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Rationale: The decades-long progression of chronic obstructive pulmonary disease (COPD) renders identifying different trajectories of disease progression challenging.Objectives: To identify subtypes of patients with COPD with distinct longitudinal progression patterns using a novel machine-learning tool called "Subtype and Stage Inference" (SuStaIn) and to evaluate the utility of SuStaIn for patient stratification in COPD.Methods: We applied SuStaIn to cross-sectional computed tomography imaging markers in 3,698 Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1-4 patients and 3,479 controls from the COPDGene (COPD Genetic Epidemiology) study to identify subtypes of patients with COPD. We confirmed the identified subtypes and progression patterns using ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) data. We assessed the utility of SuStaIn for patient stratification by comparing SuStaIn subtypes and stages at baseline with longitudinal follow-up data.Measurements and Main Results: We identified two trajectories of disease progression in COPD: a "Tissue→Airway" subtype (n = 2,354, 70.4%), in which small airway dysfunction and emphysema precede large airway wall abnormalities, and an "Airway→Tissue" subtype (n = 988, 29.6%), in which large airway wall abnormalities precede emphysema and small airway dysfunction. Subtypes were reproducible in ECLIPSE. Baseline stage in both subtypes correlated with future FEV1/FVC decline (r = -0.16 [P

The molecular mechanisms underlying metastasis in pheochromocytoma/paraganglioma (mPPGL) remain to be explored. Here, the authors perform genomic and immunogenomic profiling of mPPGL tumors and suggest potential biomarkers for risk of metastasis and immunotherapy response.

Abstract The acquisition of genetic abnormalities engendering oncogene dysregulation underpins cancer development. Certain proto-oncogenes possess several dysregulation mechanisms, yet how each mechanism impacts clinical outcome is unclear. Using T-cell acute lymphoblastic leukemia (T-ALL) as an example, we show that patients harboring 5’super-enhancer (5’SE) mutations of the TAL1 oncogene identifies a specific patient subgroup with poor prognosis irrespective of the level of oncogene dysregulation. Remarkably, the MYB dependent oncogenic 5’SE can be targeted using Mebendazole to induce MYB protein degradation and T-ALL cell death. Of note Mebendazole treatment demonstrated efficacy in vivo in T-ALL preclinical models. Our work provides proof of concept that within a specific oncogene driven cancer, the mechanism of oncogene dysregulation rather than the oncogene itself can identify clinically distinct patient subgroups and pave the way for future super-enhancer targeting therapy.

Abstract Background The contribution of artefenomel to the clinical and parasiticidal activity of ferroquine and artefenomel in combination in uncomplicated Plasmodium falciparum malaria was investigated. Methods This Phase 2a, randomized, open-label, parallel-group study was conducted from 11th September 2018 to 6th November 2019 across seven centres in Benin, Burkina Faso, Gabon, Kenya, and Uganda. Patients aged ≥ 14–69 years with microscopically confirmed infection (≥ 3000 to ≤ 50,000 parasites/µL blood) were randomized 1:1:1:1 to 400 mg ferroquine, or 400 mg ferroquine plus artefenomel 300, 600, or 1000 mg, administered as a single oral dose. The primary efficacy analysis was a logistic regression evaluating the contribution of artefenomel exposure to Day 28 PCR-adjusted adequate clinical and parasitological response (ACPR). Safety was also evaluated. Results The randomized population included 140 patients. For the primary analysis in the pharmacokinetic/pharmacodynamic efficacy population (N = 121), the contribution of artefenomel AUC0–∞ to Day 28 PCR-adjusted ACPR was not demonstrated when accounting for ferroquine AUC0–d28, baseline parasitaemia, and other model covariates: odds ratio 1.1 (95% CI 0.98, 1.2; P = 0.245). In the per-protocol population, Day 28 PCR-adjusted ACPR was 80.8% (21/26; 95% CI 60.6, 93.4) with ferroquine alone and 90.3% (28/31; 95% CI 74.2, 98.0), 90.9% (30/33; 95% CI 75.7, 98.1) and 87.1% (27/31; 95% CI 70.2, 96.4) with 300, 600, and 1000 mg artefenomel, respectively. Median time to parasite clearance (Kaplan–Meier) was 56.1 h with ferroquine, more rapid with artefenomel, but similar for all doses (30.0 h). There were no deaths. Adverse events (AEs) of any cause occurred in 51.4% (18/35) of patients with ferroquine 400 mg alone, and 58.3% (21/36), 66.7% (24/36), and 72.7% (24/33) with 300, 600, and 1000 mg artefenomel, respectively. All AEs were of mild-to-moderate severity, and consistent with the known profiles of the compounds. Vomiting was the most reported AE. There were no cases of QTcF prolongation ≥ 500 ms or > 60 ms from baseline. Conclusion The contribution of artefenomel exposure to the clinical and parasitological activity of ferroquine/artefenomel could not be demonstrated in this study. Parasite clearance was faster with ferroquine/artefenomel versus ferroquine alone. All treatments were well tolerated. Trial registration: ClinicalTrials.gov, NCT03660839 (7 September, 2018).

