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Abstract In the phase 3 Coronavirus Efficacy (COVE) trial (NCT04470427), post-dose two Ancestral Spike-specific binding (bAb) and neutralizing (nAb) antibodies were shown to be correlates of risk (CoR) and of protection against Ancestral-lineage COVID-19 in SARS-CoV-2 naive participants. In the SARS-CoV-2 Omicron era, Omicron subvariants with varying degrees of immune escape now dominate, seropositivity rates are high, and booster doses are administered, raising questions on whether and how these developments affect the bAb and nAb correlates. To address these questions, we assess post-boost BA.1 Spike-specific bAbs and nAbs as CoRs and as correlates of booster efficacy in COVE. For naive individuals, bAbs and nAbs inversely correlate with Omicron COVID-19: hazard ratios (HR) per 10-fold marker increase (95% confidence interval) are 0.16 (0.03, 0.79) and 0.31 (0.10, 0.96), respectively. In non-naive individuals the analogous results are similar: 0.15 (0.04, 0.63) and 0.28 (0.07, 1.08). For naive individuals, three vs two-dose booster efficacy correlates with predicted nAb titer at exposure, with estimates -8% (-126%, 48%), 50% (25%, 67%), and 74% (49%, 87%), at 56, 251, and 891 Arbitrary Units/ml. These results support the continued use of antibody as a surrogate endpoint.

Abstract Background Diagnosis of hereditary myopathy is often challenging owing to overlapping clinical phenotypes and muscle histopathological findings. This retrospective study aimed to identify the phenotypic and genotypic spectra of hereditary myopathies at a tertiary hospital in Riyadh, Saudi Arabia. Methods We reviewed the medical records of patients with hereditary myopathy who were evaluated between January 2018 and December 2022. Results Eighty-seven patients (78 families) were included, two-thirds were men with a mean age of 35 (SD 14.2) years. Limb-girdle muscular dystrophy (LGMD) was the most prevalent clinical diagnosis (25 cases; 29%), of whom, a genetic diagnosis was achieved in 15 of 22 patients tested (68%). In genetically confirmed LGMD, the most prevalent disorders were dysferlinopathy (27%) followed by fukutin-related protein (FKRP) - related limb girdle muscular dystrophy (20%), sarcoglycanopathy (20%), lamin A/C related myopathy (13%), and calpain-3 myopathy (13%). In 26 patients with pathogenic/likely pathogenic variants, the genetic testing method was whole exome sequencing (WES) (42%), Next generation sequencing (NGS) (31%), and targeted single gene analysis (27%). The sensitivity of each genetic testing method was as follows: 100% for targeted single-gene analysis, 100% for targeted analysis of D4Z4 repeat array units, 88% for myotonic dystrophy protein kinase (DMPK) repeat expansion analysis, 42% for NGS-neuromuscular panel, and 46% for WES. Conclusion The prevalent types of hereditary myopathies were consistent with those reported locally and internationally. This study highlights the diagnostic yield of various molecular genetic tests for the diagnosis of hereditary myopathy in an adult cohort and the need for improved access to advanced molecular testing in cases suspected to have facioscapulohumeral muscular dystrophy (FSHD) or mitochondrial myopathies.

Abstract Primary vaccination with mRNA-1273 (100-µg) was safe and efficacious at preventing coronavirus disease 2019 (COVID-19) in the previously reported, blinded Part A of the phase 3 Coronavirus Efficacy (COVE; NCT04470427) trial in adults (≥18 years) across 99 U.S. sites. The open-label (Parts B and C) primary objectives were evaluation of long-term safety and effectiveness of primary vaccination plus a 50-µg booster dose; immunogenicity was a secondary objective. Of 29,035 open-label participants, 19,609 received boosters (mRNA-1273 [n = 9647]; placebo-mRNA-1273 [n = 9952]; placebo [n = 10] groups). Booster safety was consistent with that reported for primary vaccination. Incidences of COVID-19 and severe COVID-19 were higher during the Omicron BA.1 than Delta variant waves and boosting versus non-boosting was associated with a significant, 47.0% (95% CI : 39.0-53.9%) reduction of Omicron BA.1 incidence (24.6 [23.4 − 25.8] vs 46.4 [40.6 − 52.7]/1000 person-months). In an exploratory Cox regression model adjusted for time-varying covariates, a longer median interval between primary vaccination and boosting (mRNA-1273 [13 months] vs placebo-mRNA-1273 [8 months]) was associated with significantly lower, COVID-19 risk (24.0% [16.0% − 32.0%]) during Omicron BA.1 predominance. Boosting elicited greater immune responses against SARS-CoV-2 than primary vaccination, irrespective of prior SARS-CoV-2 infection. Primary vaccination and boosting with mRNA-1273 demonstrated acceptable safety, effectiveness and immunogenicity against COVID-19, including emergent variants.

OBJECTIVES:. To investigate which independent factor(s) have an impact on the pharmacokinetics of vancomycin in critically ill children, develop an equation to predict the 24-hour area under the concentration-time curve from a trough concentration, and evaluate dosing regimens likely to achieve a 24-hour area under the concentration-time curve to minimum inhibitory concentration ratio (AUC24/MIC) greater than or equal to 400. DESIGN:. Prospective population pharmacokinetic study of vancomycin. SETTING:. Critically ill patients in quaternary care PICUs. PATIENTS:. Children 90 days old or older to younger than 18 years who received IV vancomycin treatment, irrespective of the indication for use, in the ICUs at the University of Maryland Children’s Hospital and Texas Children’s Hospital were enrolled. INTERVENTIONS:. Vancomycin was prescribed at doses and intervals chosen by the treating clinicians. MEASUREMENTS AND MAIN RESULTS:. A median of four serum levels of vancomycin per patient were collected along with other variables for up to 7 days following the first administration. These data were used to characterize vancomycin pharmacokinetics and evaluate the factors affecting the variability in achieving AUC24/MIC ratio greater than or equal to 400 in PICU patients who are not on extracorporeal therapy. A total of 302 children with a median age of 6.0 years were enrolled. A two-compartment model described the pharmacokinetics of vancomycin with the clearance of 2.76 L/hr for a typical patient weighing 20 kg. The glomerular filtration rate estimated using either the bedside Schwartz equation or the chronic kidney disease in children equation was the only statistically significant predictor of clearance among the variables evaluated, exhibiting equal predictive performance. The trough levels achieving AUC24/MIC = 400 were 5.6–10.0 μg/mL when MIC = 1 μg/mL. The target of AUC24/MIC greater than or equal to 400 was achieved in 60.4% and 36.5% with the typical dosing regimens of 15 mg/kg every 6 and 8 hours (q6h and q8h), respectively. CONCLUSIONS:. The pharmacokinetics of vancomycin in critically ill children were dependent on the estimated glomerular filtration rate only. Trough concentrations accurately predict AUC24. Typical pediatric vancomycin dosing regimens of 15 mg/kg q6h and q8h will often lead to AUC24/MIC under 400.

BACKGROUND: Despite the decline of the COVID-19 pandemic, there continues to be a persistent requirement for reliable testing methods that can be adapted to future outbreaks and areas with limited resources. While the standard approach of using reverse transcription-polymerase chain reaction (RT-PCR) with Taq polymerase is effective, it faces challenges such as limited access to high-quality enzymes and the presence of bacterial DNA contamination in commercial kits, which can impact the accuracy of test results. METHODS: This study investigates the production of recombinant Taq polymerase in yeast cells and assesses its crude lysate in a multiplex RT-PCR assay for detecting the SARS-CoV-2 RNA-dependent RNA polymerase (RdRP) and N genes, with human Ribonuclease P serving as an internal control. RESULTS: The unpurified yeast Taq polymerase demonstrates sensitivity comparable to commercially purified bacterial Taq polymerase and unpurified bacterial counterparts in detecting the RdRP and N genes. It exhibits the highest specificity, with 100% accuracy, for the N gene. The specificity for the RdRP gene closely aligns with that of commercially purified bacterial Taq polymerase and unpurified bacterial Taq polymerase. CONCLUSIONS: The use of unpurified recombinant yeast Taq polymerase shows promise as a cost-effective approach for conducting in-house COVID-19 RT-PCR testing. By eliminating the need for chromatography purification steps, the production of RT-PCR kits can be streamlined, potentially improving accessibility and scalability, especially in resource-limited settings and future pandemics.

