The post-hoc analysis presented here aimed to address the influence of endogenous vitamin D in the immunological mechanism underlying effective mite allergoid-immunotherapy (AIT). Previously, we have shown that one subpopulation of T regulatory cells results in phenotypically identifiable as functionally potentiated and memory cells in allergic children after 12 months of this immunoactive treatment. Indeed, AIT is the only known treatment able to reshape the detrimental immune response against the allergen into a not noxious one. Besides, VD is widely considered an immunoregulatory molecule endogenously produced and exogenously provided with foods and supplements that might interact with AIT mechanism and affect its outcome. Therefore, a post-hoc analysis of the clinical and immunological data of three different cohorts of allergic patients was performed. One cohort (N=70) was on standard symptoms-controlling pharmacological treatment while the other two (N=60 and N=35, respectively) were treated with AIT for 12 months. Among the first were observed a lower mean endogenous VD level (<22 ng/ml) along with worse symptoms and higher use of medications. Remarkably, the comparison between two sub-cohorts of patients with serum VD above (N=32) or below (N=28) a cut-off value set at mean value (27 ng/ml) revealed that optimal improvement of all clinical and immune parameters was achieved (as expected by effective AIT), irrespective of the VD level. Notably, the third analysis, carried out on one cohort of AIT patients also taking concomitantly VD3 as food supplement (N=19), was distinguished by uppermost overall treatment outcome (amelioration of symptoms, lowest medications requirement, and reduction of total and allergen-specific IgE) as well as the increase of allergen-specific tolerogenic memory T regulatory cells. These findings suggest that endogenous VD level affects allergy severity and allergen immunotherapy effectiveness. Also, VD3 might be investigated as an add-on supplement to get the best out of immunotherapy in VD deficient/insufficient allergic patients. The immunogenic but low-allergenic mite allergoid used as bioactive agent might have contributed to minimize allergic and highlight immunological effects described here.

Abstract ObjectivesThe aim of this perspective is to report the use of synthetic data as a viable method in women’s health given the current challenges linked to obtaining life-course data within a short period of time and accessing electronic healthcare data. Methods We used a 3-point perspective method to report an overview of data science, common applications, and ethical implications. Results There are several ethical challenges linked to using real-world data, consequently, generating synthetic data provides an alternative method to conduct comprehensive research when used effectively. The use of clinical characteristics to develop synthetic data is a useful method to consider. Aligning this data as closely as possible to the clinical phenotype would enable researchers to provide data that is very similar to that of the real-world. Discussion Population diversity and disease characterisation is important to optimally use data science. There are several artificial intelligence techniques that can be used to develop synthetic data. ConclusionSynthetic data demonstrates promise and versatility when used efficiently aligned to clinical problems. Therefore, exploring this option as a viable method in women’s health, in particular for epidemiology may be useful.

Chronic kidney disease (CKD) is actually considered a public health priority according to the increasing number of patients affected by this condition: this casuistry is not only related to specific glomerular, tubular or autoimmune diseases or a consequence of acute kidney injury (AKI) episodes leading to organ failure, but it is tied to the progression of life expectancy and the impact of comorbidities such as cardiovascular disease, diabetes and cancer. CKD and its comorbidities promote low grade inflammatory status with an impact on patients’ clinical conditions, reducing their possibility for kidney transplantation or graft survival and their survival when receiving renal replacement therapies such as hemodialysis (HD) or peritoneal dialysis (PD). CKD is often referred to as an ageing accelerator: innate immune system dysregulation, in the uraemic proinflammatory milieu, is involved in this accelerated senescence phenomena and pentraxins, particularly Pentraxin-3 (PTX-3), are of particular interest in the development of kidney disease. A complete understanding of the mechanism of CKD progression, innate immune system involvement and a proper definition of PTX-3 role in kidney disease, could redefine the approach for diagnosis and a more centered patients’ management to slow down CKD progression over time and reduce its clinical and social impact.

Our recent studies showed that the treatment of human ovarian tumor cells with NCX4040 resulted in significant depletions of cellular glutathione, formation of reactive oxygen/nitrogen species and cell death. NCX4040 is also cytotoxic to several human colorectal cancer cells (CRC) in vitro and in vivo. Here, we have examined ferroptosis-dependent mechanism(s) of cytotoxicity of NCX4040 in HT-29 and K-RAS mutant HCT116 colon cell lines. Ferroptosis is characterized by accumulation of reactive oxygen species (ROS) within the cell, leading to an iron-dependent oxidative stress-mediated cell death. However, its relevance in the mechanism of NCX4040 cytotoxicity in CRC is not known. We found that NCX4040 generated ROS in CRC cells without any depletion of cellular GSH. Combinations of NCX4040 with erastin (ER) or RSL3 (RAS-selective lethal 3), known inducers of ferroptosis, enhanced CRC death. In contrast, ferrostatin-1, an inhibitor of ferroptosis, significantly inhibited NCX404-induced cell death. Treatment of CRC cells with NCX4040 resulted in induction of lipid peroxidation in a dose- and time-dependent manner. NCX4040 treatment induced several genes related to ferroptosis (e.g., CHAC1, GPX4 and NOX4) in both cell lines. Metabolomic studies also indicated significant increases in both lipid and energy metabolism following the drug treatment in HT-29 and HCT116 cells. These observations strongly suggest that NCX4040 causes ferroptosis-mediated cell death of CRC cells. Furthermore, combinations of NCX4040 and ER or RSL3 may contribute significantly for the treatment of CRC, including those that are difficult to treat due to the presence of Ras mutation in the clinic. NCX4040 induced ferroptosis may also be a dynamic form of cell death for the treatment of other cancers.

The human respiratory syncytial virus (hRSV) poses a serious risk to global public health and is a significant cause of severe lower respiratory infections. There are currently only a few therapies available to treat RSV infections, as well as no RSV vaccinations. Therefore, there is an urgent demand for clinically feasible, safe, and affordable RSV prevention and treatment alternatives. In this study, an ion-activated in situ gel comprising broad-spectrum antiviral 18β-glycyrrhetinic acid (GA) for antiviral action on RSV was developed. In this content, mechanical properties, sprayability, drug content, pH, ex vivo mucoadhesive strength, in vitro drug release pattern, and stability were all examined. Rheological properties were also tested by utilizing in vitro gelation capacity and rheological synergism tests. Finally, the optimized in situ gel's cytotoxic and antiviral activities on RSV cultured in human laryngeal epidermoid carcinoma (HEP-2) cell line were evaluated. In conclusion, the optimized in situ gel prepared with a combination of 0.5%w/w gellan gum and 0.5%w/w sodium carboxymethylcellulose demonstrated good gelation capacity and sprayability (weight deviation between T0 and T14: 0.34%), desired rheological synergism (mucoadhesive force (Fb): 9.53), mechanical characteristics (adhesiveness: 0.300 mJ ± 0.05), ex vivo bioadhesion force (19.67 g ± 1.90), drug content uniformity (RSD%: 0.494), and sustained drug release over period of 168 h (101.57% ± 0.53). The antiviral activity test results showed that the optimized in situ gel had strong anti-HRSV activity (EC50 simultaneous = 0.05 µg/ml, SI = 306; EC50 preinfection = 0.154 µg/ml, SI= 100) which was significantly higher than that of ribavirin (EC50 =4.189 µg/ml; SI= 28) used as a positive control against hRSV. In conclusion, this research has demonstrated the formulation of an effective antiviral nasal spray that has the ability to possess both prophylactic and virucidal activity.

Secondary metabolites such as flavonoids are considered to be promising in the treatment of NAFLD, which is one of the complications of diabetes due to oxidative stress and inflammation. Some plants, such as Eryngium carlinae, have been investigated with regard to their medicinal properties in in vitro and in vivo assays, showing favorable results for the treatment of various diseases such as diabetes and obesity. The present study examined the antioxidant and anti-inflammatory effects of the phenolic compounds present in an ethyl acetate extract of the inflorescences of Eryngium carlinae on liver homogenates and mitochondria from STZ-induced diabetic rats. Phenolic compounds were identified and quantified by UHPLC-MS. In vitro assays were carried out to discover the antioxidant potential of the extract. Male Wistar rats were administered with a single intraperitoneal injection of STZ (45 mg/kg) and were given the ethyl acetate extract at a level of 30 mg/kg for 60 days. Phytochemical assays showed that the major constituents of the extract were flavonoids; in addition, the in vitro antioxidant activity was dose-dependent with IC50 = 57.97 mg/mL and IC50 = 30.90 mg/mL in the DPPH and FRAP assays, respectively. Moreover, the oral administration of the ethyl acetate extract improved the effects of NAFLD, decreasing serum and liver TG levels and oxidative stress markers and increasing the activity of the antioxidant enzymes. Likewise, it attenuated liver damage by decreasing the expression of NF-κB and iNOS, which lead to inflammation and liver damage. These results suggest that the phenolic compounds of the ethyl acetate extract of E. carlinae have antioxidant, anti-inflammatory, hypolipidemic, and hepatoprotective activity.

(1) Background: Breast cancer-associated lymphedema (BCRL) is a major complication of breast cancer treatment, affects the quality of life of breast cancer survivors who develop it. Manual lymphatic drainage has a beneficial result in combating lymphedema in patients who have undergone breast cancer surgery. The hypothesis consists in complete decongestive therapy reduces the lymphedema at the level of the upper limb on the side of mastectomy. (2) Methods: Twenty-five patients with radical mastectomy and upper limb lymphedema on the mastectomy side were included in this study. Upper limb circumferences were measured with a tape measure at the following levels: metacarpophalangeal joint; distal radioulnar joint; 10 cm distal to lateral epicondyle; 5 cm proximal to elbow joint; 10 cm proximal to lateral epicondyle. (3) Results: Patients received twice weekly manual lymphatic drainage, multi-layer compression bandaging and upper limb muscle stimulation exercises on the mastectomy side twice weekly. The circumference assessed at the level of the metacarpophalangeal joints and distal radio-carpal joint decreased at the final evaluation. Forearm perimetery - 5 and 10 cm distal to the lateral epicondyle the circumference decreased at the final assessment. (4) Conclusions: Patients with breast cancer-related lymphedema should receive comprehensive decongestive therapy in the early stage of lymphedema to achieve rapid clinical results and improved quality of life

Minimal access cardiac surgery appears to be the future. It is increasingly desired by cardiologists and demanded by patients who perceive superiority. Minimal access coronary artery revascularisation has been increasingly adopted throughout the world. Here we review the history of minimal access coronary revascularization and see that it is almost as old as the history of cardiac surgery. Modern minimal access coronary revascularization takes a variety of forms – namely minimal access direct coronary artery bypass grafting (MIDCAB), hybrid coronary revascularisation (HCR) and totally Endoscopic Coronary Artery Bypass Grafting (TECAB). It is noteworthy that there is significant variation in nomenclature and approaches for minimal access coronary surgery and this truly presents a challenge to comparing the different methods. However, these approaches are increasing in frequency and proponents demonstrate clear advantages for their patients. The challenge that remains, as for all areas of surgery, is demonstrating superiority of these techniques over tried and tested open techniques which is very difficult. There is a paucity of randomized controlled trials to help answer this question, and the future of minimal access coronary revascularisation to some extent is dependent on such trials. Thankfully some are underway and the results eagerly anticipated.

Background: Skin and soft tissue infections (SSTI) are common presentations to the emergency department. However, this is less common after contact with contaminated water, both salt or fresh. This review presents the diagnosis and the management of water-related soft tissue sepsis in this vulnerable and difficult to treat subgroup of necrotizing soft tissue sepsis. Methods: A summative literature overview regarding bacterial and fungal SSTI after contact with contaminated water, with practical diagnostic and management aspects addressed. Results: The literature indicates that these remain difficult to treat wounds and organisms. An approach using appropriate diagnostic tools with both medical and surgical management strategies is provided. Conclusion: SSTI due to water contamination of wounds involve unusual organisms with unusual resistance patterns and require a nuanced and directed diagnostic approach with adaptation of the normal antibiotic or antifungal selection to achieve cure, along with aggressive debridement and wound care.

Background: The prevalence of obesity, defined as body mass index (BMI) ≥ 30 kg/m2, has reached epidemic levels. Obesity is associated with an increased risk of various cancers, including gastrointestinal ones. Recent evidence has suggested that obesity disproportionately impacts males and females with cancer, resulting in varied transcriptional and metabolic dysregulation. Methods: This study aimed to elucidate the differences in the metabolic milieu of adenocarcinomas of the gastrointestinal (GI) track both related and unrelated to sex in obesity. To demonstrate these obesity and sex-related effects, we utilized three primary data sources: serum metabolomics from obese and non-obese patients assessed via the Biocrates MxP Quant 500 mass spectrometry-based kit, the ORIEN tumor RNA-sequencing data for all adenocarcinoma cases to assess the impacts of obesity, and publicly available TCGA transcriptional analysis to assess GI cancers and sex-related differences in GI cancers specifically. We applied and integrated our unique transcriptional metabolic pipeline in combination with our metabolomics data to reveal how obesity and sex can dictate differential metabolism in patients. Results: Differentially expressed genes (DEG) analysis of ORIEN obese adenocarcinoma as compared to normal-weight adenocarcinoma patients resulted in large-scale transcriptional reprogramming (4029 DEGs, adj. p < 0.05 and |logFC|>0.58). Gene Set Enrichment and metabolic pipeline analysis showed genes enriched for pathways relating to immunity (inflammation, and CD40 signaling, among others) and metabolism. Specifically, we found alterations to steroid metabolism and tryptophan/kynurenine metabolism in obese patients, both of which are highly associated with disease severity and immune cell dysfunction. These findings were further confirmed using the TCGA colorectal adenocarcinoma (CRC) and esophageal adenocarcinoma (ESCA) data, which showed similar patterns of increased tryptophan catabolism for kynurenine production in obese patients. These patients further showed disparate alterations between males and females when comparing obese to non-obese patient populations. Alterations to immune and metabolic pathways were validated in 6 patients (2 obese and 4 normal weight) via CD8+/CD4+ peripheral blood mononuclear cell RNA-sequencing and paired serum metabolomics, which showed differential kynurenine and lipid metabolism, which corresponded with altered T-cell transcriptome in obese populations. Conclusions: Overall, obesity is associated with differential transcriptional and metabolic program in various disease sites. Further, these alterations, like kynurenine and tryptophan metabolism, which impact both metabolism and immune phenotype, vary with sex and obesity together. This study warrants further in-depth investigation into obesity and sex-related alterations in cancers that may better define biomarkers of response to immunotherapy.

Graphene-based nanomaterials (GNMs), including graphene, graphene oxide, reduced graphene oxide, and graphene quantum dots, may have direct anticancer activity or be used as nanocarri-ers for antitumor drugs. GNMs usually enter tumor cells by endocytosis and can accumulate in lysosomes. This accumulation prevents drugs bound to GNMs from reaching their targets, sup-pressing their anticancer effects. A number of chemical modifications are made to GNMs to facili-tate the separation of anticancer drugs from GNMs at low lysosomal pH and to enable lysosomal escape of drugs. Lysosomal escape may be associated with oxidative stress, permeabilization of the unstable membrane of cancer cell lysosomes, release of lysosomal enzymes into the cytoplasm, and cell death. GNMs can prevent or stimulate tumor cell death by inducing protective autopha-gy or suppressing autolysosomal degradation, respectively. Furthermore, because GNMs prevent bound fluorescent agents from emitting light, their separation in lysosomes may enable tumor cell identification and therapy monitoring. In this review, we explain how the characteristics of the lysosomal microenvironment and the unique features of tumor cell lysosomes can be exploited for GNM-based cancer therapy.

