Role of kinin receptors in skin pigmentation.

Previous studies have shown that all kinin system is constitutively expressed in the normal and inflamed skin, with a potential role in both physiological and pathological processes. However, the understanding regarding the involvement of the kinin system in skin pigmentation and pigmentation disorders remains incomplete. In this context, the present study was designed to determine the role of kinins in the Monobenzone (MBZ)-induced vitiligo-like model. Our findings showed that MBZ induces higher local skin depigmentation in kinin receptors knockout mice (KOB1R, KOB2R and KOB1B2R) than in wild type (WT). Remarkably, lower levels of melanin content and reduced ROS generation were detected in KOB1R and KOB2R mice treated with MBZ. In addition, both KOB1R and KOB2R show increased dermal cell infiltrate in vitiligo-like skin, when compared to WT-MBZ. Additionally, lack of B1R was associated with greater skin accumulation of IL-4, IL-6, and IL-17 by MBZ, while KOB1B2R presented lower levels of TNF and IL-1. Of note, the absence of both kinin B1 and B2 receptors demonstrates a protective effect by preventing the increase in polymorphonuclear and mononuclear cell infiltrations, as well as inflammatory cytokine levels induced by MBZ. In addition, in vitro assays confirm that B1R and B2R agonists increase intracellular melanin synthesis, while bradykinin significantly enhanced extracellular melanin levels and proliferation of B16F10 cells. Our findings highlight that the lack of kinin receptors caused more severe depigmentation in the skin, as well as genetic deletion of both B1/B2 receptors seems to be linked with changes in levels of constitutive melanin levels, suggesting the involvement of kinin system in crucial skin pigmentation pathways.

Social determinants of respiratory health from birth: still of concern in the 21st century?

Respiratory symptoms are ubiquitous in children and, even though they may be the harbinger of poor long-term outcomes, are often trivialised. Adverse exposures pre-conception, antenatally and in early childhood have lifetime impacts on respiratory health. For the most part, lung function tracks from the pre-school years at least into late middle age, and airflow obstruction is associated not merely with poor respiratory outcomes but also early all-cause morbidity and mortality. Much would be preventable if social determinants of adverse outcomes were to be addressed. This review presents the perspectives of paediatricians from many different contexts, both high and low income, including Europe, the Americas, Australasia, India, Africa and China. It should be noted that there are islands of poverty within even the highest income settings and, conversely, opulent areas in even the most deprived countries. The heaviest burden of any adverse effects falls on those of the lowest socioeconomic status. Themes include passive exposure to tobacco smoke and indoor and outdoor pollution, across the entire developmental course, and lack of access even to simple affordable medications, let alone the new biologicals. Commonly, disease outcomes are worse in resource-poor areas. Both within and between countries there are avoidable gross disparities in outcomes. Climate change is also bearing down hardest on the poorest children. This review highlights the need for vigorous advocacy for children to improve lifelong health. It also highlights that there are ongoing culturally sensitive interventions to address social determinants of disease which are already benefiting children.

The Combination of Enzymes and Conidia of Entomopathogenic Fungi against Aphis gossypii Nymphs and Spodoptera frugiperda Larvae.

The slow action of fungi is one of the biggest challenges in using entomopathogenic fungi. A promising alternative to reduce the time of action is to combine conidia with extracellular enzymes. This study aimed to characterize the production of Pr1 subtilisin protease and lipases by Beauveria bassiana and Metarhizium anisopliae in different culture media and to evaluate the efficiency of the enzymatic treatment against Aphis gossypii and Spodoptera frugiperda. The isolates were cultivated in five different liquid cultures, and, after 7 days, the culture was filtered and centrifuged, and the activity of the Pr1 and lipases was measured. The fungi cultured in a Luria-Bertani broth medium had the highest activity of proteases and lipases. The mortality of A. gossypii nymphs treated with conidia 7 days after the treatment was 39% (JEF-410), 76.5% (JEF-492), 74.8% (ERL-836), and 70.9% (JEF-214). The B. bassiana JEF-410 supernatant combined with conidia increased the fungal virulence at day 5 and day 6 after treatment. When S. frugiperda larvae were treated with B. bassiana JEF-492 conidia combined with its supernatant, the time of infection was shorter compared to the larvae treated with conidia only. Once the supernatant was incubated at 37 °C, the relative activity decreased from 100% to 80% after 2 h and to 45% after 24 h. The results suggest that the supernatant of entomopathogenic fungi may be formulated and used as a biopesticide in an efficient strategy for the biological control of pests.

