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Abstract Background In the UK, unique and unforeseen factors, including COVID-19, Brexit, and Ukraine-Russia war, have resulted in an unprecedented cost of living crisis, creating a second health emergency. We present, one of the first rapid reviews with the aim of examining the impact of this current crisis, at a population level. We reviewed published literature, as well as grey literature, examining a broad range of physical and mental impacts on health in the short, mid, and long term, identifying those most at risk, impacts on system partners, including emergency services and the third sector, as well as mitigation strategies. Methods We conducted a rapid review by searching PubMed, Embase, MEDLINE, and HMIC (2020 to 2023). We searched for grey literature on Google and hand-searched the reports of relevant public health organisations. We included interventional and observational studies that reported outcomes of interventions aimed at mitigating against the impacts of cost of living at a population level. Results We found that the strongest evidence was for the impact of cold and mouldy homes on respiratory-related infections and respiratory conditions. Those at an increased risk were young children (0–4 years), the elderly (aged 75 and over), as well as those already vulnerable, including those with long-term multimorbidity. Further short-term impacts include an increased risk of physical pain including musculoskeletal and chest pain, and increased risk of enteric infections and malnutrition. In the mid-term, we could see increases in hypertension, transient ischaemic attacks, and myocardial infarctions, and respiratory illnesses. In the long term we could see an increase in mortality and morbidity rates from respiratory and cardiovascular disease, as well as increase rates of suicide and self-harm and infectious disease outcomes. Changes in behaviour are likely particularly around changes in food buying patterns and the ability to heat a home. System partners are also impacted, with voluntary sectors seeing fewer volunteers, an increase in petty crime and theft, alternative heating appliances causing fires, and an increase in burns and burn-related admissions. To mitigate against these impacts, support should be provided, to the most vulnerable, to help increase disposable income, reduce energy bills, and encourage home improvements linked with energy efficiency. Stronger links to bridge voluntary, community, charity and faith groups are needed to help provide additional aid and support. Conclusion Although the CoL crisis affects the entire population, the impacts are exacerbated in those that are most vulnerable, particularly young children, single parents, multigenerational families. More can be done at a community and societal level to support the most vulnerable, and those living with long-term multimorbidity. This review consolidates the current evidence on the impacts of the cost of living crisis and may enable decision makers to target limited resources more effectively.

A strong and effective COVID-19 and future pandemic responses rely on global efforts to carry out surveillance of infections and emerging SARS-CoV-2 variants and to act accordingly in real time. Many countries in Southeast Asia lack capacity to determine the potential threat of new variants, or other emerging infections. Funded by Wellcome, the Southeast Asia initiative to combat SARS-CoV-2 variants (SEACOVARIANTS) consortium aims to develop and apply a multidisciplinary research platform in Southeast Asia (SEA) for rapid assessment of the biological significance of SARS-CoV-2 variants, thereby informing coordinated local, regional and global responses to the COVID-19 pandemic. Our proposal is delivered by the Vietnam and Thailand Wellcome Africa Asia Programmes, bringing together a multidisciplinary team in Indonesia, Thailand and Vietnam with partners in Singapore, the UK and the USA. Herein we outline five work packages to deliver strengthened regional scientific capacity that can be rapidly deployed for future outbreak responses.

Given the increasing prevalence of online data collection, it is important to know how behavioral data obtained online compare to samples collected in the laboratory. This study compares online and in-person measurement of speech perception in older children and adolescents. Speech perception is important for assessment and treatment planning in speech-language pathology; we focus on the American English /ɹ/ sound because of its frequency as a clinical target. Two speech perception tasks were adapted for web presentation using Gorilla: identification of items along a synthetic continuum from rake to wake, and category goodness judgment of English /ɹ/ sounds in words produced by various talkers with and without speech sound disorder. Fifty typical children aged 9-15 completed these tasks online using a standard headset. These data were compared to a previous sample of 98 typical children aged 9-15 who completed the same tasks in the lab setting. For the identification task, participants exhibited smaller boundary widths (suggestive of more acute perception) in the in-person setting relative to the online setting. For the category goodness judgment task, there was no statistically significant effect of modality. The correlation between scores on the two tasks was significant in the online setting but not in the in-person setting, but the difference in correlation strength was not statistically significant. Overall, our findings agree with previous research in suggesting that online and in-person data collection do not yield identical results, but the two contexts tend to support the same broad conclusions. In addition, these results suggest that online data collection can make it easier for researchers connect with a more representative sample of participants.

Background: Melioidosis is a bacterial infection which kills an estimated 89,000 people per year in tropical and sub-tropical regions, chiefly affecting the poorest. Diabetes is the primary risk factor, conferring a 12-fold increase in risk. Despite limited funding compared to other neglected tropical diseases, melioidosis vaccine development has generated several candidates for clinical development. The most promising is CPS-CRM197/Hcp1, which will be the first to enter a phase I clinical trial, taking place in Oxford in 2023/24. As we move closer to the possibility of an effective melioidosis vaccine, it is critical to work in parallel to understand perceptions toward a vaccine among those living where melioidosis rates are high. Reasons for vaccine acceptance versus hesitancy are complex, and include perceived risk of the target disease, concern about side effects, and above all trust in government, scientists, the pharmaceutical industry and other authorities. Methods: We will carry out a qualitative study in Ubon Ratchathani, Thailand, an endemic region for melioidosis, as groundwork for a potential future melioidosis vaccine efficacy study, and in the longer-term vaccine introduction. This study seeks to explore knowledge and attitudes in three main areas; 1) melioidosis disease, 2) vaccines, and 3) participation in clinical vaccine trials. In-depth interviews and focus group discussions will take place in five participant groups of different risks and exposure to melioidosis. Purposive, convenience sampling will be used, also snowball sampling to reach some participant groups. Sample size will be based on participant’s experience, to inform the line of enquiries of study, or until data saturation, expecting 66–90 participants across all groups. Discussion: The findings of this study will be written up and published in an open access journal, and will be valuable to inform future design of clinical trials as well as engagement and communications associated with future vaccine rollout.