Acinetobacter baumannii (AB) is a bacterium that causes infections, particularly in immunocompromised patients. Treatment is challenging due to biofilm formation by AB strains, which hinders antibiotic effec-tiveness and promotes drug resistance. The aim of our study was to analyze the biofilm-producing capacity of AB isolates from various forms of infections in relation to biofilm-related genes and their drug resistance. We tested one hundred isolates for biofilm formation using the crystal violet microplate method. Drug re-sistance analyses were performed based on EUCAST and CLSI guidelines, and biofilm genes were detected using PCR. All tested strains were found to form biofilms, with 50% being ICU strains and 72% classified as strong biofilm-producers. Among these, 87% were extensively drug-resistant (XDR) and 2% were extra extensively drug-resistant (E-XDR). The most common gene set was bap, bfmS, csuE, and ompA, found in 57% of all isolates. Our research has shown that, regardless of the form of infection, biofilm-forming strains can be expected among AB isolates. The emergence of E-XDR and XDR strains among non-ICU infections highlights the necessity for the rational use of antibiotics to stop or limit the further acquisition of drug re-sistance by A. baumannii.

Recent studies have confirmed that lung microvascular endothelial injury plays a critical role in the pathophysiology of COVID-19. Our group and others have demonstrated the beneficial effects of H2S in several pathological processes and provided a rationale for considering the therapeutic implications of H2S in COVID-19 therapy. Here, we evaluated the effect of the slow-releasing H2S donor, GYY4137, on the barrier function of a lung endothelial cell monolayer in vitro, after challenging the cells with plasma samples from COVID-19 patients or inactivated SARS-CoV-2 virus. We also assessed how the cytokine/chemokine profile of patients’ plasma, endothelial barrier permeability, and disease severity correlated with each other. Alterations of barrier permeability after treatments with patient plasma, inactivated virus, and GYY4137 were monitored and assessed by electrical impedance measurements in real-time. We present evidence that GYY4137 treatment reduced endothelial barrier permeability after plasma challenge and completely reversed the endothelial barrier disruption caused by inactivated SARS-CoV-2 virus. We also showed that disease severity correlated with the cytokine/chemokine profile of the plasma but not with barrier permeability changes in our assay. Overall, these data demonstrate that treatment with H2S-releasing compounds has the potential to ameliorate SARS-CoV-2–associated lung endothelial barrier disruption.

Mucosal healing (MH) is the main treatment target in ulcerative colitis and Crohn’s disease, and it is defined by a combination of complete endoscopic and histologic remission. Indeed, the complete resolution of mucosal inflammation should be confirmed at histology. Neutrophil infiltration represents the unique histological marker in discriminating the active vs quiescent phase of disease, also including crypt injuries (cryptitis and crypt abscesses), erosions and ulcerations. Basal plasmacytosis do not qualify by itself the remission in inflammatory bowel diseases (IBD), but it represents a diagnostic clue, mostly at onset. Several histological scoring systems have been developed to evaluate therapeutic efficacy, even though they often resulted tricky and subjective. Moreover, these scores listed a heterogeneous group of histological features as parameters. The recently proposed simplified histological score on MH was based on neutrophils and their distribution in the gut mucosa was also considered, aiming to provide a simple, time-sparing and reproducible tool to be applied to the routinary diagnostic practice. The artificial intelligence could be a promising tool both in evaluating and standardizing the histological assessment of disease activity in IBD. Moreover, novel molecules involved in the inflammatory dynamics in the gut could be employed in supporting the diagnostic practice in IBD.

Accumulation of extra fats in the body results in disturbance in homeostasis causing obesity. The pathophysiology of obesity has been associated with various genetic, epigenetic factors and the disturbed lifestyles of an individual. One of the outcomes is disturbance in the sleep cycle which leads to sleep disorders. The evolutionary significance of sleep lies in the fact that it saves energy and is crucial for adjustment of an individual to ecological and environmental factors, and thus maintains homeostasis. Sleep has an anabolic function and replenishes the wakefulness-associated loss of glycogen stores. However, the modern lifestyle is well known to disrupt sleep behavior and patterns affecting human health negatively. Alteration in homeostasis leads to several acute and chronic pathophysiological conditions like obesity and related metabolic morbidities being one amongst them. Shorter sleep duration and poor sleep quality are important risk factors associated with the development of obesity and have more adverse effects on energy homeostasis. Consequently, it is crucial to comprehend the obesity and sleep relationship and its therapeutic strategies, given that strong crosstalk exists between energy balance that favors obesity and sleep apnea. It is therefore highly recommended to the people with a high risk of obesity to maintain sleep discipline and good sleep hygiene in our daily life. Interventions are required to improve both sleep quality and quantity, and associated obesity. More focused research is needed for uncovering the pieces of evidence that determine whether such interventions can improve obesity-related health consequences. The present review discusses the important findings on the therapeutic and neuroendocrine mechanisms regulating sleep and obesity.

The aim of the current study was to develop and evaluate the therapeutic potential of apocynin (APO) loaded pH-sensitive nanoparticles (NPs) based transdermal hydrogel for management of rheumatoid arthritis (RA). Slightly modified nanoprecipitation technique was used for preparation of polymeric nanoparticles. Optimization was done through design expert software. Optimized APO-NPs were loaded into carbopol-934 based hydrogel as final dosage form and further studied for physicochemical properties. Optimized APO-NPs formulation had a minimum particle size 63.44 nm, polydisperibility index 0.161, and zeta potential -15mV with a maximum encapsulation efficiency of 89%. In-vitro and ex-vivo studies of APO-NPs based hydrogel was performed at pH 5.5 (pH of normal skin) and 6.8 (pH of inflammed joint) showed a pH-responsive sustained drug release and increased penetration in comparison to free APO based hydrogel. The stability studies of APO-NPs based hydrogel were done to strengthen the potential use of the prepared formulation through transdermal route. Assessment and therapeutic efficacy of the prepared pH-sensitive nanocarriers system was evaluated in chronic inflammatory RA mice model. Parameters associated with chronic inflammation were investigated including behavioral changes and histopathological, and radiological x-rays images of joints of mice paws. In-vivo study depicts improvement in behavioral parameter, decline in synovial hyperplasia and bone structure restoration. In conclusion, APO loaded pH-sensitive NPs based transdermal is a promising carrier system that can effectively manage RA.

Cryptococcosis is a leading cause of death among people with HIV in sub-Saharan Africa. Limited diagnostic and therapeutic options significantly impair treatment options in Africa. We investigated the burden of cryptococcosis and related mortality among people with HIV and suspected sepsis in Ethiopia. We conducted a prospective cohort at 1) Adama Hospital Medical College and 2) Asella Referral and Teaching Hospital from September 2019 to November 2020. We enrolled adult HIV-infected patients presenting with suspected sepsis and assessed 28-day survival. We performed blood cultures and cryptococcal antigen (CrAg) testing. In total, 82 participants were enrolled with a median age of 35 years and 61% being female. Overall, 11(13%) had positive CrAg tests, of which 5 had Cryptococcus detected in blood cultures. Despite high-dose fluconazole (1200mg/d) monotherapy in patients with positive CrAg tests, the 28-day mortality was 64%(7/11), being significantly higher than in CrAg-negative patients (9%(6/71); p&lt;0.001). Cryptococcosis is the leading cause of mortality among HIV-infected sepsis patients. CrAg screening in HIV-infected patients attending emergency department can minimize the cryptococcosis missing case irrespective of CD4 count and viral load. These findings warrant the need of a bundle approach for diagnosis of HIV-infected persons presenting with sepsis in low- and middle-income countries.

The COVID-19 pandemic has brought marked changes worldwide to the management of airborne infectious diseases. It sparked the development of the SARS-CoV-2 vaccine and pharmacotherapeutics to prevent infection and increase the survival rate during the acute viral phase and the comorbidities associated with COVID-19. Periodontal disease may increase the morbidity and perhaps the mortality of a COVID-19 infection. However, the molecular interaction between periodontitis and COVID-19 infection remains undetermined. A potential pathogenic co-morbidity may involve periodontal pathogenic release of destructive cytokines in the highly inflamed connective tissue and risk for COVID-19. Additional biomarkers such as C-reactive proteins appear to play a role for risk and pathogenesis of COVID-19. The potential of herpesviruses, especially as it is related to aggressive periodontitis may also be a comorbidity for COVID-19. This paper reviews available evidence on the bidirectional association between periodontitis and COVID-19.

Thermoregulation is important for maintaining homeostasis of our body. It can be easily broken under anesthesia. An appropriate method to measure the core body temperature is needed, especially for elderly patients because the efficiency of thermoregulation gradually decreases with age. The aim of this study was to examine the accuracy and feasibility of using of SpotOn® sensor in lower extremity orthopedic surgery in elderly patients aged over 80 years by comparing a SpotOn® sensor with two other reliable minimal-invasive methods: a tympanic membrane thermometer and a bladder thermometer. This study enrolled 45 patients aged over 80 years who were scheduled to undergo a lower extremity surgery. Body temperature was measured using a SpotOn® sensor, tympanic membrane thermometer and bladder thermometer. Agreements between the SpotOn® sensor and the other two methods were assessed using Bland and Altman plots for repeated measures adjusted for unequal numbers of measurements per patient. Compared with TempBladder, bias and limits of agreement for TempZHF were 0.07℃ ± 0.58℃. Compared with TempTympanic, bias and limits of agreement for TempZHF were -0.28℃ ± 0.61℃. 3M SpotOn® sensor using ZHF method for patients aged over 80 years undergoing lower extremity surgery shows feasible measurement value and sensitivity.

Abstract: (1) Background: Sentinel lymph node biopsy assumes importance in the search for metastases, especially in patients with malignant breast disease. Our study approaches the new techniques to prevent complications such as possible postoperative seroma formation, pain or hypoesthesia of the axillary cord and medial arm surface, as well as motor deficits in a preventive manner to avoid disabling outcomes and presents initial data from its experience with the sentinel lymph node biopsy technique. (2) Methods: There are mainly two radioactive tracer detection techniques and a new technique using a radiotracer called Sentimag-magtrace. The positive lymph node is located and removed to perform histologic analysis. In our study, we evaluate 100 patients who underwent breast cancer surgery (3) Results: our experience allowed us to calculate the identification rate with the different methods of sentinel lymph nodes by radioactive tracer 88.9 % vs magnetic tracer technology (Sentimag) 89.5%. (4) Conclusions: Thus, this technique avoids radiation exposure for both patients and health care providers, as well as reducing costs and time.

This work aims to investigate the expression levels of four preselected miRNAs previously linked to Cancer and/or Obesity, with the purpose of finding potential biomarkers in the clinical management of Colorectal Cancer (CRC) developed by obese and non-obese patients. We analyzed samples from a total of 65 subjects, 43 affected by CRC and 22 without cancer. Serum and both subcutaneous and omental adipose tissues (SAT and OAT) were analyzed, as well as tumor and non-tumor colorectal tissues in the case of the CRC patients. The relative expression (2-∆∆Ct) levels of 4 miRNAs (miR-181a-5p, miR-143-3p, miR-132-3p and miR-23a-3p) were measured by RT-qPCR. Serum, SAT and OAT expression levels of these miRNAs showed significant differences between subjects with and without CRC, especially in the group of overweight/obese subjects. In CRC serum levels of miR-181a-5p, miR-143-3p and miR-23a-3p correlated with their levels in both SAT and OAT. Moreover, in the case of miR-181a-5p, these correlations were significantly influenced by the body mass index (BMI). From these data, we can conclude that both adiposity and CRC induce changes in the expression of the miRNAs investigated, demonstrating the potential utility of this panel of miRNAs in the diagnosis and prognosis of CRC patients.

Abstract Background. There is an inherent limit in the accuracy of our measurements, set by nature itself and predicted by Heisenberg's uncertainty principle, which defines the properties of nature in the microcosmos. There is a fundamental limit to the accuracy with which complementary phys-ical quantities of a particle can be predicted from their initial conditions. As classical physics is essentially considered at borderline of quantum mechanics, so the power of uncertainty princi-ple is limited in describing everyday life perceived or managed phenomena. Method. In this study, we apply Heisenberg's uncertainty principle to children under diagnostic uncertainty re-garding appendicitis. We analyze this phenomenon in clinical practice. Results. Medical practice is full of uncertainty. False negative decisions correlate with delays in treatment and adverse outcomes in children with atypical appendicitis. On the other hand, false-positive surgery deci-sions result in negative appendectomies. With improvement of technology, the incidence of complicated appendicitis or negative appendectomies due to diagnostic uncertainty has de-creased but cannot be ignored or eliminated. Conclusion. According to the principle, there is a fundamental limit to the accuracy with which the complementary variables of negative appen-dectomy and complicated appendicitis can be observed or measured simultaneously. What does all this mean for the physician?

The co-occurrence of depression and obesity has become a significant public health concern worldwide. Recent studies have shown that metabolic dysfunction, which is commonly observed in obese individuals and characterized by inflammation, insulin resistance, leptin resistance, and hypertension, is a critical risk factor for depression. This dysfunction may induce structural and functional changes in the brain, ultimately contributing to depression's development. Given that obesity and depression mutually increase each other's risk of development by 50-60%, there is a need for effective interventions that address both conditions. The comorbidity of depression with obesity and metabolic dysregulation is thought to be related to chronic low-grade inflammation, characterized by increased circulating levels of pro-inflammatory cytokines, and C-reactive protein (CRP). As pharmacotherapy fails in at least 30-40% of cases to adequately treat major depressive disorder, a nutritional approach is emerging as a promising alternative. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are a promising dietary intervention that can reduce inflammatory biomarkers, particularly in patients with high levels of inflammation, including pregnant women with gestational diabetes, patients with type 2 diabetes mellitus, and overweight individuals with major depressive disorder. Further effort directed to implement these strategies in clinical practice could contribute to improved outcomes in patients with depression and comorbid obesity and/or metabolic dysregulation.

Background: In this paper, it was aimed to evaluate the biomarker potential as well as the effect of the prognostic nutritional index (PNI), which is calculated using the albumin level reflecting nutritional status and lymphocyte count reflecting immune status, in determining the prognosis of metastatic castration-sensitive prostate cancer (mCSPC). Methods: This retrospective observational study included the complete data of 108 patients with mCPSC who were treated for at least three months between January 1, 2010, and June 1, 2021. The relationship between cancer specific survival (CSS), overall survival (OS), progression free survival (PFS) and PNI was evaluated. Kaplan-Meier method for OS, PFS, and CSS, as well as univariate and multivariate Cox regression models were used in statistical analyses. Results: The median age of 108 patients included in the study was 68.54 (61.05-74.19) years. While 71.3% (n = 77) of the patient population were high-volume according to CHAARTED, 52.8% (n = 57) were high-risk based on LATITUDE. 49.75 was determined as the best cut-off point for the PNI. OS (months) was found to be significantly lower in patients with low PNI (median: 34.93, 95% CI: 21.52–48.34) compared to patients with high PNI (median: 65.60, 95% CI: 39.36–91.83) (p=0.016). Patients with high PNI (median: 48.20, 95% CI: 34.66–61.73) had significantly better CSS (months) than patients with low PNI (median: 27.86, 95% CI: 24.16–31.57) (p=0.001). Conclusions: PNI calculated at the time of diagnosis strongly predicts OS and CSS but not PFS in patients with mCSPC.

