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The COVID-19 pandemic caused by the SARS-CoV-2 virus continually poses serious threats to global public health. The main protease (Mpro) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing Mpro inhibitors derived from either Boceprevir or Telaprevir, both of which are approved antivirals. All compounds inhibited SARS-CoV-2 Mpro activity in vitro with IC50 values ranging from 7.6 to 748.5 nM. The co-crystal structure of Mpro in complex with MI-23, one of the most potent compounds, revealed its interaction mode. Two compounds (MI-09 and MI-30) showed excellent antiviral activity in cell-based assays. In a SARS-CoV-2 infection transgenic mouse model, oral or intraperitoneal treatment with MI-09 or MI-30 significantly reduced lung viral loads and lung lesions. Both also displayed good pharmacokinetic properties and safety in rats.

The evolution of massive stars is influenced by the mass lost to stellar winds over their lifetimes. These winds limit the masses of the stellar remnants (such as black holes) that the stars ultimately produce. We use radio astrometry to refine the distance to the black hole X-ray binary Cygnus X-1, which we find to be kiloparsecs. When combined with archival optical data, this implies a black hole mass of 21.2 ± 2.2 solar masses, higher than previous measurements. The formation of such a high-mass black hole in a high-metallicity system (within the Milky Way) constrains wind mass loss from massive stars.

The UK Government this year hosts two important events—the G7 (June 11–13) and COP26 (Nov 1–12). The priorities set out by Prime Minister Boris Johnson for his G7 presidency are four-fold: fighting against and recovering from COVID-19; climate action; free and fair trade; and shared values as open societies. Global health will indeed be a concern for the US, Canada, Japan, France, Germany, and Italy. Some G7 countries have performed poorly in responding to the pandemic. What should be the UK's approach to global health? Last week, Lord Nigel Crisp convened the All-Party Parliamentary Group on Global Health, which he co-chairs, to define a G7 agenda.

EU Commission President Ursula von der Leyen's comments come after much scrutiny of the EU vaccination programme. Rob Hyde reports.

As evidence mounts that patients with severe mental illness are at increased risk of severe COVID-19, some countries are reassessing their vaccine priority strategies. Nayanah Siva reports.

Oncologist and tireless champion of cancer research. He was born in Glasgow, UK, on Jan 13, 1945, and died in Bristol, UK, with non-Hodgkin lymphoma and COVID-19 on Jan 20, 2021, aged 76 years.

In the past year, more Nigerians have been killed by state-sanctioned security forces than by COVID-19, according to data on the Nigeria Security Tracker and Worldometers.1 Formed in 1992, the Special Anti-Robbery Squad (SARS) has become the public threat the squad was created to prevent. Killings of young adults by the SARS has spurred peaceful demonstrations across Nigeria calling for disbandment of the SARS.2 On Oct 20, 2020, peaceful protesters were murdered by state-sanctioned forces at the Lekki Toll Gate in Lagos, Nigeria's most populous city.

Li X, Mukandavire C, Cucunubà ZM, et al. Estimating the health impact of vaccination against ten pathogens in 98 low-income and middle-income countries from 2000 to 2030: a modelling study. Lancet 2021; 397: 398–408—In appendix 2, the table legends for appendix 3 p 1 (d–f) and p 2 (d–f) should have been for under-5s by calendar view, and the table legends for appendix 3 p 1 (g–i) and p 2 (g–i) should have been for all ages by cohort view. The titles of the tables have also been corrected. These corrections have been made as of Feb 18, 2021.

Logunov DY, Dolzhikova IV, Shcheblyakov DV, et al. Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia. Lancet 2021; 397: 671–81—In this Article, the funder list has been updated by removing one that was incorrectly listed; in figure 2, the number at risk at the day 20 timepoint has been corrected to 15 117; in figure 3B, the number of male participants labelled on the graph has been corrected to 46; and in the legend of figure 3, the following sentence has been added for clarity: “Four participants are not included in the subgroup analysis by age because of missing date of birth on the case report form for this analysis”.

