Proteomic profiling identifies biomarkers of COVID-19 severity.

SARS-CoV-2 infection remains a major public health concern, particularly for the aged and those individuals with co-morbidities at risk for developing severe COVID-19. Understanding the pathogenesis and biomarkers associated with responses to SARS-CoV-2 infection remain critical components in developing effective therapeutic approaches, especially in cases of severe and long-COVID-19. In this study blood plasma protein expression was compared in subjects with mild, moderate, and severe COVID-19 disease. Evaluation of an inflammatory protein panel confirms upregulation of proteins including TNFß, IL-6, IL-8, IL-12, already associated with severe cytokine storm and progression to severe COVID-19. Importantly, we identify several proteins not yet associated with COVID-19 disease, including mesothelin (MSLN), that are expressed at significantly higher levels in severe COVID-19 subjects. In addition, we find a subset of markers associated with T-cell and dendritic cell responses to viral infection that are significantly higher in mild cases and decrease in expression as severity of COVID-19 increases, suggesting that an immediate and effective activation of T-cells is critical in modulating disease progression. Together, our findings identify new targets for further investigation as therapeutic approaches for the treatment of SARS-CoV-2 infection and prevention of complications of severe COVID-19.

Sorafenib inhibits invasion of multicellular organoids that mimic Lymphangioleiomyomatosis nodules.

Lymphangioleiomyomatosis (LAM) is a debilitating, progressive lung disease with few therapeutic options, largely due to a paucity of mechanistic knowledge of disease pathogenesis. Lymphatic endothelial cells (LECs) are known to envelope and invade clusters of LAM-cells, comprising of smooth muscle α-actin and/or HMB-45 positive "smooth muscle-like cells" however the role of LECs in LAM pathogenesis is still unknown. To address this critical knowledge gap, we investigated wether LECs interact with LAM-cells to augment their metastatic behaviour of LAM-cells. We performed in situ spatialomics and identified a core of transcriptomically related cells within the LAM nodules. Pathway analysis highlights wound and pulmonary healing, VEGF signaling, extracellular matrix/actin cytoskeletal regulating and the HOTAIR regulatory pathway enriched in the LAM Core cells. We developed an organoid co-culture model combining primary LAM-cells with LECs and applied this to evaluate invasion, migration, and the impact of Sorafenib, a multi-kinase inhibitor. LAM-LEC organoids had significantly higher extracellular matrix invasion, decreased solidity and a greater perimeter, reflecting increased invasion compared to non-LAM control smooth muscle cells. Sorafenib significantly inhibited this invasion in both LAM spheroids and LAM-LEC organoids compared to their respective controls. We identified TGFß1ι1, a molecular adapter coordinating protein-protein interactions at the focal adhesion complex and known to regulate VEGF, TGFß and Wnt signalling, as a Sorafenib-regulated kinase in LAM-cells. In conclusion we have developed a novel 3D co-culture LAM model and have demonstrated the effectiveness of Sorafenib to inhibit LAM-cell invasion, identifying new avenues for therapeutic intervention.

Basic Science Perspective on Engineering and Modeling the Large Airways.

The airway epithelium provides a physical and biochemical barrier playing a key role in protecting the lung from infiltration of pathogens and irritants and is, therefore, crucial in maintaining tissue homeostasis and regulating innate immunity. Due to continual inspiration and expiration of air during breathing, the epithelium is exposed to a plethora of environmental insults. When severe or persistent, these insults lead to inflammation and infection. The effectiveness of the epithelium as a barrier is reliant upon its capacity for mucociliary clearance, immune surveillance, and regeneration upon injury. These functions are accomplished by the cells that comprise the airway epithelium and the niche in which they reside. Engineering of new physiological and pathological models of the proximal airways requires the generation of complex structures comprising the surface airway epithelium, submucosal gland epithelium, extracellular matrix, and niche cells, including smooth muscle cells, fibroblasts, and immune cells. This chapter focuses on the structure-function relationships in the airways and the challenges of developing complex engineered models of the human airway.

