Gene therapy makes it possible to engineer chimeric antigen receptors (CARs) to create T cells that target specific diseases. However, current approaches require elaborate and expensive protocols to manufacture engineered T cells ex vivo, putting this therapy beyond the reach of many patients who might benefit. A solution could be to program T cells in vivo. Here, we evaluate the clinical need for in situ CAR T cell programming, compare competing technologies, review current progress, and provide a perspective on the long-term impact of this emerging and rapidly flourishing biotechnology field. Expected final online publication date for the Annual Review of Biomedical Engineering, Volume 23 is June 2021. Please see http//www.annualreviews.org/page/journal/pubdates for revised estimates.Microengineering advances have enabled the development of perfusable, endothelialized models of the microvasculature that recapitulate the unique biological and biophysical conditions of the microcirculation in vivo. Indeed, at that size scale ( less then 100 μm)-where blood no longer behaves as a simple continuum fluid; blood cells approximate the size of the vessels themselves; and complex interactions among blood cells, plasma molecules, and the endothelium constantly ensue-vascularized microfluidics are ideal tools to investigate these microvascular phenomena. Moreover, perfusable, endothelialized microfluidics offer unique opportunities for investigating microvascular diseases by enabling systematic dissection of both the blood and vascular components of the pathophysiology at hand. We review (a) the state of the art in microvascular devices and (b) the myriad of microvascular diseases and pressing challenges. The engineering community has unique opportunities to innovate with new microvascular devices and to partner with biomedical researchers to usher in a new era of understanding and discovery of microvascular diseases. Expected final online publication date for the Annual Review of Biomedical Engineering, Volume 23 is June 2021. Please see http//www.annualreviews.org/page/journal/pubdates for revised estimates.Objectives To compare antimicrobial and resource utilization with T2 Magnetic Resonance (T2MR) versus blood culture (BC) in patients with suspected bloodstream infection.Methods We systematically searched MEDLINE, EMBASE, and CENTRAL for randomized trials or observational controlled studies of patients with suspected bloodstream infection receiving a diagnosis with T2MR or BC. Using an inverse variance meta-analysis model, we reported mortality using the risk ratio (RR) and the remaining outcomes as the mean difference (MD).Results Fourteen studies were included in the meta-analysis. Time to detection (MD = -81 hours; p less then 0.001) and time to species identification (MD = -77 hours; p less then 0.001) were faster with T2MR. Patients testing positive on T2MR received targeted antimicrobial therapy faster (-42 hours; p less then 0.001) and patients testing negative on T2MR were de-escalated from empirical therapy faster (-7 hours; p = 0.02) vs. BC. Length of intensive care unit stay (MD = -5.0 days; p = 0.03) and hospital stay (MD = -4.8 days; p = 0.03) were shorter with T2MR. Mortality rates were comparable between T2MR and BC (28.9% vs. 29.9%, RR = 1.02, p = 0.86).Conclusion Utilization of T2MR for identification of bloodstream pathogens provides faster time to detection, faster transition to targeted microbial therapy, faster de-escalation of empirical therapy, shorter ICU and hospital stay, and with comparable mortality rate versus BC.
  The US Food and Drug Administration outlines clinical studies as postmarketing requirements and commitments to be fulfilled following approval of new drugs and biologics ("therapeutics"). Regulators have increasingly emphasized lifecycle evaluation of approved therapeutics, and postmarketing studies are intended to advance our understanding of therapeutic safety and efficacy. However, little is known about the indications that clinical studies outlined in postmarketing requirements and commitments investigate, including whether they are intended to generate evidence for approved or other clinical indications. Therefore, we characterized US Food and Drug Administration postmarketing requirements and commitments for new therapeutics approved from 2009 to 2018.
 
  We conducted a cross-sectional study of all novel therapeutics, including small-molecule drugs and biologics, receiving original US Food and Drug Administration approval from 2009 to 2018, using approval letters accessed through the Drug@FDA database.ps in the clinical evidence available for therapeutics at approval.
 The US Food and Drug Administration approves most new therapeutics with at least 1 postmarketing requirement or commitment for a clinical study, and outlines investigations of safety or efficacy for both approved and unapproved indications. The median number of 2 clinical studies outlined has remained relatively constant over the last decade. Given increasing emphasis by the US Food and Drug Administration on faster approval and lifecycle evaluation of therapeutics, these findings suggest that more postmarketing requirements and commitments may be necessary to address gaps in the clinical evidence available for therapeutics at approval.
  Chronic Fatigue Syndrome (CFS/ME) may get in the way of enjoying activities. A substantial minority of adolescents with CFS/ME are depressed. Anhedonia is a core symptom of depression. Anhedonia in adolescents with CFS/ME has not been previously investigated.
 
  One hundred and sixty-four adolescents, age 12 to 18, with CFS/ME completed a diagnostic interview (K-SADS) and questionnaires (HADS, RCADS). We used a mixed-methods approach to explore the experience of anhedonia and examine how common it is, comparing those with clinically significant anhedonia to those without.
 
  Forty-two percent of adolescents with CFS/ME reported subclinical or clinical levels of anhedonia. Fifteen percent had clinically significant anhedonia. Thematic analysis generated two themes (1) stopping activities that they previously enjoyed and (2) CFS/ME obstructs enjoyment. Most (72%) of those who reported clinically significant anhedonia met the depression diagnostic criteria.  https://www.selleckchem.com/products/oxythiamine-chloride-hydrochloride.html  Those who were depressed used more negative language to describe their experience of activities than in those who were not depressed, although the themes were broadly similar.