搜索结果：European journal of clinical investigation

Whether meat consumption increases the risk of gastric cancer (GC) and esophageal cancer or not remains unclear. Moreover, the number of prospective studies evaluating the associations by anatomical and histological types of GC is limited. We aimed to assess the associations of red, processed, and white meat with all gastric adenocarcinomas by anatomical site and histological type, and with esophageal adenocarcinoma (EAC), using data from the European Prospective Investigation into Cancer and Nutrition study of 450,112 individuals (131,426 men/318,686 women). Over 14.1 years of follow-up, 876 GC and 215 EAC cases were identified. Among the GC cases, 233 were located in cardia and 329 in non-cardia regions. Histologically, 624 were classified as intestinal type and 208 as diffuse type. The associations between meat intake and risk of GC or EAC were assessed using multivariable Cox models. A 30 g/day increase in processed meat consumption was associated with a 9% (95% CI: 2-17) increase in GC risk and a 13% (95% CI: 0-27) increase in EAC risk. Additionally, a 20 g/day increase in white meat intake was associated with a 12% (95% CI: 2-24) increase in non-cardia GC risk. Processed meat was also associated with intestinal GC (11%, 95% CI: 2-20) and higher consumption with diffuse GC. Only processed meat was associated with GC among men while processed and white meat were both positively associated with GC among women. In conclusion, processed meat may increase the risk of GC and EAC, although further research is needed to clarify the effects of white meat consumption.

The incidence of early-onset cancers (EOCs), defined as cancers diagnosed before 50 years of age, has risen globally over the past three decades. The association between modifiable lifestyle factors and EOC risk has been poorly investigated. Participants enrolled before age 50 in EPIC (39,459 men; 110,991 women) and the UK Biobank (52,188 men; 62,528 women) were analysed. We examined the association between smoking, alcohol consumption, body mass index (BMI), physical activity and diet, and risk of lifestyle-related EOCs - including cancer of the breast, lung, colorectum, stomach, liver, cervix, oesophagus, bladder, and others. Each risk factor was scored from 0 (most unfavourable) to 4 (most favourable). Cohort-specific hazard ratios (HR) with 95% confidence intervals (CI) were estimated in Cox regression models and pooled via a meta-analytic approach. We observed 361 lifestyle-related EOCs in men and 2618 in women, including 1765 breast cancers. In men, one-point increase in the smoking score, indicating less smoking, was inversely associated with risk of lifestyle-related EOC (HR 0.82, 95% CI: 0.76-0.88). In women, each one-point increase in smoking (less smoking), BMI (lower BMI), and physical activity (more active) scores was inversely associated with risk of lifestyle-related EOC excluding breast cancer (HRs: 0.89 [0.84-0.93], 0.93 [0.89-0.98], 0.95 [0.90-1.00], respectively). For breast cancer, only physical activity showed a statistically significant association (HR 0.95 [0.91-0.995]). Alcohol and diet showed no association. These findings support the importance of adopting a healthy lifestyle early in life to reduce cancer risk before the age of 50.

Over the past decade, North American and European health care systems have opted for policies based on the tenets of value-based health care (VBHC), aiming to improve health outcomes, reduce care-related expenditure, and provide care sustainably. As well as promoting healthy competition between health care providers, VBHC aims to drive collaboration between players, including those in primary and secondary care and public and private providers. Long-standing trends toward increased outsourcing of publicly owned facilities to private organizations have generated heated debate, especially in Europe, regarding potential conflicts between ensuring quality of care and implementing cost-reduction strategies to increase economic benefits. In this context, outsourcing to private networks with a strong commitment to VBHC may be a successful strategy for improving health outcomes and lowering costs while overcoming potential drawbacks voiced by opponents of outsourcing. The Regional Health Care System of Madrid (RHSM), Spain, stands out as a best practice model in European health care, providing universal coverage to around 7 million inhabitants (14% of the nation's population) through a robust network of primary care centers and hospitals, of which several are outsourced to private providers. The RHSM is characterized by a centralized database and transparent reporting system to monitor quality metrics across hospitals and other health care structures, as well as a free-choice mandate, which empowers inhabitants to seek care at the center of their choice at zero out-of-pocket cost, thus overcoming social inequalities in access to care. The authors analyzed publicly available data from 25 public hospitals in the RHSM from 2015 to 2023, comparing quality of care, efficiency, and patient experience metrics from four hospitals outsourced to the value-based Quir&#xf3;nsalud Health Care Network and 22 publicly managed hospitals. Their results provide longitudinal evidence that value-based outsourcing is associated with lower standardized inpatient mortality rates, reduced medical and surgical inpatient complications (3.22% vs. 3.75%; P<0.001), lower average lengths of hospital stays (4.93 days vs. 5.83 days; P<0.001; 95% confidence interval [CI], -0.89 to 0.90), and higher patient experience survey scores (93.1 vs. 88.6; P<0.001; 95% CI, 3.75 to 4.93) than the results from other nonoutsourced hospitals. Significantly more patients were transferred to outsourced hospitals than to nonoutsourced hospitals, with more than half of the patients coming from areas with worse socioeconomic status. The authors' findings suggest that, in the context of a regional health care system providing excellent universal coverage to residents at zero out-of-pocket cost, along with free choice of health provider, value-based outsourcing is associated with increased quality of care, efficiency, and patient satisfaction, as well as helping to reduce inequalities in access to care in areas with lower socioeconomic status. Outsourcing to value-based networks may catalyze system transformation toward VBHC, while fostering healthy, patient-centered competition between private providers.

