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Lung development genes, adult lung function and cardiovascular comorbidities
Get PDFBackground: The association between lower adult lung function and increased cardiovascular comorbidity has not been adequately explained. We investigated whether shared developmental signalling pathways, critical to lung development and repair, could partly explain it. Methods: In UK Biobank (UKB), we performed pairwise colocalisation analysis of variants in 55 lung development genes associated with adult forced vital capacity (FVC) or forced expiratory volume in 1 s (FEV1)/FVC, to see if these are also associated with coronary heart disease (CHD), blood pressure (systolic, diastolic, hypertension), pulse pressure, Arterial Stiffness index and carotid intima-media thickness. For CHD, we meta-analysed data from UKB and the CARDIoGRAM consortium. Results: We found that 12 of the 55 genes shared the same variant between one (or more) lung function trait and one (or more) cardiovascular trait (H4colocalisation). The direction of effects was always in keeping with our hypothesis (lower lung function–higher cardiovascular risk) for FVC, but not always for FEV1/FVC. The seven signals for hypertension and CHD all replicated nominally in the FinnGen study, while replication was poor in the China Kadoorie Biobank (CKB) study. In addition, we found a further 10 genes where genetic associations with lung function and cardiovascular traits were within the same gene but involved different variants (H3 colocalisation). Interestingly, six of all 22 genes (H4 and H3 colocalisation) were novel for cardiovascular traits; four replicated in FinnGen, three in CKB. Conclusion: Lung function and cardiovascular traits have shared developmental pathways that may partly explain why lower lung function, especially FVC, is associated with increased cardiovascular risk
Sotrovimab versus usual care in patients admitted to hospital with COVID-19: a randomised, controlled, open-label, platform trial (RECOVERY)
Get PDFBackground: Sotrovimab is a neutralising monoclonal antibody targeting the SARS-COV-2 spike protein that was evaluated in the RECOVERY trial, a randomised, controlled, open-label, platform trial testing treatments for COVID-19.
Methods: Patients hospitalised with COVID-19 pneumonia from 107 UK hospitals were randomly allocated to either usual care alone or usual care plus a single 1g infusion of sotrovimab, using web-based unstratified randomisation. Participants were retrospectively categorised as ‘high-antigen’ (the prespecified primary analysis population) if baseline serum SARS-CoV-2 nucleocapsid antigen was above the median concentration, and otherwise as ‘low-antigen’. The primary outcome was 28-day mortality assessed by intention to treat. Recruitment closed on 31 March 2024 when funding ended. ISRCTN (50189673) and clinicaltrials.gov (NCT04381936).
Findings: From 4 January 2022 to 19 March 2024, 1723 patients were recruited, 828 allocated sotrovimab and 895 allocated usual care. 720 (42%) were classified as high-antigen, 717 (42%) as low-antigen, and 286 (17%) had unknown antigen status. 1389 (81%) patients were vaccinated, 1179/1438 with known serostatus (82%) had anti-spike antibodies at randomisation, and almost all were infected with Omicron variants. Among high-antigen patients, 82/355 (23%) allocated sotrovimab versus 106/365 (29%) allocated usual care died within 28 days (rate ratio 0.75; 95% CI 0.56-0.99; p=0.046). In an analysis of all randomised patients (regardless of antigen status), 177/828 (21%) allocated sotrovimab versus 201/895 (22%) allocated usual care died within 28 days (rate ratio 0.95; 95% CI 0.77-1.16; p=0.60).
