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ImportanceMost research to understand postacute sequelae of SARS-CoV-2 infection (PASC), or long COVID, has focused on adults, with less known about this complex condition in children. Research is needed to characterize pediatric PASC to enable studies of underlying mechanisms that will guide future treatment.ObjectiveTo identify the most common prolonged symptoms experienced by children (aged 6 to 17 years) after SARS-CoV-2 infection, how these symptoms differ by age (school-age [6-11 years] vs adolescents [12-17 years]), how they cluster into distinct phenotypes, and what symptoms in combination could be used as an empirically derived index to assist researchers to study the likely presence of PASC.Design, setting, and participantsMulticenter longitudinal observational cohort study with participants recruited from more than 60 US health care and community settings between March 2022 and December 2023, including school-age children and adolescents with and without SARS-CoV-2 infection history.ExposureSARS-CoV-2 infection.Main outcomes and measuresPASC and 89 prolonged symptoms across 9 symptom domains.ResultsA total of 898 school-age children (751 with previous SARS-CoV-2 infection [referred to as infected] and 147 without [referred to as uninfected]; mean age, 8.6 years; 49% female; 11% were Black or African American, 34% were Hispanic, Latino, or Spanish, and 60% were White) and 4469 adolescents (3109 infected and 1360 uninfected; mean age, 14.8 years; 48% female; 13% were Black or African American, 21% were Hispanic, Latino, or Spanish, and 73% were White) were included. Median time between first infection and symptom survey was 506 days for school-age children and 556 days for adolescents. In models adjusted for sex and race and ethnicity, 14 symptoms in both school-age children and adolescents were more common in those with SARS-CoV-2 infection history compared with those without infection history, with 4 additional symptoms in school-age children only and 3 in adolescents only. These symptoms affected almost every organ system. Combinations of symptoms most associated with infection history were identified to form a PASC research index for each age group; these indices correlated with poorer overall health and quality of life. The index emphasizes neurocognitive, pain, and gastrointestinal symptoms in school-age children but change or loss in smell or taste, pain, and fatigue/malaise-related symptoms in adolescents. Clustering analyses identified 4 PASC symptom phenotypes in school-age children and 3 in adolescents.Conclusions and relevanceThis study developed research indices for characterizing PASC in children and adolescents. Symptom patterns were similar but distinguishable between the 2 groups, highlighting the importance of characterizing PASC separately for these age ranges.

Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is uncontrolled and overwhelming peroxidation of polyunsaturated fatty acids contained in membrane phospholipids, which eventually leads to rupture of the plasma membrane. Ferroptosis is unique in that it is essentially a spontaneous, uncatalyzed chemical process based on perturbed iron and redox homeostasis contributing to the cell death process, but that it is nonetheless modulated by many metabolic nodes that impinge on the cells susceptibility to ferroptosis. Among the various nodes affecting ferroptosis sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets for the treatment of numerous currently incurable diseases. Herein, the current members of a Germany-wide research consortium focusing on ferroptosis research, as well as key external experts in ferroptosis who have made seminal contributions to this rapidly growing and exciting field of research, have gathered to provide a comprehensive, state-of-the-art review on ferroptosis. Specific topics include: basic mechanisms, in vivo relevance, specialized methodologies, chemical and pharmacological tools, and the potential contribution of ferroptosis to disease etiopathology and progression. We hope that this article will not only provide established scientists and newcomers to the field with an overview of the multiple facets of ferroptosis, but also encourage additional efforts to characterize further molecular pathways modulating ferroptosis, with the ultimate goal to develop novel pharmacotherapies to tackle the various diseases associated with - or caused by - ferroptosis.

Pediatric COVID-19 vaccination is effective in preventing COVID-19-related hospitalization, but duration of protection of the original monovalent vaccine during SARS-CoV-2 Omicron predominance merits evaluation, particularly given low coverage with updated COVID-19 vaccines. During December 19, 2021-October 29, 2023, the Overcoming COVID-19 Network evaluated vaccine effectiveness (VE) of ≥2 original monovalent COVID-19 mRNA vaccine doses against COVID-19-related hospitalization and critical illness among U.S. children and adolescents aged 5-18 years, using a case-control design. Too few children and adolescents received bivalent or updated monovalent vaccines to separately evaluate their effectiveness. Most case-patients (persons with a positive SARS-CoV-2 test result) were unvaccinated, despite the high frequency of reported underlying conditions associated with severe COVID-19. VE of the original monovalent vaccine against COVID-19-related hospitalizations was 52% (95% CI = 33%-66%) when the most recent dose was administered

Second language education is a complex field that is continually evolving, shaped by the changes in teaching and learning contexts that have emerged over the past several decades. It would not be an exaggeration to say that these changes are predominantly driven by shifts in technology, shifts in educational approaches and philosophies, and shifts in societal and sociocultural perspectives, and each of them have brought with them different influences that have led second language education to where it is today. Amidst the numerous elements that contribute to its complexity, one factor that has become increasingly significant is social justice. This article provides an in-depth discussion on social justice in the context of second language teaching and learning, and how it has been impacted by technological developments, highlighting the affordances of technology and the importance of training to raise awareness of social justice issues in language education.

