Serious adverse events reporting in recent randomised clinical trials in intensive care medicine - A methodological study protocol.

BACKGROUND: Serious adverse events (SAEs) are common in intensive care unit (ICU) patients. Reporting of SAEs in randomised clinical trials (RCTs) varies why underreporting is likely. We aim to describe the reporting of SAEs from 2020 onwards and to illustrate the recent reporting of SAEs published in major medical journals. METHODS: We will conduct a methodological study assessing pharmacological interventions in RCTs including adult ICU patients. We will search 10 general medical and critical care journals in PubMed. We will include all RCTs published from 2020 onwards. The primary research question is how many RCTs report SAEs in the primary publication. Secondary research questions include how SAEs are reported in the primary publication either as (1) proportion of patients experiencing one or more SAE, (2) all single events occurred, or (3) both strategies combined. We will assess the association between the proportion of patients with reported SAEs and the following trial characteristics: multicentred versus single-centre RCTs, industry-sponsored versus academic-sponsored, published trial protocol versus unpublished work, blinding, trials sample size, and RCTs focusing on COVID-19 patients versus other populations. DISCUSSION: The outlined methodological study will provide important information on the reporting of SAEs in recent drug trials in adult ICU patients.

Implementing a pharmacogenomic-driven algorithm to guide antiplatelet therapy among Caribbean Hispanics: a non-randomised clinical trial.

OBJECTIVES: To assess whether genotype-guided selection of oral antiplatelet drugs using a clinical decision support (CDS) algorithm reduces the rate of major adverse cardiovascular and cerebrovascular events (MACCEs) among Caribbean Hispanic patients, after 6 months. DESIGN: An open-label, multicentre, non-randomised clinical trial. SETTING: Eight secondary and tertiary care hospitals (public and private) in Puerto Rico. PARTICIPANTS: 300 Caribbean Hispanic patients on clopidogrel, both genders, underwent percutaneous coronary intervention (PCI) for acute coronary syndromes, stable ischaemic heart disease and documented extracardiac vascular diseases. INTERVENTIONS: Patients were separated into standard-of-care (SoC) and genotype-guided (pharmacogenetic (PGx)-CDS) groups (150 each) and stratified by risk scores. Risk scores were calculated based on a previously developed CDS risk prediction algorithm designed to make actionable treatment recommendations for each patient. Individual platelet function, genotypes, clinical and demographic data were included. Ticagrelor was recommended for patients with a high-risk score ≥2 in the PGx-CDS group only, the rest were kept or de-escalated to clopidogrel. The intervention took place within 3-5 days after PCI. Adherence medication score was also measured. PRIMARY AND SECONDARY OUTCOMES: The occurrence rate of MACCEs (primary) and bleeding episodes (secondary). Statistical associations between patient time free of events and predictor variables (ie, treatment groups, risk scores) were tested using Kaplan-Meier survival analyses and Cox proportional-hazards regression models. RESULTS: The genotype-guided group had a clinically lower but not significantly different risk of MACCEs compared with the SoC group (8.7% vs 10.7%, p=0.56; HR=0.56). Among high-risk score patients, genotype-driven guidance of antiplatelet therapy showed superiority over SoC in reducing MACCE incidence 6 months postcoronary stenting (adjusted HR=0.104; p< 0.0001). CONCLUSIONS: The potential benefit of implementing our PGx-CDS algorithm to significantly reduce the incidence rate of MACCEs in post-PCI Caribbean Hispanic patients on clopidogrel was observed exclusively among high-risk patients, with apparently no evident effect in other patient groups. TRIAL REGISTRATION NUMBER: NCT03419325.

Factors influencing implementation and adoption of direct oral penicillin challenge for allergy delabelling: a qualitative evaluation.

