Patients who survived critical COVID-19 frequently reported post-acute sequelae of COVID-19 (PASC) such as psychosomatic and neurocognitive health problems. The goal of this study was to identify clinical risk factors and other predictors for such long-term consequences in severely ill COVID-19 patients. Adult COVID-19 intensive care unit (ICU) survivors from August 2020 to May 2021 were enrolled. A broad range of clinical, laboratory and chest computed tomography (CT) data was collected during ICU stay. The association between ICU predictors and psychosomatic, respiratory and neurocognitive assessments 12 months after ICU discharge was analyzed using univariate regression analysis. In 17 patients (mean age 58.9 ± 11.4 years), laboratory markers (CRP, lymphocytes, hemoglobin), ICU severity (SOFA, SAPS II, need for mechanical ventilation), complications (ARDS), and lung CT data (ground-glass opacity) were promising predictors of depressive and anxiety symptoms, fatigue, and sleep problems. Recovery of psychosomatic health such as fatigue, depression and anxiety correlated with lower levels of inflammation and high hemoglobin levels. ARDS, mechanical ventilation and worse SOFA and SAPS II scores were further risk factors for depressive and anxiety symptoms. Our study identified novel associations such as pulmonary ground-glass opacity being positively associated with depression, anxiety, fatigue, and insomnia levels.

Despite the diaphragm's direct connection with the heart through the phreno-pericardial ligament, little is still known about the role of this primary breathing muscle in the cardiovascular system. The purpose of the present study was to determine the relationship of diaphragm muscle thickness, thickening, and strength with selected cardiovascular parameters. Thirty participants who qualified for a three-week post-COVID physiotherapy program were examined. Diaphragm muscle thickness on the left and right sides was assessed using ultrasound. Blood pressure and heart rate were evaluated by an automatic oscillometric device, while the rest of the cardiovascular parameters were calculated using standardized formulas from the literature. We found a relationship between the left diaphragm dome thickening ratio and systolic blood pressure, pulse pressure, stroke volume, cardiac index, ejection fraction, and saturation level measured after the 6-minute walk test (6-MWT). Patients with better left diaphragm dome strength were characterized by a lower difference in systolic blood pressure, pulse pressure, stroke volume, cardiac output, cardiac power output, ejection fraction, cardiac index, and pressure-heart rate product between pre- and post-6-MWT measurements. There was no correlation between right diaphragm dome function and cardiovascular parameters. There was no association of left and right hemidiaphragm function with resting cardiovascular parameters. In conclusion, the strength of the left hemidiaphragm plays an important role in the regulation and modulation of cardiovascular parameters during physical exertion.

Background: The objective of this study was to evaluate, the clinical benefit of benralizumab in patients with uncontrolled severe asthma associated with chronic rhinosinusitis with nasal polyposis (CRSwNP). Methods: The study included patients with uncontrolled severe asthma associated with CRSwNP who started therapy with benralizumab. Pulmonary function, eosinophilia, IgE, comorbidity, changes in the Asthma Control Test (ACT), Asthma Control Questionnaire (ACQ), Visual Analogue Scale (VAS), Quality of Life (AQLQ), VAS (obstruction, drip, anosmia, facial pressure), SNOT-22, decrease or withdrawal of steroids and other medication, hospital admissions and emergency visits were analysed. The FEOS scale and EXACTO were employed in the assessment of response. Results: We analyzed 58 patients who completed minimal treatment at 12 months. After treatment with benralizumab, exacerbations were reduced by 82% (p

Epilepsy is a non-communicable neurological disease characterized by abnormal brain activity with conceivable peripheral implications. Few studies examine the role of peripheral and brain inflammation in the relationship between seizure predisposition and nonalcoholic fatty liver disease. Severe early-life infections leading to sepsis results in increased inflammation that can aggravate epilepsy and hepatic damage progression both associated with increased odds for hospital admissions in epileptic patients. Here, we examined the effect of early LPS challenge (1 mg/kg, i.p. at post-natal day3, PND3) in inducing hepatic damage in a genetic model of young epileptic WAG/Rij rats (PND45), evaluating the intra- and inter-gender differences on systemic and liver inflammation, hepatic lipid dysmetabolism and oxidative damage associated to mitochondrial functional impairment. First, epileptic rats exposed to LPS, regardless of gender, displayed increased serum hepatic enzymes and altered lipid profile. Early LPS challenge induced a major inflammatory and immune response in male epileptic rats than females in both serum and liver, increasing pro-inflammatory cytokines and hepatic immune cell recruitment. Conversely, LPS-insulted females showed a marked alteration in hepatic metabolic and lipid profile and the reduction in mitochondrial fatty acid oxidation. The two different gender-related mechanisms of LPS-induced liver injury converge in mitochondrial oxidative damage with intensified ROS production in both sexes, that notably induced a compensatory increase in antioxidant defense only in females. Our study with a translational potential points out that early postnatal infections predispose epileptic rats to develop or worsen hepatic disorders in a sex-dependent manner, amplifying inflammation, lipid dysmetabolism, and mitochondrial impairment.

Background: Infective endocarditis (IE) remains a difficult disease to diagnose and treat, with a persistently high mortality rate. There is a lack of recent data on IE in Bulgaria over the last decades. Methods: The study is retrospective, single centered, includes 270 patients diagnosed with IE, for the period 2005 - 2021. We compared the two periods 2005-2015 (n=119) and 2016-2021 (n=151) to find the characteristics changes. Results: The median age was 65 (23) years and 65.5% (177) were male. In the second period, there is a significant increase in age from 62 (29) to 67 (22), (p=0.023); Charlson comorbidities index (CCI) from 3 (3) to 4 (4), (p=0.000); cases with chronic kidney diseases (CKD) from 12.6% (15) to 36.9% (55), (p=0.001); coronary arterial diseases (CAD) from16.85% (20) to 29.1% (44), (p=0.018); atrial fibrillation (AF) from 10.9% (13) to 23.8% (36), (p=0.006). Injection fraction decreased significantly in the second period from 63 (14) to 59 (15), (p=0.000). Almost half of the patients 45.6% (123) had no known predisposing cardiac condition and 46.3 (125) had an unknown port of entry. IE was community-acquired in 173 (64.1%), healthcare-associated in 26.7% (72), and injection drug use related IE in 9.3% (25).The study population included 67.8% (183) native valve IE, 31.5% (85) prosthetic IE, and 0.74% (2) intracardiac device­related IE. The hemoculture were positive in 59.6%, and the most frequent pathogenic agent was Staphylococcus - 33.3 % ( aureus – 16.5 % and coagulase negative - 16.8 %). Only 20% of patients underwent early surgery. The all­cause 30 days mortality rate was 24.8%. There is no significant difference between the two periods in terms of the characteristics listed above. Conclusion: The profile of IE in Bulgaria has changed with increasing age and comorbidity, changing predisposing cardiac conditions and entry door. The most common pathogen was the Staphylococcus group. The 30 day mortality rate remains high.

LCK, a member of the Scr kinase family, is a non-receptor tyrosine kinase involved in immune cell activation, antigen recognition, tumor growth, and cytotoxic response. The enzyme has usually been linked to T lymphocyte activation upon antigen recognition. Lck activation is central to CD4, CD8, and NK activation. However, recently, it has become clearer that activating the enzyme in CD8 cells can be independent of antigen presentation and enhance cytotoxic response. The role of Lck in NK cytotoxic function has been controversial in a similar fashion as the role of the enzyme in CAR T cells. Inhibition of Lck has been mainly to treat hematologic malignancies with a high rate of success. They may be useful in treating other tumor types, and they may be useful to prevent cell exhaustion. New, more selective inhibitors have been documented, and they have shown inter-esting activities not only in tumor growth but in the treatment of autoimmune diseases, asthma, and graft vs host disease. Drug repurposing and bioinformatics can aid in solving several unsolved is-sues on the role of Lck in cancer. In summary, the role of Lck in immune response and tumor growth is not a simple event and requires more research.

Hypoxia contributes to tumor progression and metastasis, and hypoxically dysregulated RNA molecules may thus be implicated in poor outcomes. Canine oral melanoma (COM) has a par-ticularly poor prognosis, and some hypoxia-mediated miRNAs are known to exist in this cancer; however, equivalent data on hypoxically dysregulated other non-coding RNAs (ncRNAs) are lacking. Accordingly, we aimed to elucidate non-miRNA ncRNAs that may be mediated by hy-poxia, targeting primary-site and metastatic COM cell lines and clinical COM tissue samples in next generation sequencing (NGS), with subsequent qPCR validation and quantification in COM primary and metastatic cells, plasma and extracellular vesicles (EVs) for any identified ncRNA of interest. Findings suggested that a number of non-miRNA ncRNA species are hypoxically up- or downregulated in COM. We identified one ncRNA, the long ncRNA fragment EN-SCAFT00000084705.1, as a molecule of interest due to its consistent downregulation in COM tissues, hypoxically and normoxically cultured primary and metastatic cell lines, when compared to the oral tissues from healthy dogs. However, this molecule was undetectable in plasma and plasma EVs, suggesting that its expression may be tumor tissue-specific and it has little potential as a biomarker. Here, we provide evidence of hypoxic transcriptional dysregulation for ncRNAs other than miRNA in COM for the first time, and suggest that ncRNA ENSCAFT00000084705.1 is a molecule of interest for future research on the role of the transcriptome in hypoxia-mediated progression of this aggressive cancer.

Minimal/mild endometriosis (MME) is independently associated with reduced fecundity rates. In this review article, we discuss the role of laparoscopic surgery in enhancing fertility outcomes of patients with MME. Laparoscopic management of MME enhances fecundity and increases chances of spontaneous conception in appropriately selected cases. However, laparoscopy cannot be routinely recommended in asymptomatic patients with the sole purpose of diagnosing and treating potentially present MME. Equally, based on existing evidence, laparoscopic management of MME cannot be routinely recommended prior to in-vitro fertilisation (IVF) attempts, as robust evidence of benefit is lacking. As an overlap between unexplained infertility and MME cases likely exists, the development of reliable, widely available, non-invasive tests for the diagnosis of MME may revolutionize the management of cases currently classified as unexplained infertility. In a disease as diverse as endometriosis, management decisions should be based on a multitude of factors. Future studies should focus on reporting outcomes of interventions for MME on fertility and obstetric outcomes, clearly differentiating between disease stages and phenotypes.

Increased activity of transforming growth factor-beta (TGF-β) is a key factor mediating kidney impairment in diabetes. Glomerular podocytes, the crucial component of the renal filter, are a direct target of TGF-β action, resulting in irreversible cell loss and progression of chronic kidney disease (CKD). Urolithin A (UA) is a member of the family of polyphenol metabolites produced by gut microbiota from ellagitannins and ellagic acid-rich foods. The broad spectrum of biological ac-tivities of UA makes it a promising candidate for the treatment of podocyte disorders. In this in vitro study, we investigated whether UA influences the changes exerted in podocytes by TGF-β and high glucose. Following a 7-day incubation in normal (NG, 5.5 mM) or high (HG, 25 mM) glucose the cells were treated with UA and/or TGF-β1 for 24 hours. HG and TGF-β1, each independent and in concert reduced expression of nephrin, increased podocyte motility and up-regulated expression of b3 integrin and fibronectin. These typical for epithelial-to-mesenchymal transition (EMT) effects were inhibited by UA in both HG and NG conditions. UA also reduced the typically elevated in HG expression of TGF-β receptors and activation of TGF-β signal transducer Smad2. Our results indicate that in podocytes cultured in conditions mimicking diabetic milieu, UA inhibits and reverses changes underlying podocytopenia in diabetic kidneys. Hence, UA should be considered as a po-tential therapeutic agent in podocytopathies.

In Parkinson's disease, neuroinflammation is a complex defense mechanism. Activated microglia and Proteinase-activated receptor-2 (PAR2) are key points in the regulation of neuroinflammation. 1-Piperidin Propionic Acid (1-PPA) has been recently described as a novel inhibitor of PAR2. The aim of our study was to evaluate the effect of 1-PPA in neuroinflammation and microglial activation in Parkinson's disease. Protein aggregates and PAR2 expression were analyzed by thioflavin S assay and immunofluorescence in cultured human fibroblasts from Parkinson's patients, treated or not with 1-PPA. A significant decrease of amyloid aggregates and expression of PAR2 were observed after 1-PPA treatment in all patients. A parallel decrease of PAR2 expression, that was higher in sporadic Parkinson’s patients, was also observed both at transcriptional and protein level. In addition, in mouse LPS-activated microglia, the inflammatory profile was significantly downregulated after 1-PPA treatment, with a remarkable decrease of IL-1, IL-6 and TNF-togheter with PAR2 decreased expression.In conclusion, 1-PPA determines reduced neuroglia inflammation and amyloid aggregates formation, suggesting that pharmacological inhibition of PAR2 could be proposed as a novel strategy to control neuroinflammation.

Severe inherited alpha-1 antitrypsin deficiency (AATD) is an autosomal genetic condition linked to chronic obstructive pulmonary disease (COPD). The significance of heterozygous, milder deficiency variants (Pi*M, Pi*S, Pi*Z) is less clear. We studied AATD genotypes in 145 children (up to 72 months old) with assessed wheezing severity using the Pediatric Respiratory Assessment Measure (BCCH PRAM score). A control group of 74 children without airway obstruction was included. AAT concentration and Pi phenotype were determined from dry blood spot samples using nephelometry and real-time PCR; PiS and PiZ alleles were identified by isoelectrofocusing. Among the wheezers, the Pi*S allele incidence was 2.07% (3 cases) and Pi*Z allele was 6.9% (10 cases). The Pi*Z allele frequency was higher in wheezers compared to controls (44.8% vs. 20.27%) and the general Lithuanian population (44.8% vs. 13.6%) and was similar to adult COPD patients in Lithuania: Pi*S 10.3% vs. 15.8% and Pi*Z 44.8% vs. 46.1%. No association was found between AAT genotypes and wheezing severity. Finding that wheezer children exhibit a frequency of Z* and S* alleles like that found in adults with COPD suggests a potential genetic predisposition that links early wheezing in children to the development of COPD in adulthood. Larger cohort studies are needed to confirm this finding.

Crohn’s disease (CD) is a chronic inflammatory disease associated with a significant burden in terms of quality of life and health care costs and is frequently associated with several complications, including the development of intestinal strictures. Stricturing CD requires a careful multidisciplinary approach involving medical therapy and surgery, still posing a continuous management challenge; in this context, endoscopic treatment represents a valuable, in-between opportunity as a minimally invasive strategy, endorsed by extensive yet heterogeneous evidence and evolving research and techniques. This review summarizes current knowledge on the role of therapeutic endoscopy in stricturing CD, focusing on evidence gaps, recent updates, and novel techniques intended for optimizing efficacy, safety, and tailoring of this approach in the view of precision endoscopy.