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

With mobile phones now in the hands of virtually all of our learners, it is becoming increasingly more difficult to imagine environments that do not include learning through mobile devices in even some small capacity. The interest in mobile learning is reflected in the enormous number of publications which have appeared over the past 10 to 15 years, but there are still questions about when, how, and why learners will choose to use or not use mobile devices as a regular part of their learning (Stockwell, 2022). Furthermore, the "disruptive" nature of mobile devices (see Hampel, 2019) has caused mixed reactions from teachers, some of whom feel that they are a distraction in the classroom, while others see a shifting of responsibility to the learners as a positive that can lead to autonomous behaviours that facilitate learning. Making the most of learning through mobile learning is dependent upon understanding the expectations of teachers, learners, and administrators, and to capitalise upon the affordances of the device, the learning ecology, and the short-term and long-term goals of the learners. This paper explores how mobile learning can play a role both inside and outside of the classroom, and the impact that it may have on both formal and informal learning opportunities. It includes a discussion of the shifting roles of teachers and learners, and then going on to explore the myths associated with technology in the development and sustainment of motivation and autonomy.

Pronounced T cell exhaustion characterizes immunosuppressive tumors, with the tumor microenvironment (TME) employing multiple mechanisms to elicit this suppression. Traditional immunotherapies, such as immune checkpoint blockade, often fail due to their focus primarily on T cells. To overcome this, we utilized a proinflammatory cytokine, interleukin (IL)-12, that re-wires the immunosuppressive TME by inducing T cell effector function while also repolarizing immunosuppressive myeloid cells. Due to toxicities observed with systemic administration of this cytokine, we utilized lipid nanoparticles encapsulating mRNA encoding IL-12 for intratumoral injection. This strategy has been proven safe and tolerable in early clinical trials for solid malignancies. We report an unprecedented loss of exhausted T cells and the emergence of an activated phenotype in murine pancreatic ductal adenocarcinoma (PDAC) treated with stereotactic body radiation therapy (SBRT) and IL-12mRNA. Our mechanistic findings reveal that each treatment modality contributes to the T cell response differently, with SBRT expanding the T cell receptor repertoire and IL-12mRNA promoting robust T cell proliferation and effector status. This distinctive T cell signature mediated marked growth reductions and long-term survival in local and metastatic PDAC models. This is the first study of its kind combining SBRT with IL-12mRNA and provides a promising new approach for treating this aggressive malignancy.

New and emerging viral problems may be contributing to blueberry decline. In this research we described a new virus detected in Oregon blueberry production field and surveyed the region for its potential spread. The complete genome sequence of a putative new member of the genus Luteovirus was obtained from blueberry (Vaccinium corymbosum L.) by high throughput sequencing and 5′/3′-RACE. The new virus was tentatively named blueberry virus M (BlVM). Its genome is 5,018 nt long with four putative open reading frames. Similarly to some recently discovered luteoviruses, BlVM does not possess any movement protein (MP). Phylogenetic analysis confirmed clustering of BlVM with the group of non-MP luteoviruses, showing blueberry virus L as the most similar species. Through a small-scale high throughput sequencing survey we obtained 14 additional near complete genomic sequences. A larger survey of 2,654 samples by RT-PCR in Oregon and Washington (USA) found 52 BlVM-positive plants collected from four locations in Oregon. These findings will facilitate monitoring virus distribution and assessment of potential disease associated with this new and emerging blueberry virus.

Multiplexed antibody-based imaging enables the detailed characterization of molecular and cellular organization in tissues. Advances in the field now allow high-parameter data collection (>60 targets); however, considerable expertise and capital are needed to construct the antibody panels employed by these methods. Organ mapping antibody panels are community-validated resources that save time and money, increase reproducibility, accelerate discovery and support the construction of a Human Reference Atlas.

The Human BioMolecular Atlas Program (HuBMAP) aims to create a multi-scale spatial atlas of the healthy human body at single-cell resolution by applying advanced technologies and disseminating resources to the community. As the HuBMAP moves past its first phase, creating ontologies, protocols and pipelines, this Perspective introduces the production phase: the generation of reference spatial maps of functional tissue units across many organs from diverse populations and the creation of mapping tools and infrastructure to advance biomedical research.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by limited treatment options and high mortality. A better understanding of the molecular drivers of IPF progression is needed. Objectives: To identify and validate molecular determinants of IPF survival. Methods: A staged genome-wide association study was performed using paired genomic and survival data. Stage I cases were drawn from centers across the United States and Europe and stage II cases from Vanderbilt University. Cox proportional hazards regression was used to identify gene variants associated with differential transplantation-free survival (TFS). Stage I variants with nominal significance (P

