Carbon implications of marginal oils from market-derived demand shocks.

Expanded use of novel oil extraction technologies has increased the variability of petroleum resources and diversified the carbon footprint of the global oil supply1. Past life-cycle assessment (LCA) studies overlooked upstream emission heterogeneity by assuming that a decline in oil demand will displace average crude oil2. We explore the life-cycle greenhouse gas emissions impacts of marginal crude sources, identifying the upstream carbon intensity (CI) of the producers most sensitive to an oil demand decline (for example, due to a shift to alternative vehicles). We link econometric models of production profitability of 1,933 oilfields (~90% of the 2015 world supply) with their production CI. Then, we examine their response to a decline in demand under three oil market structures. According to our estimates, small demand shocks have different upstream CI implications than large shocks. Irrespective of the market structure, small shocks (-2.5% demand) displace mostly heavy crudes with ~25-54% higher CI than that of the global average. However, this imbalance diminishes as the shocks become bigger and if producers with market power coordinate their response to a demand decline. The carbon emissions benefits of reduction in oil demand are systematically dependent on the magnitude of demand drop and the global oil market structure.

Pharmacological Modulation of the Crosstalk between Aberrant Janus Kinase Signaling and Epigenetic Modifiers of the Histone Deacetylase Family to Treat Cancer.

Hyperactivated Janus kinase (JAK) signaling is an appreciated drug target in human cancers. Numerous mutant JAK molecules as well as inherent and acquired drug resistance mechanisms limit the efficacy of JAK inhibitors (JAKi). There is accumulating evidence that epigenetic mechanisms control JAK-dependent signaling cascades. Like JAKs, epigenetic modifiers of the histone deacetylase (HDAC) family regulate the growth and development of cells and are often dysregulated in cancer cells. The notion that inhibitors of histone deacetylases (HDACi) abrogate oncogenic JAK-dependent signaling cascades illustrates an intricate crosstalk between JAKs and HDACs. Here, we summarize how structurally divergent, broad-acting as well as isoenzyme-specific HDACi, hybrid fusion pharmacophores containing JAKi and HDACi, and proteolysis targeting chimeras for JAKs inactivate the four JAK proteins JAK1, JAK2, JAK3, and tyrosine kinase-2. These agents suppress aberrant JAK activity through specific transcription-dependent processes and mechanisms that alter the phosphorylation and stability of JAKs. Pharmacological inhibition of HDACs abrogates allosteric activation of JAKs, overcomes limitations of ATP-competitive type 1 and type 2 JAKi, and interacts favorably with JAKi. Since such findings were collected in cultured cells, experimental animals, and cancer patients, we condense preclinical and translational relevance. We also discuss how future research on acetylation-dependent mechanisms that regulate JAKs might allow the rational design of improved treatments for cancer patients. SIGNIFICANCE STATEMENT: Reversible lysine-ɛ-N acetylation and deacetylation cycles control phosphorylation-dependent Janus kinase-signal transducer and activator of transcription signaling. The intricate crosstalk between these fundamental molecular mechanisms provides opportunities for pharmacological intervention strategies with modern small molecule inhibitors. This could help patients suffering from cancer.

Two mutations in the ORF1 of genotype 1 hepatitis E virus enhance virus replication and may associate with fulminant hepatic failure.

Hepatitis E virus (HEV) infection in pregnant women has a high incidence of developing fulminant hepatic failure (FHF) with significant mortality. Multiple amino acid changes in genotype 1 HEV (HEV-1) are reportedly linked to FHF clinical cases, but experimental confirmation of the roles of these changes in FHF is lacking. By utilizing the HEV-1 indicator replicon and infectious clone, we generated 11 HEV-1 single mutants, each with an individual mutation, and investigated the effect of these mutations on HEV replication and infection in human liver cells. We demonstrated that most of the mutations actually impaired HEV-1 replication efficiency compared with the wild type (WT), likely due to altered physicochemical properties and structural conformations. However, two mutations, A317T and V1120I, significantly increased HEV-1 replication. Notably, these two mutations simultaneously occurred in 100% of 21 HEV-1 variants from patients with FHF in Bangladesh. We further created an HEV-1 A317T/V1120I double mutant and found that it greatly enhanced HEV replication, which may explain the rapid viral replication and severe disease. Furthermore, we tested the effect of these FHF-associated mutations on genotype 3 HEV (HEV-3) replication and found that all the mutants had a reduced level of replication ability and infectivity, which is not unexpected due to distinct infection patterns between HEV-1 and HEV-3. Additionally, we demonstrated that these FHF-associated mutations do not appear to alter their sensitivity to ribavirin (RBV), suggesting that ribavirin remains a viable option for antiviral therapy for patients with FHF. The results have important implications for understanding the mechanism of HEV-1-associated FHF.

