Risk Difference Research Articles

Vitamin D serum levels and temporomandibular disorders: A systematic review and meta-analysis

ObjectiveThis systematic review evaluates the connection between vitamin D serum levels, deficiency, and temporomandibular disorders (TMD), offering a meta-analysis of the existing evidence in this domain. DesignThe Scopus, ISI Web of Science, and Pubmed databases were searched for human studies concerning the connection between vitamin D and TMD comprising a control group. A random-effect model with forest plots was used for vitamin D serum levels mean difference (MD), vitamin D deficiency odds ratio (OR), and risk difference (RD) between subjects with and without TMD. Subgroup analysis was conducted based on ethnicity, overall risk of bias, TMD diagnosis method, and study designs. A p-value lower than 0.05 was considered significant. The certainty of the meta-evidence was evaluated according to the GRADE approach. ResultsOf the 2621 identified unique records, 15 studies were included in the study, eight of which were considered for the meta-analysis. The meta-analysis revealed a significant vitamin D deficiency OR (3.85; 95 % CI: 2.35 – 5.43; Certainty: Low) and RD (22 %; 95 % CI: 11 % - 32 %; Certainty: Very low), and vitamin D serum levels MD (-5.03 ng/mL; 95 % CI: −9.92 – −0.13; Certainty: Very low) between subjects with and without TMD. Among subgroup analyses, only the difference in vitamin D MD between Middle Eastern and European patients was significant (P < 0.01). ConclusionConsidering the low to very low certainty of the evidence, vitamin D serum levels are significantly lower, and vitamin D deficiency is significantly more prevalent in TMD patients.

Association between visceral adiposity index, lipid accumulation product and type 2 diabetes mellitus in US adults with hypertension: a cross-sectional analysis of NHANES from 2005 to 2018

BackgroundThe presence of hypertension significantly increases the risk of diabetes, particularly type 2 diabetes. Recently, Visceral Adiposity Index (VAI) has been introduced as a straightforward and robust alternative indicator for early detection of metabolic syndrome, cardiovascular disease, and T2DM. Visceral adiposity, more dangerous than subcutaneous fat, is associated with metabolic syndrome and cardiovascular diseases. The VAI and Lipid Accumulation Product (LAP) are indices that quantify visceral fat and lipid overaccumulation, respectively. This study aims to explore the association between VAI, LAP, and type 2 diabetes mellitus (T2DM) in US adults with hypertension using NHANES data from 2005 to 2018.MethodsWe analyzed data from 5,620 participants with hypertension in The National Health and Nutrition Examination Survey (NHANES). VAI and LAP were calculated using established formulas. The VAI is calculated based on a combination of waist circumference, body mass index (BMI), triglycerides, and high-density lipoprotein (HDL) cholesterol levels. Logistic regression models were applied to evaluate the association between these indices and T2DM, adjusting for potential confounders. Subgroup analyses by age and gender were also conducted to assess variations in risk.ResultsIn all, 5,620 participants were enrolled in our analysis, with 2,754 (49%) being female, and a mean (standard deviation, SD) age of 57 (15) years. The mean (SD) cumulative average VAI and LAP among all participants was 241 (2.71) and 75 (67), respectively. Totally, higher VAI and LAP indices were significantly associated with an increased risk of T2DM in individuals with hypertension. For VAI, the odds ratios (OR) for T2DM were higher in older adults (≥ 60 years) [95% confidence interval (CI): 1.37, 1.22–1.53, per 1 SD increase] and females [95% confidence interval (CI): 1.39, 1.27–1.52, per 1 SD increase], indicating age and gender differences in risk. Non-linear relationships were observed, suggesting thresholds beyond which the risk of T2DM escalates dramatically.ConclusionsBoth VAI and LAP are reliable markers for assessing T2DM risk in individuals with hypertension. Incorporating these indices into clinical practice could enhance the identification of high-risk individuals and facilitate early intervention strategies. Future longitudinal studies are needed to confirm these associations and explore targeted interventions.

METHA-NeP: effectiveness and safety of methadone for neuropathic pain: a controlled randomized trial.

In this randomized, double-blind, parallel placebo-controlled clinical trial, we evaluated the efficacy of methadone as an add-on therapy for people with chronic neuropathic pain (NP). Eighty-six patients were randomly assigned to receive methadone or placebo for 8 weeks. The primary outcome was the proportion of participants achieving at least 30% pain relief from baseline using a 100-mm pain Visual Analogue Scale. Secondary outcomes included global impression of change, NP symptoms, sleep quality, quality of life, pain interference in daily activities, and mood. A larger number of responders were found in the methadone (68%), compared to the placebo (33%) arm; risk difference 33.6%; 95% confidence interval 13.0%-54.3%; P = 0.003; number needed to treat = 3.0. Methadone reduced pain intensity ( P < 0.001), burning ( P = 0.023), pressing ( P = 0.005), and paroxysmal dimensions ( P = 0.006) of NP. Methadone also improved sleep ( P < 0.001) and increased the patient's global impression of improvement ( P = 0.002). Methadone did not significantly impact quality of life, pain interference, or mood. Treatment-emergent adverse events occurred in all methadone- and in 73% of placebo-treated patients ( P < 0.001). No serious adverse events or deaths occurred. Discontinuation due to adverse events was reported in 2 participants in the methadone and none in the placebo arm. Methadone use as an add-on to an optimized treatment for NP with first- and/or second-line drugs provided superior analgesia, improved sleep, and enhanced global impression of change, without being associated with significant serious adverse effects that would raise safety concerns.