Temporal trends of severity and outcomes of critically ill patients with COVID-19 after the emergence of variants of concern: A comparison of two waves.

BACKGROUND: The emergence of SARS-CoV-2 variants led to subsequent waves of COVID-19 worldwide. In many countries, the second wave of COVID-19 was marked by record deaths, raising the concern that variants associated with that wave might be more deadly. Our aim was to compare outcomes of critically-ill patients of the first two waves of COVID-19. METHODS: This retrospective cohort included critically-ill patients admitted between March-June 2020 and April-July 2021 in the largest academic hospital in Brazil, which has free-access universal health care system. We compared admission characteristics and hospital outcomes. The main outcome was 60-day survival and we built multivariable Cox model based on a conceptual causal diagram in the format of directed acyclic graph (DAG). RESULTS: We included 1583 patients (1315 in the first and 268 in the second wave). Patients in the second wave were younger, had lower severity scores, used prone and non-invasive ventilatory support more often, and fewer patients required mechanical ventilation (70% vs 80%, p<0.001), vasopressors (60 vs 74%, p<0.001), and dialysis (22% vs 37%, p<0.001). Survival was higher in the second wave (HR 0.61, 95%CI 0.50-0.76). In the multivariable model, admission during the second wave, adjusted for age, SAPS3 and vaccination, was not associated with survival (aHR 0.85, 95%CI 0.65-1.12). CONCLUSIONS: In this cohort study, patients with COVID-19 admitted to the ICU in the second wave were younger and had better prognostic scores. Adjusted survival was similar in the two waves, contrasting with record number of hospitalizations, daily deaths and health system collapse seen across the country in the second wave. Our findings suggest that the combination of the burden of severe cases and factors such as resource allocation and health disparities may have had an impact in the excess mortality found in many countries in the second wave.

Data-driven, cross-disciplinary collaboration: lessons learned at the largest academic health center in Latin America during the COVID-19 pandemic.

Introduction: The COVID-19 pandemic has prompted global research efforts to reduce infection impact, highlighting the potential of cross-disciplinary collaboration to enhance research quality and efficiency. Methods: At the FMUSP-HC academic health system, we implemented innovative flow management routines for collecting, organizing and analyzing demographic data, COVID-related data and biological materials from over 4,500 patients with confirmed SARS-CoV-2 infection hospitalized from 2020 to 2022. This strategy was mainly planned in three areas: organizing a database with data from the hospitalizations; setting-up a multidisciplinary taskforce to conduct follow-up assessments after discharge; and organizing a biobank. Additionally, a COVID-19 curated collection was created within the institutional digital library of academic papers to map the research output. Results: Over the course of the experience, the possible benefits and challenges of this type of research support approach were identified and discussed, leading to a set of recommended strategies to enhance collaboration within the research institution. Demographic and clinical data from COVID-19 hospitalizations were compiled in a database including adults and a minority of children and adolescents with laboratory confirmed COVID-19, covering 2020-2022, with approximately 350 fields per patient. To date, this database has been used in 16 published studies. Additionally, we assessed 700 adults 6 to 11 months after hospitalization through comprehensive, multidisciplinary in-person evaluations; this database, comprising around 2000 fields per subject, was used in 15 publications. Furthermore, thousands of blood samples collected during the acute phase and follow-up assessments remain stored for future investigations. To date, more than 3,700 aliquots have been used in ongoing research investigating various aspects of COVID-19. Lastly, the mapping of the overall research output revealed that between 2020 and 2022 our academic system produced 1,394 scientific articles on COVID-19. Discussion: Research is a crucial component of an effective epidemic response, and the preparation process should include a well-defined plan for organizing and sharing resources. The initiatives described in the present paper were successful in our aim to foster large-scale research in our institution. Although a single model may not be appropriate for all contexts, cross-disciplinary collaboration and open data sharing should make health research systems more efficient to generate the best evidence.