BackgroundApart from the well-established skeletal effects, vitamin D has been explored as a secretagogue influencing various adipokines, including adiponectin and irisin. Recent evidence suggests that specific forms of 25-Hydroxyvitamin D (25(OHD), such as free and bioavailable 25(OH)D, may provide more accurate measurements of vitamin D status. The relationship between vitamin D status and serum irisin and adiponectin concentrations remains largely unexplored, particularly during pregnancy.MethodsWe analyzed data from 67 healthy maternal-neonatal pairs from Northern Greece at birth. Biochemical and hormonal tests were conducted on each maternal-neonatal pair. The vitamin D forms were estimated using validated mathematical models. Subsequently, regression analyses were conducted to determine the association between the vitamin D forms and adipokine levels.ResultsBioavailable maternal 25(OH)D was inversely associated with neonatal irisin concentrations [β=-73.46 (-140.573 to -6.341), p=0.034]. No other associations were observed between maternal vitamin D status and neonatal adipokine concentrations.ConclusionIn conclusion, maternal bioavailable vitamin D concentrations are inversely associated with neonatal serum irisin concentrations, warranting further studies to evaluate the underlying mechanisms for this finding.

This work aims to evaluate the antimicrobial activity of some new quinoline derivatives linked to pyrazole derivatives. The target compounds pyrazolylvinylquinoline 11a-g and 12a-g were achieved by the reaction of 2-chloro-6-nitro-3-quinolinecarboxaldehyde (4) with bromotriphenylphosphonylmethylpyrazole derivatives 9a,b to give the new quinoline derivatives 10a,b which in turn reacted with different aryl amines to afford 11a-g and 12a-g. Pyrazole derivatives 9a,b were obtained by the reaction of hydroxymethylpyrazole derivatives 8a,b with triphenylphosphine hydrobromide. Antimicrobial evaluation of the newly synthesized compounds showed that most of the new compounds appeared active toward Gram-positive bacteria more than Gram-negative bacteria. The biological evaluation of compounds 12d-g displayed the highest antimicrobial activity against the tested microorganism strains. Additionally, compounds 12d and 12f showed excellent activity against P. aeruginosa (MIC50 0.019 mg/mL), while compounds 11d, 11f, 12e, and 12g displayed good activity against the same microorganism (MIC50 0.07 mg/mL). On the other hand, most of the new compounds have moderate activity against E. coli. Compounds 12d and 12f showed excellent activity versus C. albicans in vitro antifungal activity (MIC50 0.15 mg/mL) comparing to or slightly lower than that of Fluconazole. Using molecular docking simulations, we evaluated the binding affinities and interactions of four chosen derivatives 12d-g with a target PDB code 3WT0 protein.

The ulcerative colitis (UC) is an inflammatory bowel illness which causes persistent inflammation of the colon's innermost layers. A prominent characteristic of ulcerative colitis (UC) is the stool's blood and mucous contents. This study determined to investigate the effects of white vinegar (WV) on colon tissues in rats. Two groups of twenty rats were created; the primary group was a control, healthy group, and the WV was administered to the second group at a dose of [1 ml/kg (5%)] via orally gavage for two weeks. Findings revealed the emergence of histopathological alterations like mucosal erosions, ulceration, loss of normal architecture, mucosal atrophy, and hemorrhage; numerous crypts have inflammatory cells that entered them, blood vessels are dilated and oedema, the serosa is destroyed, which demonstrates the devastation of the mucosal lining destruction with goblet cell hyperplasia, focal necrosis of epithelium with demolished connective tissues, accumulation of inflammatory cells in the mucosa, lamina propria, and muscularis mucosa, as well as submucosal oedema when compared with the control rats. The PAS-reaction histochemical analysis showed that the treated rats had lower levels of carbohydrates than the control animals. The findings of the study demonstrated that white vinegar was a dangerous substance linked to histological alterations that resulted in acute ulcerative colitis when used daily for two weeks.

Background: Stochastic interventional vaccine efficacy (SVE) analysis is a new approach to correlate of protection (CoP) analysis of a phase III trial that estimates how vaccine efficacy (VE) would change under hypothetical shifts of an immune marker. Methods: We applied nonparametric SVE methodology to the COVE trial of messenger RNA-1273 vs placebo to evaluate post-dose 2 pseudovirus neutralizing antibody (nAb) titer against the D614G strain as a CoP against COVID-19. Secondly, we evaluated the ability of these results to predict VE against variants based on shifts of geometric mean titers to variants vs D614G. Prediction accuracy was evaluated by 13 validation studies, including 12 test-negative designs. Results: SVE analysis of COVE supported post-dose 2 D614G titer as a CoP: estimated VE ranged from 66.9% (95% confidence interval: 36.2, 82.8%) to 99.3% (99.1, 99.4%) at 10-fold decreased or increased titer shifts, respectively. The SVE estimates only weakly predicted variant-specific VE estimates (concordance correlation coefficient 0.062 for post 2-dose VE). Conclusion: SVE analysis of COVE supports nAb titer as a CoP for messenger RNA vaccines. Predicting variant-specific VE proved difficult due to many limitations. Greater anti-Omicron titers may be needed for high-level protection against Omicron vs anti-D614G titers needed for high-level protection against pre-Omicron COVID-19.

In this manuscript, we are motivated to investigate the reaction site-selectivity for the hydrazo thiazole derivatives (6a–c) with different types of active methylene groups such as malononitrile, and ethyl cyanoacetate. Based on their structural investigations and spectrum data, the results of these reactions have been established to be iminopyridazines (7a–c) and 6-oxopyridazine derivatives (8a–c). We tested the ability of the newly synthesized pyridazine derivatives to inhibit the microbes and COVID-19 proteins. Human coronavirus 229E (HCoV-229E) was used to investigate the antiviral efficacy of prepared compounds. Green monkey kidney (Vero-E6) cell lines were used to investigate MTT and cytopathic effect (CPE). The new 6-oxopyridazine derivatives (8a–c) revealed significant inhibitory efficacy and were capable of inhibiting the human coronavirus 229E. Moreover, the antimicrobial result showed that compounds iminopyridazine (7c) followed by iminopyridazine (7a) followed by iminopyridazine (7b) exhibited excellent antimicrobial properties toward all utilized strains, usually greater than that of common reference drugs, with MIC values ranging from 13 to 21 ppm, from 9 to 14 ppm, and from 8 to 19 ppm whereas, the remaining substances appeared to be promising effective. Structure-activity relationship (SAR) revealed that pyridazine scaffolds containing NH group, as well as substituted electron withdrawal group (Cl) in para-position for benzene ring attributed to thiazole moiety have the best activity. The current study successfully illustrated the possible application of heterocyclic derivatives with pyridazie nucleus including thiazole ring as the main compound in the development of dual antiviral (COVID-19) and antibacterial pharmaceuticals in the future.

Summary: Background: Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19. Methods: The protocol was prospectively registered with PROSPERO (CRD42022335397). MEDLINE, Cochrane Central Register of Controlled Trials and references of relevant articles were searched up to 01-06-2022. Authors of potentially eligible randomized controlled trials were contacted to provide data on immunocompromised patients randomized to immunomodulators vs control (i.e., placebo or standard-of-care). Findings: Eleven randomized controlled trials involving 397 immunocompromised patients hospitalized for COVID-19 were included. Ten trials had low risk of bias. There was no difference between immunocompromised patients randomized to immunomodulators vs control regarding mortality [30/182 (16.5%) vs 41/215 (19.1%); RR 0.93, 95% CI 0.61–1.41; p = 0.74], secondary infections (RR 1.00, 95% CI 0.64–1.58; p = 0.99) and change in World Health Organization ordinal scale from baseline to day 15 (weighed mean difference 0.27, 95% CI -0.09–0.63; p = 0.15). In subgroup analyses including only patients with hematologic malignancy, only trials with low risk of bias, only trials administering IL-6 inhibitors, or only trials administering immunosuppressants, there was no difference between comparators regarding mortality. Interpretation: Immunomodulators, compared to control, were not associated with harmful or beneficial outcomes, including mortality, secondary infections, and change in ordinal scale, when administered to immunocompromised patients hospitalized for COVID-19. Funding: Hellenic Foundation for Research and Innovation.