How much does the carcinogenic risk of inorganic arsenic exposure from rice increase with higher brown rice consumption? An estimation for five regions around the world

Substituting brown rice for white rice can increase the carcinogenic risk of inorganic arsenic (iAs) exposure, given that brown rice has a higher iAs content than white rice. This study estimated changes in the incremental lifetime cancer risk (ILCR) of iAs exposure from rice with increases in the proportion of brown to total rice consumption (PBT) in five regions around the world, including North America, Latin America, Europe, Asia, and Oceania. The results demonstrated that the magnitude of the increase in the ILCR of iAs exposure from rice expressed as an increase in PBT, ranged from 0.02 to 0.43 per 10,000 people for each 10 % increase in PBT. The highest increase was observed in Asia, followed by Latin America, North America, Oceania, and Europe. The daily rice consumption rate rather than the increase in iAs content is the critical factor responsible for regional differences in higher carcinogenic risk with increased PBT. This study also suggests that when considering the carcinogenic risks of iAs exposure from rice, substituting brown rice for white rice is feasible in North America and Europe but not in Asia and Latin America, while in Oceania, a partial substitution of brown rice for white rice (<55 %) is feasible.

Retrospective analysis of survival and safety of bevacizumab biosimilar and original drug combination chemotherapy in non-small cell lung cancer.

The advent of bevacizumab has considerably transformed the therapeutic landscape for non-small cell lung cancer (NSCLC) patients devoid of specific genetic mutations. A pivotal milestone has been reached with the recent approval of a bevacizumab biosimilar, following rigorous phase III clinical investigations, poised to augment NSCLC therapeutic strategies. This retrospective analysis encompasses a large-scale study conducted between January 2021 and December 2023, involving 1058 NSCLC patients (metastatic or locally advanced stages). The research design entailed a comparative assessment of the safety and efficacy profiles of combined therapies using the original bevacizumab and its biosimilar, adhering to RECIST v1.1 criteria. Adverse event grading was standardized using the National Cancer Institute's CTCAE v5.0. Notably, the biosimilar demonstrated an objective response rate (ORR) of 29.79% in 606 patients, closely paralleling the 27.41% ORR observed in 452 patients receiving the original drug, with insignificant risk differences (-0.03) and a risk ratio of 0.987, affirming equivalence. Progression-free survival (PFS) was influenced by radiation status, treatment lines, and regimen combinations, while dosage intensity and genetic factors had negligible impacts. The incidence of treatment-emergent adverse events (TEAEs) was slightly higher in the biosimilar group (75.11%) versus the original drug group (72.78%), with grade 3 or more severe TEAEs occurring in 23.6% and 18.5% of patients, respectively (Detailed criteria for the definition and assessment of TEAEs have been added to the Methods section, including the use of the National Cancer Institute's CTCAE v5.0 for grading). The study affirms that bevacizumab biosimilars offer equivalent therapeutic efficacy and a similar safety profile to the originator product in the management of locally advanced or metastatic NSCLC. The tolerability of the toxicity profile, coupled with the absence of unforeseen adverse reactions, underscores the viability of biosimilar bevacizumab as a valuable addition to NSCLC treatment regimens. These findings also imply potential benefits for a broader patient population beyond clinical trial confines through the adoption of biosimilar beta-adrenergic blocking agents.

Assessing for race, ethnicity, and socioeconomic disparities in central line-associated bloodstream infection risk in a large academic health system.

To examine the relationship between race and ethnicity and central line-associated bloodstream infections (CLABSI) while accounting for inherent differences in CLABSI risk related to central venous catheter (CVC) type. Retrospective cohort analysis. Acute care facilities within an academic healthcare system. Adult inpatients from January 2012 through December 2017 with CVC present for ≥2 contiguous days. We describe variability in demographics, comorbidities, CVC type/configuration, and CLABSI rate by patient's race and ethnicity. We estimated the unadjusted risk of CLABSI for each demographic and clinical characteristic and then modelled the effect of race on time to CLABSI, adjusting for total parenteral nutrition use and CVC type. We also performed exploratory analysis replacing race and ethnicity with social vulnerability index (SVI) metrics. 32,925 patients with 57,642 CVC episodes met inclusion criteria, most of which (51,348, 89%) were among non-Hispanic White or non-Hispanic Black patients. CVC types differed between race/ethnicity groups. However, after adjusting for CVC type, configuration, and indication in an adjusted cox regression, the risk of CLABSI among non-Hispanic Black patients did not significantly differ from non-Hispanic White patients (adjusted hazard ratio [aHR] 1.19; 95% confidence interval [CI]: 0.94, 1.51). The odds of having a CLABSI among the most vulnerable SVI subset compared to the less vulnerable was no different (odds ratio [OR] 0.95; 95% CI: 0.75-1.2). We did not find a difference in CLABSI risk between non-Hispanic White and non-Hispanic Black patients when adjusting for CLABSI risk inherent in type and configuration of CVC.

