Search Results (1,077)

Murine microglia exhibit rapid self-renewal upon removal from the postnatal brain. However, the signaling pathways that regulate microglial repopulation remain largely unclear. To address this knowledge gap, we depleted microglia from mixed glial cultures using anti-CD11b magnetic particles and cultured them for 4 weeks to monitor their repopulation ability in vitro. Flow cytometry and immunocytochemistry revealed that anti-CD11b bead treatment effectively eliminated >95% of microglia in mixed glial cultures. Following removal, the number of CX3CR1-positive microglia gradually increased; when a specific threshold was reached, repopulation ceased without any discernable rise in cell death. Cell cycle and 5-ethynyl-2′-deoxyuridine incorporation assays suggested the active proliferation of repopulating microglia at d7. Time-lapse imaging demonstrated post-removal division of microglia. Colony-stimulating factor 1 receptor-phosphoinositide 3-kinase-protein kinase B signaling was identified as crucial for microglial repopulation, as pharmacological inhibition or neutralization of the pathway significantly abrogated repopulation. Transwell cocultures revealed that resident microglia competitively inhibited microglial proliferation probably through contact inhibition. This in vitro microglial removal system provides valuable insights into the mechanisms underlying microglial proliferation. Full article

An increase in invasive group A streptococcal (iGAS) infections among children under 15 years of age was reported in several countries between late 2022 and early 2023. This retrospective study aims to describe the epidemiology and clinical features of iGAS infections in children in Cyprus during the same period. Medical records of patients under 16 years old admitted with iGAS infection to the Archbishop Makarios Hospital, the only tertiary paediatric referral centre in Cyprus, between 1 January 2021 and 30 June 2024, were reviewed. Twenty-two cases were identified, of which twenty were classified as confirmed and two as probable. Half of the cases occurred in children aged 0–4 years, and 59% were recorded between December 2022 and April 2023. Scarlet fever was diagnosed in six children, five of whom developed pneumonia and empyema. Streptococcal toxic shock syndrome (STSS) was observed in five patients, resulting in two deaths and one case requiring prolonged extracorporeal membrane oxygenation (ECMO). The overall case fatality rate was 9.1%. Emm 1, belonging to the M1UK clone, was the predominant strain (66.6%). The findings underscore the severity of iGAS infections, particularly in younger children, and highlight the importance of timely diagnosis, appropriate management and continued epidemiological surveillance. Full article

Peripheral artery disease (PAD) is associated with an elevated risk of major adverse cardiovascular events (MACE). Despite this, few reliable biomarkers exist to identify patients at heightened risk of MACE. Growth differentiation factor 15 (GDF15), a stress-responsive cytokine implicated in inflammation, atherosclerosis, and thrombosis, has been broadly studied in cardiovascular disease but remains underexplored in PAD. This study aimed to evaluate the prognostic utility of GDF15 for predicting 2-year MACE in PAD patients using explainable statistical and machine learning approaches. We conducted a prospective analysis of 1192 individuals (454 with PAD and 738 without PAD). At study entry, patient plasma GDF15 concentrations were measured using a validated multiplex immunoassay. The cohort was followed for two years to monitor the occurrence of MACE, defined as stroke, myocardial infarction, or death. Baseline GDF15 levels were compared between PAD and non-PAD participants using the Mann–Whitney U test. A machine learning model based on extreme gradient boosting (XGBoost) was trained to predict 2-year MACE using 10-fold cross-validation, incorporating GDF15 and clinical variables including age, sex, comorbidities (hypertension, diabetes, dyslipidemia, congestive heart failure, coronary artery disease, and previous stroke or transient ischemic attack), smoking history, and cardioprotective medication use. The model’s primary evaluation metric was the F1 score, a validated measurement of the harmonic mean of the precision and recall values of the prediction model. Secondary model performance metrics included precision, recall, positive likelihood ratio (LR+), and negative likelihood ratio (LR-). A prediction probability histogram and Shapley additive explanations (SHAP) analysis were used to assess model discrimination and interpretability. The mean participant age was 70 ± SD 11 years, with 32% (n = 386) female representation. Median plasma GDF15 levels were significantly higher in PAD patients compared to the levels in non-PAD patients (1.29 [IQR 0.77–2.22] vs. 0.99 [IQR 0.61–1.63] pg/mL; p < 0.001). During the 2-year follow-up period, 219 individuals (18.4%) experienced MACE. The XGBoost model demonstrated strong predictive performance for 2-year MACE (F1 score = 0.83; precision = 82.0%; recall = 83.7%; LR+ = 1.88; LR− = 0.83). The prediction histogram revealed distinct stratification between those who did vs. did not experience 2-year MACE. SHAP analysis identified GDF15 as the most influential predictive feature, surpassing traditional clinical predictors such as age, cardiovascular history, and smoking status. This study highlights GDF15 as a strong prognostic biomarker for 2-year MACE in patients with PAD. When combined with clinical variables in an interpretable machine learning model, GDF15 supports the early identification of patients at high risk for systemic cardiovascular events, facilitating personalized treatment strategies including multidisciplinary specialist referrals and aggressive cardiovascular risk reduction therapy. This biomarker-guided approach offers a promising pathway for improving cardiovascular outcomes in the PAD population through precision risk stratification. Full article