Background: Ventilator-associated pneumonia (VAP) is among the most common healthcare-associated infections in Pediatric Intensive Care Units (PICUs). Because of the lack of a gold-standard diagnostic test, early diagnosis of VAP is challenging. We investigated whether bronchial biomarkers interleukin-4 (IL-4), plasminogen activator inhibitor-1 (PAI-1) and soluble receptor for advanced glycation end products (RAGE) could contribute in early VAP diagnosis through their fluctuation in time in critically ill pediatric patients. Methods: Bronchial secretions were collected from PICU patients with VAP on days 1 and 6. PAI-1, RAGE and IL-4 levels were measured by ELISA. Protein concentrations between high and low VAP suspicion patients were compared using unpaired Student’s t or Mann–Whitney U tests. Results: Twenty PICU patients, with median age 7.75yrs (range 0.5-15.3), mechanically ventilated for ≥48hrs with increased oxygenation requirements and VAP clinical/laboratory signs were enrolled. They were divided in VAP high-suspicion (n=12) or low-suspicion (n=8) groups based on Clinical Pulmonary Infection Score (cutoff:6). ΡΑΙ-1 και RAGE levels did not differ between high- or low-VAP suspicion groups the 1st or 6th days (p-value>0.05). IL-4 was not detected in bronchial secretions. Conclusion: Bronchial concentrations of IL-4, PAI-1 and RAGE in critically ill children are not correlated with high- or low-VAP suspicion.

Background: To evaluate derived neutrophil to lymphocyte ratio (dNLR) in predicting the prognosis of patients with locally advanced oral squamous cell carcinoma (LAOSCC), and the survival benefits from docetaxel, cisplatin, and 5-FU (TPF) induction chemotherapy (IC); Methods: Patients from a phase III trial involving TPF IC in stage III/IVA OSCC patients (NCT01542931) were enrolled. Receiver operating characteristic curves were built and area under the curve was computed to determine dNLR cutoff points. Kaplan-Meier estimates of survival and Cox proportional hazards models were used for longitudinal analysis; (3) Results: 224 patients were identified (median age, 55.4 yr; range, 26 to 75 yr; median follow-up, 90 months; range, 3.2 to 93 months); Cutoff points for dNLR was 1.555. Multivariate analysis showed dNLR was an independent negative predictive factor for survival (overall survival (OS): hazard ratio (HR) = 1.154, 95% confidence interval (CI): 1.018-1.309, P = 0.025, disease-free survival (DFS): HR = 1.123, 95% CI: 0.260-1.000, P = 0.050, local recurrence-free survival (LRFS): HR = 1.134, 95% CI: 1.002-1.283, P = 0.047, distant metastasis-free survival (DMFS): HR = 1.146, 95% CI: 1.010-1.300, P = 0.035). Low dNLR combining cTNM stage III disease predicts benefit from TPF IC for the patients [OS (χ² = 4.674, P = 0.031), DFS (χ² = 7.134, P = 0.008), LRFS (χ² = 5.937, P = 0.015) and DMFS (χ² = 4.832, P = 0.028)]; (4) Conclusions: dNLR is an independent negative predictive factor in LAOSCC patients. Patients of cTNM stage III and low dNLR can benefit from TPF IC.

Endocrine disruptors are molecules that can interfere with the proper functioning of the endocrine system and lead to harmful effects in living organisms. This review focuses on the impact of synthetic fragrances, which are commonly found in personal care and household products, on the endocrine system. The article discusses the different types of hormones in the body and how they interact with receptors to produce signals. It also explores how endocrine disruptors can interfere with hormone signaling and transport, leading to adverse effects in the body. This work underscores the crucial need for further research into the impact of synthetic fragrances on the endocrine system and the importance of using safer alternatives in personal care and household products.

An HFMD outbreak spread over the city of Hải Phòng from Summer 2011 to Autumn 2012. This epidemic was chosen because it was the very first HFMD epidemic in North Vietnam, eliminating thus interferences with previous outbreaks. This epidemic displayed 3 separate waves. A complete dataset was collected for more than 9500 patients during this period, which enabled us to analyze this epidemic at different scales. Access to the healthcare system was crucial during this period, with a reorganization of the system in February-March 2012. An analysis at commune level enables us to track the epidemic along certain communication routes. The three-waves structure reveals a wide disparity at district level. We develop a mathematical model showing high accuracy at the adjustment of data for both the total number of cases and for the number of cases per week. As a consequence, the model was able to accurately determine the dates of beginning and end of each wave and to show that they overlapped. Using mathematical functions associated with this model, it was possible to calculate the probability for a patient to belong to a specific wave.

The SARS-CoV-2 nucleocapsid protein (N protein) is critical to viral replication by undergoing liquid-liquid phase separation to seed the formation of a ribonucleoprotein (RNP) complex to drive viral genomic RNA (gRNA) translation and in also suppressing both stress granules and processing bodies which is postulated to increase uncoated gRNA availability. The N protein can also form biomolecular condensates with a broad range of host endogenous proteins including RNA binding proteins (RBPs). Amongst these RBPs are proteins that are associated with pathological neuronal and glial cytoplasmic inclusions across several adult-onset neurodegenerative disorders, including TAR DNA binding protein 43 kDa (TDP-43) which forms pathological inclusions in over 95% of amyotrophic lateral sclerosis cases. In this study, we demonstrate that the N protein can form biomolecular condensates with TDP-43 and that this is dependant on the N protein C-terminus domain (N-CTD) and the intrinsically disordered C-terminus domain of TDP-43. This process is markedly accelerated in the presence of RNA. In silico modelling suggests that the biomolecular condensate that formed in the presence of RNA is composed of a N protein quadriplex in which the intrinsically disordered TDP-43 C terminus domain is incorporated.

Introduction: Treating elbow fracture-dislocation is a challenge, especially in the situation of basal-coronoid trans-ulnar fracture. The study ams to explain whether or not the minimal invasive surgery (MIS) would be feasible in elbow dislocation with coronoid fracture. Materials & Methods: At Taipei Veterans General Hospital, patients who had elbow dislocations with coronoid process fractures underwent single one surgeon’s MIS techniques which included the fluoroscopy-guided ulnar anteromedial (FGUAM) approach in the stage of reducing coronoid process. When there is a proximal ulnar fracture, the posterior incision should be necessary, followed by the incision over the lateral or medial elbow in treating radial fractures or ligament injuries. Results: The Flow Diagram about approach recommendation was established in base of defining MIS as not to do cross-plane dissection. Anteriorly rigid fixation for the coronoid process was also emphasized. Conclusions: MIS can be achieved by multiple limited surgical incisions. However, if there is an unstable ulnar metaphysis or ligament avulsion fracture, the posterior approach has to be extended and the so-called MIS fails to be established.

HIV infection is a nowadays pathology that affect persons from all of the world. Pathogenesis of the HIV-infection and cancer is a great problem, with a complexity directions in research. More important in HIV infection to patients, is also to take into consideration others things, such as prevention, diagnosis, monitoring, treatment, including control measures. This previously mentioned, should be supported by statistical studies that report on restricted or extended geographical areas, to the level of social class and age. In our written text we try to describe from our opinion, strategies in HIV, infection, status knowing as a social and as a healthcare problem.

Background: Prediction of neurorehabilitation outcomes after a Spinal Cord Injury (SCI) is crucial for healthcare resource management and improving prognosis and rehabilitation strategies. Arti-ficial neural networks (ANNs) have emerged as a promising alternative to conventional statistical approaches for identifying complex prognostic factors in SCI patients. Materials: a database of 1256 SCI patients admitted for rehabilitation was analyzed. Clinical and demographics data and SCI characteristics, were used to predict functional outcomes using both ANN and linear regression models. The former was structured with input, hidden, and output layers, while the linear regression identified significant variables affecting outcomes. Both ap-proaches aimed to evaluate and compare their predictive accuracy for rehabilitation outcomes measured by the Spinal Cord Independence Measure (SCIM) score. Results: Both ANN and linear regression models identified key predictors of functional outcomes, such as age, injury level, and initial SCIM scores (correlation with actual outcome: R=0.75 and 0.73, respectively). When alimented also with parameters recorded during hospitalization, the ANN highlighted the importance of these additional factors like motor completeness and compli-cations during hospitalization, showing an improvement in its predictive accuracy (R=0.87). Conclusion: ANN seemed to be not widely superior to classical statistics in general, but, taking into account complex and non-linear relationships among variables, emphasized the impact of complications during the hospitalization on recovery, particularly respiratory issues, deep vein thrombosis, and urological complications. These results suggested that the management of com-plications is crucial for improving functional recovery in SCI patients.

Background: Chorea is a neurological disorder characterized by random, fluid movements that may affect the limbs, trunk, neck or face. In children, Sydenham's chorea (SC) is the most common cause of acute chorea, mainly following group A beta-hemolytic streptococcal (GABHS) infection. Other autoimmune and metabolic disorders may also cause chorea. Case presentation: We report the case of a 6-year-old girl who developed chorea following cardiac surgery for mitral insufficiency. One week after discharge, the patient presented with right-sided hyposthenia, slower speech, mild dysarthria and sialorrhea. Brain MRI and intracranial MRI angiography revealed a small vascular focus consistent with a microembolic event. Extensive diagnostic investigations, including serum panels for autoimmune encephalitis, neurotropic viruses and metabolic disorders, were negative. Conclusion: Considering the patient's history, clinical course, and exclusion of other potential causes, a diagnosis of post-pump chorea was made. This case underlines the importance of a thorough differential diagnosis in pediatric chorea and highlights post-pump chorea as a significant postoperative complication in pediatric cardiac surgery. The patient's motor symptoms improved with symptomatic treatment and follow-up showed good recovery without neurological sequelae.

Background: Humankind have faced unexperienced pandemic events since 2020. After COVID-19 pandemic is calming down, we felt the need to verify whether in-hospital mortality had worsened compared to pre-pandemic conditions due to the COVID-19 pandemic. Objective: To test the hypothesis that daily food consumption is associated with in-hospital mortality during hospitalization and to provide baseline data to examine the effects of COVID-19 in post-pandemic exists or not. Methods: All hospitalized patients staying in a single institution on the third Thursday of May, August, November, and the following next February were included. Compared data: 1) among four seasons, 2) between age < vs.

The choice of dialysate buffer in hemodialysis is crucial, with acetate being widely used despite complications. Citrate has emerged as an alternative due to its favorable effects, yet concerns persist about its impact on calcium and magnesium levels. This study investigates the influence of citrate dialysate (CD) with and without additional magnesium supplementation on CKD-MBD biomarkers and assesses their ability to chelate divalent metals compared to acetate dialysates (AD). A prospective crossover study was conducted in a single center, involving patients on thrice-weekly online hemodiafiltration (HDF). Four dialysates were compared: two acetate-based and two citrate-based. Various biochemical parameters were monitored before and after each dialysis session. Seventy-two HDF sessions were performed in eighteen patients. CD showed stability in iPTH levels and reduced post-dialysis total calcium, with no significant increase in adverse events. Magnesium supplementation with CD prevented hypomagnesemia. However, no significant differences among dialysates were observed in the chelation of other divalent metals. Citrate dialysates, particularly with higher magnesium concentrations, offer promising benefits, including prevention of hypomagnesemia and stabilization of CKD-MBD parameters, suggesting citrate as a viable alternative to acetate. Further studies are warranted to elucidate long-term outcomes and optimize dialysate formulations.

Multidrug resistant organisms (MDROs) outbreaks have been steadilyincreasing in Intensive care units (ICUs). Still, healthcare institutions and workers (HCW) reached no unanimity on how and when implementing infection prevention and control (IPC) strategies. We aimed to provide a pragmatic, physician practice-oriented, resume of strategies towards different MRDOs outbreaks in ICU. We performed a narrative review on IPC in ICUs, investigating patient-to-staff ratios, education, isolation, decolonization, screening and hygiene practices, outbreak reporting, cost-effectiveness, reproduction-number(R0), and future perspectives. The most effective IPC strategy remains unknown. Most studies focus on a specific pathogen or disease, making the clinician losing the big picture. IPC strategies proved their cost-effectiveness regardless typology, country, or pathogen. A standardized, universal, pragmatic protocol for HCW education should be elaborated. Likewise, a rapid outbreak recognition tool elaboration (i.e., an easy-to-use mathematical model) would improve early diagnosis and spreading prevention. Further studies are needed to express in favor or against MDROs decolonization. New promising strategies are emerging and need to be tested in the field. The lack of IPC strategies application has made, and still makes ICUs a major MDROs reservoir into the community. In a not-too-distant future genetic engineering and phage therapies could represent a plot-twist in MDROs IPC strategies.

Objectives: To investigate the etiology of amyotrophic lateral sclerosis (ALS) in an adult female patient. Methods: We conducted trio genome sequencing on a 35-year-old woman with progressive weakness in her left upper limb, as well as on her parents. Prior to sequencing, we performed a comprehensive neurological work-up on the patient, including neurological exam, electrophysiology, biomarker assessment, and brain and spinal cord MRI. Results : The propositus experienced weakness and atrophy in her left hand 6 months before the evaluation. This was associated with brisk reflexes and Hoffman sign in the same arm. Electroneuromyography revealed lower motor neuron involvement in three body regions. Neurofilament light chains were elevated in her cerebrospinal fluid. Brain imaging showed asymmetrical T2 hyperintensity of the corticospinal tracts and T2 linear hypointensity of the precentral gyri. Genome trio sequencing identified a likely pathogenic de novo variant in the propositus’s KIF1A gene (NM_001244008.2): c.574A&gt;G, p.(Ile192Val). Discussion: Pathogenic variants in the KIF1A gene have been associated with a wide range of neurological manifestations called KIF1A-associated neurological diseases (KAND). The present report describe a likely pathogenic de novo variant in KIF1A associated with ALS, expanding the phenotypic spectrum of KAND and our understanding of the pathophysiology of ALS.

We conducted a retrospective evaluation of the clinical outcomes and prognostic factors in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) treated with first-line androgen receptor signaling inhibitors (ARSI) in real-world clinical practice in Japan. Between 2012 and 2023, a total of 127 consecutive patients with nmCRPC received ARSI treatment. Overall survival (OS), metastatic-free survival (MFS), and prostate-specific antigen progression–free survival (PSA-PFS) from ARSI initiation were assessed using Kaplan–Meier methodology. Clinical factors associated with OS in nmCRPC were analyzed using the Cox proportional hazards model. Among the patients, 72, 26, 12, and 17 received enzalutamide (ENZ), abiraterone (ABI), apalutamide (APA), and darolutamide (DARO) as first-line therapy. The median OS and MFS for all patients were 79.0 and 42.0 months, respectively. Median PSA-PFS was 27.0, 20.0, 10.0, and 14.0 months for patients treated with ENZ, ABI, APA, and DARO, respectively (p = 0.33). Multivariate analysis revealed that a baseline PSA level ≥3.67 ng/ml at ARSI initiation was significantly associated with poorer OS (p = 0.002). ARSI demonstrated favorable efficacy in nmCRPC patients. There were no significant differences in clinical outcomes among different types of ARSI therapy for nmCRP. Elevated baseline PSA at ARSI initiation was significantly associated with poorer OS.

Rhodiola rosea, a perennial herb from the Crassulaceae family, contains the bioactive compound salidroside, recognized as an adaptogen with significant therapeutic potential for bone metabolism. Salidroside promotes osteoblast proliferation and differentiation by activating critical signaling pathways, including bone morphogenetic protein-2 and adenosine monophosphate-activated protein kinase, essential for bone formation and growth. It enhances osteogenic activity by increasing alkaline phosphatase activity and mineralization markers, while upregulating key transcription factors such as runt-related transcription factor 2 and osterix. Additionally, salidroside facilitates angiogenesis via the hypoxia-inducible factor 1-alpha and vascular endothelial growth factor pathway, crucial for coupling bone formation with vascular support. Its antioxidant properties offer protection against bone loss by reducing oxidative stress and promoting osteogenic differentiation through the nuclear factor erythroid 2–related factor 2 pathway. Salidroside's ability to counteract the negative effects of glucocorticoids on bone cells and prevent steroid-induced osteonecrosis, along with its anti-inflammatory properties, enhances its potential in treating conditions like osteoarthritis. These attributes underscore its multifaceted role in bone metabolism. This article reviews the literature, including in vitro and in vivo studies primarily on rodent models, demonstrating salidroside's efficacy in mitigating bone loss, preserving bone microarchitecture, and accelerating fracture healing. Future research directions to explore salidroside’s applications in bone-related diseases are also highlighted.