No abstract available…

Objectives: Cognitive impairment is an important consequence of sepsis. We sought to determine long-term trajectories of cognitive function after sepsis. Design: Prospective study of the Reasons for Geographic and Racial Differences in Stroke cohort. Setting: United States. Patients: Twenty-one thousand eight-hundred twenty-three participants greater than or equal to 45 years, mean (SD) age 64.3 (9.2) years at first cognitive assessment, 30.9% men, and 27.1% Black. Measurements and Main Results: The main exposure was time-dependent sepsis hospitalization. The primary outcome was global cognitive function (Six-Item Screener range, 0–6). Secondary outcomes were incident cognitive impairment (Six-Item Screener score ≤ 4 [impaired] vs ≥5 [unimpaired]), new learning (Consortium to Establish a Registry for Alzheimer Disease Word List Learning range, 0–30), verbal memory (word list delayed recall range, 0–10), and executive function/semantic fluency (animal fluency test range, ≥ 30). Over a median follow-up of 10 years (interquartile range, 6–12 yr), 840 (3.8%) experienced sepsis (incidence 282 per 1,000 person-years). Sepsis was associated with faster long-term declines in Six-Item Screener (–0.02 points per year faster [95% CI, –0.01 to –0.03]; p < 0.001) and faster long-term rates of incident cognitive impairment (odds ratio 1.08 per year [95% CI, 1.02–1.15]; p = 0.008) compared with presepsis slopes. Although cognitive function acutely changed after sepsis (0.05 points [95% CI, 0.01–0.09]; p = 0.01), the odds of acute cognitive impairment (Six-Item Screener ≤ 4) immediately after sepsis was not significant (odds ratio, 0.81 [95% CI, 0.63–1.06]; p = 0.12). Sepsis hospitalization was not associated with acute changes or faster declines in word list learning, word list delayed recall, or animal fluency test. Conclusions: Sepsis is associated with accelerated long-term decline in global cognitive function. Current affiliation for Dr. Wang: Department of Emergency Medicine, The Ohio State University, Columbus, OH. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal. A full list of participating Reasons for Geographic And Racial Differences in Stroke investigators and institutions and institutions can be found at http://www.regardsstudy.org. Drs. Wang and Levine conceived the study. Drs. Wang and Safford obtained funding. Drs. Wang and Safford oversaw data collection. Mr. Kabeto conducted the analysis. Dr. Wang drafted the article and all authors contributed to its critical review. Mr. Kabeto had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr. Wang assumes overall responsibility for the article. Supported, in part, by award R01-NR012726 from the National Institute for Nursing Research, UL1-RR025777 from the National Center for Research Resources, as well as by grants from the Center for Clinical and Translational Science and the Lister Hill Center for Health Policy of the University of Alabama at Birmingham. The parent Reasons for Geographic And Racial Differences in Stroke research project is supported by a cooperative agreement U01-NS041588 from the National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Department of Health and Human Service. Dr. Wang’s institution received funding from the National Institutes of Health (NIH) National Institute of Nursing Research. Drs. Wang, Wadley, Muntner, Judd, Safford, and Levine received support for article research from the NIH. Dr. Safford reports the following potential conflicts of interest: Amgen—salary support to study patterns of statin use in Medicare and other large databases; diaDexus—salary support for a research grant on lipids and cardiovascular disease outcomes; diaDexus—consulting to help with U.S. Food and Drug Administration application; NIH, Agency for Healthcare Research and Quality (AHRQ)—salary support for research grants. Drs. Wadley’s and Judd’s institutions received funding from the NIH. Dr. Safford’s institution received funding from Amgen. Dr. Kempker’s institution received funding from AHRQ, and he received funding from Grifols; and he received support (K08HS025240) for article research from AHRQ. Dr. Levine’s institution received funding from National Institute on Aging and National Institute of Neurological Disorders and Stroke, and he disclosed government work. The remaining authors have disclosed that they do not have any potential conflicts of interest. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurologic Disorders and Stroke or the National Institutes of Health. Representatives of the funding agency have been involved in the review of the article but not directly involved in the collection, management, analysis, or interpretation of the data. For information regarding this article, E-mail: henry.wang@osumc.edu Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Therapies for patients with respiratory failure from coronavirus disease 2019 are urgently needed. Early implementation of prone positioning ventilation improves survival in patients with acute respiratory distress syndrome, but studies examining the effect of proning on survival in patients with coronavirus disease 2019 are lacking. Our objective was to estimate the effect of early proning initiation on survival in patients with coronavirus disease 2019–associated respiratory failure. Design: Data were derived from the Study of the Treatment and Outcomes in Critically Ill Patients with coronavirus disease 2019, a multicenter cohort study of critically ill adults with coronavirus disease 2019 admitted to 68 U.S. hospitals. Using these data, we emulated a target trial of prone positioning ventilation by categorizing mechanically ventilated hypoxemic (ratio of PaO2 over the corresponding FIO2 ≤ 200 mm Hg) patients as having been initiated on proning or not within 2 days of ICU admission. We fit an inverse probability–weighted Cox model to estimate the mortality hazard ratio for early proning versus no early proning. Patients were followed until death, hospital discharge, or end of follow-up. Setting: ICUs at 68 U.S. sites Patients: Critically ill adults with laboratory-confirmed coronavirus disease 2019 receiving invasive mechanical ventilation with ratio of PaO2 over the corresponding FIO2 less than or equal to 200 mm Hg. Interventions: None. Measurements and Main Results: Among 2,338 eligible patients, 702 (30.0%) were proned within the first 2 days of ICU admission. After inverse probability weighting, baseline and severity of illness characteristics were well-balanced between groups. A total of 1,017 (43.5%) of the 2,338 patients were discharged alive, 1,101 (47.1%) died, and 220 (9.4%) were still hospitalized at last follow-up. Patients proned within the first 2 days of ICU admission had a lower adjusted risk of death compared with nonproned patients (hazard ratio, 0.84; 95% CI, 0.73–0.97). Conclusions: In-hospital mortality was lower in mechanically ventilated hypoxemic patients with coronavirus disease 2019 treated with early proning compared with patients whose treatment did not include early proning. A full list of Study of the Treatment and Outcomes in Critically Ill Patients with Coronavirus Disease (STOP-COVID) Investigators is provided in the Supplemental Digital Content (http://links.lww.com/CCM/G204). Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Dr. Mathews reported receiving grants from the National Institute of Health (NIH) and the National Heart, Lung, and Blood Institute (NHLBI) during the conduct of the study and serves on the steering committee for A Multi-Center, Adaptive, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy and Safety of Gimsilumab in Subjects With Lung Injury or Acute Respiratory Distress Syndrome Secondary to COVID-19 (BREATHE) trial, funded by Roivant/Kinevant Sciences; she received support for article research from NIH. Dr. Shaefi reported receiving grants from the NIH and the National Institute on Aging and the National Institute of General Medical Sciences; he received support for article research from NIH. Dr. Coca received funding from RenalytixAI, Relypsa, Takeda Pharmaceuticals, CHF Solutions, Bayer, Boehringer Ingelheim, Akebia, inRegen, Renal Research Institute, and XORTX Therapeutics, Inc.; he owns equities in RenalytixAI and pulseData. Dr. Gupta reported receiving grants from the NIH and is a scientific coordinator for GlaxoSmithKline’s Anemia Studies in Chronic Kidney Disease: Erythropoiesis via a Novel Prolyl Hydroxylase Inhibitor Daprodustat trial. Dr. Srivastava’s institution received funding from the NIH and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); he reported receiving funding from the NIH, NIDDK, Horizon Therapeutics PLC, AstraZeneca, Tate & Latham, and CVS Caremark. Dr. Hernán reported receiving grants from the NIH. Dr. Chan’s institution received funding from NIH and Renal Research Institute; she received funding from Gerson Lehrman Group consulting and NIH; she received support for article research from NIH. Dr. Leaf’s institution received funding from NIH, NIDDK, and NHLBI; he received funding from BioPorto. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: kusum.mathews@mssm.edu Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: To determine the frequency and prognosis of invasive pulmonary aspergillosis in critically ill patients with severe influenza pneumonia. Design: Retrospective multicenter cohort study. Setting: Five French ICUs. Patients: Patients with influenza admitted to ICU between 2009 and 2018. Measurements and Main Results: Of the 524 patients admitted for severe influenza diagnosed with a positive airway reverse-transcriptase polymerase chain reaction test, 450 (86%) required mechanical ventilation. A lower respiratory tract sample yielded with Aspergillus (Asp+) in 28 patients (5.3%). Ten patients (1.9%) were diagnosed with putative or proven invasive pulmonary aspergillosis, based on the validated AspICU algorithm. A multivariate model was built to identify independent risk factors for Aspergillus-positive pulmonary culture. Factors independently associated with Aspergillus-positive culture were liver cirrhosis (odds ratio = 6.7 [2.1–19.4]; p < 0.01), hematologic malignancy (odds ratio = 3.3 [1.2–8.5]; p = 0.02), Influenza A(H1N1)pdm09 subtype (odds ratio = 3.9 [1.6–9.1]; p < 0.01), and vasopressor requirement (odds ratio = 4.1 [1.6–12.7]; p < 0.01). In-hospital mortality of Asp+ patients was 36% versus 21% in patients without Aspergillus-positive pulmonary culture (p = 0.09). Conclusions: In this large retrospective multicenter cohort of critically ill patients, putative invasive pulmonary aspergillosis according to AspICU algorithm was a relatively rare complication of influenza. Patients at higher risk of Aspergillus pulmonary colonization included those with liver cirrhosis, hematologic malignancy, H1N1pdm09 influenza A virus, and requiring vasopressors. Our results provide additional data on the controversial association between severe influenza and invasive pulmonary aspergillosis. Reaching a consensual definition of invasive pulmonary aspergillosis becomes mandatory and confers further prospective research. This work was performed at Centre Hospitalier et Universitaire de Brest, France; Centre Hospitalier et Universitaire de Rennes, France; Centre Hospitalier et Universitaire de Nantes, France; Centre Hospitalier des Pays de Morlaix, France. This study protocol was approved by the research ethics committee at the University of Brest, France (protocol number 2018CE.22, date of approval March 29, 2018). Drs. Coste and Aubron designed the study protocol. Drs. Coste, Frsten, and Raute collected data. Drs. Morin, Tran, Pronier, Coste-Burel, Nevez, Gangneux, and Le Pape contributed to the acquisition of the data. Drs. Coste and Couturaud performed the statistical analysis. Drs. Coste and Aubron drafted the article. All authors revised the article and approved the final article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Dr. Blanc received funding from Novartis. Dr. Gangneux received funding from Pfizer, Gilead, and MSD. The remaining authors have disclosed they have no potential conflicts of interest. For information regarding this article, E-mail: anne.coste@chu-brest.fr Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Sepsis is defined as a dysregulated host response to infection that leads to life-threatening acute organ dysfunction. It afflicts approximately 50 million people worldwide annually and is often deadly, even when evidence-based guidelines are applied promptly. Many randomized trials tested therapies for sepsis over the past 2 decades, but most have not proven beneficial. This may be because sepsis is a heterogeneous syndrome, characterized by a vast set of clinical and biologic features. Combinations of these features, however, may identify previously unrecognized groups, or “subclasses” with different risks of outcome and response to a given treatment. As efforts to identify sepsis subclasses become more common, many unanswered questions and challenges arise. These include: 1) the semantic underpinning of sepsis subclasses, 2) the conceptual goal of subclasses, 3) considerations about study design, data sources, and statistical methods, 4) the role of emerging data types, and 5) how to determine whether subclasses represent “truth.” We discuss these challenges and present a framework for the broader study of sepsis subclasses. This framework is intended to aid in the understanding and interpretation of sepsis subclasses, provide a mechanism for explaining subclasses generated by different methodologic approaches, and guide clinicians in how to consider subclasses in bedside care. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and social care. The funding source did not have any role in the design, conduct or interpretation of study results. Dr. Seymour helped in designing the concept. Drs. DeMerle, Angus, and Seymour helped in designing. Drs. DeMerle, Baille, Brant, Calfee, Carcillo, Chang, Dickson, Evans, Gordon, Kennedy, Knight, Lindsell, Liu, Marshall, Randolph, Scicluna, Shankar-Hari, Shapiro, Sweeney, Talis, Tang, Thompson, Tsalik, van der Poll, van Vught, Wong, Yende, Zhao, and Seymour drafted the article and critically revised the article for important intellectual content. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Dr. DeMerle’s institution received funding from R35 GM119519-03 and T32HL007820. Dr. Calfee is supported in part by grants from the National Institutes of Health (NIH; HL140026). Dr. Carcillo is supported in part by grants from the National Institutes of Health (R01GM108618). Dr. DeMerle is supported in part by grants from the National Institutes of Health (T32HL007820). Dr. Angus received funding from Ferring Pharmaceuticals, Bristol-Myers Squibb, Bayer AG, and Alung Technologies. Drs. Angus, Brant, Carcillo, Chang, Dickson, Kennedy, Lindsell, Liu, Randolph, Thompson, Tsalik, Wong, and Seymour received support for article research from the NIH. Dr. Baillie received support for article research from Wellcome Trust/Charity Open Access Fund (COAF), and Research Councils UK. Dr. Calfee’s institution received funding from Roche/Genentech and Bayer, and she received funding from Roche/Genentech, Quark, CSL Behring, Bayer, Gen1e Life Sciences, and Vasomune. Drs. Carcillo’s and Seymour’s institutions received funding from the National Institute of General Medical Sciences. Drs. Chang’s, Lindsell’s, Liu’s, Randolph’s, Shapiro’s, and Wong’s institutions received funding from the NIH. Dr. Gordon’s institution received funding from the National Institute for Health Research (NIHR) Research Professorship (RP-2015-06-18), NIHR Imperial Biomedical Research Centre, GlaxoSmithKline, and Bristol Myers Squibb. Dr. Knight received support for article research from Wellcome Trust/COAF. Dr. Lindsell’s institution received funding from the Centers for Disease Control and Prevention (CDC), Department of Defense, Marcus Foundation, Entegrion, Endpoint Health, and bioMerieux, and he disclosed he is a coinventor on patents related to risk stratification in septic shock. Dr. Marshall received funding from AM Pharma, AKPA Pharma, and the Society of Critical Care Medicine (Critical Care Medicine Associate Editor). Dr. Randolph’s institution received funding from the CDC, and she received funding from La Jolla Pharma. Dr. Shapiro’s institution received funding from rapid pathogen screening, Baxter, and Inflammatix, and he received funding from Diagnostic Robotics. Dr. Sweeney received funding from Inflammatix. Dr. Thompson’s institution received funding from the National Heart, Lung, and Blood Institute, and he received funding from Bayer and Thetis. Dr. Tsalik disclosed that he is a founder and holds equity in Predigen; he receives salary support from the Durham VA Healthcare System and Duke University; and he has received salary support and/or grant funding (paid to his university) from the NIH, DARPA, DTRA, Karius, and Sanofi US. Dr. Wong disclosed that he and his institutions hold U.S. patents for sepsis biomarkers. Dr. Yende received funding from serving as consultant for expert testimony and he disclosed government work. Dr. Knight is supported by a Wellcome Trust Investigator Award (204969/Z/16/Z) and the NIHR Oxford Biomedical Research Centre. Dr. Lindsell was supported in part by grants from the National Institutes of Health (R35GM126943, R01HL149422), a research grant to VUMC from Endpoint Health, and is also listed as co-inventor on patents for endotyping and risk-stratification in pediatric septic shock. Dr. Liu is supported in part by grants from the National Institutes of Health (R35GM128672). Dr. Marshall is supported in part by grants from the Canadian Institutes of Health Research. Dr. Randolph is supported in part by grants from the National Institutes of Health (R21HD095228). Dr. Shankar-Hari is supported by the National Institute for Health Research Clinician Scientist Award (CS-2016-16-011). Dr. Wong is supported in part by grants from the National Institutes of Health (R35 GM126943). Dr. Sweeney is an employee of, and shareholder in, Inflammatix. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: demerlekm@upmc.edu Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Rapid delivery of antibiotics is a cornerstone of sepsis therapy, although time targets for specific components of antibiotic delivery are unknown. We quantified time intervals comprising the task of antibiotic delivery and evaluated the association between interval delays and hospital mortality among patients treated in the emergency department for suspected sepsis. Design: Retrospective cohort. Setting: Twelve hospitals in Southeastern United States from 2014 to 2017. Patients: Twenty-four thousand ninety-three encounters among 20,026 adults with suspected sepsis in 12 emergency departments. Measurements and Main Results: We divided antibiotic administration into two intervals: time from emergency department triage to antibiotic order (recognition delay) and time from antibiotic order to infusion (administration delay). We used generalized linear mixed models to evaluate associations between these intervals and hospital mortality. Median time from emergency department triage to antibiotic administration was 3.4 hours (interquartile range, 2.0–6.0 hr), separated into a median recognition delay (time from emergency department triage to antibiotic order) of 2.7 hours(interquartile range, 1.5–4.7 hr) and median administration delay (time from antibiotic order to infusion) of 0.6 hours (0.3–1.2 hr). Adjusting for other risk factors, both recognition delay and administration delay were associated with mortality, but pairwise comparison with a no-delay reference group was not significant for up to 6 hours of recognition delay or up to 1.5 hours of administration delay. Conclusions: Both recognition delays and administration delays were associated with increased hospital mortality, but only for longer delays. These results suggest that both metrics may be important to measure and improve for patients with suspected sepsis but do not support targets less than 1 hour. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Presented, in part, at the annual meeting of the Society Critical Care Medicine, San Antonio, TX, February 2018. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: Stephanie.p.taylor@atriumhealth.org Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Prevention and therapy of immunothrombosis remain crucial challenges in the management of coronavirus disease 2019, since the underlying mechanisms are incompletely understood. We hypothesized that endothelial damage may lead to substantially increased concentrations of von Willebrand factor with subsequent relative deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13). Design: Prospective controlled cross-over trial. Setting: Blood samples of patients with confirmed coronavirus disease 2019 and healthy controls were obtained in three German hospitals and analyzed in a German hemostaseologic laboratory. Patients: Seventy-five patients with confirmed coronavirus disease 2019 of mild to critical severity and 30 healthy controls. Measurements and Main Results: von Willebrand factor antigen, ADAMTS13, and von Willebrand factor multimer formation were analyzed. von Willebrand factor antigen was 4.1 times higher in COVID-19 patients compared with healthy controls (p < 0.0001), whereas ADAMTS13 activities were not significantly different (p = 0.18). The ADAMTS13/von Willebrand factor antigen ratio was significantly lower in COVID-19 than in the control group (24.4 ± 20.5 vs 82.0 ± 30.7; p < 0.0001). Fourteen patients (18.7%) undercut a critical ratio of 10 as described in thrombotic thrombocytopenic purpura. Gel analysis of multimers resembled a thrombotic thrombocytopenic purpura pattern with loss of the largest multimers in 75% and a smeary triplet pattern in 39% of the patients. The ADAMTS13/von Willebrand factor antigen ratio decreased continuously from mild to critical disease (analysis of variance p = 0.026). Furthermore, it differed significantly between surviving patients and those who died from COVID-19 (p = 0.001) yielding an area under the curve of 0.232 in receiver operating characteristic curve curve analysis. Conclusion: COVID-19 is associated with a substantial increase in von Willebrand factor levels, which can exceed the ADAMTS13 processing capacity resulting in the formation of large von Willebrand factor multimers indistinguishable from thrombotic thrombocytopenic purpura. The ADAMTS13/von Willebrand factor antigen ratio is an independent predictor of severity of disease and mortality. These findings provide a rationale to consider plasma exchange as a therapeutic option in COVID-19 and to include von Willebrand factor and ADAMTS13 in the diagnostic workup. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Drs. Doevelaar, Bachmann, Budde, and Westhoff contributed equally to the work. Dr. Witzke received funding from Amgen, Alexion, Astellas, Basilea, Biotest, Bristol-Myers Squibb, Correvio, Chiesi, Gilead, Hexal, and Janssen; he is supported by an unrestricted grant of the Rudolf-Ackermann-Stiftung (Stiftung für Klinische Infektiologie). Dr. Bachmann received support for article research from the National Institutes of Health and the Department of Defense. The remaining authors have disclosed that they do not have any potential conflicts of interest. This study was performed at the Medical Department I, University Hospital Marien-Hospital Herne, Ruhr-University Bochum, Herne, Germany; the Department of Intensive Care and Ventilatory Medicine, Asklepios Klinikum Hamburg, Hamburg, Germany; the Departments of Infectiology and Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; and the section of Hemostaseology, MEDILYS Laborgesellschaft mbH, Hamburg, Germany. For information regarding this article, E-mail: innere-medizin@marienhospital-herne.de Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Transfusions of blood products are common in critically ill patients and have a potential for immunomodulation. The aim of this study is to address the impact of transfusion of blood products on the susceptibility to ICU-acquired infections in the high-risk patients with septic shock. Design: A single-center retrospective study over a 10-year period (2008–2017). Setting: A medical ICU of a tertiary-care center. Patients: All consecutive patients diagnosed for septic shock within the first 48 hours of ICU admission were included. Patients who were discharged or died within the first 48 hours were excluded. Interventions: RBC, platelet, and fresh frozen plasma transfusions collected up to 24 hours prior to the onset of ICU-acquired infection. Measurements and Main Results: During the study period, 1,152 patients were admitted for septic shock, with 893 patients remaining alive in the ICU after 48 hours of management. A first episode of ICU-acquired infection occurred in 28.3% of the 48-hour survivors, with a predominance of pulmonary infections (57%). Patients with ICU-acquired infections were more likely to have received RBC, platelet, and fresh frozen plasma transfusions. In a multivariate Cox cause-specific analysis, transfusions of platelets (cause-specific hazard ratio = 1.55 [1.09–2.20]; p = 0.01) and fresh frozen plasma (cause-specific hazard ratio = 1.38 [0.98–1.92]; p = 0.05) were independently associated with the further occurrence of ICU-acquired infections. Conclusions: Transfusions of platelets and fresh frozen plasma account for risk factors of ICU-acquired infections in patients recovering from septic shock. The occurrence of ICU-acquired infections should be considered as a relevant endpoint in future studies addressing the indications of transfusions in critically ill patients. Dr. Pène is the guarantor of the content of the article, including the data and analysis. Drs. Péju, Llitjos and Pène designed the study, collected and analyzed the data, and drafted the article. Drs. Jamme and Lambert performed the statistical analysis. Drs. Charpentier, François, Marin, Cariou, Chiche, and Mira collected the data, contributed to data interpretation and analysis, and revised the article for important intellectual content. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Presented, in part, at the congress “Réanimation 2020”, Paris, France, February 05–07, 2020. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: frederic.pene@aphp.fr Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Septic cardiomyopathy develops frequently in patients with sepsis and likely increases short-term mortality. However, whether septic cardiomyopathy is associated with long-term outcomes after sepsis is unknown. We investigated whether septic patients with septic cardiomyopathy have worse long-term outcomes than septic patients without septic cardiomyopathy. Design: Retrospective cohort study. SETTING: Adult ICU. PATIENTS: Adult ICU patients with sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Left ventricular global longitudinal systolic strain was our primary measure of septic cardiomyopathy. We employed a suite of multivariable survival analyses to explore linear and nonlinear associations between left ventricular global longitudinal systolic strain and major adverse cardiovascular events, which included death, stroke, and myocardial infarction. Our primary outcome was major adverse cardiovascular event through 24 months after ICU discharge. Among 290 study patients, median left ventricular global longitudinal systolic strain was –16.8% (interquartile range, –20.4% to –12.6%), and 38.3% of patients (n = 111) experienced a major adverse cardiovascular event within 24 months after discharge. On our primary, linear analysis, there was a trend (p = 0.08) toward association between left ventricular global longitudinal systolic strain and major adverse cardiovascular event (odds ratio, 1.03; CI, < 1 to 1.07). On our nonlinear analysis, the association was highly significant (p < 0.001) with both high and low left ventricular global longitudinal systolic strain associated with major adverse cardiovascular event among patients with pre-existing cardiac disease. This association was pronounced among patients who were younger (age < 65 yr) and had Charlson Comorbidity Index greater than 5. Conclusions: Among patients with sepsis and pre-existing cardiac disease who survived to ICU discharge, left ventricular global longitudinal systolic strain demonstrated a U-shaped association with cardiovascular outcomes through 24 months. The relationship was especially strong among younger patients with more comorbidities. These observations are likely of use to design of future trials. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). The Intermountain Institutional Review Board approved this study with waiver of informed consent. Drs Beesley, Tonna, Paine, Grissom, and Brown designed the study. Drs. Beesley, Sorensen, Tonna, Paine, and Brown analyzed and interpreted the data. Dr. Beesley drafted the report, and all other authors revised it. All authors gave final approval of the report to be published. Supported (in part or in full) by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR001067. Dr. Walkey received funding from UptoDate. Dr. Tonna’s institution received funding from National Heart, Lung, and Blood Institute (NHLBI), National Center for Advancing Translational Sciences, and LivaNova; he received funding from Philips Healthcare; he received support for article research from National Institutes of Health; and he was supported by a career development award (K23HL141596) from the NHLBI of the National Institutes of Health. Dr. Burk received funding from Intermountain Research and Medical Foundation. Dr. Paine’s institution received funding from NHLBI and the Department of Veterans Affairs. The remaining authors have disclosed that they do not have any potential conflicts of interest. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. For information regarding this article, E-mail: Sarah.beesley@imail.org Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: To identify research priorities in the management, pathophysiology, and host response of coronavirus disease 2019 in critically ill patients. Design: The Surviving Sepsis Research Committee, a multiprofessional group of 17 international experts representing the European Society of Intensive Care Medicine and Society of Critical Care Medicine, was virtually convened during the coronavirus disease 2019 pandemic. The committee iteratively developed the recommendations and subsequent document. Methods: Each committee member submitted a list of what they believed were the most important priorities for coronavirus disease 2019 research. The entire committee voted on 58 submitted questions to determine top priorities for coronavirus disease 2019 research. Results: The Surviving Sepsis Research Committee provides 13 priorities for coronavirus disease 2019. Of these, the top six priorities were identified and include the following questions: 1) Should the approach to ventilator management differ from the standard approach in patients with acute hypoxic respiratory failure?, 2) Can the host response be modulated for therapeutic benefit?, 3) What specific cells are directly targeted by severe acute respiratory syndrome coronavirus 2, and how do these cells respond?, 4) Can early data be used to predict outcomes of coronavirus disease 2019 and, by extension, to guide therapies?, 5) What is the role of prone positioning and noninvasive ventilation in nonventilated patients with coronavirus disease?, and 6) Which interventions are best to use for viral load modulation and when should they be given? Conclusions: Although knowledge of both biology and treatment has increased exponentially in the first year of the coronavirus disease 2019 pandemic, significant knowledge gaps remain. The research priorities identified represent a roadmap for investigation in coronavirus disease 2019. Drs. Coopersmtih and De Backer are cochairs of the committee who contributed equally to the final article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Dr. Coopersmith is past president of the Society of Critical Care Medicine. Dr. Antonelli is immediate past president of European Society of Intensive Care Medicine and received consulting fees from Toray, Intersurgical, and Fisher & Paykel and unrestricted research grants from GE and Estor. Dr. Bauer is a consultant for Wolters Kluwer, and he received funding from Wolters Kluwer. Dr. Deutschman is past president of the Society of Critical Care Medicine scientific editor for Critical Care Medicine, consultant for Enlivex and Lowell Therapeutics; his institution received funding from National Institute of General Medical Sciences; he received funding from the Society of Critical Care Medicine, Elsevier, Enlivex, Sage Therapeutics, and La Jolla Pharmaceuticals; and he received support for article research from the National Institutes of Health (NIH). Dr. Evans disclosed that she serves as the cochair of the Surviving Sepsis Committee and as the adult Surviving Sepsis Campaign Guidelines for the management of sepsis and septic shock. Dr. Ferrer received funding from MSD, Pfizer, and Gilead. Dr. Kesecioglu is president of the European Society of Intensive Care Medicine. Dr. Kissoon is the pediatrics guidelines cochair of the Surviving Sepsis Committee. Dr. Martin-Loeches received honoraria from MSD, Gilead, and Aspen. Dr. Nunnally is Treasurer of the Society of Critical Care Anesthesiologists. Dr. Prescott is the sepsis lead for a Michigan statewide sepsis quality improvement initiative sponsored by Blue Cross Blue Shield of Michigan, and his institution received funding from Agency for Healthcare Research and Quality, the Department of Veterans Affairs, and the NIH, and she disclosed government work. Dr. Rhodes is the adult guidelines cochair of the Surviving Sepsis Committee and a member of the Executive Committee. Dr. Talmor received speaking fees from Hamilton Medical, Clew, and Mindray. Dr Tissieres is president of the European Society of Pediatric and Neonatal Intensive Care, is the pediatrics guidelines cochair of the Surviving Sepsis Committee, and has received consulting fees or research grant from Baxter, bioMerieux, Sanofi. Dr. DeBacker is past president of the European Society of Intensive Care Medicine and has received consulting fees from Fresenius Kabi. The remaining authors have disclosed that they do not have any potential conflicts of interest. Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Cirrhosis is associated with hemodynamic and vascular disorders. However, microvascular reactivity of cirrhotic patients in the context of sepsis has poorly been investigated. Design: Prospective observational study. Setting: Medical ICU in a tertiary teaching hospital. Patients: We prospectively included adult patients admitted in the ICU for septic shock with and without cirrhosis. After initial resuscitation, global hemodynamic parameters were recorded and skin microvascular reactivity to local acetylcholine iontophoresis was measured. Interventions: None. Measurements and Main Results: Thirty patients with septic shock were included (60% male), 10 with cirrhosis and 20 without, with a median age of 61 years (54–74 yr). Cirrhotic patients were mainly classed as Child-Pugh C (80%) and all of them had ascites. Sequential Organ Failure Assessment score and ICU mortality of cirrhotic patients were higher than the noncirrhotic patients, respectively (6.5 [5.0–8.3] vs 11.5 [9.0–14.0]; p < 0.01; 15% vs 70%; p < 0.01). Peripheral tissue perfusion and global hemodynamic parameters were not different between the cirrhotic and noncirrhotic patients but arterial lactate level was three times higher in patients with cirrhosis (6.0 mmol/L [3.9–8.0 mmol/L] vs 2.0 mmol/L [0.9–3.5 mmol/L]; p < 0.01). Basal skin microvascular blood flow was not statistically different between the groups (4.94 perfusion units [3.45–8.73 perfusion units] vs 6.95 perfusion units [5.24–8.38 perfusion units]; p = 0.29). After acetylcholine simulation, skin microvascular blood flow increased more in cirrhotic patients than in noncirrhotic patients (644% [217–966%] vs 169% [73–505%], p = 0.03). Global microvascular reactivity was seven times higher in cirrhotic patients (area under the curve, 16,412 perfusion units [13,898–19,041 perfusion units] vs 2,664 perfusion units [969–4,604 perfusion units]; p < 0.001). Conclusions: We identified an exaggerated vasodilating microvascular response in cirrhotic patients with septic shock. Such a result may explain vasopressor resistance and paves the way for future therapeutic trials, targeting nitric oxide pathway specifically in this population. All authors are involved in study concept and design, and critical revision of article. Drs. Hariri, Urbina, Lavillegrand, and Ait-Oufella helped in acquisitions of data. Drs. Hariri, Urbina, Gasperment, Guidet, Maury, and Ait-Oufella drafted of the article. Drs. Hariri and Ait-Oufella are involved in statistical analysis. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: hafid.aitoufella@aphp.fr Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Individualizing a target mean arterial pressure is challenging during the initial resuscitation of patients with septic shock. The SEPSISPAM trial suggested that targeting high mean arterial pressure might reduce the occurrence of acute kidney injury among those included patients with a past history of chronic hypertension. We investigated whether the class of antihypertensive medications used before the ICU stay in chronic hypertensive patients was associated with the severity of acute kidney injury occurring after inclusion, according to mean arterial pressure target. Design: Post hoc analysis of the SEPSISPAM trial. Setting: The primary outcome was the occurrence of severe acute kidney injury during the ICU stay defined as kidney disease improving global outcome stage 2 or higher. Secondary outcomes were mortality at day 28 and mortality at day 90. Patients: All patients with chronic hypertension included in SEPSISPAM with available antihypertensive medications data in the hospitalization report were included. Measurements and Main Results: We analyzed 297 patients. Severe acute kidney injury occurred in 184 patients, without difference according to pre-ICU exposure to antihypertensive medications. Patients with pre-ICU exposure to angiotensin II receptor blockers had significantly less severe acute kidney injury in the high mean arterial pressure target group (adjusted odd ratio 0.24 with 95% CI [0.09–0.66]; p = 0.006). No statistically significant association was found after adjustment for pre-ICU exposure to antihypertensive medications and survival. Conclusions: Our results suggest that patients with septic shock and chronic hypertension treated with angiotensin II receptor blocker may benefit from a high mean arterial pressure target to reduce the risk of acute kidney injury occurrence. Drs. Demiselle and Asfar designed the study. Drs. Demiselle and Lemerle collected data in hospitalization reports. Drs. Demiselle and Seegers performed statistical analysis. Drs. Demiselle, Seegers, Guitton, Ricard, Radermacher, and Asfar drafted the article. Drs. Meziani, Grelon, Megarbane, Anguel, Mira, Dequin, Gergaud, Weiss, Legay, Le Tulzo, Conrad, Robert, Gonzalez, Guitton, Tamion, Tonnelier, Bédos, Van Der Linden, Vieillard-Baron, Mariotte, Pradel, Lesieur, Ricard, Hervé, du Cheyron, and Helms included patients in the SEPSISPAM trial and helped to have access to hospitalization reports. All the authors have revised and approved the final version of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). The SEPSISPAM trial was supported by the French Ministry of Health. Dr. Weiss perceived consultant fees from Med-Day Pharmaceuticals outside of the scope of this article. Dr. Dequin’s institution received funding from Angers University Hospital, the French Ministry of Health, Abionic, Atox Bio, Sphingotec GMBH, Adrenomed, Medspace, Aridis, Merck, Combioxin, GSK, Med-Immune, Genentech INH, Rev-Immune, Faron, Kenta, and Tigenix, and he received support for article research from the French Ministry of Health. Dr. Gonzalez disclosed work for hire. Dr. Teboul received funding from Getinge/Pulsion. Dr. Radermacher’s institution received funding from Deutsche Forschungsgemeinschaft and the German Ministry of Defense. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: piasfar@chu-angers.fr Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Cost utility analyses compare the costs and health outcome of interventions, with a denominator of quality-adjusted life year, a generic health utility measure combining both quality and quantity of life. Cost utility analyses are difficult to compare when methods are not standardized. It is unclear how cost utility analyses are measured/reported in critical care and what methodologic challenges cost utility analyses pose in this setting. This may lead to differences precluding cost utility analyses comparisons. Therefore, we performed a systematic review of cost utility analyses conducted in critical care. Our objectives were to understand: 1) methodologic characteristics, 2) how health-related quality-of-life was measured/reported, and 3) what costs were reported/measured. DESIGN: Systematic review. DATA SOURCES: We systematically searched for cost utility analyses in critical care in MEDLINE, Embase, American College of Physicians Journal Club, CENTRAL, Evidence-Based Medicine Reviews’ selected subset of archived versions of UK National Health Service Economic Evaluation Database, Database of Abstracts of Reviews of Effects, and American Economic Association electronic databases from inception to April 30, 2020. SETTING: Adult intensive care units. PATIENTS: Adult critically ill patients. Interventions: None. MEASUREMENTS AND MAIN RESULTS: Of 8,926 citations, 80 cost utility analyse studies were eligible. The time horizon most commonly reported was lifetime (59%). For health utility reporting, health-related quality-of-life was infrequently measured (29% reported), with only 5% of studies reporting baseline health-related quality-of-life. Indirect utility measures (generic, preference-based health utility measurement tools) were reported in 85% of studies (majority Euro-quality-of-life-5 Domains, 52%). Methods of estimating health-related quality-of-life were seldom used when the patient was incapacitated: imputation (19%), assigning fixed utilities for incapacitation (19%), and surrogates reporting on behalf of incapacitated patients (5%). For cost utility reporting transparency, separate incremental costs and quality-adjusted life years were both reported in only 76% of studies. Disaggregated quality-adjusted life years (reporting separate health utility and life years) were described in only 34% of studies. Conclusions: We identified deficiencies which warrant recommendations (standardized measurement/reporting of resource use/unit costs/health-related quality-of-life/methodological preferences) for improved design, conduct, and reporting of future cost utility analyses in critical care. Systematic review registration: PROSPERO CRD42020164689. All authors have 1) made substantial contributions to conception and design, acquisition of data, analysis, and interpretation of data; 2) drafted the submitted article and revised it critically for important intellectual content; and 3) provided final approval of the version to be published. Drs. Lau, Xie, Cook, and Rochwerg contributed to conception. Drs. Lau, Xie, Cook, Fowler, Iansavichene, and Rochwerg contributed to background. Drs. Lau, Xie, Cook, and Rochwerg contributed to design. Drs. Lau, Xie, Basmaji, Cook, Kiflen, Sirotich, Iansavichene, and Rochwerg contributed to acquisition of data. Drs. Lau, Xie, Basmaji, Cook, Fowler, Kiflen, Sirotich, Bagshaw, Wilcox, Lamontagne, Ferguson, and Rochwerg contributed to analysis of data. All authors contributed to drafting the article. Drs. Lau, Xie, Basmaji, Cook, Fowler, Kiflen, Sirotich, Iansavichene, Bagshaw, Wilcox, Lamontagne, Ferguson, and Rochwerg contributed to revising the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Dr. Xie receives a Career Scientist Award from Ontario Ministry of Health and Long-Term Care and a Canadian Institutes of Health Research (CIHR) New Investigator Award. Dr. Cook holds a Chair of the CIHR. Dr. Sirotich received funding from Board membership of the Canadian Arthritis Patient Alliance and Coronavirus Disease 2019 Global Rheumatology Alliance. Dr. Bagshaw received funding from Baxter and CNA Diagnostics, and he holds a Canada Research Chair in Critical Care Nephrology. Dr. Lamontagne holds a Canadian Research Chair in Patient-Centered Research in Acute Care. Dr. Ferguson received funding from Getinge and Xenios. Dr. Rochwerg is supported by a Hamilton Health Sciences Early Career Research Award. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: vince.lau@ualberta.ca Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Assess the impact of heterogeneity among established sepsis criteria (Sepsis-1, Sepsis-3, Centers for Disease Control and Prevention Adult Sepsis Event, and Centers for Medicare and Medicaid severe sepsis core measure 1) through the comparison of corresponding sepsis cohorts. Design: Retrospective analysis of data extracted from electronic health record. Setting: Single, tertiary-care center in St. Louis, MO. Patients: Adult, nonsurgical inpatients admitted between January 1, 2012, and January 6, 2018. Interventions: None. Measurements and Main Results: In the electronic health record data, 286,759 encounters met inclusion criteria across the study period. Application of established sepsis criteria yielded cohorts varying in prevalence: Centers for Disease Control and Prevention Adult Sepsis Event (4.4%), Centers for Medicare and Medicaid severe sepsis core measure 1 (4.8%), International Classification of Disease code (7.2%), Sepsis-3 (7.5%), and Sepsis-1 (11.3%). Between the two modern established criteria, Sepsis-3 (n = 21,550) and Centers for Disease Control and Prevention Adult Sepsis Event (n = 12,494), the size of the overlap was 7,763. The sepsis cohorts also varied in time from admission to sepsis onset (hr): Sepsis-1 (2.9), Sepsis-3 (4.1), Centers for Disease Control and Prevention Adult Sepsis Event (4.6), and Centers for Medicare and Medicaid severe sepsis core measure 1 (7.6); sepsis discharge International Classification of Disease code rate: Sepsis-1 (37.4%), Sepsis-3 (40.1%), Centers for Medicare and Medicaid severe sepsis core measure 1 (48.5%), and Centers for Disease Control and Prevention Adult Sepsis Event (54.5%); and inhospital mortality rate: Sepsis-1 (13.6%), Sepsis-3 (18.8%), International Classification of Disease code (20.4%), Centers for Medicare and Medicaid severe sepsis core measure 1 (22.5%), and Centers for Disease Control and Prevention Adult Sepsis Event (24.1%). Conclusions: The application of commonly used sepsis definitions on a single population produced sepsis cohorts with low agreement, significantly different baseline demographics, and clinical outcomes. Washington University in St. Louis, St. Louis, MO. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Dr. Michelson received funding as a shareholder of Pfizer. Dr. Lai received funding as a shareholder of Altria Group, Apple, Berkshire Hathaway, Barnes Group, Carnival Corp, Citigroup, Johnson & Johnson, Verizon Communications, Walt Disney, Royal Caribbean Cruises, Caterpillar, McDonald’s Corp, Ubiquiti, Westinghouse Air Brake Technologies, and Yum! Brands. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: amichels@wustl.edu Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: There is very limited information about glycemic control after discharge from the ICU. The aims of this study were to evaluate the prevalence of hypoglycemia in ICU survivors with type-2 diabetes and determine whether hypoglycemia is associated with cardiac arrhythmias. Design: Prospective, observational, two-center study. Participants underwent up to 5 days of simultaneous blinded continuous interstitial glucose monitoring and ambulatory 12-lead electrocardiogram monitoring immediately after ICU discharge during ward-based care. Frequency of arrhythmias, heart rate variability, and cardiac repolarization markers were compared between hypoglycemia (interstitial glucose ≤ 3.5 mmol/L) and euglycemia (5–10 mmol/L) matched for time of day. Setting: Mixed medical-surgical ICUs in two geographically distinct university-affiliated hospitals. Patients: Patients with type-2 diabetes who were discharged from ICU after greater than or equal to 24 hours with greater than or equal to one organ failure and were prescribed subcutaneous insulin were eligible. Measurements and Main Results: Thirty-one participants (mean ± SD, age 65 ± 13 yr, glycated hemoglobin 64 ± 22 mmol/mol) were monitored for 101 ± 32 hours post-ICU (total 3,117 hr). Hypoglycemia occurred in 12 participants (39%; 95% CI, 22–56%) and was predominantly nocturnal (40/51 hr) and asymptomatic (25/29 episodes). Participants experiencing hypoglycemia had 2.4 ± 0.7 discrete episodes lasting 45 minutes (interquartile range, 25–140 min). Glucose nadir was less than or equal to 2.2 mmol/L in 34% of episodes. The longest episode of nocturnal hypoglycemia was 585 minutes with glucose nadir less than 2.2 mmol/L. Simultaneous electrocardiogram and continuous interstitial glucose monitoring recordings were obtained during 44 hours of hypoglycemia and 991 hours of euglycemia. Hypoglycemia was associated with greater risk of bradycardia but did not affect atrial or ventricular ectopics, heart rate variability, or cardiac repolarization. Conclusions: In ICU survivors with insulin-treated type-2 diabetes, hypoglycemia occurs frequently and is predominantly nocturnal, asymptomatic, and prolonged. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by grant funding from the Australian and New Zealand Intensive Care Foundation. Dr. Ali Abdelhamid’s institution received funding from the Intensive Care Foundation and Baxter; she disclosed that Welch Allyn Australia loaned Holter recorders for the conduct of the study but was not involved in the design, conduct, analysis, or reporting of the study; and she was supported by a Royal Adelaide Hospital A. R. Clarkson Scholarship. Dr. Bernjak received support for article research from the Intensive Care Foundation. Drs. Bernjak’s, Summers’, and Heller’s institutions received funding from an Intensive Care Foundation grant, administered by Melbourne Health. Dr. Phillips was supported by a Royal Adelaide Hospital Early Career Fellowship. Dr. Heller received funding from NovoNordisk, Eli Lilly, Zealand Pharma, Sanofi, Aventis, and Astra Zeneca. Dr. Deane is supported by a National Health and Medical Research Council Career Development Fellowship. The remaining authors have disclosed that they do not have any potential conflicts of interest. Welch Allyn Australia loaned Holter recorders for the conduct of the study but was not involved in the design, conduct, analysis, or reporting of the study. This work was conducted at the Royal Adelaide Hospital, Port Road, Adelaide, SA, Australia; the University of Adelaide, SA, Australia; the Royal Melbourne Hospital, Grattan Street, Parkville, VIC, Australia; and the University of Sheffield, Western Bank, Sheffield, United Kingdom. This study was registered at the Australian and New Zealand Clinic Trials Registry (http://www.anzctr.org.au) as ACTRN 12615000099527. For information regarding this article, E-mail yasmine.aliabdelhamid@mh.org.au Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Hypercoagulability may be a key mechanism for acute organ injury and death in patients with severe coronavirus disease 2019, but the relationship between elevated plasma levels of D-dimer, a biomarker of coagulation activation, and mortality has not been rigorously studied. We examined the independent association between D-dimer and death in critically ill patients with coronavirus disease 2019. Design: Multicenter cohort study. Setting: ICUs at 68 hospitals across the United States. Patients: Critically ill adults with coronavirus disease 2019 admitted to ICUs between March 4, 2020, and May 25, 2020, with a measured D-dimer concentration on ICU day 1 or 2. Interventions: None. Measurements and Main Results: The primary exposure was the highest normalized D-dimer level (assessed in four categories: < 2×, 2–3.9×, 4–7.9×, and ≥ 8× the upper limit of normal) on ICU day 1 or 2. The primary endpoint was 28-day mortality. Multivariable logistic regression was used to adjust for confounders. Among 3,418 patients (63.1% male; median age 62 yr [interquartile range, 52–71 yr]), 3,352 (93.6%) had a D-dimer concentration above the upper limit of normal. A total of 1,180 patients (34.5%) died within 28 days. Patients in the highest compared with lowest D-dimer category had a 3.11-fold higher odds of death (95% CI, 2.56–3.77) in univariate analyses, decreasing to a 1.81-fold increased odds of death (95% CI, 1.43–2.28) after multivariable adjustment for demographics, comorbidities, and illness severity. Further adjustment for therapeutic anticoagulation did not meaningfully attenuate this relationship (odds ratio, 1.73; 95% CI, 1.36–2.19). Conclusions: In a large multicenter cohort study of critically ill patients with coronavirus disease 2019, higher D-dimer levels were independently associated with a greater risk of death. A full list of the STOP-COVID investigators is provided in the Supplemental Appendix (Supplemental Digital Content 1, http://links.lww.com/CCM/G206). Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Drs. Zakai and Leaf contributed equally. Supported, in part, by the following grants from the National Institutes of Health: F32DC017342 (to Dr. Gupta); R01HL153384 (to Dr. Hayek); R01HL144566 and R01DK125786 (to Dr. Leaf); K23DK120811(to Dr. Srivastava); K08GM134220, and R03AG060179 (to Dr. Shaefi); and R01HL141290 (to Dr. Zakai). Dr. Gupta’s institution received funding from the Foundation for the National Institutes of Health (NIH) 5 F32 DC 17342-2; she received funding from GlaxoSmithKline; she is a scientific coordinator for the Anemia Studies in CKD: Erythropoiesis via a Novel Prolyl Hydroxylase Inhibitor Daprodustat (ASCEND) trial (GlaskoSmithKline). Dr. Srivastava received funding from CVS Caremark, AstraZeneca, Horizon Therapeutics, PLC, and Tate & Latham. Dr. Shaefi’s institution received funding from the National Institute on Aging/NIH R03AG060179 and the National Institute of General Medical Sciences/NIH K08GM134220; he received support for article research from the NIH. Dr. Bagchi's institution received funding from the American Heart Association 20IPA35360009. He received funding from Lungpacer Medical, Inc. Dr. Al-Samkari received funding from Agios, Dova, Rigel, Argenx, and Amgen. Dr. Zakai’s institution received funding from the NIH and Centers for Disease Control and Prevention. Dr. Leaf received research support from BioPorto. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: DELEAF@bwh.harvard.edu Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: During the coronavirus disease 2019 pandemic, frontline healthcare professionals were asked to reorganize the provision of critical care in unprecedented ways. Our aim was to gain insight into the lived experience of clinicians who worked in ICUs during the surge. Design: Qualitative study using semistructured, in-depth interviews. Setting: Clinicians who worked in three ICUs in Paris (France) during the peak of the pandemic (April and May 2020). Participants: Twenty-seven ICU clinicians (12 physicians, 11 nurses, three nursing assistants, and one respiratory therapist). Measurements and Main Results: Interviews were audio recorded and analyzed using thematic analysis. Six themes emerged: coping with initial disorganization and creating new routines, the intensification of professional relationships and the development of unexpected collaborations, losing one’s reference points and recreating meaningful interactions with patients, working under new constraints and developing novel interactions with family members, compensating for the absence of family members and rituals at the end of life, and the full engagement of ICU clinicians during the coronavirus disease 2019 crisis. Conclusions: Among ICU clinicians, there was a sense of total professional engagement during the surge. Caring for critically ill coronavirus disease 2019 patients was fraught with challenges and generated a strong feeling of responsibility, as clinicians felt they had to compensate for the absence of family members. Rethinking policies about family visits and safeguarding positive relationships among colleagues are two important priorities for future healthcare crises. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by the French Ministry of Health, Programme Hospitalier de Recherche Clinique 2020, APHP200389. Dr. Kentish-Barnes’ institution received funding from the French Ministry of Health. Dr. Demoule received funding from Medtronic, Philips, Baxter, Hamilton, Fisher & Paykel, French Ministry of Health, Getinge, Respinor, and Lungpacer. Dr. Azoulay’s institution received funding from Fisher & Paykel, MSD, Pfizer, Baxter, and Gilead, and he received funding from Gilead, Baxter, Alexion, Ablynx, and Pfizer. The remaining authors have disclosed that they do not have any potential conflicts of interest. ClinicalTrials.gov Identifier: NCT04341519. For information regarding this article, E-mail: nancy.kentish@aphp.fr Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objective: Compared with individual-patient randomized controlled trials, cluster randomized controlled trials have unique methodological and ethical considerations. We evaluated the rationale, methodological quality, and reporting of cluster randomized controlled trials in critical care studies. Data Sources: Systematic searches of Medline, Embase, and Cochrane Central Register were performed. Study Selection: We included all cluster randomized controlled trials conducted in adult, pediatric, or neonatal critical care units from January 2005 to September 2019. Data Extraction: Two reviewers independently screened citations, reviewed full texts, protocols, and supplements of potentially eligible studies, abstracted data, and assessed methodology of included studies. Data Synthesis: From 1,902 citations, 59 cluster randomized controlled trials met criteria. Most focused on quality improvement (24, 41%), antimicrobial therapy (9, 15%), or infection control (9, 15%) interventions. Designs included parallel-group (25, 42%), crossover (21, 36%), and stepped-wedge (13, 22%). Concealment of allocation was reported in 21 studies (36%). Thirteen studies (22%) reported at least one method of blinding. The median total sample size was 1,660 patients (interquartile range, 813–4,295); the median number of clusters was 12 (interquartile range, 5–24); and the median patients per cluster was 141 (interquartile range, 54–452). Sample size calculations were reported in 90% of trials, but only 54% met Consolidated Standards of Reporting Trials guidance for sample size reporting. Twenty-seven of the studies (46%) identified a fixed number of available clusters prior to trial commencement, and only nine (15%) prespecified both the number of clusters and patients required to detect the expected effect size. Overall, 36 trials (68%) achieved the total prespecified sample size. When analyzing data, 44 studies (75%) appropriately adjusted for clustering when analyzing the primary outcome. Only 12 (20%) reported an intracluster coefficient (median 0.047 [interquartile range, 0.01–0.13]). Conclusions: Cluster randomized controlled trials in critical care typically involve a small and fixed number of relatively large clusters. The reporting of key methodological aspects of these trials is often inadequate. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Dr. Scales’ institution received funding from the Canadian Institutes for Health Research. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: brian.cuthbertson@sunnybrook.ca Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Over 5 million people in Latin America are infected with Trypanosoma cruzi, the parasitic agent of Chagas disease (Chagas disease in Latin America: an epidemiological update based on 2010 estimates, 2015). Although transmission most commonly occurs through the triatomine vector (“kissing bug”), vertical transmission from mother to infant accounts for over 20% of new cases (Howard et al., 2014). Congenitally infected infants, like other individuals with Chagas disease, have up to a 30% lifetime risk of developing severe and potentially fatal sequelae such as cardiomyopathy, arrhythmias, and gastrointestinal or neurological complications (Bern et al., 2011; Py, 2011).