BACKGROUND Typhoid fever is caused by the Gram-negative bacterium Salmonella enterica serovar Typhi and poses a substantial public health burden worldwide. Vaccines have been developed based on the surface Vi-capsular polysaccharide of S. Typhi; these include a plain-polysaccharide-based vaccine, ViPS, and a glycoconjugate vaccine, ViTT. To understand immune responses to these vaccines and their vaccine-induced immunological protection, molecular signatures were analyzed using bioinformatic approaches.METHODS Bulk RNA-Seq data were generated from blood samples obtained from adult human volunteers enrolled in a vaccine trial, who were then challenged with S. Typhi in a controlled human infection model (CHIM). These data were used to conduct differential gene expression analyses, gene set and modular analyses, B cell repertoire analyses, and time-course analyses at various post-vaccination and post-challenge time points between participants receiving ViTT, ViPS, or a control meningococcal vaccine.RESULTS Transcriptomic responses revealed strong differential molecular signatures between the 2 typhoid vaccines, mostly driven by the upregulation in humoral immune signatures, including selective usage of immunoglobulin heavy chain variable region (IGHV) genes and more polarized clonal expansions. We describe several molecular correlates of protection against S. Typhi infection, including clusters of B cell receptor (BCR) clonotypes associated with protection, with known binders of Vi-polysaccharide among these.CONCLUSION The study reports a series of contemporary analyses that reveal the transcriptomic signatures after vaccination and infectious challenge, while identifying molecular correlates of protection that may inform future vaccine design and assessment.TRIAL REGISTRATION ClinicalTrials.gov NCT02324751.

Introduction This is the first efficacy study of an oral live attenuated vaccine against Salmonella Paratyphi A using a human challenge model of paratyphoid infection. S. Paratyphi A is responsible for 3.3 million cases of enteric fever every year, with over 19 000 deaths. Although improvements to sanitation and access to clean water are vital to reduce the burden of this condition, vaccination offers a cost-effective, medium-term solution. Efficacy trials of potential S. Paratyphi vaccine candidates in the field are unlikely to be feasible given the large number of participants required. Human challenge models therefore offer a unique, cost-effective solution to test efficacy of such vaccines.Methods and analysis This is an observer-blind, randomised, placebo-controlled trial phase I/II of the oral live-attenuated vaccine against S. Paratyphi A, CVD 1902. Volunteers will be randomised 1:1 to receive two doses of CVD 1902 or placebo, 14 days apart. One month following second vaccination all volunteers will ingest S. Paratyphi A bacteria with a bicarbonate buffer solution. They will be reviewed daily in the following 14 days and diagnosed with paratyphoid infection if the predefined microbiological or clinical diagnostic criteria are met. All participants will be treated with antibiotics on diagnosis, or at day 14 postchallenge if not diagnosed. The vaccine efficacy will be determined by comparing the relative attack rate, that is, the proportion of those diagnosed with paratyphoid infection, in the vaccine and placebo groups.Ethics and dissemination Ethical approval for this study has been obtained from the Berkshire Medical Research Ethics Committee (REC ref 21/SC/0330). The results will be disseminated via publication in a peer-reviewed journal and presentation at international conferences.Trial registration number ISRCTN15485902.

BackgroundAssessment of cellular immune responses by combining intracellular cytokine staining and immunophenotyping using flow cytometry enables the simultaneous measurement of T cell phenotype and effector function in response to pathogens and vaccines. The use of whole blood samples rather than peripheral blood mononuclear cells avoids both the need for immediate processing and loss of functional antigen presenting cells due to processing and cryopreservation. Using whole blood provides the possibility to stimulate peripheral T cells in situ, and is more suitable for studies where sample volume is limited, such as those involving children, the elderly and critically ill patients. The aim of this study was to provide a robust tool for the assessment of antigen-specific T cell responses in a field site setting with limited resources.Methodology/principle findingsWe optimised a flow cytometry-based whole blood intracellular cytokine assay (WBA) with respect to duration of antigen stimulation and intracellular protein retention time. We demonstrate the ability of the WBA to capture polyfunctional T cell responses in the context of acute scrub typhus infection, by measuring IFN-γ, TNF and IL-2 in CD4+ and CD8+ T cells in response to the causative agent O. tsutsugamushi (OT). Using an optimised OT antigen preparation, we demonstrate the presence of polyfunctional antigen-specific memory CD4+ T cells in the blood of scrub typhus patients.Conclusions/significanceIn conclusion, this flow cytometry-based WBA is well-suited for use at field study sites, and enables the assessment of polyfunctional T cell responses to infectious agents and vaccines through delineation of antigen-specific cytokine secretion at the single cell level.

Diversity in specificity of polyclonal antibody (pAb) responses is extensively investigated in vaccine efficacy or immunological evaluations, but the heterogeneity in antibody avidity is rarely probed as convenient tools are lacking. Here we have developed a polyclonal antibodies avidity resolution tool (PAART) for use with label-free techniques, such as surface plasmon resonance and biolayer interferometry, that can monitor pAb-antigen interactions in real time to measure dissociation rate constant (kd) for defining avidity. PAART utilizes a sum of exponentials model to fit the dissociation time-courses of pAb-antigens interactions and resolve multiple kd contributing to the overall dissociation. Each kd value of pAb dissociation resolved by PAART corresponds to a group of antibodies with similar avidity. PAART is designed to identify the minimum number of exponentials required to explain the dissociation course and guards against overfitting of data by parsimony selection of best model using Akaike information criterion. Validation of PAART was performed using binary mixtures of monoclonal antibodies of same specificity but differing in kd of the interaction with their epitope. We applied PAART to examine the heterogeneity in avidities of pAb from malaria and typhoid vaccinees, and individuals living with HIV-1 that naturally control the viral load. In many cases, two to three kd were dissected indicating the heterogeneity of pAb avidities. We showcase examples of affinity maturation of vaccine induced pAb responses at component level and enhanced resolution of heterogeneity in avidity when antigen-binding fragments (Fab) are used instead of polyclonal IgG antibodies. The utility of PAART can be manifold in examining circulating pAb characteristics and could inform vaccine strategies aimed to guide the host humoral immune response.

