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Background The use of anonymised routine linked data in designing and conducting randomised controlled trials (RCTs) has great potential. Sample sizes can be large, inclusion rates high and follow up periods prolonged, while the disruption to participants’ usual routines may be minimised. However, challenges and limitations in using routine linked data in RCTs remain. Aims To describe, in primary and emergency settings, challenges and opportunities associated with designing and conducting RCTs using anonymised linked routine data to identify study participants and gather outcomes. Methods In each of these trials we have used routine linked data as a key part of the research study design: PRISMATIC (a stepped wedge trial of predictive risk stratification in primary care) utilised linked data outcomes related to emergency admissions to hospital, GP activity and outpatient appointments. Outcomes were included for 230,000 people registered to participating GP practices in the Swansea area SAFER 2: a cluster randomised trial of referral to falls services by ambulance paramedics included linked data outcomes related to subsequent emergency episodes for 4,655 patients across three UK regions TIME: feasibility trial of Take Home Naloxone randomised by city; routine linked data used to identify population for inclusion in follow up and outcomes Regulatory processes - ethics, research and information governance permissions - have caused delay in each trial; inclusion rates have been much higher than is usual in RCTs (outcomes for >80% of eligible patients); large trials have been achievable at reasonable cost (each trial

Discomfort in the hospitalised patient continues to be one of the healthcare system’s greatest challenges to positive patient outcomes. The patients’ ability to focus on healing is impaired by discomforts such as pain, nausea and anxiety. Alternative, non-pharmacological therapies have shown to be effective in reducing discomfort and managing pain, complementing analgesic agents and optimising pain therapy modalities. This multi-cycle project is aimed to assess the effect of alternative therapies on inpatient, progressive care patients who reported discomfort or little to no relief in discomfort from prescribed analgesics and adjuvant agents. In the first Plan Do Study Act (PDSA) cycle, patients who reported discomfort were offered aromatherapy or visual relaxation DVDs. In the second PDSA cycle, patients were offered a comfort menu that consisted of multiple alternative interventions such as aromatherapy, ice or heat and ambulation. During each cycle, participants completed a survey measuring comfort levels before and after patient-selected alternative intervention(s) were administered. In the first PDSA cycle, 88% of patients reported an increase in comfort level after the intervention, and 97% reported an interest in using alternative therapy again. In the second PDSA cycle, 47% reported increased comfort, and 89% indicated a willingness to try alternative therapies again for improvement of comfort level. Overall, the quality improvement project increased the level of comfort reported by hospitalised patients, creating a gateway to comfort with less emphasis on prescribed analgesic medications.

Dysregulation of protein degradation by the ubiquitin-proteasome system is a feature commonly associated with cancer. Here, the authors develop an orally available small molecule that inhibits CSN5, the proteolytic subunit of the COP9 signalosome, and blocks tumour growth in a xenograft model.

Background/Objectives: We aimed to evaluate the co-occurrence of language and behavioural impairment in patients with frontotemporal lobar degeneration (FTLD) spectrum pathology. Methods: Eighty-one dementia patients with pathological confirmation of FTLD were identified. Anonymized clinical records from patients' first assessment were rated for language and behavioural features from frontotemporal dementia consensus criteria, primary progressive aphasia (PPA) criteria and 1998 FTLD criteria. Results: Over 90% of patients with FTLD pathology exhibited a combination of at least one behavioural and one language feature. Changes in language, in particular, were commonly accompanied by behavioural change. Notably, the majority of patients who displayed language features characteristic of semantic variant PPA exhibited ‘early perseverative, stereotyped or compulsive/ritualistic behaviour'. Moreover, ‘executive/generation deficits with relative sparing of memory and visuospatial functions' occurred in most patients with core features of non-fluent variant PPA. Conclusion: Behavioural and language symptoms frequently co-occur in patients with FTLD pathology. Current classifications, which separate behavioural and language syndromes, do not reflect this co-occurrence.

