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Background The East Timor Hearts Fund (ETHF) is a charitable organisation of Australian cardiologists providing outreach screening in Timor-Leste. For patients requiring intervention, ETHF arranges logistics, procedures, and postoperative care. The aim of this project is to evaluate outcomes of patients requiring intervention. Methods The ETHF database of all patients was utilised to identify patients with disease warranting surgical or percutaneous intervention. Both patients who underwent intervention and those who did not proceed to intervention were included in this study. Patients who had intervention arranged by other organisations but have then had follow-up with ETHF were also included. Overall demographics and pre and postoperative factors were assessed, with sub-group analysis of adult and paediatric patients to identify any differences in care. Results Of 221 patients requiring intervention, 101 patients underwent intervention, receiving 22 different operations or procedures. Patients were predominantly young (median age 17.5 years) and female (64.7%), with rheumatic heart disease (63.8%). Twenty-four (24) (33.3%) women aged 15–45 years old with cardiac disease warranting intervention were documented as pregnant or breastfeeding at time of clinic assessment. Of patients who did not proceed to intervention, adults were more likely to be lost to follow-up (42.4% vs 18.5%) while paediatric patients were more likely to experience progression of disease (18.5% vs 7.5%, p=0.005). Median waitlist time was 5 months, with no significant difference between adults and children, correlating with a preoperative mortality rate of 5.4%. For patients who underwent intervention, post-procedure mortality was extremely low (0.9%) and attendance of at least one post-procedure review was excellent (99.0%). Eleven (11) (10.9%) patients have required repeat intervention, with no difference in rates between adult and paediatric patients. Length of follow-up extends up to 20 years for some patients. Conclusion The Timor-Leste interventional cohort was predominantly a young female population with rheumatic and congenital cardiac disease. There were also high rates of pregnancy amongst female patients with severe cardiac disease. Delayed access to intervention may result in preoperative adverse events and mortality, and is a key target for improvement. Patients who undergo intervention have very low post-procedural mortality, good adherence to early medical follow-up and good long-term outcomes.

BACKGROUND Timor-Leste is one of the poorest countries in the world. The East Timor Hearts Fund is a charitable organisation involving Australian cardiologists providing outreach screening and access to cardiac interventions. AIMS To assess ten years of clinical volume, demographics and patient outcomes. Our intention was to identify existing limitations to facilitate planning for further capacity building over the next decade. METHODS The East Timor Hearts Fund database was sectioned into 2-year intervals (2009/2010, 2011/2012, 2013/2014, 2015/2016 and 2017/2018). Demographics and clinical outcomes of patients were compared, with subgroup analysis of adult (>18 years old), paediatric and interventional patients. RESULTS Over 10 years, 2050 patient encounters have occurred; 1119 (54.6%) encounters occurred in 2017/2018; 73.6% of patients were assessed in the capital Dili. Rheumatic and congenital cardiac diseases remain very common (39.1% of adult new patients and 74.2% of paediatric new patients), with 1.4% of new patients exhibiting both pathologies. The number of new patients with rheumatic or congenital heart disease tripled in 2017/2018 compared to 2009/2010 (99 vs 34 patients, P < 0.0001). Paediatric case volume increased over 10-fold over 10 years (288 new patients in 2017/2018 vs 24 in 2009/2010, P < 0.0001), with corresponding increase in proportion of paediatric interventions (59.4% in 2017/2018 vs 25.0% in 2009/2010, P = 0.027). For patients undergoing intervention (n = 87), post-procedural complications and mortality are extremely low (3.4% and 1.1%, respectively), with all eligible patients attending at least one post-procedure appointment. CONCLUSION Demand for cardiac services in Timor-Leste is rising exponentially, with inequitable geographic coverage. Rheumatic and congenital cardiac diseases remain priorities for assessment, and paediatric case volume is increasing. Patients undergoing intervention experience good medical outcomes.

Background Echocardiographic screening in school-aged children can detect rheumatic heart disease (RHD) prior to the manifestation of symptoms of heart failure. The challenge is making this practical and affordable on a global scale. This study aims to evaluate the diagnostic utility of an ultra-abbreviated echocardiographic screening protocol involving a single parasternal-long-axis-view-sweep of the heart (SPLASH) in two dimensional (2D) and colour Doppler imaging (index test). Methods This prospective study of diagnostic accuracy compared the diagnostic utility of the index screening test with a comprehensive reference test (standard echocardiographic screening protocols) as per World Heart Federation (WHF) echocardiographic criteria. School students in Timor-Leste aged 5–20 years were enrolled. Both index and reference test images were acquired by cardiologists on Vivid I or Q machines (GE Healthcare, Marlborough, MA, USA). Results A total of 1,365 participants were screened; median age was 11 years. The estimated prevalence of definite and borderline RHD was 35.2 per 1,000. Congenital heart disease was identified in 11 children (0.8%) with two needing cardiac surgery. Abnormal SPLASH views were found in 109/1365 (7.99%). No cases of RHD or significant congenital heart disease were missed. Sensitivity and specificity of the abbreviated protocol for detecting RHD were 1.0 and 0.95 respectively. Conclusions A simplified echocardiography screening protocol using SPLASH is highly sensitive and specific and could significantly improve the efficiency of RHD screening. It has the potential to expedite training of health workers whilst protecting the modesty of students.

Introduction There is widespread variation in the management of rare orthopaedic disease, in a large part owing to uncertainty. No individual surgeon or hospital is typically equipped to amass sufficient numbers of cases to draw robust conclusions from the information available to them. The programme of research will establish the British Orthopaedic Surgery Surveillance (BOSS) Study; a nationwide reporting structure for rare disease in orthopaedic surgery. Methods The BOSS Study is a series of nationwide observational cohort studies of pre-specified orthopaedic disease. All relevant hospitals treating the disease are invited to contribute anonymised case details. Data will be collected digitally through REDCap, with an additional bespoke software solution used to regularly confirm case ascertainment, prompt follow-up reminders and identify potential missing cases from external sources of information (i.e. national administrative data). With their consent, patients will be invited to enrich the data collected by supplementing anonymised case data with patient reported outcomes. The study will primarily seek to calculate the incidence of the rare diseases under investigation, with 95% confidence intervals. Descriptive statistics will be used to describe the case mix, treatment variations and outcomes. Inferential statistical analysis may be used to analyze associations between presentation factors and outcomes. Types of analyses will be contingent on the disease under investigation. Discussion This study builds upon other national rare disease supporting structures, particularly those in obstetrics and paediatric surgery. It is particularly focused on addressing the evidence base for quality and safety of surgery, and the design is influenced by the specifications of the IDEAL collaboration for the development of surgical research.