Exposure to the plasticizer diisopentyl phthalate can cause Vero cell line death.

Phthalates are synthetic plasticizers present in the daily lives of humans, as part of the composition of different products, such as food packaging, water bottles, and toys. These compounds can migrate from plastic materials to the environment changing biological systems. Although diisopentyl phthalate (DiPeP) is largely used in Brazil, there is a lack of information on the possible toxic effects of this compound. This research aims to evaluate the toxicity of DiPeP in the Vero renal cells. These cells were exposed to the 1-1000 µM of DiPeP for 24 and 72 h and subsequently, the cytotoxicity, apoptosis and necrosis-inducing potential, and antioxidant system (SOD, GPx, and GST) were investigated. DiPeP neither caused cytotoxicity nor altered SOD and GPx activity, although GST has been increased at 100 or 1 µM (24 and 72 h, respectively). However, cell death by apoptosis and necrosis was observed. These results indicate that DiPeP caused cell death by a non-oxidative stress-mediated mechanism, which shows the relevance of investigate other process in further researches.

Assessment of Neurovascular Coupling by Spectral Analysis of Cerebral Blood Flow Velocity With Transcranial Doppler.

OBJECTIVE: Neurovascular coupling (NVC) represents the increase in regional blood flow associated with neural activity. The aim here was to describe a new approach to non-invasive measurement of NVC by spectral analysis of the cerebral blood flow velocity (CBFV) with transcranial Doppler. METHODS: In a sample of 20 healthy participants, we monitored systolic CBFV in the left posterior cerebral artery (PCA) during off (eyes closed) and on (flickering checkerboard) periods. The contralateral middle cerebral artery was simultaneously monitored as a control. Each participant was submitted to three experiments, each having five cycles, with increasing duration of the cycles, from 10 s (0.1 Hz) to 20 s (0.05 Hz) and lastly 40 s (0.025 Hz), half the time for on and for off periods, constituting a total of 6 min. The successive cycles were expected to cause oscillation in CBFV in a sinusoidal pattern that could be characterized by spectral analysis. We also measured the classic CBFV overshoot as the relative increase in percentage of systolic CBFV from baseline. The relationship and agreement between the two methods were analyzed by linear regression and Bland-Altman plots. In every participant, a clear peak of amplitude in the PCA CBFV spectrum was discernible at 0.1, 0.05 and 0.025 Hz of visual stimulation. RESULTS: On average, this amplitude was 7.1 ± 2.3%, 10.9 ± 3.5% and 17.3 ± 6.5%, respectively. This response contrasted significantly with an absent peak in middle cerebral artery monitoring (p < 0.0001). The spectral amplitude and classic overshoot were highly correlated and linearly related (p < 0.0001). CONCLUSION: NVC can be quantified by the spectral amplitude of PCA CBFV at slower and higher frequencies of visual stimulation. This method represents an alternative to classic overshoot without the need for stimulus marking or synchronization.

Use of elexacaftor+tezacaftor+ivacaftor in individuals with cystic fibrosis and at least one F508del allele: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the effect of treatment with the combination of three cystic fibrosis transmembrane conductance regulator (CFTR) modulators-elexacaftor+tezacaftor+ivacaftor (ETI)-on important clinical endpoints in individuals with cystic fibrosis. METHODS: This was a systematic review and meta-analysis of randomized clinical trials that compared the use of ETI in individuals with CF and at least one F508del allele with that of placebo or with an active comparator such as other combinations of CFTR modulators, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations and the Patients of interest, Intervention to be studied, Comparison of interventions, and Outcome of interest (PICO) methodology. We searched the following databases: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to December 26th, 2022. The risk of bias was assessed using the Cochrane risk-of-bias tool, and the quality of evidence was based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: We retrieved 54 studies in the primary search. Of these, 6 met the inclusion criteria and were analyzed (1,127 patients; 577 and 550 in the intervention and control groups, respectively). The meta-analysis revealed that the use of ETI increased FEV1% [risk difference (RD), +10.47%; 95% CI, 6.88-14.06], reduced the number of acute pulmonary exacerbations (RD, -0.16; 95% CI, -0.28 to -0.04), and improved quality of life (RD, +14.93; 95% CI, 9.98-19.89) and BMI (RD, +1.07 kg/m2; 95% CI, 0.90-1.25). Adverse events did not differ between groups (RD, -0.03; 95% CI, -0.08 to 0.01), and none of the studies reported deaths. CONCLUSIONS: Our findings demonstrate that ETI treatment substantially improves clinically significant, patient-centered outcomes.

