In adults with COVID-19 and severe hypoxemia, lower vs. higher oxygenation targets increased days alive without life support.

SOURCE CITATION: Nielsen FM, Klitgaard TL, Siegemund M, et al; HOT-COVID Trial Group. Lower vs higher oxygenation target and days alive without life support in COVID-19: the HOT-COVID randomized clinical trial. JAMA. 2024;331:1185-1194. 38501214.

Challenges for a broad international implementation of the current severe community-acquired pneumonia guidelines.

Severe community-acquired pneumonia (sCAP) remains one of the leading causes of admission to the intensive care unit, thus consuming a large share of resources and is associated with high mortality rates worldwide. The evidence generated by clinical studies in the last decade was translated into recommendations according to the first published guidelines focusing on severe community-acquired pneumonia. Despite the advances proposed by the present guidelines, several challenges preclude the prompt implementation of these diagnostic and therapeutic measures. The present article discusses the challenges for the broad implementation of the sCAP guidelines and proposes solutions when applicable.

Temporal Trends in Methamphetamine Use in Patients Admitted to the Hospital: A Retrospective Cohort Study.

OBJECTIVES: Although methamphetamine use is common, the scope of methamphetamine use and outcomes for patients admitted to the hospital is unclear. This study aims to identify the prevalence of methamphetamine use from January 2012 to January 2022, coingestions, hospital course, and readmission rate of admitted patients. METHODS: This was a retrospective cohort study conducted on patients admitted to our center with the following inclusions: age older than 18 years, positive/"pending confirm" value for methamphetamine on urine drug screen, and/or an International Classification of Diseases , Tenth Revision , code related to stimulant use disorder as an active issue. Urine drug screen data are reported as methamphetamine +/- and polysubstance (PS) +/-. Patient demographics, admission diagnosis, and hospital course were extracted. Statistical tests used included t tests and Mann-Whitney U tests. RESULTS: A total of 19,159 encounters were included, representing 12,057 unique patients. The median (interquartile range) age was 43 (33-54) years. Of all encounters, 35.3% were methamphetamine + and PS -, and 46.3% were methamphetamine + and PS +. Hospitalizations increased from 883 in 2012 to 2532 in 2021. The median (IQR) hospital stay was 48 (48-120) hours. Of all encounters, 16.8% included an intensive care unit (ICU) admission, and the median ICU stay was 42 (21-87) hours. A total of 2988 patients (24.7%) were readmitted within the study period, and 4988 (71.5%) returned within 1 year of the previous encounter. In context of all emergency department admissions from 2013 to 2022, 13.1% had a urine drug screen + for methamphetamine. CONCLUSIONS: Hospitalizations with recent methamphetamine use doubled at our institution from 2012 to 2022. In addition, 1 in 4 is readmitted (typically within 1 year), and a minority requires ICU care.

Choosing immunomodulating therapies for the treatment of COVID-19: recommendations based on placebo-controlled trial evidence.