Multiple retractions from the same author often uncover issues affecting their entire work, such as having systematically altered or fabricated data. To evaluate the contribution of authors with the most retractions (ie, superretractors) and top-cited scientists with multiple retractions to the retracted randomized clinical trial (RCT) literature. This retrospective cohort study linked an openly available cohort of retracted RCTs (VITALITY) to 3 lists of scientists: (1) superretractors, totaling most retractions in the Retraction Watch Leaderboard; (2) scientists in the top 100&#x202f;000 or 2% of their subfield in terms of citations (ie, top-cited scientists) over their entire careers who accumulated 10 or more retractions not due to editor or publisher errors; and (3) top-cited scientists in the most recent year (ie, 2024) who accumulated 10 or more retractions not due to editor or publisher errors. The VITALITY cohort was updated up to November 2024. The 3 author lists were updated in August 2025. The main outcomes were authorship and the characteristics of retracted RCTs (publication and retraction year, time between publication and retraction, number of citations). A total of 30 superretractors, 163 career-long top-cited scientists with 10 or more retractions, and 174 recent-year top-cited scientists with 10 or more retractions were included; 1330 retracted RCTs were included. Overall, 6 superretractors (20%), representing anesthesiology as well as endocrinology and metabolism, coauthored 290 retracted RCTs (22%); 18 career-long top-cited scientists with at least 10 retractions, representing 10 fields, coauthored 327 trials (25%), 275 (84%) of which were also coauthored by a superretractor; 7 single-year top-cited scientists with at least 10 retractions coauthored 50 retracted RCTs (4%), all of which were also included in the list of articles authored by career-long top-cited scientists with at least 10 retractions. Articles with superretractor authors vs not were published earlier (median [IQR], 2000 [1997-2005] vs 2020 [2014-2022]); retracted earlier (median [IQR], 2013 [2012-2019] vs 2023 [2018.5-2023]); had a longer lag between publication and retraction (median [IQR], 5111 [3560-6820] days vs 482 [330-1119] days); and accrued more citations (median [IQR], 21 [12-42] vs 5 [1-19]). In multivariable regression models, only time to retraction (&#x3b2;&#x2009;=&#x2009;0.02; P&#x2009;<&#x2009;.001) was significantly and positively associated with total citations. Results were similar when comparing retracted articles from top-cited scientists with at least 10 retractions vs other articles. In this cohort study of 1330 retracted RCTs, a small number of influential authors, often coauthors and concentrated across few fields of medicine, accounted for a significant proportion of retracted clinical trials.

