Ocular Gene Therapy in a Patient with Dystrophic Epidermolysis Bullosa.

Dystrophic epidermolysis bullosa is a rare genetic disease caused by damaging variants in COL7A1, which encodes type VII collagen. Blistering and scarring of the ocular surface develop, potentially leading to blindness. Beremagene geperpavec (B-VEC) is a replication-deficient herpes simplex virus type 1-based gene therapy engineered to deliver functional human type VII collagen. Here, we report the case of a patient with cicatrizing conjunctivitis in both eyes caused by dystrophic epidermolysis bullosa who received ophthalmic administration of B-VEC, which was associated with improved visual acuity after surgery.

Rivaroxaban in Rheumatic Heart Disease-Associated Atrial Fibrillation.

BACKGROUND: Testing of factor Xa inhibitors for the prevention of cardiovascular events in patients with rheumatic heart disease-associated atrial fibrillation has been limited. METHODS: We enrolled patients with atrial fibrillation and echocardiographically documented rheumatic heart disease who had any of the following: a CHA2DS2VASc score of at least 2 (on a scale from 0 to 9, with higher scores indicating a higher risk of stroke), a mitral-valve area of no more than 2 cm2, left atrial spontaneous echo contrast, or left atrial thrombus. Patients were randomly assigned to receive standard doses of rivaroxaban or dose-adjusted vitamin K antagonist. The primary efficacy outcome was a composite of stroke, systemic embolism, myocardial infarction, or death from vascular (cardiac or noncardiac) or unknown causes. We hypothesized that rivaroxaban therapy would be noninferior to vitamin K antagonist therapy. The primary safety outcome was major bleeding according to the International Society of Thrombosis and Hemostasis. RESULTS: Of 4565 enrolled patients, 4531 were included in the final analysis. The mean age of the patients was 50.5 years, and 72.3% were women. Permanent discontinuation of trial medication was more common with rivaroxaban than with vitamin K antagonist therapy at all visits. In the intention-to-treat analysis, 560 patients in the rivaroxaban group and 446 in the vitamin K antagonist group had a primary-outcome event. Survival curves were nonproportional. The restricted mean survival time was 1599 days in the rivaroxaban group and 1675 days in the vitamin K antagonist group (difference, -76 days; 95% confidence interval [CI], -121 to -31; P<0.001). A higher incidence of death occurred in the rivaroxaban group than in the vitamin K antagonist group (restricted mean survival time, 1608 days vs. 1680 days; difference, -72 days; 95% CI, -117 to -28). No significant between-group difference in the rate of major bleeding was noted. CONCLUSIONS: Among patients with rheumatic heart disease-associated atrial fibrillation, vitamin K antagonist therapy led to a lower rate of a composite of cardiovascular events or death than rivaroxaban therapy, without a higher rate of bleeding. (Funded by Bayer; INVICTUS ClinicalTrials.gov number, NCT02832544.).

The potential role of HIV-1 latency in promoting neuroinflammation and HIV-1-associated neurocognitive disorder.

Despite potent suppression of HIV-1 viral replication in the central nervous system (CNS) by antiretroviral therapy (ART), between 15% and 60% of HIV-1-infected patients receiving ART exhibit neuroinflammation and symptoms of HIV-1-associated neurocognitive disorder (HAND) - a significant unmet challenge. We propose that the emergence of HIV-1 from latency in microglia underlies both neuroinflammation in the CNS and the progression of HAND. Recent molecular studies of cellular silencing mechanisms of HIV-1 in microglia show that HIV-1 latency can be reversed both by proinflammatory cytokines and by signals from damaged neurons, potentially creating intermittent cycles of HIV-1 reactivation and silencing in the brain. We posit that anti-inflammatory agents that also block HIV-1 reactivation, such as nuclear receptor agonists, might provide new putative therapeutic avenues for the treatment of HAND.

Zurletrectinib is a next-generation TRK inhibitor with strong intracranial activity against NTRK fusion-positive tumours with on-target resistance to first-generation agents.