Abstract COVID-19 pandemic has increased social media engagement globally. This study examined the correlation between social media use and physical/mental health among university students, considering gender and academic year. Out of 146 responses, 119 were analyzed after excluding participants with pre-existing psychological conditions. Results showed a significant correlation between social media use and mental health for all participants (correlation coefficient = 0.30, p

Multiterminal High-Voltage Direct Current (MT-HVDC) systems offer numerous benefits compared to conventional alternating current (AC) power systems, including higher power density and improved efficiency. However, the need for adequate protection schemes for HVDC systems remains a significant obstacle to their widespread adoption. Much attention has been given to developing HVDC protection methods to address this. Moreover, the protection of MT-HVDC systems presents a challenge due to bidirectional power flow, dynamic system characteristics, and fault current characteristics that cannot be addressed using conventional methods. This paper represents a centralized protection unit based on a distance protection scheme that involves a two-stage relay process. The first stage involves fault detection by measuring voltage and current to obtain the system impedance, which is then compared to the reach point. The second stage involves identifying the fault location by selecting the correct faulty zone. This technique provides both main and backup protection. A central control unit supports the approach presented in this paper to communicate relays and update their settings. The LoRaWAN communication protocol is employed, as it provides more excellent coverage than other standardized communication technologies and can cover long distances. The proposed method is studied under different scenarios, including system contingency, simultaneous faults, fault resistances, locations, and types. The results of this technique provide the effectiveness of the proposed method. The fault can be cleared within 1.32–1.8 ms.

Abstract As part of a multicenter study evaluating homologous and heterologous COVID-19 booster vaccines, we assessed the magnitude, breadth, and short-term durability of binding and pseudovirus-neutralizing antibody (PsVNA) responses following a single booster dose of NVX-CoV2373 in adults primed with either Ad26.COV2.S, mRNA-1273, or BNT162b2 vaccines. NVX-CoV2373 as a heterologous booster was immunogenic and associated with no safety concerns through Day 91. Fold-rises in PsVNA titers from baseline (Day 1) to Day 29 were highest for prototypic D614G variant and lowest for more recent Omicron sub-lineages BQ.1.1 and XBB.1. Peak humoral responses against all SARS-CoV-2 variants were lower in those primed with Ad26.COV2.S than with mRNA vaccines. Prior SARS CoV-2 infection was associated with substantially higher baseline PsVNA titers, which remained elevated relative to previously uninfected participants through Day 91. These data support the use of heterologous protein-based booster vaccines as an acceptable alternative to mRNA or adenoviral-based COVID-19 booster vaccines. This trial was conducted under ClinicalTrials.gov: NCT04889209.

Abstract While new vaccines for SARS-CoV-2 are authorized based on neutralizing antibody (nAb) titer against emerging variants of concern, an analogous pathway does not exist for preventative monoclonal antibodies. In this work, nAb titers were assessed as correlates of protection against COVID-19 in the casirivimab + imdevimab monoclonal antibody (mAb) prevention trial (ClinicalTrials.gov #NCT4452318) and in the mRNA-1273 vaccine trial (ClinicalTrials.gov #NCT04470427). In the mAb trial, protective efficacy of 92% (95% confidence interval (CI): 84%, 98%) is associated with a nAb titer of 1000 IU50/ml, with lower efficacy at lower nAb titers. In the vaccine trial, protective efficacies of 93% [95% CI: 91%, 95%] and 97% (95% CI: 95%, 98%) are associated with nAb titers of 100 and 1000 IU50/ml, respectively. These data quantitate a nAb titer correlate of protection for mAbs benchmarked alongside vaccine induced nAb titers and support nAb titer as a surrogate endpoint for authorizing new mAbs.

IntroductionThis study aimed to assess the antimicrobial activity of carvacrol in combination with approved antibiotics against methicillin-resistant Staphylococcus aureus (MRSA). Carvacrol, a phenolic monoterpenoid component of essential oils, has demonstrated antimicrobial properties against gram positive and gram negative bacteria. The study evaluated the antimicrobial effects of carvacrol combined with sulfamethoxazole, linezolid, minocycline, and trimethoprim.MethodsThe MRSA strain (ATCC-33591) was used, and various assays, including MIC determination, checkerboard assay, and microdilution assay were conducted.ResultsThe results showed that the combination of carvacrol with antibiotics yielded better outcomes compared to monotherapy, leading to reduced bacterial colonization. Carvacrol, sulfamethoxazole, and trimethoprim exhibited weak anti-staphylococcal effects, while linezolid and minocycline demonstrated stronger effects. This suggests that conventional antibiotic therapy may not be sufficient to effectively treat MRSA infections, potentially causing delays in healing or an exacerbation of the condition. Carvacrol combinations with two antibiotics displayed superior results compared to other pairs, indicating synergistic or additive effects of carvacrol with linezolid, minocycline, and sulfamethoxazole.ConclusionThese findings propose a new approach for developing drug molecules for MRSA treatment which combine volatile oils with available regimens. Further studies are recommended to evaluate the efficacy and biosafety of these combinations using in vivo or ex vivo models, aiming to minimize side effects and facilitate human trials. This study provides valuable insights into the potential use of carvacrol-antibiotic combinations as a novel therapeutic approach against MRSA.

Background: Studies have demonstrated low hepatitis A virus (HAV) vaccination rates among persons with HIV (PWH). Methods: We conducted a retrospective study of persons entering HIV care at two clinics in Houston, Texas between 2010 and 2018. We defined those eligible for HAV vaccination as those who had no history of HAV vaccination and had a negative anti-HAV IgG at entry to care. Kaplan-Meier curves summarized time to receipt of HAV vaccines. The proportions of patients who received 1 and 2 HAV vaccines at 6, 12, and 24 months were estimated. Cox proportional hazards regression evaluated associations between patient characteristics and vaccination. Significant factors were included in a multivariable Cox proportional hazards model. Results: Of 6,515 patients, 1372 were eligible for HAV vaccination. Of eligible patients, 29.2 % received 1 HAV vaccination at 6 months, 37.1 % at 12 months, and 47.8 % at 24 months. At 6 months, 10 % received 2 HAV vaccinations, 21.1 % at 12 months, and 33.4 % at 24 months. In multivariable analysis, men who have sex with men (adjusted HR 1.35, 95 % CI 1.06, 1.73) or those who had CD4 count ≥ 200 cells/µl (adjusted HR 2.52, 95 % CI 1.89, 3.37) had their second vaccination sooner than those who were not men who have sex with men or who had CD4 counts 50 years of age had their second vaccination sooner than those aged 30–50 years (adjusted HR 1.47, 95 % CI 1.08, 1.99). Those with active substance history had a longer time to second vaccination compared to those with no substance use history (adjusted HR 0.57, 95 % CI 0.40, 0.82). Conclusions: HAV vaccination rates were low and highlight the need for effective solutions to address HAV immunization gaps in PWH, especially among young patients, those with active substance use disorders, and those with significant immunocompromise.

Defective viral genomes (DVGs) are viral genomes that contain only a partial viral RNA and so cannot replicate within cells on their own. If a cell containing DVGs is subsequently infected with a complete viral genome, the DVG can then use the missing proteins expressed by the full genome in order to replicate itself. Since the cell is producing defective genomes, it has less resources to produce fully functional virions and thus release of complete virions is often suppressed. Here, we use data from challenge studies of respiratory syncytial virus (RSV) in healthy adults to quantify the effect of DVGs. We use a mathematical model to fit the data, finding that late onset of DVGs and prolonged DVG detection are associated with lower infection rates and higher clearance rates. This result could have implications for the use of DVGs as a therapeutic.

Abstract Aim The purpose of this study was to investigate the prevalence of poststroke depression (PSD) in Saudi Arabia and its association with socio‐demographic and clinical factors. Design A predictive correlational cross‐sectional study. Methods The study adopted a non‐probability convenience sampling method to recruit 211 stroke survivors between April and October 2021 from the neurology outpatient departments of two main governmental hospitals in Saudi Arabia. PSD was measured using a self‐assessment reliable and valid scale (The Hospital Anxiety and Depression Scale [HADS]). Results More than two‐thirds (70.6%) of the study sample (Mean age = 53 years, SD = 8.5, 51.2% were males) experienced some degree of depression (Score ≥8); of these, approximately half (48.8%) were in severe depression. The final prediction model was statistically significant (χ2 [15] = 31.39, p ˂ .01). PSD is a statistically significant health issue and requires immediate attention by healthcare providers to improve the health outcomes of stroke survivors.