Understanding the emotions experienced by higher education instructors related to assessment feedback, how instructors understand student emotions, and how instructors might manage these emotions positively, can help to secure the educational benefits of feedback. In this research, we aimed to explore the emotional responses that instructors experienced through the giving and receiving of assessment feedback. We undertook qualitative data collection, carrying out individual semi-structured interviews with instructors from three universities who had administered a dialogic feed-forward intervention on one of their teaching units. The full interview transcripts were analysed inductively using thematic analysis. Five main themes emerged from the interview data: 1. Summative written feedback aroused largely negative emotions in instructors because they felt distanced from their students; 2. Instructors experienced a broad range of emotions related to dialogic feed-forward encounters, emerging from their proximity to students; 3. Dialogic feed-forward, as an affective encounter, was emotionally challenging for instructors; 4. Dialogic feed-forward built strong learning relationships between students and instructors, strengthening students’ sense of belonging; 5. Dialogic feed-forward was transformational for instructors as educators. We consider the implications of our findings for instructors and wider assessment and feedback practices, including emotional labour, promotional reward, and instructor professional development.

Introduction Despite a growing body of research on the risks of SARS-CoV-2 infection during pregnancy, there is continued controversy given heterogeneity in the quality and design of published studies.Methods We screened ongoing studies in our sequential, prospective meta-analysis. We pooled individual participant data to estimate the absolute and relative risk (RR) of adverse outcomes among pregnant women with SARS-CoV-2 infection, compared with confirmed negative pregnancies. We evaluated the risk of bias using a modified Newcastle-Ottawa Scale.Results We screened 137 studies and included 12 studies in 12 countries involving 13 136 pregnant women.Pregnant women with SARS-CoV-2 infection—as compared with uninfected pregnant women—were at significantly increased risk of maternal mortality (10 studies; n=1490; RR 7.68, 95% CI 1.70 to 34.61); admission to intensive care unit (8 studies; n=6660; RR 3.81, 95% CI 2.03 to 7.17); receiving mechanical ventilation (7 studies; n=4887; RR 15.23, 95% CI 4.32 to 53.71); receiving any critical care (7 studies; n=4735; RR 5.48, 95% CI 2.57 to 11.72); and being diagnosed with pneumonia (6 studies; n=4573; RR 23.46, 95% CI 3.03 to 181.39) and thromboembolic disease (8 studies; n=5146; RR 5.50, 95% CI 1.12 to 27.12).Neonates born to women with SARS-CoV-2 infection were more likely to be admitted to a neonatal care unit after birth (7 studies; n=7637; RR 1.86, 95% CI 1.12 to 3.08); be born preterm (7 studies; n=6233; RR 1.71, 95% CI 1.28 to 2.29) or moderately preterm (7 studies; n=6071; RR 2.92, 95% CI 1.88 to 4.54); and to be born low birth weight (12 studies; n=11 930; RR 1.19, 95% CI 1.02 to 1.40). Infection was not linked to stillbirth. Studies were generally at low or moderate risk of bias.Conclusions This analysis indicates that SARS-CoV-2 infection at any time during pregnancy increases the risk of maternal death, severe maternal morbidities and neonatal morbidity, but not stillbirth or intrauterine growth restriction. As more data become available, we will update these findings per the published protocol.

The engagement of immunological memory is a key component to the protective anti-SARS-CoV-2 B and T cell responses. Here the authors assess the B and T cells of a cohort of UK healthcare workers in response to infection and longitudinally track the compartment showing distinct trajectories following early priming.

In studies of discrimination, researchers often seek to estimate a causal effect of race or gender on outcomes. For example, in the criminal justice context, one might ask whether arrested individuals would have been subsequently charged or convicted had they been a different race. It has long been known that such counterfactual questions face measurement challenges related to omitted-variable bias, and conceptual challenges related to the definition of causal estimands for largely immutable characteristics. Another concern, which has been the subject of recent debates, is post-treatment bias: many studies of discrimination condition on apparently intermediate outcomes, like being arrested, that themselves may be the product of discrimination, potentially corrupting statistical estimates. There is, however, reason to be optimistic. By carefully defining the estimand—and by considering the precise timing of events—we show that a primary causal quantity of interest in discrimination studies can be estimated under an ignorability condition that may hold approximately in some observational settings. We illustrate these ideas by analyzing both simulated data and the charging decisions of a prosecutor’s office in a large county in the United States.

Most current statistics courses include some instruction relevant to causal inference. Whether this instruction is incorporated as material on randomized experiments or as an interpretation of associations measured by correlation or regression coefficients, the way in which this material is presented may have important implications for understanding causal inference fundamentals. Although the connection between study design and the ability to infer causality is often described well, the link between the language used to describe study results and causal attribution typically is not well defined. The current study investigates this relationship experimentally using a sample of students in a statistics course at a large western university in the United States. It also provides (non-experimental) evidence about the association between statistics instruction and the ability to understand appropriate causal attribution. The results from our experimental vignette study suggest that the wording of study findings impacts causal attribution by the reader, and, perhaps more surprisingly, that this variation in level of causal attribution across different wording conditions seems to pale in comparison to the variation across study contexts. More research, however, is needed to better understand how to tailor statistics instruction to make students sufficiently wary of unwarranted causal interpretation.

