Background: The present study investigated the effects of a micronutrient combination with proven impact on prostate cell metabolism and growth with regard to PSA dynamics. Methods: In an open single-arm multicenter study, 46 men with different baseline situations were recruited: 16 men with constantly elevated PSA values and negative prostate biopsy (group A), and 30 men with low risk prostate cancer on Active Surveillance (Group B) Results: In group A, 12 out of 16 men (75%) showed a decrease of PSA after 6 months from an average 9.26 to an average 8.84 ng/ml (4.5%), whereas in group B, PSA level decreased in 16, increased in 12 men, and remained unchanged in 1 man. The average PSA in group B dropped from 7.47 to 6.82 ng/ml (8.6%).Both PSA decreases were not statistically significant. Conclusion: The results of the present study are consistent with previous findings on the positive effects of individual micronutrients on prostate health. Longer administration of micronutrients or different dosage or combinations may further improve PSA outcomes.

In a series of publications, we attempt to demonstrate the prophylactic role of bromhexine hydrochloride (BHH) and the curative role of high colchicine doses against COVID-19. Effects of long-term prophylaxis with BHH are presented in two cases of elderly women with severe comorbidity. After long-term prophylactic use of BHH from 3 to 6 months, one does not get sick from COVID-19, and the other passes it almost asymptomatically, even though all their family members fall ill. The dramatic healing effect of colchicine was demonstrated in a family in which both spouses became ill with COVID-19 almost simultaneously. They are treated in different hospitals, and where colchicine is administered in high doses, the patient recovered. The other patient developed complications and died on standard treatment without high doses of colchicine. An outpatient accidentally overdosed on colchicine (12.5mg). The therapy was stopped immediately. Clinically, on the third day, there are absolutely no symptoms. These cases reaffirm the prophylactic effect of BRH and the curative effect of high-dose colchicine

This article provides a comprehensive overview of lung cancer from a genetic perspective, emphasizing the molecular pathways involved in its pathogenesis. This review presents the genetic syndromes and key genomic variations, including alterations and instabilities, that contribute to tumor development and progression. Furthermore, advancements in genomic testing, such as liquid biopsy, are explored, highlighting their utility in early diagnosis, prognostic evaluation, and personalized treatment strategies. The role of biomarkers in informing therapeutic decisions and optimizing patient outcomes is also examined, offering insights into their potential to refine clinical interventions. This review aims to enrich the understanding of the genetic landscape of lung cancer, providing insights that may lead to improved diagnostic and therapeutic approaches.

Objectives: Cerebral edema, a prevalent consequence of brain injury, is associated with significant mortality and disability. Timely diagnosis and monitoring are crucial for patient prognosis. There is a pressing clinical demand for a real-time, non-invasive cerebral edema monitoring method. Ultrasound methods are prime candidates for such investigations due to their non-invasiveness nature; Methods: Acute cerebral edema by permanently occluding the left middle cerebral artery (MCA) was introduced in rats. Ultrasonic echo signals were collected at nine time points over a 24-hour period to extract features from both the time and frequency domains. Concurrently, histomorphological changes were examined. We utilized support vector machine (SVM), logistic regression (LR), decision tree (DT), and random forest (RF) algorithms for classifying cerebral edema types, and SVM, RF, and feedforward neural network (FNN) for predicting the cerebral infarction volume ratio; Results: The integration of 16 ultrasonic features associated with cerebral edema development with the RF model enabled effective classification of cerebral edema types with a high accuracy rate of 97.9%. Additionally, it provided an accurate prediction of the cerebral infarction volume ratio, with an R2 value of 0.8814; Conclusions: Our proposed strategy classifies cerebral edema and predicts the cerebral infarction volume ratio with satisfactory precision. The fusion of ultrasound echo features with machine learning presents a promising non-invasive approach for the monitoring of cerebral edema.

Background: Male factors contribute to approximately 50% of infertile couples. However, obvious causes remain unknown in many cases. This observational study aimed to investigate the associations of clinical and lifestyle parameters with sperm parameters. Materials and Methods: This study enrolled 41 men of infertile couples without obvious causes for male infertility from July 2023 to April 2024. Semen samples were evaluated for sperm number, motility, DNA fragmentation, and oxidative stress (OS) marker oxidation-reduction potential (ORP). Blood samples were analyzed for biochemical parameters, including advanced glycation end products (AGEs) and systemic OS marker diacron-reactive oxygen metabolites (d-ROMs). Skin-accumulated AGEs levels were identified with an autofluorescence method. Lifestyle factors were assessed with a lifestyle questionnaire. Results: Most of the participants were under 40 years old and non-obese with normal clinical and sperm parameters. Multiple regression analyses revealed that body mass index, serum d-ROMs, and semen ORP levels were independently associated with decreased sperm number. Additionally, serum zinc and semen ORP levels were associated with sperm motility. Furthermore, serum zinc and high-density lipoprotein-cholesterol levels were associated with sperm progressive motility and DNA fragmentation, respectively. The rest of the clinical and lifestyle factors, including skin-accumulated and serum AGE levels were not correlated with any sperm parameters. Furthermore, serum d-ROMs and semen ORP levels were not correlated with each other or any of the clinical and lifestyle factors. Conclusions: Our present study indicates that both systemic and local OS may be independently involved in sperm abnormality of healthy men without obvious causes for male infertility.

Background: Conventional echocardiography used to assess volumes of the left ventricle (LV) and left atrium (LA) along with mitral regurgitation grade is routine studies before and after transcatheter edge-to-edge mitral valve repair (Mitral TEER). Previous studies focus on LV parameter changes and comparison of the functions before and a few months following Mitral TEER implantation, as well as LA reverse remodeling, by assessing LV volumes. However, less is known regarding LA strain changes in the early phase after the procedure. The objective of the study was to assess the effect of Mitral TEER on LA strain early after TEER procedure. Methods: The retrospective study included 44 patients who underwent Mitral TEER. LA strain and volumes were evaluated by speckle tracking echocardiography at baseline and 24-48 hours following the procedure. Demographic, echocardiographic, and clinical characteristics were obtained and statistically analyzed. Results: LA global longitudinal strain (GLS) reservoir improved significantly (from 12.2±7 to 14.7±6.4, p=0.0079) after Mitral TEER. Significant improvements were also seen in LA volumes (LA maximal and minimal volume), which reduced by 17% and 22.5% respectively. LV GLS was significantly changed (from -9.8% to -12.8%, p

Objective: This study aimed to explore longitudinal relationships between neurophysiological biomarkers and upper limb motor function recovery in stroke patients, focusing on electroencephalography (EEG) and transcranial magnetic stimulation (TMS) metrics. Methods: This longitudinal cohort study analyzed neurophysiological, clinical, and demographic data from 102 stroke patients enrolled in the DEFINE cohort. We investigated the associations between baseline and post-intervention changes in EEG Theta/Alpha Ratio (TAR) and TMS metrics with upper limb motor functionality, assessed by five outcomes: Fugl-Meyer Assessment (FMA), Handgrip Strength Test (HST), Pinch Strength Test (PST), Finger Tapping Test (FTT), and Nine-Hole Peg Test (9HPT). Results: Our multivariate models identified that a higher baseline TAR in the lesioned hemisphere was consistently associated with poorer motor outcomes across all five assessments. Conversely, a higher improvement in TAR was positively associated with improvements in FMA and 9HPT. Additionally, increased TMS Motor Evoked Potential (MEP) amplitude in the non-lesioned hemisphere correlated with greater FMA-diff, while lower TMS Intracortical Inhibition (ICI) in the non-lesioned hemisphere was linked to better PST improvements. These findings suggest the potential of TAR and TMS metrics as biomarkers for predicting motor recovery in stroke patients. Conclusion: Our findings highlight the significance of TAR in the lesioned hemisphere as a predictor of motor function recovery post-stroke and also a potential signature for compensatory oscillations. The observed relationships between TAR and motor improvements, as well as the associations with TMS metrics, underscore the potential of these neurophysiological measures in guiding personalized rehabilitation strategies for stroke patients.

The incidence of melanoma, the most lethal form of skin cancer, has increased due to ultraviolet exposure. The molecular characterization of melanomas has shown a high mutational burden led to the identification of some recurrent genetic alterations. BRAF gene is mutated in 40-50% of melanomas and its role in melanoma development is paramount. BRAF mutations confer constitutive activation of MAPK signalling. The large majority (abou 90%) of BRAF mutations occur at amino acid 600; the majority are BRAFV600E mutations and less frequently BRAFv600K, V600D and V600M. The introduction of drugs that directly target BRAF-mutant protein (BRAF inhibitors) and of agents that stimulate immune response through targeting of immune check inhibitor consistently improved the survival of melanoma BRAFV600-mutant patients with unresectable/metastatic disease. In parallel, studies in melanoma stage II-III patients with resectable disease have shown that adjuvant therapy with ICIs and/or targeted therapy improves PFS and RFS, but not OS compared to placebo; however, neoadjuvant therapy plus adjuvant therapy improved therapeutic response compared to adjuvant therapy alone.

Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common neuropsychiatric disorders in childhood and can persist into adulthood. Despite its prevalence, diagnosis remains primarily clinical, and it is based on behavioural observation and standardised questionnaires but with few objective tools to validate diagnoses. The use of electroencephalogram (EEG) has emerged as a potential tool to identify neurophysiological biomarkers of ADHD, and research on EEG-based neurofeedback has shown promising results as a therapeutic intervention. This article reviews recent studies looking at the role of EEG in the assessment and treatment of ADHD, with a focus on key findings, current limitations, and future directions.

(1) Background: Obsessive-Compulsive Disorder (OCD) is a psychiatric disorder with poorly detailed subtypes/dimensions, such as religious OCD (ROCD). To date, little is known about ROCD characteristics. This work aimed to describe the sociodemographic and clinical characteristics, as well as the religiosity and spirituality among Lebanese Muslim citizens diagnosed with OCD and exhibiting religious symptoms. (2) Methods: Outpatients were enrolled according to the following inclusion criteria: 18 years of age or above, diagnosis of OCD, presence of religious symptoms, and ability to read and understand the questionnaire. Exclusion criteria were as follows: other psychiatric disorders, and cognitive or physical impairments preventing participation. They filled in a questionnaire including the 25-item Arabic Scale of Obsessions and Compulsions (10 questions addressing obsessions, 10 questions addressing compulsions and five filler items, all of which rated on a 4–point Likert scale; higher total scores indicating increasing severity), the 26-item Spiritual Involvement and Beliefs Scale (rated on a 5-point Likert scale; higher scores indicating higher spirituality), and questions assessing the sociodemographic, clinical, and religiosity variables. (3) Results: Fifty adults (62% females, 52% aged between 18-29 years) completed the study. They had mild (26%), moderate (48%) and severe (26%) OCD symptoms. The majority had a family history of psychiatric disorders (48% OCD) and reported traumatic life events (58%). The majority attended religious school at least at one point in their life and described moderate to very high degree of self-religiosity and parental religiosity. Group comparisons (patients with mild vs. moderate vs. severe OCD symptoms) showed significant differences with regards to family history of psychiatric disorders (p=0.043), frequency of self-questioning if praying correctly (p=0.005), higher rating of partial ablution repetition (p=0.006), and frequency of partial ablution repetitions (p=0.041). No significant groups differences were noted with regards to sociodemographic or spirituality outcomes (4) Conclusion: Some religiosity variables (thoughts and practices) seem to be associated with OCD severity. The current results support the need for further research pertaining to ROCD.

This paper presents the development of a Generative Adversarial Network (GAN) for the generation of synthetic dental panoramic radiographs to address the scarcity of data in dental research and education. A Deep Convolutional GAN (DCGAN) with Wasserstein Loss and Gradient Penalty (WGAN-GP) was trained on a dataset of 2322 radiographs of varying quality. The focus for this study was on the dentoalveolar part of the radiographs; other structures were cropped out. Significant data cleaning and preprocessing was conducted to standardize input formats while maintaining anatomical variability. Four candidate models were identified by varying the critic iterations, number of features and the use of denoising prior to training. To assess the quality of the generated images, a clinical expert evaluated generated synthetic radiographs using a ranking system based on visibility and realism from 1 (Very Poor) to 5 (Excellent). It was found that most generated radiographs showed moderate depictions of dentoalveolar anatomical structures, although they were considerably impaired by artifacts. After averaging evaluation scores, a trade-off was observed between the model trained on non-denoised data, which showed the highest subjective quality for finer structures such as the Mandibular Canal and Trabecular Bone, and one of the models trained on denoised data, which offered better overall image quality, especially for Clarity & Sharpness, and Overall Realism. The outcome serves as a foundation for further research into GAN architectures for dental applications. A GitHub repository containing the WGAN-GP model, source code, and synthetic data has been made publicly available at https://github.com/ViktorLaden/DataProjectGAN.

The present study aimed to evaluate the potential synergy between pharmaceutical formulations containing Bixa orellana L. (granulated – CHR OR and injectable nanodispersion – CHR IN) in conjunction with a cannabidiol (CBD)-rich extract of Cannabis sativa L. (CSE) on experimental pain models in Wistar rats, including acetic acid-induced writhing, formalin, hot plate, and cold-water tail withdrawal tests. Chemical analyses by chromatography confirmed that the oil from B. orellana is rich in δ-tocotrienol (72.0 ± 1.0%), while the oil from Cannabis sativa highlighted the presence of cannabidiol (CBD). The results from the experimental pain tests indicated that the combined administration of formulations containing Bixa orellana and C. sativa, such as the granulated CHR OR (400 mg/kg, orally) with CSE (40 mg/kg, orally) or the nanodispersion CHR In (10 mg/kg, intramuscularly) with CSE (40 mg/kg, orally), demonstrated significant results (p < 0.001) in pain reduction. Although the formulations containing Bixa orellana extract showed statistical significance in the tests when used in isolation, their effects were inferior compared to the combined use with CSE or the isolated use of CSE. These findings suggest that combining formulations containing extracts of these plant species may represent a viable therapeutic option, considering the synergistic action in reducing pain under the experimental conditions employed. These results imply that combining the phytocomplexes present in B. orellana and C. sativa may be a promising approach for pain treatment.

Hearing loss (HL) is the most common disorder in newborns with a highly heterogeneous genetic background. Despite significant progress in screening and identifying genes related with congential hearing loss, there are still candidate genes implicated in HL that remain undiscovered. We investigated HL in 43 China families that segregate bilateral sensorineural via whole-exome sequencing(WES) and Sanger sequencing. Variants were found in 10 known non-syndromic hearing loss (NSHL) genes, 5 known syndromic hearing loss(SHL) genes and a candidate HL genes ATP7B. RNA sequencing reveals ATP7B mRNA expression of in developing and adult cochlea. Immunohistochemistry of the adult mouse cochlear tissue revealed prominent expression of ATP7B in the organ of Corti and the spiral ganglion neuron. Overall, we propose a new candidate genes ATP7B for congential hearing loss and novel variants in known HL genes, which expand our understanding of the etiology of HL.

