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The recent outbreak of the highly contagious coronavirus disease 2019 (COVID-19) caused by the novel coronavirus SARS-CoV-2 has created a global health crisis with socioeconomic impacts. Although, recently, vaccines have been approved for the prevention of COVID-19, there is still an urgent need for the discovery of more efficacious and safer drugs especially from natural sources. In this study, a number of quinoline and quinazoline alkaloids with antiviral and/or antimalarial activity were virtually screened against three potential targets for the development of drugs against COVID-19. Among seventy-one tested compounds, twenty-three were selected for molecular docking based on their pharmacokinetic and toxicity profiles. The results identified a number of potential inhibitors. Three of them, namely, norquinadoline A, deoxytryptoquivaline, and deoxynortryptoquivaline, showed strong binding to the three targets, SARS-CoV-2 main protease, spike glycoprotein, and human angiotensin-converting enzyme 2. These alkaloids therefore have promise for being further investigated as possible multitarget drugs against COVID-19.

Natural products are important in drug discovery because they provide structural clues for the creation of novel therapeutic treatments for a variety of ailments. The present study aims to focus on the in silico assessment of the therapeutic potential of phytochemical compounds isolated from Tarchonanthus camphoratus L. The physicochemical and pharmacokinetic parameters of the three identified compounds were predicted using various integrated web-based tools. Following that, the PharmMapper web server was used to undertake structural-based virtual screening for the probable targets. Based on the findings, molecular docking was then used to investigate the binding interactions between the most promising lead and the targets indicated by the PharmMapper server. The obtained results revealed that the hydrogen bonds and total polar surface area for all compounds were within the limit range stated for Lipinski’s rule of five and subsequently easily transported. However, only trifloculoside was found to be soluble (Log P = 2.3), permeable with no violation. Trifloculoside was suggested as potential antineoplastic agent based on its activity, safety, and binding energy to the target (− 6.8 kcal/mol). The obtained molecular dynamic simulation results were further supported the stability and flexibility of the complex. These findings suggest trifloculoside could be used as a starting point for future drug development initiatives in chemotherapy.

Introduction Nurses play a crucial role in the primary prevention of phenylketonuria (PKU) within national screening programs for newborns. This is achieved through consult with the child’s provider promptly to arrange a PKU test, accurate collection of blood samples at maternal and child health centers, enable early detection of potential cases. Aim This study aimed to assess the level of primary health care nurses’ knowledge and neonatal screening performance for phenylketonuria in Alexandria Methods A descriptive research design was used. The study included all nurses (50 nurses) who are responsible for obtaining newborn screening test from 5 primary health care centers in Alexandria. Two tools were used to collect the necessary data: nurses’ knowledge regarding phenylketonuria disease assessment sheet and nurses’ performance about newborn screening for phenylketonuria observational checklist. Results It was found that the mean age of participant was 42.94 ± 5.0 and 52% of them had completed their technical level of education and the means years of experience was 17.64 ± 4.84. The total mean score of nurses’ knowledge regarding phenylketonuria screening was 16.24 ± 1.99 with the mean percent score of 72.72 ± 8.27. It was also found the total score of nurses’ screening performance was 11.0 ± 0.97 with the mean percent score of 64.71 ± 5.70. A significant positive correlation was found between nurses’ knowledge and their screening performance with P  = < 0.001. Conclusion It was concluded that majority of participant nurses had correct knowledge in neonatal screening and many aspects of phenylketonuria disease. However, they still needed support in steps related to infection control.

Background The adverse effect of chronic kidney disease extends far beyond the primary impact on kidney function. Children undergoing Haemodialysis (HD) develop several oral complications such as decreased salivary flow rate and xerostomia. This creates a vicious cycle where the compulsive urge to drink further contributes to fluid overload. Providing a standalone program may not be sufficient to ensure full adherence to fluid restrictions. Auricular Acupressure (AA) induces parasympathetic stimulation which increases salivary flow rate and alleviate persistent feeling of thirst. Aim to assess the effect of bundling AA and fluid restriction program on salivary flow rate and fluid control adherence among children undergoing HD. Methods A single-blinded randomized control trial was conducted at Alexandria University Children’s Hospital in Smouha, Egypt. A sample of 60 children receiving HD was randomly assigned to two parallel groups. The control group received the fluid restriction program through general small-group discussion sessions, individualized consultations, and follow-up. The study group also received the intervention bundle: the fluid restriction program and twelve sessions of AA on four acupoints: Shenmen, Kidney Concha, Point Zero, and Upper Tragus. Results Subjective assessment revealed significant differences in all the parameters of salivary flow rate, such as difficulty in swallowing ( p  = 0.005), saliva rate in mouth ( p  = 0.016), dryness in mouth (0.009), dryness in lips ( p  = 0.002). The objective assessment of the salivary flow rate unveiled that applying the intervention bundle resulted in a notable increase in salivation level (from 33.3 to 86.7%) with p -value > 0.001 compared to a slight increase in the control group (23.3–36.7%). There was a significant improvement in the overall fluid control adherence in both groups with favor to the study group who received the intervention bundle as p -values were < 0.001and 0.047 respectively. Conclusion Bundling AA and fluid restriction programs effectively improved salivary flow rate and fluid control adherence among children undergoing HD attending the HD unit in Alexandria University Children’s Hospital at Smouha, Egypt. Therefore, nurses working in HD units may adopt this intervention bundle as a cost-effective, safe, and complementary tool to promote sustainable patient adherence to fluid-restriction regimen. Trial registration number [NCT06562959], ClinicalTrails.gov, Retrospectively registered (April 8th, 2024), URL of trial registry record: https://clinicaltrials.gov/study/NCT06562959 .