The emergence of the COVID-19 pandemic led to a significant transition towards online education in pre-K-12 schools, prompting school administrators to confront the disparities revealed by the remote learning model. This paper includes the findings of a multi-phase research project exploring the intersection of educational leadership, technology, and systemic inequities aimed to guide administrator preparation programs to meet relevant, post-pandemic leadership standards. Phase One of the research project, conducted early in the pandemic, highlights the findings from a survey administered to technology directors in Minnesota. The survey aimed to understand how school districts were addressing the technology disparities encountered by students and families during hybrid and distance learning models. Phase Two of the research project, conducted as the pandemic waned, focused on school leaders' evaluation of which practices developed and implemented during remote learning should be sustained. Technology directors participated in a focus group and asserted that the pandemic was an opportunity for educational leaders to reimagine schools for the success of all students. Findings call for revised administrator preparation standards, the implementation of technology plans in every state, and continued focus on identifying and addressing educational inequities.

A key debate in higher education is how assessment and feedback can be constructed to maximize opportunities for meaningful student learning. In this paper, we explore how a learning-focused model of feedback, teacher-student dialogic feed-forward, is enacted in practice, exposing many affordances but also some challenges. Adopting a small-scale intensive approach, we trace the learning journeys of four students through a second-year undergraduate unit at a British university and on into their third and final year of study, accessing verbal testimony, teacher written comments on draft and final summative coursework, and student performance within and beyond the unit. We present in-depth student responses, understanding, behaviours, and achievement with respect to the feed-forward dialogue, revealing the subtleties of their reactions. Our findings evidence the transformative power of assessment dialogue on student learning for a range of achievers. Dialogic feed-forward can act as a pivotal moment in learning, where students reflect on their work, judge their standards against criteria, and co-create positive actions for improvement. Students develop cognitively, meta-cognitively, and affectively, becoming more comfortable with challenge and more productive in their learning. We conclude by widening our frame of reference to problematize dialogic feed-forward within current debates about higher education pedagogy.

Abstract Background Speech sound disorder in childhood poses a barrier to academic and social participation, with potentially lifelong consequences for educational and occupational outcomes. While most speech errors resolve by the late school-age years, between 2 and 5% of speakers exhibit residual speech errors (RSE) that persist through adolescence or even adulthood. Previous findings from small-scale studies suggest that interventions incorporating visual biofeedback can outperform traditional motor-based treatment approaches for children with RSE, but this question has not been investigated in a well-powered randomized controlled trial. Methods/design This project, Correcting Residual Errors with Spectral, ULtrasound, Traditional Speech therapy Randomized Controlled Trial (C-RESULTS RCT), aims to treat 110 children in a parallel randomized controlled clinical trial comparing biofeedback and non-biofeedback interventions for RSE affecting the North American English rhotic sound /ɹ/. Eligible children will be American English speakers, aged 9–15 years, who exhibit RSE affecting /ɹ/ but otherwise show typical cognitive-linguistic and hearing abilities. Participants will be randomized, with stratification by site (Syracuse University or Montclair State University) and pre-treatment speech production ability, to receive either a motor-based treatment consistent with current best practices in speech therapy (40% of participants) or treatment incorporating visual biofeedback (60% of participants). Within the biofeedback condition, participants will be assigned in equal numbers to receive biofeedback in the form of a real-time visual display of the acoustic signal of speech or ultrasound imaging of the tongue during speech. The primary outcome measure will assess changes in the acoustics of children’s production of /ɹ/ during treatment, while a secondary outcome measure will use blinded listeners to evaluate changes in the perceived accuracy of /ɹ/ production after the completion of all treatment. These measures will allow the treatment conditions to be compared with respect to both efficacy and efficiency. Discussion By conducting the first well-powered randomized controlled trial comparing treatment with and without biofeedback, this study aims to provide high-quality evidence to guide treatment decisions for children with RSE. Trial registration ClinicalTrials.gov identifier NCT03737318, November 9, 2018.

Summary: Background: Typhoid fever is a major public health problem in low-resource settings. Vaccination can help curb the disease and might reduce transmission. We have previously reported an interim analysis of the efficacy of typhoid conjugate vaccine (TCV) in Nepali children. Here we report the final results after 2 years of follow-up. Methods: We did a participant-masked and observer-masked individually randomised trial in Lalitpur, Nepal, in which 20 019 children aged 9 months to younger than 16 years were randomly assigned in a 1:1 ratio to receive a single dose of TCV (Typbar TCV, Bharat Biotech International, India) or capsular group A meningococcal conjugate vaccine (MenA). Participants were followed up until April 9, 2020. The primary outcome was blood culture-confirmed typhoid fever. Cases were captured via passive surveillance and active telephone surveillance followed by medical record review. The trial is registered at ISRCTN registry, ISRCTN43385161 and is ongoing. Findings: From Nov 20, 2017, to April 9, 2018, of 20 119 children screened, 20 019 participants were randomly assigned to receive TCV or MenA vaccine. There were 75 cases of blood culture-confirmed typhoid fever included in the analysis (13 in the TCV group and 62 in the MenA group) over the 2-year period. The protective efficacy of TCV against blood culture-confirmed typhoid fever at 2 years was 79·0% (95% CI 61·9–88·5; p

Capstone experiences (CEs) serve a variety of purposes in higher education as opportunities to apply academic skills, explore post-graduate life and employment, and achieve a meaningful undergraduate event. This study investigated the purposes of CEs through a content analysis of institutional course syllabi/course outlines/module outlines and catalog/calendar descriptions at five institutions of higher education: a large public research university in Canada, a large public teaching university in the United Kingdom (UK), a college of a large public research university in the United States (US), and two medium-sized private liberal arts universities in the US. Using the CE purposes found in a review of scholarly literature as a research guide, the authors analyzed 84 institutional documents. CE purposes that appeared in the sample at lower percentages when compared with published studies included oral communication, a coherent academic experience, preparation for graduate school, preparation for life after college, and civic engagement/service learning. Implications for practice include the need for instructors and administrators to consider revising CE documents to better reflect the content and goals of the courses and to address the requirements of other audiences (e.g., program reviewers, accreditation evaluators). Moreover, the results of this study may assist educators in considering reasons for omitting explicit purposes from CE documents and/or justifying the inclusion of previously omitted purposes.