Proteomic profiling identifies biomarkers of COVID-19 severity

Abstract/SummarySARS-CoV-2 infection remains a major public health concern, particularly for the aged and those individuals with co-morbidities at risk for developing severe COVID-19. Understanding the pathogenesis and biomarkers associated with responses to SARS-CoV-2 infection remain critical components in developing effective therapeutic approaches, especially in cases of severe and long-COVID-19. In this study blood plasma protein expression was compared in subjects with mild, moderate, and severe COVID-19 disease. Evaluation of an inflammatory protein panel confirms upregulation of proteins including TNF{beta}, IL-6, IL-8, IL-12, already associated with severe cytokine storm and progression to severe COVID-19. Importantly, we identify several proteins not yet associated with COVID-19 disease, including mesothelin (MSLN), that are expressed at significantly higher levels in severe COVID-19 subjects. In addition, we find a subset of markers associated with T-cell and dendritic cell responses to viral infection that are significantly higher in mild cases and decrease in expression as severity of COVID-19 increases, suggesting that an immediate and effective activation of T-cells is critical in modulating disease progression. Together, our findings identify new targets for further investigation as therapeutic approaches for the treatment of SARS-CoV-2 infection and prevention of complications of severe COVID-19.

A mixed-methods study on evaluating an updated, francophone version of ETAT+ training in Madagascar.

Background: Madagascar needs major efforts to achieve the UN Sustainable Development Goals, despite the considerable reduction of child mortality during past years. In this context, implementation of emergency triage assessment and treatment (ETAT) plays an important role. In recent years, ETAT training activities rarely took place in Madagascar. To strengthen ETAT in Madagascar, a pilot training course was conducted in December 2019 at the University Hospital Mahajanga. Objectives: This study aims to evaluate if the ETAT+ pilot training content matches clinical needs in Madagascar and whether participants achieved their learning objectives. Methods: In this cross-sectional mixed-methods study, a 41-item questionnaire was used at the end of the ETAT+ training to evaluate their learning experience from the 12 participants (paediatricians, physicians, nurses and midwives). Six weeks after the training, guided interviews were conducted among five participants to describe how training content could be transferred into clinical practice in five health facilities. Results: Results suggest that this pilot project designed to contribute to the re-establishment of ETAT in Madagascar meets participants' needs and is adapted to clinical realities in terms of transmitted knowledge, skills and competencies. However, results also show that considerable multi-disciplinary efforts are needed to advance ETAT+ implementation in Madagascar. Conclusion: Implementation processes of ETAT training programmes need re-evaluation to assure their validity to contribute to quality of care improvements efficiently. Further operational research is required to evaluate sustainable, innovative implementation strategies adapted to contexts in Madagascar. Contributions of the study: This study aims to evaluate an updated Malagasy version of the Emergency Triage Assessment and Treatment Plus (ETAT+). The training met the participants' needs and was adapted to the clinical realities in Madagascar relating to transmitted knowledge, skills and competencies.

Current fluctuations in nonequilibrium discontinuous phase transitions.

Discontinuous phase transitions out of equilibrium can be characterized by the behavior of macroscopic stochastic currents. But while much is known about the average current, the situation is much less understood for higher statistics. In this paper, we address the consequences of the diverging metastability lifetime-a hallmark of discontinuous transitions-in the fluctuations of arbitrary thermodynamic currents, including the entropy production. In particular, we center our discussion on the conditional statistics, given which phase the system is in. We highlight the interplay between integration window and metastability lifetime, which is not manifested in the average current, but strongly influences the fluctuations. We introduce conditional currents and find, among other predictions, their connection to average and scaled variance through a finite-time version of large deviation theory and a minimal model. Our results are then further verified in two paradigmatic models of discontinuous transitions: Schlögl's model of chemical reactions, and a 12-state Potts model subject to two baths at different temperatures.

Acute Pyelonephritis in Adults: Rapid Evidence Review.

