selection, timing of initiation, and long-term outcomes. Real-world evidence can help support health care decisions and treatment using rituximab.

The efficacy of fluconazole for anti-fungal prophylaxis in peritoneal dialysis patients: A systematic review and meta-analysis.

INTRODUCTION AND OBJECTIVES: The efficacy of fluconazole as a prophylactic strategy in patients with chronic kidney disease (CKD) on peritoneal dialysis (PD) with prior antibiotic exposure is controversial in the current literature. This study aimed to compare a strategy of fluconazole prophylaxis versus no-prophylaxis for patients in PD on antibiotics for previous episodes of peritonitis. MATERIALS AND METHODS: We performed a systematic review and meta-analysis of observational studies and randomized controlled trials (RCTs) comparing fluconazole prophylaxis with no prophylaxis for PD-related peritonitis. The search was conducted on PubMed, EMBASE, and Cochrane Central in January 23, 2023. The outcome of interest was the occurrence of fungal peritonitis (FP). RESULTS: We included six studies (1 RCT, 5 observational) with 4515 occurrences of peritonitis, of which 1098 (24.8%) received fluconazole prophylaxis in variable doses, whereas 3417 (75.6%) did not receive prophylaxis during peritonitis episodes. Overall, fluconazole prophylaxis was associated with a lower incidence of FP (OR 0.22; 95% CI 0.12-0.41; p<0.001; I2=0%). Subgroup analysis of studies that administered daily doses of fluconazole also demonstrated a reduced incidence of FP in patients who received antifungal prophylaxis (OR 0.31; CI 0.14-0.69; p=0.004; I2=0%). CONCLUSIONS: In this meta-analysis of 4515 episodes of PD-related peritonitis, prophylaxis with fluconazole significantly reduced episodes of FP as compared with no antifungal prophylaxis.

The burden of skull base chordomas: insights from a meta-analysis of observational studies.

OBJECTIVE: The aim of this study was to provide a quantitative synthesis of the survival outcomes for patients with skull base chordomas, focusing on the role of 1) the extent of resection (gross-total [GTR] vs non-GTR), 2) the type of surgery (primary vs revision), 3) tumor histology, and 4) the different use of adjuvant therapies (proton beam radiotherapy [PBRT], photon radiotherapy [RT], or none). METHODS: A systematic review with a meta-analysis was conducted following the 2020 PRISMA guidelines. Observational studies describing adult and pediatric patient cohorts harboring skull base chordomas were included. The primary outcome measures were represented by the 5-year overall survival (OS) and progression-free survival (PFS) rates. The main intervention effects were represented by the extent of resection (GTR vs non-GTR), type of surgical excision (primary vs revision surgeries), tumor histology, and the different use of adjuvant therapies (PBRT, RT, or none). The pooled estimates were calculated using random forest models. The risk of bias was evaluated using the Joanna Briggs Institute checklist for case series. RESULTS: Six hundred forty-four studies were identified through a database and register search. After study selection, 51 studies and 3871 patients were included in the meta-analysis. The overall 5-year OS rate was 73%, which increased to 84% among patients undergoing GTR. The overall 5-year PFS rate was 52%, increasing to 74% for patients receiving GTR. The 5-year OS and PFS rates for patients undergoing PBRT were 86% and 71%, compared with 71% and 54% for patients receiving RT, and 55% and 25% when no adjuvant treatments were used. Patients undergoing their first surgery had 2.13-fold greater chances of being disease-free and 1.4-fold greater chances of being alive at 5 years follow-up compared with patients who received a revision surgery. Patients harboring chondroid chordomas had 1.13- and 1.9-fold greater chances of being alive at 5 years compared with patients with conventional and de-differentiated chordomas, respectively. The overall risk of bias was low in the included studies. CONCLUSIONS: The results of this comprehensive meta-analysis highlight the tremendous impact of GTR and adjuvant PBRT on improving OS and PFS of patients harboring skull base chordomas, with better survival rates demonstrated for patients with chondroid tumors. Even in experienced hands, the rate of surgical morbidity remains high. Proper management in high-volume centers is mandatory to reach the expected resection goal at the first surgical attempt and to reduce surgical morbidity. The introduction of the endoscopic endonasal approach was related to improved surgical and functional outcomes.