Hepatitis E virus infects brain microvascular endothelial cells, crosses the blood-brain barrier, and invades the central nervous system.

Hepatitis E virus (HEV) is an important but understudied zoonotic virus causing both acute and chronic viral hepatitis. A proportion of HEV-infected individuals also developed neurological diseases such as Guillain-Barré syndrome, neuralgic amyotrophy, encephalitis, and myelitis, although the mechanism remains unknown. In this study, by using an in vitro blood-brain barrier (BBB) model, we first investigated whether HEV can cross the BBB and whether the quasi-enveloped HEV virions are more permissible to the BBB than the nonenveloped virions. We found that both quasi-enveloped and nonenveloped HEVs can similarly cross the BBB and that addition of proinflammatory cytokine tumor necrosis factor alpha (TNF-α) has no significant effect on the ability of HEV to cross the BBB in vitro. To explore the possible mechanism of HEV entry across the BBB, we tested the susceptibility of human brain microvascular endothelial cells lining the BBB to HEV infection and showed that brain microvascular endothelial cells support productive HEV infection. To further confirm the in vitro observation, we conducted an experimental HEV infection study in pigs and showed that both quasi-enveloped and nonenveloped HEVs invade the central nervous system (CNS) in pigs, as HEV RNA was detected in the brain and spinal cord of infected pigs. The HEV-infected pigs with detectable viral RNA in CNS tissues had histological lesions in brain and spinal cord and significantly higher levels of proinflammatory cytokines TNF-α and interleukin 18 than the HEV-infected pigs without detectable viral RNA in CNS tissues. The findings suggest a potential mechanism of HEV-associated neuroinvasion.

Intercostal Nerve Cryoablation Reduces Opioid Use and Length of Stay Without Increasing Adverse Events: A Retrospective Cohort Study of 5442 Patients Undergoing Surgical Correction of Pectus Excavatum.

OBJECTIVE: To examine differences in opioid use, length of stay, and adverse events after minimally invasive correction of pectus excavatum (MIRPE) with and without intercostal nerve cryoablation. BACKGROUND: Small studies show that intraoperative intercostal nerve cryoablation provides effective analgesia with no large-scale evaluations of this technique. METHODS: The pediatric health information system database was used to perform a retrospective cohort study comparing patients undergoing MIRPE at children's hospitals before and after the initiation of cryoablation. The association of cryoablation use with inpatient opioid use was determined using quantile regression with robust standard errors. Difference in risk-adjusted length of stay between the cohorts was estimated using negative binomial regression. Odds of adverse events between the two cohorts were compared using logistic regression with a generalized estimating equation. RESULTS: A total of 5442 patients underwent MIRPE at 44 children's hospitals between 2016 and 2022 with 1592 patients treated after cryoablation was introduced at their hospital. Cryoablation use was associated with a median decrease of 80.8 (95% CI: 68.6-93.0) total oral morphine equivalents as well as a decrease in estimated median length of stay from 3.5 [3.2-3.9] days to 2.5 [2.2-2.9] days ( P value: 0.016). Cryoablation use was not significantly associated with an increase in any studied adverse events. CONCLUSIONS: Introduction of cryoablation for perioperative analgesia was associated with decreased inpatient opioid use and length of stay in a large sample with no change in adverse events. This novel modality for perioperative analgesia offers a promising alternative to traditional pain management in thoracic surgery.

Basic Fuchsin Dye as the First Fluorophore for Optical Sensing of Morpholine in Fruits Crust and Urine Samples.

