Coordinated nasal mucosa-mediated immunity accelerates recovery from COVID-19.

Introduction: Understanding the interplay of immune mediators in relation to clinical outcomes during acute infection has the potential to highlight immune networks critical to symptom recovery. The objective of the present study was to elucidate the immune networks critical to early symptom resolution following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Methods: In a community-based randomised clinical trial comparing inhaled budesonide against usual care in 139 participants with early onset SARS-CoV-2 (the STOIC study; clinicaltrials.gov identifier NCT04416399), significant clinical deterioration (reported need for urgent care, emergency department visit, hospitalisation: the primary outcome), self-reported symptom severity (Influenza Patient-Reported Outcome questionnaire) and immune mediator networks were assessed. Immune mediator networks were determined using pre-defined mathematical modelling of immune mediators, determined by the Meso Scale Discovery U-Plex platform, within the first 7 days of SARS-CoV-2 infection compared to 22 healthy controls. Results: Interferon- and chemokine-dominant networks were associated with high viral burden. Elevated levels of the mucosal network (chemokine (C-C motif) ligand (CCL)13, CCL17, interleukin (IL)-33, IL-5, IL-4, CCL26, IL-2, IL-12 and granulocyte-macrophage colony-stimulating factor) was associated with a mean 3.7-day quicker recovery time, with no primary outcome events, irrespective of treatment arm. This mucosal network was associated with initial nasal and throat symptoms at day 0. Conclusion: A nasal immune network is critical to accelerated recovery and improved patient outcomes in community-acquired viral infections. Overall, early prognostication and treatments aimed at inducing epithelial responses may prove clinically beneficial in enhancing early host response to virus.

Is the Absence of Manual Lymphatic Drainage-Based Treatment in Lymphedema after Breast Cancer Harmful? A Randomized Crossover Study.

(1) Background: Manual lymphatic drainage (MLD), included within the complex decongestive therapy, as a therapy for the treatment of lymphedema has raised controversy about its benefits for lymphedema after breast cancer. The aim of this research is to test the effects of MLD on lymphedema after breast cancer during the treatment maintenance phase. (2) Methods: A randomized, single-blinded, controlled crossover trial was conducted to analyze the effects of a manual lymphatic drainage intervention compared to a control group without MLD intervention for the treatment of lymphedema. Arm volume measured by circumference measurement, subcutaneous tissue thickness measured by ultrasound, and the sensation of pain, heaviness, and swelling were evaluated as outcome measures. (3) Results: For the control group, an increase in volume was found in some of the circumference and subcutaneous tissue thickness measurements, in addition to a worsening of arm pain, swelling and heaviness. (4) Conclusion: The absence of treatment based on MLD in lymphedema after breast cancer worsens volume measurements, as well as arm heaviness. Therefore, it would be advisable to carry out this type of therapy as part of the maintenance treatment for lymphedema in breast cancer.

The RNA binding proteins ZFP36L1 and ZFP36L2 are dysregulated in airway epithelium in human and a murine model of asthma.

Introduction: Asthma is the most common chronic inflammatory disease of the airways. The airway epithelium is a key driver of the disease, and numerous studies have established genome-wide differences in mRNA expression between health and asthma. However, the underlying molecular mechanisms for such differences remain poorly understood. The human TTP family is comprised of ZFP36, ZFP36L1 and ZFP36L2, and has essential roles in immune regulation by determining the stability and translation of myriad mRNAs encoding for inflammatory mediators. We investigated the expression and possible role of the tristetraprolin (TTP) family of RNA binding proteins (RBPs), poorly understood in asthma. Methods: We analysed the levels of ZFP36, ZFP36L1 and ZFP36L2 mRNA in several publicly available asthma datasets, including single cell RNA-sequencing. We also interrogated the expression of known targets of these RBPs in asthma. We assessed the lung mRNA expression and cellular localization of Zfp36l1 and Zfp36l2 in precision cut lung slices in murine asthma models. Finally, we determined the expression in airway epithelium of ZFP36L1 and ZFP36L2 in human bronchial biopsies and performed rescue experiments in primary bronchial epithelium from patients with severe asthma. Results: We found ZFP36L1 and ZFP36L2 mRNA levels significantly downregulated in the airway epithelium of patients with very severe asthma in different cohorts (5 healthy vs. 8 severe asthma; 36 moderate asthma vs. 37 severe asthma on inhaled steroids vs. 26 severe asthma on oral corticoids). Integrating several datasets allowed us to infer that mRNAs potentially targeted by these RBPs are increased in severe asthma. Zfp36l1 was downregulated in the lung of a mouse model of asthma, and immunostaining of ex vivo lung slices with a dual antibody demonstrated that Zfp36l1/l2 nuclear localization was increased in the airway epithelium of an acute asthma mouse model, which was further enhanced in a chronic model. Immunostaining of human bronchial biopsies showed that airway epithelial cell staining of ZFP36L1 was decreased in severe asthma as compared with mild, while ZFP36L2 was upregulated. Restoring the levels of ZFP36L1 and ZFP36L2 in primary bronchial epithelial cells from patients with severe asthma decreased the mRNA expression of IL6, IL8 and CSF2. Discussion: We propose that the dysregulation of ZFP36L1/L2 levels as well as their subcellular mislocalization contributes to changes in mRNA expression and cytoplasmic fate in asthma.

