Advancing Open Science

Background/Objectives: Tributyltin (TBT) remains a persistent aquatic contaminant with documented neurotoxic effects, yet the underlying mechanisms of its neurotoxicity remain poorly understood. Methods: We investigated the comprehensive molecular mechanisms of TBT-induced neurotoxicity in zebrafish (Danio rerio) through an integrated approach combining histopathological examination, metabolomics analysis, transcriptional profiling, and behavioral assays. Results: Histopathological analysis revealed significant TBT-induced damage to brain tissue architecture. Metabolomic profiling demonstrated that TBT exposure (500 ng/L) severely disrupted cellular energy metabolism, particularly the TCA cycle and purine/pyrimidine metabolism, while exhibiting hormetic responses at lower concentrations. Transcriptional analysis identified widespread downregulation of SNARE complex proteins and neurotransmitter transporters, indicating comprehensive deterioration of synaptic machinery. Conclusions: These molecular perturbations corresponded with systematic disruption of antioxidant defense mechanisms and neurotransmitter signaling pathways, establishing a direct mechanistic link to observed behavioral deficits. Our findings reveal a hierarchical cascade of molecular disruptions triggered by TBT exposure, bridging the critical gap between metabolic dysregulation and synaptic dysfunction. This mechanistic framework provides fundamental insights into the neurotoxicological impact of this widespread environmental contaminant, highlighting potential therapeutic targets for intervention.

Background/Objectives: The aim of this study is to investigate how the joint, the number and the type of prior revision surgeries influence the diagnostic thresholds for synovial cell count for patients who undergo their first total hip or knee arthroplasty revision compared to re-revisions, as different cutoffs might substantially influence treatment courses. Methods: In this retrospective single-center register analysis, data from 214 revised THAs (total hip arthroplasties) and TKAs (total knee arthroplasties) were collected, of which 103 (48.1%) have so far undergone at least one revision surgery. Diagnosis was based on the EBJIS criteria, and we identified 163 (76.2%) septic and 51 (23.8%) aseptic cases. Data on synovial cell count were collected and analyzed for their diagnostic accuracy and optimal cutoffs. For re-revisions, a covariate-adjusted ROC (receiver operating characteristic) for the joint, type of previous surgery and number of surgeries was created. Results: We found no significant differences in cell counts between patients before first revision compared to those undergoing re-revision for septic (p = 0.40) and aseptic indications (p = 0.84). The overall diagnostic accuracy was high for all re-revision cases, with a sensitivity of 0.86, specificity of 0.91, AUC (area under the curve) of 0.92, at an optimal cutoff value of 2439.50 G/L. As for re-revised hip joints, the optimal cutoffs were higher compared to knee joints (2439.5 G/L vs. 2626.5 G/L, hip AUC = 0.90, knee AUC = 0.93, p = 0.14). Furthermore, the AUCs for cell count differed significantly depending on the type of previous surgery in re-revision (p = 0.03). The covariate-adjusted analysis showed no significant differences compared to the unadjusted analysis. Conclusions: Cell count remains reliable for diagnosing periprosthetic joint infection in patients with prior revisions, with minor threshold variations from the EBJIS (European Bone and Joint Infection Society) criteria. While the type of preceding revision affects accuracy, the diagnostic value remains consistently high overall.

The Indian Diabetic Retinopathy Image Dataset (IDRiD) has been widely adopted for DR lesion segmentation research. However, it contains annotation gaps for proliferative DR lesions and labeling errors that limit its utility for comprehensive automated screening systems. We present Refined IDRiD, an enhanced version that addresses these limitations through (1) expert ophthalmologist validation and correction of labeling errors in original annotations for four non-proliferative lesions (microaneurysms, hemorrhages, hard exudates, cotton-wool spots), (2) the addition of three critical proliferative DR lesion annotations (neovascularization, vitreous hemorrhage, intraretinal microvascular abnormalities), and (3) the integration of comprehensive anatomical context (optic disc, fovea, blood vessels, retinal region). A team of three ophthalmologists (one senior specialist with >10 years’ experience, two expert fundus image annotators) conducted systematic annotation refinement, achieving an inter-rater agreement F1-score of 0.9012. The enhanced dataset comprises 81 high-resolution fundus images with pixel-level annotations for seven DR lesion types and four anatomical structures. All images were cropped to the retinal region of interest and resized to 1024 × 1024 pixels, with annotations stored as unified grayscale masks containing 12 classes enabling efficient multi-task learning. Refined IDRiD enables training of comprehensive DR screening systems capable of detecting both non-proliferative and proliferative stages while reducing false positives through anatomical context awareness.