BACKGROUND: Over 95% of penicillin allergy labels are inaccurate and may be addressed in low-risk patients using direct oral penicillin challenge (DPC). This study explored the behaviour, attitudes and acceptability of patients, healthcare professionals (HCPs) and managers of using DPC in low-risk patients. METHODS: Mixed-method, investigation involving patient interviews and staff focus groups at three NHS acute hospitals. Transcripts were coded using inductive and deductive thematic analysis informed by the Theoretical Domains Framework. FINDINGS: Analysis of 43 patient interviews and three focus groups (28 HCPs: clinicians and managers) highlighted themes of 'knowledge', 'beliefs about capabilities and consequences', 'environmental context', 'resources', 'social influences', 'professional role and identity', 'behavioural regulation and reinforcement' and a cross-cutting theme of digital systems. Overall, study participants supported the DPC intervention. Patients expressed reassurance about being in a monitored, hospital setting. HCPs acknowledged the need for robust governance structures for ensuring clarity of roles and responsibilities and confidence. CONCLUSION: There were high levels of acceptability among patients and HCPs. HCPs recognised the importance of DPC. Complexities of penicillin allergy (de)labelling were highlighted, and issues of knowledge, risk, governance and workforce were identified as key determinants. These should be considered in future planning and adoption strategies for DPC.

Immune-related [18F]FDG PET findings in patients undergoing checkpoint inhibitors treatment: correlation with clinical adverse events and prognostic implications.

BACKGROUND: Direct comparisons between [18F]FDG PET/CT findings and clinical occurrence of immune-related adverse events (irAEs) based on independent assessments of clinical and imaging features in patients receiving immune checkpoint inhibitors (ICIs) are missing. Our aim was to estimate sites, frequency, and timing of immune-related PET findings during ICIs treatment in patients with melanoma and NSCLC, and to assess their correlation with clinical irAEs. Prognostic implications of immune-related events were also investigated. METHODS: Fifty-one patients with melanoma (47%) or NSCLC (53%) undergoing multiple PET examinations during anti-PD1/PDL1 treatment were retrospectively included. Clinical irAEs were graded according to CTCAE v.5.0. Abnormal PET findings suggestive of immune activation were described by two readers blinded to the clinical data. Progression-free survival (PFS) and overall survival (OS) were analyzed with the Kaplan-Meier method in patients stratified according to the presence of irAEs, immune-related PET findings or both. RESULTS: Twenty-one patients showed clinical irAEs only (n = 6), immune-related PET findings only (n = 6), or both (n = 9). In patients whose imaging findings corresponded to clinical irAEs (n = 7), a positive correlation between SUVmax and the severity of the clinical event was observed (rs=0.763, p = 0.046). Clinical irAEs occurred more frequently in patients without macroscopic disease than in metastatic patients (55% vs. 23%, p = 0.039). Patients who developed clinical irAEs had a significantly longer PFS than patients who remained clinically asymptomatic, both in the overall cohort (p = 0.011) and in the subgroup of (n = 35) patients with metastatic disease (p = 0.019). The occurrence of immune-related PET findings significantly stratified PFS in the overall cohort (p = 0.040), and slightly missed statistical significance in patients with metastatic disease (p = 0.08). The best stratification of PFS was achieved when all patients who developed immune-related events, either clinically relevant or detected by PET only, were grouped together both in the overall cohort (p = 0.002) and in patients with metastatic disease (p = 0.004). In the whole sample, OS was longer in patients who developed any immune-related events (p = 0.032). CONCLUSION: Patients with melanoma or NSCLC under ICI treatment can develop clinical irAEs, immune-related PET findings, or both. The occurrence of immune-related events has a prognostic impact. Combining clinical information with PET assessment improved outcome stratification.

Predictive value of near-term prediction models for severe immune-related adverse events in malignant tumor PD-1 inhibitor therapy.

