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In the study reported on here we investigated the impact of Ubuntu on learner behaviour and academic achievement in secondary schools in the Gweru district of Zimbabwe. The study participants comprised 38 learners and 7 teachers from 4 secondary schools in the Gweru district. Data were collected through focus-group discussions, semi-structured interviews, participant observations and document analysis. We established that teachers and learners had a satisfactory understanding of how upholding values of Ubuntu contributed to academic achievement among learners. The findings reveal that in addition to other factors affecting academic achievement, like the school and home environment, learners who upheld the values of Ubuntu were disciplined, focused on their studies, and thus attained higher levels of academic achievement compared to learners who lacked Ubuntu and engaged in substance abuse, pre-marital sex, and lacked focus on their schoolwork. Based on the study we recommend that a course on Ubuntu be introduced in teacher training complemented by professional development workshops for teachers in the field to equip them with skills of integrating values of Ubuntu into the curriculum and thus foster the same among learners.

The research reported on in this article was mainly undertaken to determine the obstacles to the enhancement of critical thinking in the learning of history at Form 3 level in secondary schools in the Masvingo urban area of Zimbabwe, in terms of the rationale of developing the learners' critical thinking. The promotion of critical thinking abilities is vital in education, since doing so helps to improve the learners' academic performance, as well as aiding in producing graduates with a multiplicity of skills that are required in the 21st century job market and in society as a whole. We used semi-structured interviews and lesson observations to reach conclusions on what recommendations to make in addressing the research problem. Several factors were identified as hindering the learners' acquisition of critical thinking, including the learners' and teachers' lack of self-efficacy, motivation and the poor learning environment. In addition to reflecting on the possibility of improving the learning and teaching of critical thinking, we recommend that the Ministry of Primary and Secondary Education, Zimbabwe's Schools Examination Council, teacher training colleges and teachers should all work together to develop the learners' critical thinking skills within the parameters of the Zimbabwean education system.

The recent unveiling of chatbots such as ChatGPT has catalyzed vigorous debates about generative AI's impact on how learners read, write, and communicate. Largely missing from these debates is careful consideration of how young people are experiencing AI in their everyday lives and how they are making sense of the questions that these rapidly evolving cultural tools raise about ethics, power, and social participation. Engaging cultural-historical perspectives on technology, the present study drew on student survey and focus group data from English language arts classes in two culturally and linguistically diverse high schools to answer the following questions: (1) How are young people using AI in their everyday lives, if at all?; (2) What do young people identify as key considerations related to AI-mediated writing?; and (3) What ethical and critical considerations, if any, inform young people's sensemaking of and practices with AI? Young people reported using generative AI for diverse purposes in and out of school, including to accomplish routine organizational and information tasks, to entertain themselves through experimenting with AI technologies, and to catalyze their thinking and writing processes. Survey and focus group participants' responses suggested their regular navigation of ethical and critical dimensions of AI use and their contemplation of what it means to be human through and with advancing technologies. Young people also reported a lack of opportunity to examine AI practices and perspectives in school, suggesting the important role schools can play in supporting youths' development of AI ethics.

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 base pair region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologues. Using RNA sequencing, we show how 5 splice-site use is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide.

As on land, oceans exhibit high temporal and spatial temperature variation. This ocean weather contributes to the physiological and ecological processes that ultimately determine the patterns of species distribution and abundance, yet is often unrecognized, especially in tropical oceans. Here, we tested the paradigm of temperature stability in shallow waters (

Background & aimsBiliary atresia (BA) is poorly understood and leads to liver transplantation (LT), with the requirement for and associated risks of lifelong immunosuppression, in most children. We performed a genome-wide association study (GWAS) to determine the genetic basis of BA.MethodsWe performed a GWAS in 811 European BA cases treated with LT in US, Canadian and UK centers, and 4,654 genetically matched controls. Whole-genome sequencing of 100 cases evaluated synthetic association with rare variants. Functional studies included whole liver transcriptome analysis of 64 BA cases and perturbations in experimental models.ResultsA GWAS of common single nucleotide polymorphisms (SNPs), i.e. allele frequencies >1%, identified intronic SNPs rs6446628 in AFAP1 with genome-wide significance (p = 3.93E-8) and rs34599046 in TUSC3 at sub-threshold genome-wide significance (p = 1.34E-7), both supported by credible peaks of neighboring SNPs. Like other previously reported BA-associated genes, AFAP1 and TUSC3 are ciliogenesis and planar polarity effectors (CPLANE). In gene-set-based GWAS, BA was associated with 6,005 SNPs in 102 CPLANE genes (p = 5.84E-15). Compared with non-CPLANE genes, more CPLANE genes harbored rare variants (allele frequency