BACKGROUND: While NTRK fusion-positive cancers can be exquisitely sensitive to first-generation TRK inhibitors, resistance inevitably occurs, mediated in many cases by acquired NTRK mutations. Next-generation inhibitors (e.g., selitrectinib, repotrectinib) maintain activity against these TRK mutant tumors; however, there are no next-generation TRK inhibitors approved by the FDA and select trials have stopped treating patients. Thus, the identification of novel, potent and specific next-generation TRK inhibitors is a high priority. METHODS: In silico modeling and in vitro kinase assays were performed on TRK wild type (WT) and TRK mutant kinases. Cell viability and clonogenic assays as well as western blots were performed on human primary and murine engineered NTRK fusion-positive TRK WT and mutant cell models. Finally, zurletrectinib was tested in vivo in human xenografts and murine orthotopic glioma models harboring TRK-resistant mutations. RESULTS: In vitro kinase and in cell-based assays showed that zurletrectinib, while displaying similar potency against TRKA, TRKB, and TRKC WT kinases, was more active than other FDA approved or clinically tested 1st- (larotrectinib) and next-generation (selitrectinib and repotrectinib) TRK inhibitors against most TRK inhibitor resistance mutations (13 out of 18). Similarly, zurletrectinib inhibited tumor growth in vivo in sub-cute xenograft models derived from NTRK fusion-positive cells at a dose 30 times lower when compared to selitrectinib. Computational modeling suggests this stronger activity to be the consequence of augmented binding affinity of zurletrectinib for TRK kinases. When compared to selitrectinib and repotrectinib, zurletrectinib showed increased brain penetration in rats 0.5 and 2 h following a single oral administration. Consistently, zurletrectinib significantly improved the survival of mice harboring orthotopic NTRK fusion-positive, TRK-mutant gliomas (median survival = 41.5, 66.5, and 104 days for selitrectinib, repotrectinib, and zurletrectinib respectively; P < 0.05). CONCLUSION: Our data identifies zurletrectinib as a novel, highly potent next-generation TRK inhibitor with stronger in vivo brain penetration and intracranial activity than other next-generation agents.

A systematic review and meta-analysis of the efficacy and safety of Mavacamten therapy in international cohort of 524 patients with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common heritable myocardial disorder worldwide. Current pharmacological treatment options are limited. Mavacamten, a first-in-class cardiac myosin inhibitor, targets the main underlying pathology of HCM. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of Mavacamten in patients with HCM. PRISMA flow chart was utilized using PubMed, SCOPUS, and Cochrane databases for all up-to-date studies using pre-defined keywords. Pre-specified efficacy outcomes comprised several parameters, including an improvement in peak oxygen consumption (pVO2) and ≥ 1 NYHA class, the need for septal reduction therapy (SRT), change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ), changes in biochemical markers and LVEF, along with peak left ventricular outflow tract gradient at rest and after Valsalva maneuver. Safety outcomes included morbidity and serious adverse events. This systematic review included five studies, four RCTs and one non-randomized control trial comprised a total of 524 (Mavacamten [273, 54.3%] vs placebo [230, 45.7%] adult (≥ 18 years) patients with a mean age of 56 years. The study. comprised patients with Caucasian and Chinese ethnicity and patients with obstructive (oHCM) and non-obstructive (nHCM) HCM. Most baseline characteristics were similar between the treatment and placebo groups. Mavacamten showed a statistically significant increase in the frequency of the primary composite endpoint (RR = 1.92, 95% CI [1.28, 2.88]), ≥ 1 NYHA class improvement (RR = 2.10, 95% CI [1.66, 2.67]), a significant decrease in LVEF, peak left ventricular outflow tract gradient at rest and after Valsalva maneuver. Mavacamten also showed a significant reduction in SRT rates (RR = 0.29, 95% CI [0.21, 0.40], p < 0.00001), KCCQ clinical summary scores (MD = 8.08, 95% CI [4.80, 11.37], P < 0.00001) troponin levels and N-terminal pro-B-type natriuretic peptide levels. However, there was no statistically significant difference between Mavacamten and placebo regarding the change from baseline peak oxygen consumption. Mavacamten use resulted in a small increase in adverse events but no statistically significant increment in serious adverse events. Our study showed that Mavacamten is a safe and effective treatment option for Caucasian and Chinese patients with HCM on the short-term. Further research is needed to explore the long-term safety and efficacy of Mavacamten with HCM. In addition, adequately powered studies including patients with nHCM is needed to ascertain befits of Mavacamten in those patients.

A novel functionalized CuTi hybrid nanocomposites: facile one-pot mycosynthesis, characterization, antimicrobial, antibiofilm, antifouling and wastewater disinfection performance.