Computer-aided detection (CAD) systems can enhance adenoma detection, but their effectiveness in high-performance settings and among patients with positive fecal immunochemical test (FIT) results remains uncertain. To evaluate the impact of CAD on adenoma detection in routine practice, focusing on patients with positive FIT results. This multicenter, open-label, randomized clinical trial was conducted at 4 tertiary hospitals in Taiwan from February 23, 2022, to November 27, 2024. Adults aged 40 to 79 years who were scheduled for a colonoscopy owing to FIT positivity, symptoms, screening, or surveillance were randomized 1:1 to CAD-assisted or standard colonoscopy. Data were analyzed from December 1, 2024, to February 28, 2025. Colonoscopy performed with a real-time CAD system or standard high-definition colonoscopy. The primary outcome was adenoma detection rate (ADR), defined as the proportion of patients with at least 1 histologically confirmed adenoma. Secondary outcomes included adenomas per colonoscopy (APC), sessile serrated lesion detection rate (SSLDR), and postpolypectomy surveillance intervals according to the US Multi-Society Task Force (USMSTF) and European Society of Gastrointestinal Endoscopy criteria. Of 1356 randomized participants (mean [SD] age, 60.0 [9.4] years; 678 [50.0%] female and 678 [50.0%] male), CAD-assisted colonoscopy met noninferiority criteria for ADR compared with standard colonoscopy (395 of 675 [58.5%] vs 363 of 681 [53.3%]; absolute difference, 5.2 percentage points [95% CI, -0.1 to 10.5 percentage points]). Superiority was not statistically significant. CAD significantly increased mean (SD) APC (1.41 [1.95] vs 1.20 [1.88]; P&#x2009;=&#x2009;.01), driven mainly by detection of diminutive adenomas. In exploratory analyses of 864 patients with FIT-positive findings, CAD significantly increased ADR (288 of 441 [65.3%] vs 243 of 423 [57.4%]; P&#x2009;=&#x2009;.02; adjusted odds ratio [AOR],&#x2009;1.39 [95% CI, 1.05-1.86]) and APC (mean [SD], 1.64 [2.08] vs 1.39 [2.09]; P&#x2009;=&#x2009;.01). SSLDR did not differ between groups. Consequently, CAD led to more intensive surveillance recommendations under USMSTF criteria, particularly in patients with FIT-positive findings (58 of 441 [13.2%] vs 31 of 423 [7.3%]; AOR,&#x2009;1.94 [95% CI, 1.22-3.09]). In this randomized clinical trial, CAD-assisted colonoscopy met noninferiority criteria for adenoma detection. Superiority was not statistically significant overall, with significant improvements limited to the exploratory FIT-positive subgroup, driven largely by diminutive adenomas. CAD also increased intensive surveillance assignments. The incremental benefit of CAD in reducing interval cancer risk requires further investigation. ClinicalTrials.gov Identifier: NCT03842059.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, is one of the most prevalent liver diseases globally, contributing to both economic and health-related challenges. We aimed to evaluate the global, regional, and national burden of MASLD from 1990 to 2023, quantify the contribution of identified modifiable risk factors, and project future prevalence up to the year 2050. Estimates of MASLD prevalence and disability-adjusted life-years (DALYs) were produced by age, sex, region, Socio-demographic Index (SDI), and Healthcare Access and Quality (HAQ) index across 204 countries and territories from 1990 to 2023 as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023. The MASLD burden attributable to three risk factors (smoking, high BMI, and high fasting plasma glucose) was assessed as part of the GBD comparative risk assessment. As a secondary analysis, we used these estimates to forecast MASLD prevalence up to 2050 using fasting plasma glucose and mean BMI as predictors. Furthermore, to examine the relative contributions of population ageing, population growth, and changes in MASLD prevalence rate to the forecasted changes in case counts from 2023 to 2050, we conducted a decomposition analysis. In 2023, approximately 1&#xb7;3 billion (95% uncertainty interval [UI] 1&#xb7;2 to 1&#xb7;4) individuals were estimated to be living with MASLD (ie, 16&#xb7;1% of the global population), with an age-standardised prevalence rate of 14&#x2009;429&#xb7;3 (95% UI 13&#x2009;268&#xb7;3 to 15&#x2009;990&#xb7;6) per 100&#x2009;000 population, representing a percentage increase of 142&#xb7;7% (95% UI 139&#xb7;2 to 146&#xb7;7) in crude numbers from 1990 (0&#xb7;5 billion [0&#xb7;5 to 0&#xb7;6]) and of 28&#xb7;6% (27&#xb7;8 to 29&#xb7;5) in the rate (11&#x2009;217&#xb7;2 [10&#x2009;276&#xb7;8 to 12&#x2009;467&#xb7;0] per 100&#x2009;000 in 1990). An estimated 3&#xb7;6 million (2&#xb7;8 to 4&#xb7;5) total DALYs were attributable to MASLD worldwide in 2023, corresponding to an age-standardised DALY rate of 39&#xb7;6 (31&#xb7;2 to 49&#xb7;9) per 100&#x2009;000 population. Despite a 116&#xb7;3% (93&#xb7;3 to 139&#xb7;4) increase in crude DALYs (from 1&#xb7;7 million [1&#xb7;3 to 2&#xb7;1] in 1990), its age-standardised estimate remained consistent (1&#xb7;8% [-8&#xb7;6 to 12&#xb7;8]) from 1990 (38&#xb7;9 [30&#xb7;1 to 49&#xb7;8] per 100&#x2009;000) to 2023. There was substantial variation in age-standardised estimates across regions. North Africa and the Middle East had the highest prevalence rate (29&#x2009;246&#xb7;1 [26&#x2009;848&#xb7;3 to 32&#x2009;048&#xb7;7] per 100&#x2009;000) and Andean Latin America showed the highest DALY rate (152&#xb7;3 [114&#xb7;1 to 194&#xb7;7] per 100&#x2009;000). By contrast, the high-income Asia Pacific region had the lowest prevalence rate (8653&#xb7;5 [7923&#xb7;7 to 9592&#xb7;8] per 100&#x2009;000) and east Asia had the lowest DALY rate (16&#xb7;3 [13&#xb7;5 to 19&#xb7;9] per 100&#x2009;000) among all GBD regions. North Africa and the Middle East showed disproportionately higher prevalence rates relative to other regions with similar SDIs. Lower SDIs and HAQs were associated with higher age-standardised DALY rates. The age-standardised prevalence rate was consistently higher in males (15&#x2009;616&#xb7;4 [14&#x2009;349&#xb7;2 to 17&#x2009;263&#xb7;3] per 100&#x2009;000 people in 2023) than in females (13&#x2009;245&#xb7;2 [12&#x2009;132&#xb7;0 to 14&#x2009;692&#xb7;6] per 100&#x2009;000 people), and peaked at age 80-84 years in both sexes. The number of MASLD prevalent cases was the highest in younger adults, peaking at age 35-39 years for males and age 55-59 years for females. Among the risk factors for MASLD, high fasting plasma glucose presented the largest contribution to the age-standardised DALY rate of total MASLD in 2023 (2&#xb7;2 [95% UI 1&#xb7;6 to 3&#xb7;1] per 100&#x2009;000 people), followed by high BMI (1&#xb7;4 [0&#xb7;6 to 2&#xb7;4] per 100&#x2009;000 people) and smoking (1&#xb7;0 [0&#xb7;3 to 1&#xb7;8] per 100&#x2009;000 people). Our forecasting model estimates that 1&#xb7;8 billion (95% UI 1&#xb7;6 to 2&#xb7;0) individuals are likely to have MASLD by 2050, representing a 42&#xb7;0% increase from 2023. The age-standardised prevalence rate is expected to increase to 15&#x2009;774&#xb7;9 (95% UI 14&#x2009;613&#xb7;9 to 17&#x2009;336&#xb7;2) per 100&#x2009;000 people in 2050, representing an average annual percentage change of 0&#xb7;3% (95% UI 0&#xb7;3-0&#xb7;3). According to our decomposition analysis, this change will be primarily due to population growth, particularly in sub-Saharan Africa and North Africa and Middle East, and less by population ageing or epidemiological change. With a global prevalence of 16&#xb7;1% and approximately 1&#xb7;3 billion people already living with MASLD in 2023, the condition has and will continue to have substantial health and economic impacts worldwide. An inverse association between the HAQ Index and age-standardised DALY rates suggests that countries with lower health-care access and quality might be less well positioned to manage the growing MASLD burden, underscoring the need for strengthened health-system capacity in these settings. Gates Foundation.

