C-reactive protein-based tuberculosis triage testing: a multi-country diagnostic accuracy study.

Rationale: C-reactive protein (CRP)-based tuberculosis (TB) screening is recommended for people with HIV (PWH). However, its performance among people without HIV and in diverse settings is unknown. Objectives: In a multi-country study, we aimed to determine whether CRP meets the minimum accuracy targets (sensitivity ≥90%, specificity ≥70%) for an effective TB triage test. Methods/Measurements: Consecutive outpatient adults with cough ≥2 weeks from five TB endemic countries in Africa and Asia had baseline blood collected for point-of-care CRP testing and HIV and diabetes screening. Sputum samples were collected for Xpert MTB/RIF Ultra (Xpert) testing and culture. CRP sensitivity and specificity (5 mg/L cut-point) was determined in reference to sputum test results and compared by country, sex, and HIV and diabetes status. Variables affecting CRP performance were identified using a multivariate receiver operating characteristic (ROC) regression model. Results: Among 2904 participants, of whom 613 (21%) had microbiologically-confirmed TB, CRP sensitivity was 84% (95% CI: 81-87%) and specificity was 61% (95% CI: 59-63%). CRP accuracy varied geographically, with higher sensitivity in African countries (≥91%) than Asian countries (64-82%). Sensitivity was higher among men than women (87% vs. 79%, difference +8%, 95% CI: 1-15%) and specificity was higher among people without HIV than PWH (64% vs. 45%, difference +19%, 95% CI: 13-25%). ROC regression identified country and measures of TB disease severity as predictors of CRP performance. Conclusions: Overall, CRP did not achieve the minimum accuracy targets and its performance varied by setting and in some sub-groups, likely reflecting population differences in mycobacterial load.

Solicited Cough Sound Analysis for Tuberculosis Triage Testing: The CODA TB DREAM Challenge Dataset.

Cough is a common and commonly ignored symptom of lung disease. Cough is often perceived as difficult to quantify, frequently self-limiting, and non-specific. However, cough has a central role in the clinical detection of many lung diseases including tuberculosis (TB), which remains the leading infectious disease killer worldwide. TB screening currently relies on self-reported cough which fails to meet the World Health Organization (WHO) accuracy targets for a TB triage test. Artificial intelligence (AI) models based on cough sound have been developed for several respiratory conditions, with limited work being done in TB. To support the development of an accurate, point-of-care cough-based triage tool for TB, we have compiled a large multi-country database of cough sounds from individuals being evaluated for TB. The dataset includes more than 700,000 cough sounds from 2,143 individuals with detailed demographic, clinical and microbiologic diagnostic information. We aim to empower researchers in the development of cough sound analysis models to improve TB diagnosis, where innovative approaches are critically needed to end this long-standing pandemic.

A health inequality analysis of childhood asthma prevalence in urban Australia.

BACKGROUND: Long-standing health inequalities in Australian society that were exposed by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic were described as "fault lines" in a recent call to action by a consortium of philanthropic organizations. With asthma a major contributor to childhood disease burden, studies of its spatial epidemiology can provide valuable insights into the emergence of health inequalities early in life. OBJECTIVE: The aims of this study were to characterize the spatial variation of asthma prevalence among children living within Australia's 4 largest cities and quantify the relative contributions of climatic and environmental factors, outdoor air pollution, and socioeconomic status in determining this variation. METHODS: A Bayesian model with spatial smoothing was developed to regress ecologic health status data from the 2021 Australian Census against groups of explanatory covariates intended to represent mechanistic pathways. RESULTS: The prevalence of asthma in children aged 5 to 14 years averages 7.9%, 8.2%, 8.5%, and 7.6% in Sydney, Melbourne, Brisbane, and Perth, respectively. This small inter-city variation contrasts against marked intracity variation at the small-area level, which ranges from 6% to 12% between the least and most affected locations in each. Statistical variance decomposition on a subsample of Australian-born, nonindigenous children attributes 66% of the intracity spatial variation to the assembled covariates. Of these covariates, climatic and environmental factors contribute 30%, outdoor air pollution contributes 19%, and areal socioeconomic status contributes the remaining 51%. CONCLUSION: Geographic health inequalities in the prevalence of childhood asthma within Australia's largest cities reflect a complex interplay of factors, among which socioeconomic status is a principal determinant.

