Search

Online instructional delivery has always been viewed as beneficial due to its flexibility in settings and times, but the COVID-19 pandemic produced an essential need for the ability to engage in learning without direct contact with others. For students with Autism Spectrum Disorder and Intellectual Disability (ASD and ID) who have extensive support needs, developing the skills required to engage with online content is critical for utilizing and interacting with distance learning platforms and resources. Using a visual task analysis, least-to-most prompting, and reinforcement, students with ASD and ID can be taught to use technological devices for virtual instruction without adult support. By teaching students to access and use point-of-view video modeling for online instructional delivery, teachers can facilitate skills their students need to access evidence-based practices and meet diverse learning goals and objectives.

Many machine learning techniques are used as drug discovery tools with the intent to speed characterization by determining relationships between compound structure and biological function. However, particularly in anticancer drug discovery, these models often make only binary decisions about the biological activity for a narrow scope of drug targets. We present a feed-forward neural network, PECAN (Prediction Engine for the Cytostatic Activity of Natural product-like compounds), that simultaneously classifies the potential antiproliferative activity of compounds against 59 cancer cell lines. It predicts the activity to be one of six categories, indicating not only if activity is present but the degree of activity. Using an independent subset of NCI data as a test set, we show that PECAN can reach 60.1% accuracy in a six-way classification and present further evidence that it classifies based on useful structural features of compounds using a within-one measure that reaches 93.0% accuracy.

In this paper, an application of open-ended textual feedback is presented as a tool to evaluate the perceptions and needs of teachers tasked with implementing computational thinking in the K-12 curriculum. Semantic analysis tools, including sentiment analysis and thematic analysis, facilitated the identification of common themes in openended textual feedback. Results show that semantic analysis techniques can be useful in evaluating formative assessment data or open-ended feedback to discover response patterns, which may aid in determining actionable insights related to adult learner perceptions, interests, and self-efficacy. Formative assessment data were collected from a unique professional development workshop to promote computational thinking and curriculum integration in core subjects, including writing, math, science, and social studies, with the goal of discovering the barriers that rural teachers face in developing and implementing lesson plans for grades 3-8 teachers in a rural midwestern state in the USA to promote computational thinking and curriculum integration in core subjects, including writing, math, science, and social studies, with the goal of discovering the barriers that rural teachers face in developing and implementing lesson plans.

The PI3K enzymes modify phospholipids to regulate cell growth and differentiation. Somatic variants in PI3K are recurrent in cancer and drive a proliferative phenotype. Somatic mosaicism of PIK3R1 and PIK3CA are associated with vascular anomalies and overgrowth syndromes. Germline PIK3R1 variants are associated with varying phenotypes, including immunodeficiency or facial dysmorphism with growth delay, lipoatrophy, and insulin resistance associated with SHORT syndrome. There has been limited study of the molecular mechanism to unify our understanding of how variants in PIK3R1 drive both undergrowth and overgrowth phenotypes. Thus, we compiled genomic variants from cancer and rare vascular anomalies and sought to interpret their effects using an unbiased physics-based simulation approach for the protein complex. We applied molecular dynamics simulations to mechanistically understand how genetic variants affect PIK3R1 and its interactions with PIK3CA. Notably, iSH2 genetic variants associated with undergrowth destabilize molecular interactions with the PIK3CA receptor binding domain in simulations, which is expected to decrease activity. On the other hand, overgrowth and cancer variants lead to loss of inhibitory interactions in simulations, which is expected to increase activity. We find that all disease variants display dysfunctions on either structural characteristics or intermolecular interaction energy. Thus, this comprehensive characterization of novel mosaic somatic variants associated with two opposing phenotypes has mechanistic importance and biomedical relevance and may aid in future therapeutic developments.

IMPORTANCE: The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or Long COVID) in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults. OBSERVATIONS: We describe the protocol for the Pediatric Observational Cohort Study of the NIHs REsearching COVID to Enhance Recovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of four cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study (n = 10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n = 6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n = 6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n = 600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science. CONCLUSIONS AND RELEVANCE: RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions. CLINICAL TRIALS.GOV IDENTIFIER: Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011.

In England and Wales, diocesan inspectors are charged with assessing the overall quality of Catholic education provided by Catholic schools. As part of this assessment, inspectors are required to give an account of the liturgical life of the school. Often the reports which result from these inspections refer to the degree of students' "active participation" in liturgy. This terminology has its roots in Biblical and patristic theological literature. Its meaning has evolved over time and has been used to describe a wide range of seemingly diffuse human behaviours. This article casts light on the meaning of "active participation" in the context of Diocesan inspectors and offers some reflections on how this term could be refined in order to make diocesan inspections more informative.

