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CochraneSystematic review
The Cochrane database of systematic reviews · Cochrane
BACKGROUND: Hormone therapy is widely provided to control menopausal symptoms and has been used for the management and prevention of cardiovascular disease, osteoporosis and dementia in older women. This is an updated version of a Cochrane review first published in 2005.
OBJECTIVES: To assess the long-term effects of prolonged use (at least one year) of hormone therapy on mortality, cardiovascular outcomes, cancer, gallbladder disease, fractures and cognition in perimenopausal and postmenopausal women.
SEARCH METHODS: We used the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, three other databases and two trial registers, together with reference checking, citation searching and contact with study authors to identify the studies included in the review. The latest search date was 26 September 2024.
SELECTION CRITERIA: We included randomised, double-blind trials in which peri- or postmenopausal women took hormone therapy or placebo for at least one year. We included various oestrogen formulations, with or without progestogens. We focused on studies assessing hormone therapy's effects on long-term clinical outcomes, including death, coronary events and cancer. Hormone therapy's efficacy in managing menopausal symptoms was beyond the scope of this review, and is assessed in other Cochrane reviews.
DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias and extracted data. We calculated risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data, along with 95% confidence intervals (CIs). We assessed the certainty of the evidence using GRADE.
MAIN RESULTS: We included 24 studies - with two newly added in this update - involving 45,660 participants. We derived nearly 70% of the data from two well-conducted studies: the Heart and Estrogen/progestin Replacement Study (HERS 1998) and the large, multi-component Women's Health Initiative research programme, which included two hormone therapy arms (WHI 1998). Across all the studies, most participants were postmenopausal American women with one or more comorbidities. The mean participant age in most studies was over 60 years. Only one included study focused on perimenopausal women. We present full results for all included studies with available data in the main review. The results presented below are drawn from WHI 1998, in which the combined hormone therapy arm and the oestrogen-only arm were run concurrently, with women assigned to the appropriate trial based on their uterus status. One study with 16,608 postmenopausal women with an intact uterus compared combined continuous hormone therapy (conjugated equine oestrogen and medroxyprogesterone acetate) to placebo, and measured outcomes at an average of 5.6 years of follow-up. Based on this study, combined continuous hormone therapy probably makes little to no difference to the risk of a coronary event (RR 1.17, 95% CI 0.95 to 1.44; moderate-certainty evidence). It may increase the risk of stroke (RR 1.39, 95% CI 1.09 to 2.09; low-certainty evidence) and venous thromboembolism (RR 2.03, 95% CI 1.55 to 6.64; low-certainty evidence). Compared to placebo, combined continuous hormone therapy probably increases the risk of breast cancer (RR 1.27, 95% CI 1.03 to 1.56; moderate-certainty evidence) and probably makes little to no difference to the risk of lung cancer (RR 1.06, 95% CI 0.77 to 1.46; moderate-certainty evidence). It may increase gallbladder disease requiring surgery (RR 1.64, 95% CI 1.30 to 2.06; 14,203 participants; low-certainty evidence), and probably reduces the risk of all clinical fractures (RR 0.78, 95% CI 0.71 to 0.86; moderate-certainty evidence). One study including 10,739 postmenopausal women who had undergone a hysterectomy compared oestrogen-only (conjugated equine oestrogen) hormone therapy to placebo, and measured outcomes at an average of seven years' follow-up. Based on this study, oestrogen-only hormone therapy probably makes little to no difference to the risk of coronary events (RR 0.94, 95% CI 0.78 to 1.13), venous thromboembolism (RR 1.32, 95% CI 1.00 to 1.74) and breast cancer (RR 0.79, 95% CI 0.61 to 1.01), all with moderate-certainty evidence. It may make little to no difference to the risk of lung cancer (RR 1.04, 95% CI 0.73 to 1.48; low-certainty evidence). Oestrogen-only hormone therapy probably increases the risk of stroke (RR 1.33, 95% CI 1.06 to 1.67) and gallbladder disease requiring surgery (RR 1.78, 95% CI 1.42 to 2.24), and probably reduces the risk of all clinical fractures (RR 0.73, 95% CI 0.65 to 0.80), all with moderate-certainty evidence. We judged most included studies to have a low risk of bias for most domains. The overall certainty of evidence for the main comparisons was moderate. The main limitation was that only about 30% of women were 50 to 59 years old at baseline, the age group most likely to consider hormone therapy for vasomotor symptoms.
AUTHORS' CONCLUSIONS: Long-term follow-up of women using hormone therapy suggests that the risk profiles vary between combined hormone therapy and oestrogen-only therapy. Oestrogen-only hormone therapy probably makes little to no difference to coronary events, and probably increases the risk of stroke and gallbladder disease. It probably makes little to no difference in the risk of breast cancer, and probably reduces the risk of all fractures. Combined hormone therapy may increase the risk of thromboembolism and probably increases the risk of breast cancer. These results should be interpreted with caution as they are based on one study using oral hormone therapy, which may not represent the risks of the hormone therapy currently used in clinical practice.
BACKGROUND: Magnesium sulphate is a common therapy in perinatal care. Its benefits when given to women at risk of preterm birth for fetal neuroprotection (prevention of cerebral palsy for children) were shown in a 2009 Cochrane review. Internationally, use of magnesium sulphate for preterm cerebral palsy prevention is now recommended practice. As new randomised controlled trials (RCTs) and longer-term follow-up of prior RCTs have since been conducted, this review updates the previously published version.
OBJECTIVES: To assess the effectiveness and safety of magnesium sulphate as a fetal neuroprotective agent when given to women considered to be at risk of preterm birth.
SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) on 17 March 2023, as well as reference lists of retrieved studies.
SELECTION CRITERIA: We included RCTs and cluster-RCTs of women at risk of preterm birth that assessed prenatal magnesium sulphate for fetal neuroprotection compared with placebo or no treatment. All methods of administration (intravenous, intramuscular, and oral) were eligible. We did not include studies where magnesium sulphate was used with the primary aim of preterm labour tocolysis, or the prevention and/or treatment of eclampsia.
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed RCTs for inclusion, extracted data, and assessed risk of bias and trustworthiness. Dichotomous data were presented as summary risk ratios (RR) with 95% confidence intervals (CI), and continuous data were presented as mean differences with 95% CI. We assessed the certainty of the evidence using the GRADE approach.
MAIN RESULTS: We included six RCTs (5917 women and their 6759 fetuses alive at randomisation). All RCTs were conducted in high-income countries. The RCTs compared magnesium sulphate with placebo in women at risk of preterm birth at less than 34 weeks' gestation; however, treatment regimens and inclusion/exclusion criteria varied. Though the RCTs were at an overall low risk of bias, the certainty of evidence ranged from high to very low, due to concerns regarding study limitations, imprecision, and inconsistency. Primary outcomes for infants/children: Up to two years' corrected age, magnesium sulphate compared with placebo reduced cerebral palsy (RR 0.71, 95% CI 0.57 to 0.89; 6 RCTs, 6107 children; number needed to treat for additional beneficial outcome (NNTB) 60, 95% CI 41 to 158) and death or cerebral palsy (RR 0.87, 95% CI 0.77 to 0.98; 6 RCTs, 6481 children; NNTB 56, 95% CI 32 to 363) (both high-certainty evidence). Magnesium sulphate probably resulted in little to no difference in death (fetal, neonatal, or later) (RR 0.96, 95% CI 0.82 to 1.13; 6 RCTs, 6759 children); major neurodevelopmental disability (RR 1.09, 95% CI 0.83 to 1.44; 1 RCT, 987 children); or death or major neurodevelopmental disability (RR 0.95, 95% CI 0.85 to 1.07; 3 RCTs, 4279 children) (all moderate-certainty evidence). At early school age, magnesium sulphate may have resulted in little to no difference in death (fetal, neonatal, or later) (RR 0.82, 95% CI 0.66 to 1.02; 2 RCTs, 1758 children); cerebral palsy (RR 0.99, 95% CI 0.69 to 1.41; 2 RCTs, 1038 children); death or cerebral palsy (RR 0.90, 95% CI 0.67 to 1.20; 1 RCT, 503 children); and death or major neurodevelopmental disability (RR 0.81, 95% CI 0.59 to 1.12; 1 RCT, 503 children) (all low-certainty evidence). Magnesium sulphate may also have resulted in little to no difference in major neurodevelopmental disability, but the evidence is very uncertain (average RR 0.92, 95% CI 0.53 to 1.62; 2 RCTs, 940 children; very low-certainty evidence). Secondary outcomes for infants/children: Magnesium sulphate probably resulted in little to no difference in severe intraventricular haemorrhage (grade 3 or 4) (RR 0.81, 95% CI 0.64 to 1.04; 6 RCTs, 6542 infants; moderate-certainty evidence) and may have resulted in little to no difference in chronic lung disease/bronchopulmonary dysplasia (average RR 0.92, 95% CI 0.77 to 1.10; 5 RCTs, 6689 infants; low-certainty evidence). Primary outcomes for women: Magnesium sulphate may have resulted in little or no difference in severe maternal outcomes potentially related to treatment (death, cardiac arrest, respiratory arrest) (RR 0.32, 95% CI 0.01 to 7.92; 4 RCTs, 5300 women; low-certainty evidence). However, magnesium sulphate probably increased maternal adverse effects severe enough to stop treatment (average RR 3.21, 95% CI 1.88 to 5.48; 3 RCTs, 4736 women; moderate-certainty evidence). Secondary outcomes for women: Magnesium sulphate probably resulted in little to no difference in caesarean section (RR 0.96, 95% CI 0.91 to 1.02; 5 RCTs, 5861 women) and postpartum haemorrhage (RR 0.94, 95% CI 0.80 to 1.09; 2 RCTs, 2495 women) (both moderate-certainty evidence). Breastfeeding at hospital discharge and women's views of treatment were not reported.
AUTHORS' CONCLUSIONS: The currently available evidence indicates that magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus, compared with placebo, reduces cerebral palsy, and death or cerebral palsy, in children up to two years' corrected age. Magnesium sulphate may result in little to no difference in outcomes in children at school age. While magnesium sulphate may result in little to no difference in severe maternal outcomes (death, cardiac arrest, respiratory arrest), it probably increases maternal adverse effects severe enough to stop treatment. Further research is needed on the longer-term benefits and harms for children, into adolescence and adulthood. Additional studies to determine variation in effects by characteristics of women treated and magnesium sulphate regimens used, along with the generalisability of findings to low- and middle-income countries, should be considered.
IMPORTANCE: SARS-CoV-2 remains a substantial cause of respiratory illness, morbidity, and mortality. Evidence to date has demonstrated that COVID-19 vaccines reduce the risk of severe disease, including hospitalization and death.
OBJECTIVE: This systematic review identifies and summarizes newly published studies reporting on the effectiveness and safety of COVID-19 vaccines and COVID-19 epidemiology in the US.
EVIDENCE REVIEW: Cochrane Central Register of Controlled Trials, PubMed/MEDLINE, Embase, and Scopus were searched from August 1, 2025, through June 29, 2026. Studies were eligible if they reported on the effectiveness, efficacy, or safety of a US-licensed COVID-19 vaccine or SARS-CoV-2 epidemiology in the US.
FINDINGS: From 11 829 identified references, 155 publications were eligible (15 randomized clinical trials, 84 observational studies with a comparator group, 38 product safety studies without a comparator group [single group], and 18 descriptive studies of disease burden). Consistent with prior evidence, studies reported that updated COVID-19 vaccines were associated with a reduction in the risk of hospitalization among both older adults (≥65 years; vaccine effectiveness [VE], 53.0%; 95% CI, 37.0%-65.0%; 2025-2026 season) and adults (18-64 years; VE, 54.0%; 95% CI, 1.0%-78.0%; 2024-2025 season). Maternal vaccination was associated with reduced risk of COVID-19-associated emergency department/urgent care encounters among individuals vaccinated (VE, 58.0%; 95% CI, 24.0%-77.0%) and with fewer COVID-19-related hospital contacts in the first 2 months of life among infants born subsequently (VE range, 50.0%-54.0%), regardless of trimester of vaccination. Vaccination was also associated with a significant reduction in COVID-19-related pediatric emergency department visits (9 months to 4 years; VE, 76.0%; 95% CI, 58.0%-87.0%). Vaccination was associated with a reduced risk of critical COVID-19 illness (intensive care unit admission or death) in immunocompromised adults (VE range, 32.0%-53.0%, depending on condition and other factors). Health care personnel who received 3 to 5 vaccine doses were less likely to develop laboratory-confirmed COVID-19 illness (VE, 41.0%; 95% CI, 34.0%-47.0%) and postacute COVID-19 symptoms (VE, 57.0%; 95% CI, 46.0%-66.0%) compared with those who received only 2 doses. Across adverse events of special interest (eg, stroke, thrombosis, myocarditis), safety profiles were consistent with those of previous reviews. No identified studies conducted under the updated guidance on extended dosing intervals for the primary series reported an increased risk of myocarditis or pericarditis. No new safety signals were reported in the recently published studies eligible for this updated review of US-licensed COVID-19 vaccines.
CONCLUSIONS AND RELEVANCE: COVID-19 vaccines were consistently associated with a reduction in the risk of hospitalization and other outcomes, including among individuals at high risk of severe COVID-19, such as infants, and those who were pregnant. No new safety concerns were identified.
IMPORTANCE: Influenza continues to cause significant mortality and morbidity in the US. Seasonal influenza vaccines reduce the severity of disease and prevent hospitalizations and death, especially among individuals at high risk.
OBJECTIVE: To identify and summarize the most recently published research spanning several influenza seasons reporting on the epidemiology of influenza in the US and the effectiveness and safety of US-licensed seasonal influenza vaccines, updating a prior evidence review through August 2025.
EVIDENCE REVIEW: This systematic review searched Medline (PubMed), Embase, Cochrane CENTRAL, and Scopus from August 1, 2025, through June 30, 2026, for all English-language studies. Eligible publications reported on the epidemiology of influenza in the US or vaccine effectiveness and safety for any influenza vaccine formulation approved for use in the US. Data extraction included effectiveness and safety estimates reported among older adults; adults; during pregnancy; infants, children, and young adults; and persons who were immunocompromised. Risk of bias assessment was conducted.