Evaluation of the Xpert MTB Host Response assay for the triage of patients with presumed pulmonary tuberculosis: a prospective diagnostic accuracy study in Viet Nam, India, the Philippines, Uganda, and South Africa.

BACKGROUND: Non-sputum-based triage tests for tuberculosis are a priority for ending tuberculosis. We aimed to evaluate the diagnostic accuracy of the late-prototype Xpert MTB Host Response (Xpert HR) blood-based assay. METHODS: We conducted a prospective diagnostic accuracy study among outpatients with presumed tuberculosis in outpatient clinics in Viet Nam, India, the Philippines, Uganda, and South Africa. Eligible participants were aged 18 years or older and reported cough lasting at least 2 weeks. We excluded those receiving tuberculosis treatment in the preceding 12 months and those who were unwilling to consent. Xpert HR was performed on capillary or venous blood. Reference standard testing included sputum Xpert MTB/RIF Ultra and mycobacterial culture. We performed receiver operating characteristic (ROC) analysis to identify the optimal cutoff value for the Xpert HR to achieve the target sensitivity of 90% or more while maximising specificity, then calculated diagnostic accuracy using this cutoff value. This study was prospectively registered with ClinicalTrials.gov, NCT04923958. FINDINGS: Between July 13, 2021, and Aug 15, 2022, 2046 adults with at least 2 weeks of cough were identified, of whom 1499 adults (686 [45·8%] females and 813 [54·2%] males) had valid Xpert HR and reference standard results. 329 (21·9%) had microbiologically confirmed tuberculosis. Xpert HR had an area under the ROC curve of 0·89 (95% CI 0·86-0·91). The optimal cutoff value was less than or equal to -1·25, giving a sensitivity of 90·3% (95% CI 86·5-93·3; 297 of 329) and a specificity of 62·6% (95% CI 59·7-65·3; 732 of 1170). Sensitivity was similar across countries, by sex, and by subgroups, although specificity was lower in people living with HIV (45·1%, 95% CI 37·8-52·6) than in those not living with HIV (65·9%, 62·8-68·8; difference of 20·8%, 95% CI 13·0-28·6; p<0·0001). Xpert HR had high negative predictive value (95·8%, 95% CI 94·1-97·1), but positive predictive value was only 40·1% (95% CI 36·8-44·1). Using the Xpert HR as a triage test would have reduced confirmatory sputum testing by 57·3% (95% CI 54·2-60·4). INTERPRETATION: Xpert HR did not meet WHO minimum specificity targets for a non-sputum-based triage test for pulmonary tuberculosis. Despite promise as a rule-out test that could reduce confirmatory sputum testing, further cost-effectiveness modelling and data on acceptability and usability are needed to inform policy recommendations. FUNDING: National Institute of Allergy and Infectious Diseases of the US National Institutes of Health. TRANSLATIONS: For the Vietnamese and Tagalog translations of the abstract see Supplementary Materials section.

A fluorescent splice-switching mouse model enables high-throughput, sensitive quantification of antisense oligonucleotide delivery and activity.

While antisense oligonucleotides (ASOs) are used in the clinic, therapeutic development is hindered by the inability to assay ASO delivery and activity in vivo. Accordingly, we developed a dual-fluorescence, knockin mouse model that constitutively expresses mKate2 and an engineered EGFP that is alternatively spliced in the presence of ASO to induce expression. We first examined free ASO activity in the brain following intracerebroventricular injection revealing EGFP splice-switching is both ASO concentration and time dependent in major central nervous system cell types. We then assayed the impact of lipid nanoparticle delivery on ASO activity after intravenous administration. Robust EGFP fluorescence was observed in the liver and EGFP+ cells were successfully isolated using fluorescence-activated cell sorting. Together, these results show the utility of this animal model in quantifying both cell-type- and organ-specific ASO delivery, which can be used to advance ASO therapeutics for many disease indications.

ASIS-Seq: Transgene Insertion Site Mapping by Nanopore Adaptive Sampling.