Epilepsy is one of the most prevalent chronic medical conditions that really can affect individuals at any age. A broader study of the pathogenesis of the epileptic condition will probably serve as the cornerstone for the development of new antiepileptic remedies that aim to treat epilepsy symptomatically as well as prevent the epileptogenesis process or regulate its progression. Cellular changes in the brain include oxidative stress, neuroinflammation, inflammatory cell invasion, angiogenesis, and extracellular matrix associated changes. The extensive molecular profiling of epileptogenic tissue has revealed details on the molecular pathways that might start and sustain cellular changes. In healthy brains, epilepsy develops because of vascular disruptions, such as blood–brain barrier permeability and pathologic angiogenesis. Key inflammatory mediators are elevated during epileptic seizures, increasing the risk of recurrent seizures and resulting in secondary brain injury. Prostaglandins and cytokines are well-known inflammatory mediators in the brain and, after seizures, their production is increased. These inflammatory mediators may serve as therapeutic targets in the clinical research of novel antiepileptic medications. The functions of inflammatory mediators in epileptogenesis are covered in this review. Oxidative stress also plays a significant role in the pathogenesis of various neurological disorders, specifically epilepsy. Antioxidant therapy seems to be crucial for treating epileptic patients, as it prevents neuronal death by scavenging excess free radicals formed during the epileptic condition. The significance of antioxidants in mitochondrial dysfunction prevention and the relationship between oxidative stress and inflammation in epileptic patients are the major sections covered in this review. Full article

Background and Aims: Ornidazole, a nitroimidazole antibiotic, is widely used for protozoal and anaerobic infections and is generally considered safe. However, ornidazole-induced liver injury (OILI) is an underrecognized yet potentially severe adverse reaction. This multicenter study aims to characterize the clinical features, histopathology, and outcomes of OILI to improve the awareness and management of this rare entity worldwide. Methods: We conducted a retrospective analysis of 101 patients with OILI from eight tertiary centers between 2006 and 2023. Cases were included based on liver enzyme elevations temporally linked to ornidazole and the exclusion of other causes. Causality was assessed using the Roussel Uclaf Causality Assessment Method (RUCAM) score. Clinical data, laboratory parameters, autoantibody profiles, histology, treatments, and outcomes were evaluated. Results: OILI was classified as highly probable in 42.6% of cases (n = 43), probable in 51.5% of cases (n = 52), and possible in 5.9% (n = 6) of cases. The predominant pattern was acute hepatocellular injury (83.2%) (n = 84). Autoimmune-like hepatitis occurred in 5% of cases (n = 5), with ANA positivity in 16.8% of cases (n = 17). Corticosteroids were used in 24.8% of cases (n = 25) and were associated with higher ANA positivity and a 20% (n = 5) relapse rate post-discontinuation. Recovery was achieved in 87.7% of cases (n = 88), while 7.9% of cases (n = 8) required liver transplantation and 4% (n = 4) died. Conclusions: Ornidazole can cause serious idiosyncratic liver injury, including autoimmune phenotypes, and should be considered in the differential diagnosis of acute hepatitis. Given the notable risk of liver failure and death, early recognition, drug discontinuation, and close monitoring are essential. In select cases, corticosteroids and plasmapheresis may be beneficial, though the evidence remains limited. Full article