Myxozoans are highly diverse and globally distributed cnidarian endoparasites in freshwater and marine habitats. They have adopted a heteroxenous life cycle, including invertebrate and fish hosts, and have been associated with diseases in aquaculture and wild fish stocks. Despite their importance, genomic resources of myxozoans have proven difficult to obtain due to their miniaturized and derived genome character and close associations with fish tissues. The first ‘omic’ datasets have now become the main resource for a better understanding of host–parasite interactions, virulence, and diversity, but also the evolutionary history of myxozoans.

by Jesus Serrano-Lomelin, Anne Hicks, Manoj Kumar, David W. Johnson, Radha Chari, Alvaro Osornio-Vargas, Susan Crawford, Jeffrey Bakal, Maria B. Ospina Introduction Adverse birth outcomes have important consequences for future lung health. We evaluated patterns of respiratory health services utilization in early childhood among children born preterm (PTB), small and large for gestational age at term (SGA and LGA, respectively), and appropriate-for-gestational age at term. Materials and methods We conducted a population-based retrospective cohort study using administrative health data of all singleton live births in Alberta, Canada between 2005–2010. Data on hospitalizations and emergency department (ED) visits from birth to 5 years were collected for asthma, bronchitis, bronchiolitis, croup, influenza, pneumonia, and other acute upper and lower respiratory tract infections (other URTI and other LRTI, respectively). Adjusted rate ratios were estimated for respiratory ED visits and hospitalizations for adverse birth outcomes using the appropriate-for-gestational age at term group as reference. Age-specific trajectories of total respiratory health services utilization rates for each group were estimated in Poisson models. Results A total of 293,764 episodes of respiratory care from 206,994 children were analyzed. Very PTB children had the highest rates of health services use for all respiratory conditions, particularly for asthma, pneumonia, and bronchiolitis hospitalizations. Moderate/late PTB children also had elevated ED visits and hospitalizations for all respiratory conditions. Children born SGA showed high rates of ED visits for other LRTI, and of hospitalizations for bronchitis, bronchiolitis, and other URTI. Children born LGA had high rates of croup and other URTI ED visits, and of bronchiolitis and bronchiolitis hospitalizations. Age-specific trajectories showed a decreasing trend in the rates of total respiratory health service utilization from birth to five years of age for all groups studied. Children born PTB and LGA at term significantly required more respiratory health services over time compared to the reference group. Conclusion Patterns of paediatric respiratory health services utilization vary according to gestational age and fetal growth.

