Single-cell analysis of CX3CR1 + cells reveal a pathogenic role for BIRC5 + myeloid proliferating cells driven by Staphylococcus aureus leukotoxins.

Our previous studies identified a population of stem cell-like proliferating myeloid cells within inflamed tissues that could serve as a reservoir for tissue macrophages to adopt different activation states depending on the microenvironment. By lineage tracing cells derived from CX3CR1 + precursors in mice during infection and profiling by scRNA-seq, here we identify a cluster of BIRC5 + myeloid cells that expanded in the liver during either chronic infection with the parasite Schistosoma mansoni or the bacterial pathogen Staphylococcus aureus . In the absence of tissue damaging toxins, S. aureus infection does not elicit these BIRC5 + cells. Moreover, deletion of BIRC5 from CX3CR1 expressing cells results in improved survival during S. aureus infection. Hence, the combination of scRNA-Seq and genetic fate mapping CX3CR1 + cells revealed a toxin dependent pathogenic role for BIRC5 in myeloid cells during S. aureus infection.

Most common over-the-counter medications and effects on patients.

OBJECTIVE: The self-medicating practice of using over-the-counter (OTC) medications are more common than prescription drug use worldwide. OTC drugs are primarily used to treat conditions that do not require direct medical attention or supervision, and OTC drugs must be demonstrated to be reasonably safe and well-tolerated. The pharmacy profession describes their role in dispensing over-the-counter (OTC) products as "selecting the best medication according to reported symptoms". This study aimed to evaluate the use of most common over-the-counter (OTC) medications and their effect on patients. PATIENTS AND METHODS: A cross-sectional survey-based study was conducted on 442 participants who used OTC drugs from June to November 2021. RESULTS: The most common OTC drugs used by patients involved in the study were paracetamol (13.35%), followed by ibuprofen (2.04%). Gender of patients was significantly related to (duration, frequency, suggestion, and misuse) of OTC use and patient counseling by the pharmacist (p<0.05). CONCLUSIONS: OTC medications can easily be obtained at pharmacies for the purpose of self-treatment. The most common OTC drugs used by the studied patients were paracetamol, followed by ibuprofen. It is suggested that an awareness program among community people be conducted at the community level regarding over-the-counter (OTC) drugs.

CD169+ macrophage intrinsic IL-10 production regulates immune homeostasis during sepsis.

Macrophages facilitate critical functions in regulating pathogen clearance and immune homeostasis in tissues. The remarkable functional diversity exhibited by macrophage subsets is dependent on tissue environment and the nature of the pathological insult. Our current knowledge of the mechanisms that regulate the multifaceted counter-inflammatory responses mediated by macrophages remains incomplete. Here, we report that CD169+ macrophage subsets are necessary for protection under excessive inflammatory conditions. We show that in the absence of these macrophages, even under mild septic conditions, mice fail to survive and exhibit increased production of inflammatory cytokines. Mechanistically, CD169+ macrophages control inflammatory responses via interleukin-10 (IL-10), as CD169+ macrophage-specific deletion of IL-10 was lethal during septic conditions, and recombinant IL-10 treatment reduced lipopolysaccharide (LPS)-induced lethality in mice lacking CD169+ macrophages. Collectively, our findings show a pivotal homeostatic role for CD169+ macrophages and suggest they may serve as an important target for therapy under damaging inflammatory conditions.

Comparison of Oleocanthal-Low EVOO and Oleocanthal against Amyloid-ß and Related Pathology in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by several pathological hallmarks, including the deposition of amyloid-ß (Aß) plaques, neurofibrillary tangles, blood-brain barrier (BBB) dysfunction, and neuroinflammation. Growing evidence support the neuroprotective effects of extra-virgin olive oil (EVOO) and oleocanthal (OC). In this work, we aimed to evaluate and compare the beneficial effects of equivalent doses of OC-low EVOO (0.5 mg total phenolic content/kg) and OC (0.5 mg OC/kg) on Aß and related pathology and to assess their effect on neuroinflammation in a 5xFAD mouse model with advanced pathology. Homozygous 5xFAD mice were fed with refined olive oil (ROO), OC-low EVOO, or OC for 3 months starting at the age of 3 months. Our findings demonstrated that a low dose of 0.5 mg/kg EVOO-phenols and OC reduced brain Aß levels and neuroinflammation by suppressing the nuclear factor-κB (NF-κB) pathway and reducing the activation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasomes. On the other hand, only OC suppressed the receptor for advanced glycation endproducts/high-mobility group box 1 (RAGE/HMGB1) pathway. In conclusion, our results indicated that while OC-low EVOO demonstrated a beneficial effect against Aß-related pathology in 5xFAD mice, EVOO rich with OC could provide a higher anti-inflammatory effect by targeting multiple mechanisms. Collectively, diet supplementation with EVOO or OC could prevent, halt progression, and treat AD.