Immune-related adverse events (irAEs) impact outcomes, with most research focusing on early prediction (baseline data), rather than near-term prediction (one cycle before the occurrence of irAEs and the current cycle). We aimed to explore the near-term predictive value of neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), absolute eosinophil count (AEC) for severe irAEs induced by PD-1 inhibitors. Data were collected from tumor patients treated with PD-1 inhibitors. NLR, PLR, and AEC data were obtained from both the previous and the current cycles of irAEs occurrence. A predictive model was developed using elastic net logistic regression Cutoff values were determined using Youden's Index. The predicted results were compared with actual data using Bayesian survival analysis. A total of 138 patients were included, of whom 47 experienced grade 1-2 irAEs and 18 experienced grade 3-5 irAEs. The predictive model identified optimal α and λ through 10-fold cross-validation. The Shapiro-Wilk test, Kruskal-Wallis test and logistic regression showed that only current cycle data were meaningful. The NLR was statistically significant in predicting irAEs in the previous cycle. Both NLR and AEC were significant predictors of irAEs in the current cycle. The model achieved an area under the ROC curve (AUC) of 0.783, with a sensitivity of 77.8% and a specificity of 80.8%. A probability ≥ 0.1345 predicted severe irAEs. The model comprising NLR, AEC, and sex may predict the irAEs classification in the current cycle, offering a near-term predictive advantage over baseline models and potentially extending the duration of immunotherapy for patients.

Investigating drug-induced urinary retention: a pharmacovigilance analysis of FDA adverse event reports from 2004 to 2024.

BACKGROUND: Drug-induced urinary retention (DIUR) can severely impact patient quality of life and complicate treatment. This study investigates the incidence and characteristics of DIUR using data from the FDA Adverse Event Reporting System (FAERS) over 20 years. METHODS: FAERS reports related to urinary retention (UR) from Q1 2004 to Q1 2024 were analyzed. Potential causative drugs were identified, and the top 30 drugs with the most UR reports were ranked. Statistical disproportionality analyses, including Proportional Reporting Ratio (PRR) and Reporting Odds Ratio (ROR), were conducted to detect significant safety signals. RESULTS: Out of 17,703,515 reports in the FAERS database 28,423 cases of UR were identified. Anticholinergics, antidepressants, and opioids were the most frequently implicated drug classes. The highest ROR and PRR values were observed for drugs like ezogabine. Additionally, less commonly associated drugs, such as adalimumab and others, were implicated, suggesting potential under-recognition of this adverse effect. However, these associations should be interpreted with caution, as they do not confirm a direct causal relationship. CONCLUSION: This study underscores the importance of pharmacovigilance in identifying and understanding DIUR. Further research is needed to confirm these findings and develop strategies to manage and reduce the risk, improving patient outcomes.

Impact of Sevoflurane and Propofol on Perioperative Respiratory Adverse Events in Pediatrics: A Systematic Review and Meta-analysis.

PURPOSE: Perioperative respiratory adverse events continue to pose significant challenges in pediatric anesthesia. Research has hinted at a lower incidence of these complications in children anesthetized with propofol than sevoflurane. This study aimed to assess and compare respiratory complications in children undergoing general anesthesia with either sevoflurane or propofol during surgery. DESIGN: Systematic review and meta-analysis. METHODS: We conducted comprehensive searches of the PubMed, Embase, and Cochrane Library databases and manual searches to identify pertinent randomized controlled trials (RCTs) published up to August 19, 2023. The Cochrane risk assessment tool was employed to evaluate the risk of bias in the selected studies. The pooled analysis of relevant data compared respiratory complications, vomiting, agitation, anesthesia duration, extubation time, and recovery time in pediatric patients undergoing anesthesia with sevoflurane and propofol. FINDINGS: A total of 17 RCTs, containing 1,758 pediatric participants, were included and analyzed. Respiratory adverse events were examined, encompassing laryngospasm, apnea, cough, and SpO2. In comparison to sevoflurane, children subjected to propofol anesthesia demonstrated a significant reduction in the risk of laryngospasm (P = .001), vomiting (P < .001), and agitation (P = .029). Especially in patients receiving laryngeal mask airway, propofol anesthesia significantly reduced the incidence of laryngospasm (P = .003) and agitation (P < .001). At the same time, they exhibited an increased risk of apnea (P = .039). Notably, no statistically significant disparities were observed between sevoflurane and propofol concerning cough, SpO2 < 95%, anesthesia time, extubation time, and recovery time. Administration of propofol following sevoflurane anesthesia did not significantly impact the occurrence of vomiting or the recovery time. CONCLUSIONS: While propofol presents an elevated risk of apnea, it concurrently yields a significant reduction in laryngospasm, vomiting, and agitation. Consequently, propofol emerges as a favorable anesthetic option for pediatric patients.

