According to the International Agency for Research on Cancer (IARC) of the World Health Organization (data of year 2020), Breast Cancer (BC) is one of the most common cancer types worldwide, with large geographical variations occurring between countries and world regions and highest incidence rates in countries that have undergone economic transition. The risk factors for BC include women ageing, genetic mutations, reproductive history, dense breast tissues, personal history of BC or specific non-cancerous breast diseases, family history of breast or ovarian cancer, previous treatment using radiation therapy, and exposure to hormone-like drugs such as diethylstilbestrol (DES). Additional risk factors include being overweight or having obesity after menopause, and taking hormones. MicroRNAs (miRNAs or miRs) are small non-coding RNA molecules that have an essential role in gene expression and are significantly linked to the tumor development and angiogenesis process in different types of cancer, including BC. In the last years, the knowledge about miRNAs role in BC has significantly improved, and complex interactions among coding and non-coding RNA has been elucidated. In this context, an increasing number of papers had been published regarding the role of miR-125 in BC. In this review, we summarize the state-of-the-art about this research topic in addition to elaborating on the need to set novel ethical and legal standards for the governance of such innovations in healthcare.

Recent studies have discovered that functional connections are impaired in patients with Parkinson's disease (PD) accompanied by hallucinations(PD-H), even at the preclinical stage. The cerebellum has been implicated as playing a role in cognitive processes. However, the functional connectivity (FC) between cognitive sub-regions of the cerebellum of PD patients with hallucinations needs to be further clarified. Resting-state functional magnetic resonance imaging (rs-fMRI) data from three groups (17 PD-H, 13 no hallucinations accompanying the (PD-NH), and 26 healthy controls (HC) ) was collected in this study to explore the role of cerebellar FC changes in the cognitive performance. Additionally, we define cerebellar FC as a training feature for classifying all subjects using Support Vector Machine(SVM). We found that PD-H patients' cerebellum(Vermis_4_5 ) FC had increased within the left side of the precuneus(PCUN) compared to HC, cerebellum(Vermis_1_2) had increased within bilateral opercular part of the inferior frontal gyrus(IFGoprec) and triangular part of the inferior frontal gyrus(IFCtriang), left side of postcentral gyrus(PoCG), Inferior parietal lobe(IPL), and PCUNs compared to PD-NH. In the training results of machine learning, cerebellar FC has also been proven to be an effective biomarker feature, with a recognition rate of over 90% for PD-H. These findings indicate that cortico-cerebellar FC in PD-H and PD-NH patients were significantly disrupted with different distributions. The proposed pipeline offers a promising low-cost alternative for the diagnosis of preclinical PD-H and can be useful for other degenerative brain disorders.

Background: Galectin-3 (Gal-3) is a biomarker involved in a wide range of diseases including cardiac remodeling following acute myocardial infarction (AMI). Identification of prognostic markers in patients with AMI can guide strategies towards improved survival and the quality of life. Methods: Our study included 59 patients with AMI and preserved ejection fraction. We determined the Gal-3 plasma concentration within 24 hours of chest pain onset from aortic root, femoral/radial artery, coronary sinus and cubital vein. Major adverse cardiovascular events (MACE) were evaluated at six months follow-up. Results: MACE at six months post-AMI was recorded in 20 patients (34%). The Gal-3 plasma concentration from aortic root and the femoral/radial artery were independent predictors of MACE at six months follow-up after the first AMI (OR 1.228; 95%CI: 1.011-1.491; p=0.038; OR 3.438; 95%CI: 1.275-9.265; p=0.015). ROC analysis identifies the Gal-3 plasma concentration from aortic root as a better predictor of MACE or death (cut-off >10.86 ng/ml; AUC 0.858; 95%CI: 0.744-0.973; p<0.001) than Gal-3 plasma concentration from femoral/radial artery (cut-off >10.18 ng/ml; AUC 0.742; 95%CI: 0.596-0.888; p=0.006). Conclusion: The Gal-3 plasma concentration in patients with AMI determined during coronary angiography, especially from the aortic root, within 24 hours after chest pain onset is a valuable biomarker of prognosis at six months follow-up.

Age-related declines in vitamin D receptor (VDR) expression have been implicated in the onset of sarcopenia. The increased expression of VDR in muscle is known to increase muscle mass, whereas VDR knockout in the muscle decreases muscle mass in rats. Similar to VDR, the age-related decline in protein deacetylase sirtuin (SIRT) expression is linked to the development of sarcopenia and age-related muscle dysfunction. This study aimed to investigate whether the VDR agonist 1,25-dihydroxyvitamin D3 (1,25VD3) exerts beneficial effects on muscles through interactions with sirtuins and, if so, the underlying molecular mechanisms. 1,25VD3 treatment increases the expression of VDR, SIRT1, and SIRT3 in C2C12 myotubes. Additionally, it stimulates the differentiation of C2C12 myoblasts into myotubes. Furthermore, 1,25VD3 significantly enhanced the expression of key myogenic markers, including myosin heavy chain (MyHC) proteins (MyHC I and II), MyoD, and MyoG, and increased the phosphorylation of AMPK and AKT. Conversely, VDR knockdown in myoblasts induces myotube atrophy by downregulating SIRT1 and SIRT3 expression. Furthermore, 1,25VD3 ameliorated muscle atrophy and apoptosis induced by IFN-γ/TNF-α co-treatment to C2C12 myotube. Moreover, 1,25VD3 downregulated the increased expression of muscle atrophy-associated proteins, including FoxO3a, MAFbx, and MuRF1 in IFN-γ/TNF-α induced atrophy model. Importantly, IFN-γ/TNF-α significantly reduced the mtDNA copy number in C2C12 myotube, whereas the presence of 1,25VD3 effectively prevented this decrease. These results indirectly suggest that 1,25VD3 has the potential to develop as a therapeutic or preventive agent for age-mediated muscle atrophy by enhancing the VDR/SIRT1/SIRT3 axis and inhibiting the FoxO3-mediated atrophy pathway.

Pathophysiology of depression is related with reduced volume of the hippocampus and amygdala and hypertrophy of the nucleus accumbens. The mechanism of these changes is not well under-stood, but clinical studies have shown that administration of the fast-acting antidepressant keta-mine reversed the decrease in hippocampus and amygdala volume in depressed patients, and the magnitude of this effect correlated with the reduction of depressive symptoms. In the present study, we attempted to find out whether the psychedelic substance psilocybin affects neurotransmission in the limbic system in comparison to ketamine. Psilocybin and ketamine increased the release of dopamine (DA) and serotonin (5-HT) in the nucleus accumbens of naive rats as demonstrated using microdialysis. Both drugs influenced glutamate and GABA release in the nucleus accumbens, hippocampus and amygdala and increased ACh levels in the hippocampus. The changes in D2, 5-HT1A and 5-HT2A receptor density in the nucleus accumbens and hippocampus was observed as a long-lasting effect. A marked anxiolytic effect of psilocybin in acute phase and 24 h post-treatment was shown in the open field test. These data provide the neurobiological background for psilocybin effect on stress, anxiety and structural changes in the limbic system and translate into antidepres-sant effect of psilocybin in depressed patients.

Background: The potential impact of the pandemic on mental health should not be overlooked, especially among vulnerable populations such as women who gave birth during the COVID-19 pandemic. The aim of the study was to assess the mental health status of women who gave birth during a pandemic and to examine the possible links between the onset of depressive disorder symptoms in close proximity to the time of delivery and the socio-demographic conditions, health status and obstetric circumstances of the patients. Materials and Methods: The study is a cross-sectional survey conducted from 01.03.2020 to 01.03.2023, during the period of SARS-CoV-2 (COVID-19) pandemic, based on a retrospective evaluation of 860 postpartum women. The screening tool used to assess symptoms of postpartum depression was the Edinburgh Postnatal Depression Rating Scale (EPDS) questionnaire. The questionnaire was completed both in the Obstetrics and Gynaecology Clinical Sections I and II of the "Pius Brînzeu" County Emergency Hospital from Timisoara, Romania and online using Google Forms. Results: The highest severity of postpartum depression symptoms was observed during the COVID-19 pandemic. The results of the study conducted during the period of SARS-CoV-2 pandemic (COVID-19) showed that the prevalence of major postpartum depressive disorder (EPDS ≥ 13) was 54.2% (466 patients), while 15.6% (134) had minor depressive disorder (10 < EPDS ≤ 12) in the first year after delivery. Comparing these results with those obtained in research conducted before the onset of the pandemic period shows an alarming increase in the prevalence of postpartum depression. Risk factors associated with postpartum depression included type of delivery, level of education, socio-economic conditions, health status, age, background, personal obstetric history (number of abortions on demand, parity). Conclusions: The effects of the pandemic on mental health are of particular concern for women in the first year after childbirth. Observing these challenges and developing effective measures to prepare our health system early can help and facilitate effective mental health screening for postpartum women, promoting maternal and child health.

Background: There have been few reports of cutaneous skin lesions in severe COVID-19 hospitalized patients which exhibit different behavior compared to outpatients. Furthermore, a notable lack of rigorous studies exits. In this study we included patients with generalized rash during the first wave of the pandemic for characterization.Methods: Hospitalized patients with severe confirmed pulmonary COVID-19 infection and a generalized cutaneous rash during the first wave in March-May 2020 were included. The study received approval from the ethics committee. Clinical presentation, histo-logical examination, blood test, and complete blood interleukin profile were assessed. Special immunohistochemical investigations were conducted. Long term follow-up of the patient was performed throuhg a phone call 24 months later. Results: A total 28 patients were studied and classified by histological examination into three groups: G1: perivascular dermatitis (18/28, 64%); G2: Drug reaction (7/28, 25%); and G3: Generalized exanthema and chilblain (3/28, 11%). The virus was not detected in the skin, by PCR and by immunohistochemical analysis, and the interleukin expression in the skin were undetectable results. Vascular cell adhesion molecule 1 (VCAM1), E-selectine, and IT Galpha 5 were unspecific. G1 exhibited the least inflammation, G2 the most in-flammatory, and G3 had previous inflammation. Discussion: Our data suggest that generalized exanthemas during severe SARS-Cov-2 infection exhibit unspecific finding and are similar to other rashes caused by inflammation. Drug reaction should be considered, as they accounted for 25% of the rashes. Further studies including higher number of patients are necessary.

Pregestational and gestational diabetes mellitus are relevant complications of pregnancy and antidiabetic drugs are prescribed to obtain glycemic control and improve perinatal outcomes. The objective of this study was to highlight the prescription pattern of antidiabetics before, during and after pregnancy in Italy and to evaluate its appropriateness. A multi-database cross sectional population study using a Common Data Model was performed. In a cohort of about 450,000 women, the prescribing profile of antidiabetics seemed to be in line with the Italian standards for the treatment of GDM which currently do not recommend the use of oral antidiabetics and non-insulin injection, even if a small share of new users (up to 3.8% in the third trimester) used oral antidiabetics. A substantial variability in the prescription pattern was observed among the Italian regions considered: the highest increase was registered in Tuscany (4.2%), Umbria (3.5%) and Emilia-Romagna (2.6%) while the lowest in Lombardy (1.5%), Veneto (1.7%) and Apulia (1.7%). Analysing the prevalence of use of antidiabetics between foreign women we observed that the consumption during pregnancy was higher than Italians (second trimester: 1,8% vs 0,9%, third trimester: 3,6% vs 1,8%).

Background Posttraumatic stress disorder (PTSD) is a complex condition that represents a significant burden in terms of individual disability and societal costs. Despite decades of research investigating treatment options, PTSD remains a major cause of quality-of-life impairment. We hypothesized that patients with PTSD might benefit from peripheral somatosensory stimulation (PSS) therapy. Methods Six adult patients with clinically diagnosed PTSD were enrolled to undergo daily PSS therapy over a 4-week period. Patients completed two surveys evaluating satisfaction with treatment and overall well-being (Survey 1) and severity of PTSD symptoms (Survey 2). Survey 1 was completed weekly during the course of the study. Survey 2 was based on the 9-question National Stressful Events Survey PTSD Short Scale (NSESSS) and was completed as a baseline prior to initiation of therapy and then at the conclusion of the trial. All data were analyzed by an independent statistician. Results Six male patients were enrolled in the study; all completed the trial. All patients demonstrated a decrease in symptoms within one week of initiation of therapy. This benefit was sustained and appeared to further improve over the course of the trial. For Survey 1, the overall median scores demonstrated a significant time-dependent improvement across measurement times (p < 0.001). For Survey 2, patients had statistically significant improvements from baseline regarding feelings of being emotionally upset and being overly alert. Results from a cumulative link mixed model demonstrated that treatment yielded a 38.2-fold higher likelihood of transitioning from a higher PTSD score at baseline to a lower (improved) score at week 4. No adverse events were described by the patients. Conclusions PSS stimulation appeared to improve symptoms in all six patients with PTSD symptoms in this trial. Patients had unanimous and clinically meaningful improvement in overall PTSD symptoms with treatment. By week 4, all patients responded that they enjoyed the treatment and would like to keep their device. We suggest that further investigation into the potential usefulness of PSS therapy in patients with PTSD is warranted.

The molecular basis of Down syndrome (DS) predisposition to leukemia is not fully understood but involves various factors such as chromosomal abnormalities, oncogenic mutations, epigenetic alterations, and changes in selection dynamics. Myeloid leukemia associated with DS (ML-DS) is preceded by a preleukemic phase called transient abnormal myelopoiesis driven by GATA1 gene mutations and progresses to ML-DS through additional mutations in cohesin genes, CTCF, RAS, or JAK/STAT pathway genes. DS-related ALL (ALL-DS) differs from non-DS ALL in terms of cytogenetic subgroups and genetic driver events and aberrant expression of CRLF2, JAK2 mutations, and RAS pathway activating mutations are frequent in ALL-DS. Recent advancements in single-cell multi-omics technologies have provided unprecedented insights into the cellular and molecular heterogeneity of DS-associated hematologic neoplasms. Single-cell RNA sequencing and digital spatial profiling enable the identification of rare cell subpopulations, characterization of clonal evolution dynamics, and exploration of the tumor microenvironment's role. These approaches may help identify new druggable targets and tailor therapeutic interventions based on distinct molecular profiles, ultimately improving patient outcomes with the potential to guide personalized medicine approaches and the development of targeted therapies.

Pharmacogenomic (PGx) testing to inform antidepressant medication selection and dosing is gaining attention from healthcare professionals, patients, and payors in Australia. However, there is often uncertainty regarding which test is most suitable for a particular patient. Here, we identified and evaluated the coverage of CYP2D6 and CYP2C19 variants in commercial antide-pressant PGx testing panels in Victoria, a large and ethnically diverse state of Australia. Test characteristics and star alleles tested for both genes were obtained directly from pathology la-boratories offering PGx testing and compared against the Association of Molecular Pathology’s recommended minimum (Tier 1) and extended (Tier 2) allele sets. Although all tests covered the minimum recommended alleles for CYP2C19, this was not the case for CYP2D6. This study em-phasizes that PGx tests might not be suitable for all individuals in Australia due to the limited range of star alleles assessed. Inadequate haplotype coverage may risk misclassification of an individual’s predicted metabolizer phenotype which has ramifications for depression medica-tion selection and dosage. The study underscores the urgent need for greater standardization in PGx testing and emphasizes the importance of considering genetic ancestry when choosing a PGx testing panel to ensure optimal clinical applicability.

