BACKGROUND Enteric infectious diseases claim more than 1 million lives annually and are among the top ten causes of death in children younger than 5 years. Remarkable global investment has been dedicated to enteric infectious disease prevention and control; however, the shifting global health landscape is testing the continuance of progress. To evaluate the current status and guide future interventions, we present the latest epidemiological estimates of enteric infectious diseases from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 and assess progress towards the Global Action Plan for the Prevention and Control of Pneumonia and Diarrhoea (GAPPD) mortality target of fewer than 20 deaths per 100 000 children younger than 5 years by 2025. METHODS We quantified the incidence, mortality, and disability-adjusted life-years (DALYs) of enteric infectious diseases by age, sex, and year across 204 countries and territories from 1990 to 2023. In GBD 2023, the following were considered under the category of enteric infectious diseases: diarrhoeal diseases, enteric fever (typhoid and paratyphoid), invasive non-typhoidal Salmonella spp (iNTS) infections, and other intestinal infectious diseases. We also examined 15 aetiologies contributing to diarrhoeal diseases. Incidence and prevalence were estimated with DisMod-MR (version 2.1), a Bayesian meta-regression tool, drawing on data from systematic reviews, population-based surveys, claims data, and hospital sources. Cause-specific mortality was modelled with Cause of Death Ensemble Modelling based on data from sources including vital registration, mortality surveillance, verbal autopsy, and minimally invasive tissue sampling. Years of life lost and years lived with disability were computed and combined to derive DALYs. For aetiology-specific estimation, population-attributable fractions (PAFs) for 15 pathogens were derived with a counterfactual framework. Point estimates and 95% uncertainty intervals (UIs) were generated from 250 draws from the posterior distribution. FINDINGS In 2023, enteric infectious diseases resulted in an estimated 1·27 million (95% UI 0·963-1·68) deaths globally, declining from 3·69 million (3·04-4·56) in 1990. The global age-standardised mortality rate (ASMR) decreased from 74·1 (62·0-92·9) per 100 000 population to 16·4 (12·6-21·3) per 100 000 population during the same period. Diarrhoeal diseases accounted for most deaths in 2023 (1·11 million [0·811-1·54]), followed by enteric fever and iNTS. South Asia and sub-Saharan Africa remained the most affected regions in 2023, with 599 000 (441 000-882 000) and 501 000 (373 000-648 000) deaths due to enteric infectious diseases, respectively, predominantly from diarrhoeal disease. Rotavirus was the leading cause of all-age diarrhoeal disease deaths (PAF 16·3% [12·0-21·5]), followed by norovirus (10·2% [2·4-17·0]) and Shigella spp (9·3% [5·4-15·2]). Among children younger than 5 years, PAFs of deaths due to diarrhoeal diseases were 40·2% (32·5-48·5) for rotavirus, 24·0% (15·1-36·7) for Shigella spp, and 23·4% (13·7-34·3) for adenovirus. Across 204 countries and territories, 141 met the GAPPD mortality target in 2023. The driving aetiologies among countries that did not meet the target in 2023 varied slightly by GBD super-region, but the highest or second-highest number of deaths in children younger than 5 years were consistently attributed to rotavirus. Astrovirus and sapovirus, newly included in GBD 2023, were responsible for 24 600 (6290-49 000) and 18 800 (4650-44 400) deaths, respectively, in 2023, mainly in children younger than 5 years. INTERPRETATION Our findings show that mortality and ASMRs of enteric infectious diseases declined substantially between 1990 and 2023. This decline is consistent with the expansion of public health measures and broader socioeconomic development. However, the burden in 2023 remains considerably high, with the highest mortality concentrated in sub-Saharan Africa and south Asia. Considering that more than a quarter of all countries had yet to meet the GAPPD mortality target in 2023, sustained efforts are needed to address the persistent burden in affected countries and to adapt to the changing global health landscape. FUNDING Gates Foundation.

Background: Hofbauer cells (HBCs) are the only immunocompetent cells within the stroma of chorionic villi and play a key role in immune regulation and placental development throughout gestation. Their phenotype, abundance, and proliferative activity change in accordance with the needs of the fetoplacental unit. Methods: Thirty healthy human placentas across all three trimesters were analyzed. Samples were processed using standard histological protocols and immunohistochemically stained with CD45, CD68, CD86, and Ki-67 markers. Morphometric analysis was performed to determine the following parameters: percentage of HBCs, numerical areal density, and proliferative index. Results: HBCs were immunoreactive for CD45 and CD68, while CD86 immunoreactivity was not observed in any trimester. The proportion of HBCs was highest in the second trimester and lowest in the third. Numerical areal density was highest in the second trimester (22.21 ± 3.86) and lowest in the first (8.27 ± 4.18). The proliferative index was highest in the first trimester (82.45 ± 10.19%), decreased significantly in the second, and was completely absent in the third trimester. Conclusions: During physiological placental development, Hofbauer cells maintain a predominantly non-M1 macrophage phenotype, accompanied by a gradual reduction in proliferative activity.