IMPACT OF SEX AND GENDER IN STROKE IN SOUTH-AND-SOUTHEAST ASIA: A RAPID SCOPING REVIEW.

South Asia and Southeast Asia account for more than 40% of the global stroke burden, with differences in stroke risk factors, mortality, and outcomes compared to high-income countries. Socio-cultural norms compound the pre-existing biological risk differences, resulting in a disproportionate burden of stroke in women in this region. This review summarizes the sex and gender differences across the stroke care continuum in South Asia and Southeast Asia over the past 20 years. Despite a higher incidence of stroke in men than women in South-and-Southeast Asia, women have greater stroke severity and poorer outcomes after stroke. Higher levels of pre-morbid disability and poor physical health at baseline may be contributory. There is a high prevalence of vascular risk factors such as hypertension, dyslipidemia, cardiac sources of embolism, as well as metabolic syndrome and insulin resistance, among the women in this region. Smoking is uncommon among women, however other forms of smokeless tobacco (SLT), such as tobacco leaf and betel nut chewing are more prevalent, especially in the rural areas in these countries. Women are more likely to have delayed presentations to the hospital due to untimely recognition of stroke symptoms, however, with regards to door-to-needle times or intravenous thrombolysis (IVT) rates, we found equivocal data. Wide gaps exist in stroke awareness and healthcare-seeking behaviors, with women more commonly opting for public hospitals and low-cost wards, more likely to discontinue treatment, and less likely to adhere to post-stroke rehabilitation. This review exposes the gender lacunae in stroke service provision across South Asia and Southeast Asia while acknowledging the many knowledge gaps in our understanding. Although the biological risk differences are non-modifiable, educational, policy, and economic measures to mitigate socio-cultural barriers are much needed in the region. Sound epidemiological data is needed from more countries to better understand these differences and bridge this gap. It is imperative to advocate and implement policies and programs for stroke care viable for women, cognizant of the gender and cost bias, as well as the interplay of social and cultural structures specific to the regions.

Black shale high geological background potential toxic elements(PTEs) in middle reaches of the Yangtze River tributary basin water environment, China: Distribution, pollution sources, and risk assessment

As a typical high geological background area in the middle reaches of the Yangtze River tributary basin in China, the Loushao Basin in Hunan is covered with high mineral black shale, with an average element value 4.76–8.97 times higher than the world average rock level. The aim of this study is to analyze the water environment pollution in the middle reaches of the Yangtze River tributary basin under high geological background based on the spatial distribution differences of black shale concentration. PCA source analysis is used to track the source of pollution and highlight the differences in body shape to assess regional health risks. The research results show that Cd in water quality exceeds the background value by 7.5 times. There is a strong homology among Pb, Cd, Cr, As, and Hg elements in water bodies, mainly derived from the natural weathering, migration, and enrichment of rocks. Hg element is a pollution caused by human factors, and water pollution is more severe in areas close to high concentrations, with severe exceedance of Cr element in water quality. The main controlling factor for individual health risk differences is body shape, and men's health is more susceptible to threats.

External validation of dementia prediction models in Black or African American and White older adults: A longitudinal population-based study in the United States.

Identifying people at high risk of Alzheimer's disease (AD) dementia allows for timely intervention, which, if successful, will result in preventing or delaying the onset of the disease. Utilizing data from the Chicago Health and Aging Project (CHAP; n=2130), we externally evaluated four risk-prediction models for AD dementia, including Cardiovascular Risk Factors, Aging, and Dementia (CAIDE), Australian National University Alzheimer's Disease Risk Index (ANU-ADRI), Brief Dementia Screening Indicator (BDSI), and Dementia Risk Score (DRS), in Black or African American and White adults. BDSI had the highest discriminate abilities for AD dementia (c-statistics of 0.79 in Black and 0.77 in White adults), followed by ANU-ADRI, within the age range and follow-up period of the original development cohort. CAIDE had the lowest discriminating power (c-statistic≤0.55). With increasing follow-up periods (i.e., 10-15 years), the discrimination abilities for all models declined. Because of racial disparities in AD dementia and longer preclinical and prodromal stages of disease development, race-specific models are needed to predict AD risk over 10 years. Utilizing risk-prediction models to identify individuals at higher risk of Alzheimer's disease (AD) dementia could benefit clinicians, patients, and policymakers. Clinicians could enroll high-risk individuals in clinical trials to test new risk-modifiable treatments or initiate lifestyle modifications, which, if successful, would slow cognitive decline and delay the onset of the disease. Current risk-prediction models had good discriminative power during the first 6 years of follow-up but decreased with longer follow-up time. Acknowledging the longer preclinical phase of AD dementia development and racial differences in dementia risk, there is a need to develop race-specific risk-prediction models that can predict 10 or 20 years of risk for AD and related dementias.