The NOAA Chemical Sciences Laboratory (CSL) conducted the Southwest Urban NOx and VOCs Experiment (SUNVEx) to study emissions and the role of boundary layer (BL) dynamics and sea-breeze (SB) transitions in the evolution of coastal air quality. The study presented utilizes remote sensing and in situ observations in Pasadena, California. Separate analyses are conducted on the synoptic conditions during ozone (O3) exceedance (>70 ppb) and non-exceedance ( ppb) days, as well as the fine-structure variability of in situ chemistry measurements during BL growth and SB transitions. Diurnal analyses spanning August 2021 revealed a markedly different wind direction during evenings preceding O3 exceedance (northerly) versus non-exceedance (easterly) days. Increased O3 occurred simultaneously with warmer and drier conditions, a reduction in winds, and an increase in volatile organic compounds (VOCs) and fine particulate matter (PM2.5). While the average BL height was lower and surface pressure was higher, the day-to-day variability of these quantities led to an overall weak statistical relationship. Investigations focused on the fine-structure variability of in situ chemistry measurements superimposed on background trends were conducted using a novel multivariate spectral coherence mapping (MSCM) technique that combined the spectral structure of two or more independent measurements through a wavelet analysis as reported by maximum-normalized scaleograms. A case study was chosen to illustrate the MSCM technique, where the dominant peaks in scaleograms were identified and compared to BL height during the growth phase. The temporal widths of peaks (τmax) derived from VOC and nitrogen oxide (NOx) scaleograms, as well as scaleograms combining VOCs, NOx, and variations in BL height, indicated a broadening with respect to time as the BL increased in depth. A separate section focused on comparisons between τmax and BL height during August 2021 revealed uncorrelated or weakly correlated scatter, except in the case of VOCs when really large τmax and relatively deep BL heights were ignored. Instances of large τmax and relatively deep BL heights occurred near sunrise and as onshore flow entered Pasadena, respectively. Wind transitions likely influenced both the dynamical evolution of the BL and tracer advection and thus offer additional challenges when separating factors contributing to the fine structure. Other insights gained from this work include observations of descending wind jets from the San Gabriel Mountains that were not resolved by the High-Resolution Rapid Refresh (HRRR) model and the derivation of intrinsic properties of oscillations observed in NOx and O3 during the interaction between an SB and enhanced winds above the BL that flowed in opposition to the SB.

Music is a unique form of verbal stimuli (Reynolds & Hayes, "The Psychological Record," 67(3), 413-421, 2017) and the literature has indicated some success in using procedures involving the frame of coordination or stimulus equivalence to teach early piano skills to learners with and without autism spectrum disorder (ASD; Hill et al., "Journal of Applied Behavior Analysis," 53(1), 188-208, 2020). However, these studies only targeted narrow skills rather than a complete repertoire. Also, whether such teaching procedure is effective for young children with ASD at different ages, with different needs, and with common accompanied diagnosis, is unknown. The current study (a) explored the possibility of applying relational frame theory (RFT; Hayes, Barnes-Holmes, & Roche, 2001) in piano program development that aims to teach a complete early piano repertoire, and (b) confirmed the effectiveness of an adjusted teaching procedure using the frame of coordination on teaching early piano skills to six young children on the autism spectrum. A multiple probe across participants design was used. After direct training of two relations (AC & AE), post-instructional tests were conducted on eight relations. The results showed that with remedial training, five out of six participants demonstrated mutual entailment, combinatorial entailment, and transformation of stimulus function in these relations. All participants could read and play the song on keyboard without extra training. The study provided practical guidance on applying the procedure to these young learners. Implications of RFT in piano curriculum development were also discussed.

This introduction to the special issue examines the integration of ChatGPT and similar generative AI technologies in language teaching and learning. It examines the rapid evolution of AI tools since 2022, with particular focus on their applications in educational settings and the mixed responses they have generated among educators and learners. While some educators embrace these tools for their potential to automate and enhance instructional tasks, others express concern over issues such as academic integrity, accuracy, and potential job displacement. This special issue explores various perspectives on the use of ChatGPT, including its benefits in providing non-judgmental feedback, aiding material creation, and enhancing language practice, alongside challenges like ethical use, student over-reliance, and the evolving digital literacy demands for both teachers and students. The collection of articles in this special issue seeks to balance the hype with practical insights and offers a framework for understanding the nuanced impacts of generative AI on second language education.

BackgroundAdolescents and young adults frequently present to the emergency department (ED) for medical care and continue to have many unmet sexual health needs. Digital interventions show promise to improve adolescent and young adult sexual health; yet, few interventions focus on male ED patients, despite their infrequent use of contraceptives and rising rates of sexually transmitted infections. ObjectiveThis paper describes the design and development of Dr. Eric (Emergency Room Interventions to Improve Care), a digital app focused on promoting condom use among sexually active adolescent and young adult male ED patients. MethodsThis study followed 4 phases of app development, which were based on user-centered design and the software development lifecycle. In phase 1, define, we explored our target population and target health problem (infrequent condom use among male ED patients) by collecting key stakeholder input and conducting in-depth interviews with male patients and urban ED medical providers. In phase 2, discover, we partnered with a digital product agency to explore user experience and digital strategy. In phase 3, design, we refined Dr. Eric’s content, a 5-part sexual health educational module and a 10-week SMS text messaging program that focuses on condom use and partner communication about effective contraceptives. We conducted semistructured interviews with male adolescent and young adults to gather feedback on the app and perform usability testing, editing the app after each interview. We also interviewed informatics experts to assess the usability of a high-fidelity prototype. Interviews were recorded and analyzed via descriptive thematic analysis; informatic expert feedback was categorized by Nielsen’s heuristic principles. In phase 4, develop, we created the technical architecture and built a responsive web app. These findings were gathered leading to the final version of the digital Dr. Eric program. ResultsUsing data and key stakeholder input from phases 1 and 2, we iteratively created the Dr. Eric prototype for implementation in the ED setting. Interviews with 8 adolescent and young adult male ED patients suggested that users preferred (1) straightforward information, (2) a clear vision of the purpose of Dr. Eric, (3) open-ended opportunities to explore family planning goals, (4) detailed birth control method information, and (5) games presenting novel information with rewards. Five usability experts provided heuristic feedback aiming to improve the ease of use of the app. These findings led to the final version of Dr. Eric. ConclusionsFollowing these mobile health development phases, we created a digital sexual health mobile health intervention incorporating the principles of user experience and interface design. Dr. Eric needs further evaluation to assess its efficacy in increasing condom use among adolescent and young adult male ED patients. Researchers can use this framework to form future digital health ED-based digital interventions.

Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is uncontrolled and overwhelming peroxidation of polyunsaturated fatty acids contained in membrane phospholipids, which eventually leads to rupture of the plasma membrane. Ferroptosis is unique in that it is essentially a spontaneous, uncatalyzed chemical process based on perturbed iron and redox homeostasis contributing to the cell death process, but that it is nonetheless modulated by many metabolic nodes that impinge on the cells’ susceptibility to ferroptosis. Among the various nodes affecting ferroptosis sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets for the treatment of numerous currently incurable diseases. Herein, the current members of a Germany-wide research consortium focusing on ferroptosis research, as well as key external experts in ferroptosis who have made seminal contributions to this rapidly growing and exciting field of research, have gathered to provide a comprehensive, state-of-the-art review on ferroptosis. Specific topics include: basic mechanisms, in vivo relevance, specialized methodologies, chemical and pharmacological tools, and the potential contribution of ferroptosis to disease etiopathology and progression. We hope that this article will not only provide established scientists and newcomers to the field with an overview of the multiple facets of ferroptosis, but also encourage additional efforts to characterize further molecular pathways modulating ferroptosis, with the ultimate goal to develop novel pharmacotherapies to tackle the various diseases associated with – or caused by – ferroptosis.

IntroductionFungal fruit rots are a perennial threat to the production of cranberries. Eleven genera of fungi have been reported to cause cranberry rot in the field and/or during cold storage. Oregon and Washington rank fourth and fifth in the production of cranberries in the USA, but much of the research on cranberry fruit rots has been conducted in Wisconsin, New Jersey, and Massachusetts.ObjectiveThe primary objective of this project was to describe the current composition of cranberry fruit rot complex in Oregon and Washington.MethodsA survey of fungal fruit rot pathogens was conducted over four years in commercial cranberry farms located in the Pacific Ocean coastal zone in Oregon and Washington.ResultsYield, rot incidence, and fungal pathogens isolated varied year-to-year. Pathogens isolated frequently from field-rotted cranberries included the cranberry fruit rot genera described in other cranberry production regions of the USA, such as Colletotrichum, Coleophoma, and Physalospora. Neofabraea actinidiae, a recently described cranberry fruit rot, was isolated consistently from field-rotted cranberries from beds with specific fungicide usage patterns. N. actinidiae also was one of the more common storage rot pathogens in this region, alongside other well-established storage rots like Coleophoma and black rots caused by Allantophomopsis cytisporea, A. lycopodina, and Strasseria geniculata.ConclusionsThese findings may have important implications for Washington cranberry production because a large proportion of the crop is dry-harvested, placed in cold storage, and then sold as fresh cranberries. Climatic differences among the cranberry production areas across the United States may affect the disease incidence and prevalence of different genera of cranberry fruit rot pathogens, as summer months in Oregon and Washington are often much cooler and dryer than in Wisconsin and east coast states and may account for differing presence of various cranberry fruit rot fungi.