The aim of the present study was to evaluate the efficacy and safety of the long-term use of a dietary supplement containing red yeast rice (RYR), combined with other natural compounds, in children and adolescents with primary hypercholesterolemia. A nutraceutical, containing RYR, polycosanols, coenzyme Q10, astaxanthin and folic acid (commercial name: Armolipid), was administered once-daily in 84 children/adolescents with moderate or severe primary hypercholesterolemia. Moreover, 19 of the participants consumed 1.5-2.5g of phytosterols daily until the initiation of dietary supplementation with Armolipid. Clinical and laboratory evaluation took place before and 6 and 16 months after treatment. Nutraceutical consumption resulted in a significant decrease in total cholesterol, low density lipoprotein - cholesterol, non-high density lipoprotein – cholesterol and apolipoprotein B levels, that remained at the long-term administration (p

Colorectal cancer (CRC) arises through a combination of genetic and epigenetic alterations that affect key pathways involved in tumor growth and progression. This review examines the major molecular pathways driving CRC, including Chromosomal Instability (CIN), Microsatellite Instability (MSI), and the CpG Island Methylator Phenotype (CIMP). Key mutations in genes such as APC, KRAS, NRAS, BRAF, and TP53 activate signaling pathways like Wnt, EGFR, and PI3K/AKT, contributing to tumorigenesis and influencing responses to targeted therapies. Resistance mechanisms, including mutations that bypass drug action, remain challenging in CRC treatment. The review highlights the role of molecular profiling in guiding the use of targeted therapies such as tyrosine kinase inhibitors and immune checkpoint inhibitors. Novel combination treatments are also discussed as strategies to improve outcomes and overcome resistance. Understanding these molecular mechanisms is critical to advancing personalized treatment approaches in CRC and improving patient prognosis.

Cardiovascular diseases (CVDs), which comprise coronary heart disease, hypertension and stroke, collectively represent the number one cause of death globally. Atherosclerosis is the dominant cause of CVDs; and its risk factors are elevated levels of low-density lipoprotein-cholesterol and triglycerides, hypertension, cigarette smoking, obesity and diabetes mellitus. In addition, diverse evidence highlighted the role played by inflammation and clonal haematopoiesis, eventually leading to the immunity involvement. The human microbiota project and subsequent studies using next-generation sequencing technology have highlighted that thousands of different microbial species are present in the human gut. The disturbances in the gut microbiota (GM) composition, i.e., gut dysbiosis, have been associated with diseases ranging from localized gastrointestinal disorders to metabolic and cardiovascular illnesses. Of note, experimental studies suggested that GM, host immune cells and marine-derived ingredients work together to ensure the intestinal wall integrity. This review discusses current evidence concerning the links among GM, marine-derived ingredients and human inflammatory disease. In detail, we summarize the impact of fish-derived proteins and algae components, on CVDs risk factors and gut microbiome. Furthermore, we describe the interplay among these dietary components, probiotics/prebiotics and CVDs.

Autism in childhood is a heterogeneous disease with around 110 phenotypes. Around 800 genes are affiliated with autism including members of neuro-ligand, neurexin, cadherin, GABA receptors, SHANK gene families, mutated UBE3 A on chromosome 15 and SNORD 116 precursor interaction. A predominant 4:1 male to female ratio is found in autistic spectrum disorder. 50 per cent of all autistic children show chromosome deletions and duplications, these are often found on the 15th and 16th chromosome. Copy number repeat variants in DNA are also well described in pathogenesis of autism patients. There is an overlap with other neurodevelopmental syndromes like tuberous sclerosis, Williams-syndrome, Phelan McDermid syndrome and Sphrintzen syndrome. The hypothesis of the term “atypical connectivity” in different brain regions with partial under- and overconnectivity with reduced brain networking at the psychosocial level was described. Different hypothesis about the origin of autism in children were described. The hypothesis of early lack of basic trust, mercury intoxication and different aspects concerning the origin of this extraordinary disease of 2 percent of children were stated but not confirmed to date. Especially low immature production of IgF-1 by oligodendrocytes in the corpus callosum leads to slowing of the PI3K/AKT chain activation of myelination that Ig-F1 could play an important role in the origin of the disease. Synaptic dysfunction with hypomyelination and impaired impulse transmission seem to play an extraordinary role with under- and overconnectivity with reduced brain networking at the psychosocial level in autistic children. Functional underconnectivity is found in 5 different brain areas, prefrontal, parieto-occipital, motor, somatosensory and the temporal region. Functional overconnectivity is often present in temporo-thalamic regions. Recent research shed light on synaptic dysfunctions with disrupted normal impulse signaling. In this review the different neurochemical findings and the correlation of synaptic dysfunction in autistic children will be closely evaluated.

Purpose: To evaluate the impact of intravitreal bevacizumab (IVB) therapy on anatomical and visual outcomes in patients with macular neovascularization (MNV) secondary to chronic cen-tral serous chorioretinopathy (cCSC). Methods: This retrospective observational study reviewed the medical records of treatment-naïve patients diagnosed with cCSC complicated by MNV, treated with IVB injections over a 5-year period. The presence of MNV was confirmed using op-tical coherence tomography angiography (OCTA). Best-corrected visual acuity (BCVA), subfoveal choroidal thickness (SFCT), and subretinal fluid (SRF) were recorded pre- and post-IVB treat-ment. Results: Twenty-two eyes of 22 patients (mean age, 68 ± 11 years) were included. After a mean follow-up of 21.0 ± 14.6 months, SRF significantly decreased from baseline (176.86 ± 115.62 µm) to the final follow-up (80.95 ± 87.32 µm, P = 0.003). Greater SRF reduction was associated with more injections (>7) (P = 0.047). However, no significant changes were observed in BCVA (P > 0.05) or SFCT (P > 0.05), irrespective of follow-up duration or injection frequency. Complete res-olution of SRF was achieved in 9 patients (40.9%), and a significantly greater reduction in SFCT was observed in complete responders compared to non-responders (P = 0.03). Conclusion: IVB therapy significantly reduced SRF in cCSC patients with secondary MNV, though it did not lead to visual improvement or significant changes in SFCT. However, greater choroidal thinning in patients with complete fluid resorption may suggest distinct underlying mechanisms or alterna-tive sources of subretinal fluid beyond the MNV itself.

This in vitro study evaluated the protective effect of a Si-containing toothpaste associated with different fluoride concentrations by reducing the depth of demineralized lesions in dentin after cariogenic pH cycling. Methods: Sixty bovine dentin blocks (4x4x2mm) were randomly assigned into five groups (n = 12/group): RGS1 (Si-toothpaste with 1450 ppm F), RGS2 (Si-toothpaste with 1100 ppm F), RGS3 (fluoride-free Si-toothpaste), negative control-NC (fluoride-free toothpaste), and positive control-PC (1450 ppm F toothpaste). The specimens underwent a three-day pH cycling model simulating the oral environment with twice-daily brushing. Mineral loss (ΔF) and lesion depth (ΔFmax) were assessed using quantitative light-induced fluorescence (QLF), and scanning electron microscopy (SEM) provided morphological analysis. Elemental analyses were determined with an energy-dispersive X-ray spectrometer (EDS). ANOVA/Tukey's test were used for data analysis (α = 5%). Results: The groups treated with fluoride silicon-toothpastes (RGS1, RGS2) significantly reduced the mineral loss and lesion depth compared to the PC group. The NC group exhibited the greatest mineral loss and lesion depth. SEM images revealed occluded superficial dentin tubules and a protective mineral layer in groups treated with Si-toothpaste, whereas no deposition (NC group) or a limited mineral deposition (PC group) was observed in the control groups. EDS confirmed Si in the toothpaste formulations. Conclusions: Findings suggest that Si-toothpastes favored protection against dentin demineralization even at a lower concentration or free of fluoride, with dentin tubule occlusion, thus consisting of a promising oral care product over traditional fluoride toothpastes.

Background: Bariatric surgery is a safe and effective procedure for treating obesity and metabolic conditions such as type 2 diabetes mellitus (T2DM). Remodeling of the extracellular matrix (ECM) supports adipose tissue expansion and its metabolic activity, where matrix metalloproteinases (MMPs) play a key role in ECM regulation. The substrates of MMPs, particularly MMP-2 and MMP-9, are elevated in patients with morbid obesity, metabolic syndrome, and T2DM. Objectives: To evaluate the effect of weight loss in bariatric surgery patients using oxidative stress markers and to compare MMP levels in patients undergoing Roux-en-Y gastric bypass (RYGB) and vertical gastrectomy (VG). Methods: This was a prospective, controlled study including 45 morbidly obese patients with T2DM (BMI > 35 kg/m²) who underwent RYGB (n=24) or VG (n=21). Weight loss was assessed through anthropometric measurements (weight, height, BMI). MMP-2 and MMP-9 levels were measured preoperatively and at 3 and 12 months postoperatively. Results: Significant and sustained weight loss was observed after surgery in both groups, with reductions in BMI. MMP-2 and MMP-9 levels decreased significantly after one year of follow-up. Conclusions: Bariatric surgery is an effective long-term intervention for weight loss and associated comorbidities, including T2DM. MMP-2 and MMP-9 proved to be effective inflammatory markers, with significant reductions following surgery.

Over the past few decades, the landscape for multiple myeloma (MM) therapy has significantly advanced, largely due to the approval and introduction of new-generation proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs). Despite these advancements, MM remains incurable. In March 2021, the U.S. FDA approved the chimeric antigen receptor T-cell (CAR-T) therapy idecabtagene vicleucel (ide-cel) for relapsed/refractory multiple myeloma (R/R MM), heralding the advent of cellular therapies for R/R MM. However, due to factors such as the downregulation or loss of tumor antigen expression, T-cell exhaustion, and the influence of the tumor immune microenvironment, most R/R MM patients inevitably experience relapse following CAR-T cell therapy. Consequently, salvage therapy in the post-CAR-T setting has emerged as a critical area of research. This review discusses the potential factors leading to CAR-T therapy failure in R/R MM patients and discusses subsequent salvage therapeutic strategies, offering recommendations for addressing treatment failure in this context.

Clinicians have long faced challenges and decisions regarding sodium management in their patients. They must have a good understanding of the physiology of sodium, its metabolism, distribution in the body, and the consequences of changes in sodium content and concentration seen frequently in different settings of patient care and across different specialties. Multiple studies and several formulas are currently available to help manage cases with dysnatremia. These tools require a detailed focus to benefit patients in the short and long term and to avoid consequences due to poor decisions leading to severe and potentially fatal complications, including osmotic demyelination syndrome. This review will consider different aspects of sodium metabolism, the role sodium has in patients with edema, the evolution sodium management based on Edelman’s studies and related formulas, and other considerations regarding sodium storage in the skin currently relevant for a more in-depth approach to the management of patients with dysnatremias.

The objective of this research was to examine apoptosis status in the laminar tissue of dairy cows with OF-induced laminitis. A total of 12 clinically healthy non-pregnant Holstein cows were randomly allocated into 2 groups of 6 cows each: the control group and the oligofructose treated group (OF group), respectively. At 0 h, 17 g/kg BW of oligofructose dissolved in 20 mL/kg BW of warm deionized water were administered to the dairy cows of OF group via a stomach tube, and dairy cows in control group were received with the said volume of deionized water by the same method. At -72 h before and 0 h, 6 h, 12 h, 18 h, 24 h, 36 h, 48 h, 60 h, and 72 h after OF overload, clinical examination in both groups were performed. After 72 h, laminar tissues of dairy cows in both groups were taken to determine genes and proteins. We observed that the gene expression of Bax (P<0.01), and P53 (P<0.05) significantly up-regulated, whereas that of Bcl2 significantly down-regulated (P<0.01) in the afflicted cows compared to the control cows. The protein expression of Bax (P<0.01), Bif1 (P<0.01), caspase3 (P<0.01), caspase8 (P<0.05), and caspase9/9p (P<0.05) significantly up-regulated, while that of Bcl2 significantly downregulated (P<0.01) in the afflicted cows compared to the control cows. Moreover, the distribution of Bax (P<0.01) and P53 (P<0.01) proteins in laminar tissue significantly up-regulated (P<0.01) in the sick cows compared with the control cows. These results suggested that unregulated genes and proteins status of apoptosis-associated indicators may be a typical cause for epidermal attachment failure which serves a key role in the pathogenesis of dairy cow laminitis. Nevertheless, further large-scale gene and protein-level studies are required to fully explain the pathogenesis of laminitis in dairy cows.

The rare abscopal effect during radiotherapy is thought to be caused by the release of immune-stimulated damage-associated molecular patterns, such as high mobility group box-1 protein (HMGB1), from cancer cells. Although external irradiation of cancer cells increases HMGB1 release, it is not clear if HMGB1 is released from cells after administering 131I-labeled m-iodobenzylguanidine (131I-MIBG) as an internal targeted radiotherapeutic agent. This study aimed to determine if HMGB1 is released from human-derived cancer and normal cells after administering 131I-MIBG. Methods: Extracellular lactate dehydrogenase (LDH) and HMGB1 released from H441 (human-derived lung adenocarcinoma cell line) and HaCaT (human keratinocyte cell line) 1 day after 2- and 10-Gy X-ray irradiation were measured. Accumulations of 131I-MIBG in SH-SY5Y (human-derived neuroblastoma cell line) and HaCaT were measured 60 min after administering 131I-MIBG (0.37, 1.85, 3.7 MBq/well). Extracellular LDH and HMGB1 released from SH-SY5Y and HaCaT 1 day after administering 131I-MIBG were also measured. Results: The extracellular LDH and HMGB1 released from H441 after 10-Gy X-ray irradiation were significantly increased. However, the extracellular LDH and HMGB1 released from HaCaT after 2-Gy and 10-Gy X-ray irradiation were not increased. After administering 1.85 MBq and 3.7 MBq 131I-MIBG, the extracellular LDH and HMGB1 released from SH-SY5Y were both significantly increased, but only the extracellular LDH released from HaCaT was significantly increased. Conclusions: HMGB1 was released from neuroblastomas but not from normal cells after 131I-MIBG administration, suggesting that a combination of 131I-MIBG and immunotherapy may be feasible.

To date, SARS Cov-2 virus has caused more than 775 million cases worldwide and led to 7 million deaths. The virus enters cells with the aid of the ACE2 receptor located in the airway epithelium, but also in endothelial cells lining the inner walls of vessels. Endothelial damage results in impaired blood flow and gas exchange. Statins have been shown to have a pleiotropic effects on the vascular epithelium. Aim of the study: Assessment of the efficacy and safety of statin therapy in patients with COVID-19. Methods: Two hundred and one COVID-19 patients hospitalized at the Jerzy Gromkowski Regional Specialist Hospital between March 2020 and December 2021 (i.e. during the period dominated by Alpha, Beta, Gamma and Delta variants). Patients were divided into three groups: (I) patients treated with statins prior to the admission to the hospital; (II) patients started on statins after admission due to Covid-19; (III) control patients with Covid-19, not treated with statins either prior to or during hospitalization. Met Statistica 13.1 calculations were used in the paper. Shapiro-Wilk, Kruskal-Wallis and ANOVA tests were also performed. Results: Out of the 201 patients total, group I comprised 66 patients with a mean age of 66.2 years; group II comprised 33 patients with a mean age of 75.3 years; and the control group comprised 97 patients with a mean age of 61.1 years. The groups characteristics did not show significant differences in terms of gender, place of hospitalization, percentage of Covid-19 vaccinations, number of convalescents. Death was observed in: 12% of patients in group I, 6% of patients in group II, and 6% of patients in group III. Body Mass Index (BMI) in group I was 31.3: a value significantly higher than the control group’s 28.3, (p<0.05). The severity of Covid-19 assessed on admission in group I – 4.09 – was statistically higher than in the control group 3.52 (p<0.05). The number of pulmonary embolism incidents did not differ between groups. Conclusions: During the period dominated by Alpha, Beta, Gamma and then Delta variants, we found no statistically significant positive or negative effects of statin therapy on the duration of hospitalization, number of complications or percentage of deaths between the two studied groups of patients: those who received statins prior to hospitalization, and those who received statins during hospitalization.