Interpretation: In patients hospitalised with COVID-19, sotrovimab was associated with reduced mortality in the primary analysis population who had a high serum SARS-CoV-2 antigen concentration at baseline, but not in the overall population. Treatment options for hospitalised patients are limited, and mortality in those receiving current standard care was high. The emergence of high-level resistance to sotrovimab among subsequent SARS-CoV-2 variants limits its current usefulness, but these results indicate that targeted neutralising antibody therapy could potentially still benefit high-risk hospitalised patients in an era of widespread vaccination and Omicron infection
The use of physiologic markers of anemia intolerance to guide transfusion practice in pediatric intensive care units: an international survey
Get PDFObjectives: To explore how red blood cell (RBC) transfusion practice of pediatric intensivists is modulated by physiologic markers of anemia intolerance, in addition to the hemoglobin (Hb) concentration. Background: Most research to date has tested transfusion policies based on Hb threshold alone. Use of physiologic parameters to guide RBC transfusion in pediatric intensive care units (PICU) is not well described. Methods/materials: Scenario-based self-administered survey among pediatric intensivists in tertiary-care PICUs in Belgium, Canada, France, Japan and United Kingdom. Pediatric intensivists were approached through national networks and by e-mail. Five case scenarios were developed for non-bleeding critically ill children who were hemodynamically stable at baseline. Respondents were asked to select a Hb threshold for each scenario and indicate how alternative thresholds of different physiologic parameters would modify their baseline hemoglobin (Hb) threshold. Results: One hundred thirty-two participant responses were received (response rate 56%). Findings indicate that pediatric intensivists do incorporate physiologic parameters when deciding to transfuse RBCs. The most significant determinants of RBC transfusion, in addition to Hb threshold, were baseline co-morbidity (cyanotic cardiac vs. other patients), ScvO2, blood lactate, increasing inotrope or vasoactive-inotropic score, and a drop ≥ 3 g/dL in the Hb concentration. Conclusions: Stated transfusion practice by pediatric intensivists involves physiologic parameters, in addition to Hb concentration. Both static and dynamic parameters (single value and trend over time) were considered by clinicians. The striking variation in practice pattern reported strongly supports the need for further studies that would identify and assess the impact of physiologic biomarkers for RBC transfusion in PICU
Students’ multimodal meaning making of nature of science: from individual scientific practices to coherent scientific methods
No full textOur previous research has demonstrated that students’ meaning-making of nature of science (NOS) involves different modes of representation, such as the visual, verbal, and written modes. As NOS ideas are interconnected, different modes could help students connect separate NOS ideas into a coherent picture. This book chapter presents one case of how seventh graders in Hong Kong connect individual scientific practices into a coherent picture of scientific methods using various modes of representation to reflect on their understanding of NOS. Multimodal discourse analysis was conducted on the video recording of students’ composition of NOS representations. Our findings show that students anchor their understanding of scientific practices to a more elaborated understanding of scientific methods. More importantly, students strategically rearranged the sequence of scientific practices by the visual and written modes to communicate a sequence of scientific methods alternative to the typical scientific method represented in science textbooks. Findings further suggest multimodal connections in students’ meaning making of NOS, as well as propose how teaching and learning can harness such multimodal connections in supporting students’ development of sophisticated NOS understanding
The Prostate cancer–Exercise and Metformin randomised controlled feasibility Trial (Pre-EMpT) in men following active surveillance, radical prostatectomy and radiotherapy