Abstract The absence or presence of a lunar paleomagnetosphere is important because it bears directly on the volatile content of the regolith and exploration targets for Artemis and other missions to the Moon. Recent paleointensity study of samples from the Apollo missions has readdressed this question. Multiple specimens from a young 2-million-year-old glass shows a strong magnetization compatible with that induced by charge-separation in an impact plasma, whereas paleointensities of single crystals yield evidence for null magnetizations spanning 3.9 to 3.2 Ga. Together, these data are consistent with an impact mechanism for the magnetization of some lunar samples, and absence of a long-lived lunar core dynamo and paleomagnetosphere recorded in other samples. Here, we present a dataset that allows researchers to examine replicates of these measurements. For the glass, we present data from specimens that fail standard paleointensity selection criteria but nevertheless imply a complex, changing magnetic field environment. For the single crystals, the replicate measurements further illustrate the initial zero magnetization state of these materials.

Abstract Immunodominance of antibodies targeting non-neutralizing epitopes and the high level of somatic hypermutation within germinal centers (GCs) required for most HIV broadly neutralizing antibodies (bnAbs) are major impediments to the development of an effective HIV vaccine. Rational protein vaccine design and non-conventional immunization strategies are potential avenues to overcome these hurdles. Here, we report using implantable osmotic pumps to continuously deliver a series of epitope-targeted immunogens to rhesus macaques over the course of six months to prime and elicit antibody responses against the conserved fusion peptide (FP). GC responses and antibody specificities were tracked longitudinally using lymph node fine-needle aspirates and electron microscopy polyclonal epitope mapping (EMPEM), respectively, to show antibody responses to the FP/N611 glycan hole region were primed, although exhibited limited neutralization breadth. Application of cryoEMPEM delineated key residues for on-target and off-target responses that can drive the next round of structure-based vaccine design.

Abstract Background Pregnant women are a vulnerable population to COVID-19 given an increased susceptibility to severe SARS-CoV-2 infection and pregnancy complications. However, few SARS-CoV-2 serological surveys have been performed among this population to assess the extent of the infection in sub-Saharan countries. The objectives of this study were to determine SARS-CoV-2 seroprevalence among Beninese pregnant women, to identify spatial seropositivity clusters and to analyse factors associated with the infection. Methods A cross-sectional study including women in their third trimester of pregnancy attending the antenatal care (ANC) clinics at Allada (south Benin) and Natitingou (north Benin) was conducted. Rapid diagnostic tests (RDT) for detection of IgG/IgM against the SARS-CoV-2 spike protein were performed using capillary blood. Seroprevalence of SARS-CoV-2 antibodies and associations between SARS-CoV-2 serostatus and maternal characteristics were analyzed by multivariate logistic regression. Spatial analyses were performed using the spatial scan statistics to identify spatial clusters of SARS-CoV-2 infection. Results A total of 861 pregnant women were enrolled between May 4 and June 29, 2022. 58/861 (6.7%) participants reported having received COVID-19 vaccine. None of the participants had been diagnosed with COVID-19 during their pregnancy. SARS-CoV-2 antibodies were detected in 607/802 (75.7%; 95% CI 72.56%–78.62%) of unvaccinated participants. Several urban and rural spatial clusters of SARS-CoV-2 cases were identified in Allada and one urban spatial cluster was identified in Natitingou. Unvaccinated participants from Allada with at least one previous morbidity were at a three-times higher risk of presenting SARS-CoV-2 antibodies (OR = 2.89; 95%CI 1.19%-7.00%). Conclusion Three out of four pregnant women had SARS-CoV-2 antibodies, suggesting a high virus circulation among pregnant women in Benin, while COVID-19 vaccination coverage was low. Pregnant women with comorbidities may be at increased risk of SARS-CoV-2 infection. This population should be prioritized for COVID-19 diagnosis and vaccination in order to prevent its deleterious effects. Trial registration NCT06170320 (retrospectively registered on December 21, 2023).

The identification of molecular structure is essential for understanding chemical diversity and for developing drug leads from small molecules. Nevertheless, the structure elucidation of small molecules by Nuclear Magnetic Resonance (NMR) experiments is often a long and non-trivial process that relies on years of training. To achieve this process efficiently, several spectral databases have been established to retrieve reference NMR spectra. However, the number of reference NMR spectra available is limited and has mostly facilitated annotation of commercially available derivatives. Here, we introduce DeepSAT, a neural network-based structure annotation and scaffold prediction system that directly extracts the chemical features associated with molecular structures from their NMR spectra. Using only the 1H-13C HSQC spectrum, DeepSAT identifies related known compounds and thus efficiently assists in the identification of molecular structures. DeepSAT is expected to accelerate chemical and biomedical research by accelerating the identification of molecular structures.