BACKGROUND: Immunomodulatory therapy has been extensively studied in randomized clinical trials for the treatment of patients hospitalized for COVID-19 with inconsistent findings. Guideline committees, reviewing the same clinical trial data, have generated different recommendations for immunomodulatory therapy. OBJECTIVES: We hypothesize that trial design differences, specifically whether the study utilized an open-label or placebo-controlled design, accounted for the inconsistent mortality effects reported in clinical trials of immunomodulator therapies for COVID-19. SOURCES: We reviewed COVID-19 treatment guidelines (World Health Organization [WHO], Infectious Diseases Society of America [IDSA] and The National Institutes of Health [NIH]) and identified the meta-analyses associated with glucocorticoids, IL-6 inhibitors, JAK kinase inhibitors, and complement C5a inhibitors that were available to the guideline authors at the time recommendations were either made or updated. CONTENT: We identified a meta-analysis for each of the immunomodulator classes that are included in current COVID-19 treatment guidelines: glucocorticoids [WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group; Shankar-Hari M, Vale CL, Godolphin PJ, Fisher D, Higgins JPT, et al. Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19: A meta-analysis. JAMA. 2021;326:499-518] (cited 419), IL-6 antagonists [WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group; Shankar-Hari M, Vale CL, Godolphin PJ, Fisher D, Higgins JPT, et al. Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19: A meta-analysis. JAMA. 2021;326:499-518] (cited 419), JAK inhibitors [Kramer A, Prinz C, Fichtner F, Fischer AL, Thieme V, Grundeis F, et al. Janus kinase inhibitors for the treatment of COVID-19. Cochrane Database Syst Rev. 2022;6:CD015209] (cited 34), and complement C5a inhibitors [Tsai CL, Lai CC, Chen CY, Lee HS. The efficacy and safety of complement C5a inhibitors for patients with severe COVID-19: A systematic review and meta-analysis. Expert Rev Anti Infect Ther. 2023;21:77-86] (cited 1). Using the same randomized clinical trials, we evaluated the four meta-analyses accounting for trial design: placebo-controlled or open-label. Glucocorticoids (Risk Ratio [RR] 0.91 [95% CI, 0.49-1.69]), IL-6 inhibitors sarilumab (RR 1.17 [95% CI, 0.96-01.43]), and tocilizumab (RR 0.95 [95% CI, 0.76-1.19]) did not reduce mortality in placebo-controlled trials, whereas baricitinib did confer a large survival benefit (RR 0.65 [95% CI, 0.52-0.81]). The complement C5a inhibitor, vilobelimab, also reduced mortality in a single placebo-controlled trial (RR 0.76 [95% CI, 0.57-1.0]). IMPLICATIONS: Placebo-controlled trial evidence indicates that baricitinib should be the first choice immunomodulator for patients hospitalized for COVID-19 who require any form of oxygen support-low- or high-flow oxygen, non-invasive or invasive ventilation. Vilobelimab warrants study in a large placebo-controlled trial. Treatment guidelines for future pandemics should prioritize the results of placebo-controlled trials.

Improving Sepsis Outcomes in the Era of Pay-for-Performance and Electronic Quality Measures: A Joint IDSA/ACEP/PIDS/SHEA/SHM/SIDP Position Paper.

The Centers for Medicare & Medicaid Services (CMS) introduced the Severe Sepsis/Septic Shock Management Bundle (SEP-1) as a pay-for-reporting measure in 2015 and is now planning to make it a pay-for-performance measure by incorporating it into the Hospital Value-Based Purchasing Program. This joint IDSA/ACEP/PIDS/SHEA/SHM/SIPD position paper highlights concerns with this change. Multiple studies indicate that SEP-1 implementation was associated with increased broad-spectrum antibiotic use, lactate measurements, and aggressive fluid resuscitation for patients with suspected sepsis but not with decreased mortality rates. Increased focus on SEP-1 risks further diverting attention and resources from more effective measures and comprehensive sepsis care. We recommend retiring SEP-1 rather than using it in a payment model and shifting instead to new sepsis metrics that focus on patient outcomes. CMS is developing a community-onset sepsis 30-day mortality electronic clinical quality measure (eCQM) that is an important step in this direction. The eCQM preliminarily identifies sepsis using systemic inflammatory response syndrome (SIRS) criteria, antibiotic administrations or diagnosis codes for infection or sepsis, and clinical indicators of acute organ dysfunction. We support the eCQM but recommend removing SIRS criteria and diagnosis codes to streamline implementation, decrease variability between hospitals, maintain vigilance for patients with sepsis but without SIRS, and avoid promoting antibiotic use in uninfected patients with SIRS. We further advocate for CMS to harmonize the eCQM with the Centers for Disease Control and Prevention's (CDC) Adult Sepsis Event surveillance metric to promote unity in federal measures, decrease reporting burden for hospitals, and facilitate shared prevention initiatives. These steps will result in a more robust measure that will encourage hospitals to pay more attention to the full breadth of sepsis care, stimulate new innovations in diagnosis and treatment, and ultimately bring us closer to our shared goal of improving outcomes for patients.

Secondary infections in critically ill patients with COVID-19 receiving steroid therapy.

Secondary infections can occur during or after the treatment of an initial infection. Glucocorticoids may decrease mortality in patients with severe COVID-19; however, risk of secondary infection is not well described. Our primary objective was to investigate the risk of secondary infection among critically ill patients with COVID-19 treated with glucocorticoids. We examined patients with COVID-19 being treated in the intensive care unit at two academic medical centers from 1 to 7/2020. One hundred-seven patients were included. Of these, 31 received steroids and 76 patients did not. Analysis of the larger cohort was performed followed by a matched pairs analysis of 22 steroid and 22 non-steroid patients. Secondary infection was seen in 14 patients (45.2%) receiving steroids compared to 35(46.1%) not receiving steroids (p = 0.968). Secondary infections were most frequently encountered in the respiratory tract. Escherichia coli and Staphylococcus aureus were the most frequently identified organisms. Mortality was 16.1% in the steroid-treated group compared to 23.7% in the control group (p = 0.388). After performing matched pairs analysis and multivariable logistic regression there was no significant difference between secondary infection or mortality and steroid receipt. Secondary infections were common among critically ill patients with COVID-19, but the incidence of secondary infection was not significantly impacted by steroid treatment.