Antimicrobial resistance (AMR), a serious global public health challenge, may have accelerated development during the COVID-19 pandemic because antibiotics were prescribed for COVID-19. This study aimed to assess antibiotics use before and during the pandemic and correlate the results with the rate of resistant microorganisms detected in hospitalized patients during the study period. This single centre study looked retrospectively at four years of data (2018–2021) from Royal Hospital, Muscat, Oman. The consumption rate was presented as the antibiotic consumption index, the ratio of defined daily dose (DDD) per 100 bed-days. Analyses were performed using the nonparametric test for trend across the study period. Correlation between antibiotic consumption indexes and the isolated microorganisms in the four-year study period was performed using Spearman’s rank correlation coefficient. We compared data from the pre-COVID-19 to the COVID-19 period. Though more patients were admitted pre-COVID-19 (132,828 versus 119,191 during COVID-19) more antibiotics were consumed during the pandemic; vancomycin and ceftriaxone had higher consumption during than before the pandemic (p-values 0.001 and 0.036, respectively). Vancomycin-resistant Enterococcus (VRE) and Candida. auris were detected more during the COVID-19 period with p-values of 0.026 and 0.004, respectively. Carbapenem-resistant Enterobacterales (CRE), vancomycin resistant Enterococcus spp., and C. auris were detected more often during the pandemic with p-values of 0.011, 0.002, and 0.03, respectively. Significant positive correlations between antibiotic consumption and drug resistant isolates were noted. This study confirms that the overuse of antibiotics triggers the development of bacterial resistance; our results emphasize the importance of antibiotic control.

Several eye-tracking technologies have been developed in the last 20 years. This paper aims to present a new kind of eye tracker that can produce detailed information on both eye and head movements using an array of magnetoresistive detectors fixed on the patient’s head and a small magnet inserted in a contact lens, tailored to the subject’s cornea curvature. The software used for data analysis can combine or compare the eye and the head movements and can draw them up as 2D or 3D images. Preliminary data concern a starter patient that was asked to perform several tasks to establish the accuracy, reliability and tolerance of the magnetic eye tracker and the software. The tasks included the evaluation of saccadic eye movements and pursuit, “drawing” shapes or alphabetical letters and reading. Finally, a Head Impulse Test (HIT) was performed for VOR gain estimation, comparing the standard deviation established through vHIT to the one established through this magnetic eye tracker (mHIT). This prototypic device is low invasive, light, relatively low cost and tolerable, with a high grade of reliability and accuracy. All these features might lead to future use of the magnetic eye tracker in neurological and otoneurological fields.

Here we performed a comparative experimental analysis by EPR spectroscopy of the intensity of nitric oxide (NO) production and copper content in the injured and uninjured areas of the frontal lobes and the hippocampus of the brain of male Wistar rats, after modeling of combined brain and spinal cord injury. Brain and spinal cord injury were modelled by local destruction of the left precentral region of the brain using a stylet followed by hemorrhage injury at the level of the first lumbar vertebra of the spinal cord. We found a significant decrease in NO production 7 days after injury modeling in the injured and uninjured (contralateral) brain regions, but the copper content remained unchanged one week after injury modeling. Thus, combined brain and spinal cord injury is not accompanied by a radical change in the activity of the antioxidant system in the brain, which is also confirmed by the absence of changes in NO production and copper content in the hippocampus.

Background: Depression, a multifaceted mental health condition, necessitates a multidimensional approach to treatment. This study aimed to elucidate the potential efficacy of various mitochondrial interventions, ranging from pharmacological treatments to lifestyle modifications, in alleviating depressive symptoms and enhancing overall mental well-being and assess the diverse range of mitochondrial assessments for managing depression by synthesizing findings from selected studies. Methods: A systematic compilation of studies, employing observational, interventional, and animal-based designs, was undertaken to elucidate the intricate relationship between mitochondrial function and depression as well as depressive signs and symptoms. The PRISMA guidelines were employed for conducting this review and a specific set of selection criterion were formulated by a team of reviewers for selection of relevant papers. Results: The synthesized results from the 21 selected papers highlighted the potential of these interventions to target diverse aspects of depression. Hyperbaric oxygen therapy and psychotherapy demonstrated significant reductions in depression and anxiety scores, with hyperbaric oxygen therapy particularly effective in improving nerve function and daily living activities. Whole-body cryotherapy displayed substantial improvements in depressive symptoms and quality of life. Frequent sauna bathing exhibited a lower risk of depressive symptoms in males. Dietary patterns, including Paleolithic and Mediterranean diets, showcased potential protective effects against depression, anxiety, and stress. The ketogenic diet revealed promise in ameliorating depression and psychosis symptoms alongside positive metabolic changes. Fasting interventions, though challenging, were associated with lower anxiety and depression levels without increased fatigue. Bright white light therapy enhanced remission rates and reduced depression scores in bipolar depression. Probiotic supplementation exhibited potential in reducing depression scores and improving metabolic markers, although further investigation is warranted. Conclusion: The diverse array of interventions explored in this study underlines the multifaceted nature of depression treatment. While these findings offer hope for more personalized and effective approaches, it is imperative to consider the variability in study designs, sample sizes, and methodologies among the selected papers. The mechanisms underlying the observed effects remain partially understood, emphasizing the need for continued mechanistic research. This study sets the stage for future investigations and clinical practices, showcasing the potential of various interventions in mitigating the challenges posed by depression and paving the way for more effective treatment strategies.

The recently reported microbial natural product N-benzoyl-tryptophane (1) along with twenty-two diverse known bioactive compounds were isolated from the marine Aspergillus terreus LGO13 after its re-cultivation using liquid culture fermentation. Structures of the isolated compounds were established on the basis of HR-ESIMS 1D/2D NMR spectroscopy, and comparison with literature data. The antimicrobial, cytotoxicity, and antiviral activities of the microbial extract and the obtained compounds were investigated using a set of microorganisms, cervix carcinoma KB-3-1, non-small cell lung cancer (NSCLC) A549, and coronavirus (SARS-CoV-2), respectively. Molecular docking (MD) simulation was employed to explore the theoretical targets of the isolated metabolites as anti-SARS-CoV-2 agents. Chaetominine (2) seemed to be a potential candidate against papain-like protease (PLpro), one of the viral proteins being aimed by recent research as a possible target of anti-covid agents. Inspired by the MD results, we accordingly assessed the antiviral efficacy of chaetominine (2), fumitremorgin C (6), and azaspirofuran A (9) against SARS-CoV-2. Fumitremorgin C (6) showed a high selectivity index (SI = 20.3), while chaetominine (2) and azaspirofuran A (9) showed moderate selectivity index (SI = 6.6 and 3.2, respectively). These results showed a promising antiviral activity of Fumitremorgin C against SARS-CoV-2 virus.

Polycystic ovary syndrome (PCOS) is a prevalent condition characterized by manifestations that can influence self-image and potentially result in psychological distress; however, data from literature on sexual function (SF) in PCOS women are contradictory. We aimed to evaluate sexual dysfunction (SD) in PCOS women by carrying out a systematic review and meta-analysis, using the gold-standard assessment tool SD-diagnosis (Female Sexual Function Index:FSFI). Seven databases were analyzed until August-2023; study quality was assessed by risk of bias and Newcastle Ottawa Scale. Our analysis encompassed 25 case-control studies (9933 women). PCOS group presented significantly lower scores in arousal (MD= -0.36 CI95%-0.60;-0.11), lubrication (MD= -0.52 CI95%-0.75;-0.28), orgasm (MD= -0.39 CI95%-0.57;-0.20), satisfaction (MD= -0.32 CI95%-0.50;-0.14) and pain subdomains (MD= -0.46 CI95%-0.75;-0.16), as in overall FSFI score (MD= -2.27 CI95%-3.23;-1.31). Overweight/obese (OW/O) patients exhibited significantly higher overall FSFI than OW/O controls (MD=1.98 CI95%0.68;3.27), particularly in lubrication (MD= -0.34), orgasm (MD= -0.26) and satisfaction (MD= -0.25) subdomains. These findings offer insights regarding SD in PCOS women and emphasize the need to incorporate SF assessment into multidisciplinary care. By this way, PCOS can be also considered a gateway diagnosis to other long-term consequences. Further research should focus on controlling variables, as ethnicity, culture, religion and economic disparities.

The 1,2,3-triazole derivative 2-(4-chlorophenyl)-5-(pyrrolidin-1-yl)-2H-1,2,3-triazole-4-carboxylic acid with potential anticancer activity was used as a ligand in complex formation with the lan-thanum(III) ion. The molecular structure and vibrational spectra of the complex were optimized at three DFT levels and the scaled IR and Raman spectra were compared to the experimental ones. Several scaling procedures were used. Through a detailed analysis, the structure predicted for the newly synthetized La(III) complex was confirmed by the good accordance of the calculat-ed-experimental IR and Raman spectra. The best DFT method appears to be M06-2X with the Lanl2mb basis set, followed closely by Lanl2dz. The effect of the lanthanide atom on the molecular structure and atomic charge distribution of the triazole ring was evaluated. Potential free radical scavenging activity of both, ligand and complex, was investigated in several radical-generating model systems. Potential mechanisms of antioxidant action (hydrogen atom transfer – HAT and single electron transfer - SET) were elucidated.

Spinal muscular atrophy is a neuromuscular disorder caused by mutationsin both copies of the survival motor neuron gene 1 (SMN1) which lead to reduction in the production of the SMN protein. Currently, there are several therapies that have been approved for SMA, with much more undergoing active research. While various biomarkers have been proposed for assessing the effectiveness of SMA treatment, a universally accepted one still hasnot been identified. This study aimed to investigate whether the number of gems in cell nuclei could serve as a potential biomarker for SMA. To gain insight into whether the number of gems in cell nuclei varies based on their SMN genotype and whether the increase in gems number is associated with therapeutic response, we utilized fibroblast cell cultures obtained from a patient with SMA type II and from healthy individual. We have discovered a remarkable difference in the number of gems found in the nuclei of these cells, specifically when counting gems per 100 nuclei. Then the SMA fibroblasts were treated with antisense oligonucleotides the beneficial effects in correcting the abnormal splicing of SMN2 exon 7 have been demonstrated. It was observed that there was a significant increase in the number of gems in the treated cells compared to the intact SMA cells. The results obtained significantly correlate with an increase of full-length SMN transcripts share. Based on our findings, it is evident that the quantity of gems can be regarded as a reliable biomarker for SMA drugs development.

Background: Diffuse large B-cell lymphoma is the most common type of non-Hodgkin's lymphoma. Due to the variety of clinical manifestations, accurate diagnosis can be challenging. Here, we present a case of DLBCL that was initially misdiagnosed as a hematoma, highlighting the importance of considering malignancy in the setting of non-responsive soft tissue swelling. Methods: A 76-year-old man presented to the emergency department with right periorbital swelling and ecchymosis. The symptoms first appeared after an injury and did not resolve spontaneously. The patient was taking warfarin for atrial fibrillation. A facial bone CT revealed a large irregular homogeneous mass. An extraconal hematoma was suspected based on clinical history and radiologic findings. Incision and drainage were performed, resulting in evacuation of old blood. Despite continued drainage, the patient's symptoms worsened. A comparison with the previous CT revealed an increase in the size of the lesion. As a result, a surgical excisional biopsy was performed. Results: Biopsy of the mass showed a diffuse infiltrate of lymphocytes around the tissue. The diagnosis of diffuse large B-cell lymphoma was confirmed pathologically. The patient was referred to hematology for further management. Conclusions: DLBCL is a rare disease associated with a poor prognosis. Due to the previous injury and the use of anticoagulants, the patient was initially misdiagnosed as having a hematoma. This delayed the prompt diagnosis and affected the timing of treatment initiation. We must be aware that a malignant mass is a potential cause of unresponsive soft tissue swelling.

AIM Non-alcoholic　fatty liver disease (NAFLD) is the most common cause of chronic liver disease. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator (SPPARMα), has been reported to ameliorate liver function among patients with dyslipidemia. However, there are not many reports of the clinical effects of the pemafibrate. This study aims to summarize the experience of using pemafibrate and analyze the effects on liver function in patients with dyslipidemia. METHODS One hundred twelve cases of hyperlipidemia receiving pemafibrate 0.2 mg/day were retrospectively enrolled in this study. Age, gender, BMI, complications, concomitant medications, serum parameters (TG, HDL-C, LDL-C, AST, ALT, γGTP, ALP, platelets, M2BPGi, Cre, eGFR, HbA1c, blood glucose level at any time) were investigated and evaluated. RESULTS Pemafibrate administration significantly improved serum TG and HDL-C, but not in LDL-C. Serum AST, ALT, γGTP, and ALP were also significantly improved. The fib-4 index, a liver fibrosis score, did not change significantly, but M2-BPGi, an index of fibrosis, decreased significantly. No correlation was observed between each lipid parameter and ALT, and ALT decreased independently of the lipid parameters. Conclusions As we expected, pemafibrate demonstrated a lipid-improving effect without adversely affecting hepatic and renal functions. An unexpected finding was the decrease in ALT that was independent of lipid parameters.

Background and Objectives: Similar to diabetes, the presence of left ventricular (LV) diastolic function (DD) has been reported in various studies which were conducted with people with a diagnosis of impaired fasting blood glucose (FBG). The study aimed to examine the effects of fasting blood glucose (FBG) levels on left atrial strain (LAS) estimated by two-dimensional echocardiography speckle tracking analyses in patients without known diabetes. Material and Methods: The study included 148 participants (74 female and 74 male) without a history of diabetes mellitus or chronic disease. The patients were divided into two groups as follows: individuals with FBG <100 mg/dl and those with FBG between 100-125 mg/dl after at least 8 hours of overnight fasting and according to these FBG levels STE measures were compared. Results: There was a significant decrease in the LA reservoir (52.3±15 vs. 44.5±10.7; p=0.001) and conduit strain (36.9±11.7 vs. 28.4±9.7; p=0.001) in the impaired FBG group. When the STE findings of both ventricles were compared, no significant difference was observed between the groups in right and LV strain imaging. Conclusion: In the earliest stage of LVDD, changes in atrial functional parameters become particularly evident. Echocardiographic analyses of these parameters can help to diagnose and determine the degree of LVDD while the morphological parameters are still normal. The addition of LAS imaging to the routine TTE study in patients with impaired FBG but without a DM diagnosis may be helpful in demonstrating subclinical LVDD or identifying patients at risk for LVDD in this patient group.

Hu7691 represents a novel Pan-Akt kinase inhibitor, demonstrating excellent selectivity towards non-AGC kinase families and pronounced inhibitory effects on the proliferation of multiple tumor cell lines. However, there is currently a notable absence of in vivo toxicological research evidence concerning Hu7691. This study represents the first investigation into the 14-day repeated dose toxicity of Hu7691 in male and female Sprague-Dawley (SD) rats. Male rats were administered daily doses of 12.5, 50, 100, and 150 mg/kg, while female rats received doses of 12.5, 25, 50, and 75 mg/kg for 14 consecutive days. Hematological assessments, organ weights, and histopathological examinations revealed corresponding alterations, suggesting potential target organs for toxicity including the spleen, thymus, and gastrointestinal tract. It is worth noting that the test substance may also impact the liver, kidneys, heart, and ovaries. The No Observed Effect Level (NOAEL) was determined to be no greater than 12.5 mg/kg. Based on the observed gender-related toxicity differences in preliminary trials, it is recommended that the high dose reference dose for male animals in formal experiments should not be less than 100 mg/kg, while for female animals, it should be less than 50 mg/kg.

Maxillofacial fractures are a prevalent occurrence, and the widespread use of miniplates to stabilize and secure these fractures during surgery is common. However, the post-surgical fate of these miniplates remains a subject of contention among surgeons. Some advocate for their removal, while others suggest leaving them in place. This study aims to perform an extensive meta-analysis of pertinent studies to ascertain the destiny of miniplates employed in maxillofacial surgery and discuss the consequences of either their extraction or retention. To execute this meta-analysis, an exhaustive search was conducted across multiple databases, encompassing PubMed, Scopus, and Google Scholar. Keywords such as "titanium miniplates," "screws," "maxillofacial surgery," "complications," and "removal" were utilized to identify pertinent studies. The search was constrained to studies published between 1989 and 2022. The analysis encompassed only studies reporting outcomes related to miniplates in maxillofacial surgery, including complication rates and removal frequencies. Eleven studies conformed to the inclusion criteria and were incorporated into the meta-analysis, encompassing a total of 2240 patients. All the studies had a retrospective design, with the largest study involving 800 patients. The overall complication rate was determined to be 13.3%. The most prevalent reasons for miniplate removal included patient preference, tooth extraction, and infections. The average time span for miniplate removal was 10.7 months, with the most prolonged reported duration being 24 years. These findings imply that immediate removal might not be imperative in the majority of instances. In conclusion, our meta-analysis underscores the necessity of removing miniplates in cases where hardware leads to a variety of complications and physical discomfort. Principal factors driving plate removal included patient requests, tooth extractions, and infections. Ordinarily, plate removal took place within the span of 6 to 12 months, with the mandible being the most frequent site for removal. These findings accentuate the significance of extended monitoring to assess the trajectory of miniplates in maxillofacial surgery and provide valuable insights for future clinical decisions. To validate these conclusions and gain deeper insights into the factors influencing plate removal in maxillofacial surgery, further research with larger participant cohorts and standardized outcome reporting is imperative.