Background and Objectives: Schizophrenia is a disabling psychiatric condition, affecting around 1% of people worldwide. It has been ranked among the ten most disabling conditions globally. Alongside the psychological and social burdens imposed on individuals suffering from this disease, there are also serious complications regarding the physical health of these patients. Pneumonia is a significant cause of death in patients with schizophrenia. This group of patients also has a higher risk of developing pneumonia and all-cause mortality compared to those without schizophrenia, along with an increased overall mortality rate. A retrospective study revealed that advanced age, underweight, smoking, and the use of high-dose atypical antipsychotics increase the risk of pneumonia-related mortality in hospitalized patients. Our study aims to examine differences in factors associated with pneumonia in hospitalized patients with schizophrenia, before and after the COVID-19 pandemic, as well as to identify potential changes in clinical characteristics and outcomes. Materials and Methods: This is an observational, retrospective analysis, based on the review of medical records of psychiatric inpatients diagnosed with schizophrenia according to the DSM-5 criteria. Patients were selected according to the following criteria: both schizophrenia and pneumonia diagnoses, hospitalized in Spitalul Clinic de Psihiatrie si Neurologie Brasov during 1 March 2018–1 March 2020, and 1 March 2022–1 March 2024, respectively. Results: A total of 27 patients met the inclusion criteria; 13 patients (48%) were in the pre-pandemic group and 14 patients (52%) in the post-pandemic group. Contrary to other reports, our results showed relatively low pneumonia rates in hospitalized schizophrenia patients (1.02% pre-pandemic and 1.63% post-pandemic), and rates were higher in female patients (61.54% pre-pandemic and 71.43% post-pandemic). Post-pandemic, most cases (42.86%) were registered during summer, in a schizophrenia population with mostly urban residence and with lower smoking rates than the pre-pandemic group. Physical restraints were, however, more frequently utilized in the post-pandemic group. Conclusions: Pneumonia risk factors might register a change in the post-pandemic years. Polypharmacy and physical restraints are probably underestimated risk factors for pneumonia in schizophrenia patients, while a multidisciplinary approach and preventive measures might exert a protective role. Full article

The Field Guide “Paleopathology Collection at the University of Granada” includes one of the most important collections of human bone remains that present anomalies or specific characteristics that can be used to determine the existence of diseases, accidents or malformations in each subject’s life, as well as the probable cause of death. The collection consists of several thousand skeletons or parts of them. It is located at the Faculty of Medicine of the University of Granada and has been created and managed by Professor Miguel C. Botella López, founder and director of the Anthropology Laboratory of the University of Granada, between 1971 and 2024. Professor Botella is the author of the diagnoses made for each specimen from different geographical areas of Spain in a time period ranging from the Neolithic to the present day. The collection is of special interest to students and professionals in medicine, archaeology, criminology or law. Full article