Ceg1 depletion reveals mechanisms governing degradation of non-capped RNAs in Saccharomyces cerevisiae.

Most functional eukaryotic mRNAs contain a 5' 7-methylguanosine (m7G) cap. Although capping is essential for many biological processes including mRNA processing, export and translation, the fate of uncapped transcripts has not been studied extensively. Here, we employed fast nuclear depletion of the capping enzymes in Saccharomyces cerevisiae to uncover the turnover of the transcripts that failed to be capped. We show that although the degradation of cap-deficient mRNA is dominant, the levels of hundreds of non-capped mRNAs increase upon depletion of the capping enzymes. Overall, the abundance of non-capped mRNAs is inversely correlated to the expression levels, altogether resembling the effects observed in cells lacking the cytoplasmic 5'-3' exonuclease Xrn1 and indicating differential degradation fates of non-capped mRNAs. The inactivation of the nuclear 5'-3' exonuclease Rat1 does not rescue the non-capped mRNA levels indicating that Rat1 is not involved in their degradation and consequently, the lack of the capping does not affect the distribution of RNA Polymerase II on the chromatin. Our data indicate that the cap presence is essential to initiate the Xrn1-dependent degradation of mRNAs underpinning the role of 5' cap in the Xrn1-dependent buffering of the cellular mRNA levels.

[Transcultural adaptation and validation of the DASH questionnaire in Mexican healthy volunteers and patients with neurogenic disorders of the upper extremity]. / Adaptación transcultural y validación de la versión mexicana del cuestionario DASH en individuos sanos y pacientes con trastornos neurogénicos del miembro superior.

Background: The Disability of the Arm, Shoulder and Hand (DASH) questionnaire assesses the impact of upper extremity disorders on quality of life. However, its use in the Mexican population has not been formally validated. Objective: To conduct a cultural adaptation and validation of the DASH questionnaire to evaluate the perspective of patients with neurogenic disorders of the upper extremity regarding the impact on their quality of life. Method: We performed an adaptation of the Spanish version of the DASH questionnaire to the Mexican vocabulary and applied it to 478 volunteers. Ceiling effect, floor effect, item-total correlation, descriptive statistics of items and total score, internal consistency, precision, cross-sectional and longitudinal validity were estimated by comparing healthy controls and affected individuals with different disability levels. Results: Our DASH questionnaire version was equivalent to those previously approved and showed homogeneity of the items with respect to the total value of the questionnaire (Cronbach's alpha > 0.96). In addition, it showed an accuracy of 7.25 points and the crosssectional and longitudinal validity was documented with significant differences between groups and subgroups with distinct disability levels. Conclusions: The DASH questionnaire can be used with a high level of confidence in the Mexican population.