We collected >40,000 mosquitoes from 5 provinces in South Africa during 2011–2018 and screened for zoonotic flaviviruses. We detected West Nile virus in mosquitoes from conservation and periurban sites and potential new mosquito vectors; Banzi virus was rare. Our results suggest flavivirus transmission risks are increasing in South Africa.

Impaired single breath carbon monoxide diffusing capacity (DLCO) is associated with emphysema. Small airways disease (SAD) may be a precursor lesion to emphysema, but the relationship between SAD and DLCO is undescribed. We hypothesized that in mild COPD, functional SAD (fSAD) defined by computed tomography (CT) and Parametric Response Mapping methodology would correlate with impaired DLCO. Using data from ever-smokers in the COPDGene cohort, we established that fSAD correlated significantly with lower DLCO among both non-obstructed and GOLD 1-2 subjects. The relationship between DLCO with CT-defined emphysema was present in all GOLD stages, but most prominent in severe disease. TRIAL REGISTRATION: NCT00608764. Registry: COPDGene. Registered 06 February 2008, retrospectively registered.

BackgroundDiffusing capacity of the lung for carbon monoxide (Dlco) is inconsistently obtained in patients with COPD, and the added benefit of Dlco testing beyond that of more common tools is unknown.ObjectiveThe goal of this study was to determine whether lower Dlco is associated with increased COPD morbidity independent of emphysema assessed via spirometry and CT imaging.MethodsData for 1,806 participants with COPD from the Genetic Epidemiology of COPD (COPDGene) study 5-year visit were analyzed, including pulmonary function testing, quality of life, symptoms, exercise performance, and exacerbation rates. Dlco percent predicted was primarily analyzed as a continuous variable and additionally categorized into four groups: (1) Dlco and FEV1 > 50% (reference); (2) only Dlco ≤ 50%; (3) only FEV1 ≤ 50%; and (4) both ≤ 50% predicted. Outcomes were modeled by using multivariable linear and negative binomial regression, including emphysema and FEV1 percent predicted among other confounders.ResultsIn multivariable analyses, every 10% predicted decrease in Dlco was associated with symptoms and quality of life (COPD Assessment Test, 0.53 [P < .001]; St. George's Respiratory Questionnaire, 1.67 [P < .001]; Medical Outcomes Study Short Form 36 Physical Function, -0.89 [P < .001]), exercise performance (6-min walk distance, -45.35 feet; P < .001), and severe exacerbation rate (rate ratio, 1.14; P < .001). When categorized, severe impairment in Dlco alone, FEV1 alone, or both Dlco and FEV1 were associated with significantly worse morbidity compared with the reference group (P < .05 for all outcomes).ConclusionsImpairment in Dlco was associated with increased COPD symptoms, reduced exercise performance, and severe exacerbation risk even after accounting for spirometry and CT evidence of emphysema. These findings suggest that Dlco should be considered for inclusion in future multidimensional tools assessing COPD.

Willingness to communicate (WTC) reflects an intersection between instructed second language acquisition and learner psychology. WTC results from the coordinated interaction among complex processes that prepare second language (L2) learners to choose to use their L2 for authentic communication. Prior research has revealed considerable complexity in the influences on dynamic changes in WTC from moment-to-moment. The heuristic 'pyramid model' of WTC (MacIntyre et al., 1998) proposes interactions among approximately 30 different variables that may influence WTC. The present study uses the pyramid model to interpret data from three focal participants, all English as a second language (ESL) learners and international students in Canada, with varying degrees of experience in an English-speaking context. Using the idiodynamic method, all participants were recorded while describing a self-selected, personally meaningful photo. Second, participants rated their WTC in English using software that played a recording of their speech and collected continuous WTC ratings. Finally, participants were interviewed about their WTC ratings. Triangulating the data revealed how processes on multiple timescales interact during L2 communication about the photos. WTC changes as speakers' motivations and emotions are influenced by the deep, personal relevance of the topics under discussion. Pedagogical implications for the results of this study and the use of the idiodynamic method in L2 classrooms are discussed.

Abstract Adequate hand hygiene practices throughout the continuum of care of maternal and newborn health are essential for infection prevention. However, the hand hygiene compliance of facility-based birth attendants, parents and other caregivers along this continuum is low and behavioural-science informed interventions targeting the range of caregivers in both the healthcare facility and home environments are scarce. We assessed the limited efficacy of a novel multimodal behaviour change intervention, delivered at the facility, to improve the hand hygiene practices among midwives and caregivers during childbirth through the return to the home environment. The 6-month intervention was implemented in 4 of 8 purposively selected facilities and included environmental restructuring, hand hygiene infrastructure provision, cues and reminders, and participatory training. In this controlled before-and-after study, the hand hygiene practices of all caregivers present along the care continuum of 99 women and newborns were directly observed. Direct observations took place during three time periods; labour, delivery and immediate aftercare in the facility delivery room, postnatal care in the facility ward and in the home environment within the first 48 h following discharge. Multilevel logistic regression models, adjusted for baseline measures, assessed differences in hand hygiene practices between intervention and control facilities. The intervention was associated with increased odds of improved practice of birth attendants during birth and newborn care in the delivery room (Adjusted odds ratio [AOR] = 4.7; 95% confidence interval [CI] = 2.7, 7.7), and that of parental and non-parental caregivers prior to newborn care in the post-natal care ward (AOR = 9.2; CI = 1.3, 66.2); however, the absolute magnitude of improvements was limited. Intervention effects were not presented for the home environment due COVID-19 related restrictions on observation duration at endline which resulted in too low observation numbers to warrant testing. Our results suggest the potential of a facility-based multimodal behaviour change intervention to improve hand hygiene practices that are critical to maternal and neonatal infection along the continuum of care.