In dairy cattle, abomasal ulcers are a serious but sometimes disregarded ailment that can have detrimental effects on health and cause financial losses. Due to inconclusive clinical symptoms, abomasal ulcers are typically misdiagnosed and treated improperly. Specialized diagnostic methods should be considered to ensure a correct diagnosis and the well-being of cattle. This report focuses on a 4-year-old Holstein-Friesian cow which began her third lactation two weeks before she started showing general clinical signs of an elevated fat–protein ratio in the milk and was diagnosed with an abomasum displacement. The clinical signs can also be mistaken for other conditions such as traumatic reticuloperitonitis and left dislocated abomasum. The patient was brought to the LUHS Large Animal Clinic, and after a short while, sudden death occurred. The autopsy concluded that death had occurred due to hypovolemic shock caused by abomasal ulcer perforation, which caused bleeding into the abomasum and intestines. Also, the type 3 ulcer caused severe peritonitis and anemia, and feed and fibrin could be seen on the outside of organs in the abdomen. Blood clots mixed with feed had formed in the inside of the abomasum and intestinal tract. Based on the work of previous scientific studies, it has been established that the occurrence of ulcers is more frequent in dairy cows during the first four to six weeks of lactation. And the most probable cause could be intensive feeding and dietary changes. Ulcers in the abomasum are very difficult to diagnose, because they require special diagnostic equipment such as an ultrasound or surgical interventions. Due to the similarity with other diseases, this pathological condition of the abomasum is most frequently only identified in post-mortem examinations. Full article

Flooding is a recurrent natural hazard in Romania, causing significant socio-economic impacts. Historical data highlights the severity of floods, particularly the unprecedented flood of 1926. Between 1960 and 2010, Romania experienced over 400 major floods, which significantly impacted its infrastructure and population. Particularly, the floods in 2005 and 2006 affected over 1.5 million people, resulting in 93 deaths and causing damages exceeding EUR 2 billion. In compliance with the Floods Directive, EU member states must assess and map flood hazards and risks. This study aims to develop a frequency analysis to determine discharges as a predictive indicator for different hazard levels: frequent events (10-year return period), medium probability events (100-year return period), and extreme events. The Casimcea catchment in central Dobrogea, drained by the Casimcea River into Lake Tasaul, serves as the study area. The annual maximum discharge data analysis, conducted through frequency analysis and the ELECTRE method, indicates that EV3-Min-Weibull, L-moments, and GEV-Min (L-moments) are the most effective probability density functions (PDFs). To conclude, although a single PDF model cannot be determined for the Casimcea River and its tributaries, it contributes to predictive modeling efforts. Full article

At crime scenes, apart from the detection of blood, it may be important to determine whether a person was alive at the time of blood deposition. Based on the rapid onset of fibrinolysis after death, this pathway could be considered to identify potential biomarkers for postmortem blood. Fibrinolysis is the natural process that breaks down blood clots after healing a vascular injury. One of its products, D-dimer, could be a potential biomarker for postmortem blood. SERATEC^® (SERATEC^® GmbH, Göttingen, Germany) has developed the PMB immunochromatographic assay to simultaneously detect human hemoglobin and D-dimer. The main goals of this study were to assess the possibility of using this test to detect postmortem blood, evaluate D-dimer levels in antemortem, menstrual, and postmortem blood, and assess the ability to obtain STR profiles from postmortem blood. Except for one degraded sample, all postmortem blood samples reacted positively for the presence of D-dimer using the SERATEC^® PMB test. All antemortem blood samples from living individuals showed negative results for D-dimer detection, except for one liquid sample with a weak positive result, probably due to pre-existing health conditions. Menstrual blood samples gave variable results for D-dimer. The DIMERTEST^® Latex assay was used for semi-quantitative measurement of D-dimer concentrations, with postmortem and menstrual blood yielding higher D-dimer concentrations compared to antemortem blood. Full STR profiles were developed for all postmortem samples tested except for one degraded sample, pointing to the possibility of not only detecting postmortem blood at the crime scene but also the potential identification of the victim. Full article