Antecedentes: El cuestionario de discapacidad de brazo, hombro y mano (DASH, Disabilities of the Arm, Shoulder and Hand) mide el impacto de patologías del miembro superior en la calidad de vida. Sin embargo, su uso en la población mexicana no ha sido formalmente validado. Objetivo: Realizar la adaptación cultural y validación del cuestionario DASH para conocer la perspectiva de pacientes con trastornos neurogénicos del miembro superior respecto al impacto en su calidad de vida. Método: Se realizó una adaptación al vocabulario mexicano de la versión española del cuestionario DASH y se aplicó en 478 voluntarios. Se estimaron el efecto techo, el efecto suelo, la correlación ítem-total, las medidas de tendencia central de ítems y el puntaje total, la consistencia interna, la precisión y la validez transversal y longitudinal mediante la comparación de individuos sanos y enfermos con diferente nivel de discapacidad. Resultados: Nuestra versión del cuestionario DASH resultó equivalente a las previamente aprobadas y mostró homogeneidad de los ítems respecto al valor total del cuestionario (alfa de Cronbach > 0.96). Además, tuvo una precisión de 7.25 puntos y se documentó la validez transversal y longitudinal con diferencias significativas entre grupos y subgrupos con diferente nivel de discapacidad. Conclusiones: El cuestionario DASH puede ser empleado con un nivel de confianza alto en la población mexicana.

Entrenamiento de equilibrio en la inestabilidad crónica de tobillo. Una revisión sistemática / Treino de equilíbrio na instabilidade crónica do tornozelo. Uma revisão sistemática. / Balance training in chronic ankle instability. A systematic review

Introducción: El objetivo de este trabajo es conocer la evidencia científica de los tratamientos centrados en el equilibrio en pacientes con inestabilidadcrónica de tobillo. Métodos: Se realizó una revisión de la literatura científica mediante una búsqueda sistematizada en febrero de 2022 en las siguientes bases de datos:PubMed, Scopus, PEDro, Web of Science, y Medline. Resultados: Se incluyeron ensayos clínicos aleatorizados en los últimos 5 años, obteniendo un total de 16 artículos para el análisis de esta revisiónsistemática. La calidad metodológica fue evaluada mediante la escala PEDro. Los principales resultados obtenidos mostraron mejoras en el equilibrioestático y dinámico en comparación con el grupo control. Sin embargo, en su mayoría, se muestran diferencias poco significativas entre gruposexperimentales. Conclusión: Los efectos que produce el entrenamiento de equilibrio en pacientes con inestabilidad crónica de tobillo parecen ser positivos.(AU)

Background: The aim of this work is to know the scientific evidence of treatments focused on balance in patients with chronic ankle instability. Methods: A review of the scientific literature was carried out by means of a systematized search in February 2022 in the following databases: PubMed,Scopus, PEDro, Web of Science, and Medline. Results: Randomized clinical trials in the last 5 years were included, obtaining a total of 16 articles for the analysis of this systematic review. Themethodological quality was evaluated using the PEDro scale. The main results obtained showed improvements in static and dynamic balance comparedto the control group. However, for the most part, insignificant differences between experimental groups were shown. Conclusion: The effects of balance training in patients with chronic ankle instability appear to be positive.(AU)

Introdução: O objectivo deste estudo é descobrir as provas científicas de tratamentos centrados no equilíbrio em pacientes com instabilidade crónica dotornozelo. Métodos: Foi realizada uma revisão da literatura científica através de uma pesquisa sistematizada em Fevereiro de 2022 nas seguintes bases de dados:PubMed, Scopus, PEDro, Web of Science, e Medline. Resultados: Foram incluídos ensaios clínicos aleatórios nos últimos 5 anos, obtendo-se um total de 16 artigos para a análise desta revisão sistemática. Aqualidade metodológica foi avaliada utilizando a escala PEDro. Os principais resultados obtidos mostraram melhorias no equilíbrio estático e dinâmicoem comparação com o grupo de controlo. No entanto, na sua maioria, foram mostradas diferenças insignificantes entre os grupos experimentais.Conclusão: Os efeitos do treino de equilíbrio em pacientes com instabilidade crónica do tornozelo parecem ser positivos.(AU)

Asthma innovations from the first International Collaborative Asthma Network forum.