Abstract Background and Aim Low serum Vitamin D levels have been associated with diabetic nephropathy (DN). Our study aimed to analyse the serum levels of vitamin D in patients suffering from DN and the subsequent changes in serum vitamin D levels as the disease progresses. Methods PubMed, Embase, SCOPUS and Web of Science were searched using keywords such as ‘25 hydroxyvitamin D’ and ‘diabetic nephropathy’. We included observational studies that reported the association between the serum 25 hydroxy vitamin D levels and diabetic nephropathy without restriction to age, gender, and location. R Version 4.1.2 was used to perform the meta‐analysis. The continuous outcomes were represented as mean difference (MD) and standard deviation (SD) and dichotomous outcomes as risk ratios (RR) with their 95% confidence interval (CI). Results Twenty‐three studies were included in our analysis with 7722 patients. Our analysis revealed that vitamin D was significantly lower in diabetic patients with nephropathy than those without nephropathy (MD: −4.32, 95% CI: 7.91–0.74, p‐value = .0228). On comparing diabetic patients suffering from normoalbuminuria, microalbuminuria, or macroalbuminuria, we found a significant difference in serum vitamin D levels across different groups. Normoalbuminuria versus microalbuminuria showed a MD of −1.69 (95% CI: −2.28 to −1.10, p‐value = .0002), while microalbuminuria versus macroalbuminuria showed a MD of (3.75, 95% CI: 1.43–6.06, p‐value = .0058), proving that serum vitamin D levels keep declining as the disease progresses. Notwithstanding, we detected an insignificant association between Grade 4 and Grade 5 DN (MD: 2.29, 95% CI: −2.69–7.28, p‐value = .1862). Conclusion Serum Vitamin D levels are lower among DN patients and keep declining as the disease progresses, suggesting its potential benefit as a prognostic marker. However, on reaching the macroalbuminuria stage (Grades 4 and 5), vitamin D is no longer a discriminating factor.

BackgroundPrevious studies have assessed the impact of age and body mass index (BMI) on surgery outcomes separately. This retrospective cohort study aimed to investigate the combined effect of age and BMI on postoperative mortality and morbidity in patients undergoing laparoscopic cholecystectomy.MethodsData from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database for laparoscopic cholecystectomy patients between 2008 and 2020 were analyzed. Patient demographics, functional status, admission sources, preoperative risk factors, laboratory data, perioperative variables, and 30-day postoperative outcomes were included in the dataset. Logistic regression was used to determine the association of age, BMI, and age/BMI with mortality and morbidity. Patients were stratified into different subcategories based on their age and BMI, and the age/BMI score was calculated. The chi-square test, independent sample t-test, and ANOVA were used as appropriate for each category.ResultsThe study included 435,052 laparoscopic cholecystectomy patients. Logistic regression analysis revealed that a higher age/BMI score was associated with an increased risk of mortality (adj OR 13.13 95% CI, 9.19–18.77, p

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health.

In our current research, an intriguing magnetic nano sorbent Fe3O4@Zr-MOF was synthesized in the lab. We used this adsorbent for successfully removing tetracycline (TC) from water. We performed a number of experiments and studies to further support this, including the following: vibrating sample magnetometer (VSM), Fourier transform infrared spectroscopy (FTIR), energy-dispersive X-ray photoelectron spectroscopy (XPS), scanning electron microscope (SEM), X-ray diffraction (XRD), and Brunauer-Emmett-Teller surface area (BET). Our studies have determined that the Fe3O4@Zr-MOF boasts a considerable surface area of 868 m2/g with the highest adsorption capacity (qmax) of 942.12 mg/g. Study the factors that effect on adsorption process such as pH, TC concentration, adsorbent dose, and temperature. The adsorption isotherm was fitted to the Langmuir equation, whereas the kinetic isotherm to the pseudo-second-order equation. The adsorption process was chemisorption as well as the adsorption energy was 20 kJ/mol. Adsorption thermodynamics indicated that the adsorption process was both endothermic and spontaneous. As temperatures increased, the amounts of materials absorbed also increased. The Fe3O4@Zr-MOF has magnetic properties as it easily to remove from the solution after adsorption process. The adsorbent was used for five cycles with high efficiency and without change in the chemical composition as well as the XRD was the same before and after reusability. The mechanism of the interaction between Fe3O4@Zr-MOF and TC was expected on: Electrostatic interaction, π-π interaction, hydrogen bonding, and pore filling. The adsorption results were optimized using Box Behnken-design (BBD).

The COVID-19 pandemic necessitated an extensive testing for active SARS-CoV-2 infection. However, securing affordable diagnostic tests is a struggle for low-resource settings. We report herein the development and validation of an in-house multiplex real-time RT-PCR diagnostic test for the detection of active COVID-19 infection (ScriptTaq COVID PCR). Furthermore, we describe two methods for RNA extraction using either an in-house silica column or silica-coated magnetic beads to replace commercial RNA extraction kits. Different buffer formulations for silica column and silica-coated magnetic beads were tested and used for RNA isolation. Taq polymerase enzyme and thermostable reverse transcriptase enzyme were purified from bacterial clones. Primers/probes sequences published by the WHO and CDC were used for the qualitative detection of the RNA-dependent RNA polymerase (RdRp) and nucleocapsid (N) genes, respectively. ScriptTaq COVID PCR assay was able to detect up to 100 copies per reaction of the viral RdRP and N genes. The test demonstrated an overall agreement of 95.4%, a positive percent agreement (PPA) of 90.2%, and a negative percent agreement (NPA) of 100.0% when compared with two commercially available kits. ScriptTaq COVID PCR diagnostic test is a specific, sensitive, and low-cost alternative for low-resource settings.

Zika virus (ZIKV) is a flavivirus primarily transmitted by Aedes species mosquitoes, first discovered in Africa in 1947, that disseminated through Southeast Asia and the Pacific Islands in the 2000s. The first ZIKV infections in the Americas were identified in 2014, and infections exploded through populations in Brazil and other countries in 2015/16. ZIKV infection during pregnancy can cause severe brain and eye defects in offspring, and infection in adults has been associated with higher risks of Guillain-Barré syndrome. We initiated a study to describe the natural history of Zika (the disease) and the immune response to infection, for which some results have been reported. In this paper, we identify ZIKV-specific CD4+ and CD8+ T cell epitopes that induce responses during infection. Two screening approaches were utilized: an untargeted approach with overlapping peptide arrays spanning the entire viral genome, and a targeted approach utilizing peptides predicted to bind human MHC molecules. Immunoinformatic tools were used to identify conserved MHC class I supertype binders and promiscuous class II binding peptide clusters predicted to bind 9 common class II alleles. T cell responses were evaluated in overnight IFN-γ ELISPOT assays. We found that MHC supertype binding predictions outperformed the bulk overlapping peptide approach. Diverse CD4+ T cell responses were observed in most ZIKV-infected participants, while responses to CD8+ T cell epitopes were more limited. Most individuals developed a robust T cell response against epitopes restricted to a single MHC class I supertype and only a single or few CD8+ T cell epitopes overall, suggesting a strong immunodominance phenomenon. Noteworthy is that many epitopes were commonly immunodominant across persons expressing the same class I supertype. Nearly all of the identified epitopes are unique to ZIKV and are not present in Dengue viruses. Collectively, we identified 31 immunogenic peptides restricted by the 6 major class I supertypes and 27 promiscuous class II epitopes. These sequences are highly relevant for design of T cell-targeted ZIKV vaccines and monitoring T cell responses to Zika virus infection and vaccination.