Assessment feedback should be an integral part of learning in higher education, but students can find this process emotionally and cognitively challenging. Instructors need to consider how to manage students’ responses to feedback so that students feel capable of improving their work and maintaining their wellbeing. In this paper, we examine the role of instructor-student relational feed-forward, enacted as a dialogue relating to ongoing assessment, in dissipating student anxiety, enabling productive learning attitudes and behaviours, and supporting wellbeing. We undertook qualitative data collection within two undergraduate teaching units that were adopting a relational feed-forward intervention over the 2019–2020 academic year. Student responses were elicited via small group, semi-structured interviews and personal reflective diaries, and were analysed inductively using thematic analysis. The results demonstrate that relational feed-forward promotes many elements of student feedback literacy, such as appreciating the purpose and value of feedback, judging work against a rubric, exercising volition and agency to act, and managing affect. Students were keen for instructors to help them manage their emotions related to assessment, believing this would promote their wellbeing. We conclude by exploring academic strategies and pedagogies that position relational instructor feed-forward as an act of care, and we summarize the key characteristics of emotionally resonant relational feed-forward meetings.

The COVID-19 pandemic ushered in a dramatic shift to online learning for K-12 public schools, requiring school districts to address inequities that surfaced in the remote learning model. This paper includes the findings of the second study of a multi-year research project exploring the intersection of technology and educational inequities through the pandemic. As the pandemic waned, practitioners evaluated which practices developed during remote learning should be sustained. Five Minnesota technology directors participated in a focus group to discuss how inequities are being addressed in their schools post-pandemic. Technology directors explained that the pandemic was an opportunity to reimagine schools for the success of all students through an infrastructure that includes actions relative to three domains: effective instruction, school-home partnerships, and law and policy. Further research is recommended, such as broadening the geographical location of participants outside of Minnesota, expanding participants beyond the role of technology director (i.e., students, teachers, parents), and analyzing student enrollment in K-12 online schools through a longitudinal study.

Summative assessments tend to be viewed as high-stakes episodes by students, directly exposing their capabilities as learners. As such, receiving feedback is likely to evoke a variety of emotions that may interact with cognitive engagement and hence the ability to learn. Our research investigated the emotions experienced by undergraduate students in relation to assessment feedback, exploring if these emotions informed their learning attitudes and behaviours. Respondents were drawn from different years of study and subject/major. A qualitative approach was adopted, using small group, semi-structured interviews and reflective diaries. Data were analysed thematically and they revealed that receiving feedback was inherently emotional for students, permeating their wider learning experience positively and negatively. Many students struggled to receive and act upon negative feedback, especially in early years, when it was often taken personally and linked to a sense of failure. Negative emotional responses tended to reduce students’ motivation, self-confidence, and self-esteem. Some students, especially in later years of study, demonstrated resilience and engagement in response to negative feedback. By contrast, positive feedback evoked intense but fleeting emotions. Positive feedback made students feel cared about, validating their self-worth and increasing their confidence, but it was not always motivational. The paper concludes with recommendations for instructors, highlighting a need to communicate feedback carefully and to develop student and staff feedback literacies.

Summary: Data analysis and knowledge discovery has become more and more important in biology and medicine with the increasing complexity of biological datasets, but the necessarily sophisticated programming skills and in-depth understanding of algorithms needed pose barriers to most biologists and clinicians to perform such research. We have developed a modular open-source software, SIMON, to facilitate the application of 180+ state-of-the-art machine-learning algorithms to high-dimensional biomedical data. With an easy-to-use graphical user interface, standardized pipelines, and automated approach for machine learning and other statistical analysis methods, SIMON helps to identify optimal algorithms and provides a resource that empowers non-technical and technical researchers to identify crucial patterns in biomedical data. The Bigger Picture: Over the past years, technological advances have enabled the generation of large amounts of data at multiple scales. The integration of high-dimensional data is particularly important in biomedical sciences, as they can be used to identify biological mechanisms and predict clinical outcomes well in advance of their occurrence. Because of the lack of powerful analytical tools that can be used by the average biomedical researcher, translation of such knowledge has been extremely slow. We have developed an open-source software, SIMON, to facilitate the application of machine learning to high-dimensional biomedical data. In SIMON, analysis is performed using an intuitive graphical user interface and standardized, automated machine learning approach allowing non-technical researchers to identify patterns and extract knowledge from high-dimensional data and build high-quality predictive models.

Vi-polysaccharide conjugate vaccines are efficacious against cases of typhoid fever; however, an absolute correlate of protection is not established. In this study, we investigated the leukocyte response to a Vi-tetanus toxoid conjugate vaccine (Vi-TT) in comparison with a plain polysaccharide vaccine (Vi-PS) in healthy adults subsequently challenged with Salmonella Typhi. Immunological responses and their association with challenge outcome was assessed by mass cytometry and Vi-ELISpot assay. Immunization induced significant expansion of plasma cells in both vaccines with modest T follicular helper cell responses detectable after Vi-TT only. The Vi-specific IgG and IgM B cell response was considerably greater in magnitude in Vi-TT recipients. Intriguingly, a significant increase in a subset of IgA+ plasma cells expressing mucosal migratory markers α4β7 and CCR10 was observed in both vaccine groups, suggesting a gut-tropic, mucosal response is induced by Vi-vaccination. The total plasma cell response was significantly associated with protection against typhoid fever in Vi-TT vaccinees but not Vi-PS. IgA+ plasma cells were not significantly associated with protection for either vaccine, although a trend is seen for Vi-PS. Conversely, the IgA- fraction of the plasma cell response was only associated with protection in Vi-TT. In summary, these data indicate that a phenotypically heterogeneous response including both gut-homing and systemic antibody secreting cells may be critical for protection induced by Vi-TT vaccination.