Plate tectonics is a fundamental factor in the sustained habitability of Earth, but its time of onset is unknown, with ages ranging from the Hadaean to Proterozoic eons1-3. Plate motion is a key diagnostic to distinguish between plate and stagnant-lid tectonics, but palaeomagnetic tests have been thwarted because the planet's oldest extant rocks have been metamorphosed and/or deformed4. Herein, we report palaeointensity data from Hadaean-age to Mesoarchaean-age single detrital zircons bearing primary magnetite inclusions from the Barberton Greenstone Belt of South Africa5. These reveal a pattern of palaeointensities from the Eoarchaean (about 3.9 billion years ago (Ga)) to Mesoarchaean (about 3.3 Ga) eras that is nearly identical to that defined by primary magnetizations from the Jack Hills (JH; Western Australia)6,7, further demonstrating the recording fidelity of select detrital zircons. Moreover, palaeofield values are nearly constant between about 3.9 Ga and about 3.4 Ga. This indicates unvarying latitudes, an observation distinct from plate tectonics of the past 600 million years (Myr) but predicted by stagnant-lid convection. If life originated by the Eoarchaean8, and persisted to the occurrence of stromatolites half a billion years later9, it did so when Earth was in a stagnant-lid regime, without plate-tectonics-driven geochemical cycling.

This mixed methods research design focuses on post-secondary institutions in Saskatchewan, Canada, its employees' experiences of working remotely, and the impact of the global COVID-19 pandemic on school leadership. Presented are the perceived challenges as well as the benefits of the "new" workplace since the COVID-19 crisis. Administrative and instructional leadership had changed dramatically. Most identified their quality of work as better or the same because of having fewer distractions, interruptions, and less wasted time at the workplace. The participants' interviews and survey responses describe the necessary adaptation, flexibility, mental health and wellness, accountability, workload intensification, and future expectations of the workplace and leadership once the pandemic is over.

Abstract Background The joint evidence of the cost and the effectiveness of family-based therapies is modest. Objective To study the cost-effectiveness of family therapy (FT) versus treatment-as-usual (TAU) for young people seen after self-harm combining data from an 18-month trial and hospital records up to 60-month from randomisation. Methods We estimate the cost-effectiveness of FT compared to TAU over 5 years using a quasi-Markov state model based on self-harm hospitalisations where probabilities of belonging in a state are directly estimated from hospital data. The primary outcome is quality-adjusted life years (QALY). Cost perspective is NHS and PSS and includes treatment costs, health care use, and hospital attendances whether it is for self-harm or not. Incremental cost-effectiveness ratios are calculated and deterministic and probabilistic sensitivity analyses are conducted. Results Both trial arms show a significant decrease in hospitalisations over the 60-month follow-up. In the base case scenario, FT participants incur higher costs (mean +£1,693) and negative incremental QALYs (-0.01) than TAU patients. The associated ICER at 5 years is dominated and the incremental health benefit at the £30,000 per QALY threshold is -0.067. Probabilistic Sensitivity Analysis finds the probability that FT is cost-effective is around 3 − 2% up to a maximum willingness to pay of £50,000 per QALY. This suggest that the extension of the data to 60 months show no difference in effectiveness between treatments. Conclusion Whilst extended trial follow-up from routinely collected statistics is useful to improve the modelling of longer-term cost-effectiveness, FT is not cost-effective relative to TAU and dominated in a cost-utility analysis.

Abstract Earth’s magnetic field was in a highly unusual state when macroscopic animals of the Ediacara Fauna diversified and thrived. Any connection between these events is tantalizing but unclear. Here, we present single crystal paleointensity data from 2054 and 591 Ma pyroxenites and gabbros that define a dramatic intensity decline, from a strong Proterozoic field like that of today, to an Ediacaran value 30 times weaker. The latter is the weakest time-averaged value known to date and together with other robust paleointensity estimates indicate that Ediacaran ultra-low field strengths lasted for at least 26 million years. This interval of ultra-weak magnetic fields overlaps temporally with atmospheric and oceanic oxygenation inferred from numerous geochemical proxies. This concurrence raises the question of whether enhanced H ion loss in a reduced magnetic field contributed to the oxygenation, ultimately allowing diversification of macroscopic and mobile animals of the Ediacara Fauna.

