Summary Background Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021. Methods The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk–outcome pairs. Pairs were included on the basis of data-driven determination of a risk–outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk–outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk–outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws. Findings Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7–9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4–9·2]), smoking (5·7% [4·7–6·8]), low birthweight and short gestation (5·6% [4·8–6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8–6·0]). For younger demographics (ie, those aged 0–4 years and 5–14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9–27·7]) and environmental and occupational risks (decrease of 22·0% [15·5–28·8]), coupled with a 49·4% (42·3–56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9–21·7] for high BMI and 7·9% [3·3–12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6–1·9) for high BMI and 1·3% (1·1–1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4–78·8) for child growth failure and 66·3% (60·2–72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP). Interpretation Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions. Funding Bill & Melinda Gates Foundation.

Background Non-publication, incomplete publication and excessively slow publication of clinical trial outcomes contribute to research waste and can harm patients. While research waste in German academic trials is well documented, research waste in Germany related to a specific disease area across non-commercial and commercial sponsors has not previously been assessed. Methods In this cohort study, we used public records from three clinical trial registries to identify 70 completed or terminated clinical trials involving women with metastatic breast cancer with trial sites in Germany. We then searched registries and the literature for trial outcomes and contacted sponsors about unreported studies. Results We found that 66/70 trials (94.3%) had made their results public. Only 13/70 (18.6%) trials had reported results within one year of completion as recommended by the World Health Organisation (WHO). The outcomes of 4/70 trials (5.7%) had not been made public at all, but only one of those trials had recruited a significant number of patients. Conclusions Discussions about research waste in clinical trials commonly focus on weakly designed or unreported trials. We believe that late reporting of results is another important form of research waste. In addition, a discussion regarding the appropriate ethical and legal rules for reporting the results of terminated trials might add value. German legislation now requires sponsors to upload the results of some clinical trials onto a trial registry within one year of trial completion, but these laws only cover around half of all trials. Our findings highlight the potential benefits of extending the scope of national legislation to cover all interventional clinical trials involving German patients.

An increasing number of countries are investigating options to stop the spread of the emerging zoonotic infection Salmonella (S.) Dublin, which mainly spreads among bovines and with cattle manure. Detailed surveillance and cattle movement data from an 11-year period in Denmark provided an opportunity to gain new knowledge for mitigation options through a combined social network and simulation modeling approach. The analysis revealed similar network trends for non-infected and infected cattle farms despite stringent cattle movement restrictions imposed on infected farms in the national control program. The strongest predictive factor for farms becoming infected was their cattle movement activities in the previous month, with twice the effect of local transmission. The simulation model indicated an endemic S. Dublin occurrence, with peaks in outbreak probabilities and sizes around observed cattle movement activities. Therefore, pre- and post-movement measures within a 1-mo time-window may help reduce S. Dublin spread.

The need for a systematic approach in developing new metal-based drugs with dual anticancer-antimicrobial properties is emphasized by the vulnerability of cancer patients to bacterial infections. In this context, a novel organometallic assembly was designed, featuring ruthenium(II) coordination with p-cymene, one chlorido ligand, and a bidentate neutral Schiff base derived from 4-methoxybenzaldehyde and N,N-dimethylethylenediamine. The compound was extensively characterized in both solid-state and solution, employing single crystal X-ray diffraction, nuclear magnetic resonance, infrared, ultraviolet-visible spectroscopy, and density functional theory, alongside Hirshfeld surface analysis. The hydrolysis kinetic was thoroughly investigated, revealing the important role of the chloro-aqua equilibrium in the dynamics of binding with deoxyribonucleic acid and bovine serum albumin. Notably, the aqua species exhibited a pronounced affinity for deoxyribonucleic acid, engaging through electrostatic and hydrogen bonding interactions, while the chloro species demonstrated groove-binding properties. Interaction with albumin revealed distinct binding mechanisms. The aqua species displayed covalent binding, contrasting with the ligand-like van der Waals interactions and hydrogen bonding observed with the chloro specie. Molecular docking studies highlighted site-specific interactions with biomolecular targets. Remarkably, the compound exhibited wide spectrum moderate antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans, coupled with low micromolar cytotoxic activity against human colorectal adenocarcinoma cells and significant activity against human leukemic monocyte lymphoma cells. The presented findings encourage further development of this compound, promising avenues for its evolution into a versatile therapeutic agent targeting both infectious diseases and cancer.

Prediction of short-term mortality in patients with acute decompensation of liver cirrhosis could be improved. We aimed to develop and validate two machine learning (ML) models for predicting 28-day and 90-day mortality in patients hospitalized with acute decompensated liver cirrhosis. We trained two artificial neural network (ANN)-based ML models using a training sample of 165 out of 290 (56.9%) patients, and then tested their predictive performance against Model of End-stage Liver Disease-Sodium (MELD-Na) and MELD 3.0 scores using a different validation sample of 125 out of 290 (43.1%) patients. The area under the ROC curve (AUC) for predicting 28-day mortality for the ML model was 0.811 (95%CI: 0.714- 0.907; p < 0.001), while the AUC for the MELD-Na score was 0.577 (95%CI: 0.435–0.720; p = 0.226) and for MELD 3.0 was 0.600 (95%CI: 0.462–0.739; p = 0.117). The area under the ROC curve (AUC) for predicting 90-day mortality for the ML model was 0.839 (95%CI: 0.776- 0.884; p < 0.001), while the AUC for the MELD-Na score was 0.682 (95%CI: 0.575–0.790; p = 0.002) and for MELD 3.0 was 0.703 (95%CI: 0.590–0.816; p < 0.001). Our study demonstrates that ML-based models for predicting short-term mortality in patients with acute decompensation of liver cirrhosis perform significantly better than MELD-Na and MELD 3.0 scores in a validation cohort.