In this work, basic fuchsin (BF) dyestuff was presented as the first optical sensor used for the spectrofluorimetric assessment of morpholine (MOR) where BF exhibits morpholine-sensing behavior. The developed fluorimetric avenue is sensitive, facile, selective, and validated for assaying the sensitizing influence of MOR on the BF fluorescence in an aprotic dioxane solvent. Parameters like solvents, BF concentration, order, and time of addition that influence the fluorescence intensity of the probing system were addressed. Optimizing the analytical methodology revealed a linear fluorescence sensitization within the addition of MOR in the two concentration ranges of 5 × 10-9 to 1.0 × 10-7 mol L-1 and 2.0 × 10-7 to 3 × 10-6 mol L-1. The limit of detection (LOD) and limit of quantification (LOQ) were estimated to be 2.0 × 10-9 mol L-1 (0.17 ng mL-1) and 6.66 × 10-9 mol L-1 (0.567 ng mL-1), respectively. High levels of accuracy and precision are achieved when assaying spiked MOR either in pure solutions or samples of fruit peel extract and human urine. Moreover, the green character and practicality/applicability of the method were evaluated by AGREE and BAGI metric tools. These merit outcomes provide insights into the development of fluorescent sensors for MOR detection using fluorescent dyes and meet the Food and Drug Administration's requirements for morpholine detection in real-life applications.

Hindering the biofilm of microbial pathogens and cancer cell lines development using silver nanoparticles synthesized by epidermal mucus proteins from Clarias gariepinus.

Scientists know very little about the mechanisms underlying fish skin mucus, despite the fact that it is a component of the immune system. Fish skin mucus is an important component of defence against invasive infections. Recently, Fish skin and its mucus are gaining interest among immunologists. Characterization was done on the obtained silver nanoparticles Ag combined with Clarias gariepinus catfish epidermal mucus proteins (EMP-Ag-NPs) through UV-vis, FTIR, XRD, TEM, and SEM. Ag-NPs ranged in size from 4 to 20 nm, spherical in form and the angles were 38.10°, 44.20°, 64.40°, and 77.20°, Where wavelength change after formation of EMP-Ag-NPs as indicate of dark brown, the broad band recorded at wavelength at 391 nm. Additionally, the antimicrobial, antibiofilm and anticancer activities of EMP-Ag-NPs was assessed. The present results demonstrate high activity against unicellular fungi C. albicans, followed by E. faecalis. Antibiofilm results showed strong activity against both S. aureus and P. aeruginosa pathogens in a dose-dependent manner, without affecting planktonic cell growth. Also, cytotoxicity effect was investigated against normal cells (Vero), breast cancer cells (Mcf7) and hepatic carcinoma (HepG2) cell lines at concentrations (200-6.25 µg/mL) and current results showed highly anticancer effect of Ag-NPs at concentrations 100, 5 and 25 µg/mL exhibited rounding, shrinkage, deformation and granulation of Mcf7 and HepG2 with IC50 19.34 and 31.16 µg/mL respectively while Vero cells appeared rounded at concentration 50 µg/mL and normal shape at concentration 25, 12.5 and 6.25 µg/ml with IC50 35.85 µg/mL. This study evidence the potential efficacy of biologically generated Ag-NPs as a substitute medicinal agent against harmful microorganisms. Furthermore, it highlights their inhibitory effect on cancer cell lines.

Using the Stratum-Specific Likelihood Ratio Method to Derive Outcome-Based Hospital Volume Categories for Total Knee Replacement.

BACKGROUND: Evidence of higher hospital volume being associated with improved outcomes for patients undergoing total knee replacement (TKR) is mostly based on arbitrary distribution-based thresholds. OBJECTIVE: We aimed to define outcome-based volume thresholds using data from a national database. METHODS: We used the MedPAR Limited Data Set inpatient data from 2010-2015 to identify patients who had undergone primary TKR. Surgical and TKR specific complications occurring within the index hospitalization and all-cause readmission within 90 days were considered adverse events. We derived an average annual TKR case volume for each hospital and applied the stratum-specific likelihood ratio method to determine volume categories indicative of a similar likelihood of 90-day post-operative complications. Hierarchical multivariable logistic regression with a random intercept for hospital nested within study year and adjusted for patient and hospital characteristics was performed to determine if these volume thresholds were still associated with the odds of 90-day readmission for complications after adjustment. RESULTS: SSLR analysis yielded 4 hospital volume categories based on the likelihood of 90-day postoperative complications: 1-31 (low), 32-127 (medium), 128-248 (high), and 429+ (very high) TKRs performed per year. The results of the hierarchical multivariable logistic regression showed significantly increased odds of 90-day complications at lower volume categories. Sensitivity analyses confirmed our main findings. CONCLUSIONS: This study is the first to provide national-level volume categories that are evidence-based. Publicizing these thresholds may enhance quality measures available to patients, providers, and payors.