BackgroundHypoxia plays a critical role in the tumor microenvironment by affecting cellular proliferation, metabolism, apoptosis, DNA repair, and chemoresistance. Since hypoxia provokes a distinct shift of microRNA, it is important to illustrate the relative contribution of each hypoxamiR to cancer progression.AimsThe present study aims to shed light on the hypoxamiRs that are involved in pancreatic and breast cancer progression to highlight novel targets for the development of new therapies.MethodsFor 20 cycles, MCF7 breast cancer cells and PANC-1 pancreatic cancer cells were subjected to chronic cyclic hypoxia, which consisted of 72 hours of hypoxia followed by 24 hours of reoxygenation. After 10 and 20 cycles of hypoxia, miRNA expression alterations were profiled using RT-PCR array and further analyzed using a visual analytics platform. The MTT cell proliferation assay was used to determine hypoxic cells’ chemoresistance to doxorubicin.ResultsUnder chronic cyclic hypoxia, hypoxic PANC-1 cells have a comparable doubling time with their normoxic counterparts, whereas hypoxic MCF7 cells show a massive increase in doubling time when compared to their normoxic counterparts. Both hypoxic cell lines developed EMT-like phenotypes as well as doxorubicin resistance. According to the findings of miRNet, 6 and 10 miRNAs were shown to play an important role in enriching six hallmarks of pancreatic cancer in the 10th and 20th cycles of hypoxia, respectively, while 7 and 11 miRNAs were shown to play an important role in enriching the four hallmarks of breast cancer in the 10th and 20th cycles of hypoxia, respectively.ConclusionsmiR-221, miR-21, miR-155, and miR-34 were found to be involved in the potentiation of hypoxic PANC-1 hallmarks at both the 10th and 20th cycles, while miR-93, miR-20a, miR-15, and miR-17 were found to be involved in the potentiation of hypoxic MCF7 hallmarks at both the 10th and 20th cycles. This variation in miRNA expression was also connected to the emergence of an EMT-like phenotype, alterations in proliferation rates, and doxorubicin resistance. The chemosensitivity results revealed that chronic cyclic hypoxia is critical in the formation of chemoresistant phenotypes in pancreatic and breast cancer cells. miR-181a and let-7e expression disparities in PANC1, as well as miR-93, miR-34, and miR-27 expression disparities in MCF7, may be associated with the formation of chemoresistant MCF7 and PANC-1 cells following 20 cycles of chronic cyclic hypoxia. Indeed, further research is needed since the particular mechanisms that govern these processes are unknown.

Three novel complexes with the formulae of [Ni(L)2(H2O)2], [Zn(HL)2(OAc)2] and [UO2(L)2].2H2O were synthesized from simple thiosemicarbazide derivative. The ligand in such bis-form binds either as mononegative bidentate or neutral bindentate mode. The NS donors were the binding centers towards all central atoms inside an octahedral geometry. This geometry was supported by 3A2g→3T1g(P,υ3) and 3A2g→3T1g(F,υ2) transitions that assigned from the bands in UV–Vis spectrum of Ni(II) complex. All structures were optimized under DFT method by using B3LYP/6-31G (d) basis set to estimate valuable quantum data. The charges of N11 (-0.197790) and S14 (-0.067486) donors describe their sufficient nucleophilicity for coordination. Cyclic voltammograms of Ni+2 were studied in presence of the ligand to measure the shift in redox peak that affected by the Ni2+-ligand covalency. The elevated stability constants (βML) and Gibbs free energies (ΔG) suggest the successive building to stable complex in solution. The antimicrobial screening showed an excellent inhibition role from the ligand towards the tested bacteria. Moreover, the genotoxicity of the new compounds was assessed using DNA/ methyl green assay. The ligand exhibited the best decay for the green color results from DNA/ methyl green solution. This in vitro investigation was strengthened by silico ways among that the interaction with DNA-polymerase proteins (1bpy, 5szt and 1zqa). A drug with code number MolPort-002–822-252 has high similarity to our ligand in its binding with DNA beside a low Root Mean Square Deviation value (RMSD = 0.266). Further, the ligand interacted perfectly to DG 6(T) residue in 1bpy protein via H-donor bond and the scoring energy value of the docking pose was excellent (S = −6.1512 kcal/mol). The BOILED-Egg indicates the ability of the ligand to absorb in brain barrier. While, there is no ability for such compound to absorb in gastrointestinal tract. Additionally, the ligand doesn't play as a substrate of P-gp protein, which is considered favorable for protecting tissues and organisms.

The valorisation of waste from rose-based industrial products produces value-added substances and paves the way for advanced composites. The rose waste generated from the essential oil industry of the Taif rose ( Rosa damascena trigintipetala Dieck) is significant, and its management or disposal is a source of concern. In this study, it was valorised to produce a value-added nanomaterial. The synthesis of biochar nanoparticles via high-energy ball milling has gained tremendous research interest in recent times because of its low cost and eco-friendliness. Ball milling is a solvent-free technology with strong potential for waste volatilisation and eco-sustainability through the production of engineered biochar nanoparticles. Different biochar samples were produced and characterised to harness the synergistic combination of biochar production and ball milling. They were prepared at a constant pyrolysis temperature of 300 °C by varying the pyrolysis times for 2 h, 5 h, and 10 h. The characterisation results showed that pyrolysis confirms a high content of carbon, minerals, graphitic structure, novel morphology and chemical characteristics attached to the biochar surface controlled by different pyrolysis durations. These properties were further enhanced by ball milling for 10 h. The results showed that ball milling enhanced the porosity, surface area, surface functional groups, visible light absorption, crystallinity, and carbon content, and these were accompanied by a reduction in the particle size and mineral impurities. The engineered biochar can be an important tool, with promising potential in novel composites for water purification and energy harvesting.

Pathological cardiac remodeling is associated with cardiovascular disease and can lead to heart failure. Nuclear factor-kappa B (NF-κB) is upregulated in the hypertrophic heart. Moreover, the expression of the G-protein-coupled receptor kinase 2 (GRK2) is increased and linked to the progression of heart failure. The inhibitory effects of paroxetine on GRK2 have been established. However, its protective effect on IκBα/NFκB signaling has not been elucidated. This study investigated the cardioprotective effect of paroxetine in an animal model of cardiac hypertrophy (CH), focusing on its effect on GRK2-mediated NF-κB-regulated expression of prohypertrophic and profibrotic genes. Wistar albino rats were administered normal saline, paroxetine, or fluoxetine, followed by isoproterenol to induce CH. The cardioprotective effects of the treatments were determined by assessing cardiac injury, inflammatory biomarker levels, histopathological changes, and hypertrophic and fibrotic genes in cardiomyocytes. Paroxetine pre-treatment significantly decreased the HW/BW ratio (p < 0.001), and the expression of prohypertrophic and profibrotic genes Troponin-I (p < 0.001), BNP (p < 0.01), ANP (p < 0.001), hydroxyproline (p < 0.05), TGF-β1 (p < 0.05), and αSMA (p < 0.01) as well as inflammatory markers. It also markedly decreased pIκBα, NFκB(p105) subunit expression (p < 0.05) and phosphorylation. The findings suggest that paroxetine prevents pathological cardiac remodeling by inhibiting the GRK2-mediated IκBα/NF-κB signaling pathway.

Tetracycline antibiotic has been widely used in veterinary and aquafarming medicines to prevent and treat infectious diseases. However, the overall use of tetracycline results in its accumulation in the organism organs, which then migrates to food and eventually increases the risk of developing various diseases. As one of the most well-known contaminants, sugarcane bagasse (SCB) agricultural waste has been a serious problem worldwide. In order to develop luminous carbon dots doped with nitrogen (NCDs), a simple and environmentally friendly approach was devised to reprocess sugarcane bagasse agricultural waste. A passivating agent, ammonium hydroxide (NH4OH), was used during the hydrothermal carbonization of NCDs in a single-pot procedure. Carbon dots nanoparticles (5–8 nm) embedded in cellulose paper assay were used to prepare the testing strip. With an emission wavelength of 447 nm upon excitation at 355 nm and, NCDs displayed a quantum yield (QY) of up to 24.81%. As a result of the inner filter effect (IFE), the fluorescence of NCDs was clearly quenched by tetracycline, demonstrating their exceptional tetracycline selectivity. The detection limit was set in the concentration range of 0–110 μM. Tetracycline is detected and measured using the current cellulose paper strip, which contains a fluorescent signal that could be turned off to eliminate the signal. The fluorescence quenching feature of cellulose carbon dots in the existence of tetracycline affects the fluorescence activity of the paper strip assay.

We present the formation of cerium oxide (CeO2) anchored with trace amounts of platinum oxide (PtO) nanostructures. These mesoporous photocatalysts were employed for the photodestruction of atrazine (AZ) in water. Descriptions by X-ray diffraction, transmission electron microscopy, and X-ray photoelectron spectroscopy designated the growth of PtO nanoparticles attached to the CeO2 nanocubes. The visible-light absorption of PtO-anchored samples was widened than CeO2 thanks to the bandgap minimization to 2.20 eV. The 1.6 g L−1 dose of 0.9% PtO/CeO2 at indicated the ability to mineralize AZ after 40 min with rate of 82.82 × 10−3 min−1 and 97% of reusability.