BACKGROUND: The continuous progress in nanotechnology is rapid and extensive with overwhelming futuristic aspects. Through modernizing inventive synthesis protocols, a paradigm leapfrogging in novelties and findings are channeled toward fostering human health and sustaining the surrounding environment. Owing to the overpricing and jeopardy of physicochemical synthesizing approaches, the quest for ecologically adequate schemes is incontestable. By developing environmentally friendly strategies, mycosynthesis of nanocomposites has been alluring. RESULTS: Herein, a novel architecture of binary CuO and TiO2 in nanocomposites form was fabricated using bionanofactory Candida sp., for the first time. For accentuating the structural properties of CuTi nanocomposites (CuTiNCs), various characterization techniques were employed. UV-Vis spectroscopy detected SPR at 350 nm, and XRD ascertained the crystalline nature of a hybrid system. However, absorption peaks at 8, 4.5, and 0.5 keV confirmed the presence of Cu, Ti and oxygen, respectively, in an undefined assemblage of polygonal-spheres of 15-75 nm aggregated in the fungal matrix of biomolecules as revealed by EDX, SEM and TEM. However, FTIR, ζ-potential and TGA reflected long-term stability (- 27.7 mV) of self-functionalized CuTiNCs. Interestingly, a considerable and significant biocide performance was detected at 50 µg/mL of CuTiNCs against some human and plant pathogens, compared to monometallic counterparts. Further, CuTiNCs (200 µg/mL) ceased significantly the development of Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans biofilms by 80.3 ± 1.4, 68.7 ± 3.0 and 55.7 ± 3.0%, respectively. Whereas, 64.63 ± 3.5 and 89.82 ± 4.3% antimicrofouling potentiality was recorded for 100 and 200 µg/ml of CuTiNCs, respectively; highlighting their destructive effect against marine microfoulers cells and decaying of their extracellular polymeric skeleton as visualized by SEM. Moreover, CuTiNCs (100 and 200 µg/ml) exerted significantly outstanding disinfection potency within 2 h by reducing the microbial load (i.e., total plate count, mold & yeast, total coliforms and faecal Streptococcus) in domestic and agricultural effluents reached >50%. CONCLUSION: The synergistic efficiency provided by CuNPs and TiNPs in mycofunctionalized CuTiNCs boosted its recruitment as antiphytopathogenic, antibiofilm, antimicrofouling and disinfectant agent in various realms.

Association between a diagnosis of diabetes mellitus and smoking abstinence: An analysis of the National Health Interview Survey.

OBJECTIVE: Both diabetes and smoking significantly increase the risk of cardiovascular disease (CVD). Understanding whether a diagnosis of diabetes can be leveraged to promote smoking cessation is a gap in the literature. METHODS: We used data from the US National Health Interview Survey, 2006 to 2018, to investigate the relationship between self-report of diagnosis of diabetes and subsequent smoking abstinence among 142,884 respondents who reported regular smoking at baseline. Effect sizes were presented as hazard ratios (HRs) derived from multivariable Cox regression models adjusted for potential confounders using diabetes as a time-dependent covariate. Subgroup-specific estimates were obtained using interaction terms between diabetes and variables of interest. RESULTS: A self-reported diagnosis of diabetes was associated with smoking abstinence (HR: 1.21; 95% CI: 1.16 to 1.27). The strength of the association varied based on race (P for interaction: 0.004), where it was strongest in African Americans (HR: 1.44; 95% CI: 1.29 to 1.60); income (P for interaction <0.001), where it was strongest in those with a yearly income less than $35,000 (HR: 1.45; 95% CI: 1.36 to 1.53); and educational attainment (P for interaction <0.001), where it was strongest in those who did not attend college (HR: 1.48; 95% CI: 1.40 to 1.57). CONCLUSION: Among adults who smoke, a diagnosis of diabetes is significantly associated with subsequent smoking abstinence. The association is strongest in socially disadvantaged demographics, including African Americans, low-income individuals, and those who did not attend college.

Insights into the current state of knowledge, practice, and attitudes of physicians regarding gastrointestinal motility disorders in Egypt.

BACKGROUND: Gastrointestinal (GI) motility disorders are common in clinical settings, but physicians still lack sufficient understanding and effective management of these conditions. METHODS: This research assessed Egyptian physicians' knowledge, practices, and attitudes towards GI motility disorders. A cross-sectional survey employing a self-administered questionnaire was carried out among physicians in Egypt. The questionnaire addressed various aspects of physicians' understanding, practices, and attitudes regarding GI motility disorders. Data analysis was conducted using descriptive statistics and presented as frequencies and percentages. RESULTS: A total of 462 physicians took part in the study. Although nearly two-thirds of them knew about GI motility studies, a notable proportion lacked adequate knowledge about GI motility disorders. Notably, 84.2% correctly identified dysphagia as a critical symptom suggestive of an upper GI motility disorder. However, 13.4% incorrectly linked hematemesis with an upper GI motility disorder, and 16.7% expressed uncertainty. In terms of practice, around half of the participants encountered a small number of patients with GI motility disorders (less than 5 per week or even fewer). Only 29.7% felt confident in managing patients with motility disorders. Most participating physicians expressed a willingness to participate in training programs focused on motility disorders. CONCLUSIONS: This study underscores a knowledge gap among Egyptian physicians concerning GI motility disorders. It suggests the necessity of tailored education and training programs to improve their competency and practice in this domain.

Ginger and its constituents in asthma: a mini-review.