The influence of SARS-CoV-2 on male reproduction and men's health.

BACKGROUND: SARS-CoV-2, the virus responsible for COVID-19, primarily affects the respiratory system by targeting the Angiotensin-converting enzyme 2 (ACE2) receptor and TMPRSS2. However, these receptors are also present in other organs, including the testes, where a higher concentration of ACE2 receptors has been observed. This raises concerns about the potential impact of the virus on male fertility. AIMS: In this study, we aimed to assess the effects of SARS-CoV-2 on semen parameters by comparing samples during and after infection in the same patients. MATERIALS & METHOD: The study enrolled 51 individuals who had contracted COVID-19 and analysed various parameters related to sperm quality and quantity, including C-reactive protein, testosterone levels, total sperm concentration, motility and morphology. A comparison was made between these parameters during the initial infection with SARS-CoV-2 and after a 2- and 5-month recovery period. RESULTS: The results indicated that all of the mentioned parameters were significantly affected during COVID-19 infection (PCR-ct, CRP, WBCs LH, FSH and testosterone levels, p-value = .0001). Furthermore, the study assessed TC, TM and sperm morphology in patients infected with SARS-CoV-2 and found that these parameters were also significantly influenced during the infection, (p-value = .0001; Morphology, p-value = .0004). We observed significant alterations in sperm count and morphology during infection, suggesting a potential negative impact on sperm quality. Additionally, lower hormone levels were observed during COVID-19 infection, possibly due to increased inflammatory cytokines. However, both hormones and inflammation markers returned to normal following recovery. Our findings indicate a statistically significant change in total sperm count, motility and morphology post-infection, which aligns with previous studies. Discussion, COVID-19 have a transient impact on sperm parameters and fertility, emphasizing the importance of further investigation into the long-term implications.

The protein phosphatase-2A subunit PR130 is involved in the formation of cytotoxic protein aggregates in pancreatic ductal adenocarcinoma cells.

As a major source of cellular serine and threonine phosphatase activity, protein phosphatase-2A (PP2A) modulates signaling pathways in health and disease. PP2A complexes consist of catalytic, scaffolding, and B-type subunits. Seventeen PP2A B-type subunits direct PP2A complexes to selected substrates. It is ill-defined how PP2A B-type subunits determine the growth and drug responsiveness of tumor cells. Pancreatic ductal adenocarcinoma (PDAC) is a disease with poor prognosis. We analyzed the responses of murine and human mesenchymal and epithelial PDAC cells to the specific PP2A inhibitor phendione. We assessed protein levels by immunoblot and proteomics and cell fate by flow cytometry, confocal microscopy, and genetic manipulation. We show that murine mesenchymal PDAC cells express significantly higher levels of the PP2A B-type subunit PR130 than epithelial PDAC cells. This overexpression of PR130 is associated with a dependency of such metastasis-prone cells on the catalytic activity of PP2A. Phendione induces apoptosis and an accumulation of cytotoxic protein aggregates in murine mesenchymal and human PDAC cells. These processes occur independently of the frequently mutated tumor suppressor p53. Proteomic analyses reveal that phendione upregulates the chaperone HSP70 in mesenchymal PDAC cells. Inhibition of HSP70 promotes phendione-induced apoptosis and phendione promotes a proteasomal degradation of PR130. Genetic elimination of PR130 sensitizes murine and human PDAC cells to phendione-induced apoptosis and protein aggregate formation. These data suggest that the PP2A-PR130 complex dephosphorylates and thereby prevents the aggregation of proteins in tumor cells.

Cefepime pharmacokinetics in adult extracorporeal membrane oxygenation patients.

