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Abstract BackgroundEffective therapies to combat coronavirus 2019 (COVID-19) are urgently needed. Hydroxychloroquine (HCQ) has in vitro antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the clinical benefit of HCQ in treating COVID-19 is unclear. Randomized controlled trials are needed to determine the safety and efficacy of HCQ for the treatment of hospitalized patients with COVID-19. MethodsWe conducted a multicenter, double-blind randomized clinical trial of HCQ among patients hospitalized with laboratory-confirmed COVID-19. Subjects were randomized in a 1:1 ratio to HCQ or placebo for 5 days and followed for 30 days. The primary efficacy outcome was a severe disease progression composite end point (death, intensive care unit admission, mechanical ventilation, extracorporeal membrane oxygenation, and/or vasopressor use) at day 14. ResultsA total of 128 patients were included in the intention-to-treat analysis. Baseline demographic, clinical, and laboratory characteristics were similar between the HCQ (n = 67) and placebo (n = 61) arms. At day 14, 11 (16.4%) subjects assigned to HCQ and 6 (9.8%) subjects assigned to placebo met the severe disease progression end point, but this did not achieve statistical significance (P = .350). There were no significant differences in COVID-19 clinical scores, number of oxygen-free days, SARS-CoV-2 clearance, or adverse events between HCQ and placebo. HCQ was associated with a slight increase in mean corrected QT interval, an increased D-dimer, and a trend toward an increased length of stay. ConclusionsIn hospitalized patients with COVID-19, our data suggest that HCQ does not prevent severe outcomes or improve clinical scores. However, our conclusions are limited by a relatively small sample size, and larger randomized controlled trials or pooled analyses are needed. Treatments for patients hospitalized with COVID-19 are urgently needed. In this multicenter, double-blind, randomized trial, five days of hydroxychloroquine (N=67) did not suggest benefit compared to placebo (N=61). Hydroxychloroquine increased qT interval, D-dimer, and trended towards an increased length of stay. Larger trials are needed.

Participants who had been fully vaccinated with current Covid-19 vaccines received homologous or heterologous boosters, and their immune response was measured on days 15 and 29. Homologous boosters increased neutralizing antibody titers by a factor of 4 to 20, whereas heterologous boosters increased titers by a factor of 6 to 73.

Vaccine protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection wanes over time, requiring updated boosters. In a phase 2, open-label, randomized clinical trial with sequentially enrolled stages at 22 US sites, we assessed safety and immunogenicity of a second boost with monovalent or bivalent variant vaccines from mRNA and protein-based platforms targeting wild-type, Beta, Delta and Omicron BA.1 spike antigens. The primary outcome was pseudovirus neutralization titers at 50% inhibitory dilution (ID 50 titers) with 95% confidence intervals against different SARS-CoV-2 strains. The secondary outcome assessed safety by solicited local and systemic adverse events (AEs), unsolicited AEs, serious AEs and AEs of special interest. Boosting with prototype/wild-type vaccines produced numerically lower ID 50 titers than any variant-containing vaccine against all variants. Conversely, boosting with a variant vaccine excluding prototype was not associated with decreased neutralization against D614G. Omicron BA.1 or Beta monovalent vaccines were nearly equivalent to Omicron BA.1 + prototype or Beta + prototype bivalent vaccines for neutralization of Beta, Omicron BA.1 and Omicron BA.4/5, although they were lower for contemporaneous Omicron subvariants. Safety was similar across arms and stages and comparable to previous reports. Our study shows that updated vaccines targeting Beta or Omicron BA.1 provide broadly crossprotective neutralizing antibody responses against diverse SARS-CoV-2 variants without sacrificing immunity to the ancestral strain. ClinicalTrials.gov registration: NCT05289037 . Analysis of antibody responses to COVID-19 vaccines encoding variant-specific spike, with or without ancestral spike, suggests no loss of neutralization of the ancestral virus with variant-only vaccines, which may simplify future vaccine updates.