FINDINGS: The search identified 69 eligible studies: 21 randomized clinical trials (RCTs) and 23 observational studies with a comparator group, 7 product safety studies without a comparator group, and 18 descriptive studies of disease burden. Across multiple seasons, influenza vaccines were associated with reduced risk of influenza-related hospitalization (vaccine effectiveness [VE] ranging from 19.0%; 95% CI, 0.0%-34.0% to 43.0%; 95% CI, 30.0%-53.0%) and mortality (VE ranging from 29.0%; 95% CI, 16.0%-40.0% to 65.8%; 95% CI, 54.6%-76.9%) among older adults. Vaccines were also associated with reduced risk of severe influenza among infants, children, adolescents, and young adults; a case-cohort analysis of national surveillance data over 8 seasons (2016-2020 and 2021-2025) among infants, children, and adolescents aged 6 months to 17 years reported that VE was 80.0% (95% CI, 75.0%-84.0%) against laboratory-confirmed influenza-associated deaths. Vaccination during pregnancy was associated with a VE against symptomatic disease in infants of 44.4% (95% CI, 31.4%-54.9%) based on a retrospective cohort study from 2011 to 2022. RCT data published in 2025 for seasons 2022 to 2025 reported higher efficacy against hospitalization with the high-dose compared with standard-dose vaccine among older adults (relative VE, 43.6%; 95% CI, 27.5%-56.3%). A large self-controlled case series among 9 973 703 individuals receiving vaccines found no association with increased risk of serious adverse events, including Guillain-Barré syndrome, after the seasonal influenza vaccine was administered alone or when coadministered with respiratory syncytial virus or COVID-19 immunizations. Another self-controlled case series reported no association with increased risk of febrile seizure during the interval 0 to 7 days after vaccination.
CONCLUSIONS AND RELEVANCE: This systematic review found that evidence published August 1, 2025, through June 30, 2026, continued to demonstrate that influenza vaccines were associated with reduced risk of severe disease and hospitalization, especially among older adults, infants, children, and young adults. No new safety concerns were identified.
IMPORTANCE: Respiratory syncytial virus (RSV) is a leading cause of acute respiratory tract infection and a contributor to morbidity and mortality.
OBJECTIVE: To synthesize evidence from recent randomized clinical trials and observational studies reporting on the effectiveness and safety of RSV vaccines and monoclonal antibodies and the epidemiology of RSV in the US.
EVIDENCE REVIEW: Databases including MEDLINE (PubMed), Embase, Cochrane CENTRAL, and Scopus were searched from August 1, 2025, through June 29, 2026, for studies evaluating the safety and effectiveness of US-licensed RSV vaccines or RSV monoclonal antibody products or describing RSV epidemiology. Data were extracted for older adults (≥60 years), adults, immunocompromised persons, infants, children, and individuals vaccinated during pregnancy. Reviewers assessed risk of bias (RoB) using Cochrane tools for randomized and observational studies.
FINDINGS: A total of 75 eligible studies were identified, including 12 randomized clinical trials (RCTs), 33 observational studies with a comparator group, 16 observational studies without a comparator group, and 14 descriptive studies on RSV epidemiology. Among older adults, RSV vaccination was associated with a reduction in RSV-related hospitalization (vaccine effectiveness [VE], 83.3%; 95% CI, 42.9% to 96.9%). Point estimates for RSV VE against hospitalization and laboratory-confirmed RSV illness among older adults were significantly higher during the first season after vaccination compared with 12 to 18 months of follow-up in 1 study, although the difference was not significant when comparing VE after 1 season vs 2 seasons in another study. The VE for maternal vaccination (between 32-36 weeks' gestation) ranged from 51.0% (95% CI, -29.6% to 83.3%) to 70.0% (95% CI, 37.0% to 86.0%) against RSV-related infant hospitalization. Estimates for effectiveness of nirsevimab among infants varied by timing ranged from 63.6% (95% CI, 26.9% to 81.9%) to 93.0% (95% CI, 83.0% to 97.0%) for RSV-related hospitalization within 6 to 12 months. No cases of Guillain-Barré syndrome (GBS) were identified across 3 RCTs; among older adults, 1 self-controlled case series reported a possible increased risk of GBS during the 42 days following vaccination. None of the comparative studies included in this review found an association of RSV vaccination during pregnancy with preterm birth or other adverse pregnancy outcomes.
CONCLUSIONS AND RELEVANCE: RSV immunizations were associated with reduced risk of severe RSV and RSV-related hospitalizations; evidence among older adults suggests that RSV VE may be lower in subsequent seasons. Reported adverse events of special interest (including GBS and preterm birth) were consistent with prior reviews. The results of this updated review are both consistent with previously reported evidence and provide new insight into several aspects of RSV immunizations.
OBJECTIVE: Individuals with single islet autoantibody positivity exhibit a highly variable risk for type 1 diabetes progression. We evaluated whether metabolic measures identify those at higher progression risk.
RESEARCH DESIGN AND METHODS: Among first- and second-degree relatives of persons with type 1 diabetes who screened and confirmed positive for a single autoantibody in the TrialNet Pathway to Prevention Natural History study, we used Cox proportional hazards models to assess associations between metabolic measures and time to progression, defined as the development of multiple autoantibody-positive or stage 3 type 1 diabetes. Random forest models were used to estimate the relative importance of each variable. Analyses were conducted in the overall cohort and stratified by age (0-8, ≥8-16, and ≥16 years).
RESULTS: Individuals with single autoantibody positivity exhibited wide variation in metabolic function. Measures incorporating both oral glucose tolerance test-stimulated glucose and C-peptide to assess β-cell dysfunction showed strong and consistent associations with progression across age-groups and antibody profiles. Associations for traditional risk factors, isolated glucose or C-peptide measures, or indices of insulin resistance differed by age and autoantibody type. Data-driven cutoffs for combined metabolic measures identified small subsets at very high risk (>50% 2-year progression) and large low-risk groups with <10% 5-year progression.
CONCLUSIONS: β-Cell dysfunction is present in many individuals with single autoantibody positivity and is associated with an increased risk of disease progression. Incorporating stimulated measures of β-cell function alongside age and autoantibody profiles may enable more personalized monitoring, help identify persons most likely to benefit from disease-modifying therapies, and delineate lower-risk individuals who require less intensive surveillance.
IMPORTANCE: Mitigating the harmful effects of digitalization on youth mental health is essential.
OBJECTIVES: To evaluate the effectiveness of cognitive behavioral therapy (CBT) compared with a media literacy-based intervention for gaming disorder and unspecified internet use disorder and to determine whether universal or indicated prevention yields stronger benefits.
DESIGN, SETTING, AND PARTICIPANTS: PROTECTconfirm was a randomized clinical trial conducted from July 1, 2020, to August 31, 2024, across 44 secondary schools in Baden-Württemberg, Germany, with 1-, 4-, and 12-month follow-up. All students were included in universal prevention analyses, whereas indicated prevention analyses included a subgroup of adolescents at high risk meeting 2 or more Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria for gaming disorder or unspecified internet use disorder at baseline.
INTERVENTIONS: Students were individually randomized within 90 classes to PROTECTtraining, a CBT-based program; or PROTECTinfo, a structurally parallel media literacy program. Both consisted of four 90-minute sessions delivered weekly during school hours by trained local prevention professionals under live supervision and adherence protocols.
MAIN OUTCOMES AND MEASURES: The primary outcome was gaming disorder symptom severity and unspecified internet use disorder symptom severity, assessed at 12 months with a modified version of the Video Game Dependency Scale. Secondary outcomes included internalizing, externalizing, and transdiagnostic symptoms. Primary and secondary outcomes were analyzed according to the intention-to-treat principle.
RESULTS: A total of 1793 students were randomized to PROTECTtraining (n = 896; mean [SD] age, 13.1 [1.5] years; 498 male students [56.1%]) or PROTECTinfo (n = 897; mean [SD] age, 13.1 [1.5] years; 484 male students [54.8%]). Participants in the subsample of 205 adolescents at high risk showed significantly lower 12-month severity of gaming disorder and unspecified internet use disorder symptoms with PROTECTtraining than with PROTECTinfo (mean [SD] Modified Video Game Dependency Scale score: 14.7 [9.7] vs 17.7 [10.3]; within-group Cohen d = -0.91 [95% CI, -1.10 to -0.72] vs Cohen d = -0.61 [95% CI, -0.80 to -0.42]; between-group Cohen d = -0.30 [95% CI, -0.55 to -0.05]), but not in the total sample (mean [SD] Modified Video Game Dependency Scale score: PROTECTtraining, 8.8 [8.3] vs PROTECTinfo, 9.4 [8.4]; within-group Cohen d = -0.11 [95% CI, -0.18 to -0.05] vs Cohen d = -0.04 [95% CI, -0.11 to 0.02]; between-group Cohen d = -0.07 [95% CI, -0.16 to 0.01]). Secondary outcomes did not differ significantly between groups.
CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of 1793 adolescents, the CBT-based intervention reduced gaming disorder symptoms and unspecified internet use disorder symptoms more effectively than the media literacy-based intervention among adolescents at high risk. These findings support the use of CBT-based approaches primarily within indicated, rather than universal, prevention.
TRIAL REGISTRATION: German Clinical Trials Register (DRKS) trial registration: DRKS00033989.
BACKGROUND: The COVID-19 pandemic, declared in 2020, brought unprecedented challenges to our healthcare services in relation to the prevention and treatment of the disease. Additionally, preventing transmission within healthcare settings was critical. Infection Prevention and Control (IPC) guidelines are important for providing strategies on the use of personal protective equipment (PPE), the separation of patients with respiratory infections from others, and stricter cleaning routines. It is important to examine how the context of the pandemic impacts healthcare workers' (HCW) ability to adhere to IPC guidance in pandemic situations in the future. This is an update of an earlier review version, published in 2020, titled 'Barriers and facilitators to healthcare workers' adherence with infection prevention and control (IPC) guidelines for respiratory infectious diseases: a rapid qualitative evidence synthesis'. We built on available evidence for infectious respiratory diseases, but also importantly, given the unprecedented global scale of COVID-19 and its unique challenges for healthcare systems, explored additional factors influencing IPC adherence specific to respiratory diseases with pandemic potential, i.e. infectious respiratory pathogens (such as novel influenza subtypes or coronaviruses) judged capable of causing a pandemic.
OBJECTIVES: Our primary objective is to identify the factors that impact on HCWs' adherence to IPC guidelines for COVID-19. A second objective is to update an existing rapid review, published in 2020, to identify similarities, differences, and novel insights specific to COVID-19 compared with other respiratory infectious diseases.
SEARCH METHODS: We searched MEDLINE (Ovid), CINAHL (EBSCO), Scopus, Ovid PsycINFO (EBSCO), and Epistemonikos. We did not apply any language limits but only searched from 2020 to the present (last search 5 April 2024). In the interest of timeliness and relevance, we only included studies published from 2020. We chose this as it marks the year when the COVID-19 pandemic was declared.
SELECTION CRITERIA: We included qualitative and mixed methods studies that focused on the experiences and perceptions of HCWs towards factors that impact on their ability to adhere to IPC guidelines for COVID-19. We included studies of any type of healthcare worker with responsibility for patient care. We included studies that focused on IPC guidelines (local, national, or international) for COVID-19 in any healthcare setting. We excluded studies that collected data using qualitative methods (e.g. open-ended survey questions) in which the response data were analysed only with descriptive statistics.
DATA COLLECTION AND ANALYSIS: We used a purposive sampling frame to identify data-rich studies that represented a range of HCWs, healthcare settings, and geographical spread. We assessed methodological strengths and limitations in the same studies using an adapted version of the Critical Skills Appraisal Programme (CASP) tool for qualitative studies. We used the 'best-fit framework approach' to analyse and synthesise the evidence from our included studies. We used the GRADE-CERQual (Confidence in the Evidence from Reviews of Qualitative research) approach to assess our confidence in each finding. We examined each review finding to identify factors that may influence guideline adherence and developed implications for practice.
MAIN RESULTS: We found 170 studies eligible for inclusion; of these, 26 were sampled for analysis using a purposive sampling frame for a balance of variation and richness of data. Seven of the 26 sampled studies were from high-income countries. Of the 15 middle-income countries, seven were upper middle-income countries, and eight were lower middle-income countries. There were four low-income countries included in the sample. In terms of geographical spread, ten were from Asia, eight from Africa, three were from North America, one from South America, one from Oceania, and three from Europe. Most of the studies included nurses (15 studies) or doctors (11 studies). Other types of healthcare workers included in the studies were other clinical staff (11 studies), such as midwives, allied health professionals, medical and radiologic technologists, dental professionals, neonatologists, radiographers, pharmacists, and support staff (7 studies), such as hospital cleaners, clerical staff, technicians, and hospital attendants. Healthcare settings ranged across and within studies, including hospitals, long-term care settings, and community healthcare settings. Specific units such as maternity, intensive care, emergency care, critical care, and operating rooms were identified in five of the sampled studies. We identified 27 findings that outline the factors that impact on HCWs' adherence to IPC guidelines. We have low (n = 3), moderate (n = 12), and high (n = 12) confidence in these findings. HCWs found it easier to follow IPC guidelines with managerial support, and when IPC guidelines were communicated in a clear, structured, and accessible way. They found it more difficult to follow guidelines if they were busy, short-staffed, or when patients and visitors refused to wear masks and maintain social distancing. Training was considered very important, but not all HCWs had the opportunity to attend IPC training. In terms of the working environment, HCWs need adequate space, hand-washing stations, and showers to follow the IPC guidelines. HCWs worried about infecting other people, but some worried less once people started being vaccinated. It was very important that all HCWs had sufficient and equitable access to PPE and other supplies to follow guidelines. If PPE did not fit properly or was not of good quality, it was more difficult for HCWs to practice IPC. Many factors affect HCWs' willingness and ability to follow IPC guidelines. Our review includes a set of questions based on our findings to help healthcare providers plan, implement, or manage IPC strategies to help their workers follow IPC guidelines for pandemic diseases like COVID-19. It is worth noting that our included studies were conducted primarily during the earlier phase of the pandemic, based on practical considerations to not update the search after April 2024.
AUTHORS' CONCLUSIONS: We identified several factors that influence the ability of healthcare workers to adhere to IPC guidelines. Practical implications, such as communication strategies and the provision of training and supplies, should guide policymakers and decision-makers in disease outbreaks and future pandemics.
FUNDING: This Cochrane review had no dedicated funding.
REGISTRATION: This Cochrane review extends the work by a published rapid review, available via DOI: 10.1002/14651858.CD013582.
IMPORTANCE: Gestational age at birth plays a critical part in childhood neurodevelopment, especially for individuals born preterm (<37 weeks' gestation).