Sick sinus syndrome (SSS) is a disease of sinus rhythm abnormalities. This study aimed to establish an SSS model by injecting 3% NaOH into the jugular vein(JV). Sprague-Dawley rats were randomly divided into sham, 3% NaOH, and 10% NaOH groups. Anesthetized rats underwent electrocardiogram recording before right JV exposure. Rats in the experimental groups received NaOH injections at 0.01 ml/s, while the sham group did not. Model success was evaluated after one hour. Heart rate(HR) and rhythm were documented at 1 hour, 1 week, and 2 weeks post-molding, including HE staining, membrane ion transcription and expression, and calcium ion content test. In the 3% NaOH group, the model establishment rate was 87%, and the mortality rate was 13%, whereas in the 10% NaOH group, they were 57% and 43% respectively (P < 0.01). The HR of the 3% NaOH group decreased at multiple time points post-molding (P < 0.001), presenting as arrhythmias such as sinus bradycardia. The JV sustained less damage, with necrosis of P cells, changes in membrane ion channels, and reduced calcium ion distribution. In conclusion, JV injection of 3% NaOH can establish the SSS model and benefit animals.

Introduction. Anesthesia is widely used in various fields of dentistry to reduce patient discomfort when the treatment would be painful. The dentist may need to infiltrate the anesthetic into multiple locations and this is usually done with the same needle which passes through the soft tissues several times to distribute the anesthetic solution over a larger area. The present study aims to evaluate, through a morphological analysis under a scanning electron microscope (SEM), how the beveled tip of a 30G needle, used to inject anesthetic several times into different areas of the vestibular mucosa, changes. Materials and methods. 30G needles with two different brands were tested, in vivo used for a variable number of sequential injections from 1 to 6 on 192 patients. The specimens were analyzed under SEM observation to evaluate any deformations induced by contact with the vestibular soft tissues. Results. The amount of deformation, measured along the axis parallel to the needle, was proportional to the number of injections. The protrusion of deformations, measured on an axis perpendicular to the needle, were maximum on the needles used 3 times. For the needles used 4,5 and 6 injections, no further increase in deformations was noted. Conclusion. From the data it seems that the tested needles are not produced to withstand multiple injections consequently after the first injection on soft tissues, they undergo a deformation which could increase the risk of injury to the mucosa itself or to nerves and vessels with which they come into contact. It would be advisable to use the single needle for a reduced number of injections.

Pulmonary artery stenosis represents a group of disorders involving main, branch or peripheral pulmonary arteries resulting either in pain, dyspnea, hemoptysis or even no symptoms. Early diagnosis and timely intervention are crucial for reducing mortality, while timely diagnosis is challenging due to the nonspecific symptoms. Computed tomography pulmonary angiography (CTPA) is useful in the diagnosis because it can provide more details about the abnormal changes in the lumen, vessel wall and adjacent mediastinal structures. Congenital and acquired pulmonary artery anomalies have some characteristics on CTPA, which can be useful for differential diagnosis. Awareness of these conditions and is important for the radiologists. This pictorial review provides an overview of CTPA imaging features of pulmonary artery stenosis.

Celiac disease is a gluten-sensitive immune-mediated enteropathy of the small intestine that occurs in genetically predisposed individuals. Abnormal immune response results in mucosal inflammation, villous atrophy, and crypt hyperplasia. This study was a proof-of-concept exercise that used a convolutional neural network to classify hematoxylin and eosin (H&E) histological images of celiac disease, normal small intestine control, and non-specified duodenal inflammation; 7294, 11,642, and 5966 images, respectively. The trained network classified celiac disease images with high performance (accuracy 99.7%, precision 99.6%, recall 99.3%, F1-score 99.5%, and specificity 99.8%). Interestingly, when the same network (already trained for the 3 class images), analyzed duodenal adenocarcinoma (3723 images), the new images were classified as duodenal inflammation in 63.65%, small intestine control in 34.73%, and celiac disease in 1.61% of the cases. Finally, when the network was retrained using the 4 histological subtypes of images, all performance parameters were above 99% for celiac disease. In conclusion, the convolutional neural network (CNN)-based deep neural system was able to classify medical histological images with high performance. Narrow artificial intelligence (AI) is designed to perform tasks that typically require human intelligence, but it operates within limited constraints and is task specific.

Intermittent religious fasting increases a risk of hypo- and hyperglycemia in individuals with diabetes, but its impact in those without diabetes is poorly investigated. The study aim was to examine the effects of religious Bahá'í fasting (BF) on glycemic control and variability and compare these effects with time-restricted eating (TRE). In a three-arm randomized controlled trial, 16 subjects without diabetes were assigned to a BF, 16:8 TRE or control group. Continuous glucose monitoring and food intake documentation was conducted before and during the 19 days of intervention, and 24-hour mean glucose, glycemic variability indices, and glucotypes were assessed. BF and TRE groups, but not the control group, markedly reduced the daily eating window while maintaining macronutrient composition. Only the BF group decreased caloric intake (-677.8 ± 357.6 kcal, p=0.013), body weight (-1.92 ± 0.95 kg, p=0.011) and BMI (-0.65 ± 0.28 kg, p=0.006). Higher maximum glucose values were observed during BF in the within-group (+1.41 ± 1.04, p=0.039) and between-group comparison (BF vs. Control: p= 0.010 and TRE vs. BF: p= 0.022). However, there were no alterations of 24-hour mean glucose, intra- and inter-day glycemic variability indices, or glucotypes in any group. Proportions of time above and below range (70-180mg/dl) and HbA1c values remained unchanged. BF and TRE do not exhibit negative effects on glycemic control and variability in subjects without diabetes.

We present a case report of a 26-years-old female suffering from Coffin Siris Syndrome, who underwent orthodontic treatment and surgery to solve her malocclusion and improve her aes-thetics and functional occlusion. Methods: The presurgical phase involved multibracket self-ligating attachments, Damon prescription. The patient underwent maxillofacial surgery to correct the severe skeletal malocclusion and relocate the bone bases in the right relationship. The post-surgical orthodontic treatment was performed to complete the alignment. Results: The pa-tient improved her aesthetics and functional abilities. Conclusions: Syndromic patients can un-dergo orthodontictreatment if comorbidities and collaboration allow it. Support and collaboration of families and psychotherapists must be considered, but clinical cases of syndromic patients can be faced and solved. Obviously, each syndromic patient is considered unique, and the risk-benefit ratio must be correctly assessed for each one.

Percutaneous aortic valve replacement (TAVI) has become the treatment of choice for elderly patients with severe aortic valve stenosis because of its less invasiveness compared to surgery. However, it introduces new complications, such as vascular lesions, access site problems, paravalvular leaks, and aortic dissection. Aortic dissection after TAVI is rare but serious, occurring in 0.2% to 0.3% of cases, with both intraprocedural and late cases reported. This case study concerns a 68-year-old woman who developed Stanford B aortic dissection, external iliac artery dissection, and right common femoral artery occlusion after TAVI. Treatment included stenting of the iliac and common femoral arteries, followed by a staged procedure: debranching, thoracic endovascular aortic repair (TEVAR) and endovascular aneurysm repair (EVAR), with satisfactory results. This case, underscores the importance of vigilance in the management of TAVI-related complications to optimize patient care and outcomes.

Sickle cell disease (SCD) is a hereditary blood disorder characterized by abnormal hemoglobin, leading sickle shape of red blood cells. It has several vascular complications and the cerebrovascular ones are among the most frequent and severe both in children and in adults. This review summarizes the main neurovascular manifestations of SCD, including acute stroke, silent cerebral infarction, large vessel diseases (moyamoya arteriopathy and aneurysms) and brain bleeding. Both epidemiology, pathophysiology and treatment issues are addressed and prevention of cerebrovascular events, including silent cerebral infarctions, is particularly relevant in SCD patients, being associated to poor functional outcome and cognitive complaints. Transfusions and hydroxyurea are the main available therapy at the moment, but contraindications, availability and complications might prevent their long term use, particularly in low income countries. The role of Transcranial Doppler in monitoring the patients (mainly children) is analyzed and a practical approach has been selected in order to give the main messages from the actual knowledge for a better management of the SCD patients.

Recent advancements in mass spectrometry have significantly enhanced our understanding of complex lipid profiles, opening new avenues for oncological diagnostics. This review highlights the importance of lipidomics in the comprehension of certain metabolic pathways and its potential for the detection and characterization of various cancers, in particular melanoma. Through detailed case studies, we demonstrate how lipidomic analysis has led to significant breakthroughs in the identification and understanding of cancer types and its potential for detecting unique biomarkers that are instrumental in its diagnosis. Additionally, the review addresses the technical challenges and future perspectives of these methodologies, including their potential expansion and refinement for clinical applications. The discussion underscores the critical role of lipidomic profiling in advancing cancer diagnostics, proposing a new paradigm in how we approach this devastating disease, with particular emphasis on its application in comparative oncology.

Postoperative RT is recommended after breast conserving surgery and mastectomy (with risk factors). Consideration of pros and cons including potential side effects demands for optimization of adjuvant RT and a risk-adapted approach. There is clear de-escalation in fractionation - hypofractionation should be considered standard. For selected low risk situations PBI only or even the omission of RT might be appropriate. In contrast, tendencies in escalating RT are obvious. Preoperative RT seems attractive for patients in whom breast reconstruction is planned or for defining the tumor location more precisely with the potential of giving ablative doses. Dose escalation by a (simultaneous integrated) boost or the combination with new compounds/systemic treatments may increase antitumor efficacy but also toxicity. Despite low evidence, RT for oligometastatic disease is becoming increasingly popular. The omission of axillary dissection in node-positive disease led to an escalation of regional RT. Studies are ongoing to test if any axillary treatment can be omitted and which oligometastatic patients do really benefit from RT. Besides technical improvements the incorporation of molecular risk profiles but also the response to neoadjuvant systemic therapy have the potential to optimize the decision-making if and how local and/or regional RT should be administered.

Neurofibromas, rare benign tumors of the peripheral nerve sheath, present diagnostic challenges, particularly in diabetic patients with toe ulcers. This case involves a 55-year-old female with type 2 diabetes mellitus who developed an enlarging ulcer on her right second toe. The initial evaluation suggested a diabetic ulcer; however, advanced imaging revealed a mass-like lesion. Partial excision and biopsy confirmed a neurofibroma with spindle cells within the myxoid stroma and S100 protein expression. One month later, total excision and Z-plasty reconstruction were performed under general anesthesia. The patient’s postoperative recovery was uneventful, and the patient was discharged without complications. Follow-up revealed successful healing with no recurrence or functional issues. This case highlights the importance of considering neurofibromas in the differential diagnosis of diabetic toe ulcers to avoid misdiagnosis and ensure appropriate management.

This study is a retrospective analysis aimed to understand the incidence and risk factors of proximal junctional kyphosis (PJK) following long instrumented spinal fusion from L1 to the sacrum in patients with mild to moderate sagittal imbalance. It recruited consecutive patient undergone instrumented fusion from L1 to the sacrum for degenerative lumbar disease between June 2006 and November 2019 in a single institution. The patients’ preoperative clinical data, muscle status at T12-L1 on magnetic resonance images, and sagittal spinopelvic parameters were analyzed. Univariate analysis was used to compare clinical and radiographic data between PJK and non-PJK patients. Logistic regression analysis was used to investigate the independent risk factors for PJK. A total of 56 patients were included in the study. The mean age at surgery was 67.3 years and mean follow-up period was 37.3 months. Seven were male and 34 were female. PJK developed in 23 (41.1%) out of 56; of these patients, 20 (87.0%) developed PJK within postoperative 1 year. On univariate analysis between PJK and non-PJK patients, PJK group showed more frequent osteoporosis, lower body mass index, smaller cross-sectional area (CSA) and more fat infiltration (FI) in erector spinae muscle at T12-L1, larger preoperative TLK and PT with statistical significance (p&lt;0.05). On logistic regression analysis, severe (&gt;50%) FI in erector spinae muscle (OR=43.60, CI 4.10-463.06, R2N =0.730, p=0.002) and osteoporosis (OR=20.49, CI 1.58-264.99, R2N =0.730, p=0.021) were statistically significant. Preexisting severe (&gt;50%) fat infiltration in erector spinae muscle and osteoporosis were significant independent risk factors associated with PJK following instrumented fusion from L1 to the sacrum, but age was not a risk factor.

Esophageal cancer is an extremely deadly tumor that accounts for 5% of all cancer deaths. The two main subtypes of the disease are esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). To date, few studies analyse EAC for transcriptional signatures associated with diagnosis and/or prognosis, while most focus on the analysis of transcriptional profiles of ESCC. In this study, we used single-cell RNA sequencing (scRNA-seq) analysis of CD45+ cells enriched from Tumors and matched Non Tumor tissues from therapy naїve patients to identify all types of immune cells present in tumor immune infiltrate and its transcriptional profile. In addi-tion, we analysed the entire transcriptome in a cohort of 23 patients whose tissue biopsies were taken from Tumors and matched with Non Tumor tissue. The transcriptional signatures we obtained were then used to stratify a large cohort of TCGA EAC patients, demonstrating a strong association with their prognosis, as well as the ability to predict a patient's clinical outcome and better define the prognosis of EAC after surgery. In addition, these features may lead patients to effective therapies including immunotherapy approaches.

Heart failure (HF) is a syndrome characterized by signs and symptoms resulting from structural or functional cardiac abnormalities, confirmed by elevated natriuretic peptides or evidence of congestion. HF patients are classified according to left ventricular ejection fraction (LVEF). Worsening HF (WHF) is associated with increased short- and long-term mortality, re-hospitalization, and healthcare costs. Standard treatment of HF includes angioten-sin-converting enzyme inhibitors, angiotensin receptor-neprilysin inhibitors, mineralocorti-coid-receptor antagonists, beta-blockers, and sodium-glucose co-transporter 2 inhibitors. To manage systolic HF by reducing mortality and hospitalizations in patients experiencing WHF, treatment with vericiguat, a direct stimulator of soluble guanylate cyclase (sGC), is indicated. This drug acts by stimulating sGC enzymes, part of the nitric oxide (NO)-sGC-cyclic guanosine monophosphate (cGMP) signaling pathway, regulating the cardiovascular system by catalyzing cGMP synthesis in response to NO. cGMP acts as a second messenger, triggering various cellular effects. Deficiencies in cGMP production, often due to low NO availability, are implicated in cardiovascular diseases. Vericiguat stimulates sGC directly, bypassing the need for a functional NO-sGC-cGMP axis, thus preventing myocardial and vascular dysfunction associated with de-creased sGC activity in heart failure. Approved by the FDA in 2021, vericiguat administration should be considered, in addition to the four pillars of HFrEF therapy, in symptomatic patients with LVEF < 45% following a worsening event. Cardiac rehabilitation represents an ideal setting where there is more time to implement therapy with vericiguat and incorporate a greater num-ber of medications for the management of these patients. This review covers vericiguat's metab-olism, molecular mechanisms, and drug-drug interactions.

