Drug repositioning identifies salvinorin A and deacetylgedunin (DCG) enriched plant extracts as novel inhibitors of Mpro, RBD-ACE2 and TMPRRS2 proteins.

The coronavirus disease 2019 (COVID-19) has spread worldwide with severe health, social, and economic repercussions. Although vaccines have significantly reduced the severity of symptoms and deaths, alternative medications derived from natural products (NPs) are vital to further decrease fatalities, especially in regions with low vaccine uptake. When paired with the latest computational developments, NPs, which have been used to cure illnesses and infections for thousands of years, constitute a renewed resource for drug discovery. In the present report, a combination of computational and in vitro methods reveals the repositioning of NPs and identifies salvinorin A and deacetylgedunin (DCG) as having potential anti-SARS-CoV-2 activities. Salvinorin A was found both in silico and in vitro to inhibit both SARS-CoV-2 spike/host ACE2 protein interactions, consistent with blocking viral cell entry, and well as live virus replication. Plant extracts from Azadirachta indica and Cedrela odorata, which contain high levels of DCG, inhibited viral cell replication by targeting the main protease (Mpro) and/or inhibited viral cell entry by blocking the interaction between spike RBD-ACE2 protein at concentrations lower than salvinorin A. Our findings suggest that salvinorin A represent promising chemical starting points where further optimization may result in effective natural product-derived and potent anti-SARS-CoV-2 inhibitors to supplement vaccine efforts.

Practical quality improvement changes for a low-resourced pediatric unit.

Background: This work describes a sustainable and replicable initiative to optimize multi-disciplinary care and uptake of clinical best practices for patients in a pediatric intensive care unit in Low/Middle Income Countries and to understand the various factors that may play a role in the reduction in child mortality seen after implementation of the Quality Improvement Initiative. Methods: This was a longitudinal assessment of a quality improvement program with the primary outcome of intubated pediatric patient mortality. The program was assessed 36 months following implementation of the quality improvement intervention using a t-test with linear regression to control for co-variates. An Impact Pathway model was developed to describe potential pathways for improvement, and context was added with an exploratory analysis of adoption of the intervention and locally initiated interventions. Results: 147 patients were included in the sustainability cohort. Comparing the initial post-implementation cohort to the sustainability cohort, the overall PICU unexpected extubations per 100 days mechanical ventilation decreased significantly from baseline (6.98) to the first year post intervention (3.52; p < 0.008) but plateaued without further significant decrease in the final cohort (3.0; p = 0.73), whereas the mortality decreased from 22.4 (std 0.42) to 9.5% (std 0.29): p value: 0.002 (confidence intervals: 0.05;0.21). The regression model that examined age, sex, diagnosis and severity of illness (via aggregate Pediatric Risk of Mortality (PRISM) scores between epochs) yielded an adjusted R-squared (adjusting for the number of predictors) value of 0.046, indicating that approximately 4.6% of the variance in mortality was explained by the predictors included in the model. The overall significance of the regression model was supported by an F-statistic of 3.198 (p = 0.00828). age, weight, diagnosis, and severity of illness. 15 new and locally driven quality practices were observed in the PICU compared to the initial post-implementation time period. The Impact Pathway model suggested multiple unique potential pathways connecting the improved patient outcomes with the intervention components. Conclusion: Sustained improvements were seen in the care of intubated pediatric patients. While some of this improvement may be attributable to the intervention, it appears likely that the change is multifactorial, as evidenced by a significant number of new quality improvement projects initiated by the local clinical team. Although currently limited by available data, the use of Driver Diagram and Impact Pathway models demonstrates several proposed causal pathways and holds potential for further elucidating the complex dynamics underlying such improvements.

A Color Indicator Based on 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium Bromide (MTT) and a Biodegradable Poly(ester amide) for Detecting Bacterial Contamination.