Meta-analysis: Persistence of advanced therapies in the treatment of inflammatory bowel disease.

BACKGROUND: The expanding options in advanced therapies for ulcerative colitis (UC) and Crohn's disease (CD) present challenges in treatment selection. Persistence analysis assesses drug durability in real-world settings, acting as a surrogate marker for medication efficacy and tolerance. Unlike traditional comparative studies, persistence analysis provides insights extending beyond the initial year of treatment. AIM: To provide real-world evidence on treatment effectiveness, tolerability and preferences of physicians and patients regarding various advanced therapies for IBD. METHODS: We conducted a systematic review of observational studies up to March 2023 assessing advanced therapies' persistence in UC and CD. Advanced therapies under examination included infliximab, adalimumab, vedolizumab, ustekinumab, golimumab, certolizumab and tofacitinib. We pooled the persistence of each agent and conducted a meta-analysis to compare the persistence of newer agents with traditional TNF inhibitors (TNFi)-specifically infliximab and adalimumab. RESULTS: Among 63 observational studies, vedolizumab had the highest 1-year persistence in UC (73.8%, 95% CI: 70.0%-77.6%) and ustekinumab in CD (77.5%, 95% CI: 72.9%-82.1%). Compared to TNFi, vedolizumab demonstrated increased persistence with a relative risk (RR) of 1.30 (95% CI: 1.19-1.41) for UC and 1.14 (95% CI: 1.09-1.20) for CD at 1 year, while ustekinumab demonstrated a RR of 1.15 (95% CI: 1.07-1.23) for CD at 1 year. Vedolizumab exhibited sustained increased persistence in UC over 2 years compared to TNFi (RR: 1.33, 95% CI 1.14-1.54). CONCLUSION: This meta-analysis highlights the superior persistence of ustekinumab and vedolizumab over TNFi, and offers valuable insights for clinicians navigating the challenging landscape of UC and CD therapeutic choices.

Air leak test in the Paediatric Intensive Care Unit (ALTIPICU): rationale and protocol for a prospective multicentre observational study.

INTRODUCTION: In children, respiratory distress due to upper airway obstruction (UAO) is a common complication of extubation. The quantitative cuff-leak test (qtCLT) is a simple, rapid and non-invasive test that has not been extensively studied in children. The objective of the ongoing study whose protocol is reported here is to investigate how well the qtCLT predicts UAO-related postextubation respiratory distress in paediatric intensive care unit (PICU) patients. METHODS AND ANALYSIS: Air Leak Test in the Paediatric Intensive Care Unit is a multicentre, prospective, observational study that will recruit 900 patients who are aged 2 days post-term to 17 years and ventilated through a cuffed endotracheal tube for at least 24 hours in any of 19 French PICUs. Within an hour of planned extubation, the qtCLT will be performed as a sequence of six measurements of the tidal volume with the cuff inflated then deflated. The primary outcome is the occurrence within 48 hours after extubation of severe UAO defined as combining a requirement for intravenous corticosteroid therapy and/or ventilator support by high-flow nasal cannula and/or by non-invasive ventilation or repeat invasive mechanical ventilation with a Westley score ≥4 with at least one point for stridor at each initiation. The results of the study are expected to identify risk factors for UAO-related postextubation respiratory distress and extubation failure, thereby identifying patient subgroups most likely to require preventive interventions. It will also determine whether qtCLT appears to be a reliable method to predict an increased risk for postextubation adverse events as severe UAO. ETHICS AND DISSEMINATION: The study was approved by the Robert Debré University Hospital institutional review board (IRB) on September 2021 (approval #2021578). The report of Robert Debré University Hospital IRB is valid for all sites, given the nature of the study with respect to the French law. The results will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT05328206.

Ninety-Day Stroke Recurrence in Minor Stroke: Systematic Review and Meta-Analysis of Trials and Observational Studies.