From tumor to tolerance: A comprehensive review of immune checkpoint inhibitors and immune-related adverse events.

The advent of immune checkpoint inhibitors (ICIs) has revolutionized the treatment landscape for various malignancies by harnessing the body's immune system to target cancer cells. However, their widespread use has unveiled a spectrum of immune-related adverse events, highlighting a critical balance between antitumor immunity and autoimmunity. This review article delves into the molecular immunology of ICIs, mapping the journey from their therapeutic action to the unintended induction of immune-related adverse events. We provide a comprehensive overview of all available ICIs, including cytotoxic T-lymphocyte-associated protein 4, programmed cell death protein 1, programmed death-ligand 1 inhibitors, and emerging targets, discussing their mechanisms of action, clinical applications, and the molecular underpinnings of associated immune-related adverse events. Special attention is given to the activation of autoreactive T cells, B cells, cytokine release, and the inflammatory cascade, which together contribute to the development of immune-related adverse events. Through a molecular lens, we explore the clinical manifestations of immune-related adverse events across organ systems, offering insights into diagnosis, management, and strategies to mitigate these adverse effects. The review underscores the importance of understanding the delicate interplay between enhancing antitumor responses and minimizing immune-related adverse events, aiming to guide future research and the development of next-generation ICIs with improved drug safety profiles.

Bruton tyrosine kinase inhibitor monotherapy in B-cell lymphoma and risk of infection: A systematic review and meta-analysis of randomized controlled trials.

Bruton's tyrosine kinase (BTK) inhibitors are important therapeutic advances with promising efficacy outcomes in the treatment of patients with chronic lymphocytic leukemia and other B-cell lymphoma subtypes. However, the utility of BTK inhibitors can be limited by adverse events such as infections. In this systematic review and meta-analysis, we aim to determine the risk of various infections associated with BTK inhibitor monotherapy in B-cell lymphoma patients. A comprehensive search was conducted in MEDLINE/PubMed, Embase, and Web of Science databases from their inception until October 2023. ClinicalTrials.gov, bibliographies, and relevant conference abstracts were also searched for additional records. Randomized controlled trials that included any B-cell lymphoma patients treated with BTK inhibitor monotherapy and reported infection were included. Meta-analysis was performed to calculate risk ratio (RR) using a random-effects model in R Statistical Software, version 4.3.2. Of 3292 studies retrieved, we included 12 studies in this systematic review and meta-analysis. The median age of patients across the study arms ranged between 64 and 73 years. The overall pooled RR for any grade upper respiratory tract infections (URTI) associated with BTK inhibitor treatment was 1.55 (95% Confidence Interval (CI) 1.22-1.97). The RR of grade ≥3 URTI was reported in 14 out of 1046 patients, yielding an RR of 1.46 (95% CI 0.61-3.54), which was not statistically significant. The pooled RR of any grade pneumonia was 1.20 (95% CI 0.68-2.10) and grade ≥3 pneumonia was 1.12 (95% CI 0.67-1.85), both of which were not statistically significant. Patients with B-cell lymphoma who are undergoing BTK inhibitor monotherapy face an elevated risk of developing URTI. Clinicians prescribing BTK inhibitors should be aware of the potential infectious events that may occur. Close monitoring and the implementation of effective prophylactic measures are essential for managing these patients.

Hepatobiliary complications of immune checkpoint inhibitors in cancer.

Immune checkpoint inhibitors (ICIs) have dramatically changed the landscape of cancer therapy. Over the last decade, both their primary focus in trials and clinical application have exponentially risen, with repeated demonstrations of their efficacy in improving survival in various cancer types. The adverse effects of these drugs on various organ systems were recognised in early phase studies. Given their relatively new emergence on the market, there has been increasing interest into short- and long-term effects and management of ICIs in real-world settings. ICI-related hepatobiliary toxicities are often challenging to diagnose and difficult to distinguish from other causes of deranged liver biochemical tests. The aim of this review is to provide an up-to-date and detailed exploration of the hepatobiliary complications of ICIs, including pathogenesis and approaches to diagnosis and management.