Background Acute respiratory distress syndrome (ARDS) is a common and disabling disease with high rates of mortality and morbidity. The role of steroids in treating ARDS remains controversial. We aim to examine the evidence behind using glucocorticoids in the management of ARDS from the available studies. Methods We performed a literature review of major electronic databases for randomized controlled trials (RCTs) comparing glucocorticoids versus placebo in treating patients with ARDS. Our primary outcome was hospital mortality. Other outcomes included ICU mortality, number of ventilator-free days at day 28, incidence of nosocomial infections, and hyperglycemia. We performed a meta-analysis using a random effects model to calculate risk ratios (RR) and mean difference (MD) with their corresponding 95% confidence intervals (CI). A subsequent trial sequential analysis was performed to examine the strength of evidence and to guard against statistical type I and type II errors for our results. Results Eight RCTs were included in the final analysis totaling of 1091 patients, with a mean age of 57 ± 16, and 56.2% were male. In our pooled analysis, use of glucocorticoids was associated with a significant reduction in hospital mortality (RR 0.79; 95% CI 0.64–0.98; P = 0.03) and ICU mortality (RR 0.64; 95% CI 0.42–0.97; P = 0.04). Furthermore, glucocorticoid use was associated with an increased number of ventilator-free days at day 28 (MD 4.06 days; 95% CI 2.66–5.45; P < 0.01). Regarding adverse events, glucocorticoids use was not associated with an increased risk for nosocomial infections (RR 0.82; 95% CI 0.68–1.00; P = 0.05); however, it was associated with an increased risk of hyperglycemia (RR 1.11; 95% CI 1.01–1.24; P = 0.04). In our trial sequential analysis, the required diversity-adjusted information size (sample size = 2692 patients) was not reached, and the evidence was insufficient from the available RCTs. Conclusion Among patients with ARDS, use of glucocorticoids is associated with a significant reduction in mortality and duration of mechanical ventilation, without increased risk of hospital-acquired infections. However, based on a trial sequential analysis, these findings may be secondary to a false-positive (type I) error. Further studies are needed for a firm conclusion with guarding against possible statistical errors.

Background: In livestock breeding, oocyte cryopreservation is crucial for preserving and transferring superior genetic traits. This study was conducted to examine the additional effect of melatonin to maturation and vitrification media on the in vitro developmental capacity, mitochondrial distribution, and intensity of buffalo oocytes. The study involved obtaining ovaries from a slaughterhouse and conducting two phases. In the first phase, high-quality oocytes were incubated in a maturation medium with or without 10 −9 M melatonin for 22 h (at 38.5°C in 5% CO 2 ). Matured oocytes were fertilized in vitro and cultured in SOF media for seven days. In the second phase, vitrified in vitro matured oocytes were stored in vitrified media (basic media (BM) containing a combination of cryoprotectants (20% Ethyl Glycol and 20% Dimethyl sulfoxide), with or without melatonin, and then stored in liquid nitrogen. Normal vitrified/thawed oocytes were fertilized in vitro and cultured as described. Finally, the matured oocytes from the fresh and vitrified/thawed groups, both with and without melatonin, were stained using DAPI and Mitotracker red to detect their viability (nuclear maturation), mitochondrial intensity, and distribution using a confocal microscope. The study found that adding 10 −9 M melatonin to the maturation media significantly increased maturation (85.47%), fertilization rate (84.21%)cleavage (89.58%), and transferable embryo (48.83%) rates compared to the group without melatonin (69.85%,79.88%, 75.55%, and 37.25% respectively). Besides that, the addition of melatonin to the vitrification media improved the recovery rate of normal oocytes (83.75%), as well as the cleavage (61.80%) and transferable embryo (27.00%) rates when compared to the vitrified TCM group (67.46%, 51.40%, and 17.00%, respectively). The diffuse mitochondrial distribution was higher in fresh with melatonin (TCM + Mel) (80%) and vitrified with melatonin (VS2 + Mel groups) (76.70%), Furthermore, within the same group, while the mitochondrial intensity was higher in the TCM + Mel group (1698.60) than other group. In conclusion, Melatonin supplementation improves the developmental competence and mitochondrial distribution in buffalo oocytes in both cases(in vitro maturation and vitrification).