Background: Many patients have uncontrolled asthma despite available treatments. Most of the new asthma therapies have focused on type 2 (T2) inflammation, leaving an unmet need for innovative research into mechanisms of asthma beyond T2 and immunity. An international group of investigators developed the International Collaborative Asthma Network (ICAN) with the goal of sharing innovative research on disease mechanisms, developing new technologies and therapies, organising pilot studies and engaging early-stage career investigators from across the world. This report describes the purpose, development and outcomes of the first ICAN forum. Methods: Abstracts were solicited from interdisciplinary early-stage career investigators with innovative ideas beyond T2 inflammation for asthma and were selected for presentation at the forum. Breakout sessions were conducted to discuss innovation, collaboration and research translation. Results: The abstracts were categorised into: 1) general omics and big data analysis; 2) lung-brain axis and airway neurology; 3) sex differences; 4) paediatric asthma; 5) new therapeutic targets inspired by airway epithelial biology; 6) new therapeutics targeting airway and circulating immune mediators; and 7) lung anatomy, physiology and imaging. Discussions revealed that research groups are looking for opportunities to further their findings using larger scale collaboration and the ability to translate their in vitro findings into clinical treatment. Conclusions: Through ICAN, teams that included interdisciplinary early-stage career investigators discussed innovation, collaboration and translation in asthma and severe asthma research. With a combination of fresh ideas and energetic, collaborative, global participation, ICAN has laid a firm foundation and model for future collaborative global asthma research.

Efficacy of perturbation-based balance training in anterior cruciate ligament tears. A systematic review

Anterior cruciate ligament (ACL) tear is a serious and debilitating injury with significant physical, psychological, and socioeconomic consequences. Perturbation-based balance training (PBBT) is a type of neuromuscular training that involves the manipulation of mobile support surfaces, using controlled, unpredictable, multidirectional forces, in order to perturb the balance of the trained individual and thus improve the efficiency of muscle contraction patterns and the dynamic stability of the lower extremity joints. The aim of this review is to analyze the efficacy of the PBBT as a neuromuscular re-education method of choice for the recovery of functional capacity in individuals with ACL knee rupture. A systematic search was carried out in PubMed, Cinahl, Cochrane Library, Medline, PEDro Physiotherapy Evidence Database, Scopus, Web of Science and Sport Discus during January 2022. Only randomized clinical trials conducted in humans and published in English or Spanish were considered. The methodological quality was assessed using the PEDro scale and the risk of bias using the Risk-of-Bias tool of The Cochrane.12 studies were included. In 3 of them, the intervention with PBBT took place before ACL reconstruction, in 7 after ACL reconstruction and in 2 the subjects did not undergo surgical intervention. PBBT appears to be effective in the non-surgical recovery, improving joint stability and neuromuscular control. It was also effective as a preoperative treatment in normalizing knee excursion after ACL surgery. In contrast, the evidence does not support its efficacy as the neuromuscular re-education method of choice in the return-to-sport phase in previously operated athletes. (AU)

Menstrual Cycle and Sport Injuries: A Systematic Review.

The presence of female athletes has only increased in recent years, as has the incidence of injuries in female sports activities. These injuries are conditioned by multiple factors, including hormonal agents. It is estimated that the menstrual cycle may be related to the predisposition to suffer an injury. However, a causal relationship has not yet been established. The aim of this study was to analyse the relationship between the menstrual cycle and injuries in female sports practice. A systematic search of the scientific literature available in PubMed, Medline, Scopus, Web of Science, and Sport Discus was carried out in January 2022. With 138 articles, only eight studies were found that met the selection criteria for this study. Peak estradiol is associated with increased laxity, strength, and poor use of neuromuscular control. Thus, the ovulatory phase is associated with an increased risk of injury. In conclusion, it seems that hormonal fluctuations throughout the menstrual cycle alter values such as laxity, strength, body temperature, and neuromuscular control, among others. This fact causes women to constantly adapt to hormonal variations, which exposes them to a higher risk of injury.

Tackling the global impact of substandard and falsified and unregistered/unlicensed anti-tuberculosis medicines.