Abstract Background NHS Health Check (NHSHC) is a national cardiovascular disease (CVD) risk identification and management programme. However, evidence suggests a limited understanding of the most used metric to communicate CVD risk with patients (10-year percentage risk). This study used novel application of video-stimulated recall interviews to understand patient perceptions and understanding of CVD risk following an NHSHC that used one of two different CVD risk calculators. Methods Qualitative, semi-structured video-stimulated recall interviews were conducted with patients (n = 40) who had attended an NHSHC using either the QRISK2 10-year risk calculator (n = 19) or JBS3 lifetime CVD risk calculator (n = 21). Interviews were transcribed and analysed using reflexive thematic analysis. Results Analysis resulted in the development of four themes: variability in understanding, relief about personal risk, perceived changeability of CVD risk, and positive impact of visual displays. The first three themes were evident across the two patient groups, regardless of risk calculator; the latter related to JBS3 only. Patients felt relieved about their CVD risk, yet there were differences in understanding between calculators. Heart age within JBS3 prompted more accessible risk appraisal, yet mixed understanding was evident for both calculators. Event-free survival age also resulted in misunderstanding. QRISK2 patients tended to question the ability for CVD risk to change, while risk manipulation through JBS3 facilitated this understanding. Displaying information visually also appeared to enhance understanding. Conclusions Effective communication of CVD risk within NHSHC remains challenging, and lifetime risk metrics still lead to mixed levels of understanding in patients. However, visual presentation of information, alongside risk manipulation during NHSHCs can help to increase understanding and prompt risk-reducing lifestyle changes. Trial registration ISRCTN10443908. Registered 7th February 2017.

Abstract Vaccine priming immunogens that activate germline precursors for broadly neutralizing antibodies (bnAbs) have promise for development of precision vaccines against major human pathogens. In a clinical trial of the eOD-GT8 60mer germline-targeting immunogen, higher frequencies of vaccine-induced VRC01-class bnAb-precursor B cells were observed in the high dose compared to the low dose group. Through immunoglobulin heavy chain variable (IGHV) genotyping, statistical modeling, quantification of IGHV1-2 allele usage and B cell frequencies in the naive repertoire for each trial participant, and antibody affinity analyses, we found that the difference between dose groups in VRC01-class response frequency was best explained by IGHV1-2 genotype rather than dose and was most likely due to differences in IGHV1-2 B cell frequencies for different genotypes. The results demonstrate the need to define population-level immunoglobulin allelic variations when designing germline-targeting immunogens and evaluating them in clinical trials.

Abstract The northeastern Pacific (NEP) Ocean spans the coast of British Columbia (Canada) and is impacted by anthropogenic activities including oil pipeline developments, maritime fossil fuel tanker traffic, industrial chemical effluents, agricultural and urban emissions in tandem with stormwater and wastewater discharges, and forest wildfires. Such events may expose surrounding marine environments to toxic polycyclic aromatic hydrocarbons (PAHs) and impact critical habitats of threatened killer whales (Orcinus orca). We analyzed skeletal muscle and liver samples from stranded Bigg’s killer whales and endangered Southern Resident killer whales (SRKWs) for PAH contamination using LRMS. C3-phenanthrenes/anthracenes (mean: 632 ng/g lw), C4-dibenzothiophenes (mean: 334 ng/g lw), and C4-phenanthrenes/anthracenes (mean: 248 ng/g lw) presented the highest concentrations across all tissue samples. Diagnostic ratios indicated petrogenic-sourced contamination for SRKWs and pyrogenic-sourced burdens for Bigg’s killer whales; differences between ecotypes may be attributed to habitat range, prey selection, and metabolism. A mother-fetus skeletal muscle pair provided evidence of PAH maternal transfer; low molecular weight compounds C3-fluorenes, dibenzothiophene, and naphthalene showed efficient and preferential exposure to the fetus. This indicates in-utero exposure of PAH-contamination to the fetus. Our results show that hydrocarbon-related anthropogenic activities are negatively impacting these top predators; preliminary data found here can be used to improve oil spill and other PAH pollution management and regulation efforts, and inform policy to conserve killer whale habitats in the NEP.

OBJECTIVE: Increased social risk data collection in health care settings presents new opportunities to apply this information to improve patient outcomes. Clinical decision support (CDS) tools can support these applications. We conducted a participatory engagement process to develop electronic health record (EHR)-based CDS tools to facilitate social risk-informed care plan adjustments in community health centers (CHCs). MATERIALS AND METHODS: We identified potential care plan adaptations through systematic reviews of hypertension and diabetes clinical guidelines. The results were used to inform an engagement process in which CHC staff and patients provided feedback on potential adjustments identified in the guideline reviews and on tool form and functions that could help CHC teams implement these suggested adjustments for patients with social risks. RESULTS: Partners universally prioritized tools for social risk screening and documentation. Additional high-priority content included adjusting medication costs and changing follow-up plans based on reported social risks. Most content recommendations reflected partners interests in encouraging provider-patient dialogue about care plan adaptations specific to patients social needs. Partners recommended CDS tool functions such as alerts and shortcuts to facilitate and efficiently document social risk-informed care plan adjustments. DISCUSSION AND CONCLUSION: CDS tools were designed to support CHC providers and staff to more consistently tailor care based on information about patients social context and thereby enhance patients ability to adhere to care plans. While such adjustments occur on an ad hoc basis in many care settings, these are among the first tools designed both to systematize and document these activities.