BackgroundUnstable ankle fractures represent a substantial burden of disease, accounting for a mean hospital stay of nine days, a mean cost of £4,491 per patient and 20,000 operations per year. There is variation in UK practice around weight-bearing instructions after operatively managed ankle fracture. Early weight-bearing may reduce reliance on health services, time off work, and improve functional outcomes. However, concerns remain about the potential for complications such as implant failure. This is the protocol of a multicentre randomised non-inferiority clinical trial of weight-bearing following operatively treated ankle fracture.MethodsAdults aged 18 years and over who have been managed operatively for ankle fracture will be assessed for eligibility. Baseline function (Olerud and Molander Ankle Score [OMAS]), health-related quality of life (EQ-5D-5L), and complications will be collected after informed consent has been obtained. A randomisation sequence has been prepared by a trial statistician to allow for 1:1 allocation to receive either instruction to weight-bear as pain allows from the point of randomisation, two weeks after the time of surgery (‘early weight-bearing’ group) or to not weight-bear for a further four weeks (‘delayed weight -bearing’ group). All other treatment will be as per the guidance of the treating clinician.Participants will be asked about their weight-bearing status weekly until four weeks post-randomisation. At four weeks post-randomisation complications will be collected. At six weeks, four months, and 12 months post-randomisation, the OMAS, EQ-5D-5L, complications, physiotherapy input, and resource use will be collected. The primary outcome measure is ankle function (OMAS) at four months post-randomisation.A minimum of 436 participants will be recruited to obtain 80% power to detect a non-inferiority margin of -6 points on the OMAS 4 months post-randomisation. A within-trial health economic evaluation will be conducted to estimate the cost-effectiveness of the treatment options.DiscussionThe results of this study will inform national guidance with regards to the most clinically and cost-effective strategy for weight-bearing after surgery for unstable ankle fractures.Trial registrationISRCTN12883981, Registered 02 December 2019.

Radioresistance is a major hurdle in the treatment of head and neck squamous cell carcinoma (HNSCC). Here, we report that concomitant treatment of HNSCCs with radiotherapy and mevalonate pathway inhibitors (statins) may overcome resistance. Proteomic profiling and comparison of radioresistant to radiosensitive HNSCCs revealed differential regulation of the mevalonate biosynthetic pathway. Consistent with this finding, inhibition of the mevalonate pathway by pitavastatin sensitized radioresistant SQ20B cells to ionizing radiation and reduced their clonogenic potential. Overall, this study reinforces the view that the mevalonate pathway is a promising therapeutic target in radioresistant HNSCCs. info:eu-repo/semantics/acceptedVersion

Introduction There are limited data pertaining to comparative outcomes of remaining on dialysis versus kidney transplantation as the threat of coronavirus disease 2019 (COVID-19) remains. In this study we delineate the differential risks involved using serologic methods to help define exposure rates. Methods From a cohort of 1433 patients with end-stage kidney disease (ESKD), we analyzed COVID-19 infection rates and outcomes in 299 waitlist patients compared with 237 transplant recipients within their first year post-transplant. Patients were followed over a 68-day period from the time our transplant program closed due to COVID-19. Results The overall mortality rates in waitlist and transplant populations were equivalent (P = 0.69). However, COVID-19 infection was more commonly diagnosed in the waitlist patients (P = 0.001), who were more likely to be tested by reverse transcriptase polymerase chain reaction (P = 0.0004). Once infection was confirmed, mortality risk was higher in the transplant patients (P = 0.015). The seroprevalence in dialysis and transplant patients with undetected infection was 18.3% and 4.6%, respectively (P = 0.0001). After adjusting for potential screening bias, the relative risk of death after a diagnosis of COVID-19 remained higher in transplant recipients (hazard ratio = 3.36 [95% confidence interval = 1.19–9.50], P = 0.022). Conclusions Although COVID-19 infection was more common in the waitlist patients, a higher COVID-19‒associated mortality rate was seen in the transplant recipients, resulting in comparable overall mortality rates.

Introduction A better understanding of factors influencing perceived life expectancy (PLE), interactions between patient prognostic beliefs, experiences of illness, and treatment behavior is urgently needed. Methods Case-notes at 3 hemodialysis units were screened: patients with ≥20% 1-year mortality risk were included. Patients and their health care professionals (HCPs) were invited to complete a structured interview or mixed-methods questionnaire. Four hundred eleven patient notes were screened. Seventy-seven eligible patients were approached and 51 were included. Results Patients predicted significantly higher life expectancies than HCPs (P < 0.0001). Documented cognitive impairment, gender, or increasing age did not affect 1- or 5-year PLE. PLE influenced priorities of care: one-fifth of patients who estimated themselves to have >95% 1-year survival preferred “care focusing on relieving pain and discomfort,” compared with nearly three-quarters of those reporting a ≤50% chance of 1-year survival. Twenty of 51 (39%) patients believed transplantation was an option for them, despite only 4 being waitlisted at the time of the interview. Patients who thought they were transplant candidates were significantly more confident they would be alive at 1 and 5 years and to want resuscitation attempted. Cognitive impairment had no effect on perceived transplant candidacy. A high symptom burden was present and underrecognized by HCPs. High symptom burden was associated with significantly lower PLE at both 1 and 5 years, increased anxiety/depression scores, and treatment choices more likely to prioritize relief of suffering. Conclusion There is a disparity between patient PLE and those of their HCPs. Severity of symptom burden and beliefs regarding PLE or transplant candidacy affect patient treatment preferences., Graphical abstract

Aims Torus fractures are the most common childhood fracture, accounting for 500,000 UK emergency attendances per year. UK treatment varies widely due to lack of scientific evidence. This is the protocol for a randomized controlled equivalence trial of ‘the offer of a soft bandage and immediate discharge’ versus ‘rigid immobilization and follow-up as per the protocol of the treating centre’ in the treatment of torus fractures . Methods Children aged four to 15-years-old inclusive who have sustained a torus/buckle fracture of the distal radius with/without an injury to the ulna are eligible to take part. Baseline pain as measured by the Wong Baker FACES pain scale, function using the Patient-Reported Outcomes Measurement Information System (PROMIS) upper limb, and quality of life (QoL) assessed with the EuroQol EQ-5D-Y will be collected. Each patient will be randomly allocated (1:1, stratified by centre and age group (four to seven years and ≥ eight years) to either a regimen of the offer of a soft bandage and immediate discharge or rigid immobilization and follow-up as per the protocol of the treating centre. Results At day one, three, and seven, data on pain, function, QoL, immobilization, and analgesia will be collected. Three and six weeks after injury, the main outcomes plus data on complications, resource use, and school absence will be collected. The primary outcome is the Wong-Baker FACES pain scale at three days post-randomization. All data will be obtained through electronic questionnaires completed by the participants and/or parents/guardian. Cite this article: Bone Joint Open 2020;1-6:214–221.