Bacterial contamination is a hazard in many industries, including food, pharmaceuticals, and healthcare. The availability of a rapid and simple method for detecting this type of contamination in sterile areas enables immediate intervention to avoid or reduce detrimental effects. Among these methods, colorimetric indicators are becoming increasingly popular due to their affordability, ease of use, and quick visual interpretation of the signal. In this article, a bacterial contamination indicator system was designed by incorporating MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) into an electrospun PADAS matrix, which is a biodegradable poly(ester amide) synthesized from L-alanine, 1,12-dodecanediol, and sebacic acid. Uniaxial stress testing, thermogravimetric analysis and scanning electron microscopy were used to examine the mechanical properties, thermal stability, and morphology of the mats, respectively. The capacity for bacterial detection was not only analyzed with agar and broth assays but also by replicating important environmental conditions. Among the MTT concentrations tested in this study (0.2%, 2%, and 5%), it was found that only with a 2% MTT content the designed system produced a color response visible to the naked eye with optimal intensity, a sensitivity limit of 104 CFU/mL, and 86% cell viability, which showed the great potential for its use to detect bacterial contamination. In summary, by means of the process described in this work, it was possible to obtain a simple, low-cost and fast-response bacterial contamination indicator that can be used in mask filters, air filters, or protective clothing.

Use and Outcomes of Dexamethasone in the Management of Malignant Small Bowel Obstruction.

Objective: To describe rates of dexamethasone use in the nonoperative management of malignant small bowel obstruction (mSBO) and their outcomes. Background: mSBO is common in patients with advanced abdominal-pelvic cancers. Management includes prioritizing quality of life and avoiding surgical intervention when possible. The use of dexamethasone to restore bowel function is recommended in the National Comprehensive Cancer Network guidelines for mSBO. Yet, it is unknown how often dexamethasone is used for mSBO and whether results from nonresearch settings support its use. Methods: This is a multicenter retrospective cohort study including unique admissions for mSBO from January 1, 2019 to December 31, 2021. Dexamethasone use and management outcomes were summarized with descriptive statistics and multiple logistic regression. Results: Among 571 admissions (68% female, mean age 63 years, 85% history of abdominal surgery) that were eligible and initially nonoperative, 26% [95% confidence interval (CI) = 23%-30%] received dexamethasone treatment (69% female, mean age 62 years, 87% history of abdominal surgery). Dexamethasone use by site ranged from 13% to 52%. Among dexamethasone recipients, 13% (95% CI = 9%-20%) subsequently required nonelective surgery during the same admission and 4 dexamethasone-related safety-events were reported. Amongst 421 eligible admissions where dexamethasone was not used, 17% (95% CI = 14%-21%) required nonelective surgery. Overall, the unadjusted odds ratio (OR) for nonelective surgery with dexamethasone use compared to without its use was 0.7 (95% CI = 0.4-1.3). Using multiple logistic regression, OR after adjusting for site, age, sex, history of abdominal surgery, nasogastric tube, and Gastrografin use was 0.6 (95% CI = 0.3-1.1). Conclusion: Dexamethasone was used in about 1 in 4 eligible mSBO admissions with high variability of use between tertiary academic centers. This multicenter retrospective cohort study suggested an association between dexamethasone use and lower rates of nonelective surgery, representing a potential opportunity for quality improvement.

Innate and adaptive immune responses that control lymph-borne viruses in the draining lymph node.

The interstitial fluids in tissues are constantly drained into the lymph nodes (LNs) as lymph through afferent lymphatic vessels and from LNs into the blood through efferent lymphatics. LNs are strategically positioned and have the appropriate cellular composition to serve as sites of adaptive immune initiation against invading pathogens. However, for lymph-borne viruses, which disseminate from the entry site to other tissues through the lymphatic system, immune cells in the draining LN (dLN) also play critical roles in curbing systemic viral dissemination during primary and secondary infections. Lymph-borne viruses in tissues can be transported to dLNs as free virions in the lymph or within infected cells. Regardless of the entry mechanism, infected myeloid antigen-presenting cells, including various subtypes of dendritic cells, inflammatory monocytes, and macrophages, play a critical role in initiating the innate immune response within the dLN. This innate immune response involves cellular crosstalk between infected and bystander innate immune cells that ultimately produce type I interferons (IFN-Is) and other cytokines and recruit inflammatory monocytes and natural killer (NK) cells. IFN-I and NK cell cytotoxicity can restrict systemic viral spread during primary infections and prevent serious disease. Additionally, the memory CD8+ T-cells that reside or rapidly migrate to the dLN can contribute to disease prevention during secondary viral infections. This review explores the intricate innate immune responses orchestrated within dLNs that contain primary viral infections and the role of memory CD8+ T-cells following secondary infection or CD8+ T-cell vaccination.