An educational intervention study on mandatory reporting of intimate partner violence: changes in knowledge and attitudes among healthcare providers

BackgroundIntimate partner violence (IPV) is a major public health concern. Healthcare providers can play a crucial role in reporting cases of IPV or suspected IPV injuries to the police or the criminal justice system, commonly referred to as mandatory reporting. However, mandatory reporting of intimate partner violence (MR-IPV) is a debated topic that can pose complex challenges for healthcare providers. This underscores the importance of training programs to ensure that healthcare providers can fulfill their MR-IPV obligations.MethodsWe developed an educational intervention on MR-IPV and assessed its impact on healthcare providers’ knowledge and attitudes. The study used a pre- and post-test design with three measurement points: baseline (T0), immediately after the intervention (T1), and six months later (T2). The intervention was conducted at a university college in Norway, with data collected between October 2022 and May 2023. The intervention was delivered to 37 healthcare providers who were currently part-time students in mental healthcare. Changes in knowledge and attitudes between T0 and T1, and T0 and T2 were analyzed through nonparametric tests on related samples using the Marginal homogeneity (Stuart–Maxwell) test. Risk differences (RD), along with their corresponding 95% confidence intervals (CI), were calculated for selected categories.ResultsThe number of participants knowing the MR law increased from 2.9% at baseline to 62.9% at T1 (RD = 0.60, 95% CI: 0.41—0.79) and to 31.4% at T2 (RD = 0.29, 95% CI: 0.11–0.46). The number of participants reporting knowing relevant criteria increased from 0.0% at baseline to 68.6% at T1 (RD = 0.69, 95% CI: 0.50–0.87) and to 34.3% at T2 (RD = 0.34, 95% CI: 0.16—0.53). We observed several persistent changes in healthcare providers' attitudes towards MR, including finding MR to be a useful instrument and generally complying with MR requirements.ConclusionsThe findings suggest that this educational intervention can have a positive impact on healthcare providers' attitudes and compliance with MR-IPV. Before the intervention, few participants reported knowing the MR law and its application criteria, demonstrating the importance of continuous learning and evidence-based training programs.

Incidence of respiratory depression between ciprofol and propofol after anesthesia: A systematic review and meta-analysis.

Respiratory depression is a common complication during operative procedures, meanwhile, ciprofol can provide effective sedation for surgical operations. However, there is not enough evidence to prove the advantage of ciprofol in reducing respiratory depression. So, this meta-analysis aimed to assess the efficacy of ciprofol on the incidence of respiratory depression compared with propofol. Two individual researchers conducted searches for randomized controlled trials in PubMed, Embase, and Cochrane Central Register of Controlled Trials. The meta-analysis was performed using Review Manager software. Seven trials with a total of 1408 patients were included in this meta-analysis. The results showed that ciprofol could reduce the incidence of respiratory depression compared with propofol (risk difference [RD] = -0.09, 95% confidence interval [CI]: -0.15 to -0.04). Ciprofol significantly reduced the incidence of respiratory depression when the method of administration was intravenous injection (RD = -0.06, 95% CI: -0.10 to -0.03), or continuous infusion (RD = -0.30, 95% CI: -0.45 to -0.15). Meanwhile, ciprofol significantly reduced the incidence of respiratory depression with the dosage not only greater than or equal to 0.4 mg/kg (RD = -0.11, 95% CI: -0.20 to -0.02), but also <0.4 mg/kg (RD = -0.08, 95% CI: -0.13 to -0.02). And ciprofol significantly reduced the incidence of hypoxemia (risk ratio [RR] = 0.47, 95% CI: 0.28 to 0.80), injection pain (RD = -0.32, 95% CI: -0.46 to -0.17), body movement (RR = 0.60, 95% CI: 0.43 to 0.84), dizziness (RR = 0.75, 95% CI: 0.62 to 0.90). Finally, ciprofol did not increase awakening time (standard mean difference [SMD] = 0.15, 95% CI: -0.02 to 0.31). From this meta-analysis, it is demonstrated that ciprofol might reduce the incidence of respiratory depression and injection pain. These benefits are important in surgery to ensure safe and rapid postoperative recovery. So, ciprofol may be a safe and appropriate drug with fewer adverse effects used in clinical anesthesia.

Peer-led recovery groups for people with psychosis in South Africa (PRIZE): Results of a randomized controlled feasibility trial.