Purpose: With the rapid advancement of generative artificial intelligence (AI), it is important to consider how young people are making sense of these tools in their everyday lives. Drawing on critical postdigital approaches to learning and literacy, this study aims to center the experiences and perspectives of young people who encounter and experiment with generative AI in their daily writing practices. Design/methodology/approach: This critical case study of one digital platform -- Character.ai -- brings together an adolescent and adult authorship team to inquire about the intertwining of young people's playful and critical perspectives when writing on/with digital platforms. Drawing on critical walkthrough methodology (Light et al., 2018), the authors engage digital methods to study how the creative and "fun" uses of AI in youths' writing lives are situated in broader platform ecologies. Findings: The findings suggest experimentation and pleasure are key aspects of young people's engagement with generative AI. The authors demonstrate how one platform works to capitalize on these dimensions, even as youth users engage critically and artfully with the platform and develop their digital writing practices. Practical implications: This study highlights how playful experimentation with generative AI can engage young people both in pleasurable digital writing and in exploration and contemplation of platforms dynamics and structures that shape their and others' literate activities. Educators can consider young people's creative uses of these evolving technologies as potential opportunities to develop a critical awareness of how commercial platforms seek to benefit from their users. Originality/value: This study contributes to the development of a critical and humanist research agenda around generative AI by centering the experiences, perspectives and practices of young people who are underrepresented in the burgeoning research devoted to AI and literacies.

BACKGROUND: There is a clinical need for therapeutics for COVID-19 patients with acute hypoxemic respiratory failure whose 60-day mortality remains at 30-50%. Aviptadil, a lung-protective neuropeptide, and remdesivir, a nucleotide prodrug of an adenosine analog, were compared with placebo among patients with COVID-19 acute hypoxaemic respiratory failure. METHODS: TESICO was a randomised trial of aviptadil and remdesivir versus placebo at 28 sites in the USA. Hospitalised adult patients were eligible for the study if they had acute hypoxaemic respiratory failure due to confirmed SARS-CoV-2 infection and were within 4 days of the onset of respiratory failure. Participants could be randomly assigned to both study treatments in a 2 × 2 factorial design or to just one of the agents. Participants were randomly assigned with a web-based application. For each site, randomisation was stratified by disease severity (high-flow nasal oxygen or non-invasive ventilation vs invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), and four strata were defined by remdesivir and aviptadil eligibility, as follows: (1) eligible for randomisation to aviptadil and remdesivir in the 2 × 2 factorial design; participants were equally randomly assigned (1:1:1:1) to intravenous aviptadil plus remdesivir, aviptadil plus remdesivir matched placebo, aviptadil matched placebo plus remdesvir, or aviptadil placebo plus remdesivir placebo; (2) eligible for randomisation to aviptadil only because remdesivir was started before randomisation; (3) eligible for randomisation to aviptadil only because remdesivir was contraindicated; and (4) eligible for randomisation to remdesivir only because aviptadil was contraindicated. For participants in strata 2-4, randomisation was 1:1 to the active agent or matched placebo. Aviptadil was administered as a daily 12-h infusion for 3 days, targeting 600 pmol/kg on infusion day 1, 1200 pmol/kg on day 2, and 1800 pmol/kg on day 3. Remdesivir was administered as a 200 mg loading dose, followed by 100 mg daily maintenance doses for up to a 10-day total course. For participants assigned to placebo for either agent, matched saline placebo was administered in identical volumes. For both treatment comparisons, the primary outcome, assessed at day 90, was a six-category ordinal outcome: (1) at home (defined as the type of residence before hospitalisation) and off oxygen (recovered) for at least 77 days, (2) at home and off oxygen for 49-76 days, (3) at home and off oxygen for 1-48 days, (4) not hospitalised but either on supplemental oxygen or not at home, (5) hospitalised or in hospice care, or (6) dead. Mortality up to day 90 was a key secondary outcome. The independent data and safety monitoring board recommended stopping the aviptadil trial on May 25, 2022, for futility. On June 9, 2022, the sponsor stopped the trial of remdesivir due to slow enrolment. The trial is registered with ClinicalTrials.gov, NCT04843761. FINDINGS: Between April 21, 2021, and May 24, 2022, we enrolled 473 participants in the study. For the aviptadil comparison, 471 participants were randomly assigned to aviptadil or matched placebo. The modified intention-to-treat population comprised 461 participants who received at least a partial infusion of aviptadil (231 participants) or aviptadil matched placebo (230 participants). For the remdesivir comparison, 87 participants were randomly assigned to remdesivir or matched placebo and all received some infusion of remdesivir (44 participants) or remdesivir matched placebo (43 participants). 85 participants were included in the modified intention-to-treat analyses for both agents (ie, those enrolled in the 2 x 2 factorial). For the aviptadil versus placebo comparison, the median age was 57 years (IQR 46-66), 178 (39%) of 461 participants were female, and 246 (53%) were Black, Hispanic, Asian or other (vs 215 [47%] White participants). 431 (94%) of 461 participants were in an intensive care unit at baseline, with 271 (59%) receiving high-flow nasal oxygen or non-invasive ventiliation, 185 (40%) receiving invasive mechanical ventilation, and five (1%) receiving ECMO. The odds ratio (OR) for being in a better category of the primary efficacy endpoint for aviptadil versus placebo at day 90, from a model stratified by baseline disease severity, was 1·11 (95% CI 0·80-1·55; p=0·54). Up to day 90, 86 participants in the aviptadil group and 83 in the placebo group died. The cumulative percentage who died up to day 90 was 38% in the aviptadil group and 36% in the placebo group (hazard ratio 1·04, 95% CI 0·77-1·41; p=0·78). The primary safety outcome of death, serious adverse events, organ failure, serious infection, or grade 3 or 4 adverse events up to day 5 occurred in 146 (63%) of 231 patients in the aviptadil group compared with 129 (56%) of 230 participants in the placebo group (OR 1·40, 95% CI 0·94-2·08; p=0·10). INTERPRETATION: Among patients with COVID-19-associated acute hypoxaemic respiratory failure, aviptadil did not significantly improve clinical outcomes up to day 90 when compared with placebo. The smaller than planned sample size for the remdesivir trial did not permit definitive conclusions regarding safety or efficacy. FUNDING: National Institutes of Health.