Aplicativos móveis sobre segurança do paciente idoso no ambiente cirúrgico: uma prospecção tecnológica / Mobile applications on the safety of elderly patients in the surgical environment: a technological prospecting

OBJETIVO: Descrever os aplicativos voltados para a segurança do paciente idoso cirúrgico nos períodos pré e pós-operatório. MÉTODO: Prospecção tecnológica com abordagem qualitativa realizada nas lojas virtuais Apple Store, Google Play e aplicativo web. Como estratégia de busca utilizou-se os termos: 'autocuidado idoso', 'pré-operatório', 'pós-operatório', 'segurança do paciente', 'segurança do paciente idoso'. RESULTADOS: Foram identificados 12 aplicativos na loja virtual Apple Store, 17 na Google Play e um web app, os quais estavam voltados a gamificação de profissionais da saúde e da população; aplicativos educacionais aos profissionais de saúde e usuários do sistema de saúde; aplicativos relacionados como ferramenta de trabalho para os profissionais de saúde; aplicativos como ferramenta de autocuidado para usuários do sistema de saúde; e, aplicativos voltados para pós-operatório de usuários do sistema de saúde. CONCLUSÃO: Não foram encontradas tecnologias voltadas para o autocuidado e segurança do paciente idoso nos períodos pré e pós-operatório

OBJECTIVE: To describe applications focused on the safety of elderly surgical patients in the pre- and postoperative periods. METHOD: Technology prospecting with a qualitative approach in the Apple Store, Google Play virtual stores, and web application. As a search strategy, the following terms were used: 'elderly self-care', 'preoperative', 'postoperative', 'patient safety', 'elderly patient safety'. RESULTS: 12 applications were identified in the Apple Store, 17 in Google Play, and a web app, which focused on the gamification of health and population professionals; educational applications to health professionals and health system users; related applications as a work tool for health professionals; applications as a self-care tool for health system users; and, post-operative applications for health system users. CONCLUSION: Technologies aimed at self-care and the safety of elderly patients were not found in the pre- and postoperative periods.

Discovery of pyrimidoindol and benzylpyrrolyl inhibitors targeting SARS-CoV-2 main protease (Mpro) through pharmacophore modelling, covalent docking, and biological evaluation.

The main protease (Mpro) enzyme has an imperative function in disease progression and the life cycle of the SARS-CoV-2 virus. Although the orally active drug nirmatrelvir (co-administered with ritonavir as paxlovid) has been approved for emergency use as the frontline antiviral agent, there are a number of limitations that necessitate the discovery of new drug scaffolds, such as poor pharmacokinetics and susceptibility to proteolytic degradation due to its peptidomimetic nature. This study utilized a novel virtual screening workflow that combines pharmacophore modelling, multiple-receptor covalent docking, and biological evaluation in order to find new Mpro inhibitors. After filtering and analysing ∼66,000 ligands from three different electrophilic libraries, 29 compounds were shortlisted for experimental testing, and two of them exhibited ≥20% inhibition at 100 µM. Our top candidate, GF04, is a benzylpyrrolyl compound that exhibited the highest inhibition activity of 38.3%, with a relatively small size (<350 Da) and leadlike character. Interestingly, our approach also identified another hit, DR07, a pyrimidoindol with a non-peptide character, and a molecular weight of 438.9 Da, reporting an inhibition of 26.3%. The established approach detailed in this study, in conjunction with the discovered inhibitors, has the capacity to yield novel perspectives for devising covalent inhibitors targeting the COVID-19 Mpro enzyme and other comparable targets.