The aim of our research was to evaluate and analyze serum 25(OH) vitamin D and parathyroid hormone (PTH) levels to investigate whether vitamin D deficiency serves as a risk factor for an increased incidence of acute respiratory infections (ARI) in children. Serum PTH levels were used as an indicator of vitamin D sufficiency, as normal PTH levels require an optimal concentration of 25(OH) vitamin D. The study included 129 children, divided into five subgroups: children with acute bronchopneumonia (n=42), acute laryngotracheitis (n=7), acute bronchiolitis (n=32), acute bronchitis (n=18), and a control group (n=30). No statistically significant differences in 25(OH)D levels were observed between the overall population of children with ARI and the control group (p=0.073). However, significant differences in 25(OH)D levels were identified between the control group and children with bronchopneumonia, acute bronchitis, and laryngotracheitis (p<0.01, p<0.05). Vitamin D insufficiency was found in 28.3% of children with ARIs and 10% in the healthy group. Sufficient levels were present in 60% of healthy children and 48.5% of those with ARIs. Deficiency was observed in 4% of ARI patients and 3.3% of the control group. Regarding PTH levels, statistical significance was found between the control group and the acute bronchiolitis group, due to the high percentage of children with hypervitaminosis in this subgroup. These results highlight the crucial role of vitamin D in the onset and progression of acute respiratory tract infections in children, emphasizing its impact on their overall respiratory health.

Myxomatous mitral valve disease (MMVD) is a leading cause of cardiac morbidity and mortality in dogs, requiring targeted intervention at various stages of disease progression. MMVD is characterized by thickening of the mitral valve leaflets, leading to mitral regurgitation and cardiac remodeling. This progressive disease impairs valve function, causing volume overload in the left atrium and ventricle, which can eventually lead to congestive heart failure. MMVD involves complex mechanisms, including genetic predisposition, neurohormonal activation, and mechanical stress on the valve. Thickened valve leaflets fail to seal properly during systole, resulting in mitral regurgitation and increased left atrial pressure. This triggers compensatory mechanisms like activation of the renin-angiotensin-aldosterone system (RAAS), contributing to further cardiac remodeling. Chronic RAAS activation results in fluid retention, vasoconstriction, and fibrosis, all of which can worsen heart failure. This mini-review provides an overview of current therapeutic strategies for the management of MMVD and discusses preliminary findings from our consortium regarding the preclinical and clinical efficacy of the sodium-glucose co-transporter type-2 (SGLT-2) inhibitor, dapagliflozin, in dogs.

Reactive oxygen species (ROS) encompass various molecular oxygen derivatives naturally produced during aerobic metabolism, including superoxide anion, hydrogen peroxide, and hydroxyl radical. Excessive ROS production leads to oxidative distress, causing cellular damage and contributing to various pathologies, often alongside inflammation. Endogenous sources of ROS include mitochondrial activity and NADPH oxidases. The antioxidant system, comprising enzymes such as superoxide dismutase, peroxiredoxin, and catalase, mitigates ROS-induced damage. This review explores the regulation of ROS by membrane receptors, focusing on B1 and B2 kinin receptors and histamine H2 receptors, which are implicated in vasodilation, angiogenesis, inflammation, and gastric acid secretion. Understanding these interactions provides insights into ROS modulation and its role in disease mechanisms.

Among women globally, breast cancer is a major cause of cancer-related death. Accurate and timely diagnosis is essential, and results can be significantly improved. A new era in image analysis has been brought about by the emergence of artificial intelligence (AI), which has made significant progress in the diagnosis and customization of treatment plans for breast cancer possible. This study aimed to develop a comprehensive AI framework for breast cancer detection by integrating convolutional neural networks (CNNs) for image analysis with an artificial neural network (ANN) for clinical data. Using a dataset of ultrasound and pathology images, along with clinical features from 569 patients, we trained CNN models to classify breast tissue as benign or malignant, and the ANN to process clinical data for the same task. The combined approach significantly enhanced the accuracy of breast cancer diagnosis, achieving over 96% accuracy by leveraging both imaging and clinical data. Class Activation Maps (CAM) and heatmaps provided valuable interpretability for CNN predictions, improving trust and transparency in the model’s decision-making process. The results demonstrate that the fusion of CNNs and ANNs enhances diagnostic accuracy and offers a promising tool for early breast cancer detection, while providing crucial insights for clinical validation.

Background/Objectives: Biallelic pathogenic variants in the CEP290 gene are typically associated with severe, early-onset inherited retinal dystrophies (IRDs) in both syndromic and non-syndromic forms. This study highlights the phenotypic variability of CEP290-related non-syndromic IRDs, focusing on two siblings with biallelic CEP290 variants. One sibling presents with a milder phenotype, expanding the known spectrum of CEP290-related IRDs and emphasizing the importance of personalized clinical monitoring; Methods: Whole-exome sequencing (WES) was used to identify CEP290 pathogenic variants in the siblings. Comprehensive ophthalmologic evaluations were performed to assess the severity and progression of retinal degeneration; Results: Both siblings were found to carry compound heterozygous pathogenic variants in CEP290, inherited in trans. Clinical evaluations revealed significantly preserved retinal function in the sister, whereas the brother exhibited a more aggressive and progressive retinal dystrophy; Conclusions: This study expands the phenotypic spectrum of non-syndromic CEP290-related IRDs, demonstrating that biallelic CEP290 variants can result in a wide range of severity, from mild to severe. These findings highlight the need for personalized monitoring and tailored management strategies in CEP290-related IRDs.

Background/Objectives: Thoracic aortic aneurysms (TAA) represent medical conditions having causes that can range from genetic determinations to various risk factors, having potential life-threatening complications, the familial TAA (FTAA) being a cluster of non-syndromic thoracic aortic aneurysms. This review aims to emphasize the importance of genetic testing in patients diagnosed with thoracic aortic aneurysms, the genetic implications accounting for roughly 20% of these cases. The reported case presents a patient who was genetically tested 10 years after a Bentall procedure, which was performed for acute DeBakey type I aortic dissection developed in her second pregnancy, when the patient started presenting recurrent prolonged febrile syndrome. She was tested positive for a missense variant in the actin alpha-2 (ACTA2) gene, in heterozygous status, but also serological tests revealed the presence of an infection with Coxiella burnetii. Methods: For a better understanding of both conditions, our research was conducted on two directions, one reviewing the literature on patients with Coxiella burnetii blood culture-negative infective endocarditis (BCNIE) and the other one, focusing on patients having familial thoracic aortic aneurysm (FTAA) due to ACTA2 mutation. This review incorporates studies found on PubMed and ResearchGate up to August 2024. Conclusions: BCNIE represents a condition with several diagnosis challenges and may lead to severe complications if timely treatment is not initiated. Also, diagnosing FTAA requires more frequent genetic testing, enabling a better follow-up and management.

Cardiovascular surgeries, though lifesaving, can lead to complications requiring further interventions, including amputations. This study uses Sankey diagrams, Sunburst plots, and Icicle plots to analyze treatment pathways in patients with peripheral artery disease (PAD), focusing on those that lead to amputation versus those that do not. We found that non-amputation outcomes commonly involve anti-platelet and lipid-lowering medications, while amputation pathways, although less frequent, often share similar initial treatments but diverge later, suggesting areas for early intervention. These visualizations highlight patterns in patient care and emphasize the importance of tailored treatment strategies to reduce amputations, offering insights to predict likely outcomes based on treatment sequences.

Background: Congenital coronary artery anomalies (CAAs) are a significant cause of sudden cardiac death and a key factor in determining athletes’ eligibility for competitive sports. Their prevalence varies with diagnostic modalities and may present as asymptomatic or with life-threatening ischemic or arrhythmic events. This case series highlights the diverse manifestations of CAAs and the clinical approaches used to determine sports eligibility. Cases description: five competitive athletes with different CAAs are presented. These cases include anomalous coronary origins, intramyocardial bridges, and coronary fistulas. Diagnostic tools, including coronary CT angiography (CCTA), cardiac magnetic resonance imaging (CMR), and stress tests, were essential in evaluating these anomalies and determining treatment strategies. In some cases, such as intramyocardial bridges, surgical intervention was necessary, while others required conservative management or exclusion from competitive sports. Conclusions: CAAs require individualized care based on risk stratification through advanced imaging techniques and functional assessment. Surgical interventions are reserved for high-risk anomalies, while others may be managed conservatively. Early detection and tailored management are crucial for ensuring athletes’ safety, and ongoing research is needed to optimize long-term outcomes.

Abstract Background andAims: During liver transplantation, hepatocellular carcinoma (HCC) recurrence remains a critical challenge for patient survival. Targeted therapies, such as Sorafenib and Regorafenib, have been utilized to manage relapsed HCC in this unique setting. This study aimed to assess the efficacy of Sorafenib and Regorafenib in patients with HCC who experienced recurrence after liver transplantation. We focused on survival outcomes, treatment responses, and the management of side effects in this patient group. Methods: We conducted a retrospective analysis of 73 patients who experienced HCC recurrence post-liver transplantation between 2012 and 2022, across 11oncology centers in Turkey. Patients were categorised according to Child-Pugh classification and treated with Sorafenib as first-line therapy and Regorafenib in case of progression. Survival rates were analysed by Kaplan-Meier method and risk factors were evaluated by Cox regression analysis. Results: Of the 73 patients included in the study, 62 were male (84,9%) and 11 were female (15,1%) with a mean age of 61,5 ± 10,9 years. All patients received sorafenib as first-line treatment. Among patients who experienced progression with sorafenib or discontinued treatment due to toxicity, 45,2% (n=33) continued treatment with regorafenib. The median progression-free survival (PFS1) time with Sorafenib was 5,6 months and the one-year survival rate was 24,3%. The median progression-free survival (PFS2) time with Regorafenib, which was administered as second-line treatment, was also calculated as 5,9 months. Overall survival (OS) duration was determined as 35,9 months. The most common side effects associated with both drugs included fatigue, hand-foot syndrome and hypertension. Significantly better survival outcomes were shown in the Child-Pugh A group compared to other patients. Conclusion: These results suggest that Sorafenib and Regorafenib treatments offer a survival advantage in patients with relapsed HCC post-transplantation. However, individualized treatment strategies and close follow-up are crucial for optimizing outcomes. Further studies are needed to refine therapeutic protocols and enhance the care of this specific patient group.

Background: The increasing prevalence of Mycoplasma genitalium infections with macrolide resistance causing high azithromycin failure rates is a major concern internationally. In response to this challenge, diagnostics that simultaneously detect M. genitalium and genetic markers for macrolide resistance enable the therapy to be individually tailored, i.e. to implement resistance-guided therapy (RGT). Objectives: This study aimed to evaluate patient treatment outcomes of M. genitalium therapy guided by a macrolide-resistance assay in Bulgaria; Methods: Consecutively referred M. genitalium infection cases (n=17) were analyzed for macrolide-resistance mutations (MRMs) and specific antimicrobial treatment was recommended accordingly (MRMs-negative infections received azithromycin and MRMs-positive received moxifloxacin). Treatment outcome based on test-of-cure was recorded and treatment failure rates and time to microbiological cure were compared with treatment outcomes in patients treated before the implementation of RGT; Results: Among patients given RGT (n=17), the overall treatment failure rate was 1/17 (5.9%). This was significantly lower than the rate (47.6%) observed in patients treated pre-RGT (p=0.002). The time to microbiological cure was 29.4 days (CI 24.5 – 34.3) compared to 45.2 days (CI 36.5 – 53.7) pre-RGT (p=0.001); Conclusions: Implementation of M. genitalium diagnostics with macrolide-resistance detection improved treatment outcomes in Bulgaria with significantly lower treatment failure rates and reduced time to microbiological cure. In light of limited treatment options and concerns about their decreasing efficacy in response to misuse and overuse, diagnostic macrolide-resistance assay is critical to direct appropriate first-line treatment, to maintain the efficacy of antimicrobial treatment (antibiotic stewardship) and to minimize the spread of antimicrobial resistance.

This study evaluates the effectiveness of adaptive binaural beamforming in a realistic cafeteria noise environment. The motivation stems from the common challenge faced by hearing aid users in such environments, where communication often demands significant mental effort. The study employed a combination of behavioural, neurophysiological, and self-reported measures to assess speech intelligibility and listening effort. Results showed that the adaptive binaural beamformer improved speech-in-noise intelligibility at signal-to-noise ratios (SNRs) yielding 80% and 95% intelligibility. Additionally, when this technology was enabled, listening effort was reduced across various metrics: faster reaction times on a dual task, decreased pre-stimulus alpha power (8-12 Hz), indicating less inhibition was needed, and increased alpha power during the encoding and retention phases, consistent with greater working memory load due to improved intelligibility. Self-reports indicated lower perceived effort in the more challenging SNR condition. The use of realistic background noise enhances the ecological validity of the findings, contributing to a better understanding of how this hearing aid technology performs in real-world listening environments. Overall, the study demonstrates that adaptive binaural beamforming can ease the cognitive burden on users in noisy, everyday environments, thereby enhancing their overall auditory experience.

Background. A direct clinical and morphological comparison of non-COVID myocarditis than was diagnosed before the SARS-CoV-2 pandemic and post-COVID myocarditis has not been performed so far. Purpose: to compare morphological activity, toll-like receptors expression and response to the immunosuppressive therapy in patients with non-COVID and post-COVID myocarditis. Metodhs. Seventy-seven patients (52 male and 25 female, 48.7±11.7 y.o.) with biopsy proven myocarditis, NYHA class 2 or more heart failure, ejection fraction (EF) <45% were included. A history of myocardial infarction, verified cardiomyopathies, systemic autoimmune diseases, viral DNA in the myocardium, except parvovirus B19, were exclusion criteria. The right ventricular endomyocardial biopsy with hematoxylin and eosin, Van Gieson stains, PCR for virus (herpes viruses, parvovirus B19, adeno-, enteroviruses and SARS-CoV-2), immunohistochemical study for CD3, CD45, CD68, CD20, nucleocapsid / spike proteins of SARS-CoV-2 and in addition toll-like receptors (TLR) type 4 and 9 expression (in 38 patients) were performed. The steroids (methylprednisolone 24-40 mg per day), azathioprine, mycophenolate mofetil were prescribed. The mean follow-up was 16 [6; 30] month. Results. In 45 patients, myocarditis was diagnosed before the SARS-CoV-2 pandemic (giant-cell in one case and lymphocytic in the others). Other 32 patients had post-COVID myocarditis positive for RNA or/and proteins of SARS-CoV-2 (giant-cell in one case, eosinophilic in three cases and lymphocytic in the others). There were no differences in age, NYHA class, CRP and anti-heart antibodies level, echocardiographic parameters (mean EF 30.2±7.8 vs 28.7±6.7%), parvovirus B19 positivity (22 vs 34%), doses of methylprednisolone (24-40 mg/day) and death / transplantation rate (11.1 vs 9.4%). Differences between non-COVID vs post-COVID myocarditis focused on higher CD3, CD 45*, TLR 4 (4+ vs 6+), TLR 9 (0 vs 2+) expression and better response to therapy [10% or more increase in EF in 53 vs 86%* of patients, mean EF (43.9±12.3 vs 49.8±7.6%*) by the end of follow-up], *p<0.05. Conclusion. Post-COVID myocarditis is characterised by different morphological types, higher morphological activity, tendency to higher TLR expression and the best response to the immunosupressive therapy in comparison with non-COVID myocarditis.