Abstract Background Rotavirus is a leading cause of hospitalized diarrhea cases in Indonesia. Despite the rotavirus vaccine being recommended by the Indonesian Pediatric Society since 2011, it has yet to be been included in the Indonesian national immunization program (NIP) schedule. Objective To explore maternal knowledge of and attitudes towards rotavirus diarrhea, as well as barriers to vaccine acceptance in Yogyakarta, Indonesia. Methods We conducted 26 in-depth interviews in two districts (rural and urban areas) of Yogyakarta Province, Indonesia. Participants included women in their third trimester of pregnancy and mothers of infants younger than 14 weeks. We then proceeded with thematic analysis. Results Participants did not perceive diarrhea as being a priority health problem. Very few had heard of rotavirus diarrhea or were aware of vaccine availability. While participants would accept vaccinating their children against rotavirus, some key barriers impacted vaccine use. As the rotavirus vaccine is not included in the Indonesian NIP, parents perceived it as not essential. Parents were concerned about the safety and benefit of the vaccine due to its perceived newness. Other concerns were cost and halal status. Participants expressed a need for more information on the vaccine's effectiveness and safety, with their primary healthcare providers (HCPs) considered to play the most important role in vaccine acceptance. Conclusions In Yogyakarta, Indonesia, awareness of the seriousness of rotavirus disease and the availability of the rotavirus vaccine is low. Its newness, safety, efficacy, and cost, and doubts about its halal status, were barriers to vaccine acceptance. Information and recommendations from HCPs play an essential role in vaccine acceptance.

Abstract Human cervicovaginal fluid (CVF) is a complex, functionally important and glycan rich biological fluid, fundamental in mediating physiological events associated with reproductive health. Using a comprehensive glycomic strategy we reveal an extremely rich and complex N-glycome in CVF of pregnant and non-pregnant women, abundant in paucimannose and high mannose glycans, complex glycans with 2–4 N-Acetyllactosamine (LacNAc) antennae, and Poly-LacNAc glycans decorated with fucosylation and sialylation. N-glycosylation profiles were observed to differ in relation to pregnancy status, microbial composition, immune activation, and pregnancy outcome. Compared to CVF from women experiencing term birth, CVF from women who subsequently experienced preterm birth showed lower sialylation, which correlated to the presence of a diverse microbiome, and higher fucosylation, which correlated positively to pro-inflammatory cytokine concentration. This study is the first step towards better understanding the role of cervicovaginal glycans in reproductive health, their contribution to the mechanism of microbial driven preterm birth, and their potential for preventative therapy.

Abstract The unprecedented threat of COVID‐19 and the likelihood of other emerging infectious diseases have accentuated the need for sustainable and effective masks and respirators (MAR). MAR assists in minimizing the risk of infection and controlling the spread of pathogens. However, during the COVID‐19 pandemic, there was a worldwide scarcity of MAR due to unprecedented global demand. There are also notable limitations in commonly used MAR, such as low filtration efficiency, poor fit, non‐reusability, physiological impact, lack of biocompatibility and non‐biodegradability, and inability to kill pathogens. Therefore, there remains an unmet need for a comprehensive study focusing on potential materials and new technologies for MAR. Here we outline a comprehensive overview of the limitations of conventional MAR followed by required potential solutions (such as using nanofibers/graphene base filters/metal‐organic framework as filter media, laser scanning and 3D printing for fit and seal, applying antimicrobial nanomaterials coating on filter media, using reusable and biodegradable materials, developing high‐performing cloth masks, improving hydrophobicity, etc.). The information on potential materials and new technologies of MAR and research evidence outlined here can inform further research and development of high‐performing and sustainable respiratory protection technologies to improve the health and safety of the first responders and the community.

Efficient mobilization and expression of biosynthetic gene clusters (BGCs) into heterologous hosts is needed for microbial natural products discovery. Here, the authors improve the CONKAT-seq strategy by simultaneously capturing the BCGs into a single large insert library and demonstrate its ability to discover natural products with new structures and potent antibacterial activity.

This paper explores the complex relationship between environmental education and researcher activism from the perspective of transgressive learning. With increasing interest within academia for more radical learning-based transformations for confronting sustainability challenges, come calls for more instrumental warrior stances in methodologies and research fields so as to more aggressively change ingrained unsustainable behaviour at the societal level. At the same time, in an increasingly polarized and unstable world, there is also a desire for more empathic learning approaches so as to build critical thinking and empowerment at the grassroots level through emancipatory learning. Based on case study research of a Colombian network of sustainability initiatives, this paper argues that key capacities of reflection, empathy, and courage are imperative in order for the transgressive researcher to address deep-seated socioecological challenges.