Diabetic nephropathy (DN) is a major microvascular complication of diabetes mellitus and the leading cause of end‐stage renal disease. Oxidative stress and inflammation are central drivers of DN progression, yet no effective therapies exist to prevent or delay renal injury. This study investigated the renoprotective effects of glycine (GLY), N‐acetylcysteine (NAC), and their combination administered at early versus late stages of streptozotocin induced diabetes. Forty‐eight male Wistar rats (n = 48) were allocated into five groups: healthy controls (Group 1, n = 6), untreated diabetic rats (Group 2, n = 6), and three treatment groups (Groups 3–5, each n = 12). Diabetes was induced by a single intraperitoneal streptozotocin injection (55 mg/kg). Group 3 received NAC (100 mg/kg), Group 4 received GLY (250 mg/kg), and Group 5 received NAC + GLY. Each treatment group was subdivided into early (6 week, n = 6) and late (12 week, n = 6) intervention subgroups. Treatments were administered orally. Renal tissue was evaluated using classic histology, geometric morphometric analysis, and biochemical assays of superoxide dismutase (SOD) and myeloperoxidase (MPO). Statistical analyzes were performed using ANOVA with appropriate post hoc tests (p < 0.05). Untreated diabetic rats (Group 2) showed significantly decreased SOD activity, increased MPO levels, marked mesangial matrix expansion, glomerular hypercellularity, tubular epithelial degeneration, and interstitial inflammation with fibrosis. NAC (Group 3) and GLY (Group 4) each improved oxidative stress markers and partially restored glomerular and tubular morphology, with early treatment subgroups exhibiting more substantial benefit than late subgroups. The combined NAC + GLY therapy (Group 5) demonstrated the strongest renoprotective effect, preserving renal structure and biochemical parameters closest to healthy controls. To conclude, early combined administration of glycine and N‐acetylcysteine yields superior protection against diabetes‐induced renal injury compared with individual treatments. These findings support the therapeutic potential of antioxidant‐amino acid combinations in preventing or delaying diabetic nephropathy.

BACKGROUND Severe atherosclerotic internal carotid artery stenosis may progress to complete internal carotid artery occlusion (ICAO). Therefore, ICAO represents an advanced form of carotid artery disease. We sought to investigate the association between ICAO with atherosclerotic disease in other arterial beds and vascular risk factors and to identify the patient implications of the diagnosis of ICAO. MATERIALS AND METHODS Using the term "Internal carotid artery occlusion", a search of PubMed/MEDLINE, Scopus and Embase between 1980 and 2025 revealed 10,588 results. After exclusion of case reports, letters to the Editor and Editorials, 5,771 reports were identified. Following meticulous screening of the identified reports, 28 studies specifically addressing ICAO patient cohorts were included in the final analysis. A quantitative and qualitative synthesis analysis was performed. A questionnaire was subsequently developed and sent out to 63 participants from the United States (n=21) and several European countries (n=42), aiming to achieve consensus regarding the optimal management of patients with ICAO. Three participants did not respond. The Consensus Coordinator abstained from voting to avoid introducing bias, resulting in a final voting panel of 60 participants. RESULTS Across included studies, the proportion of patients with ICAO presenting with neurologic symptoms varied widely, ranging from 38-100%, while approximately 24-27% of patients were asymptomatic at the time of diagnosis. Consensus (≥75%) was achieved in 11 of the 17 (64.7%) pre-specified statements. Most participants agreed that atherosclerotic ICAO represents a systemic manifestation of advanced atherosclerosis rather than isolated cerebrovascular pathology (56/60; 93.3%). Duplex ultrasound should be used as the first-line diagnostic tool for suspected ICAO, with CTA or MRA confirmation if necessary (59/60; 98.3%). Optimal medical therapy (including antiplatelet, antihypertensives, statins, and glycemic control) remains the cornerstone of ICAO management (59/60; 98.3%). Lifestyle and metabolic risk factor optimization, smoking cessation, optimizing body weight, a healthy diet and exercise, should be strongly advised in all ICAO patients (60/60; 100%). Most participants concurred that ICAO revascularization should be centralized in specialized vascular-neuro centers equipped for intra-operative neuromonitoring and advanced hemodynamic control (57/60; 95.0%). Finally, most participants agreed that current evidence for ICAO intervention is insufficient and that a global registry should be created to record outcomes and guide future trials (56/60; 93.3%). CONCLUSIONS This international, multi-specialty consensus highlights ICAO as a marker of advanced, systemic atherosclerosis. Management should emphasize comprehensive evaluation for multisystem vascular disease and aggressive modification of cardiovascular risk factors. Best medical therapy remains the cornerstone of the management of patients with ICAO, with conservative or invasive interventions considered selectively based on symptom status, anatomic considerations, procedural risk, and institutional expertise, to reduce the overall cardiovascular disease burden.