Dermacentor (D.) reticulatus ticks carry and transmit a wide range of pathogens to vertebrate hosts. Limited information is available about the existence of emerging tick-borne pathogens and the distribution of D. reticulatus in Bosnia and Herzegovina. The study aimed to investigate the occurrence and distribution of D. reticulatus and to detect the presence of Anaplasma spp., Borrelia (B.) burgdorferi s.l., Rickettsia spp., and Babesia spp. in samples originating from questing ticks and ticks collected from domestic animals in various regions of Bosnia and Herzegovina. A total of 402 collected D. reticulatus ticks were widely distributed throughout the country. Of the 41 pools consisting of 205 individual D. reticulatus ticks, 21 (51.2%) indicated the presence of Rickettsia spp., 17 (41.4%) of Babesia spp., 2 (4.8%) of Anaplasma spp., and 1 (2.4%) of B. burgdorferi s.l. after real-time PCR screening. Our study indicates that D. reticulatus has significantly expanded its distribution and host range in Bosnia and Herzegovina. Moreover, our results represent the first detection of Babesia spp. in D. reticulatus in Bosnia and Herzegovina. Given the demonstrated presence of emerging pathogens in questing and feeding ticks, there is an urge to establish a surveillance system for ticks and tick-borne pathogens in Bosnia and Herzegovina.

ABSTRACT Context: Since beginning of the coronavirus disease (COVID-19) it became clear that severe forms of this infection have primarily affected patients with chronic conditions. Aims: The aim of the study was to explore clinical and epidemiological characteristics associated with COVID 19 outcomes. Settings and Design: The retrospective observational study included 40,692 citizens of Banja Luka County, Bosnia and Herzegovina, who were confirmed as reverse transcriptase polymerase chain reaction (RT-PCR) positive on COVID-19 at a primary healthcare centre from March 2020 to September 2022. Methods and Materials: Epidemiological data were obtained from Web-Medic medical records of patients. The COVID-19 data were obtained from COVID-19 data sheets comprised of patients’ RT-PCR testing forms, surveillance forms for severe acute respiratory syndrome coronavirus-2 status, and a map of their positive and isolated contacts. Statistical Analysis Used: Differences regarding the distributions of patients between groups were analysed using the Pearson chi-square test and Mantel-Haenszel chi-square test for trends, while differences in mean values were compared using an independent sample t-test. Results: The average age of hospitalised patients was significantly higher compared to the age of non-hospitalised patients (P < 0.001). The average age of patients with lethal outcomes was nearly twice as high in comparison to patients with non-lethal outcomes (P < 0.001). Male patients had a higher hospitalization and mortality rate (P < 0.001). The highest hospitalization rate was in patients with chronic renal failure (CRF), diabetes and cardiovascular diseases (CVDs), while the death rate was the highest among patients with CRF and hearth comorbidities. Patients with fatigue and appetite loss had a higher percentage of lethal outcomes. Vaccinated patients had a significantly lower rate of lethal outcome. Conclusions: Clinical symptoms, signs and outcomes, are posing as predictive parameters for further management of COVID-19. Vaccination has an important role in the clinical outcomes of COVID-19.

Introduction Technical advances and the increasing role of interdisciplinary decision-making may warrant formal definitions of expertise in surgical neuro-oncology. Research question The EANS Neuro-oncology Section felt that a survey detailing the European neurosurgical perspective on the concept of expertise in surgical neuro-oncology might be helpful. Material and methods The EANS Neuro-oncology Section panel developed an online survey asking questions regarding criteria for expertise in neuro-oncological surgery and sent it to all individual EANS members. Results Our questionnaire was completed by 251 respondents (consultants: 80.1%) from 42 countries. 67.7% would accept a lifetime caseload of >200 cases and 86.7% an annual caseload of >50 as evidence of neuro-oncological surgical expertise. A majority felt that surgeons who do not treat children (56.2%), do not have experience with spinal fusion (78.1%) or peripheral nerve tumors (71.7%) may still be considered experts. Majorities believed that expertise requires the use of skull-base approaches (85.8%), intraoperative monitoring (83.4%), awake craniotomies (77.3%), and neuro-endoscopy (75.5%) as well as continuing education of at least 1/year (100.0%), a research background (80.0%) and teaching activities (78.7%), and formal interdisciplinary collaborations (e.g., tumor board: 93.0%). Academic vs. non-academic affiliation, career position, years of neurosurgical experience, country of practice, and primary clinical interest had a minor influence on the respondents’ opinions. Discussion and conclusion Opinions among neurosurgeons regarding the characteristics and features of expertise in neuro-oncology vary surprisingly little. Large majorities favoring certain thresholds and qualitative criteria suggest a consensus definition might be possible.