Three new functionalized 4-aminopyrazole derivatives were synthesized and cyclized with phenyl isothiocyanate to yield the corresponding three pyrazolo[4,3-d]pyrimidine analogues. The DFT quantum chemical calculations were utilized in the determination of the frontier molecular orbital energies and Fukui’s indices. The data showed that they have a low HOMO-LUMO energy gap, ranging from 1.16 to 2.35 eV for 5 and 6, respectively. The newly created analogues' cytotoxic qualities were evaluated in comparison to the reference 5-florouracil (5-Fu) using an in vitro MTT cytotoxicity screening investigation toward four different cell lines, including HCT-116, HepG2, MCF-7, and WI38. The results showed variable potency against human cell lines, with MCF-7 and HepG-2 showing cytotoxic selectivity. The most potent agent against MCF-7 and HCT-116 human cancer cells were found to be aminopyrazole and pyrazolopyrimidine derivatives 4–9. The structure–activity relationships (SAR) for the synthesized compounds were discussed. The examined compounds had superior cytotoxic properties; the most potent derivative 7, had an IC50 ranged from 11.51 ± 0.35 to 21.25 ± 0.37 µM. Meanwhile, quantum chemical computation used independent variables EH, EL, ΔEH-L, χ and η were applied to determine the best way to describe activity. As a result, an increase in the HOMO-LUMO gap and hardness will result in an increase in the anticancer activity. While the EH, EL, and showed negative coefficients, increasing them will decrease the anticancer activity. Furthermore, 5IVE protein's crystal structure for KDM5A was docked with the newly created aminopyrazole and pyrazolopyrimidine derivatives to afford the theoretical prediction on the KDM5A enzyme.

BackgroundRecombinant Schistosoma mansoni Tetraspanin-2 formulated on Alhydrogel (Sm-TSP-2/Alhydrogel) is being developed to prevent intestinal and hepatic disease caused by S. mansoni. The tegumentary Sm-TSP-2 antigen was selected based on its unique recognition by cytophilic antibodies in putatively immune individuals living in areas of ongoing S. mansoni transmission in Brazil, and preclinical studies in which vaccination with Sm-TSP-2 protected mice following infection challenge.MethodsA randomized, observer-blind, controlled, Phase 1b clinical trial was conducted in 60 healthy adults living in a region of Brazil with ongoing S. mansoni transmission. In each cohort of 20 participants, 16 were randomized to receive one of two formulations of Sm-TSP-2 vaccine (adjuvanted with Alhydrogel only, or with Alhydrogel plus the Toll-like receptor-4 agonist, AP 10-701), and 4 to receive Euvax B hepatitis B vaccine. Successively higher doses of antigen (10 μg, 30 μg, and 100 μg) were administered in a dose-escalation fashion, with progression to the next dose cohort being dependent upon evaluation of 7-day safety data after all participants in the preceding cohort had received their first dose of vaccine. Each participant received 3 intramuscular injections of study product at intervals of 2 months and was followed for 12 months after the third vaccination. IgG and IgG subclass antibody responses to Sm-TSP-2 were measured by qualified indirect ELISAs at pre- and post-vaccination time points through the final study visit.ResultsSm-TSP-2/Alhydrogel administered with or without AP 10-701 was well-tolerated in this population. The most common solicited adverse events were mild injection site tenderness and pain, and mild headache. No vaccine-related serious adverse events or adverse events of special interest were observed. Groups administered Sm-TSP-2/Alhydrogel with AP 10-701 had higher post-vaccination levels of antigen-specific IgG antibody. A significant dose-response relationship was seen in those administered Sm-TSP-2/Alhydrogel with AP 10-701. Peak anti-Sm-TSP-2 IgG levels were observed approximately 2 weeks following the third dose, regardless of Sm-TSP-2 formulation. IgG levels fell to low levels by Day 478 in all groups except the 100 μg with AP 10-701 group, in which 57% of subjects (4 of 7) still had IgG levels that were ≥4-fold higher than baseline. IgG subclass levels mirrored those of total IgG, with IgG1 being the predominant subclass response.ConclusionsVaccination of adults with Sm-TSP-2/Alhydrogel in an area of ongoing S. mansoni transmission was safe, minimally reactogenic, and elicited significant IgG and IgG subclass responses against the vaccine antigen. These promising results have led to initiation of a Phase 2 clinical trial of this vaccine in an endemic region of Uganda.Trial registrationNCT03110757.

Abstract Primary B lymphocytes rapidly respond to lipopolysaccharide (LPS) and cytosine linked to a guanine by a phosphate bond deoxyribonucleic acid (CpG DNA) stimulation to promote adaptive immune function through increased surface marker expression. Here we examined expression of surface markers in LPS and CpG DNA stimulated Epstein-Barr virus transformed B lymphoblasts from control and BTHS patients with different mutations. The percentage of cluster of differentiation (CD) positive cells including CD38 + , CD138 + , CD80 + surface expression and programmed cell death protein 1 (PD1 +) surface expression was similar between control and BTHS lymphoblasts incubated plus or minus LPS. The percentage of CD24 + , CD38 + and CD138 + cells was similar between control and BTHS lymphoblasts incubated plus or minus CpG DNA. CD27 + surface marker expression was reduced in both BTHS lymphoblasts and controls incubated with CpG DNA and PD1 + surface marker expression was higher in BTHS cells compared to controls but was unaltered by CpG DNA treatment. Thus, Epstein-Barr virus transformed control and BTHS lymphoblasts fail to increase selected surface markers upon stimulation with LPS and exhibit variable surface marker expression upon stimulation with CpG DNA. Since B lymphocyte surface marker expression upon activation is involved in B cell proliferation and differentiation, cell–cell interaction and the adaptive immune response, we suggest that caution should be exercised when interpreting immunological data obtained from Epstein-Barr virus transformed BTHS cells. Based upon our observations in control cells, our conclusions may be more broadly applicable to other diseases which utilize transformed B lymphocytes for the study of immune biology.

Steel slag waste produced by the steel industry accumulates in open areas or is disposed of in landfills, causing harm to the environment and human health. Valorizing steel slag through comprehensive data analysis is imperative and could add value to the product with respect to energy conversion and storage applications. This study investigated the morphological, structural, and optical characteristics of a thermally annealed steel slag composite generated from iron and steel factories. Scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), Raman spectroscopy, and UV–visible spectrophotometry were subsequently used to evaluate the impact of thermal treatment on the morphology, structure, elemental composition, and optical properties. It was found that the pre-treated slag composites contained a variety of irregular grain sizes and microscale fragments, primarily composed of C (18.55%), O (50.85%), and Fe (29.41%), with lower amounts of Mg (0.31%), Si (0.44%), and Ca (0.44%), indicating the natural formation of a disordered iron composite. Thermal treatment at different temperatures (300 °C, 600 °C, and 900 °C) increased the grain density and clustering, resulting in denser two-dimensional microstructures at 900 °C. Additionally, XRD and Raman analyses of both untreated and thermally treated slag composites revealed the presence of a disordered iron oxide composite, including (Fe3O4), hematite (α-Fe2O3), and maghemite (γ-Fe2O3) phases. A significant increase in optical absorbance was also observed after annealing at 600 °C, highlighting the successful optimization of the elemental composition of the slag composite. A band gap energy of approximately 2.2 eV was obtained from this optimization at 600 °C. The optical conductivity of the composite reached 2.1 × 106 S−1 at 600 °C, which indicates an enhancement in charge transfer among the optimized chemical elements in the waste composite. These findings suggest an optimization method for novel composites derived from steel slag waste, indicating its potential as a low-cost material for energy storage systems (batteries, supercapacitors, and fuel cells) and optoelectronic devices.