Substandard and falsified (SF) medicines are a global health challenge with the World Health Organization (WHO) estimating that 1 in 10 of medicines in low- and middle-income countries (LMICs) are SF. Antimicrobials (i.e. antimalarials, antibiotics) are the most commonly reported SF medicines. SF medicines contribute significantly to the global burden of infectious diseases and antimicrobial resistance (AMR). This article discusses the challenges associated with the global impact of SF and unregistered/unlicensed antimicrobials with a focus on anti-TB medicines. Tuberculosis (TB) is the 13th leading cause of death worldwide, and is currently the second leading cause of death from a single infectious agent, ranking after COVID-19 and above HIV/AIDS. Specifically in the case of TB, poor quality of anti-TB medicines is among the drivers of the emergence of drug-resistant TB pathogens. In this article, we highlight and discuss challenges including the emergence of SF associated AMR, patient mistrust and lack of relevant data. We also present study reports to inform meaningful change. Recommended solutions involve the adaptation of interventions from high-income countries (HICs) to LMICS, the need for improvement in the uptake of medication authentication tools in LMICs, increased stewardship, and the need for global and regional multidisciplinary legal and policy cooperation, resulting in improved legal sanctions.

Cellular and molecular mechanisms of IMMunE dysfunction and Recovery from SEpsis-related critical illness in adults: An observational cohort study (IMMERSE) protocol paper.

Sepsis is a common illness. Immune responses are considered major drivers of sepsis illness and outcomes. However, there are no proven immunomodulator therapies in sepsis. We hypothesised that in-depth characterisation of sepsis-specific immune trajectory may inform immunomodulation in sepsis-related critical illness. We describe the protocol of the IMMERSE study to address this hypothesis. We include critically ill sepsis patients without documented immune comorbidity and age-sex matched cardiac surgical patients as controls. We plan to perform an in-depth biological characterisation of innate and adaptive immune systems, platelet function, humoral components and transcriptional determinants of the immune system responses in sepsis. This will be done at pre-specified time points during their critical illness to generate an illness trajectory. The sample size for each biological assessment is different and is described in detail. In summary, the overall aim of the IMMERSE study is to increase the granularity of longitudinal immunology model of sepsis to inform future immunomodulation trials.

Drug repurposing based on a quantum-inspired method versus classical fingerprinting uncovers potential antivirals against SARS-CoV-2.

The COVID-19 pandemic has accelerated the need to identify new antiviral therapeutics at pace, including through drug repurposing. We employed a Quadratic Unbounded Binary Optimization (QUBO) model, to search for compounds similar to Remdesivir, the first antiviral against SARS-CoV-2 approved for human use, using a quantum-inspired device. We modelled Remdesivir and compounds present in the DrugBank database as graphs, established the optimal parameters in our algorithm and resolved the Maximum Weighted Independent Set problem within the conflict graph generated. We also employed a traditional Tanimoto fingerprint model. The two methods yielded different lists of lead compounds, with some overlap. While GS-6620 was the top compound predicted by both models, the QUBO model predicted BMS-986094 as second best. The Tanimoto model predicted different forms of cobalamin, also known as vitamin B12. We then determined the half maximal inhibitory concentration (IC50) values in cell culture models of SARS-CoV-2 infection and assessed cytotoxicity. We also demonstrated efficacy against several variants including SARS-CoV-2 Strain England 2 (England 02/2020/407073), B.1.1.7 (Alpha), B.1.351 (Beta) and B.1.617.2 (Delta). Lastly, we employed an in vitro polymerization assay to demonstrate that these compounds directly inhibit the RNA-dependent RNA polymerase (RdRP) of SARS-CoV-2. Together, our data reveal that our QUBO model performs accurate comparisons (BMS-986094) that differed from those predicted by Tanimoto (different forms of vitamin B12); all compounds inhibited replication of SARS-CoV-2 via direct action on RdRP, with both models being useful. While Tanimoto may be employed when performing relatively small comparisons, QUBO is also accurate and may be well suited for very complex problems where computational resources may limit the number and/or complexity of possible combinations to evaluate. Our quantum-inspired screening method can therefore be employed in future searches for novel pharmacologic inhibitors, thus providing an approach for accelerating drug deployment.

Homebrew: Protocol for glassmilk-based nucleic-acid extraction for SARS-CoV-2 diagnostics.

The gold standard protocol for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection detection remains reverse transcription quantitative polymerase chain reaction (qRT-PCR), which detects viral RNA more sensitively than any other approach. Here, we present Homebrew, a low-cost protocol to extract RNA using widely available reagents. Homebrew is as sensitive as commercially available RNA extraction kits. Homebrew allows for sample pooling and can be adapted for automation in high-throughput settings. For complete details on the use and execution of this protocol, please refer to Page et al. (2022).