Development of Subcutaneous Panniculitis-Like T-cell Lymphoma After Immune Checkpoint Inhibitor Treatment.

Program death 1 (PD-1) inhibitors such as nivolumab are immune checkpoint inhibitors that have revolutionized the treatment of metastatic melanoma. Despite its success in treating melanoma, immune activation can lead to immune-related adverse effects, which are experienced by half of melanoma patients treated with PD-1 inhibitors. Despite the common frequency of immune-mediated adverse events, the development of a secondary lymphoma is exceedingly rare. We present the case of a 53-year-old woman diagnosed with stage IV metastatic melanoma, treated with nivolumab, who subsequently developed fatal subcutaneous panniculitis-like T-cell lymphoma (SPTCL).

Mass chemotherapy with niclosamide for the control of Taenia solium: population-based safety profile and treatment effectiveness.

Background: Mass drug administration (MDA) with niclosamide (NSM) can be used to control taeniasis, the cause of neurocysticercosis. NSM is 84.3% effective against taeniasis and is considered safe as it is not absorbed from the intestinal tract. However, information on its safety and effectiveness during MDA is limited. We evaluated the effectiveness of NSM and reported adverse events (AEs) during a cysticercosis elimination program in Tumbes, Peru. Methods: Three rounds of NSM at 4-month intervals were offered to 77,397 eligible residents. We revisited all participants in their homes 72 h after each round to collect information regarding AEs. We also collected post-treatment stool samples to diagnose taeniasis after the first round, followed by a second sample at 30 days from those infected to evaluate NSM's effectiveness. Findings: During implementation, 68,751 individuals were administered at least one dose of NSM (mean age 29 years, SD 20; 52% male), and 65,551 (95.3%) were visited post-treatment. 988 (1.5%) reported experiencing at least one AE. Almost all AEs (99.2%) were of mild intensity, with no severe AEs recorded. Of 211 participants diagnosed with taeniasis, 188 provided a follow-up stool sample 30-days after treatment and 141 were cured (treatment effectiveness 75.0%). Older age and higher coproantigen levels were significantly associated with treatment failure. Interpretation: MDA with NSM is safe in Taenia solium endemic settings. However, the effectiveness following one dose is lower than expected, which suggests additional treatment may be necessary to enhance the infection control efforts. Funding: The Bill and Melinda Gates Foundation.

Safety profile of levonorgestrel intrauterine system: Analysis of spontaneous reports submitted to FAERS.

The levonorgestrel-releasing intrauterine system (LNG-IUS) is an established, long-acting contraceptive option. With the widespread use of the LNG-IUS, drug-reported adverse events (AEs) have also garnered significant attention. In this study, we conducted a real-world analysis using the FDA's Adverse Event Reporting System (FAERS) database to assess the incidence of AEs associated with LNG-IUS use. Data from FAERS spanning from 2004Q1 to 2024Q1 were reviewed, with a focus on reports in which LNG-IUS was the primary suspected and secondary suspect drug. Signal detection was carried out utilizing Standardized MedDRA Queries (SMQ) and Preferred Terms (PT), with reporting odds ratio (ROR), proportional reporting ratio (PRR), and information component (IC) employed to identify Signals of Disproportionate Reporting (SDR) for AEs. A positive SDR was defined when all three methods indicated significance. Analysis of 13 SMQs revealed notable SDRs in ear and eye disorders, cardiac arrhythmias, and lipodystrophy. Of the 61 suspected SDRs identified at the PT level, nearly half were not previously documented in labeling. Key potential signals of AEs associated with LNG-IUS use included increased heart rate, papilledema, idiopathic intracranial hypertension, cervical dysplasia, ruptured ovarian cyst, and uterine embedment and perforation. The findings underscore the importance of signal detection using FAERS data for identifying safety concerns related to LNG-IUS. Long-term observational studies are warranted to confirm and further elucidate these potential safety signals.