Background/Objective: In this study, for the first time, we examined and compared the sensitivity of four patient-derived cutaneous melanoma cell lines to alpha radiation in vitro and analyzed it in view of cell nucleus area and the formation of double strand breaks (DSB). Melanoma cells sensitivity to alpha radiation was compared to photon radiation effects. Furthermore, we compared the sensitivity of the melanoma cells to squamous cell carcinoma. Methods: Human melanoma cell lines YDFR.C, DP.C, M12.C and M16.C, and the squamous cell carcinoma cell line, CAL 27, were irradiated in-vitro using Americium-241 as alpha-particle source. Cells were irradiated with doses of 0 to 2.8 gray (Gy). Cell viability, DNA DSB and nuclear size were measured. Results: 1. Alpha radiation caused death and proliferation arrest of all four melanoma cell lines, but inter-tumor heterogeneity was observed. 2. The most sensitive cell line (DP.C) had a significantly larger nucleus area (408 mM²) and the highest mean number of DSB per cell (9.61) compared to more resistant cells. 3. The most resistant cell, M16.C, had a much lower nucleus area (236.99 mM²) and DSB per cell (6.9). 4. Alpha radiation was more lethal than photon radiation for all melanoma cells. 5. The SCC cell, CAL 27, was more sensitive to alpha radiation than all melanoma cells, yet, had a similar number of DSB (6.67) and nucleus size (175.49 mM²) as the more resistant cells. 6. The cytotoxic effect of alpha radiation was not affected by proliferation arrest after serum starvation. 7. Killing of cells by alpha radiation was marginally elevated by ATR or topoisomerase 1 inhibition. Conclusions: This study demonstrates that various human melanoma cells can be killed by alpha radiation but exhibit variance in sensitivity to alpha radiation. Alpha radiation applied using Intra-tumoral Diffusing alpha-emitters Radiation Therapy (Alpha DaRT) methodology may serve as an efficient treatment for human melanoma.

Gastric cancer is among the prevalent types of cancer that cause high mortality rates globally, due to which worrisome new therapeutic approaches cannot be ruled out. The present review aims at providing an extensive overview of the recent development in the field of immunotherapy for gastric cancer, with a special reference to exosomes and their potential for regulating tumor progression. In this review, we provide a stepwise approach towards understanding of the status of knowledge of exosomes in intercellular communication comprehensively discussing biochemical contents, immune modulation, drug resistance and disease progression. Inclusive in our search strategy are the articles published in the last 15 years, and using keywords such as “exosomes,” “immunotherapy,” and “gastric cancer.” For this systematic review, two rounds of article filtering were conducted before reviewing of the articles and their findings thoroughly. This field’s specific areas of focus embrace the functionalities attached to the exosome-associated microRNAs, processes on which the exosome signalling depends on, and the utilization of non-tumor cell-derived exosomes in the tumor microenvironments. Combining these findings, this review seeks to systematically identify and discuss the roles of exosomes in biomarkers and novel targets for GC treatment. In conclusion, our current study supports further exploration of the application of exosomal biology to enhance immunotherapeutic approaches in gastric cancer treatment.’

Senescence-associated secretory phenotype (SASP) is a particular expression profile portrayed by senescent cells, which includes the secretion of cytokines, proteases, and chemokines, among other signalling molecules, exerting great influence on local as well as systemic environment which participates in cell senescence, immunoregulation, angiogenesis, cell proliferation, tumor invasion, etc. We performed a clinic-pathological, immunohistochemical and ultrastructural analysis with the aim of studying the association between the different histological characteristics of craniopharyngioma, the effects of OMF exposure and its potential role in the induction of SASP. We observed that cells of the outer epithelium can secrete lipoproteins and glycoproteins into the external tumor environment, inducing an intense inflammatory response. Neoplastic cells protrude out of the tumor and are able to grow rapidly and form wet keratin, which calcifies afterward. This limited growth ability is acquired by interacting with the aforementioned growth factors, proinflammatory molecules, angioblast and fibroblast activation, angiogenesis, cell proliferation, and brain invasion, associated with glycoproteins secretion of tumor cells associated with SASP.

Canine monocytic ehrlichiosis (CME) is an infectious disease caused by Ehrlichia canis, a globally recognized obligate intracellular bacterium. In addition to dogs, other animals, including humans, may be affected. Despite its epidemiological importance and impact on public health, there is currently no commercial vaccine against E. canis. This study aimed to present relevant aspects of the challenges and advances encountered in the development of vaccines for CME and highlight perspectives for future investigations. High genetic variability, along with the various evasion mechanisms employed by E. canis, has hindered the identification of an antigen that targets Th1 cells and is immunogenic to most E. canis isolates, considering their distinct antigenic characteristics. To achieve robust immunity, the vaccine must predominantly confer cellular and humoral immunity. Early production efforts have been challenging owing to low immunogenicity, difficulties in establishing long-term protection, and limitations of the techniques used. However, with the refinement of bioinformatic tools, research in this area will be facilitated, thereby accelerating the development of effective vaccines for CME. According to these authors, a vaccine should consist of multiple epitopes.

Metabolic syndrome (MetS), first conceptualized in 1923, encompasses a cluster of metabolic abnormalities, including insulin resistance (IR), hyperglycemia, dyslipidemia, hypertension, and central obesity. This syndrome significantly increases the risk for cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). Its global prevalence has surged, largely attributed to lifestyle factors such as poor diet and physical inactivity. Recent research highlights the crucial role of caveolae, small cellular structures, in the pathophysiology of MetS, particularly in insulin signaling, lipid metabolism, and vascular function. Managing MetS effectively requires a comprehensive strategy focused on lifestyle modifications and pharmacological treatments. Dietary approaches, environmental factors, regular physical activity and behavioral changes have demonstrated positive impacts on metabolic health. Despite current pharmacological options to individual conditions of MetS, emerging therapies targeting caveolae offer promising new avenues for treatment. While, microbiome modulation and certain natural agents may assist in managing the syndrome. Public health initiatives, including educational campaigns and stress reduction programs, are essential for the prevention and management of MetS. A multifaceted approach combining lifestyle changes, pharmacotherapy, and personalized interventions is vital for effective management. Future strategies may benefit from precision medicine and the integration of emerging biomarkers for targeted therapies.

There is currently no clinically valid biomarker for predicting the growth and prognosis of abdominal aortic aneurysms (AAA). The most promising candidates with highest diagnostic values are plasma D-dimers and markers of activated neutrophils, i.e. myeloperoxidase (MPO) or cell-free DNA. So far, case-control studies on these markers were almost exclusively performed by using healthy individuals for control. To validate the value of these markers in the clinical setting of a vascular surgery department, we analysed the diagnostic and prognostic potential of plasma D-dimers and MPO in 177 AAA patients versus 138 non-AAA patients with different vascular diseases. Significantly elevated levels of D-dimers were recorded for AAA patients compared with non-AAA patients, although the difference between the two groups was significantly smaller than in other studies comparing AAA patients with healthy controls. Surprisingly, MPO levels were significantly higher in non-AAA patients than in AAA patients. After adjusting for the confounding factors sex, peripheral artery disease (PAD) and internal carotid stenosis in multivariate regression models, neither D-dimers nor MPO remained independent correlates of AAA. In contrast, D-dimer plasma levels correlated well with the maximal aortic diameter. Combined analysis of D-dimers and circulating cell-free DNA levels derived from a previous study, failed to improve the predictive values for the maximal aortic diameter. In conclusion, our data show that D-dimers and MPO are no suitable biomarkers for monitoring AAA in a real-world setting of mixed vascular surgery patients.

Objective To screen and systematically analyze the differential proteins in rats suffer from SCI after treating with HPL and thus explore the therapeutic mechanism of HPL on SCI rats. Method 30 SD rats were selected and randomly divided into three groups: control group, injury group, and treatment group. Allen Test was performed to establish the rat models with injured spinal cord, and2 mL of HPL was intraperitoneally injected into rats in the treatment group every day. After 14 consecutive days of injection, the thoracic spine of rats was sampled and analyzed by proteomics. Result A total of 61 differential proteins were screened in the injury and treatment groups, including 7 up-regulated proteins and 14 down-regulated proteins. The GO enrichment analysis results showed that the differential proteins included cellular components such as ATP dependent chromatin remodeling complex composed of multiple subunits, recycling endosome, extracellular space, and ATP synthase complex. These differential proteins promote serine-type endopeptidase inhibitor activity, myosin-binding protein and peptidase inhibitor molecular functions, and are involved in biological processes including fibrinolysis, sulfur component synthesis and metabolism, cellular modification of amino acid metabolism, and myelination. The KEGG analysis results mainly suggested the therapeutic mechanism of HPL for SCI through nitrogen metabolism, sodium taurocholate hydrate, complement coagulation cascade, and alcoholic liver disease. Conclusion HPL has a good therapeutic effect on SCI via the bioinformatic mechanisms above.

This article introduces a new paradigm in nutritional science for long-term weight management, based on the integration of bioneurofeedback and bioimpedance analysis. Bioneurofeedback, a technique that combines the monitoring of physiological parameters with the modulation of brain activity, is employed to improve the self-regulation of eating behaviors by adjusting brainwave activity and reducing stress. Bioimpedance analysis provides a precise evaluation of body com-position, enabling the personalization of interventions according to individual physiological and metabolic characteristics. This integrated approach utilizes the principles of cybernetics and complex systems theory to better understand the interaction between mind and body, enhancing weight regulation through a dual top-down and bottom-up strategy. Additionally, the article discusses how an excess or deficiency in specific brainwaves can affect disordered eating behaviors, proposing biofeedback integration as a method to mitigate the yo-yo effect and promote sus-tainable lifestyle changes.

In our previous study of 291 cancer patients, we showed that 20% did not respond to two doses of COVID-19 vaccine administered six weeks apart. Here we investigated if psychological factors (distress, anxiety and depressive symptoms) affected antibody response and markers of vaccine activation (D-dimer) after 6 months from initial vaccination. Overall, 31 subjects (14.2%) had no antibody response at 6 months. Our analysis revealed significant predictors of vaccine failure, including stage of metastatic disease and high stress levels (OR=2.46, 95% CI, 1.05-5.77, p=0.04). Notably, nonresponders showed twice the prevalence of distress than responders (21% vs. 10%, p=0.04). Longitudinal measurements of IgG levels indicated that participants with high depressive symptoms at baseline maintained lower antibody levels over six months (p=0.003). In addition, women with high anxiety showed reduced levels of D-dimer at 6 month time (p=0.03). The data also showed that smokers and former smokers had significantly lower antibody levels than their nonsmoking counterparts (p=0.0004). At baseline, the high discomfort rate (≥5) was 34.4% in women and 23.8% in men; only men experienced an increase in median discomfort during the observation period. Moreover, higher educational level was related to increased distress among women (p=0.046). These findings underscore a critical association between elevated psychological distress and reduced immune responses to the COVID-19 vaccine, emphasizing the urgent need for targeted psychological and behavioral support within this vulnerable population.

Background: Infections caused by S. aureus strains encoding Panton-Valentine leukocidin (PVL-SA) have become increasingly relevant in community settings and can cause severe conditions in pediatric populations. We present a pediatric case of invasive disease caused by PVL-SA and provide a literature review of severe manifestations caused by these strains in children. Methods: A PubMed search (February 2024) evidenced studies that included relevant clinical outcomes, diagnostics, and treatments, excluding cases of asymptomatic infection or adult populations. Logistical multivariate analysis was used to find predictors of the need for intensive care. Results: A 10-year-old boy came to the attention of our Pediatric Infectious Diseases Unit with fever, chest pain, and tachypnea. A rapid worsening of his clinical conditions was observed, with the development of necrotizing pneumonia, osteomyelitis, deep vein thrombosis (DVT), and multiple abscesses. Blood cultures confirmed the presence of PVL-producing methicillin-resistant S. aureus (MRSA). The initial treatment included linezolid and ceftaroline and was later adjusted to clindamycin, daptomycin, and fosfomycin, with clinical improvement. Discussion: Our review collected 36 articles, including 156 pediatric cases of severe PVL-SA infection. Bacteremia was present in 49% of cases, lung infection in 47%, and osteomyelitis in 37%. The presence of pulmonary localization was predictive of the need for intensive care, O.R. 25.35 (7.46 - 86.09; p&lt;0.001). Anti-toxin molecules were used in about half the cases where information on treatment was reported. Our report highlights the capacity of PVL-SA to cause life-threatening complications in children, while also discussing the full range of its clinical spectrum and the most effective therapeutic approaches.

Background: Hypopituitarism is a potentially serious but often underdiagnosed condition that can occur following non-traumatic subarachnoid hemorrhage (SAH). The condition is characterized by the partial or complete deficiency of one or more pituitary hormones, leading to a range of clinical manifestations that may complicate the recovery process. This narrative review aims to synthesize the current literature on the prevalence, pathophysiology, and clinical implications of hypopituitarism associated with non-traumatic SAH. Methods: A comprehensive review of the literature was conducting by authors using databases such as PubMed, MEDLINE, and Scopus, focusing on studies published in the last two decades. Studies were selected based on their relevance to the topic, with an emphasis on those that reported on the prevalence, diagnostic approaches, pathophysiological mechanisms, and clinical outcomes of hypopituitarism post-SAH. Results: The review revealed a wide variability in the reported prevalence of hypopituitarism following non-traumatic SAH, ranging from 14% to 92.3%, depending on the diagnostic criteria, timing of assessment, and hormonal axes evaluated. Commonly affected hormones include growth hormone, gonadotropins, and cortisol. The pathophysiology of hypopituitarism in this context is multifactorial, involving ischemic damage, inflammation, and direct mechanical injury to the hypothalamic-pituitary axis. While some studies suggest a link between hypopituitarism and adverse clinical outcomes, the evidence remain inconclusive, highlighting the need for standardized diagnostic protocols and longitudinal studies. Conclusion: Hypopituitarism is a prevalent but often overlooked complication of non-traumatic SAH, with significant potential implications for long-term health outcomes. Routine endocrine evaluation and management of pituitary deficiencies are recommended to improve patient care. Future research should focus on refining diagnostic criteria, elucidating the underlying mechanisms, and evaluating the long-term impact of hormone replacement therapy in this patient population.

Neonatal brain injury remains a significant issue with limited treatment options. The endogenous neurosteroids dehydroxyepiandrosterone (DHEA) and its sulfate ester (DHEAS) have demonstrated promising therapeutic potential in adult brain injury models due to their neuroprotective mechanisms. This study aimed to analyze the neuroprotective potential of DHEA and DHEAS with a particular interest in anti-oxidative properties in a mouse model of neonatal hypoxic-ischemic brain injury. Using the modified Rice-Vanucci model, brain injury was induced in 7-day-old mouse pups, followed by treatment with various concentrations of DHEA and DHEAS (0.1, 1, and 10 µg/g body weight) via intraperitoneal injection after a 2-hour recovery period. Mice were sacrificed after 24 hours for analysis of somatometry, brain injury, apoptosis, microglial activation, and oxidative stress markers (NOX2, 4-HNE, 8-OHdG), along with the anti-oxidant marker SOD1. No statistically significant effects of the treatments were observed at the tested doses and time points. Although this study did not conclusively demonstrate the anti-oxidative neuroprotective potential of DHEA or DHEAS, neither substance exhibited toxic or harmful effects. Several factors may have contributed to the lack of observable effects, underscoring the need for further refinement in future studies of DHEA(S) and other treatments of neonatal hypoxic-ischemic brain injury.