Cardiovascular diseases (CVDs) are the leading cause of death in the globally. Morbidity and disability related to non-fatal events are increasing exponentially. There are several symptoms that may arise after invasive therapeutic approaches such as coronary artery bypass graft (CABG), including chronic pain in anatomical areas connected to the mediastinum; these pains can be found not only initially after surgery, but also years later. We present a case where non-specific neck pain (NNP), in a patient undergoing CABG five years earlier, was approached with an osteopathic technique, working the pericardial area. To the knowledge of the Authors, it is the first case report where osteopathy is associated with a gentle treatment on the pericardial area to resolve a NNP.

Canine mammary tumors represent one of the leading malignant pathology in female dogs, displaying the importance of efficient therapeutic findings, beside the golden standard surgery, able to limit the development of the disease. Studies in human cancers demonstrated that Doxorubicin presents a good effect in different biological processes like apoptosis, autophagy, cell cycle, cell invasion and epithelial to mesenchymal transition. Our study following the effects of Doxorubicin on two canine mammary cancer cell lines P114 and CMT-U27, showing an inhibitory effect in cell proliferation and an expression alteration of the EMT related genes.

Abstract: The widespread and popular use of TADs for orthodontic anchoring has become a daily routine in clinical orthodontic treatment. However, as there have been many accidents over the past decade, safety action is needed to help reduce these accidents. We have advocated using the surgical guide and developed a procedure that can benefit patients and orthodontists. The first part of this paper is about the rationale for making the surgical guide for various implant placements that were observed. Due to their anatomical structure, some placements may require particular attention, which is focused on and discussed in length. The second part deals with fabricating the surgical guide in the laboratory procedure. The data from the intraoral SLT acquisition was extracted, and with the DICOM data from CBCT and in a 3-Shapes software, the guidance was designed. The detailed and step-by-step laboratory procedure, CAD/CAM, and 3D printers to make the surgical guide for TADs are explained. The procedure is performed in an easy-to-understand manner to make using the surgical guide possible for the daily practice of orthodontics (Pubmed).

Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disorder characterized by marked clinical and genetic heterogeneity. Ethnic groups underrepresented in studies may have distinctive characteristics. We sought to evaluate the clinical and genetic landscape of Russian HCM patients. A total of 193 patients (52% male; 95% Eastern Slavic origin; median age 56 years) were clinically evaluated, including genetic testing, and prospectively followed to document outcomes. As a result, 48% had obstructive HCM, 25% had HCM in family, 21% were asymptomatic, and 68% had comorbidities. During 2.8 years of follow-up, the all-cause mortality rate was 2.86%/year. A total of 5.7% received an implantable cardioverter-defibrillator (ICD), 21% septal reduction therapy. Sequencing analysis of 176 probands identified 64 causative variants in 66 patients (38%); recurrent variants were MYBPC3 p.Q1233* (8), MYBPC3 p.R346H (2), MYH7 p.A729P (2), TPM1 p.Q210R (3) and FLNC p.H1834Y (2); 10 were multiple variant carriers (5.7%); 5 had non-sarcomeric HCM, ALPK3, TRIM63 and FLNC; thin filament variant carriers had a worse prognosis for heart failure (HR = 7.9, p=0.007). In conclusion, in the Russian HCM population, the low use of ICD and relatively high mortality should be noted by clinicians; some distinct recurrent variants are suspected to have a founder effect; family studies on some rare variants enriched the worldwide knowledge in HCM.

Abstract: Background: Coronary angiography CT scans play a pivotal role in diagnosing cardiovascular diseases, providing crucial information for treatment planning. However, concerns regarding radiation exposure have prompted the need for establishing region-specific diagnostic reference levels (DRLs) to ensure patient safety. This study aims to assess radiation exposure during coronary angiography CT scans in the Northeast Assam population and establish DRLs tailored to this demographic. Methods: A total of 380 patients were referred to the Primus Diagnostic Centre and Heath City Hospital, Guwahati Assam, during the study with coronary artery disturbances. Data on the technical parameters used in CT procedures were taken in 2021-2022. The aim and study's objective was Organ and surface dose to specific radiosensitive organs (Chest) estimation using software imPACT 1.0.4 from National Radiological Protection Board (NRPB) SR250 Monte Carlo dataset. Results: The study population (n = 380) comprised 190 men and 190 women with an average age of 29 to 75 years. The Mean ± SD of BMI and ED are 22.42±1.06 and 21.57±4.27 respectively. The mean DLP is 854.67, and the mean ED is 21.57. The effective doses for males (13- 27) mSv were in females (13-29) mSv. The DRL for Male population was found to be 24.26mSv.cm2 whereas for female population it was 24.69mSv.cm2. Conclusions: This study highlights the necessity of establishing tailored diagnostic reference levels for coronary angiography CT scans in the Northeast Assam population. By doing so, healthcare providers can ensure optimal image quality while minimizing radiation exposure, ultimately enhancing patient safety and quality of care. These findings have implications for radiological practice in the region and contribute to the ongoing efforts to standardize radiation doses in medical imaging procedures.

Postpartum depression (PPD) is a disorder that impairs the formation of the relationship between mother and child, and reduces the quality of life for affected women to a functionally significant degree. Studying markers associated with PPD can help in early detection, prevention, or monitoring treatment. The purpose of this paper is to review biomarkers linked to PPD and to present selected theories on the pathogenesis of the disease based on data from biomarker studies. The complex etiology of the disorder reduces the specificity and sensitivity of markers, but they remain a valuable source of information to help clinicians. The biggest challenge of the future will be to translate high-tech methods for detecting markers associated with postpartum depression into more readily available and less costly ones. Population-based studies are needed to test the utility of potential PPD markers.

Memory and emotion, fundamental components of our mental existence, are highly vulnerable to psychiatric disorders like post-traumatic stress disorder (PTSD). This condition has been linked to serotonin (5-HT) metabolism disruptions. Over 95% of the 5-HT precursor tryptophan (Trp) is metabolized through the Trp-kynurenine (KYN) metabolic pathway, but little is known about its role in behavior. Kynurenine aminotransferases are responsible for the production of the Trp-KYN metabolite kynurenic acid. The gene aadat codes for mitochondrial kynurenine aminotransferase isotype 2. We generated CRISPR/Cas9-induced aadat knockout (kat2−/−) mice to examine the consequence of the gene deletion on negative valence in emotion, memory, and motor function in males 8 weeks of age and compared them to their wild-type counterparts. The forced swim test showed increased depression-like behaviors in transgenic mice. Anxiety and memory tests showed no significant differences. The transgenic mice had fewer center field and corner entries, shorter ambulation distances, and fewer jumping counts in the open field test. Overall, the transgenic mice exhibit depression-like behavior in a learned helplessness model, emotional indifference, and motor deficits. Here we present the first evidence that the deletion of the aadat gene triggers depression-like behaviors, uniquely associated with despair experience rather than fear memory. These findings have profound implications, opening avenues for further exploration into the main causes of experience-based depression linked to despair. This investigation has the potential to advance our understanding of these complex conditions and pave the way for improved therapeutic strategies by elucidating the relationship between Trp metabolism and the pathogenesis of PTSD.

Background: The current review was conducted to determine the effectiveness of atenolol on all-cause mortality rate among Asian patients with chronic progressive diseases, mainly diabetes mellitus, primary hypertension, and coronary artery disease. Methods: We searched the COCHRANE, MEDLINE, TRIP, and EMBASE databases for published articles up to 31 March 2023. Studies that compared all-cause mortality rates among Asian patients who were on atenolol or other medications were included. Results: The review included 79603 Asian patients from three cohort studies. Out of the studied patients, 36046 were atenolol users and 43557 were non-atenolol users. The review revealed that atenolol users recorded lower all-cause mortality rates compared to non-users with a significant difference (OR= 0.57, CI= 0.44-0.75, P<0.001). The pooled estimate of the all-cause mortality rate was also lower among atenolol users (7.02%) compared to metoprolol tartrate users (13.15%) with a significant difference (OR= 0.50, CI= 0.47-0.53, p < 0.0001). Although the included studies were categorized as having a low risk of bias for most of the studied domains, significant heterogeneity was recorded across these studies (I2 =88%, P=0.001). Conclusion: This review found that atenolol when compared to a control or metoprolol tartrate, has a significant effect in reducing the all-cause mortality rate among Asian patients with chronic progressive disease.

Kratom (Mitragyna speciosa Korth. Havil) has been considered a narcotic drug for years, barred by the law in many parts of the world, while extensive research over the past few decades proves its several beneficial effects some of which are still in ambiguity. In many countries, including Thailand, the indiscriminate use and abuse of Kratom have led to the loss of life. Nonetheless, researchers have isolated almost fifty pure compounds from Krat-om, most of which are alkaloids. The most prevalent compounds, mitragynine and 7-hydroxy mitragynine, are reported to display agonist morphine-like effects on human μ-opioid receptors and antagonists at κ- and δ-opioid receptors with multimodal effects at oth-er central receptors. Mitragynine is also credited to be one of the modulatory molecules for the Keap1-Nrf2 pathway and SOD, CAT, GST, and associated gene’s upregulatory cascades leading to play a pivotal role in neuroprotective actions while its long-high dose is evident to cause the neuronal disorder. Additionally, the anti-inflammatory, antioxidative, antibac-terial, and gastroprotective effects are well-cited. In this context, this review focuses on the research gap to resolve the ambiguities about the neuronal effects of kratom to demonstrate its prospects as a therapeutic target for neurodisorders connecting with other pharmacologi-cal effects.

This case report presents a critical clinical scenario involving a 55-year-old patient who developed severe Plasmodium falciparum malaria with renal complications despite receiving doxycycline prophylaxis while travelling in a malaria-endemic region. The case emphasizes the potential failure of doxycycline prophylaxis and highlights the importance of considering malaria in patients with a history of travel to endemic areas, even if they have adhered to prophylactic treatment. The patient's clinical presentation included fever, extreme fatigue, and loss of consciousness, leading to hospitalization. Laboratory findings revealed severe anaemia, elevated liver enzymes, and impaired renal function, consistent with the criteria for severe malaria. The diagnosis was confirmed by the presence of Plasmodium falciparum parasites on blood smears. Due to limited access to parenteral antimalarial medications, the patient received oral artemether-lumefantrine, resulting in clinical improvement. Supportive care and dialysis played a vital role in the patient's recovery. This case report underscores the need for increased awareness of prophylaxis failure, the challenges of managing severe malaria in non-endemic countries, and the importance of timely and appropriate interventions to improve outcomes in severe malaria cases, particularly those with renal involvement. Further research is warranted to evaluate alternative preventive strategies in regions with drug-resistant malaria strains.

The aim of the study is to evaluate the predictive factors of response to induction chemotherapy in patients with resectable NSCLC, treated at the unit of Thoracic Surgery of Siena University Hospital with radical surgery. From January 1, 2013 to December 31, 2020, 78 patients were recruited. We analyzed the outcomes in terms of 5-years OS based on the Estimated Regression Rate, N2 downstaging and age; two patients’ subgroups were created by age (Group A: age &lt;66 years-old; Group B: age &gt;66 years-old). No 5-year OS difference was observed based on age, while it was observed in patients with N2 downstaging (p=0.031). Bewtween patients with N2 downstaging, only patients in Group A had a significantly increased 5-year OS (p=0.019), while this was not observed in Group B (p=0-321); the same result was observed with the Estimated Regression Rate &gt; 50% (Group A p=0.005; Group B p=0.391). The percentage of disease regression and the N2 down-staging after induction chemotherapy have great value on the survival, although this advantage seems to be observed mostly in younger patients. A multidisciplinary oncologic discussion of clinical cases could provide support in the careful selection of the ideal patients to undergo neoadjuvant treatment before radical surgery.

Disrupted lipid metabolism is a characteristic of gliomas. This study utilizes an ultrastructural approach to characterize the prevalence and distribution of lipids within gliomas. This study made use of tissue from IDH1 wild type (IDH1-wt) glioblastoma (n=18) and IDH1 mutant (IDH1-mt) astrocytoma (n=12) tumors. We uncover a prevalent and intriguing surplus of lipids. The bulk of the lipids manifested as sizable cytoplasmic inclusions and extracellular deposits in the tumor microenvironment (TME); in some tumors the lipids were stored in the classical mem-braneless spheroidal lipid droplets (LDs). Frequently, lipids accumulated inside mitochondria, suggesting possible dysfunction of the beta-oxidation pathway. Additionally, the tumor vascula-ture are shown to have lipid deposits in their lumen and vessel walls; this lipid could have shifted in from the tumor microenvironment or have been produced by the vessel-invading tumor cells. Overproduction of lipids by the tumor is suspected to be due to a combination of two processes: i) dysfunctional oxidative phosphorylation in mitochondria that causes metabolic backup and ac-cumulation of acetyl-CoA, as well as ii) the overproduction of pyruvate due to the tumor cell reli-ance on overactive glycolysis. Tumor cells use lipids for structural components but cannot use them for energy if their oxidative phosphorylation is dysfunctional, which seems to be the case in the tumor cells we examined. This lipid-rich environment, however, offers tumor cells certain advantages: protection from the immune system, non-lipophilic drugs, and oxidative stress. Our research highlights the significant presence of lipid overproduction in both IDH1-wild type glio-blastoma and IDH1-mutant astrocytoma tumors, leading to diverse lipid accumulations in var-ious cellular compartments and structures. This lipid excess stems from disrupted beta-oxidation and dysfunctional oxidative phosphorylation pathways. The implications of this lipid-driven environment include structural support for the tumor cells and protection against immune re-sponses, non-lipophilic drugs, and free radicals.

Polycystic ovary syndrome (PCOS) is increasingly being viewed as an evolutionary mismatch disorder that manifests in women after exposure to a range of lifestyle and environmental factors. Although there is ongoing debate regarding the pathogenesis, international guidelines recommend lifestyle treatment, with diet and exercise, as the first line of management in all women with PCOS. In addition, accumulating evidence suggests that environmental factors such as endocrine disrupting chemicals (EDC) may be involved in the pathogenesis of PCOS due to their known hormonal and metabolic effects. As a result, international professional bodies have recommended that all pregnant women be advised of the risks of EDC and that education programs be developed to inform health professionals. Microparticulate air pollution (MAP) is also a significant environmental exposure that has been associated with a variety of chronic diseases, including PCOS. We performed a systematic review of studies examining the relationship between MAP and PCOS using the PRISMA methodology. The review identified 214 records from PubMed, Cochrane, and Scopus databases, and 4 studies that met the inclusion criteria for qualitative assessment. Preliminary data suggest that MAP may contribute to the pathogenesis of PCOS via a number of mechanisms. This review highlights the need for greater awareness and further research on the effects of MAP in women with PCOS.

Our knowledge of biology and mast cell (MC) function, as well as disorders associated with the pathologic activation of MCs has been evolving over the last few decades. Anaphylaxis, mast cell activation syndrome (MCAS) and mastocytosis are interrelated yet distinct conditions within the spectrum of mast cell activation disorders. Nevertheless, all three conditions can co-exist in one and same patient, as pathologic MC activation is the key finding in all three. When mediator release is excessive and involves multiple systems, anaphylaxis and MCAS may occur. Furthermore, mastocytosis is a clonal disorder of MCs and often presents with anaphylaxis and MCAS. Nevertheless, in some cases even proliferative and accumulative features of MCs in mastocytosis can account for symptoms and disease progression. In each case, diagnosis can be only made when diagnostic consensus criteria are fulfilled. The current article aims to provide a concise clinical update and pinpoint main difficulties in diagnosing these puzzling disorders of MCs in medical practice.