Aim: Evaluation of role of supplementation of omega-3 polyunsaturated fatty acids on endothelial function in patients with metabolic syndrome. Methods: Total of 80 patients with metabolic syndrome were enrolled to two groups. We evaluated endothelial function in subjects before and after three-month treatment with omega-3 polyunsaturated fatty acids in dose 2.4g daily (800mg 3 times a day) vs placebo. Using the Endo-PAT2000 device (Itamar Medical Ltd. Caesarea, Israel), reactive hyperemia index – a parameter of endothelial function and augmentation index– a parameter of arterial stiffness were measured. Plasmatic level of glutation peroxidase, homocysteine, apolipoprotein B and lipoprotein (a) were also evaluated. Results: The average values of reactive hyperemia index before the treatment with n-3PUFA was 1.62 ± 0.42 , whereas 1.96 ± 0.62 at the end of the study (p<0.005). Augmentation index changed from 14.66 ± 19.55 to 9.21 ± 15.64 after the treatment (p=0.003). We also observed statistically significant decrease of apolipopotein B (0.94 ± 0.36 vs 1.13 ± 0.35, p = 0.001) and homocysteine (19.31 ± 5.29 vs. 13.78 ± 3.05, p = 0.001) and increase of the glutathion perxidase plasma levels (41.65 ± 8.90 vs. 45.20 ± 8.01), p=0.001. Conclusion: We have observed significant improvement of the endothelial function in subjects with metabolic syndrome treated with omega-3 polyunsaturated fatty acids in dose 2.4g daily.

Depression and anxiety in cardiovascular disease worsen the prognosis of patients. Treatments for these disorders often provide limited improvement. The present study aimed to test, for the first time, the impact of educational technology on anxiety and depressive symptoms in patients participating in a cardiac rehabilitation program. A 12-month randomized controlled trial was conducted, in which 207 patients were randomly assigned to either the experimental (n=76) or control (n=69) groups. The intervention involved a structured patient education program provided by medical students who had undergone specially designed training in cardiac rehabilitation. The primary outcomes were death, hospitalization, heart failure, and recurrent myocardial infarction. The study also assessed anxiety and depression. A year later, the experimental group showed a statistically significant decrease in anxiety and depression on the HADS scale, with reductions of 2.0 and 1.9 points respectively (p&lt;0.05). The control group showed reductions of 1.5 and 1.2 points (p&lt;0.05). The difference in depression (HRDS) between the groups at 12 months was -1.29 in favor of the main group (95% CI, -0.7 to -1.88), and the standardized effect size (SMD) was 0.36 (95% CI, 0.03 to 0.69). No treatment-related adverse events were observed. The results suggest that educational interventions can have a positive impact on mental health. The study's strengths include a structured intervention, randomization, and long-term follow-up. Limitations include the lack of blinding of study participants and a relatively small sample size.

Systematic reviews and meta-analyses have become an important way to summarize data. The hierarchy of evidence-based medicine confers a high platform to meta-analyses. Hence, it is imperative that the analytical and reporting strategy associated with a meta-analysis be standardized. The modern tradition of reporting and publishing a meta-analysis is riddled with several methodological flaws. The most common of these flaws involve the choice of the model used to conduct the meta-analysis and the way that the heterogeneity of studies is assessed. The use of the I² statistic as a means of detecting within-study heterogeneity is a common methodological flaw encountered in reporting summary statistics.One of the ways to rectify the above flaws is to arm reviewers with an objective way to scrutinize the manuscript. This narrative review enlists six checklists for reviewers to improve the reporting of meta-analyses. The first two checklists address reporting of the risk of bias and assessment of publication bias with the help of a funnel plot. Checklists 3, 4, and 5 address the choice of model selected for the meta-analysis, the method to assess the confidence interval, and the measures of heterogeneity. The final checklist addresses the question asked in the meta-analysis, binary versus an effect size estimate. Although there are many more aspects which can help improve the assessment of a manuscript, these basic checklists can be employed by reviewers without the need for an external statistical analysis to enhance and improve meta-analyses.

Multiple sclerosis (MS) is a heterogeneous disease of the central nervous system that is governed by neural tissue loss and dystrophy during its progressive phase, with complex reactive pathological cellular changes. The immune-mediated mechanisms that promulgate the demyelinating lesions during the relapses of acute episodes are not characteristic of chronic lesions during progressive MS. This has limited our capacity to target the disease effectively as it evolves within the central nervous system white and gray matter, thereby leaving neurologists without effective options to manage individuals as they transition to a secondary progressive phase. The current review highlights the molecular and cellular sequelae that have been identified to cooperate and/or contribute to neurodegeneration that identifies individuals with progressive forms of MS. We emphasize the need for appropriate monitoring via known and novel molecular and imaging biomarkers that can accurately detect and predict progression for the purposes of newly designed clinical trials that may demonstrate efficacy of neuroprotection and potentially neurorepair. To achieve neurorepair, we focus on the modifications required in the reactive cellular and extracellular milieu, in order to enable endogenous cell growth as well as transplanted cells that can integrate and/or renew the degenerative MS plaque.

Background. The course of the COVID-19 epidemic process depends on population immunity which prevents pathogen spread among the population. Aim: to study the evolution of SARS-CoV-2 humoral immunity in the Belarusian population relative to COVID-19 pandemic dynamics. Materials and methods. The work was carried out according to a methodology for assessing population immunity developed by Rospotrebnadzor (Russia) and the Belarusian Ministry of Health with the participation of the St. Petersburg Pasteur Institute (SPPI), taking into account WHO recommendations. The study was approved by the Bioethics Committee of Belarus and the SPPI Bioethics Committee. Participant selection was carried out by questionnaire using a cloud (internet server) service. To monitor population immunity, a cohort of 4,661 people (participating in all stages of seromonitoring) was formed from the overall volunteer group. Volunteers were randomized by age group (1-17, 18-29, 30-39, 40-49, 50-59, 60-69, 70+ years), region, and professional group. For the detection of antibodies (Abs) to nucleocapsid (Nc) and S glycoprotein receptor-binding domain (RBD), corresponding assay systems were used following manufacturer instructions. The study was conducted in 4 stages according to a single scheme. Results. In the 1st stage (pandemic month 15), collective immunity was due mainly to Nc+RBD+ Ab status alone. By the 2nd stage (carried out after 4 months), their share decreased 1.2-fold, while the share of volunteers who had only RBD Abs increased 1.7-fold. In the 3rd and 4th stages (carried out after 9 and 19 months), the share of persons with RBD+Nc‒ compared to the 2nd stage decreased by 3.5%; the proportion of persons with Nc+RBD‒ Abs increased by 1.5-fold. The most important factor in population immunity was vaccination of the population, the coverage of which reached 70% by the 4th stage. Among vaccines, the Sputnik V and Sputnik Light vector designs were used most often. The whole-virion, inactivated BIBP-CorV vaccine was used less often. Conclusion. The evolution of collective SARS-CoV-2 humoral immunity included a set of changes in circulating Ab levels (Nc, RBD). The hybrid immunity formed helped to reduce the incidence to nearly zero.

To examine the association of clinical, treatment, and dose parameters with late urinary toxicity after low-dose-rate brachytherapy (LDR-BT) for prostate cancer, we retrospectively studied patients with prostate cancer who underwent LDR-BT from January 2007 through December 2016. Urinary toxicity was assessed using the International Prostate Symptom Score (IPSS) and Overactive Bladder (OAB) Symptom Score (OABSS). Severe and moderate lower urinary tract symptoms (LUTS) were defined as IPSS ≥ 20 and ≥ 8, respectively; OAB was defined as a nocturnal frequency of ≥ 2 and a total OABSS of ≥ 3. In total, 203 patients (median age, 66 years) were included, with a mean follow-up of 8.4 years after treatment. The IPSS and OABSS worsened after 3 months of treatment; these scores improved to pretreatment levels after 18–36 months in most patients. Patients with a higher baseline IPSS and OABSS had a lower frequency of moderate and severe LUTS and OAB at 24 and 60 months, respectively. LUTS and OAB at 24 and 60 months were not correlated with the dosimetric factors of LDR-BT. Although the rate of long-term urinary toxicities assessed using IPSS and OABSS was low, the baseline scores were related to long-term function. Refining patient selection may further reduce long-term urinary toxicity.

Ibrutinib, a first-in-class Bruton’s Tyrosine Kinase inhibitor (BTKi), is a commonly deployed therapeutic option for previously untreated, and relapsed/refractory (R/R) patients with chronic lymphocytic leukemia (CLL). The use of ibrutinib is, however, partially limited by significant off-target side effects. Zanubrutinib (zanu) is a second-generation BTKi with enhanced target selectivity and occupancy of the kinase binding site. The SEQUOIA study showed that zanu significantly prolonged progression-free survival (PFS) when compared to bendamustine–rituximab (BR) in treatment-naive CLL patients with an acceptable safety profile. More recently, data from the phase III ALPINE trial which directly compared zanu with ibrutinib has demonstrated that zanu’s advantages are both an improved safety profile and enhanced clinical efficacy. Based on the results of the SEQUOIA and ALPINE pivotal trials the Food and Drug Administration (FDA) and European Medicines Agency (EMA) licensed zanu for the treatment of patients with CLL or small lymphocytic lymphoma (SLL) in January 2023. The updated (v2.2023) National Comprehensive Cancer Network (NCCN) guidelines and newly released German CLL algorithm, suggest that zanu may replace first-generation BTKi as one of the preferred therapeutic options for patients with CLL/SLL due to its increased selectivity for the kinase binding site, improved therapeutic efficacy, and favorable toxicity profile.

A chairside polishing kit is an alternative to a laboratory polishing technique. This study aimed to evaluate the effects of different polishing techniques on the surface roughness of three-dimensional (3D)-printed acrylic denture bases (ADB). One hundred twenty disc-shaped specimens were fabricated from one conventional heat-polymerized (HP) ADB resin and two 3D-printed (Asiga (AS) and NextDent (ND)) ADB resins (n=40 per ADB resin). Each group was furtherly divided based on the polishing protocol (n=10) as follows: convectional polishing protocol (C), Microdont chairside polishing kit (M), Shofu chairside polishing kit (S), and unpolished group (U). The surface roughness (surface roughness average (Ra) and average maximum profile height (Rz)) of the printed specimens were measured using an optical profilometer, and the scanning electron microscope (SEM) was used to capture the surface at ×1000. Two-way ANOVA and post hoc tests were used for data analysis (α = 0.05) at significant levels. In unpolished groups, there was a statically significant difference between HP vs 3D-printed ADBs (p &lt; 0.0001). For Ra values, the lowest values were presented in HP-C, AS-S, and ND-C. While the highest values were shown in all unpolished groups. Within the material, there were statistically significant differences between the three polishing protocols (C, M, and S) vs unpolished (p &lt; 0.0001), while there was no significant between C, M, and S groups (p = 0.05). The Rz values had the same pattern as the Ra values. The two chairside polishing kits were comparable to conventional polishing technique, and it could be recommended for the clinical application.

The aim of this study was to determine the most common maternal and neonatal complications related to cesarean section at Sultan Qaboos University Hospital (SQUH) and to compare the outcomes between emergency and elective cesarean sections. A retrospective cohort study was conducted in the department of Obstetrics and Gynecology at SQUH from 1st January 2016 to 31st December 2016. This comparative study involved 300 women who underwent cesarean section, 150 in elective cesarean section group and 150 in emergency cesarean section group. Data was collected from the delivery ward maternity registry and Electronic Patient Records. SPSS software version 23 was used to analyze the data.The mean maternal age was 29.66 (± 4.96) and 33.22 (± 4.63) years in the elective and emergency cesarean section groups respectively (p=001). The main risk factor for both the groups was maternal diabetes and the most common indication for both was previous cesarean section. Hypotension related anesthetic complication was noted more in elective cesarean section (15.3%) than in emergency cesarean section group (4.0%) with p value=0.002. The most common major intraoperative complication in both groups was postpartum hemorrhage, 66.9% women in emergency group and 63.0% women in elective group. Post-partum fever was seen in 12.0% of women in emergency group as compared to 4% in elective group (p=0.019). Anemia was observed in 79.2% and 65.3% in emergency and elective groups respectively (p=0.011). Respiratory distress syndrome and transient tachypnea of the newborn were the main neonatal complications in both groups. There was no significant difference between emergency and elective cesarean section related maternal and neonatal complications except for transient intraoperative hypotension, maternal postoperative febrile morbidity and anemia. Future prospective studies including larger sample size and multiple centers is recommended.

Several noninvasive vascular biomarkers have been suggested for improving the risk stratification for atherothrombotic events. To identify biomarkers suitable for detecting intermediate-risk individuals who might benefit from lipid-lowering treatment (L-LT) in primary prevention, the present study tested the association of plasma LDL-cholesterol with coronary artery calcification (CAC) Agatston score, high carotid and femoral intima-media thickness (IMT), low carotid distensibility and high carotid-femoral pulse-wave velocity in 260 asymptomatic individuals at intermediate cardiovascular risk and free of diabetes and L-LT. High or low vascular biomarkers were considered when their value was above the 95th or below the 5th percentile, respectively, of the distribution in the healthy or in the study population. LDL-cholesterol was independently associated with the CAC score =0 (OR 0.67; 95%CI 0.48-0.92, P=0.01), CAC score >100 (1.59; 1.08-2.39, P=0.01) and with high femoral IMT (1.89; 1.19-3.06, P<0.01), but not with other biomarkers. Our data confirm that in the presence of CAC score =0 in individuals at intermediate risk, L-LT can be avoided, while it should be used in those with CAC score >100. Femoral artery IMT could represent a useful biomarker for decision regarding L-LT, however the reference values according to sex and age should be established in a large healthy population

Eurycomanone and eurycomalactone are known quassinoids present in the roots and stems of Eurycoma longifolia. These compounds had been reported to have cytotoxic effects, however, their mechanism of action in a few cancer cell lines have yet to be elucidated. This study was aimed to investigate the anti-cancer effects and mechanisms of action of eurycomanone and eurycomalactone in cervical (HeLa), colorectal (HT29) and ovarian (A2780) cancer cell lines via Sulforhodamine B assay. Their mechanism of cell death was evaluated based on Hoechst 33342 assay and in silico molecular docking toward DHFR and TNF-α as putative protein targets. Eurycomanone and eurycomalactone exhibited in vitro anti-cancer effects manifesting IC50 values of 4.58 ± 0.090 µM and 1.60 ± 0.12 µM (HeLa), 1.22 ± 0.11 µM and 2.21 ± 0.049 µM (HT-29), and 1.37 ± 0.13 µM and 2.46 ± 0.081 µM (A2780) respectively. They induced apoptotic cancer cell death in dose- and time-dependent manners. Both eurycomanone and eurycomalactone were also predicted to have good inhibitory potential as demonstrated by the docking into TNF-α with binding affinity of -8.83 and -7.51 kcal/mol, respectively, as well as into DHFR with binding affinity results of -8.05 and -8.87 kcal/mol, respectively. These results support the evidence of eurycomanone and eurycomalactone as anti-cancer agents via apoptotic cell death mechanism that could be associated with TNF-α and DHFR inhibition as among possible protein targets.