Gliomas are malignant tumours arising from glial cells in the central nervous system (CNS), presenting significant clinical challenges. High-grade gliomas (HGGs) are particularly concerning as they are the primary cause of CNS cancer-related deaths. Low-grade gliomas (LGGs), which include diffuse types, represent only 15% of all glioma cases. this review aims to identify the critical hub genes associated with HGG and LGG, understand their proliferation, apoptosis, and mutation role in glioma, and their therapeutic potential as well. First, we identified the gene interaction networks by employing bioinformatics techniques, such as differential expression analysis, Venn enrichment, Cytoscape, and CytoHubba analyses. Next, we summarized the role of hub genes, addressing recent advancements and emerging evidence related to the identified hub genes to provide a comprehensive understanding. The analysis revealed ten hub genes: CCNB1, TOP2A, CENPF, NEK2, ASPM, TPX2, PBK, RRM2, KIF15, and ATAD2. Most hub genes showed elevated expression in HGG compared to LGG, and a strong positive correlation with glioma pathology. Also, might hold significant therapeutic potential, particularly CCNB1, CENPF, NEK2, and TPX2, due to their crucial biological functions and the results of gene mania analysis. This review offers an overview and comprehensive knowledge of the hub genes in glioma pathology, which may inform future research and clinical trials aimed at developing targeted therapeutic strategies.

Aim: This study sought to evaluate the effectiveness of lactate/albumin ratio for ICU mortality prediction in a large cohort of patients with severe Coronavirus Disease-2019 (COVID-19) admitted to the intensive care unit (ICU). Methods: This is a single-center retrospective cohort study of prospectively collected data derived from the COVID-19 dataset for all critically ill patients admitted to an academic ICU. Data were used to determine the relation between lactate/albumin ratio and other laboratory parameters measured on the first day of ICU stay and to evaluate the prognostic performance for ICU mortality prediction. Results: A total of 805 ICU patients were included, the median age (IQR) was 67 (57-76) years, with 68% being male. ICU mortality was 48% and the median lactate/albumin ratio was 0.53 (0.39-0.59). Survival analysis showed that patients with higher lactate/albumin ratio values had significantly lower survival rates (Log Rank p

Placebo effects are acknowledged and no longer considered inert, as they can trigger neural and organic responses working through circuits involving the rostral anterior cingulate cortex, pontine nucleus, and cerebellum. Recent findings of quantum tunneling have expanded the possible functions of placebo interventions that may explain the rigidity of belief systems and functionality of homeopathy, opening a new chapter of the future of medicine, drawn from the prefrontal cortex, amygdala, anterior cingulate cortex, and striatum. The choice of current interventions, such as psychedelic substances, SSRIs, TMS, and DBS, can be expanded as our knowledge about the placebo intervention improves. At the same time, we need to understand the pros and cons of placebo-controlled clinical trials to ensure that stereotyped clinical trial designs do not hamper new drug development.

Background/Objectives: Clinical decision support systems (CDSS) consisting of computerized physician order entry (CPOE) and oncology pathways serve as the foundation of high-quality cancer care. However, the resources needed to develop and maintain these systems have not been characterized for oncology enterprises. Methods: Missing CPOEs for oncology treatments were identified by comparing current CPOEs to those in the Elsevier ClinicalPath treatment pathways. New FDA oncology drug approvals were used to estimate ongoing CPOE build needs. The impacts of missing orders on clinicians and pharmacists were surveyed. Benchmarking from two other large oncology enterprises supported new resource needs to build and maintain CPOE in our EPIC Beacon system. A program to manage oncology pathways and CPOE for an enterprise using EPIC was developed and implemented. Results: Resources and impacts of CDSS for oncology enterprises are described. Program management is described. Conclusions: Updating and maintaining CDSS for an oncology enterprise requires program management and resources for which a framework has not been previously reported. We present this work as a framework for others to understand the components and resources for budgeting and management of CDSS. We report on the work of the City of Hope enterprise using the EPIC electronic health record.

Acute cardiovascular disorders are incriminated in up to 33% of maternal death and the presence of sickle cell anaemia (SCA) aggravates the risk of peripartum complications. Herein, we present a 24-year Caribbean old woman with known SCA who developed vaso-occlusive crisis at 36-week gestation that justified emergency caesarean section in Pointe à Pitre (Guadeloupe). In the early postpartum period, she experienced acute res-piratory distress in the context of COVID-19 infection that required tracheal intubation with mechanical ventilation. Cardiogenic shock with severe biventricular dysfunction developed that was initially treated with inotropes and vasopressors. As the hemody-namic condition worsened, the cardiac surgical and intensive care team at the Universi-ty Hospital of Martinique (UHM) was requested to apply veno-arterial extracorporeal membrane oxygenation (ECMO) support and, a few hours later, the patient was trans-ferred by helicopter to the UHM. Administration of cardiovascular drugs was rapidly tapered off, there were no signs of ongoing hemolysis and progressive recovery of ven-tricular function allowed weaning of ECMO support, three days after implantation. The patient was extubated one day later, chest-X-Rays showing partial resolution of lung edema and she was transported back to Guadeloupe under medical treatment.

Background/Objectives: Urinary tract infections represent a global problem with implications on mortality and morbidity. Published data present different bacterial incidence and different antibiotics resistances. With this study, we aimed to evaluate bacteria distribution and antibiotic resistance in a tertiary care hospital from the Western part of Romania. Methods: we evaluated all the positive urine culture from the year 2021 from the Emergency County Hospital “Pius Brinzeu” from Timisoara, Romania. We evaluated 1264 urine cultures and identified the following bacteria: Escherichia Coli, Klebsiella spp, Proteus spp., Pseudomonas auruginosa, Staphylococcus aureus, Enteroccocus spp., Enterobacter spp., Acinetobacter baumanii, Providencia spp., Corynebacterium spp. Results: Median age was 67 with 65.6% females. Diabetes mellitus incidence was 12%. Most common bacteria was E. coli – 44.1%, followed by Enterococcus spp. – 17.1%, Klebsiella spp. -15.7% and Proteus spp. – 5.4% E. coli presented the highest resistance rate to amoxicillin-clavulanic acid (50%), Enterococcus spp. to ciprofloxacin (71.3%), Klebsiella spp. to piperacillin-tazobactam (43.3%) and Proteus spp. to trimetroprime-sulfometoxazole (33%). The highest incidence of MDR bacteria was among Acinetobacter baumanii (40%), followed by MRSA (31.8%) and Klebsiella spp. (25.3%). Conclusions: Bacteria distribution is similar in all the Romanian regions among the positive urine cultures. Antibiotics resistance differ among regions and the MDR bacteria incidence is rising.

The present study investigates the relationship between cocaine- and amphetamine-regulated transcript (CART) expression, leptin, and hormone profiles (progesterone, testosterone, androstenedione, estradiol, FSH, and hCG) across four ovulation induction protocols (HMG, HMG/hCG, rFSH, and rFSH/hCG), as well as the association between FSH receptor (FSHR) Ser680Asn polymorphisms, CART expression, and IVF outcomes. Data were acquired from 94 women who underwent controlled ovarian stimulation (COS). The outcomes showed no significant variations in BMI between the four stimulation protocols (p-values ranged from 0.244 to 0.909). CART expression had no significant correlation with hormone levels in the entire cohort (progesterone, testosterone, androstenedione, FSH, hCG, and estradiol; p > 0.05). However, CART levels were shown to be adversely linked with the number of follicles >12 mm (r = -0.251, p = 0.018), total oocytes (r = -0.247, p = 0.019), and oocyte maturity (r = -0.212, p = 0.048). A significant negative association was also revealed between CART expression and the thyroid hormone T3 (r = -0.319, p = 0.048). In terms of FSHR polymorphisms, the SER/SER genotype was linked to greater CART levels (mean 4.198 ± 2.257) than the SER/ASN and ASN/ASN groups (p = 0.031). These data indicate that CART expression and FSHR polymorphisms may affect ovarian response and oocyte quality in IVF patients.

Background: Suicidal behavior has been a dilemma in Alzheimer's disease. Many ethical debates have been raised about euthanasia in patients with neurodegenerative diseases, and there is a finding of increased suicide rates in the early stages of dementia. However, little is known about the history of suicide ideations or attempts in people with Alzheimer's disease. We aim to measure questionnaire adequacy and acceptability in this specific study to investigate the history of behaviors and factors associated with suicidal behavior across the lifespan in patients with Alzheimer's disease. Methods: This study is an excerpt from case-control research, where the sample was calculated at 150 participants, 75 for the case group and 75 for the control group. Here, the descriptive statistics of the first third of the case group sample, 25 participants, were made. Adequacy was observed by comprehension of questionnaires, and acceptability was measured by participants' understanding of the study object.Results: The prevalence of suicidal ideation throughout life was 8%, and 4% attempted suicide at some point in their lives. The total score of QLoS had a median of 71, which demonstrated the consideration of a moderate quality of life. The total score of the SAF-quest had a median of 12, which showed a low suicidal behavior history. All patients were included in understanding the questionnaires.Conclusions: This study demonstrated the adequacy, acceptability, and scarcity of suicidality histories throughout life in Alzheimer’s disease patients.

Background/Objectives: Fats, although essential for the proper functioning of the body, have been linked to an increased risk of developing chronic diseases, especially cardiovascular disease. The aim of this study was to evaluate the intake of total fat, and its components (saturated, monounsaturated, polyunsaturated, and trans fats) in men and women aged 15 to 65 years of the urban population in eight Latin American countries. Methods: Survey data were collected for the ELANS, including 9218 subjects from Argentina, Brazil, Chile, Colombia, Costa Rica, Ecuador, Peru, and Venezuela. Results: In general, 76.2% of the subjects consumed fat within normal ranges (20-35% of the total caloric value (TCV)). When analyzing its components, a majority of the subjects consumed saturated and polyunsaturated fats within the recommended ranges. However, 94.5% of the population does not comply with the recommended maximum intake of MUFA (10-20%) and only 57.5% comply with the intake recommendation for TFA (0 - 2%). Likewise, on average, women had a significantly higher intake of all types of fat compared to men. Finally, the average fat intake by age indicates that regardless of the age range, the consumption of all fats except MUFA and TRANS are within the recommended ranges, with MUFA being slightly below and TRANS above. Conclusions: Even though the fat intake of the population falls within the recommended range, it is necessary to improve the quality by favoring the consumption of MUFA and reducing the consumption of TRANS.

Background:Lower socioeconomic status (SES) has been associated with increased mortality from coronary heart disease. This excess risk, relative to affluent patients, may be due to a combination of more adverse cardiovascular‐risk factors, inequalities in access to cardiac investigations, longer waiting times for cardiac revascularisation and lower use of secondary prevention drugs. We sought to investigate whether socio-economic status influenced long-term all-cause mortality after PCI in a large metropolitan city (London), which serves a population of 11 million people with a mixed social background over a 10-year period. Methods: We conducted an observational cohort study of 123,780 consecutive PCI procedures from the Pan-London (United Kingdom) PCI registry. This data set is collected prospectively and includes all patients treated between January 2005 to December 2015. The database includes PCI performed for stable angina and ACS (ST-elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction (NSTEMI) and unstable angina). Patient socio-economic status was defined by the English Index of Multiple Deprivation (IMD) score, according to residential postcode. Patients were analysed by quintile of IMD score (Q1, least deprived; Q5, most deprived). Median follow-up was 3.7 (IQR: 2.0-5.1) years and the primary outcome was all-cause mortality. Results: The mean age of the patients was 64.3±12.1 years and 25.2% were female. 22.4% of patients were diabetic and 27.3% had a history of previous myocardial infarction. The rates of long-term all-cause mortality increased progressively across quintiles of IMD score, with patients in Q5 showing significantly higher long-term mortality rates compared with patients in Q1 (p=0.0044). This persisted following the inclusion of a propensity score in the proportional hazard model as a covariate (HR for Q5 compared to Q1: 1.15 [95% CI: 1.10-1.42]). Conclusion: This study has demonstrated that low SES is an independent predictor of adverse clinical outcomes following PCI for in a large diverse metropolitan city of London. Hence, attention to reduce the burden of cardiovascular risk factors and improve primary prevention, particularly in patients with lower SES, is required.

In recent years, the chemo-photodynamic combinational therapy has become increasingly popular in treating breast cancer. However, the limited accumulation of nanodrugs into tumor (less than 1% of injected dose) extremely impacts therapeutic efficacy. Herein, the photosensitizer Chlorin e6 (Ce6) and the chemotherapeutic drug rhein (Rhe) were self-assembled to form a carrier-free nanodrug (RC NPs) with good stability and high drug loading rate. Ultrasound (US) irradiation was applied to increase the permeability of tumor blood vessels thus greatly enhance the drug accumulation of RC NPs in tumor tissues. After uptake by tumor cells, Ce6 could produce a sig-nificant amount of reactive oxygen species (ROS) when exposed to laser irradiation, while rhein could inhibit tumor cell proliferation and affect mitochondrial membrane potential, inducing tumor cell apoptosis through the mitochondria-dependent apoptosis pathway, thus effectively realizing the combined effect of PDT and chemotherapy. Taken together, RC NPs have an enhanced EPR effect when exposed to US irradiation and exhibit better tumor suppression, which provides new insights into chemo-photodynamic combination treatment for clinical breast cancer.

Introduction: There are no clear guidelines to support adequate nutrition and growth for our neonates. We have used the difference in weight Z-score medians between birth and discharge (∆ Z-score) to assess the nutritional outcomes in EpicLatino. The ∆ Z-score is often negative, accounting for the desirable fluid contraction at birth that sends the preterm baby usually between 0.5-1 weight Z-score point down the curve. From then on, most researchers accepted a healthy and safe growth parallel to the intrauterine rate. No consensus on the optimal timing for assessment or the ideal growth monitoring tool has been achieved, and an ongoing debate persists on the appropriate terminology to express poor postnatal growth.Methods: We analyzed data from the past 8 years (2015-2022) in surviving home to at least 34 weeks corrected age infants with ≤ 32 weeks gestational age at birth (GA). We conducted a series of statistical comparisons with variables that have been mentioned as potential causes of poor nutrition in the literature. We used the weight ∆ Z-score from birth to discharge as a surrogate for nutrition. We obtained the weight median and interquartile range (IQR) from all the EpicLatino units. We also calculated the correlation between weight ∆ Z-score and gestational age and head circumference (HC) at discharge.Results: There were 480 cases that meet the established criteria. Gestational age at birth, necrotizing enterocolitis (NEC), unit of origin, rupture of membranes (ROM) > 24 hours, temperature at admission, and intraventricular hemorrhage (IVH) were significantly different. There was a negative correlation between ∆ Z-score and corrected gestational age at discharge. Head circumference at discharge also correlated with weight ∆ Z-score.Discussion: There is an important variability in the different units of origin. Also, when looking for risk factors, we confirmed that the characteristics of the study population are determinant to extrauterine growth restriction (EUGR) at discharge. As is known, these associations do not establish causality, some of these variables may identify the challenge of nourishing a sick or very small preterm infant, but the unit of origin variable identifies nutrition policies and practices that can be modified through a quality improvement program.