BACKGROUND: Risk of recurrence after minor ischemic stroke is usually reported with transient ischemic attack. No previous meta-analysis has focused on minor ischemic stroke alone. The objective was to evaluate the pooled proportion of 90-day stroke recurrence for minor ischemic stroke, defined as a National Institutes of Health Stroke Scale severity score of ≤5. METHODS AND RESULTS: Published papers found on PubMed from 2000 to January 12, 2021, reference lists of relevant articles, and experts in the field were involved in identifying relevant studies. Randomized controlled trials and observational studies describing minor stroke cohort with reported 90-day stroke recurrence were selected by 2 independent reviewers. Altogether 14 of 432 (3.2%) studies met inclusion criteria. Multilevel random-effects meta-analysis was performed. A total of 6 randomized controlled trials and 8 observational studies totaling 45 462 patients were included. The pooled 90-day stroke recurrence was 8.6% (95% CI, 6.5-10.7), reducing by 0.60% (95% CI, 0.09-1.1; P=0.02) with each subsequent year of publication. Recurrence was lowest in dual antiplatelet trial arms (6.3%, 95% CI, 4.5-8.0) when compared with non-dual antiplatelet trial arms (7.2%, 95% CI, 4.7-9.6) and observational studies 10.6% (95% CI, 7.0-14.2). Age, hypertension, diabetes, ischemic heart disease, or known atrial fibrillation had no significant association with outcome. Defining minor stroke with a lower National Institutes of Health Stroke Scale threshold made no difference - score ≤3: 8.6% (95% CI, 6.0-11.1), score ≤4: 8.4% (95% CI, 6.1-10.6), as did excluding studies with n<500%-7.3% (95% CI, 5.5-9.0). CONCLUSIONS: The risk of recurrence after minor ischemic stroke is declining over time but remains important.

Higher odds of periodontitis in systemic lupus erythematosus compared to controls and rheumatoid arthritis: a systematic review, meta-analysis and network meta-analysis.

Introduction: Periodontitis as a comorbidity in systemic lupus erythematosus (SLE) is still not well recognized in the dental and rheumatology communities. A meta-analysis and network meta-analysis were thus performed to compare the (i) prevalence of periodontitis in SLE patients compared to those with rheumatoid arthritis (RA) and (ii) odds of developing periodontitis in controls, RA, and SLE. Methods: Pooled prevalence of and odds ratio (OR) for periodontitis were compared using meta-analysis and network meta-analysis (NMA). Results: Forty-three observational studies involving 7,800 SLE patients, 49,388 RA patients, and 766,323 controls were included in this meta-analysis. The pooled prevalence of periodontitis in SLE patients (67.0%, 95% confidence interval [CI] 57.0-77.0%) was comparable to that of RA (65%, 95% CI 55.0-75.0%) (p>0.05). Compared to controls, patients with SLE (OR=2.64, 95% CI 1.24-5.62, p<0.01) and RA (OR=1.81, 95% CI 1.25-2.64, p<0.01) were more likely to have periodontitis. Indirect comparisons through the NMA demonstrated that the odds of having periodontitis in SLE was 1.49 times higher compared to RA (OR=1.49, 95% CI 1.09-2.05, p<0.05). Discussion: Given that RA is the autoimmune disease classically associated with periodontal disease, the higher odds of having periodontitis in SLE are striking. These results highlight the importance of addressing the dental health needs of patients with SLE. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/ identifier CRD42021272876.

Protocol for a magnetic resonance imaging study of participants in the fever RCT: Does fever control prevent brain injury in malaria?