OBJECTIVE: To investigate the association between gestational age and educational outcomes at primary and high school age, controlling for unmeasured confounding by family-level factors.
DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study conducted in Australia included all individuals born at 23 to 42 weeks' gestation in New South Wales (NSW) between 2001 and 2011 and in Victoria between 2005 and 2012 who had school outcomes assessed by standardized assessments in grade 3 (age 8-9 years) and/or grade 9 (age 14-15 years). Analyses were conducted between June 2024 and February 2026.
EXPOSURE: Gestational age at birth.
MAIN OUTCOMES AND MEASURES: Standardized numeracy and reading assessment z-scores were calculated in grade 3 and grade 9 and compared across gestational age groups using multivariable general linear mixed models. A clinically meaningful difference was considered an adjusted mean difference (AMD) in z-score of 0.2 or greater.
RESULTS: The study included 1 095 816 children in grade 3 (772 589 NSW-born [50.7% male] and 323 227 Victoria-born [50.5% male]) and 292 027 NSW-born adolescents in grade 9 (50.7% male). Among children assessed at grade 3, 6.4% in NSW and 7.0% in Victoria were born before 37 weeks' gestation and 54.1% in NSW and 41.1% in Victoria were born at 39 to 40 weeks' gestation; 6.3% of NSW adolescents assessed at grade 9 were born before 37 weeks' gestation and 53.8% at 39 to 40 weeks' gestation. Compared with children born at 39 to 40 weeks, children born at 38 weeks had lower numeracy (AMD, -0.02; 95% CI, -0.03 to -0.02) and reading (AMD, -0.02; 95% CI, -0.02 to -0.01) z-scores in grade 3. z-Scores decreased in a stepwise manner for each gestational age group, with the greatest difference for those born at 23 to 27 weeks vs 39 to 40 weeks (numeracy: AMD, -0.54 [95% CI, -0.58 to -0.49]; reading: AMD, -0.29 [95% CI, -0.34 to -0.25]). However, among siblings at grade 3, these differences were attenuated, and clinically meaningful differences compared with birth at 39 to 40 weeks were only seen for numeracy in children born at 28 to 31 weeks (AMD, -0.23; 95% CI, -0.27 to -0.19) and 23 to 27 weeks (AMD, -0.45; 95% CI, -0.53 to -0.38) and for reading, only for children born at 23 to 27 weeks (AMD, -0.28; 95% CI, -0.36 to -0.21). Results were similar in grade 9, with clinically meaningful differences for numeracy (AMD, -0.53; 95% CI, -0.62 to -0.45) and reading (AMD, -0.39; 95% CI, -0.48 to -0.30) only seen for adolescents born at 23 to 27 vs 39 to 40 weeks' gestation in the full-cohort analysis.
CONCLUSIONS AND RELEVANCE: In this cohort study of over 1 million Australian children, the independent association of gestational age at birth with educational performance was most pronounced for children born at less than 28 weeks' gestation; for children born from 28 to 38 weeks' gestation, differences were not clinically meaningful and were likely primarily attributable to unmeasured confounding by shared familial factors. These findings support prioritizing prevention of the earliest preterm births and suggest that children born before 28 weeks' gestation may benefit from early identification of learning difficulties and targeted educational support.
IMPORTANCE: Geographic variation in breast cancer screening may reflect persistent structural inequities in access to preventive care. Understanding whether historical redlining remains associated with screening, independent of contemporary social vulnerability, neighborhood conditions, and geographic access, is critical for targeting interventions within cancer center catchment areas.
OBJECTIVES: To examine the association between historical redlining and breast cancer screening prevalence, accounting for social vulnerability, neighborhood characteristics, and geographic access, and to characterize spatiotemporal screening patterns.
DESIGN, SETTING, AND PARTICIPANTS: This cohort study used Census tract-level data from 2016 to 2024 across the University of Kansas Cancer Center catchment area, including communities in Kansas and adjacent Missouri counties. The analytic sample included Census tracts with available Homeowners' Loan Corporation (HOLC) grades A (indicating the least redlining) to D (indicating the most redlining). Statistical analysis was performed from July to December 2025.
EXPOSURES: HOLC grades; Social Vulnerability Index quintiles (with the first quintile indicating the lowest vulnerability and the fifth quintile indicating the highest); Census tract-level socioeconomic, housing, and transportation indicators; and distance to the nearest mammography facility.
MAIN OUTCOMES AND MEASURES: Census tract-level breast cancer screening prevalence from the Centers for Disease Control and Prevention's PLACES database, reported as odds ratios (ORs) with 95% credible intervals (CrIs).
RESULTS: A total of 1152 historically redlined Census tracts were analyzed. Tracts were categorized by HOLC grades A (n = 27), B (n = 99), C (n = 423), and D (n = 603). The median (IQR) screening prevalence was highest in grade A tracts (79.6% [79.0%-80.0%]) and lowest in grade D tracts (75.2% [71.7%-79.2%]). Models demonstrated substantial spatial and temporal dependence with geographic clustering and localized variability. Compared with grade A tracts, grade C (OR, 0.94; 95% CrI, 0.90-0.99) and grade D tracts (OR, 0.94; 95% CrI, 0.89-0.99) had lower screening prevalence after adjustment. The highest Social Vulnerability Index quintile was associated with increased screening odds (OR, 1.08; 95% CrI, 1.01-1.14). Lower educational attainment (OR, 0.94; 95% CrI, 0.92-0.96) and higher mobile home prevalence (OR, 0.98; 95% CrI, 0.97-1.00) were associated with lower screening odds. Residual spatial heterogeneity persisted (711 of 1152 tracts [61.7%] excluding the null). Screening peaked in 2018 to 2019, stabilized through 2023, and declined in 2024, with most areas remaining below the Healthy People 2030 target of 80.3%.
CONCLUSIONS AND RELEVANCE: This study found that historical redlining was associated with lower breast cancer screening prevalence independent of contemporary social vulnerability, neighborhood conditions, and geographic access. These findings support sustained, place-based strategies addressing structural and socioeconomic barriers to improve screening uptake and progress toward national screening targets.
Preeclampsia and fetal growth restriction (FGR) are major causes of global morbidity and mortality. Both conditions are associated with impaired invasion of the uterus by extravillous trophoblast (EVT). We performed proteomics in maternal serum obtained at ~12 weeks of gestational age in a prospective pregnancy cohort (Pregnancy Outcome Prediction Study). Here we show that low maternal serum isthmin-2 (ISM2) was the strongest protein signal (out of 2,904) in the first trimester of pregnancy for preeclampsia or FGR. We validated the association in two independent cohorts (Pregnancy Outcome Prediction Study 2 and Improving Maternal Pregnancy And Child ouTcomes study). ISM2 protein and mRNA are almost exclusively produced in the placenta, and, within the placenta, ISM2 mRNA is highly enriched in EVT. Knocking down ISM2 in cultured human trophoblast stem cells profoundly inhibited EVT invasion. Conversely, expressing ISM2 in a cell line lacking endogenous ISM2 (HEK293 cells) promoted migration. We conclude that ISM2 may be causally involved in the early pathophysiology of failed trophoblast invasion and that the protein and its associated pathways are potential targets for the prediction and prevention of preeclampsia and FGR.
IMPORTANCE: Perinatal depression is the most common maternal morbidity, but few US studies have examined whether perinatal depression is associated with infant mortality.
OBJECTIVES: To examine the association between maternal depressive symptoms and infant mortality, assess heterogeneity by maternal and infant demographic and socioeconomic characteristics and risk factors, and explore heterogeneity across leading causes of infant mortality.
DESIGN, SETTING, AND PARTICIPANTS: This population-based retrospective cohort study used birth records from 2016 to 2020 linked to death records from 2016 to 2021 in New Jersey, which mandates screening for depressive symptoms in the immediate postpartum period. The cohort included singleton infants born in New Jersey between 2016 and 2020. Statistical analysis was performed between October 2025 and June 2026.
EXPOSURES: Edinburgh Postnatal Depression Scale score of 10 or higher, which indicated maternal depressive symptoms.
MAIN OUTCOMES AND MEASURES: The primary outcome was infant death within 364 days after birth. Adjusted relative risk (ARR) of infant death was estimated using log-link generalized linear models.
RESULTS: Among the 414 890 infants (212 760 males [51.3%]) with complete data included in the analysis, 413 984 (99.8%) did not die and 906 (0.2%) died. Their mothers had a mean (SD) age of 30.5 (5.7) years, and 63.0% were born in the US, 60.0% were privately insured, and 70.6% completed high school or college. The infant mortality rate was 7.2 per 1000 births for infants whose mothers had depressive symptoms and 2.0 per 1000 births for infants whose mothers did not have depressive symptoms. After statistical adjustment for covariates, the relative risk of death within 364 days after birth was higher for infants of mothers with depressive symptoms compared with infants of mothers without depressive symptoms (model 2: ARR, 2.89; 95% CI, 2.36-3.54). This association was consistent across maternal race and ethnicity, educational level, insurance status, and infant preterm birth. Associations were found between maternal depressive symptoms and infant deaths with these leading causes: prematurity-related conditions (ARR, 4.07; 95% CI, 2.82-5.87), perinatal conditions (ARR, 5.12; 95% CI, 3.39-7.73), congenital malformations and chromosomal abnormalities (ARR, 3.56; 95% CI, 2.14-5.94), and sudden infant death syndrome (ARR, 2.08; 95% CI, 1.11-3.89).
CONCLUSIONS AND RELEVANCE: In this cohort study, infants born to mothers with depressive symptoms had a higher risk of death before 1 year of age compared with infants whose mothers had no depressive symptoms. Expanding maternal depression screening and interventions for individuals with depressive symptoms is critical for improving maternal and infant health.
IMPORTANCE: Geographic disparities in cancer clinical trial access are well described in the US, but patterns in bladder cancer remain poorly defined.
OBJECTIVE: To evaluate bladder cancer trial availability across US counties and its associations with epidemiologic and socioeconomic factors.
DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study of completed, open, or active bladder cancer clinical trials from June 1, 2019, to June 1, 2025, on ClinicalTrials.gov used data on county-level incidence, mortality, and Social Vulnerability Index (SVI) obtained from the Centers for Disease Control and Prevention, the National Cancer Institute, and the Agency for Toxic Substances and Disease Registry and included interventional bladder cancer clinical trials of adults at 1 or more US sites. Data were analyzed from July 1, 2025, to October 20, 2025.
EXPOSURES: Epidemiologic and socioeconomic characteristics of bladder cancer clinical trials.
MAIN OUTCOME AND MEASURES: Trial availability was defined as 1 or more bladder cancer trial sites per county. Trial volume (number of unique trials per county) was modeled using a multivariable zero-inflated negative binomial regression and reported as incidence rate ratios. Associations between trial characteristics and location in highest vs lowest bladder cancer mortality quintile counties were assessed using a generalized linear mixed-effects logistic regression model.
RESULTS: The study identified 436 bladder cancer trials across 713 US counties. Of 3145 counties, 713 (22.7%) had 1 or more trial sites, and 2432 (77.3%) had none. Most trials were sponsored by pharmaceutical companies (211 [48.4%]) or academic institutions (170 [39%]). Most trials were drug focused (350 [80.2%]) and early phase (phase 1 or phase 2; 314 [72%]). Higher bladder cancer incidence was associated with higher trial rates (incidence rate ratio [IRR], 1.03; 95% CI, 1.003-1.06). A higher bladder cancer mortality rate was associated with lower trial rates (IRR, 0.80; 95% CI, 0.73-0.88). Compared with counties with a high SVI, trial rates were higher in counties with a lower-middle (IRR, 1.57; 95% CI, 1.18-2.08), middle-high (IRR, 1.60; 95% CI, 1.22-2.11), and low SVI (IRR, 2.53; 95% CI, 1.89-3.38). Of 7091 trial sites, 225 (3.2%) were located in counties in the highest quintile for bladder cancer mortality. Pharmaceutical company-sponsored trials were less likely than academic trials to be in counties with the highest mortality rate (odds ratio, 0.11; 95% CI, 0.04-0.29; P < .001), as were trials enrolling fewer than 100 participants compared with more than 100 participants (odds ratio, 0.20; 95% CI, 0.09-0.46; P < .001).
CONCLUSIONS AND RELEVANCE: In this cross-sectional study of 436 bladder cancer clinical trials across US counties, most counties lacked trials, with geographic availability concentrated in counties with a high bladder cancer incidence and low social vulnerability. Expanding trial sites to counties with a high mortality rate or a high SVI may improve the geographic availability of bladder cancer clinical trials.
BACKGROUND: In patients with syncope who present to the emergency department for evaluation, diagnosing an underlying cardiac arrhythmia remains difficult.
METHODS: We conducted an open-label, randomized, controlled trial at 45 hospitals in the United Kingdom to assess the effects of 14-day cardiac monitoring on diagnosis, treatment, and outcomes among patients with syncope. Adults with syncope that remained unexplained after an evaluation in the emergency department were assigned in a 1:1 ratio to undergo 14-day ambulatory electrocardiographic (ECG) monitoring (the intervention group) or to receive the standard care provided for patients with unexplained syncope at each participating site (the standard-care group). The primary outcome was the mean number of patient-reported episodes of syncope at 1 year.
RESULTS: A total of 2234 patients underwent randomization: 1123 were assigned to the intervention group and 1111 to the standard-care group. The mean age of the patients was 58.3 years, and 52.1% were male. After the exclusion of patients who did not complete any follow-up, a total of 1970 patients (1004 in the intervention group and 966 in the standard-care group) were included in the primary analysis. The mean (±SD) number of patient-reported syncope episodes at 1 year was 1.37±5.10 in the intervention group and 1.58±8.56 in the standard-care group (incidence rate ratio, 0.89; 95% confidence interval, 0.68 to 1.18; P = 0.42). A total of 49 adverse events were reported in the intervention group, and 8 adverse events were reported in the standard-care group, with 1 serious adverse event in each group.
CONCLUSIONS: Among patients with syncope that remained unexplained after evaluation in the emergency department, the use of 14-day ambulatory ECG monitoring did not result in significantly fewer patient-reported syncope episodes at 1 year than standard care. (Funded by the British Heart Foundation and National Health Service Research Scotland; ASPIRED ISRCTN Registry number, ISRCTN10278811.).
BACKGROUND: Following transcatheter aortic valve replacement (TAVR), subclinical leaflet thrombosis-visualized on cardiac computed tomography (CT) as hypoattenuated leaflet thickening (HALT)-is common and might be associated with thromboembolic events.