BACKGROUND: The impact of extracorporeal membrane oxygenation (ECMO) on the pharmacokinetics/dynamics (PK/PD) of beta-lactam antibiotics have not been well studied in general, but cefepime specifically has the least amount of data. We aimed to investigate whether ECMO alters the PK of cefepime in adult intensive care unit (ICU) patients. METHODS: This single-center, retrospective case-control study evaluated cefepime therapeutic drug monitoring (TDM) results from ECMO patients that were matched 1:1 with TDM results in non-ECMO patients for drug regimen and renal function. The primary outcome was the difference in PK/PD of cefepime in ECMO compared with non-ECMO ICU patients. Secondary outcomes included hospital length of stay, treatment failure, superinfection, bacterial resistance, and survival to discharge. RESULTS: Eighty-two patients were included with 44 matched cefepime concentrations in each group. ECMO patients had higher free maximum concentrations (fCmax) (p = 0.003), lower free minimum concentration (fCmin)/1x minimum inhibitory concentration (MIC) ratios (p = 0.040), and lower attainment of free Cmin/4x MIC (p = 0.010). There were no differences between the groups for free Cmin, time above 1xMIC or 4x MIC, and pharmacokinetic parameters (ke, half-life, and Vd). Of those who survived to discharge, hospital length of stay was longer in the ECMO group (p < 0.001). Patients on ECMO were more likely to experience treatment failure (p = 0.036). The incidence of bacterial resistance, superinfection, or survival were similar among the groups. CONCLUSION: These data suggest that more aggressive empiric dosing may be warranted in patients on ECMO. Therapeutic drug monitoring and future prospective studies would provide more evidence to guide decision making regarding dose adjustments.

Bimetallic nanoparticles supported on Ce-BTC for highly efficient and stable reduction of nitroarenes: Towards environmental sustainability.

The development of a catalyst with a consistent and clearly defined crystal structure is crucial for establishing an efficient catalytic performance system. This study focuses on catalyzing the reduction of nitroarenes to amino-derivatives in an aquatic environment at ambient temperature, employing metallic (Au) and bimetallic (Au-Pd or Au-Ag) nanoparticles loaded on a Ce-BTC metal-organic framework using a facile sol-immobilization approach. Diverse analytical instruments, comprising SEM, TEM, XRD, FT-IR, XPS, TGA, and N2 isotherm, have been utilized to characterize the synthesized catalysts. Among the catalysts that were fabricated, Au-Pd@Ce-BTC displayed the maximum catalytic efficacy, offering a rate constant (kapp) of 0.5841 min-1, conversion percentages reaching 99.7%, and a KAF of 116.8 min-1g-1. Moreover, it exhibited remarkable recyclability over five consecutive cycles. This catalyst offers the advantages of operating under ambient reaction conditions and exhibiting tolerance to a broad range of substrates containing various functional moieties. The mechanistic understanding of nitroarene reduction and the factors contributing to the superior activity of Au-Pd/Ce-BTC are explored through spectroscopic and porosity analyses. Spectroscopic measurements indicate that the elevated Auo and Pdo/Pd2+ ratio, increased surface area, and the synergistic collaboration of the bimetallic NPs are key factors contributing to the heightened activity of Au-Pd/Ce-BTC. These findings hold significant appeal from both an industrial and academic standpoint.

Exploring predictors and prevalence of postpartum depression among mothers: Multinational study.

BACKGROUND: Postpartum depression (PPD) affects around 10% of women, or 1 in 7 women, after giving birth. Undiagnosed PPD was observed among 50% of mothers. PPD has an unfavorable relationship with women's functioning, marital and personal relationships, the quality of the mother-infant connection, and the social, behavioral, and cognitive development of children. We aim to determine the frequency of PPD and explore associated determinants or predictors (demographic, obstetric, infant-related, and psychosocial factors) and coping strategies from June to August 2023 in six countries. METHODS: An analytical cross-sectional study included a total of 674 mothers who visited primary health care centers (PHCs) in Egypt, Yemen, Iraq, India, Ghana, and Syria. They were asked to complete self-administered assessments using the Edinburgh Postnatal Depression Scale (EPDS). The data underwent logistic regression analysis using SPSS-IBM 27 to list potential factors that could predict PPD. RESULTS: The overall frequency of PPD in the total sample was 92(13.6%). It ranged from 2.3% in Syria to 26% in Ghana. Only 42 (6.2%) were diagnosed. Multiple logistic regression analysis revealed there were significant predictors of PPD. These factors included having unhealthy baby adjusted odds ratio (aOR) of 11.685, 95% CI: 1.405-97.139, p = 0.023), having a precious baby (aOR 7.717, 95% CI: 1.822-32.689, p = 0.006), who don't receive support (aOR 9.784, 95% CI: 5.373-17.816, p = 0.001), and those who are suffering from PPD. However, being married and comfortable discussing mental health with family relatives are significant protective factors (aOR = 0.141 (95% CI: 0.04-0.494; p = 0.002) and (aOR = 0.369, 95% CI: 0.146-0.933, p = 0.035), respectively. CONCLUSION: The frequency of PPD among the mothers varied significantly across different countries. PPD has many protective and potential factors. We recommend further research and screenings of PPD for all mothers to promote the well-being of the mothers and create a favorable environment for the newborn and all family members.