The aims of this feasibility trial were to assess the acceptability and feasibility of peer-led recovery groups for people with psychosis in a low-resource South African setting, to assess the feasibility of trial methods, and to determine key parameters in preparation for a definitive trial. The design was an individually randomised feasibility trial comparing recovery groups in addition to treatment as usual (TAU) with TAU alone. Ninety-two isiXhosa-speaking people with psychosis and forty-seven linked caregivers were recruited from primary care clinics and randomly allocated to trial arms in a 1:1 allocation ratio. TAU comprised anti-psychotic medication delivered in primary care. The intervention arm comprised six recovery groups including service users and caregivers. Two-hour recovery group sessions were delivered weekly in a 2-month auxiliary social worker (ASW)-led phase, then a 3-month peer-led phase. To explore acceptability and feasibility, a mixed methods process evaluation included 25 in-depth interviews and 2 focus group discussions at 5months with service users, caregivers and implementers, and quantitative data collection including attendance and facilitator competence. To explore potential effectiveness, quantitative outcome data (functioning, relapse, unmet needs, personal recovery, stigma, health service use, medication adherence and caregiver burden) were collected at baseline, 2months and 5months post randomisation. Trial registration: PACTR202202482587686. Qualitative interviews revealed that recovery groups were broadly acceptable with most participants finding groups to be an enjoyable opportunity for social interaction, and joint problem-solving. Peer facilitation was a positive experience; however a minority of participants did not value expertise by lived experience to the same degree as expertise of professional facilitators. Attendance was moderate in the ASW-led phase (participants attended 59% sessions on average) and decreased in the peer-led phase (41% on average). Participants desired a greater focus on productive activities and financial security. Recovery groups appeared to positively impact on relapse. Relapse occurred in 1 (2.2%) of 46 participants in the recovery group arm compared to 8 (17.4%) of 46 participants in the control arm (risk difference -0.15 [95% CI: -0.26; -0.05]). Recovery groups also impacted on the number of days in the last month totally unable to work (mean 1.4days recovery groups vs 7.7days control; adjusted mean difference -6.3 [95%CI: -12.2; -0.3]). There were no effects on other outcomes. Peer-led recovery groups for people with psychosis in South Africa are potentially acceptable, feasible and effective. A larger trial, incorporating amendments such as increased support for peer facilitators, is needed to demonstrate intervention effectiveness definitively.

Electronic Nudges to Increase Influenza Vaccination in Patients With Chronic Diseases

Despite strong worldwide guideline recommendations, influenza vaccination rates remain suboptimal among young and middle-aged patients with chronic diseases. Effective scalable strategies to increase vaccination are needed. To investigate whether electronically delivered letter-based nudges informed by behavioral science could increase influenza vaccination uptake among patients aged 18 to 64 years with chronic diseases. Nationwide pragmatic registry-based randomized clinical implementation trial conducted between September 24, 2023, and May 31, 2024, enrolling all Danish citizens aged 18 to 64 years who met criteria for free-of-charge influenza vaccination in light of preexisting chronic disease. All trial data were sourced from nationwide administrative health registries. Randomized in 2.45:1:1:1:1:1:1 ratio to no letter (usual care) or 6 different behaviorally informed electronic letters. The primary end point was receipt of influenza vaccination on or before January 1, 2024, assessed in 7 prespecified coprimary comparisons (all intervention groups pooled vs usual care and each individual intervention group vs usual care). Absolute risk difference in proportions and a crude relative risk were calculated for each comparison. A total of 299 881 participants (53.2% [159 454] female, median age, 52.0 [IQR, 39.8-59.0] years) were randomized. Compared with usual care, influenza vaccination rates were higher among those receiving any intervention letter (any intervention letter, 39.6% vs usual care, 27.9%; difference, 11.7 percentage points; 99.29% CI, 11.2-12.2 percentage points; P < .001). Each individual letter type significantly increased influenza vaccination with the largest effect sizes observed with a repeated letter sent 10 days after the initial letter (repeated letter, 41.8% vs usual care, 27.9%; difference, 13.9 percentage points; 99.29% CI, 13.1-14.7 percentage points; P < .001) and a letter emphasizing potential cardiovascular benefits of vaccination (cardiovascular gain, 39.8% vs usual care, 27.9%; difference, 11.9 percentage points; 99.29% CI, 11.1-12.7 percentage points; P < .001). Vaccination rates were improved across major subgroups. In a nationwide randomized clinical implementation trial, electronically delivered letter-based nudges markedly increased influenza vaccination compared with usual care among young and middle-aged patients with chronic diseases. The results of this study suggest that simple, scalable, and cost-efficient electronic letter strategies may have substantial public health implications. ClinicalTrials.gov Identifier: NCT06030739.