Embracing midcareer in the tenure system.

Midcareer faculty are the "keystone" of academia. Faculty in midcareer experience an increase or change in responsibilities and expectations as well as reduced support and mentorship usually extended to junior faculty. Nonetheless, midcareer can be an ideal time for re-evaluating and defining one's career path and taking advantage of leadership and service opportunities. Successful navigation of midcareer is essential to ensure nursing faculty remain in the academic setting, contribute to nursing science, and have a satisfying career. In this paper, we present strategies midcareer nurse faculty can consider to maintain balance and advance their careers even during challenging times. These strategies include appraising career goals, maintaining and expanding mentoring relationships, seeking and utilizing opportunities for leadership development, selecting service strategically to advance career goals, preparing for the unexpected, maintaining/expanding scholarly productivity, learning when to say yes or no, embracing lifelong learning, and improving visibility of one's work.

Evaluation of ultrasound airway assessment parameters in pregnant patients and their comparison with that of non-pregnant women: a prospective cohort study.

BACKGROUND: Clinical airway assessment parameters differ significantly between pregnant and non-pregnant patients, however literature comparing their ultrasound (US) airway parameters is limited. We planned a prospective cohort study to compare US-assessed airway parameters between pregnant and non-pregnant women. METHODS: We enrolled 82 pregnant females scheduled for elective cesarean section under neuraxial anesthesia and 80 age-matched non-pregnant females scheduled for elective surgery. Pre-operative clinical airway assessment was performed in both groups. The US airway assessment was done pre-operatively in non-pregnant and postoperatively in pregnant patients. Our primary objective was to compare US-assessed parameters, and secondary objectives included a comparison of clinical airway assessment parameters and investigating a relationship between a difficult airway (defined as a modified Mallampati grade (MMG) ≥ 3) and other airway assessment parameters. RESULTS: Among several US airway parameters, pregnant patients had significantly higher hyomental distance, anterior neck soft tissue thickness at the hyoid and vocal cord level, and oral cavity height, while the tongue thickness and mandibular condylar movements were significantly lower than in non-pregnant patients. Similarly, for the clinical airway assessment, pregnant patients had significantly higher MMG and upper lip bite test scores, mentohyoid distance, and neck circumference. Pregnancy, the ratio of pre-epiglottic space and epiglottis-to-vocal cords distance (Pre-E/E-VC), and hyoid bone visibility were independent predictors of a difficult airway. CONCLUSION: The US airway assessment parameters differ significantly between pregnant and non-pregnant patients. Pregnancy, hyoid bone visibility, and Pre-E/E-VC ratio were independent predictors of the difficult airway in female patients.

Impact of valproic acid on busulfan pharmacokinetics: In vitro assessment of potential drug-drug interaction.

Busulfan (Bu) is an alkylating agent commonly used at high doses in the preparative regimens of hematopoietic stem cell transplantation (HSCT). It has been shown that such high doses of Bu are associated with generalized seizures which are usually managed by prophylactic antiepileptic drugs (AEDs) such as valproic acid (VPA). Being a strong enzyme inhibitor, VPA may inhibit Bu metabolism and thus increase its potential toxicity. Despite its clinical relevance, the potential interaction between Bu and VPA has not yet been evaluated. The aim of the present study was to assess and evaluate the potential drug-drug interaction (DDI) between Bu and VPA. This study was carried out by incubating Bu in laboratory-prepared rat liver-subcellular fractions including S9, microsomes, and cytosol, alone or in combination with VPA. The liver fractions were prepared by differential centrifugation of the liver homogenate. Analysis of Bu was employed using a fully validated LC-MS/MS method. The validation parameters were within the proposed limits of the international standards guidelines. Bu metabolic stability was assessed by incubating Bu at a concentration of 8 µg/ml in liver fractions at 37°C. There were significant reductions in Bu levels in S9 and cytosolic fractions, whereas these levels were not significantly (P ˃ 0.05) changed in microsomes. However, in presence of VPA, Bu levels in S9 fraction remained unchanged. These results indicated, for the first time, the potential metabolic interaction of Bu and VPA being in S9 only. This could be explained by inhibiting Bu cytosolic metabolism by the interaction with VPA either by sharing the same metabolic enzyme or the required co-factor. In conclusion, the present findings suggest, for the first time, a potential DDI between Bu and VPA in vitro using rat liver fractions. Further investigations are warranted in human-derived liver fractions to confirm such an interaction.