Background Current National Health Service policy in England encourages enhanced digital access in primary care service provision. In this study, we investigate ‘digital facilitation’ – that range of processes, procedures and personnel which seeks to support National Health Service primary care patients in their uptake and use of online services. Objectives Identify, characterise and explore the potential benefits and challenges associated with different models of digital facilitation currently in use in general practice which are aimed at improving patient access to online services in general practice in England. Use the resulting intelligence to design a framework for future evaluations of the effectiveness and cost effectiveness of such interventions. Explore how patients with mental health conditions experience digital facilitation and gauge their need for this support. Design Observational mixed-methods study (literature review, surveys, ethnographic observation and interviews); formal synthesis of findings. Setting General practice in four regions of England. Participants Practice survey: 156 staff. Patient survey: 3051 patients. Mental health survey: 756 patients. General practitioner patient survey: 3 million responders. Ethnographic case-studies: 8 practices; interviews with 36 staff, 33 patients and 10 patients with a mental health condition. Stakeholder interviews: 19 participants. Intervention Digital facilitation as undertaken in general practice. Main outcome measures Patient and practice staff reported use of, and views of, digital facilitation. Data sources Surveys, qualitative research; national General Practitioner Patient Survey (2019–22). Review methods Scoping-review methodology applied to academic and grey literature published 2015–20. Results While we did find examples of digital facilitation in routine practice, these often involved using passive or reactive modes of support. The context of COVID, and the necessary acceleration (at that time) of the move to a digital-first model of primary care, shaped the way digital facilitation was delivered. There was lack of clarity over where the responsibility for facilitation efforts lay; it was viewed as the responsibility of ‘others’. Patients living with mental health conditions had similar needs and experiences regarding digital facilitation to other patients. Limitations The context of the COVID pandemic placed limitations on the project. Fewer practices responded to the practice survey than anticipated; reconfiguration of general practices to support COVID measures was a key consideration during non-participant observation with social distancing and other measures still in place during fieldwork. Conclusions Digital facilitation, while not a widely recognised concept, is important in supporting the move to a National Health Service with enhanced digital opportunities and enhanced digital access. General practice staff are allocating resources to provide such efforts in general practices in England. The establishment of clear lines of responsibility, the development of digital tools and platforms that work for patients and practice staff, and investment in staff time and training are needed if digital facilitation is to support the intended digital revolution. Future work We did not find one single dominant or preferred model of digital facilitation which might reasonably be considered to form the basis of an intervention to be tested. Rather, there is a need to co-develop such an intervention with patients, general practice staff and relevant policy experts. We outline a framework for a future evaluation of such an intervention. Study registration This study is registered as ResearchRegistry6523 (www.researchregistry.com/browse-the-registry#home/?view_2_search=Di-Facto&view_2_page=1) and PROSPERO CRD42020189019 (www.crd.york.ac.uk/prospero/display_record.php?RecordID=189019). Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: NIHR128268) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 32. See the NIHR Funding and Awards website for further award information. Plain language summary Background Online services are common in the National Health Service. This research looked at ‘digital facilitation’ in general practices. Digital facilitation is about supporting National Health Service patients in their use of online services. We aimed to understand how much digital facilitation is being used by general practices. We also looked at how digital facilitation happens and if it affects the number of people using online services. Methods We looked at previous research to help us understand what approaches have been used to support patients to use online services. We used surveys to ask staff at general practices what they were already doing, and to ask patients about their experiences. We observed digital facilitation in general practices and spoke to patients and staff to help us understand the benefits and challenges of different approaches. We combined findings from the three stages outlined above to identify key aspects of digital facilitation. All stages of our research included discussions with the project’s patient advisory group. Key findings We found that digital facilitation is seen as important and has many forms. Most general practices are using passive and reactive types of facilitation. An example of passive facilitation, initiated by the service but not involving direct inter-personal interaction, is the use of text messaging relating to ordering of repeat prescriptions online. An example of reactive facilitation is providing a response to a patient-initiated query regarding online access. There is clear scope to develop a more proactive approach to facilitation that actively engages patients. Our research highlights a lack of clarity over who is responsible for digital facilitation. Different people (patients, staff, policy-makers) often think that the responsibility lies with others. Investment in digital facilitation is needed. Tools and platforms for digital facilitation that meet patients’ and general practices’ needs should be developed. Scientific summary Background The NHS is facing the increasing demands of a growing and ageing population, technological progress and changing public expectations. Current NHS policy in England encourages enhanced digital opportunities and enhanced digital access in primary care provision. Drivers behind this move include the assumption that online services lead to improved choice, convenience, and ease of access for users, improved triage systems and streamlining of service delivery. In this research, we addressed ‘digital facilitation’ [digital facilitation (DF)] – ‘that range of processes, procedures and personnel which seeks to support NHS patients in their uptake and use of online services’. We investigated the provision by general practices to support access to NHS online primary care services by their registered patients and carers of those patients. Support in accessing and using services is required at all stages: initial registration for online services; subsequent continued use; and navigating the wide range of NHS online provision. Hence, it is important to understand the extent to which approaches to DF are applied, how they are applied, the impact such efforts have on uptake of online services, and how such uptake may affect patient health and access to healthcare information and services. Aims Identify, characterise and explore the potential benefits and challenges associated with different models of DF currently in use in general practice in England which are aimed at improving patient access to online primary care services. Use the resulting intelligence to design a framework for future evaluations of the effectiveness and cost effectiveness of such interventions. Explore how patients with mental health conditions experience DF and gauge their need for this support. Methods The project comprised four interlinked elements. Initially we undertook a scoping review and narrative synthesis of published literature, seeking to understand and characterise the range, effectiveness and cost effectiveness of models of DF for improving access to online services within health. Searches of academic databases and grey literature published between 2015 and 2020 were undertaken, including snowballing from the publications they cited. We surveyed general practice staff and patients (with an additional boost sample of patients living with mental health conditions, which was in direct response to a National Institute for Health and Care Research commissioning brief) and undertook analyses of data from the national General Practice Patient Survey (GPPS). The practice staff questionnaire included items addressing which online services were being used and what steps had been implemented in practices to promote and support the use of such services. We implemented a sequential mixed mode when inviting staff from 500 general practices to complete the survey online or on paper. The patient questionnaire addressed patients’ familiarity and confidence with information technology (IT) and internet use, their awareness and uptake of online services, and their experiences of any support provided by their practice. Questionnaires were sent by post with the option of replying online or by post. We also analysed responses to questions from the English national GPPSs (2019–22) concerning awareness and use of online booking of appointments, ordering repeat prescriptions and accessing medical records, and additionally the use of online consultations. Logistic regression models were used to examine how the awareness and use of online services, the awareness and use of facilitation efforts, and experience of other support varied by patient characteristics. We undertook a qualitative exploration of DF comprising two elements: focused ethnographic case studies in general practices, and an interview study with key stakeholders. Focused ethnography was used to explore, in-depth, the use of DF in general practices. Eight general practice case study sites were recruited to provide variation in terms of their DF offering, and in terms of a range of practice characteristics (practice setting, deprivation status and size, and the age profile of registered patients). We undertook: non-participant observation of the process of DF and how practice staff and patients/carers interact with different types of DF, semistructured interviews with staff members and patients in each practice, and collected secondary analysis of documentation pertaining to digital services or facilitation within the practice. This was augmented by 10 interviews with patients living with mental health conditions from the case study sites; these sought to explore their experiences of DF. The interview study with key stakeholders sought understanding of the broader context and wider drivers of DF in primary care. We conducted semistructured interviews with stakeholders providing a level of insight beyond individual practices, including policy-makers, commissioners and third- sector organisations. Data from the focused ethnographic case studies and stakeholder interviews were analysed together using thematic analysis. We conducted a synthesis of the evidence generated by each element of the study. We employed Weiss’s approach to theory-based evaluation as a theoretical framework. A pragmatic, iterative and cumulative approach was applied to synthesising the findings from all elements and to developing programme and implementation theories. We triangulated findings, summarising the results in a matrix, which evolved into thematic groupings as the study progressed and as evidence from our work packages (WPs) became available. Findings were brought together in a series of three workshop meetings of researchers and patient/public participants as individual WPs were completed. The synthesis process concluded following an online discussion with national and regional stakeholders. We used the synthesised findings to identify the key aspects of a framework aimed at informing future research on DF. Patient and public involvement and engagement (PPIE) was embedded throughout this research, from the original conception through to the design and conduct of the research, and the synthesis and interpretation of findings. Our team has benefited from a patient co-investigator, a dedicated PPIE co-ordinator, and an actively engaged Patient Advisory Group (PAG). All WPs have worked with the PAG to ensure the research is patient focused and addresses patient needs. The PAG was augmented with additional members with lived experience of mental health conditions to ensure that the additional work focused on patients living with mental health conditions was appropriately framed. Members of the PAG were fully involved as equal voices alongside the research team in the synthesis workshops. Results The synthesis of findings from the literature review, surveys and qualitative work resulted in the identification of 11 thematic groups (distinct from, but incorporating, the results of the qualitative thematic analysis): 3 scene-setting themes relating to the context in which DF takes place, and 8 themes related to types of DF, their implementation and effectiveness. Scene-setting themes: The first theme related to the value and purpose of digital services. The qualitative exploration found that the need for, and value of, digital services are not always clear and that there is a lack of shared understanding or belief about what digital services should achieve. The second theme related to conflation of the digital environment with other routes to access. For example, the qualitative exploration found that digital services can both enable access and be a barrier to access, and that patient priorities are often to navigate the system to access health care, making access a more important concept than DF to many. The third theme related to the impact of the COVID pandemic. Many practices responding to the practice survey reported increased digital service offerings and reduced provision of traditional forms of access. The exception to this was in relation to online appointment booking, where 44% of responding practices reported that they had offered this service pre-pandemic but did not do so at the time of the survey. Furthermore, in the qualitative exploration we found that the pandemic was associated with some initiatives being halted that have not subsequently resumed. Digital facilitation themes: The fourth theme related to how people define and identify DF. While, as a research team, we proposed a definition of digital facilitation, it is not yet a widely recognised concept and the qualitative exploration found that it was often difficult to have a working definition for DF given that it is movable and relative to a person’s circumstance. The fifth theme related to the types of DF. In our literature review, we found a focus on interventions that require practices to actively support patients to use digital services. This was in striking contrast with our practice survey where we found that the majority of practices reported passive and reactive modes of facilitation (e.g. 88% of practices used text messages or e-mails for DF and 91% provided ad hoc support to patients). The sixth theme relates to the differing foci of DF on initial sign-up versus supporting sustained use over time. The majority of research found in our review focused on initial sign-up. While in the patient survey we did find that registration was a substantial barrier (20% of responders to the patient survey cited not knowing how to register or finding registration too difficult as a reason for not using online services), the qualitative exploration found that supporting patients to register was often still reactive. Furthermore, although recognising that DF could go beyond initial sign-up, some practices felt that this was their only required contribution to the task of extending digital access. The seventh theme relates to who delivers facilitation. There was a mismatch between existing evidence identified in WP1, which suggested that general practitioners (GPs) and nurses undertake most facilitation, and our survey and qualitative findings that most facilitation efforts were conducted by receptionists and administrative staff. We also found a ‘bystander effect’, with patients, different staff groups and stakeholders all assuming that responsibility for DF lies elsewhere. The eighth and ninth themes related to the enablers and barriers of DF, respectively. Findings from our qualitative work were consistent with much of what emerged from the literature review. Enablers of DF include someone having specific responsibility for such efforts, with associated funding, time and other resources, platforms that enable easy registration and use, and a clear rationale for the digital services that can be understood by practice and patient (i.e. products that have a ‘good fit’ with what is needed). Barriers to effective facilitation include confusion about who is responsible for DF and why; practices using a variety of digital platforms; lack of consideration for the individual circumstances of patients; and assumptions being made about what people can and cannot do digitally based on stereotypes. In our patient survey, we found very low awareness of DF activities (apart from use of e-mail and text messages). Few (13%) responders to the patient survey reported being given help to use online services, but when that help was given, it was generally rated as useful. The 10th theme focuses on digital access and DF for patient subgroups. Age emerged as a common important dimension across the WPs. The literature review identified that older people may particularly benefit from direct, human support in accessing digital services. In the practice survey, most practices reported targeting older adults. However, in the patient survey we found that older patients were less likely to be aware of or make use of DF and were less likely to be told about or receive help to use digital services. In the qualitative work we found that the age of the individual is perceived to have an impact on both staff and patients’ digital knowledge, understanding, experience and confidence. Responders to the patient survey who were from ethnic minorities had long-term health conditions, did not speak English as a first language, or were in receipt of repeat prescriptions, were more likely to report awareness of and use of (passive) facilitation than other patients. But these groups were also less likely to be told about online services or to have received help to use them. The findings of our work focusing on patients living with mental health conditions were largely concordant with the findings of the main patient survey and qualitative research. There were some differences in the way that specific mental health conditions impacted on individuals’ contact with their practice, and consequently in the use by such individuals of digital services and in their need for DF. Responders in the patient survey mental health sample were more likely to report using digital services and to being aware of DF efforts than were responders to the main survey, but this was largely explained by differences in the sample demographics. The final theme considered the effectiveness of DF. There was no evidence around the cost effectiveness of DF, and the limited existing evidence on effectiveness almost entirely focused on initial sign-up of services. Reflecting this, our qualitative exploration found that some practices focused on the number of patients signed up to a service as evidence of the effectiveness of their facilitation efforts. Conclusions Digital facilitation is important in the context of the move to an NHS-enhanced digital opportunities and enhanced digital access in primary care service provision. Staff are spending time and effort to provide DF in general practices in England. Digital facilitation is viewed to have value and potential to increase the uptake of online services. Digital facilitation can take many forms, though most such efforts are reactive and passive. There is clear scope to develop a more proactive approach to facilitation that actively engages patients. There is currently a disconnect between the expectations and perceptions of what DF is happening and its potential effectiveness, and the reality seen in everyday practice. This is related to a lack of clarity over the responsibility for delivering DF and pressures on the time of general practice staff. Establishing clear lines of responsibility, and the development of digital tools and platforms that work for patients and practice staff, will both be needed, alongside investment in staff time and training, if DF is to deliver on the intended digital revolution. This project set out to explore DF that was already underway, with the potential of identifying good practice. However, we did not find an example of what might form a complete, practical intervention package. Future research should therefore focus on: co-development, involving patients and general practice staff, of DF, seeking to ensure a responsive and adaptive approach improving the presentation of practice websites for patient engagement with the intent of increasing uptake of digital tools and reducing the need for DF the best approaches to tailoring DF to different patient groups and identifying which patient groups are most likely to benefit from such efforts ensuring that the digital exclusion of certain groups, including, but not limited to, older patients, is investigated monitoring the sustained use of online services, not merely initial sign-up. Study registration This study is registered as ResearchRegistry6523 (www.researchregistry.com/browse-the-registry#home/?view_2_search=Di-Facto&view_2_page=1) and PROSPERO CRD42020189019 (www.crd.york.ac.uk/prospero/display_record.php?RecordID=189019). Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: NIHR128268) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 32. See the NIHR Funding and Awards website for further award information.

