Metagenomics: DNA sequencing of environmental samples

While genomics has classically focused on pure, easy-to-obtain samples, such as microbes that grow readily in culture or large animals and plants, these organisms represent but a fraction of the living or once living organisms of interest. Many species are difficult to study in isolation, because they fail to grow in laboratory culture, depend on other organisms for critical processes, or have become extinct. DNA sequence-based methods circumvent these obstacles, as DNA can be directly isolated from live or dead cells in a variety of contexts, and have led to the emergence of a new field referred to as metagenomics

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Temporal changes in tolerance of uncertainty among medical students: insights from an exploratory study

Background: Physicians’ tolerance of uncertainty (TU) is a trait potentially associated with desirable outcomes, and emerging evidence suggests it may change over time. Past studies of TU, however, have been cross-sectional and have not measured tolerance of the different, specific types of uncertainty that physicians confront. We addressed these limitations in a longitudinal exploratory study of medical students. Methods: At the end of medical school (Doctor of Medicine degree) Years 1 and 4, a cohort of 26 students at a US medical school completed measures assessing tolerance of different types of uncertainty: 1) complexity (uncertainty arising from features of information that make it difficult to comprehend); 2) risk (uncertainty arising from the indeterminacy of future outcomes); and 3) ambiguity (uncertainty arising from limitations in the reliability, credibility, or adequacy of information). Change in uncertainty-specific TU was assessed using paired t-tests. Results: Between Years 1 and 4, there was a significant decrease in tolerance of ambiguity (t=3.22, p=0.004), but no change in students’ tolerance of complexity or risk. Conclusions: Tolerance of ambiguity – but not other types of uncertainty – decreases during medical school, suggesting that TU is a multidimensional, partially mutable state. Future studies should measure tolerance of different uncertainties and examine how TU might be improved

Temporal changes in tolerance of uncertainty among medical students: insights from an exploratory study.

BACKGROUND: Physicians\u27 tolerance of uncertainty (TU) is a trait potentially associated with desirable outcomes, and emerging evidence suggests it may change over time. Past studies of TU, however, have been cross-sectional and have not measured tolerance of the different, specific types of uncertainty that physicians confront. We addressed these limitations in a longitudinal exploratory study of medical students. METHODS: At the end of medical school (Doctor of Medicine degree) Years 1 and 4, a cohort of 26 students at a US medical school completed measures assessing tolerance of different types of uncertainty: 1) complexity (uncertainty arising from features of information that make it difficult to comprehend); 2) risk (uncertainty arising from the indeterminacy of future outcomes); and 3) ambiguity (uncertainty arising from limitations in the reliability, credibility, or adequacy of information). Change in uncertainty-specific TU was assessed using paired t-tests. RESULTS: Between Years 1 and 4, there was a significant decrease in tolerance of ambiguity (t=3.22, p=0.004), but no change in students\u27 tolerance of complexity or risk. CONCLUSIONS: Tolerance of ambiguity--but not other types of uncertainty--decreases during medical school, suggesting that TU is a multidimensional, partially mutable state. Future studies should measure tolerance of different uncertainties and examine how TU might be improved

Temporal changes in tolerance of uncertainty among medical students: insights from an exploratory study

Background: Physicians’ tolerance of uncertainty (TU) is a trait potentially associated with desirable outcomes, and emerging evidence suggests it may change over time. Past studies of TU, however, have been cross-sectional and have not measured tolerance of the different, specific types of uncertainty that physicians confront. We addressed these limitations in a longitudinal exploratory study of medical students. Methods: At the end of medical school (Doctor of Medicine degree) Years 1 and 4, a cohort of 26 students at a US medical school completed measures assessing tolerance of different types of uncertainty: 1) complexity (uncertainty arising from features of information that make it difficult to comprehend); 2) risk (uncertainty arising from the indeterminacy of future outcomes); and 3) ambiguity (uncertainty arising from limitations in the reliability, credibility, or adequacy of information). Change in uncertainty-specific TU was assessed using paired t-tests. Results: Between Years 1 and 4, there was a significant decrease in tolerance of ambiguity (t=3.22, p=0.004), but no change in students’ tolerance of complexity or risk. Conclusions: Tolerance of ambiguity – but not other types of uncertainty – decreases during medical school, suggesting that TU is a multidimensional, partially mutable state. Future studies should measure tolerance of different uncertainties and examine how TU might be improved

Effect of Amoxicillin dose and treatment duration on the need for antibiotic re-treatment in children with Community-Acquired Pneumonia: The CAP-IT randomized clinical trial

Importance: The optimal dose and duration of oral amoxicillin for children with community-acquired pneumonia (CAP) are unclear. Objective: To determine whether lower-dose amoxicillin is noninferior to higher dose and whether 3-day treatment is noninferior to 7 days. Design, Setting, and Participants: Multicenter, randomized, 2 × 2 factorial noninferiority trial enrolling 824 children, aged 6 months and older, with clinically diagnosed CAP, treated with amoxicillin on discharge from emergency departments and inpatient wards of 28 hospitals in the UK and 1 in Ireland between February 2017 and April 2019, with last trial visit on May 21, 2019. Interventions: Children were randomized 1:1 to receive oral amoxicillin at a lower dose (35-50 mg/kg/d; n = 410) or higher dose (70-90 mg/kg/d; n = 404), for a shorter duration (3 days; n = 413) or a longer duration (7 days; n = 401). Main Outcomes and Measures: The primary outcome was clinically indicated antibiotic re-treatment for respiratory infection within 28 days after randomization. The noninferiority margin was 8%. Secondary outcomes included severity/duration of 9 parent-reported CAP symptoms, 3 antibiotic-related adverse events, and phenotypic resistance in colonizing Streptococcus pneumoniae isolates. Results: Of 824 participants randomized into 1 of the 4 groups, 814 received at least 1 dose of trial medication (median [IQR] age, 2.5 years [1.6-2.7]; 421 [52%] males and 393 [48%] females), and the primary outcome was available for 789 (97%). For lower vs higher dose, the primary outcome occurred in 12.6% with lower dose vs 12.4% with higher dose (difference, 0.2% [1-sided 95% CI -∞ to 4.0%]), and in 12.5% with 3-day treatment vs 12.5% with 7-day treatment (difference, 0.1% [1-sided 95% CI -∞ to 3.9]). Both groups demonstrated noninferiority with no significant interaction between dose and duration (P =.63). Of the 14 prespecified secondary end points, the only significant differences were 3-day vs 7-day treatment for cough duration (median 12 days vs 10 days; hazard ratio [HR], 1.2 [95% CI, 1.0 to 1.4]; P =.04) and sleep disturbed by cough (median, 4 days vs 4 days; HR, 1.2 [95% CI, 1.0 to 1.4]; P =.03). Among the subgroup of children with severe CAP, the primary end point occurred in 17.3% of lower-dose recipients vs 13.5% of higher-dose recipients (difference, 3.8% [1-sided 95% CI, -∞ to10%]; P value for interaction =.18) and in 16.0% with 3-day treatment vs 14.8% with 7-day treatment (difference, 1.2% [1-sided 95% CI, -∞ to 7.4%]; P value for interaction =.73). Conclusions and Relevance: Among children with CAP discharged from an emergency department or hospital ward (within 48 hours), lower-dose outpatient oral amoxicillin was noninferior to higher dose, and 3-day duration was noninferior to 7 days, with regard to need for antibiotic re-treatment. However, disease severity, treatment setting, prior antibiotics received, and acceptability of the noninferiority margin require consideration when interpreting the findings. Trial Registration: ISRCTN Identifier: ISRCTN76888927