Beta-Blocker Interruption or Continuation after Myocardial Infarction

BackgroundThe appropriate duration of treatment with beta-blocker drugs after a myocardial infarction is unknown. Data are needed on the safety and efficacy of the interruption of long-term beta-blocker treatment to reduce side effects and improve quality of life in patients with a history of uncomplicated myocardial infarction.MethodsIn a multicenter, open label, randomized, noninferiority trial conducted at 49 sites in France, we randomly assigned patients with a history of myocardial infarction, in a 1:1 ratio, to interruption or continuation of beta-blocker treatment. All the patients had a left ventricular ejection fraction of at least 40% while receiving long-term beta-blocker treatment and had no history of a cardiovascular event in the previous 6 months. The primary end point was a composite of death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for cardiovascular reasons at the longest follow-up (minimum, 1 year), according to an analysis of noninferiority (defined as a between-group difference of <3 percentage points for the upper boundary of the two-sided 95% confidence interval). The main secondary end point was the change in quality of life as measured by the European Quality of Life–5 Dimensions questionnaire.ResultsA total of 3698 patients underwent randomization: 1846 to the interruption group and 1852 to the continuation group. The median time between the last myocardial infarction and randomization was 2.9 years (interquartile range, 1.2 to 6.4), and the median follow-up was 3.0 years (interquartile range, 2.0 to 4.0). A primary-outcome event occurred in 432 of 1812 patients (23.8%) in the interruption group and in 384 of 1821 patients (21.1%) in the continuation group (risk difference, 2.8 percentage points; 95% confidence interval [CI], <0.1 to 5.5), for a hazard ratio of 1.16 (95% CI, 1.01 to 1.33; P=0.44 for noninferiority). Beta-blocker interruption did not seem to improve the patients’ quality of life.ConclusionsIn patients with a history of myocardial infarction, interruption of long-term beta-blocker treatment was not found to be noninferior to a strategy of beta-blocker continuation. (Funded by the French Ministry of Health and ACTION Study Group; ABYSS ClinicalTrials.gov number, NCT03498066; EudraCT number, 2017-003903-23.)

Dual Antiplatelet Versus Alteplase for Early Neurologic Deterioration in Minor Stroke With Versus Without Large Vessel Occlusion: Prespecified Post Hoc Analysis of the ARAMIS Trial.

Dual antiplatelet therapy (DAPT) was noninferior to alteplase in minor nondisabling strokes in the ARAMIS trial (Antiplatelet Versus R-tPA for Acute Mild Ischemic Stroke); however, early neurological deterioration (END) associated with vessel stenosis may benefit from DAPT. We investigated whether the efficacy of DAPT was greater than alteplase in minor strokes with no large vessel occlusion (LVO). This study was a prespecified post hoc analysis of the ARAMIS trial and included patients with responsible vessel examination in the as-treated analysis set of the ARAMIS trial who were divided into LVO group and non-LVO group. In each group, patients were further classified into DAPT and intravenous alteplase treatments. Primary outcome was END at 24 hours defined as more than or equal to 4-point National Institutes of Health Stroke Scale score increase compared with baseline, and safety outcomes were symptomatic intracerebral hemorrhage and bleeding events during study. The primary analysis was estimated with a risk difference calculated by a generalized linear model including adjusted different baseline characteristics between treatments. Of 723 patients from the ARAMIS trial, 480 patients were included: 36 were categorized into LVO group and 444 into non-LVO group, of whom 20 patients had END. Compared with intravenous alteplase, a lower proportion of END was found after DAPT treatment in the non-LVO group (adjusted risk difference, -4.8% [95% CI, -6.9% to -2.6%]; P<0.001), but not in the LVO group (adjusted risk difference, 2.3% [95% CI, -17.6% to 22.3%]; P=0.82). The interaction was marginally significant between groups (P=0.06). In the non-LVO group, a lower proportion of bleeding events was found after DAPT treatment than intravenous alteplase (adjusted risk difference, -6.4% [95% CI, -8.9% to -3.9%]; P<0.001). Other safety outcomes were similar between the 2 treatments. Among minor nondisabling acute ischemic stroke without LVO, DAPT may be superior to intravenous alteplase regarding preventing END with a better safety profile. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03661411.

Adjunctive linezolid versus clindamycin for toxin inhibition in β-lactam-treated patients with invasive group A streptococcal infections in 195 US hospitals from 2016 to 2021: a retrospective cohort study with target trial emulation.