The declining trend in vehicle emissions has underscored the growing significance of volatile organic compound (VOC) emissions from volatile chemical products (VCPs). However, accurately representing VOC chemistry in simplified chemical mechanisms remains challenging due to its chemical complexity including speciation and reactivity. Previous studies have predominantly focused on VOCs from fossil fuel sources, leading to an underrepresentation of VOC chemistry from VCP sources. We developed an integrated chemical mechanism, RACM2B-VCP, that is compatible with WRF-Chem and is aimed at enhancing the representation of VOC chemistry, particularly from VCP sources, within the present urban environment. Evaluation against the Air Quality System (AQS) network data demonstrates that our model configured with RACM2B-VCP reproduces both the magnitude and spatial variability of O3 and PM2.5 in Los Angeles. Furthermore, evaluation against comprehensive measurements of O3 and PM2.5 precursors from the Reevaluating the Chemistry of Air Pollutants in California (RECAP-CA) airborne campaign and the Southwest Urban NOx and VOC Experiment (SUNVEx) ground site and mobile laboratory campaign confirm the model's accuracy in representing NOx and many VOCs and highlight remaining biases. Although there exists an underprediction in the total VOC reactivity of observed VOC species, our model with RACM2B-VCP exhibits good agreement for VOC markers emitted from different sectors, including biogenic, fossil fuel, and VCP sources. Through sensitivity analyses, we probe the contributions of VCP and fossil fuel emissions to total VOC reactivity and O3. Our results reveal that 52 % of the VOC reactivity and 35 % of the local enhancement of MDA8 O3 arise from anthropogenic VOC emissions in Los Angeles. Significantly, over 50 % of this anthropogenic fraction of either VOC reactivity or O3 is attributed to VCP emissions. The RACM2B-VCP mechanism created, described, and evaluated in this work is ideally suited for accurately representing ozone for the right reasons in the present urban environment where mobile, biogenic, and VCP VOCs are all important contributors to ozone formation.