Leptospira spp. and Rickettsia spp. as pathogens with zoonotic potential causing acute undifferentiated febrile illness in a central-eastern region of Peru.

OBJETIVE: this study was to determine the relationship between acute febrile illness and bacterial pathogens with zoonotic potential that cause emerging and re-emerging diseases in a central-eastern region of Peru. RESULTS: Out of the 279 samples analyzed, 23 (8.2%) tested positive for infection by Rickettsia spp., while a total of 15 (5.4%) tested positive for Leptospira spp. Women had a higher frequency of infection by Rickettsia spp., with 13 cases (53.3%), while men had a higher frequency of infection by Leptospira spp., with 10 cases (66.7%). The most frequently reported general symptom was headache, with 100.0% (n = 23) of patients with Rickettsia (+) and 86.7% (n = 13) of patients with Leptospira (+) experiencing it. Arthralgia was the second most frequent symptom, reported by 95.6% (n = 22) and 60% (n = 9) of patients with Rickettsia (+) and Leptospira (+), respectively. Myalgia was reported by 91.3% (n = 21) and 66.7% (n = 10) of patients with Rickettsia (+) and Leptospira (+), respectively. Retroocular pain, low back pain, and skin rash were also present, but less frequently. Among the positives, no manifestation of bleeding was recorded, although only one positive case for Leptospira spp. presented a decrease in the number of platelets.

Psychosocial risk and protective factors for youth problem behavior are associated with food addiction in the Generation Z.

Objective: Food Addiction (FA) and other well-known risk behavior as substance misuse tend to co-occur and may share similar risk and protective factors. The aim of this study was to assess the association between the diagnosis/severity of FA and psychosocial domains typically related to risk behavior syndrome in a large, nationally representative community sample of Generation Z underage Italian students. Method: The sample consisted of 8,755 students (3,623 from middle schools, 5,132 from high schools). A short version of the Yale Food Addiction Scale 2.0 was administered to evaluate FA. Risk and protective factors related to demographic, personality, behavior, and family variables were examined. Stepwise multivariate logistic and linear regressions were conducted. Results: The prevalence of FA was 30.8%. Female gender, social anxiety and depression symptoms, social withdrawal risk, Internet gaming disorder, social media addiction, current substance use, social challenge engagement and experienced doxing boosted the chance of FA diagnosis, whereas eating fruit and vegetables, playing competitive sports and an average sleep duration of 7-8 h per night reduced these odds. FA severity was significantly and positively associated with trait impulsiveness, social anxiety and depressive symptoms, risk of social withdrawal, recent substance use, social media, and gaming addiction, doxing suffered and risky social challenges participation. Negative associations between the severity of FA and fruit and vegetable diet habits were found. Conclusion: Our findings confirm that FA is widespread among Italian adolescents. The associations between the diagnosis and severity of FA and psychosocial risk factors for health, including, addictive and deviant behaviors related to digital misuse, suggest its belonging to the risk behavior constellation. Health promotion schemes based on a multicomponent strategy of intervention should consider the inclusion of FA and its psychosocial correlates.

Corrigendum: Progression of functional and structural glaucomatous damage in relation to diurnal and nocturnal dips in mean arterial pressure.

[This corrects the article DOI: 10.3389/fcvm.2022.1024044.].

Assessing the Potential of N-Butyl-l-deoxynojirimycin (l-NBDNJ) in Models of Cystic Fibrosis as a Promising Antibacterial Agent.

Over the past few years, l-iminosugars have revealed attractive pharmacological properties for managing rare diseases including Cystic Fibrosis (CF). The iminosugar N-butyl-l-deoxynojirimycin (l-NBDNJ, ent-1), prepared by a carbohydrate-based route, was herein evaluated for its anti-inflammatory and anti-infective potential in models of CF lung disease infection. A significant decrease in the bacterial load in the airways was observed in the murine model of Pseudomonas aeruginosa chronic infection in the presence of l-NBDNJ, also accompanied by a modest reduction of inflammatory cells. Mechanistic insights into the observed activity revealed that l-NBDNJ interferes with the expression of proteins regulating cytoskeleton assembly and organization of the host cell, downregulates the main virulence factors of P. aeruginosa involved in the host response, and affects pathogen adhesion to human cells. These findings along with the observation of the absence of an in vitro bacteriostatic/bactericidal action of l-NBDNJ suggest the potential use of this glycomimetic as an antivirulence agent in the management of CF lung disease.