Obesity has increasingly become a worldwide epidemic, as demonstrated by epidemiological and clinical studies. Obesity may lead to development of a broad spectrum of cardiovascular diseases (CVDs), such as coronary heart disease (CHD), hypertension, heart failure (HF), cerebrovascular disease, atrial fibrillation (AF), ventricular arrhythmias, and sudden cardiac death (SCD). In addition to hypertension, there are other cardiometabolic risk factors (CRFs) such as visceral adiposity, dyslipidemia, insulin resistance, diabetes, elevated levels of fibrinogen, and C-reactive protein and others, all of which increase the risk of CVD events. Mechanisms involved between obesity and CVD mainly include insulin resistance, oxidative stress, inflammation, and adipokines dysregulation, which cause maladaptive structural and functional alterations of the heart, particularly left ventricular (LV) remodeling and diastolic dysfunction. Natural products of plants, provide a diversity of nutrients and different bioactive compounds, including phenolics, flavonoids, terpenoids, carotenoids, anthocyanins, vitamins, minerals, fibers, and others, which possess a wide range of biological activities including antihypertensive, antilipidemic, antidiabetic, and other activities, thus conferring cardiometabolic benefits. In this review, we discussed the main therapeutic interventions using extracts from herbs and plants in preclinical and clinical trials with protective properties targeting CRFs. Molecular mechanisms and therapeutic targets of herbs and plants extracts for the prevention and treatment of CRFs are also reviewed.

Hyaluronic acid, in the form of a gel or viscoelastic colloidal solution, is currently used for viscosupplementation of joints affected by osteoarthritis, but its effectiveness is under debate in relation to newer alternatives. Based on meta-analytical arguments, the present article reinforces the opinion that there are still no decisive arguments for its complete replacement, but for its use adapted to the peculiarities of the disease manifestation and of the patients. A “broad” comparison is first made with almost all alternatives studied in the last decade, and then a meta-regression study is performed to compare and predict the effect size induced by viscosupplementation and platelet-rich plasma therapies. If they are computerized, the developed models can represent tools for clinicians in determining the appropriateness of the option or not for viscosupplementation, in a manner adapted to the pain felt by the patients, to their age, or to other clinical circumstances. The models were generated using the latest algorithms for meta-analysis and meta-regression implemented in the R language and assembled in different R packages. All primary data and necessary R scripts are provided in accordance with the philosophy of reproducible research. Finally, HA-based products, currently under circumspection, are still clinically useful.

Neurobrucellosis in cetaceans, caused by Brucella ceti, is a relevant cause of death in striped dolphins (Stenella coeruleoalba) from the Mediterranean Sea. Serological tests are not used as a routinary technique for the diagnosis of this infection. We briefly describe the pathological findings of 10 free-ranging stranded cetaceans diagnosed with Brucella infection in our veterinary necropsy service from 2012 to 2023. Findings included focal diskospondylitis, non-suppurative meningitis, choroiditis and radiculitis. Additionally, an exploratory serological study was conducted in 66 frozen sera collected in the period 2012-2022 from 57 striped dolphins, 5 Risso’s dolphins (Grampus griseus), 2 common bottlenose dolphins (Tursiops truncatus), 1 common dolphin (Delphinus delphis) and 1 pilot whale (Globicephala melas), to compare antibody levels in Brucella-infected (n=8) and non-infected (n=58) animals, classified by cause of death, sex, age class and cetacean morbillivirus (CeMV) infection status. We performed a commercial competition ELISA (cELISA) using serial serum dilutions for each sample, considering a percentage of inhibition (PI) of ≥40% as positive. A titer of 1:160 was arbitrarily determined as the seropositivity threshold. Seropositive species included striped dolphins and Risso’s dolphins. Seroprevalence was higher in animals with neurobrucellosis (87.5%) compared to the overall prevalence (31.8%) and to other causes of death, indicating a high sensitivity but low specificity for neurobrucellosis. Animals with chronic CeMV seemed to have higher seroprevalences, as well as juveniles, which also had more disease prevalence. These results suggest that high antibody titers are not always protective against clinical brucellosis, although they may indicate a carrier state, and that CeMV may potentially condition Brucella epidemiology. More research is required to elucidate the epidemiology and pathogenesis and to disentangle the complicated host-pathogen interaction in Brucella species.

Objective biomarkers have been a critical challenge for the field of psychiatry, where diagnostic, prognostic and theranostics assessments are still based on subjective narratives. Psychopathology operates with idiographic knowledge and subjective evaluations incorporated into clinical as-sessment inventories, but is considered to be a medical discipline and, as such, uses medical in-tervention methods (e.g., pharmacological, ECT; rTMS; tDCS), and therefore is supposed to oper-ate with the language and methods of nomothetic networks. The idiographic assessments are pro-visionally “quantified” into “structured clinical scales” to in some way resemble nomothetic measures. Instead of fostering data merging and integration, this approach further encapsulates the clinical psychiatric methods, as all other, biological tests (molecular, neuroimaging) are per-formed separately, only after the clinical assessment has provided diagnosis. Translational cross-validation of clinical assessment instruments and fMRI is an attempt to address the gap. The aim of this approach is to investigate whether there exist common and specific neural circuits, which underpin differential item responses to clinical self-rating scales during fMRI session in pa-tients suffering from the two main spectra of mental disorders: schizophrenia and major depres-sion. The current status of this research program and future implications to promote the devel-opment of psychiatry as a medical discipline are discussed.

Chronic administration of atypical antipsychotics (AAPs) is commonly associated with in-creased cardiovascular disease load. Although the increase in weight gain and related dis-ease risk is generally considered the main contributing factor, direct interference with mi-tochondrial bioenergetics, particularly in the liver, where these drugs are catabolized, is emerging as an additional relevant contributor to metabolic disease risk that needs to be considered. In this study, we compared the effects of two AAPs with disparate metabolic profiles, olanzapine (OLA), which is obesogenic, and aripiprazole (ARI), which is not, on the response of Fao cells to oxidative stress. We found that Fao cells treated with ARI sur-vive better a challenge with H2O2 while OLA treatment has the opposite effect. This en-hanced survival is not related to a reduction in the apoptosis rate. In fact, ARI treated cells display higher apoptotic rates than control cells exposed to H2O2. Gene expression analysis of pro and anti-apoptotic factors revealed that the changes induced by H2O2 were generally dampened in ARI treated cells, but not in OLA treated cells, suggesting a reduced respon-siveness to stimuli, a notion that was consistent with a reduced activation of MAPK and STAT3 phosphorylation in response to H2O2, while OLA enhanced their activation in re-sponse to H2O2. Loss of stress response in ARI treated cells is consistent with the elevation of mitochondrial production of O2•-, a known desensitizing factor. The physiological rele-vance of the increased production of O2•- in ARI treated cells is further supported by the observed elevation of the mitophagy flux in ARI treated cells, likely related to mitochon-drial damage. An additional relevant finding was that OLA treatment protected the pro-teasome activity in Fao cells exposed to H2O2, an effect possibly related to the better preservation of stress signaling and mitochondrial function in OLA treated cells. In sum, this study highlights the underlying alterations in cell physiology derived from the inter-ference of ARI with mitochondrial function, that de-sensitize cells to stress signaling, while OLA has the opposite effect.

In this review, we have included current information on the use of photodynamic therapy in the treatment of gliomas. We mainly focused on the discussion and regarding the use of photodynamic therapy in patients with genetically determined syndromes that are associated with an increased risk of glioma. The review also uses information on genetic syndromes that are associated with an increased risk of glioma.

Introduction Emergency laparotomy is a surgical procedure associated with significantly higher mortality rates compared to elective surgeries. Awake laparotomy under neuraxial anaesthesia has recently emerged as a promising approach in abdominal surgery to improve patient outcomes. This study aims to evaluate the feasibility and potential benefits of using lumbar spinal anaesthesia as the primary anaesthetic technique in emergency laparotomies. Methods We conducted a case series involving 16 patients who underwent emergency laparotomy for bowel ischemia, perforation, or occlusion. Lumbar spinal anaesthesia was employed as the main anaes-thetic technique. We analysed patient demographics, clinical characteristics, intraoperative details, and postoperative outcomes. The primary outcome measures included the adequacy of postoper-ative pain control, the incidence of postoperative complications, and mortality rates. Results Among the 16 patients, adequate postoperative pain control was achieved, with only 2 patients requiring additional analgesia. Postoperative complications, including sepsis, wound dehiscence, and pneumonia, were observed in 7 patients (44%). The observed mortality rate was relatively low at 6% (1 patient). Notably, conversion to general anaesthesia was not necessary in any of the cases, and no early readmissions were reported. Discussion Our findings highlight the feasibility and potential benefits of using neuraxial anaesthesia in emergency laparotomies. The observed low mortality rate and the avoidance of conversion to general anaesthesia suggest that lumbar spinal anaesthesia may be a useful alternative in emer-gency settings. However, the occurrence of postoperative complications in 44% of patients indi-cates the need for cautious patient selection and close monitoring. Further research with larger sample sizes is warranted to fully elucidate the efficacy, safety, and potential impact of this tech-nique on patient outcomes in emergency laparotomies.

The causal networks are important for understanding the signaling alterations in diseases. To reveal the network pathways affected in epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs), which are related to poor prognosis of cancer, the molecular networks and gene expression in diffuse- and intestinal-type gastric cancer (GC) have been analyzed. The network pathways in GC were analyzed in Ingenuity Pathway Analysis (IPA). The analysis of the probe sets of which gene expression has significant differences between diffuse- and intestinal-type GC in RNA Sequencing publicly available data identified 1099 causal networks in diffuse- and intestinal-type GC. Master regulators of the causal networks included lenvatinib, pyrotinib, histone deacetylase 1 (HDAC1), mir-196, and erb-b2 receptor tyrosine kinase 2 (ERBB2). The analysis of the HDAC1-interacting network identified the involvement of regulation of EMT by growth factors pathway, coronavirus pathogenesis pathway, and vorinostat. The network had RNA-RNA interactions with microRNAs such as mir-10, mir-15, mir-17, mir-19, mir-21, mir-217, mir-223, mir-25, mir-27, and mir-34. These molecular networks revealed in the study may lead to the identification of drug targets for GC.

Tori are bony growths in the mouth caused in general by genetic and environmental factors. Oral tori may grow over time and interfere with oral hygiene, speech, mastication and the application of dentures. The aim of this study is to evaluate the prevalence and patterns of torus mandibularis and torus palatinus according age and gender among patients attending the Diamond Dental Hospital in Tirana. Methodology. A case-series study conducted at DDH from February 1-30 April 2024. Written consent was taken from each participant and the questionnaire comprises some variables. The patients were examined intraoral only by one examiner and were taken photos from participants having positive findings. Results. The prevalence of oral tori in Albania was very high 48.4% and the peak incidence was 18-29 age group (54.2%). The most common type was TM 39.3%. The most prevalent form for TP was flat (71.4%) and for TM was solitary bilateral (47.9%). Conclusions. The prevalence of oral tori was found to be very high and not related to gender or bruxism. Dental professionals should be aware of the high occurrence of oral tori and their importance in dental practice. Nevertheless, further assessment of the prevalence of tori in a larger sample is required.

Background: This study aimed to evaluate the burden and impact of cardiac and cerebrovascular disease (CCD) on hospital inpatients with type 1 diabetes mellitus (T1DM). Methods: This is a retrospective nationwide cohort study of people with T1DM with or without CCD in the US National Inpatient Sample between 2016 to 2019. The in-hospital mortality rates, length of stay (LoS) and healthcare costs were determined. Results: A total of 59,860 T1DM patients had a primary diagnosis of CCD and 1,382,934 did not. The median LoS was longer for patients with CCD compared to no CCD (4.6 vs. 3 days). Patients with T1DM and CCD had greater in-hospital mortality compared to those without CCD (4.1% vs. 1.1%, p&lt;0.001). The estimated total care cost for all patients with T1DM with CCD was approximately US $326 million. The adjusted odds of mortality compared to patients with non-CCD admission was greatest for intracranial hemorrhage (OR 17.37, 95%CI 12.68-23.79), pulmonary embolism (OR 4.39, 95%CI 2.70-7.13), endocarditis (OR 3.46, 95%CI 1.22-9.84), acute myocardial infarction (OR 2.31, 95%CI 1.92-2.77) and stroke (OR 1.47, 95%CI 1.04-2.09). Conclusions: The burden of CCD in patients with T1DM is substantial and significantly associated with increased hospital mortality and high healthcare expenditures.

Background and Objectives: The trends in metabolic dysfunction-associated steatotic liver disease (MASLD) and related metabolic dysfunctions in Japan is unknown. Thus, we aimed to clarify the trends of these before the novel coronavirus disease 2019 pandemic in Japan. Materials and Methods: We included Japanese individuals aged 25-79 years who underwent health examinations at our center. We analyzed anthropometry, lifestyle-related disease, and nutritional intake in relation to MASLD trends from 2010-2019. Results: The prevalence of MASLD increased in all ages and body mass index (BMI) classes, reaching 30.3% in males and 16.1% in females, with MASLD accounting for 75% of steatotic liver cases and more than half of all type 2 diabetes mellitus (T2DM) and high waist circumference (HWC) cases. The increase in the prevalence of MASLD was due to an increase in that of steatotic liver itself, and there was no increase in the prevalence of other factors, such as overweight, T2DM, hypertension, and dyslipidemia. The prevalence of glucose metabolic disorders (GMDs) and hypertension decreased. National nutritional data showed an increase in energy intake, total fat, saturated fatty acids, monounsaturated fatty acids, and polyunsaturated fatty acids, which correlated with a decrease in GMDs. Salt intake also decreased, which correlated with hypertension. The MASLD group had a higher prevalence of all related metabolic factors than the non-MASLD group, especially HWC, T2DM, and hyperlipidemia. Conclusion: The prevalence of MASLD increased with that of steatotic liver, regardless of age or BMI. A relationship between increased dietary fat, increased steatotic liver, and decreased GMDs was suggested.

Iron metabolism plays a crucial role in the management of hemoglobinopathies, particularly in conditions such as β-thalassemia and sickle cell anemia (SCA). This paper describes the mechanisms of iron overload in patients with transfusion-dependent thalassemia (TDT), non-transfusion-dependent thalassemia (NTDT), and SCA, highlighting the distinct paths leading to iron accumulation in each condition. The primary focus of this review article is on the role of genetic modifiers influencing iron metabolism and the variability in iron overload presentation among patients. Genetic mutations in genes such as HFE, HAMP, TFR2, SLC40A1, and others significantly impact iron regulation. These modifiers can exacerbate or ameliorate iron overload, and understanding these genetic factors is important for explaining the diverse disease severity and differences in the mechanism and clinical presentation of iron overload in these patients. The ongoing INHERENT study aims to further elucidate the influence of these genetic modifiers through a comprehensive genome-wide association study, potentially leading to novel therapeutic interventions for managing iron homeostasis in hemoglobinopathy patients.