OBJECTIVE: The primary objective of this review is to focus on research findings that aim to determine the immunomodulatory action of ginger's active components and the molecular mechanisms that reduce asthma. The study aims to provide an overview of the scientific literature available on ginger's efficacy in treating allergic asthma. DATA SOURCE: The mouse model of asthma has been used to investigate the actions of ginger and its active compounds on allergies and asthma. Various studies and scientific literature on ginger's health-improving qualities and its traditional use have been examined. RESULTS: The findings indicate that ginger and its active ingredients have anti-asthmatic features and a suppressive impact on mast cell production of histamine. Animals given ginger and compounds derived from ginger demonstrate a notable reduction in allergic response, suggesting a significant role in lowering the allergic reaction. CONCLUSION: While ginger shows promise as a potential treatment for allergies and asthma due to its anti-inflammatory, antibacterial, antidiabetic, anticancer, and antioxidant effects, further examination, extrapolation, and confirmation of these results are necessary before utilizing ginger and its active components in human treatments. This review highlights the need for additional research and provides an overview of the current scientific literature on ginger's efficacy in treating allergic asthma.

New 2-oxoindole derivatives as multiple PDGFRα/ß and VEGFR-2 tyrosine kinase inhibitors.

Two new series of N-aryl acetamides 6a-o and benzyloxy benzylidenes 9a-p based 2-oxoindole derivatives were designed as potent antiproliferative multiple kinase inhibitors. The results of one-dose NCI antiproliferative screening for compounds 6a-o and 9a-p elucidated that the most promising antiproliferative scaffolds were 6f and 9f, which underwent five-dose testing. Notably, the amido congener 6f was the most potent derivative towards pancreatic ductal adenocarcinoma MDA-PATC53 and PL45 cell lines (IC50 = 1.73 µM and 2.40 µM, respectively), and the benzyloxy derivative 9f was the next potent one with IC50 values of 2.85 µM and 2.96 µM, respectively. Both compounds 6f and 9f demonstrated a favorable safety profile when tested against normal prostate epithelial cells (RWPE-1). Additionally, compound 6f displayed exceptional selectivity as a multiple kinase inhibitor, particularly targeting PDGFRα, PDGFRß, and VEGFR-2 kinases, with IC50 values of 7.41 nM, 6.18 nM, and 7.49 nM, respectively. In contrast, the reference compound Sunitinib exhibited IC50 values of 43.88 nM, 2.13 nM, and 78.46 nM against the same kinases. The derivative 9f followed closely, with IC50 values of 9.9 nM, 6.62 nM, and 22.21 nM for the respective kinases. Both 6f and 9f disrupt the G2/M cell cycle transition by upregulating p21 and reducing CDK1 and cyclin B1 mRNA levels. The interplay between targeted kinases and these cell cycle regulators underpins the G2/M cell cycle arrest induced by our compounds. Also, compounds 6f and 9f fundamentally resulted in entering MDA-PATC53 cells into the early stage of apoptosis with good percentages compared to the positive control Sunitinib. The in silico molecular-docking outcomes of scaffolds 6a-o and 9a-p in VEGFR-2, PDGFRα, and PDGFRß active sites depicted their ability to adopt essential binding interactions like the reference Sunitinib. Our designed analogs, specifically 6f and 9f, possess promising antiproliferative and kinase inhibitory properties, making them potential candidates for further therapeutic development.

Insight into hazards and control of transfusion-transmitted infections in Egypt: A narrative review.

Blood transfusion is a critical life-saving medical intervention, but it carries the risk of transfusion-transmitted infections (TTIs) that can lead to serious consequences. TTIs include viral, bacterial, parasitic, and prion infections, transmitted through asymptomatic donor blood, contamination of stored blood products, or transfusion-related immunosuppression. Recognized global agents posing challenges to blood safety include human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis B virus (HBV), Syphilis, etc. Emerging pathogens like SARS-CoV-2, hepatitis E, and others present additional risks. The residual risk of TTIs, representing the likelihood of infected donations passing screening tests, varies globally. High-income countries generally show lower prevalence rates than low-income countries. In Egypt, the estimated prevalence rates for HIV, HBV, HCV, and syphilis markers among the donors are 0.23 %, 0.76 %, 2.33 %, and 0.24 %, respectively. In Egypt, specific residual risk estimates are scarce, but prevalence rates for key infections highlight existing challenges. The World Health Organization promotes a global blood safety strategy, advocating for national blood systems, voluntary non-remunerated donors, and quality-assured testing. Despite these measures, the establishment of a haemovigilance system which is critical for monitoring and preventing adverse events, including TTIs, is reported as lacking in Egypt. This highlights the importance of comprehensive surveillance and safety measures in the blood donation process to ensure universal access to safe blood. Primary health care can play a pivotal role in preventing TTIs.

Effects of antioxidant vitamins (A, D, E) and trace elements (Cu, Mn, Se, Zn) administration on gene expression, metabolic, antioxidants and immunological profiles during transition period in dromedary camels.