BACKGROUND: Despite eradication efforts, ~135,000 African children sustained brain injuries as a result of central nervous system (CNS) malaria in 2021. Newer antimalarial medications rapidly clear peripheral parasitemia and improve survival, but mortality remains high with no associated decline in post-malaria neurologic injury. A randomized controlled trial of aggressive antipyretic therapy with acetaminophen and ibuprofen (Fever RCT) for malarial fevers being conducted in Malawi and Zambia began enrollment in 2019. We propose to use neuroimaging in the context of the RCT to further evaluate neuroprotective effects of aggressive antipyretic therapy. METHODS: This observational magnetic resonance imaging (MRI) ancillary study will obtain neuroimaging and neurodevelopmental and behavioral outcomes in children previously enrolled in the Fever RCT at 1- and 12-months post discharge. Analysis will compare the odds of any brain injury between the aggressive antipyretic therapy and usual care groups based upon MRI structural abnormalities. For children unable to undergo imaging without deep sedation, neurodevelopmental and behavioral outcomes will be used to identify brain injury. DISCUSSION: Neuroimaging is a well-established, valid proxy for neurological outcomes after brain injury in pediatric CNS malaria. This MRI ancillary study will add value to the Fever RCT by determining if treatment with aggressive antipyretic therapy is neuroprotective in CNS malaria. It may also help elucidate the underlying mechanism(s) of neuroprotection and expand upon FEVER RCT safety assessments.

The association between inflammatory biomarkers and low back disorder: a systematic review and meta-analysis.

INTRODUCTION: Low back disorder (LBD) is a major cause of disability worldwide. Inflammation results in proliferation of cytokines or consequent degradation products (collectively known as inflammatory biomarkers) that activate pain pathways which can result in non-specific LBD. This systematic review and meta-analysis aim to evaluate the relationship between inflammatory biomarkers and clinical outcomes in patients with LBD. METHODS: The PRISMA guideline was followed for the systematic reivew. Three online databases were searched. Four RCTs and sixteen observational studies with 1142 LBD patients were analysed. The primary outcomes were back and leg pain scores, back-specific disability scores and expression of inflammatory biomarkers. Standardized mean difference (SMD) and their 95% confidence intervals (CI) were evaluated. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to summarize the strength of evidence. RESULTS: Four RCTs and sixteen observational studies were included in the analysis of 1142 patients with LBD. There was a statistically significant reduction in back pain score and IL-1 beta and increase in the expression of CTX-1 and IL-10 levels post treatment. There was a significant relationship between increase in the expression of MCP- and reduction in the expression of hsCRP with increase in back pain. Significant relationship was also observed between increase in the expression of MCP-1 and reduction in the expression of IL-6 with increase in leg pain. Increase in the expression of IL-8 and reduction in the expression of hsCRP was also associated with increased disability score. CONCLUSION: Inflammatory biomarkers play a significant role in the pathogenesis of LBD. CTX-1, IL-10 and IL-1 beta may be responsible for the decrease in back pain scores post treatment. There is a relationship between MCP-1, IL-6, IL-8 and hsCRP with clinical and functional assessments for LBD. Further studies will improve understanding of the pathogenesis of LBD and aid in targeted management strategies.

Gender Difference in sidE eFfects of ImmuNotherapy: a possible clue to optimize cancEr tReatment (G-DEFINER): study protocol of an observational prospective multicenter study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have significantly improved outcomes in various cancers. ICI treatment is associated with the incidence of immune-related adverse events (irAEs) which can affect any organ. Data on irAEs occurrence in relation to sex- differentiation and their association with gender-specific factors are limited. AIMS: The primary objective of the G-DEFINER study is to compare the irAEs incidence in female and male patients who undergo ICI treatment. Secondary objectives are: to compare the irAEs incidence in pre- and postmenopausal female patients; to compare the irAEs incidence in female and male patients according to different clinical and gender-related factors (lifestyle, psychosocial, and behavioral factors). Exploratory objectives of the study are to compare and contrast hormonal, gene-expression, SNPs, cytokines, and gut microbiota profiles in relation to irAEs incidence in female and male patients. METHODS AND RESULTS: The patients are recruited from Fondazione IRCCS Istituto Nazionale dei Tumori, Italy, St Vincent's University Hospital, Ireland, Oslo University Hospital, Norway, and Karolinska Insitutet/Karolinska University Hospital, Sweden. The inclusion of patients was delayed due to the Covid pandemic, leading to a total of 250 patients recruited versus a planned number of 400 patients. Clinical and translational data will be analyzed. INTERPRETATION: The expected outcomes are to improve the management of cancer patients treated with ICIs, leading to more personalized clinical approaches that consider potential toxicity profiles. The real world nature of the trial makes it highly applicable for timely irAEs diagnosis.