Enhancement of orthodontic tooth movement (OTM) through local administration of biofunctional molecules has become increasingly significant, particularly for adult patients seeking aesthetic and functional improvements. This comprehensive systematic review analyzes the efficacy of various biofunctional molecules in modulating OTM, focusing on the method of administration and its feasibility, especially considering the potential for topical application. A search across multiple databases yielded 36 original articles of experimental human and animal OTM models, which examined biofunctional molecules capable of interfering with the biochemical reactions that cause tooth movement during orthodontic therapy, accelerating the OTM rate through their influence on the bone metabolism (Calcitriol, Prostaglandins, Recombinant human Relaxin, RANKL and RANKL expression plasmid, growth factors, PTH, osteocalcin, vitamin C and E, biocompatible reduced graphene oxide, exogenous thyroxine, sclerostin protein, a specific EP4 agonist (ONO-AE1-329), carrageenan and herbal extracts). The results indicated a variable efficacy in accelerating OTM, with Calcitriol, Prostaglandins (PGE1 and PGE2), RANKL, growth factors and PTH, among others, showing promising outcomes. PGE1, PGE2 and Calcitriol experiments had statistically significant outcomes in both human and animal studies, and, while other molecules underwent only animal testing, they could be validated in the future for human use. Notably, only one of the animal studies explored topical administration, which also suggests a future research direction. This review concluded that while certain biofunctional molecules demonstrated potential for OTM enhancement, the evidence is not definitive. The development of suitable topical formulations for human use could offer a patient-friendly alternative to injections, emphasizing comfort and cost-effectiveness. Future research should focus on overcoming current methodological limitations and advancing translational research to confirm these biomolecules' efficacy and safety in clinical orthodontic practice.

Cardiovascular diseases, which are the leading cause of death in Croatia, are linked to the high prevalence of hypertension. Both are associated with high salt intake which was determined almost two decades ago when Croatian Action on Salt and Health (CRASH) was launched. The main objective of the present study was to evaluate salt, potassium, and iodine intake using 24-hour urine samples in a random sample of adult Croatian population, and to analyse trends in salt consumption after the CRASH has intensively started. Methods: In this national population-based EH-UH 2 study performed in 2018-2021 (participation rate 72 %) in which we analysed a single 24-hour urine sample, 1067 adult participants (mean age 57.12 (SD 13.9), men 35%) were included. Results: Mean salt and potassium intakes were 8.6 g/day (IQR 6.2-11.2) and 2.8 g/day (IQR 2.1-3.5), respectively, with sodium-to-potassium ratio of 2.6 (IQR 1.8-3.3). We detected a decrease of 17.6% (2 g/day less) in salt consumption compared to our previous salt-mapping study. However, only 13.7%, and 8.9 % met the WHO salt and potassium recommended target of 5 g/day, and 3.5 g/day, respectively. Salt intake was higher, and potassium ingestion was lower in rural vs. urban regions, and in continental vs. Mediterranean parts of Croatia. Moderate to severe iodine insufficiency was determined in only 3% adult participants. Conclusion: In the last fifteen years, salt consumption has been significantly reduced in Croatian adult population because of intensive and broad CRASH program led by the Croatian Society of Hypertension and the Croatian Hypertension League. However, salt intake is still too high, and potassium ingestion is too low. With expected more active engagement and help of the government, obtained results could be significantly improved. Salt reduction programs are most cost-effective methods of cardiovascular disease prevention and should be considered more seriously by the government and health policy makers.

Colorectal cancer (CRC), found in the intestinal tract, is initiated, and progresses through various mechanisms, including dysregulation of signalling pathways. Several signalling pathways, such as EGFR and MAPK, involved in cell proliferation, migration, and apoptosis, are often dysregulated in CRC. Although cannabidiol (CBD) has previously induced apoptosis and cell cycle arrest in vitro in CRC cell lines, its effects on signalling pathways have not yet been determined. An in silico analysis was used here to assess partner proteins that can bind to CBD and docking simulations were used to predict precisely where CBD would bind to these selected proteins. A survey of current literature was used to hypothesize the effect of CBD binding on such proteins. The results predict that CBD could interact with EGFR, RAS/RAF isoforms, MEK1/2, and ERK1/2. The predicted CBD-induced inhibition might be due to CBD binding to the ATP binding site of the target proteins. This prevents the required phosphoryl transfer to activate substrate proteins and/or CBD binding to the DFG motif, thus reducing catalytic activity.

Background: Acute kidney injury (AKI) and contrast-induced nephropathy (CIN) are common complications following percutaneous coronary intervention (PCI) or coronary angiography (CAG), presenting significant clinical challenges. Machine learning (ML) models offer promise for improving patient outcomes through early detection and intervention strategies. Methods: A comprehensive literature search following PRISMA guidelines was conducted in PubMed, Scopus, and Embase from inception to June 11, 2024. Study characteristics, ML Models, performance metrics (AUC, accuracy, sensitivity, specificity, precision), and risk of bias assessment using the PROBAST tool were extracted. Statistical analysis used a random-effects model to pool AUC values, with heterogeneity assessed via the I² statistic. Results: From 431 initial studies, 14 met the inclusion criteria. Gradient Boosting Machine (GBM) and Support Vector Machine (SVM) models showed the highest pooled AUCs of 0.87 (95% CI: 0.82-0.92) and 0.85 (95% CI: 0.80-0.90), respectively, with low heterogeneity (I² < 30%). Random Forest (RF) had a similar AUC of 0.85 (95% CI: 0.78-0.92) but significant heterogeneity (I² > 90%). Multilayer Perceptron (MLP) and XGBoost models had moderate pooled AUCs of 0.79 (95% CI: 0.74-0.84) with high heterogeneity. RF showed strong accuracy (0.83, 95% CI: 0.70-0.96), while SVM had balanced sensitivity (0.69, 95% CI: 0.63-0.75) and specificity (0.73, 95% CI: 0.60-0.86). Age, serum creatinine, left ventricular ejection fraction, and hemoglobin consistently influenced model efficacy. Conclusions: GBM and SVM models, with robust AUCs and low heterogeneity, are effective in predicting AKI and CIN post-PCI/CAG. RF, MLP, and XGBoost, despite competitive AUCs, showed considerable heterogeneity, emphasizing the need for further validation.

The IMbrave150 trial established atezolizumab with bevacizumab (A+B) as standard care for hepatocellular carcinoma (HCC), recommending an esophagogastroduodenoscopy (EGD) within 6 months of treatment initiation to prevent bleeding from esophagogastric varices. The necessity of mandatory EGD for all patients remains unclear. We retrospectively analyzed 112 HCC patients treated with A+B at five Canadian cancer centers from July 1, 2020, to August 31, 2022. A+B was the first-line therapy for 90% of patients, with median overall survival at 20.3 months and progression-free survival at 9.6 months. There was no survival difference between patients with bleeding and those without. Before A+B, 71%(79) of patients underwent an EGD within 6 months, revealing varices in 41%(32) and requiring intervention in 19%(15). The overall bleeding rate was 15%(17), with GI-specific bleeding occurring in 83%(5) of the EGD group and 17%(1) of the non-EGD group (p=0.24). Non-GI bleeding was observed in 10%(11) of patients. Outcomes for HCC patients treated with A+B in Canada were comparable to IMbrave150. Our study showed twice the rate of varices detection and treatment compared to IMbrave150, reflecting real-world treatment of high-risk populations. There was no increased GI bleeding in patients without pre-treatment EGD, supporting a selective EGD approach.

Given the importance of peroxisome proliferator-activated receptor (PPAR)-gamma in epidermal inflammation and carcinogenesis, we analyzed transcriptomic changes observed in epidermal PPARγ deficient mice (Pparg-/-epi). Gene set enrichment analysis revealed a close association with epithelial malignancy, inflammatory cell chemotaxis and cell survival. Single cell sequencing of Pparg-/-epi mice verified changes to the stromal compartment, including increased inflammatory cell infiltrates, particularly neutrophils and an increase in fibroblasts expressing myofibroblast marker genes. A comparison of transcriptomic data from Pparg-/-epi and publicly available human and or mouse actinic keratoses (AK) and cutaneous squamous cell carcinomas (SCCs) revealed strong correlation between the datasets. Importantly, PPAR signaling was the top common inhibited canonical pathway in AK and SCC. Both AKs and SCCs also had significantly reduced PPARG expression and PPARγ activity z-scores. Smaller reductions in PPARA expression and PPARα activity and increased PPARD expression but reduced PPARδ activation were also observed. Reduced PPAR activity was also associated with reduced PPARα/RXRα activity while LPS/IL1-mediated inhibition of RXR activity was significantly activated in the tumor datasets. Notably. these changes are not observed in normal sun-exposed skin relative to non-exposed skin. Finally, Ppara and Pparg were heavily expressed in sebocytes while Ppard was highly expressed in myofibroblasts, suggesting a role for PPARδ in myofibroblast differentiation. In conclusion, these data indicate PPARγ and possibly PPARα represent key tumor suppressors by acting as master inhibitors of the inflammatory changes found in AKs and SCCs.

(1) Background: This study aimed to compare the effect of polyetheretherketone (PEEK) and titanium abutments on implant prosthetic systems and supporting bone using three-dimensional finite element analysis (FEA); (2) Methods: A three-dimensional finite element analysis was conducted using CATIA and Abaqus software to model mandibular first molar implant systems with titanium and PEEK abutments. Under external loading conditions, finite element analysis was conducted for the stresses in implant components and surrounding bones of each group; (3) Results: The implant fixture of the PEEK model exhibited the highest von Mises stress (VMS). The lowest VMS was observed in the abutment screw of the titanium model. Both implant systems demonstrated similar stress distribution and magnitudes in cortical and cancellous bones; (4) Conclusion: PEEK abutments show similar stress distribution in surrounding bone compared to titanium. However, PEEK absorbs the stresses within the implant system and exhibits the highest VMS values due to its low mechanical and physical properties. Therefore, PEEK abutments need improved mechanical properties for better clinical application.

Protein glycation impacts enzymatic activity, disrupts metabolic processes, and is associated with chronic degenerative diseases. The human glycolytic enzyme triosephosphate isomerase (HsTIM, TPI1, or HsTPI) is associated with various disorders, such as enzymopathies originating from mutations. It also possesses moonlighting functions and is now recognized as a cancer marker. Previous reports of HsTPI mutants have demonstrated a significant increase of methyl-glyoxal (MGO) due to trioses accumulation. We compared how catalytic activity exerts differen-tial kinetic and structural stability effects due to mutations by tracking fluorescent argpyrimi-dine adduct (ARGp) through interaction with Arginine-MGO. Circular dichroism and fluores-cence spectroscopy were explored in HsTPI-WT and mutants HsTPI-C217K “Like-WT”, HsTPI-N16D accumulated in cancer, and HsTPI-E104D human deficiency mutant, by cysteines accessibility and time loss of activity and unfolding propensity in mutant enzymes with aggre-gates refractory to proteolysis in the C217K. Our study sheds new light on the increased suscep-tibility of mutants to generate MGO adducts due to TPI isomerization of MGO precursor sub-strates. Nevertheless, mutations enhance a negative feedback cycle, in which accumulated MGO access promotes accelerated loss of activity that leads to unfolding and aggregation. The cumu-lative and accelerated increase in MGO adducts, which probably are responsible for the patho-logical state in this TPI variant, are partially reversed by adding MGO-scavenger molecules.

This Dataset reports the clinical information and measurements of 231 patients who underwent multifrequency low-level laser-assisted mastopexy. The Dataset was collected between February 2021 and November 2023. These data were used to assess the effect of this procedure on breast ptosis degree and the nipple to sternal notch distance to know the evolution of breast ptosis. This article presents demographic, personal and familial history, anthropometric measurements, pto-sis degree according to the Regnault system, Nipple-to-Sternal Notch distance (SNND), and complications according to the Clavien-Dindo System. The collected data were in English, and the responses were anonymised to ensure the Colombian legal framework. The data were stored in a .csv file.

Bacillus Calmette-Guérin (BCG) immunotherapy has been a cornerstone treatment for non-muscle invasive bladder cancer for decades and still faces challenges, such as severe immune adverse reactions, which reduce its use as a first-line treatment. This review examines BCG therapy’s history, mechanisms, and current status, highlighting how nanotechnology and bioengineering are revitalizing its application. We discuss novel nanocarrier systems aimed at enhancing BCG's efficacy while mitigating specific side effects. These approaches promise improved tumor targeting, better drug loading, and enhanced stimulation of anti-tumor immune responses. Key strategies involve using functional BCG cell wall components and co-delivering BCG with chemotherapeutics to achieve synergistic effects. While most studies remain experimental, this research direction offers hope for overcoming BCG's limitations and advancing bladder cancer immunotherapy. Further elucidation of BCG's mechanisms and rigorous safety evaluations of new delivery systems will be crucial for translating these innovations into clinical practice.

Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory tract infection in young children globally. Following the COVID-19 pandemic, RSV infections have become more prevalent. Consequently, a new vaccine targeting RSV infections in pregnant women has been introduced worldwide. To estimate the effectiveness of this new vaccine for pregnant women, we investigated neutralizing antibodies against RSV in samples taken from 51 mothers and their babies. The prevalence rate of neonatal antibodies, defined as a titer of ≥16, was 39.2%. We found no significant differences in neonatal neutralizing antibodies based on factors, such as sex, gestational age at birth, birth weight, presence of siblings, neonatal problem, and usage of palivizumab. Neonatal neutralizing antibodies were equal to or higher than those of their mother. A new RSV vaccine targeting all pregnant women is promising, as approximately 60% of neonates had low antibody titers against RSV. However, predicting low antibody titer against RSV remains challenging. Moreover, our findings indicate efficient transmission of RSV antibodies from babies to their mothers.

Bicuspid Aortic valve Stenosis (BCAS) with an incidence of 3% of the world's population constitutes the most frequent Congenital Heart Disease whereas all other subtypes collectively constitute 1% of all life births. Most and the extreme severity spectrum of valvular Aortic Stenosis (VAS) in adulthood are cases of congenital bicuspid aortic valve. It seems that the congenital occurrence of the bicuspid aortic valve is a major prerequisite of the pathological calcifications and fibrosis seen in adults. Those progressive changes can't be explained by sole hemodynamic destructive forces but other factors inherent to the bicuspid valve tissue are also contributing. Therapeutic options of (VAS) are relatively stagnant and have been limited to invasive and surgical options. Prudent observation of the risk factors of some CHDs including BCAS was the epigenetic effect of planetary electromagnetic field on the delicate process of endothelial mesenchymal transformation (EndoMT). The incidence of BCAS is progressively increasing as we depart north from the equator to the north pole. A deeper understanding of the cellular and molecular mechanisms underlying EndoMT in congenital as well as acquired heart diseases is expected to open a new era in reversing heart disease in the human species. The potential to manipulate EndoMT and its signaling pathways or to reverse it with external electromagnetic power is an exciting therapeutic option for a wide array of congenital and acquired heart diseases including bicuspid aortic stenosis (BCAS) in the human species.

The neurologic effects of long-COVID are a therapeutic challenge. This article discusses the immunologic manifestations of long-COVID and proposes a non-androgenic, synthetic analog of dehydroepiandrosterone (DHEA), bromo-epi-androsterone (BEA), as a candidate for clinical trials for this exigent collection of neurologic conditions. Moreover, because there is an association between long-COVID and Alzheimer’s disease, the evaluation of BEA in long-COVID may serve as a proxy for its effect on neuroinflammatory biomarkers of Alzheimer’s disease that are shared with long-COVID.