OBJECTIVES: The NOTION-4 trial investigates different antithrombotic treatment strategies for the prevention of HALT.
METHODS: NOTION-4 was a randomized controlled trial enrolling patients without an indication for oral anticoagulation shortly after successful TAVR. Patients were randomized to lifelong single antiplatelet therapy (SAPT) or 3 months of direct oral anticoagulant (DOAC) therapy followed by lifelong SAPT (DOAC-3m). The primary endpoint was HALT prevalence at 12 months. The trial was powered for superiority of the experimental strategy.
RESULTS: Of 352 patients randomized 1:1, 5 were screen failures or withdrew consent, leaving 176 in the SAPT group and 171 in the DOAC-3m group. At 3 months, HALT was observed in 31.8% of patients receiving SAPT compared with 12.1% of those receiving DOAC-3m. At 1 year, HALT occurred in 32.2% of SAPT patients and 28.3% of DOAC-3m patients with available CT scans (risk difference: -3.9%; 95% CI: -14.4% to 6.6%; P = 0.54). The combined risk of all-cause mortality, stroke, or major/life-threatening bleeding at 12 months was 2.3% in the SAPT group vs 8.2% in the DOAC-3m group (risk difference: 5.9%; 95% CI: 1.2% to 10.6%).
CONCLUSIONS: Among TAVR patients without an indication for oral anticoagulation, 3 months of DOAC therapy significantly reduced the prevalence of HALT at 3 months compared with SAPT; however, this effect was attenuated by 9 months after discontinuation of DOAC therapy. (The Nordic Aortic Valve Intervention Trial 4 [NOTION-4]; NCT06449469).
BACKGROUND: The effectiveness and safety of statins for the primary prevention of cardiovascular events and the extension of disability-free survival among older adults remain uncertain.
METHODS: We conducted a double-blind, randomized, placebo-controlled trial at general medical practices across Australia. Community-dwelling adults at least 70 years of age with no history of cardiovascular disease, diabetes, or dementia were randomly assigned in a 1:1 ratio to receive atorvastatin at a dose of 40 mg once daily or identical placebo. The two primary end points were a composite of death from cardiovascular causes, nonfatal myocardial infarction or stroke, or coronary revascularization (to assess effects on major cardiovascular events) and a composite of death from any cause, dementia, or persistent physical disability (to assess effects on disability-free survival). Analyses were performed according to a hierarchical testing plan.
RESULTS: A total of 9971 participants were enrolled: 4984 were assigned to receive atorvastatin and 4987 to receive placebo. The mean (±SD) age of the participants was 74.7±4.5 years, and 51.9% were women. After a median of 5.9 years, a primary cardiovascular event had occurred in 297 participants (10.9 events per 1000 person-years) in the atorvastatin group and in 412 participants (15.5 events per 1000 person-years) in the placebo group (hazard ratio, 0.70; 95% confidence interval [CI], 0.61 to 0.82; P<0.001). Death from any cause, dementia, or persistent physical disability occurred in 637 participants (21.6 events per 1000 person-years) in the atorvastatin group and in 676 participants (23.0 events per 1000 person-years) in the placebo group (hazard ratio, 0.94; 95% CI, 0.84 to 1.05; P = 0.25). Serious adverse events occurred in 131 participants (2.7%) in the atorvastatin group and in 129 (2.7%) in the placebo group, with musculoskeletal, hepatobiliary, and diabetes-related adverse events occurring more commonly in the atorvastatin group.
CONCLUSIONS: Treatment with atorvastatin led to a lower risk of major cardiovascular events than placebo at a median of 5.9 years but did not result in longer disability-free survival among community-dwelling older adults without clinical cardiovascular disease. (Funded by the National Health and Medical Research Council and others; STAREE ClinicalTrials.gov number, NCT02099123.).
IMPORTANCE: Statin nonadherence is a leading, addressable driver of preventable cardiovascular events. Although health systems routinely use outreach to promote preventive care, most strategies are static and lack evidence from randomized clinical trials.
OBJECTIVE: To determine whether an adaptive, sequential digital outreach strategy improves short-term statin refill vs usual communication among adults with established atherosclerotic cardiovascular disease (ASCVD) or high ASCVD risk and recent nonadherence within a rapidly implemented, health system-embedded randomized clinical trial.
DESIGN, SETTING, AND PARTICIPANTS: Pragmatic, health system-embedded, prospective randomized open blinded end point (PROBE) clinical trial using a 2-stage sequential, multiple assignment, randomized trial (SMART) design. The trial was conducted via Kaiser Permanente Northern California, an integrated health care delivery system serving more than 4.6 million members. Eligible participants were adults 18 years or older with established ASCVD or high ASCVD risk, recent statin nonadherence, and eligibility for all study communication modalities.
INTERVENTIONS: Participants were randomized 1:1:1:1 to receive secure portal messaging, SMS/text messaging, nonsecure email, or usual communication. Initial nonresponders within 14 days underwent prespecified second-stage randomization to repeat the same outreach, switch communication modality, or receive usual communication.
MAIN OUTCOMES AND MEASURES: Rates of 14-day statin refill following each randomization, with 28-day follow-up.
RESULTS: Among 20 604 participants (mean [SD] age, 54.8 [9.0] years; 40.9% female; 27.8% Asian, 10.9% Black, 33.6% Hispanic; 15.3% with established ASCVD), initial digital outreach increased 14-day statin refill vs usual communication (14.4% vs 12.0%; adjusted risk difference, 2.3 percentage points [95% CI, 1.3-3.4]; adjusted risk ratio, 1.20 [95% CI, 1.10-1.30]). Among initial nonresponders, second-stage outreach further increased refill (13.0% vs 10.4%; adjusted risk difference, 2.5 percentage points [95% CI, 1.3-3.7]; adjusted risk ratio, 1.25 [95% CI, 1.11-1.39]). Switching communication modalities did not improve refill vs repeating the same modality (13.2% vs 12.5%; adjusted risk ratio, 1.06 [95% CI, 0.94-1.17]). Cumulative statin refill through 28 days was higher in those receiving any digital outreach vs usual communication (24.9% vs 21.2%; adjusted hazard ratio, 1.21 [95% CI, 1.13-1.30]). Results were consistent across prespecified subgroups.
CONCLUSIONS AND RELEVANCE: Among adults with a statin indication and recent statin nonadherence, adaptive outreach improved short-term refill vs usual communication. A second outreach produced additional gains among initial nonresponders, although switching communication modalities provided no additional benefit. These findings support adaptive, sequential health system outreach strategies to improve cardiovascular prevention when integrated into population health programs.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT07522645.
IMPORTANCE: Current guidelines do not recommend primary prevention implantable cardioverter-defibrillators (ICDs) unless a patient's left ventricular ejection fraction (LVEF) is 35% or less. Many sudden cardiac deaths (SCD) occur when LVEF is 36% to 50%. Myocardial scar (a key arrhythmic substrate) can be assessed by late gadolinium enhancement on cardiovascular magnetic resonance (CMR), but robust evidence is lacking regarding a scar-based approach to ICD insertion.
OBJECTIVE: To determine whether implantation of ICDs reduces SCD or hemodynamically significant ventricular arrhythmia (HSVA) in patients with an LVEF of 36% to 50% and myocardial scar.
DESIGN, SETTING, AND PARTICIPANTS: An open-label randomized clinical trial enrolled adults between 2015 and 2022 who had ischemic or nonischemic cardiomyopathy, an LVEF of 36% to 50%, CMR-defined myocardial scar, and were receiving guideline-directed medical therapy at 18 sites in Australia, Germany, and the UK. Follow-up assessments were completed in 2026.
INTERVENTIONS: A primary prevention ICD (n = 180) vs an implantable loop recorder (ILR) (n = 173).
MAIN OUTCOMES AND MEASURES: The primary composite outcome was SCD or HSVA. Five secondary outcomes were evaluated: SCD, HSVA, heart failure-related hospitalization, cardiovascular mortality, and all-cause mortality.
RESULTS: Of 353 patients randomized (median age, 65 years [IQR, 57-61 years]; 18% female; and 72% had an ischemic etiology), 70% had an LVEF of 40% or greater. The median follow-up was 6.3 years (IQR, 4.8-7.6 years). The primary composite outcome occurred in 14 patients (7.8%) in the ICD group compared with 16 patients (9.2%) in the ILR group (hazard ratio [HR], 0.76 [95% CI, 0.37-1.58]). For the individual components of the primary composite outcome, SCD occurred in 3 patients (1.7%) vs 10 patients (5.8%) in the ILR group (HR, 0.26 [95% CI, 0.07-0.95]) and HSVA occurred in 12 patients (6.7%) vs 6 patients (3.5%), respectively (HR, 1.77 [95% CI, 0.65-4.81]). The rates for all-cause mortality, cardiovascular mortality, and heart failure-related hospitalization were similar between groups. In a prespecified analysis of 6 subgroups, the primary outcome occurred less often in patients younger than 70 years in the ICD group (3.3%) vs patients in the ILR group (10.0%) (HR, 0.28 [95% CI, 0.09-0.89]) but not in those aged 70 years or older (16.9% vs 7.5%, respectively) (HR, 2.33 [95% CI, 0.75-7.26]; P = .01 for interaction).
CONCLUSIONS AND RELEVANCE: Implantation of an ICD did not reduce the composite outcome of SCD or HSVA in patients with an LVEF of 36% to 50% and myocardial scar.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01918215.
IMPORTANCE: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a treatable cause of heart failure, but diagnosis is often delayed. Accessible tools to prioritize confirmatory evaluation could reduce missed diagnoses when cardiac imaging is limited.
OBJECTIVE: To develop and validate a locally deployable artificial intelligence (AI)-enabled system that identifies patients for further ATTR-CM evaluation from routine electrocardiography (ECG) images.
DESIGN, SETTING, AND PARTICIPANTS: This diagnostic test study used an AI-ECG model developed within Yale New Haven Health (using ECGs from August 2015-June 2023) and temporally validated (July 2023-July 2025). External validation included 5 multinational cohorts and 3 screening cohorts (older Black and Hispanic adults with heart failure; adults with prior carpal tunnel surgery; 99-3902 individuals per cohort).
EXPOSURE: Use of AI-ECG for detecting ATTR-CM from routine ECG images or raw 12-lead signals.
MAIN OUTCOMES AND MEASURES: Area under the receiver operating characteristic curve (AUROC), sensitivity, specificity, and positive and negative predictive values for ATTR-CM confirmed by cardiac amyloid radionuclide imaging (CARI) or biopsy. An exploratory analysis evaluated sequential screening with AI-ECG followed by AI-enabled echocardiography.
RESULTS: Development used 28 174 ECGs from 11 291 patients (293 with ATTR-CM). In internal validation (44 123 patients; mean age, 68.5 years; 49.7% female), AUROC was 0.84 (95% CI, 0.79-0.89), with sensitivity of 0.72 and specificity of 0.86 at the prespecified threshold, and was maintained in a specificity stress test among patients with features that mimic ATTR-CM (left ventricular hypertrophy or severe aortic stenosis without amyloid; AUROC, 0.81 [95% CI, 0.75-0.86]) and those referred for CARI (AUROC, 0.78 [95% CI, 0.73-0.84]). Across 5 external cohorts, AUROCs ranged from 0.78 to 0.89. In 3 screening cohorts, AUROCs were 0.76 (95% CI, 0.68-0.83) in the SCAN-MP study (n = 645) and 0.79 (95% CI, 0.65-0.93) and 0.91 (95% CI, 0.82-0.97) in 2 CACTUS study cohorts (n = 251, n = 121). Sequential AI-ECG and AI-enabled echocardiography increased the positive predictive value from 0.24 to 0.66 and reduced sensitivity from 0.84 to 0.68.
CONCLUSIONS AND RELEVANCE: Locally deployable AI applied to ECG images discriminated ATTR-CM across multinational retrospective and screening cohorts. This approach may provide an accessible first step to prioritize selected patients for echocardiography and confirmatory imaging, although intended use and calibration require prospective evaluation.
RATIONALE: Electronic cigarettes (EC) are handheld electronic vaping devices that produce an aerosol by heating a liquid. People who smoke, healthcare providers, and regulators want to know if EC can help people quit smoking, and if they are safe to use for this purpose. This update was conducted as part of a living systematic review.
OBJECTIVES: To examine the safety, tolerability, and effectiveness of EC for helping people who smoke tobacco achieve long-term smoking abstinence, in comparison to non-nicotine EC, other smoking cessation treatments, and no treatment.
SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PsycINFO to 1 January 2026, reference-checked, and contacted study authors.
ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) randomising people who smoked to an EC or control condition. Studies had to measure an eligible outcome.
OUTCOMES: Critical outcomes were abstinence from smoking after at least six months, adverse events (AEs), and serious adverse events (SAEs). Important outcomes were biomarkers, toxicants/carcinogens, long-term study product use and long-term patterns of EC and combustible cigarette use.
RISK OF BIAS: We used the RoB 1 tool to assess risk of bias for each study and GRADE to assess evidence certainty.
SYNTHESIS METHODS: We followed standard Cochrane methods for screening and data extraction. Where appropriate, we pooled data using random-effects models to calculate risk ratios (RRs) with 95% confidence intervals (CI) for dichotomous outcomes apart from SAEs. For SAEs, we calculated risk differences (RD) and 95% CI. For continuous outcomes, we calculated mean differences (MD) or standardised mean differences (SMD) with 95% CIs.
INCLUDED STUDIES: We included 80 completed RCTs, representing 29,861 participants. Nine of these RCTs were new to this update. We rated 12 included studies as being at low risk of bias, 41 at high risk, and the remainder at unclear risk overall.