BACKGROUND: Nutrition has a primary role for optimum expression of genetic potential, and most of the farmers have limited resources of green fodder. Hence, a fat-soluble vitamin, especially vitamin A and E and trace elements remained most critical in the animal's ration and affects their productive and reproductive performance adversely. Animals cannot be able to produce these vitamins in their bodies; hence, an exogenous regular supply is needed to fulfil the physiological needs and to maintain high production performance. This study elucidated effects of antioxidant vitamins (A, D, E) and trace elements (Cu, Mn, Se, Zn) administration on gene expression, metabolic, antioxidants and immunological parameters in dromedary camels during transition period. RESULTS: At 0 day, there were no appreciable differences in the expression patterns of the metabolic (IGF-I, ACACA, SCD, FASN, LPL, and BTN1A1) genes between the control and treatment groups, despite lower levels. A substantial variation in the mRNA levels of SOD1, SOD3, PRDX2, PRDX3, PRDX4, PRDX6, and AhpC/TSA was observed between the control and treatment groups, according to the antioxidant markers. In comparison to the control group, the treatment group displayed a significant up-regulation at 0 and 21 days. The treatment and control groups exhibited substantial differences in the mRNA values of IL-1α, IL-1ß, IL-6, and TNFα, as indicated by immunological markers. In comparison to the control group, there was a noticeable down-regulation in the treatment group at 0 and + 21 days. But IL10 produced the opposite pattern. No significant difference was observed in glucose, cholesterol, triglyceride, HDL, total protein, NEFA, BHBA, cortisol and IGF-1 levels between control and treatment group. The activity of serum GPx, SOD and TAC was significantly affected by time and treatment x time in supplemented groups as compared with control group. IL-1, IL-1, IL-6, and TNF were noticeably greater in the control group and lower in the treatment group. Additionally, in all groups, the concentration of all pro-inflammatory cytokines peaked on the day of delivery and its lowest levels showed on day 21 following calving. The IL-10 level was at its peak 21 days prior to calving and was lowest on calving day. CONCLUSION: The results demonstrated a beneficial effect of antioxidant vitamins and trace elements on the metabolic, antioxidant and immunological markers in dromedary camels throughout their transition period.

Metabolic profile and gene expression pattern of cytokines and antioxidants markers during different physiological stages in Barki ewes.

BACKGROUND: In livestock, identifying the physiological and reproductive stages is valuable in guiding management decisions related to nutrition, veterinary procedures, and breeding programs. To achieve this goal, a cohort of Barki ewes in this research underwent observation across three pivotal physiological conditions: pre-pregnancy, late pregnancy, and early lactation. Blood samples were collected to investigate the changes in serum metabolic profile as well as gene expression pattern of cytokines and antioxidants markers during these stages. RESULTS: Our results showed that during late pregnancy, there was a significant (P < 0.05) increase in red blood cells (11.9 ± 0.5 1012/L), hemoglobin (10.8 ± 0.4 g/dl) and neutrophils count (7 ± 0.1 109/L) with significant decrease (P < 0.05) of total white blood cell count (9.1 ± 0.05 109/L). The packed cell volume (%) and monocyte count showed a significant (P < 0.05) decrease during both late pregnancy and early lactation stages. The serum concentrations of glucose, cholesterol, GSH, GPx, SOD and catalase displayed significant (P < 0.05) decrease during late pregnancy and early-lactation. Notably, during late pregnancy, there was a significant (P < 0.05) increase in the serum concentrations of albumin, globulin, urea, IGF-1, and malondialdehyde with significant decrease (P < 0.05) of total protein (4.9 ± 0.08 g/dl). Additionally, during early lactation, there was a significant (P < 0.05) increase in the serum levels of non-esterified fatty acids, triiodothyronine (T3), and thyroxin (T4). The gene expression profiles of cytokines (IL-4, IL-6, IL-8, and NFKB) were decreased in the ewes during late pregnancy compared to pre-pregnant and early lactation stages. In addition, the expression profile of antioxidant genes (SOD, CAT, GPX, and Nrf2) was significantly upsurged in the non-pregnant ewes compared to late pregnancy and early lactation ones. CONCLUSIONS: The results concluded that different physiological status significantly affects the blood metabolic profile and gene expression pattern in Barki sheep. Our findings can be helpful in monitoring animal health and applying in breeding programs of Barki sheep under harsh environmental conditions.

Assessment of vitamin status; A, E and D in Egyptian neonates with IUGR: a cross sectional study.