The COVE trial randomized participants to receive two doses of mRNA-1273 vaccine or placebo on Days 1 and 29 (D1, D29). Anti-SARS-CoV-2 Spike IgG binding antibodies (bAbs), anti-receptor binding domain IgG bAbs, 50% inhibitory dilution neutralizing antibody (nAb) titers, and 80% inhibitory dilution nAb titers were measured at D29 and D57. We assessed these markers as correlates of protection (CoPs) against COVID-19 using stochastic interventional vaccine efficacy (SVE) analysis and principal surrogate (PS) analysis, frameworks not used in our previous COVE immune correlates analyses. By SVE analysis, hypothetical shifts of the D57 Spike IgG distribution from a geometric mean concentration (GMC) of 2737 binding antibody units (BAU)/mL (estimated vaccine efficacy (VE): 92.9% (95% CI: 91.7%, 93.9%)) to 274 BAU/mL or to 27,368 BAU/mL resulted in an overall estimated VE of 84.2% (79.0%, 88.1%) and 97.6% (97.4%, 97.7%), respectively. By binary marker PS analysis of Low and High subgroups (cut-point: 2094 BAU/mL), the ignorance interval (IGI) and estimated uncertainty interval (EUI) for VE were [85%, 90%] and (78%, 93%) for Low compared to [95%, 96%] and (92%, 97%) for High. By continuous marker PS analysis, the IGI and 95% EUI for VE at the 2.5th percentile (519.4 BAU/mL) vs. at the 97.5th percentile (9262.9 BAU/mL) of D57 Spike IgG concentration were [92.6%, 93.4%] and (89.2%, 95.7%) vs. [94.3%, 94.6%] and (89.7%, 97.0%). Results were similar for other D29 and D57 markers. Thus, the SVE and PS analyses additionally support all four markers at both time points as CoPs.

With the advent of rapid multiplex PCR, physicians have been able to test for multiple viral pathogens when a patient presents with influenza-like illness. This has led to the discovery that many respiratory infections are caused by more than one virus. Antiviral treatment of viral coinfections can be complex because treatment of one virus will affect the time course of the other virus. Since effective antivirals are only available for some respiratory viruses, careful consideration needs to be given on the effect treating one virus will have on the dynamics of the other virus, which might not have available antiviral treatment. In this study, we use mathematical models of viral coinfections to assess the effect of antiviral treatment on coinfections. We examine the effect of the mechanism of action, relative growth rates of the viruses, and the assumptions underlying the interaction of the viruses. We find that high antiviral efficacy is needed to suppress both infections. If high doses of both antivirals are not achieved, then we run the risk of lengthening the duration of coinfection or even of allowing a suppressed virus to replicate to higher viral titers.

During the course of the 2015-2017 outbreak of Zika virus (ZIKV) in the Americas, the emerging virus was recognized as a congenital infection that could damage the developing brain. As the Latin American ZIKV outbreak advanced, the scientific and public health community questioned if this newly recognized neurotropic flavivirus could affect the developing brain of infants and young children infected after birth. We report here the study design, methods and the challenges and lessons learned from the rapid operationalization of a prospective natural history cohort study aimed at evaluating the potential neurological and neurodevelopmental effects of postnatal ZIKV infection in infants and young children, which had become epidemic in Central America. This study enrolled a cohort of 500 mothers and their infants, along with nearly 400 children 1.5-3.5 years of age who were born during the initial phase of the ZIKV epidemic in a rural area of Guatemala. Our solutions and lessons learned while tackling real-life challenges may serve as a guide to other researchers carrying out studies of emerging infectious diseases of public health priority in resource-constrained settings.

Novel multi-stimuli responsive cotton fibers were developed via spray-coating with an acylhydrazone-based polyviologen (AHPV). Polyviologen was prepared by supramolecular condensation polymerization of bipyridinium dialdehyde with a hydroxyl-substituted aryldihydrazide in an acidified aqueous medium. Transparent AHPV/resin nanocomposite film was deposited onto the surface of cotton fabric by well-dispersion of AHPV as a chromogenic substance in a resin binding agent. Increasing the temperature of the AHPV-coated cotton fabric from room temperature to 85 °C reversibly triggered a change in color from pale yellow (437 nm) to green (607 nm), respectively. The transparent layer immobilized onto the white cotton surface transformed into green under ultraviolet source as demonstrated by CIE Lab parameters. The photochromic impacts were explored at various AHPV. In addition, the AHPV-coated cotton immediately displayed a vapochromic activity upon exposure to NH3(g), and then recovered to pale yellow after removing the ammonia source away. The current AHPV-coated cotton fabric displayed a limit of detection (LOD) to NH3(aq) in the range of 50–150 ppm. The spray-coated cotton fabrics demonstrated a reversible photochromism, thermochromism and vapochromism with high stability. The produced AHPV nanoparticles were also studied by transmission electron microscopy (TEM), demonstrating particle diameter of 74–92 nm. The mechanical and morphological properties of the spray-coated cotton fabrics were also explored. The surface morphology of AHPV-finished samples was examined by Fourier-transform infrared (FTIR) and scanning electron microscopy (SEM). No considerable defects were observed in permeability to air and bending length of AHPV-finished samples. Additionally, high colorfastness was monitored for the AHPV-finished cotton substrates. The cytotoxic activity of the AHPV-finished cotton was also examined. Mechanistic study accounting for the multichromic activity of acylhydrazone-based polyviologen is explored.

Oncolytic adenoviruses (OAds) present a promising path for cancer treatment due to their selectivity in infecting and lysing tumor cells and their ability to stimulate the immune response. In this study, we use an ordinary differential equation (ODE) model of tumor growth inhibited by oncolytic virus activity to parameterize previous research on the effect of genetically re-engineered OAds in A549 lung cancer tumors in murine models. We find that the data are best fit by a model that accounts for an immune response, and that the immune response provides a mechanism for elimination of the tumor. We also find that parameter estimates for the most effective OAds share characteristics, most notably a high infection rate and low viral clearance rate, that might be potential reasons for these viruses’ efficacy in delaying tumor growth. Further studies observing E1A and P19 recombined viruses in different tumor environments may further illuminate the extent of the effects of these genetic modifications.

The chromophore 2-(3-cyano-4-((2-(4,6-dimethyl-5-nitro-1H-pyrazolo[3,4-b]pyridin-3-yl) hydrazono)methyl)-5,5-dimethylfuran-2(5H)-ylidene)malononitrile (PPHTCF) was synthesized through coupling of diazotized 3-amino-4,6-dimethyl-5-nitropyrazolo[3,4-b]pyridine with 3-cyano-2-(dicyanomethylene)-4,5,5-trimethylfuran (TCF). The absorption solvatochromism behaviour of PPHTCF, in various solvents, presented ΔEmax = +5.40 where the positive sign suggested red shift occurrence, implying that the PPHTCF has more polar lowest excited state than its ground one. While, the PPHTCF fluorescence spectra afforded λem, in 575–633 nm range, and was more dependent on the solvent polarity than the absorption λmax, despite both exhibited red shift by 58 and 42 nm, respectively. To discover the PPHTCF solvatochromism behaviour in term of “Stokes’ shift”, both of Lippert-Mataga and linear solvation-energy relationship (LSER) formulations have been utilized and the outcomes endorsed that the later was better than the former (R2 = 0.9728). Finally, TD-DFT simulated absorption and emission spectra in EtOH revealed that λmax has been resulted mainly from HOMO → LUMO; HOMO-5 → LUMO and HOMO-2 → LUMO transitions, respectively.

Barth Syndrome (BTHS) is a rare X-linked genetic disease caused by a mutation in the TAFAZZIN gene, which codes for the protein tafazzin involved in cardiolipin remodeling. Approximately 70% of patients with BTHS exhibit severe infections due to neutropenia. However, neutrophils from BTHS patients have been shown to exhibit normal phagocytosis and killing activity. B lymphocytes play a crucial role in the regulation of the immune system and, when activated, secrete cytokines known to attract neutrophils to sites of infection. We examined the expression of chemokine (C-X-C motif) ligand 1 (CXCL1), a known chemotactic for neutrophils, in Epstein–Barr virus transformed control and BTHS B lymphoblasts. Age-matched control and BTHS B lymphoblasts were incubated with Pseudomonas aeruginosa for 24 h and then cell viability, CD27+, CD24+, CD38+, CD138+ and PD1+ surface marker expression and CXCL1 mRNA expression determined. Cell viability was maintained in lymphoblasts incubated in a ratio of 50:1 bacteria:B cells. Surface marker expression was unaltered between control and BTHS B lymphoblasts. In contrast, CXCL1 mRNA expression was reduced approximately 70% (p < 0.05) in untreated BTHS B lymphoblasts compared to control and approximately 90% (p < 0.05) in bacterial treated BTHS B lymphoblasts compared to the control. Thus, naïve and bacterial-activated BTHS B lymphoblasts exhibit reduced mRNA expression of the neutrophil chemoattractant factor CXCL1. We suggest that impaired bacterial activation of B cells in some BTHS patients could influence neutrophil function via impairing neutrophil recruitment to sites of infection and this could potentially contribute to these infections.