Nanoemulsions represent to cosmetic industry new options of formulations which are easier to apply, better functional benefit and potentially safer formulations. They are very interesting for cosmetic products intended for skin care and also for health products, due to the reduced size (range 20 to 500 nm) of the globules, which avoids processes of instability; they present transparency, fluidity, wettability, spreadability, increase skin penetration and good sensorial sensation. The main mechanism of instability of nanoemulsions is called Ostwald ripening, responsible to increase the average diameter of the emulsion globules, which, over time, the smaller globules have their contents enveloped by the larger ones. Recent research has investigated the effects of specific plant oils on skin hydration and barrier function, providing insights for personal care formulators. Among the so-called moisturizing agents commonly used in the cosmetic industry and which reduce Trans Epidermal Water Loss (TEWL) avoiding damage to the skin barrier, there are vegetable oils, especially sesame oil, raspberry seed oil. High-quality vegetable oils present specific compounds with common properties such as antimicrobial, antioxidant and anti-inflammatory activities and even moisturizing, emollient and sunscreen actions, making them attractive alternative and complementary treatments to soften the process of skin aging. This research proposes the development of nanoemulsions containing Sesame Oil (SO) added with Raspberry Oil (RO) by low energy method and consists and to evaluate in vitro SO and RO antioxidant activity; formulation studies; to instability process and in vitro evaluation HET CAM.

Flaxseed has been suggested as a viable solution to improve sex hormones. However, conflicting and uncertain evidence regarding its impact on sex hormone profiles exists. This meta-analysis assesses the effects of flaxseed on sex hormone profiles. PubMed, Scopus, Embase, and the Web of Science were searched for relevant articles in August 2021. The Cochrane Collaboration tool was used for the quality assessment, and the evidence's trustworthiness was assessed using the Grading of Assessment, Development, and Evaluation of Recommendations (GRADE). A total of ten articles revealed that flaxseed might not have a significant effect on follicle-stimulating hormone (FSH) ((WMD: 0.84; 95% CI: -5.53, 7.00, p =0.791; I²= 88.6%, p<0.001, level of confidence: low), sex hormone-binding globulin (SHBG) ((WMD: 2.17; 95% CI: -1.19, 5.54, p =0.206; I²= 66.3%, p=0.011, level of confidence: low), total testosterone (TT) (WMD: -0.00; 95% CI: -0.07, 0.07, p=0.968; I²= 41.3%, p =0.146, level of confidence: low), free androgen index (FAI) (WMD: -0.13; 95% CI: -0.68, 0.42; p=0.645; I²= 85.4%, p<0.001, level of confidence: low) and dehydroepiandrosterone sulfate (DHEAS) (WMD: 0.62; 95% CI: -3.35, 4.59, p=0.761; I²=63.6%, p =0.064, level of confidence: very low). It is demonstrated that flaxseed might not affect sex hormones in adults. Flaxseed supplementation had no significant effect on sex hormones in adults. Nevertheless, due to the limited included trials, this topic is still open and needs further studies in future RCTs.

Given the pivotal role played by the microbiome in skin health it is important to understand how its composition varies with age, gender and body site, and regular use of topical products. Four studies have been carried out to determine the effects of long term (4 week) use of different dexpanthenol containing topical products on the skin microbiome of a varied population with cosmetically dry skin. Skin microbiome composition was assessed before and after product usage. No significant changes in microbiome richness or diversity were found for the individual test products, however meta-analysis of the combined dataset did show changes in microbiome composition as a function of subject sex, age and body site. The work presented here demonstrates how the use of carefully formulated topical products on skin, when used in a way which is representative of real life usage conditions, can respect the microbial diversity present on skin across a widely varied study population.

Background: Human β-defensin 2 (HBD2) is a protein important in immune system activation, produced by epithelial cells, mainly as a result of contact with microorganisms or the action of various pro-inflammatory cytokines. According to previous research, it has proven to be important in chronic urticaria, leading us to research on the HBD2 in isolated chronic angioedema. Methods: This cross-sectional study involved 102 participants (three groups): 33 patients with isolated chronic non-hereditary angioedema (AE); 33 patients with angioedema associated with chronic urticaria (CU+AE); and 35 healthy controls (CTRL). They provided saliva and serum samples to determine HBD2 levels using the Enzyme-Linked Immunosorbent Assay-ELISA. Results: Salivary HBD2 levels were significantly higher in those with CU+AE than in the CTRL (p=0.019). While salivary HBD2 values differed between those with angioedema and CTRL, the serum HBD2 values did not. Also, no correlation between the levels of HBD2 in saliva and serum was found. Conclusions: Since we found that salivary HBD2 values were significantly higher in those with CU+AE than in CTRL, this points to a possible role of the HBD2 molecule in pathogenesis of AE. Therefore, more research is needed to determine how reliabile salivary HBD2 measurement is and its significance.

Background/Objectives: Chronic pain syndromes pose a significant global health challenge to patients and physicians with a complex relationship of biological and psychosocial factors that are only partly understood. Emerging research suggests an association between prenatal and childhood adversity and the development of somatic syndromes, particularly in females. This study aims to explore the relationship between sexual dimorphic epigenetic changes in the connectome and prenatal and early life adversity (ELA). Methods: A review of existing literature was conducted, examining studies utilising MRI to identify critical periods of environmental influence on neural phenotypes. Results: The findings indicate a significant association between prenatal and childhood adversity and the emergence of central sensitisation syndromes, particularly among females. Notably, alterations in grey matter volume and neural connectivity patterns were observed, suggesting that early adverse experiences can influence pain signalling mechanisms. Conclusions: Understanding the role of sex differences in brain circuitry is crucial for developing personalised pain management strategies. This study highlights the importance of considering both biological and psychosocial factors in addressing chronic pain, as interventions based predominantly on male subjects may be less effective for females. Further research is warranted to explore these differences and refine therapeutic approaches.

Background/Objectives: Type 1 Diabetes Mellitus (T1DM) is the reduction or non-production of insulin. As T1DM increases cardiovascular risk, in addition to glycemic control, the monitoring of other risk factors, such as lipid profile, has gained attention. Vitamin D deficiency has been associated with the pathophysiology of T1DM, metabolic syndrome, and cardiovascular diseases. This study investigated the relationship between vitamin D, glycemic control, and lipid profiles in children and adolescents with T1DM. Methods: This observational study consisted of 81 patients with T1DM. Laboratory test data were collected to determine the lipid profile. Glycated hemoglobin (HbA1c) and fasting glucose levels assessed glycemic control. Results: A significant association was observed between serum vitamin D levels and a pubertal stage and a moderate negative correlation between vitamin D, age, and HbA1c. There is a negative correlation between vitamin D levels and age, as well as with HbA1c, and a positive correlation of HbA1c with glucose, total cholesterol, triglycerides, Low-density lipoprotein (LDL-c), non-HDL cholesterol (non-HDL cholesterol), apolipoprotein B (apoB), and the apolipoprotein B/apolipoprotein A ratio. Finally, the study indicated that vitamin D levels, insulin administration method, and total cholesterol, when considered together, explained approximately 43.6% of the observed variation in HbA1c, highlighting the complex interdependence of these factors in regulating glycemia. Conclusions: Our results show that Vitamin D levels are associated with glycemic control and other biochemical parameters and its control can bring benefits to the patient with T1DM.

A seven-year-old spayed female dog presented with multiple, small spindle-shaped masses on the abdominal skin. The excised tissue was submitted for histopathological evaluation. Routine his-tology revealed basaloid nodules with stippled chromatin and pleomorphic nuclei. Mor-pho-logically, the tumor resembled a solid papillary carcinoma of the breast or an endocrine mucin-producing sweat gland carcinoma (EMPSGC). EMPSGC is a rare neuroendo-crine-differentiated neoplasm. This study aimed to compare different immunohistochemical markers for distinguishing between canine sweat gland carcinoma (SGC) and mammary gland carcinoma (MGC). CK19 and Sox9 were useful in identifying SGC. Additionally, the tumor was positive for CK5, AE1/AE3+CK8/18, p63, vimentin, E-cadherin, and synaptophysin, while estrogen receptor staining was negative. The final diagnosis of canine EMPSGC was based on the tumor’s morphological and neuroendocrine immunohistopathological features. Our report provides the first detailed description of a canine EMPSGC, an exceedingly rare tumor in dogs.

4-aminopyridine (4-AP) is a non-selective blocker of voltage-dependent K+ channels used to im-prove walking in multiple sclerosis patients, and it may be useful in the treatment of cerebellar diseases. In animal models, 4-AP is used as a convulsant agent. Intrahippocampal 4-AP induces acute local glucose hypermetabolism and significant brain damage, while i.p. administration causes less neuronal damage. This study aimed to investigate the effects of a single i.p. admin-istration of 4-AP on acute brain glucose metabolism and to assess the short-term effects on neu-ronal viability and signs of neuroinflammation. We evaluated 4-AP-induced acute changes in brain glucose metabolism by [18F]FDG PET neuroimaging evaluated by standard volumes of interest (VOIs) and voxel-based (SPM) analyses. We show that 4-AP induces acute generalized brain glucose hypometabolism, except in the cerebellum, area that was significantly more resilient to this effect. Accordingly, to the appropriate neurohistochemical assays, 4-AP induced hippocampal astrocyte reactivity 3 days after the insult, without changes in signs of neuronal integrity or micro-glia-mediated neuroinflammation. Thus, acute brain glucose metabolic and short-term neuroin-flammatory profiles in response to 4-AP i.p. clearly differ from that reported for intracerebral administration. Our results also suggest cerebellar metabolism as a potential marker of the effects of 4-AP.

Opioid analgesics have been used for more than 5,000 years and remain the principal pain medications prescribed today. Although morphine is considered the gold standard for pain relief, this µ-opioid receptor (MOP)-selective agonist provides only moderate relief for many chronic pain conditions and promotes several unwanted effects that can adversely affect patient quality-of-life, prevent adherence to treatment or generate addiction. In addition to the lack of progress in the development of better analgesics, there have been no significant breakthroughs to date that have addressed side effects mentioned above. Fortunately, a better understanding of opioid pharmacology has restored hope for the development of better and safer pain medications. In this review, we describe how clinically approved opioids were initially characterized as biased ligands and what impact this approach could have on clinical practice. We also looked at the preclinical and clinical development of MOP biased agonists, with an emphasis on the oliceridine story, as the first specifically designed biased painkiller. Moreover, we explore the discrepancies between ligands with low intrinsic efficacy and those with biased properties. Finally, we examine the rationale behind biased ligand development during the opioid crisis era.

In this study we summarized our work on various aspects of colorectal adenocarcinomas, 1 focusing on tumor distribution (left- sided, right- sided, and rectal cancers), histologycal type, patient 2 age, gender and several factors affecting prognosis. These predictive and prognostic factors include 3 peritumoral budding, lymphovascular ant perineural invasion, lymph node metastasis, mismatch 4 repair status, and corellations with some frequently known mutations in colorectal adenocarcinomas, 5 detected using Next- Generation Sequencing (NGS) platform. This comprehensive approach allowed 6 us to explore how these factors interplay and influence the clinical outcome of patients with colorectal 7 adenocarcinoma. Additionaly, our findings contribute to the understanding of how genetic mutations 8 may correlate with histological features and prognostic markers, potentially guiding personalized 9 treatment strategies in the future. In our study, we do not claim to have exhausted the research on 10 the topic, and we fully recognized the need for more extensive and in-depth studies in this area of 11 tumor pathology.

Argentina is the current and three-time “World Cup” Champion, as well as the current and most successful team in “Copa América” history. We aimed to evaluate the cardiopulmonary fitness profile of youth soccer players from the first league of the Argentine Football Association (AFA). We evaluated ten highly trained youth soccer players from the AFA by applying an on-field cardiopulmonary exercise test (20-meter Shuttle Run Test - 20m-SRT) with wearable gas analyzer (mix-chamber mode). Mean velocity at maximal oxygen uptake (vO_2max) was 12.3±0.7 km·h^-1. The maximal oxygen uptake (O_2max) on-field was 67.1 ± 5.3 mL·kg⁻¹·min⁻¹. The O₂ at the first and second ventilatory thresholds (VT1 and VT2) were identified at 67.0±3.0% and 84.7 ± 3.7%, respectively. Argentine soccer players exhibit exceptional cardiopulmonary fitness, comparable to that of professional athletes, underscoring their potential for high performance. Support staff, fitness or health professionals, and researchers can now compare cardiopulmonary differences between Argentine youth soccer players and other populations.

Background: The aim of this study was to determine the effect of Sparstolonin B (SsnB) on cell proliferation and apoptosis in human breast cancer (MCF-7) and human ovarian epithelial cancer (OVCAR-3) cell lines in the presence and absence of estradiol hemihydrate (ES). Phosphoinositol-3 kinase (PI3K), phosphorylated protein kinase B alpha (p-AKT), phosphorylated mTOR (mechanistic target of rapamycin) signaling proteins and sphingomyelin/ceramide metabolites were also measured within the scope of the study. Methods: The anti-proliferative effects of SsnB therapy were evaluated over a range of times and concentrations. Cell proliferation was determined by measurement of Proliferating Cell Nuclear Antigen (PCNA). PCNA was quantified by ELISA and cell distribution was assessed by immunofluorescence microscopy. MTT analysis was used to test the vitality of the cells, while LC-MS/MS was used to analyze the amounts of ceramides (CERs), sphingosine-1-phosphate (S1P), and sphingomyelins (SMs). TUNEL labeling was used to assess apoptosis, while immunofluorescence staining and enzyme-linked immunosorbent assay (ELISA) were used to measure the levels of PI3K, p-AKT, and p-mTOR proteins. Results: Sparstolonin B administration significantly decreased cell viability in MCF-7 and OVCAR-3 cells both in the presence and absence of ES, while it did not cause toxicity in healthy human fibroblasts. In comparison to controls, cancer cells treated with SsnB showed a significant drop in the levels of S1P, PI3K, p-AKT, and p-mTOR. In cancer cells cultured with SsnB, a significant increase in intracellular concentrations of C16-C24 CERs and apoptosis was observed. Conclusions: SsnB downregulated the levels of S1P, PI3K, p-AKT, and p-mTOR while reducing cell proliferation and promoting ceramide buildup and apoptosis.

Despite the enormous efforts and funds spent to find an effective treatment for COVID-19, the results have been disappointing. In previous publications, we have demonstrated the remarkable effect of high-dose colchicine in inhibiting the cytokine storm and preventing multiorgan damage and death. However, this treatment is beneficial only after virus entry into the cell. The question of prophylaxis and entry prohibition should also be explored. We now demonstrate the prophylactic effect of bromhexine hydrochloride (BRH), an over-the-counter, non-invasive, effective, well-tolerated medicine, with proven safety, affordable, and inexpensive on 125 men and women. The effect of BRH is best when given continuously for prophylaxis during peaks in contagion in the wave of COVID-19. Then the probability of infection drops sharply, and if a disease does occur, it proceeds mildly. BRH is also effective when given by inhalation for post-exposure prophylaxis.When COVID-19 manifests itself clinically, the efficacy of BRH drops sharply because the virus is already in the cell. However, BRH inhalations are useful because they limit the spread of the virus and have an anti-inflammatory and possibly antiviral effect.