BACKGROUND: Neonates with intrauterine growth retardation (IUGR) may present with fatal complications and permanent serious consequences. Vitamin status may influence fetal development. In this study we assessed vitamin A, E and D concentrations in umbilical cord blood in newborns with IUGR. METHODS: Maternal data were obtained. Neonatal assessment included; age of gestation calculated from last menstrual period, Ultrasound (U/S), new Ballard, Apgar scores and anthropometric measurements including; Head circumference, length and weight. WHO growth percentile curves were used. Vitamin A, E and D in cord blood samples were measured by high performance liquid chromatography (HPLC) and ELISA consecutively. RESULTS: A total of 86 full term newborns were enrolled in this study, 42 (48.8%) with IUGR with gestational age (33.59 ± 1.20) week by U/S and 44 (51.2%) appropriate for gestational age neonates with gestational age (38.70 ± 1.50). Ballard and Apgar scores (p < 0.05) and Z scores for weight, length and head circumference (p < 0.001) at birth were significantly lower in neonates with Intrauterine growth retardation (IUGR) than appropriate for gestational age (AGA) neonates. The levels of Vitamin A, E and D were significantly lower in the IUGR group than the AGA (p < 0.05) for all. Significant positive correlations of weight with vitamin A, and E cord blood levels were found (p < 0.05), while length was significantly positively correlated only with vitamin A (p < 0.05). Head circumference showed significant positive correlations with the three vitamins (p < 0.05) for all. CONCLUSION: Neonates with IUGR had significantly lower levels of Vitamin A, E and D than AGA neonates. Significant positive correlations of weight with vitamin A, and E cord blood levels was detected, while neonatal length was associated only with vitamin A level. The present study highlights the significance of nutritional policies for inhibiting deficiency of these vitamins during pregnancy and childhood.

Lack of leisure time physical activity and variations in cardiovascular mortality across US communities: a comprehensive county-level analysis (2011-2019).

OBJECTIVES: To investigate the associations between county-level proportions of adults not engaging in leisure-time physical activity (no LTPA) and age-adjusted cardiovascular mortality (AACVM) rates in the overall US population and across demographics. METHODS: Analysing 2900 US counties from 2011 to 2019, we used the Centers for Disease Control and Prevention (CDC) databases to obtain annual AACVM rates. No LTPA data were sourced from the CDC's Behavioural Risk Factor Surveillance System survey and county-specific rates were calculated using a validated multilevel regression and poststratification modelling approach. Multiple regression models assessed associations with county characteristics such as socioeconomic, environmental, clinical and healthcare access factors. Poisson generalised linear mixed models were employed to calculate incidence rate ratios (IRR) and additional yearly deaths (AYD) per 100 000 persons. RESULTS: Of 309.9 million residents in 2900 counties in 2011, 7.38 million (2.4%) cardiovascular deaths occurred by 2019. County attributes such as socioeconomic, environmental and clinical factors accounted for up to 65% (adjusted R2=0.65) of variance in no LTPA rates. No LTPA rates associated with higher AACVM across demographics, notably among middle-aged adults (standardised IRR: 1.06; 95% CI (1.04 to 1.07)), particularly women (1.09; 95% CI (1.07 to 1.12)). The highest AYDs were among elderly non-Hispanic black individuals (AYD=68/100 000). CONCLUSIONS: Our study reveals a robust association between the high prevalence of no LTPA and elevated AACVM rates beyond other social determinants. The most at-risk groups were middle-aged women and elderly non-Hispanic black individuals. Further, county-level characteristics accounted for substantial variance in community LTPA rates. These results emphasise the need for targeted public health measures to boost physical activity, especially in high-risk communities, to reduce AACVM.

Evaluation of Pyrazolyl-Indolizine Derivatives as Antimicrobial Agents: Synthesis, In vitro, In silico ADMET and Molecular Docking Studies.

Herein, we report analogues of s-indacene by the synthesis of novel indolizine derivatives. Using chloroform as an appropriate solvent, sixteen derivatives of pyrazolyl-indolizine (4--19) were prepared by the reaction of 3-(dimethylamino)-1-(1H-pyrrol-2-yl)prop-2-en-1-one (1) with hydrazonoyl chloride derivatives (2) in the presence of triethylamine in good to excellent yields. We used NMR spectra, IR, mass spectrometry, as well as elemental analyses to prove the chemical structures and the purity of the synthesized compounds 4-19. Among all tested compounds 5, 9, 13 and 19 had a potent antimicrobial efficiency against Bacillus subtilis, Staphylococcus aureus, Pseudomonas aerginousea, Sallmonella typhemerium, and Candida albicans. Furthermore, a significant increase in lipid peroxidation (LPO) toward the Gram-negative bacteria, Pseudomonas aeruginosa when treated with compound 9 was observed, while compound 13 remarkably increased the cell membrane oxidation of Salmonella typhimurium. Additionally, we utilized docking studies and in silico methods to evaluate the drug-likeness, physicochemical properties, and ADMET profiles of the compounds. The results of the molecular docking simulation revealed that the synthesized compounds displayed decreased binding energy when interacting with the active sites of important enzymes, including Sterol 14-demethylase of C. albicans, Dihydropteroate synthase of S. aureus, LasR of P. aeruginosa, Glucosamine-6-phosphate synthase of S. typhimurium, and Gyrase B of B. subtilis.