Generation of transgenic mice by direct microinjection of foreign DNA into fertilized ova has become a routine technique in biomedical research. It remains an essential tool for studying gene expression, developmental biology, genetic disease models, and their therapies. However, the random integration of foreign DNA into the host genome that is inherent to this technology can lead to confounding effects associated with insertional mutagenesis and transgene silencing. Locations of most transgenic lines remain unknown because the methods are often burdensome (Nicholls et al., G3: Genes Genomes Genetics 9:1481-1486, 2019) or have limitations (Goodwin et al., Genome Research 29:494-505, 2019). Here, we present a method that we call Adaptive Sampling Insertion Site Sequencing (ASIS-Seq) to locate transgene integration sites using targeted sequencing on Oxford Nanopore Technologies' (ONT) sequencers. ASIS-Seq requires only about 3 ug of genomic DNA, 3 hours of hands-on sample preparation time, and 3 days of sequencing time to locate transgenes in a host genome.

Advanced Technologies and Automation in mES Cell Workflow.

Gene targeting in mouse ES cells replaces or modifies genes of interest; conditional alleles, reporter knock-ins, and amino acid changes are common examples of how gene targeting is used. To streamline and increase the efficiency in our ES cell pipeline and decrease the timeline for mouse models produced via ES cells, automation is introduced in the pipeline. Below, we describe a novel and effective approach utilizing ddPCR, dPCR, automated DNA purification, MultiMACS, and adenovirus recombinase combined screening workflow that reduces the time between therapeutic target identification and experimental validation.

Immunogenicity of an adjuvanted SARS-CoV-2 trimeric S-protein subunit vaccine (SCB-2019) in SARS-CoV-2-naïve and exposed individuals in a phase 2/3, double-blind, randomized study.

BACKGROUND: We evaluated immunogenicity of SCB-2019, a subunit vaccine candidate containing a pre-fusion trimeric form of the SARS-CoV-2 spike (S)-protein adjuvanted with CpG-1018/alum. METHODS: The phase 2/3, double-blind, randomized SPECTRA trial was conducted in five countries in participants aged ≥ 18 years, either SARS-CoV-2-naïve or previously exposed. Participants were randomly assigned to receive two doses of SCB-2019 or placebo administered intramuscularly 21 days apart. In the phase 2 part of the study, on days 1, 22, and 36, neutralizing antibodies were measured by pseudovirus and wild-type virus neutralization assays to SARS-CoV-2 prototype and variants, and ACE2-receptor-binding antibodies and SCB-2019-binding antibodies were measured by ELISA. Cell-mediated immunity was measured by intracellular cytokine staining via flow cytometry. RESULTS: 1601 individuals were enrolled between 24 March and 13 September 2021 and received at least one vaccine dose. Immunogenicity analysis was conducted in a phase 2 subset of 691 participants, including 428 SARS-CoV-2-naïve (381 vaccine and 47 placebo recipients) and 263 SARS-CoV-2-exposed (235 vaccine and 28 placebo recipients). In SARS-CoV-2-naïve participants, GMTs of neutralizing antibodies against prototype virus increased 2 weeks post-second dose (day 36) compared to baseline (224 vs 12.7 IU/mL). Seroconversion rate was 82.5 %. In SARS-CoV-2-exposed participants, one SCB-2019 dose increased GMT of neutralizing antibodies by 48.3-fold (1276.1 IU/mL on day 22) compared to baseline. Seroconversion rate was 92.4 %. Increase was marginal post-second dose. SCB-2019 also showed cross-neutralization capability against nine variants, including Omicron, in SARS-CoV-2-exposed participants at day 36. SCB-2019 stimulated Th1-biased cell-mediated immunity to the S-protein in both naïve and exposed participants. The vaccine was well tolerated, no safety concerns were raised from the study. CONCLUSIONS: A single dose of SCB-2019 was immunogenic in SARS-CoV-2-exposed individuals, whereas two doses were required to induce immune response in SARS-CoV-2-naïve individuals. SCB-2019 elicited a cross-neutralizing response against emergent SARS-CoV-2 variants at antibody levels associated with clinical protection, underlining its potential as a booster. CLINICALTRIALS: gov: NCT04672395; EudraCT: 2020-004272-17.

1.2-kW all-fiber Yb-doped multicore fiber amplifier.