B-cell chronic lymphocytic leukemia (B-CLL) is the most common type of leukemia in the Western world. Mutations in different genes, such as TP53 and ATM, and deletions in specific chromosomal regions, including 11q or 17p, have been associated with a worse prognosis for the disease. Recent research from our group has demonstrated that, contrary to the usual cancer development process through missense mutations, B-CLL is driven by the overexpression of the small GTPase RRAS2 in its wild-type form, without activating mutations. While some mouse models of this disease have been developed to date and are commonly used in B-CLL research, they come with various disadvantages, such as a long waiting period until the leukemia fully develops, the need for cell engraftment, or, in some cases, a failure to replicate the alterations found in human patients. We have recently introduced Rosa26-RRAS2fl/flxmb1-Cre as a new mouse model of B-CLL with full disease penetrance. In this work, we have validated this mouse model as a novel tool for the development of new therapies for B-CLL by testing two of the most widely applied targeted agents: ibrutinib and venetoclax. This also paves the way for the development of new targeted agents against R-RAS2 itself, an approach that has not yet been explored in clinical practice.

Background: Cardiovascular disease (CVD) increases the risk of mortality and morbidity in patients with rheumatoid arthritis (RA). Patients with RA have a 50-60% increased risk for CVD compared with the general population. Cardiovascular risk is commonly meas-ured using the Systemic Coronary Risk Estimation 2 calculator modified for patients with RA. Traditional modifiable risk factors for CVD include arterial hypertension, dyslipidemia, insulin resistance, diabetes, cigarette smoking, and low physical activity. In this study, we analyzed the effects of smoking and the risk of CVD in patients with RA. Methods: This was a prospective, clinical, cohort study with an eight-year follow-up pe-riod. A total of 201 patients, 124 with RA (study group) and 77 with osteoarthritis (OA) (control group), were included in this study. However, only 137 patients (82 with RA and 55 with OA) completed the study. Fifty-eight patients (41 with RA and 17 with OA) died during the study period. We compared the prevalence of smoking and its association with the risk for CVD and RA. Results: The prevalence of smoking in the RA group was higher than that in the OA group (p<0.0001). Trends in the prevalence of smoking in both groups did not change signifi-cantly during the follow-up period. In the RA group, smoking was associated with the in-cidence of CVD in current smokers (p=0.028) and in patients with a history of smoking (p=0.016). These results suggest that smokers have an increased risk for RA. The trend of continued smoking in patients with RA may be attributed to attempts to reduce stress caused by RA symptoms. Conclusions: Previous studies have shown that current and former smokers with RA have more severe symptoms, more joint damage, and poorer response to therapy than those who have never smoked. However, the reason underlying the trend of continued cigarette smoking in patients with RA remains unclear. Further studies are needed to clarify the trend of continued smoking in patients with RA.

Alzheimer’s disease (AD) and vascular dementia (VaD) together contribute to almost 90% of all dementia cases leading to major health challenges of our time with a substantial global socioeconomic burden. While in Alzheimer’s disease, the improved understanding of Amyloid beta (Aß) mismetabolism and tau hyperphosphorylation as pathophysiological hallmarks has led to significant clinical breakthroughs, similar advances in VaD are lacking. We thus highlight here the importance of shared pathomechanisms found in AD and VaD: Endothelial damage, blood brain barrier (BBB) breakdown and hypoperfusion inducing oxidative stress, inflammation and demyelination and thus trophic uncoupling in the neurovascular unit. A dysfunctional endothelium and BBB lead to the accumulation of neurotoxic molecules and Aß through impaired clearance, which in turn leads to neurodegeneration. In this context we discuss possible neuropathological parameters, which might serve as biomarkers and thus improve diagnostic accuracy or reveal targets for novel therapeutic strategies for both forms of dementia.

BACKGROUND: Head and Neck Sarcomas (HNSs) are rare malignant tumors derived from mesenchymal cells characterized by rapid growth, local aggressive behavior, and multiple re-lapses. The Rhabdomyosarcoma (RMS) and the Osteosarcoma (OS) are the more frequent HNS. The present study aims to evaluate the clinical impact of multimodal treatment in patients diagnosed with HNS. METHODS: A retrospective analysis of medical records from patients diagnosed with HNS multimodal treated, four groups were formed: a) surgery and chemotherapy (CTX); b) surgery, CTX, and RT; c) surgery and RT; d) CTX and RT exclusively. The overall survival (OSS), disease-free survival (DFS) and progression-free survival (PFS) rates were calculated using the Kaplan-Meier test. RESULTS: Among 39 patients, 23.1% were diagnosed with RMS , 66.7% with OS and 10.3% with other subtypes of HNS. Moreover, 59% showed initial clinical staging (T1/T2) and of those 35.9% were T1. Surgery was performed in 87.2% patients, RT in 35.9% and CTX in 84.7%. RT performed showed not statistically significant clinical role regarding OSS (p=0.74), DFS (p=0.09) and PFS (p=0.90) rates independent of histological subtype. Finally, OSS (p=0.89), DFS (p=0.13) and PFS (p=0.50) rates were not statistically different for patients treated with monotherapy or multimodal therapy. CONCLUSION: RT has not showed a clinically important role referred to improve OSS, DFS and PFS rates in patients with HNS, regardless of the histological subtype of the primary tumor. Multimodal treatment could influence in survival rates and locoregional control of the disease; however, longitudinal studies such as randomized clinical trials must be conducted.

The microbiota–gut–brain axis has garnered increasing attention in recent years for its role in various health conditions, including neuroinflammatory disorders like complex regional pain syndrome (CRPS). CRPS is a debilitating condition characterized by chronic neuropathic pain, and its etiology and pathophysiology remain elusive. Emerging research suggests that alterations in the gut microbiota composition and function could play a significant role in CRPS development and progression. Our paper explores the implications of microbiota in CRPS and the potential therapeutic role of boron (B). Studies have demonstrated that individuals with CRPS often exhibit dysbiosis, with imbalances in beneficial and pathogenic gut bacteria. Dysbiosis can lead to increased gut permeability and systemic inflammation, contributing to the chronic pain experienced in CRPS. B, an essential trace element, has shown promise in modulating the gut microbiome positively and exerting anti-inflammatory effects. Recent preclinical and clinical studies suggest that B supplementation may alleviate neuropathic pain and improve CRPS symptoms by restoring microbiota balance and reducing inflammation. Our review highlights the complex interplay between microbiota, inflammation, and neuropathic pain in CRPS and underscores the potential of B as a novel therapeutic approach to target the microbiota–gut–brain axis, offering hope for improved management of this challenging condition.

The objective of the study was to apply the principles of analytical quality by design (AQbD) to the analytical method for the determination of the radiochemical purity (PQR) of the radiopharmaceutical sodium iodide 131I oral solution, by means of thin layer chromatography (TLC) with a Radio-TLC scanner, the same one that allows to evaluate the quality of the product. For the AQbD, the analytical objective profile (ATP), critical quality attributes (CQA), risk management, the method operable design region (MODR) were defined through the response surface methodology for method optimization using the MINITAB ® software, Control Strategy and the validation of the method where the parameters of selectivity, linearity, precision, robustness, detection limit, quantification limit, range and stability of the sample solution were evaluated. Under the experimental conditions, the conditions of the method were demonstrated by TLC-Scanner and optimization was carried out for an injection volume of 3 µL, radioactive concentration of 10 mCi/mL and carrier volume of 40 µL. It was statistically demonstrated that the method is selective for the 131I iodide band Rf of 0,8 and for the radiochemical impurity IO₃⁻ Rf of 0.6, linearity from 6,0 to 22.0 mCi/mL, intermediate precision with Global RSD of 0,624%, robustness with global RSD 0,101%, detection limit of 0,09 mCi/mL, quantification limit of 0.53 Ci/mL, conforming range, and stability of the sample solution evaluated over time 0, 2 and 20 hours with a global RSD of 0,362%, obtaining consistent results. The development of the method based on AQbD allowed the generation of a design space and an operational space with knowledge of all the characteristics and limitations of the method, likewise in all the operations the conformity of the tests to the acceptance criteria was verified. The validity of our method is concluded under the established conditions, suitable for use in the manufacturing process of sodium iodide 131I and application in nuclear medicine services.

Endurance triathlons impose substantial physiological stress, yet effects of short-course formats remain relatively unexplored. In this preliminary study, we assessed proteinuria and hydration levels in 27 well-trained triathletes (41.9 [7.4] years) who completed a sprint triathlon consisting of a 1500-m swim, 26-km cycle, and 8-km run. Urine samples were collected before and after the race. The results showed an increase in cases of post-race proteinuria from four to nine (p=0.03). Also, one case of urobilinuria and ketoacidosis was observed after the race. Pre-race glucosuria, which was present in nine cases, decreased to three cases post-race. Although hematuria cases decreased from six to two (p=0.13), pre-race leukocyturia (found in two cases) resolved post-race. There was a significant increase in urine specific gravity (from 1.018 to 1.023, p=0.03), indicating dehydration. In conclusion, short-course triathlons were found to induce post-race proteinuria, urobilinuria, and dehydration without exacerbating pre-race glucosuria, hematuria, or leukocyturia. These preliminary findings contribute to our understanding of medical guidelines for sprint triathlons, an area of endurance sports that has received limited research attention. Further investigation, both mechanistic and longitudinal, is warranted in this regard.

Clinical management in neuro-oncology has changed to an integrative approach that incorporates molecular profile alongside histopathology and imaging findings. While the WHO guideline recommends genotyping of informative alterations as a routine clinical practice for central nervous system (CNS) tumors, acquisition of tumor tissue in the CNS is invasive and not always possible. Liquid biopsy is a non-invasive approach that provides the opportunity to capture the complex molecular heterogeneity of the whole tumor through detection of circulating tumor biomarkers in body fluids, such as blood or cerebrospinal fluid. Despite all the advantages, the low abundance of tumor-derived biomarkers, particularly in CNS tumors, as well as their short half-life has limited the application of liquid biopsy in clinical practice. Thus, it is crucial to identify factors that are associated with the presence of these biomarkers and explore possible strategies that can increase the shedding of these tumoral components into biological fluids. In this review, we first describe the clinical applications of liquid biopsy in CNS tumors including its roles in early detection of recurrence and monitoring of treatment response. We then discuss the utilization of imaging in identifying factors that affect the detection of circulating biomarkers as well as how image-guided interventions such as focused ultrasound can help enhance the presence of tumor biomarkers through blood-brain barrier disruption.

Background: The global pandemic of coronavirus disease 2019 (COVID-19) resulted to many deaths from fulminant respiratory failure. Chronic obstructive pulmonary disease (COPD) is the leading cause of morbidity and mortality worldwide. There has been great concern regarding the impact of COPD on COVID-19 illness. Methods: Data from the Philippine CORONA Study were analyzed to determine the association of COPD and COVID-19 in terms of mortality, disease severity, respiratory failure, mechanical ventilation, and lengths of stay in the intensive care unit (ICU) and hospital. The influence of smoking on COVID-19 disease severity and mortality were also reviewed. Results: A total of 10,881 patients were included in the study and 156 (1.4%) patients had been diagnosed with COPD. Majority of COVID-19 patients with COPD had other existing comorbidities: hypertension, diabetes mellitus, chronic cardiac disease, and chronic kidney disease. COPD patients more commonly present with severe or critical COVID-19. COPD patients with COVID-19 were at higher risk to experience in-hospital mortality, respiratory failure, and to be admitted in the ICU. Smokers were more likely to present with higher COVID-19 severity and experience in-hospital mortality. Conclusion: Our study supports that the growing evidence that COPD among COVID-19 patients is a risk for higher mortality, more severe form of COVID-19, higher ICU admission, and higher respiratory failure needing ventilatory support. Smoking increases risk for developing severe COVID-19 and mortality.

Today, dental implantology is a reliable technique for the treatment of partial and total edentulism. The fixing of dentures on dental implants can be achieved by a number of different techniques. The choice of technique depends on the specific needs of the patient, the condition of the jawbone and the design of the prosthesis itself. Currently, the two most common types of prosthetic abutment connections are cemented or screwed connections, both of which have disadvantages and ad-vantages. The aim of this study is to analyze, with Finite Element Analysis (FEA), a new Cone Morse connection system between the prosthesis and implant. The connection retention has been analyzed by adopting three different approaches: analytical, in vitro and the FEA method. The systems formed by abutment, healing-cap, and crown with three different inclination conditions were modeled in 3D: 0°, 15° and 30°. With Ansys finite element software, the effect of tilt on system retention was studied. The FEA analysis showed comparable results with in vitro studies regarding the retention strength for an abutment-cap system with a taper of 4°, obtaining 66.6 N compared to 68 N calculated through an in vitro study. The inclination of the abutment affects the retention of the system because the hole made on the surface of the abutment, decreases the contact area between the components. The Cone Morse prosthesis implant connection system is the most stable and efficient system compared to the threaded or cemented system. Retention is influenced by factors such as abutment conicity, insertion strength and the contact surface be-tween components.

In recent years, the field of drug delivery has seen a significant shift towards the exploration and utilisation of nanoparticles (NPs) as versatile carriers for therapeutic agents. With its ability to provide exact control over NPs' characteristics, microfluidics has emerged as a potent platform for the efficient and controlled synthesis of NPs. Microfluidic devices designed for precise fluid ma-nipulation at the micro-scale offer a unique platform for tailoring NP properties, enabling en-hanced control over NP properties such as size, morphology and size distribution while ensuring high batch-to-batch reproducibility. Microfluidics can be used to produce liposomes, solid lipid nanoparticles, polymer-based NPs and lipid-polymer hybrid NPs, as well as a variety of inorganic NPs such as silica, metal, metal oxide, quantum dots and carbon-based NPs, offering precise control over composition and surface properties. Its unique precision in tailoring NP properties holds great promise for advancing NP-based drug delivery systems in both clinical and industrial set-tings. Although challenges with large-scale production still remain, microfluidics offers a trans-formative approach to NP synthesis. In this review, starting from the historical development of microfluidic systems, the materials used to create the systems, microfabrication methods and system components will be discussed in order to provide the reader with an overview of micro-fluidic systems. In the following, studies on the fabrication of nanoparticles such as lipid NPs, polymeric NPs and inorganic NPs in microfluidic devices are included.

Background and Objectives: Uveitis, a prevalent eye disorder characterized by inflammatory processes, often leads to cataract formation and significant visual impairment. This study aimed to evaluate preoperative conditions and postoperative outcomes following cataract surgery in uveitis patients. Materials and Methods: A retrospective study was conducted at the University Hospital Center Rebro Zagreb, Croatia, involving uveitis patients who underwent cataract surgery between 2013 and 2022. Eligible patients had uveitic cataracts affecting visual acuity or posterior segment visualization in a "quiet eye" and were disease-inactive for at least three months. Patients with certain preexisting ocular conditions were excluded. Data collected included patient demographics, uveitis type, preoperative therapy, preexisting lesions, and postoperative outcomes such as visual acuity, intraocular pressure, central macular thickness, and complications. Statistical analysis was performed to identify risk factors associated with complications. Results: The study included 105 patients. After cataract surgery, there was a significant improvement in visual acuity at various time points, with 90% of eyes showing improvement. Intraocular pressure decreased over time. Central macular thickness increased at three months post-surgery but remained stable thereafter. Early and late complications were observed in 52.4% and 63.8% of eyes, respectively. The most common complications were posterior capsular opacification, macular edema, and epiretinal membrane. Factors associated with complications varied between early and late stages but included age, age at onset of uveitis, and uveitis type. Conclusion: Cataract surgery in uveitis patients presents challenges but can lead to significant visual improvement. This study highlights the importance of careful patient selection, preoperative and postoperative inflammation management, and precise surgical techniques. Although complications were common, they were manageable, and most patients experienced improved vision, emphasizing the benefits of cataract surgery in this population. However, future investigations should address the study's limitations and further refine perioperative strategies.