Targeted radionuclide therapy is become increasingly prominent as a nuclear medicine subspe-cialty. For many decades, treatment with radionuclides has been mainly restricted to the use of iodine-131 in thyroid disorders. Currently, radiopharmaceuticals, consisting of a radionuclide coupled to a vector that binds to a desired biological target with high specificity, are being de-veloped. The objective is to be as selective as possible at the tumor level, while limiting the dose received at the healthy tissue level. In recent years, a better understanding of molecular mecha-nisms of cancer, as well as the appearance of innovative targeting agents (antibodies, peptides, small molecules) and the availability of new radioisotopes, have enabled considerable advances in the field of vectorized internal radiotherapy with a better therapeutic efficacy, radiation safety and personalized treatments. For instance, targeting the tumor microenvironment, instead of the cancer cells, now appears as particularly attractive. Several radiopharmaceuticals for therapeutic targeting have shown clinical value in severals types of tumors and have been or will soon be approved and authorized for clinical use.

We present a case of neglected atypical high grade prostatic stromal sarcoma (PSS) at the transitional zone , invading the peripheral zone, prostatic capsule & peri prostatic fat reaching to pelvic side wall, it showed T2WI hyperintense signal (compared to typical cases of PSS showing T2WI hypointense signal) corresponding to developing on top of pre-existing nodular hyperplasia. Careful reviewing of prostatic central / transitional zone lesions is mandatory especially at T2WI, diffusion & contrast images to exclude malignancy which can be easily missed due to multiple signal patterns described. Most common tumors at transitional zone is stromal sarcoma which could be typical showing T2 hypointense signal or atypical showing T2 hyperintense signal intensity.

Introduction: When analyzing the current situation in Spain, derived from our current lifestyles far from following a Mediterranean lifestyle, there is an alarming prevalence of diabesity, which increases the global risk of suffering from cardiovascular disease (CVD) and decreases the quality of life related to health (QLRH). In order to guarantee, beyond glycemic control of patients with type 2 diabetes (DM2), adequate control of cardiovascular risk factors (CVRF) in DM2, it will be necessary to carry out a community intervention focused on the application of education programs focused on promoting the acquisition of healthy eating habits through the Mediterranean diet (DMED). This dietary pattern, together with physical exercise, has been shown to contribute to improving the QLRH of patients. Objective: To analyze the quality of life related to health, present in patients with poorly controlled type 2 diabetes, to determine the possible relationship between this and the degree of adherence to the Mediterranean diet and to examine whether there are differences between the sexes. Material and methods: Observational descriptive study in 93 patients diagnosed with DM2 with poor glycemic control (1Ac ≥ 7%), carried out in various health centers in Albacete and Cuenca, in which the baseline relationship between adherence to DMed and the HRQoL. They were administered a data collection sheet that included a survey of the degree of adherence to the DMed (MEDAS-14) and QLRH (SF-12v2) in the Primary Care (PC) medical and nursing consultations. The variables were analyzed: age groups, sex, years of evolution of DM2, body mass index (BMI), as well as basal glycemia (GB) and glycosylated hemoglobin (HbA1c). The “MEDAS-14” (adherence to DMED) was the main variable and the “SF-12v2” (QLRH) was the secondary variable. Material and methods: Observational descriptive study in 93 patients diagnosed with DM2 with poor glycemic control (1Ac ≥ 7%), carried out in various health centers in Albacete and Cuenca, in which the baseline relationship between adherence to DMed and the HRQoL. They were administered a data collection sheet that included a survey of the degree of adherence to the DMed (MEDAS-14) and QLRH (SF-12v2) in the Primary Care (PC) medical and nursing consultations. The variables were analyzed: age groups, sex, years of evolution of DM2, body mass index (BMI), as well as basal glycemia (GB) and glycosylated hemoglobin (HbA1c). The “MEDAS-14” (adherence to DMED) was the main variable and the “SF-12v2” (QLRH) was the secondary variable. Results: Patients with poorly controlled DM2 and with low adherence to the MedDM show a non-significantly greater affectation in the physical sphere: fair general state of health, physical function I (limitation to make moderate efforts such as moving a table, vacuuming or walk more than an hour), physical function II (limitation to climb several flights of stairs), physical role (problems at work or daily activities doing less than loved ones), physical role II (they had to stop performing some tasks at work or activities of daily living) and regular body pain. Presenting less affectation in the mental field: emotional role I, emotional role II, mental health I, vitality and mental health II. Without affectation in the social function since they consider that rarely the emotional or physical problems have hindered their social activities. Conclusions: Diabetic patients with poor glycemic control have low adherence to the MedMD (<9 points) and have poor QLRH. Low adherence to the DMed and obesity are related to a greater affectation in the physical dimension and less affectation in the mental dimension without affectation in the "social function".

Treating relapsed and refractory diffuse large B-cell lymphoma is still challenging for clinicians, but the available CAR-T and bispecific antibodies revolutionized therapy. Autologous stem cell transplantation was the most effective treatment modality previously. The authors report data from a single center over ten years. The retrospective study included 116 patients. There were 53 relapsed, 39 primary refractory cases, 19 had CNS involvement, and 5 received primary consolidation transplants. The median duration of follow-up was 46 months. The median event-free survival was 75 months, and the median overall survival was 105 months for all cases. Five-year overall survival was 59%, and event-free survival was 54%. Pretreatment prognostic factors at diagnosis had no effect on the outcome of transplantation. The authors found no difference between survival in relapsed or refractory cases, and the number of salvage lines or the germinal center / activated B-cell type also did not influence the results. Complete metabolic response before transplant confirmed by 18FDG PET/CT strongly affected survival. The pretransplant creatinine and CRP levels significantly influenced the long-term outcome. The number of stem cells infused did not affect survival, but engraftment within nine days did result in better survival. These data support the finding that the response to salvage therapy did select a better prognostic group who may still benefit from autologous transplantation.

Keywords: head-and-neck cancer; chemoradiation; cisplatin; carboplatin; loco-regional control; metastases-free survival; overall survival; toxicity.

Functional somatic disorders (FSD) characterized by persistent and disabling physical symptoms are common in adolescents. Diagnostic uncertainty and insufficient illness explanations are proposed perpetuating factors that may constitute barriers for treatment engagement. This study evaluates the impact of manualized assessment and psychoeducation on diagnostic certainty and various clinical outcomes in adolescents with multi-system FSD. Ninety-one adolescents (15-19 years) included in a randomized trial testing group-based therapy (AHEAD) received systematic assessment (4 hrs.) and a subsequent psychiatric consultation (1.5 hrs.). Clinical outcomes included self-reported physical health, symptom severity, illness perception, illness related behavior, and psychological flexibility assessed before and approximately two months after assessment, prior to specialized treatment. Data were analyzed using t-tests. Immediately following assessment 71 (80.7%) adolescents out of 88 reported a higher diagnostic certainty and 74 (84.1%) reported that attending assessment gave them positive expectations for future treatment. A clinically relevant improvement of physical health was not observed at two months but considerable reductions were seen on symptom severity, illness worry, negative illness perceptions, limiting illness behavior and psychological inflexibility. The results underpin the importance of systematic assessment and psychoeducation which may be effective in their own right in specialized treatment of adolescents with severe FSD.

Long COVID (LC) encompasses a constellation of long-term symptoms experienced by at least 10% of people after the initial SARS-CoV-2 infection, and so far has affected about 65 million people. The etiology of LC remains unclear; however, many pathophysiological pathways may be involved, including viral persistence; chronic, low grade inflammatory response; immune dysregulation and defective immune response; reactivation of latent viruses; autoimmunity; persistent endothelial dysfunction and coagulopathy; gut dysbiosis; hormonal dysregulation, mitochondrial dysfunction; and autonomic nervous system dysfunction. There are no specific tests for the diagnosis of LC, and clinical features including laboratory findings and biomarkers may not specifically relate to LC. Therefore, it is of paramount importance to develop and validate biomarkers that can be employed for the prediction, diagnosis and prognosis of LC and its therapeutic response. Promising candidate biomarkers that are found in some patients are markers of systemic inflammation including acute phase proteins, cytokines and chemokines; biomarkers reflecting SARS-CoV-2 persistence, reactivation of herpesviruses and immune dysregulation; biomarkers of endotheliopathy, coagulation and fibrinolysis; microbiota alterations; diverse proteins and metabolites; hormonal and metabolic biomarkers; as well as cerebrospinal fluid biomarkers. At present, there are only two reviews summarizing relevant biomarkers; however, they do not cover the entire umbrella of current biomarkers or their link to etiopathogenetic mechanisms, and the diagnostic work-up in a comprehensive manner. Herein, we aim to appraise and synopsize the available evidence on the typical laboratory manifestations and candidate biomarkers of LC, their classification based on main LC symptomatology in the frame of the epidemiological and pathogenetic aspects of the syndrome, and furthermore assess limitations and challenges as well as potential implications in candidate therapeutic interventions.

We aimed to explore symptoms severity and adherence to therapy for patients with myelofibrosis treated with ruxolitinib in Bulgaria. It is a prospective, non-interventional study performed at the Specialized hospital for active treatment of hematological diseases in Sofia during 2022 - 2023. Date of diagnosis, demographic characteristics, clinical indicators, ruxolitinib dose, and other data points were collected. Clinical indicators were assessed at baseline, in the middle and at the end of observation. Severity of symptoms was measured with MPN-SAF TSS and adherence to therapy with the Morisky 4 questionnaire 6 times during the observation. The mean age of diagnosis was 58.5 years, with the average duration of disease of 3 years. Pa-tients’ laboratory results were within physiological ranges, with spleen size experiencing a con-stant decrease. The average value for the severity of the symptoms per MPN-SAF TSS results decreased significantly, indicating better disease control. The average adherence to therapy did not change and remained high at around 9 points, except for one patient. In conclusion the treatment of myelofibrosis patients with ruxolitinib decreased symptoms se-verity and spleen size. Patients were adherent to the therapy over the observed period but as treatment duration increases the risk of adherence decreasing.

The unsolved problem in three-dimensional surgical planning for patients with facial deformity, dysgnathia, or asymmetry is the lack of a normative database of “norm skulls” that can be used as treatment objectives. A study was conducted on 90 Eurasian persons (46 male and 44 female adults) with normal and balanced facial appearance, skeletal Class I pattern, and proper interincisal relationship with normal occlusion. Cone-beam computed tomography was performed. 18 landmarks were digitized and 3D cephalometric measurements of overall facial features, skull, midface and mandible were performed and analyzed by means of proportions calculated from the landmarks. Male and female skulls were analyzed as well as subdivisions revealed by cluster analysis. The data showed that four subtypes of skulls were distinguishable with statistical significance (p< 0,05). A male and a female type subdivided in a brachiocephalic and dolichocephalic phenotype could be identified. For each type then a mean shape was calculated by a Procrustes transformation, which in turn was used to create four template skulls from a male and a female skull by means of a thin plate spline transformation. The normative data of the subtypes can individually serve as a guide for orthodontic surgery, especially helpful in 3D plan-ning and execution of craniofacial operations.

Background: This study aimed to evaluate survival rate, marginal bone levels, and full arch prosthetic success on short implants when placed in areas of severely resorbed and edentulous mandibles. Methods: This is a systematic review of all randomized controlled trials of at least 10 patients with a control group in which bone augmentations were performed that were published between January 2010 and February 2023. Only 3 relevant studies met the inclusion criteria. Results: It obtained demonstrate that short-term dental implant survival rates ranged from 94.2% to 97.4% with a 5-year follow-up and the prosthetic success rate varied by 62% during the same follow-up. The mean marginal bone level values ​​of the affected short implants ranged from 0.2 mm to 0.6 mm. Conclusions: The data obtained demonstrated that short dental implants positioned with criterion and precision as a full-arch fixed support are a valid therapeutic choice for the medium-long term rehabilitation of severe edentulous mandibular atrophy.

Aim of the study: To draw inferences from a retrospective evaluation of PSMA PET CT scans performed for the evaluation of biochemical recurrence. Material and Methods: Retrospective analysis of 295 PSMA PET CT scans spanning 3 years between 2020 and 2022 was undertaken. Results: Of 295 PET CT scans, 179 were positive, 66 negative and 50 had indeterminate findings. In positive group, 67 had radical prostatectomy and PSMA avid lesions were seen most commonly in pelvic lymph nodes. Remaining 112 positive scans, in non-radical prostatectomy group; 25 had recurrence only in prostate, 17 had recurrence involving prostate bed; 28 had no recurrence in prostate gland, while 42 had recurrence in prostate as well as extra prostatic sites. Overall, in non-prostatectomy group, 75 % population was harbouring a PSMA avid lesion in prostate gland while in remaining 25% population recurrence did not involve prostate gland. Majority of indeterminate findings were seen in small pelvic or retroperitoneal lymph nodes or skeletal regions (ribs/others) and in 9 patients indeterminate focus was seen in the prostate bed only. Follow up PSMA PET CT was helpful in prior indeterminate findings and unexplained PSA rise. Conclusion: A higher recurrence in prostate bed while evaluating biochemical recurrence prompts us to think; whether prostatectomy should be offered more proactively? Follow up PSMA PET CT is helpful for indeterminate findings; a PSA rise of 0.7 ng/ml in 6 months can result in positive PSMA PET CT while negative scan can be seen upto 2ng/ml PSA rise in 6 months.

The present study aims at valorizing Moroccan Henna (Lawsonia inermis) by developing healing formulations for cosmetic and therapeutic uses. For such a goal, the plant was collected from three locations in Southeastern Morocco (Alnif, Tafraoute Sidi Ali and Tazarine). Phytochemical anal-yses of aqueous extracts of Henna leaves was performed by determining phenolic compounds contents, flavonoids and tannins in the extracts. Then, specific formulations were prepared using aqueous extracts of L. inermis to assess their in vivo wound healing potential in Swiss Albino mice as animal model. Results disclosed that phenolic compound contents (13.48%), flavonoids (9.25%) and tannins (2.57%) are higher in Henna leaf extracts from Alnif, while Tazarine Henna aqueous extract was found to be richer in saponins (0.32%). Exclusion chromatographic analysis on Se-phadex G50 gel corroborates the obtained results and shows that Lawsone levels (Henna coloring agent) are higher in Henna collected from Alnif. Aqueous Henna leaf extracts, at a dose of 10% in petroleum jelly, have been tested for their ability to heal induced burns in mice. Healing moni-toring, carried out with Henna extracts on mice batches and those of two control batches (Mice batch treated with petroleum jelly alone and batch treated with petroleum jelly containing 1% flamazine), showed a great reduction in burnt surface with an accentuated contraction percentage (CP) and complete re-epithelialization duration (CRD) at 21 days in the three studied Henna-based formulations. These findings suggest the interest of potential development of Henna-based for-mulations, as source of phenolic compounds, for further dermatological, cosmetic and therapeutic applications.