Ethnographic-epidemiological (“ethno-epi”) research methodologies are increasingly being used to examine health-related issues, including the experiences of people who use drugs. However, the complementary application of random sampling from a well characterised cohort and qualitative data collection methods in a single study has not been described. We address this gap by sharing insights from the implementation of a novel random stratified sampling technique to recruit participants from two large prospective observational studies of people who use drugs into a qualitative study about impacts of the COVID-19 pandemic on their lived experience. We aim to describe how an ethno-epi approach we used can enhance the validity, reliability and generalizability of research findings in mixed methods investigations. We do so by providing a step-by-step description of the process we used to determine participant eligibility and recruitment into the qualitative study. Although the approach is not without limitations, findings underscore how ethno-epi random sampling approaches can increase the credibility and trustworthiness of qualitative findings without compromising data depth and integrity. Our study makes an important contribution to the growing number of new creative approaches being developed in the mixed methods research field and we hope that by sharing our account it will encourage and support others to consider the use of ethno-epi approaches in health-related research.

BackgroundLarge-scale trials of multidomain interventions show that modifying lifestyle and psychological risk factors can slow cognitive decline. We aim to determine if a lower intensity, personally tailored secondary dementia prevention programme for older people with subjective or mild objective memory decline, informed by behaviour change theory, reduces cognitive decline over 2 years.MethodsA multi-site, single-blind randomised controlled trial recruiting 704 older adults at high dementia risk due to mild cognitive impairment (MCI) or subjective cognitive decline (SCD). Participants are randomised using 1:1 allocation ratio to the APPLE Tree intervention versus control arm (dementia prevention information), stratified by site. The intervention explores and implements strategies to promote healthy lifestyle, increase pleasurable activities and social connections and improve long-term condition self-management. Two facilitators trained and supervised by a clinical psychologist deliver ten, 1-h group video call sessions over 6 months (approximately every fortnight), video-call 'tea breaks' (less structured, facilitated social sessions) in intervening weeks and individual goal-setting phone calls every 2 weeks. From 6 to 12 months, participants meet monthly for 'tea breaks', with those not attending receiving monthly goal-setting phone calls. Participants receive a food delivery, pedometer and website access to cognitive training and information about lifestyle modification. Follow-ups for all outcome measures are at 12 and 24 months. The primary outcome is cognition (Neuropsychological Test Battery (NTB) score) at 24 months. Secondary outcomes are quality of life, cost per quality-adjusted life year (QALY) and wellbeing and lifestyle factors the intervention targets (diet, vascular risk, body weight, activity, sleep, anxiety, depression, social networks and loneliness, alcohol intake and smoking). Participants from purposively selected sites participate in qualitative process evaluation interviews, which will be analysed using thematic analytic methods.DiscussionIf effective, the intervention design, involving remote delivery and non-clinical facilitators, would facilitate intervention roll-out to older people with memory concerns.Trial registrationISRCTN17325135 . Registration date 27 November 2019.