SARS-CoV-2 post-acute sequelae in previously hospitalised patients: systematic literature review and meta-analysis.

BACKGROUND: Many individuals hospitalised with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection experience post-acute sequelae of SARS-CoV-2 infection (PASC), sometimes referred to as "long COVID". Our objective was to conduct a systematic literature review and meta-analysis to identify PASC-associated symptoms in previously hospitalised patients and determine the frequency and temporal nature of PASC. METHODS: Searches of MEDLINE, Embase, Cochrane Library (2019-2021), World Health Organization International Clinical Trials Registry Platform and reference lists were performed from November to December 2021. Articles were assessed by two reviewers against eligibility criteria and a risk of bias tool. Symptom data were synthesised by random effects meta-analyses. RESULTS: Of 6942 records, 52 studies with at least 100 patients were analysed; ∼70% were Europe-based studies. Most data were from the first wave of the pandemic. PASC symptoms were analysed from 28 days after hospital discharge. At 1-4 months post-acute SARS-CoV-2 infection, the most frequent individual symptoms were fatigue (29.3% (95% CI 20.1-40.6%)) and dyspnoea (19.6% (95% CI 12.8-28.7%)). Many patients experienced at least one symptom at 4-8 months (73.1% (95% CI 44.2-90.3%)) and 8-12 months (75.0% (95% CI 56.4-87.4%)). CONCLUSIONS: A wide spectrum of persistent PASC-associated symptoms were reported over the 1-year follow-up period in a significant proportion of participants. Further research is needed to better define PASC duration and determine whether factors such as disease severity, vaccination and treatments have an impact on PASC.

Evaluating Demographic Representation in Clinical Trials: Use of the Adaptive Coronavirus Disease 2019 Treatment Trial (ACTT) as a Test Case.

Background: Clinical trials initiated during emerging infectious disease outbreaks must quickly enroll participants to identify treatments to reduce morbidity and mortality. This may be at odds with enrolling a representative study population, especially when the population affected is undefined. Methods: We evaluated the utility of the Centers for Disease Control and Prevention's COVID-19-Associated Hospitalization Surveillance Network (COVID-NET), the COVID-19 Case Surveillance System (CCSS), and 2020 United States (US) Census data to determine demographic representation in the 4 stages of the Adaptive COVID-19 Treatment Trial (ACTT). We compared the cumulative proportion of participants by sex, race, ethnicity, and age enrolled at US ACTT sites, with respective 95% confidence intervals, to the reference data in forest plots. Results: US ACTT sites enrolled 3509 adults hospitalized with COVID-19. When compared with COVID-NET, ACTT enrolled a similar or higher proportion of Hispanic/Latino and White participants depending on the stage, and a similar proportion of African American participants in all stages. In contrast, ACTT enrolled a higher proportion of these groups when compared with US Census and CCSS. The proportion of participants aged ≥65 years was either similar or lower than COVID-NET and higher than CCSS and the US Census. The proportion of females enrolled in ACTT was lower than the proportion of females in the reference datasets. Conclusions: Although surveillance data of hospitalized cases may not be available early in an outbreak, they are a better comparator than US Census data and surveillance of all cases, which may not reflect the population affected and at higher risk of severe disease.

Going for Broke: The Impact of Cost of Living on Surgery Resident Stipend Value.

OBJECTIVE: The objective of this study was to provide a direct comparison of first-year general surgery resident stipends across states and major cities, using the Cost-of-Living Index (COLI) to determine stipend value. BACKGROUND: Financial challenges are among residents' top sources of stress, and this may be exacerbated in areas with high costs of living. A 2021 survey found that the mean first-year medical resident stipend increased by 0.6%, or $358, from 2020 to 2021, and only 33% of institutions used cost-of-living to determine annual resident stipend adjustments. METHODS: An American Medical Association database was used to identify accredited general surgery residency programs. The 2021-2022 stipend data for first-year general surgery positions were obtained, then data were grouped by state and major city and averaged. Major cities were defined as cities with >4 programs.A direct comparison of stipends was performed using the COLI. RESULTS: Stipend data were available for 337 of 346 general surgery programs. The national average first-year residency stipend was $60,064±$4233. The average COLI-adjusted stipend was $57,090±$5742, with a value loss of -$3493, or 5%.For major cities, the average stipend was $63,383±$4524, and the average COLI-adjusted stipend was $46,929±$8383, with an average value loss of -$16,454, or 26%. CONCLUSIONS: The financial burdens that residents face cannot be overlooked, and the cost of living has a meaningful impact on resident stipend value. The current Graduate Medical Education compensation structure limits federal and institutional capacity to adjust for the cost of living and creates an insulated market in which residents are under-compensated.