Osteoconductive granulated biopolymers (OGB) are used to restore the lost volume of the jaw bone. OGB is employed as a loose fraction and exhibits physical traits common to bulk mixtures. By removing air bubbles and industrial dust from the OGB fraction through special processing, more accessible spaces are left over for the adsorption of bone growth factors. The recipient site's biological environment alters the OGB fraction's physical characteristics. This is the cause of the OGB fraction's volume changing uncontrollably during the first three weeks following surgery. Predictive indicators for describing the physical processes of osteoconduction include the compaction coefficient and adsorption capacity. Taking into account the prognostic indicators of the dynamics of changes in the physical properties of the OGB fraction in the postoperative period, 3D planning of the bioengineered structure should be done. The OGB fraction's adsorption and drainage properties are optimized by raising the purity of OGB production and preparing the biopolymer for clinical studies.

Understanding the complex interactions between metabolism and the immune system (“meta-flammation”) is crucial for the identification of key immunomodulatory factors as potential therapeutic targets in obesity and in cardiovascular diseases. Cathelicidin antimicrobial peptide (CAMP) is an important factor of innate immunity and is expressed in adipocytes. CAMP therefore might play a role as an adipokine in metaflammation and adipose inflammation. Toll-like receptor (TLR) 9 is another component of the innate immune system that is expressed and functionally active in adipocytes. The aim of the present study was to investigate the impact of TLR9 signaling on CAMP expression in adipocytes and in adipose tissue. CAMP gene expression in murine 3T3-L1 and human SGBS adipocytes and in murine and human adipose tissues was quantified by real-time PCR. TLR9 knockdown was applied in murine 3T3-L1 adipocytes via siRNA transfection. Adipocyte inflammation was induced in vitro by TNFα stimulation. Serum CAMP concentrations in TLR9 knockout (KO) and in wildtype mice were quantified by ELISA. CAMP gene expression was considerably increased in 3T3-L1 adipocytes during differentiation. TNFα significantly induced CAMP gene expression in mature adipocytes, which was antagonized by inhibitors of NF-κB and PI3K signaling. Cell-free nucleic acids (cfDNA) as endogenous TLR9 ligand significantly impaired CAMP gene expression, whereas synthetic agonistic and antagonistic TLR9 ligands had no effect. Cellular TLR9 knockdown reduced adipocyte CAMP gene expression in vitro and male TLR9 knockout mice exhibited lower systemic CAMP concentrations than wildtype mice. CAMP and TLR9 gene expression were correlated positively in murine and human subcutaneous but not in intraabdominal/visceral adipose tissues. These findings suggest a regulatory role of TRL9 in adipocytic CAMP expression as a novel putative molecular mechanism in adipose tissue innate immunity.

Different types of disasters, whether natural or human character, lead to the significant loss of human lives. In the latter case, the quick action of identification of corpses and human remains is mandatory. There are a variety of protocols to identify victims, however, genetics is one of the tools that allow an exact identification of the victim. However, several factors may interfere with this identification, from the biological samples’ degradation not allowing the analysis of nuclear information, to failure to dispose of biological samples from family members. Access to certain family members could be a determinant of the proper choice of genetic markers that allow the identification of the victim, or his/her inclusion in a given genetic maternal or paternal lineage. With the new advances in the genetic field, it is expected to allow soon the identification of victims from disasters only with his/her biological postmortem samples, being possible to draw a robot portrait and its most likely physical characteristics. In all cases, genetics is the only modern tool with universal character and can be used in essentially all biological samples, giving and identification of more or less accurate statistical character, depending on whether nuclear or lineage markers are used.

Gamma-aminobutyric acid (GABA), a non-protein-producing amino acid, is extensively found in microorganisms, plants and vertebrates, and is abundantly expressed in the spinal cord and brain. To date, GABA is considered to be the major inhibitory neurotransmitter in the central nervous system. Its physiological effects are related to the regulation of synaptic transmission, the promotion of neuronal development and relaxation, and the prevention of insomnia and depres-sion. Mediated through its specific receptors, it plays a pivotal role in the control of neuronal ex-citability, which can serve as anovel target for developing analgesics for pain management. This review provides an update on the accumulating evidence of specific GABA receptors and their subtypes in the involvement of pain analgesia.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with high heterogeneity and has a prevalence of 0.7% to 3.2% in children. Gut microbiota are a collection of microorganisms that inhabit in human guts, which can produce various metabolites that affect the homeostasis and functions of nervous and endocrine systems. There are many studies on the relationship between various gut microbiota and ASD, but the alteration pattern of microbial profiles in ASD children is not conclusive. In order to more robustly describe the deregulations of gut microbiota compositions in ASD, a meta-analysis was performed. The related investigations from PubMed, Embase and Web of Science were collected and manually reviewed. By procedure, 26 eligible studies until 2023, with a total of 1021 ASD and 951 typically developed children and adolescents, were included for the meta-analysis. RevMan5.4 was used to assess the overall effect of 8 microbes at the phylum level and 19 microbes at the genus level. Results demonstrated relatively up-regulated abundance of Bacteroidetes, Verrucomicrobia, Bacteroides, Clostridium, Dorea and Sutterella, and down-regulated abundance of Proteobacteria, Bifidobacterium, Coprococcus, and Akkermansia in ASD children, indicating partly agreement in the ASD-associated microbes, albeit the heterogeneity of ASD.

Sepsis is associated with dysregulated cortisol secretion, leading to abnormal levels of cortisol in the blood. In the early stages of sepsis, cortisol levels are typically elevated due to increased secretion from the adrenal glands. However, as the disease progresses, cortisol levels may decline due to impaired adrenal function, leading to relative adrenal insufficiency. The latter is thought to be caused by a combination of factors, including impaired adrenal function, decreased production of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) by the hypothalamus and pituitary gland, and increased breakdown of cortisol by enzymes such as 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). The dysregulation of cortisol secretion in sepsis is thought to contribute to the pathophysiology of the disease by impairing the body's ability to mount an appropriate inflammatory response. The actions of cortisol are mediated through two types of corticosteroid receptors: the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GCR). In sepsis, the expression and activity of GCR is altered, contributing to the pathophysiology of the disease. GCR expression and activity are typically downregulated in sepsis, impairing the body's ability to mount an appropriate inflammatory response. Given the dysregulation of cortisol secretion and corticosteroid receptors in sepsis, there has been considerable interest in the use of steroids as a treatment for sepsis. The rationale for steroid-based treatment is to supplement the body's endogenous cortisol production, restore normal cortisol levels, and improve the body's ability to mount an appropriate inflammatory response. However, the use of steroids in sepsis remains controversial, and clinical trials have yielded mixed results. Some studies have shown that steroid-based treatment can improve shock reversal, reduce the need for vasopressors, and improve overall survival in patients with septic shock, whereas other studies have found no benefit or even harm from steroid-based treatment in sepsis.

Canine hemangiosarcoma (HSA) is a relatively common neoplasia, occurring mainly in the skin, spleen, liver and right atrium. Despite the numerous studies investigating the treatment of canine HSA, no significant improvement in survival has been achieved in the last 20 years. Advancements in genetic and molecular profiling presented molecular similarities of canine HSA with human angiosarcoma. It could therefore serve as a valuable model for investigating new and more effective treatments in people and dogs. The most common genetic abnormalities in canine HSA have been found in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and neuroblastoma RAS viral oncogene homolog (NRAS) pathways. Mutations are also found in tumor protein p53 (TP53), phosphatase and tensin homolog (PTEN) and cyclin dependent kinase inhibitor 2A (CDKN2A). Known abnormal protein expression could be exploited to trial new target treatments that could be beneficial for both canine and human patients. Despite the high expression of vascular endothelial growth factor (VEGF) and its receptor (VEGFR), no correlation with overall survival time has ever been found. In this review, we explore the most recent developments in molecular profiling in canine HSA and discuss their possible applications in the prognosis and treatment of this fatal disease.

Prolonged fatigue is associated with non-pathological causes, and lacks an established therapeutic approach. The current study is aimed at assessing the efficacy of a new food supplement (Improve® Response) based on a chemically characterized pomegranate extract and hydro-soluble vitamins (B complex and C). UHPLC-HRMS analysis of pomegranate extract showed the presence of 59 compounds, with gallotannins and ellagitannins being the most abundant phytochemicals. For the clinical study, 58 subjects were randomized into two groups, 1 and 2 (n = 29, each), which received either the food supplement or placebo. The effects of the food supplement against fatigue were assessed via validated questionnaires, recorded at time intervals t0 (at baseline), t1 (after 28 days), t2 (56 days), and t3 (after follow-up) in combination with the analysis of biochemical markers at t0 and t2. Fatigue Severity Scale (FSS) questionnaire scores were significantly decreased at the t2 and t3 time intervals in subjects treated with the food supplements, while the effect of the food supplement on a 12-Item Short Form Survey (SF-12) was not considerable. Moreover, the food supplement did not significantly affect biochemical parameters associated with fatigue and stressed conditions. This study shows that the food supplement tested reduces prolonged fatigue following two months supplementation in healthy subjects with mild prolonged fatigue.

Insulin resistance, as a common pathological process of many metabolic diseases, including diabetes and obesity, has attracted much attention due to its relevant influencing factors. To date, studies have mainly focused on the mechanisms between mitochondrial stress and insulin resistance, and they are now pursued as a very attractive therapeutic target due to their extensive involvement in many human clinical settings. In view of the complex pathogenesis of diabetes, natural drugs have become new players in diabetes prevention and treatment because of their wide targets and few side effects. In particular, plant phenolics have been paid more attention because of their close relationship with oxidative stress. In this review, we briefly review the mechanisms by which mitochondrial stress leads to insulin resistance. Moreover, we list some cytokines and genes that have recently been found to play roles in mitochondrial stress and insulin resistance. Furthermore, we describe several natural drugs that are currently widely used and give a brief overview of their therapeutic mechanisms. Finally, we suggest possible ideas for future research related to the unique role that natural drugs play in the treatment of insulin resistance through the above targets.

Abstract: Cancer patients are explored by CT-scans more than others. The study reports the local prevalence of these embolisms, the oncological profile of the cases as well as the therapeutic management. Patients and methods: The work was based on the Analysis of the CT-examinations performed on patients of the Radiology department, for reasons other than the search for pulmonary embolism. The examinations are interpreted by 2 radiologist doctors. Results: In 389 patients, 12 cases of asymptomatic pulmonary embolism were detected, representing a prevalence of the order of 3%. The mean age of onset is 67 years. 11 patients had metastatic cancer at the time of diagnosis of pulmonary embolism. 4 PE patients are proximal, while 8 others had segmental and / or sub-segmental PE. 10 patients are treated for carcinomas, the rest for melanoma and splenic lymphoma. After analysis of clinical records, 3 of the 4 proximal pulmonary embolisms were manifested by a discrete clinical symptom attributed to diagnoses other than pulmonary embolism. 10 patients are undergoing chemotherapy alone or combined with radiotherapy, surgery or hormone therapy. At the time of the diagnosis of pulmonary embolism, 3 patients were hospitalized, while 9 were followed up on an outpatient basis. Conclusion: Asymptomatic pulmonary embolism in cancer patients is becoming more frequent. Asymptomatic pulmonary embolisms are mainly peripheral, segmental or sub-segmental. As for symptomatic VTE, asymptomatic pulmonary embolism is diagnosed in patients with metastatic cancer, especially carcinoma type, and treated with chemotherapy.

It is believed that fetal hemoglobin (HbF) expression in adults is largely genetically regulated. The increased expression of HbF in pregnancy has been reported in a small number of articles. Different mechanisms have been proposed, but the description of HbF expression during pregnancy remains unclear. The objectives of this study were to document HbF expression during peri and postpartum periods, confirm its maternal origin, and assess clinical and biochemical parameters potentially associated with HbF modulation. In this observational prospective study, 345 pregnant women were followed. At baseline, 169 had HbF expression (≥1% of total hemoglobin) and 176 did not have HbF expression. Women were followed at the obstetric clinic during their pregnancy. Clinical and biochemical parameters were measured at each visit. Analyses were made to determine which parameters had a significant correlation to HbF expression. Results show that HbF expression of ≥ 1% during peri and postpartum periods in pregnant women without influencing comorbidities is at its highest peak during the first trimester. In all women, it was proven that HbF was of maternal origin. A significant positive correlation between HbF expression, β-HCG, and HbA1C was present. A significant negative association between HbF expression and total hemoglobin was found. HbF expression induction during pregnancy is probably associated with increase in β-HCG and HbA1C, and decrease of total hemoglobin, which could temporarily reactivate the fetal erythropoietic system.

Pimobendan is an inotropic and vasodilator drug with no sympathomimetic effects. This study aimed to evaluate the haemodynamic effects of pimobendan during anaesthesia in healthy senior dogs. A prospective, randomised, triple-blinded, placebo-controlled clinical study was conducted. Thirty-three dogs (median [range]: 9 [7, 12] years) were anaesthetised for surgical procedures. Dogs were randomly allocated into two groups: eighteen dogs received pimobendan 0.15 mg kg-1 IV (PIMOBENDAN) and 15, saline solutions 0.2 ml kg-1 IV (PLACEBO). Data were recorded before, 1 minute, 10 minutes and 20 minutes after injection. Velocity-time integral (VTI), peak-velocity (PV) and mean-acceleration (MA) were measured using an oesophageal Doppler monitor (ODM). Heart rate and mean arterial pressure were also registered. Data were analysed using a two-way ANOVA for trimmed means. Statistical differences were considered if p &lt; 0.05. Twenty minutes after injection, VTI (13.0 cm [10.4, 22.3]), PV (95.0 [83.0, 160] m sec-1), and MA (12.6 [9.40, 17.0] m sec-2) were higher in PIMOBENDAN when compared to PLACEBO (VTI: 10.5 [6.50, 17.4] cm, PV: 80.0 [62.0, 103] m sec-1 and MA: 10.2 [7.00, 16.0] m sec-2). No differences were observed in the rest of the variables. Using pimobendan during anaesthesia increases VTI, PV and MA measured by an ODM.

UVA radiation inducing oxidative stress is harmful for the skin cells. The most sensitive are dermal fibroblasts. Exposure of the cells to prolonged UVA radiation induces apoptosis. Although, skin cells have a number of defense mechanisms that protect them against UV-induced oxidative stress, they are insufficient during long-lasting UV exposure. Therefore, there is a need for effective skin protection compounds with cytoprotective and antioxidant properties. One of their sources is Amaranthus cruentus L. seed oil, rich in unsaturated fatty acids, squalene, vitamin E derivatives, and phytosterols. The aim of this study was to evaluate whether Amaranthus cruentus seed oil evokes protective effect on the apoptosis stimulated by UVA radiation in human skin fibroblasts. UVA radiation at an applied dose of 10 J/cm2 caused a significant reduction in the survival of human skin fibroblasts and directed them into apoptosis pathway. Increased expression of p53, caspase 3, and caspase 9 and PARP proteins in UVA-treated fibroblasts suggests the intrinsic mechanism of apoptosis. The application of Amaranthus cruentus seed oil at 0.1% and 0.15% concentrations to UVA-treated cells decreased the expression of these proteins, which was accompanied by increased cell survival. Similarly, the UVA-dependent decrease in expression of p-Akt and mTOR proteins was restored, under the effect of studied oil. The molecular mechanism of this phenomenon is related to the stimulation of antioxidant processes through activation of Nrf2. This suggests that Amaranthus cruentus seed oil stimulate the antioxidant system in fibroblast cells and prevent the effects of UVA-induced oxidative stress and may find application in pharmacy and cosmetology as a sun- protective substance.