Impact of the immune profiles of hypertensive patients with and without obesity on COVID-19 severity.

BACKGROUND: Comorbidities such as obesity, hypertension, and diabetes are associated with COVID-19 development and severity, probably due to immune dysregulation; however, the mechanisms underlying these associations are not clear. The immune signatures of hypertensive patients with obesity with COVID-19 may provide new insight into the mechanisms of immune dysregulation and progression to severe disease in these patients. METHODS: Hypertensive patients were selected prospectively from a multicenter registry of adults hospitalized with COVID-19 and stratified according to obesity (BMI ≥ 30 kg/m²). Clinical data including baseline characteristics, complications, treatment, and 46 immune markers were compared between groups. Logistic regression was performed to identify variables associated with the risk of COVID-19 progression in each group. RESULTS: The sample comprised 213 patients (89 with and 124 without obesity). The clinical profiles of patients with and without obesity differed, suggesting potential interactions with COVID-19 severity. Relative to patients without obesity, patients with obesity were younger and fewer had cardiac disease and myocardial injury. Patients with obesity had higher EGF, GCSF, GMCSF, interleukin (IL)-1ra, IL-5, IL-7, IL-8, IL-15, IL-1ß, MCP 1, and VEGF levels, total lymphocyte counts, and CD8+ CD38+ mean fluorescence intensity (MFI), and lower NK-NKG2A MFI and percentage of CD8+ CD38+ T cells. Significant correlations between cytokine and immune cell expression were observed in both groups. Five variables best predicted progression to severe COVID-19 in patients with obesity: diabetes, the EGF, IL-10, and IL-13 levels, and the percentage of CD8+ HLA-DR+ CD38+ cells. Three variables were predictive for patients without obesity: myocardial injury and the percentages of B lymphocytes and HLA-DR+ CD38+ cells. CONCLUSION: Our findings suggest that clinical and immune variables and obesity interact synergistically to increase the COVID-19 progression risk. The immune signatures of hypertensive patients with and without obesity severe COVID-19 highlight differences in immune dysregulation mechanisms, with potential therapeutic applications.

Neonatal screening for spinal muscular atrophy: A pilot study in Brazil.

Spinal muscular atrophy (SMA) is considered one of the most common autosomal recessive disorders, with an estimated incidence of 1 in 10,000 live births. Testing for SMA has been recommended for inclusion in neonatal screening (NBS) panels since there are several therapies available and there is evidence of greater efficacy when introduced in the pre/early symptomatic phases. In Brazil, the National Neonatal Screening Program tests for six diseases, with a new law issued in 2021 stating that it should incorporate more diseases, including SMA. In the present study, dried blood spot (DBS) samples collected by the Reference Services of Neonatal Screening of RS and SP, to perform the conventional test were also screened for SMA, using real-time PCR, with SALSA MC002 technique. A total of 40,000 samples were analyzed, enabling the identification of four positive cases of SMA, that were confirmed by MLPA. Considering our sampling, Brazil seems to have an incidence comparable to the described in other regions. This work demonstrated that the use of the MC002 technique in samples routinely collected for the conventional NBS program is suitable to screen for SMA in our conditions and can be included in the expansion of the neonatal screening programs.

Effects of atelectatic areas on the surrounding lung tissue during mechanical ventilation in an experimental model of acute lung injury induced by lipopolysaccharide / Efeitos das áreas atelectásicas no tecido pulmonar circundante durante a ventilação mecânica em um modelo experimental de lesão pulmonar aguda induzida por lipopolissacarídeo

