There is a general consensus that supports the need for standardized reporting of metadata or information describing large-scale metabolomics and other functional genomics data sets. Reporting of ...standard metadata provides a biological and empirical context for the data, facilitates experimental replication, and enables the re-interrogation and comparison of data by others. Accordingly, the Metabolomics Standards Initiative is building a general consensus concerning the minimum reporting standards for metabolomics experiments of which the Chemical Analysis Working Group (CAWG) is a member of this community effort. This article proposes the minimum reporting standards related to the chemical analysis aspects of metabolomics experiments including: sample preparation, experimental analysis, quality control, metabolite identification, and data pre-processing. These minimum standards currently focus mostly upon mass spectrometry and nuclear magnetic resonance spectroscopy due to the popularity of these techniques in metabolomics. However, additional input concerning other techniques is welcomed and can be provided via the CAWG on-line discussion forum at http://msi-workgroups.sourceforge.net/ or http://Msi-workgroups-feedback@lists.sourceforge.net. Further, community input related to this document can also be provided via this electronic forum.
The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of heme ...metabolism, with nanomolar affinity. Using cryo-electron microscopy and x-ray crystallography, we mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD). At physiological concentrations, biliverdin significantly dampened the reactivity of SARS-CoV-2 spike with immune sera and inhibited a subset of neutralizing antibodies. Access to the tetrapyrrole-sensitive epitope is gated by a flexible loop on the distal face of the NTD. Accompanied by profound conformational changes in the NTD, antibody binding requires relocation of the gating loop, which folds into the cleft vacated by the metabolite. Our results indicate that SARS-CoV-2 spike NTD harbors a dominant epitope, access to which can be controlled by an allosteric mechanism that is regulated through recruitment of a metabolite.
SARS-CoV-2 variant Omicron rapidly evolved over 2022, causing three waves of infection due to sub-variants BA.1, BA.2 and BA.4/5. We sought to characterise symptoms and viral loads over the course of ...COVID-19 infection with these sub-variants in otherwise-healthy, vaccinated, non-hospitalised adults, and compared data to infections with the preceding Delta variant of concern (VOC).
In a prospective, observational cohort study, healthy vaccinated UK adults who reported a positive polymerase chain reaction (PCR) or lateral flow test, self-swabbed on alternate weekdays until day 10. We compared participant-reported symptoms and viral load trajectories between infections caused by VOCs Delta and Omicron (sub-variants BA.1, BA.2 or BA.4/5), and tested for relationships between vaccine dose, symptoms and PCR cycle threshold (Ct) as a proxy for viral load using Chi-squared (χ2) and Wilcoxon tests.
563 infection episodes were reported among 491 participants. Across infection episodes, there was little variation in symptom burden (4 IQR 3-5 symptoms) and duration (8 IQR 6-11 days). Whilst symptom profiles differed among infections caused by Delta compared to Omicron sub-variants, symptom profiles were similar between Omicron sub-variants. Anosmia was reported more frequently in Delta infections after 2 doses compared with Omicron sub-variant infections after 3 doses, for example: 42% (25/60) of participants with Delta infection compared to 9% (6/67) with Omicron BA.4/5 (χ2 P < 0.001; OR 7.3 95% CI 2.7-19.4). Fever was less common with Delta (20/60 participants; 33%) than Omicron BA.4/5 (39/67; 58%; χ2 P = 0.008; OR 0.4 CI 0.2-0.7). Amongst infections with an Omicron sub-variants, symptoms of coryza, fatigue, cough and myalgia predominated. Viral load trajectories and peaks did not differ between Delta, and Omicron, irrespective of symptom severity (including asymptomatic participants), VOC or vaccination status. PCR Ct values were negatively associated with time since vaccination in participants infected with BA.1 (β = -0.05 (CI -0.10-0.01); P = 0.031); however, this trend was not observed in BA.2 or BA.4/5 infections.
Our study emphasises both the changing symptom profile of COVID-19 infections in the Omicron era, and ongoing transmission risk of Omicron sub-variants in vaccinated adults.
NCT04750356.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVES:Deteriorating ward patients are at increased risk. Electronic automated advisory vital signs monitors may help identify such patients and improve their outcomes.