Neutralizing antibody titer has been a surrogate endpoint for guiding COVID-19 vaccine approval and use, although the pandemic’s evolution and the introduction of variant-adapted vaccine boosters raise questions as to this surrogate’s contemporary performance. For 985 recipients of an mRNA second bivalent or monovalent booster containing various Spike inserts [Prototype (Ancestral), Beta, Delta, and/or Omicron BA.1 or BA.4/5] in the COVAIL trial (NCT05289037), titers against 5 strains were assessed as correlates of risk of symptomatic COVID-19 (“COVID-19”) and as correlates of relative (Pfizer-BioNTech Omicron vs. Prototype) booster protection against COVID-19 over 6 months of follow-up during the BA.2-BA.5 Omicron-dominant period. Consistently across the Moderna and Pfizer-BioNTech vaccine platforms and across all variant Spike inserts assessed, both peak and exposure-proximal (“predicted-at-exposure”) titers correlated with lower Omicron COVID-19 risk in individuals previously infected with SARS-CoV-2, albeit significantly less so in naïve individuals [e.g., exposure-proximal hazard ratio per 10-fold increase in BA.1 titer 0.74 (95% CI 0.59, 0.94) for naïve vs. 0.41 (95% CI 0.23, 0.64) for non-naïve; interaction p = 0.013]. Neutralizing antibody titer was a strong inverse correlate of Omicron COVID-19 in non-naïve individuals and a weaker correlate in naïve individuals, posing questions about how prior infection alters the neutralization correlate. Here the authors analyze data from COVAIL trial participants receiving an mRNA second COVID-19 vaccine boost and show that, while neutralizing antibody titer is correlated with Omicron COVID-19 risk, the correlation is weak in naïve individuals compared to previously infected ones. _

Children account for a growing share of coronavirus disease 2019 (COVID-19) infections in the United States. Since the widespread availability of COVID-19 vaccine in adults, there has been an upward trend of cases in children, accounting for approximately 20% of the weekly new cases. The majority (38.3%) reported in high school students age 14 to 17 years. Children are also at risk of a postinflammatory condition, known as multisystem inflammatory syndrome in children, after COVID-19. In addition, infected children could transmit the virus to vulnerable adults, contributing to ongoing pandemic. We believe that children need to be vaccinated against COVID-19 and review the available evidence. [Pediatr Ann. 2022;51(5):e180–e185.]

AbstractAs part of a multicenter study evaluating homologous and heterologous COVID-19 booster vaccines, we assessed the magnitude, breadth, and short-term durability of binding and pseudovirus-neutralizing antibody (PsVNA) responses following a single booster dose of NVX-CoV2373 in adults primed with either Ad26.COV2.S, mRNA-1273, or BNT162b2 vaccines. NVX-CoV2373 as a heterologous booster was immunogenic and associated with no safety concerns through Day 91. Fold-rises in PsVNA titers from baseline (Day 1) to Day 29 were highest for prototypic D614G variant and lowest for more recent Omicron sub-lineages BQ.1.1 and XBB.1. Peak humoral responses against all SARS-CoV-2 variants were lower in those primed with Ad26.COV2.S than with mRNA vaccines. Prior SARS CoV-2 infection was associated with substantially higher baseline PsVNA titers, which remained elevated relative to previously uninfected participants through Day 91. These data support the use of heterologous protein-based booster vaccines as an acceptable alternative to mRNA or adenoviral-based COVID-19 booster vaccines. This trial was conducted under ClinicalTrials.gov: NCT04889209.