Selenoproteins are a group of proteins containing selenium in the form of selenocysteine (Sec, U) as the 21st amino acid coded in the genetic code. Their synthesis is dependent on dietary selenium uptake and a common set of cofactors. Selenoproteins accomplish diverse roles in the body and cell processes by acting, for example, as antioxidants, modulators of the immune function, detoxification agents for heavy metals, and other xenobiotics, key compounds in thyroid hormone metabolism. Although the functions of all this protein family are still unknown, several disorders in their structure, activity or expression have been described by researchers. They concluded that selenium or cofactors deficiency, on one hand, or the polymorphism in selenoproteins genes and synthesis, on the other hand, are involved in a large variety of pathological conditions, including type 2 diabetes, cardiovascular, muscular, oncological, hepatic, endocrine, immuno-inflammatory, neurodegenerative diseases. This review is focused on specific roles in medicine only of selenoproteins that are each named after an alphabet letter, less known than the rest of them, regarding their implications in patho-logical processes of several prevalent diseases and also in disease prevention.

C-reactive protein to lymphocyte ratio (CLR) has been shown to be associated with diseases characterized by chronic, low-grade inflammation. Since type 2 diabetes (T2DM) is also associated with inflammation, we aimed to study the association between CLR and T2DM. Patients with T2DM who presented to internal medicine outpatient clinics of our institution were divided into 2 groups according to their glycosylated hemoglobin (HbA1c) levels as well-controlled (HbA1c&lt;7%) and poorly controlled (HbA1c≥7%) T2DM groups. Subjects assigned as healthy in routine check-up were included as control group. CLR values of the well and poorly controlled diabetics and control cases were compared. CLR of T2DM group (3.51 (0.03-21.78)) was significantly higher than that of the controls (0.65 (0.02-2.92)) (p&lt;0.001). CLR was found to have a sensitivity of 63.2% and a specificity of 97.3% in predicting T2DM. The CLR value of patients with poor diabetic control was 4.76 (0.06-21.78), while the CLR value of patients with well controlled disease was 2.53 (0.03-12.07) (p&lt;0.001). The sensitivity and specificity of the CLR in demonstrating poor diabetic control was 41.2% and the 86.1%, respectively. In conclusion, elevated CLR in T2DM patients and even more increased levels in poorly controlled diabetics suggest that CLR could be a useful additional diagnostic tool in treatment follow-up of the T2DM population.

This study presents a transversal investigation, that we performed at Fundeni hospital, into the therapeutic benefits and efficacy of Emicizumab, a non-factor therapy, in the context of hemophilia A. Ten patients diagnosed with hemophilia A were closely monitored, using clinical and laboratory resources, during the course of Emicizumab treatment, with an average of 12.8 months. Among these patients, six exhibited anti-factor VIII inhibitors, changing the medical approach and adding complexity to their clinical profiles. A comprehensive approach was adopted to assess the coagulation status of patients under Emicizumab therapy. The study employed several key coagulation monitoring tools, of which including thrombin generation time (TGT) and thrombelastography (TEG). These methodologies proved highly valuable results in evaluating the patients' coagulation profiles during the treatment regimen. Additionally, traditionally coagulation assays were utilized to gain a comprehensive understanding of the overall coagulation dynamics. Noteworthy, impressive outcomes emerged from the study. During prophylaxis with Emicizumab all patients had experienced a reduced number of bleeding events. Moreover, a subset of these patients underwent major surgical procedures (orthopedic joint replacements) with successful outcomes. These findings underscore the potential of Emicizumab therapy as an effective option for hemophilia A patients, including those that presented a prompt production of anti-factor VIII inhibitors. As for the outcomes, this transversal study sheds some light on the positive impact of Emicizumab therapy in addressing the coagulation challenges posed by hemophilia A. The utilization of global coagulation assays, such as thrombin generation time, thrombelastography and combined with traditional coagulation assays, used as monitoring tools highlights their significance once more in evaluating the therapeutic response. This research contributes by providing physicians with valuable insights to the field, offering a potential avenue for improved patients’ care and treatment strategies that translate in enhanced quality of life for hemophilia A patients undergoing Emicizumab therapy.

This study proposes a cephalometric analysis that can be used for biomechanical simulation by considering the important and complex relationship between craniofacial morphology and masseter muscle (MM) size and inclination and by including muscle values. The MM line of action drawn between the Gonion (Go) and Orbital (Or) point relative to dental and skeletal references (occlusal and Frankfort planes) were analyzed. A total of 510 pre-treatment lateral cephalometric tracings (217 males, 293 females, 6-50 years) and lateral Bolton standard tracings (6-18 years) were analyzed. The study examined the following: a) skeletal-cutaneous class (linear distance in mm between the projections of points A' and B' on the occlusal plane), b) the angle between the perpendicular line to the occlusal plane and the Go-Or line at the molar occlusal point, and c) the angle between the Go-Or line and the Frankfort plane. The skeletal classes of the patients ranged from -14.5 to 15.5 mm and did not differ by sex or age; the angle between the Go-Or line and the normal to the occlusal plane averaged 39° (range 15° to 53°) and decreased with age, while the angle between the Go-Or line and the Frankfort plane averaged 42° (range 30° to 54°), increased in older patients. No effect of gender was observed. The two angles were also significantly correlated with each other, but not with sagittal jaw discrepancy. Similar results were obtained with Bolton tracings; the positional relationship of the Go-Or line to the teeth and skeletal landmarks is partially consistent with the literature. The present cephalometric analysis can be usefully used to estimate the mechanical advantage of MM in biomechanical simulations of masticatory muscle performance.

Breast cancer stands as the prevailing malignancy across all six Gulf Cooperation Council (GCC) nations. In this literature review, we highlighted the incidence and trend of BC in the GCC. Most of the studies reported a consistent increase in BC incidence over the past decades, which was particularly attributed to the adoption of a westernized lifestyle in the region and the implications of emerging risk factors and other environmental and societal factors, the increase in screening uptake, as well as the improvement in data collection and reporting in the GCC. The data about BC risk factors in GCC was limited. In this geographic region, breast cancer frequently manifests with distinctive characteristics, including an early onset, typically occurring before the age of 50, an advanced stage at presentation, and a higher pathological grade. Additionally, it often exhibits more aggressive features such as human epidermal growth factor receptor 2 (HER2) positivity or the presence of triple-negative (TN) attributes, particularly among younger patients. Despite the growing body of literature on breast cancer in the GCC, data pertaining to survival rates are, regrettably, meager. Reports on breast cancer survival rates emanating from the GCC region are largely confined to Saudi Arabia and the United Arab Emirates (UAE). In the UAE, predictive modeling reveals 2-year and 5-year survival rates of 97% and 89%, respectively, for the same period under scrutiny. These rates, when compared to Western counterparts such as Australia (89.5%) and Canada (88.2%), fall within the expected range. Conversely, Saudi Arabia reports a notably lower 5-year survival rate, standing at 72%. This disparity in survival rates underscores the need for further research directed towards elucidating risk factors and barriers that hinder early detection and screening. Additionally, there is a pressing need for expanded data reporting on survival outcomes within the GCC. In sum, a more comprehensive and nuanced understanding of breast cancer dynamics in this region is imperative to inform effective strategies for prevention, early detection, and improved patient outcomes.

This paper reviews the appearance of joint lesions during arthroscopic surgery of inter-est to the arthroscopic surgeon and their interpretation within the continuum of joint disease. It also points out the relevance of surgical findings as well as giving directions to the surgeon as to how to approach an appropriate decision-making process during an arthroscopic procedure and what therapeutic options are optimal.

MRI is the gold standard for treatment response assessment in glioblastoma. However, there is no consensus regarding the optimal interval for MRI follow-up during standard treatment. Moreover, reliable assessment of treatment response is hindered by the occurrence of pseudoprogression. It is unknown if a radiological follow-up strategy with 2-3 months intervals actually benefits patients and how it influences clinical decision making about continuation or discontinuation of treatment. This study assessed the consequences of scheduled follow-up scans (post-chemoradiotherapy [post-CCRT], after 3 cycles of adjuvant chemotherapy [TMZ3/6], after completion of treatment [TMZ6/6]) and unscheduled scans on treatment decisions during standard concomitant and adjuvant treatment in glioblastoma patients. Additionally, we evaluated how often follow-up scans resulted in diagnostic uncertainty (tumor progression versus pseudoprogression), and whether perfusion MRI improved clinical decision making. Scheduled follow-up scans during standard treatment in glioblastoma patients rarely resulted in early termination of treatment (2.3% post-CCRT, 3.2% TMZ3/6, and 7.8% TMZ6/6), but introduced diagnostic uncertainty in 27.7% of cases. Unscheduled scans resulted in more major treatment consequences (30%; p&lt;0.001). Perfusion MRI caused less diagnostic uncertainty (p=0.021) but did not influence treatment consequences (p=0.871). This study does not support the current pragmatic follow-up strategy and suggests a more tailored follow-up approach.

Cochlear implantation (CI) allows rehabilitation for patients with severe to profound hearing impairment. Although the use of a robotic assistant provides technical assistance to the surgeon, the assessment of the impact of its use on auditory outcomes remains uncertain. We aim to com-pare the hearing results of patients who underwent bilateral cochlear implantation, one side was performed with manual insertion and the other side with robot-assisted insertion. The electrode array intrascalar positioning and the surgery duration were also studied. This retrospective intra-individual study involved 10 patients who underwent bilateral cochlear implantation. The study included 2 infants and 8 adults. The unique composition of this cohort enabled us to utilize each patient as their own control. Regarding speech disyllabic recognition, pure tone average, ECAP, ratio of array translocation, basilar membrane rupture, percentage of translocated electrodes there was no difference between manual and robot-assisted CI groups. This study is the first to compare intra-individual hearing performance after cochlear implantation either manually or robot-assisted. The number of patients and the time delay between manual and robotic implantation may have led to a lack of power, but there was no apparent difference in hearing performance between manual and robotic implantation.

Since decades, oxybutynin hydrochloride is prescribed to improve bladder control in cases of incontinence and excessive urination frequency. This review summarizes synthetic methods enabling preparation of the racemic drug and, in a detailed manner, preparation of (S)-2-cyclohexyl-2-hydroxy-2-phenylacetic acid, a key intermediate in the synthesis of (S)-oxybutynin. Mode of action and metabolism are briefly commented in order to explain the main adverse effects associated with its use and to justify the evolution observed in the diverse commercial formulations. Repositioning opportunities are discussed in terms of clinical trials for the management of hyperhidrosis, hot flashes, and obstructive sleep apnea.

Characterized by severe and fatal arrhythmias induced by cardiac ischemia/reperfusion (CIR), acute myocardial infarction (AMI) is the main cause of morbidity and mortality worldwide. To investigate the cardioprotective role of cardiac Ca2+/cAMP/adenosine signaling in AMI, the effects of L-type Ca2+ channels (LTCC) blocker Nifedipine (NIF) and Verapamil (VER), in the absence and presence of A1-adenosine receptors (A1R) blocker (DPCPX), on the incidence of ventricular arrhythmias (VA), atrioventricular block (AVB) and lethality (LET) induced by CIR in rats were evaluated. CIR was induced in adult male Wistar rats (290-320 g) by occlusion of the left anterior descendent coronary artery (10 min) followed by reperfusion (75 min). VA, AVB and LET incidences were evaluated by ECG analysis and compared between control (CIR group) and intravenously treated 5 min before CIR with NIF 1, 10, and 30 mg/kg (NIF+CIR groups) or DPCPX 100 µg/kg plus NIF 10 mg/kg (DPCPX+NIF+CIR group) and VER 1 mg/kg (VER+CIR group) or DPCPX 100 µg/kg plus VER 1 mg/kg (DPCPX+VER+CIR group). Serum levels of cardiac injury biomarkers (TCK and CK-MB) were quantified. In CIR group, VA, AVB and LET incidences were 90, 80 and 70%, respectively. In NIF+CIR group, incidence of VA was reduced to 50, 30 and 30%, AVB to 25, 10 and 20%, and LET to 25, 20 and 20%, and respectively. In DPCPX+NIF+CIR group, these incidences were not different from CIR group. TCK and CK-MB levels were similar in all groups. These results indicate that pharmacological modulation of the Ca2+/cAMP/adenosine signaling in cardiac cells by LTCC blockade and A1R stimulation could be a new strategy cardioprotective for human AMI therapy.

The anterior cruciate ligament (ACL) injury is the most serious injury in judo. Therefore, its prevention is of great importance. The main mechanism of injury is the collapse of the knee in valgus, which usually occurs when there are deficits of strength and neuromuscular control of the core, external rotators and hip abductors, as well as limitations of ankle and hip mobility. In most sports there is a difference in the prevalence of this injury between both sexes, being more common in women. Therefore, in the present study we observed this possible intersexual disparity in the difference of movement patterns among elite judokas according to their sex, in order to identify those athletes with a higher risk of ACL injury. In addition, it was not observed differences between sexes in the performance of the Single Leg Squat test (SLS test); There was worse neuromuscular control of the non-dominant leg in men and women; No differences were observed in in the range of motion of ankle dorsiflexion and hip external rotation between men and women, but there were differences in internal rotation, a movement whose restriction may be related to an increased risk of ACL injury.

Different bone bruise patterns observed on magnetic resonance imaging (MRI) after non-contact anterior cruciate ligament (ACL) rupture and lateral patellar dislocation may indicate different injury mechanism of knee. In order to investigate the typical bone bruising patterns after ACL rupture and patellar dislocation. In this study, 77 ACL rupture and 77 patellar dislocation patients’ knee MR images with bone bruises between August 2020 and March 2022at our institution were selected and analyzed, respectively. Sagittal and transverse planes images were used to determine the bone bruise location in the lateral-medial and superior-inferior directions of the MR images. The presence, location, and intensity of the bone bruises within specific compartments of the femur and tibial after ACL rupture and patellar dislocation were recorded. Relative bone bruise patterns of the ACL rupture and patellar dislocation were classified and analyzed. Results showed that there were 4 kinds of bone bruise (1-,2-,3-,4- bone bruises) patterns after ACL rupture. The most common two patterns after ACL rupture were 3- bone bruises (including lateral side of femur and both lateral and medial side of tibia, LF+BT; both lateral and medial side of femur and lateral side of tibia, BF+LT, medial side of femur and both lateral and medial side of tibia, MF+BT) followed by 4- bone bruises (both lateral and medial side of femur and tibia, BF+BT), 2- bone bruises (LF+LT, lateral side of femur and tibia; MF+LT, medial side of femur and lateral side of tibia; LF+MT, lateral side of femur and medial side of tibia; MF+MT, medial side of femur and tibia; 0+BT, both lateral and medial side of tibia;), and 1- bone bruise (0+LT, only lateral side of tibia). There was only 1 pattern bone bruise (latera femur and medial patella bone bruise) of patellar dislocation, the most common pattern of patellar dislocation was in the inferior medial patella and lateral anterior inferior femur. The results suggest that the pattern of bone bruise after ACL rupture and patellar dislocation is completely different. There were 4 kinds of bone bruise patterns after non-contact ACL rupture while there was only 1 kind of bone bruise pattern after patellar dislocation bone bruise patients which was in the inferior medial patella and lateral anterior inferior femur.

Eosinophilic Granulomatosis with Polyangiitis (EGPA) is a rare systemic necrotizing vasculitis, affecting small-to-medium sized vessels. EGPA’s clinical manifestations are heterogeneous affecting different organs and systems and the upper respiratory tract can be affected with Ear, Nose and Throat (ENT) involvement. The aim of our study was to assess type manifestations at time of diagnosis in a cohort of EGPA patients and correlate findings with baseline variables (sex, age, antineutrophil cytoplasmic antibodies –ANCA- status) and literature reports. Main ENT manifestations in our patients at time of diagnosis were: nasal polyposis (CRSwNP) (52%), turbinate hypertrophy (48%), nasal swelling (40%), rhinorrhoea (40%), chronic rhinosinusitis without nasal polyposis (CRSsNP) (32%), nasal bone deformities (32%), nasal crusts (20%), nasal mucosal ulcers (12%), corditis (12%), hoarseness/dysphonia (12%), hearing loss (12%), mucoceles(4%) eosinophilic rhinitis (4%). No correlations were found between sex, age, ANCA status and ENT clinical manifestations. A polymorphic ENT involvement is often observed at early stages of EGPA. The presence of nasal, sinus, ear and/or laryngeal manifestations in patients with asthma and hypereosinophilia, independently of sex, age or ANCA status, should raise allert for further investigation and differential diagnosis for EGPA. ENT specialists should be aware of their leading position in this diagnostic race.