Cooking is a source of volatile organic compounds (VOCs), which degrade air quality. Cooking VOCs have been investigated in laboratory and indoor studies, but the contribution of cooking to the spatial and temporal variability in urban VOCs is uncertain. In this study, a proton-transfer-reaction time-of-flight mass spectrometer (PTR-ToF-MS) is used to identify and quantify cooking emission in Las Vegas, NV, with supplemental data from Los Angeles, CA, and Boulder, CO. Mobile laboratory data show that long-chain aldehydes, such as octanal and nonanal, are significantly enhanced in restaurant plumes and regionally enhanced in areas of Las Vegas with high restaurant densities. Correlation analyses show that long-chain fatty acids are also associated with cooking emissions and that the relative VOC enhancements observed in regions with dense restaurant activity are very similar to the distribution of VOCs observed in laboratory cooking studies. Positive matrix factorization (PMF) is used to quantify cooking emissions from ground site measurements and to compare the magnitude of cooking with other important urban sources, such as volatile chemical products and fossil fuel emissions. PMF shows that cooking may account for as much as 20 % of the total anthropogenic VOC emissions observed by PTR-ToF-MS. In contrast, emissions estimated from county-level inventories report that cooking accounts for less than 1 % of urban VOCs. Current emissions inventories do not fully account for the emission rates of long-chain aldehydes reported here; thus, further work is likely needed to improve model representations of important aldehyde sources, such as commercial and residential cooking.