¿Hay mejores parámetros diagnósticos de la luteinización precoz que el valor aislado de los niveles de progesterona o el cociente progesterona/es-tradiol el día de administración de hCG? / There are better parameters Diagnostics for premature luteinization thanisolate value of Progesterone level or progesterone/estradiol ratio on theday of hCG administration?

Objetivo: Tanto el valor absoluto de progesterona (P) como el cociente progesterona/estradiol (P/E)son utilizados para el diagnóstico de la luteinización precoz (LP), sin llegar a un acuerdo en el umbraladecuado y con resultados muy dispares en cuanto a su capacidad predictiva. El cociente P/E ha creadoademás una gran confusión entre el concepto de LP y la baja respuesta ovárica a la hiperestimulación.La única alternativa viable es encontrar un parámetro que resulte independiente del grado de respuestaovárica y los valores de estradiol.Método:Se analizaron 434 ciclos consecutivos de FIV con estimulación mediante FSH y/o LH y fre-nado hipofisario con agonistas o antagonistas de GnRH sin ningún tipo de criterio de exclusión previopara determinar la relación matemática existente entre progesterona y estradiol en el momento previoa la ovulación.Resultados:La relación empírica entre progesterona y estradiol viene establecida por la fórmula E=4P2,de la que podemos deducir las fórmulas descriptivas de P=0,5E0,5, P/E=0,5E-0,5 y P2/E=0,25, siendoP2/E la única que corresponde a una constante sin dependencia del nivel de estradiol y, por tanto, el cri-terio ideal para el diagnóstico de LP. (AU)

Introduction: Both the absolute value of progesterone (P) and the progesterone/estradiol ratio (P/E) are used for the diag-nosis of early luteinization (EL), without reaching an agreement on the appropriate threshold and with very differentresults in terms of its predictive ability. The P/E ratio has also created a great deal of confusion between the concept of LPand low ovarian response to hyperstimulation. The objective of this study is to find a parameter that is independent of the degree of ovarian response and estradiol va-lues.Methods: We analyzed 434 consecutive IVF cycles with FSH and/or LH stimulation and pituitary down regulation withagonist or antagonists without any prior exclusion criteria to determine the mathematical relationship between progesteroneand estradiol at the time prior to ovulation.Results: The empirical relationship between progesterone and estradiol is established by the formula E=4P2, from whichwe can deduce the descriptive formulas of P=0,5E0,5, P/E=0,5E-0,5 an P2/E=0,25, being P2/E the only one that corres-ponds to a constant without dependence on the estradiol level and, therefore, the ideal criterion for the diagnosis of early. (AU)

Homebrew: An economical and sensitive glassmilk-based nucleic-acid extraction method for SARS-CoV-2 diagnostics.

Management of COVID-19 and other epidemics requires large-scale diagnostic testing. The gold standard for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains reverse transcription quantitative PCR (qRT-PCR) analysis, which detects viral RNA more sensitively than any other method. However, the resource use and supply-chain requirements of RT-PCR have continued to challenge diagnostic laboratories worldwide. Here, we establish and characterize a low-cost method to detect SARS-CoV-2 in clinical combined nose and throat swabs, allowing for automation in high-throughput settings. This method inactivates virus material with sodium dodecylsulfate (SDS) and uses silicon dioxide as the RNA-binding matrix in combination with sodium chloride (NaCl) and isopropanol. With similar sensitivity for SARS-CoV-2 viral targets but a fraction of time and reagent expenditure compared with commercial kits, our method also enables sample pooling without loss of sensitivity. We suggest that this method will facilitate more economical widespread testing, particularly in resource-limited settings.

miR-155-overexpressing monocytes resemble HLAhighISG15+ synovial tissue macrophages from patients with rheumatoid arthritis and induce polyfunctional CD4+ T-cell activation.