A three-year collaborative research project in a K-6 elementary school is underway. The collaboration entails participating educators and their students exploring curricular enactment that embraces critical and creative thinking within its conduct. This article reveals whole-school efforts over Year One to build educators' and students' confidence to do so, sustaining such curricular practices. Chronicled as a case study, narrative inquiry fittingly unfolds the particularities encountered within the specifics of the case during Year One. Educators' belief in the worthiness of curricular play, as well as concretely negotiating critical and creative thinking with their students, arises as a necessary issue to address in order to invest in the research intents over three years. The integral role of participants' commitments to professional growth through curricular play and experimentation, actively seeking resources, entering wholly into curricular-making efforts, conversing sincerely with colleagues through inquiry conversations, and seeking organizational structures that support and strengthen curricular-making efforts, are found to be key to fostering the pedagogically oriented context needed to grow and sustain project intents.

The role of basic emotions in SLA has been underestimated in both research and pedagogy. The present article examines 10 positive emotions ("joy," "gratitude," "serenity," "interest," "hope," "pride," "amusement," "inspiration," "awe," and "love") and 9 negative emotions ("anger," "contempt," "disgust," "embarrassment," "guilt," "hate," "sadness," "feeling scared," and "being stressed"). The emotions are correlated with core variables chosen from three well-known models of L2 motivation: Gardner's integrative motive, Clément's social-contextual model, and Dörnyei's L2 self system. Respondents came from Italian secondary schools, and most participants were from monolingual Italian speaking homes. They described their motivation and emotion with respect to learning German in a region of Italy (South Tyrol) that features high levels of contact between Italians and Germans. Results show that positive emotions are consistently and strongly correlated with motivation-related variables. Correlations involving negative emotions are weaker and less consistently implicated in motivation. The positivity ratio, that is, the relative prevalence of positive over negative emotion, showed strong correlations with all of the motivation constructs. Regression analysis supports the conclusion that a variety of emotions, not just one or two key ones, are implicated in L2 motivation processes in this high-contact context.

In this study, we evaluated the impact of viral variant, in addition to other variables, on within-host viral burden, by analysing cycle threshold (Ct) values derived from nose and throat swabs, collected as part of the UK COVID-19 Infection Survey. Because viral burden distributions determined from community survey data can be biased due to the impact of variant epidemiology on the time-since-infection of samples, we developed a method to explicitly adjust observed Ct value distributions to account for the expected bias. By analysing the adjusted Ct values using partial least squares regression, we found that among unvaccinated individuals with no known prior exposure, viral burden was 44% lower among Alpha variant infections, compared to those with the predecessor strain, B.1.177. Vaccination reduced viral burden by 67%, and among vaccinated individuals, viral burden was 286% higher among Delta variant, compared to Alpha variant, infections. In addition, viral burden increased by 17% for every 10-year age increment of the infected individual. In summary, within-host viral burden increases with age, is reduced by vaccination, and is influenced by the interplay of vaccination status and viral variant.

Exposure to ambient ozone (O3) O3 is associated with impacts on human health. O3 is a secondary pollutant whose concentrations are determined inter alia by emissions of precursors such as oxides of nitrogen (NOx) and volatile organic compounds (VOCs), and thus future health burdens depend on policies relating to climate and air quality. While emission controls are expected to reduce levels of PM2.5 and NO2 and their associated mortality burdens, for secondary pollutants like O3 the picture is less clear. Detailed assessments are necessary to provide quantitative estimates of future impacts to support decision-makers. We simulate future O3 across the UK using a high spatial resolution atmospheric chemistry model with current UK and European policy projections for 2030, 2040 and 2050, and use UK regional population-weighting and latest recommendations on health impact assessment to quantify respiratory emergency hospital admissions associated with short-term effects of O3. We estimate 60,488 admissions in 2018, increasing by 4.2%, 4.5% and 4.6% by 2030, 2040 and 2050 respectively (assuming a fixed population). Including future population growth, estimated emergency respiratory hospital admissions are 8.3%, 10.3% and 11.7% higher by 2030, 2040 and 2050 respectively. Increasing O3 concentrations in future are driven by reduced nitric oxide (NO) in urban areas due to reduced emissions, with increases in O3 mainly occurring in areas with lowest O3 concentrations currently. Meteorology influences episodes of O3 on a day-to-day basis, although a sensitivity study indicates that annual totals of hospital admissions are only slightly impacted by meteorological year. While reducing emissions results in overall benefits to population health (through reduced mortality due to long-term exposure to PM2.5 and NO2), due to the complex chemistry, as NO emissions reduce there are associated local increases in O3 close to population centres that may increase harms to health.