Background: Heart failure (HF) remains a challenging healthcare issue, necessitating innovative therapies like cardiac resynchronization-defibrillation therapy (CRT-D). However, defining CRT-D responders lacks uniformity, impeding effective clinical evaluation. This study explores diverse CRT-D responder definitions, encompassing functional, echocardiographic, and laboratory criteria. Materials & Methods: A single-center study involving 132 CRT-D patients scrutinized responder criteria, including NYHA stage, LVEF increase, and proBNP decrease. Statistical analyses, such as Kaplan–Meier curves and Cox hazard regression, were employed to evaluate responder characteristics and survival outcomes. Results: Responder rates varied across criteria, revealing nuanced patient profiles. CRT-D responders, defined by NYHA decrease, LVEF increase, or proBNP decrease, exhibit improved survival rates after 2 and 3 years (p < 0.050). Young age, absence of recent myocardial infarction, and normal right ventricular, echocardiographic parameters emerge as predictors for positive response. In part, drug-based HF therapy correlates with increased responder rates. Cox regression identified LVEF ≥ 5% and proBNP decrease ≥ 25% as independent predictors of extended survival. Conclusions: CRT-D responder definitions exhibit considerable variability, emphasizing the need for a nuanced, patient-centered approach. Factors like right ventricular function, drug therapy, atrial fibrillation, and renal function influence responses. The study enriches our understanding of CRT-D response, contributing to the foundation for personalized HF management.

Background: Leishmaniasis is a significant global public health issue that is caused by parasites from Leishmania genus. With limited treatment options and rising drug resistance, there is a pressing need for new therapeutic approaches. Molecular chaperones, particularly Hsp90, play a crucial role in parasite biology and are emerging as promising targets for drug development. Objective: This study evaluates the efficacy of 17-DMAG in treating BALB/c mice from cutane-ous leishmaniasis through in vitro and in vivo approaches. Materials and Methods: We assessed 17-DMAG cytotoxic effect on bone marrow-derived mac-rophages (BMMΦ) and its effects against L. braziliensis promastigotes and intracellular amastigotes. Additionally, we tested the compound's efficacy in BALB/c mice infected with L. braziliensis via intraperitoneal administration to evaluate the reduction of lesion size and de-crease of parasite load in the ears and lymph nodes of infected animals. Results: 17-DMAG showed selective toxicity [selective index=432) towards Leishmania amastigotes, causing minimal damage to host cells. The treatment significantly reduced lesion sizes in mice and results in parasite clearance from ears and lymph nodes. It also diminished in-flammatory responses and reduced the release of pro-inflammatory cytokines (IL-6, IFN-g, TNF) and the regulatory cytokine, IL-10, underscoring its dual leishmanicidal and anti-inflammatory properties. Conclusion: Our findings confirm the potential of 17-DMAG as a viable treatment for cutaneous leishmaniasis and support further research into its mechanisms and potential applications against other infectious diseases.

Ambiguity exists over treatment and surveillance strategies after endoscopic submucosal dissec-tion (ESD) for esophageal squamous cell neoplasia (ESCN) with unfavorable histologic features. This study investigated the long-term outcomes of ESD in high-risk ESCN patients. We retro-spectively included early ESCN patients treated with ESD at two medical centers in Taiwan be-tween August 2010 and December 2023. Demographic, endoscopic, and pathological data were collected. Among 146 patients (mean age 59.17 years) with 183 lesions, 73 (50%) had a history of head and neck cancer (HNC). En bloc and R0 resection were achieved in 100% and 95.6% of the lesions, respectively. The 5-year overall survival (OS), disease-specific survival (DSS) and local recurrence rates were 42.7%, 94.7% and 11%. R0 resection was significantly associated with re-currence in univariate analysis (adjusted OR: 0.23, 95% CI: 0.05-0.99, P=0.05). Alcohol abstinence was independently associated with lower recurrence (adjusted OR: 0.20, 95% CI: 0.08-0.48, P

Aquaporins (AQPs) are a family of integral membrane proteins that selectively transport water and glycerol across the cell membrane. Because AQPs are involved in a wide range of physiological functions and pathophysiological conditions, AQP-based therapeutics may have broad potential for clinical utility, including disorders of water and energy balance. However, AQP modulators have not yet been developed as suitable candidates for clinical applications. In this study, to identify potential modulators of AQPs, we screened 32 natural products by measuring the water and glycerol permeability of mouse erythrocyte membranes using a stopped-flow light scattering method. None of the tested natural compounds substantially affected osmotic water permeability. However, several compounds considerably affected glycerol permeability. Stichoposide C increased the glycerol permeability of mouse erythrocyte membranes, whereas rhizochalin decreased it at nanomolar concentrations. Immunohistochemistry revealed that AQP7 was the main aquaglyceroporin in mouse erythrocyte membranes. We further verified the effects of stichoposide C and rhizochalin on aquaglyceroporins using human AQP3 expressing keratinocyte cells. Stichoposide C, but not stichoposide D, increased AQP3-mediated transepithelial glycerol transport, whereas the peracetyl aglycon of rhizochalin was the most potent inhibitor of glycerol transport among the tested rhizochalin derivatives. Collectively, stichoposide C and the peracetyl aglycon of rhizochalin might function as modulators of AQP3 and AQP7, and suggest the possibility of these natural products as potential drug candidates for aquaglyceroporin modulators

Background/Objectives: An age-associated increase in serum levels of sex hormone binding globulin (SHBG) is considered to be one of the factors leading to the development of male hy-pogonadism. Aim of the study: to study the relationship between the concentration of sex hor-mone-binding globulin in the blood serum and the age of the man, the level of total and free testosterone. A single-center retrospective cross-sectional study was conducted. The results of laboratory tests of 162 male patients aged from 18 to 56 years (median - 34 years) were analyzed. Methods: The level of total testosterone and sex hormone binding globulin (SHBG) was deter-mined by chemiluminescent immunoassay. The level of free testosterone was determined by the calculation method according to Vermeullen. Statistical analysis was performed using SPSS Sta-tistics v23. Results: Correlation analysis did not reveal a significant relationship between age and SHBG levels, as well as between age and total testosterone levels. Serum SHBG concentration showed a significant (p

This study uses machine learning to identify key factors influencing the cost-effectiveness of over-the-counter (OTC) medications. By developing a novel cost-effectiveness rating (CER) from user ratings and prices, we analyzed data from Amazon. The findings indicate that FSA/HSA eligibility, symptom treatment range, safety warnings, special effects, active ingredients, and packaging size significantly impact cost-effectiveness across cold, allergy, digestion, and pain relief medications. Medications eligible for FSA or HSA funds, treating a broader range of symptoms, and having smaller packaging are perceived as more cost-effective. Cold medicines with safety warnings were found to be cost-effective due to their lower average price and effective ingredients like phenylephrine and acetaminophen. Allergy medications with kid-friendly features showed higher cost-effectiveness, and ingredients like calcium, famotidine, and magnesium boosted the cost-effectiveness of digestion medicines. These insights help consumers make informed purchasing decisions and assist manufacturers and retailers in enhancing product competitiveness. Overall, this research supports better decision-making in the pharmaceutical industry by highlighting factors that drive cost-effective medication purchases.

Remimazolam was derived from its parent compound by adding an ester linkage into its structure, so that the drug becomes a substrate for ester metabolism. As a result, it undergoes organ independent ester hydrolysis, although the clinical benefits in terms of shorter recovery are not uniformly observed in clinical practice. Remimazolam is mainly tested in procedural sedation. In comparison to propofol, the current gold standard for procedural sedation, its proposed attractiveness is shorter wake-up times and a clear-headed recovery Its clear advantage over propofol is better hemodynamic stability, lack of pain on injection and availability of a reversal agent in the form of flumazenil. Data on patient and proceduralist’s satisfaction are lacking. Remimazolam is also used for induction and maintenance of general anesthesia in Japan (where it is approved for this purpose). In this scenario, it is not clear if it can achieve the same degree of lack of recall as propofol. The use of remimazolam in obstetrics, pediatrics and in high-risk population is an emerging area.

Background/Objectives: Head and neck free flap reconstructions are often required to treat tumors or extensive post-traumatic jaw defects. The facial artery is the standard receiving vessel for intraoral microvascular anastomoses. However, its use is associated with several disadvantages, such as lesions of buccal nerve branches or the parotid duct and variability in course and diameter. This study aims to investigate whether sublingual artery branches can be considered an alternative intraoral supply vessel to the facial artery to avoid these drawbacks. Methods: 12 formalin-fixed cadaveric heads with 24 sides were dissected. The sublingual artery's origin, course, branching pattern, and distribution were examined. In addition, the diameters of the branches of the sublingual artery were assessed to identify potential supply vessels for anastomoses. Results: In ten of the 24 cases (41.7 %), the sublingual artery originated from the lingual artery and nine cases (37.5 %) from the facial artery. The main trunk of the sublingual artery was present in the floor of the mouth in all cases (100 %) with a diameter of ≥ 0.9 mm in vitro (1 mm in vivo). In 15 of the 24 half heads (62.5 %), branches of the sublingual artery with ≥ 0.9 mm were identified in this space. Conclusions: The large diameter of the sublingual artery on the floor of the mandible suggests that this vessel or its branches could be considered alternative pedicles for intraoral anastomoses in mandibular microvascular free flap grafts.

Mesenchymal stem cells (MSCs) are one of the main residents in the bone marrow (BM), having an essential role in the regulation of hematopoietic stem cell (HSCs) differentiation and proliferation. Myelodysplastic syndromes (MDS) are a group of myeloid disorders impacting hematopoietic stem and progenitor cells (HSCPs) and characterised by BM failure, ineffective haematopoiesis, cytopenia, a high risk of transformation through the expansion of MDS clones together with additional genetic defects. It has been indicated that MSCs play anti-tumorigenic roles such as cell cycle arrest and pro-tumorigenic roles including induction of metastasis in MDS and leukaemia. Growing evidence has shown that MSCs have impaired functions in MDS, such as decreased proliferation capacity, differentiation ability, haematopoiesis support, immunomodulation function, and increased inflammatory alterations within the BM through some intracellular pathways such as Notch and Wnt and extracellular modulators secreted by MSCs abnormally, including increased expressions of inflammatory factors and decreased expressions of hematopoietic factors, contributing to the development and progression of MDS. Therefore, MSCs can be targeted for the treatment of MDS and leukaemia. However, it remains unclear what drives MSCs to behave abnormally. In this review, dysregulations in MSCs and their contributions to myeloid haematological malignancies will be discussed.

Introduction: In Part II of this three-part series, we expose techniques that can be used by the U.S. Centers for Disease Control and prevention (CDC) and Food and Drug Administration (FDA) to manipulate and throttle the Vaccine Adverse Event Reporting System (VAERS), a vaccine safety monitoring system open to the public. The U.S. government’s recommendation of COVID-19 vaccines during pregnancy was more a product of propaganda than of science and plagued with conflicts of interest. The extreme breach of COVID-19 vaccine pregnancy complication safety signals documented in VAERS cannot be disregarded or concealed. As a result, CDC/FDA are moving to closed, government captured platforms, including V-safe, Vaccine Safety Datalink (VSD) system, and the Biologics Effectiveness and Safety (BEST) system. Public transparency of adverse events following COVID-19 vaccination in pregnancy should be increased, not thwarted. Methods: In Part I the CDC/FDA Vaccine Adverse Event Reporting System (VAERS) database was queried from January 1, 1990, to April 26, 2024 for adverse events (AEs) involving pregnancy complications following vaccination. In Part II we investigate tactics discovered in VAERS that concealed vaccine injuries and deaths. Conflicts of interest, as well as specific communications and publications from the CDC/FDA and the New England Journal of Medicine (NEJM) are analyzed. Results: Of all VAERS AE reports, 8.47% (138,983) of COVID-19 reports had no vaccination date and thus were missing from the data presented in Part I of this series. We unconcealed data presented in Part I of this series to include VAERS case reports that were excluded when using standard queries because of an “unknown vaccination date”. The unconcealed data in the 37 AE cases reported in this study (Part II) ranged from 0 - 38% with a mean of 8.2% (standard deviation 9.7%) and the significant breaches of VAERS safety signals in Part I of this series were largely underestimated. Another method of concealing vaccine associated AEs is to exclude the specific vaccine type rendering it as an “unknown vaccine type”. “Unknown vaccine type” has logarithmically increased since the rollout of the COVID-19 vaccines in 2021, ranging from 1 to 400 cases between 1990 to 2018 to 11,461 cases in 2021. CDC/FDA granted $67 million via a Cooperative Agreement grant to Massachusetts Department of Public Health (MDPH) between July 1, 2019, to June 30, 2025. MDPH then made subawards under this grant to 21 influential public and private health and civic organizations, including NEJM’s owner, Massachusetts Medical Society (MMS). As one of the subawardees under the grant, MMS as owner of NEJM received over $426,000 in federal HHS/CDC grant money from 2019 to 2020 for “public health and medical emergency preparedness projects”. Conclusions: CDC/FDA has failed to capture and account for a significant number of AE case reports following COVID-19 in VAERS by a variety of techniques in an apparent attempt to sanitize the data. CDC’s Rochelle Walensky and NEJM’s Editor-in-Chief Eric Rubin pushed novel untested COVID-19 vaccines in pregnant women despite clear evidence from multiple sources that safety signals had been breached.

Recent years have been abundant in research concerning human microbiome and its impact on the host’s health. Studies have shown, that not only the commensal bacteria itself, but also postbiotics, understood as unalived microorganisms, possibly with the presence of their components, may have themselves effect on various elements of human physiology. In this article we take a closer look on the specific ways in which postbiotics can alter immune response in allergic asthma, which is one of the most prevalent allergic diseases in today’s world being a serious subject of concern. Through altering patients’ immune response, not only to allergens but also to pathogens, postbiotics could have a significant role in lowering the number of asthma exacerbations. We suggest that more profound research should be undertaken in order to launch postbiotics into clinical standards of asthma treatment, given greatly promising findings in the field of their immunomodulating potential.