We have shown that lipid-associated loci discovered by genome-wide association studies (GWAS) have pleiotropic effects on lipid metabolism, carotid intima-media thickness (CIMT), and CAD risk. Here, we investigated the impact of lipid-associated GWAS loci on the efficacy of rosuvastatin therapy in terms of changes in plasma lipid levels and CIMT. The study comprised 116 CAD patients with hypercholesterolemia. CIMT, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) were measured at baseline and after 6 and 12 months of follow-up, respectively. Genotyping of fifteen lipid-associated GWAS loci was performed by the MassArray-4 System. Linear regression analysis adjusted for sex, age, body mass index, and rosuvastatin dose was used to estimate the phenotypic effects of polymorphisms, and P-values were calculated through adaptive permutation tests. Over one-year therapy, a decrease in CIMT was linked to rs1689800, rs4846914, rs12328675, rs55730499, rs9987289, rs11220463, rs16942887, and rs881844 polymorphisms (Pperm&lt;0.05). TC change was associated with rs55730499, rs11220463, and rs6065906; LDL-C change was linked to the rs55730499, rs1689800, and rs16942887 polymorphisms; and TG change was linked to polymorphisms rs838880 and rs1883025 (Pperm&lt;0.05). In conclusion, the polymorphisms rs1689800, rs55730499, rs11220463, and rs16942887 were found to be predictive markers for multiple antiatherogenic effects of rosuvastatin in CAD patients.

Background. The treatment for patients with high-grade gliomas includes radiation therapy and temozolomide. However, some patients do not respond to temozolomide because they have a methylation reversal mechanism through the enzyme O6-methylguanine-DNA-methyltransferase. This biomarker has been used as a prognostic factor in patients receiving treatment with temozolomide. However, not all patients respond in the same way, which suggests the existence of other genes involved in resistance to temozolomide. Materials and Methods. A group of 31 patients with high-grade gliomas was recruited and were clinically, image pattern, and pathologically characterized. The sequencing of 324 genes related to different types of cancer was performed to detect mutations. Subsequently, a statistical analysis was conducted to determine the mutated genes that were most related to resistance to treatment. Results. The genes related to the second relapse of patients with high-grade glioma after the use of temozolomide according to Stupp protocol and metronomic dose were PIK3C2B, KIT, ERBB3, and MLH1. Conclusions. Considering the results obtained, we suggest that the mutations in the four genes and the methylation of the gene promoter that codes for MGMT protein could be related to the clinical evolution of patients with high-grade gliomas and its response to treatment with temozolomide.

Respiratory tract infections (RTIs) are one of the main causes of hospitalization and mortality causing substantial economic burden to healthcare systems globally. As opposed to the previous belief that respiratory infections are caused by a single pathogen, studies have shown that most RTIs are a result of a combination of bacterial and/or viral pathogens infecting the host. The clinical manifestation of RTIs is very similar (i.e., syndrome), often showing Influenza-like illness (ILI) symptoms. While COVID-19 has dominated ILI over the past few years, there are many other pathogens that are responsible for ILI. In addition, it is not uncommon to have coinfections with multiple pathogens in patients presenting with ILI and that such coinfections can even exacerbate the disease severity of RTIs. Therefore, an insight into coinfections can help with accurate disease prognosis, patient care management and outcomes. The goal of this study was to identify the different organisms in symptomatic patients presenting with ILI.

The concept of gray-zone lymphoma (GZL) has been progressively refined since its in-troduction in the literature in 1998. For several years, it was applied to a rather broad spectrum of conditions, posing the problem of the differential diagnosis between any type of Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma, with special reference to primary mediasti-nal forms (PMBL). Officially recognized as a provisional entity in the 4th and revised 4th editions of the WHO Classification of Tumour of Haematopoietic and Lymphoid Tissues with the term “B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lym-phoma and classical Hodgkin lymphoma”, it was limited to tumours, which showed either morphologic features reminiscent of classical HL (CHL) but carrying a complete B-cell pheno-type or conversely provided with a PMBL morphology but revealing CHL phenotypic charac-teristics. The definition of GZL has been further revised in the recently published International Lymphoma Classification and 5th Edition of the WHO Classification of Haemato-lymphoid Tu-mours, which have limited it to mediastinal neoplasms based on emerging molecular evidences. The aim of this review is to critically discuss the issue of GZL, also in the light of the suboptimal response to current therapies.

Endometriosis is a complex chronic condition characteristic of chronic pelvic pain, dysmenorrhea, anxiety and fatigue. This can often lead to multimorbidity which is defined by the presence of two or more long term conditions. Delayed diagnosis of endometriosis is a crucial issue that leads to poor quality of life and clinical management. There are a variety of limitations linked to conducting endometriosis research including lack of dedicated funding. Additionally, accessing existing electronic healthcare records can be challenging due to governance and regulatory restrictions. Missing data issues are another concern that has been commonly identified among real-world studies. Considering these challenges, data science technique could provide a solution by way of using synthetic datasets that could be generated using known characteristics of endometriosis to explore the possibility of predicting multimorbidity. This study aimed to develop an exploratory machine learning model that can predict multimorbidity among women with endometriosis using real-world and synthetic data. A sample size of 1012 was used from two endometriosis specialized centres in the UK. In addition, 1000 synthetic data records per centre were generated using the widely used Synthetic Data Vault’s Gaussian Copula model based on patients’ records’ characteristics. Three standard classification models, Logistic Regression (LR), Support Vector Machine (SVM), and Random Forest (RF), were used for classification. The average accuracies for all three models (LR, SVM and RF), given as “model accuracy-centre1: accuracy-centre2” were found to be: LR 64.26%:69.04%, SVM 67.35%:68.61%, and RF 58.67%:73.76% on real-world data, and LR 69.9%:72.29%, SVM 69.39%:70.13, and RF 68.88%:74.62 on synthetic data, respectively. The findings of this report show machine learning models trained on synthetic data performed better than models trained on real-world data. Our findings suggest synthetic data holds great promise for shows value to conduct clinical epidemiology and clinical trials that could devise better precision treatments and possibly reduce the burden of multimorbidity.

Introduction: The choice of Cardiac Preservation Solution (CPS) for myocardial protection at the time of heart procurement remains controversial and uncertainties persist regarding its effect on the early and midterm Heart Transplantation (HTx) outcomes. Thus, we retrospectively analyzed our adult HTx performed with two different CPS, during a period of 12 years, in terms of hospital mortality, mid-term survival, inotropic score, primary graft dysfunction and rejection score. Methods: From January 2009 to December 2020, 154 adult HT were performed in our hospital. Patients were divided in two groups according to the CPS used: St. Thomas (n=75, group P 1) and HTK-Custodiol (n=79, group P 2). The choice of CPS was related to an institutional policy; from 2009 to 2015, St. Thomas solution was exclusively used, and after that, HTK-Custodiol alone. Results: There was no significant difference between the two groups in terms of preoperative and intraoperative features. Postoperatively, the Custodiol group showed significantly lower inotropic score (p&lt;0.0001), mean rejection score (p= 0.036) and 30 days mortality (p=0.0068). The use of HTK-Custodiol was the only variable that improved midterm survival (HTK-Custodiol vs St Thomas, HR= 0.20 (95% CI: 0.069 -0.6) p=0.0039). Conclusion: In our single center experience, using HTK-Custodiol as myocardial protection during heart procurement leads to improved outcomes after HTx, including postoperative inotropic score, rejection score, 30-days mortality and midterm survival.

Background & aims. The fourth dose of anti-SARS-CoV-2 vaccine slightly improved the humoral response among previously seronegative liver transplant (LT) recipients. Mycophenolate (MMF) treatment worsens the vaccination response. This study aimed to evaluate whether temporary MMF interruption might improve immunogenicity of the fourth anti-SARS-CoV-2 BNT16b2 vaccine dose in nonresponsive LT recipients. Methods. LT recipients negative for anti-spike glycoprotein-specific immunoglobulin G receptor-binding domain (s-RBD) antibodies after the third vaccine dose were enrolled. Anti-SARS-CoV-2 spike-specific T cell responses were measured before and two months following the fourth vaccine dose, and anti-SARS-CoV-2-s-RBD antibodies also 6 months thereafter. MMF was suspended two weeks before and after vaccination. Results. Five LT recipients were enrolled. After a mean of 78 days after vaccination, all patients tested positive for anti-SARS-CoV-2-s-RBD antibodies. The mean antibody titer was 8944 UI/ml. The positive antibody response was maintained during a mean of 193 days of follow-up. Three patients developed a positive T cell response. Two patients (one positive for T cell response) developed a self-limited SARS-CoV-2 infection. Conclusions. Suspending MMF prior to the fourth dose of anti-SARS-CoV-2 mRNA vaccine seems feasible and safe. This procedure could restore vaccine-induced immunogenicity in a large portion of previously nonresponsive LT recipients.

Alphaherpesviruses cause genital lesions and reproductive failure in both humans and animals. Their control is mainly based on prevention by hygienic prophylactic measures, due to the ab-sence of vaccines and limitations of antiviral drug therapy. Ozone is an oxidating gas showing a strong microbicidal activity on bacteria, fungi, viruses, and protozoa. The present study assessed the in vitro virucidal and antiviral activity of ozone against Caprine herpesvirus type 1. Virucidal activity of a gaseous mixture containing O3 at 20 and 50 μg /mL was assessed against the virus for different contact times (30 s, 60s, 90s, 120s, 180s and 300s). Antiviral activity of a gaseous mix-ture containing O3 at 20 and 50 μg /mL was evaluated against the virus to for 30s and 60s. Ozone displayed significant virucidal activity when used at all the tested concentrations whilst signifi-cant antiviral activity was observed using ozone at 50 μg/ml. The gaseous mixture, tested in the present study, showed virucidal and antiviral activity against CpHV-1 with a dose- and a time-contact -dependent fashion. Ozone therapy could be evaluated in vivo for the treatment of CpHV-1-induced genital lesions in goats, through topical applications.

Background and Objectives: Ultrasound (US) is a non-invasive tool for the in-vivo detection of peripheral nerve alterations. Materials and Methods: In this study we applied nerve US to assist the discrimination between the spectrum of Amyotrophic Lateral Sclerosis (ALS, n=11), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, n=5) and genetically confirmed Charcot-Marie-Tooth disease (CMT, n=5). All participants and n=15 controls without neurological diseases underwent high-resolution US of the bilateral tibial nerve. Nerve cross-sectional area (CSA) and nerve microvascular blood flow were compared between the groups and related to cerebrospinal fluid (CSF) measures, clinical symptoms and nerve conduction studies. Analyses are part of a larger multimodal study on the comparison between US and 7 Tesla (T) magnetic resonance neurography (MRN). Results: Patients and controls were matched with respect to their demographical data. CMT had the longest disease duration, followed by CIDP and ALS. CSA was related to age, weight and disease duration. CSA was larger in CMT and CIDP compared to ALS and controls. Blood flow was greatest in CIDP, and higher than in CMT, ALS and controls. In ALS, greater CSA was correlated with greater CSF total protein and higher albumin quotient. US measures did not correlate with clinical scores or nerve conduction studies in any of the subgroups. Conclusion: Our results point towards the feasibility of CSA and blood flow to discriminate between ALS, CIDP and CMT, even in small sample sized groups. In ALS, larger CSA could indicate an inflammatory disease subtype characterized by reduced blood-nerve barrier integrity. Our upcoming analysis will focus on the additive value of 7T MRN in combination with US to disentangle the spectrum between more inflammatory or more degenerative disease variants along the disease groups.

Considering tumors from an evolucionary perspective, successive tumor cells undergo turnover in response to stressful conditions which pressures tumor cells to adapt to a new environment. Tumor cells uses parts of themselves to communicate and share biological information, known as extracellular vesicles (EV) secretion to promote their survival and “survive to each and every metabolic cost”. Tumor microenvironment (TME) is a miscellaneous of cells, factors, extracellular matrix proteins and EVs. EVs include smalls (<160nm, exosomes) and larger (100-1,000nm, microvesicles) lipid bilayer enclosed packages of biomolecules that are shed by tumors to TME. Tumor-derived extracellular vesicles transfer adaptative stress signaling to recipient cells, reprograming these cells. Heat Shock Proteins (HSP) are more prominent stress response regulators found in exosomes. HSP-loaded exosomes actively reprogram tumor and TME cells to acquire mechanisms that contribute to tumor progression and therapy resistance. The intercellular communication mediated by HSP-loaded EVs favors the escape of tumor cells from, endoplasmic reticulum (ER) stress, hypoxia, apoptosis and anti-cancer therapies. Extracellular HSPs activate and deactivate immune response, induce cell differentiation, changes vascular homeostasis, and help to augment the pre-metastatic niche formation. Here we will explore the EV mechanism of HSP transmission among TME cells and the relevance of these intercellular communications for resistance to therapies in cancer.

Proteinuria is known to be associated with all-cause and cardiovascular mortality, and nephrotic syndrome is defined by the level of proteinuria and hypoalbuminemia. With advances in medicine, new causative genes for genetic kidney diseases are being discovered increasingly frequently. We reviewed articles on proteinuria/nephrotic syndrome, focal segmental glomerulosclerosis, membranous nephropathy, diabetic kidney disease/nephropathy, hypertension/nephrosclerosis, Alport syndrome, and rare diseases, which have been studied in mouse models. Significant progress has been made in understanding the genetics and pathophysiology of kidney diseases thanks to advances in science, but research in this area is ongoing. In the future, genetic analyses of patients with proteinuric kidney disease/nephrotic syndrome may ultimately lead to personalized treatment options.

Background: Pulmonary emboli (PE) is a life threatening condition that is discovered in many patients only "post mortem". Adequate and timely detection of PE is crucial, because of the high mortality and morbidity and the sudden unexpected hemodynamic collapse that may occur in patients with PE. Objectives: To assess the ability to predict clinical outcome of patients with acute PE, using a non-gated computed tomography pulmonary angiography (CTPA), based on the dimensions of the right ventricle. Methods: A retrospective study that analyzed CTPA images of patients admitted with acute PE during the years 2012-2017 in Baruch Padeh Medical Center. The cohort study included 300 patients with documented acute PE, among them 255 were hospitalized in medical (non-intensive care unit) wards, and 45 were patients were hospitalized in an intensive care unit (ICU). Results: Among the 45 patients admitted to the ICU, 8% died. Larger RV diameters predicted mortality (OR=10.14, 95% CI [1.09-93.86]) as well as lower systolic and diastolic blood pressure measurements (p=0.001 and 0.01). Among the 255 patients that were admitted in the Internal Medicine Ward 7% died. Older age (p=0.028), sepsis and cancer (both p<0.001), high WBCs count (p<0.001), and renal failure (p<0.001) predicted death. Overall, of all 300 patients that were admitted, lower blood pressure (systolic and diastolic) (p<0.001, 0.008), older age (p<0.007), sepsis (p<0.001), cancer (p=0.006), higher WBCs count (p<0.001), and impaired renal function (p<0.001) predicted death among patients admitted with confirmed acute PE. Conclusions: Clinical parameters and hematological parameters could predict the outcome of patients admitted with acute PE. RV diameter, measured by the non-ECG gated CTPA had an additive predictive value for patients who were hemodynamically unstable on admission and were hospitalized in the ICU.