Esophageal adenocarcinoma (EAC) represents one of the most increasing malignancies in Western countries. The disease is multifactorial, involving modifiable risk factors and genetic susceptibility variants. These variants can be aggregated to a polygenic risk score (PRS) that reflects individual genetic risk. Investigation of the effects of lifestyle factors, PRS, and co-medication on EAC age at onset (AAO) is critical for shaping prevention strategies. A detailed questionnaire was used to assess pre-diagnostic exposure to lifestyle factors and clinical information from a large German EAC cohort. Linear regression analysis was performed to identify factors associated with EAC AAO in 1742 EAC patients. PRS was available for 1190 patients. Subgroup analyses were conducted to estimate the effects of the analyzed factors on AAO according to age group (early vs. late onset), sex, and prior diagnosis of Barrett's esophagus (BE). Earlier AAO was significantly associated with gastroesophageal reflux (GER), smoking and a higher PRS, whereas later AAO was associated with physical activity and higher consumption of fish and fruits. Among co-medication, combined use of proton pump inhibitors (PPIs) and acetylsalicylic acid (ASA) showed the most significant effect on AAO, whereas the use of PPIs and ASA alone showed weaker effects. This study represents the largest questionnaire-based analysis to date investigating factors influencing EAC development. Our findings show that the combined use of PPIs and ASA, both cost-effective medications, is associated with delayed EAC onset. In addition, lifestyle and genetics contribute to EAC AAO.

Narcolepsy types 1 and 2 (NT1/NT2) and idiopathic hypersomnia (IH) are central disorders of hypersomnolence (CDHs) that significantly impact patients' quality of life (QoL). We investigated the recent medication use, comorbidities, and clinical burden among participants with CDHs from six European countries. In this cross-sectional observational study, self-reported data were collected from adults with CDHs using a three-part survey. Assessed endpoints included the Epworth Sleepiness Scale (ESS), Narcolepsy Severity Scale for Clinical Trials (NSS-CT), IH Severity Scale (IHSS), and EuroQoL-5 dimension-5 level (EQ-5D-5L). EQ-5D health state utilities were evaluated by ESS category to measure the impact of symptom severity. Of 2797 surveys, 1818 (65%) were completed (NT1, 51.1%; NT2, 11.2%; IH, 19.9%; undefined CDH, 17.8%). Most participants reported receiving narcolepsy/IH medication in the past 30 days (NT1, 91.3%/NT2, 84.5%/IH, 79.4%). The most common comorbidities were back pain (NT1, 27.4%/NT2, 25.5%/IH, 30.4%), headache/migraine (22.4%/27.2%/34.7%), and depression (22.5%/24.5%/29.5%). For NT1/NT2/IH, mean (interquartile range) ESS total scores were 15.5 (12-19)/14.4 (11-18)/13.6 (10-17), NSS-CT scores (excluding cataplexy items) were 17.4 (11-23)/14.6 (9-20)/12.1 (7-17), IHSS scores were 27.0 (20-34)/27.5 (22-35)/32.4 (27-38), and EQ-5D VAS scores were 62.4 (50-78)/63.6 (50-79)/61.0 (48-79). Mean (SD) health state utilities decreased from 0.914 (0.152) in the lowest ESS category to 0.726 (0.259) in the highest (severe) ESS total score category. These findings underscore the ongoing clinical burden in individuals with CDHs, including those receiving treatment. Symptom persistence and QoL impacts highlight the limitations of current treatments and the need for more comprehensive management strategies for CDHs.