The association of TMPRSS6 gene polymorphism with iron status in Egyptian children (a pilot study).

Several studies have shown association of single nucleotide polymorphisms (SNPs) of hepcidin regulatory pathways genes with impaired iron status. The most common is in the TMPRSS6 gene. In Africa, very few studies have been reported. We aimed to investigate the correlation between the common SNPs in the transmembrane protease, serine 6 (TMPRSS6) gene and iron indicators in a sample of Egyptian children for identifying the suitable candidate for iron supplementation.Patients and methods One hundred and sixty children aged 5-13 years were included & classified into iron deficient, iron deficient anemia and normal healthy controls. All were subjected to assessment of serum iron, serum ferritin, total iron binding capacity, complete blood count, reticulocyte count, serum soluble transferrin receptor and serum hepcidin. Molecular study of TMPRSS6 genotyping polymorphisms (rs4820268, rs855791 and rs11704654) were also evaluated.Results There was an association of iron deficiency with AG of rs855791 SNP, (P = 0.01). The minor allele frequency for included children were 0.43, 0.45 & 0.17 for rs4820268, rs855791 & rs11704654 respectively. Genotype GG of rs4820268 expressed the highest hepcidin gene expression fold, the lowest serum ferroportin & iron store compared to AA and AG genotypes (p = 0.05, p = 0.05, p = 0.03 respectively). GG of rs855791 had lower serum ferritin than AA (p = 0.04), lowest iron store & highest serum hepcidin compared to AA and AG genotypes (p = 0.04, p = 0.01 respectively). Children having CC of rs11704654 had lower level of hemoglobin, serum ferritin and serum hepcidin compared with CT genotype (p = 0.01, p = 0.01, p = 0.02) respectively.Conclusion Possible contribution of SNPs (rs855791, rs4820268 and rs11704654) to low iron status.

Killed whole-genome reduced-bacteria surface-expressed coronavirus fusion peptide vaccines protect against disease in a porcine model.

As the coronavirus disease 2019 (COVID-19) pandemic rages on, it is important to explore new evolution-resistant vaccine antigens and new vaccine platforms that can produce readily scalable, inexpensive vaccines with easier storage and transport. We report here a synthetic biology-based vaccine platform that employs an expression vector with an inducible gram-negative autotransporter to express vaccine antigens on the surface of genome-reduced bacteria to enhance interaction of vaccine antigen with the immune system. As a proof-of-principle, we utilized genome-reduced Escherichia coli to express SARS-CoV-2 and porcine epidemic diarrhea virus (PEDV) fusion peptide (FP) on the cell surface, and evaluated their use as killed whole-cell vaccines. The FP sequence is highly conserved across coronaviruses; the six FP core amino acid residues, along with the four adjacent residues upstream and the three residues downstream from the core, are identical between SARS-CoV-2 and PEDV. We tested the efficacy of PEDV FP and SARS-CoV-2 FP vaccines in a PEDV challenge pig model. We demonstrated that both vaccines induced potent anamnestic responses upon virus challenge, potentiated interferon-γ responses, reduced viral RNA loads in jejunum tissue, and provided significant protection against clinical disease. However, neither vaccines elicited sterilizing immunity. Since SARS-CoV-2 FP and PEDV FP vaccines provided similar clinical protection, the coronavirus FP could be a target for a broadly protective vaccine using any platform. Importantly, the genome-reduced bacterial surface-expressed vaccine platform, when using a vaccine-appropriate bacterial vector, has potential utility as an inexpensive, readily manufactured, and rapid vaccine platform for other pathogens.