Background: Wild-type transthyretin amyloidosis (ATTRwt) diagnosis remains challenging. Echocardiographic “red flags” play a significant role in raising diagnostic suspicion. Methods: Retrospective study including 33 patients diagnosed with ATTRwt. All patients underwent comprehensive echocardiographic evaluation focusing on the red flags for ATTRwt. Left ventricular hypertrophy (LVH) was defined as interventricular septal wall thickness (IVST) ≥ 12 mm and/or LV mass indexed for body surface area (LVMI) ≥ 115 g/m² in men and ≥ 95 g/m² in women. Results: Relative wall thickness > 0.42 and early diastolic myocardial velocity < 7 cm/s were detected in 100% of patients. Severe diastolic dysfunction (grade ≥ 3) (72.7%), apical sparing (36.4%), granular sparkling pattern (30.3%), and pericardial effusion (39.4%) were also observed. Females were younger than males (median age 68 vs. 74.5 years), and IVST ≥ 12 mm was lower in females than in males (64.4% vs. 100%, respectively, p < 0.05). The combined criterion of IVST ≥ 12 mm in men and LVMI ≥ 95 g/m² in women was encountered in 100% of the global cohort. Conclusions: IVST is a good predictor of LVH in males but shows limited sensitivity for ATTRwt in females; a gender-differenced approach (IVST for men and LVMI for women) might better stratify for ATTRwt suspicion.

Diabetic ketoacidosis (DKA) remains a life-threatening complication of diabetes mellitus with suboptimal outcomes despite standard management. Emerging evidence suggests that thiamine (vitamin B1) deficiency may play an under-recognized role in DKA pathophysiology and clinical course. This narrative review synthesizes current evidence regarding thiamine deficiency in diabetes and DKA, examining molecular mechanisms, clinical implications, and the rationale for thiamine supplementation as adjunctive therapy. Thiamine deficiency is highly prevalent in diabetes, with plasma concentrations reduced by approximately 75% compared to healthy controls. In DKA specifically, 25–35% of patients present with thiamine deficiency, which often worsens during insulin therapy. The primary mechanism involves hyperglycemia-induced downregulation of renal thiamine transporters (THTR-1 and THTR-2), resulting in 16–24-fold increased renal clearance and massive urinary losses. Thiamine pyrophosphate serves as an essential cofactor for three critical enzymes in glucose metabolism: pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and transketolase. Deficiency impairs these pathways, causing pyruvate accumulation with conversion to lactate (resulting in lactic acidosis), compromised TCA cycle function (reducing ATP production by 40–48%), and decreased NADPH generation (increasing oxidative stress). Clinical manifestations include persistent metabolic acidosis despite standard therapy, myocardial dysfunction with elevated cardiac biomarkers, neurological impairment, and prolonged recovery times. Cellular studies demonstrate that thiamine supplementation significantly improves mitochondrial oxygen consumption in DKA patients. The high prevalence of thiamine deficiency in DKA, compelling biochemical rationale, excellent safety profile, and preliminary mechanistic evidence support the urgent need for large-scale randomized controlled trials examining thiamine supplementation to definitively establish efficacy, optimal dosing, and patient selection criteria.