Adjunctive clindamycin use is associated with survival in invasive group A streptococcus (GAS) infections but increasing clindamycin resistance in GAS has called into question its durability for this indication. Linezolid also inhibits GAS toxin and virulence factor production, but clinical efficacy data remain sparse. We retrospectively emulated a target multicentre, non-blinded, non-inferiority trial to assess the efficacy of adjunctive linezolid compared with clindamycin in adult inpatients with invasive GAS infection treated with a β-lactam using the PINC AI database between 2016 and 2021. Patients were eligible if they had a monomicrobial GAS culture and received adjunctive therapy within 3 days of culture either concurrently or after β-lactam initiation and completed at least 3 days of β-lactam therapy. The primary outcome was adjusted risk ratio (aRR) of in-hospital mortality assessed by overlap-weighting using propensity scores. Secondary outcomes were length of stay among survivors and Clostridium difficile infection. Of 1095 β-lactam-treated patients with GAS, 829 (76%) received clindamycin and 266 (24%) received linezolid. In the overlap weighted cohort, the receipt of linezolid was not associated with a statistically significant different aRR of in-hospital mortality compared with clindamycin (linezolid: 9·8% [26/266] vs clindamycin: 7·0% [58/829]; aRR: 0·92 [95% CI 0·42 to 1·43]; p=0·76). The risk difference was -0·005 (95% CI -0·05 to 0·04; p=0·81) and fell within the non-inferiority margin of 0·05. The primary analysis results were consistent across important subgroups and sensitivity analyses. Among survivors, median length of stay (adjusted ratio 0·96 [95% CI 0·16 to 0·08]; p=0·47) and C difficile infection risk (aRR 1·76 [95% CI 0·37 to 1·75]; p=0·29) were not statistically significantly different between the two groups. In this emulated trial of adult patients with invasive GAS infections treated with β-lactam, linezolid appeared non-inferior to clindamycin suggesting linezolid as an alternative for adjunctive antitoxin therapy. The Intramural Research Program of the US National Institutes of Health Clinical Center and the National Institute of Allergy and Infectious Disease.

Serum liver enzymes and risk of stroke: Systematic review with meta-analyses and Mendelian randomization studies.

Previous observational studies have identified correlations between liver enzyme levels and stroke risk. However, the strength and consistency of these associations vary. To comprehensively evaluate the relationship between liver enzymes and stroke risk, we conducted meta-analyses complemented by Mendelian randomization (MR) analyses. Following the PRISMA guidelines, we performed meta-analyses of prospective studies and conducted subgroup analyses stratified by sex and stroke subtype. Subsequently, adhering to the STROBE-MR guidelines, we performed two-sample bidirectional univariable MR (UVMR) and multivariable MR (MVMR) analyses using the largest genome-wide association studies summary data. Finally, the single-nucleotide polymorphisms associated with liver enzymes on sex differences underwent gene annotation, gene set enrichment, and tissue enrichment analyses. In the meta-analyses of 17 prospective studies, we found the relative risks for serum γ-glutamyl transferase (GGT) and alkaline phosphatase (ALP) were 1.23 (95% CI: 1.16-1.31) and 1.3 (95% CI: 1.19-1.43), respectively. Subgroup analyses revealed sex and stroke subtype differences in liver enzyme-related stroke risk. Bidirectional UVMR analyses confirmed that elevated GGT, alanine aminotransferase, and aspartate aminotransferase levels were associated with increased stroke occurrence. The primary results from the MVMR analyses revealed that higher ALP levels significantly increased the risk of stroke and ischemic stroke. Gene set and tissue enrichment analyses supported genetic differences in liver enzymes across sexes. Our study provides evidence linking liver enzyme levels to stroke risk, suggesting liver enzymes as potential biomarkers for early identification of high-risk individuals. Personalized, sex-specific interventions targeting liver enzymes could offer new strategies for stroke prevention.

Neuropsychiatric adverse events in tenofovir disoproxil fumarate- and tenofovir alafenamide-based HIV therapy and prophylaxis: a systematic review and meta-analysis.

Tenofovir is integral to antiretroviral therapy (ART) and preexposure prophylaxis (PrEP) for HIV, but its neuropsychiatric adverse events (NPAEs) have not been systematically investigated. This systematic review aims to characterize common NPAEs during tenofovir-based ART and PrEP and to assess tenofovir's specific role in their emergence. Four literature databases and three trial registries were searched up to December 31, 2023, for randomized controlled trials reporting NPAEs in treatment-naïve adults receiving tenofovir-based ART or PrEP. Meta-analyses compared tenofovir (with/without emtricitabine) to placebo and tenofovir alafenamide- to tenofovir disoproxil fumarate-based regimens. Sixty-nine trials (62 on ART, 7 on PrEP) with 29 340 patients on tenofovir-based therapies revealed headache, dizziness, insomnia, and depression as common NPAEs, especially in HIV studies. Meta-analyses of tenofovir (with/without emtricitabine) versus placebo only indicated an increased risk of dizziness (OR 1.32; CI 1.09-1.59; P = 0.004). Comparisons between tenofovir alafenamide and disoproxil fumarate did not reveal significant differences in NPAE risks, although sensitivity analyses suggested a higher risk of headache with tenofovir alafenamide in HIV studies (OR 1.24; CI 1.01-1.52; P = 0.04). Common NPAEs in tenofovir-based HIV multi-drug regimens highlight the need to screen HIV patients for neuropsychiatric complications. The lack of effect of tenofovir compared to placebo for most analyzable NPAEs suggests that tenofovir itself is mostly safe regarding NPAEs. However, a possible increase in dizziness risk with tenofovir, and a potential rise in headache risk with tenofovir alafenamide- compared to tenofovir disoproxil fumarate-based regimens in HIV therapy, merit further investigation.