IntroductionPreterm birth is one of the major causes of neonatal morbidity and mortality across the world. Both term and preterm labour are preceded by inflammatory activation in uterine tissues. This includes increased leukocyte infiltration, and subsequent increase in chemokine and cytokine levels, activation of pro-inflammatory transcription factors as NF-κB and increased prostaglandin synthesis. Prostaglandin F2α (PGF2α) is one of the myometrial activators and stimulators.MethodsHere we investigated the role of PGF2α in pro-inflammatory signalling pathways in human myometrial cells isolated from term non-labouring uterine tissue. Primary myometrial cells were treated with G protein inhibitors, calcium chelators and/or PGF2α. Nuclear extracts were analysed by TranSignal cAMP/Calcium Protein/DNA Array. Whole cell protein lysates were analysed by Western blotting. mRNA levels of target genes were analysed by RT-PCR.ResultsThe results show that PGF2α increases inflammation in myometrial cells through increased activation of NF-κB and MAP kinases and increased expression of COX-2. PGF2α was found to activate several calcium/cAMP-dependent transcription factors, such as CREB and C/EBP-β. mRNA levels of NF-κB-regulated cytokines and chemokines were also elevated with PGF2α stimulation. We have shown that the increase in PGF2α-mediated COX-2 expression in myometrial cells requires coupling of the FP receptor to both Gαq and Gαi proteins. Additionally, PGF2α-induced calcium response was also mediated through Gαq and Gαi coupling.DiscussionIn summary, our findings suggest that PGF2α-induced inflammation in myometrial cells involves activation of several transcription factors – NF-κB, MAP kinases, CREB and C/EBP-β. Our results indicate that the FP receptor signals via Gαq and Gαi coupling in myometrium. This work provides insight into PGF2α pro-inflammatory signalling in term myometrium prior to the onset of labour and suggests that PGF2α signalling pathways could be a potential target for management of preterm labour.

OBJECTIVES:. While opioids are part of usual care for analgesia in the ICU, there are concerns regarding excess use. This is a systematic review of nonsteroidal anti-inflammatory drugs (NSAIDs) use in postoperative critical care adult patients. DATA SOURCES:. We searched Medical Literature Analysis and Retrieval System Online, Excerpta Medica database, Cumulative Index to Nursing and Allied Health Literature, Cochrane Library, trial registries, Google Scholar, and relevant systematic reviews through March 2023. STUDY SELECTION:. Titles, abstracts, and full texts were reviewed independently and induplicate by two investigators to identify eligible studies. We included randomized control trials (RCTs) that compared NSAIDs alone or as an adjunct to opioids for systemic analgesia. The primary outcome was opioid utilization. DATA EXTRACTION:. In duplicate, investigators independently extracted study characteristics, patient demographics, intervention details, and outcomes of interest using predefined abstraction forms. Statistical analyses were conducted using Review Manager software Version 5.4. (The Cochrane Collaboration, Copenhagen, Denmark). DATA SYNTHESIS:. We included 15 RCTs (n = 1,621 patients) for admission to the ICU for postoperative management after elective procedures. Adjunctive NSAID therapy to opioids reduced 24-hour oral morphine equivalent consumption by 21.4 mg (95% CI, 11.8–31.0 mg reduction; high certainty) and probably reduced pain scores (measured by Visual Analog Scale) by 6.1 mm (95% CI, 12.2 decrease to 0.1 increase; moderate certainty). Adjunctive NSAID therapy probably had no impact on the duration of mechanical ventilation (1.6 hr reduction; 95% CI, 0.4 hr to 2.7 reduction; moderate certainty) and may have no impact on ICU length of stay (2.1 hr reduction; 95% CI, 6.1 hr reduction to 2.0 hr increase; low certainty). Variability in reporting adverse outcomes (e.g., gastrointestinal bleeding, acute kidney injury) precluded their meta-analysis. CONCLUSIONS:. In postoperative critical care adult patients, systemic NSAIDs reduced opioid use and probably reduced pain scores. However, the evidence is uncertain for the duration of mechanical ventilation or ICU length of stay. Further research is required to characterize the prevalence of NSAID-related adverse outcomes.

BackgroundOn February 25, 2022, Russian forces took control of the Chernobyl power plant after continuous fighting within the Chernobyl exclusion zone. Continual events occurred in the month of March, which raised the risk of potential contamination of previously uncontaminated areas and the potential for impacts on human and environmental health. The disruption of war has caused interruptions to normal preventive activities, and radiation monitoring sensors have been nonfunctional. Open-source intelligence can be informative when formal reporting and data are unavailable. ObjectiveThis paper aimed to demonstrate the value of open-source intelligence in Ukraine to identify signals of potential radiological events of health significance during the Ukrainian conflict. MethodsData were collected from search terminology for radiobiological events and acute radiation syndrome detection between February 1 and March 20, 2022, using 2 open-source intelligence (OSINT) systems, EPIWATCH and Epitweetr. ResultsBoth EPIWATCH and Epitweetr identified signals of potential radiobiological events throughout Ukraine, particularly on March 4 in Kyiv, Bucha, and Chernobyl. ConclusionsOpen-source data can provide valuable intelligence and early warning about potential radiation hazards in conditions of war, where formal reporting and mitigation may be lacking, to enable timely emergency and public health responses.

In this paper, we treat VR as a new writing space in the long tradition of inscription. Constructing Virtual Reality (VR) narratives can then be understood as a process of inscribing text in space, and consuming them as a process of “reading” the space. Our research objective is to explore the meaning-making process afforded by spatial narratives—to test whether VR facilitates traditional ways of weaving complex, multiple narrative strands and provides new opportunities for leveraging space. We argue that, as opposed to the linear space of a printed book, a VR narrative space is similar to the physical space of a museum and can be analyzed on three distinct levels: (1) the architecture of the space itself, (2) the collection, and (3) the individual artifacts. To provide a deeper context for designing VR narratives, we designed and implemented a testbed called RealityMedia to explore digital remediations of traditional narrative devices and the spatial, immersive, and interactive affordances of VR. We conducted task-based user study using a VR headset and follow-up qualitative interviews with 20 participants. Our results highlight how the three semantic levels (space, collection, and artifacts) can work together to constitute meaningful narrative experiences in VR.