SYNTHESIS OF RESULTS: Nicotine EC result in increased quit rates compared to nicotine replacement therapy (NRT) (high-certainty evidence) (RR 1.61, 95% CI 1.23 to 2.12; I² = 55%; 11 studies, 4114 participants). In absolute terms, this might translate to an additional four quitters per 100 (95% CI 1 to 7 more). The proportion of participants experiencing AEs may be similar between groups (low-certainty evidence, limited by imprecision and inconsistency) (RR 0.95, 95% CI 0.72 to 1.24; I² = 72%; 8 studies, 3107 participants) and the proportion of participants experiencing SAEs is probably similar between groups (moderate-certainty evidence, limited by imprecision) (RD 0.01, 95% CI -0.01 to 0.02; I² = 0%; 10 studies, 4045 participants). Nicotine EC probably result in increased quit rates compared to non-nicotine EC (moderate-certainty evidence, limited by imprecision) (RR 1.34, 95% CI 1.05 to 1.69; I² = 0%; 7 studies, 1918 participants). In absolute terms, this might lead to an additional two quitters per 100 (95% CI 0 to 4 more). There is probably little to no difference in the proportion of participants experiencing AEs between these groups (moderate-certainty evidence, limited by imprecision) (RR 1.01, 95% CI 0.95 to 1.08; I² = 0%; 6 studies, 909 participants) and there may be similar proportions of SAEs (RD 0.00, 95% CI -0.01 to 0.01; I² = 0%; 11 studies, 1786 participants; low-certainty evidence downgraded due to very serious imprecision). Compared to behavioural support only or no support, quit rates may be higher for participants randomised to nicotine EC (low-certainty evidence due to risk of bias) (RR 1.75, 95% CI 1.39 to 2.20; I² = 13%; 11 studies, 7214 participants). In absolute terms, this represents an additional two quitters per 100 (95% CI 2 to 6 more). There was some evidence that people randomised to nicotine EC may be more likely to experience (non-serious) AEs (RR 1.22, 95% CI 1.00 to 1.49; I² = 58%; 11 studies, 2801 participants; very low-certainty evidence due to imprecision and risk of bias), but the evidence is uncertain. There was insufficient evidence to determine whether rates of SAEs differed between groups (RD 0.00, 95% CI -0.00 to 0.01; I² = 0%; 18 studies, 5032 participants; very low-certainty evidence downgraded due to imprecision and risk of bias).
AUTHORS' CONCLUSIONS: There is high-certainty evidence that nicotine EC increase quit rates compared to NRT, and moderate-certainty evidence that they probably increase quit rates compared to EC without nicotine. Evidence comparing nicotine EC with behavioural support or no support also suggests benefit, but is less certain due to risk of bias inherent in the study designs. Overall incidence of SAEs was low across all study arms and there is now moderate-certainty evidence that SAE rates are similar when comparing nicotine EC with NRT. There was also no evidence of a difference in AEs between nicotine and non-nicotine EC nor between nicotine EC and NRT, but low-certainty evidence for increased AEs compared with behavioural support/no support. We did not detect evidence of serious short-term harm from nicotine EC, but longer, larger trials are needed to fully evaluate safety. The included studies tested regulated nicotine-containing EC; illicit products and/or products containing other active substances (e.g. tetrahydrocannabinol (THC)) may have different harm profiles. The main limitation of the evidence base remains imprecision for some comparisons. Further RCTs are underway. To ensure the review continues to provide up-to-date information, this is a living systematic review. We run and screen searches monthly, with the review updated when relevant new evidence becomes available. Please refer to the Cochrane Database of Systematic Reviews for the most recent version of this review.
FUNDING: Cancer Research UK (PICCTR-2024/100012). The addition of new outcomes relating to vaping and smoking at six months or more was supported by the National Cancer Institute of the National Institutes of Health (NIH) and FDA Center for Tobacco Products (CTP) under Award Number 2U54CA229974. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the Food and Drug Administration. The funders were not involved in the decision to submit for publication.
REGISTRATION: Protocol (2012) available via DOI: 10.1002/14651858.CD010216 (updates to 2012 protocol available via https://osf.io/upgjc/overview.
The recombinant herpes zoster (shingles) vaccine may reduce risks of cardiovascular disease. However, existing studies have compared vaccine recipients with non-recipients and, thus, are susceptible to confounding. To mitigate these biases, we conducted a natural experiment created by the rapid transition from the live attenuated to the recombinant shingles vaccine in the United States. We compared incidences of a composite cardiovascular endpoint (ischemic heart disease, heart failure or ischemic stroke) among adults aged ≥60 years vaccinated immediately before versus immediately after this transition. The recombinant vaccine was associated with a 9% decrease in cardiovascular burden over 7 years (restricted mean time lost (RMTL) ratio = 0.91, 95% confidence interval (CI): 0.88-0.95). The association attenuated over time and was significant for ischemic heart disease (10% decrease in burden; RMTL ratio = 0.90, 95% CI: 0.87-0.94) and heart failure (12% decrease in burden; RMTL ratio = 0.88, 95% CI: 0.83-0.93) in both sexes and ischemic stroke in males (12% decrease; RMTL ratio = 0.88, 95% CI: 0.78-0.98). An association was also seen for atrial fibrillation (7% decrease in burden; RMTL = 0.93, 95% CI: 0.88-0.98) but not other cardiac, peripheral and cerebrovascular outcomes. Results were consistent in secondary analyses. These results justify clinical trials and mechanistic studies to investigate potential cardioprotective effects of shingles vaccines.
Vaccination is one of the greatest triumphs in human history. Traditionally, vaccines were designed to stimulate antibody responses that block infection, but this overlooks the immune system's complex and multifaceted defence mechanisms. Here we review the current state of the field of systems vaccinology, which has transformed vaccine research by using vaccines as controlled probes of the human immune system and by applying multi-omics and computational approaches to reveal the nature of human immunity. These approaches have identified molecular signatures that predict the magnitude and durability of immune responses and revealed new human biology, including how host genetics, metabolism and the microbiome shape immunity, and demonstrated that host defence emerges from coordinated immune programs spanning baseline immune state, early response dynamics and tissue-level interactions. Rapid advances in artificial intelligence are beginning to accelerate the distillation of knowledge and understanding from vast multi-omics datasets. These developments position systems vaccinology as a powerful framework for rational vaccine design. However, despite its considerable impact on discovery and human immunology, considerable challenges remain in translating these insights into clinical and regulatory practice. Addressing this translational gap will be essential for realizing the full potential of systems vaccinology to deliver safer, more effective vaccines against existing and emerging infectious threats.
RATIONALE: Intravenous oxytocin is widely used to induce labour or to augment labour (i.e. enhance contractions to promote progression), with approximately one-quarter of pregnant women at term receiving the medication. While continuous administration of intravenous oxytocin stimulation from induction until birth is recommended by most clinical guidelines, this may increase the risk of uterine hyperstimulation, foetal distress, and adverse maternal and neonatal outcomes. Discontinuation of oxytocin in the active phase of labour could reduce these risks without compromising labour progression. However, evidence from randomised trials is conflicting, and optimal management is unclear.
OBJECTIVES: To assess the effects of the discontinuation of intravenous oxytocin stimulation in pregnant women during the active phase of induced or augmented labour.
SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, Scopus, and Web of Science Core Collection, as well as ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform. We also screened reference lists of included studies and relevant reviews, and contacted trial authors for additional data. No language or date restrictions were applied. The last search was conducted on 17 November 2025.
ELIGIBILITY CRITERIA: We included randomised controlled trials comparing continuation versus discontinuation (or placebo) of intravenous oxytocin in the active phase of labour (≥ 4 cm cervical dilation) in term singleton pregnant women undergoing labour induction or augmentation. No restrictions to inclusion were applied regarding parity, maternal age, comorbidities, labour setting, or presence or absence of previous caesarean section.
OUTCOMES: The critical outcome was caesarean section. Important maternal outcomes included instrumental vaginal birth (vacuum extraction or forceps delivery), postpartum haemorrhage, maternal infection, maternal satisfaction, duration of the active phase of labour, uterine hyperstimulation (tachysystole with abnormal CTG (cardiotocography)), and uterine tachysystole with normal CTG. Important neonatal outcomes included admission to neonatal unit, hypoxic ischaemic encephalopathy or therapeutic hypothermia, neonatal infection, perinatal death, acidotic cord blood gases (arterial pH < 7.10), and Apgar score < 7 at five minutes.
RISK OF BIAS: Two review authors independently assessed the risk of bias for each trial using Cochrane's risk of bias tool RoB 1, following the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions. We assessed random sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other potential sources of bias. We resolved disagreements through discussion or by involving a third review author. We assessed potentially eligible and included trials using the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool.
SYNTHESIS METHODS: For dichotomous outcomes, we calculated risk ratios (RR) with 95% confidence intervals (CIs). For continuous outcomes, we calculated mean differences (MDs) with 95% CIs. For our primary analysis, we used the fixed-effect model, implemented using the Mantel-Haenszel method for dichotomous outcomes and inverse variance for continuous outcomes. We prespecified random-effects meta-analysis as a secondary analysis to explore the robustness of the findings in the presence of between-study heterogeneity. We conducted sensitivity and subgroup analyses for the critical outcome only. We assessed statistical heterogeneity using Tau², I² and Chi² statistics. We evaluated the certainty of evidence using the GRADE approach for the prespecified outcomes included in our summary of findings table.
INCLUDED STUDIES: During the study selection process, we placed 10 studies in the 'awaiting classification' category because we needed additional information to assess eligibility or trial trustworthiness. These studies could potentially change the review's conclusions once verified and incorporated. This review includes a total of nine trials evaluating nine comparisons and involving 4814 women. The overall risk of bias of included trials varied. Several studies were open label, and allocation concealment was unclear in some. The certainty of evidence ranged from high to low, mainly due to risk of bias, inconsistency, and imprecision across studies.
SYNTHESIS OF RESULTS: Discontinuation of oxytocin at the onset of the active phase of induced or augmented labour may make little or no difference to the risk of caesarean section compared with continuation (RR 0.98, 95% CI 0.85 to 1.13; I² = 5%; 8 studies, 4710 participants; low-certainty evidence). In a sensitivity analysis for the critical outcome excluding trials with high risk of bias in one or more domains, only one trial remained (RR 1.17, 95% CI 0.90 to 1.53; 1198 women). Discontinuation makes little or no difference to the risk of instrumental vaginal birth (RR 1.05, 95% CI 0.90 to 1.21; I² = 0%; 5 studies, 3776 participants; high-certainty evidence). The duration of the active phase of labour may be longer after discontinuation, with a mean difference of 34.72 minutes compared to continued stimulation, but the certainty of this evidence is very low (MD 34.72, 95% CI 26.34 to 43.11; I² = 82%; 8 studies, 4141 participants; very low-certainty evidence). Discontinuation may reduce uterine hyperstimulation (RR 0.65, 95% CI 0.55 to 0.77; I² = 56%; 3 studies, 1371 participants; low-certainty evidence). Discontinuation makes little or no difference to admission to a neonatal unit (RR 0.98, 95% CI 0.76 to 1.27; I² = 0%; 7 studies, 4606 participants; high-certainty evidence) or acidotic cord gasses at birth (arterial pH < 7.10) (RR 1.01, 95% CI 0.75 to 1.35; I² = 0%; 6 studies, 4086 participants; high-certainty evidence). Discontinuation probably makes little or no difference to the risk of having an Apgar score less than seven at five minutes (RR 0.92, 95% CI 0.40 to 2.11; I² = 0%; 5 studies, 2096 participants; moderate-certainty evidence).
AUTHORS' CONCLUSIONS: Discontinuation of oxytocin in the active phase of induced or augmented labour may have little or no effect on caesarean birth and has little or no effect on instrumental birth. It may reduce uterine hyperstimulation at the expense of a longer duration of the active phase of labour, but this evidence is of very low certainty. The discontinuation strategy appears safe for both mother and baby, provided that adequate monitoring of uterine activity and foetal heart rate is maintained.
FUNDING: None REGISTRATION: The protocol for this Cochrane review was published in November 2024.
This is a protocol for a Cochrane review (intervention). The objectives are as follows: To evaluate the benefits and harms of whole-body magnetic resonance imaging (MRI) or computed tomography (CT) scans for screening in asymptomatic adults, compared with no intervention, usual care, or alternative screening strategies not involving whole-body MRI or whole-body CT.
Rapid whole-genome sequencing (rWGS) enables timely diagnosis and management of critically ill patients, particularly in consanguineous populations with a high burden of recessive diseases. Here we report Little Falcon, a citywide rWGS program implemented within centralized neonatal and pediatric intensive care units in Dubai. In total, 100 critically ill patients from 18 Middle Eastern and Asian countries underwent trio rWGS with a median turnaround time of 3.4 days. The overall diagnostic yield was 53% (95% CI 43.3-62.5%), rising to 80% in consanguineous families (P < 0.001). Multiple molecular findings were identified in 12% of patients, including dual diagnoses (5%), while additional actionable findings included newborn screening-relevant variants (4%) and American College of Medical Genetics secondary or incidental findings (3%). rWGS led to clinically meaningful management changes in 53% of patients including those with (n = 45) or without (n = 8) molecular diagnoses, altering disease trajectories in 16%. Compared with a matched historical cohort of critically ill patients receiving standard genetic testing, rWGS significantly reduced diagnostic time (3.4 versus 38 days, P < 0.001), increased diagnostic yield (53% versus 30%, P < 0.01) and improved clinical management (53% versus 18%, P < 0.001). These findings support integrating rWGS into routine neonatal and pediatric intensive care units within a citywide healthcare system.
BACKGROUND: Dengue remains a pressing global health challenge, particularly in low- and middle-income countries (LMIC). Despite a growing volume of research on prevention strategies, there is a notable lack of consolidated, high-level research capturing the full scope of existing knowledge. The current evidence landscape is fragmented, with studies varying widely in design, focus, and quality. A structured map that includes both primary studies and systematic reviews is urgently needed. Such evidence and gap maps (EGMs) serve as a decision-support tool for funders, policymakers, and researchers by identifying where research exists and where future investments are most needed.
OBJECTIVES: To: 1. comprehensively identify the published literature on dengue prevention strategies; 2. critically appraise systematic reviews; 3. present the findings of objectives 1 and 2 in a single evidence gap map; and 4. identify critical knowledge gaps to inform future primary studies and systematic reviews.
SEARCH METHODS: We searched MEDLINE (Ovid), Embase (Ovid), CINAHL (EBSCO), Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR) in the Cochrane Library, and LILACS (BIREME) on 6 August 2025. We did not apply any date or language restrictions to the searches.
SELECTION CRITERIA: We included randomised controlled trials (RCTs), quasi-randomised trials, non-randomised studies of interventions (NRSIs) and systematic reviews. NRSIs had to have a comparator. We included study designs such as cohort studies, interrupted time series designs, controlled before-after studies, and case-control studies. We did not include case studies or animal studies conducted in a laboratory or semi-field environment. We did not have any restrictions on date or language of publication. We included studies that compared dengue prevention strategies against placebo, no intervention, or usual care. We developed intervention and outcomes categories through a structured stakeholder engagement process and an existing theoretical framework.
