Favipiravir for Treatment of Outpatients With Asymptomatic or Uncomplicated Coronavirus Disease 2019: A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Trial.

BACKGROUND: Favipiravir, an oral, RNA-dependent RNA polymerase inhibitor, has in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite limited data, favipiravir is administered to patients with coronavirus disease 2019 (COVID-19) in several countries. METHODS: We conducted a phase 2, double-blind, randomized controlled outpatient trial of favipiravir in asymptomatic or mildly symptomatic adults with a positive SARS-CoV-2 reverse-transcription polymerase chain reaction assay (RT-PCR) within 72 hours of enrollment. Participants were randomized to receive placebo or favipiravir (1800 mg twice daily [BID] day 1, 800 mg BID days 2-10). The primary outcome was SARS-CoV-2 shedding cessation in a modified intention-to-treat (mITT) cohort of participants with positive enrollment RT-PCRs. Using SARS-CoV-2 amplicon-based sequencing, we assessed favipiravir's impact on mutagenesis. RESULTS: We randomized 149 participants with 116 included in the mITT cohort. The participants' mean age was 43 years (standard deviation, 12.5 years) and 57 (49%) were women. We found no difference in time to shedding cessation overall (hazard ratio [HR], 0.76 favoring placebo [95% confidence interval {CI}, .48-1.20]) or in subgroups (age, sex, high-risk comorbidities, seropositivity, or symptom duration at enrollment). We detected no difference in time to symptom resolution (initial: HR, 0.84 [95% CI, .54-1.29]; sustained: HR, 0.87 [95% CI, .52-1.45]) and no difference in transition mutation accumulation in the viral genome during treatment. CONCLUSIONS: Our data do not support favipiravir at commonly used doses in outpatients with uncomplicated COVID-19. Further research is needed to ascertain if higher favipiravir doses are effective and safe for patients with COVID-19. CLINICAL TRIALS REGISTRATION: NCT04346628.

June: open-source individual-based epidemiology simulation.

We introduce June, an open-source framework for the detailed simulation of epidemics on the basis of social interactions in a virtual population constructed from geographically granular census data, reflecting age, sex, ethnicity and socio-economic indicators. Interactions between individuals are modelled in groups of various sizes and properties, such as households, schools and workplaces, and other social activities using social mixing matrices. June provides a suite of flexible parametrizations that describe infectious diseases, how they are transmitted and affect contaminated individuals. In this paper, we apply June to the specific case of modelling the spread of COVID-19 in England. We discuss the quality of initial model outputs which reproduce reported hospital admission and mortality statistics at national and regional levels as well as by age strata.

The IRE1 pathway regulates honey bee Unfolded Protein Response gene expression.

Our molecular understanding of honey bee cellular stress responses is incomplete. Previously, we sought to identify and began functional characterization of the components of the Unfolded Protein Response (UPR) in honey bees. We observed that UPR stimulation resulted in induction of target genes upon IRE1 pathway activation, as assessed by splicing of Xbp1 mRNA. However, we were not able to determine the relative role of the various UPR pathways in gene activation. Our understanding of honey bee signal transduction and transcriptional regulation has been hampered by a lack of tools. After using RNA-seq to expand the known UPR targets in the honey bee, we used the Drosophila melanogaster S2 cell line and honey bee trans and cis elements to investigate the role of the IRE1 pathway in the transcriptional activation of one of these targets, the honey bee Hsc70-3 gene. Using a luciferase reporter, we show that honey bee Hsc70 promoter activity is inducible by UPR activation. In addition, we show that this activation is IRE1-dependent and relies on specific cis regulatory elements. Experiments using exogenous honey bee or fruit fly XBP1S proteins demonstrate that both factors can activate the Hsc70-3 promoter and further support a role for the IRE1 pathway in control of Hsc70-3 expression in the honey bee. By providing foundational knowledge about the UPR in the honey bee and demonstrating the usefulness of a heterologous cell line for molecular characterization of honey bee pathways, this work stands to improve our understanding of this critical species.

The heat shock response and humoral immune response are mutually antagonistic in honey bees.

The honey bee is of paramount importance to humans in both agricultural and ecological settings. Honey bee colonies have suffered from increased attrition in recent years, stemming from complex interacting stresses. Defining common cellular stress responses elicited by these stressors represents a key step in understanding potential synergies. The proteostasis network is a highly conserved network of cellular stress responses involved in maintaining the homeostasis of protein production and function. Here, we have characterized the Heat Shock Response (HSR), one branch of this network, and found that its core components are conserved. In addition, exposing bees to elevated temperatures normally encountered by honey bees during typical activities results in robust HSR induction with increased expression of specific heat shock proteins that was variable across tissues. Surprisingly, we found that heat shock represses multiple immune genes in the abdomen and additionally showed that wounding the cuticle of the abdomen results in decreased expression of multiple HSR genes in proximal and distal tissues. This mutually antagonistic relationship between the HSR and immune activation is unique among invertebrates studied to date and may promote understanding of potential synergistic effects of disparate stresses in this critical pollinator and social insects more broadly.

Self-management goal setting: identifying the practice patterns of community-based physical therapists.

