Citations

Abstract Background It is unclear how acute coronavirus disease 2019 (COVID-19)-directed therapies are used in children with life-threatening COVID-19 in US hospitals. We described characteristics of children hospitalized in the intensive care unit or step-down unit (ICU/SDU) who received COVID-19-directed therapies and the specific therapies administered. Methods Between March 15, 2020 and December 27, 2020, children <18 years of age in the ICU/SDU with acute COVID-19 at 48 pediatric hospitals in the United States were identified. Demographics, laboratory values, and clinical course were compared in children who did and did not receive COVID-19-directed therapies. Trends in COVID-19-directed therapies over time were evaluated. Results Of 424 children in the ICU/SDU, 235 (55%) received COVID-19-directed therapies. Children who received COVID-19-directed therapies were older than those who did not receive COVID-19-directed therapies (13.3 [5.6-16.2] vs 9.8 [0.65-15.9] years), more had underlying medical conditions (188 [80%] vs 104 [55%]; difference = 25% [95% CI: 16% to 34%]), more received respiratory support (206 [88%] vs 71 [38%]; difference = 50% [95% CI: 34% to 56%]), and more died (8 [3.4%] vs 0). Of the 235 children receiving COVID-19-directed therapies, 172 (73%) received systemic steroids and 150 (64%) received remdesivir, with rising remdesivir use over the study period (14% in March/April to 57% November/December). Conclusion Despite the lack of pediatric data evaluating treatments for COVID-19 in critically ill children, more than half of children requiring intensive or high acuity care received COVID-19-directed therapies.

Abstract New gene-editing tools challenge conventional policy proscriptions of research aimed at either human germline gene editing or human enhancement by potentially lowering technical barriers to both kinds of intervention. Some recent gene-editing reports have begun to take up the prospect of germline editing, but most experts are in broad agreement that research should prioritize medical applications over attempts to enhance human traits. However, there is little consensus about what counts as human enhancement in this context, or how to deal with the issues it flags. Moreover, several influential reports interpret medical applications to include disease prevention as well as treatment as a goal for gene-editing research. This challenges the current policy consensus because using gene editing to prevent disease would incidentally facilitate human enhancement applications in a variety of ways. If such research efforts are penalized by policy concerns about enhancement, then their preventive health benefits could be lost. To avoid being caught off guard by such challenges, science policy makers will need to think more carefully about what “prevention” might mean in the gene-editing context, and develop research governance that can anticipate and address the human enhancement concerns it will raise. To accomplish the latter, the scope of policy making will need to expand from its narrow focus on human clinical trials to engage with basic researchers driving the translational pipeline toward preventive gene editing and the science policy makers who have to address its “off-label” uses.

Introduction and hypothesis There has been an increasing need for the terminology on the conservative management of female pelvic floor dysfunction to be collated in a clinically based consensus report. Methods This Report combines the input of members and elected nominees of the Standardization and Terminology Committees of two International Organizations, the International Urogynecological Association (IUGA) and the International Continence Society (ICS), assisted at intervals by many external referees. An extensive process of nine rounds of internal and external review was developed to exhaustively examine each definition, with decision‐making by collective opinion (consensus). Before opening up for comments on the webpages of ICS and IUGA, five experts from physiotherapy, neurology, urology, urogynecology, and nursing were invited to comment on the paper. Results A Terminology Report on the conservative management of female pelvic floor dysfunction, encompassing over 200 separate definitions, has been developed. It is clinically based, with the most common symptoms, signs, assessments, diagnoses, and treatments defined. Clarity and ease of use have been key aims to make it interpretable by practitioners and trainees in all the different specialty groups involved in female pelvic floor dysfunction. Ongoing review is not only anticipated, but will be required to keep the document updated and as widely acceptable as possible. Conclusion A consensus‐based terminology report for the conservative management of female pelvic floor dysfunction has been produced, aimed at being a significant aid to clinical practice and a stimulus for research.

Significance Ubiquitin-specific protease 6 (USP6) is a deubiquitylase that is overexpressed by chromosome translocation in two human neoplasms, aneurysmal bone cyst and nodular fasciitis. The relevant substrates of this ubiquitin-specific protease are not clear. Here, we identify the Wnt receptor Frizzled (Fzd) as a key target of the USP6 oncogene. Increased expression of USP6 increases the membrane abundance of Fzd, and hence increases cellular sensitivity to Wnts. USP6 opposes the activity of the ubiquitin ligase and tumor suppressor ring finger protein 43 (RNF43). This study identifies a new mechanism for pathological Wnt pathway activation in human disease and suggests a new approach to regulate Wnt activity therapeutically.