Evidence is needed about how to effectively support health care providers in implementing screening for social risks (adverse social determinants of health) and providing related referrals meant to address identified social risks. This need is greatest in underresourced care settings. The authors tested whether an implementation support intervention (6 months of technical assistance and coaching study clinics through a five-step implementation process) improved adoption of social risk activities in community health centers (CHCs). Thirty-one CHC clinics were block-randomized to six wedges that occurred sequentially. Over the 45-month study period from March 2018 to December 2021, data were collected for 6 or more months preintervention, the 6-month intervention period, and 6 or more months postintervention. The authors calculated clinic-level monthly rates of social risk screening results that were entered at in-person encounters and rates of social risk-related referrals. Secondary analyses measured impacts on diabetes-related outcomes. Intervention impact was assessed by comparing clinic performance based on whether they had versus had not yet received the intervention in the preintervention period compared with the intervention and postintervention periods. In assessing the results, the authors note that five clinics withdrew from the study for various bandwidth-related reasons. Of the remaining 26, a total of 19 fully or partially completed all 5 implementation steps, and 7 fully or partially completed at least the first 3 steps. Social risk screening was 2.45 times (95% confidence interval [CI], 1.32-4.39) higher during the intervention period compared with the preintervention period; this impact was not sustained postintervention (rate ratio, 2.16; 95% CI, 0.64-7.27). No significant difference was seen in social risk referral rates during the intervention or postintervention periods. The intervention was associated with greater blood pressure control among patients with diabetes and lower rates of diabetes biomarker screening postintervention. All results must be interpreted considering that the Covid-19 pandemic began midway through the trial, which affected care delivery generally and patients at CHCs particularly. Finally, the study results show that adaptive implementation support was effective at temporarily increasing social risk screening. It is possible that the intervention did not adequately address barriers to sustained implementation or that 6 months was not long enough to cement this change. Underresourced clinics may struggle to participate in support activities over longer periods without adequate resources, even if lengthier support is needed. As policies start requiring documentation of social risk activities, safety-net clinics may be unable to meet these requirements without adequate financial and coaching/technical support.

As online enrollment increases in the United States, it is important to understand the impact of course modality on student outcomes. In particular, there has been limited research on the effect of course enrollment at Hispanic-serving institutions (HSI). The current study evaluated the effect of online course enrollment on student grades and on student withdrawal rates by comparing outcomes in online and face-to-face classes. The main innovation of this study is to use propensity score analysis to control for 15 different student characteristics as a way to control for the selection bias introduced when students self-select into different course modalities. The study used data from a large, public, HSI in the mountain west during the 2017-2018 and 2018-2019 academic years. Baseline results on a two-sample t-test indicated that online students have significantly higher course grades, and non-significantly different withdrawal rates before controlling for student characteristics. The study used a propensity score analysis (PSA) to control for 15 confounding covariates after testing three different PSA models: near-neighbor matching, Mahalanobis' metric, and optimal matching. After evaluating each model for validity and sensitivity, a near-neighbor 1:2 matching PSA shows a non-significant difference in student grades, and higher withdrawal rates in online classes than face-to-face classes. Given these results, institutions should ensure that they are providing adequate academic support for online students to improve retention and success rates for online students.

Despite advances in screening, diagnosis, and treatment for prostate cancer (PCa), Black men tend to be diagnosed at younger ages, have higher mortality rates, and are at increased risk of recurrence or metastasis compared to their White counterparts. PCa disparities among Black men are caused by a complex interaction of social, behavioral, and biological factors across the public policy, community, organizational, interpersonal, and individual levels. Key contributing factors include mistrust in the health care system, poor communication between patients and providers, low awareness of screening guidelines, and high medical costs. These disparities are further exacerbated by the low representation of Black men in clinical trials, which limits access to high-quality cancer care and generalizability for PCa treatments. In this narrative review of the existing literature, we examined the epidemiology and identified contributing factors, and propose multi-level strategies to address and mitigate disparities among Black men with PCa.