A boundary element method of bidomain modeling for predicting cellular responses to electromagnetic fields.

Objective.Commonly used cable equation approaches for simulating the effects of electromagnetic fields on excitable cells make several simplifying assumptions that could limit their predictive power. Bidomain or 'whole' finite element methods have been developed to fully couple cells and electric fields for more realistic neuron modeling. Here, we introduce a novel bidomain integral equation designed for determining the full electromagnetic coupling between stimulation devices and the intracellular, membrane, and extracellular regions of neurons.Approach.Our proposed boundary element formulation offers a solution to an integral equation that connects the device, tissue inhomogeneity, and cell membrane-induced E-fields. We solve this integral equation using first-order nodal elements and an unconditionally stable Crank-Nicholson time-stepping scheme. To validate and demonstrate our approach, we simulated cylindrical Hodgkin-Huxley axons and spherical cells in multiple brain stimulation scenarios.Main Results.Comparison studies show that a boundary element approach produces accurate results for both electric and magnetic stimulation. Unlike bidomain finite element methods, the bidomain boundary element method does not require volume meshes containing features at multiple scales. As a result, modeling cells, or tightly packed populations of cells, with microscale features embedded in a macroscale head model, is simplified, and the relative placement of devices and cells can be varied without the need to generate a new mesh.Significance.Device-induced electromagnetic fields are commonly used to modulate brain activity for research and therapeutic applications. Bidomain solvers allow for the full incorporation of realistic cell geometries, device E-fields, and neuron populations. Thus, multi-cell studies of advanced neuronal mechanisms would greatly benefit from the development of fast-bidomain solvers to ensure scalability and the practical execution of neural network simulations with realistic neuron morphologies.

Metabolomic Analysis and Antiviral Screening of a Marine Algae Library Yield Jobosic Acid (2,5-Dimethyltetradecanoic Acid) as a Selective Inhibitor of SARS-CoV-2.

Current small-molecule-based SARS-CoV-2 treatments have limited global accessibility and pose the risk of inducing viral resistance. Therefore, a marine algae and cyanobacteria extract library was screened for natural products that could inhibit two well-defined and validated COVID-19 drug targets, disruption of the spike protein/ACE-2 interaction and the main protease (Mpro) of SARS-CoV-2. Following initial screening of 86 extracts, we performed an untargeted metabolomic analysis of 16 cyanobacterial extracts. This approach led to the isolation of an unusual saturated fatty acid, jobosic acid (2,5-dimethyltetradecanoic acid, 1). We confirmed that 1 demonstrated selective inhibitory activity toward both viral targets while retaining some activity against the spike-RBD/ACE-2 interaction of the SARS-CoV-2 omicron variant. To initially explore its structure-activity relationship (SAR), the methyl and benzyl ester derivatives of 1 were semisynthetically accessed and demonstrated acute loss of bioactivity in both SARS-CoV-2 biochemical assays. Our efforts have provided copious amounts of a fatty acid natural product that warrants further investigation in terms of SAR, unambiguous determination of its absolute configuration, and understanding of its specific mechanisms of action and binding site toward new therapeutic avenues for SARS-CoV-2 drug development.

A semi-automated pipeline for finite element modeling of electric field induced in nonhuman primates by transcranial magnetic stimulation.

BACKGROUND: Transcranial magnetic stimulation (TMS) is used to treat a range of brain disorders by inducing an electric field (E-field) in the brain. However, the precise neural effects of TMS are not well understood. Nonhuman primates (NHPs) are used to model the impact of TMS on neural activity, but a systematic method of quantifying the induced E-field in the cortex of NHPs has not been developed. NEW METHOD: The pipeline uses statistical parametric mapping (SPM) to automatically segment a structural MRI image of a rhesus macaque into five tissue compartments. Manual corrections are necessary around implants. The segmented tissues are tessellated into 3D meshes used in finite element method (FEM) software to compute the TMS induced E-field in the brain. The gray matter can be further segmented into cortical laminae using a volume preserving method for defining layers. RESULTS: Models of three NHPs were generated with TMS coils placed over the precentral gyrus. Two coil configurations, active and sham, were simulated and compared. The results demonstrated a large difference in E-fields at the target. Additionally, the simulations were calculated using two different E-field solvers and were found to not significantly differ. COMPARISON WITH EXISTING METHODS: Current methods segment NHP tissues manually or use automated methods for only the brain tissue. Existing methods also do not stratify the gray matter into layers. CONCLUSION: The pipeline calculates the induced E-field in NHP models by TMS and can be used to plan implant surgeries and determine approximate E-field values around neuron recording sites.