Gastropleural fistulas are a complication of peptic ulcers in hiatal hernias, trauma, infections, surgical complications, and malignancy. Presenting symptoms may include gastric and chest pain with respiratory failure in the setting of pneumonitis, hydropneumothorax, or tension pneumothorax. We describe a 57-year-old male with a history of transhiatal esophagectomy and esophago-gastroanastomosis who presented in the setting of dyspnea and dark orogastric tube output. Upper endoscopy revealed multiple gastric ulcers with a dominant ulceration communicating with an adjacent space, and a fistulous tract was demonstrated on computed tomography chest, confirming a gastropleural fistula, a rare life-threatening condition.

Background Digital health interventions have the potential to improve the delivery of psychoeducation to people with mental health problems and their relatives. Despite substantial investment in the development of digital health interventions, successful implementation into routine clinical practice is rare. Objectives Use the implementation of the Relatives’ Education And Coping Toolkit (REACT) for psychosis/bipolar disorder to identify critical factors affecting uptake and use, and develop an implementation plan to support the delivery of REACT. Design This was an implementation study using a mixed-methods, theory-driven, multiple case study approach. A study-specific implementation theory for REACT based on normalisation process theory was developed and tested, and iterations of an implementation plan to address the key factors affecting implementation were developed. Setting Early-intervention teams in six NHS mental health trusts in England (three in the north and three in the south). Participants In total, 281 staff accounts and 159 relatives’ accounts were created, 129 staff and 23 relatives took part in qualitative interviews about their experiences, and 132 relatives provided demographic data, 56 provided baseline data, 21 provided data at 12 weeks’ follow-up and 20 provided data at 24 weeks’ follow-up. Interventions REACT is an online supported self-management toolkit, offering 12 evidence-based psychoeducation modules and support via a forum, and a confidential direct messaging service for relatives of people with psychosis or bipolar disorder. The implementation intervention was developed with staff and iteratively adapted to address identified barriers. Adaptations included modifications to the toolkit and how it was delivered by teams. Main outcome measures The main outcome was factors affecting implementation of REACT, assessed primarily through in-depth interviews with staff and relatives. We also assessed quantitative measures of delivery (staff accounts and relatives’ invitations), use of REACT (relatives’ logins and time spent on the website) and the impact of REACT [relatives’ distress (General Health Questionnaire-28), and carer well-being and support (Carer Well-being and Support Scale questionnaire)]. Results Staff and relatives were generally positive about the content of REACT, seeing it as a valuable resource that could help services improve support and meet clinical targets, but only within a comprehensive service that included face-to-face support, and with some additional content. Barriers to implementation included high staff caseloads and difficulties with prioritising supporting relatives; technical difficulties of using REACT; poor interoperability with trust information technology systems and care pathways; lack of access to mobile technology and information technology training; restricted forum populations leading to low levels of use; staff fears of managing risk, online trolling, or replacement by technology; and uncertainty around REACT’s long-term availability. There was no evidence that REACT would reduce staff time supporting relatives (which was already very low), and might increase it by facilitating communication. In all, 281 staff accounts were created, but only 57 staff sent relatives invitations. In total, 355 relatives’ invitations were sent to 310 unique relatives, leading to the creation of 159 relatives’ accounts. The mean number of logins for relatives was 3.78 (standard deviation 4.43), but with wide variation from 0 to 31 (median 2, interquartile range 1–8). The mean total time spent on the website was 40.6 minutes (standard deviation 54.54 minutes), with a range of 0–298 minutes (median 20.1 minutes, interquartile range 4.9–57.5 minutes). There was a pattern of declining mean scores for distress, social dysfunction, depression, anxiety and insomnia, and increases in relatives’ well-being and eHealth literacy, but no changes were statistically significant. Conclusions Digital health interventions, such as REACT, should be iteratively developed, evaluated, adapted and implemented, with staff and service user input, as part of a long-term strategy to develop integrated technology-enabled services. Implementation strategies must instil a sense of ownership for staff and ensure that they have adequate training, risk protocols and resources to deliver the technology. Cost-effectiveness and impact on workload and inequalities in accessing health care need further testing, along with the generalisability of our findings to other digital health interventions. Limitations REACT was offered by the same team running the IMPlementation of A Relatives’ Toolkit (IMPART) study, and was perceived by staff and relatives as a time-limited research study rather than ongoing clinical service, which affected engagement. Access to observational data was limited. Trial registration Current Controlled Trials ISRCTN16267685. Funding This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 8, No. 37. See the NIHR Journals Library website for further project information.

To augment HIV-1 pox-protein vaccine immunogenicity using a next generation adjuvant, a prime-boost strategy of recombinant modified vaccinia virus Ankara and multimeric Env gp145 was evaluated in macaques with either aluminum (alum) or a novel liposomal monophosphoryl lipid A (MPLA) formulation adsorbed to alum, ALFA. Binding antibody responses were robust and comparable between arms, while antibody-dependent neutrophil and monocyte phagocytotic responses were greatly enhanced by ALFA. Per-exposure vaccine efficacy against heterologous tier 2 SHIV mucosal challenge was 90% in ALFA-adjuvanted males (P = 0.002), while alum conferred no protection. Half of the ALFA-adjuvanted males remained uninfected after the full challenge series, which spanned seven months after the last vaccination. Antibody-dependent monocyte and neutrophil phagocytic responses both strongly correlated with protection. Significant sex differences in infection risk were observed, with much lower infection rates in females than males. In humans, MPLA-liposome-alum adjuvanted gp120 also increased HIV-1-specific phagocytic responses relative to alum. Thus, next-generation liposome-based adjuvants can drive vaccine elicited antibody effector activity towards potent phagocytic responses in both macaques and humans and these responses correlate with protection. Future protein vaccination strategies aiming to improve functional humoral responses may benefit from such adjuvants., Author summary A clinically safe liposomal adjuvant can drive antibody effector activity towards increased phagocytic function relative to alum and this activity mediates protection against stringent mucosal SHIV infection in macaques.