Recent updates in laryngeal hemangioma management: a scoping review.

PURPOSE: To provide a comprehensive review of the current strategies in the management of laryngeal hemangiomas, with an aim to introduce a management algorithm that aligns with the variable clinical presentations and anatomical complexities of these lesions. METHODS: We conducted an extensive literature search across major databases using specific and general terms, combined with Boolean operators, to ensure comprehensiveness. Articles from January 2004 to August 2023 were included, with findings categorized by management approach. RESULTS: Laryngeal hemangiomas exhibit a spectrum of manifestations, ranging from asymptomatic lesions to those causing severe airway obstruction. Optimal management demands an individualized approach tailored to the patient's unique presentation and anatomical considerations. Diverse treatment modalities, each with distinct indications, advantages, and limitations, are explored. Notable highlights encompass the prominent role of Beta-blockers, notably Propranolol, in addressing problematic infantile hemangiomas, the nuanced efficacy of laser therapies contingent upon hemangioma type and depth, and the critical relevance of tracheotomy in emergencies. Novel approaches like transoral robotic surgery and transoral ultrasonic surgery, demonstrate promise in specific scenarios. We propose a management algorithm based on the complexity and presentation of laryngeal hemangiomas, emphasizing individualized treatment strategies, thereby addressing the unique challenges and nuances of each case. CONCLUSION: Laryngeal hemangioma management requires personalized approaches informed by diverse therapies, clinical expertise, and collaboration. The review introduces an algorithm spanning observation to advanced interventions, adapting to each case's complexity. Ongoing research promises innovative treatments.

Mass online training of health care workers during COVID-19: approach, impact, and outcomes for over 10,000 health care providers.

OBJECTIVES: COVID-19 revealed major shortfalls in healthcare workers (HCWs) trained in acute and critical care worldwide, especially in low-resource settings. We aimed to assess mass online courses' efficacy in preparing HCWs to manage COVID-19 patients and to determine whether rapidly deployed e-learning can enhance their knowledge and confidence during a pandemic. STUDY DESIGN: Retrospective cohort study. METHODS: This international retrospective cohort study, led by a large Academic Medical Centre (AMC), was conducted via YouTube and the AMC's online learning platform. From 2020 to 2021, multidisciplinary experts developed and deployed six online training courses based on the latest evidence-based management guidelines. Participants were selected through a voluntary sample following an electronic campaign. Training outcomes were assessed using pre-and post-test questionnaires, evaluation forms, and post-training assessment surveys. Kirkpatrick's Model guided training evaluation to measure self-reported knowledge, clinical skills, and confidence improvement. We also captured the number and type of COVID-19 patients managed by HCWs after the trainings. RESULTS: Every 22.8 reach/impression and every 1.2 engagements led to a course registration. The 10,425 registrants (56.8% female, 43.1% male) represented 584 medical facilities across 154 cities. The largest segments of participants were students/interns (20.6%) and medical officers (13.4%). Of the 2169 registered participants in courses with tests, 66.9% completed post-tests. Test scores from all courses increased from the initial baseline to subsequent improvement post-course. Participants completing post-training assessment surveys reported that the online courses improved their knowledge and clinical skills (83.5%) and confidence (89.4%). Respondents managed over 19,720 COVID-19 patients after attending the courses, with 47.7% patients being moderately/severely ill. CONCLUSIONS: Participants' confidence in handling COVID-19 patients is increased by rapidly deploying mass training to a substantial target population through digital tools. The findings present a virtual education and assessment model that can be leveraged for future global public health issues, and estimates for future electronic campaigns to target.

The varied clinical and radiological manifestations of contrast-induced encephalopathy following coronary angiography.