Ultraviolet (UV) radiation is a strong environmental carcinogen responsible for the pathogenesis of most skin cancers, such as malignant melanoma (MM) and non-melanoma (keratinocyte) skin cancers. The carcinogenic role of UV was firmly established based on epidemiological evidence and molecular findings of the characteristic mutation signatures which occur during excision repair of cyclobutane pyrimidine dimers and 6,4-photoproducts. The role of UV in the pathogenesis of mycosis fungoides (MF), the most common primary cutaneous T-cell lymphoma, remains controversial. Here, we performed whole exome sequencing of 61 samples of MF cells microdissected from the cutaneous lesions, and compared their mutational signatures to 340 MM. The vast majority of MM mutations had a typical UV mutational signature (SBS 7, SBS 38, DSB 1) underscoring the key role of ultraviolet as a mutagen. In contrast, the SBS 7 signature in MF comprised &lt;5% of all mutations. SBS 7 was higher in the intraepidermal MF cells (when compared to the dermal cells) and in the cells from tumors as compared to early-stage plaques. In conclusion, our data do not support the pathogenic role of UV in the pathogenesis of MF and suggest that the UV mutations are the result of the cumulative, environmental ultraviolet exposure of cutaneous lesions, rather than an early mutagenic event.

Abstract: Our research analyzed the characteristics of phase IV clinical trials in oncology using data from the ClinicalTrials.gov registry. The included trials were conducted between January 2013 and December 2022 and were examined for key characteristics, including outcome measures, interventions, sample sizes, and study design, different cancer types, and geographic regions. Our analysis included 368 phase IV oncology studies. We found that 50% of these studies aimed to examine both safety and efficacy, while 43.5% only reported efficacy outcome measures, and 6.5% only described safety outcome measures. Only 16.9% of studies were powered to detect adverse events with a frequency of 1 in 100. Targeted therapies accounted for the majority of included studies (53.5%), with breast (32.91%) and hematological cancers (25.82%) being the most frequently investigated malignancies. Most phase IV oncology studies lacked sufficient power to detect rare adverse events due to their small sample sizes and instead focused on effectiveness. To ensure that there is no gap in drug safety data collection and detection of rare adverse events due to limited phase IV clinical trials, there is a significant need for additional education and participations by both health care providers and patients in spontaneous reporting processes.

Pre-exposure prophylaxis (PrEP) is a highly effective HIV prevention strategy that involves the continuous administration of antiretroviral drugs to HIV-negative individuals wit a substantial risk of contracting an HIV infection. The use of PrEP has shown a reduction in the risk of HIV acquisition through sexual intercourse by up to 99%. Despite its effectiveness, PrEP uptake remains low among populations at high risk of HIV infection. This highlights the need for further research in stratetegies to enhance awareness and uptake of PrEP amongst these specific populations

Currently, aortic valve (AV) disease is the most common reason for heart valve surgery. The gold standard of care for people with aortic pathology is thought to be AV replacement. The issue of prosthesis selection has always been important. Although mechanical prosthesis are robust, lifelong anticoagulation medication is necessary due to the significant risk of thromboembolic consequences. Biological prostheses have a flow structure that is similar to the physiological one, and as malfunction gradually sets in, scheduled recurrent surgery can be carried out. The purpose of this study is to evaluate the short- and long-term effects of biological prosthetic aortic valve replacement (AVR) in elderly individuals. The study included 198 patients with AV pathology [85 men (42.9%)/113 women (57.1%)]. The median age was 70 [66–73] years. There were 175 (88.4%) patients with degenerative AV, 5 (2.5%) with infective endocarditis, and 30 patients (15.2%) had bicuspid AV. The median follow-up period was 26.3±1.4 months. Hospital mortality was 4.5%. No wound complications were detected. Thirty-one patients died in the long-term period. The causes of lethality were: cardiovascular disease (13 patients), malignant neoplasm (5 patients), gastrointestinal disease (2 patients), urinary system disease (1 patient), COVID-19 (1 patient), unknown cause (9 patients). Thus, the five-year postoperative survival rate was 63%, respectively. Throughout the observation period, two patients (2.9%) underwent reoperation on AV. 97.1% of patients were free of reoperation after five years. The five-year survival rate was 63% due to the history of severe concomitant pathology and mean age of the patients of 70 years.

Caffeine is a naturally occurring alkaloid found in various plants. It acts as a stimulant, antioxidant, anti-inflammatory and even an aid in pain management, and is found in several over-the-counter medications. This naturally derived bioactive compound is the best-known ingredient in coffee and other beverages, such as tea, soft drinks, and energy drinks, and is the most widely consumed substance worldwide. Therefore, it is extremely important to research the effects of this substance on the human body. With this in mind, caffeine and its derivatives have been extensively studied to evaluate its ability to prevent diseases and exert anti-aging and neuroprotective effects. This review is intended to provide an overview of the effects of caffeine on cancer, cardiovascular, immunological, inflammatory, and neurological diseases, among others. The heavily researched area of caffeine in sports will also be discussed. Finally, recent advances in the development of novel formulations, in the form of dietary supplements of caffeine and nanocarriers, to enhance the bioavailability of caffeine and its beneficial effects will be discussed. On the other hand, caffeine may contribute to elevated blood pressure, anemia, and migraine.

The frequency of selected polymorphisms, one in each gene coding for proteins with antioxidative properties (CAT, SOD2, GPX1, NQO1) was compared between patients suffering from pain-related temporomandibular disorders (TMDp;n=85) and control subjects (CTR;n=85). According to the Oral Behaviours Checklist score participants were divided into high-frequency parafunction (HFP;n=98) and low-frequency parafunction (LFP;n=72) groups. In addition, we have investigated the association of selected polymorphisms with participants' psychological (anxiety, depression) and psychosomatic (hypervigilance, somatosensory amplification) characteristics. Polymorphisms rs1001179, rs4880, rs1050450, rs689452 were genotyped using the genomic DNA extracted from buccal mucosa swabs and real-time TaqMan genotyping assays. No differences in genotype distribution between TMDp patients and control subjects were found. Still, TMDp patients who were homozygous for minor allele A, related to the GPX1 polymorphism rs1050450 reported significantly more waking-state oral behaviours compared to GA+GG genotype carriers (score: 30 vs. 23, p=0.019). Frequency of genotype AA for rs1050450 polymorphism was higher in HFP compared to LFP participants (14.3% vs. 4.2%, p =0.030). Most important predictors of waking-state oral behaviours were depression, anxiety, AA genotype (rs1050450) and female sex. Explored genetic factors were not found to be significant risk factors for either TMDp or sleep-related oral behaviours. The association of waking-state oral behaviours with selected gene polymorphisms additionally supports previous assumptions that the daytime bruxism is more closely linked to various stress manifestations, which might also be reflected through the variability related to cellular antioxidative activity.

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative diseases in elderly. The key histopathological features of these diseases are the presence of abnormal protein aggregates and the progressive and irreversible loss of neurons in specific brain regions. The exact mechanisms underlying the etiopathogenesis of AD or PD remain unknown, but there is extensive evidence indicating that excessive generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) along with a depleted antioxidant system, mitochondrial dysfunction, and intracellular Ca2+ dyshomeostasis play a vital role in the pathophysiology of these neurological disorders. Due to an improvement in life expectancy, the incidence of age-related neurodegenerative diseases has significantly increased. However, there is no effective protective treatment or therapy available but rather only very limited palliative treatment. Therefore, there is an urgent need for the development of preventive strategies and disease-modifying therapies to treat AD/PD. Because dysregulated Ca2+ metabolism drives oxidative damage and neuropathology in these diseases, the identification or development of compounds capable of restoring Ca2+ homeostasis and signaling may provide a neuroprotective avenue for the treatment of neurodegenerative diseases. In addition, a set of strategies to control mitochondrial Ca2+ homeostasis and signaling has been reported, including decreased Ca2+ uptake through voltage-operated Ca2+ channels (VOCCs). In this article, we review the modulatory effects of several heterocyclic compounds on Ca2+ homeostasis and trafficking, and their ability to regulate compromised mitochondrial function and associated free radical production during the onset and progression of AD or PD. This comprehensive review also describes the chemical synthesis of the heterocycles and summarizes the clinical trial outcomes.

The length of stay (LOS) in the hospital emergency department (ED) is a crucial key performance indicator that is used to track and manage the performance of the ED as a whole. Our study had two objectives. Firstly, we aimed to evaluate the association between LOS and the most common primary ICD-10 diagnoses. To achieve this, we examined LOS in groups with specific (internal, surgical, neurological, and traumatic diseases) and non-specific diagnoses in adult ED visits at a tertiary referral hospital between 2017 and 2019 (134,675 visits in total). Our secondary objective was to measure LOS by age, day of the week, time of day, and season. The mean LOS was 254 minutes and was the shortest in the traumatic group (160 minutes), while in other groups it was significantly longer: neurological by 185 minutes, internal medicine by 158 minutes, surgical by 36 minutes, and non-specific by 24 minutes. In conclusion, non-specific diagnoses accounted for 21% of all ICD-10 primary diagnoses. In this group of patients, the percentage of hospitalizations was the highest. Other significant determinants of LOS were the patients’ age, the day of the week, the time of arrival, and repeated visits.

Nonalcoholic fatty liver disease (NAFLD) has become a widely studied subject due to its increasing prevalence and links to diseases such as type 2 diabetes and obesity. It has severe complications, including nonalcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma, and portal hypertension that can lead to liver transplantation in some cases. To better prevent and treat this pathology, it is important to understand its underlying physiology. Here, we identify three main factors that play a crucial role in the physiopathology of NAFLD: oxidative stress, insulin resistance, and the key role of carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1). We discuss the pathophysiology linking these factors to NAFLD pathophysiology.

The aim of the present study was to investigate whether chronic undernutrition modifies the response to rostafuroxin in juvenile rats. Chronic undernutrition was induced in male rats using a multideficient diet known as Regional Basic Diet (RBD), mimicking alimentary habits in impoverished regions worldwide. Animals were given RBD – or a control/CTRL normal diet for rodents – from weaning to 90 days, and rostafuroxin (1 mg/kg body mass) or vehicle were orally administered during the last 30 days. Undernourished rats became hypertensive at 55–60 days of age (tail-cuff recording). During the last two days, the rats were hosted in metabolic cages to measure food/energy, water, Na+ ingestion, and urinary volume. Blood and kidneys were collected after euthanasia. Rostafuroxin increased food/energy and Na+ intake in CTRL and RBD rats but had opposite effects on Na+ balance (intake minus urinary excretion): negative in CTRL and positive in RBD. The drug normalized the decreased plasma Na+ concentration found in RBD rats, increased urinary volume in RBD but not in CTRL, and decreased and increased urinary Na+ concentration in the RBD and CTRL groups, respectively. Rostafuroxin decreased the ouabain-sensitive (Na++K+)ATPase and increased the ouabain-resistant, furosemide-sensitive Na+-ATPase from proximal tubule cells in both groups, and normalized the systolic blood pressure in RBD without effect in CTRL rats. We conclude that chronic undernutrition modifies the response of blood pressure, caloric metabolism, Na+ distribution in liquid compartments, mobilization of Na+ from non-osmotic compartments, Na+ and water balance, and activity of renal Na+-transporting ATPases to rostafuroxin.

Background: Thoracic endovascular aortic repair (TEVAR) has become the standard treatment for blunt thoracic aortic injury (BTAI). Some small observational studies revealed aortic morphological changes after TEVAR in patients with BTAI. However, these studies were limited by the rarity of the condition and small sample sizes. To address this gap, the current study aims to conduct a systematic review and meta-analysis of existing literature to provide evidence on the degree of immediate and long-term aortic diameter change following TEVAR for BTAI. Methods: This systematic review and meta-analysis of studies published up to March 2023, was conducted in accordance with the PRISMA statement. Studies eligible for inclusion were studies evaluating aortic diameter change post-TEVAR in BTAI patients. Results: 14 articles, including 353 patients, were included after review. Treatment and measurement protocols varied among individual studies resulting in high heterogeneity of the results. Our meta-analysis demonstrated an immediate post-intervention dilation 2.41 mm and 2.63 mm of the proximal and distal aortic necks’, respectively, as well as continuous dilation of the respective regions at a rate of 0.35 mm/year and 0.49 mm/year. Conclusion: TEVAR in BTAI leads to immediate post-intervention and continuous aortic dilation and morphological changes with possible future important clinical consequences.

Immune checkpoint blockade (ICB) has revolutionized the prognosis of several advanced-stage solid tumors. However, its success has been far more limited in hematological malignancies and is mostly restricted to classical Hodgkin lymphoma (cHL) and primary mediastinal B cell lymphoma (PMBCL). In patients with non-Hodgkin lymphoma (NHL), response to PD-1/PD-L1 ICB monotherapy has been relatively limited, although some subtypes are more sensitive than others. Numerous predictive biomarkers have been investigated in solid malignancies, such as PD-L1 expression, tumor mutational burden (TMB) and microsatellite instability (MSI), among others. This case-illustrated review aims to appraise the current knowledge on PD-1/PD-L1 ICB efficacy in lymphoid malignancies, when used either as monotherapy or combined with other agents, and describes potential biomarkers of response in this specific setting.

The epidemiology of invasive fungal infections (IFIs) is currently changing, driven by aggressive immunosuppressive therapy, leading to an expanded spectrum of patients at risk of IFIs. Aspergillosis is a leading cause of IFIs, which usually affects immunocompromised patients. There is a limited number of antifungal medications available for treating IFIs and their effectiveness is often hindered by rising resistance rates and practical limitations. Consequently, new antifungals, especially those with novel mechanisms of action, have become increasingly required. This study assessed the activity of four novel antifungal agents with different mechanisms of activity: manogepix, rezafungin, ibrexafungerp, and olorofim against 100 isolates of Aspergillus section Terrei, containing amphotericin B (AmB) wildtypes/non-wildtypes and azole-susceptible/-resistant strains, according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) method. In general, all tested agents showed potent and consistent activity against tested isolates, exhibiting a geometric mean (GM) and minimum effective concentration (MEC)/minimum inhibitory concentrations (MIC) range respectively as follows: manogepix (0.048 mg/L, 0.032-0.5 mg/L), rezafungin (0.020 mg/L, 0.016-0.5 mg/L), ibrexafungerp (0.071 mg/L, 0.032-2 mg/L), and olorofim (0.008 mg/L, 0.008-0.032 mg/L). In terms of MIC90/MEC90, olorofim had the lowest values (0.008 mg/L), followed by rezafungin (0.032 mg/L), manogepix (0.125 mg/L), and ibrexafungerp (0.25 mg/L). All antifungals tested demonstrated promising in vitro activity against Aspergillus section Terrei, including A. terreus and cryptic species that were azole-resistant and AmB non-wildtype.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent condition among postmenopausal women that can lead to severe liver dysfunction and increased mortality. In recent years, research has focused on identifying potential lifestyle dietary interventions that may prevent or treat NAFLD in this population. Due to the complex and multifactorial nature of NAFLD in postmenopausal women, the disease can present as different subtypes, with varying levels of clinical presentation, and variable treatment responses. By recognizing the significant heterogeneity of NAFLD in postmenopausal women, it may be possible to identify specific subsets of individuals who may benefit from targeted nutritional interventions. In this review, we sought to examine the current evidence supporting the role of three specific nutritional factors - choline, soy isoflavones, and probiotics – as potential nutritional adjuvants in the prevention and treatment of NAFLD in postmenopausal women. There is promising evidence supporting the potential benefits of these nutritional factors for NAFLD prevention and treatment, particularly in postmenopausal women, and further research is warranted to confirm their effectiveness in alleviating hepatic steatosis in this population.