We have demonstrated a record-high 1.2 kW, all-fiber multicore amplifier using a six-core single-mode Yb-doped fiber and a multicore pump-signal combiner (PSC). The output power is limited by the pump power of 1.9 kW. We have developed double-clad six-core fibers and PSCs for this demonstration. Each of the six Yb-doped cores has a 17-µm mode-field diameter (MFD) with a trench index profile and is capable of kW-class operation. The potential power scaling to the 10-kW level in a single amplifier with high brightness should be feasible with advanced thermal management and coherent beam combination.

Circulating Cell-Free RNA in Blood as a Host Response Biomarker for the Detection of Tuberculosis.

Tuberculosis (TB) remains a leading cause of death from an infectious disease worldwide. This is partly due to a lack of tools to effectively screen and triage individuals with potential TB. Whole blood RNA signatures have been extensively studied as potential biomarkers for TB, but they have failed to meet the World Health Organization's (WHOs) target product profiles (TPPs) for a non-sputum triage or diagnostic test. In this study, we investigated the utility of plasma cell-free RNA (cfRNA) as a host response biomarker for TB. We used RNA profiling by sequencing to analyze plasma samples from 182 individuals with a cough lasting at least two weeks, who were seen at outpatient clinics in Uganda, Vietnam, and the Philippines. Of these individuals, 100 were diagnosed with microbiologically-confirmed TB. Our analysis of the plasma cfRNA transcriptome revealed 541 differentially abundant genes, the top 150 of which were used to train 15 machine learning models. The highest performing model led to a 9-gene signature that had a diagnostic accuracy of 89.1% (95% CI: 83.6-93.4%) and an area under the curve of 0.934 (95% CI: 0.8674-1) for microbiologically-confirmed TB. This 9-gene signature exceeds the optimal WHO TPPs for a TB triage test (sensitivity: 96.2% [95% CI: 80.9-100%], specificity: 89.7% [95% CI: 72.4-100%]) and was robust to differences in sample collection, geographic location, and HIV status. Overall, our results demonstrate the utility of plasma cfRNA for the detection of TB and suggest the potential for a point-of-care, gene expression-based assay to aid in early detection of TB.

Association Between Hypercholesterolemia and Neck Pain in a Cross-sectional Population-based Study.

STUDY DESIGN: Retrospective cross-sectional analysis. SUMMARY OF BACKGROUND DATA: Degenerative changes are a major contributor to chronic neck pain. According to the vascular hypothesis of disk disease, atherosclerosis of the segmental arteries contributes to ischemia of the lumbar disks and resulting degenerative changes. Prior studies have demonstrated an association between atherosclerotic risk factors and lumbar degenerative disease. Similarly, atherosclerosis may contribute to cervical disk degeneration. Cardiovascular disease is associated with the development of atherosclerosis, particularly in small vessels to the cervical spine. Hypercholesterolemia is a major contributor to the morbidity associated with cardiovascular disease. This study aims to examine the relationship between hypercholesterolemia and neck pain. MATERIALS AND METHODS: Analysis was focused on the respondents to neck pain items of the standardized questionnaire. Odds ratios were calculated, and logistic regression analyses adjusted for demographic, education, and mental health conditions. RESULTS: There were 30,461 participants in the 2018 Medicare Expenditure Panel Survey (MEPS) survey. Of those, 1049 (3.4%) subjects responded to presence of a diagnosis of cervical disorders with neck pain. Mean age of respondents was 62.6±16.1. Overall prevalence of neck pain was 21.1%. Prevalence of neck pain was similar by age, sex, education level, and occupation ( P >0.05 for each). Neck pain was more prevalent in white race and lower total family income ( P <0.05). Current everyday smokers also had higher prevalence of neck pain ( P <0.05). Logistic regression analysis revealed a higher prevalence of neck pain in those with hypercholesterolemia after controlling for relevant covariates (adjusted odds ratio=1.54, 95% CI: 1.08-2.22, P =0.018). CONCLUSIONS: Subjects with hypercholesterolemia were 54% more likely to have neck pain after controlling for confounders. This suggests that hypercholesterolemia has a role to play in degeneration of the cervical spine. Therefore, prevention and proper management of high cholesterol may curtail the development and progression of degenerative cervical disk disease and thus, neck pain.

Cost-Effectiveness of Intraoperative Electromyography to Determine Adequate Screw Position.