Determination of the fetal gender in the first trimester is important in twin pregnancy cases of familial X-linked genetic syndromes and helps determine chorionicity. We assessed and compared the accuracy of first-trimester ultrasound scans, and circulating cell-free fetal DNA (cffDNA) performed by non-invasive prenatal screening (NIPS) in determining fetal gender in the first trimester of twin pregnancies. For this purpose, we enrolled prospectively pregnant women with twin during the first trimester, gestational week (GA) 11-13. The fetal gender was determined using both ultrasound scans and cffDNA screening. Both results were compared to the newborn gender at delivery. A total of 113 women with twin pregnancies were enrolled. There was 100% sensitivity and specificity in Y chromosome detection using cffDNA. The accuracy of gender assignment using ultrasound in any first-trimester scans was 79.7%. Accuracy level increased from 54.2% in CRL 45-54 mm to 87.7% in CRL 55-67 mm and 91.5% in CRL 67-87 mm. Male fetuses had significantly higher chances of a gender assignment error compared to female fetuses, odds ratio = 23.57 (CI 7.356 - 75.66). This is the first study that compared the accuracy of gender determination in the first trimester by cffDNA and by ultrasound scanning in twin pregnancy. It was concluded that the cffDNA is highly sensitive and specific in determining the presence of the Y chromosome in twin pregnancies in the first trimester. Between CRL 67-87 mm, ultrasound scanning offers a highly accurate determination of fetal gender in twin pregnancies. Larger cohorts of multi-center studies are warranted.

Zoon balanitis (ZB) is a mild and chronic inflammatory dermatosis that mostly affects uncircumcised men of middle and old age. The etiology of this disease remains unknown. Moreover, some authors have questioned the presence of this type of balanitis. Our study aimed to assess the expression of proinflammatory cytokines in ZB and demonstrate the presence of a characteristic expression pattern, different from that reported in the literature for penile lichen sclerosus(LS) and penile cancer. Skin biopsies from four foreskins affected by Zoon’s balanitis with surrounding morphologically unchanged skin and 13 from nonlesional foreskins (healthy control adult males undergoing circumcision) were obtained. RNA was extracted from each biopsy, followed by quantitative assessment of the gene expression of interleukin 1-A(IL-1A), interleukin 1-B(IL-1B),interleukin 1 receptor antagonist(IL-1RN),interleukin 6(IL-6), transforming growth factor β1(TGF-β1), and interferon-gamma(INF-γ). The decreased level of IL-1A mRNA was observed in Zoon’s balanitis in both inflamed and healthy skin compared to control samples. There were no statistically significant differences in other investigated cytokines gene expression between Zoon’s balanitis and the control group. In conclusion, the expression of proinflammatory cytokines was not related to the course of zoon balanitis. Moreover, in the case of IL-1A, we observed the suppression of the immune response.

Myelodysplastic syndromes and myeloproliferative neoplasms both represent hematologic diseases associated with bone marrow failure often resulting in anemia. For those patients, transfusion of red blood cell (RBC) units is essential, but results in iron overload (IOL) that may affect various organ functions. Therefore, iron chelation therapy plays a major role in anemic patients, not only because it reduces IOL, but also because it may improve hematopoietic function by increasing hemoglobin or diminishing requirement of RBC transfusions. To assess the utility, efficacy and safety of the different iron chelation medication approved in Germany as well as to examine the effect of chelation on hematopoietic insufficiency, a prospective, multicenter, non-interventional study named EXCALIBUR was designed. In total, 502 patients from 106 German hospitals and medical practices were enrolled. A large proportion of patients switched from deferasirox dispersible tablet to deferasirox film-coated tablet, mainly due to more convenient application which was reflected in the treatment satisfaction questionnaire for medication scores. Iron chelation was effective in lowering serum ferritin levels, with the observed adverse drug reactions being in line with the known safety profile. Hematologic response occurred in a few patients, comparable to other studies that examined hematologic improvement in patients with MDS.

Background: Wilms tumor (WT) is the main renal tumor in children. SIOP-UMBRELLA Guidelines admit Nephron sparing surgery (NSS) in syndromic patients, and in small (&lt;300 ml) nonsyndromic unilateral WTs, without lymph node involvement, and with a substantial expected remnant renal function, after neoadjuvant chemotherapy. We report our prechemotherapy transperitoneal robot-assisted partial nephrectomy (RAPN) in a unilateral non-syndromic Wilms tumor. Methods: A 6-year-old-child showed an exophytic 3.6 cm diameter solid rounding mass involving the upper right renal pole at an incidental abdominal echotomography. CT-scan and abdominal MRI proved no local infiltration neither lymph node involvement was appreciated, suggesting an exophytic mass easily resectable through a NSS robotic approach, with a low risk of rupture and no subverted renal anatomy. The preoperative imaging was not suggestive for WT. A virtual 3D reconstruction of the tumor was performed. Results: the oncologic board approved a robot-assisted partial nephrectomy with the intraperitoneal approach. The histopathologic analysis displayed a WT. The patient underwent 10 vincristine-doses adjuvant chemotherapy. 28-months follow-up showed no tumor recurrence. Conclusions: Intraperitoneal RAPN can represent an opportunity for WT and needs to be assessed as a challenging possibility. This case suggests a potential role of prechemotherapy RAPN in the near future for highly selected patients.

Healthcare workers have atypical working schedule and are exposed to experienced stress that led to poor sleep health and frequent mental complaints, particularly since the Covid-19 crisis. We conducted a cross-sectional study to determine the prevalence of poor sleep hygiene and mental complaints and their associations among healthcare workers. Usual sleep-wake timings were ex-plored during workdays and free days and used to compute sleep duration, sleep efficiency and social jetlag. Insomnia, sleepiness, anxiety and depressive symptoms, and fatigue were calculated using validated scales. A total of 1,562 participants were included (80.5% of women and mean age of 40.0). Among them, 25.9% slept less than 6 hours, 24.3% had a poor sleep efficiency, and 11.5% reported a social jetlag. A total of 33.9% of participants reported insomnia, 45.1% reported EDS, 13.1% reported fatigue, 16.5% reported depression and 35.7% reported anxiety. After ad-justment, sleep duration and sleep efficiency were associated with mental complaints. Social jetlag was associated with significant insomnia but not with anxiety or depression symptoms. Healthcare workers have a high prevalence of poor sleep hygiene and mental complaints. The promotion of sleep health through behavioral sleep strategies should be encouraged to ensure good health for these professionals.

(1) Background: Persistent postural-perceptual dizziness (PPPD) is a syndrome described as secondary when it is the consequence of an organic disorder (s-PPPD) or primary when no somatic triggers cannot be identified. We evaluated a group of patients diagnosed as s-PPPD with Benign Positional Paroxysmal Vertigo (BPPV) as the main somatic trigger with the aim to identify predictive clinical elements of evolution towards PPPD.; (2) Methods: We compared the clinical characteristics of the 51 patients with s-PPPD having as trigger a BPPV (group 1) with 107 subjects diagnosed as BPPV but with no evolution in PPPD (control group). Results: A significant statistical difference in the mean age was found between s-PPPD and the non-s-PPPD group. The latency between the onset of BPPV and the final diagnosis was 25.2 days in the group 1 and 12.8 days in the control group; (4) Conclusions: The parameters mostly involved as potential precipitants of PPPD after BPPV are represented by the age of the patients and a long latency between the onset of BPPV and the final diagnosis: the mean age of the subjects who developed a PPPD following BPPV is significantly higher. These findings lead us to emphasize the importance of an early identification and treatment of BPPV, especially in older patients.

Cytological diagnosis of pleural mesothelioma (PM) is controversial even using ancillary markers (BAP1, MTAP and CDKN2A). Here, we aimed to prospectively validate a previously developed 117-gene expression panel for the differential cytological diagnosis of epithelioid, biphasic PM and mesothelial hyperplasia. Seventy-seven pleural effusions were classified using the 117-gene expression levels (NanoString system). Sixty-eight cases were also screened for ancillary markers. The performance of both gene panel and ancillary markers was evaluated using ROC metrics. A score using the top consistently deregulated genes between epithelioid and biphasic PM was built to subtype malignant effusions. The panel alone reached a diagnostic accuracy (0.89) comparable to the best marker combination (BAP1 plus MTAP: 0.88). Ancillary tests missed 8 PMs, seven of which were correctly classified by the panel. The score built by averaging the expression levels of MSLN, CLDN15 and CFB showed an accuracy of 0.80 in subtyping epithelioid and biphasic effusions. The 117-gene panel is effective for PM cytological diagnosis of epithelioid and biphasic PM. This tool can be complementary to ancillary markers, reducing invasive procedures and allowing an earlier diagnosis. Finally, the possibility to subtype PM on effusions strengthens the panel role in PM diagnosis and management.

Background: The seasonal variation of peptic ulcers is a rhythmic phenomenon reported worldwide, exhibiting diverse patterns and controversies. Unfortunately, it has remained an unresolved mystery for more than 90 years. Numerous studies have found that this phenomenon was closely associated with multiple environmental factors, but the underlying mechanism has never been elucidated. Objectives: This study aims to elucidate the seasonal variation of peptic ulcers and identify the role of environmental factors in the disease. Methods: Based on a recently identified etiology of peptic ulcers, two inverse operations in calculus, differentiation and integration, are iterated to analyze the existing data. First, the fluctuation curve in the seasonal variation is differentiated twice into the monthly incidences caused by multiple individual environmental factors, and the fluctuation curve due to each individual environmental factor is generated separately. Second, the monthly incidences caused by the individual environmental factors are integrated twice to reproduce the fluctuation curves in the seasonal variation of peptic ulcers. Results: The differentiations of the fluctuation curves in the season variation reveal a parallel relationship between the psychological impacts of each individual environmental factor and the monthly incidences of peptic ulcers. The integrations of the monthly incidences caused by 3 environmental factors reproduce the fluctuation curves in 3 representative seasonal patterns of peptic ulcers but make the parallel relationships invisible. Discussion: The parallel relationships revealed a causal role of environmental factors in peptic ulcers, whereas the reproduction of the fluctuation curves elucidated that multiple environmental factors cause the seasonal variation of peptic ulcers by Superposition Mechanism. The regional differences in environmental factors result in the diverse patterns, as well as the controversy questioning the seasonality of peptic ulcers. Significantly, the data analyses exemplify the application of a new concept, Superposition Mechanism, which might be an indispensable methodological complement to life science and medicine.

The clinical requirement for a good esthetic result for immediate implant placement is the absence of dehiscence in the anterior facial alveolar bone. In the presence of a dehiscence, it is recommend-ed to use a connective tissue graft in addition to immediate implant placement or to change to ear-ly implant placement. However, the literature focusing on dehiscence is scarce, and the influence of different placement times and combined use of connective tissue graft on postoperative esthetics in cases with dehiscence is unclear. Therefore, we quantitatively evaluated the pre-extraction de-hiscence morphology and postoperative changes in the facial tissue of implants in three groups: immediate implant placement (Group I), immediate implant placement with connective tissue graft (Group IC), and early implant placement (Group E). Fifty-two implants were obtained (20 in Group I, 16 in Group IC, and 16 in Group E). A wider dehiscence increases the risk of soft tissue regression, which was one reason for choosing early implant placement. A combination of imme-diate implant placement and connective tissue graft, or early implant placement, tended to result in less soft tissue regression due to the thicker postoperative facial soft tissue volume.

Objective Our objective was to observe the benefits and limitations of WES (Whole Exome Sequencing) in the prenatal setting, in the Romanian population. The scope was to observe the diagnostic yield in comparison to molecular karyotyping testing, which had negative results, as well as a case of consanguinity. Methods The first criteria was selecting pregnancies with abnormal ultrasound findings. These findings would not lead the medical team to a certain known syndrome. Second, we performed SNP-array, which tested negative in all cases, except for Case number 9 which had an abnormal result. The ulterior testing method was WES, using Massive Parallel Sequencing of the whole coding region of the human genome on Next Generation Sequencing Platform, NovaSeq 6000 (average coverage >100X, read length: 2x100bp). The Twist Human Core Exome kit RefSeq & Mitochondrial panel (Twist Bioscience) was used for the library preparation. Bioinformatic analysis was performed by direct comparison of the genome of the test sample with the human reference sequence (hg38). Results Our small cohort of 10 patients, resulted in a 50% diagnostic yield. After receiving the results whether a diagnose or a negative result, 2 couples chose to terminate the pregnancy, 5 were born affirmatively without symptoms, and are still monitored up to date. One of the pregnancies led to a stillbirth. We have also found 3 incidental findings that helped the multidisciplinary team better manage the patient as well as the members at risk. Conclusion In this article we present 10 cases which were tested through prenatal WES, showing the great diagnostic yield in comparison to SNP-array in our selected cases. As a closing remark, we wish to highlight the benefits of WES testing in prenatal cases. Further testing is needed to get a clearer picture of the prenatal diagnostic yield in the Romanian population.

Familial Exudative Vitreoretinopathy (FEVR), Norrie disease, and persistent fetal vascular syn-drome (PFVS) are extremely rare retinopathies that are clinically distinct but are unified by ab-normal retinal endothelial cell function – and subsequent irregular retinal vascular development and/or aberrant inner blood-retinal-barrier (iBRB) function. The early angiogenesis of the retina and its iBRB is a delicate process that is mediated by the canonical Norrin Wnt-signaling pathway in retinal endothelial cells. Pathogenic variants in genes that play key roles within this pathway such as NDP, FZD4, TSPAN12, and LRP5, have been associated with the incidence of these retinal diseases. Recent efforts to further elucidate the etiology of these conditions have not only highlighted their multigenic nature but have also resulted in the discovery of pathological variants in additional genes such as CTNNB1, KIF11, and ZNF408, some of which operate outside of the Norrin Wnt-signaling pathway. The goals of this review are to briefly highlight the current understanding of the roles of their encoded proteins in retinal endothelial cells to understand the essential functional mechanisms that can be altered to cause these very rare pediatric retinal vascular diseases.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder that has significant impact on quality of life and work capacity. Treatment of RA aims to control inflammation and alleviate pain, however achieving remission with minimal toxicity is frequently not possible with the current suite of drugs. This review aims to summarise current treatment practices and highlight the urgent need for alternative pharmacogenomic approaches to novel drug discovery. These approaches can elucidate new relationships between drugs, genes, and diseases to identify additional effective and safe therapeutic options. This review discusses how computational approaches such as connectivity mapping offers the ability to repurpose FDA approved drugs beyond their original treatment indication. This review also explores the concept of drug sensitisation, to predict co-prescribed drugs with synergistic effects that produce enhanced anti-disease efficacy by involving multiple disease pathways. Challenges of this computational approach are discussed including the availability of suitable high-quality datasets for comprehensive analysis and other data curation issues. The potential benefits include accelerated identification of novel drug combinations, and ability to trial and implement established treatments in a new index disease. This review underlines the huge opportunity to incorporate disease-related data and drug-related data to develop methods and algorithms which have strong potential to determine novel and effective treatment regimens.

Colorectal liver metastases (CRLM) patients combined with hepatic lymph node metastases was a negative prognostic factor associated with outcomes. Up to now, there was still lack of a reliable method to identify the status of hepatic lymph nodes. The aim of this study was to investigate the predictive ability of mono-exponential, bi-exponential, and stretched-exponential diffusion-weighted imaging (DWI) models to distinguish between benign and malignant hepatic lymph nodes in CRLM patients who underwent neoadjuvant chemotherapy prior to surgery. In total, 97 CRLM patients with pathologically proved hepatic lymph node status were included. Various quantitative parameters, including the apparent diffusion coefficient (ADC) from mono-exponential model, D, D*, and f derived from intravoxel incoherent motion (IVIM) model, as well as DDC and α from stretched-exponential model (SEM), were measured. Multivariate analysis revealed that the pre- treatment DDC value and the short diameter of the largest lymph node after treatment were independent predictors of metastatic hepatic lymph nodes. A nomogram combining these two factors demonstrated excellent performance in distinguishing between benign and malignant lymph nodes in CRLM patients, with an area under the curve (AUC) of 0.873. Therefore, the nomogram can serve as a preoperative assessment tool for determining the status of hepatic lymph nodes and aiding in the decision-making process for surgical treatment in CRLM patients.