MicroRNAs (miRs) are known to regulate pro-inflammatory effector functions of myeloid cells, and miR dysregulation is implicated in rheumatoid arthritis (RA), a condition characterized by inflammation and destruction of the joints. We showed previously that miR-155 is increased in myeloid cells in RA and induces pro-inflammatory activation of monocytes and macrophages; however, its role at the interface between innate and adaptive immunity was not defined. Here, RNA-sequencing revealed that overexpression of miR-155 in healthy donor monocytes conferred a specific gene profile which bears similarities to that of RA synovial fluid-derived CD14+ cells and HLAhighISG15+ synovial tissue macrophages, both of which are characterized by antigen-presenting pathways. In line with this, monocytes in which miR-155 was overexpressed, displayed increased expression of HLA-DR and both co-stimulatory and co-inhibitory molecules, and induced activation of polyfunctional T cells. Together, these data underpin the notion that miR-155-driven myeloid cell activation in the synovium contributes not only to inflammation but may also influence the adaptive immune response.

Resilient SARS-CoV-2 diagnostics workflows including viral heat inactivation.

There is a worldwide need for reagents to perform SARS-CoV-2 detection. Some laboratories have implemented kit-free protocols, but many others do not have the capacity to develop these and/or perform manual processing. We provide multiple workflows for SARS-CoV-2 nucleic acid detection in clinical samples by comparing several commercially available RNA extraction methods: QIAamp Viral RNA Mini Kit (QIAgen), RNAdvance Blood/Viral (Beckman) and Mag-Bind Viral DNA/RNA 96 Kit (Omega Bio-tek). We also compared One-step RT-qPCR reagents: TaqMan Fast Virus 1-Step Master Mix (FastVirus, ThermoFisher Scientific), qPCRBIO Probe 1-Step Go Lo-ROX (PCR Biosystems) and Luna® Universal Probe One-Step RT-qPCR Kit (Luna, NEB). We used primer-probes that detect viral N (EUA CDC) and RdRP. RNA extraction methods provided similar results, with Beckman performing better with our primer-probe combinations. Luna proved most sensitive although overall the three reagents did not show significant differences. N detection was more reliable than that of RdRP, particularly in samples with low viral titres. Importantly, we demonstrated that heat treatment of nasopharyngeal swabs at 70°C for 10 or 30 min, or 90°C for 10 or 30 min (both original variant and B 1.1.7) inactivated SARS-CoV-2 employing plaque assays, and had minimal impact on the sensitivity of the qPCR in clinical samples. These findings make SARS-CoV-2 testing portable in settings that do not have CL-3 facilities. In summary, we provide several testing pipelines that can be easily implemented in other laboratories and have made all our protocols and SOPs freely available at https://osf.io/uebvj/.

Control inadecuado del dolor agudo postoperatorio: prevalencia, prevención y consecuencias. Revisión de la situación en Latinoamérica / Inadequate management of acute postoperative pain: prevalence, prevention, and consequences. Review of the situation in Latin America

Resumen: Introducción: El dolor postoperatorio tiene un alto impacto, es una de las principales causas médicas de retraso en el alta hospitalaria. Asimismo, es causa frecuente de readmisión hospitalaria, retrasos en la recuperación y mayores costos para el sistema de salud y los pacientes. El objetivo del presente trabajo es conocer mejor la situación del dolor agudo postoperatorio en Latinoamérica mediante una revisión bibliográfica para poder establecer su prevalencia y evaluar su magnitud. Material y métodos: Se efectuó una búsqueda bibliográfica en SciELO y PubMed tratando de recopilar la información más detallada, precisa y actualizada. Resultados: En Latinoamérica la falta de políticas claras para la evaluación y el tratamiento del dolor postoperatorio, así como de formación, conduce a un control inadecuado del mismo con una prevalencia de dolor agudo postoperatorio moderado/severo superior a 40%. Conclusiones: El manejo del dolor agudo postoperatorio continúa siendo un problema en Latinoamérica. Muchos pacientes refieren dolor moderado o severo tras la cirugía, lo que puede conducir a dolor crónico. Se necesitan más estudios al respecto para poder establecer aún con mayor precisión la prevalencia del dolor agudo postoperatorio y los efectos derivados de su pobre control.