STUDY DESIGN: Prospective observational cohort. OBJECTIVES: To examine the cost-effectiveness of IntraOperative ElectroMyeloGraphy (IO-EMG) by evaluating how often an abnormal IO-EMG signal changed the surgeon's surgical plan, or replaced a pedicle screw either intra-operatively or as a second unplanned surgery. METHODS: Patients undergoing instrumented posterolateral lumbar fusion were monitored with intraoperative triggered EMG's. Pedicle screws were placed freehand from L1 to S1 by attending physicians and fellows. Concern for pedicle breach was a screw stimulation<10 mA. RESULTS: There were 145 cases with a total of 725 pedicle screws placed. Mean age was 57.8 ± 14.2 yrs, OR time was 238 ± 95 minutes, EBL was 426.8 ± 354.3cc. Mean number of surgical levels fused was 2.7 ± 1.1. 686 (95%) screws stimulated at >10 mA and 39 (5%) screws stimulated at <10 mA. All 39 screws were removed and pedicles re-examined. Intraoperative screw repositioning was necessary in 8 of 145 cases (6%). No patient required a return to the OR for screw repositioning. As a worst case cost analysis, assuming the 8 patients requiring intraoperative screw positioning would have returned to the OR at a cost of $11,798 per readmission, the per patient cost is $651 which is less than the ION per patient cost of $750. CONCLUSIONS: Only 1% of the 725 lumbar pedicle screws placed in 8 of 145 cases required repositioning. Due to the infrequency of pedicle wall breaches and the cost of ION, the utility of this modality in straightforward lumbar fusions should be critically evaluated.

A WISP1 antibody inhibits MRTF signaling to prevent the progression of established liver fibrosis.

Fibrosis is the major risk factor associated with morbidity and mortality in patients with non-alcoholic steatohepatitis (NASH)-driven chronic liver disease. Although numerous efforts have been made to identify the mediators of the initiation of liver fibrosis, the molecular underpinnings of fibrosis progression remain poorly understood, and therapies to arrest liver fibrosis progression are elusive. Here, we identify a pathway involving WNT1-inducible signaling pathway protein 1 (WISP1) and myocardin-related transcription factor (MRTF) as a central mechanism driving liver fibrosis progression through the integrin-dependent transcriptional reprogramming of myofibroblast cytoskeleton and motility. In mice, WISP1 deficiency protects against fibrosis progression, but not fibrosis onset. Moreover, the therapeutic administration of a novel antibody blocking WISP1 halted the progression of existing liver fibrosis in NASH models. These findings implicate the WISP1-MRTF axis as a crucial determinant of liver fibrosis progression and support targeting this pathway by antibody-based therapy for the treatment of NASH fibrosis.

Realistic model of entanglement-enhanced sensing in optical fibers.

Experimental limitations such as optical loss and noise have prevented entanglement-enhanced measurements from demonstrating a significant quantum advantage in sensitivity. Holland-Burnett entangled states can mitigate these limitations and still present a quantum advantage in sensitivity. Here we model a fiber-based Mach-Zehnder interferometer with internal loss, detector efficiency, and external phase noise and without pure entanglement. This model features a practical fiber source that transforms the two-mode squeezed vacuum (TMSV) into Holland-Burnett entangled states. We predict that a phase sensitivity 28% beyond the shot noise limit is feasible with current technology. Simultaneously, a TMSV source can provide about 25 times more photon flux than other entangled sources. This system will make fiber-based quantum-enhanced sensing accessible and practical for remote sensing and probing photosensitive materials.

Accelerated embryonic stem cell screening with a highly efficient genotyping pipeline.

INTRODUCTION: Gene targeting in mouse ES cells replaces or modifies genes of interest; conditional alleles, reporter knock-ins, and amino acid changes are common examples of how gene targeting is used. For example, enhanced green fluorescent protein or Cre recombinase is placed under the control of endogenous genes to define promoter expression patterns. METHODS AND RESULTS: The most important step in the process is to demonstrate that a gene targeting vector is correctly integrated in the genome at the desired chromosomal location. The rapid identification of correctly targeted ES cell clones is facilitated by proper targeting vector construction, rapid screening procedures, and advances in cell culture. Here, we optimized and functionally linked magnetic activated cell sorting (MACS) technology as well as multiplex droplet digital PCR (ddPCR) to our ES cell screening process to achieve a greater than 60% assurance that ES clones are correctly targeted. In a further refinement of the process, drug selection cassettes are removed from ES cells with adenovirus technology. We describe this improved workflow and illustrate the reduction in time between therapeutic target identification and experimental validation. CONCLUSION: In sum, we describe a novel and effective implementation of ddPCR, multiMACS, and adenovirus recombinase into a streamlined screening workflow that significantly reduces timelines for gene targeting in mouse ES cells.