A Complete Response in a Metastatic Melanoma Patient After a Single Dose of Dual Checkpoint Inhibitors Blockade Could Be Predictable: A Case Report.

Cutaneous malignant melanoma is one of the most aggressive forms of skin cancer and thus, a high mortality has been reported over decades. The prognosis for melanoma varies widely based on several factors, including the stage at which it is diagnosed, the location and thickness of the tumor, the patient's age and overall health, and specific genetic factors associated with melanoma. Therapeutic options include checkpoint inhibitors, regardless of V-Raf Murine Sarcoma Viral Oncogene Homolog B status (BRAF), and targeted therapy (anti-BRAF) in the adjuvant or metastatic setting. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but predicting which patients will benefit from these therapies remains challenging. Biomarkers like leukocytes, neutrophils, eosinophils, basophils, platelets, and other peripheral blood biomarkers have been investigated for their potential to predict responses to ICIs. Tumor mutational burden (TMB), circulating tumor DNA (ctDNA), and soluble PD-L1 (sPD-L1) have emerged as potential biomarkers for predicting responses to ICIs. Elevated baseline levels of ctDNA and elevated sPD-L1 levels have been associated with worse prognosis in melanoma patients. High TMB is often associated with better responses to ICIs in melanoma. Here we present a case from our department, of a 57-year-old patient, diagnosed in 2019 with stage IV - pT4cNx cM1 (lymph nodes metastases) and suspicion of lung metastases, BRAF wild-type right hallux malignant melanoma. Due to impressive results, first-line treatment with ICIs nivolumab and ipilimumab was the preferred treatment of choice, which showed a favorable response, with regression of oncological disease after the first cycle, and achieving complete response afterward. Unfortunately, the treatment was discontinued due to severe hepatic and pancreatic toxicity, but the favorable response to immunotherapy has been maintained for four years and is ongoing. Identifying predictive biomarkers is important to achieve the best response for the patient, with minimal adverse events, especially if long-term clinical benefit can be reached.

Safety assessment of anti-B cell maturation antigen chimeric antigen receptor T cell therapy: a real-world study based on the FDA adverse event reporting system database.

Background: On April 18, 2024, the U.S. Food and Drug Administration officially required updating of the "boxed warning" for T cell malignancies for all chimeric antigen receptor T cell (CAR-T) therapies. Given the clinical significance of these therapies, a rigorous safety assessment is paramount. However, comprehensive real-world safety studies have been lacking for the newly marketed CAR-T products idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), which target B cell maturation antigen, especially regarding the risk of secondary malignancies. Therefore, we aimed to thoroughly analyze the adverse events (AEs) information in the FDA Adverse Event Reporting System (FAERS) database to comprehensively understand the safety risks of ide-cel and cilta-cel. Methods: We extracted AE reports related to ide-cel and cilta-cel from the FAERS database (https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html.) from January 1, 2019 to December 31, 2023. Disproportionality analysis and Bayesian analysis were used to identify risk signals across subgroups and specific cases (including for death and secondary malignancies). Weibull distribution analysis was employed to determine the time to AE onset. Results: A total of 695 AE reports for ide-cel and 848 for cilta-cel were included in the FAERS database. This analysis identified 81 positive signals for ide-cel and 74 for cilta-cel. Notably, comparisons with the drug labels revealed "unexpected signals," including febrile bone marrow aplasia (reporting odds ratio=69.10; confidence interval 39.12-122.03) and plasma cell myeloma (12.45; 8.18-18.95) for ide-cel, and increased serum ferritin (24.98; 8.0-77.58) and large intestine perforation (18.57; 5.98-57.69) for cilta-cel. Both drugs showed a higher AE incidence among male recipients and patients aged ≥65 years, although female recipients faced a greater risk. Most AEs occurred at the early stage of administration. However, secondary malignancies were detected for both drugs, primarily occurring one-year post-administration. Conclusion: This study provides a foundation for understanding the safety profile of CAR-T cell therapy, particularly in relation to the emergence of secondary malignancies. Such insights are helpful for clinical decision-making and the safe and effective utilization of these therapeutic agents.