PURPOSE: To describe the collaborative goal-setting practices of community-based physical therapists trained in a self-management (SM) approach who work with clients with chronic conditions and to describe clients' goal-achievement rates. Methods : A retrospective chart review was conducted for 296 randomly selected home-care clients from July 2009 through July 2010 using a chart-abstraction form created to capture demographic data and information related to goal setting and achievement. Data were analyzed using frequencies, percentages, and Pearson's chi-square tests. RESULTS: There was no significant relationship between sex, age, or number of chronic conditions and setting SM or non-self-management (NSM) goals or the type of SM goal set. The majority of goals set were "action" as opposed to "verbal" goals. A high proportion (89-100%) of both SM and NSM goals were met. CONCLUSIONS: Clinicians should be aware that it is possible to set SM goals regardless of the client's sex, age, or number of chronic conditions. Other possible influences on goal setting, such as severity of chronic conditions and challenges of the health care system, should be further investigated.

Objectif : Décrire les méthodes d'établissement d'objectifs en collaboration des physiothérapeutes communautaires qui ont reçu une formation en autogestion et qui travaillent avec des clients vivant avec un problème chronique et décrire les taux d'atteinte des objectifs chez les clients. Méthodes : On a procédé à un examen rétrospectif des dossiers de 296 clients de services de soins à domicile choisis au hasard entre juillet 2009 et juillet 2010 en utilisant un résumé de dossier créé pour saisir des données démographiques et des renseignements portant sur l'établissement et l'atteinte d'objectifs. On a analysé les données en utilisant les fréquences, les pourcentages et des tests chi-carré de Pearson. Résultats : Il n'y avait pas de lien significatif entre le sexe, l'âge ou le nombre de problèmes chroniques et l'établissement d'objectifs liés ou non à l'autogestion, ou les types d'objectifs liés à l'autogestion établis. La majorité des objectifs établis portaient sur « l'action ¼ plutôt que sur le « verbe ¼. Un pourcentage élevé (89 à 100 %) des deux types d'objectifs a été atteint. Conclusions : Les cliniciens devraient savoir qu'il est possible d'établir des objectifs liés à l'autogestion sans égard au sexe, à l'âge ou au nombre de problèmes chroniques du client. Il convient d'étudier plus à fond d'autres facteurs qui peuvent avoir une influence sur l'établissement d'objectifs comme la gravité des problèmes chroniques et les défis posés au système de santé.

Cardiac arrest with residual blindness after overdose of Tessalon® (benzonatate) perles.

BACKGROUND: The extent to which benzonatate (Tessalon®), a structurally similar agent to other local anesthetics including tetracaine and procaine, poses a risk to the public is not fully appreciated as it is still one of the most widely prescribed antitussives available. OBJECTIVES: To report a case of cardiac arrest with residual blindness after Tessalon® overdose, review its clinical manifestations, toxicology and management considerations, and describe the need for rational prescribing. CASE REPORT: A 17-year-old woman with no previous medical history presented to the Emergency Department (ED) status post cardiac arrest. One to two hours prior, the patient had ingested at least 10 200-mg Tessalon® capsules as part of a suicide attempt. The patient was sedated, intubated, and given magnesium as prophylaxis against recurrent dysrhythmias. Emergent gastric lavage was performed and well tolerated. A 24-h hypothermia protocol with 6-h cooling period was initiated. Toxicological studies, chest radiograph, and a computed tomography scan of the head were all unremarkable. The patient was admitted to the Pediatric Intensive Care Unit for further work-up and supportive care. The patient was extubated and able to follow some commands 1 week post-admission. The patient developed blindness and experienced generalized confabulations, which did not resolve. CONCLUSION: Ingestion of Tessalon®, a seemingly innocuous and widely prescribed antitussive, may pose a risk to patients due to its potential for the rapid development of life-threatening adverse events and limited treatment options in the overdose setting. Rational prescribing and patient education is needed.

Detection of recombinant human erythropoietin in urine by isoelectric focusing.

BACKGROUND: Doping with erythropoietic proteins such as recombinant human erythropoietin (rHuEPO) and darbepoetin alfa is a serious issue in sport. There is little information on the time course of detection of rHuEPO in urine and on methods to evaluate electrophoresis-based data. METHODS: We used a recently described isoelectric focusing method for detecting rHuEPO and endogenous EPO in urine obtained from individuals treated with placebo or epoetin alfa. The latter was administered subcutaneously at 50 IU/kg on days 0, 2, 4, 7, 9, 11, 14, 16, and 18. Blood and urine samples were collected during the morning of study days -3, 0, 2, 4, 7, 9, 11, 14, 16, and 18 and on days 2, 3, 4, and 7 postadministration. We developed visual and numerical (two-band ratio) techniques to evaluate the electropherograms for the presence of rHuEPO. RESULTS: Compared with the placebo group, the epoetin alfa-treated group responded with increases in hematocrit, reticulocytes, macrocytes, serum EPO, and serum soluble transferrin receptor. The electropherograms showed that the pattern of bands arising from urinary rHuEPO is different from that of endogenous urinary EPO. Both the two-band ratio and the visual technique detected rHuEPO in all 14 epoetin alfa-treated individuals 3 days after the last dose. On the 7th day after the last dose, both techniques detected rHuEPO in approximately one-half of the participants. rHuEPO was not detected in the placebo-treated individuals. CONCLUSIONS: The isoelectric focusing method detects rHuEPO in most urine samples collected 3 days after nine doses of epoetin alfa. The numerical two-band ratio was equivalent to a visual method for detecting rHuEPO in urine.