Baricitinib Treatment of Coronavirus Disease 2019 Is Associated With a Reduction in Secondary Infections.

We performed a secondary analysis of the National Institutes of Health-sponsored Adaptive COVID-19 Treatment Trial (ACTT-2) randomized controlled trial and found that baricitinib was associated with a 50% reduction in secondary infections after controlling for baseline and postrandomization patient characteristics. This finding provides a novel mechanism of benefit for baricitinib and supports the safety profile of this immunomodulator for the treatment of coronavirus disease 2019.

Malting quality and preharvest sprouting traits are genetically correlated in spring malting barley.

KEY MESSAGE: Malt for craft "all-malt" brewing can have high quality, PHS resistance, and malted in normal timeframes. Canadian style adjunct malt is associated with PHS susceptibility. Expansion of malting barley production into non-traditional growing regions and erratic weather has increased the demand for preharvest sprouting (PHS) resistant, high quality malting barley cultivars. This is hindered by the relatively unknown relationships between PHS resistance and malting quality. Here we present a three-year study of malting quality and germination at different after-ripening durations post physiological maturity. Malting quality traits alpha amylase (AA) and free amino nitrogen (FAN) and germination rate at six days post PM shared a common association with a SNP in HvMKK3 on chromosome 5H in the Seed Dormancy 2 (SD2) region responsible for PHS susceptibility. Soluble protein (SP) and soluble over total protein (S/T) both shared a common association with a marker in the SD2 region. Significant genetic correlations between PHS resistance and the malting quality traits AA, FAN, SP, S/T were detected across and within HvMKK3 allele groups. High adjunct malt quality was related to PHS susceptibility. Selection for PHS resistance led to a correlated response in malting quality traits. Results strongly suggest pleiotropy of HvMKK3 on malting quality traits and that the classic "Canadian-style" malt is caused by a PHS susceptible allele of HvMKK3. PHS susceptibility appears to benefit the production of malt intended for adjunct brewing, while PHS resistance is compatible with all-malt brewing specifications. Here we present our analysis on the effect of combining complexly inherited and correlated traits with contrasting goals to inform breeding practice in malting barley, the general principles of which can be extended to other breeding programs.

How to use biomarkers of infection or sepsis at the bedside: guide to clinicians.

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. In this context, biomarkers could be considered as indicators of either infection or dysregulated host response or response to treatment and/or aid clinicians to prognosticate patient risk. More than 250 biomarkers have been identified and evaluated over the last few decades, but no biomarker accurately differentiates between sepsis and sepsis-like syndrome. Published data support the use of biomarkers for pathogen identification, clinical diagnosis, and optimization of antibiotic treatment. In this narrative review, we highlight how clinicians could improve the use of pathogen-specific and of the most used host-response biomarkers, procalcitonin and C-reactive protein, to improve the clinical care of patients with sepsis. Biomarker kinetics are more useful than single values in predicting sepsis, when making the diagnosis and assessing the response to antibiotic therapy. Finally, integrated biomarker-guided algorithms may hold promise to improve both the diagnosis and prognosis of sepsis. Herein, we provide current data on the clinical utility of pathogen-specific and host-response biomarkers, offer guidance on how to optimize their use, and propose the needs for future research.

Continuous Suprascapular Catheter and Axillary Nerve Block for Analgesia for Reverse Total Shoulder Arthroplasty: A Case Report.