Association between COVID-19 Vaccination (ChAdOx1-S) and Thromboembolic, Thrombocytopenic, Hemorrhagic Events: A Systematic Review and Meta-analysis of Analytical Epidemiological Studies.

We conducted a systematic review of analytical epidemiological studies to assess the association between ChAdOx1-S vaccination and thromboembolic, thrombocytopenic, and hemorrhagic events. We searched Medline, Embase, Google Scholar, WHO-COVID-19 database, and medRxiv for studies evaluating the association between ChAdOx1-S and vascular events. Primary outcomes of interest were cerebral venous sinus thrombosis, peripheral venous thrombosis (PVT), and thrombocytopenia. Two independent reviewers screened for eligible studies, extracted data, and assessed the risk of bias. The DerSimonian-Laird random effects model was used to pool the incidence rate ratios (IRRs) separately for the first and second doses. Heterogeneity was assessed using I2 statistics. Twenty studies were included, of which 11 were self-controlled case series, and nine were cohort studies (254 million participants). Pooling of 17 studies showed a higher risk of cerebrovascular thrombosis (IRR = 3.5, 95% CI = 2.2-5.4, I2 = 79%), PVT (IRR = 2.0, 95% CI = 1.1-3.5, I2 = 95%) and thrombocytopenia (IRR = 1.6, 95% CI = 1.4-1.9, I2 = 93%) among those who received ChAdOx1-S vaccination as compared to controls. No increased risk was seen after the second dose or for secondary outcomes. There is moderate-to-high certainty of the evidence for the increased risk of cerebral venous sinus thrombosis, PVT, and thrombocytopenia following the first dose of the ChAdOx1-S vaccine. Systematic Review Registration: PROSPERO CRD42022372768.

Exploring Novel Adverse Events of Nefecon.

Introduction: Nefecon, the first innovative drug approved by both the US Food and Drug Administration (FDA) and European Medicines Agency for IgA nephropathy (IgAN), lacked comprehensive real-world assessments of its adverse events (AEs). Methods: We leveraged postmarketing data of Nefecon from the US FDA Adverse Event Reporting System (FAERS), employing disproportionate analysis (DPA) to detect positive signals at the system organ class (SOC) and preferred terms (PTs) levels. Duplicate AEs related to budesonide and those previously reported in studies were excluded through the use of the Medical Dictionary of Regulatory Activities (MedDRA). Our analysis encompassed time-to-onset (TTO), Weibull shape parameter (WSP) evaluation, cumulative incidence, clinical prioritization evaluation, and subgroup analysis based on gender and age. Results: A total of 1515 individuals with IgAN were included. Five positive SOC signals and 23 positive PT signals were identified, including 4 PTs (asthenia, malaise, product dose omission issue, and anxiety) representing novel AEs newly identified in this study. None of the positive PTs were classified as high clinical priority, with only acne, hypertension, swelling face, and weight increased considered as moderate clinical priority events. The median time to TTO was 31 days. All WSP test results indicated an early failure type profile. Lastly, subgroup analysis provided further insights into the relative risk of specific AEs. Conclusion: Nefecon demonstrates a favorable safety profile, with no high-priority clinical events identified. The identification of novel AEs and subgroup-specific relative high-risk events fills a gap in existing studies and offers valuable insights for early clinical vigilance.

Unveiling hope: how social support reciprocity shields against the shadows of intimate partner violence and suicidal ideation in rural Chinese older adults.