In this study, self-reported survey results from the National Survey of Student Engagement (NSSE) 2017 and 2018 are examined to understand the extent to which students who were academically at-risk and academically prepared engaged in active learning versus traditional learning methods across bachelor's, master's, and doctoral degree-granting institutions. The NSSE Report Builder Public (2018) was utilized to create a data set from first year student responses selecting for teaching methodologies, Carnegie Institutional Categories, and student academic level as determined by course grades. Researchers used chi-square analyses to establish associations between the variables; all chi-square results were statistically significant except for one; there was no association found between students who were academically at-risk and coursework that emphasized evaluative learning activities. Next, researchers analyzed the frequencies of types of learning activities reported by students. Students who were were academically at-risk reported lower frequencies of using active learning techniques and tended to engage in study for fewer hours across all institution types. From this analysis, suggestions for improving the instruction for students who are academically at-risk include increased use of active learning teaching strategies for the various types of degree-granting institutions.

Creating healthy and sustainable cities should be a global priority. Some cities prioritize 15-minute cities as a planning approach with co-benefits for health, climate change mitigation, equity, and economic recovery from COVID-19. Yet, as our recent Lancet Global Health series on “Urban Design, Transport, and Health” showed, many cities have a long way to go to achieve this vision. This policy guideline summarizes the main findings of the series, which assessed health and sustainability indicators for 25 cities in 19 countries. We then outline steps governments can take to strengthen policy frameworks and deliver more healthy, equitable, and sustainable built environments.The Lancet Global Health series provided clear evidence that cities need to transform urban governance to enable integrated planning for health and sustainability and commit to policy implementation. Evidence-informed indicators should be used to benchmark and monitor progress. Cities need policy frameworks that are comprehensive and consistent with evidence, with measurable policy targets to support implementation and accountability. The series provided evidence-informed thresholds for some key urban design and transport features, which can be embedded as policy targets. Policies and interventions must prioritize identifying and reducing inequities in access to health-supportive environments. Governments should also invest in open data and promote citizen-science programmes, to support indicator development and research for public benefit. We provide tools to replicate our indicators and an invitation to join our 1000 Cities Challenge via the Global Observatory of Healthy and Sustainable Cities.

BackgroundLevels of plasma SARS-CoV-2 nucleocapsid (N) antigen may be an important biomarker in patients with COVID-19 and enhance our understanding of the pathogenesis of COVID-19.ObjectiveTo evaluate whether levels of plasma antigen can predict short-term clinical outcomes and identify clinical and viral factors associated with plasma antigen levels in hospitalized patients with SARS-CoV-2.DesignCross-sectional study of baseline plasma antigen level from 2540 participants enrolled in the TICO (Therapeutics for Inpatients With COVID-19) platform trial from August 2020 to November 2021, with additional data on day 5 outcome and time to discharge.Setting114 centers in 10 countries.ParticipantsAdults hospitalized for acute SARS-CoV-2 infection with 12 days or less of symptoms.MeasurementsBaseline plasma viral N antigen level was measured at a central laboratory. Delta variant status was determined from baseline nasal swabs using reverse transcriptase polymerase chain reaction. Associations between baseline patient characteristics and viral factors and baseline plasma antigen levels were assessed using both unadjusted and multivariable modeling. Association between elevated baseline antigen level of 1000 ng/L or greater and outcomes, including worsening of ordinal pulmonary scale at day 5 and time to hospital discharge, were evaluated using logistic regression and Fine-Gray regression models, respectively.ResultsPlasma antigen was below the level of quantification in 5% of participants at enrollment, and 1000 ng/L or greater in 57%. Baseline pulmonary severity of illness was strongly associated with plasma antigen level, with mean plasma antigen level 3.10-fold higher among those requiring noninvasive ventilation or high-flow nasal cannula compared with room air (95% CI, 2.22 to 4.34). Plasma antigen level was higher in those who lacked antispike antibodies (6.42 fold; CI, 5.37 to 7.66) and in those with the Delta variant (1.73 fold; CI, 1.41 to 2.13). Additional factors associated with higher baseline antigen level included male sex, shorter time since hospital admission, decreased days of remdesivir, and renal impairment. In contrast, race, ethnicity, body mass index, and immunocompromising conditions were not associated with plasma antigen levels. Plasma antigen level of 1000 ng/L or greater was associated with a markedly higher odds of worsened pulmonary status at day 5 (odds ratio, 5.06 [CI, 3.41 to 7.50]) and longer time to hospital discharge (median, 7 vs. 4 days; subhazard ratio, 0.51 [CI, 0.45 to 0.57]), with subhazard ratios similar across all levels of baseline pulmonary severity.LimitationsPlasma samples were drawn at enrollment, not hospital presentation. No point-of-care test to measure plasma antigen is currently available.ConclusionElevated plasma antigen is highly associated with both severity of pulmonary illness and clinically important patient outcomes. Multiple clinical and viral factors are associated with plasma antigen level at presentation. These data support a potential role of ongoing viral replication in the pathogenesis of SARS-CoV-2 in hospitalized patients.Primary funding sourceU.S. government Operation Warp Speed and National Institute of Allergy and Infectious Diseases.