Enteric fever is a systemic infection caused by Salmonella Typhi or Paratyphi A. In many endemic areas, these serovars co-circulate and can cause multiple infection-episodes in childhood. Prior exposure is thought to confer partial, but incomplete, protection against subsequent attacks of enteric fever. Empirical data to support this hypothesis are limited, and there are few studies describing the occurrence of heterologous-protection between these closely related serovars. We performed a challenge-re-challenge study using a controlled human infection model (CHIM) to investigate the extent of infection-derived immunity to Salmonella Typhi or Paratyphi A infection. We recruited healthy volunteers into two groups: naïve volunteers with no prior exposure to Salmonella Typhi/Paratyphi A and volunteers previously-exposed to Salmonella Typhi or Paratyphi A in earlier CHIM studies. Within each group, participants were randomised 1:1 to oral challenge with either Salmonella Typhi (104 CFU) or Paratyphi A (103 CFU). The primary objective was to compare the attack rate between naïve and previously challenged individuals, defined as the proportion of participants per group meeting the diagnostic criteria of temperature of ≥38°C persisting for ≥12 hours and/or S. Typhi/Paratyphi bacteraemia up to day 14 post challenge. The attack-rate in participants who underwent homologous re-challenge with Salmonella Typhi was reduced compared with challenged naïve controls, although this reduction was not statistically significant (12/27[44%] vs. 12/19[63%]; Relative risk 0.70; 95% CI 0.41-1.21; p = 0.24). Homologous re-challenge with Salmonella Paratyphi A also resulted in a lower attack-rate than was seen in challenged naïve controls (3/12[25%] vs. 10/18[56%]; RR0.45; 95% CI 0.16-1.30; p = 0.14). Evidence of protection was supported by a post hoc analysis in which previous exposure was associated with an approximately 36% and 57% reduced risk of typhoid or paratyphoid disease respectively on re-challenge. Individuals who did not develop enteric fever on primary exposure were significantly more likely to be protected on re-challenge, compared with individuals who developed disease on primary exposure. Heterologous re-challenge with Salmonella Typhi or Salmonella Paratyphi A was not associated with a reduced attack rate following challenge. Within the context of the model, prior exposure was not associated with reduced disease severity, altered microbiological profile or boosting of humoral immune responses. We conclude that prior Salmonella Typhi and Paratyphi A exposure may confer partial but incomplete protection against subsequent infection, but with a comparable clinical and microbiological phenotype. There is no demonstrable cross-protection between these serovars, consistent with the co-circulation of Salmonella Typhi and Paratyphi A. Collectively, these data are consistent with surveillance and modelling studies that indicate multiple infections can occur in high transmission settings, supporting the need for vaccines to reduce the burden of disease in childhood and achieve disease control. Trial registration NCT02192008; clinicaltrials.gov.

Background: Recent studies have reveled the presence of a complex fungal community (mycobiome) in the oral cavity. However, the role of oral mycobiome in dental caries and its interaction with caries-associated bacteria is not yet clear. Methods: Whole-mouth supragingival plaque samples from 30 children (6–10 years old) with no caries, early caries, or advanced caries were sequenced for internal transcribed spacer 2 (ITS-2). The mycobiome profiles were correlated with previously published bacteriome counterparts. Interaction among selected fungal and bacterial species was assessed by co-culture or spent media experiments. Results: Fungal load was extremely low. Candida, Malassezia, Cryptococcus, and Trichoderma spp. were the most prevalent/abundant taxa. Advanced caries was associated with significantly higher fungal load and prevalence/abundance of Candida albicans. Cryptococcus neoformans and Candida sake were significantly over-abundant in early caries, while Malassezia globosa was significantly enriched in caries-free subjects. C. albicans correlated with Streptococcus mutans and Scardovia wiggsiae among other caries-associated bacteria, while M. globosa inversely correlated with caries-associated bacteria. In-vitro, M. globosa demonstrated inhibitory properties against S. mutans. Conclusions: the results substantiate the potential role of the oral mycobiome, primarily Candida species, in dental caries. Inter-kingdom correlations and inhibition of S. mutans by M. globosa are worth further investigation.

Vaccination against Salmonella Typhi using the Vi capsular polysaccharide, a T-cell independent antigen, can protect from the development of typhoid fever. This implies that antibodies to Vi alone can protect in the absence of a T cell-mediated immune response; however, protective Vi antibodies have not been well-characterized. We hypothesized that variability in the biophysical properties of vaccine-elicited antibodies, including subclass distribution and avidity, may impact protective outcomes. To interrogate the relationship between antibody properties and protection against typhoid fever, we analyzed humoral responses from participants in a vaccine efficacy (VE) trial using a controlled human infection model (CHIM) who received either a purified Vi polysaccharide (Vi-PS) or Vi tetanus toxoid conjugate (Vi-TT) vaccine followed by oral challenge with live S. Typhi. We determined the avidity, overall magnitude, and vaccine-induced fold-change in magnitude from before immunization to day of challenge of Vi IgA and IgG subclass antibodies. Amongst those who received the Vi-PS vaccine, Vi IgA magnitude (FDR p = 0.01) and fold-change (FDR p = 0.02) were significantly higher in protected individuals compared with those individuals who developed disease (“diagnosed”). In the Vi-TT vaccine group, the responses of protected individuals had higher fold-change in Vi IgA (FDR p = 0.06) and higher Vi IgG1 avidity (FDR p = 0.058) than the diagnosed Vi-TT vaccinees, though these findings were not significant at p < 0.05. Overall, protective antibody signatures differed between the Vi-PS and Vi-TT vaccines, thus, we conclude that although the Vi-PS and Vi-TT vaccines were observed to have similar efficacies, these vaccines may protect through different mechanisms. These data will inform studies on mechanisms of protection against typhoid fever, including identification of antibody effector functions, as well as informing future vaccination strategies.