The paper titled "A systematic review of psychosocial protective factors against suicide and suicidality among older adults" by Ki and colleagues is a thought-provoking review that emphasizes the importance of improving protective factors for the development of suicide prevention and intervention in older adults, rather than just focusing on risk factors. Since the coronavirus disease 2019 (COVID-19) pandemic, media coverage of mental health and suicide has gained widespread attention. Suicide may become a more pressing issue due to the enormous economic and social toll of the spreading epidemic. Therefore, this systematic review is relevant in preventing suicide among older adults in the "post-pandemic" periods of COVID-19.In this study, the authors highlight the importance of examining the moderating or mediating role of protective factors in suicide, due to the fact that suicide prevention must take into account a variety of factors simultaneously. More importantly, most studies focused primarily on received support among interpersonal protective factors, neglecting the role of support given to others, which might be more beneficial for older adults' well-being. The thought that ensues is what role will social support reciprocity play in specific risk factors and suicidal behavior.

Evaluation and analysis of risk factors for adverse events of the fractured vertebra post-percutaneous kyphoplasty: a retrospective cohort study using multiple machine learning models.

BACKGROUND: Adverse events of the fractured vertebra (AEFV) post-percutaneous kyphoplasty (PKP) can lead to recurrent pain and neurological damage, which considerably affect the prognosis of patients and the quality of life. This study aimed to analyze the risk factors of AEFV and develop and select the optimal risk prediction model for AEFV to provide guidance for the prevention of this condition and enhancement of clinical outcomes. METHODS: This work included 383 patients with primary osteoporotic vertebral compression fracture (OVCF) who underwent PKP. The patients were grouped based on the occurrence of AEFV postsurgery, and data were collected. Group comparisons and correlation analysis were conducted to identify potential risk factors, which were then included in the five prediction models. The performance indicators served as basis for the selection of the best model. RESULTS: Multivariate logistic regression analysis revealed the following independent risk factors for AEFV: kissing spine (odds ratio (OR) = 8.47, 95% confidence interval (CI) 1.46-49.02), high paravertebral muscle fat infiltration grade (OR = 29.19, 95% CI 4.83-176.04), vertebral body computed tomography value (OR = 0.02, 95% CI 0.003-0.13, P < 0.001), and large Cobb change (OR = 5.31, 95% CI 1.77-15.77). The support vector machine (SVM) model exhibited the best performance in the prediction of the risk of AEFV. CONCLUSION: Four independent risk factors were identified of AEFV, and five risk prediction models that can aid clinicians in the accurate identification of high-risk patients and prediction of the occurrence of AEFV were developed.

Clinical features, treatment, and outcome of nivolumab-induced cholangitis.

BACKGROUND: Cholangitis is an uncommon and severe adverse reaction of nivolumab with unclear clinical features. The purpose of this study was to investigate the clinicopathological features, imaging, and treatment of nivolumab-induced cholangitis. METHODS: Case reports, case series, and clinical studies of nivolumab-induced cholangitis were retrospectively analyzed by searching Chinese and English databases from January 1, 2017 to December 31, 2023. RESULTS: Thirty-eight patients entered the study. The median number of cycles of cholangitis onset was seven cycles after administration (range 1, 28) and the median time was 11 days (range 78, 390). Abdominal pain (42.1%) and fever (18.4%) were the most important initial symptoms. Some patients (15.8%) showed elevated liver enzymes without any clinical symptoms. The median alkaline phosphatase level was 1721 IU/L (range 126, 9118), and the median γ-glutamyltranspeptidase level was 829 IU/L (range 104, 3442). Anti-nuclear antibodies, anti-mitochondrial antibodies, and IgG4 typically show negative results. Imaging shows extrahepatic bile duct and intrahepatic bile duct dilation, hypertrophy, and stenosis. Liver biopsy and biliary tract biopsy mainly found CD8 inflammatory cell infiltration. Systemic steroids (84.2%) and ursodeoxycholic acid (UDCA) (34.2%) were administered, and 24 patients (63.2%) had poor to moderate response to steroids. Thirty-one patients (81.6%) improved and seven patients (18.4%) did not improve. CONCLUSIONS: Clinicians must remain vigilant for patients experiencing cholestasis while on nivolumab and should assess for cholangitis and carry out appropriate imaging tests. Considering the excellent efficacy of UCDA in cholangitis, steroids combined with UDCA may be a viable treatment option in cases where steroids are ineffective for cholangitis.