Denifanstat for the treatment of metabolic dysfunction-associated steatohepatitis: a multicentre, double-blind, randomised, placebo-controlled, phase 2b trial.

Denifanstat, an oral fatty acid synthase (FASN) inhibitor, blocks de-novo lipogenesis, a key pathway driving progressive lipotoxicity, inflammation, and fibrosis in metabolic dysfunction-associated steatohepatitis (MASH). This study aimed to examine the safety and efficacy of denifanstat for improving liver histology in individuals with MASH and moderate to advanced fibrosis. This multicentre, double-blind, randomised, placebo-controlled, phase 2b trial was conducted at 100 clinical sites in the USA, Canada, and Poland. After a screening period of up to 90 days, participants aged 18 years and older with biopsy-confirmed MASH and stage F2 or F3 fibrosis were randomly assigned (2:1) to receive either 50 mg oral denifanstat or placebo once per day for 52 weeks. Participants were dynamically allocated to treatment groups via a centrally administered interactive web-based response system and stratified by type 2 diabetes, region, and fibrosis stage. Investigators, patients, and the sponsor were masked to group allocation until database lock. The primary efficacy endpoints were a 2-point or greater improvement in non-alcoholic fatty liver disease activity score (NAS) without a worsening of fibrosis or MASH resolution with a 2-point or greater improvement in NAS without a worsening of fibrosis at week 52, assessed by intention to treat. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04906421, and is closed for enrolment. Of the 1087 individuals screened between June 2, 2021, and June 28, 2022, 168 eligible participants were randomly assigned to receive a dose of 50 mg denifanstat once per day (n=112) or placebo (n=56). All 168 participants (100 female, 68 male) received at least one dose of study treatment. In the ITT population, 42 (38%) of 112 participants in the denifanstat group had a 2-point or greater improvement in NAS without a worsening of fibrosis versus nine (16%) of 56 participants in the placebo group (common risk difference 21·0%, 95% CI 8·1-33·9; p=0·0035). 29 (26%) of 112 participants in the denifanstat group showed MASH resolution with a 2-point or greater improvement in NAS without a worsening of fibrosis compared with six (11%) of 56 participants in the placebo group (common risk difference 13·0%, 0·7-25·3; p=0·0173). The most common treatment-emergent adverse events were COVID-19 (19 [17%] of 112 in the denifanstat group vs six [11%] of 56) in the placebo group, dry eye symptoms (ten [9%] of 112 vs eight [14%] of 56), and alopecia (21 [19%] of 112 vs two [4%] of 56). All adverse events considered to be related to the study drug were of grade 1 or grade 2. None of the serious adverse events (13 [12%] of 112 participants in the denifanstat group vs three [5%] of 56 in the placebo group) were considered drug-related. Treatment with denifanstat resulted in statistically significant and clinically meaningful improvements in disease activity, MASH resolution, and fibrosis. The results of this phase 2b trial support the advancement of denifanstat to phase 3 development. Sagimet Biosciences.

Betamethasone Exposure and Neonatal Respiratory Morbidity Among Late Preterm Births by Planned Mode of Delivery and Gestational Age.

To estimate the effect of late preterm antenatal steroids on the risk of respiratory morbidity among subgroups of patients on the basis of the planned mode of delivery and gestational age at presentation. This was a secondary analysis of the ALPS (Antenatal Late Preterm Steroid) Trial, a multicenter trial conducted within the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network of individuals with singleton gestations and without preexisting diabetes who were at high risk for late preterm delivery (34-36 weeks of gestation). We fit binomial regression models to estimate the risk of respiratory morbidity, with and without steroid administration, by gestational age and planned mode of delivery at the time of presentation. We assumed a homogeneous effect of steroids on the log-odds scale, as was reported in the ALPS trial. The primary outcome was neonatal respiratory morbidity, as defined in the ALPS Trial. The analysis included 2,825 patients at risk for late preterm birth. The risk of respiratory morbidity varied significantly by planned mode of delivery (adjusted risk ratio [RR] 1.90, 95% CI, 1.55-2.33 for cesarean delivery vs vaginal delivery) and week of gestation at presentation (adjusted RR 0.56, 95% CI, 0.50-0.63). For those planning cesarean delivery and presenting in the 34th week of gestation, the risk of neonatal respiratory morbidity was 39.4% (95% CI, 30.8-47.9%) without steroids and 32.0% (95% CI, 24.6-39.4%) with steroids. In contrast, for patients presenting in the 36th week and planning vaginal delivery, the risk of neonatal respiratory morbidity was 6.9% (95% CI, 5.2-8.6%) without steroids and 5.6% (95% CI, 4.2-7.0%) with steroids. The absolute risk difference of neonatal respiratory morbidity between those exposed and those unexposed to late preterm antenatal steroids varies considerably by gestational age at presentation and planned mode of delivery. Because only communicating the relative risk reduction of antenatal steroids for respiratory morbidity may lead to an inaccurate perception of benefit, more patient-specific estimates of risk expected with and without treatment may inform shared decision making.