Mobile-assisted language learning has expanded beyond relatively humble beginnings of replicating computer-based activities assigned in formal language learning contexts, and it now often consists of a complex mix of formal and informal learning activities that take place at different times and places throughout learners' daily lives. Decisions about what tools to use are often driven by the costs, choice of hardware, and the knowledge of what tools actually exist, and how these tools are then used will depend on learners' skills, motivation, as well as their short- and long-term goals. Language learning no longer needs to be an activity that is separated from learners' daily lifestyles, but can be an integral part of their lives in the long term. The complexities involved in understanding each individual learner's own ecological context and how these ecologies shift over time will be discussed with an eye on optimising learning opportunities for learners that will keep them engaged in learning throughout their lives.

Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.

Blueberry is an important perennial fruit crop with expanding consumption and production worldwide. Consumer demand for blueberries has grown due to the desirable flavor and numerous health benefits, and fresh market production in the U.S. has risen in turn. U.S. imports have also increased to satisfy year-round consumer demand for fresh blueberries. Pre- and post-harvest fruit diseases such as anthracnose (caused by Colletotrichum spp.) and botrytis fruit rot (caused by Botrytis spp.) have a significant impact on fruit quality and consumer acceptance. These are also among the most difficult diseases to control in the blueberry cropping system. These latent pathogens can cause significant losses both in the field, and especially during transport and marketplace storage. Although both diseases result in rotted fruit, the biology and infection strategies of the causal pathogens are very different, and the management strategies differ. Innovations for management, such as improved molecular detection assays for fungicide resistance, postharvest imaging, breeding resistant cultivars, and biopesticides have been developed for improved fruit quality. Development and integration of new strategies is critical for the long-term success of the blueberry industry.

Objectives To report the development, implementation, acceptability and feasibility of vending machines offering HIV and sexually transmitted infection (STI) testing kits.Design A qualitative study using the Person-Based Approach with patient and public involvement workshops and stakeholder involvement and interviews with machine users, sexual health service (SHS) staff, venue staff and local authority sexual health commissioners. Transcripts were analysed thematically.Setting Bristol, North Somerset and South Gloucestershire (BNSSG).Participants 15 machine users, 5 SHS staff, 3 venue staff and 3 local authority commissioners.Intervention Four vending machines dispensing free HIV self-testing and STI self-sampling kits in publicly accessible venues across BNSSG were introduced to increase access to testing for groups at higher risk of HIV and STI infection who are less likely to access SHS clinic testing services (young people, people from black communities, and gay, bisexual and other men who have sex with men).Results Machine users reported the service was convenient, easy to use and accessible; however, concerns regarding privacy related to machine placement within the venues and issues of maintenance were raised. Promotional material was inclusive and informative; however, awareness of the service through the promotional campaign was limited. Vending machines were acceptable to venue staff once clear processes for their management were agreed with the SHS. SHS staff identified challenges with the implementation of the service related to the limited involvement of the whole SHS team in the planning and development.Conclusions The codeveloped vending machine service was acceptable, addressing some barriers to testing. Resources and protected staff time are needed to support greater involvement of the whole SHS team and service providers in venues. Adopting a similarly robust coproduction approach to the implementation of the machines could avoid the challenges reported. The placement of the machines to assure users privacy and repeated, targeted promotion could encourage service use among target groups.

Objective The increase in reliance on online services for general practice has the potential to increase inequalities within some populations. Patients with a mental health condition are one such group. Digital facilitation is defined as a range of processes, procedures, and people, which seek to support NHS patients in using online services. This study aimed to examine the views and experiences of digital facilitation in primary care amongst patients living with a mental health condition. Methods Semi-structured interviews were conducted with patients living with a mental health condition, recruited from general practices across England participating in the Di-Facto study. Thematic analysis was conducted on interview transcripts. Results Interviews were conducted with ten participants with a mental health condition, recruited from five general practices. Three themes were identified: (1) familiarity with online services; (2) experiences of those using online services; (3) the need for digital facilitation. The need for digital facilitation was identified in the registration for online services, and in trusting online services. Conclusions Online services offer convenience for patients, but registration for the use of such services remains a potential area of difficulty. Participants had difficulties with registering for online services and had concerns about trust in using them. Support offered by general practices in using online services needs to be varied and adaptable to meet the needs of individual patients.