Background Vibriosis is one of the most serious bacterial diseases and causes high morbidity and mortality among cultured sea breams . This study was undertaken to track the surveillance of Vibrio infection and its correlation to environmental factors . A total of 115 gilthead sea breams were collected seasonally from a private earthen pond fish farm in the Shatta area of Damietta, Egypt from September 2022 to July 2023. Physicochemical parameters of water were analyzed, and heavy metal levels were measured. The fish samples were subjected to clinical, bacteriological, Enterobacterial Repetitive Intergenic Consensus (ERIC) fingerprinting, and hematoxylin and Eosin histopathological staining. Results The results revealed significant variations in the water quality parameters over different seasons, in addition to an increase in heavy metals. Naturally infected fish showed external signs and postmortem lesions that were relevant to bacterial infection. Two dominant Vibrio subspecies of bacteria were identified: V. alginolyticus (205 isolates) and V. fluvialis (87 isolates). PCR confirmed the presence of V. alginolyticus using the species-specific primer collagenase at 737 bp. The highest prevalence of V. alginolyticus was detected during the summer season (57.72%), and the lowest prevalence was observed in autumn (39.75%). The correlation analysis revealed a positive relationship between V. alginolyticus and water temperature ( r  = 0.69). On the other hand, V. fluvialis showed a high prevalence during the autumn season (25.30%) and the lowest prevalence during the summer season (10.56%), where it was negatively correlated with water temperatures ( r  =—0.03). ERIC fingerprinting showed genetic variation within the Vibrio isolates. Antimicrobial susceptibility testing revealed sensitivity to ciprofloxacin and doxycycline, and resistance to amoxicillin and erythromycin. The multiple antibiotic resistance (MAR) index values for V. alginolyticus and V. fluvialis ranged from 0.3 to 0.7, with a multi-drug resistance pattern to at least three antibiotics. Histopathological alterations in the affected tissues revealed marked hemorrhage, vascular congestion, and hemosiderosis infiltration. Conclusion This study provides insights into the potential propagation of waterborne diseases and antibiotic resistance in the environment. Ensuring that the environment does not serve as a reservoir for virulent and contagious Vibrio species is a critical concern for regional aquaculture industries. Therefore, we recommend implementing environmental context-specific monitoring and surveillance tools for microbial resistance.

Disclosure: E. Ismail: None. L. Jacobsen: None. Background: X-linked adrenal hypoplasia congenita (AHC) is a rare disorder due to a mutation in DAX-1/NR0B1, a nuclear factor that is important for the development and function of the adrenals and reproductive system. It usually presents with adrenal insufficiency in infancy and later hypogonadotropic hypogonadism. Here we describe a patient who presented with a salt wasting crisis due to hypoaldosteronism and genetic testing revealed a novel frameshift mutation in NR0B1/DAX-1 resulting in premature protein termination. Clinical Case: A 4 week old male presented with poor feeding, failure to thrive, hyponatremia, hyperkalemia, and acidosis. No hypoglycemia present. He also had an undetectable aldosterone level, high renin, normal cortisol, high ACTH, and normal 17OHP. Adrenal ultrasound (US) failed to show the right adrenal gland. With suspicion for primary hypoaldosteronism, he was started on salt supplementation and fludrocortisone with improved growth, electrolytes, and renin. His genitalia were that of a typical male infant without cutaneous hyperpigmentation. ACTH level continued to trend up despite appropriate baseline cortisol. Stimulation test with 250 mcg of Cosyntropin was done which revealed suboptimal peak cortisol of 11.5 mcg/dL (normal >18 mcg/dL), so he was started on stress dose precautions of hydrocortisone without physiologic replacement. Repeat US 2 months later did not visualize his adrenals. With suspicion for AHC, genetic testing was obtained which revealed a novel frame shift variant in NR0B1 (c.1069del, p.Gln357Argfs*15, hemizygous), resulting in premature protein termination. He was then started on daily hydrocortisone replacement. As this is an X-linked mutation, genetic testing for mother and older brother is pending. To the best of our knowledge this variant has not been reported in the literature. Conclusion: DAX-1 mutations should be considered in male infants presenting with primary hypoaldosteronism. ACTH stimulation testing is necessary to assess glucocorticoid function, especially if ACTH is elevated, which can precede cortisol deficiency. There is a wide heterogeneity in the presentation of this rare disorder, so genetic diagnosis is important to guide management, later monitoring for hypogonadism and fertility, and family testing. Presentation: Friday, June 16, 2023