COVID-19 and influenza A (FluA) cause severe respiratory infections in elderly patients, with cytokine dysregulation playing a central role. Direct comparative data in older adults remains limited. We aimed to characterize cytokine dynamics and their prognostic value in hospitalized elderly patients with COVID-19 vs. FluA. We performed a prospective cohort study including adults ≥ 60 years hospitalized with respiratory failure due to COVID-19 or FluA between March 2023 and March 2024. Serum IL-1β, IL-6, IL-10, IL-17A, IL-34, MCP-1, and CXCL10 were measured on Day 1 and Day 5 of hospitalization using Luminex^®. Cytokines and associations with non-invasive ventilation (NIV) were assessed by ROC analysis and multivariate logistic regression. 83 patients were included (39 COVID-19, median age 79 years; 44 FluA, median 77 years). At Day 1, COVID-19 exhibited significantly higher IL-6, IL-10, and CXCL10; FluA showed an attenuated cytokine response. At Day 5, cytokines declined in both groups. Baseline IL-6 independently predicted NIV (adjusted OR 3.02), whereas higher MCP-1 was associated with reduced NIV requirement. Early cytokine differences between COVID-19 and FluA are evident in elderly patients, but values converged by Day 5. IL-6 remains an informative early predictor of respiratory deterioration; MCP-1 may reflect a regulated innate response.

Peripartum depression (PPD) represents one of the most prevalent and disabling psychiatric conditions among women, yet its underlying biology remains poorly integrated across medical disciplines. Emerging evidence highlights PPD as a prototypical disorder of the heart–brain axis, where neuroendocrine changes, immune activation, and cardiovascular dysregulation converge to shape maternal vulnerability. During pregnancy and the postpartum period, abrupt fluctuations in estrogen, progesterone (P4), and placental corticotropin-releasing hormone (CRH) interact with a sensitized hypothalamic–pituitary–adrenal (HPA) axis, altering neural circuits involved in mood regulation, stress reactivity, and maternal behavior. Parallel cardiovascular adaptations, including endothelial dysfunction, altered blood pressure variability, and reduced heart rate variability (HRV), suggest a profound perturbation of autonomic balance with potential long-term implications for maternal cardiovascular health. Neuroinflammation, microglial activation, and systemic cytokine release further mediate the bidirectional communication between the heart and the brain, linking emotional dysregulation with vascular and autonomic instability. Evidence also indicates that conditions such as preeclampsia and peripartum cardiomyopathy share biological pathways with PPD, reinforcing the concept of a unified pathophysiological axis. This review synthesizes current knowledge on the neurobiological, cardiovascular, endocrine, and inflammatory mechanisms connecting PPD to maternal heart–brain health, while discussing emerging biomarkers and therapeutic strategies aimed at restoring integrative physiology. Understanding PPD as a multisystem heart–brain disorder offers a transformative perspective for early detection, risk stratification, and personalized intervention during one of the most biologically vulnerable periods of a woman’s life.

Background: Diabetes mellitus is known to affect the prognosis of critically ill patients; however, its impact on independence in activities of daily living (ADL) at hospital dis-charge remains unclear. This study aimed to investigate whether preexisting diabetes is associated with reduced ADL independence at hospital discharge among critically ill patients. Methods: In this prospective cohort study, 423 adult intensive care unit (ICU) patients who were admit-ted for ≥48 h were enrolled and categorized by the presence or absence of diabetes. Primary outcomes included time to achieve walking independence (unassisted walking over 50 m) and the Barthel Index at discharge. Secondary outcomes were handgrip strength, ICU length of stay, and highest ICU Mobility Scale (IMS) scores. Multivariable analyses adjusted for age, illness severity, and other confounders. Results: Among the 101 patients with diabetes, time to achieve walking independence at discharge was significantly longer compared to those without diabetes (p = 0.013). The diabetes group also had a lower Barthel Index (p = 0.020), longer ICU stays (p = 0.003), weaker handgrip strength (p = 0.041), and lower maximum IMS scores (p = 0.002). Multivariable analysis confirmed that diabetes was independently associated with reduced ADL independence and poorer physical function at discharge. Conclusions: Preexisting diabetes is an independent predictor of impaired ADL independence in critically ill patients. These findings highlight the importance of early and individualized rehabilitation strategies for patients with diabetes in the ICU.