Reverse total shoulder arthroplasty (RTSA) is a widely employed surgical intervention for managing advanced shoulder arthritis. Postoperatively, patients frequently experience intense pain, particularly within the first 48 hours. Effective pain management through regional analgesia not only facilitates a quicker hospital discharge but also minimizes the reliance on opioids. One such regional analgesic approach is the combined suprascapular and axillary nerve block, which targets the glenohumeral joint, rotator cuff muscles, and the shoulder's lateral region for effective pain alleviation. Previous research indicates that this dual nerve block method offers sustained pain relief while circumventing the respiratory complications commonly associated with interscalene brachial plexus blocks, which may inadvertently block the phrenic nerve and affect respiration. We report the case of a 75-year-old female, diagnosed with severe chronic obstructive pulmonary disease (COPD) and bronchiectasis on multiple inhalers, who presented for RTSA. The patient had a strong desire to avoid opioids for pain control due to adverse side effects. Through a suprascapular nerve catheter and axillary nerve single shot, regional analgesia was administered, which minimized the risk of respiratory complications due to potential phrenic nerve involvement from an interscalene approach. There were no opioids taken in the postoperative period after discharge, and the patient only received oral acetaminophen. The patient experienced a successful recovery without any respiratory complications and was extremely satisfied with her management.

Supportive Care in Patients with Critical Coronavirus Disease 2019.

Specific therapies for the treatment of coronavirus disease 2019 (COVID-19) have limited efficacy in the event a patient worsens clinically and requires admission to the intensive care unit (ICU). Thus, providing quality supportive care is essential to the overall management of patients with critical COVID-19. Patients with respiratory failure not requiring intubation should be supported with noninvasive positive pressure ventilation, continuous positive airway pressure, or high flow oxygenation. Use of these respiratory modalities may prevent patients from subsequently requiring intubation. Basic components of supportive care for the critically ill should be applied equally to patients with COVID-19 in the ICU.

Temporal Improvements in COVID-19 Outcomes for Hospitalized Adults: A Post Hoc Observational Study of Remdesivir Group Participants in the Adaptive COVID-19 Treatment Trial.

BACKGROUND: The COVID-19 standard of care (SOC) evolved rapidly during 2020 and 2021, but its cumulative effect over time is unclear. OBJECTIVE: To evaluate whether recovery and mortality improved as SOC evolved, using data from ACTT (Adaptive COVID-19 Treatment Trial). DESIGN: ACTT is a series of phase 3, randomized, double-blind, placebo-controlled trials that evaluated COVID-19 therapeutics from February 2020 through May 2021. ACTT-1 compared remdesivir plus SOC to placebo plus SOC, and in ACTT-2 and ACTT-3, remdesivir plus SOC was the control group. This post hoc analysis compared recovery and mortality between these comparable sequential cohorts of patients who received remdesivir plus SOC, adjusting for baseline characteristics with propensity score weighting. The analysis was repeated for participants in ACTT-3 and ACTT-4 who received remdesivir plus dexamethasone plus SOC. Trends in SOC that could explain outcome improvements were analyzed. (ClinicalTrials.gov: NCT04280705 [ACTT-1], NCT04401579 [ACTT-2], NCT04492475 [ACTT-3], and NCT04640168 [ACTT-4]). SETTING: 94 hospitals in 10 countries (86% U.S. participants). PARTICIPANTS: Adults hospitalized with COVID-19. INTERVENTION: SOC. MEASUREMENTS: 28-day mortality and recovery. RESULTS: Although outcomes were better in ACTT-2 than in ACTT-1, adjusted hazard ratios (HRs) were close to 1 (HR for recovery, 1.04 [95% CI, 0.92 to 1.17]; HR for mortality, 0.90 [CI, 0.56 to 1.40]). Comparable patients were less likely to be intubated in ACTT-2 than in ACTT-1 (odds ratio, 0.75 [CI, 0.53 to 0.97]), and hydroxychloroquine use decreased. Outcomes improved from ACTT-2 to ACTT-3 (HR for recovery, 1.43 [CI, 1.24 to 1.64]; HR for mortality, 0.45 [CI, 0.21 to 0.97]). Potential explanatory factors (SOC trends, case surges, and variant trends) were similar between ACTT-2 and ACTT-3, except for increased dexamethasone use (11% to 77%). Outcomes were similar in ACTT-3 and ACTT-4. Antibiotic use decreased gradually across all stages. LIMITATION: Unmeasured confounding. CONCLUSION: Changes in patient composition explained improved outcomes from ACTT-1 to ACTT-2 but not from ACTT-2 to ACTT-3, suggesting improved SOC. These results support excluding nonconcurrent controls from analysis of platform trials in rapidly changing therapeutic areas. PRIMARY FUNDING SOURCE: National Institute of Allergy and Infectious Diseases.