The COVID-19 pandemic resulted in profound disruption to geography higher education. A pivot to online teaching required staff to rapidly adapt their practices to novel digital spaces. Whilst many studies have reported the different pedagogic approaches adopted, fewer have evaluated the resultant student learning experience. In this study, we aimed to create an evidence base regarding the benefits and challenges of online learning during the pandemic, mapped against the teaching, cognitive and social presences of the Community of Inquiry framework. We adopted a mixed-methods approach of online surveys (105 students) and focus groups (14 students), undertaken across two undergraduate geography programmes in a British university, exploring the benefits of asynchronous and synchronous online learning, and assessment and feedback strategies. We discovered flexibility in student work patterns and use of technology to facilitate engagement in learning. We also identified key challenges for students such as time management, maintaining motivation, engaging in online classes, and feeling part of an online learning community. We identify best practice in collaborative-constructivist online learning, so that in the event of any future remote pivot, or with sustained adoption of blended modes of delivery, we can achieve a high-quality student learning experience.

Vi-polysaccharide conjugate vaccines are efficacious against typhoid fever in children living in endemic settings, their recent deployment is a promising step in the control of typhoid fever. However, there is currently no accepted correlate of protection. IgG and IgA antibodies generated in response to Vi conjugate or Vi plain polysaccharide vaccination are important but there are no definitive protective titre thresholds. We adapted a luminescence-based serum bactericidal activity (SBA) for use with S. Typhi and assessed whether bactericidal antibodies induced by either Vi tetanus toxoid conjugate (Vi-TT) or Vi plain polysaccharide (Vi-PS) were associated with protection in a controlled human infection model of typhoid fever. Both Vi-PS and Vi-TT induced significant increase in SBA titre after 28 days (Vi-PS; p < 0.0001, Vi-TT; p = 0.003), however higher SBA titre at the point of challenge did not correlate with protection from infection or reduced symptom severity. We cannot eliminate the role of SBA as part of a multifactorial immune response which protects against infection, however, our results do not support a strong role for SBA as a mechanism of Vi vaccine mediated protection in the CHIM setting.

Sepsis has a complex pathophysiology in which both excessive and refractory inflammatory responses are hallmark features. Pro-inflammatory cytokine responses during the early stages are responsible for significant endothelial dysfunction, loss of endothelial integrity, and organ failure. In addition, it is now well-established that a substantial number of sepsis survivors experience ongoing immunological derangement and immunosuppression following a septic episode. The underpinning mechanisms of these phenomena are incompletely understood yet they contribute to a significant proportion of sepsis-associated mortality. Epigenetic mechanisms including DNA methylation, histone modifications, and non-coding RNAs, have an increasingly clear role in modulating inflammatory and other immunological processes. Recent evidence suggests epigenetic mechanisms are extensively perturbed as sepsis progresses, and particularly play a role in endothelial dysfunction and immunosuppression. Whilst therapeutic modulation of the epigenome is still in its infancy, there is substantial evidence from animal models that this approach could reap benefits. In this review, we summarize research elucidating the role of these mechanisms in several aspects of sepsis pathophysiology including tissue injury and immunosuppression. We also evaluate pre-clinical evidence for the use of “epi-therapies” in the treatment of poly-microbial sepsis.

Studies of the microbiome associated with dental caries have largely relied on 16S rRNA sequence analysis, which is associated with PCR biases, low taxonomic resolution, and inability to accurately study functions. Here, we employed whole metagenome shotgun sequencing, coupled with high-resolution analysis algorithm, to analyze supragingival microbiomes from 30 children with or without dental caries. A total of 726 bacterial strains belonging to 406 species, in addition to 34 bacteriophages were identified. A core bacteriome was identified at the species and strain levels. Species of Prevotella, Veillonella, as yet unnamed Actinomyces, and Atopobium showed strongest association with caries; Streptococcus sp. AS14 and Leptotrichia sp. Oral taxon 225, among others, were overabundant in caries-free. For several species, the association was strain-specific. Furthermore, for some species, e.g. Streptococcus mitis and Streptococcus sanguinis, sister strains showed differential associations. Noteworthy, associations were also identified for phages: Streptococcus phage M102 with caries and Haemophilus phage HP1 with caries-free. Functionally, potentially relevant features were identified including urate, vitamin K2, and polyamine biosynthesis in association with caries; and three deiminases and lactate dehydrogenase with health. The results demonstrate new associations between the microbiome and dental caries at the strain and functional levels that need further investigation.

In mammals the regulation of genomic instability plays a key role in tumor suppression and also controls genome plasticity, which is important for recombination during the processes of immunity and meiosis. Most studies to identify regulators of genomic instability have been performed in cells in culture or in systems that report on gross rearrangements of the genome, yet subtle differences in the level of genomic instability can contribute to whole organism phenotypes such as tumor predisposition. Here we performed a genome-wide association study in a population of 1379 outbred Crl:CFW(SW)-US_P08 mice to dissect the genetic landscape of micronucleus formation, a biomarker of chromosomal breaks, whole chromosome loss, and extranuclear DNA. Variation in micronucleus levels is a complex trait with a genome-wide heritability of 53.1%. We identify seven loci influencing micronucleus formation (false discovery rate

Human challenge models, in which volunteers are experimentally infected with a pathogen of interest, provide the opportunity to directly identify both natural and vaccine-induced correlates of protection. In this review, we highlight how the application of transcriptomics to human challenge studies allows for the identification of novel correlates and gives insight into the immunological pathways required to develop functional immunity. In malaria challenge trials for example, innate immune pathways appear to play a previously underappreciated role in conferring protective immunity. Transcriptomic analyses of samples obtained in human challenge studies can also deepen our understanding of the immune responses preceding symptom onset, allowing characterization of innate immunity and early gene signatures, which may influence disease outcome. Influenza challenge studies demonstrate that these gene signatures have diagnostic potential in the context of pandemics, in which presymptomatic diagnosis of at-risk individuals could allow early initiation of antiviral treatment and help limit transmission. Furthermore, gene expression analysis facilitates the identification of host factors contributing to disease susceptibility, such as C4BPA expression in enterotoxigenic Escherichia coli infection. Overall, these studies highlight the exceptional value of transcriptional data generated in human challenge trials and illustrate the broad impact molecular data analysis may have on global health through rational vaccine design and biomarker discovery.