Identification of terrestrial gastropods families found in district Swat, Pakistan / Identificação de famílias de gastropódeos terrestres encontradas no distrito Swat, Paquistão

Abstract Very little is known about the malacofauna in district Swat of Khyber Pakhtunkhwa province, situated in the Northern part of Pakistan. The Swat valley possesses a variety of suitable environmental conditions, providing different types of habitats for both flora and fauna. Taken into consideration these points, the present study was conducted to explore the terrestrial snails diversity in agricultural and non-agricultural fields in the lower Swat valley. A total of 417 shells were collected from three sites: Kokarai, Kanju Township, and Deolai. Based on conchological features, three families: Bradybaenidae, Hygromiidae, and Zonitidae were identified using different terrestrial snail keys. In Kokarai and Deolai, shells of members of all the above-mentioned families were found from agricultural fields. In Kanju Township, shells of members of the family Bradybaenidae and Zonitidae were found. From these findings, it was concluded that district Swat possesses a significant malacofauna which was unexplored before and aided more to the existing literature on malacofauna. It also supports the idea that the agroecosystem is rich in species diversity. Further in-depth and extensive study is recommended to be carried out for a detailed taxonomy of the described terrestrial gastropod families.

Resumo Muito pouco se sabe sobre a malacofauna no distrito de Swat, na província de Khyber Pakhtunkhwa, situada na parte norte do Paquistão. O vale do Swat possui uma variedade de condições ambientais adequadas, proporcionando diferentes tipos de habitats para a flora e a fauna. Levando em consideração esses pontos, o presente estudo foi conduzido para explorar a diversidade dos caracóis terrestres em campos agrícolas e não agrícolas no vale inferior de Swat. Um total de 417 conchas foram coletadas em três locais: Kokarai, Kanju Township e Deolai. Com base em características concológicas, três famílias: Bradybaenidae, Hygromiidae e Zonitidae foram identificadas usando diferentes chaves de caramujos terrestres. Em Kokarai e Deolai, conchas de membros de todas as famílias mencionadas acima foram encontradas em campos agrícolas. No município de Kanju, foram encontradas conchas de membros da família Bradybaenidae e Zonitidae. A partir dessas constatações, concluiu-se que o distrito de Swat possui uma malacofauna significativa que antes era inexplorada e ajudava mais a literatura existente sobre a malacofauna. Também apoia a ideia de que o agroecossistema é rico em diversidade de espécies. Recomenda-se a realização de um estudo mais aprofundado e extenso para uma taxonomia detalhada das famílias de gastrópodes terrestres descritas.

Associations of community-level particulate matter with high-acuity visit presentation for sinusitis.

BACKGROUND: Exposure to particulate matter <2.5 µm in diameter (PM2.5) has been linked to increased sinusitis prevalence and morbidity. However, studies analyzing environmental exposures and sinusitis have not explored the effect of PM2.5 on healthcare presentation patterns. OBJECTIVE: This study aims to characterize the relationship of community-level PM2.5 with high-acuity visits in sinusitis patients. METHODS: A retrospective analysis based on medical records of 2092 adults presenting with chronic rhinosinusitis, acute rhinosinusitis, or sinus/nasal polyps to an urban academic medical center from 2010 to 2019 was conducted. We linked medical records (individual-level) with data on PM2.5 exposure at the community level, using residential zip-code data from the Chicago Health Atlas covering the years 2015-2019. Multivariable binary logistic regression with Generalized Estimating Equations examined adjusted associations between PM2.5 and high-acuity visits - including emergency department and inpatient settings. RESULTS: Our sample was 69 % female, with a mean age of 46.9 years. From 2015 to 2019, the average PM2.5 exposure in zip-codes examined was 11.66 µg/m3 with a range of 11.14-11.79 µg/m3. In adjusted models, odds of a high-acuity visit were significantly higher in patients residing in zip-codes in the top tertile of PM2.5 exposure compared to the bottom tertile (OR: 1.74; CI: 1.20-2.51). CONCLUSION: Community-level PM2.5 exposure was associated with high-acuity visits among sinusitis patients. These associations need to be studied through more rigorous, prospective investigations, as they may have potential public health implications and underscore a need to mitigate PM2.5 exposures at a community-level.

Design, Synthesis and Biological Evaluation of Syn and Anti-like Double Warhead Quinolinones Bearing Dihydroxy Naphthalene Moiety as Epidermal Growth Factor Receptor Inhibitors with Potential Apoptotic Antiproliferative Action.