Introduction Atherosclerotic disease is a major contributor to heart failure, stroke, and myocardial infarction, significantly lowering the quality of life and life expectancy, with a significant burden on healthcare. Not all lesions deemed non-significant are benign, and conversely, not all significant lesions are causative of ischemia. Fractional flow reserve (FFR) provides a functional assessment of coronary lesions, while optical coherence tomography (OCT) offers detailed imaging of plaque morphology, aiding in therapeutic decision-making. The objective of this study was to evaluate the utility of OCT and FFR as adjunctive tools in the catheterization laboratory for guiding therapeutic decisions in patients with multivessel disease for non-culprit vessels. Specifically, we aimed to assess how OCT and FFR influence therapeutic decision-making in patients with multi-vessel coronary artery disease. Methods 36 patients with acute coronary syndrome (ACS) and multivessel disease were randomized 1:1 into two groups: one guided by FFR alone, and the other by a combination of FFR and OCT. For the FFR group, revascularization decisions for non culprit lesions were based solely on FFR measurements. If the FFR was >0.8, the procedure concluded, and the patient received maximal medical treatment. If the FFR was ≤0.8, a stent was placed. For the FFR + OCT group, if the FFR was >0.8, the revascularization decision was based on OCT findings. If there were no vulnerable plaques (VP), the procedure concluded, and the patient received maximal medical treatment. If OCT imaging indicated VP, then the patient underwent revascularization. If the FFR was ≤0.8, the patient underwent revascularization regardless of OCT findings. Results OCT imaging altered the therapeutic decision in 11 cases where FFR measurements were above 0.8, but the lesions were characterized as VP. Analyzing the total change in the decision to stent, 4 cases in the FFR group and 15 cases in the FFR and OCT group (4 based on FFR and 11 on OCT) revealed a statistically significant difference (p = 0.0006; Relative Risk = 0.2556; 95% CI: 0.1013 to 0.5603). When analyzing the change in the total decision both to stent and not to stent, we observed a statistically significant difference, with Group 1 having 7 cases and Group 2 having 15 cases (p = 0.0153; Relative Risk = 0.4050; 95% CI: 0.2004 to 0.7698) Conclusion Based on the findings of this study, OCT significantly increases the percentage of stenting procedures by identifying vulnerable lesions. The use of intracoronary imaging facilitates the timely identification and treatment of these vulnerable lesions. This underscores the crucial role of OCT in enhancing the precision of coronary interventions by ensuring timely intervention for vulnerable lesions, thereby potentially improving patient outcomes Acknowledgment funding „This work was supported by the University of Medicine, Pharmacy, Science and Technology ,, George Emil Palade’’ of Targu Mures Research Grant number 510/14/17.01.2022”

Purpose: To compare the efficacy and safety of trabeculectomy with a collagen matrix implant (Ologen®) versus trabeculectomy with mitomycin C (MMC) versus trabeculectomy with both Ologen® and MMC (OLO+MMC). Methods: This non-randomized study included 119 eyes of 101 patients with uncontrolled open-angle glaucoma who underwent trabeculectomy, either alone or combined with phacoemulsification. Data were initially registered following a standard surgical protocol and using an electronic database with structured fields. Patients were divided into three groups: 44 received trabeculectomy with adjunctive MMC (MMC group), 34 with Ologen® (OLO group), and 41 with both Ologen® and MMC (OLO+MMC group). The main outcome measures were the change in intraocular pressure (IOP), change in number of medications needed, complete success rate (defined as IOP≤20 mmHg and at least 20% IOP reduction without hypotensive medications), rate of complications, and rate of postoperative interventions. The follow-up period was 36 months.
 Results: IOP significantly decreased (p=0,01) in all groups across all study visits, decreasing from 19.8 ± 4.6 mmHg to 12.7 ± 4.2 mmHg in the MMC group, from 20.5 ± 4.7 mmHg to 13.9 ± 3.5 mmHg in the OLO group, and from 23.5 ± 6.1 mmHg to 13.1 ± 3.5 mmHg in the OLO+MMC group. After correcting for baseline IOP, only the first two postoperative visits (first week and first month) showed significantly greater IOP reduction in the OLO+MMC group. The number of hypotensive medications was significantly reduced from 3.1±0.6 to 0.56±1.1 in the MMC group, from 2.9±0.4 to 0.83±1.1 in the OLO group, and from 3.0±0.6 to 0.45±0.95 in OLO + MMC group, with no statistically significant differences among the groups (p=0,57). Complete success rates were 63,6% in the MMC group, 67,6% in the OLO group, and 80,5% in the OLO +MMC group, with no statistically significant differences among the groups (p=0,21). Suture release was significantly more frequent in the MMC group (86,1%) than in the OLO group (62,1%) and in the OLO + MMC group (45,9%; p=0,02). Bleb needling, with (33.3%; p=0.005) or without (66.7%; p=0.0001) 5-Fluorouracil injection (5-FU), was significantly more common in the MMC group. The highest complete-success rate (61%) was offered by the OLO+MMC group. Conclusion: The use of Ologen® and Mitomycin C provided similar surgical IOP reduction in glaucoma surgery compared with MMC or Ologen® either alone but significantly reduced the need for postoperative interventions.

Rasagiline (Azilect®) is a selective monoamine oxidase B (MAO-B) inhibitor that provides symp-tomatic benefit in Parkinson’s disease (PD) treatment and found to exert preclinical neuroprotec-tive effects. Here, we investigated the neuroprotective signaling pathways of rasagiline in the PC12 neuronal cultures exposed to an ischemic-like insult. Exposure of neurons to oxy-gen-glucose deprivation for 4 h followed by 18 h of reoxygenation caused 40% aponecrotic cell death. Rasagiline induced dose-dependent neuroprotection by decreasing cell death and produc-tion of the neurotoxic reactive oxygen species, and reducing the nuclear translocation of glycer-aldehyde-3-phosphate dehydrogenase (GAPDH). Rasagiline increased protein kinase B (Akt) phosphorylation and decreased protein expression of the ischemia-induced α-synuclein protein, in correlation to the neuroprotective effect. Treatment with rasagiline induced nuclear shuttling of transcription factor Nrf2 and increased the mRNA levels of the antioxidant enzymes heme oxy-genase-1, (NAD (P) H- quinone dehydrogenase, and catalase. These results indicate that rasagiline provides neuroprotection in the ischemic neuronal cultures with inhibition of α-synuclein and GAPDH-mediated aponecrotic cell death, and via mitochondrial protection, as by increasing mi-tochondria-specific antioxidant enzymes by a mechanism involving the Akt/Nrf2 redox-signaling pathway. These findings may be exploited for neuroprotective drug development in PD and stroke therapy.

The relationship between antitumor response and tumor marker changes was evaluated in patients with advanced hepatocellular carcinoma treated with durvalumab plus tremelimumab (Dur/Tre). Thirty-two patients were enrolled in this retrospective evaluation of treatment outcomes. According to Response Evaluation Criteria for Solid Tumors at 8 weeks, the objective response rate (OR) was 25% and the disease control rate (DC) was 56.3%. Median alpha-fetoprotein (AFP) ratio at 4 weeks was 0.310 in patients who achieved OR at 8 weeks (8W-OR group), significantly lower than the 1.105 in the non-8W-OR group (p=0.0020), but was 1.210 in patients who did not achieve DC at 8 weeks (non-8W-DC group), significantly higher than the 0.470 in the 8W-DC group (p=0.0006). Similarly, median des-γ-carboxy-prothrombin (DCP) ratio at 4 weeks was 0.125 in the 8W-OR group, significantly lower than the 1.225 in the non-8W-OR group (p=0.0001), but was 1.120 in the non-8W-DC group, significantly higher than the 0.480 in the 8W-DC group (p=0.0255). Early changes in tumor markers after Dur/Tre initiation were associated with antitumor response. In particular, changes in AFP and DCP at 4 weeks may offer useful biomarkers for early prediction of both response and progressive disease following Dur/Tre.

Genome-wide association studies (GWAS) have accelerated the exploration of genotype-phenotype associations, facilitating the discovery of replicable genetic markers associated with specific traits or complex diseases. This narrative review explores the statistical methodologies developed using GWAS data to investigate relationships between various phenotypes, focusing on endometrial cancer, the most prevalent gynecological malignancy in developed nations. Advancements in analytical techniques such as genetic correlation, colocalization, cross-trait locus identification, and causal inference analyses have enabled deeper exploration of associations between different phenotypes, enhancing statistical power to uncover novel genetic risk regions. These analyses have unveiled shared genetic associations between endometrial cancer and many phenotypes, enabling identification of novel endometrial cancer risk loci and furthering our understanding of risk factors and biological processes underlying this disease. The current status of research in endometrial cancer is robust; however, this review demonstrates that further opportunities exist in statistical genetic that hold promise for advancing the understanding of endometrial cancer and other complex diseases.

The incidence of diabetes mellitus (DM) continues to rise worldwide and one of the most serious microvascular complications is diabetic kidney disease (DKD), which is the leading cause of end-stage renal disease. Current bi-omarkers such as urinary albumin excretion rate have limitation for early detection of DKD. In our study we used ultra-high-performance liquid chromatography coupled with electrospray ionization-quadrupole-time of flight-mass spectrometry (UHPLC-QTOF-ESI+-MS) techniques to quantify previously analyzed metabolites, such as tryptophan, kynurenic acid, taurine, l-acetylcarnitine, glycine, and tiglylglycine. We performed the targeted analy-sis of metabolites from urine and serum samples, collected from 110 subjects. Of these, 90 patients with type 2 DM (T2DM) were divided according to the urinary albumin/creatinine ratio (UACR) into normoalbuminuria 300 mg/g groups, respectively, while 20 subjects were rep-resented by healthy controls. Through various validation methods, we identified several metabolites as potential biomarkers, such as kynurenic acid, glycine, and l-tryptophan in serum and l-acetylcarnitine, tiglylglycine, and tau-rine in urine.

Abstract: Acute coronary syndrome (ACS) represents the most severe manifestation of coronary artery disease (CAD), characterized by a particularly poor prognosis. Consequently, primary percutaneous coronary intervention (PPCI) is imperative in the event of acute ST-elevation myocardial infarction (STEMI). Interleukin-22 (IL-22) may be a new CAD biomarker because it signals and regulates immune and inflammatory responses. Objectives: To investigate the differences in circulating IL-22 levels between patients with STEMI undergoing PPCI and healthy controls; and to determine if these differences are associated with the culprit coronary artery, door-to-balloon time (DBT), final angiographic result, CAD classification, and the presence of diabetes mellitus (DM). Methods: A total of 280 participants were recruited, comprising 210 STEMI cases and 70 healthy controls. Participants underwent clinical and angiographic evaluation, and serum IL-22 levels were measured using enzyme-linked immunosorbent assay (ELISA). Data analysis was performed using the Mann-Whitney and Fisher’s tests, with a p < 0.05 significant. Results: Serum IL-22 levels were lower in cases (149.63, 84.99–294.56) than in controls (482.67, 344.33–641.00), p < 0.001. Lower IL-22 levels were associated with the right coronary artery (RCA) (144.57, 70.84–242.43; 146.00, 63.60–279.67; 191.71, 121.80–388.97), p = 0.033. IL-22 was lower with shorter DBT (≤ 60 minutes, 106.00, 49.60–171.71; > 60 minutes, 153.00, 88.86–313.60), p = 0.043. Conclusions: IL-22 levels were significantly lower in patients with STEMI compared to healthy controls.

Direct-acting antivirals (DAAs) revolutionized therapeutics of chronic hepatitis C. The emergence and transmission of HCV variants with resistance-associated substitutions (RASs) can undermine HCV treatment. This study aimed to assess the prevalence and temporal trends of RASs in HCV with a particular focus on the clinically-relevant RASs (cr-RASs). Near-complete HCV GenBank sequences archived in the Los Alamos HCV Database were analyzed. The study period was divided into two phases; before 2011 and 2011 onwards. Identification of RASs across three DAA classes; NS3, NS5A, and NS5B inhibitors was based on the 2020 EASL guidelines. The AASLD-IDSA recommendations were used to identify cr-RASs for three HCV genotypes/subtypes (1a, 1b, and 3) for four DAA regimens; ledipasvir/sofosbuvir; elbasvir/grazoprevir; sofosbuvir/velpatasvir; and glecaprevir/pibrentasvir. The final HCV dataset comprised 3443 sequences and the prevalences of RASs were 50.4%, 60.2%, and 25.3% in NS3, NS5A, and NS5B, respectively. In subtype 1a, resistance to ledipasvir/sofosbuvir was 32.8%, while resistance to elbasvir/grazoprevir was 33.0%. For genotype 3, resistance to sofosbuvir/velpatasvir and glecaprevir/pibrentasvir was 4.2% and 24.9%, respectively. Significant increase in cr-RASs was observed across the two study phases as follows: for ledipasvir/sofosbuvir in subtype 1a, cr-RASs increased from 30.2% to 35.8% (p=0.019); for elbasvir/grazoprevir in subtype 1a, cr-RASs increased from 30.4% to 36.1% (p=0.018); In subtype 1b, neither ledipasvir/sofosbuvir nor elbasvir/grazoprevir showed any cr-RASs in the first phase, but both were present at a prevalence of 6.5% in the second phase (p&lt;0.001); for sofosbuvir/velpatasvir in genotype 3, cr-RASs increased from 0.9% to 5.2% (p=0.006); and for glecaprevir/pibrentasvir, cr-RASs increased from 12.0% to 29.1% (p&lt;0.001). Rising prevalence of HCV RASs and cr-RASs was discernible. This highlights the necessity for ongoing surveillance and adaptation of novel therapeutics to manage resistance effectively. Updating of the clinical guidelines and treatment regimens are recommended to counteract the evolving resistance to DAAs.

Glucocorticoids (GCs) are widely used in blood cancer treatment despite their multiple adverse effects. Biological response to GCs is mediated by glucocorticoid receptor (GR) by transactivation (TA), associated with side effects, and transrepression (TR), mediating anticancer effects. Selective GR agonists (SEGRAs) preferentially activating GR TR could be better option for cancer treatment. One of well-characterized SEGRAs is 2-(4-acetoxyphenyl)-2-chloro-N-methylethylammonium-chloride (CpdA), demonstrated anticancer activity in vitro and in vivo, however its translational potential is limited due to chemical instability. CpdA derivatives CpdA-01-08 were designed by two synthetic strategies. Derivative CpdA-03 demonstrated superior GR affinity and stability compared to CpdA. Analysis of CpdA-03 ligand properties in lymphoma Granta and leukemia CEM cell lines revealed its SEGRA profile: it induced GR TR without triggering GR TA, as evidenced by changes in expression of GR target genes. Effects of CpdA-03 on cell viability, growth, and apoptosis were similar to reference GR ligand, dexamethasone (Dex), and the proto-type compound CpdA. In vivo testing of CpdA-03 anti-lymphoma activity in transplantable P388 murine lymphoma model showed that CpdA-03 reduced tumor volume threefold, outperforming Dex and CpdA. In conclusion, this work introduces CpdA-03 as promising new SEGRA with potential for further development as anti-lymphoma drug with fewer side effects.

Background: Knowledge of the anatomy of pulmonary arteries is essential in many invasive procedures concerning pulmonary circulation. In the diagnosis and treatment of chronic thromboembolic pulmonary hypertension (CTEPH), two-dimensional (2D) pulmonary angiography is used. Recognizing the topographic course of the pulmonary arteries and understanding the status in three-dimensions (3D) is paramount. The study aimed to evaluate and describe the branching variant of pulmonary arteries in a single case, as well as morphological parameters of the segmental arteries, like length, diameter and branching angles. Methods: One pair of embalmed human cadaver lungs were dissected by scalpel, surgical forceps and measured until the subsegmental arteries. Results: The diameters (ranging from 3.04 to 9.29 mm) and lengths (ranging from 9.09 to 53.91 mm) of the pulmonary segmental arteries varied. The proximal branching angles were wide and close to perpendicular, while distally, the angles between the segmental and subsegmental arteries were narrower (30-45°). Upon evaluating the branching, rare variations were identified and delineated, notably in the lower lobes of both lungs. Conclusions: Utilizing knowledge and data in clinical settings is instrumental for effectively diagnosing and treating CTEPH. Further research is required to explore the complications in invasive procedures related to various anatomical variations.

Dermatological consultations are a significant aspect of daily operations at small animal clinics, with atopic dermatitis (CAD) affecting almost 15% of the canine population. The ECS role in the skin reveals its direct action on homeostasis and deregulation, contributing to dermatopathies. It also details its presence in specialized skin cells, revealing a delicate and complex therapeutic potential. Due to the difficulties and the growing scientific evidence of the therapeutic benefits of cannabis, this work aimed to evaluate the anti-inflammatory effect of cannabis oil in treating CAD. Thus, canines diagnosed with CAD were divided into two groups: the group treated using full spectrum high cannabidiol (CBD) [cannabis oil orally] and the control group (olive oil). The evaluation methods for the effectiveness of the therapy were based on the measurement RNAm of interleukins 6, 10, and 31 and oxidative stress in the blood. Despite the theoretical basis, no significant results were obtained between the groups in this work. Thus, it is concluded that oral administration of full spectrum high CBD cannabis oil 2,5 mg/kg twice a day is not efficient in reducing IL and oxidative stress compared to placebo; nevertheless, it still presents a promising approach in the multi-target treatment of CAD.