Summary: Changes in lymphocyte production patterns occurring across human ontogeny remain poorly defined. In this study, we demonstrate that human lymphopoiesis is supported by three waves of embryonic, fetal, and postnatal multi-lymphoid progenitors (MLPs) differing in CD7 and CD10 expression and their output of CD127−/+ early lymphoid progenitors (ELPs). In addition, our results reveal that, like the fetal-to-adult switch in erythropoiesis, transition to postnatal life coincides with a shift from multilineage to B lineage-biased lymphopoiesis and an increase in production of CD127+ ELPs, which persists until puberty. A further developmental transition is observed in elderly individuals whereby B cell differentiation bypasses the CD127+ compartment and branches directly from CD10+ MLPs. Functional analyses indicate that these changes are determined at the level of hematopoietic stem cells. These findings provide insights for understanding identity and function of human MLPs and the establishment and maintenance of adaptative immunity.

Learning a second/foreign language (L2) is a long process and L2 learners certainly will encounter setbacks and discouragements during this process. However, their reactions to these failures might be different based on their perceptions of L2 learning ability and their subsequent effort put into L2 learning. Based on this, the present study aimed at exploring two underresearched constructs within the field of applied linguistics, namely grit (continuous effort and interest for long-term goals) and language mindset (individuals' perceptions of their language learning ability). We had five main aims: to examine (a) the factor structure of grit, (b) the factor structure of language mindset, (c) whether there are gender differences in grit or language mindset, (d) the relationships between language mindset and grittiness, and (e) the roles of grit and language mindset as predictors of L2 achievement. To address these aims, a total number of 1,178 university students who were taking general English courses took part in our study and completed the questionnaires. Results of confirmatory factor analysis indicated that the two-factor structure for both grit and language mindset fit the data better than the single-factor structure. We also tested several structural equation models and found that a growth language mindset weakly, but positively, predicted one component of grit (perseverance of effort, or POE), but not the other (consistency of interest, or COI). A fixed language mindset did not predict POE, but did negatively predict COI. Finally, only growth language mindset was a weak, positive predictor of L2 achievement. At the end, theoretical and pedagogical implications regarding the role of grit and language mindset in L2 learning are presented.

Abstract Background COVID-19 mass vaccination programs place an additional burden on healthcare services. We aim to model the queueing process at vaccination sites to inform service delivery. Methods We use stochastic queue network models to simulate queue dynamics in larger mass vaccination hubs and smaller general practice (GP) clinics. We estimate waiting times and daily capacity based on a range of assumptions about appointment schedules, service times and staffing and stress-test these models to assess the impact of increased demand and staff shortages. We also provide an interactive applet, allowing users to explore vaccine administration under their own assumptions. Results Based on our assumed service times, the daily throughput for an eight-hour clinic at a mass vaccination hub ranged from 500 doses for a small hub to 1400 doses for a large hub. For GP clinics, the estimated daily throughput ranged from about 100 doses for a small practice to almost 300 doses for a large practice. What-if scenario analysis showed that sites with higher staff numbers were more robust to system pressures and mass vaccination sites were more robust than GP clinics. Conclusions With the requirement for ongoing COVID-19 booster shots, mass vaccination is likely to be a continuing feature of healthcare delivery. Different vaccine sites are useful for reaching different populations and maximising coverage. Stochastic queue networks offer a flexible and computationally efficient approach to simulate vaccination queues and estimate waiting times and daily throughput to inform service delivery.

BackgroundMenstrual cups (MCs) are increasingly used to collect cervicovaginal secretions to characterise vaginal mucosal immunology, in conjunction with high vaginal swabs (HVS) for metataxonomics, particularly in HIV transmission studies. We hypothesised that both methods of collecting bacterial biomass are equivalent for 16S rRNA gene sequencing.Material and MethodsCervicovaginal fluid (CVF) samples from 16 pregnant women with HIV-1 (PWWH) were included to represent the major vaginal bacterial community state types (CST I-V). Women underwent sampling during the second trimester by liquid amies HVS followed by a MC (Soft disc™) and samples were stored at -80°C. Bacterial cell pellets obtained from swab elution and MC (500 µL, 1 in 10 dilution) were resuspended in 120 µL PBS for DNA extraction. Bacterial 16S rRNA gene sequencing was performed using V1-V2 primers and were analysed using MOTHUR. Paired total DNA, bacterial load, amplicon read counts, diversity matrices and bacterial taxa were compared by sampling method using MicrobiomeAnalyst, SPSS and R.ResultsThe total DNA eluted from one aliquot of diluted CVF from an MC was similar to that of a HVS (993ng and 609ng, p=0.18); the mean bacterial loads were also comparable for both methods (MC: 8.0 log10 16S rRNA gene copies versus HVS: 7.9 log10 16S rRNA gene copies, p=0.27). The mean number of sequence reads generated from MC samples was lower than from HVS (MC: 12730; HVS:14830, p=0.05). The α-diversity metrices were similar for both techniques; MC Species Observed: 41 (range 12-96) versus HVS: 47 (range 16-96), p=0.15; MC Inverse Simpson Index: 1.98 (range 1.0-4.0) versus HVS: 0.48 (range 1.0-4.4), p=0.22). The three most abundant species observed were: Lactobacillus iners, Lactobacillus crispatus and Gardnerella vaginalis. Hierarchical clustering of relative abundance data showed that samples obtained using different techniques in an individual clustered in the same CST group.ConclusionThese data demonstrate that despite sampling slightly different areas of the lower genital tract, there was no difference in bacterial load or composition between methods. Both are suitable for characterisation of vaginal microbiota in PWWH. The MC offers advantages, including a higher volume of sample available for DNA extraction and complimentary assays.