Our investigation includes the synthesis of new naphthalene-bis-triazole-bis-quinolin-2(1H)-ones 4a−e and 7a−e via Cu-catalyzed [3 + 2] cycloadditions of 4-azidoquinolin-2(1H)-ones 3a−e with 1,5-/or 1,8-bis(prop-2-yn-1-yloxy)naphthalene (2) or (6). All structures of the obtained products have been confirmed with different spectroscopic analyses. Additionally, a mild and versatile method based on copper-catalyzed [3 + 2] cycloaddition (Meldal−Sharpless reaction) was developed to tether quinolinones to O-atoms of 1,5- or 1,8-dinaphthols. The triazolo linkers could be considered as anti and syn products, which are interesting precursors for functionalized epidermal growth factor receptor (EGFR) inhibitors with potential apoptotic antiproliferative action. The antiproliferative activities of the 4a−e and 7a−e were evaluated. Compounds 4a−e and 7a−e demonstrated strong antiproliferative activity against the four tested cancer cell lines, with mean GI50 ranging from 34 nM to 134 nM compared to the reference erlotinib, which had a GI50 of 33 nM. The most potent derivatives as antiproliferative agents, compounds 4a, 4b, and 7d, were investigated for their efficacy as EGFR inhibitors, with IC50 values ranging from 64 nM to 97 nM. Compounds 4a, 4b, and 7d demonstrated potent apoptotic effects via their effects on caspases 3, 8, 9, Cytochrome C, Bax, and Bcl2. Finally, docking studies show the relevance of the free amino group of the quinoline moiety for antiproliferative action via hydrogen bond formation with essential amino acids.

Benzofuran as a promising scaffold for the synthesis of novel antimicrobial agents.

INTRODUCTION: The benzofuran moiety constitutes a main component of enormous biologically active natural and synthetic heterocycles. Such heterocycles have distinctive therapeutic potential and are employed in various clinical drugs. A number of publications have dealt with the synthesis and extraction of benzofuran-based heterocycles to investigate their antimicrobial potential. AREAS COVERED: This review describes the antimicrobial activity of various natural and synthetic benzofuran scaffolds. The antimicrobial activity of benzofurans is thoroughly investigated against several bacterial (Gram-positive and Gram-negative) and fungal microorganisms compared with several reference antibiotic drugs. The effects of the electronic nature of substituents on the activity of benzofurans through SAR study were reported. This article also highlights the recent natural and synthetic benzofuran-based organic molecules between 2019-2022 that have had success in terms of their antimicrobial activity. EXPERT OPINION: Many of the described benzofurans are promising candidates as antimicrobial agents based on their activity. Most used antibiotics target infections caused by the gram-positive pathogen S. aureus. Interestingly, most of the described benzofurans are promising inhibitors against S. aureus with either equipotent or more potent activity than the reference antibiotic drugs. These findings will encourage medicinal chemists to explore these new avenues for human health promotion to reduce suffering.

Energy efficiency in residential buildings amid COVID-19: A holistic comparative analysis between old and new normal occupancies.

Stringent lockdowns have been one of the defining features of the COVID-19 pandemic. Lockdowns have brought about drastic changes in living styles, including increased residential occupancy and telework practices predicted to last long. The variation in occupancy pattern and energy use needs to be assessed at the household level. Consequently, the new occupancy times will impact the performance of energy efficiency measures. To address these gaps, this work uses a real case study, a two-story residential building in the Okanagan Valley (British Columbia, Canada). Further, steady-state building energy simulations are performed on the HOT2000 tool to evaluate the resiliency of energy efficiency measures under a full lockdown. Three-year monitored energy data is analyzed to study the implications of COVID-19 lockdowns on HVAC and non-HVAC loads at a monthly temporal scale. The results show a marked change in energy use patterns and a higher increase in May 2020 compared to the previous two years. Calibrated energy models built on HOT2000 are then used to study the impacts of pre-COVID-19 (old normal occupancy) and post-COVID-19 (new normal occupancy) on energy upgrades performance. The simulations show that under higher occupancy times, the annual electricity use increased by 16.4%, while natural gas use decreased by 7.6%. The results indicate that overall residential buildings following pre-COVID-19 occupancy schedules had higher energy-saving potential than those with new normal occupancy. In addition, the variation in occupancy and stakeholder preferences directly impact the ranking of energy efficiency measures. Furthermore, this study identifies energy efficiency measures that provide flexibility for the decision-makers by identifying low-cost options feasible under a range of occupancy schedules.