Get PDFBackground: Moderate to vigorous physical activity and metformin are associated in epidemiological studies with reduced biochemical recurrence and mortality in men with prostate cancer. This study assessed the feasibility of a home-based physical activity and/or metformin intervention in men with non-metastatic prostate cancer following radical treatment (surgery or radiotherapy) or active surveillance. Methods: A 2 × 2 factorial design randomised men into one of four groups for 6 months: (1) physical activity (defined as brisk walking ≥ 30 min for ≥ 5 days per week, aiming for ≥ 10,000 steps a day); (2) metformin (one 500 mg slow-release tablet daily); (3) physical activity and metformin; and (4) control. Men were recruited from a single tertiary referral centre in the South West of England, UK, (September 2018–March 2020 which terminated slightly early due to the COVID-19 pandemic). Co-primary outcomes were rates of randomisation and adherence which was defined as men brisk walking ≥30 minutes on at least 5 days with 10,000 steps daily (measured over one week 6-months after randomisation) with ≥ 60% adherence to metformin between 3- and 6 months post-randomisation using returned pill count. Secondary outcomes included self-reported adverse events and physical activity, feasibility of wearing activity monitors and questionnaire completion. Results: In total, 295 men were eligible and 110 were randomised (37.3%, 95% confidence interval [CI] 31.8 to 43.1). Adherence to the physical activity and metformin interventions was 46.9% (95% CI 32.5 to 62.0) and 47.1% (95% CI 32.9 to 61.5) respectively. Adherence was > 60% for both the physical activity and metformin interventions on a complete case basis. Adverse events were infrequent (n = 7) across randomised groups. Completion of self-reported measures of physical activity, urinary incontinence, sexual function, quality of life and stages of change was over 80%. Step counts were not higher in men wearing activity monitors that alerted them about their step counts and sedentary behaviour. Retention over 6 months was 91.3% (95% CI 84.2 to 96.0). Follow up and intervention prompts were impacted by the pandemic. Conclusion: Home-based physical activity and metformin interventions show some promise for men with prostate cancer following radical treatment or active surveillance. Trial registration: ISRCTN, ISRCTN13543667. Registered 2 August 2018, https://www.isrctn.com/ISRCTN1354366
Topological phase locking in stochastic oscillators
Get PDFThe dynamics of many nanoscale biological and synthetic systems such as enzymes and molecular motors are activated by thermal noise, and driven out-of-equilibrium by local energy dissipation. Because the energies dissipated in these systems are comparable to the thermal energy, one would generally expect their dynamics to be highly stochastic. Here, by studying a thermodynamically-consistent model of two coupled noise-activated oscillators, we show that this is not always the case. Thanks to a novel phenomenon that we term topological phase locking (TPL), the coupled dynamics become quasi-deterministic, resulting in a greatly enhanced average speed of the oscillators. TPL is characterized by the emergence of a band of periodic orbits that form a torus knot in phase space, along which the two oscillators advance in rational multiples of each other. The effectively conservative dynamics along this band coexists with the basin of attraction of the dissipative fixed point. We further show that TPL arises as a result of a complex, infinite hierarchy of global bifurcations. Our results have implications for understanding the dynamics of a wide range of systems, from biological enzymes and molecular motors to engineered nanoscale electronic, optical, or mechanical oscillators
Photometric detection at 7.7 μm of a galaxy beyond redshift 14 with JWST/MIRI
Get PDFThe James Webb Space Telescope (JWST) has spectroscopically confirmed numerous galaxies at z > 10. While weak rest-frame ultraviolet emission lines have only been seen in a handful of sources, the stronger rest-frame optical emission lines are highly diagnostic and accessible at mid-infrared wavelengths with the Mid-Infrared Instrument (MIRI) of JWST. We report the photometric detection of the distant spectroscopically confirmed galaxy JADES-GS-z14-0 at z=14.32−0.20+0.08 with MIRI at 7.7 μm. The most plausible solution for the stellar-population properties is that this galaxy contains half a billion solar masses in stars with a strong burst of star formation in the most recent few million years. For this model, at least one-third of the flux at 7.7 μm originates from the rest-frame optical emission lines Hβ and/or [O iii]λλ4959, 5007. The inferred properties of JADES-GS-z14-0 suggest rapid mass assembly and metal enrichment during the earliest phases of galaxy formation. This work demonstrates the unique power of mid-infrared observations in understanding galaxies at the redshift frontier
Criminal Justice System Contacts among Suicide Decedents in Toronto, 1998-2020: An Observational Study: Démêlés avec le système de justice pénale parmi les personnes décédées par suicide à Toronto, entre 1998 et 2020 : Une étude d'observation