DATA COLLECTION AND ANALYSIS: We used Cochrane Crowd, Cochrane's citizen science platform designed to host classification tasks, to help identify and describe health-related research. The results collectively identified by the Crowd as being potentially relevant to the EGM were then imported into EPPI Reviewer for further assessment and coding by the author team. Two review authors independently extracted data from the included studies using a structured coding framework developed during the pilot stage. Following coding, we exported data from EPPI Reviewer to EPPI Mapper to generate an interactive, online map that visually displays the distribution of evidence and identifies key gaps by intervention and outcome. We sought to identify evidence and map it, but did not seek to provide a critical appraisal of that evidence. However, to support systematic review teams in understanding where there are evidence synthesis gaps, and to minimise research duplication, we decided to critically appraise the systematic reviews. Two review authors independently appraised the quality of systematic reviews, using A MeaSurement Tool to Assess Systematic Reviews (AMSTAR 2). We partnered with Instituto Veredas, a Brazilian non-governmental organisation, that aims to build bridges between public management, academia, and civil society, to conduct stakeholder engagement.
MAIN RESULTS: The searches identified 20,355 records. After deduplication, we screened 16,468 titles and abstracts, then assessed 720 full-text articles for further eligibility. In total, we included 550 studies in the EGM. Evidence from primary studies We included a total of 505 primary studies, comprising 197 RCTs and 308 NRSIs, with 219 published in the past decade. Most studies were conducted at the community level with mixed adult and child populations, predominantly in high-prevalence regions of South America and South Asia. Brazil accounted for the largest share of studies (64 studies), and Aedes aegypti was the most frequently targeted vector species. Of our five main intervention domains (vaccines, environmental, community education, targetting of aquatic stages of the vector and targetting of adult vectors), community education was the most extensively studied (47 RCTs and 140 NRSIs), largely focusing on behavioural and entomological outcomes. These interventions overlapped with vector control interventions targeting both aquatic and adult stages of the mosquito. Evidence from systematic reviews We included 45 systematic reviews. We rated only eight as high or moderate quality using the AMSTAR 2 tool, with the majority classified as low or critically low quality due to methodological weaknesses. Common deficiencies included lack of protocol registration, inadequate justification for study exclusions, and insufficient consideration of risk of bias in interpreting findings. Of the eight high- or moderate-quality reviews, most of which evaluated multiple interventions, two included environmental interventions, three evaluated community education, four assessed vaccines, one evaluated vector control interventions exclusively targeting aquatic stages, and three included vector control of adult mosquitoes. Key gaps For community education, a clear gap exists for implementation outcomes, where the substantial evidence base of 25 primary studies has not been synthesised by any high- or moderate-quality systematic reviews. Adult vector interventions present multiple synthesis gaps despite extensive primary studies, as existing reviews are outdated or restricted to Wolbachia-infected mosquitoes. Aquatic-stage interventions show consistent synthesis gaps across all outcome domains. For vaccines, evidence is particularly limited for implementation outcomes and entirely absent for behavioural outcomes, indicating minimal evidence in these domains. Finally, environmental interventions display synthesis gaps for behavioural and implementation outcomes, where primary studies are available but high- or moderate-quality systematic reviews are lacking.
AUTHORS' CONCLUSIONS: The primary challenge in the dengue prevention evidence base is not the absence of studies, but the lack of strategic synthesis aligned with decision-making needs. Priority areas for future research include: • updated and comprehensive systematic reviews for adult and aquatic-stage vector interventions; • synthesis of implementation and behavioural evidence across all non-vaccine interventions; and • systematic evaluation of adverse effects beyond vaccine technologies. From a policy perspective, reliance on entomological outcomes alone remains insufficient. Greater emphasis on epidemiological and implementation outcomes is essential to support effective, scalable, and context-sensitive dengue control strategies. Aligning future research agendas with these gaps may substantially enhance the usability of the evidence for public health decision-making, particularly in endemic and resource-constrained settings.
FUNDING: The Cochrane Collaboration funded stakeholder engagement work, information specialist expertise, and some of the authors.
REGISTRATION: Protocol (2025): DOI: 10.1002/14651858.CD016299.
Accurate diagnosis of diabetes has important therapeutic consequences, yet 10-15% of individuals with type 1 diabetes are autoantibody negative, leaving the etiology of diabetes unconfirmed. We estimated what proportion of autoantibody negative, clinically diagnosed type 1 diabetes is misdiagnosed nonautoimmune diabetes. Upwards of 7.6% of autoantibody negative individuals are nonautoimmune. Our findings support the use of autoantibody screening and genetic testing of autoantibody negative patients as standard of care for type 1 diabetes.
We read with great interest about the study by Pop-Busui et al. ( 1 ), which demonstrated the prognostic value of natriuretic peptide (NP) levels in a large, real-world cohort of 116,466 individuals with diabetes. While the association between NP levels and future risk is compelling, the definition used for incident heart failure (HF) raises important questions regarding potential bias.
Gestational diabetes mellitus (GDM) has long been viewed as a metabolic condition first recognized during pregnancy. However, research now demonstrates that underlying metabolic abnormalities are detectable during the preconception period in individuals who subsequently develop GDM and that GDM carries long-term implications for both mothers and offspring. In this article, I provide an overview of the work that my colleagues and I have conducted over the past 25 years, aimed at understanding when GDM risk emerges, how risk can be modified, and how intrauterine exposure to hyperglycemia and its treatment influences health across the life course. This work spans population-based epidemiology, preconception biomarker studies, efficacy prevention trials, and pragmatic interventions embedded within an integrated health care system. Together, these findings affirm Norbert Freinkel's concept of fuel-mediated teratogenesis and underscore the need for precision prevention and treatment strategies that address biological, behavioral, and social determinants of health risk factors.
RATIONALE: Late preterm infants (34 0/7 to 36 6/7 weeks' gestation, i.e. 34 weeks and 0 days to 36 weeks and 6 days) are at increased risk of intermittent hypoxemia and respiratory insufficiency due to physiological immaturity, compared to full-term infants. Methylxanthines, most frequently caffeine, are used to improve respiratory function and long-term outcomes in very preterm infants. However, the use of methylxanthines in late preterm infants for preventing or treating intermittent hypoxemia and respiratory insufficiency needs to be assessed, also to avoid the risk of over-treatment.
OBJECTIVES: To assess the benefits and harms of methylxanthines in preventing or treating intermittent hypoxemia or respiratory insufficiency in late preterm infants.
SEARCH METHODS: Searches were conducted up to December 2025 in MEDLINE, CENTRAL, Embase, Epistemonikos, and two clinical trial registries. We also screened the reference lists of relevant reviews and included studies.
ELIGIBILITY CRITERIA: We included randomized controlled trials enrolling late preterm infants, comparing any methylxanthine (aminophylline, theophylline, or caffeine) with placebo or no methylxanthine. Studies with a cross-over design were excluded.
OUTCOMES: Critical outcomes were the number of intermittent hypoxemia episodes and apnea after 24 hours and over one week from starting treatment, and major neurodevelopmental disability. Important outcomes included respiratory support, duration of hospital stay, all-cause mortality prior to discharge, and adverse effects leading to treatment discontinuation.
RISK OF BIAS: We assessed risk of bias using the Cochrane RoB 2 tool.
SYNTHESIS METHODS: We used a fixed-effect model to calculate risk ratios (RRs) with 95% confidence intervals (CIs) for the outcomes: respiratory support, all-cause mortality before discharge, and adverse effects leading to treatment discontinuation. For intermittent hypoxemia and duration of hospital stay, we calculated ratios of geometric means. We assessed the certainty of the evidence using GRADE methods. Study authors were contacted for additional data when required.
INCLUDED STUDIES: We included one randomized controlled trial involving 132 late preterm infants in New Zealand. Infants were assigned to receive either caffeine or placebo for the prevention of intermittent hypoxemia. Reported outcomes included episodes of intermittent hypoxemia, respiratory support, duration of hospital stay, all-cause mortality, and adverse effects leading to treatment discontinuation. No eligible studies assessed methylxanthines for the treatment of intermittent hypoxemia, apnea, or respiratory insufficiency. We identified five ongoing trials: the largest is expected to enroll 478 late preterm infants and to be completed in 2026.
SYNTHESIS OF RESULTS: The included study did not report the critical outcome of the number of episodes of intermittent hypoxemia after 24 hours from starting treatment (i.e. from day two through the end of the first week). Methylxanthines may reduce the number of episodes of intermittent hypoxemia over one week from starting treatment compared to placebo or no treatment (ln [ratio of geometric means] -0.58, 95% CI -1.14 to -0.02; I² not applicable; 1 study, 132 participants; low-certainty evidence). The evidence is very uncertain about the effect of methylxanthines on respiratory support after 24 hours from starting treatment (RD 0.00, 95% CI -0.05 to 0.05; I² not applicable; 1 study, 132 participants; very low-certainty evidence); on duration of hospital stay (ln [ratio of geometric means] 0.23, 95% CI -0.01 to 0.47; I² not applicable; 1 study, 132 participants; very low-certainty evidence); and on any adverse effects leading to treatment discontinuation at the end of study compared to placebo or no treatment (RR 2.57, 95% CI 0.65 to 10.22; I² not applicable; 1 study, 132 participants; very low-certainty evidence). Methylxanthines may result in little to no difference in all-cause mortality prior to hospital discharge compared to placebo or no treatment (RD 0.00, 95% CI -0.05 to 0.05; I² not applicable; 1 study, 132 participants; low-certainty evidence). No studies reported on apnea or major neurodevelopmental disability. The certainty of the evidence is limited by the inclusion of only one study, with all outcomes downgraded for serious or very serious imprecision. For most outcomes, we also downgraded the certainty of the evidence due to some concerns about the risk of bias. These findings should be considered preliminary and are likely to change with future research.
AUTHORS' CONCLUSIONS: Overall, methylxanthine therapy in late preterm infants may reduce the number of intermittent hypoxemia episodes over one week from starting treatment, but likely results in little to no difference in all-cause mortality prior to hospital discharge. The effects of methylxanthines on other important outcomes, such as respiratory support, duration of hospital stay and adverse effects, remain highly uncertain due to limited and low-certainty evidence. A few outcomes were not reported, and no studies addressed the treatment of established intermittent hypoxemia or respiratory insufficiency. Current evidence is limited, and further high-quality trials are needed to clarify the efficacy and safety of methylxanthines in late preterm infants. The identified ongoing trials are planning to recruit over 900 infants, with the largest (n = 478) expected to be completed in 2026.
FUNDING: This Cochrane review was supported by Cochrane Sweden, Region Skåne and Skåne University Hospital, Lund University, and Vermont Oxford Network. No dedicated funding was received.
REGISTRATION: Protocol (2024) DOI: 10.1002/14651858.CD016113.
OBJECTIVE: Waist circumference-based measures can improve diabetes risk assessment beyond BMI. Yet, evidence to guide their integration into screening guidelines in low- and middle-income countries (LMICs) is limited, particularly to assess risk among individuals at intermediate BMI ranges. We evaluated the associations of waist circumference (WC), relative fat mass (RFM), and BMI with diabetes across 82 LMICs.
RESEARCH DESIGN AND METHODS: Individual-level data were analyzed from nationally representative surveys across 82 LMICs, comprising 598,883 adults aged ≥25 years with a BMI of 18.5-29.9 kg/m2. Associations of anthropometric measures with diabetes were estimated as risk ratios using Poisson regression and area under the curve (AUC), stratified by sex and geographic region.
RESULTS: Pooled diabetes prevalence was 9.1% (95% CI 8.51-9.68). Overall, risk of diabetes was greatest for WC and RFM at the highest quintile, compared with BMI. The AUC for WC and RFM as a classifier of diabetes status was higher than the AUC for BMI in men (AUC: WC 0.69, RFM 0.69, BMI 0.64) and women (AUC: WC 0.69, RFM 0.69, BMI 0.63). Generally, the AUC for RFM was higher than the AUC for BMI and either higher than or equal to WC across regions and sex.
CONCLUSIONS: WC and RFM outperformed BMI as classifiers of diabetes status among adults with a BMI of 18.5-29.9 kg/m2 across 82 LMICs. Inclusion of WC-based measures in diabetes screening guidelines could improve timely diabetes detection and resource allocation in LMICs among individuals at intermediate BMI ranges.
IMPORTANCE: Despite existing prevention strategies, infections remain a major cause of morbidity and mortality in children in Africa with sickle cell anemia.
OBJECTIVE: To determine the safety and effectiveness of daily zinc supplementation to prevent all-cause infection in children with sickle cell anemia in Uganda.
DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled trial of children aged 1.00 to 4.99 years with sickle cell anemia at Jinja Regional Referral Hospital in Jinja, Uganda, from February 10, 2025, to April 30, 2025, with 6 months of follow-up through November 7, 2025.
INTERVENTIONS: Participants received zinc sulfate at 20 mg daily or placebo daily for 6 months.
MAIN OUTCOMES AND MEASURES: The primary outcome was all-cause infections per 100 person-years, using standardized clinical criteria to define infections.
RESULTS: Among 118 children screened for eligibility, 100 were randomly assigned to receive zinc supplementation (n = 50) or placebo (n = 50) (mean [SD] age, 36.0 [13.2] months; 45 female [45%]). At enrollment, 45 participants (45%) were receiving hydroxyurea therapy. All participants initiated or continued receiving hydroxyurea after enrollment. During the 6-month follow-up, there was complete ascertainment for all participants and no loss to follow-up. There were 80 all-cause infections in the zinc group and 124 in the placebo group, corresponding to a significantly lower infection rate in the zinc group than the placebo group (305.7 [95% CI, 242.4-380.4] infections per 100 person-years vs 480.7 [95% CI, 399.8-573.1] infections per 100 person-years; rate difference, -176.0 [95% CI, -300.8 to -51.3]; incidence rate ratio after adjustment for baseline age, sex, and hydroxyurea use, 0.62 [95% CI, 0.45-0.86]). No adverse events requiring discontinuation of the study intervention were observed in either group.
CONCLUSIONS AND RELEVANCE: Zinc supplementation at 20 mg per day reduced all-cause infection in children with sickle cell anemia younger than 5 years in Uganda. Multisite clinical trials are needed to validate these findings and to assess effectiveness in older children.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06561061.