Sodium-reduction initiatives have been a cornerstone of preventing hypertension and broader atherosclerotic cardiovascular disease (ASCVD) since the early 1970s. For nearly 50 years, public health and clinical guidelines have concentrated on consumer education, behavioral change, and, to a lesser extent, food policy to help reduce sodium intake among Americans. While these efforts undoubtedly helped improve awareness, average sodium consumption remains at approximately 4200 mg/day in men and 3000 mg/day in women, well above the United States Dietary Guidelines of 2300 mg/day. Culinary medicine is an emerging discipline in clinical and public-health education that provides healthcare professionals and community members with food-based knowledge and skills. With the hands-on teaching of kitchen education to individuals, culinary medicine provides eaters with tangible strategies for reducing sodium through home cooking. Here, we review opportunities for culinary medicine to help improve both individual- and population-level sodium-reduction outcomes through five main areas: increasing adherence to a plant-forward dietary pattern, food literacy, the enhancement of complementary flavors, disease-specific teaching-kitchen modules, and the delivery of culturally specific nutrition education. Through this process, we hope to further underline the value of formal, hands-on teaching-kitchen education among healthcare professionals and community members for ASCVD prevention.

Activating mutations in thyrotropin receptor (TSHR) have been previously described in the context of nonautoimmune hyperthyroidism and thyroid adenomas. We describe, for the first time, a mutation in TSHR contributing to follicular thyroid carcinoma (FTC) in an adolescent. A 12-year-old girl presented with a right-sided neck swelling, increasing in size over the previous four weeks. Clinical examination revealed a firm, nontender thyroid nodule. Ultrasound scan of the thyroid showed a heterogeneous highly vascular mass. Thyroid function tests showed suppressed TSH [C, p.Ile568Thr) in TSHR. Papillary thyroid carcinomas constitute the most common thyroid malignancy in childhood, while FTC is rare. FTC due to TSHR mutation suggests an underlying, yet to be explored, molecular pathway leading to the development of malignancy. The case is also unique in that the clinical presentation of FTC as a toxic thyroid nodule has not been previously reported in children.

Strength-based programs that incorporate technology have gained increasing popularity as an approach to improve outcomes for individuals with autism spectrum disorder (ASD). Despite this, the core elements of strength-based technology programs remain poorly described. This study aimed to identify the core elements of strength-based technology programs for youth with ASD through a systematic review of the literature. Electronic databases were searched for qualitative studies delivering strength-based technology-driven interventions to youth on the spectrum. Ten of the 874 studies identified met the criteria. Qualitative analysis revealed three core elements of strength-based technology programs for this population: mutual respect, demonstrating skills, and interests. The findings underpin the design of future strength-based technology programs for youth with ASD.

This technical report records and discusses the Second Workshop on Sustainable Software for Science: Practice and Experiences (WSSSPE2). The report includes a description of the alternative, experimental submission and review process, two workshop keynote presentations, a series of lightning talks, a discussion on sustainability, and five discussions from the topic areas of exploring sustainability; software development experiences; credit & incentives; reproducibility & reuse & sharing; and code testing & code review. For each topic, the report includes a list of tangible actions that were proposed and that would lead to potential change. The workshop recognized that reliance on scientific software is pervasive in all areas of world-leading research today. The workshop participants then proceeded to explore different perspectives on the concept of sustainability. Key enablers and barriers of sustainable scientific software were identified from their experiences. In addition, recommendations with new requirements such as software credit files and software prize frameworks were outlined for improving practices in sustainable software engineering. There was also broad consensus that formal training in software development or engineering was rare among the practitioners. Significant strides need to be made in building a sense of community via training in software and technical practices, on increasing their size and scope, and on better integrating them directly into graduate education programs. Finally, journals can define and publish policies to improve reproducibility, whereas reviewers can insist that authors provide sufficient information and access to data and software to allow them reproduce the results in the paper. Hence a list of criteria is compiled for journals to provide to reviewers so as to make it easier to review software submitted for publication as a “Software Paper.”