Hybrid method for monitoring large Fabry-Pérot cavity displacements with nanometer precision.

The change in length of an optical fiber-based Fabry-Pérot cavity (FPC) can be precisely measured using phase tracking, but the displacement range is limited by phase ambiguity. Period tracking techniques determine the absolute FPC length, but with larger uncertainties from tracking the spacing between multiple peaks. A hybrid method is demonstrated that identifies appropriate peaks for phase tracking using a coarse estimate obtained from the free spectral range to effectively maintain the high precision (∼1 nm) of phase tracking techniques to measure ∼24 µm displacements, well beyond the range limitations (typically <1 µm) of phase tracking methods.

Unraveling the Treatment Effect of Baricitinib on Clinical Progression and Resource Utilization in Hospitalized COVID-19 Patients: Secondary Analysis of the Adaptive COVID-19 Treatment Randomized Trial-2.

Background: The Adaptive COVID Treatment Trial-2 (ACTT-2) found that baricitinib in combination with remdesivir therapy (BCT) sped recovery in hospitalized coronavirus disease 2019 (COVID-19) patients vs remdesivir monotherapy (RMT). We examined how BCT affected progression throughout hospitalization and utilization of intensive respiratory therapies. Methods: We characterized the clinical trajectories of 891 ACTT-2 participants requiring supplemental oxygen or higher levels of respiratory support at enrollment. We estimated the effect of BCT on cumulative incidence of clinical improvement and deterioration using competing risks models. We developed multistate models to estimate the effect of BCT on clinical improvement and deterioration and on utilization of respiratory therapies. Results: BCT resulted in more linear improvement and lower incidence of clinical deterioration compared with RMT (hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.95). The benefit was pronounced among participants enrolled on high-flow oxygen or noninvasive positive-pressure ventilation. In this group, BCT sped clinical improvement (HR, 1.21; 95% CI, 0.99 to 1.51) while slowing clinical deterioration (HR, 0.71; 95% CI, 0.48 to 1.02), which reduced the expected days in ordinal score (OS) 6 per 100 patients by 74 days (95% CI, -8 to 154 days) and the expected days in OS 7 per 100 patients by 161 days (95% CI, 46 to 291 days) compared with RMT. BCT did not benefit participants who were mechanically ventilated at enrollment. Conclusions: Compared with RMT, BCT reduces the clinical burden and utilization of intensive respiratory therapies for patients requiring low-flow oxygen or noninvasive positive-pressure ventilation compared with RMT and may thereby improve care for this patient population.

Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial.

BACKGROUND: Baricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19. METHODS: In this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168. FINDINGS: Between Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012). INTERPRETATION: In hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered. FUNDING: National Institute of Allergy and Infectious Diseases.

The diagnostic utility of procalcitonin is limited in the setting of methamphetamine toxicity.

Procalcitonin (PCT) is a biomarker with greater specificity for bacterial infection than other current laboratory markers. However, PCT can also be elevated in the setting of several noninfectious conditions. A recent case report describes a patient with elevated PCT in the context of acute methamphetamine intoxication, but without evidence of infection. Thus far, no studies have evaluated the diagnostic utility of PCT in patients with active methamphetamine use. We seek to test the hypothesis that PCT has diminished utility in patients who use methamphetamine presenting to the Emergency Department (ED). We performed a retrospective cohort study of patients presenting to an academic ED between May 2017 and July 2019. We included patients ≥18 years of age with a positive urine methamphetamine test and at least two PCT results. Pregnant patients were excluded. Cases were classified as microbiologically documented infection, clinically documented infection, possible infection, or no infection by clinician review. A positive PCT value was defined as ≥0.5 ng/ml. The performance of PCT as a diagnostic test for bacterial infection in this population was then evaluated using sensitivity, specificity, false positive rate, false negative rate, and area under the receiver operating characteristic curve. We identified 143 patients, including 75 with recorded PCT levels ≥0.5 ng/ml and 93 with microbiologically or clinically documented bacterial infection. The sensitivity and specificity of PCT for bacterial infection in this study population was 60% and 64%, respectively. The false positive rate was 36% while the false negative rate was 40%. The area under the ROC curve was 0.65. Additionally, we describe 8 patients with confirmed absence of infection but with elevated PCT, 4 of whom had serum values >10 ng/ml. The results suggest that PCT has poor diagnostic utility for bacterial infection in patients with active methamphetamine use presenting to the ED.