1645 Background: Access to innovative oncology medicines is often assumed to depend primarily on available financial resources. In health systems organized under the Bismarck model, however, access is frequently constrained by structural and policy-related factors, including fragmented governance, rigid reimbursement pathways, and infrequent updating of positive drug lists. These limitations may result in delayed access, restricted indications, and misalignment with contemporary clinical standards, even in the absence of absolute budget shortages. In Bosnia and Herzegovina, such constraints are compounded by complex administrative arrangements, leading to pronounced regional disparities in cancer care. In Sarajevo Canton prolonged waiting times and loss of treatment eligibility underscored that the key barrier was not lack of money, but lack of timely policy action. In October 2024, Sarajevo Canton launched a program shifting financing responsibility locally to improve timely access. Methods: We analyzed drug access before and after program initiation in 641 patients, assessing waiting times from indication to treatment approval and the proportion of patients losing indication prior to therapy availability. Results: Patients whose indication was established before the program were significantly more likely to remain without therapy compared to those after initiation (23.8% vs. 10.3%, p < 0.001). Among 547 patients with available waiting time data, mean waiting time decreased from 251.6 days (SD ≈ 190; range 21–910) to 40.4 days (SD ≈ 21; range 6–199), representing a >6-fold reduction. Variability also decreased, making access more predictable and equitable. Levene’s test indicated unequal variances (F = 517.3, p < 0.001), and Welch’s t-test confirmed the difference (t(157.5) = 13.91, p < 0.001; 95% CI 181–241 days), with a very large effect size (Cohen’s d ≈ 2.0). Conclusions: This policy intervention dramatically reduced waiting times and improved equity in therapy access. This demonstrates that substantial improvements in oncology drug access can be achieved without increasing overall healthcare spending. The observed gains were the result of a deliberate policy and governance shift—redefining responsibility, prioritization, and accountability—rather than additional financial input. This intervention highlights that, within Bismarck-type systems, access gaps are often policy failures rather than funding failures, and that targeted policy change can serve as a powerful lever to rapidly improve equity and quality of cancer care.

BACKGROUND Developing countries face limited access to targeted treatments for patients with advanced epithelial ovarian cancer (EOC). The CA-125 ELIMination rate constant K (KELIM), calculated from longitudinal CA-125 measurements during the first 100 days of treatment, serves as an early indicator of tumour chemosensitivity. The primary objective of this study was to evaluate the value of the KELIM score in predicting progression-free survival (PFS) and overall survival (OS) in patients with EOC treated with adjuvant or neoadjuvant chemotherapy. METHODS The records of patients with EOC (International Federation of Gynecology and Obstetrics stage II-IV) treated at the University Clinical Hospital Mostar (Bosnia and Herzegovina) between 2013 and 2023 were analysed retrospectively. Patient characteristics, outcomes and KELIM score were assessed during the first 100 days of treatment. KELIM scores were categorized as favourable (≥1.0) or unfavourable (<1.0). RESULTS KELIM scores were assessed in 92 patients: 36 (39 %) were classified in the favourable group and 56 (61 %) in the unfavourable group. Patients in the favourable KELIM group achieved complete cytoreduction significantly more often (p < 0.001) and demonstrated longer platinum-free intervals (PFI), with most having PFI > 12 months (p = 0.005). In contrast to OS (p = 0.442), PFS was significantly longer in the favourable KELIM group [29.0 months, 95 % confidence interval (CI) 8.45-49.55] compared with the unfavourable KELIM group (13.0 months, 95 % CI 10.56-15.44; p < 0.001). CONCLUSION In this real-world cohort from a resource-limited setting, a favourable KELIM score was associated with greater early chemosensitivity, longer PFI, improved PFS, and a higher rate of complete cytoreduction in patients with EOC. The KELIM score has been validated in real-world settings and post-hoc analyses of prospective studies, and can be applied easily in routine clinical practice for patients with EOC treated with adjuvant or neoadjuvant chemotherapy, providing a useful prognostic, predictive, pragmatic and cost-effective tool to support risk stratification and inform therapeutic decision-making. Further prospective validation is still required for biomarker-guided treatment selection.

This paper compiles results from six systematic reviews and meta-analyses on associations between environmental and occupational exposure to chemicals and levels of DNA strand breaks in human leukocytes, measured by the comet assay. There are no differences in effect sizes when using different comet descriptors. However, lower central tendencies are obtained by using a non-parametric test as compared to the standard parametric analysis, indicating that the standard meta-analyses tend to overestimate the effect size. The compiled results indicate that exposures can be sorted into three groups with decreasing effect size: high (pesticides), moderate (volatile organic compounds, heavy metals and antineoplastic drugs), and low (anaesthetic gases and air pollution). Interestingly, studies from middle-income countries have higher effect sizes than those seen in studies from high-income countries. This may be related to higher exposures or lower socioeconomic status in middle-income countries. However, there is also some co-variability between studies from middle-income countries and the risk of comet assay measurement bias, assessed as information provided in published papers. Lack of information on assay controls and blinded/coded sample analysis appears to be a general issue in studies on comet assay results. Risk of exposure misclassification is mainly related to the type of exposure; there are good biomarkers for some exposures (e.g. heavy metals), whereas other exposures are more challenging to assess with biomarkers (e.g. pesticides). In conclusion, all examined exposures result in significant increases in DNA strand breaks at the population level, though to varying degrees.