Multidrug-resistant Acinetobacter baumannii , Klebsiella pneumoniae, and Pseudomonas aeruginosa have become common in many regions, often requiring therapy with colistin or polymyxin B. An increase in resistance to these agents would render many infections untreatable. We tested the activity of polymyxin B and the novel polymyxin analogue CB-182,804 against over 5,000 recent Gram-negative clinical isolates from New York City, a region with a high prevalence of multiresistant strains. Over 96% of Escherichia coli , K. pneumoniae , A. baumannii, and P. aeruginosa were susceptible to polymyxin B; only 76% of Enterobacter spp. was susceptible. The MICs of CB-182,804 were generally two-fold higher than polymyxin B and cross-resistance was observed. The addition of rifampin resulted in synergistic inhibition and bactericidal activity in time kill studies, and restored activity against all polymyxin-resistant strains. The synergistic effect of the combination with rifampin was most pronounced against A. baumannii strains, and was slightly greater with CB-182,804 than with polymyxin B against K. pneumoniae and Enterobacter spp. Despite considerable usage of polymyxin B and colistin in this region, polymyxin B retains excellent activity against most Gram-negative isolates. CB-182,804 shows similar activity, particularly when combined with rifampin. The clinical utility of CB-182,804 remains to be determined.

In patients with moderate to very severe COPD and a blood eosinophil count of 220 cells per cubic millimeter or greater, treatment with benralizumab, an anti–interleukin-5 receptor antibody (administered at doses similar to or higher than those used for severe asthma) did not change the rate of COPD exacerbations.

Whole genome sequencing (WGS) has been proposed as a tool for diagnosing drug resistance in tuberculosis. However, reports of its effectiveness in endemic countries with important numbers of drug resistance are scarce. The goal of this study was to evaluate the effectiveness of this procedure in isolates from a tuberculosis endemic region in Mexico. WGS analysis was performed in 81 tuberculosis positive clinical isolates with a known phenotypic profile of resistance against first-line drugs (isoniazid, rifampin, ethambutol, pyrazinamide and streptomycin). Mutations related to drug resistance were identified for each isolate; drug resistant genotypes were predicted and compared with the phenotypic profile. Genotypes and transmission clusters based on genetic distances were also characterized. Prediction by WGS analysis of resistance against isoniazid, rifampicin, ethambutol, pyrazinamide and streptomycin showed sensitivity values of 84%, 96%, 71%, 75% and 29%, while specificity values were 100%, 94%, 90%, 90% and 98%, respectively. Prediction of multidrug resistance showed a sensitivity of 89% and specificity of 97%. Moreover, WGS analysis revealed polymorphisms related to second-line drug resistance, enabling classification of eight and two clinical isolates as pre- and extreme drug-resistant cases, respectively. Lastly, four lineages were identified in the population (L1, L2, L3 and L4). The most frequent of these was L4, which included 90% (77) of the isolates. Six transmission clusters were identified; the most frequent was TC6, which included 13 isolates with a L4.1.1 and a predominantly multidrug-resistant condition. The results illustrate the utility of WGS for establishing the potential for prediction of resistance against first and second line drugs in isolates of tuberculosis from the region. They also demonstrate the feasibility of this procedure for use as a tool to support the epidemiological surveillance of drug- and multidrug-resistant tuberculosis.

Purpose Echocardiography is a common tool for cardiac and hemodynamic assessments in critical care research. However, interpretation (and applications) of results and between-study comparisons are often difficult due to the lack of certain important details in the studies. PRICES (Preferred Reporting Items for Critical care Echocardiography Studies) is a project endorsed by the European Society of Intensive Care Medicine and conducted by the Echocardiography Working Group, aiming at producing recommendations for standardized reporting of critical care echocardiography (CCE) research studies. Methods The PRICE panel identified lists of clinical and echocardiographic parameters (the “items”) deemed important in four main areas of CCE research: left ventricular systolic and diastolic functions, right ventricular function and fluid management. Each item was graded using a critical index (CI) that combined the relative importance of each item and the fraction of studies that did not report it, also taking experts’ opinion into account. Results A list of items in each area that deemed essential for the proper interpretation and application of research results is recommended. Additional items which aid interpretation were also proposed. Conclusion The PRICES recommendations reported in this document, as a checklist, represent an international consensus of experts as to which parameters and information should be included in the design of echocardiography research studies. PRICES recommendations provide guidance to scientists in the field of CCE with the objective of providing a recommended framework for reporting of CCE methodology and results.