Noise in the operating room during induction of anesthesia: impact of a quality improvement initiative.

PURPOSE: Noise in the operating room (OR) is common and associated with negative effects on anesthesiologists, surgeons, and patient outcomes. Induction of anesthesia is among the loudest perioperative periods. Despite its critical nature, there is little data on noise levels during induction, associated patient and anesthesiologist satisfaction, and the effects of noise reduction strategies. METHODS: We conducted a two-part prospective interventional quality improvement project on the care of adult patients receiving general anesthesia for elective noncardiac surgery. For part A, we measured average and peak noise (dB[A]) levels during anesthesia induction in N = 100 cases and administered a satisfaction questionnaire to anesthesiologists. We then applied a multidisciplinary educational program to OR personnel on active noise reduction strategies and subsequently collected data during N = 109 cases in a post-intervention phase. For part B, we administered satisfaction questionnaires to N = 100 patients pre- vs postintervention, respectively. RESULTS: Median [interquartile range] noise levels throughout induction were 66.0 [62.5-68.6] dB(A) preintervention vs 63.5 [60.1-65.4] dB[A] post-intervention (Hodges-Lehmann estimator of the difference, - 2.7 dB[A]; 95% confidence interval [CI], - 4.0 to - 1.5; P < 0.001). Peak noise levels during induction were 87.3 [84.0-90.5] dB(A) preintervention and 86.2 [81.8-89.3] dB(A) postintervention (Hodges-Lehmann estimator of the difference, - 1.8 dB[A]; 95% CI, - 3.3 to - 0.3; P = 0.02). Noise-related anesthesiologist satisfaction postintervention was significantly improved in multiple domains, including assessment of noise having distracted anesthesiologists. Patient satisfaction was high pre-intervention and did not significantly improve further. CONCLUSION: In this quality improvement project, average noise levels during induction of anesthesia, anesthesiologist satisfaction, and anesthesiologists' perceived ability to perform were improved following a multidisciplinary educational program on noise reduction in the OR. STUDY REGISTRATION: www. CLINICALTRIALS: gov (NCT04204785); registered 19 December 2019.

RéSUMé: OBJECTIF: Le bruit en salle d'opération (SOP) est fréquent et associé à des effets négatifs sur les anesthésiologistes, les chirurgiens et les issues des patients. L'induction de l'anesthésie est l'une des périodes périopératoires les plus bruyantes. Malgré sa nature critique, il existe peu de données sur les niveaux sonores pendant l'induction, la satisfaction des patients et des anesthésiologistes qui y est reliée, et les effets des stratégies de réduction du bruit. MéTHODE: Nous avons mené un projet prospectif et interventionnel, en deux parties, d'amélioration de la qualité sur les soins aux patients adultes recevant une anesthésie générale pour une chirurgie non cardiaque non urgente. Dans le cadre de la première partie A, nous avons mesuré les niveaux de bruit moyen et maximaux (dB[A]) pendant l'induction de l'anesthésie dans n = 100 cas et administré un questionnaire de satisfaction aux anesthésiologistes. Nous avons ensuite appliqué un programme de formation multidisciplinaire au personnel de la salle d'opération sur les stratégies de réduction active du bruit et avons ensuite recueilli des données pour n = 109 cas dans une phase post-intervention. Pour la deuxième partie B, nous avons administré des questionnaires de satisfaction à n = 100 patients pré- vs post-intervention, respectivement. RéSULTATS: Les niveaux de bruit médians [écart interquartile] tout au long de l'induction étaient de 66,0 [62,5­68,6] dB(A) avant l'intervention vs 63,5 [60,1­65,4] dB[A] après l'intervention (estimateur de Hodges-Lehmann, − 2,7 dB[A]; intervalle de confiance [IC] 95 %, − 4,0 à − 1,5; P < 0,001). Les niveaux maximaux de bruit pendant l'induction étaient de 87,3 [84,0­90,5] dB(A) avant l'intervention et de 86,2 [81,8­89,3] dB(A) après l'intervention (estimateur de Hodges-Lehmann, − 1,8 dB[A]; IC 95 %, − 3,3 à − 0,3; P = 0,02). La satisfaction des anesthésiologistes par rapport au bruit après l'intervention a été considérablement améliorée dans de nombreux domaines, y compris l'évaluation du bruit ayant distrait les anesthésiologistes. La satisfaction des patients était élevée avant l'intervention et ne s'est pas améliorée de manière significative. CONCLUSION: Dans ce projet d'amélioration de la qualité, les niveaux de bruit moyens lors de l'induction de l'anesthésie, la satisfaction des anesthésiologistes et la capacité perçue des anesthésiologistes à réaliser leurs tâches ont été améliorés à la suite d'un programme de formation multidisciplinaire sur la réduction du bruit en salle d'opération. ENREGISTREMENT DE L'éTUDE: www.ClinicalTrials.gov (NCT04204785); enregistrée le 19 décembre 2019.