Summary: Sudden losses or shocks to food production can impact food security as well as local industries and livelihoods. To build more resilient food systems, understanding the trends and drivers of shocks is crucial. We analyzed shocks in 195 fisheries and aquaculture production time series in Australia, using established methods. We detected 39 shocks over three decades, but only one shock was associated with aquaculture. Historic overfishing was the dominant driver of shocks, yet management change was implicated in over half of all shocks, largely in response to stock declines. Shock numbers peaked in the late 1990s to early 2000s and then declined—a trend that aligns with a period of major fisheries reform. Our study suggests that proactive and responsive fisheries management, alongside a diverse aquaculture sector, could act as a local stabilizing force for seafood production and potentially reduce the ever-growing threat of climate change. Science for society: Maintaining food systems that are resilient to shock events is a priority for many nations. Understanding the trends and drivers of food shocks or sudden losses in production can help nations understand vulnerabilities in the system and build resilience. However, research on food shocks is largely focused on cereal crops, and there is a need to examine different food systems. We examined trends and drivers to shocks in Australian seafood production. Our study found that wild-capture fisheries were more vulnerable to shocks compared with the younger, but rapidly expanding, aquaculture sector. However, our results also show that shocks declined over time and were absent in recent years, a trend that was likely influenced by major fisheries reform 20 years ago and a responsive fisheries management regime. Our findings highlight the benefits that can be achieved by acting on and learning from past shock events to build food system resilience at a local level.

Background Self-harm is common in adolescents and a major public health concern. Evidence for effective interventions is lacking. An individual patient data meta-analysis has the potential to provide more reliable estimates of the effects of therapeutic interventions for self-harm than conventional meta-analyses, to explore which treatments are best suited to certain groups. Method A systematic review and individual patient data meta-analysis of randomised controlled trials of therapeutic interventions to reduce repeat self-harm in adolescents who had a history of self-harm and presented to clinical services. Primary outcome was repetition of self-harm. The methods employed for searches, study screening and selection, and risk of bias assessment are described, with an overview of the outputs of the searching, selection and quality assessment processes. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance is followed. Results We identified a total 39 eligible studies, from 10 countries, where we sought Individual Patient Data (IPD), of which the full sample of participants were eligible in 18 studies and a partial sample of participants were eligible in 21 studies. We obtained IPD from 26 studies of 3448 eligible participants. For our primary outcome, repetition of self-harm, only 6 studies were rated as low risk of bias with 10 rated as high risk (although 2 of these were for secondary outcomes only). Conclusions Obtaining individual patient data for meta-analyses is possible but very time-consuming, despite clear guidance from funding bodies that researchers should share their data appropriately. More attention needs to be paid to seeking appropriate consent from study participants for (pseudo) anonymised data-sharing and institutions need to collaborate on agreeing template data-sharing agreements. Researchers and funders need to consider issues of research design more carefully. Our next step is to analyse all the data we have collected to see if it will tell us more about how we might prevent repetition of self-harm in young people. Funding This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 17/117/11. A plain language summary of this research article is available on the NIHR Journals Library Website https://doi.org/10.3310/GTNT6331. Plain language summary Self-harm is very common in young people and leads to an increased risk of death by suicide. Research so far has not provided clear evidence about which interventions can help to prevent self-harm repetition when young people present to services having harmed themselves. One way to understand what might help is to pool the results from lots of different clinical trials – this is known as a meta-analysis. This has already been done using the data published in research articles but has not led to clearer conclusions. In part this is because the information available in published articles is patchy and inconsistent which makes pooling the information and analysing it, difficult. A more useful approach is to ask researchers who led the clinical trials for their original ‘raw’ data and then pool and analyse all that data – this is known as an individual patient data meta-analysis. This has the added benefit that it is possible to include studies where only some of the participants are young people. We did this, and were able to identify many more study participants along with their data, compared to earlier meta-analyses. In this article, we describe how we searched for relevant research studies and the methods we used to obtain individual patient data from other researchers. We also describe our rating of the research quality of the studies we identified. We identified more studies, with many more participants in total, than in previous pooled study research. Gathering the data from other researchers was very time-consuming and not everyone was willing or able to share their data. When we rated the quality of the studies that we found, many were not of high quality. Our next step is to analyse all the data we have collected to see if it will tell us more about how we might prevent repetition of self-harm in young people.