To investigate whether coronary CT angiography (CCTA) misses calcified plaques detected by thin-slice non-contrast CT (NCCT). This study included patients from two sites in the DISCHARGE trial for whom both 0.5&#x2009;mm thin-slice NCCT and CCTA were available. Plaques on CCTA were defined as missed if they showed no spatial overlap with NCCT-detected plaques after deep learning-aided co-registration. Comparisons of plaque volume, density, and local coronary luminal attenuation between plaques missed and those detected by CCTA were performed using the Mann-Whitney U-test. In addition, the presence of these plaques on standard calcium scoring CT was assessed. Interobserver agreement was assessed using the intraclass correlation coefficient and Bland&#x2012;Altman analysis. This study included 45 patients (40% female, mean age 62&#x2009;&#xb1;&#x2009;11 years), in whom CCTA missed 37.6% of calcified plaques detected by NCCT (121/322). Missing calcified plaques on CCTA misclassified 8.9% of patients (4/45) as having no plaques. Compared with detected plaques, plaques missed by CCTA were both significantly smaller in volume (3.0&#x2009;mm&#xb3; [IQR, 1.5-4.9] vs. 9.2&#x2009;mm&#xb3; [IQR, 4.3-21.9], p&#x2009;<&#x2009;0.001) and had lower density (212.7 HU [IQR, 174.5-242.4] vs. 292.7 HU [IQR, 243.2-361.3], p&#x2009;<&#x2009;0.001). Only 44.0% of plaques (53/121) missed by CCTA were detected by standard calcium scoring CT. Interobserver analysis demonstrated excellent agreement for calcified plaque volume on CCTA (ICC&#x2009;=&#x2009;0.91) and NCCT (ICC&#x2009;=&#x2009;0.98). CCTA missed more than one-third of coronary calcified plaques that are identifiable on co-registered thin-slice NCCT, which suggests an underutilized role of thin-slice NCCT in clinical practice. Question Accurate detection of all coronary plaques is crucial for risk stratification. CCTA misses calcified plaques, which are detectable by thin-slice non-contrast CT (NCCT). Findings CCTA misses over one-third of calcified plaques, nearly half of which are also missed by calcium scoring CT. NCCT detected these calcified plaques. Clinical relevance Deep learning-aided registration enables multimodal CCTA-NCCT assessment, improving detection of calcified plaques overlooked by CCTA alone and providing more accurate plaque burden quantification that may support better clinical decision-making, which should be investigated in future studies.

Despite being a common reason for Emergency Department (ED) admission, information about the management of acute pericarditis is limited in this setting. In this retrospective study conducted at the ED of Ospedale di Circolo in Varese (Italy) from 2019 to 2023, patients with acute pericarditis were included. The primary endpoint was the occurrence of the 12-month composite outcome (treatment failure, recurrent pericarditis, cardiac tamponade, constrictive pericarditis or death). One-hundred and sixty-nine patients were included (median age 54&#x2009;years, 65.1% males). Chest pain was the main symptom (96.4%). On admission, aspirin was more frequently given over non-steroidal anti-inflammatory drugs (NSAIDs), and colchicine was prescribed in 40% of patients. At discharge, more patients were prescribed ibuprofen, and colchicine prescription significantly increased to 71%. Drug doses were compliant with guidelines in a limited number of patients at admission and increased at discharge. The composite outcome occurred in 20.1% of patients (n&#x2009;=&#x2009;34), mainly driven by recurrences (n&#x2009;=&#x2009;18) and treatment failure. Patients with a complicated course were older, of female sex, with a larger proportion of comorbidities and higher CRP levels. Diabetes (HR 3.9, 95% CI 1.7-9.1), COPD (HR 6.2, 95% CI 2.3-17.1), recent percutaneous cardiac procedures (HR 6.5, 95% CI 2.1-19.6), and recent SARS-CoV-2 vaccination (HR 3.0, 95% CI 1.1-8.2) were independent risk factors for the composite outcome. A significant proportion of patients with acute pericarditis experience long-term complications. Sub-optimal adherence to guideline-recommended doses of anti-inflammatory drugs was commonly observed, suggesting an area for improvement in the management of these patients.