ABSTRACT Objective: To assess the effect of atelectasis during mechanical ventilation on the periatelectatic and normal lung regions in a model of atelectasis in rats with acute lung injury induced by lipopolysaccharide. Methods: Twenty-four rats were randomized into the following four groups, each with 6 animals: the Saline-Control Group, Lipopolysaccharide Control Group, Saline-Atelectasis Group, and Lipopolysaccharide Atelectasis Group. Acute lung injury was induced by intraperitoneal injection of lipopolysaccharide. After 24 hours, atelectasis was induced by bronchial blocking. The animals underwent mechanical ventilation for two hours with protective parameters, and respiratory mechanics were monitored during this period. Thereafter, histologic analyses of two regions of interest, periatelectatic areas and the normally-aerated lung contralateral to the atelectatic areas, were performed. Results: The lung injury score was significantly higher in the Lipopolysaccharide Control Group (0.41 ± 0.13) than in the Saline Control Group (0.15 ± 0.51), p < 0.05. Periatelectatic regions showed higher lung injury scores than normally-aerated regions in both the Saline-Atelectasis (0.44 ± 0.06 x 0.27 ± 0.74 p < 0.05) and Lipopolysaccharide Atelectasis (0.56 ± 0.09 x 0.35 ± 0.04 p < 0.05) Groups. The lung injury score in the periatelectatic regions was higher in the Lipopolysaccharide Atelectasis Group (0.56 ± 0.09) than in the periatelectatic region of the Saline-Atelectasis Group (0.44 ± 0.06), p < 0.05. Conclusion: Atelectasis may cause injury to the surrounding tissue after a period of mechanical ventilation with protective parameters. Its effect was more significant in previously injured lungs.

RESUMO Objetivo: Avaliar o efeito da atelectasia durante a ventilação mecânica nas regiões periatelectáticas e pulmonares normais em um modelo de atelectasia em ratos com lesão pulmonar aguda induzida por lipopolissacarídeo. Métodos: Foram distribuídos aleatoriamente 24 ratos em quatro grupos, cada um com 6 animais: Grupo Salina-Controle, Grupo Lipopolissacarídeo-Controle, Grupo Salina-Atelectasia e Grupo Lipopolissacarídeo-Atelectasia. A lesão pulmonar aguda foi induzida por injeção intraperitoneal de lipopolissacarídeo. Após 24 horas, a atelectasia foi induzida por bloqueio brônquico. Os animais foram submetidos à ventilação mecânica por 2 horas com parâmetros ventilatórios protetores, e a mecânica respiratória foi monitorada durante esse período. Em seguida, foram realizadas análises histológicas de duas regiões de interesse: as áreas periatelectásicas e o pulmão normalmente aerado contralateral às áreas atelectásicas. Resultados: O escore de lesão pulmonar foi significativamente maior no Grupo Controle-Lipopolissacarídeo (0,41 ± 0,13) do que no Grupo Controle-Solução Salina (0,15 ± 0,51), com p < 0,05. As regiões periatelectásicas apresentaram escores maiores de lesão pulmonar do que as regiões normalmente aeradas nos Grupos Atelectasia-Solução Salina (0,44 ± 0,06 versus 0,27 ± 0,74, p < 0,05) e Atelectasia-Lipopolissacarídeo (0,56 ± 0,09 versus 0,35 ± 0,04, p < 0,05). O escore de lesão pulmonar nas regiões periatelectásicas foi maior no Grupo Atelectasia-Lipopolissacarídeo (0,56 ± 0,09) do que na região periatelectásica do Grupo Atelectasia-Solução Salina (0,44 ± 0,06), p < 0,05. Conclusão: A atelectasia pode causar lesão no tecido circundante após um período de ventilação mecânica com parâmetros ventilatórios protetores. Seu efeito foi mais significativo em pulmões previamente lesionados.

The II Brazilian Guidelines for the pharmacological treatment of patients hospitalized with COVID-19 Joint Guidelines of the Associação Brasileira de Medicina de Emergência, Associação de Medicina Intensiva Brasileira, Associação Médica Brasileira, Sociedade Brasileira de Angiologia e Cirurgia Vascular, Sociedade Brasileira de Infectologia, Sociedade Brasileira de Pneumologia e Tisiologia and Sociedade Brasileira de Reumatologia.