by Christian Salbach, Matthias Mueller-Hennessen, Moritz Biener, Kiril M. Stoyanov, Mehrshad Vafaie, Michael R. Preusch, Lars P. Kihm, Uta Merle, Paul Schnitzler, Hugo A. Katus, Evangelos Giannitsis Background An established objective and standardized reporting of clinical severity and disease progression in COVID-19 is still not established. We validated and compared the usefulness of two classification systems reported earlier–a severity grading proposed by Siddiqi and a system from the National Australian COVID-19 guideline. Both had not been validated externally and were now tested for their ability to predict complications. Methods In this retrospective, single-centre observational study, patients hospitalized with confirmed COVID-19 across all severity stages were enrolled. The clinical severity was graded at admission and during hospitalization. Multivariate Cox regression was used to identify independent risk factors for mortality, a composite primary (mortality, incident acute respiratory distress syndrome, incident mechanical ventilation), a secondary endpoint (mortality, incident acute myocardial injury, incident venous thrombosis, pulmonary embolism or stroke) and progression of severity grades. Results Of 109 patients 17 died, 31 and 48 developed the primary and secondary endpoint, respectively. Worsening of the severity grade by at least one stage occurred in 27 and 28 patients, respectively. Siddiqi and Australian classification were identified as independent predictors for the primary endpoint (adjusted hazard ratio (aHR) 2.30, p<0.001 and aHR 2.08, p<0.001), for the secondary endpoint (aHR 2.12, p<0.001 and aHR 1.79, p<0.001) and mortality (aHR 2.30, p = 0.071 and aHR 1.98, p = 0.017). Both classification systems showed very good agreement regarding initial grading and good agreement regarding progression of severity stages. Conclusions Standardized and objective severity grading is useful to unequivocally stratify patients presenting with COVID-19 for their individual risk of complications.

by Liliana Sánchez-González, Talia M. Quandelacy, Michael Johansson, Brenda Torres-Velásquez, Olga Lorenzi, Mariana Tavarez, Sanet Torres, Luisa I. Alvarado, Gabriela Paz-Bailey Background Acute febrile illness (AFI) is an important cause for seeking health care among children. Knowledge of the most common etiologic agents of AFI and its seasonality is limited in most tropical regions. Methodology/Principal findings To describe the viral etiology of AFI in pediatric patients (≤18 years) recruited through a sentinel enhanced dengue surveillance system (SEDSS) in Southern Puerto Rico, we analyzed data for patients enrolled from 2012 to May 2018. To identify seasonal patterns, we applied time-series analyses to monthly arboviral and respiratory infection case data. We calculated coherence and phase differences for paired time-series to quantify the association between each time series.A viral pathogen was found in 47% of the 14,738 patients. Influenza A virus was the most common pathogen detected (26%). The incidence of Zika and dengue virus etiologies increased with age. Arboviral infections peaked between June and September throughout the times-series. Respiratory infections have seasonal peaks occurring in the fall and winter months of each year, though patterns vary by individual respiratory pathogen. Conclusions/Significance Distinct seasonal patterns and differences in relative frequency by age groups seen in this study can guide clinical and laboratory assessment in pediatric patients with AFI in Puerto Rico.

by Axel Franzen, Fabienne Wöhner The health risk of the coronavirus pandemic is age-specific. The symptoms of a COVID-19 infection are usually mild in the healthy population below the age of 65; however, the measures laid down to prevent the spread of the virus apply typically to the whole population. Hence, those who have a low risk of severe symptoms face a social dilemma in cooperating and complying with the safety measures: Cooperating in preventing the spread of the disease is good for society but comes with individual costs. These costs provide an incentive not to cooperate with the safety measures. In this paper we analyze via structural equation modelling a sample of young adults (N = 510) who were surveyed right after the end of the first lockdown period in Switzerland. We investigate why and to what extent they cooperated in preventing the epidemic by following the recommendation to stay at home as much as possible. We hypothesize that those respondents who perceive themselves to be personally at risk, or who have relatives belonging to the risk group, complied more often with the safety measures as compared to those without severe risks. Cooperating should also be linked to individuals’ pro-social orientation. Furthermore, we hypothesize that those who believe that the virus is dangerous for society or who have a personal interest in protection show higher support for the general safety measures. Our empirical results show that compliance with the coronavirus social distancing measures was generally very high during the first lockdown. Although young adults perceived themselves to be at low personal risk, they still believed that the virus is dangerous for society. Those who had a personal interest in staying at home because they had relatives belonging to the risk group complied more often with the safety measures. Overall, the results suggest that the support of the preventive measures is the most important promoter of cooperation to prevent the spread of COVID-19.

by Prakhar Godara, Stephan Herminghaus, Knut M. Heidemann In the framework of homogeneous susceptible-infected-recovered (SIR) models, we use a control theory approach to identify optimal pandemic mitigation strategies. We derive rather general conditions for reaching herd immunity while minimizing the costs incurred by the introduction of societal control measures (such as closing schools, social distancing, lockdowns, etc.), under the constraint that the infected fraction of the population does never exceed a certain maximum corresponding to public health system capacity. Optimality is derived and verified by variational and numerical methods for a number of model cost functions. The effects of immune response decay after recovery are taken into account and discussed in terms of the feasibility of strategies based on herd immunity.

by Jesús Díez-Manglano, Marta Nataya Solís-Marquínez, Andrea Álvarez García, Nicolás Alcalá-Rivera, Irene Maderuelo Riesco, Martín Gericó Aseguinolaza, José Luis Beato Pérez, Manuel Méndez Bailón, Ane-Elbire Labirua-Iturburu Ruiz, Miriam García Gómez, Carmen Martínez Cilleros, Paula María Pesqueira Fontan, Lucy Abella Vázquez, Julio César Blázquez Encinar, Ramon Boixeda, Ricardo Gil Sánchez, Andrés de la Peña Fernández, José Loureiro Amigo, Joaquín Escobar Sevilla, Marcos Guzmán Garcia, María Dolores Martín Escalante, Jeffrey Oskar Magallanes Gamboa, Ángel Luis Martínez González, Carlos Lumbreras Bermejo, Juan Miguel Antón Santos, for the SEMI-COVID-19 Network Aim To determine whether healthcare workers (HCW) hospitalized in Spain due to COVID-19 have a worse prognosis than non-healthcare workers (NHCW). Methods Observational cohort study based on the SEMI-COVID-19 Registry, a nationwide registry that collects sociodemographic, clinical, laboratory, and treatment data on patients hospitalised with COVID-19 in Spain. Patients aged 20–65 years were selected. A multivariate logistic regression model was performed to identify factors associated with mortality. Results As of 22 May 2020, 4393 patients were included, of whom 419 (9.5%) were HCW. Median (interquartile range) age of HCW was 52 (15) years and 62.4% were women. Prevalence of comorbidities and severe radiological findings upon admission were less frequent in HCW. There were no difference in need of respiratory support and admission to intensive care unit, but occurrence of sepsis and in-hospital mortality was lower in HCW (1.7% vs. 3.9%; p = 0.024 and 0.7% vs. 4.8%; p<0.001 respectively). Age, male sex and comorbidity, were independently associated with higher in-hospital mortality and healthcare working with lower mortality (OR 0.211, 95%CI 0.067–0.667, p = 0.008). 30-days survival was higher in HCW (0.968 vs. 0.851 p<0.001). Conclusions Hospitalized COVID-19 HCW had fewer comorbidities and a better prognosis than NHCW. Our results suggest that professional exposure to COVID-19 in HCW does not carry more clinical severity nor mortality.

by Courtney M. Yuen, Ana Karina Millones, Daniela Puma, Judith Jimenez, Jerome T. Galea, Roger Calderon, Gabriela S. Pages, Meredith B. Brooks, Leonid Lecca, Tom Nicholson, Mercedes C. Becerra, Salmaan Keshavjee Background Targeted testing and treatment of TB infection to prevent disease is a pillar of TB elimination. Despite recent global commitments to greatly expand access to preventive treatment for TB infection, there remains a lack of research on how best to expand preventive treatment programs in settings with high TB burdens. Methods We conducted implementation research in Lima, Peru, around a multifaceted intervention to deliver TB preventive treatment to close contacts of all ages, health care workers, and people in congregate settings. Key interventions included use of the interferon gamma release assay (IGRA), specialist support for generalist physicians at primary-level health facilities, and treatment support by community health workers. We applied a convergent mixed methods approach to evaluate feasibility and acceptability based on a care cascade framework. Findings During April 2019-January 2020, we enrolled 1,002 household contacts, 148 non-household contacts, 107 residents and staff of congregate settings, and 357 health care workers. Cumulative completion of the TB preventive care cascade was 34% for contacts…

by Kimia Kardani, Azam Bolhassani Among various delivery systems for vaccine and drug delivery, cell-penetrating peptides (CPPs) have been known as a potent delivery system because of their capability to penetrate cell membranes and deliver some types of cargoes into cells. Several CPPs were found in the proteome of viruses such as Tat originated from human immunodeficiency virus-1 (HIV-1), and VP22 derived from herpes simplex virus-1 (HSV-1). In the current study, a wide-range of CPPs was identified in the proteome of SARS-CoV-2, a new member of coronaviruses family, using in silico analyses. These CPPs may play a main role for high penetration of virus into cells and infection of host. At first, we submitted the proteome of SARS-CoV-2 to CellPPD web server that resulted in a huge number of CPPs with ten residues in length. Afterward, we submitted the predicted CPPs to C2Pred web server for evaluation of the probability of each peptide. Then, the uptake efficiency of each peptide was investigated using CPPred-RF and MLCPP web servers. Next, the physicochemical properties of the predicted CPPs including net charge, theoretical isoelectric point (pI), amphipathicity, molecular weight, and water solubility were calculated using protparam and pepcalc tools. In addition, the probability of membrane binding potential and cellular localization of each CPP were estimated by Boman index using APD3 web server, D factor, and TMHMM web server. On the other hand, the immunogenicity, toxicity, allergenicity, hemolytic potency, and half-life of CPPs were predicted using various web servers. Finally, the tertiary structure and the helical wheel projection of some CPPs were predicted by PEP-FOLD3 and Heliquest web servers, respectively. These CPPs were divided into: a) CPP containing tumor homing motif (RGD) and/or tumor penetrating motif (RXXR); b) CPP with the highest Boman index; c) CPP with high half-life (~100 hour) in mammalian cells, and d) CPP with +5.00 net charge. Based on the results, we found a large number of novel CPPs with various features. Some of these CPPs possess tumor-specific motifs which can be evaluated in cancer therapy. Furthermore, the novel and potent CPPs derived from SARS-CoV-2 may be used alone or conjugated to some sequences such as nuclear localization sequence (NLS) for vaccine and drug delivery.