Annonaceae fruits such as soursop (Annona muricata) may worsen symptoms of Parkinson's disease (PD) in tropical regions. Here, we investigate whether PD is more severe in an Annonaceae-exposed compared with a nonexposed population. Motor and cognitive symptoms of two PD groups (Caribbean, N = 74; mainland France, N = 104) were compared after imputation, propensity matching, and multivariate adjustment according to age, disease duration, education, and dopaminergic therapy. Ninety-six percent of Caribbean (71/74) but none of interviewed mainland France (0/20) PD patients had been exposed to Annonaceae fruits. Caribbean PD patients exhibited more severe motor and cognitive symptoms than mainland France PD patients (Unified&#x2009;PD&#x2009;Rating&#x2009;Scale - 3 = 24.39 [&#xb1;&#x2009;14.06] vs. 18.50 [&#xb1;&#x2009;11.13], p < 0.001; Mattis&#x2009;Dementia&#x2009;Rating&#x2009;Scale = 127.21 [&#xb1;14.30] vs. 130.80 [&#xb1;&#x2009;11.15], p = 0.005). Given the growing evidence supporting Annonaceae fruits toxicity, health policy makers should raise public awareness about the risks of such consumption. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03368300.

The g formula is a cornerstone method for estimating causal effects of time-varying treatments using longitudinal observational data in the presence of time-varying confounders that are affected by prior treatment. Standard regression techniques often fail in this setting because adjustment for such covariates can distort the very effects under study. The g-formula addresses this problem by expressing the mean potential outcome under specified static or dynamic treatment regimes as a function of the joint distribution of covariates, treatments and outcomes, which can be approximated via parametric or semi-parametric models and simulation. This review presents the g-formula, emphasizing intuitive explanations. After outlining the causal framework and the core identification assumptions-consistency, sequential exchangeability and positivity-the article describes practical parametric g-formula: model specification for covariate and outcome processes, implementation via forward simulation, and the interpretation of marginal causal contrasts between clinically relevant regimes. The g-formula is then situated within the family of g-methods alongside inverse probability weighting and targeted maximum likelihood estimation, highlighting complementary strengths and limitations. A dedicated section discusses concrete applications, including analyses of highly active antiretroviral therapy and AIDS or death, dynamic 'when to start' antiretroviral strategies in HIV and electronic health record-based evaluations of blood pressure treatment targets. Practical guidance on modelling choices, diagnostics and transparent reporting is provided to support applied researchers considering g-formula in clinical and epidemiological investigations.

Science is a self-correcting process, and scientific research aims to improve adequacy, accuracy, and utility. However, improving scientific research is a demanding task, especially when currently some key principles of science are challenged and renegotiated. Key challenges in the current environment include the increasing loss of trust in scientists; the production of most of the published scientific literature in countries without full democracy and/or in countries without fundamental freedoms, e.g., freedom of the press; limited public availability and transparency as most research is funded by non-public sponsors that do not prioritize or even seek publication of results; and rapid developments on the frontier of artificial intelligence where non-human agents can supplement and/or replace human researchers. Concurrently, there have been many proposals on how to improve research. Among a plethora of suggestions and guidance, some may not be useful or may even be harmful, and most lack evidence. Revisiting some key proposals shows mixed track records of failures and successes. Examples are provided from efforts to enhance collaboration, team science, and large studies; replication culture; registration and open science; containment of conflicts of interest; and statistical, computational, and informatics improvements. The optimal stages to improve research (early and/or late in the scientific process) may be debated, and the role, function, and mode of optimal peer review are also under scrutiny. Eventually, science and scientific research are demanding, hard enterprises. Genuine progress requires openness, honesty, and selflessness.