INTRODUCTION:Screening for atrial fibrillation (AF) in primary care has been recommended; however, the views of healthcare professionals (HCPs) are not known. This study aimed to determine the opinions of HCP about the feasibility of implementing screening within a primary care setting. METHODS:A cross-sectional mixed methods census survey of 418 HCPs from 59 inner-city practices (Nottingham, UK) was conducted between October-December 2014. Postal and web-surveys ascertained data on existing methods, knowledge, skills, attitudes, barriers and facilitators to AF screening using Likert scale and open-ended questions. Responses, categorized according to HCP group, were summarized using proportions, adjusting for clustering by practice, with 95% C.Is and free-text responses using thematic analysis. RESULTS:At least one General Practitioner (GP) responded from 48 (81%) practices. There were 212/418 (51%) respondents; 118/229 GPs, 67/129 nurses [50 practice nurses; 17 Nurse Practitioners (NPs)], 27/60 healthcare assistants (HCAs). 39/48 (81%) practices had an ECG machine and diagnosed AF in-house. Non-GP HCPs reported having less knowledge about ECG interpretation, diagnosing and treating AF than GPs. A greater proportion of non-GP HCPs reported they would benefit from ECG training specifically for AF diagnosis than GPs [proportion (95% CI) GPs: 11.9% (6.8-20.0); HCAs: 37.0% (21.7-55.5); nurses: 44.0% (30.0-59.0); NPs 41.2% (21.9-63.7)]. Barriers included time, workload and capacity to undertake screening activities, although training to diagnose and manage AF was a required facilitator. CONCLUSION:Inner-city general practices were found to have adequate access to resources for AF screening. There is enthusiasm by non-GP HCPs to up-skill in the diagnosis and management of AF and they may have a role in future AF screening. However, organisational barriers, such as lack of time, staff and capacity, should be overcome for AF screening to be feasibly implemented within primary care.

OBJECTIVES/SPECIFIC AIMS: Provide an innovative, integrative, and interdisciplinary training program which will leverage a unique and internationally recognized strength of BU and establish an environment that facilitates translational team science interactions with MD scientists and clinicians, thereby synergistically bridging research strengths with interdisciplinary approaches. METHODS/STUDY POPULATION: This overall mission of the RMTP is pursued through 2 independent aims. Aim 1: Provide an innovative, integrative, and interdisciplinary training program which will leverage a unique and internationally recognized strength of BU. Aim 2: Establish an environment that facilitates translational team science interactions with MD scientists and clinicians, thereby synergistically bridging research strengths with interdisciplinary approaches. To achieve these aims, we have developed a specialized didactic curriculum that is fully integrated in graduate school training and can be shared for the benefit of others outside of the BU community. We are also developing online iPSC practicum workshops for more efficient distribution of didactic content. Interdisciplinary team science approaches to stem cell research related to cures for human diseases are fostered across investigators across diverse hubs at BU, BU Medical Center, the Charles River Campus and the Framingham Heart Study. All methodology, data and materials are provided in a transparent and open-source manner to benefit the greater scientific community and ensure rigorous reproducibility. RESULTS/ANTICIPATED RESULTS: As a nascent TL1 training program, we are just arriving at the end of our second year. At this point, 5 out of a total of 11 appointed trainees have concluded RMTP support, all of whom have transitioned into biomedical science-related pursuits; 2 predoctoral trainees were awarded F31 fellowships, 2 postdoctoral trainees were awarded career transition grants (K99/R00 and LERN fellowship), and 1 postdoctoral trainee became a Senior Scientist at a Biopharmaceutical company. Given the quality of our trainees and their RMTP mentors, we anticipate that close to 100% of those supported by this mechanism will continue their career development in the biomedical sciences. DISCUSSION/SIGNIFICANCE OF IMPACT: Implementation of the RMTP TL1 would not only serve to increase the capacity of trainees within the CReM, but would also extend the scope of regenerative medicine research to other CTSI-participating hubs and more broadly to other scientific disciplines.

Background: There is clinical uncertainty of the benefits and costs of different treatment options for children with Down syndrome who have glue ear. This study was designed to assess the extent of this lack of knowledge and determine if pursuing further information would be practical, beneficial and cost-effective. Objectives: To assess the level and practical effect of current uncertainty around treatment options for children with Down syndrome and glue ear. To assess the feasibility of studying the options for management of glue ear in children with Down syndrome via a randomised controlled trial (RCT) or multicentre prospective cohort study by evaluating the willingness of (1) parents to agree to randomisation for their children and (2) clinicians to recruit participants to a definitive study. To undertake value of information analyses to demonstrate the potential economic benefit from undertaking further research. Design: A feasibility study exploring the views of parents of children with Down syndrome and professionals who have responsibility for the health and education of children with Down syndrome, on the participation in, and value of, future research into interventions for glue ear. Data were collected from parents via self-completed questionnaires, face-to-face interviews and focus groups and from professionals via online questionnaires and a Delphi review exercise. Development of economic models to represent clinical pathways of care and a RCT informed a value of information (VOI) analysis. Setting: UK (professionals); East Midlands region of the UK (parents). Participants: Parents of children aged 1–11 years with Down syndrome (n = 156). Professionals including audiologists, ear, nose and throat surgeons, audiological physicians, speech and language therapists, and teachers of the deaf (n = 128). Main outcome measures: Quantitative and qualitative data on parental views and experiences of glue ear and its effects; interventions and treatment received; taking part in research and factors that would encourage or discourage participation; and the importance of various outcome domains to them and for their children. For professionals: information on caseloads; approaches to clinical management; opinions on frequency and significance of the consequences of glue ear for this population; importance of different outcome measures; opinions of interventions and their role in future research; views on health research; facilitators and barriers to recruitment, and participation in research involving RCTs. Results: The complexity of the experience and individual characteristics of children with Down syndrome poses challenges for the design of any future research but these challenges were not considered by professionals to raise sufficient barriers to prevent it being undertaken. Parents were generally supportive of the need for, and value of, research but identified practical and emotional issues that would need addressing. Glue ear was considered to impact more on speech, language and communication than on hearing. Outcome measures for future research would need to evaluate these elements but measures should be designed specifically for the population. Parents and professionals identified randomisation as a significant barrier to participation. The VOI analyses identified lack of data as problematic but concluded that a future trial involving surgical intervention would be feasible at costs of