The Rayleigh distribution is a continuous probability distribution that is inherently asymmetric and commonly used to model right-skewed data. It holds significant importance across a wide range of scientific and engineering disciplines and exhibits structural relationships with several other asymmetric probability distributions, for example, Weibull and exponential distribution. This research proposes techniques for establishing credible intervals and confidence intervals for the single mean of the zero-inflated two-parameter Rayleigh distribution. The study introduces methods such as the percentile bootstrap, generalized confidence interval, standard confidence interval, approximate normal using the delta method, Bayesian credible interval, and Bayesian highest posterior density. The effectiveness of the proposed methods is assessed by evaluating coverage probability and expected length through Monte Carlo simulations. The results indicate that the Bayesian highest posterior density method outperforms the other approaches. Finally, the study applies the proposed methods to construct confidence intervals for the single mean using real-world data on COVID-19 total deaths in Singapore during October 2022. Full article

Background/Objectives: Sepsis is one of the most common causes of death worldwide, and its diagnosis remains a challenge for clinicians. The main purpose of this study was to appraise the diagnosis and antibiotic prescription pattern for sepsis admitted to the Emergency Department (ED), comparing Sepsis-2 to Sepsis-3 criteria. Methods: The study was conducted in an ED of a tertiary care medical center in Hungary. We included all adult patients who were diagnosed with sepsis in 2023. Data collection was made manually from UD MED System. Diagnosis was assessed based on Sepsis-2 and Sepsis-3 criteria, then compared. Further analyses were made only in cases with confirmed sepsis diagnosis. Antibiotic guideline adherence was determined according to the local guideline in force. Fisher’s exact test, t-test, and ANOVA were applied to compare categorical and continuous variables between groups. The Kaplan–Meier test was applied for probability of survival. Significant p-values were defined as below 0.05. Results: The substantial majority of patients recorded with sepsis in the ED met both the Sepsis-2 and Sepsis-3 criteria (80%), while the rate of misdiagnosis was similar (Sepsis-2: 16/91, 17.6% and Sepsis-3: 14/91, 15.4%). The most important identified risk factors in sepsis were old age (60+ years) and comorbidities (CCI ≥ 4). Elevated LDH (median 325 mg/dL) and decreased albumin levels (median 26 g/L) can be used as early indicators of sepsis. Although the time to first antibiotic administration was not associated with significantly better clinical outcomes, the guideline-adherent agent selection (Sepsis-2: 18/43, 41.9% and Sepsis-3: 19/46: 41.3%) led to a significantly longer survival (median 37 vs. 4 days). Conclusions: No significant differences were found in diagnostic accuracy or prediction of mortality between Sepsis-2 and Sepsis-3. Guideline-adherent antibiotics may lead to significantly higher survival rate in sepsis. Full article

Background: The Patient Outcome Assessment and Decision Support (PADS) model is a real-time framework designed to predict both mortality and the likelihood of discharge within 48 h in critically ill patients. By combining these predictions, PADS enables clinically meaningful stratification of patient trajectories, supporting bedside decision-making and the planning of critical care resources such as nursing allocation and surgical scheduling. Methods: PADS integrates routinely collected clinical data: SOFA variables, age, gender, admission type, and comorbidities. It consists of two Long Short-Term Memory (LSTM) neural networks—one predicting the probability of death and the other the probability of discharge within 48 h. The combination places each patient into one of four states: alive/discharged within 48 h, alive/not discharged, dead within 48 h, or dead later. The model was trained using MIMIC-IV data, emphasizing ease of implementation in units with electronic health records. Out of the 76,540 stays present in MIMIC-IV (53,150 patients), 32,875 (25,555 patients) were used after excluding those with short stays (<48 h) or life support treatment limitations. The code is open, well-documented, and designed for reproducibility and external validation. Results: The model achieved strong performance: AUCROC of 0.94 (±0.03) for mortality and 0.89 (±0.07) for discharge on training data, and 0.87 (±0.02) and 0.88 (±0.03), respectively, on the test set. As a comparison, benchmark models obtain worse accuracy (−13.4% for APS III, −19% for OASIS, and −7.4% for SAPS II). Predictions are visualized in an intuitive format to support clinical interpretation. Conclusions: PADS offers a transparent, reproducible, and practical tool that supports both individual patient care and the strategic organization of intensive care resources by anticipating short-term outcomes. Full article