SETTING:A total of 349 ...beds, in 12 general wards in ten hospitals in the United States, Europe, and Australia.
PATIENTS:Cohort of 18,305 patients.
DESIGN:Before-and-after controlled trial.
INTERVENTION:We deployed electronic automated advisory vital signs monitors to assist in the acquisition of vital signs and calculation of early warning scores. We assessed their effect on frequency, type, and treatment of rapid response team calls; survival to hospital discharge or to 90 days for rapid response team call patients; overall type and number of serious adverse events and length of hospital stay.
MEASUREMENTS AND MAIN RESULTS:We studied 9,617 patients before (control) and 8,688 after (intervention) deployment of electronic automated advisory vital signs monitors. Among rapid response team call patients, intervention was associated with an increased proportion of calls secondary to abnormal respiratory vital signs (from 21% to 31%; difference 95% confidence interval 9.9 0.1–18.5; p = .029). Survival immediately after rapid response team treatment and survival to hospital discharge or 90 days increased from 86% to 92% (difference 95% confidence interval 6.3 0.0–12.6; p = .04). Intervention was also associated with a decrease in median length of hospital stay in all patients (unadjusted p < .0001; adjusted p = .09) and more so in U.S. patients (from 3.4 to 3.0 days; unadjusted p < .0001; adjusted ratio 95% confidence interval 1.03 1.00–1.06; p = .026). The time required to complete and record a set of vital signs decreased from 4.1 ± 1.3 mins to 2.5 ± 0.5 mins (difference 95% confidence interval 1.6 1.4–1.8; p < .0001).
CONCLUSIONS:Deployment of electronic automated advisory vital signs monitors was associated with an improvement in the proportion of rapid response team-calls triggered by respiratory criteria, increased survival of patients receiving rapid response team calls, and decreased time required for vital signs measurement and recording (NCT01197326).
Summary Background The ICON7 trial previously reported improved progression-free survival in women with ovarian cancer with the addition of bevacizumab to standard chemotherapy, with the greatest ...effect in patients at high risk of disease progression. We report the final overall survival results of the trial. Methods ICON7 was an international, phase 3, open-label, randomised trial undertaken at 263 centres in 11 countries across Europe, Canada, Australia and New Zealand. Eligible adult women with newly diagnosed ovarian cancer that was either high-risk early-stage disease (International Federation of Gynecology and Obstetrics FIGO stage I–IIa, grade 3 or clear cell histology) or more advanced disease (FIGO stage IIb–IV), with an Eastern Cooperative Oncology Group performance status of 0–2, were enrolled and randomly assigned in a 1:1 ratio to standard chemotherapy (six 3-weekly cycles of intravenous carboplatin AUC 5 or 6 and paclitaxel 175 mg/m2 of body surface area) or the same chemotherapy regimen plus bevacizumab 7·5 mg per kg bodyweight intravenously every 3 weeks, given concurrently and continued with up to 12 further 3-weekly cycles of maintenance therapy. Randomisation was done by a minimisation algorithm stratified by FIGO stage, residual disease, interval between surgery and chemotherapy, and Gynecologic Cancer InterGroup group. The primary endpoint was progression-free survival; the study was also powered to detect a difference in overall survival. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN91273375. Findings Between Dec 18, 2006, and Feb 16, 2009, 1528 women were enrolled and randomly assigned to receive chemotherapy (n=764) or chemotherapy plus bevacizumab (n=764). Median follow-up at the end of the trial on March 31, 2013, was 48·9 months (IQR 26·6–56·2), at which point 714 patients had died (352 in the chemotherapy group and 362 in the bevacizumab group). Our results showed evidence of non-proportional hazards, so we used the difference in restricted mean survival time as the primary estimate of effect. No overall survival benefit of bevacizumab was recorded (restricted mean survival time 44·6 months 95% CI 43·2–45·9 in the standard chemotherapy group vs 45·5 months 