Dimethyl fumarate (DMF) and diroximel fumarate (DRF) are two treatments used in multiple sclerosis (MS), that have been shown to be effective in controlling MS patients. DRF was intro-duced in 2019, with the aim of decreasing the gastrointestinal side effects caused by DMF. Few real-life studies verify the data provided in the clinical trials. Methods: A retrospective descriptive study was conducted in MS patients at the Hospital Universitario Torrecárdenas under treatment with DRF and DMF. Demographic, clinical, and analytical variables were studied and compared between groups. Results: 60 patients were recruited, 30 with each treatment, observing similar baseline characteristics. Fewer gastrointestinal (GI) effects were observed in the DRF group, while more infections were detected in the DMF group. We recorded lower levels in the DRF group, with 4 moderate-severe lymphopenia in the DRF group vs. none in the DMF group. In addition, we observed a decrease in lymphocytes after the change from DMF to DRF in patients with a change. Conclusions: Our real-life analysis of patients treated with DMF or DRF supports studies’ findings of decreased GI side effects with DRF vs. DMF, without decreasing efficacy. However, our data show greater reduction in lymphocytes in patients with DRF compared to DMF, so more studies are necessary.

Background: RO and ChRCC are kidney tumours with overlapping characteristics, making differentiation between them challenging. Objectives: The objective of this research is to create a radiogenomics map by correlating radiomic features to molecular phenotypes in ChRCC and RO, using resection as the gold standard. Methods: Fourteen patients (6 RO and 8 ChRCC) were included in the study. A total of 1,875 radiomic features were extracted from CT scans, alongside 632 cytobands containing 16,303 genes from the genomic data. Results: Feature selection algorithms applied to the radiomic features resulted in 13 key features. From the genomic data, 24 cytobands highly correlated with histology were selected and cross-correlated with the radiomic features. The analysis identified four radiomic features that were strongly associated with seven genomic features. Conclusion: These findings demonstrate the potential of integrating radiomic and genomic data to enhance the differential diagnosis of RO and ChRCC, paving the way for more precise and non-invasive diagnostic tools in clinical practice.

Background: Bone marrow aspiration concentrate (BMAC) has garnered increasing interest due to its potential for healing musculoskeletal injuries. While the iliac crest remains a common harvest site, the aspiration technique’s efficacy in offering the highest yield and prevalence of mesen-chymal stem cells (MSCs) is controversial. This study aimed to compare two different techniques of bone marrow aspiration over the anterior iliac crest from a single level (SL) versus multiple level (ML). Methods: Anterior iliac crests were selected in 9 adult patients (aged between 31 and 59 years old). Aspiration was achieved using an 11-gauge needle (length: 100 mm; diameter: 2.3 mm) specifically manufactured for bone marrow collection (BD, Becton, US) connected to a 10-mL syringe. On one side, 4cc of bone marrow was aspirated at an SL to a depth of 7cm without changing the needle direction. On the other side, over the same portion of the iliac crest, 1 cc of bone marrow was obtained from ML of different depths during needle retrieval, maintaining a distance of 1cm and changing the tip direction. The samples were blindly sent to the laboratory without indicating whether they came from an SL or ML. Fluorescence-activated cell sorting (FACS) and osteoblast differentiation were analyzed and compared. Results: In the FACS analysis, the SL resulted in a higher population of MSCs that were positive for CD105, CD73, and CD90 and negative for CD34, compared to the ML method. In the process of osteoblast differentiation, it was observed that MSCs exhibited more advanced features of en-hanced osteoblastic abilities in the SL method rather than the ML method. Conclusion: An SL aspiration technique at the anterior iliac crest may produce a high-quality bone marrow aspirate. This technique may help obtain specific populations of MSCs with the desired characteristics for use in regenerative therapies for musculoskeletal injuries.

We present a case of successful treatment of a mall-sized parasagittal meningioma (14x11x12mm), combined with chronic migraines, which significantly improved the patient's quality of life. After endovascular surgery -embolization of the middle meningeal artery (MMA) branches using non-adhesive embolic agents of various viscosities (Squid 12/Squid 18), we observed not only complete resolution of the meningioma, but also almost complete elimination of headache attacks. On the third day after the procedure, the patient reported that headaches, which previously occurred almost every day, changed to short episodes about once in 4 months. This clinical observation and the literature data suggest that embolization of the distal branches of the MMA could be an effective treatment for small-sized parasagittal and convexital meningiomas as well as chronic subdural hematomas (ChSDH). Additionally, it can lead to a reduction in the intensity of migraine headaches. Embolization of the MMA distal branches could provide relief from migraines and improve the quality of life for patients. However, there is a lack of sufficient data on this topic in the current literature. Therefore, it may be worthwhile to investigate this side effect further and conduct a study on the efficacy of MMA embolization for chronic migraines.

Candida glabrata (Nakaseomyces glabratus), the second most prevalent Candida pathogen globally, has emerged as a major clinical threat due to its ability to develop high-level azole resistance. In this study, two new 5,6-dihydrotetrazolo[1,5-c]quinazoline derivatives (c11 and c12) were synthesized and characterized using IR, LC-MS, 1Н and 13C NMR spectra. Along with 13 previously reported analogues, these compounds underwent in vitro antifungal testing against clinical C. glabrata isolates using a serial dilution method (0.125-64 mg/L). Remarkably, compounds c5 and c1 exhibited potent antifungal activity, with minimum inhibitory concentrations of 0.37 μM and 0.47 μM, respectively – about 20-fold improvement over standard drugs like amphotericin B, caspofungin, and micafungin. A detailed structure-activity relationship analysis revealed crucial molecular features enhancing antifungal potency. Extensive molecular docking studies across 18 protein targets explored potential binding pockets and affinities of the lead compounds. A robust 3D-QSAR model, incorporating molecular descriptors Mor26m and Mor29e, displayed good predictive ability for antifungal activity. In silico predictions indicated an absence of herbicidal effect, negligible environmental toxicity (to honeybees, avian species, and aquatic organisms), and mild human toxicity concerns for these compounds. This comprehensive approach aims to develop novel and effective antifungal compounds against the clinically relevant pathogen C. glabrata.

Breast cancer is the most common and the leading cause of cancer death in women worldwide; treating invasive breast carcinomas is challenging due to the side effects of chemotherapeutics. Compounds isolated from natural sources have been proposed as potential molecules for cancer therapy; for instance, the homoisoflavonoid brazilin has shown pharmacological properties, including anti-tumoral and anti-inflammatory activities. In this study, we isolated brazilin from the heartwood of Haematoxylum brasiletto (Pacific coast of Mexico and Central America); then, we performed a semi-synthesis by adding three methyl or acetyl groups to the core structure of brazilin. We confirmed brazilin and its derivatives identity by spectroscopic data (1H NMR and 13C NMR) and measured their purity by optical rotation. Then, we analyzed the effects of brazilin and derivatives in three mammary gland-derived cell lines: the TNBC MDA-MB-231, the ER(+) MCF7, and the non-tumorigenic MCF10A. We evaluated the cell viability by MTT assays, cell migration by wound-healing assays and focal adhesion kinase (FAK) activation by Western blot. Regarding biological assays, the MTT assay showed that brazilin and its derivatives showed cytotoxic effects on MCF7 and MDA-MB-231 breast cancer cells at 20 µM but was not toxic in non-tumorigenic MCF10A mammary epithelial cells. These effects were dose and time-dependent, as well as a decrease in the levels of cell migration and FAK activation.

Emanating from several decades of study into the effects of the aging process after spinal cord injury (SCI), "accelerated aging" has become a common expression as the SCI accelerates the onset of age-related pathologies. However, the aging process follows a distinct trajectory, characterized by unique patterns of decline that differ from those observed in the general population without SCI. Aging brings significant changes to muscles, bones, and hormones, impacting overall physical function. Muscle mass and strength begin to decrease with a reduction in muscle fibers and impaired repair mechanisms. Bones become susceptible to fractures as bone density decreases. Hormonal changes combined with decreased physical activity accelerate the reduction of muscle mass and increase in body fat. Muscle atrophy and skeletal muscle fiber type transformation occur rapidly and in a unique pattern after SCI. Bone loss develops more rapidly and results in an increased risk of fractures in body regions unique to individuals with SCI. Other factors, such as excessive adiposity, decreased testosterone and human growth hormone, and increased systemic inflammation, contribute to a higher risk of neuropathically driven obesity, dyslipidemia, glucose intolerance, insulin resistance, and increasing cardiovascular disease risk. Cardiorespiratory changes after SCI result in lower exercise heart rates, decreased oxygenation, and mitochondrial dysfunction. While it is important to acknowledge the accelerated aging processes after SCI, it is essential to recognize the distinct differences in the aging process between individuals without physical disabilities and those with SCI. These differences, influenced by neuropathology, indicate that it may be more accurate to describe the aging process in individuals with chronic SCI as neurogenic accelerated aging (NAA). Research should continue to address conditions associated with NAA and how to ameliorate the accelerated rate of premature age-related conditions. This review focuses on the processes of NAA and the differences compared to the aging process in those without SCI. Recommendations are provided to help slow the development of premature aging conditions.

Background/Objectives: Systematic quality review of ultrasound exams is recommended to assure accurate diagnosis. Our primary objectives were to develop a quantitative method for quality review of estimated fetal weight (EFW) and to assess accuracy of EFW for an entire practice and for individual personnel. A secondary objective was to evaluate accuracy of fetal sex determination. Methods: This is a retrospective cohort study. Eligible ultrasound exams included singleton pregnancies with live birth and known birth weight (BW). A published method was used to predict BW from EFW for exams with ultrasound-to-delivery intervals up to 12 weeks. Mean error and median absolute error (AE) were compared between different personnel. Image audits were performed for exams with AE&gt;30% and exams with reported fetal sex different than newborn sex. Results: We analyzed 1,938 exams from 890 patients. In the last exam before birth, median AE was 5.9% and predicted BW was within ±20% of actual BW in 97.2% of patients. AE was &gt;30% in 28 exams (1.4%); image audit found correct caliper placement in all 28. Only 2 patients (0.2%) had AE&gt;30% on the last exam before birth. One sonographer systematically over-measured head and abdominal circumferences, leading to EFWs that were overestimated. Reported fetal sex differed from newborn sex in 7 exams (0.4%), 5 patients (0.6%). Images in 4 of these patients were annotated with correct fetal sex but a clerical error was made in the report. In 1 patient, the unclear image was labeled “probably female” but the newborn was male. Conclusions: Accuracy of EFW in this practice was similar to literature reports. Quantitative analysis identified a sonographer with outlier measurements. Time-consuming image audits could be focused on a small number of exams with large errors. We suggest some enhancements to ultrasound reporting software that may help to reduce clerical errors. We provide tools to help other practices perform similar quality reviews.

Adopting an immune response and tissue-based nomenclature in food allergies brings the field closer to precision and personalized medicine. An updated classification of non-IgE-mediated food hypersensitivity highlights mechanisms through a complex pathophysiological perspective and endotype-driven framework. This approach aligns with the essential goals of discovering new diagnostic and therapeutic biomarkers, enhancing the understanding of clinical presentations, and refining immunotherapy and targeted treatments, such as monoclonal antibodies and small molecule drugs, to improve patient management and quality of life. Endotype-focused and molecular-based decision-making also endows translational and clinical research, fostering the ongoing scientific quest for more innovative solutions.

Our ongoing research focuses on developing imipridone derivatives capable of complete and selective eradication of cancer cells after relatively short treatment. We have synthetized systematically designed novel hybrids and evaluated their antiproliferative activity on PANC-1 and Fadu cell lines. We have also conducted preliminary studies on the mechanism including colony formation as well as dose-response tests in HEK293T wild-type (WT) and HEK293T CLPP-/- cells. Following gradual structural fine-tuning based on high throughput screening we identified two imipridone hybrids as the most potent derivatives. Their unique substitution pattern includes N-methylated propargylamine and ferrocenyl/phenyltriazole moieties on the benzyl groups attached to opposite sides of the imipridone core. The compounds with IC50 values similar to those of ONC201 were found capable of complete eradication of cancer cells at ca. 4 M, while ONC201 treatment at even higher concentrations left 30-50% of viable cells behind. Both compounds were found to exert equal activity in WT and CLPP-/- HEK293T cells, indicating a ClpP-independent mechanism. Further development is needed to improve the tumor selectivity of the two potent imipridone derivatives in order to develop novel drug candidates that evade resistance and can be applied in a sufficiently broad therapeutic window.

It was assumed that only autogenous bone had appropriate osteoconductive and osteoindutive properties for bone regeneration, but this assumption has been challenged. Many studies have shown that synthetic biomaterials must be considered as the best choice for bone guided regeneration. The objective of this work is to compare the performances of nano-hydroxyapatite/β-Tricalcium phosphate (n-HA/β-TCP) composite and autogenous bone graft in bone regeneration applications. Th composite was characterized by scanning electron microscopy (SEM) and used as an allograft in bone defects made in adult Wistar rats. The bone defects in the dorsal cranium were grafted with autogenous bone on one side and the n-HA/β-TCP composite on the other. Histomorphometry evaluation by different staining methods (Goldner trichrome, PAS, Sirius red) and TRAP histochemistry were performed. The immunohistomorphometries to OPN, Cathepsin-K, TRAP, Acid phosphatase, VEGF, NFκ-β, MMP-2, MMP-9, and TGF-β were carried out. The RT-PCR method to RANK-L, Osteocalcine, Alcaline Phosphatase, Osterix, and Runx2 were conducted as well. The results showed that all morphometric evaluations on the different staining methods, histochemistry and immunohistochemistry, VEGF and NFκ-β, were higher on the n-HA/β-TCP composite group than in the autogenous bone graft group. The RT-PCR markers were higher in the autogenous bone group than on the n-HA/β-TCP composite group. The n-HA/β-TCP composite exhibited enhanced cell-matrix interactions in bone remodeling, higher adhesion, proliferation, and differentiation, and increased vascularization. These results suggests that the n-HA/β-TCP composite induces faster bone formation than autogenous bone.

microRNAS (miRNAs) maintain cellular homeostasis by blocking mRNAs through binding with t-RNA to fine-tune the expression of genes across numerous biological pathways. The 2024 Nobel Prize in Medicine and Physiology for the discovery of miRNA was long overdue and now we anticipate a deluge of research work involving miRNA to repeat the history with other RNA prizes. While miRNA therapies include several complex diseases, the realization that miRNA regulates genes, its role in addressing therapies of hundreds of diseases is expected but with advancement in drug discovery tools, we anticipate faster entry of new drug entities; to promote this, we provide details of the current science, logic, intellectual property, formulations and regulatory process with anticipation that now many more researchers will deliver novel therapies based on the discussion and advice provided in this paper.

Background: Decision, whether to de-label patient with suspected BL hypersensitivity, is based on the risk stratification. The aim of the study was to prepare a characteristic of diagnostic risk groups and to create a model enabling the identification of the low-risk diagnostic group. Methods: We analyzed medical records of patients hospitalized due to suspected hypersensitivity to BL antibiotics. Based on the history data, patients were divided into three diagnostic risk groups, using the criteria proposed by Shenoy et al. Univariate and multivariate analysis model were used to create a diagnostic tool. Results: Among 263 patients referred for BL hypersensitivity diagnosis, 88 (33.5%) were qualified to group I, 129 (49%) to group II, and 46 (17.5%) to group III. There were significant differences between diagnostic risk groups regarding history of hypersensitivity to penicillins (p<0.001), cephalosporins (p<0.001), >1 BL (p<0.05), several episodes of BL hypersensitivity (p<0.001), medical intervention (p<0.001), documented hypersensitivity (p<0.001), time from drug intake to symptoms (p<0.001), time from hypersensitivity to diagnosis (p<0.001). 81 patients (30.8%) were de-labeled: 52 (59.8%) in group I, 27 (20.9%) in group II and 2 (4.3%) in group III. In univariate analysis, model of the low diagnostic risk group applied to the de-labeled part showed 90% specificity and 21.93% sensitivity. NPV and PPV were estimated at 72.04% and 49.53%, respectively. Multivariate model had high specificity but low sensitivity; its NPV was 76% with 68% PPV. Conclusions: The tool enabling the identification of low diagnostic risk patients based on anamnesis is not sensitive enough, to de-label patients on its basis.