OBJECTIVE: To update the recommendations to support decisions regarding the pharmacological treatment of patients hospitalized with COVID-19 in Brazil. METHODS: Experts, including representatives of the Ministry of Health and methodologists, created this guideline. The method used for the rapid development of guidelines was based on the adoption and/or adaptation of existing international guidelines (GRADE ADOLOPMENT) and supported by the e-COVID-19 RecMap platform. The quality of the evidence and the preparation of the recommendations followed the GRADE method. RESULTS: Twenty-one recommendations were generated, including strong recommendations for the use of corticosteroids in patients using supplemental oxygen and conditional recommendations for the use of tocilizumab and baricitinib for patients on supplemental oxygen or on noninvasive ventilation and anticoagulants to prevent thromboembolism. Due to suspension of use authorization, it was not possible to make recommendations regarding the use of casirivimab + imdevimab. Strong recommendations against the use of azithromycin in patients without suspected bacterial infection, hydroxychloroquine, convalescent plasma, colchicine, and lopinavir + ritonavir and conditional recommendations against the use of ivermectin and remdesivir were made. CONCLUSION: New recommendations for the treatment of hospitalized patients with COVID-19 were generated, such as those for tocilizumab and baricitinib. Corticosteroids and prophylaxis for thromboembolism are still recommended, the latter with conditional recommendation. Several drugs were considered ineffective and should not be used to provide the best treatment according to the principles of evidence-based medicine and to promote resource economy.

Risk factors associated to incisional hernia in stoma site after stoma closure: A systematic review and meta-analysis.

BACKGROUND: This study aims to identify which risk factors are associated with the appearance of an incisional hernia in a stoma site after its closure. This in the sake of identifying which patients would benefit from a preventative intervention and thus start implementing a cost-effective protocol for prophylactic mesh placement in high-risk patients. METHODS: A systematic review of PubMed, Cochrane library, and ScienceDirect was performed according to PRISMA guidelines. Studies reporting incidence, risk factors, and follow-up time for appearance of incisional hernia after stoma site closure were included. A fixed-effects and random effects models were used to calculate odds ratios' estimates and standardized mean values with their respective grouped 95% confidence interval. This to evaluate the association between possible risk factors and the appearance of incisional hernia after stoma site closure. RESULTS: Seventeen studies totaling 2899 patients were included. Incidence proportion between included studies was of 16.76% (CI95% 12.82; 21.62). Out of the evaluated factors higher BMI (p = 0.0001), presence of parastomal hernia (p = 0.0023), colostomy (p = 0,001), and end stoma (p = 0.0405) were associated with the appearance of incisional hernia in stoma site after stoma closure, while malignant disease (p = 0.0084) and rectum anterior resection (p = 0.0011) were found to be protective factors. CONCLUSIONS: Prophylactic mesh placement should be considered as an effective preventative intervention in high-risk patients (obese patients, patients with parastomal hernia, colostomy, and end stoma patients) with the goal of reducing incisional hernia rates in stoma site after closure while remaining cost-effective.

The Discovery of Novel Small Oxindole-Based Inhibitors Targeting the SARS-CoV-2 Main Protease (Mpro ).

With the potential for coronaviruses to re-emerge and trigger future pandemics, the urgent development of antiviral inhibitors against SARS-CoV-2 is essential. The Mpro enzyme is crucial for disease progression and the virus's life cycle. It possesses allosteric sites that can hinder its catalytic activity, with some of these sites located at or near the dimerization interface. Among them, sites #2 and #5 possess druggable pockets and are predicted to bind drug-like molecules. Consequently, a commercially available ligand library containing ~7 million ligands was used to target site #2 via structure-based virtual screening. After extensive filtering, docking, and post-docking analyses, 53 compounds were chosen for biological testing. An oxindole derivative was identified as a Mpro non-competitive reversible inhibitor with a Ki of 115 µM and an IC50 of 101.9 µM. Throughout the 200 ns-long MD trajectories, our top hit has shown a very stable binding mode, forming several interactions with residues in sites #2 and #5. Moreover, derivatives of our top hit were acquired for biological testing to gain deeper insights into their structure-activity relationship. To sum up, drug-like allosteric inhibitors seem promising and can provide us with an additional weapon in our war against the recent pandemic, and possibly other coronaviruses-caused diseases.