The mechanisms by which oral, live-attenuated vaccines protect against typhoid fever are poorly understood. Here, we analyze transcriptional responses after vaccination with Ty21a or vaccine candidate, M01ZH09. Alterations in response profiles were related to vaccine-induced immune responses and subsequent outcome after wild-type Salmonella Typhi challenge. Despite broad genetic similarity, we detected differences in transcriptional responses to each vaccine. Seven days after M01ZH09 vaccination, marked cell cycle activation was identified and associated with humoral immunogenicity. By contrast, vaccination with Ty21a was associated with NK cell activity and validated in peripheral blood mononuclear cell stimulation assays confirming superior induction of an NK cell response. Moreover, transcriptional signatures of amino acid metabolism in Ty21a recipients were associated with protection against infection, including increased incubation time and decreased severity. Our data provide detailed insight into molecular immune responses to typhoid vaccines, which could aid the rational design of improved oral, live-attenuated vaccines against enteric pathogens.

There is a rich descriptive history on Bambara tonology in the published literature (e.g. Bird 1966; Courtenay 1974; Creissels 1978, 1988, 1992; Diarra 1976; Dumestre 1987; Dwyer 1976). Despite the existence of several seminal works on the subject, certain details of the language’s tonal system remain unclear. Scholars have developed deep knowledge about the lexical and grammatical functions of Bambara tone, yet the dependency of tones and tonal processes on prosodic structure has only more recently been explored in detail (Green 2013, 2015; Leben 2002, 2003; Weidman and Rose 2006; Vydrine 2002, 2010). In this paper, we aim to contribute to this ongoing trend by considering a role played by prosodic structure in one particular set of Arabic borrowings for which the assignment of tonal melodies differs from that found in words of non-Arabic origin. We explore possible explanations for this divergence that relate to contemporary scholarship on the properties of Bambara’s prosodic structure. Our point of view on this subject differs from earlier analyses (e.g., Dumestre 1987) in that we propose that prosodic structure plays an important role in the assignment of Bambara tonal melodies. Finally, we relate our findings to a taxonomic model of loanword prosody in Davis et al. (2012) and consider the bearing that our findings may have on the typology of Bambara prosodic structure alongside other Mande languages.

Scholars in higher education increasingly recognize the transformative potential of student-faculty partnerships focused on inquiry into teaching and learning. However, some students tend to be privileged in SoTL initiatives while others are discouraged, implicitly or explicitly, from engaging in this work. In this paper, we consider why certain students tend to be excluded from SoTL, summarize the possible developmental gains made by students and faculty when diverse student voices are included, and highlight strategies for generating a more inclusive SoTL. We call for expanding student engagement in SoTL by encouraging a diversity of student voices to engage in co-inquiry with faculty. Inclusive engagement has tremendous potential to enhance student and faculty learning, to deepen SoTL initiatives, and to help redress the exclusionary practices that too often occur in higher education.

The environmental toxin bisphenol A (BPA) is a known mammalian hormone disrupter but its effects on plants have not been well established. The effect of BPA on gene expression in Arabidopsis thaliana was determined using microarray analysis and quantitative gene PCR. Many hormone responsive genes showed changes in expression after BPA treatment. BPA disrupted flowering by a mechanism that may involve disruption of auxin signaling. The results presented here indicate that BPA is a plant hormone disrupter.

Two lineages of Salmonella enterica serovar Typhimurium (S. Typhimurium) of multi-locus sequence type ST313 have been linked with the emergence of invasive Salmonella disease across sub-Saharan Africa. The expansion of these lineages has a temporal association with the HIV pandemic and antibiotic usage. We analysed the whole genome sequence of 129 ST313 isolates representative of the two lineages and found evidence of lineage-specific genome degradation, with some similarities to that observed in S. Typhi. Individual ST313 S. Typhimurium isolates exhibit a distinct metabolic signature and modified enteropathogenesis in both a murine and cattle model of colitis, compared to S. Typhimurium outside of the ST313 lineages. These data define phenotypes that distinguish ST313 isolates from other S. Typhimurium and may represent adaptation to a distinct pathogenesis and lifestyle linked to an-immuno-compromised human population.

Indirect questioning attempts to overcome social desirability bias in survey research. However, to properly analyze the resulting data, it is crucial to understand how it impacts responses. This study analyzes results from a randomized experiment that tests whether direct versus indirect questioning methods lead to different results in a sample of 8,426 youths in Kenya and Pakistan. Through an examination of differential item functioning and regression analyses, we find that question wording leads to differences in how scales should be scored. We conclude that the use of indirect questioning should be undertaken with caution as a method to replace direct questioning.

Our mi package in R has several features that allow the user to get inside the imputation process and evaluate the reasonableness of the resulting models and imputations. These features include: choice of predictors, models, and transformations for chained imputation models; standard and binned residual plots for checking the t of the conditional distributions used for imputation; and plots for comparing the distributions of observed and imputed data. In addition, we use Bayesian models and weakly informative prior distributions to construct more stable estimates of imputation models. Our goal is tohave a demonstration package that (a) avoids many of the practical problems that arise with existing multivariate imputation programs, and (b) demonstrates state-of-the-art diagnostics that can be applied more generally and can be incorporated into the software of others.