Anoctamin pharmacology.

TMEM16 proteins, also known as anoctamins, are a family of ten membrane proteins with various tissue expression and subcellular localization. TMEM16A (anoctamin 1) is a plasma membrane protein that acts as a calcium-activated chloride channel. It is expressed in many types of epithelial cells, smooth muscle cells and some neurons. In airway epithelial cells, TMEM16A expression is particularly enhanced by inflammatory stimuli that also promote goblet cell metaplasia and mucus hypersecretion. Therefore, pharmacological modulation of TMEM16A could be beneficial to improve mucociliary clearance in chronic obstructive respiratory diseases. However, the correct approach to modulate TMEM16A activity (activation or inhibition) is still debated. Pharmacological inhibitors of TMEM16A could also be useful as anti-hypertensive agents given the TMEM16A role in smooth muscle contraction. In contrast to TMEM16A, TMEM16F (anoctamin 6) behaves as a calcium-activated phospholipid scramblase, responsible for the externalization of phosphatidylserine on cell surface. Inhibitors of TMEM16F could be useful as anti-coagulants and anti-viral agents. The role of other anoctamins as therapeutic targets is still unclear since their physiological role is still to be defined.

Yearlong Near-Syncope: Presentation of a Rare Right Atrial Myxoma.

Atrial myxomas are the most common form of primary benign cardiac tumors. The left atrium is typically the most common location while right atrial myxomas are much rarer and only occur in about 15%-25% of all myxoma patients. Typically, left atrial myxomas have the ability to cause symptoms such as syncope. We report a case of a 67-year-old female who presented with complaints of palpitations, dizziness, and near-syncope that had been ongoing for about a year. Other causes of syncope were investigated and ruled out. A transthoracic echocardiogram (TTE) found a large 4.3 x 4.0 cm spherical mass in the right atrium which was confirmed by surgical resection and immunohistochemistry to be a myxoma. The patient's condition of syncope-like symptoms warrants elevating atrial myxomas to a higher position in the diagnostic differential.

Targeting LxCxE cleft pocket of retinoblastoma protein in M2 macrophages inhibits ovarian cancer progression.

Ovarian cancer remains a major health threat with limited treatment options available. It is characterized by immunosuppressive tumor microenvironment (TME) maintained by tumor- associated macrophages (TAMs) hindering anti-tumor responses and immunotherapy efficacy. Here we show that targeting retinoblastoma protein (Rb) by disruption of its LxCxE cleft pocket, causes cell death in TAMs by induction of ER stress, p53 and mitochondria-related cell death pathways. A reduction of pro-tumor Rb high M2-type macrophages from TME in vivo enhanced T cell infiltration and inhibited cancer progression. We demonstrate an increased Rb expression in TAMs in women with ovarian cancer is associated with poorer prognosis. Ex vivo, we show analogous cell death induction by therapeutic Rb targeting in TAMs in post-surgery ascites from ovarian cancer patients. Overall, our data elucidates therapeutic targeting of the Rb LxCxE cleft pocket as a novel promising approach for ovarian cancer treatment through depletion of TAMs and re-shaping TME immune landscape. Statement of significance: Currently, targeting immunosuppressive myeloid cells in ovarian cancer microenvironment is the first priority need to enable successful immunotherapy, but no effective solutions are clinically available. We show that targeting LxCxE cleft pocket of Retinoblastoma protein unexpectedly induces preferential cell death in M2 tumor-associated macrophages. Depletion of immunosuppressive M2 tumor-associated macrophages reshapes tumor microenvironment, enhances anti-tumor T cell responses, and inhibits ovarian cancer. Thus, we identify a novel paradoxical function of Retinoblastoma protein in regulating macrophage viability as well as a promising target to enhance immunotherapy efficacy in ovarian cancer.