Background Gliomas are the most prevalent primary malignant brain tumors worldwide. Recent studies highlight the potential of long non-coding RNAs (lncRNAs) in tumor progression, with LINC01354 being upregulated in various malignancies. This study investigates the role of LINC01354 in glioma prognosis to provide novel insights for early prognosis prediction.Methods This study involved four cohorts of low-grade glioma tissue samples collected from hospitals in Xinjiang, Beijing, and Guangzhou, China. Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) was used to measure LINC01354 expression levels. Clinical information and survival data were analyzed using Cox regression and ROC analysis to evaluate the association between LINC01354 expression and overall survival. Clinical comparisons were conducted to identify potential discrepancies in clinical parameters across different cohorts.Results Elevated LINC01354 levels were associated with poorer overall survival in the West China cohort (Xinjiang) but not in the North (Beijing) or South China (Guangzhou) cohorts. Clinical parameter comparisons revealed no significant differences among the cohorts that could explain the regional discrepancy. Further analysis within the West China cohort indicated that LINC01354's prognostic value was consistent across Han and non-Han ethnic groups and unaffected by dietary staples. However, LINC01354's prognostic significance was more pronounced in patients born in Xinjiang compared to those born elsewhere. A prognostic model incorporating LINC01354 expression and birth location demonstrated good predictive accuracy with ROC AUC values of 0.777 in the training cohort and 0.757 in the validation cohort.Conclusion LINC01354 is a potential prognostic biomarker for low-grade glioma in the West China population, particularly among patients born in Xinjiang.

In recent years, bioengineered and biotechnological products have gained tremendous attention to identify unique biologic features associated with oncology. To overwhelm the complexity of tumor personalized medicines (PM) or vaccines could be a promising way-out to be considered. Cancer is a heterogeneous disease. This characteristic variability of cancer provides itself to the emergent era of PM i.e., precision oncology. The prime objective of PM is merely to deliver the right treatment to the right patient at the right time. For instance, imatinib was effectively targeted chronic myeloid leukemia. To date, attainment in using PM approaches to cancer treatment have been mixed. The next-generation sequencing (NGS), and the use of several biomarkers (e.g., HER2, BRAF, ALK, etc.), to drive precise cancer treatment through a timely and cost-effective manner. In current review, author summarizes the advancement in the field of PM such as CRISPR-Cas9, NGS, pharmacogenomics, and the benefits of machine learning techniques. The precise communication between healthcare professionals, regulatory bodies, and patients is essential to translate advances in PM into immense benefits for patients with cancer globally.

Endometriosis is known to be a chronic, debilitating disease. The pathophysiological mechanisms of endometriosis development include local chronic inflammation and a certain degree of local immune deficit. We investigated the relationship between the endometriosis severity, IL-8, IL-10, BDNF, VEGF-A serum and tissue levels, patient-related pain, and physical activity in a cohort of 46 patients diagnosed with endometriosis who underwent surgery. The same panel of biomarkers was investigated in a control group of 44 reproductive-aged patients with non-endometriotic gynecological pathology who underwent surgical intervention. Our data show a high statistical significance between tissue expression of IL-8, IL-10, patient-related pain and the severity of endometriosis. No relationship was identified between serum or tissue levels of VEGF-A and BDNF and the severity of endometriosis. These results validate the presence of local chronic inflammation and immune deficit, thereby creating, alongside other studies in the field, an opportunity for the development of innovative and personalized treatment approaches in endometriosis.

Background and Objectives: Recent studies have focused on the association between the risk of diabetic retinopathy (DR) and rs1501299 and rs2241766 polymorphisms of the ADIPOQ gene, whereas their results remain inconclusive. Thus, a systematic review and meta-analysis was car-ried out to clarify the role of these polymorphisms in the development of DR. Materials and Methods: A systematic research of electronic databases (PubMed, Scopus, and Cochrane Library) was conducted until June 16, 2023, and a reference list of relevant articles was collected, which explored the association between rs1501299 and rs2241766 polymorphisms of the ADIPOQ gene and the risk of DR. The pooled odds ratios (OR) and 95% confidence intervals (CI) were estimated via random-effects model and the meta-analysis was implemented by using Review Manager 5.4. Results: In total, 6 out of 178 studies, with 1,888 cases (DR) and 2,285 controls (without DR), were included in the meta-analysis. A statistically significant association between rs1501299 poly-morphism and DR risk was recorded in G vs. T in the overall analysis (OR=0.84, 95% CI=0.72-0.99, p=

Introduction: In Part I of this three-part series we report a retrospective, population-based cohort study assessing rates of adverse events (AEs) in pregnancy after COVID-19 vaccines compared to the same AEs after influenza vaccines and after all other vaccines. Methods: Data were collected from the U.S. Centers for Disease Control and prevention (CDC) and the U.S. Food and Drug Administration (FDA). The CDC/FDA Vaccine Adverse Event Reporting System (VAERS) database was queried from January 1, 1990, to April 26, 2024, for adverse events (AEs) involving pregnancy complications following COVID-19 vaccination. The time-period included 412 months for all vaccines except COVID-19 vaccines, having been used for only 40 of the 412 months (December 1, 2020, to April 26, 2024). Proportional reporting ratios (PRR) by time compared AEs after COVID-19 vaccination to those after influenza vaccination, and after all other vaccine products administered to pregnant women. In cases in which the PRR was not applicable, Chi-square analysis and Fisher’s exact tests were used according to CDC/FDA guidance. CDC/FDA stipulate a safety concern if a PRR is ≥ 2 or if a Chi-square is ≥ 4. Results: The CDC/FDA’s safety signals were breached for all 37 AEs following COVID-19 vaccination in pregnancy: miscarriage, fetal chromosomal abnormality, fetal malformation, cervical insufficiency, premature rupture of membranes, premature labor, premature delivery, placental calcification, placental infarction, placental thrombosis, placenta accreta, placental abruption, placental insufficiency, placental disorder, fetal maternal hemorrhage, fetal growth restriction, reduced amniotic fluid volume, preeclampsia, fetal heart rate abnormality, fetal cardiac disorder, fetal vascular mal-perfusion, fetal arrhythmia, fetal distress, fetal biophysical profile abnormal, hemorrhage in pregnancy, fetal cardiac arrest, fetal death (stillbirth), premature infant death, neonatal asphyxia, neonatal dyspnea, neonatal infection, neonatal hemorrhage, insufficient breast milk, neonatal pneumonia, neonatal respiratory distress, neonatal respiratory distress syndrome, and neonatal seizure. All p values were ≤ 0.001 with the majority being <0.000001. Summary statistics for the deviation from the CDC/FDA safety signals mean (n, range) are as follows: PRR 69.3 (46, 5.37 - 499); z statistic 9.64 (46, 3.29 - 27.0); and Chi-square was 74.7 (26, 28.9 - 148). Conclusions: We found unacceptably high breaches in safety signals for 37 AEs after COVID-19 vaccination in pregnant women. An immediate global moratorium on COVID-19 vaccination during pregnancy is warranted. The United States government, medical organizations, hospitals, and pharmaceutical companies have misled and/or deceived the public regarding the safety of COVID-19 vaccination in pregnancy. Promotion of these products must be immediately halted.

Similar to humans, the renin-angiotensin-aldosterone system (RAAS) plays a key role in regulating blood pressure and body fluid homeostasis in dogs and cats. The classical RAAS pathway, which involves the conversion of angiotensin I to angiotensin II by the angiotensin converting enzyme (ACE), leads to aldosterone production and associated maladaptive effects in cardiovascular and renal diseases. Recent studies have highlighted the alternative RAAS pathway, which counteracts these effects through angiotensin 1-7, promoting vasodilation and reducing inflammation. Beyond RAAS modulation, RAAS inhibitors have been shown to exert significant anti-inflammatory properties. This is particularly relevant given the American Heart Association's recent focus on Cardiovascular-Kidney-Metabolic (CKM) health, which emphasizes the interconnected risks of cardiovascular disease, chronic kidney disease (CKD), type 2 diabetes, and obesity. These conditions share common pathophysiological pathways, including chronic inflammation, oxidative stress, and metabolic dysregulation. Advances in biomedical research, including the development of adult stem cell-derived canine organoids, provide impetus to study the effects of RAAS modulators and new CVD drugs on CKM health, with a focus on epithelial inflammation within the context of One Health.

: Rasmussen’s encephalitis (RE) stands as a rare neurological disorder marked by progressive cerebral hemiatrophy and epilepsy resistant to medical treatment. Despite extensive study, the primary cause of RE remains elusive, while its histopathological features encompass cortical inflammation, neuronal degeneration, and gliosis. The underlying molecular mechanisms driving disease progression remain largely unexplored. In this case study, we present a patient with RE who underwent hemispherectomy and has remained seizure-free for over six months, experiencing gradual motor improvement. Further-more, we conducted molecular analysis on the excised brain tissue, unveiling a decrease in the expres-sion of cell cycle-associated genes coupled with elevated levels of BDNF and TNF-α proteins. These findings suggest potential involvement of cell cycle regulators in the progression of RE.

Objectives: To assess the concordance of the preoperative application of the #Enzian classification (#ENZIANi) with the postoperative result (#ENZIANs) using surgical findings as the reference standard. Methods: This retrospective study included 282 consecutive patients with deep endometriosis undergoing surgical treatment. Preoperative assessment with transvaginal sonography and magnetic resonance imaging was compared with postoperative assessment. Concordance and diagnostic test evaluation were calculated. Results: The highest concordance was observed in the F (abdominal wall endometriosis) with k Cohen of 0.837, following the values for pelvic locations, with 0.795 for T left, 0.791 for T right, 0.776 for F (adenomyosis), 0.766 for C (rectum), and 0.75 and 0.72 for O right k and O left, respectively. The highest sensitivity was demonstrated for the P compartment *(98%), T compartment (both sides 97%), and A, B, C (94%- 96%), corresponding with deep endometriosis. Conclusions: Preoperative assessment using TVS/TAS+MRI with the ENZIANi score correlates well with the ENZIANs postoperative score and demonstrates good concordance in the detection and localization of deep endometriosis, thereby minimizing false negative results and ensuring accurate preoperative staging. The ENZIAN classification is well-suited to surgeons&#39; needs and benefits from continuous development. Future improvements, such as adding the expanded C module, may be considered in the next edition.

Abstract Background: Occipital neuralgia is a debilitating condition and traditional treatments often provide limited or temporary relief. Recently, ultrasound-guided hydrodissection of the greater occipital nerve (GON) has emerged as a promising minimally invasive approach. Objectives: To describe two novel ultrasound-guided hydrodissection with 5% dextrose for GON and discuss their advantages, disadvantages, and considerations. Methods: Two case reports are presented. Case 1 describes a lateral decubitus approach for hydrodissecting the GON between the semispinalis capitis (SSC) and obliquus capitis inferior (OCI) muscles. Case 2 details a cranial-to-caudal approach for hydrodissecting the GON within the SSC and upper trapezius (UT) muscles when the GON pass through these two muscles. Results: Both patients experienced significant and sustained pain relief with improvements in function and quality of life. Conclusions: Ultrasound-guided GON hydrodissection using 5% dextrose is a promising treatment for occipital neuralgia. The lateral decubitus and cranial to caudal approaches provide additional options to address patient-specific anatomical considerations and preferences.

The detection of early biomarkers and molecular mechanisms in Parkinson’s disease (PD) remains a challenge. Recent research has pointed to potential roles for peptidylarginine deiminases (PADs), a family of calcium activated enzymes, and associated post-translational protein citrul-lination/deimination in early stages of the disease, with a focus on hippocampal and cortex re-gions of the brain. Further analysis of brain region specific changes in PAD isozymes and identi-fication of brain-region specific citrullinomes, therefore remain to be studied. This study assessed brain-region specific PAD isozyme expression (PADs 1-4; PAD6) and associated citrullinated protein targets in the 6-hydroxydopamine (6-OHDA) induced rat model of pre-motor PD. Cortex, hippocampus, striatum, midbrain, cerebellum and olfactory bulb were compared between con-trols/shams and the PD model. In cortex, a significant increase of PAD2 and PAD3 was observed in the PD model. In hippocampus, PAD3, PAD4 and PAD6 showed strongest levels, but with no significant changes observed between PD and controls. In striatum, a significant reduction in all PAD isozymes was observed in the PD model. In the olfactory bulb, PAD3 was significantly el-evated in PD. In midbrain, PAD2, PAD4 and PAD6 showed strongest signal but with no signifi-cant changes between PD and controls. In cerebellum, a significant increase was seen in PAD3, PAD4 and PAD6 in the PD model. Citrullinated protein hits were most abundant in cortex and hippocampus, while for the PD model an increase in citrullinated hits was particularly observed in cortex and cerebellum, compared to controls. For all brain regions there was a considerable difference in citrullinated protein IDs between the PD model and the controls. Citrullinome as-sociated KEGG pathways differed in the six brain regions; some were overlapping for controls and PD, some were identified for the PD model only, and some were identified in control brains only. KEGG pathways identified in PD brains onlywere: “Axon guidance”; “Spinocerebellar ataxia”; “Hippo signalling pathway”; “NOD-like receptor signalling pathway”; “Phosphatidyl-inositol signalling system”; “Rap1 signalling pathway”; “Platelet activation”; “Yersinia infection”; “Fc gamma R-mediated phagocytosis”; “Human cytomegalovirus infection”; “Inositol phosphate metabolism”; “Thyroid hormone signalling pathway”; “Progesterone-mediated oocyte matura-tion”; “Oocyte meiosis”; and “Choline metabolism in cancer”. Our findings highlight differences in PAD isozymes, citrullinated proteins and associated KEGG pathways between brain regions, in pre-motor PD.

Prostate cancer (PCa) ranks as the second most fatal and sixth most prevalent cancer among males globally. This study focuses on leveraging deep learning networks to detect the Gleason grading of prostate cancer from histopathology images stained with Hematoxylin and Eosin (H&amp;E). Six pathologists annotated the images, resulting in six distinct labels for each input image. A common ground truth label was established through majority voting approach. Subsequently, the dataset was trained using architectures: UNeT, UNeT++, DeepLabV3, DeepLabV3+, and GAN based segmentation network. Notably, GAN based network demonstrated superior performance, achieving an F1-score of 0.872 and a Jaccard Index of 0.777, outperforming the other architectures considered in this study.

The intranasal route of drug administration is characterized by high bioavailability and is considered promising for rapid delivery of drugs with systemic action to the central nervous system, bypassing the blood-brain barrier. This is particularly important for the use of neuroprotective drugs in the treatment of brain tissue damage in infants caused by the effects of intrauterine hypoxia. Creation of new dosage forms for neonatology with the use of software and mathematical technologies in pharmaceutical development allows to create cerebroprotective drugs with controlled pharmaco-technological properties, thus reducing time and resources for necessary research. We developed a formulation of a new nasal gel formulation with Angiolin using Box-Benken experiment design for the therapy of prenatal CNS damage. It was found that the consistency properties of the nasal gel were significantly influenced by the gelling agent and mucoadhesive component - sodium salt of carboxymethylcellulose. We have optimized the composition of nasal gel formulation with Angiolin using the formed models and relationships between the factors. The optimized composition of the obtained nasal gel has satisfactory parameters of thixotropic properties. The developed 1% gel for neuroprotection with Angiolin meets all the requirements for harmlessness and safety to drug forms of this group - low toxicity, absence of local irritant and allergic effect.