There has been a growth in the number of web-based trials of web-based interventions, adding to an increasing evidence base for their feasibility and effectiveness. However, there are challenges associated with such trials, which researchers must address. This discussion paper follows the structure of the Down Your Drink trial methodology paper, providing an update from the literature for each key trial parameter (recruitment, registration eligibility checks, consent and participant withdrawal, randomization, engagement with a web-based intervention, retention, data quality and analysis, spamming, cybersquatting, patient and public involvement, and risk management and adverse events), along with our own recommendations based on designing the Relatives Education and Coping Toolkit randomized controlled trial for relatives of people with psychosis or bipolar disorder. The key recommendations outlined here are relevant for future web-based and hybrid trials and studies using iterative development and test models such as the Accelerated Creation-to-Sustainment model, both within general health research and specifically within mental health research for relatives. Researchers should continue to share lessons learned from conducting web-based trials of web-based interventions to benefit future studies. International Registered Report Identifier (IRRID) RR2-10.1136/bmjopen-2017-016965

Background Relatives caring for people with severe mental health problems find information and emotional support hard to access. Online support for self-management offers a potential solution. Objective The objective was to determine the clinical effectiveness and cost-effectiveness of an online supported self-management tool for relatives: the Relatives’ Education And Coping Toolkit (REACT). Design and setting This was a primarily online (UK), single-blind, randomised controlled trial, comparing REACT plus a resource directory and treatment as usual with the resource directory and treatment as usual only, by measuring user distress and other well-being measures at baseline and at 12 and 24 weeks. Participants A total of 800 relatives of people with severe mental health problems across the UK took part; relatives who were aged ≥ 16 years, were experiencing high levels of distress, had access to the internet and were actively seeking help were recruited. Intervention REACT comprised 12 psychoeducation modules, peer support through a group forum, confidential messaging and a comprehensive resource directory of national support. Trained relatives moderated the forum and responded to messages. Main outcome measure The main outcome was the level of participants’ distress, as measured by the General Health Questionnaire-28 items. Results Various online and offline strategies, including social media, directed potential participants to the website. Participants were randomised to one of two arms: REACT plus the resource directory (n = 399) or the resource directory only (n = 401). Retention at 24 weeks was 75% (REACT arm, n = 292; resource directory-only arm, n = 307). The mean scores for the General Health Questionnaire-28 items reduced substantially across both arms over 24 weeks, from 40.2 (standard deviation 14.3) to 30.5 (standard deviation 15.6), with no significant difference between arms (mean difference –1.39, 95% confidence interval –3.60 to 0.83; p = 0.22). At 12 weeks, the General Health Questionnaire-28 items scores were lower in the REACT arm than in the resource directory-only arm (–2.08, 95% confidence interval –4.14 to –0.03; p = 0.027), but this finding is likely to be of limited clinical significance. Accounting for missing data, which were associated with higher distress in the REACT arm (0.33, 95% confidence interval –0.27 to 0.93; p = 0.279), in a longitudinal model, there was no significant difference between arms over 24 weeks (–0.56, 95% confidence interval –2.34 to 1.22; p = 0.51). REACT cost £142.95 per participant to design and deliver (£62.27 for delivery only), compared with £0.84 for the resource directory only. A health economic analysis of NHS, health and Personal Social Services outcomes found that REACT has higher costs (£286.77), slightly better General Health Questionnaire-28 items scores (incremental General Health Questionnaire-28 items score adjusted for baseline, age and gender: –1.152, 95% confidence interval –3.370 to 1.065) and slightly lower quality-adjusted life-year gains than the resource directory only; none of these differences was statistically significant. The median time spent online was 50.8 minutes (interquartile range 12.4–172.1 minutes) for REACT, with no significant association with outcome. Participants reported finding REACT a safe, confidential environment (96%) and reported feeling supported by the forum (89%) and the REACT supporters (86%). No serious adverse events were reported. Limitations The sample comprised predominantly white British females, 25% of participants were lost to follow-up and dropout in the REACT arm was not random. Conclusions An online self-management support toolkit with a moderated group forum is acceptable to relatives and, compared with face-to-face programmes, offers inexpensive, safe delivery of National Institute for Health and Care Excellence-recommended support to engage relatives as peers in care delivery. However, currently, REACT plus the resource directory is no more effective at reducing relatives’ distress than the resource directory only. Future work Further research in improving the effectiveness of online carer support interventions is required. Trial registration Current Controlled Trials ISRCTN72019945. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 32. See the NIHR Journals Library website for further project information.

Background The Relatives Education And Coping Toolkit (REACT) is an online supported self-management toolkit for relatives of people with psychosis or bipolar designed to improve access to NICE recommended information and emotional support. Aims Our aim was to determine clinical and cost-effectiveness of REACT including a Resource Directory (RD), versus RD-only. Methods A primarily online, observer-blind randomised controlled trial comparing REACT (including RD) with RD only (registration ISRCTN72019945). Participants were UK relatives aged > = 16, with high distress (assessed using the GHQ-28), and actively help-seeking, individually randomised, and assessed online. Primary outcome was relatives’ distress (GHQ-28) at 24 weeks. Secondary outcomes were wellbeing, support, costs and user feedback. Results We recruited 800 relatives (REACT = 399; RD only = 401) with high distress at baseline (GHQ-28 REACT mean 40.3, SD 14.6; RD only mean 40.0, SD 14.0). Median time spent online on REACT was 50.8 min (IQR 12.4–172.1) versus 0.5 min (IQR 0–1.6) on RD only. Retention to primary follow-up (24 weeks) was 75% (REACT n = 292 (73.2%); RD-only n = 307 (76.6%)). Distress decreased in both groups by 24 weeks, with no significant difference between the two groups (− 1.39, 95% CI -3.60, 0.83, p = 0.22). Estimated cost of delivering REACT was £62.27 per person and users reported finding it safe, acceptable and convenient. There were no adverse events or reported side effects. Conclusions REACT is an inexpensive, acceptable, and safe way to deliver NICE-recommended support for relatives. However, for highly distressed relatives it is no more effective in reducing distress (GHQ-28) than a comprehensive online resource directory. Trial registration ISRCTN72019945 prospectively registered 19/11/2015.