This dissertation presents the development and characterization of shear-responsive platforms for targeted therapeutic delivery, inspired by the mechanosensitive properties of von Willebrand Factor (VWF), a key blood-clotting protein. By leveraging biomolecular insights into VWF unraveling under flow, a Single-Molecule-Based Material with Structures and Functions Responsive to Shear (SMORES) platform was engineered to address critical challenges in vascular disorders and enhance hemostatic regulation.The initial studies investigated how flow dynamics influence VWF conformation, particularly the effect of pulse frequency on VWF extension, to elucidate the disease mechanism underlying acquired von Willebrand syndrome (AVWS), a bleeding disorder observed in patients supported by continuous-flow ventricular assist devices (CF-VADs). CF-VADs, implantable mechanical pumps designed to maintain systemic circulation in patients with advanced heart failure, are associated with an elevated risk of non-surgical bleeding. This complication has been attributed to the loss of physiological pulsatility, which destabilizes VWF structure, promoting its unraveling and enzymatic degradation, thereby impairing clotting function. Although artificial pulsatility has been incorporated into some device designs, the specific impact of pulse frequency on VWF conformational stability remains poorly defined. To address this gap, in vitro microfluidic models were developed to study endothelial membrane-bound VWF and single-tethered immobilized VWF within devices connected to programmable fluidic pumps, enabling precise generation of continuous and pulsatile flow waveforms replicating physiological shear forces. These platforms facilitated real-time visualization of VWF conformational dynamics under distinct flow conditions. By comparing continuous flow to pulsatile profiles, this work aims to uncover mechanistic insights that inform the optimization of flow modulation protocols, including the identification of pulse frequencies that preserve VWF integrity and mitigate bleeding complications.Building on mechanistic insights into how flow modulates the structure and function of VWF, the SMORES platform was developed to enable shear-triggered molecular release. A well-established aptamer, selected for its high affinity to the VWF A1 domain, was incorporated into a construct designed for the controlled release of VWF A1—the platelet-binding domain—under pathological shear conditions indicative of vascular injury. This strategy aims to initiate clot formation at sites of vascular damage, particularly in patients with acquired von Willebrand syndrome (AVWS), where VWF is either dysfunctional or deficient. Each SMORES construct employs an aptamer molecule as the flow transducer and a microparticle to sense and amplify the hydrodynamic force. Within the construct, the aptamer, ARC1172, undergoes conformational changes beyond a shear stress threshold, mimicking the shear-responsive behavior of VWF. This conformational alteration modulates the bioavailability of its target, the VWF A1 domain, ultimately releasing it at elevated shear. Single-molecule optical tweezer experiments were used to characterize the force-responsive behavior of the aptamer, while flow-based microfluidic assays confirmed shear-dependent release. Functional assays demonstrated that the released A1 domain retained its biological activity. Building on aptamer biomechanics, this platform presents a new strategy for engineering shear-responsive biomaterials based on single-molecule designs.Building on the modularity of the SMORES platform, the shear-responsive system was adapted for the targeted delivery of tissue plasminogen activator (TPA), a clot-dissolving enzyme used in thrombolytic therapy. An anti-PLAT (plasminogen activator) aptamer with high affinity for TPA was incorporated into the construct, which also employed a shear-amplifying microparticle to facilitate force transmission. Upon exposure to pathological shear stresses, indicative of occluded vessels, conformational changes in the aptamer modulate the availability of TPA, enabling its release at the clot site. To enhance selective targeting, the construct was functionalized with monoclonal anti-αIIbβ3 antibodies, allowing specific binding to activated platelets within thrombi. Shear-triggered release of TPA was demonstrated using microfluidic flow models, and a clot dissolution assay was developed to further confirm the biological activity of the released payload. By combining shear-responsive release with platelet-specific targeting, this platform offers a promising strategy for localized thrombolysis with reduced systemic exposure, addressing key limitations of current thrombolytic therapies.Altogether, this work establishes SMORES as a promising strategy for shear-responsive, targeted therapeutic delivery in vascular diseases, and advances the development of physiologically relevant in vitro models for neurodegenerative disease research.