Acute pyelonephritis is a bacterial infection of the kidney and renal pelvis and should be suspected in patients with flank pain and laboratory evidence of urinary tract infection. Urine culture with antimicrobial susceptibility testing should be performed in all patients and used to direct therapy. Imaging, blood cultures, and measurement of serum inflammatory markers should not be performed in uncomplicated cases. Outpatient management is appropriate in patients who have uncomplicated disease and can tolerate oral therapy. Extended emergency department or observation unit stays are an appropriate option for patients who initially warrant intravenous therapy. Fluoroquinolones and trimethoprim/sulfamethoxazole are effective oral antibiotics in most cases, but increasing resistance makes empiric use problematic. When local resistance to a chosen oral antibiotic likely exceeds 10%, one dose of a long-acting broad-spectrum parenteral antibiotic should also be given while awaiting susceptibility data. Patients admitted to the hospital should receive parenteral antibiotic therapy, and those with sepsis or risk of infection with a multidrug-resistant organism should receive antibiotics with activity against extended-spectrum beta-lactamase-producing organisms. Most patients respond to appropriate management within 48 to 72 hours, and those who do not should be evaluated with imaging and repeat cultures while alternative diagnoses are considered. In cases of concurrent urinary tract obstruction, referral for urgent decompression should be pursued. Pregnant patients with pyelonephritis are at significantly elevated risk of severe complications and should be admitted and treated initially with parenteral therapy.

Entropy production as a tool for characterizing nonequilibrium phase transitions.

Nonequilibrium phase transitions can be typified in a similar way to equilibrium systems, for instance, by the use of the order parameter. However, this characterization hides the irreversible character of the dynamics as well as its influence on the phase transition properties. Entropy production has been revealed to be an important concept for filling this gap since it vanishes identically for equilibrium systems and is positive for the nonequilibrium case. Based on distinct and general arguments, the characterization of phase transitions in terms of the entropy production is presented. Analysis for discontinuous and continuous phase transitions has been undertaken by taking regular and complex topologies within the framework of mean-field theory (MFT) and beyond the MFT. A general description of entropy production portraits for Z_{2} ("up-down") symmetry systems under the MFT is presented. Our main result is that a given phase transition, whether continuous or discontinuous has a specific entropy production hallmark. Our predictions are exemplified by an icon system, perhaps the simplest nonequilibrium model presenting an order-disorder phase transition and spontaneous symmetry breaking: the majority vote model. Our work paves the way to a systematic description and classification of nonequilibrium phase transitions through a key indicator of system irreversibility.

Etiological characterization of 512 severely mentally retarded institutionalized patients in havana.

OBJECTIVE: To investigate etiological factors in severe mental retardation (SMR). METHODS: An etiological study is presented of 512 SMR patients in five specialized institutions in Havana. RESULTS: Prenatal, perinatal and postnatal causes were apparent in 58.0, 24.8 and 11.1% of the patients, respectively; infantile psychosis was determined in only 0.4%. The remaining 5.6% were classified as having SMR of undeterminable origin, i.e. patients with apparently normal pre-, peri- and postnatal histories who had neither dysmorphism nor affected first-degree relatives, and had a normal karyotype and metabolic screen. Among prenatal causes, genetic factors were the most frequent (82.8%), while environmental factors were apparent in only 5.3% of these cases. Of the cases with prenatal genetic etiology, chromosomal aberrations were present in 86.5% (Down syndrome 96.2% and 3.7% other chromosomal aberrations), monogenic disorders in 11.3% [neurocutaneous diseases (32.1%) and fragile X syndrome (25%) were the most frequent], and multifactorial disorders in 2.0%. Thirty-five patients (11.7%) presented multiple congenital anomalies of 'prenatal unknown' causes. The latter group may include unidentifiable chromosomal aberrations, uniparental disomy, de novo mutations and multifactorial or teratogenic factors. CONCLUSION: Accurate determination of the etiology of SMR is important not only for genetic counseling purposes, but also in identifying prenatal events which make infants more vulnerable to perinatal risk factors.