Contrast-induced encephalopathy (CIE) is a rare complication of imaging using ionidated contrast media. Its pathogenesis remains unknown, and its clinical presentation is variable. We present two cases of CIE following coronary angiography (CAG) that underscore the multitude of clinical manifestations and imaging findings associated with the disorder. In patient 1, CIE manifested during the CAG with agitation and decreased consciousness, followed by left hemiparesis and visual neglect. Native computed tomography (CT) of the head was unremarkable but CT perfusion (CTP) showed extensive hypoperfusion of the right hemisphere with corresponding slow-wave activity in the electroencephalogram (EEG). These findings were more pronounced the next day. Magnetic Resonance Imaging (MRI) revealed multiple small dot-like ischemic lesions across the brain. By day 6, she had fully recovered. Patient 2 developed transient expressive aphasia during the CAG followed by migraineous symptoms. Native head CT showed a large area of parenchymal edema, sulcal effacement and variable subarachnoid hyperdensity in the right hemisphere. He developed mild left-side hemiparesis, spontaneous gaze deviation and inattention. Brain MRI showed small dot-like acute ischemic lesions across the brain. The next morning, he had a generalized tonic-clonic seizure (GTCS) after which native head CT was normal, but the EEG showed a post-ictal finding covering the right hemisphere. His hemiparesis resolved within 2 months. The diversity in clinical and radiographic presentations suggest that CIE involve many pathophysiological processes.

Nitroimidazole derivatives potentiated against tumor hypoxia: Design, synthesis, antitumor activity, molecular docking study, and QSAR study.

A hypoxic environment occurs predominantly in tumors. During the growth phase of a tumor, it grows until it exceeds its blood supply, leaving regions of the tumor in which the oxygen pressure is dramatically low. They are virtually absent in normal tissues, thus creating perfect conditions for selective bioreductive therapy of tumors. To this aim, a novel series of cytotoxic radiosensitizer agents were synthesized by linking the nitroimidazole scaffold with oxadiazole or triazole rings. The majority of the compounds exhibited moderate to excellent antiproliferative activities toward HCT116 cell line under normoxic and hypoxic conditions. The structure-activity relationship study revealed that compounds containing the free thiol group either in the oxadiazoles 11a,b or the triazoles 21a,b-23a,b demonstrated the strongest antiproliferative activity, which proves that the free thiol group plays a crucial role in the antiproliferative activity of our compounds under both normoxic (half-maximal inhibitory concentration [IC50 ] = 12.50-24.39 µM) and hypoxic conditions (IC50 = 4.69-11.56 µM). Radiosensitizing assay of the four most active cytotoxic compounds 11b and 21-23b assured the capability of the compounds to enhance the sensitivity of the tumor cells to the DNA damaging activity of γ-radiation (IC50 = 2.23-5.18 µM). To further investigate if the cytotoxicity of our most active compounds was due to a specific signaling pathway, the online software SwissTargetPrediction was exploited and a molecular docking study was done that proposed cyclin-dependent kinase 2 (CDK2) enzyme to be the most promising target. The CDK2 inhibitory assay assured this assumption as five out of six compounds demonstrated a comparable inhibitory activity with roscovitine, among which compound 21b showed threefold more potent inhibitory activity in comparison with the reference compound. A further biological evaluation proved compound 21b to have an apoptotic activity and cell cycle arrest activity at the G1 and S phases. During the AutoQSAR analysis, the model demonstrated excellent regression between the predicted and experimental activity with r2 = 0.86. Subsequently, we used the model to predict the activity of the test set compounds that came with r2 = 0.95.

Optimization of asymmetric bioreduction conditions of 1-indanone by Leuconostoc mesenteroides N6 using a face-centered design-based multi-objective optimization model.

There has been an increasing interest in biocatalysts over the past few decades in order to obtain high efficiency, high yield, and environmentally benign procedures aiming at the manufacture of pharmacologically relevant chemicals. Lactic Acid Bacteria (LAB), a microbial group, can be employed as biocatalysts while performing asymmetric reduction of prochiral ketones. In this study, Leuconostoc mesenteroides N6 was used for the asymmetric bioreduction 1-indanone. And then, a novel and innovative face-centered design-based multi-objective optimization model was used to optimize experimental conditions. Also, the experimental design factors were defined as agitation speed, incubation period, pH, and temperature for optimization to acquire the maximum enantiomeric excess (ee) and conversion rate (cr) values. When using the face-centered design-based multi-objective optimization model, the optimum culture conditions corresponded to 96.34 and 99.42%, ee and cr responses, respectively, were pH = 5.87, incubation temperature = 35 °C, incubation period = 50.88 h, and agitation speed = 152.60 rpm. Notably, the validation experiment under the optimum model conditions confirmed the model results. This study demonstrated the importance of the optimization and the efficiency of the face-centered design-based multi-objective model.