BackgroundThe role of multidisciplinary clinics for psychosocial care is increasingly recognized for those living with inherited cardiac conditions (ICC). In Canada, access to healthcare providers differ between clinics. Little is known about the relationship between access to specialty care and a patient's ability to cope with, and manage their condition.MethodsWe leveraged the Hearts in Rhythm Organization (HiRO) to conduct a cross-sectional, community-based survey of individuals with ICC and their family members. We aimed to describe access to services, and explore the relationships between participants’ characteristics, cardiac history and self-reported health status and self-efficacy (GSE: General Self-Efficacy Scale) and empowerment (GCOS-24: Genetic Counseling Outcome Scale).ResultsWe collected 235 responses from Canadian participants in 10 provinces and territories. Overall, 63% of participants reported involvement of a genetic counsellor in their care. Access to genetic testing was associated with greater empowerment [mean GCOS-24: 121.14 (SD = 20.53) vs. 105.68 (SD = 21.69); p = 0.004]. Uncertain genetic test results were associated with lower perceived self-efficacy (mean GSE: uncertain = 28.85 vs. positive = 33.16, negative = 34.13; p = 0.01). Low global mental health scores correlated with both lower perceived self-efficacy and empowerment scores, with only 11% of affected participants reporting involvement of psychology services in their care.ConclusionDifferences in resource accessibility, clinical history and self-reported health status impact the perceived self-efficacy and empowerment of patients with ICC. Future research evaluating interventions to improve patient outcomes is recommended.

High-grade serous ovarian carcinoma (HGSOC) is the most genomically complex cancer, characterized by ubiquitous TP53 mutation, profound chromosomal instability, and heterogeneity. The mutational processes driving chromosomal instability in HGSOC can be distinguished by specific copy number signatures. To develop clinically relevant models of these mutational processes we derived 15 continuous HGSOC patient-derived organoids (PDOs) and characterized them using bulk transcriptomic, bulk genomic, single-cell genomic, and drug sensitivity assays. We show that HGSOC PDOs comprise communities of different clonal populations and represent models of different causes of chromosomal instability including homologous recombination deficiency, chromothripsis, tandem-duplicator phenotype, and whole genome duplication. We also show that these PDOs can be used as exploratory tools to study transcriptional effects of copy number alterations as well as compound-sensitivity tests. In summary, HGSOC PDO cultures provide validated genomic models for studies of specific mutational processes and precision therapeutics.

Air pollution is the greatest environmental risk to public health. Future air pollution concentrations are primarily determined by precursor emissions, which are driven by environmental policies relating to climate and air pollution. Detailed health impact assessments (HIA) are necessary to provide quantitative estimates of the impacts of future air pollution to support decision-makers developing environmental policy and targets. In this study we use high spatial resolution atmospheric chemistry modelling to simulate future air pollution concentrations across the UK for 2030, 2040 and 2050 based on current UK and European policy projections. We combine UK regional population-weighted concentrations with the latest epidemiological relationships to quantify mortality associated with changes in PM2.5 and NO2 air pollution. Our HIA suggests that by 2050, population-weighted exposure to PM2.5 will reduce by 28% to 36%, and for NO2 by 35% to 49%, depending on region. The HIA shows that for present day (2018), annual mortality attributable to the effects of long-term exposure to PM2.5 and NO2 is in the range 26,287 – 42,442, and that mortality burdens in future will be substantially reduced, being lower by 31%, 35%, and 37% in 2030, 2040 and 2050 respectively (relative to 2018) assuming no population changes. Including population projections (increases in all regions for 30+ years age group) slightly offsets these health benefits, resulting in reductions of 25%, 27%, and 26% in mortality burdens for 2030, 2040, 2050 respectively. Significant reductions in future mortality burdens are estimated and, importantly for public health, the majority of benefits are achieved early on in the future timeline simulated, though further efforts are likely needed to reduce impacts of air pollution to health.

The use of artificial intelligence (AI) to generate automated early warnings in epidemic surveillance by harnessing vast open-source data with minimal human intervention has the potential to be both revolutionary and highly sustainable. AI can overcome the challenges faced by weak health systems by detecting epidemic signals much earlier than traditional surveillance. AI-based digital surveillance is an adjunct to—not a replacement of—traditional surveillance and can trigger early investigation, diagnostics and responses at the regional level. This narrative review focuses on the role of AI in epidemic surveillance and summarises several current epidemic intelligence systems including ProMED-mail, HealthMap, Epidemic Intelligence from Open Sources, BlueDot, Metabiota, the Global Biosurveillance Portal, Epitweetr and EPIWATCH. Not all of these systems are AI-based, and some are only accessible to paid users. Most systems have large volumes of unfiltered data; only a few can sort and filter data to provide users with curated intelligence. However, uptake of these systems by public health authorities, who have been slower to embrace AI than their clinical counterparts, is low. The widespread adoption of digital open-source surveillance and AI technology is needed for the prevention of serious epidemics.