Background/Objectives: Acetylsalicylic acid (ASA) medication has been suggested to have a beneficial effect on cancer risk and survival. Therefore, this retrospective case–control study investigated the correlation between ASA and HNC in over 11,000,000 patients to investigate the impact of ASA intake on the risk of developing HNC, five-year survival rates, and the likelihood of secondary malignant neoplasms and malignant lymph node involvement. Methods: Retrospective clinical data was retrieved from a federated EHR network. Patients prescribed ASA were assigned to Cohort I, while those who were not prescribed ASA were assigned to Cohort II. Moreover, patients diagnosed with HNC, and prescribed ASA were assigned to Cohort III, while those with HNC but no history of ASA use were assigned to Cohort IV. Results: After matching, Cohorts I and II included 5,716,056 patients each. HNC incidence was significantly lower (OR 0.88; 95% CI 0.86–0.90) in Cohort I (+ASA) compared to Cohort II (−ASA). Furthermore, five-year survival was higher for patients taking ASA medication (survival probability 67.93%) compared to patients who did not (65.54%). These findings coincide with a lower risk of death of 22.8% (+ASA) compared to 23.6% (−ASA), which was statistically significant (p = 0.006). Patients with ASA intake also showed a lower risk of malignant neoplasms of lymph nodes (17.4% vs. 18.5%). Conclusions: Our analyses revealed a lower risk of HNC, a higher five-year survival rate, and a lower risk of malignant neoplasms of lymph nodes in patients with ASA medication. However, the retrospective design and the lack of evaluation of confounders limit the significance of our data, and, therefore, further analyses should be considered. Full article

Background: Tariquidar (Tq) is an inhibitor of the multidrug resistance (MDR) proteins relevant to ATP-binding cassette transporters (ABC transporters), which suppresses the ATP-dependent efflux of a variety of hydrophilic and amphipathic compounds, including anticancer drugs. Tq is a representative of a new generation of MDR inhibitors with high affinity to ABC proteins. However, there are still no data on the possible effect of Tq on mitochondria as an important target in the regulation of cell death or survival. Methods: We investigated the influence of Tq on the Ca²⁺-dependent mitochondrial permeability transition pore (mPTP). The effect of Tq was assessed using several parameters, including the calcium load, membrane potential, and mitochondrial swelling. To evaluate the specific targets of Tq, selective inhibitors of components of the mitochondrial pore were used, including adenine nucleotides, carboxyatractylozide (Catr) and bongkrekic acid (BA), oligomycin, and cyclosporine A. Results: Tq decreased the calcium retention capacity, activated mitochondrial swelling, and lowered the influence of ADP and ATP, the inhibitors of the Ca²⁺-induced pore opening, at their low concentrations. These effects of Tq were observed in both calcium-load and swelling assays, thus mimicking the effect of Catr, a selective inhibitor of adenine nucleotide translocase (ANT). Tq also decreased the protective effect of BA, an inhibitor of ANT and mPTP, on the calcium retention capacity of mitochondria. Further, Tq dose-dependently decreased the inhibitory effect of a low ATP concentration but not of high concentrations, at which the effect of Tq was activated by oligomycin, an inhibitor of F-ATP synthase. Conclusions: The influence of Tq extends to mitochondria, specifically to the regulation of membrane permeability, promoting the activation of pore opening, probably through an interaction with ANT, a component of the pore-forming complex. The effect of Tq on the opening of mPTP is strongly dependent on the concentrations of adenine nucleotides and, consequently, on the functional state of mitochondria. The direct influence of Tq on mitochondria can be considered as a new activity that promotes the sensitization of cells to various treatments and stimuli. Full article