The ubiquitous peptide endothelin is currently under investigation as a modulatory factor of autonomic responses to acute emotional stress. Baseline plasma levels of endothelin alter blood pressor responses, but it remains unclear whether autonomic activity and arrhythmogenesis are affected. We recorded sympathetic and vagal indices (derived from heart rate variability analysis), rhythm disturbances, voluntary motion, and blood pressure after acute emotional stress in conscious rats with implanted telemetry devices. Two strains were compared, namely wild-type and ETB-deficient rats, the latter displaying elevated plasma endothelin. No differences in heart rate or blood pressure were evident, but sympathetic responses were blunted in ETB-deficient rats, contrasting prompt activation in wild-type rats. Vagal withdrawal was observed in both strains at the onset of stress, but vagal activity was subsequently restored in ETB-deficient rats, accompanied by low voluntary motion during recovery. Reflecting such distinct autonomic patterns, frequent premature ventricular contractions were recorded in wild-type rats, as opposed to sinus pauses in ETB-deficient rats. Thus, chronically elevated plasma endothelin levels blunt autonomic responses to acute emotional stress, resulting in vagal dominance and bradyarrhythmias. Our findings provide further insights into the pathophysiology of stress-induced tachyarrhythmias and syncope.

Background: Systemic treatment options for hepatocellular carcinoma (HCC) after liver transplantation (LT) are limited in patients in whom sorafenib treatment was failed. The purpose of our study was to compare outcomes among sorafenib, regorafenib, and nivolumab treatment groups in patients with recurrent HCC after LT. Methods: This study retrospectively evaluated patients who received sorafenib for recurrent HCC treatment after LT at a single center from March 2007 to December 2018. Some patients received regorafenib or nivolumab after sorafenib treatment failure. Results: Fifty-six patients were treated with sorafenib due to HCC recurrence. Among these, 38 patients (67.9%) continued treatment with sorafenib only; the other 18 patients (32.1%) were converted to regorafenib treatment. Ten patients (17.9%) of these 18 were converted to nivolumab after sorafenib and regorafenib therapy failed. The disease-free survival and overall survival (OS) from LT were not different among the three groups. In addition, OS from HCC recurrence, sorafenib usage, and usage of each systemic therapeutic agent were not different among the three groups. Three cases in the nivolumab group developed acute rejection; one of these led to graft failure and death due to antibody-mediated rejection. Conclusion: Sequential regorafenib or nivolumab treatment in recurrent HCC LT patients does not improve OS compared sorafenib treatment.

The rapid progress in artificial intelligence, machine learning, and natural language processing has led to the emergence of increasingly sophisticated large language models (LLMs) enabling their use in healthcare. The study assesses the performance of two LLMs: the GPT-3.5 and GPT-4 models in passing the medical examination for access to medical specialist training in Spain MIR. Our objectives included gauging the model's overall performance, analyzing discrepancies across different medical specialties, discerning between theoretical and practical questions, estimating error proportions, and assessing the hypothetical severity of errors committed by a physician. We studied the 2022 Spanish MIR examination after excluding those questions requiring image evaluations or having acknowledged errors. The remaining 182 questions were presented to the LLM ChatGPT4 and GPT-3.5 in Spanish and English. Logistic regression models analyzed the relationships between question length and question sequence d performance. GPT-4 outperformed GPT -3.5, scoring 86.81% in Spanish (p<0.001). English translations had a slightly enhanced performance. Among medical specialties, GPT-4 achieved a 100% correct response rate in several areas, with specialties like Pharmacology, ICU, and Infectious Diseases showing lower performance. The error analysis revealed that while a 13.2% error rate existed, gravest categories like "error requiring intervention to sustain life" and "error resulting in death" had a 0% rate. Conclusions: GPT-4 performs robustly on the Spanish MIR examination, varying its capability to discriminate knoweldge across specialties. While the model's high success rate is commendable, understanding the error severity is critical, especially when considering AI's potential role in real-world medical practice and its implication on patient safety.

(1) Background: Globally, neck pain is prevalent, affecting around thirty percent of the population annually. To better understand the influence of pain on the myofascial layers, the present study investigated these on the upper trapezius muscle in unilateral, more severe neck pain. (2) Methods: This study was a cross-sectional study. Forty patients (42.2 ± 14.7) with a confirmed diagnosis of unilateral neck pain were examined using durometry and indentometry. The study evaluated stiffness, elasticity, and pressure pain threshold of both sides of the neck (symptomatic side: SS; healthy side: HS). Furthermore, the range of motion of the cervical spine (lateral flexion, rotation) was quantified using a digital goniometer. (3) Results: A significant lateral discrepancy was observed in stiffness between groups (durometry: SS – 33.76 ± 7.78, HS – 29.75 ± 7.45, p&lt;0.001; indentometry: SS – 59.73 ± 33.93, HS – 4.18 ± 12.69, p=0.024). In contrast, no differences were found between the comparison sides of the upper trapezius for the parameter’s elasticity (SS – 0.101 ± 1.09, HS – -0.006 ± 0.29, p=0.416), cervical spine mobility (lateral flexion: SS – 37.08 ± 8.15, HS – 37.73 ± 7.61, p=0.559; rotation: SS – 73.55 ± 12.37, HS – 72.85 ± 11.10, p=0.660) and algometry (SS – 36.41 ± 17.53, HS – 37.22 ± 17.00, p=0.657). (4) Conclusion: Overall, it can be concluded that more severe neck pain unilaterally shows differences in stiffness on the same side. Future research is needed to investigate the links.

Anesthesia ensures the welfare of the animal, enables safe and effective procedures, and allows accurate data collection [1]. In clinical veterinary practice, proper training and expertise in anesthesia administration and monitoring are essential. Pigs are commonly used in medical and scientific research as models for studying various aspects of human health, physiology, and disease due to their physiological and anatomical similarities to humans [2–4]. Pigs are suitable experimental animals for many surgery techniques because they are similar in size to humans and have a short reproductive cycle. This makes them ideal for research concerning organ transplantation, cardiovascular surgery, and other procedures that require a large animal model. Pigs also have a similar anatomy to humans, which makes them a good choice for studying diseases and developing new treatments [5]. Sedation and premedication should be administered at the lowest dose to be effective with predictable results and reduced adverse effects, to ensure the safety of both the animal and the team involved in the procedure, with a fast onset and optimizing the induction and maintenance of anesthesia. The goal of induction is to achieve a safe and effective level of anesthesia that ensures the patient's safety and facilitates the research. Most of the time, inhalation anesthesia with endotracheal intubation is the ideal choice for maintenance., allowing efficient anesthetic management. The difficulties related to the endotracheal intubation of pigs can be overcome by knowing the anatomical peculiarities related to the species and the multiple methods cited in the literature. Effective analgesia tailored to the specific procedure, the pig's condition, and individual responses to medications should complete the maintenance and recovery protocols, reducing perioperative complications.

Frontotemporal lobar degeneration (FTLD) belongs to a heterogeneous group of highly complex neurodegenerative diseases and represents the second cause of presenile dementia in individuals under 65. Frontotemporal-TDP is a subgroup of frontotemporal dementia characterized by the aggregation of abnormal protein deposits, predominantly transactive response DNA-binding protein 43 (TDP-43), in the frontal and temporal brain regions. These deposits lead to progressive degeneration of neurons resulting in cognitive and behavioral impairments. Limbic age-related encephalopathy (LATE) pertains to age-related cognitive decline primarily affecting the limbic system which is crucial for memory, emotions, and learning. Though distinct, emerging research suggests a potential overlap in pathogenic processes, with some cases of limbic encephalopathy displaying TDP-43 pathology. Genetic factors play a pivotal role in both disorders. Mutations in various genes, such as progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72), have been identified as causative in frontotemporal-TDP. Similarly, specific genetic variants have been associated with an increased risk of developing LATE. Understanding these genetic links provides crucial insights into disease mechanisms and the potential for targeted therapies.

(1) Background: The aim of this study is to investigate the diagnostic-therapeutic problem of pelvic recurrence of rectum cancer, highlighting current surgical standards and the possible role of the minimally invasive approach. This retrospective analysis of our surgical case study wishes to enter this debate while suggesting a possible line of action, based on the site of recurrence; (2) Methods: We examined, retrospectively, all the patients diagnosed, between 2008 and 2018, with cancer of the rectum at the "Pietro Valdoni" Department of Surgery and monitored their follow-up for 5 years. The sample consisted of 368 patients with rectal neoplasm, 136 females and 232 males, with an average age of 65.8 (ranging from 37 to 86); (3) Results: In 103 of the cases, the neoplasm was located in the upper rectum (28%), in 119 cases in the middle rectum (32.3%), in 102 cases in the lower rectum (27.7%), in 31 cases (8.4%) at the level of the right/sigma junction and in 13 cases it was not possible to define the site with certainty (3.5%); (4) Conclusions: The discussion re-mains open as to which approach is best at surgical level, whether laparoscopic, robotic or open-air. Our experience informs us that the most dangerous site remains on the anastomotic site.

Cardiac resynchronization therapy (CRT) via biventricular pacing (BiVP-CRT) is considered a mainstay treatment for symptomatic heart failure patients with reduced ejection fraction and wide QRS. However, up to one third of patients receiving BiVP-CRT are considered non-responders to the therapy. Multiples strategies have been proposed to maximize the percentage of CRT responders including two new physiological pacing modalities that have emerged during the lasts years: His bundle pacing (HBP) and left bundle branch area pacing (LBBAP). Both pacing techniques aim at restoring the normal electrical activation of the ventricles through the native conduction system in opposition to the cell-to-cell activation of conventional right ventricular myocardial pacing. Conduction system pacing (CSP), including both HBP and LBBAP appears to be a promising pacing modality for delivering CRT and has proven to be safe and feasible in this particular setting. This article will review the current state of the art of CSP-based CRT, its limitations and future directions.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) is one of the most controversial diseases in pediatric rheumatology. Despite its first description being published more than 25 years ago as the sudden and rapid onset of obsessive-compulsive disorder (OCD) and/or tic disorder symptoms as complications of a Group A beta-hemolytic Streptococcus (GAS) infection, precise epidemiological data are still lacking, and there are no strong recommendations for its treatment. Recent advances in the comprehension of PANDAS pathophysiology are largely attributable to animal model studies and the understanding of the roles of Ca++/calmodulin-dependent protein kinase (CaM kinase) II, disrupted dopamine re-lease in the basal ganglia, and striatal cholinergic interneurons. The diagnosis of PANDAS should be made after an exclusion process and should include prepubescent children with a sudden onset of OCD and/or a tic disorder, with a relapsing/remitting disease course, a clear temporal association between GAS infection and onset or exacerbation of symptoms, and the association with other neurological abnormalities such as motoric hyperactivity and choreiform movements. Antibiotic medications are the primary therapeutic modality. Nonetheless, there is a paucity of randomized studies and validated data, resulting in a scarcity of solid recommendations.

The landscape of therapeutic measures to treat multiple myeloma has undergone a seismic shift since the dawn of the current century. This has been driven largely by the introduction of new classes of small molecules, such as proteasome blockers (e.g., bortezomib) and immunomodulators (e.g., lenalidomide), as well as by immunotherapeutic agents starting with the anti-CD38 monoclonal antibody daratumumab in 2015. Recently, other immunotherapies have been added to the armamentarium of drugs available to fight this malignancy. These include the bispecifics teclistamab, talquetamab, and elranatamab, and the chimeric antigen receptor (CAR) T-cell products idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). While the accumulated benefits of these newer agents have resulted in a more than doubling of the disease’s five-year survival rate to nearly 60% and improved quality of life, the disease remains incurable, as patients become refractory to the drugs and experience relapse. This review covers the current scope of anti-myeloma immunotherapeutic agents, both those in clinical use and in development. Included in the discussion are additional monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), bi- and multi-targeted mAbs, and CAR T-cells and emerging natural killer (NK) cells, including products intended for “off-the-shelf” (allogeneic) applications. Emphasis is placed on the benefits of each along with the challenges that need to be surmounted if MM is to be cured.

Low 25 OH vitamin D (25(OH)D) in preterm infants is a risk factor of bronchopulmonary dysplasia (BPD), but increased supplementation failed to demonstrate beneficial effect on BPD. In neonatal animal models, deficiency and excessive vitamin D exposure have been associated with increased mortality and lung histological alterations evocative of BPD. Our hypothesis is that 25(OH)D levels ≥ 120nmol/L is also a risk factor for BPD or death. This retrospective single-center cohort study included all infants born <31 weeks gestational age without major malformation with at least a determination of 25(OH)D <36 weeks corrected age and no determination <50 nmol/L. Routine 25(OH)D determination was performed at 1 month and monthly thereafter. A total of 175 infants were included. Infants with BPD or who died had a significantly lower term and weight, but a similar frequency of 25(OH)D ≥120nmol/L (50.5% vs 43.9%, p=0.53). The logistic regression identified weight (OR 0.997, 95%CI [0.995-0.998]) and term (OR 0.737, 95%CI [0.551-0.975]) as significantly associated with BPD or death; the occurrence of excessive 25(OH)D was not significantly associated (OR 1.029, 95%CI [0.503-2.093]). The present study did not demonstrate any significant association between excessive 25(OH)D after one month of age and BPD or death.

Aims: The objective of this study was to assess the cost-effectiveness of the CardioMEMS HF system in a HF Clinic in Spain by evaluating the real-time remote monitoring of pulmonary artery pressures, which has shown to reduce heart failure (HF) related hospitalizations and improve the quality of life for selected HF patients. Particularly, the study aimed to determine the value of CardioMEMS in Southern Europe, where healthcare costs are significantly lower and its effectiveness remains uncertain. Methods: This single-centre study enrolled all consecutive HF patients who had been implanted with a pulmonary artery pressure sensor (CardioMEMS-HF system, Abbott Laboratories, Abbott Park, IL, USA). The number of HF hospitalizations in the year before and the year after the sensor implantation was compared and quality-adjusted life years (QALY) gained based on a literature review of previous studies was calculated. Results: The rate of HF hospitalisations was significantly lower at 1 year compared with the year before CardioMEMS implantation (0.25 versus 1.10 events/patient-years, HR 0.22, p=0.001). At the end of first year, the usual management outperformed the CardioMEMS HF system, resulting in a net monetary value difference of 2,540€ per patient and a benefit-cost ratio of 0.38. However, by the end of the second year, the CardioMEMS system is estimated to reduce costs compared to usual management. Conclusions: Based on the results, we suggest that remote monitoring of pulmonary artery pressure with the CardioMEMS HF system represents a long-term cost-effective strategy in a healthcare setting in Southern Europe.

(1) Background: The study aimed to investigate compressive strength for three computer-aided design/computer-aided manufacturing (CAD/CAM) dental materials: glassceramic IPS Empress CAD (IvoclarVivadent), hybrid ceramic Cerasmart (GC) and polymer-reinforced graphene G-CAM (Graphenano Dental). (2) Methods: 45 samples consisted of the molar crowns fabricated by three CAD/CAM materials were cemented adhesively on 3D printed abutments (Asiga DentalResin). The samples were divided into 3 groups (n=15) according to the crowns thickness; group 1 under the cusps/cervical margins - 0.6 mm/0.4 mm, group 2 - 1 mm/0.7 mm respectively, and group 3 - 1.5 mm/1 mm. Additionally, 20 cylindrical specimens fabricated by the three crowns and abutments material (n=5) were prepared by CAD/CAM technique. All samples and specimens were subjected to an axial compressive load by using a universal testing machine (Instron 3366-10kN, USA) until fracture. (3) Results: The compressive strength were for Empress CAD 1258 MPa, Cerasmart 501.3 MPa, G-CAM 435 MPa and Asiga resin 360 MPa. G-CAM crowns exhibited a higher maximum compressive load (1701.5-2011.8N) than both Cerasmart (1295.4-1642.9N) and Empress CAD (494.3-597.5N). (4) Conclusions: The CAD/CAM crown materials presented different mechanical behavior; Empress CAD and Cerasmart presented a fragile behavior, with a high compressive strength when compared to G-CAM and Asiga resins.