Aims Slipped capital femoral epiphysis (SCFE) is one of the most common hip diseases of adolescence that can cause marked disability, yet there is little robust evidence to guide treatment. Fundamental aspects of the disease, such as frequency, are unknown and consequently the desire of clinicians to undertake robust intervention studies is somewhat prohibited by a lack of fundamental knowledge. Methods The study is an anonymized nationwide comprehensive cohort study with nested consented within the mechanism of the British Orthopaedic Surgery Surveillance (BOSS) Study. All relevant hospitals treating SCFE in England, Scotland, and Wales will contribute anonymized case details. Potential missing cases will be cross-checked against two independent external sources of data (the national administrative data and independent trainee data). Patients will be invited to enrich the data collected by supplementing anonymized case data with patient-reported outcome measures. In line with recommendations of the IDEAL Collaboration, the study will primarily seek to determine incidence, describe case mix and variations in surgical interventions, and explore the relationships between baseline factors (patients and types of interventions) and two-year outcomes. Discussion This is the first disease to be investigated using the BOSS Study infrastructure. It provides a robust method to determine the disease frequency, and a large unbiased sample of cases from which treatment strategies can be investigated. It may form the basis for definitive robust intervention studies or, where these are demonstrated not to be feasible, this may be the most robust cohort study.

Background Despite the potential of digital health interventions to improve the delivery of psychoeducation to people with mental health problems and their relatives, and substantial investment in their development, there is little evidence of successful implementation into clinical practice. We report the first implementation study of a digital health intervention: Relatives Education And Coping Toolkit (REACT), into routine mental healthcare. Our main aim was to identify critical factors affecting staff uptake and use of this online self-management tool for relatives of people with psychosis or bipolar. Methods A mixed-methods, theory-driven (Normalisation Process Theory), iterative multiple case study approach using qualitative analysis of interviews with staff and quantitative reporting of uptake. Carer researchers were part of the research team. Results In all, 281 staff and 159 relatives from Early Intervention teams across six catchment areas (cases) in England registered on REACT; 129 staff took part in qualitative interviews. Staff were positive about REACT helping services improve support and meet clinical targets. Implementation was hindered by: high staff caseloads and difficulties prioritising carers; perception of REACT implementation as research; technical difficulties using REACT; poor interoperability with trust computer systems and care pathways; lack of access to mobile technology and training; restricted forum populations; staff fears of risk, online trolling, and replacement by technology; and uncertainty around REACT’s long-term availability. Conclusions Digital health interventions, such as REACT, should be iteratively developed, evaluated, adapted and implemented, in partnership with the services they aim to support, and as part of a long term national strategy to co-develop integrated technology-enabled mental healthcare. Implementation strategies must instil a sense of ownership for staff and ensure they have adequate IT training, appropriate governance protocols for online working, and adequate mobile technologies. Wider contextual factors including adequate funding for mental health services and prioritisation of carer support, also need to be addressed for successful implementation of carer focussed digital interventions. Trial registration Study registration: ISCTRN 16267685.

Numerous studies have confirmed that prelinguistic utterances are precursors to speech, and there is ample evidence that, for example, frequency of canonical syllables and syllable inventory size correlate with speech and language measures at older ages. Traditionally, prelinguistic utterances have been assessed by phonetic transcription which is difficult and time-consuming in infants. Recently, a more time-efficient methodology to assess prelinguistic utterances in real time, called naturalistic listening, was developed (Ramsdell et al., 2012). In a large international NIDCR-funded randomized controlled trial, Timing of Primary Surgery for with Cleft Palate (TOPS), including many coders, a software program (TimeStamper) was developed to assist in coding of prelinguistic vocalizations in real time, to ensure consistency of the coding procedures. Coders upload a video (or audio) file and watch and listen to the recording in real time without any possibility of pausing or taking notes. In real time, the coder registers each speech-like syllable as canonical or non-canonical. TimeStamper automatically calculates the percentage of canonical syllables of all syllables registered (canonical babbling ratio). At the end of a recording, TimeStamper assists in assessing presence/absence of canonical babbling and syllable inventory size. The software is presented and instructions for free access are provided.

IntroductionCurrently, all people with diabetes (PWD) aged 12 years and over in the UK are invited for screening for diabetic retinopathy (DR) annually. Resources are not increasing despite a 5% increase in the numbers of PWD nationwide each year. We describe the rationale, design and methodology for a randomised controlled trial (RCT) evaluating the safety, acceptability and cost-effectiveness of personalised variable-interval risk-based screening for DR. This is the first randomised trial of personalised screening for DR and the largest ophthalmic RCT in the UK.Methods and analysisPWD attending seven screening clinics in the Liverpool Diabetic Eye Screening Programme were recruited into a single site RCT with a 1:1 allocation to individualised risk-based variable-interval or annual screening intervals. A risk calculation engine developed for the trial estimates the probability that an individual will develop referable disease (screen positive DR) within the next 6, 12 or 24 months using demographic, retinopathy and systemic risk factor data from primary care and screening programme records. Dynamic, secure, real-time data connections have been developed. The primary outcome is attendance for follow-up screening. We will test for equivalence in attendance rates between the two arms. Secondary outcomes are rates and severity of DR, visual outcomes, cost-effectiveness and health-related quality of life. The required sample size was 4460 PWD. Recruitment is complete, and the trial is in follow-up.Ethics and disseminationEthical approval was obtained from National Research Ethics Service Committee North West – Preston, reference 14/NW/0034. Results will be presented at international meetings and published in peer-reviewed journals. This pragmatic RCT will inform screening policy in the UK and elsewhere.Trial registration numberISRCTN87561257; Pre-results.