Get PDFObjectiveThis exploratory correlational study explored the demographic, clinical, and offence-type characteristics of people with documented past-year contact with the criminal justice system (CJS) in Toronto, Canada who died by suicide. We aimed to compare demographic and clinical factors among individuals with CJS contact who died by suicide to those without recorded CJS contact who died by suicide.MethodsCoroners' final death reports from all recorded suicide deaths in Toronto between 1 January 1998 and 31 December 2020 were retrieved by research staff and coded at the Office of the Chief Coroner (OCC) of Ontario. A series of bivariate analyses and binary logistic regression analyses were performed to compare demographic and clinically relevant characteristics between these groups. Descriptive statistics relating to demographic, clinical, and offence-type characteristics were reported.ResultsA total of 5,288 people died by suicide, of whom 251 (4.7% of all suicides) had recorded CJS contact prior to death. Assault, physical assault, impaired driving, serious/death threats, and sexual assault were the most common criminal charges among those in the CJS contact group. When compared with the no recorded CJS contact group, the CJS contact group was slightly younger (M = 40.0, SD = ±13.4 vs. M = 47.5, SD = ±18.1, p < 0.001), had a higher proportion of males (85.6% vs. 69.9%, p < 0.001), more commonly experienced interpersonal (36.3% vs. 14.5%, p < 0.001) and/or relationship break-up/breakdown stressors (16.7% vs. 7.5%, p < 0.001), and substance misuse or substance use disorders (37.5% vs. 18%, p < 0.001).ConclusionsOur findings highlight that younger men with interpersonal stressors and/or substance misuse characterize suicide decedents with recorded CJS contact in Toronto, Canada. Suicide prevention efforts and strategies should consider the profile differences among those navigating the CJS
Strengthening neonatal care through ward assistants: a Kenyan case study in enhancing infection prevention and control practices
Get PDFBackground: Infection prevention and control (IPC) is a critical component of neonatal care, particularly in low- and middle-income countries (LMICs), where healthcare settings face unique challenges. Neonates, especially preterm and low birth weight infants, are at higher risk for infections, including healthcare-associated infections. In Kenya, neonatal units struggle with limited resources, understaffing, and shortages of essential supplies, significantly impeding effective IPC practices. Methods: This study employed a mixed methods approach in four public neonatal units in Kenya to assess the impact of deploying ward assistants on IPC practices. Data collection included structured and unstructured observations, in-depth interviews, and focus group discussions with healthcare workers and caregivers. The intervention aimed to address gaps in routine cleanliness, waste management, and adherence to IPC protocols. Results: The introduction of ward assistants led to noticeable improvements in overall ward cleanliness and waste disposal, highlighting the potential for enhanced infection control. Mothers’ hand hygiene practices improved, driven by targeted sensitization efforts. Despite these gains, significant challenges remained. Hand hygiene adherence among healthcare providers was inconsistent, and equipment cleaning and decontamination were frequently compromised by insufficient supplies and overwhelming patient demand. The findings underscored the critical role of resources and the need for consistent supervision and training to support sustainable IPC improvements. Conclusion: Deploying ward assistants in neonatal units can positively influence IPC practices, particularly in addressing environmental cleanliness and waste management. However, these benefits alone are insufficient to address systemic barriers to IPC, including resource constraints and variability in adherence among staff. To sustain these gains, robust training, consistent supervision, and adequate resourcing are imperative. Future research should explore the long-term impact of such interventions and design context-specific strategies to overcome persistent barriers, ensuring safer neonatal care in resource-limited settings. Clinical trial number: Not applicable
RTSMS: randomized Tucker with single-mode sketching
Get PDFWe propose RTSMS (Randomized Tucker with Single-Mode-Sketching), a randomized algorithm for approximately computing a low-rank Tucker decomposition of a given tensor. It uses sketching and least-squares to compute the Tucker decomposition in a sequentially truncated manner. RTSMS essentially only sketches one mode at a time, so the sketch matrices are significantly smaller than alternative approaches. It uses a rank estimator to adap7 tively find an appropriate rank for the Tucker decomposition, without requiring it as input. RTSMS is demonstrated to be competitive with existing methods, sometimes outperforming them by a large margin