AimThe phase 4 RESOLUTION trial showed that, in comparison with placebo, adding eptinezumab-an anti-calcitonin gene-related peptide monoclonal antibody-to a brief educational intervention (BEI) reduced the monthly frequency of migraine, headache, and acute medication use in participants with chronic migraine (CM) and medication-overuse headache (MOH). Herein, we report data from multiple patient-reported outcomes (PROs) evaluating treatment impact on disease burden and health-related productivity and quality of life in the RESOLUTION trial.MethodsRESOLUTION was a multi-national (conducted at 76 sites across 11 countries), double-blind, randomized, placebo-controlled trial. The trial comprised a 4-week screening period; a 12-week, double-blind, placebo-controlled period; a 12-week, open-label, extension period; and an 8-week, safety follow-up period, with results of the placebo-controlled period presented in this paper. Adults diagnosed with CM and MOH received a BEI and were randomized 1:1 to intravenous infusion with either eptinezumab 100&#x2005;mg or placebo. Several PROs were assessed at baseline, Week 4, and Week 12, including the six-item Headache Impact Test (HIT-6), modified Migraine Disability Assessment (mMIDAS), Migraine-specific Work Productivity and Activity Impairment questionnaire (WPAI:M), Patient Global Impression of Change (PGIC; assessed only at follow-up), patient-identified most bothersome symptom (PI-MBS; assessed only at follow-up), Migraine-Specific Quality-of-Life questionnaire version 2.1 (MSQ v2.1), EQ-5D-5L visual analogue scale, and nine-item Treatment Satisfaction Questionnaire for Medication (TSQM-9; assessed only at follow-up). Post hoc analyses included responder rates for HIT-6 (i.e., participants with &#x2265;5-point reduction from baseline), as well as for PGIC and PI-MBS (i.e., participants who reported "much improved" or "very much improved").ResultsOf 608 participants randomized, the full-analysis set included 302 participants in the eptinezumab arm and 300 in the placebo arm. Eptinezumab with BEI was associated with more favorable PRO scores compared to placebo with BEI, starting at Week 4 (p&#x2009;<&#x2009;0.05 for all comparisons) and up to Week 12 (p&#x2009;<&#x2009;0.01 for all comparisons except WPAI:M absenteeism). Responder rates for HIT-6, PGIC, and PI-MBS also favored eptinezumab versus placebo.ConclusionsIn participants with CM and MOH who also received patient education, eptinezumab treatment resulted in greater reductions in headache impact and migraine disability than placebo, with greater improvements in productivity, quality of life, overall disease status, and treatment satisfaction starting from Week 4 and sustained to Week 12. Eptinezumab in combination with patient education is an effective treatment for reducing disease burden and improving overall quality of life in people with CM and MOH.Trial registrationClinicalTrials.gov Identifier: NCT05452239 (https://clinicaltrials.gov/study/NCT05452239); EudraCT Number: 2021-003049-40 (https://www.clinicaltrialsregister.eu/ctr-search/search?query=2021-003049-40).

Osteosarcopenia, the combination of osteoporosis and sarcopenia, is a geriatric syndrome linked to functional decline, falls, and fragility fractures. The interaction among bone, muscle, and their shared pathophysiology is driven by mechanical, metabolic, and hormonal factors. With global population aging and increasing healthcare demands, early detection of osteosarcopenia has become essential. This narrative review summarizes current evidence on the epidemiology, pathophysiology, clinical findings, diagnosis, and treatment of osteosarcopenia, based on international consensus guidelines, large-scale population cohorts, interventional studies, and translational research. The occurrence of osteosarcopenia reflects the combined impact of low bone mineral density (BMD), loss of muscle mass and strength, and age-related metabolic changes such as chronic inflammation, lipotoxicity, and disruptions in tryptophan (TRP) metabolism. Diagnostic evaluation requires combining bone assessment through Dual-energy X-ray Absorptiometry with functional and structural evaluations of sarcopenia, using criteria established by the European and global consensus on Sarcopenia. Management includes established pharmacological therapies for osteoporosis, while for sarcopenia, to date, it is mainly based on resistance exercise and adequate protein intake. Supplementation with protein, leucine, vitamin D, calcium, and creatine may further enhance outcomes. Promising emerging strategies include hormonal modulators, anti-inflammatory agents, metabolic pathway-oriented therapies, and cell-based interventions. Osteosarcopenia significantly raises the risk of falls, fractures, disability, and death. Effective management requires a comprehensive treatment approach that targets both bone and muscle decline. Further research is necessary to refine diagnostic criteria and assess the success of combined interventions through clinical trials.

Atrial fibrillation (AF) is the most common arrhythmia in the elderly, and is associated with an increased risk of cardiovascular events (CVE). Hypoalbuminemia is an independent predictor of all-cause and cardiovascular mortality in general population. The purpose of this work is to evaluate the possible predictive value of serum albumin (SA) on MACE occurrence, in a cohort of elderly patients with non-valvular AF and several comorbidities for long-term follow-up. 1057 elderly with non-valvular AF were enrolled (75.92&#x2009;&#xb1;&#x2009;6.1years; 295 on VKAs and 762 on DOACs) and stratified according to median value of SA, 532 patients with SA &#x2264;&#x2009;3.6&#x2009;g/dL and 525 patients with SA >&#x2009;3.6&#x2009;g/dL. MACE (non-fatal ischemic stroke, non-fatal myocardial infarction and cardiovascular death), and non-cardiovascular mortality occurrence were evaluated during a median follow-up of 5.5&#x2009;years (IQR 2.1-7.2). In the whole observational study, patients with SA &#x2264;&#x2009;3.6&#x2009;g/dL are associated with an increased risk of MACEs by 59%. In addition, 10-year ageing are associated with an increased risk of MACE; in contrast, a MNA score >&#x2009;24 pt and therapy with DOACs are associated with a reduced risk of MACE. Elderly patients with non-valvular AF with SA &#x2264;&#x2009;3.6&#x2009;g/dL show a higher risk of MACE and non-cardiovascular mortality.