Efficacy of the adjuvanted subunit protein COVID-19 vaccine, SCB-2019: a phase 2 and 3 multicentre, double-blind, randomised, placebo-controlled trial.

BACKGROUND: A range of safe and effective vaccines against SARS CoV 2 are needed to address the COVID 19 pandemic. We aimed to assess the safety and efficacy of the COVID-19 vaccine SCB-2019. METHODS: This ongoing phase 2 and 3 double-blind, placebo-controlled trial was done in adults aged 18 years and older who were in good health or with a stable chronic health condition, at 31 sites in five countries (Belgium, Brazil, Colombia, Philippines, and South Africa). The participants were randomly assigned 1:1 using a centralised internet randomisation system to receive two 0·5 mL intramuscular doses of SCB-2019 (30 µg, adjuvanted with 1·50 mg CpG-1018 and 0·75 mg alum) or placebo (0·9% sodium chloride for injection supplied in 10 mL ampoules) 21 days apart. All study staff and participants were masked, but vaccine administrators were not. Primary endpoints were vaccine efficacy, measured by RT-PCR-confirmed COVID-19 of any severity with onset from 14 days after the second dose in baseline SARS-CoV-2 seronegative participants (the per-protocol population), and the safety and solicited local and systemic adverse events in the phase 2 subset. This study is registered on EudraCT (2020-004272-17) and ClinicalTrials.gov (NCT04672395). FINDINGS: 30 174 participants were enrolled from March 24, 2021, until the cutoff date of Aug 10, 2021, of whom 30 128 received their first assigned vaccine (n=15 064) or a placebo injection (n=15 064). The per-protocol population consisted of 12 355 baseline SARS-CoV-2-naive participants (6251 vaccinees and 6104 placebo recipients). Most exclusions (13 389 [44·4%]) were because of seropositivity at baseline. There were 207 confirmed per-protocol cases of COVID-19 at 14 days after the second dose, 52 vaccinees versus 155 placebo recipients, and an overall vaccine efficacy against any severity COVID-19 of 67·2% (95·72% CI 54·3-76·8), 83·7% (97·86% CI 55·9-95·4) against moderate-to-severe COVID-19, and 100% (97·86% CI 25·3-100·0) against severe COVID-19. All COVID-19 cases were due to virus variants; vaccine efficacy against any severity COVID-19 due to the three predominant variants was 78·7% (95% CI 57·3-90·4) for delta, 91·8% (44·9-99·8) for gamma, and 58·6% (13·3-81·5) for mu. No safety issues emerged in the follow-up period for the efficacy analysis (median of 82 days [IQR 63-103]). The vaccine elicited higher rates of mainly mild-to-moderate injection site pain than the placebo after the first (35·7% [287 of 803] vs 10·3% [81 of 786]) and second (26·9% [189 of 702] vs 7·4% [52 of 699]) doses, but the rates of other solicited local and systemic adverse events were similar between the groups. INTERPRETATION: Two doses of SCB-2019 vaccine plus CpG and alum provides notable protection against the entire severity spectrum of COVID-19 caused by circulating SAR-CoV-2 viruses, including the predominating delta variant. FUNDING: Clover Biopharmaceuticals and the Coalition for Epidemic Preparedness Innovations.