by Victoria L. Harrod, Russell L. Groves, Matthew A. Maurice, Jeri D. Barak The human enteric bacterial pathogen Salmonella enterica causes approximately 1.35 million cases of food borne illnesses annually in the United States. Of these salmonellosis cases, almost half are derived from the consumption of fresh, raw produce. Although epiphytic S. enterica populations naturally decline in the phyllosphere, a subset of phytophagous insects have recently been identified as biological multipliers, consequently facilitating the growth of bacterial populations. We investigated whether tomato leaves with macroscopic feeding damage, caused by infestation of adult Western flower thrips (Frankliniella occidentalis), support higher S. enterica populations. To explore this hypothesis, we assessed S. enterica populations in response to thrips feeding by varying insect density, plant age, and the gender of the insect. As a reference control, direct leaf damage analogous to thrips feeding was also evaluated using directed, hydraulic pressure. In a supplementary set series of experiments, groups of F. occidentalis infested tomato plants were later inoculated with S. enterica to determine how prior insect infestation might influence bacterial survival and persistence. Following an infestation period, leaves visibly damaged by adult F. occidentalis supported significantly higher S. enterica populations and resulted in greater amounts of electrolyte leakage (measured as electrical conductivity) than leaves lacking visible feeding damage. Plant age did not significantly influence S. enterica populations or estimates of electrolyte leakage, independent of initial infestation. Additionally, the gender of the insect did not uniquely influence S. enterica population dynamics. Finally, applications of aggressive water bombardment resulted in more electrolyte leakage than leaves damaged by F. occidentalis, yet supported comparable S. enterica populations. Together, this study indicates that F. occidentalis feeding is one of the many potential biological mechanisms creating a more habitable environment for S. enterica.

by Yaser A. Al Naam, Salah H. Elsafi, Zeyad S. Alkharraz, Othman A. Alfahad, Khalid M. Al-Jubran, Eidan M. Al Zahrani Community face masking is possibly of great value in reducing COVID-19 transmission, especially when universally adopted with high compliance. The aim of this study is to investigate the knowledge, common misconceptions, barriers, and the compliance of the community with the use of face masks for the prevention of COVID-19. A validated questionnaire was administered to the participants through a web link by using various social media. The collected data were statistically analyzed for significant differences according to demographic variables. The average knowledge of face masks and their role in preventing COVID-19 transmission was 95.64%, with no differences among most of the demographical factors. Older groups and females demonstrated a better attitude towards wearing face masks than other groups did (p<0.001). Another significant difference in the participant’s attitude was noticed between the various educational levels, employment, and nationality (p<0.001). Of the total respondents, 88.2% encouraged wearing face masks. Misconceptions about wearing face masks were very low. The frequency of wearing face masks at public places, workplaces, or social gatherings was 87.2%, 80.5%, and 47.5% respectively. There was a significant variation in the compliance with wearing face masks between the various groups based on age, gender, nationality, and employment status (p<0.001). The inconvenience in wearing face masks was reported by 36.3%. Face irritation and ear pain were reported by 70.2% and 43.5%, respectively. The inconvenience of wearing face masks with eyeglasses was reported by 44.3% of those wearing eyeglasses. In general, the study demonstrated a good attitude among participants towards wearing face masks. Although the respondents in the study were aware of the benefits of wearing face masks, the barriers may have decreased their desire to do so. These barriers include difficulty in breathing, discomfort, face irritation, and ear pain.

by Tewodros Tesfa, Behailu Hawulte, Abebe Tolera, Degu Abate Background Hepatitis B virus (HBV) is a highly contagious pathogen that has become a severe public health problem and a major cause of morbidity and mortality, particularly in developing countries. Medical students are at high occupational risk during their training. However, no facility-based studies were found among medical students in eastern Ethiopia. Thus, this study aimed to investigate the seroprevalence of Hepatitis B Virus and associated factors among medical students in eastern Ethiopia. Methods A facility-based cross-sectional study was conducted among 407 randomly selected medical students from March to June 2018. A pretested and structured questionnaire was used to collect data on socio-demographic characteristics and other risk factors. A 5ml blood was collected, and the serum was analyzed for Hepatitis B surface antigen (HBsAg) using the Instant Hepatitis B surface antigen kit. Data were entered using Epidata version 3.1 and analyzed using SPSS statistical packages version 22. Outcome and explanatory variables were described using descriptive summary measures. Binary and multivariable logistic regression was conducted at 95% CI and an association at P-value < 0.05 was declared statistically significant. Results The seroprevalence of hepatitis B virus surface antigen was 11.5% (95%CI = 8.6, 14.7). Poor knowledge of universal precaution guideline (AOR = 2.58; 95% CI = [1.35–4.93]), history of needle stick injury (AOR = 2.11; 95% CI = [1.07–4.18]) and never been vaccinated for HBV (AOR = 2.34; 95% CI = [1.17–4.69]) were found statistically significantly associated with HBsAg positivity after multivariate analysis. Conclusion Hepatitis B virus infection rate is high among health care trainees in eastern Ethiopia. Improvement at health care practice centers safety through training on universal precaution guidelines, and scaling up HBV vaccination is mandatory.

by Alexander Henzi, Gian-Reto Kleger, Matthias P. Hilty, Pedro D. Wendel Garcia, Johanna F. Ziegel, on behalf of RISC-19-ICU Investigators for Switzerland Rationale The COVID-19 pandemic induces considerable strain on intensive care unit resources. Objectives We aim to provide early predictions of individual patients’ intensive care unit length of stay, which might improve resource allocation and patient care during the on-going pandemic. Methods We developed a new semiparametric distributional index model depending on covariates which are available within 24h after intensive care unit admission. The model was trained on a large cohort of acute respiratory distress syndrome patients out of the Minimal Dataset of the Swiss Society of Intensive Care Medicine. Then, we predict individual length of stay of patients in the RISC-19-ICU registry. Measurements The RISC-19-ICU Investigators for Switzerland collected data of 557 critically ill patients with COVID-19. Main results The model gives probabilistically and marginally calibrated predictions which are more informative than the empirical length of stay distribution of the training data. However, marginal calibration was worse after approximately 20 days in the whole cohort and in different subgroups. Long staying COVID-19 patients have shorter length of stay than regular acute respiratory distress syndrome patients. We found differences in LoS with respect to age categories and gender but not in regions of Switzerland with different stress of intensive care unit resources. Conclusion A new probabilistic model permits calibrated and informative probabilistic prediction of LoS of individual patients with COVID-19. Long staying patients could be discovered early. The model may be the basis to simulate stochastic models for bed occupation in intensive care units under different casemix scenarios.

by Robert R. Dobos, Kaitlin Benedict, Brendan R. Jackson, Orion Z. McCotter Coccidioidomycosis, also known as Valley fever, is a disease that can result in substantial illness and death. It is most common in the southwestern United States and areas of Latin America with arid climates, though reports increasingly suggest its range is wider than previously recognized. The natural habitat of the causative organisms, Coccidioides spp., have been associated with certain soil properties and climatic conditions. Current understanding of its geographic range is primarily defined by skin test studies and outbreak locations. We developed a fuzzy system model to predict suitable soil habitats for Coccidioides across the western United States based on parameters (electrical conductivity, organic matter content, pH, water holding capacity, temperature, and precipitation) from sites where soil sampling has confirmed the presence of Coccidioides. The model identified high coccidioidomycosis incidence areas as having high suitability and identified pockets of elevated suitability corresponding with outbreak locations outside the traditional range. By providing high-resolution estimates of Coccidioides suitability, including areas without public health surveillance for coccidioidomycosis, this model may be able to aid public health and clinical provider decision making. Awareness of possible Coccidioides soil habitats could help mitigate risk during soil-disturbing activities and help providers improve coccidioidomycosis diagnosis and treatment.

by Eyasu Alem Lake, Birhanu Wondimeneh Demissie, Natneal Atnafu Gebeyehu, Addisu Yeshambel Wassie, Kelemu Abebe Gelaw, Gedion Asnake Azeze Background The World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) a global pandemic on 11th March, 2020. In Ethiopia, more than 90,490 and 1,300 confirmed cases and deaths were reported by the Federal Ministry of Health at the time of writing up this project. As health care providers are frontline workers managing the COVID-19 pandemic, this systematic review and meta-analysis aimed to assess the pooled level of knowledge, attitude, and practice towards COVID-19 among health professionals in Ethiopia. Methods PubMed, Google Scholar, Excerpta Medica database (EMBASE), Cochrane Library, Web of Science, and African Journal of Online (AJOL) were searched. The data were extracted using Microsoft Excel and analyzed using STATA version 14. Publication bias was checked by funnel plot and more objectively through Egger’s regression test, with P < 0.05 considered to indicate potential publication bias. The heterogeneity of studies was checked using I2 statistics. Pooled analysis was conducted using a weighted inverse variance random-effects model. Subgroup analysis was done related to geographic region and time. A leave-one-out sensitivity analysis was also employed. Result A total of 11 studies with 3,843 study participants for knowledge, eight studies with 2,842 study participants for attitude and 10 studies with 3, 435 study participants for practice were used to estimate the pooled level of good knowledge, positive attitude and poor practice among health professionals. The overall estimated good level of knowledge, positive attitude and poor practice towards COVID-19 was found to be 79.4% (95% CI: 73.5%-85.2%; I2 = 96%), 73.7% (95%CI: 63.09%-84.4%; I2 = 98.3%) and 40.3% (95%CI: 31.1%-49.6%; I2 = 97.1%) respectively. Conclusion Study findings showed that there were significant gaps in COVID-19 related knowledge, attitude and practice with respect to World Health Organization recommendations on COVID-19 management and personal protection practices. This study therefore recommends that institutions provide with immediate effect accurate and up-to-date information on COVID-19 and training that encourages improved knowledge, attitude and practice to mitigate this pandemic.

E. Won et al.

C. V. Nonaka et al.

Tropical Medicine & International Health, Accepted Article.