Abstract: Introduction: Postoperative pain has a profound impact. It is one of the main causes of delayed hospital discharge and it is associated with hospital readmission, recovery problems, and higher costs both for the healthcare system and the patients. The aim of this work is to shed light on the postoperative acute pain management in Latin America through a review of the literature, in order to have a better understanding of its prevalence and the extent of the problem. Material and methods: A bibliographical search was performed in SciELO and PubMed trying to gather the most precise, detailed and updated information. Results: In Latin America, the absence of clear policies for the evaluation and treatment of postoperative pain, as well as the lack of training, leads to its inadequate control with a prevalence of moderate/severe acute postoperative pain greater than 40%. Conclusions: Postoperative acute pain continues to be a problem in Latin America. Many patients still suffer moderate to severe pain after surgery, leading to a chronic or persistent painful condition. More studies are needed to get a clear picture of the prevalence of acute postoperative pain and the deleterious effects of an inadequate management.

Drug repurposing based on a Quantum-Inspired method versus classical fingerprinting uncovers potential antivirals against SARS-CoV-2 including vitamin B12.

The COVID-19 pandemic has accelerated the need to identify new therapeutics at pace, including through drug repurposing. We employed a Quadratic Unbounded Binary Optimization (QUBO) model, to search for compounds similar to Remdesivir (RDV), the only antiviral against SARS-CoV-2 currently approved for human use, using a quantum-inspired device. We modelled RDV and compounds present in the DrugBank database as graphs, established the optimal parameters in our algorithm and resolved the Maximum Weighted Independent Set problem within the conflict graph generated. We also employed a traditional Tanimoto fingerprint model. The two methods yielded different lists of compounds, with some overlap. While GS-6620 was the top compound predicted by both models, the QUBO model predicted BMS-986094 as second best. The Tanimoto model predicted different forms of cobalamin, also known as vitamin B12. We then determined the half maximal inhibitory concentration (IC 50 ) values in cell culture models of SARS-CoV-2 infection and assessed cytotoxicity. Lastly, we demonstrated efficacy against several variants including SARS-CoV-2 Strain England 2 (England 02/2020/407073), B.1.1.7 (Alpha), B.1.351 (Beta) and B.1.617.2 (Delta). Our data reveal that BMS-986094 and different forms of vitamin B12 are effective at inhibiting replication of all these variants of SARS-CoV-2. While BMS-986094 can cause secondary effects in humans as established by phase II trials, these findings suggest that vitamin B12 deserves consideration as a SARS-CoV-2 antiviral, particularly given its extended use and lack of toxicity in humans, and its availability and affordability. Our screening method can be employed in future searches for novel pharmacologic inhibitors, thus providing an approach for accelerating drug deployment.

Resilient SARS-CoV-2 diagnostics workflows including viral heat inactivation.

There is a worldwide need for reagents to perform SARS-CoV-2 detection. Some laboratories have implemented kit-free protocols, but many others do not have the capacity to develop these and/or perform manual processing. We provide multiple workflows for SARS-CoV-2 nucleic acid detection in clinical samples by comparing several commercially available RNA extraction methods: QIAamp Viral RNA Mini Kit (QIAgen), RNAdvance Blood/Viral (Beckman) and Mag-Bind Viral DNA/RNA 96 Kit (Omega Bio-tek). We also compared One-step RT-qPCR reagents: TaqMan Fast Virus 1-Step Master Mix (FastVirus, ThermoFisher Scientific), qPCRBIO Probe 1-Step Go Lo-ROX (PCR Biosystems) and Luna ® Universal Probe One-Step RT-qPCR Kit (Luna, NEB). We used primer-probes that detect viral N (EUA CDC) and RdRP (PHE guidelines). All RNA extraction methods provided similar results. FastVirus and Luna proved most sensitive. N detection was more reliable than that of RdRP, particularly in samples with low viral titres. Importantly, we demonstrate that treatment of nasopharyngeal swabs with 70 degrees for 10 or 30 min, or 90 degrees for 10 or 30 min (both original variant and B 1.1.7) inactivates SARS-CoV-2 employing plaque assays, and that it has minimal impact on the sensitivity of the qPCR in clinical samples. These findings make SARS-CoV-2 testing portable to settings that do not have CL-3 facilities. In summary, we provide several testing pipelines that can be easily implemented in other laboratories and have made all our protocols and SOPs freely available at https://osf.io/uebvj/ .