44·2–46·7 in the bevacizumab group; log-rank p=0·85). In an exploratory analysis of a predefined subgroup of 502 patients with poor prognosis disease, 332 (66%) died (174 in the standard chemotherapy group and 158 in the bevacizumab group), and a significant difference in overall survival was noted between women who received bevacizumab plus chemotherapy and those who received chemotherapy alone (restricted mean survival time 34·5 months 95% CI 32·0–37·0 with standard chemotherapy vs 39·3 months 37·0–41·7 with bevacizumab; log-rank p=0·03). However, in non-high-risk patients, the restricted mean survival time did not differ significantly between the two treatment groups (49·7 months 95% CI 48·3–51·1) in the standard chemotherapy group vs 48·4 months 47·0–49·9 in the bevacizumab group; p=0·20). An updated analysis of progression-free survival showed no difference between treatment groups. During extended follow-up, one further treatment-related grade 3 event (gastrointestinal fistula in a bevacizumab-treated patient), three grade 2 treatment-related events (cardiac failure, sarcoidosis, and foot fracture, all in bevacizumab-treated patients), and one grade 1 treatment-related event (vaginal haemorrhage, in a patient treated with standard chemotherapy) were reported. Interpretation Bevacizumab, added to platinum-based chemotherapy, did not increase overall survival in the study population as a whole. However, an overall survival benefit was recorded in poor-prognosis patients, which is concordant with the progression-free survival results from ICON7 and GOG-218, and provides further evidence towards the optimum use of bevacizumab in the treatment of ovarian cancer. Funding The National Institute for Health Research through the UK National Cancer Research Network, the Medical Research Council, and Roche.
Summary
1. Current national and international frameworks for assessing threats to species have not been developed in the context of climate change, and are not framed in a way that recognises new ...opportunities that arise from climate change.
2. The framework presented here separates the threats and benefits of climate change for individual species. Threat is assessed by the level of climate‐related decline within a species’ recently occupied (e.g. pre‐1970s) historical distribution, based on observed (e.g. repeat census) and/or projected changes (e.g. modelled bioclimate space). Benefits are assessed in terms of observed and/or projected increases outside the recently occupied historical range.
3. Exacerbating factors (e.g. small population size, low dispersal capacity) that might increase levels of threat or limit expansion in response to climate change are taken into consideration within the framework. Protocols are also used to identify levels of confidence (and hence research and/or monitoring needs) in each species’ assessment.
4. Observed and projected changes are combined into single measures of expected decline and increase, together with associated measures of confidence. We weight risk classifications towards information that is most certain. Each species is then placed in one of six categories (high risk, medium risk, limited impact, equivalent risks & benefits, medium benefit, high benefit) reflecting whether climate change is expected (or has been observed) to cause net declines or increases in the region considered, based on the balance of benefits and threats.
5. We illustrate the feasibility of using the framework by applying it to (i) all British butterflies (N = 58 species) and (ii) an additional sample of British species: 18 species of plants, bats, birds and beetles.
6. Synthesis. Our framework assesses net declines and increases associated with climate change, for individual species. It could be applied at any scale (regional, continental or global distributions of species), and complements existing conservation assessment protocols such as red‐listing. Using observed and projected population and/or range data, it is feasible to carry out systematic conservation status assessments that inform the development of monitoring, adaptation measures and conservation management planning for species that are responding to climate change.