Prenatal alcohol exposure may have adverse effects on the developing foetus resulting in significant growth restriction, characteristic craniofacial features, and central nervous system dysfunction. The toxic effects of alcohol on the developing brain are well recognised. However, little is known about the effects of alcohol on the developing gastrointestinal tract or their mechanism. There are few case reports showing an association between foetal alcohol syndrome and gastrointestinal neuropathy. We report a rare association between foetal alcohol syndrome and severe gastrooesophageal reflux disease in an infant who ultimately required fundoplication to optimise her growth and nutrition. The child had failed to respond to maximal medical treatment (domperidone and omeprazole), high calorie feeds, PEG feeding, or total parenteral nutrition. The effect of alcohol on the developing foetus is not limited to the central nervous system but also can have varied and devastating effects on the gastrointestinal tract.

Reports about superior mesenteric vein thrombosis in childhood are very rare and have not been associated with gastrointestinal bleeding. We describe two cases of severe bleeding from the upper and lower gastrointestinal tract in children who had undergone complex abdominal surgery at considerable time before. The first child had a tracheoesophageal fistula, corrected by division, gastrostomy insertion, and repair of duodenal rupture. The child presented with severe bleeding from the gastrostomy site and was diagnosed with a thrombosis of the proximal superior mesenteric vein. The second child had a gastroschisis and duodenal atresia, and required duodenoplasty, gastrostomy insertion, hemicolectomy, and adhesiolysis. The child presented with intermittent severe lower gastrointestinal bleeding, resulting from collateral vessels at location of the surgical connections. He was diagnosed with a thrombosis of the superior mesenteric vein. In both children, the extensive previous surgery and anastomosis were considered the cause of the mesenteric thrombosis. CT angiography confirmed the diagnosis in both cases, in addition to characteristic findings on endoscopy. Paediatricians should suspect this condition in children with severe gastrointestinal bleeding, particularly in children with previous, complex abdominal surgery.

Resolving the debate surrounding the nature and controls of seasonal variation in the structure and metabolism of Amazonian rainforests is critical to understanding their response to climate change. In situ studies have observed higher photosynthetic and evapotranspiration rates, increased litterfall and leaf flushing during the Sunlight-rich dry season. Satellite data also indicated higher greenness level, a proven surrogate of photosynthetic carbon fixation, and leaf area during the dry season relative to the wet season. Some recent reports suggest that rainforests display no seasonal variations and the previous results were satellite measurement artefacts. Therefore, here we re-examine several years of data from three sensors on two satellites under a range of sun positions and satellite measurement geometries and document robust evidence for a seasonal cycle in structure and greenness of wet equatorial Amazonian rainforests. This seasonal cycle is concordant with independent observations of solar radiation. We attribute alternative conclusions to an incomplete study of the seasonal cycle, i.e. the dry season only, and to prognostications based on a biased radiative transfer model. Consequently, evidence of dry season greening in geometry corrected satellite data was ignored and the absence of evidence for seasonal variation in lidar data due to noisy and saturated signals was misinterpreted as evidence of the absence of changes during the dry season. Our results, grounded in the physics of radiative transfer, buttress previous reports of dry season increases in leaf flushing, litterfall, photosynthesis and evapotranspiration in well-hydrated Amazonian rainforests.