Bacteria and bacteriophages are in a constant arms race to develop defence and anti-defence systems, respectively. Currently known phage-encoded anti-defence systems are specific to the activity of the targeted bacterial defence system. Here we identify a mechanism by which the T7 bacteriophage broadly counteracts bacterial defences using protein phosphorylation. Its kinase (T7K), which has been reported to redirect the function of a few host proteins, is actually a hyperpromiscuous dual-specificity kinase that phosphorylates nearly all host and phage proteins during infection. The scale of phosphorylation vastly exceeds known phosphosites in Escherichia coli, has no sequence motif specificity and results in a higher proteome-wide phosphorylation density than mammalian cells with around 500 kinases. Stoichiometry analysis of phosphorylation sites revealed strong bias in T7K activity towards nucleic-acid-binding substrates mediated by its C-terminal DNA-binding domain. This highly stoichiometric phosphorylation enables the deactivation of DNA-targeting or DNA-containing bacterial defence systems. We provide mechanistic insights into how T7K weakens DNA-containing Retron-Eco9 through specific phosphorylation events, with single phosphomimetic mutations in key sites of the toxin abolishing defence. Moreover, by screening a large collection of E. coli strains, we provide evidence of broad anti-defence abilities of T7K in nature, as counteracted strains contain diverse bacterial defence systems. T7K homologues are found almost exclusively in phages, with hyperpromiscuous kinase activity probably being enabled by a divergent DFG-like motif in the catalytic centre.
Prior large-scale multicountry studies of traumatic brain injury (TBI) have either focused on surgically managed patients across development settings or characterized the full case-mix in predominantly high-income regions, leaving operative and nonoperative TBI across the human development spectrum incompletely defined. We present the Global Neurosurgical Study-1, integrating operative and nonoperative TBI across all Human Development Index (HDI) tiers. This prospective cohort included 2,165 patients from 100 hospitals in 29 countries between 2019 and 2022. Disparities were noted: median age ranged from 32 years (high-HDI) to 63 years (very-high-HDI); traffic injuries were the predominant cause of TBI in low-HDI (65.8%) versus falls in very-high-HDI (66%); and 69.3% of patients in the low-HDI tier arrived via private vehicles versus 13% for the very-high-HDI tier. Using mixed-effects logistic regression with inverse probability weighting, the adjusted mortality odds were highest in high-HDI tier (odds ratio 3.13, 95% confidence intervals 1.12-8.78) relative to the very-high-HDI, with no statistically significant elevation in low- or medium-HDI tiers. No dose-response relationship was noted between mortality and HDI. Inequities in injury mechanisms, patient demographics and prehospital access were drivers of outcome disparities. These findings suggest that HDI-stratified prevention targeting injury mechanisms and prehospital care may reduce the global TBI burden more effectively than hospital-based measures alone.
The United States declared measles eliminated in 2000. In 2025-2026, more than 3,500 cases have placed that status under formal review. Vaccine hesitancy, accelerated by COVID-19 disruption and misinformation, has eroded the immunological buffers sustaining elimination. Current surveillance compounds this threat: county-level vaccination aggregates structurally obscure the fine-scale susceptibility clustering where outbreaks originate. We assembled a nationwide multiscale vaccination database spanning 45 US states and Washington, DC (2013-2025), encompassing over 50,000 schools, 13,000 districts and 3,000 counties, and developed a transmission model to quantify epidemic risk across different spatial scales. School-level effective reproduction numbers crossed the epidemic threshold in 2022-2023, a transition invisible to aggregated surveillance. Average susceptibility doubled from approximately 5% to 10% following the pandemic. We also show that county boundary misalignment creates cross-boundary corridors that push well-vaccinated counties above threshold through spillover from less-vaccinated populations. State trajectories diverge markedly, shaped by exemption policies and vaccination infrastructure. The spatial architecture of US measles vulnerability has fundamentally shifted: transmission potential is supercritical in schools but invisible at the scale monitored by surveillance. Preventing measles re-endemicity requires surveillance and interventions operating at school and district levels, where imported cases can be intercepted before igniting sustained transmission.
The International Diabetes Federation estimated that in 2024, 215 million adults-more than one-third of the global diabetes population-were living with diabetes within the Western Pacific Region (WPR), which includes nations with some of the highest prevalence worldwide. Rapid urbanization and economic development have profoundly reshaped lifestyles, which interact with biological predispositions resulting in an earlier onset of type 2 diabetes. These predispositions are not uniform across the heterogeneous populations within the WPR. Asian individuals tend to have a β-cell secretory failure phenotype with type 2 diabetes arising at lower adiposity, distinct from the high-adiposity phenotype with pronounced insulin resistance common among Pacific peoples. Improvements in diabetes care in high-income countries have reduced vascular complications and improved survival, shifting the clinical profile of individuals with type 2 diabetes toward an older population characterized by multimorbidity. In contrast, low-income settings continue to face a high prevalence of type 2 diabetes, compounded by limited access to medications and diagnostic tools, shortage of trained health care professionals, and other logistical barriers to care. In this diverse region where countries are at different stages of health care development, there are considerable opportunities for sharing of best practices through collaborative and translational research. These may include social and public health policies, health care delivery, use of registers to track disease patterns and care standards, and use of technologies to support self-management. For implementation of these actions, a major shift is required, toward prevention, capacity building, and demonstrating the impact of value-based prevention and data-driven care.
Atrial fibrillation (AF) is increasing in incidence, prevalence, and lifetime risk, and contributes to substantially greater health care costs and increased risks of stroke, heart failure, and mortality. Improving adherence to evidence-based recommendations equitably in AF is critical to advancing clinical care, patient outcomes, and public health. The writing committee developed a comprehensive set of 5 performance measures, which are appropriate for public reporting or pay-for-performance programs, and 16 quality measures, which are useful to clinicians and health care organizations for quality improvement. The writing committee selected the measures from the strongest recommendations (Class 1 or 3) in the "2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation." The purpose of the writing committee's performance measures is meant to ensure that patients with newly diagnosed AF receive a basic clinical evaluation, with an emphasis on secondary prevention for patients at all stages of AF, documenting stroke risk, and, if indicated, providing appropriate anticoagulation. AF quality measures cover a variety of topics including measuring and addressing health inequities, optimizing antiarrhythmic or anticoagulant treatment, engaging in shared decision-making for rate- versus rhythm-control strategies, and, in appropriate patients, offering catheter ablation for those with heart failure with reduced ejection fraction. The performance and quality measures are intended to advance the quality and equity of AF care across all patient populations with AF.
Menstrual patterns can indicate overall health and reflect changes in endocrine, metabolic, or other systemic functions. Primary amenorrhea, defined as the lifelong absence of menses, warrants evaluation by age 15 years or 3 years postthelarche. Secondary amenorrhea is defined as the cessation of previously regular menses for 3 months or irregular menses for 6 months. Evaluation begins with a focused medical history, including prior menstrual patterns; eating and exercise habits; psychosocial stressors; medication use; chronic illness; and neurologic, vasomotor, or hyperandrogenic symptoms. Physical examination should assess anthropometric trends and pubertal development. Routine laboratory testing includes pregnancy testing and serum estradiol, follicle-stimulating hormone, luteinizing hormone, prolactin, and thyroid-stimulating hormone (thyrotropin) levels. Additional testing, including karyotyping, serum androgen evaluation, and pelvic or brain imaging, is individualized. Functional hypothalamic amenorrhea may indicate treatment for underlying disordered eating or low bone density. Patients with premature ovarian insufficiency benefit from hormone therapy until the average age of natural menopause. Addressing lifetime metabolic disease and endometrial cancer risk is necessary for patients with polyendocrine metabolic ovarian syndrome (formerly polycystic ovary syndrome).
Atypical moles are melanocytic lesions that clinically present with asymmetry, border irregularity, color variegation, or diameter 6 mm or greater. They are more common in patients with fair skin and high cumulative sun exposure. High mole density (more than 100) and presence of atypical moles are associated with increased risk of melanoma and should prompt periodic, systematic skin examinations. The US Preventive Services Task Force recommends patient or parent counseling for individuals with fair skin who are 6 months to 24 years of age on sun protection to reduce skin cancer risk and selective counseling for adults older than 24 years with fair skin and certain risk factors. To distinguish benign moles from melanoma, clinicians should use the ugly duckling assessment and ABCDE (asymmetry, border irregularity, color unevenness, diameter 6 mm or greater, evolution) mnemonic during clinical examination, incorporating dermoscopy if appropriately trained. Biopsy is sometimes necessary to exclude melanoma. Excisional biopsy should include 1- to 3-mm circumferential margins and sufficient depth. Postbiopsy management is guided by the degree of histopathologic atypia determined by the dermatopathologist, margin involvement, and patient risk factors.
OBJECTIVE: To estimate Bell's palsy incidence and evaluate the prevalence and associations with diabetes and other cardiometabolic conditions.
STUDY DESIGN: Population-based cohort study.
SETTING: Clalit Health Services, the largest healthcare provider organization in Israel (2005-2022).
METHODS: Bell's palsy cases were identified by ICD-10 code G51.0 (n = 11,255). To optimize specificity, individuals with secondary facial palsy codes or competing acute etiologies within ±30 days were excluded. Members without Bell's palsy served as controls. Annual incidence per 100,000 person-years. Multivariable logistic regression adjusted for age, gender, socioeconomic status, and ethnicity; Bonferroni correction applied. Age-stratified and ≥40-year sensitivity analyses were performed. Systemic corticosteroid dispensing was evaluated in peri-index and extended capture windows.
RESULTS: Among 5,489,298 members, 11,255 were diagnosed with Bell's palsy (median age, 51 years); about one-third occurred at ages 50 to 69 years. Incidence was ~18 per 100,000 person-years. Diabetes was more prevalent among cases than controls (21% vs 6%; standardized mean difference [SMD] = 0.45) and independently associated with Bell's palsy (adjusted odds ratio [aOR], 1.63), persisting across age groups and in the ≥40-year sensitivity analysis. Diabetic retinopathy and nephropathy were also associated (aOR 1.97 and 1.41). Stroke, smoking and obesity were also independently associated with Bell's palsy. Hypertension was more prevalent among cases but was not independently associated after Bonferroni correction and age-restricted analyses.
CONCLUSION: Bell's palsy incidence remained stable throughout the 18-year study period and was associated with diabetes and diabetes-related complications. While current guidelines do not recommend routine HbA1c testing in patients with Bell's palsy, our findings support considering targeted diabetes screening and assessment of glycemic status and diabetes-related complications.
Childhood obesity shows large differences in body composition and health risk that are not well captured by BMI or simple metabolic classifications, prompting the need for more precise characterization. This study aimed to determine whether a data-driven framework integrating detailed body composition measures could better describe obesity-related phenotypic heterogeneity and its relationship with cardiometabolic risk in children. We delineated a continuous body composition manifold encompassing fat-dominant, lean-dominant, and concomitant high-mass phenotypes, which captured diverging cardiometabolic risk trajectories and yielded modest incremental improvements in risk prediction. These findings support more precise risk stratification and provide a practical tool to improve early identification and prevention of obesity-related health complications in children.
Climate change continues to accelerate, driving more frequent and severe weather events, particularly extreme heat. These environmental changes have broad adverse health effects, including increased all-cause mortality, cardiovascular and respiratory disease, mental health effects, and burden of vector-borne diseases. Air pollution from fossil fuel combustion, which is a major contributor to climate change, remains one of the leading global risk factors for death. Health burdens surrounding climate change fall disproportionately on vulnerable populations, including children, outdoor workers, people experiencing housing insecurity, and low-income communities. Physicians increasingly encounter and manage adverse effects from climate change in clinical care. During preventive care visits, physicians can counsel patients on environmental health risks, plant-forward diets, active transportation, and protection from heat and air pollution. In acute and disaster-related encounters, clinicians can assist patients in creating individualized action plans for disaster and heat preparedness and manage medical conditions exacerbated by climate change. Other strategies such as incorporating telehealth, practicing high-value care, and using sustainable prescribing can improve access, efficiency, and clinical outcomes while reducing pollution and emissions from health care systems. Physicians can advocate for policies that promote public health and support a more resilient and sustainable health care system.
Eye pain is a common presentation in outpatient, urgent care, and emergency settings. Causes range from benign to vision-threatening. Family physicians should promptly identify red-flag features that require urgent or emergent ophthalmology referral. A painful eye with vision loss, severe photophobia, proptosis, hyphema, or corneal ulceration is a medical emergency. Patient history should include onset, associated vision changes, contact lens use, trauma, chemical exposure, systemic symptoms, and rheumatologic disease. Physical examination should include evaluation of visual acuity (eg, using a Snellen or Rosenbaum chart), pupillary reactions, and extraocular movements. The eyes should be inspected for redness, discharge, and corneal lesions with fluorescein, if available. Findings of significant photophobia, anisocoria, dendritic corneal lesions, or restricted eye movement should prompt immediate referral. Common emergent causes of eye pain include acute angle-closure glaucoma, orbital cellulitis, infectious keratitis, scleritis, and anterior uveitis. An algorithmic approach that distinguishes urgent vs nonurgent etiologies and ophthalmic vs nonophthalmic causes of eye pain can direct next steps.
Knee pain is common, with more than 30% to 45% of middle-aged and older adults having symptomatic osteoarthritis, and 25% to 40% of younger adults having patellofemoral pain syndrome. Components of a detailed history include time of onset; pain duration, quality, and localization; trauma/mechanism of injury; swelling; popping/clicking; aggravating and alleviating factors; sports activities; and limitations to current activity. The physical examination for evaluating knee pain involves five overall components: inspecting the joint for obvious abnormalities, palpating the joint to identify effusion or points of tenderness that may be the source of the pain; testing active and passive range of motion; testing strength; and performing specialized maneuvers that evaluate specific knee joint structures. These maneuvers are most accurate when performed in combination, rather than relying on one specific maneuver to make the diagnosis. In addition to these five examination components, imaging should be obtained if appropriate, with plain radiography typically being the first step. With traumatic injuries, clinical decision rules such as the Ottawa Knee Rule can determine if radiography is needed to detect fractures or other injuries that may require referral. Additional evaluations can include arthrocentesis when joint effusion is present, optimally guided by point-of-care ultrasonography when available, and laboratory testing if infection or inflammatory disorders are suspected.
OBJECTIVE: Meniere's disease is a complex chronic inner ear condition that is characterized by vertigo, tinnitus, aural fullness, and progressive hearing loss. Currently, diagnostic strategies remain symptom-driven, and treatments focus on management of discrete episodes rather than targeting underlying pathophysiology. This review sets out to evaluate the diagnostic and therapeutic utility of molecular biomarkers derived from blood and endolymphatic fluid in MD.