IMPORTANCE: In patients who require mechanical ventilation for acute hypoxemic respiratory failure, further reduction in tidal volumes, compared with conventional low tidal volume ventilation, may ...improve outcomes. OBJECTIVE: To determine whether lower tidal volume mechanical ventilation using extracorporeal carbon dioxide removal improves outcomes in patients with acute hypoxemic respiratory failure. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, randomized, allocation-concealed, open-label, pragmatic clinical trial enrolled 412 adult patients receiving mechanical ventilation for acute hypoxemic respiratory failure, of a planned sample size of 1120, between May 2016 and December 2019 from 51 intensive care units in the UK. Follow-up ended on March 11, 2020. INTERVENTIONS: Participants were randomized to receive lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal for at least 48 hours (n = 202) or standard care with conventional low tidal volume ventilation (n = 210). MAIN OUTCOMES AND MEASURES: The primary outcome was all-cause mortality 90 days after randomization. Prespecified secondary outcomes included ventilator-free days at day 28 and adverse event rates. RESULTS: Among 412 patients who were randomized (mean age, 59 years; 143 35% women), 405 (98%) completed the trial. The trial was stopped early because of futility and feasibility following recommendations from the data monitoring and ethics committee. The 90-day mortality rate was 41.5% in the lower tidal volume ventilation with extracorporeal carbon dioxide removal group vs 39.5% in the standard care group (risk ratio, 1.05 95% CI, 0.83-1.33; difference, 2.0% 95% CI, −7.6% to 11.5%; P = .68). There were significantly fewer mean ventilator-free days in the extracorporeal carbon dioxide removal group compared with the standard care group (7.1 95% CI, 5.9-8.3 vs 9.2 95% CI, 7.9-10.4 days; mean difference, −2.1 95% CI, −3.8 to −0.3; P = .02). Serious adverse events were reported for 62 patients (31%) in the extracorporeal carbon dioxide removal group and 18 (9%) in the standard care group, including intracranial hemorrhage in 9 patients (4.5%) vs 0 (0%) and bleeding at other sites in 6 (3.0%) vs 1 (0.5%) in the extracorporeal carbon dioxide removal group vs the control group. Overall, 21 patients experienced 22 serious adverse events related to the study device. CONCLUSIONS AND RELEVANCE: Among patients with acute hypoxemic respiratory failure, the use of extracorporeal carbon dioxide removal to facilitate lower tidal volume mechanical ventilation, compared with conventional low tidal volume mechanical ventilation, did not significantly reduce 90-day mortality. However, due to early termination, the study may have been underpowered to detect a clinically important difference. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02654327
Compositional changes in surfactant and/or decreased surfactant content of the lungs are common features in patients with acute respiratory failure. Instillation of exogenous surfactant into the ...lungs of neonates with respiratory distress syndrome or pediatric patients with acute respiratory distress syndrome (ARDS) has resulted in improved survival.
We conducted this trial to determine whether the instillation of exogenous surfactant would improve the Day 28 outcome of adult patients with acute lung injury (ALI) or ARDS.
A total of 418 patients with ALI and ARDS were included in an international, multicenter, stratified, randomized, controlled, open, parallel-group study. We randomly assigned 418 patients to receive usual care either with or without instillation of exogenous natural porcine surfactant HL 10 as large boluses.
The primary endpoint was death rate before or on Day 28. Secondary endpoints were adverse event and death rate on day 180. The 28-day death rate in the usual care group was 24.5% compared with 28.8% in the HL 10 group. The estimated odds ratio for death at Day 28 in the usual care group versus the HL 10 group was 0.75 (95% CI, 0.48-1.18; P = 0.22). The most common adverse events related to HL 10 administration were temporary hypoxemia defined as oxygen saturation less than 88% (51.9% in HL 10 group vs. 25.2% in usual care) and hypotension defined as mean arterial blood pressure less than 60 mm Hg (34.1% in HL 10 group vs. 17.1% in usual care).
In this study, instillation of a large bolus of exogenous natural porcine surfactant HL 10 into patients with acute lung injury and ARDS did not improve outcome and showed a trend toward increased mortality and adverse effects. Clinical trial registered with www.clinicaltrials.gov (NCT 00742482).
A method is described for using a limited number (typically 10–50) of low-dose radiographs to reconstruct the three-dimensional (3D) distribution of x-ray attenuation in the breast. The method uses ...x-ray cone-beam imaging, an electronic digital detector, and constrained nonlinear iterative computational techniques. Images are reconstructed with high resolution in two dimensions and lower resolution in the third dimension. The 3D distribution of attenuation that is projected into one image in conventional mammography can be separated into many layers (typically 30–80 1-mm-thick layers, depending on breast thickness), increasing the conspicuity of features that are often obscured by overlapping structure in a single-projection view. Schemes that record breast images at nonuniform angular increments, nonuniform image exposure, and nonuniform detector resolution are investigated in order to reduce the total x-ray exposure necessary to obtain diagnostically useful 3D reconstructions, and to improve the quality of the reconstructed images for a given exposure. The total patient radiation dose can be comparable to that used for a standard two-view mammogram. The method is illustrated with images from mastectomy specimens, a phantom, and human volunteers. The results show how image quality is affected by various data-collection protocols.
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