Comprehending the disruptive influence of workplace gaslighting behaviours and mobbing on nurses' career entrenchment: A multi-centre inquiry.

AIM: To explore the disruptive influence of workplace gaslighting behaviours and mobbing on nurses' career entrenchment across multiple healthcare centres. DESIGN: A multi-centre cross-sectional. METHODS: Data were collected from 483 nurses from various healthcare settings in Egypt, spanning from January 2024 to February 2024. The Gaslighting at Work Questionnaire, Luxembourg Workplace Mobbing Scale and Career Entrenchment Scale were employed for data collection. RESULTS: The study revealed moderate levels of gaslighting, mobbing and nurses' career entrenchment. Also, there is a negative correlation between nurses' career entrenchment and both gaslighting and mobbing, while gaslighting and mobbing exhibit a positive correlation. The study also highlighted regional disparities in the prevalence of these phenomena, with the highest incidences noted in urban healthcare settings. CONCLUSION: The findings underscore the critical impact of workplace gaslighting and mobbing on nurses' career entrenchment. REPORTING METHOD: The relevant reporting method has been adhered to, that is, STROBE. IMPLICATION FOR THE PROFESSION: The future of the nursing profession requires building productive nurses who can cope with negative workplace experiences. This could be achieved by cultivating a workplace culture that has zero tolerance for these experiences. Offering counselling services or employee assistance programmes to help nurses cope with the emotional toll of these negative experiences is a promising strategy. IMPACT: This study is the first to examine serious workplace practices like gaslighting and mobbing in a nursing context, emphasizing their effect on nursing-sensitive indicators like career entrenchment. It is one of the important initiatives geared towards upgrading the competitiveness and magnetism of healthcare organizations in the era of green human resources management. Results provide valuable insights for nurse leaders to control nursing turnover and shortage crises in different endeavours. PATIENT OR PUBLIC CONTRIBUTION: In our study, nurses from diverse geographical regions and varied specialties actively participate, offering a rich tapestry of experiences and perspectives.

Design, synthesis, structure elucidation, antimicrobial, molecular docking, and SAR studies of novel urea derivatives bearing tricyclic aromatic hydrocarbon rings.

The targeted compounds were prepared using both (9H-fluoren-9-ylidene)hydrazine (1) and 10H-phenothiazine (2) as starting materials. The treatment of 1 or 2 with different isocyanates afforded the title compounds 7a-d, 8a, and 8b in excellent yield. All compounds were characterized and ascertained by infrared, nuclear magnetic resonance, and elemental analyses as well as single-crystal X-ray diffraction. The antimicrobial efficiency of all was tested in vitro, and a noticeable inhibition activity against Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Candida albicans was obtained by compounds 7a, 7b, 8a, and 8b. Moreover, the biofilm mechanism activity was strongly inhibited by compounds 7b and 8b for all bacterial pathogens, with a percentage ratio of more than 55%. The findings from the molecular docking simulation revealed that compounds 7a, 7b, 8a, and 8b exhibited favorable binding energies and interacted effectively with the active sites of sterol 14-demethylase, dihydropteroate synthase, gyrase B, LasR (major transcriptional activator of P. aeruginosa), and carbapenemase for C. albicans, S. aureus, B. subtills, K. pneumoniae, and P. aeruginosa, respectively. These results suggest that the compounds have the potential to inhibit the activity of these enzymes and demonstrate promising antimicrobial properties. Moreover, the in silico evaluation of drug likeness and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles for compounds 7a, 7b, 8a, and 8b demonstrated their compatibility with Lipinski's, Ghose's, Veber's, Muegge's, and Egan's rules. These findings suggest that these compounds possess favorable physicochemical properties, making them promising candidates for continued drug development efforts.

Secure Enhancement for MQTT Protocol Using Distributed Machine Learning Framework.