During early ischemic brain injury, glutamate receptor hyperactivation mediates neuronal death via osmotic cell swelling. Here we show that ischemia and excess NMDA receptor activation cause actin to rapidly and extensively reorganize within the somatodendritic compartment. Normally, F-actin is concentrated within dendritic spines. However,

Urban liveability is a global priority for creating healthy, sustainable cities. Measurement of policy-relevant spatial indicators of the built and natural environment supports city planning at all levels of government. Analysis of their spatial distribution within cities, and impacts on individuals and communities, is crucial to ensure planning decisions are effective and equitable. This paper outlines challenges and lessons from a 5-year collaborative research program, scaling up a software workflow for calculating a composite indicator of urban liveability for residential address points across Melbourne, to Australia's 21 largest cities, and further extension to 25 global cities in diverse contexts.

Rationale: Uncertainty regarding the natural history of coronavirus disease (COVID-19) led to difficulty in efficacy endpoint selection for therapeutic trials. Capturing outcomes that occur after hospital discharge may improve assessment of clinical recovery among hospitalized patients with COVID-19. Objectives: Evaluate 90-day clinical course of patients hospitalized with COVID-19, comparing three distinct definitions of recovery. Methods: We used pooled data from three clinical trials of neutralizing monoclonal antibodies to compare: 1) the hospital discharge approach; 2) the TICO (Therapeutics for Inpatients with COVID-19) trials sustained recovery approach; and 3) a comprehensive approach. At the time of enrollment, all patients were hospitalized in a non-ICU setting without organ failure or major extrapulmonary manifestations of COVID-19. We defined discordance as a difference between time to recovery. Measurements and Main Results: Discordance between the hospital discharge and comprehensive approaches occurred in 170 (20%) of 850 enrolled participants, including 126 hospital readmissions and 24 deaths after initial hospital discharge. Discordant participants were older (median age, 68 vs. 59 years; P

BackgroundEnsovibep (MP0420) is a designed ankyrin repeat protein, a novel class of engineered proteins, under investigation as a treatment of SARS-CoV-2 infection.ObjectiveTo investigate if ensovibep, in addition to remdesivir and other standard care, improves clinical outcomes among patients hospitalized with COVID-19 compared with standard care alone.DesignDouble-blind, randomized, placebo-controlled, clinical trial. (ClinicalTrials.gov: NCT04501978).SettingMultinational, multicenter trial.ParticipantsAdults hospitalized with COVID-19.InterventionIntravenous ensovibep, 600 mg, or placebo.MeasurementsEnsovibep was assessed for early futility on the basis of pulmonary ordinal scores at day 5. The primary outcome was time to sustained recovery through day 90, defined as 14 consecutive days at home or place of usual residence after hospital discharge. A composite safety outcome that included death, serious adverse events, end-organ disease, and serious infections was assessed through day 90.ResultsAn independent data and safety monitoring board recommended that enrollment be halted for early futility after 485 patients were randomly assigned and received an infusion of ensovibep (n = 247) or placebo (n = 238). The odds ratio (OR) for a more favorable pulmonary outcome in the ensovibep (vs. placebo) group at day 5 was 0.93 (95% CI, 0.67 to 1.30; P = 0.68; OR > 1 would favor ensovibep). The 90-day cumulative incidence of sustained recovery was 82% for ensovibep and 80% for placebo (subhazard ratio [sHR], 1.06 [CI, 0.88 to 1.28]; sHR > 1 would favor ensovibep). The primary composite safety outcome at day 90 occurred in 78 ensovibep participants (32%) and 70 placebo participants (29%) (HR, 1.07 [CI, 0.77 to 1.47]; HR