Accumulating evidence supports the potential protective effects of vitamin D against chronic diseases such as Alzheimer’s disease, autoimmune diseases, cancers, cardiovascular disease (ischaemic heart disease and stroke), type 2 diabetes, hypertension, chronic kidney disease, stroke, and infectious diseases such as acute respiratory tract diseases, COVID-19, influenza, and pneumonia, as well as adverse pregnancy outcomes. The respective evidence is based on ecological and observational studies, randomized controlled trials, mechanistic studies, and Mendelian randomization studies. However, randomized controlled trials on vitamin D supplementation have largely failed to show benefits, probably due to poor design and analysis. In this work, we aim to use the best available evidence on the potential beneficial effects of vitamin D to estimate the expected reduction in incidence and mortality rates of vitamin D-related diseases in the Kingdom of Saudi Arabia and the United Arab Emirates if minimum serum 25(OH)D concentrations were to be raised to 30 ng/mL. Estimated reductions by 25% for myocardial infarction incidence, 35% for stroke incidence, 20 to 35% for cardiovascular disease mortality, and 35% for cancer mortality rates depicted a promising potential for raising serum 25(OH)D. Methods to increase serum 25(OH)D concentrations at the population level could include food fortification with vitamin D3, vitamin D supplementation, improved dietary vitamin D intake, and sensible sun exposure.

Vitamin D plays a crucial role in modulating the innate immune response by interacting with its intracellular receptor, VDR. In this review, we address vitamin D/VDR signaling and how it contributes to the regulation of intestinal and respiratory microbiota. We additionally review some components of the innate immune system, such as the barrier function of the pulmonary and intestinal epithelial membranes and secretion of mucus, with their respective modulation by vitamin D. We also explore the mechanisms by which this vitamin D/VDR signaling mounts an antimicrobial response through the transduction of microbial signals and the production of antimicrobial peptides that constitute one of the body’s first lines of defense against pathogens. Additionally, we highlight the role of vitamin D in clinical diseases, namely inflammatory bowel disease and acute respiratory distress syndrome, where excessive inflammatory responses and dysbiosis are hallmarks. Increasing evidence suggests that vitamin D supplementation may have potentially beneficial effects on those diseases.

The immunologic mechanisms underlying the improved serologic responses to heterologous prime-boost avian influenza vaccination are unclear. An exploratory analysis of the immune responses following 1 dose of influenza A/H7N9 inactivated vaccine in subjects who received an influenza A/H7N7 inactivated vaccine (N = 17) 8 years earlier or who were influenza A/H7-naïve (10) was performed. Plasma IL-6 and IL-21 concentrations by ELISA, the frequency of A/H7N7-specific memory B cells and antibody secreting cells by ELISpot, the frequency of circulating T follicular helper cells and the frequency of T cells expressing IL-6 and IL-21 by flow cytometry were assessed at baseline (D1), and 8 days (D9) and 28 days (D29) after vaccination. We assessed the correlation between these measurements and the D29 serologic responses to the boost vaccine. Plasma IL-6 concentration on D9 significantly correlated with the H7N7 and H7N9 hemagglutination inhibition (HAI) antibody levels (P = .03 and 0.02 respectively); and the percentage of T cells expressing IL-21 on D9 significantly correlated with H7N9 HAI antibody seroconversion (P

Aromatic nucleophilic substitution (SNAr) reactions have been known to be regioselective to the para position on a variety of substituted perfluorobenzenes. In the current study, a series of fluoroaryl 1, 3, 4-oxadiazole derivatives substituted with different para terminal ethers were synthesized using SNAr chemistry to afford fluorescent and thermally reversible low molecular weight organogelators (LMWOs). SNAr was used to synthesize these highly fluorinated organogelators in high purity and good yields starting from pentafluorobenzoic acid and 4′-hydroxy-4-biphenylcarbonitrile. These fluorinated 1, 3, 4-oxadiazole derivatives were characterized by elemental analysis, FTIR, and 1H, 13C, and 19F NMR spectroscopy. The photophysical properties of those organogelators were described. Both UV–visible absorption and fluorescence spectral profiles displayed a solvatochromic and solvatofluorochromic properties. The absorption maxima for the developed organogelators were monitored in the range of 260–289 nm, whereas the emission maxima were monitored in the range of 278–305 nm. The best gelation properties were monitored for the hexyloxy-substituted 2-(biphenylyl)-5-(perflurophenyl)-1, 3, 4-oxadiazole gelator in different solvents with critical gel concentrations in the range of 1.86–5.07 mM. The self-assembly process was monitored to occur via van der Waals forces and π-π stacks to result in gelation of solvents. Scanning electron microscope (SEM) demonstrated nanofiber-like structures (350–550 nm). The thermal stability of the hexyloxy-substituted organogel was monitored at 48 °C. Both cytotoxicity and antimicrobial activity of the produced fluoroaryl 1, 3, 4-oxadiazole derivatives were explored to verify their potential use for biomedical applications, such as drug delivery and bioimaging.

Some viruses have the ability to block or suppress growth of other viruses when simultaneously present in the same host. This type of viral interference or viral block has been suggested as a potential interaction between some respiratory viruses including SARS-CoV-2 and other co-circulating respiratory viruses. We explore how one virus' ability to block infection with another within a single host affects spread of the viruses within a susceptible population using a compartmental epidemiological model. We find that population-level effect of viral block is a decrease in the number of people infected with the suppressed virus. This effect is most pronounced when the viruses have similar epidemiological parameters. We use the model to simulate co-circulating epidemics of SARS-CoV-2 and influenza, respiratory syncytial virus (RSV), and rhinovirus, finding that co-circulation of SARS-CoV-2 and RSV causes the most suppression of SARS-CoV-2. Paradoxically, co-circulation of SARS-CoV-2 and influenza or rhinovirus results in almost no change in the SARS-CoV-2 epidemic, but causes a shift in the timing of the influenza and rhinovirus epidemics.

Abstract Objectives Increasing physical activity reduces the risk of chronic illness including Type 2 diabetes, cardiovascular disease and certain types of cancer. Lifestyle interventions can increase physical activity but few successfully engage men. This study aims to investigate the 5 year cost-effectiveness of EuroFIT, a program to improve physical activity tailored specifically for male football (soccer) fans compared to a no intervention comparison group. Methods We developed a Markov cohort model in which the impact of improving physical activity on five chronic health conditions (colorectal cancer, Type 2 diabetes, coronary heart disease, stroke and depression) and mortality was modelled. We estimated costs from a societal perspective and expressed benefits as quality adjusted life years (QALYs). We obtained data from a 4-country (England, Netherlands, Portugal and Norway) pragmatic randomised controlled trial evaluating EuroFIT, epidemiological and cohort studies, and meta-analyses. We performed deterministic and probabilistic sensitivity analyses to assess the impact of uncertainty in the model’s parameter values on the cost-effectiveness results. We used Monte Carlo simulations to estimate uncertainty and presented this using cost-effectiveness acceptability curves (CEACs). We tested the robustness of the base case analysis using five scenario analyses. Results Average costs over 5 years per person receiving EuroFIT were €14,663 and per person receiving no intervention €14,598. Mean QALYs over 5 years were 4.05 per person for EuroFIT and 4.04 for no intervention. Thus, the average incremental cost per person receiving EuroFIT was €65 compared to no intervention, while the average QALY gain was 0.01. This resulted in an ICER of €5206 per QALY gained. CEACs show that the probability of EuroFIT being cost-effective compared to no intervention is 0.53, 0.56 and 0.58 at thresholds of €10,000, €22,000 and €34,000 per QALY gained, respectively. When using a time horizon of 10 years, the results suggest that EuroFIT is more effective and less expensive compared to (i.e. dominant over) no intervention with a probability of cost-effectiveness of 0.63 at a threshold of €22,000 per QALY gained. Conclusions We conclude the EuroFIT intervention is not cost-effective compared to no intervention over a period of 5 years from a societal perspective, but is more effective and less expensive (i.e. dominant) after 10 years. We thus suggest that EuroFIT can potentially improve public health in a cost-effective manner in the long term.