Characterization of the spatial distribution and abundance of proteins and mRNAs with morphological context within tissues enables a better understanding of biological systems in many research areas, including immunology and oncology. The GeoMxTM Digital Spatial Profiler (DSP) enables the highly-multiplexed detection of mRNA or protein targets within distinct regions of tissues, including FFPE. This assay utilizes in situ hybridization (ISH) probes or antibodies linked to indexing oligo barcodes via a photo-cleavable linker. The GeoMx DSP enables profiling of RNA or protein targets by releasing and collecting these barcodes from user-defined regions-of-interest. Manual preparation of FFPE tissue uses conventional immuno-fluorescence (IF) and ISH reagents, however it requires greater than two hours of hands-on-time over 2 days. Protocols have been developed to enable the automation of these tissue preparation protocols using the Leica Biosystems BOND RX and BOND RXm Fully Automated Research Stainers. Here we describe protocols for the semi-automated preparation of GeoMx RNA and protein assays as well as the fully-automated preparation of GeoMx RNA assays. These protocols reduce the hands-on time of performing the assay to 72 minutes and 35 minutes for the semi- and fully-automated protocols, respectively. Signal-to-noise ratios (SNR) are highly concordant between serial sections processed manually and processed on the Leica BOND RXm using the GeoMx Immune Cell Profiling Panel for protein (58-plex) and GeoMx Immune Pathways Panel for RNA (84-plex). Furthermore, automated assays show high concordance between the BOND RX and BOND RXm instruments. Lastly, we demonstrate the use of the fully automated slide preparation protocol with the GeoMx Cancer Transcriptome Atlas, a panel that targets >1,600 key cancer mRNAs that are read out by next-generation sequencing. GeoMx Assays are for RESEARCH USE ONLY. Not for use in diagnostic procedures. Citation Format: Daniel R. Zollinger, Sarah Ketting, Kristina Sorg, Oliver Appelbe, Danielle Aaker, Damian Cockfield, Chris Merritt, Joseph M. Beechem. High-throughput slide preparation for spatially-resolved, multiplexed quantification of protein or mRNA in tumor tissues with automation of GeoMx™ DSP Assays on Leica Biosystems BOND RX [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5237.

Background The evaluation of web-based interventions (defined as an intervention that can be downloaded or accessed on the internet through a web browser) in randomized controlled trials (RCTs) has increased over the past two decades. Little is known about how participants’ use of the intervention is measured, reported, and analyzed in these studies. Objective This study aimed to review the evaluation of web-based interventions in RCTs, assessing study characteristics and the methods used to record, and adjust for, intervention usage. Methods A systematic review of the literature was undertaken to identify all published reports of RCTs that involved a web-based intervention. A random sample of 100 published trials was selected for detailed data extraction. Information on trial characteristics was extracted, including whether web usage data were recorded, and if so, the methods used to gather these data and whether these data were used to inform efficacy analyses. Results A PubMed search identified 812 trials of web-based interventions published up to the end of 2017 and demonstrated a growing trend over time. Of the 100 studies reviewed, 90 studies collected web usage data, but more than half (49/90, 54%) of these studies did not state the method used for recording web usage. Only four studies attempted to check on the reliability of their web usage data collection methods. A total of 39% (35/90) studies reported patterns or levels of web intervention use, of which 21% (19/90) studies adjusted for intervention use in their outcome analysis, but only two of these used appropriate statistical methods. Conclusions Trialists frequently report a measure of web-based intervention usage but do not always report the collection method or provide enough detail on their analysis of web usage. Appropriate statistical methods to account for intervention use are rarely used and are not well reported even in the very few trials in which they are used. The number of trialists who attempt to check on the reliability of their web usage collection methods is extremely low.

Background: Web-based interventions to support people to manage long-term health conditions are available and effective but rarely used in clinical services. The aim of this study is to identify critical factors impacting on the implementation of an online supported self-management intervention for relatives of people with recent onset psychosis or bipolar disorder into routine clinical care and to use this information to inform an implementation plan to facilitate widespread use and inform wider implementation of digital health interventions. Methods: A multiple case study design within six early intervention in psychosis (EIP) services in England, will be used to test and refine theory-driven hypotheses about factors impacting on implementation of the Relatives' Education And Coping Toolkit (REACT). Qualitative data including behavioural observation, document analysis, and in-depth interviews collected in the first two EIP services (wave 1) and analysed using framework analysis, combined with quantitative data describing levels of use by staff and relatives and impact on relatives' distress and wellbeing, will be used to identify factors impacting on implementation. Consultation via stakeholder workshops with staff and relatives and co-facilitated by relatives in the research team will inform development of an implementation plan to address these factors, which will be evaluated and refined in the four subsequent EIP services in waves 2 and 3. Transferability of the implementation plan to non-participating services will be explored. Discussion: Observation of implementation in a real world clinical setting, across carefully sampled services, in real time provides a unique opportunity to understand factors impacting on implementation likely to be generalizable to other web-based interventions, as well as informing further development of implementation theories. However, there are inherent challenges in investigating implementation without influencing the process under observation. We outline our strategies to ensure our design is transparent, flexible, and responsive to the timescales and activities happening within each service whilst also meeting the aims of the project. Trial registration: ISCTRN 16267685 (09/03/2016). © 2017 The Author(s).

BACKGROUND: Improving the diagnosis of serious bacterial infections (SBIs) in the children’s emergency department is a clinical priority. Early recognition reduces morbidity and mortality, and supporting clinicians in ruling out SBIs may limit unnecessary admissions and antibiotic use. METHODS: A prospective, diagnostic accuracy study of clinical and biomarker variables in the diagnosis of SBIs (pneumonia or other SBI) in febrile children RESULTS: There were 1101 children studied, of whom 264 had an SBI. A diagnostic model discriminated well between pneumonia and no SBI (concordance statistic 0.84, 95% confidence interval 0.78–0.90) and between other SBIs and no SBI (0.77, 95% confidence interval 0.71–0.83) on internal validation. A published model discriminated well on external validation. Model updating yielded good calibration with good performance at both high-risk (positive likelihood ratios: 6.46 and 5.13 for pneumonia and other SBI, respectively) and low-risk (negative likelihood ratios: 0.16 and 0.13, respectively) thresholds. Extending the model with procalcitonin and resistin yielded improvements in discrimination. CONCLUSIONS: Diagnostic models discriminated well between pneumonia, other SBIs, and no SBI in febrile children in the emergency department. Improvements in the classification of nonevents have the potential to reduce unnecessary hospital admissions and improve antibiotic prescribing. The benefits of this improved risk prediction should be further evaluated in robust impact studies.