The Message Queuing Telemetry Transport (MQTT) protocol stands out as one of the foremost and widely recognized messaging protocols in the field. It is often used to transfer and manage data between devices and is extensively employed for applications ranging from smart homes and industrial automation to healthcare and transportation systems. However, it lacks built-in security features, thereby making it vulnerable to many types of attacks such as man-in-the-middle (MitM), buffer overflow, pre-shared key, brute force authentication, malformed data, distributed denial-of-service (DDoS) attacks, and MQTT publish flood attacks. Traditional methods for detecting MQTT attacks, such as deep neural networks (DNNs), k-nearest neighbor (KNN), linear discriminant analysis (LDA), and fuzzy logic, may exist. The increasing prevalence of device connectivity, sensor usage, and environmental scalability become the most challenging aspects that novel detection approaches need to address. This paper presents a new solution that leverages an H2O-based distributed machine learning (ML) framework to improve the security of the MQTT protocol in networks, particularly in IoT environments. The proposed approach leverages the strengths of the H2O algorithm and architecture to enable real-time monitoring and distributed detection and classification of anomalous behavior (deviations from expected activity patterns). By harnessing H2O's algorithms, the identification and timely mitigation of potential security threats are achieved. Various H2O algorithms, including random forests, generalized linear models (GLMs), gradient boosting machine (GBM), XGBoost, and the deep learning (DL) algorithm, have been assessed to determine the most reliable algorithm in terms of detection performance. This study encompasses the development of the proposed algorithm, including implementation details and evaluation results. To assess the proposed model, various evaluation metrics such as mean squared error (MSE), root-mean-square error (RMSE), mean per class error (MCE), and log loss are employed. The results obtained indicate that the H2OXGBoost algorithm outperforms other H2O models in terms of accuracy. This research contributes to the advancement of secure IoT networks and offers a practical approach to enhancing the security of MQTT communication channels through distributed detection and classification techniques.

Evaluation of the role of repeated inferior vena cava sonography in estimating first 24 h fluid requirement in resuscitation of major blunt trauma patients in emergency department Suez Canal University Hospital.

INTRODUCTION: The assessment of hemodynamic status in polytrauma patients is an important principle of the primary survey of trauma patients, and screening for ongoing hemorrhage and assessing the efficacy of resuscitation is vital in avoiding preventable death and significant morbidity in these patients. Invasive procedures may lead to various complications and the IVC ultrasound measurements are increasingly recognized as a potential noninvasive replacement or a source of adjunct information. AIMOF THIS STUDY: The study aimed to determine if repeated ultrasound assessment of the inferior vena cava (diameter, collapsibility (IVC- CI) in major trauma patients presenting with collapsible IVC before resuscitation and after the first hour of resuscitation will predict total intravenous fluid requirements at first 24 h. PATIENTS & METHODS: The current study was conducted on 120 patients presented to the emergency department with Major blunt trauma (having significant injury to two or more ISS body regions or an ISS greater than 15). The patients(cases) group (shocked group) (60) patients with signs of shock such as decreased blood pressure < 90/60 mmHg or a more than 30% decrease from the baseline systolic pressure, heart rate > 100 b/m, cold, clammy skin, capillary refill > 2 s and their shock index above0.9. The control group (non-shocked group) (60) patients with normal blood pressure and heart rate, no other signs of shock (normal capillary refill, warm skin), and (shock index ≤ 0.9). Patients were evaluated at time 0 (baseline), 1 h after resucitation, and 24 h after 1st hour for:(blood pressure, pulse, RR, SO2, capillary refill time, MABP, IVCci, IVCmax, IVCmin). RESULTS: Among 120 Major blunt trauma patients, 98 males (81.7%) and 22 females (18.3%) were included in this analysis; hypovolemic shocked patients (60 patients) were divided into two main groups according to IVC diameter after the first hour of resuscitation; IVC repleted were 32 patients (53.3%) while 28 patients (46.7%) were IVC non-repleted. In our study population, there were statistically significant differences between repleted and non-repleted IVC cases regarding IVCD, DIVC min, IVCCI (on arrival) (after 1 h) (after 24 h of 1st hour of resuscitation) ( p-value < 0.05) and DIVC Max (on arrival) (after 1 h) (p-value < 0.001). There is no statistically significant difference (p-value = 0.075) between repleted and non-repleted cases regarding DIVC Max (after 24 h).In our study, we found that IVCci0 at a cut-off point > 38.5 has a sensitivity of 80.0% and Specificity of 85.71% with AUC 0.971 and a good 95% CI (0.938 - 1.0), which means that IVCci of 38.6% or more can indicate fluid responsiveness. We also found that IVCci 1 h (after fluid resuscitation) at cut-off point > 28.6 has a sensitivity of 80.0% and Specificity of 75% with AUC 0.886 and good 95% CI (0.803 - 0.968), which means that IVCci of 28.5% or less can indicate fluid unresponsiveness after 1st hour of resuscitation. We found no statistically significant difference between repleted and non-repleted cases regarding fluid requirement and amount of blood transfusion at 1st hour of resuscitation (p-value = 0.104). CONCLUSION: Repeated bedside ultrasonography of IVCD, and IVCci before and after the first hour of resuscitation could be an excellent reliable invasive tool that can be used in estimating the First 24 h of fluid requirement in Major blunt trauma patients and assessment of fluid status.