Summary: Infants and children infected with human immunodeficiency virus (HIV)-1 have been shown to develop neutralizing antibodies (nAbs) against heterologous HIV-1 strains, characteristic of broadly nAbs (bnAbs). Thus, having a neonatal model for the induction of heterologous HIV-1 nAbs may provide insights into the mechanisms of neonatal bnAb development. Here, we describe a neonatal model for heterologous HIV-1 nAb induction in pathogenic simian-HIV (SHIV)-infected rhesus macaques (RMs). Viral envelope (env) evolution showed mutations at multiple sites, including nAb epitopes. All 13 RMs generated plasma autologous HIV-1 nAbs. However, 8/13 (62%) RMs generated heterologous HIV-1 nAbs with increasing potency over time, albeit with limited breadth, and mapped to multiple nAb epitopes, suggestive of a polyclonal response. Moreover, plasma heterologous HIV-1 nAb development was associated with antigen-specific, lymph-node-derived germinal center activity. We define a neonatal model for heterologous HIV-1 nAb induction that may inform future pediatric HIV-1 vaccines for bnAb induction in infants and children.

Anthropogenic climate change will have a detrimental impact on global health, including the direct impact of higher ambient temperatures. Existing projections of heat-related health outcomes in a changing climate often consider increasing ambient temperatures alone. Population growth and structure has been identified as a key source of uncertainty in future projections. Age acts as a modifier of heat risk, with heat-risk generally increasing in older age-groups. In many countries the population is ageing as lower birth rates and increasing life expectancy alter the population structure. Preparing for an older population, in particular in the context of a warmer climate should therefore be a priority in public health research and policy. We assess the level of inclusion of population growth and demographic changes in research projecting exposure to heat and heat-related health outcomes. To assess the level of inclusion of population changes in the literature, keyword searches of two databases were implemented, followed by reference and citation scans to identify any missed papers. Relevant papers, those including a projection of the heat health burden under climate change, were then checked for inclusion of population scenarios. Where sensitivity to population change was studied the impact of this on projections was extracted. Our analysis suggests that projecting the heat health burden is a growing area of research, however, some areas remain understudied including Africa and the Middle East and morbidity is rarely explored with most studies focusing on mortality. Of the studies pairing projections of population and climate, specifically SSPs and RCPs, many used pairing considered to be unfeasible. We find that not including any projected changes in population or demographics leads to underestimation of health burdens of on average 64 %. Inclusion of population changes increased the heat health burden across all but two studies.

This research investigated whether a mental health literacy resource could increase Grade 12 students' mental health literacy. Bachelor of Education students (N = 8) from a university in rural Atlantic Canada created a board game and mental health seminar based on the resource. They applied the resource through the board game and seminar to Grade 12 students at two local high schools. There were positive albeit modest outcomes across a number of measures related to mental health literacy and post-secondary schooling preparation. Participants regarded the resource as helpful, and they were likely to recommend it to their peers. This resource holds promise for supporting students as they transition from high school to post-secondary settings.

Purpose: Exercise dependence, an unhealthy preoccupation with exercise that results in physiological and psychological symptoms, may be particularly prevalent among college students given sociocultural exercise and body ideals in this population. Yet few studies have examined this phenomenon in diverse college samples. The aims of the present study were to examine gender and Black-White race differences in the prevalence of exercise dependence and associated disordered eating. Method: Undergraduates (N = 839) completed online measures of exercise dependence and disordered eating. Chi square tests were used to test for differences in prevalence, and linear regression was used to examine race and gender moderating effects on the exercise dependence-disordered eating association. Results: More men reported exercise dependence symptoms than women. More White participants reported symptoms than Black participants. Of the four gender and race combinations examined, White men had the highest proportion and Black women the lowest proportion experiencing symptoms. Gender, but not race, moderated the exercise dependence-disordered eating association. Conclusions: Although more men experience exercise dependence symptoms, women experience stronger associations between exercise dependence symptoms and disordered eating. The number of students who reported exercise dependence symptoms underscores the need for further research in this population and the development of culturally sensitive interventions.

Every person's response to adversity is unique. Whereas some come out stronger as a result of responding to a challenge, others find their fundamental assumptions about themselves and their lives severely challenged. In education, while some teachers might burn out and leave the profession precipitously, many survive the challenges and transform teaching into their lifelong passion. What factors help explain why some language teachers remain resilient and experience growth after trauma, while others suffer a sense of loss, depleted psychological resources, and ultimately succumb to the pressures of the job, leaving the profession or burning out? The purpose of this study was to seek answers to this question in the context of teaching during the COVID-19 pandemic, which represents a specific unprecedented type of adversity. To do this, 765 foreign language teachers worldwide answered an online questionnaire that asked three open-ended questions about the stressors and uplifts they were experiencing during the first few months of the pandemic. Respondents were invited to offer their advice to other language teachers who were facing the challenge of teaching during this time.