Background/Objectives: After the earthquakes in Turkey, many citizens were injured, and a long process requiring physiological and psychological treatments started in the ongoing process. The aim of this study was to observe the pain and psychological changes in earthquake victims in light of the QoR-15 score. Methods: After approval by the local ethics committee (Decision No. 2023-194), earthquake victims with catheters in trauma and reconstructive surgery were retrospectively evaluated. Demographic and catheterization data were collected. Baseline, 24-hour, and 72-hour QoR-15 (Quality of Recovery-15) and VAS (Visual Analog Scala) scores were compared for changes over time. Results: A total of 40 catheters were placed in 29 patients (after the exclusion of children, 36 catheters were evaluated in 26 (15 w/11 m) patients). The mean age of the patients was 35.57 ± 13.69 years, and the duration of catheterization was 8 (4.25–12.75) days. Infusion of 0.1% bupivacaine 0.5–1 mg/kg/24 h was started routinely. The QoR-15 scores of the patients at baseline, 24-hour, and 72-hour were 80.45 ± 17.76, 95.27 ± 15.16, and 101.06 ± 15.52, respectively (p<0.001). The VAS scores of the patients at baseline, 24-hour, and 72-hour were 4.61 ± 1.41, 1.79 ± 1.36, and 0.76 ± 0.86, respectively (p<0.001). Conclusions: In this study, a significant improvement in QoR-15 and VAS scores was achieved as a result of catheter insertion in earthquake victims. Considering that post-traumatic injuries require repeated surgeries and that pain aggravates the existing psychological state, it can be said that catheterization is beneficial.

Polycystic ovary syndrome (PCOS) is the predominant endocrine disorder among women of re-productive age and represents the leading cause of anovulatory infertility, which imposes a con-siderable health and economic burden. Currently, medications used to treat PCOS can lead to certain adverse reactions, such as affecting fertility and increasing the risk of venous thrombosis. Drug delivery systems utilizing nanomaterials, characterized by prolonged half-life, preci-sion-targeted delivery, enhanced bioavailability, and reduced toxicity, are currently being em-ployed in the management of PCOS. This innovative approach is gaining traction as a favored strategy for augmenting the therapeutic efficacy of medications. Consequently, this paper dis-cusses the roles of nanoparticles, nanocarriers, and targeted ligands within nanomaterial-based drug delivery systems, aiming to identify optimal methodologies for treating PCOS using nano-materials. Additionally, prospective research avenues concerning nanomaterial-based delivery systems in the context of PCOS, as well as the implications of existing insights on the advancement of novel therapies for PCOS, are highlighted.

Background: Gastric carcinoma in the Belgian Shepherd dog varieties Tervueren and Groenendael is commonly recognized and carries a grave prognosis. Information on incidence and heritability is necessary to design an effective selection strategy against this disease. Methods: A database of cases and controls was built including cases with tier 1 (confirmed by endoscopy or post-mortem) and tier 2 evidence of gastric carcinoma. From the database, a birth cohort from dogs born in the Netherlands in the period 2000-2010 was used, together with pedigree information to calculate heritability using a mixed models approach. Univariate linear regression was used to test the influence of gastric carcinoma status of the parents on gastric carcinoma occurrence in offspring. Results: For Tervueren the 10-year cumulative incidence is 4.7%, for the Groenendael this was 2.1%. There was no sex predilection. The odds of gastric carcinoma were 5.0 (2.4-11.0) in offspring when at least one parent was known to be affected versus at least one parent was known to be unaffected. Heritability, based on analysis using pedigree information from 338 dogs with gastric carcinoma and 159 controls was 0.53 (se 0.15). Conclusions: Gastric carcinoma in the Belgian Shepherd Tervueren and Groenendael has a high incidence in the Dutch population and has a strong genetic component. Because it is a late onset disease, dogs are often already used for breeding before they are diagnosed. An effective breeding strategy for reducing the incidence therefore relies on the identification of genetic risk factors influencing the development of the disease.

Stereotactic Body Radiotherapy has been established as a viable treatment option for inoperable early-stage Non-Small Cell Lung Cancer or secondary lesions mainly in oligoprogressive/oligometastatic scenarios. Treating lesions in the so-called “no flight zone” has always been challenging and conflicting data never cleared how to safely treat these lesions. This is truer considering ultra-central lesions, i.e. directly abutting or whose PTV is overlapping critical mediastinal organs. While historical retrospective data is abundant but mostly heterogenous in terms of definition of ultra-central lesions, dosing regimens and outcomes, prospective data remains scarce, even though recently published studies have given new encouraging results for such delicate treatment scenarios. For this reason, we aimed to review and summarize current knowledge on stereotactic radiation treatment for ultra-central thoracic lesions, highlighting the most recent advances and the messages that can be taken from them. Lastly, we propose a workflow of the necessary steps to identify and treat such patients, therefore helping in elucidating them with advantages and caveats of such treatment option.

Background: Elexacaftor/Tezacaftor/Ivacaftor (ETI) is a CFTR modulator therapy approved for people with cystic fibrosis (pwCF) who have at least one phe508del mutation. However, its approval in the EU for pwCF with non-phe508del mutations is lacking, with limited data on treatment response in this subgroup. Methods: This retrospective study analyzed data from six pwCF (ages 6 to 66) with responsive CFTR mutations (M1101K, R347P, 2789+5G>A, G551D) undergoing off-label ETI therapy. Evaluations were conducted at 0, 3, 6, 9, and 12 months, assessing lung function (FEV1), sweat chloride levels, BMI, quality of life (CFQ-R), medication satisfaction (TSQM), ENT symptoms (SNOT-22), and physical performance. A control group of four pwCF with classic symptoms and no ETI treatment was included. Results: FEV1 improved significantly after 3 and 6 months (p<0.05) and stabilized by 12 months. Sweat chloride levels decreased significantly, with four pwCF achieving levels below 60 mmol/l. Improvements in ENT and respiratory symptoms, medication satisfaction, and increased BMI were noted. Conclusion: ETI demonstrates high efficacy in selected non-phe508del mutations, offering an effective treatment option that warrants further monitoring and evaluation.

Despite their increasing prevalence epidemiological data on thoracic spine injuries(TSI) is under-presented in the literature. Furthermore, these studies fail to correlatemechanisms of injury to the specific spinal regions injured. Team ball sports appear tobe common activities undertaken in these age groups. A narrative review wasconducted to understand the aetiology of traumatic TSI, with a focus on sporting causes in youth populations. A literature search was conducted through various databases (from inception to April 2024) such as PubMed, CINAHL, Medline, ProQuest Central, Science Direct and SPORTDiscus. Seven studies, including 1670 patients were included in the dataset. TSI, particularly fractures, were found to be more common in adolescent age groups. Common sporting causes of spinal trauma included equestrian and team ball/contact sports. This review found few studies failed to correlate the mechanism of injury and the specific spinal level affected, supporting the need for further research.

Background: Patients undergoing brain tumor resection experience neurological and cognitive (i.e., neurocognitive) changes reflected in altered performance on neuropsychological tests. These changes can be difficult to explain or predict. Brain connectivity, measured with neuroimaging, offers one potential model for examining these changes. In this study, we evaluated whether longitudinal changes in brain connectivity correlated with changes in neurocognitive abilities in patients before and after brain tumor resection.

Methods: Patients underwent functional and diffusion MR scanning and neuropsychological evaluation before tumor resection followed by repeat scanning and evaluation two weeks post-resection. Using this functional and diffusion imaging data, we measured changes in the topology of the functional and structural networks. From the neuropsychological testing scores, we derived a composite score that described a patient’s overall level of neurocognitive functioning. We then used a multiple linear regression model to test whether structural and functional connectivity measures were correlated with changes in composite scores.

Results: Multiple linear regression on 21 subjects showed that connectivity changes were highly correlated with changes in neuropsychological evaluation scores (R² adjusted = 0.79, p<0.001). Changes in functional local efficiency (p<0.001) and global efficiency (p<0.05) were inversely correlated with changes in composite score, while changes in modularity (p<0.01) as well as the patient’s age (p<0.05) were directly correlated with changes in composite score.

Conclusion: Short interval changes in brain connectivity markers were strongly correlated with changes in the composite neuropsychological test scores in brain tumor resection patients. Our findings support the need for further exploration of brain connectivity as a biomarker relevant to brain tumor patients.

Nitazenes represent a New Synthetic Opioids sub-class, belonging to the New Psychoactive Substances (NPS). Their high pharmacological potency has led to numerous intoxications and fatalities, even at minimum doses. The aim of this study was to assess the stability of four nitazenes (etazene, flunitazene, isotonitazene and protonitazene) in dried blood spot (DBS) samples at different storage temperatures (room temperature and 4°C), using a newly developed and validated liquid chromatography-high resolution mass spectrometry method. Two concentrations, 1 and 5 ng/mL were chosen based on the available data on nitazene-related intoxications and stability was evaluated at day 0 (control), 1, 7 and 30. Results showed that all analytes at 1 ng/mL were not detectable after 30 days at room temperature; a similar pattern was observed for 1 ng/mL etazene and isotonitazene samples when stored at 4°C, whereas flunitazene and protonitazene decreased to a mean of 66% and 69% initial concentration, respectively, at day 30. Differently, all analytes at 5 ng/mL were quantified above 44% and 41% initial concentration at room temperature and 4°C, respectively, showing a higher stability. The study of nitazenes stability in DBS represents an important tool to determine the optimal samples storage conditions, such as temperature and time between sample collection and analysis.

Background/Objectives: Cancer is caused by disruptions in the homeostatic state of normal cells, which results in dysregulation of the cell cycle, and uncontrolled growth and proliferation in affected cells to form tumors. Successful development of tumorous cells proceeds through the activation of pathways promoting cell development and functionality, as well as the suppression of immune signaling pathways; thereby providing these cells with proliferative advantages, which subsequently metastasize into surrounding tissues. These effects are primarily caused by the upregulation of oncogenes, of which SPP1 is one of the most well-known. Methods: In this study, we conducted a further examination of the transcriptomic expression profile of SPP1 (Osteopontin) during the progression of cancer in four human tissues, in order to understand the circumstances conducive to its activation and dysregulation, the biological pathways and other mechanisms involved, as well as differences in its splicing patterns influencing its expression and functionality. Results: A significant overexpression of SPP1 as well as a set of other highly correlated genes, was seen in a majority of tissues, indicating their extensive implication in cancer. Increased expression was observed with higher tumor stages, while applying therapeutic modalities targeting these genes dampened this effect. Pathway analyses showed gene signatures related to cell growth and development enriched in tumorigenic conditions and earlier cancer stages, while later stages of cancer showed pathways associated with weakened immune response. Moreover, the utilization of therapeutic methods showed the activation of immunogenic pathways, thereby confirming their viability. Further analyses of differential transcript expression levels in these oncogenes showed their exonic regions to be selectively overexpressed similarly in tumorigenic samples, while also displaying significant differences in exon selectivity between constituent transcripts, providing a basis for their high degree of multifunctionality in cancer. Conclusions: Overall, this study corroborates the entrenched role of SPP1 in cancer, while also highlighting its promising role in therapeutic development.

Background/Objective: Biological females experience more autoimmune disease than males and more treatment-related adverse events (TRAEs) after immune checkpoint blockade therapy. However, little is known about sex-related differences in TRAEs after cancer vaccines. Methods: The Mel44 clinical trial (NCT00118274) enrolled patients with high-risk melanoma to either of two melanoma vaccines. We hypothesized that females would experience higher rates and grades of TRAEs. TRAE rates and grades were compared between sexes, with adjustment for multiple comparisons, and with mixed-effects models. Results: Multiple sex-related differences in TRAE rate and grade were observed in unadjusted comparisons, but only hyperglycemia and hypopigmentation were significantly higher grade by sex after correcting for multiple comparisons: they were increased in males. In mixed-effect mod-els, vaccination strategy, but not patient sex, was independently associated with TRAE rates and grades. Conclusions: These data do not support our hypothesis that TRAEs would be increased in females. Vaccine safety was supported for both males and females.

Objectives: early identification of infection-causing microorganisms through multiplex PCR panels enables prompt and targeted antibiotic therapy. The study aimed to assess the performance of the BioFire® Joint Infection Panel (BF-JIP) in analysing non-synovial fluid samples. Methods: we conducted a retrospective cohort study at Trieste University Hospital, Italy, on hospitalised adults with non-synovial fluid samples tested by both BF-JIP and traditional culture methods (November 2022-April 2024). Results: we evaluated 48 samples from 45 patients, including 24 abscess drainage fluids and 10 biopsies. The BF-JIP showed high concordance (85.4%) and enhanced detection (4.3%) compared to culture methods. The BF-JIP excelled in CSF (100% accuracy and concordance) and in abscess drainage fluids (accuracy: 95.8%; concordance: 91.7%), and maintained high performance in patients under antibiotics. Conclusions: these findings suggest that BF-JIP is a valuable tool for accurate pathogen detection in various clinical samples, offering the additional advantage of being a rapid method.

Diabetes complications appear with the severity of hyperglycemia and the age of the disease. In type 2 diabetes mellitus (T2DM), herbal medicines are also effective in reducing hyperglycemia and can be used for this purpose to manage complications. This study aimed to prove the effectiveness of Amaranthus spinosus root extract on type 2 diabetes (T2D) and its microvascular complications. A high-fat diet and low-dose streptozocin were used for 20 days to induce T2D syndrome and complications in rats. The validated animal models were treated orally with the dried hydroethanolic extract of A. spinosus for three weeks; then the hematological, biochemical, and histological markers were evaluated. The results showed that the extract at a dose of 500 mg/kg bw was effective against diabetes and its complications. This effectiveness was linked to a significant reduction (p &lt; 0.0001) in basal blood glucose, tissue oxidative stress, serum cardiovascular and hepato-renal markers, and an improvement in insulin secretion and utilization. The protective activity of the extract against macular edema and renal fibrosis was confirmed by histopathological examinations. These findings prove that A. spinosus root extract contains bioactive compounds that may be useful in preventing or reversing diabetic retinopathy and renal fibrosis.

Heart aging involves a complex interplay of genetic and environmental influences, leading to a gradual deterioration of cardiovascular integrity and function. Age-related physiological changes, including ventricular hypertrophy, diastolic dysfunction, myocardial fibrosis, increased arterial stiffness, and endothelial dysfunction, are influenced by key mechanisms like autophagy, inflammation, and oxidative stress. This review aims to explore the therapeutic potential of plant-derived bioactive antioxidants in mitigating heart aging. These compounds, often rich in polyphenols, flavonoids, and other phytochemicals, exhibit notable antioxidant, anti-inflammatory, and cardioprotective properties. Through a comprehensive analysis of preclinical and clinical studies, this work highlights the mechanisms associated with heart aging and the promising effects of plant-derived antioxidants. The findings may helpful for researchers in identifying specific molecules with therapeutic and preventive potential for cardiovascular aging.