Influenza viruses cause acute respiratory infections responsible for significant mortality and morbidity around the world. Various factors, such as antigenic drift, allow influenza strains to avoid being fully suppressed by seasonal vaccines. This has led to the increased scrutiny of antivirals as treatment and prophylaxis options for seasonal outbreaks and potential pandemics. Unfortunately, many influenza antivirals suffer from a lack of adequate clinical trials, as well as a lack of toxicity data. This is especially true of umifenovir (arbidol), a drug popularly used for the prevention and treatment of influenza strains in China and Russia. Neuraminidase inhibitors, though widely prescribed, display a potential for future resistance. Adamantanes, while proven to be effective in treating influenza A, are already encountering rapid and widespread cross-resistance and are effectively obsolete. Baloxavir marboxil, a newer antiviral, shows promise in treating acute uncomplicated influenza and may avoid the development of resistance when co-administered with other antiviral drugs. Indeed, the low genetic barrier to resistance associated with influenza antivirals could potentially be overcome by co-administration with other antivirals. This review explores the most widely prescribed antivirals for influenza treatment, their mechanisms of action, and the data currently available about their susceptibility to resistance and efficacy.

The coronavirus disease 2019 (COVID-19) pandemic clearly has had a great influence on the lifestyle of the population, especially on patients with type 2 diabetes mellitus. During the COVID-19 outbreak, many countries/regions implemented social isolation measures, leading to an increase in negative behaviors and impairing the capability of diabetic patients to resist the COVID-19, ultimately causing a severe prognosis. Moreover, multiple studies have emphasized the significance of physical exercise in the management of type 2 diabetic patients infected with COVID-19 as the epidemic progressed. In our study, we selected research focusing on COVID-19-infected diabetic patients from Dec 1, 2019 to Aug 9, 2023 and sought to investigate the impact of type 2 diabetes on the immune function, inflammation factor levels, lung injury and mental disorders of patients, as well as to assess the risk of novel coronavirus pneumonia in these patients. And we also summarized the effects of high-intensity, moderate-intensity and low-intensity exercise on novel coronavirus pneumonia infection in type 2 diabetic patients and the mechanisms of their effects. Finally, diabetic patients with COVID-19 are suggested to perform low-intensity exercise to facilitate their recovery. Our study offers guidance for a proper understanding of the dangers of diabetes and the use of appropriate measures to reduce the risk of novel coronavirus pneumonia infections in type 2 diabetic patients.

Advances in cardiovascular therapies and cancer treatments result in longer patient survival. The coexistence of cancer and cardiovascular disease has been recognized as a complex clinical scenario. Beside cardiovascular disease, older people with cancer are at greater risk of experiencing multimorbidity and the geriatric syndromes such as frailty. In older people, the concurrent presence of cancer and cardiovascular disease increased the risk of mortality, and the presence of frailty can exacerbate their conditions and hinder the treatment effectiveness. Given the significant intersection among frailty, cardiovascular disease and cancer in older people, this paper aims to provide an overview of the current research in this field and identifies gaps in research to understand the burden and impact of frailty in these populations. While many studies have examined the prevalence and impact of frailty on adverse outcomes in patients with cancer or with cardiovascular disease, evidence of frailty in individuals with both conditions is lacking. There is no universally accepted definition of frailty, which leads to inconsistencies in identifying and measuring frailty in older adults with cardiovascular disease and cancer. The frailty index seems to be a preferred frailty definition in studies in patients with cancer, while the frailty phenotype seems to be more commonly used in cardiovascular research. However, differences in how the frailty index was categorised and in how patients were classified as ‘frail’ depending on the cut points may have negative effect on understanding the impact of frailty in the studied populations. This makes it challenging to compare findings across different studies and limits our understanding of the prevalence and impact of frailty in these populations. Addressing these research gaps will contribute to our understanding of the burden of frailty in older people with cardiovascular disease and cancer, and improved clinical care protocols in this vulnerable population.

Although adult spontaneous (non-diabetic) hypoglycaemia is rare, its recognition is important for the preventative or curative treatment of the underlying cause. Establishing Whipple’s triad; low blood glucose, neuroglycopaenia and resolution of neuroglycopaenia on increasing blood glucose levels to normal or above, is essential to verify hypoglycaemia. Awareness that hypoglycaemia may occur in severely ill patients is important for its prevention. Further investigation in such cases is unnecessary unless another cause of hypoglycaemia is suspected. Patients are often asymptomatic and normoglycaemic at review. History of medication, self-medication, access to hypoglycaemic drugs, alcohol and comorbidity may provide aetiological clues. The investigation involves obtaining blood samples during symptoms for laboratory glucose measurement or provoking fasting or postprandial hypoglycaemia as directed by symptoms. If confirmed, insulin, c-peptide, proinsulin, beta-hydroxybutyrate are analysed in hypoglycaemic samples. These will classify hypoglycaemia due to non-ketotic hyperinsulinaemia, non-ketotic hypoinsulinaemia and ketotic hypoinsulinaemia and direct investigations to identify the underlying cause. There are, however, many pitfalls, which may mislabel healthy individuals as “hypoglycaemic” or misdiagnose treatable or preventable causes of spontaneous hypoglycaemia. Clinical acumen and appropriate investigations will mostly identify hypoglycaemia and its cause.

Metabolic surgery can promote comprehensive physiological improvements to alleviate metabolic disorders, particularly for patients with type 2 diabetes. Nevertheless, the therapeutic scope has been limited owing to unexpectedly inconsistent surgical outcomes. Therefore, this study to overcome these obstacles by determining the fundamental mechanism underlying the conflicting outcomes. The surgical anatomy, clinical course, and outcomes of various metabolic surgeries, including modified duodenal-jejunal bypass (DJB) procedures, were compared to understand the specific surgical patterns from different perspectives comprehensively. Patients in the nonobese group were exclusively included to prevent confounding effects from overweight patients with type 2 diabetes. Following intestinal anastomosis, the epithelial identity of the succeeding intestine was replaced by that of the proximal epithelium owing to altered crosstalk between the epithelium and opposing mesenchymal cells. Subsequent intestinal compensatory proliferation and rapid turnover rate accelerate the spread of the replaced epithelium. The main factors contributing to inconsistent outcomes of metabolic surgery are inadequate duodenal exclusion and inappropriate biliopancreatic limb length. Replacement of enteroendocrine cells during regeneration can lead to inconsistent outcomes in metabolic surgery. The type and density of enteroendocrine cells distributed at the terminal end of the proximal intestine play a significant role in diverse outcomes of metabolic surgery.

The amino acids (AAs) and vitamins imbalances are observed in celiac disease (CD). This study evaluated the plasma profile of vitamin A and AAs and the expression level of IL-2, IL-4, IL-10, IL-12 and TGFβ in CD patients. A total of 60 children and adults with CD and 40 healthy controls (HCs) were included. Plasma profile of Vitamin A and AAs and the mRNA expression levels of target genes were assessed. Active adult patients exhibited a decrease in Vitamin A levels (p=0.04) and an increase in IL-2 (p=0.008) and IL-12 (p=0.007) mRNA expression compared to HCs. Treated adult patients showed elevated Serine (p=0.003) and Glycin (p=0.04) levels, as well as increased IL-12 (P&lt;0.0001) mRNA expression, and a decrease in Tryptophan (p=0.04) levels relative to the controls. Additionally, treated adult patients had higher plasma levels of Threonine compared to both active (p=0.04) and control (p=0.02) subjects, and increased mRNA expression of IL-4 (p=0.01) in comparison to active patients. In active children with CD, IL-2 mRNA level was found to be higher than in controls (P&lt;0.0001) and in treated children (p=0.005). Treated children with CD exhibited decreased plasma levels of Tryptophan (p=0.01) and Isoleucine (p=0.01) relative to the controls, and increased mRNA expression of TGFβ (p=0.04) relative to active patients. Managing Retinoic acid levels is crucial to alleviate intestinal inflammation of CD patients. Threonine, tryptophan, and Isoleucine are potential therapeutic options for treating CD, and targeting serine, histidine, tyrosine, and aspartate may hold promise as therapeutic targets for CD patients.

Background: Galectin-3 (Gal-3) overexpression is associated with fibroblastic proliferation and the production of collagen, resulting in increased cardiac fibrosis and remodelling. Aim of the study was to investigate on the expression of Gal-3 in hypertrophic hearts. We examined 19 surgical specimens taken from interventricular septum of 8 patients with Tetralogy of Fallot, 4 patients with aortic valve stenosis, 1 cardiac explant affected from dilated cardiomyopathy, and 6 myocardial biopsies of patients submitted to heart transplantation. Methods: All the samples were routinely processed, stained with Hematoxylin-Eosin, Trichromic stain and elastic fiber stain and selected by having the morphological features of myocardial hy-pertrophy: myocytolysis, nuclear pleomorphism, interstitial fibrosis. Results: At immunohistochemistry, myocardial fibers showed cytoplasmic expression of Gal-3 in the 4 patients with aortic valve stenosis (diffuse in 3 and mild in 1), in the 1 patient with cardiac explant (mild) and in the 4/6 transplanted hearts (mild and focal in 3 and diffuse in 1). The 8 patients affected from Tetralogy of Fallot and 2 patients with transplanted hearts resulted negative. Conclusions: The results agreed with the hypothesis that Gal-3 may play a role in cardiac hyper-trophy; its expression in myocardial fibers is not related with the morphological aspects as suggested by the absence in pediatric cases. The presence in myocardial biopsies taken from transplanted hearts would suggest a possible role in predicting clinical outcome of such patients.

: (1) Background: Healthcare workers (HCWs) are a well-known risk group for coronavirus infections with increased working hours in a potentially infectious environment. We evaluated both IgG and Neutralizing antibody levels, with IgG avidity index and persistence among health workers. (2) Methods: 1001 HCWs were tested for both IgG and Neutralizing antibodies. IgG avidity testing and one-year follow-up testing were done on selected HCWSs. (3) Results: COVID-19 IgG antibody levels were high among 299 (94.62%) HCWs with a history of COVID-19 infection (p &lt;0.0001) compared with 479 (69.92%) HCWs who were not infected with COVID-19 during the first and second wave. A total of 899 (89.81%) HCWs had more than 50% neutralizing antibodies while the remaining 102 (10.19%) HCWs had less than 50% of Neutralizing antibodies. The avidity index was maintained at almost 40% (Gray zone). Both antibody levels were found markedly increased after one year when compared to initial results. (4) Conclusions: Healthcare workers are at a 2.29-fold higher risk of infection; Two folds higher IgG levels in HCWs involved in COVID-19 duty and their persistence for a longer time than in other groups signifies IgG antibody role in the prevention of severe disease in HCWs involved in Covid-19 patient care.

Cancer is second leading cause of death, worldwide. Lung cancer is the leading cause of cancer-related mortality. Plant-based therapeutics and herbal medicine have played a vital role in the development of several anti-cancerous agents, and has been used to reduce the severe side effects of chemotherapy as well. Since the anti-lung cancer properties of the plant Medicago. orbicularis are not explored yet, we identified its phytochemical composition and investigated the anti-oxidant, anti-hemolytic, and anti-cancerous properties of extracts of this plant in A549 human lung adenocarcinoma cells. Results show that all parts of M. orbicularis (stems, leaves, and fruits) exhibit remarkable anti-oxidant and hemolytic activities. In addition, all extracts showed a dose-dependent anti-cancerous cytotoxic activity against A549 cells; with fruit extracts being the most potent. This cytotoxic effect could be related, at least partly, to the induction of apoptosis, where M. orbicularis fruit extracts activated Caspase-3 and PARPP-1, and reduced the ratio of anti-apoptotic BCL-2/ pro-apoptotic BAX, thereby promoting cellular death. Furthermore, the use of M. orbicularis, in combination with a conventional chemotherapeutic agent, cisplatin, was assessed. Indeed, combination of cisplatin and M. orbicularis fruit extracts was more cytotoxic and induced more aggregation of A549 cells than either treatment alone. GC-MS analysis and total polyphenol and flavonoid content determination indicated that M. orbicularis is rich in compounds that have anti-cancerous effects. M. orbicularis may be a potential source of anti-cancerous agents to manage progression of lung cancer and its resistance to therapy.

BRCA1 and 2 pathogenic variants increase lifetime risks of breast (50-75%) and ovarian cancer (15-20%). Guidelines recommend breast screening (MRI and mammogram) or risk-reducing mastectomy with salpingo-oophorectomy for ovarian cancer prevention. We sought to 1) characterize the population of BRCA1/2 carriers in Newfoundland and Labrador (NL) 2) evaluate risk-reducing interventions 3) identify factors influencing screening and prevention adherence. Methods: This is a retrospective study from a population-based provincial cohort of BRCA1/2 carriers. Eligibility criteria for risk-reducing interventions were defined for each case and patients were categorized based on their level of adherence with recommended screening or prevention. Chi-squared and regression analyses were used to determine which factors influenced uptake and level of adherence. Results: 276 BRCA1/2 carriers were identified; 156 living NL females composed the study population. Unaffected females were younger at testing than those with a cancer diagnosis (44.4 y versus 51.7 y; p=0.002). Categorized by eligibility, 61.0%, 61.6%, 39.0% and 75.7% of patients underwent MRI, mammogram, risk-reducing mastectomy, and risk-reducing salpingo-oophorectomy, respectively. Individuals with breast cancer were more likely to have risk-reducing mastectomy (64.7% versus 35.3%; p<0.001), and those who attended specialty hereditary cancer clinic were more likely to be adherent with breast/ovarian cancer recommendations (73.2% versus 13.4%; p<0.001) and to undergo risk-reducing salpingo-oophorectomy(84.1% versus 15.9%; p<0.001). Conclusions: Nearly 40% of female BRCA1/2 carriers were not receiving breast surveillance according to evidence-based recommendations. Cancer risk reduction and uptake of breast imaging and prophylactic breast and pelvic surgeries are significantly higher in patients who receive dedicated specialty care. Organized hereditary cancer prevention programs will be a valuable component of Canadian health care systems and have the potential to reduce the burden of disease country-wide.

The risk of developing cardiovascular diseases (CVD) in patients suffering from rheumatoid arthritis (RA) is 1.5 times higher compared to the general population. The objective of this retrospective study was to determine the type of cardiovascular complications that can appear in patients with rheumatoid arthritis. Reducing the cardiovascular risk, through an aggressive management of the traditional and non-traditional risk factors, is another objective of this study. Early diagnosis and initiation of therapeutic measures to reduce the progression rate of rheumatoid arthritis, while also maintaining an active lifestyle, are the most important problems in young patients. We included a number of 200 patients with rheumatoid arthritis, presenting various stages of disease, concomitant with cardiovascular complications. The incidence by gender was higher in women, while men presented a higher incidence of traditional and non-traditional cardiovascular risk factors. All the patients presented an atherogenic coefficient over 2, indicating a significant risk of atherogenesis. An increased incidence of coronary artery disease was found in men. The patients presented cardiac arrhythmias, especially in the active stage of the condition, while the incidence of atrial fibrillation was higher in women. The active stage of the disease was evaluated using inflammatory biomarkers (ESR, PCR). ESR is not a specific tool for diagnosing the disease, but its important role in monitoring the activity of RA should not be ignored. Moreover, ESR has a significant role in monitoring the evolution and determining the prognostic of congestive heart failure. A target treatment prescribed a target treatment to reduce inflammation and prevent exacerbations was prescribed for all patients. However, in daily clinical practice, the screening for RA is poorly done. Thus, patients are often undiagnosed, while the risk factors are not assessed. In conclusion, even nowadays, RA patients continue to present an increased risk of developing CVD.