Introduction Despite clinical guidelines recommendations, many relatives of people with psychosis or bipolar disorder do not currently receive the support they need. Online information and support may offer a solution. Methods and analysis This single-blind, parallel, online randomised controlled trial will determine clinical and cost-effectiveness of the Relatives Education And Coping Toolkit (REACT) (including an online resource directory (RD)), compared with RD only, for relatives of people with psychosis or bipolar disorder. Both groups continue to receive treatment as usual. Independent, web-based variable, block, individual randomisation will be used across 666 relatives. Primary outcome is distress at 24 weeks (measured by General Health Questionnaire; GHQ-28) compared between groups using analysis of covariance, adjusting for baseline score. Secondary clinical outcomes are carer well-being and support. Cost-effectiveness analysis will determine cost of a significant unit change (three-point reduction) in the GHQ-28. Costs include offering and supporting the intervention in the REACT arm, relevant healthcare care costs including health professional contacts, medications prescribed and time off (or ability to) work for the relative. Cost utility analysis will be calculated as the marginal cost of changes in quality-adjusted life years, based on EuroQol. We will explore relatives’ beliefs, perceived coping and amount of REACT toolkit use as possible outcome mediators. We have embedded two methodological substudies in the protocol to determine the relative effectiveness of a low-value (£10) versus higher value (£20) incentive, and an unconditional versus conditional incentive, on improving follow-up rates. Ethics and dissemination The trial has ethical approval from Lancaster National Research Ethics Service (NRES)Committee (15/NW/0732) and is overseen by an independent Data Monitoring and Ethics Committee and Trial Steering Committee. Protocol version 1.5 was approved on 9 January 2017. All updates to protocols are uploaded to the National Institute for Health Research (NIHR) Journals Library. A full statistical analysis plan is available at https://figshare.com/account/home#/projects/19975. Publications will be in peer-reviewed journals (open access wherever possible). Requests for access to the data at the end of the study will be reviewed and granted where appropriate by the Trial Management Group. Trial registration number ISRCTN72019945, pre-results.

Background It is unclear whether obesity and type 2 diabetes (T2D), either alone or in combination, induce left ventricular hypertrophy (LVH) independent of hypertension. In the current study, we provide clarity on this issue by rigorously analysing patient left ventricular (LV) structure via clinical indices and via LV geometric patterns (more commonly used in research settings). Importantly, our sample consisted of hypertensive patients that are routinely screened for LVH via echocardiography and normotensive patients that would normally be deemed low risk with no further action required. Methods This cross sectional study comprised a total of 353 Caucasian patients, grouped based on diagnosis of obesity, T2D and hypertension, with normotensive obese patients further separated based on metabolic health. Basic metabolic parameters were collected and LV structure and function were assessed via transthoracic echocardiography. Multivariable logistic and linear regression analyses were used to identify predictors of LVH and diastolic dysfunction. Results Metabolically healthy normotensive obese patients exhibited relatively low risk of LVH. However, normotensive metabolically non-healthy obese, T2D and obese/T2D patients all presented with reduced normal LV geometry that coincided with increased LV concentric remodelling. Furthermore, normotensive patients presenting with both obesity and T2D had a higher incidence of concentric hypertrophy and grade 3 diastolic dysfunction than normotensive patients with either condition alone, indicating an additive effect of obesity and T2D. Alarmingly these alterations were at a comparable prevalence to that observed in hypertensive patients. Interestingly, assessment of LVPWd, a traditional index of LVH, underestimated the presence of LV concentric remodelling. The implications for which were demonstrated by concentric remodelling and concentric hypertrophy strongly associating with grade 1 and 3 diastolic dysfunction respectively, independent of sex, age and BMI. Finally, pulse pressure was identified as a strong predictor of LV remodelling within normotensive patients. Conclusions These findings show that metabolically non-healthy obese, T2D and obese/T2D patients can develop LVH independent of hypertension. Furthermore, that LVPWd may underestimate LV remodelling in these patient groups and that pulse pressure can be used as convenient predictor of hypertrophy status. Electronic supplementary material The online version of this article (doi:10.1186/s12933-017-0504-z) contains supplementary material, which is available to authorized users.

Introduction and Aims Injecting drug use (IDU) is a major risk factor for infective endocarditis (IE). An understanding of the epidemiology of IE and IDU is vital for delivery of health care for this disease. Our aim was to examine the rates of IDU-associated IE (IDU-IE) in a single centre over the last 12 years. Design and Methods Retrospective analysis of two cohorts of consecutive patients (n = 226) admitted with IE from 2002 to 2013. Numbers of cases and rates of IE were compared between two cohorts (2002–2006 and 2009–2013). Rate ratios were calculated using Poisson distributions. Poisson regression was used to examine relationship over time. Results One hundred thirty cases of endocarditis were seen in the first observation period (6 IDU-IE) and 96 in the second observation period (15 IDU-IE). The estimated incidence rate of IE had fallen from 10.1 to 6.45 per 100 000 person-years [rate ratio 0.64, 95% confidence interval (CI) 0.48, 0.85]. In contrast, the estimated incidence rate of IDU-E has risen from 0.48 to 0.79 per 100 000 person-years (rate ratio 1.65, 95% CI 0.59, 4.57). Incidence rate regression suggests that the number of IDU-IE cases is expected to increase by a factor of 1.25 (95%CI 1.09–1.44) for each increase of 1 year. Discussion and Conclusions Over the last decade, there has been a decrease in incidence rate and total number of cases of IE but a rise in rate and number of cases of IDU-IE. This may indicate increasing IDU or increased rates of endocarditis in intravenous drug users in this region. This finding may inform health-care planning in the area. [Tung MKY, Light M, Giri R, Lane S, Appelbe A, Harvey C, Athan E. Evolving epidemiology of injecting drug use-associated infective endocarditis: A regional centre experience. Drug Alcohol Rev 2015;34:412–417]

Staphylococcus aureus bacteraemia (SAB) is an important cause of community and nosocomial sepsis, with a significant mortality rate. Infective endocarditis (IE) is a serious complication, occurring in up to 25 % of cases. Transoesophageal echocardiography (TOE) significantly improves the sensitivity of diagnosis. We compared the sensitivity and specificity of clinical evaluation alone in diagnosing IE. We evaluated all adult patients with SAB at our centre from 1998 to 2006 in order to determine what proportion of clinically unsuspected cases were diagnosed with IE on TOE. IE was defined according to modified Duke criteria. The median age of the patients was 68 years, 77 % were male and the majority of cases did not have a known pre-existing condition. Twenty-one percent were methicillin-resistant Staphylococcus aureus (MRSA). Intravascular device was the most common cause of bacteraemia. TOE was performed in 144 (100 %) of the cases. IE was suspected clinically in 15 % of cases, and the overall prevalence of possible or definite IE on TOE-inclusive Duke criteria was 29 % (n = 41). Following TOE, 22 (15 %) cases were reclassified as either possible or definite endocarditis. TOE detected a vegetation in 37 (90 %) of the 41 cases of IE. Nineteen (46 %) were not suspected clinically by Duke criteria. Sensitivity improved in the presence of pre-existing valve lesion or community acquisition. The overall in-hospital mortality was 10 %. There is a high incidence of endocarditis in SAB and a large percentage of cases are not evident on clinical grounds. TOE evaluation is indicated for all medically suitable adult patients with SAB in order to improve the detection of endocarditis.