DATA SOURCES: A comprehensive literature search was conducted using OVID Medline, Ovid EMBASE, EBSCO CINAHL, Web of Science Core Collection, ProQuest Dissertations, and the Cochrane Library, utilizing controlled vocabulary (MeSH/Emtree terms) and related keywords.
REVIEW METHODS: Following PRISMA guidelines, 2 independent reviewers performed the study screening, data extraction, and bias assessment of the isolated studies.
RESULTS: The 21 studies consisted of case-control (71.4%), randomized trials or reviews (14.4%), cohort (9.5%), and case series (4.8%). Isolated biomarkers were classified as structural (24%), regulatory (24%), immunologic/oxidative stress (38%), and miscellaneous (14%). Structural proteins, such as otolin-1, otoconin-90, demonstrated potential in distinguishing MD from other vestibular disorders. Regulatory biomarkers (aquaporin-2, vasopressin-related peptides) were linked to fluid abnormalities. Inflammatory cytokines (TNF-α, IL-6, and IL-1β) and oxidative stress markers (4-HNE) highlighted disease heterogeneity. Additional findings such as unique vitamin D, estradiol, and altered metabolomic profiles suggested hormonal and metabolic changes.
CONCLUSION: Molecular biomarkers offer critical insights into MD pathogenesis as well as potential diagnostic and therapeutic advancements. However, methodological variability and lack of replication necessitate standardized validation before formal clinical application.
The NCCN Guidelines for Survivorship offer guidance for health care providers who care for survivors of adult-onset cancer. These guidelines include screening, evaluation, and treatment recommendations for common physical and psychosocial problems resulting from cancer and its treatment and provide a framework for care coordination. They also present guidance for helping cancer survivors to enhance their wellness and maintain a healthy lifestyle. This article summarizes the panel's current recommendations and recent updates regarding anxiety, depression, distress, and trauma in cancer survivors.
The researchers are doing this study to see if people with unexplained weight loss who have lung cancer screening are more likely to have or develop lung cancer than people without unexplained weight loss. The lung cancer screening will involve use of low-dose computed tomography (LDCT), a CT scan that gives off very low doses of radiation and can make detailed pictures of the lungs to help find tumors. The study researchers will also analyze participants' blood samples to determine if blood testing can be used to help to diagnose lung cancer.
The primary objective of this study is to evaluate the effect of 24-weeks of once daily treatment with TPIP compared with placebo on exercise capacity in adults with PAH.
This clinical trial is being done to better understand how daily treatment with Tetrahydrocannabinol (THC), Cannabidiol (CBD), or the combination of CBD plus THC affects knee osteoarthritis pain and other related symptoms.
Consented participants will have a screening period and visit (up to 30 days to treatment start). If participants pass the screening phase, they will be randomly assigned to take one of the investigational study drugs. For this study, participants will not know when or if they are taking CBD, THC, THC plus CBD, and when or if taking placebo.
Clinical pain will be assessed at multiple times throughout the study, and eligibility will be re-assessed at two weeks into the treatment period. It is possible that subjects will not be able to participate in the study after 14 days of of treatment. The treatment period will take approximately 16 weeks and then a follow-up period for approximately 2 weeks. In addition to treatment, participants will have clinical assessments, blood draws, questionnaires, daily pain diaries, sensory testing, as well as have functional connectivity magnetic resonance imaging (fcMRI).
Prostate biopsy is the definitive examination to establish the diagnosis of prostate cancer, but up to 40% of these biopsies overestimate or underestimate the severity of the disease. A novel biopsy needle system captures substantially more tissue than standard of care needles, but it is important to assess the retrieval of tissue for pathologic analyses. This study will compare quality and quantity of tissue retrieved by both systems. Further, tissue will be analyzed using computational pathology algorithms for atypical small acinar proliferation and Gleason scores in terms of tissue area, tissue length, and tissue tortuosity.
The specific aims of the clinical studies are to:
* Develop a directional high-resolution OCT and OCT angiography prototype to improve imaging of structure and perfusion.
* Validate wide-field OCT and OCT angiography parameters to improve early glaucoma detection.
* Simulate visual field results by combining structural and angiography OCT data.
* Assess abilities of above technologies and OCT-derived parameters on predicting glaucoma detection, conversion, and progression.
Preeclampsia is a hypertensive pregnancy disorder that can quickly lead to serious, potentially life-threatening outcomes for both the mother and the fetus. Typical features of preeclampsia are by endothelial and microvascular dysfunctionsNotably, such impairments in endothelial function may precede preeclampsia diagnosis and canpersist for years postpartum. In clinical practice, however, no predictive methods have yet been established that specifically reflect endothelial dysfunction in the context of preeclampsia.
Hyperspectral imaging represents a new and non-invasive imaging modality that allows contact-free visualization of peripheral microcirculatory dynamics and tissue perfusion. Despite its growing use in other medical fields, this technology has not yet been systematically studied to determine its predictive potential in preeclampsia.
The HIPPA project (Systematic Evaluation of Hyperspectral Analysis for Prediction of Preeclampsia) is a prospective observational study to evaluate the applicability of hyperspectral imaging as a new tool for prediction of preeclampsia.
Background:
CGD is caused by a gene mutation. For people with CGD, their cells cannot kill germs well, so they can get frequent or life-threatening infections. Researchers want to see if a new procedure can help a person s cells kill germs for a short time. It uses messenger RNA (mRNA) to deliver correct instructions for the gene mutation to the cells.
Objective:
To test a procedure in which mRNA is added to a person s blood cells.
Eligibility:
Males aged 18-75 with CGD with a mutation in the gene that makes the protein gp91phox.
Design:
Participants will be screened with:
Medical history
Physical exam
Blood and urine tests
Swab to test for strep throat
Some screening tests will be repeated during the study.
Participants will be admitted to the NIH Clinical Center hospital for at least 7 days. They will have apheresis. For this, a medicine is injected under their skin to prepare their white blood cells for collection. An IV line is placed into an arm vein. Blood goes through the IV line into a machine that divides whole blood into red blood cells, plasma, and white blood cells. The white blood cells are removed, and the rest of the blood is returned to the participant through an IV line in their other arm. The next day, they will get their mRNA-corrected cells via IV. They will be monitored for 3 more days.
After discharge, participants will keep a symptom diary. They will be contacted weekly for one month, and then once a month. They will have a follow-up visit 3 months after the infusion....
This study is a randomized, double-blind, placebo-controlled, multiple-dose, dose-escalation phase I clinical trial aiming to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of MWN105 injection in Chinese non-diabetic overweight or obese participants.
The study plans to enroll 36 male and female participants. Three dose groups were preset, with 12 participants in each. They were randomly assigned to receive MWN105 injection or placebo at a ratio of 5:1 and were administered the treatment in a titration manner, once a week, with a dose increase every two weeks until reaching the target dose. The administration lasted for 8 weeks.
The study consists of a 2-week screening period, an 8-week administration/observation period, and a 4-week follow-up period, totaling 14 weeks. The primary endpoint is the incidence of adverse events. Secondary endpoints include pharmacokinetics, pharmacodynamics, and immunogenicity.
This is a single-center, randomized, double-blind, placebo-controlled, single ascending-dose phase 1 clinical study, aimed at evaluating the safety, tolerability, PK, PD and immunogenicity of single subcutaneous administration of MWX401 Injection in healthy Chinese participants and participants with primary mild hypertension.
The study comprises five dose cohorts with a planned enrollment of 46 subjects. The primary endpoint is the incidence and severity of treatment-emergent adverse events. Secondary endpoints include plasma and urinary PK parameters, changes in serum AGT and RAAS components, changes in blood pressure and hemodynamics, and immunogenicity indicators.
Sulfonylurea medications are unsafe for older patients with diabetes. They are associated not only with hypoglycemia, but also with falls and increased cardiovascular risk. Yet they continue to be prescribed frequently. Indeed, older adults with type 2 diabetes, who are especially prone to adverse effects, are more likely to be prescribed sulfonylureas than younger patients. This is unfortunate since over the past several years, newer, safer, and more effective classes of medications (GLP-1 agonists and SGLT2-inhibitors) have emerged. The investigators acknowledge that sulfonylureas are inexpensive and that their low cost is a driver of continued use. However, the investigators believe patients and providers should have discussions about the risks of sulfonylureas and safer and more effective alternatives, to make diabetes care safer overall in ambulatory settings. Our research is designed to promote such discussions. The investigators will first identify patients taking sulfonylureas regularly. Next, using recommendations from AHRQ and the Canadian Deprescribing Network, the investigators will empower patients to discuss their medications with their providers through a simple question prompt sheet. Patients will be divided into an intervention group which receives explicit prompting questions, and a control group that receives a general brochure on diabetes medications. Health care providers will receive education about newer diabetes medications through case-based discussions and academic detailing. Finally the investigators will measure key outcomes including the proportion of patients who have discussions about sulfonylureas and alternatives, rates of discontinuation, and measures of control of diabetes and associated cardiovascular risks. The investigators will also evaluate the experiences of patients and providers qualitatively through brief, semi-structured interviews. Should our multi-faceted, patient-oriented intervention prove effective in promoting discussions of sulfonylureas and alternatives, and also discontinuation of sulfonylureas and switching to newer alternatives, the investigators will incorporate our prompting questions into routine care for patients taking sulfonylureas. Our intervention can be easily disseminated to other settings and therefore has considerable potential to improve safety among patients with type 2 diabetes nationwide.
Background:
Obstructive sleep apnea (OSA) is a sleep disorder characterized by recurrent collapse of the upper airway during sleep, resulting in intermittent hypoxia and fragmented sleep. The condition is more prevalent among individuals with hypertension, atrial fibrillation, type 2 diabetes, and other chronic diseases compared with the general population. Evidence indicates that untreated OSA is associated with adverse health outcomes, whereas treatment of OSA provides significant clinical benefits. However, a substantial proportion of individuals with OSA remain undiagnosed, highlighting the need to improve detection and reduce underdiagnosis.
Devices currently used to diagnose OSA are not suitable for screening; however, newer alternatives may be appropriate.
The study:
This study is a pilot feasibility study. All participants will undergo an interview and examination at a baseline visit and will subsequently use OSA testing devices at home for three consecutive nights. The study includes a questionnaire assessing participants' experience with the devices and technology in general. The objective of this study is to test the feasibility of conducting a study in which adult participants with type 2 diabetes undergo three different home sleep apnea tests over three nights, including issues to be optimized in a subsequent main/definitive study.
The main study aims to assess the diagnostic agreement between the devices and will be registered independently.
Colorectal cancer (CRC), the third most diagnosed cancer and second most common cause of cancer death. CRCs develop from precursors like adenomas (about 70% of CRCs) or serrated lesions (SSLs) (about 25-30% of CRCs). Colonoscopy is the cornerstone in CRC screening, in screening programmes often as a work-up examination after a positive primary screening test such as faecal immunochemical test (FIT). Norway and Sweden have recently launched a nationwide faecal haemoglobin CRC screening programmes. Recently, both a Dutch and an Austrian study showed that SSL detection rate (SSLDR) is inversely correlated to CRC at follow-up. Consequently, improved SSLDR can reduce the risk of post-colonoscopy CRC. SSLs are typically located in the right colon. They are flat, with indistinctive boarders, and consequently easily missed or incompletely resected. A Norwegian study showed incomplete resection of 40% of proximal SSLs. The prevalence of SSLs is higher in women than in men, with women being on a threefold risk of developing CRC from SSLs. It seems like post-colonoscopy CRC more often is caused by SSLs than by adenomas. Total underwater colonoscopy (TUC) is a technique replacing conventional CO2 insufflation by water infusion to distend the lumen and visualise the mucosa during withdrawal of the colonoscope and simultaneously removal of water. There are several reasons to advocate TUC:
1. SSLs will be more visible as they "float" on the submucosa and contract into the lumen, while full distension by gas stretches the mucosa, making detection of flat lesions more difficult.
2. Water works like a magnifying lens, making detection and detailed characterisation of lesions easier.
3. uEMR is eased.
4. Improved bowel cleansing
The goal of this clinical trial is to compare colonoscopy outcomes for standard gas (CO2) insufflation and TUC during withdrawal in patients participating in colonoscopy in the Norwegian and Swedish colorectal cancer screening programme after a positive fecal immunochemical test.
The overarching research questions of the present trial is whether colonoscopy outcomes are improved when CO2 insufflation is replaced by TUC during withdrawal and whether the new technique reduces the ecological footprint of the colonoscopy examination.
The project has five main hypotheses:
1. TUC is superior to the standard approach (CO2 withdrawal) regarding detection of proximal SSLs.
2. TUC increases the rate of complete resection of lesions \>= 10mm.
3. TUC reduces the rate of painful colonoscopies and vasovagal reactions.
4. TUC reduces the health care costs by reduced use of single use accessories and reduced number of redundant colonoscopies to obtain polypfree colon.
5. TUC reduces the carbon footprint by reduced use of single use accessories.
If TUC is superior to gas insufflation, the technique may be implemented rapidly since the technique is easy to learn. This study will increase endoscopy competence at participating centres. The centres are involved in national colonoscopy training programs, so the technique will quickly be passed on to other hospitals and screening centres.
The trial can be linked to three of the Global Goals:
* Good health and well-being: The increased detection and improved complete removal of sessile serrated lesions can subsequently decrease the risk of CRC and CRC mortality during follow-up. TUC will probably reduce the rate of painful procedures and vasovagal reactions and thus increase the acceptance of a screening programme. Consequently, the project can contribute significantly to improve screening effectiveness in Norway and Sweden, particularly in women (women have a higher risk for SSLs and a higher risk of colorectal cancer developing from this type of precursor).
* Gender equality: Women have a similar lifetime risk for CRC as men but less benefit of screening regardless of whether they are screened by sigmoidoscopy, FIT or colonoscopy. The reason is probably missed sessile serrated lesions in the proximal colon. If TUC improves SSLDR and complete lesion resection, this may lead to an equal benefit from CRC screening for women and men. Women have also a higher risk of discomfort and pain during colonoscopy than men. It has been shown that women prefer non-invasive screening modalities, potentially to avoid pain during colonoscopy, even if colonoscopy may be the most beneficial screening method for women. If TUC reduces the rate of painful colonoscopies, it can reduce women's barriers to attend screening.
* Responsible consumption and production: The TUC technique will also reduce the ecological footprint of colonoscopy activity due to reduced consumption of single use accessories and reduced number of colonoscopies to achieve polyp free colon. Furthermore, the cost for the health care system will be substantially reduced.
Colorectal Neoplasia · Screening Colonoscopy · Colorectal Cancer · Colorectal Cancer Screening