Anaemia is a common comorbidity in patients with atrial fibrillation (AF) receiving oral anticoagulants (OACs). While its relationship with bleeding is well established, the prothrombotic role and ethnic variations remain unclear. We analysed two large prospective AF registries from Europe (EORP-AF) and East Asia (APHRS-AF). Patients were classified by anaemia status at enrolment. Logistic regression assessed clinical correlates and treatment patterns, while multivariable Cox models and propensity score matching (PSM) evaluated outcomes. Restricted cubic spline analyses explored the haemoglobin-risk relationship across ethnic groups. The primary outcome was a composite of all-cause death and major adverse cardiovascular events (MACE); secondary outcomes included individual components and major bleeding (MB). Among 10,857 patients with AF (mean age 69&#x2009;&#xb1;&#x2009;11&#x2009;years, 40.0% women), 3372 (31.0%) had anaemia, which clustered with multimorbidity and frailty. Anaemic patients were less likely to receive OACs (OR 0.67, 95% CI 0.58-0.78) and rhythm-control (OR 0.91, 95% CI 0.81-1.02). Anaemia was independently associated with higher risk of the composite outcome (HR 1.54, 95% CI 1.34-1.78), all-cause death (HR 1.81, 95% CI 1.51-2.15), MACE (HR 1.39, 95% CI 1.16-1.66), CV death (HR 1.90, 95% CI 1.43-2.54) and MB (HR 1.79, 95% CI 1.31-2.46) consistent also after PSM. Risk increased progressively with anaemia severity, particularly below 10&#x2009;g/dL. Associations were consistent across Asian and European cohorts. Anaemia identifies a vulnerable AF phenotype associated with excess mortality, adverse cardiovascular outcomes and increased bleeding risk, which remains frequently undertreated. Risk rises with anaemia severity, and although biological effects appear consistent across ethnicities, treatment disparities persist. Anaemia should refine, not restrict, therapy within integrated AF care.

BACKGROUND: Cisplatin chemoresistance is a critical challenge in treating head and neck squamous cell carcinoma (HNSCC). Previous research from Manyanga et al. (2021) suggested that e-cigarette (e-cig) aerosol, including formulations with and without nicotine, might increase cisplatin resistance in oral cancer cells. This multicenter replication study aimed to validate the findings and evaluate the oncologic impacts of e-cigarette use during chemotherapy. METHODS: This in vitro study utilized standardized and harmonized protocols across international laboratories to examine the effects of cigarette smoke (1R6F) and e-cig aerosols with different concentrations of nicotine (0, 12, and 20&#xa0;mg/ml nicotine) on cisplatin sensitivity in HNSCC cell lines (SCC-25, FaDu, and UM-SCC-1). Aqueous extracts from 1R6F smoke and e-cig vapor were collected using a smoking and a vaping machine, respectively, following ISO20778:2018 and ISO20768:2018 puffing regimes. The smoke and vapor were collected in PBS and diluted to 10 puffs/5L for HNSCC cell treatment. Chemosensitivity, clonogenicity, DNA repair gene expression related to cisplatin-induced damage, and gene/protein expression of cisplatin transporters, were assessed by MTS, NRU, trypan blue exclusion, qRT-PCR, and Western blot assays, respectively. RESULTS: Contrary to previous findings, exposure to e-cig aerosols did not significantly modulate cisplatin sensitivity in all cell lines. IC50 values, cytotoxicity assays, and clonogenic survival rates remained similar between cells treated with e-cig aerosols and those exposed to cisplatin alone. Analysis of gene and protein expression revealed occasional variations in the levels of cisplatin transporters and DNA repair mechanisms, but these changes were inconsistent. CONCLUSIONS: This study did not fully substantiate previous claims that aerosols generated from e-cigarette, with and without nicotine, increase cisplatin resistance. The variability in gene and protein expression among different cell lines underscores the need for cautious interpretation and further investigation of the role of e-cigarette components in cancer treatment. These findings provide a critical perspective for shaping public health policies and clinical practices regarding e-cigarette use during chemotherapy.

The same dataset can be analysed in different justifiable ways to answer the same research question, potentially challenging the robustness of empirical science1-3. In this crowd initiative, we investigated the degree to which research findings in the social and behavioural sciences are contingent on analysts' choices. We examined a stratified random sample of 100 studies published between 2009 and 2018, in which, for one claim per study, at least five reanalysts independently reanalysed the original data. The statistical appropriateness of the reanalyses was assessed in peer evaluations, and the robustness indicators were inspected along a range of research characteristics and study designs. We found that 34% of the independent reanalyses yielded the same result (within a tolerance region of &#xb1;0.05 Cohen's d) as the original report; with a four times broader tolerance region, this indicator increased to 57%. Of the reanalyses conducted, 74% reached the same conclusion as the original investigation, 24% yielded no effects or inconclusive results and 2% reported the opposite effect. This exploratory study indicates that the common single-path analyses in social and behavioural research should not be simply assumed to be robust to alternative analyses4. Therefore, we recommend the development and use of practices to explore and communicate this neglected source of uncertainty.