Regulatory T cells (Treg) play a prominent role in utero tolerating non-inherited maternal antigens and in regulating immune responses against pathogens at birth. This study investigates Treg immunity in newborns in West Africa, where sepsis remains a major public health problem. Treg phenotypes on neonates subgroups with early-onset sepsis (EOS), presumed sepsis, and healthy newborn with and without prenatal risk factors were evaluated. Treg phenotypes varied according to prenatal conditions, with increase in Treg frequency and Foxp3 expression in healthy newborns with prenatal risk factors compared to those with none risk. Compared to healthy newborns with prenatal risk factors, EOS neonates had a significantly reduced frequency of Treg and Foxp3 expression. In the Treg pool, higher frequency of activated Treg was observed in EOS neonates, suggesting an in-utero activation upstream of the sepsis onset. Their migration to the infection site may explain the reduced frequency of circulating Integrin α4β1+ Treg suggestive of homing to the endothelial tissue. EOS neonates show increases expression of CTLA-4, PD-1 and CD39 on Treg, which negatively regulate the activation of effector T cells (Teff) corroborating by the lower frequency of Teff in EOS neonates. The higher frequency of CD39+ Treg and the lower frequency of integrinα4β1+ Treg in EOS non-survivor suggests that Treg exhaustement and endothelial homing are associated with outcome severity. Neonates developing EOS are born with an altered Treg phenotypic profile. Treg expression of CTLA-4, PD-1, CD39, and integrinα4β1 cell markers can be considered as early warning or diagnostic markers of EOS.

Abstract Ensemble forecasts have been shown to better predict observed Atlantic climate variability than that of their own ensemble members. This phenomenon—termed the signal‐to‐noise paradox—is found to be widespread across models, timescales, and climate variables, and has wide implications. The signal‐to‐noise paradox can be interpreted as forecasts underestimating the amplitude of predictable signals on seasonal‐to‐decadal timescales. The cause of this remains unknown. Here, we examine sea level pressure variability from a very large multi‐model ensemble of uninitialized atmosphere‐only simulations, focusing on boreal winter. To assess signal‐to‐noise errors, the ratio of predictable components (RPC) is examined globally, as well as for regional climate indices: the North Atlantic Oscillation, Arctic Oscillation, Southern Annular Mode, and an Arctic index. Our analyses reveal significant correlations between the multi‐model ensemble‐mean and observations over large portions of the globe, particularly the tropics, North Atlantic, and North Pacific. However, RPC values greater than one are apparent over many extratropical regions and in all four climate indices. Higher‐resolution models produce greater observation‐model correlations and greater RPC values than lower‐resolution models in all four climate indices. We find that signal‐to‐noise errors emerge more clearly at higher resolution, but the amplitudes of predictable signals do not increase with resolution, at least across the range of resolutions considered here. Our results suggest that free‐running atmospheric models underestimate predictable signals in the absence of sea surface temperature biases, implying that signal‐to‐noise errors originate in the atmosphere or in ocean–atmosphere coupling.

Virologic suppression with antiretroviral therapy (ART) has significantly improved health outcomes for people living with HIV, yet challenges related to chronic inflammation in the central nervous system (CNS)-known as Neuro-HIV- persist. As primary targets for HIV-1 with the ability to survey and populate the CNS and interact with myeloid cells to co-ordinate neuroinflammation, CD4 T cells are pivotal in Neuro-HIV. Despite their importance, our understanding of CD4 T cell distribution in virus-targeted CNS tissues, their response to infection, and potential recovery following initiation of ART remain limited. To address these gaps, we studied ten SIVmac251-infected rhesus macaques using an ART regimen simulating suboptimal adherence. We evaluated four macaques during the acute phase pre-ART and six during the chronic phase. Our data revealed that HIV target CCR5+ CD4 T cells inhabit both the brain parenchyma and adjacent CNS tissues, encompassing choroid plexus stroma, dura mater, and the skull bone marrow. Aligning with the known susceptibility of CCR5+ CD4 T cells to viral infection and their presence within the CNS, high levels of viral RNA were detected in the brain parenchyma and its border tissues during acute SIV infection. Single-cell RNA sequencing of CD45+ cells from the brain revealed colocalization of viral transcripts within CD4 clusters and significant activation of antiviral molecules and specific effector programs within T cells, indicating CNS CD4 T cell engagement during infection. Acute infection led to marked imbalance in the CNS CD4/CD8 ratio which persisted into the chronic phase. These observations underscore the functional involvement of CD4 T cells within the CNS during SIV infection, enhancing our understanding of their role in establishing CNS viral presence. Our findings offer insights for potential T cell-focused interventions while underscoring the challenges in eradicating HIV from the CNS, particularly in the context of sub-optimal ART.

Abstract Quiescence, a reversible state of cell-cycle arrest, is an important state during both normal development and cancer progression. For example, in glioblastoma (GBM) quiescent glioblastoma stem cells (GSCs) play an important role in re-establishing the tumour, leading to relapse. While most studies have focused on identifying differentially expressed genes between proliferative and quiescent cells as potential drivers of this transition, recent studies have shown the importance of protein oscillations in controlling the exit from quiescence of neural stem cells. Here, we have undertaken a genome-wide bioinformatic inference approach to identify genes whose expression oscillates and which may be good candidates for controlling the transition to and from the quiescent cell state in GBM. Our analysis identified, among others, a list of important transcription regulators as potential oscillators, including the stemness gene SOX2, which we verified to oscillate in quiescent GSCs. These findings expand on the way we think about gene regulation and introduce new candidate genes as key regulators of quiescence.