The Neurodegenerative Diseases are, according to recent studies, one of the main causes of disability and death worldwide. Interest in molecular genetics has started to have an exponential growth thanks to numerous advancements in tech, shifts in the understanding of the disease as a phenomenon, and the change of perspective regarding gene editing and the upsides of this action. The aim of this paper is to analyse the newest approaches in genetics and molecular sciences regarding four of the most important neurodegenerative disorders: Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease and Amyotrophic Lateral Sclerosis. We intend through this review to focus on the newest treatment, diagnosis and predictions plans regarding this large group of diseases, in order to obtain a better accuracy analysing and spotting the emerging signs that could lead to a better outcome in order to increase both the quality and the life span of the patient. Moreover, this review could provide future evidence of possible novelty therapies that target the specific genes and could be useful to be taken into consideration when the classical approaches fail to shed light.

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder characterised by poor social interaction and communication, as well as restricted and stereotyped interests. Due of the high prevalence of gastrointestinal disorders in individuals with ASD, researchers have investigated the gut microbiota as a potential contributor to its aetiology. The relationship between the microbiome, gut, and brain (microbiome-gut-brain axis) has been acknowledged as a key factor in modulating brain function and social behaviour, but its connection to the aetiology of ASD is not well understood. Recently, there has been increasing attention on the relationship between the immune system, gastrointestinal disorders, and neurological issues in ASD, particularly in relation to the loss of specific species or a decrease in microbial diversity. It focuses on how gut microbiota dysbiosis can affect gut permeability, immune function, and microbiota metabolites in ASD. Although a very complete study suggests that dysbiosis is a consequence of the disease and that it has practically no effect on autistic manifestations. This is a review of the relationship between the immune system, microbial diversity, and the microbiome-gut-brain axis in the development of autistic symptoms severity and, a proposal of a novel role of gut microbiome in ASD, where dysbiosis is a consequence of ASD-related behaviour and where dysbiosis in turn accentuates the autistic manifestations of the patients via microbiome-gut-brain axis in a feedback circuit.

The adipose-derived mesenchymal stem cells are becoming the tool of choice for many clinical applications and nowadays, nearly 200 clinical trials are running worldwide to prove the efficacy of this cell type for many diseases and pathological conditions. To reach the goal of cell therapies and produce ATMPs as drugs for regenerative medicine, it is necessary to properly standardize the GMP processes and thus collection methods, transportation strategies, extraction protocols and characterization procedures without forgetting that all the tissues of the human body are characterized by a wide inter-individual variability genetically determined and acquired during life. Here we compare 302 samples processed under GMP rules to exclude the influence of the operator and of the anatomical site of collection. Variability in the age of patients, gender and laboratory parameters like total cell number, cell viability, stem cell number and other stromal vascular fraction cell sub-populations have been compared to each other. Results show that, when the laboratory protocol is standardized, the variability in quantifiable cell parameters is widely statistically non-significant, meaning that we can make a further step toward standardized advanced cell therapy products.

Classic Hodgkin lymphoma (cHL) is a lymphoid neoplasm composed of rare neoplastic Hodgkin and Reed-Sternberg (HRS) cells surrounded by a reactive tumor microenvironment (TME) with suppressive properties against anti-tumor immunity. TME is mainly composed of T-cells (CD4 helper, CD8 cytotoxic and regulatory), and tumor-associated macrophages (TAMs) but the impact of these cells on the natural course of the disease is not absolutely understood. TME contributes to the immune evasion of neoplastic HRS cells through production of various cytokines and/or aberrant expression of immune checkpoint molecules, in ways that have not been fully understood yet. Herein, we present a comprehensive review of findings regarding the cellular components and the molecular features of the immune TME in cHL, its correlation with treatment response and prognosis as well as the potential targeting of the TME with novel therapies. Among all cells, macrophages appear to be a most appealing target for immunomodulatory therapies, based on their functional plasticity and antitumor potency.

Excessive extracellular histones can damage cells despite their importance in DNA structure and gene regulation. We previously showed the harmful effect of histone 3.3 (H3.3) and its acetylated form (AcH3.3) in chronic obstructive pulmonary disease (COPD), but further research is needed to understand the in vivo underlying mechanisms. To investigate this, we administered a single dose of recombinant histones via intra-tracheal instillation in C57BL/6 mice and analyzed the outcomes after 48 hours. Both rH3.3 and rAcH3.3 effectively reached the bronchial and alveolar space. Lung histology revealed severe immune cell infiltration, rupture, damage, and thickening of many alveolar walls. Micro-CT scans showed macroscopic structure changes with a decreased tissue volume to total volume ratio. The administration of rH3.3 and rAcH3.3 induced lung apoptotic activity, as indicated by increased levels of cleavage caspase 3 and 9. Moreover, elevated plasma levels of pro-inflammatory cell mediators, including TNF-alpha, IL-6, MCP-3, and CXCL-1, were observed. The pathological changes and pro-inflammatory cytokine response were more pronounced in animals treated with rAcH3.3, which also exhibited leukocytosis and lymphocytosis. These findings emphasize the crucial role of extracellular H3.3 acetylation in inducing cytotoxicity and a robust, acute inflammatory response similar to what occurs in the lungs of COPD patients.

Appropriate nutrition during pregnancy and the post-partum period is vital to both the parent and their offspring. Both under- and over-nourished status may have important microbial implications on the parental and infant gut microbiomes. Alterations to the microbiome can have implications for a person’s risk of obesity and metabolic diseases. In this review, we examine alterations in the parental gut, vaginal, placental, and milk microbiomes in the context of pre-pregnancy BMI, gestational weight gain, body composition, gestational diabetes, and parental diet. We also investigate how the infant gut microbiome may be altered by these different parameters. Many of the microbial changes seen in under- and over-nourished states in birthing parents may result in long-term implications to the health of offspring. Differences in diet appear to be a major driver of the parental, and subsequently milk and offspring microbiomes. Further prospective longitudinal cohort studies are needed examining nutrition and the microbiome to better understand its implications. Additionally, trials involving dietary interventions in child-bearing age adults should be explored to improve the parent and child’s risks for metabolic diseases.

The indications for TACE in the treatment of hepatocellular carcinoma have become more stringent with the development of systemic pharmacotherapy. Radical TACE is expected to be used only in situations such as for tumors with small volume which fulfill the “up-to-7”. Furthermore, a combination of molecular-targeted agents is expected to maximize the efficacy of TACE. In the intermediate stage, TACE and drug therapy play complementary roles, and it is important to select a treatment strategy that considers tumor status and hepatic reserve. However, no studies have investigated the various types of TACE in the treatment of such patients. Currently, TACE in Japan is broadly classified into conventional TACE, balloon occluded TACE (B-TACE), and drug-eluting beads TACE (DEB-TACE). This article outlines the evolution of B-TACE for hepatocellular carcinoma in the drug therapy era.

The mRNA vaccines for SARS-CoV-2 have demonstrated efficacy and immunogenicity in the re-al-world setting. However, most of the research on vaccine immunogenicity has been centered on characterizing the antibody response, with limited exploration into the persistence of spike-specific memory B cell response. Here we monitored the durability of the memory B cell response and characterize the trajectory of spike-specific B cell phenotypes in healthy individuals who have received two doses of the BNT162b2 vaccine up to 9 months post-vaccination. To profile the spike-specific B cell response we applied the tSNE and Cytotree automated approaches. Our data showed the induction of spike-specific IgA+ and IgG+ plasmablasts and IgA+ activated cells 7 days after the second dose which disappeared 3 months later, while subsets of spike-specific IgG+ resting memory B cells became predominant 9 months after vaccination, and they were capable to differentiate into spike-specific IgG secreting cells when in vitro restimulated. Other subsets of spike-specific B cells, such as IgM+ or unswitched IgM+IgD+ or IgG+ double negative/atypical cells, were also elicited by the BNT162b2 vaccine and persisted up to month 9. The analysis of circulating spike-specific IgG, IgA and IgM was in line with the plasmablasts observed. The longitudinal analysis of the antigen-specific B cell response elicited by mRNA-based vaccines provides valuable insights into our understanding of the immunogenicity of this novel vaccine platform destined to a future widespread use, and it is crucial in guiding future decisions and vaccination schedules.

For centuries, Foeniculi fructus (F. fructus) has been used as a traditional herbal medicine in China and Europe and is widely used as a natural therapy for digestive disorders, including indigestion, flatulence, and bloating. The mechanism by which F. fructus alleviates functional dyspepsia was analyzed through network pharmacology, and its therapeutic effect on an animal model of functional dyspepsia was investigated. The compounds, targets, and related diseases of F. fructus were studied utilizing the traditional Chinese medicine systems pharmacology (TCMSP) database. Information on the target genes was classified using the UniProt database. A network was built using Cytoscape 3.9.1, and functional dyspepsia-related genes were checked using the Cytoscape string application. The efficacy of F. fructus on functional dyspepsia, including gastroparesis and gastrointestinal motility, was confirmed by treatment with its extract in a mouse model of loperamide-induced functional dyspepsia. Seven compounds targeted twelve functional dyspepsia-associated genes. In a functional dyspepsia mouse model, F. fructus significantly suppressed the symptoms when compared to that in the control group. Our animal studies showed that the mechanism of action of F. fructus is closely related to gastrointestinal motility. Based on animal experimental results, the results showed that F. fructus provides a potential means to treat functional dyspepsia, suggesting that its medical mechanism for functional dyspepsia can be described by the relationship between seven key compounds of F. fructus, including oleic acid and β-sitosterol, and 12 functional dyspepsia-related genes.

We survey the diversity of antimicrobial resistance profiles of Escherichia coli (E. coli) isolates and molecular genotypes by means of phylogenetic groups circulating in complex aquatic habitats, such as sewage and receiving waters bodies as well as in clinical environment in Boeotia regional district of Greece. The predominant resistant profile among all environmental and clinical isolates was to penicillins - ampicillin (AMP) and piperacillin (PIP). ESBLs resistance related profiles were observed both in environmental and clinical isolates. Phylogenetic group B2 was the predominant in clinical isolates, whilst group A was dominant in environmental isolates. We report that reclaimed river water and wastewater are reservoirs of R and MDR E. coli to commonly used antibiotics in clinical practice posing putative threats for human and animal health.

Pseudomyxoma peritonei (PMP) is a rare malignant growth characterized by the production of mucin and the potential for peritoneal relapse. This study aimed to investigate the immunohistochemical and biological characteristics of mucin in patients with cellular and acellular PMP. We prospectively analyzed mucin specimens obtained from our patient cohort and described the composition and type of mucin present in each sample. A metagenomic analysis of the samples was performed to investigate the bacterial composition of the PMP microbiome. Secreted mucins 2 and 5AC and membrane-associated mucin-1 were the primary components of mucin in both cellular and acellular tumor specimens. The metagenomic study revealed a predominance of the phylum Proteobacteria and the genus Pseudomonas. Notably, Pseudomonas plecoglossicida, a species not previously reported in the human microbiome, was found to be the most abundant organism in the mucin of pseudomyxoma peritonei. Our findings suggest that the presence of MUC-2 and mucin colonization by Pseudomonas is a characteristic feature of both cellular and acellular disease. These results may have significant implications for the diagnosis and treatment of this rare entity.

Deep-Brain Stimulation (DBS) is a a highly effective and safe medical treatment that improves the lives of patients with a wide range of neurological and psychiatric deceases, and has been consolidated as a first-line tool in the treatment of these conditionsin the last two decades. Closed Loop Deep-Brain Stimulation (CLDBS) pushes this tool further by automatically adjusting the stimulation parameters to the brain response in real time. In this context, this paper presents a Low-Noise Amplifier (LNA) and a Neurostimulator circuits fabricated in the low-power/low-voltage 65 nm CMOS process from the TSMC, which were designed targeting implantable applications. To achieve the best trade-off between input-referred noise and power consuption, metaheuristic algorithms were employed to determine and optimizes the dimentions of the LNA devices during the design phase. The measurement results showed that the LNA had a gain of 40.6 dB, a 3 dB bandwidth spanning over three decades from 10 Hz to 8.6 kHz, and a power consumption of 6.19 uW. Simulations results indicated an input-referred noise of 4.86 uVrms for the LNA. The circuit of the Neurostimulator is a programmable Howland Current-Pump, whose measurements showed its ability to generate currents with arbitrary shapes ranging from between 325 uA to +318 uA. The simulations showed a quiescent power consumption of 0.13 W with a zero neurostimulation current. The LNA and the Neurostimulator circuits are supplied with 1.2 V voltage and occupy a microdevice area of 145 um x 311 um and 88 um x 89 um, respectively, making them suitable for implantation in applications involving Closed Loop Deep-Brain Stimulation.

The tobacco cembranoid (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol (4R) is known to induce neuroprotection against brain ischemia, systemic inflammation, Parkinson's disease, and organophosphate toxicity in rodents. Studies examining the compound's safety in male and female Sprague Dawley rats demonstrated no significant side effects after a single injection of 4R at various concentrations (6, 24, or 98 mg/kg). To evaluate the neurotherapeutic feasibility of 4R for clinical trials, we have assessed the safety of this compound in nonhuman primates. We investigated whether 4R induces toxicity in male Macaca mulatta when administered for 11 consecutive days via intravenous injection at a dose of 1.4 mg/kg. Electroencephalogram, somatosensory evoked potential, and transcranial motor evoked potentials were measured at days 0, 4, 8, and 12 and remained unaffected during the experimental study. Spontaneous behavior was not affected between the groups. Small histopathological changes in the organs were observed in some animals, both treated and non-treated; thus, these changes cannot be attributed to 4R. Minor hematological and blood composition variations with no clinical significance were detected in the experimental animals. In conclusion, our data support previous findings that 4R is a non-toxic compound that proved safe in nonhuman primates during the given period and dose.

Multifocal hepatic hemangiomas (MHHs) are the most common benign vascular tumours of the liver that are detected in children with concomitant multiple infantile hemangiomas. They still pose a diagnostic problem for GPs and are thus often detected far too late, due to their low prevalence rates. MHHs are usually undetectable at birth, usually detected within the first few weeks of life when the lesions proliferate. The heterogeneity of the lesions and the presence of comorbidities make often the management of infantile hepatic hemangiomas a true challenge, also for highly specialised medical professionals. Ultrasound (USG) should be the imaging examination performed in the first instance in search for vascular anomalies in children. In pharmacotherapy, the first choice treatment is propranolol and prednisone, administered orally. Invasive treatment is usually indicated in symptomatic or progressive multiple hepatic hemangiomas only. Recently published studies show a significant decrease in the incidence rate of the disease, which now ranges between 11% and 18% for treated and untreated hepatic hemangiomas, respectively.