Galectin-9 protects humanized-ACE2 immunocompetent mice from SARS-CoV-2 infection.

SARS-CoV-2 remains a global health crisis even with effective vaccines and the availability of FDA approved therapies. Efforts to understand the complex disease pathology and develop effective strategies to limit mortality and morbidity are needed. Recent studies reveal circulating Galectin-9 (gal-9), a soluble beta-galactoside binding lectin with immunoregulatory properties, are elevated in SARS-CoV-2 infected individuals with moderate to severe disease. Moreover, in silico studies demonstrate gal-9 can potentially competitively bind the ACE2 receptor on susceptible host cells. Here, we determined whether early introduction of exogenous gal-9 following SARS-CoV-2 infection in humanized ACE2 transgenic mice (K18-hACE2) may reduce disease severity. Mice were infected and treated with a single dose of a human recombinant form of gal-9 (rh-gal-9) and monitored for morbidity. Subgroups of mice were humanely euthanized at 2- and 5- days post infection (dpi) for viral levels by plaque assay, immune changes measures by flow cytometry, and soluble mediators by protein analysis from lung tissue and bronchoalveolar Lavage fluid (BALF). Mice treated with rh-gal-9 during acute infection had improved survival compared to PBS treated controls. At 5 dpi, rh-gal-9 treated mice had enhanced viral clearance in the BALF, but not in the lung parenchyma. Increased T and dendritic cells and decreased neutrophil frequencies in the lung at 5 dpi were observed, whereas BALF had elevated levels of type-I interferons and proinflammatory cytokines. These results suggest a role for rh-gal-9 in limiting acute COVID-19. Further studies are required to determine the optimal design of gal-9 treatment to effectively ameliorate COVID-19 disease.

Practical Guide to Ethical Considerations in Clinical Trials in Surgery.

This Guide to Statistics and Methods provides an overview of current ethical considerations and standards for clinical research.

Practical Guide to Statistical Considerations in Clinical Trials in Surgery.

This Guide to Statistics and Methods discusses key statistical considerations in the conduct of randomized clinical trials in surgery.

Practical Guide to Design Choice of Randomized Clinical Trials in Surgery.

This Guide to Statistics and Methods provides an overview of the strengths and weaknesses of several randomized clinical trial design options.

High-Pressure Metal-Free Catalyzed One-Pot Two-Component Synthetic Approach for New 5-Arylazopyrazolo[3,4-b]Pyridine Derivatives.

An appropriate and efficient Q-tube-assisted ammonium acetate-mediated protocol for the assembly of the hitherto unreported 5-arylazopyrazolo[3,4-b]pyridines was demonstrated. This methodology comprises the cyclocondensation reaction of 5-amino-2-phenyl-4H-pyrazol-3-one with an assortment of arylhydrazonals in an NH4OAc/AcOH buffer solution operating a Q-tube reactor. This versatile protocol exhibited several outstanding merits: easy work-up, mild conditions, scalability, broad substrate scope, safety (the Q-tube kit is simply for pressing and sealing), and a high atom economy. Consequently, performing such reactions under elevated pressures and utilizing the Q-tube reactor seemed preferable for achieving the required products in comparison to the conventional conditions. Diverse spectroscopic methods and X-ray single-crystal techniques were applied to confirm the proposed structure of the targeted compounds.

A neonatal mouse model characterizes transmissibility of SARS-CoV-2 variants and reveals a role for ORF8

Summary paragraphSmall animal models have been a challenge for the study of SARS-CoV-2 transmission, with most investigators using golden hamsters or ferrets 1,2. Mice have the advantages of low cost, wide availability, less regulatory and husbandry challenges, and the existence of a versatile reagent and genetic toolbox. However, adult mice do not transmit SARS-CoV-2 3. Here we establish a model based on neonatal mice that allows for transmission of clinical SARS-CoV-2 isolates. We characterize tropism, respiratory tract replication and transmission of ancestral WA-1 compared to variants alpha (B.1.1.7), beta (B.1.351), gamma (P.1), delta (B.1.617.2) and omicron (B.1.1.529). We identify inter-variant differences in timing and magnitude of infectious particle shedding from index mice, both of which shape transmission to contact mice. Furthermore, we characterize two recombinant SARS-CoV-2 lacking either the ORF6 or ORF8 host antagonists. The removal of ORF8 shifts viral replication towards the lower respiratory tract, resulting in significantly delayed and reduced transmission. Our results demonstrate the potential of our neonatal mouse model to characterize viral and host determinants of SARS-CoV-2 transmission, while revealing for the first time a role for an accessory protein this context.