Abstract Background Cancers exhibit complex transcriptomes with aberrant splicing that induces isoform-level differential expression compared to non-diseased tissues. Transcriptomic profiling using short-read sequencing has utility in providing a cost-effective approach for evaluating isoform expression, although short-read assembly displays limitations in the accurate inference of full-length transcripts. Long-read RNA sequencing (Iso-Seq), using the Pacific Biosciences (PacBio) platform, can overcome such limitations by providing full-length isoform sequence resolution which requires no read assembly and represents native expressed transcripts. A constraint of the Iso-Seq protocol is due to fewer reads output per instrument run, which, as an example, can consequently affect the detection of lowly expressed transcripts. To address these deficiencies, we developed a concatenation workflow, PacBio Full-Length Isoform Concatemer Sequencing (PB_FLIC-Seq), designed to increase the number of unique, sequenced PacBio long-reads thereby improving overall detection of unique isoforms. In addition, we anticipate that the increase in read depth will help improve the detection of moderate to low-level expressed isoforms. Results In sequencing a commercial reference (Spike-In RNA Variants; SIRV) with known isoform complexity we demonstrated a 3.4-fold increase in read output per run and improved SIRV recall when using the PB_FLIC-Seq method compared to the same samples processed with the Iso-Seq protocol. We applied this protocol to a translational cancer case, also demonstrating the utility of the PB_FLIC-Seq method for identifying differential full-length isoform expression in a pediatric diffuse midline glioma compared to its adjacent non-malignant tissue. Our data analysis revealed increased expression of extracellular matrix (ECM) genes within the tumor sample, including an isoform of the Secreted Protein Acidic and Cysteine Rich (SPARC) gene that was expressed 11,676-fold higher than in the adjacent non-malignant tissue. Finally, by using the PB_FLIC-Seq method, we detected several cancer-specific novel isoforms. Conclusion This work describes a concatenation-based methodology for increasing the number of sequenced full-length isoform reads on the PacBio platform, yielding improved discovery of expressed isoforms. We applied this workflow to profile the transcriptome of a pediatric diffuse midline glioma and adjacent non-malignant tissue. Our findings of cancer-specific novel isoform expression further highlight the importance of long-read sequencing for characterization of complex tumor transcriptomes.

Abstract Background Osteoarthritis is a common, painful and disabling long-term condition. Delivery of high-quality guideline-informed osteoarthritis care that successfully promotes and maintains supported self-management is imperative. However, osteoarthritis care remains inconsistent, including under use of core non-pharmacological approaches of education, exercise and weight loss. Community pharmacies are an accessible healthcare provider. United Kingdom government initiatives are promoting their involvement in a range of long-term conditions, including musculoskeletal conditions. It is not known what an enhanced community pharmacy role for osteoarthritis care should include, what support is needed to deliver such a role, and whether it would be feasible and acceptable to community pharmacy teams. In this (PharmOA) study, we aim to address these gaps, and co-design and test an evidence-based extended community pharmacy model of service delivery for managing osteoarthritis. Methods Informed by the Theoretical Domains Framework, Normalisation Process Theory, and the Medical Research Council (MRC) framework for developing complex interventions, we will undertake a multi-methods study involving five phases: 1. Systematic review to summarise currently available evidence on community pharmacy roles in supporting adults with osteoarthritis and other chronic (non-cancer) pain. 2. Cross-sectional surveys and one-to-one qualitative interviews with patients, healthcare professionals and pharmacy staff to explore experiences of current, and potential extended community pharmacy roles, in delivering osteoarthritis care. 3. Stakeholder co-design to: a) agree on the extended role of community pharmacies in osteoarthritis care; b) develop a model of osteoarthritis care within which the extended roles could be delivered (PharmOA model of service delivery); and c) refine existing tools to support community pharmacies to deliver extended osteoarthritis care roles (PharmOA tools). 4. Feasibility study to explore the acceptability and feasibility of the PharmOA model of service delivery and PharmOA tools to community pharmacy teams. 5. Final stakeholder workshop to: a) finalise the PharmOA model of service delivery and PharmOA tools, and b) if applicable, prioritise recommendations for its wider future implementation. Discussion This novel study paves the way to improving access to and availability of high-quality guideline-informed, consistent care for people with osteoarthritis from within community pharmacies.