Current strategies to target tumors with nanomedicines rely on passive delivery via the enhanced permeability and retention effect, leveraging the disorganized tumor microvasculature to promote macromolecule extravasation and the reduced lymphatic and venous drainage that favor retention. Nonetheless, FDA approvals and clinical use of nanomedicines have lagged, reflecting failure to display superiority over conventional formulations. Here, we have exploited image-guided X-irradiation to augment nanoparticle accumulation in tumors. A single 5 Gy dose of radiation, below that required to significantly delay tumor growth, can markedly enhance delivery of macromolecules and nanoparticles. The radiation effect was independent of endothelial cell integrity, suggesting a primary role for damage to microvascular pericytes and/or interstitial extracellular matrix. Significantly, radiation-guided delivery potentiated the therapeutic effects of PEGylated liposomal doxorubicin on experimental tumors. Applied to patients, these results suggest repurposing image-guided radiotherapy as a tool to guide cancer nanomedicine delivery, enhancing local control for primary tumors and metastatic disease while limiting systemic toxicity.

Transthoracic echocardiography plays a central role in diagnosing a variety of cardiac and pericardial disorders. However its use in identifying extra-cardiac thoracic pathology is less well recognised. We describe an unusual case of intrathoracic intestinal strangulation detected by transthoracic echocardiography. The recognition of bowel loops within the left hemithorax enabled rapid confirmatory computed tomographic imaging and subsequent life-saving surgery. This case demonstrates the utility of bedside echocardiography in the assessment of intrathoracic pathology and emphasises the need for cardiologists to be familiar with the echocardiographic appearance of these disorders.

Aim: To explore the diagnosis, treatment and referral patterns of chronic oro-facial pain patients by generalist primary care dentists (GDPs) in the UK. Methods: A cross-sectional survey was conducted using a non-stratified random sample of 500 GDPs who were selected from the General Dental Council register. A self-complete postal questionnaire with four hypothetical clinical case scenarios describing sub-types of chronic oro-facial pain (COFP) was used to investigate diagnosis, treatment and referral options of GDPs. Results: Two hundred and twenty (44%) GDPs responded. The majority correctly diagnosed temporomandibular disorder (TMD; 88%) and burning mouth syndrome (BMS; 92%). There was more variation in the diagnosis of the other cases related to persistent oro-facial pain. For TMD there was a clear preference for treatment with occlusal splint therapy, and referral to a temporomandibular joint (TMJ) specialist. The BMS scenario showed drug therapy and referral to an oral medicine specialist to be most popular. The chronic oro-facial pain cases had greater variation in management and choice of psychotherapy was related to duration of pain symptoms. Conclusions: The greater variation in responses to scenarios based on patients with chronic oro-facial pain may reflect the difficulty clinicians face in diagnosing and treating this condition. Management appears to follow a biomedical model and most clinicians chose to refer patients for treatment. There are few specialist services to cater for such referrals, indicating a need to train primary care practitioners in management of chronic COFP, along with the establishment of evidence-based guidelines.

The Virtual Kidney uses a web interface and distributed computing to provide experimental scientists and analysts with access to computational simulations and knowledge databases hosted in geographically separated laboratories. Users can explore a variety of complex models without requiring the specific programming environment in which applications have been developed. This initiative exploits high-bandwidth communication networks for collaborative research and for shared access to knowledge resources. The Virtual Kidney has been developed within a specialist community of renal scientists but is transferable to other areas of research requiring interaction between published literature and databases, theoretical models and simulations and the formulation of effective experimental designs. A web-based three-dimensional interface provides access to experimental data, a parameter database and mathematical models. A multi-scale kidney reconstruction includes blood vessels and serially sectioned nephrons. Selection of structures provides links to the database, returning parameter values and extracts from the literature. Models are run locally or remotely with a Grid resource broker managing scheduling, monitoring and visualization of simulation results and application, credential and resource allocation. Simulation results are viewed graphically or as scaled colour gradients on the Virtual Kidney structures, allowing visual and quantitative appreciation of the effects of simulated parameter changes.

ISDR is a 5 year NIHR funded programme of applied research aiming to introduce a step-change in screening for sight threatening diabetic retinopathy utilising personalised risk based intervals. The research programme includes a Randomised Controlled Trial (RCT) to assess the validity of these intervals. The RCT aims to recruit 4400 participants from a pool of 18,000 subjects in Liverpool. Due to the size of the cohort and that much of the data required for the study is collected routinely in multiple NHS organisations, the RCT relies heavily on the integration of multiple databases/data sources and automated systems across multiple networks to reduce the workload on the study team and medical practitioners and to maintain data quality. Data for the RCT is obtained from the following systems: EMIS Web (GP Data), OptoMize (screening software provided by Digital Healthcare), OpenClinica (study database), randomisation system (bespoke system), risk engine (a bespoke application to calculate personalised screening intervals) and a record of those subjects who have consented for their data to be used by the ISDR programme. This paper will present the processes and solutions undertaken to automate, test and validate the import/export of data, create bespoke systems to clean these data and integrate the different data sources. Thereby ensuring the timely transfer and format of data minimise the disruption to patient care while ensuring integrity of the trials data. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

Background Juvenile dermatomyositis (JDM) is a rare autoimmune inflammatory disorder associated with significant morbidity and mortality. International collaboration is necessary to better understand the pathogenesis of the disease, response to treatment and long-term outcome. To aid international collaboration, it is essential to have a core set of data that all researchers and clinicians collect in a standardised way for clinical purposes and for research. This should include demographic details, diagnostic data and measures of disease activity, investigations and treatment. Variables in existing clinical registries have been compared to produce a provisional data set for JDM. We now aim to develop this into a consensus-approved minimum core dataset, tested in a wider setting, with the objective of achieving international agreement. Methods/Design A two-stage bespoke Delphi-process will engage the opinion of a large number of key stakeholders through Email distribution via established international paediatric rheumatology and myositis organisations. This, together with a formalised patient/parent participation process will help inform a consensus meeting of international experts that will utilise a nominal group technique (NGT). The resulting proposed minimal dataset will be tested for feasibility within existing database infrastructures. The developed minimal dataset will be sent to all internationally representative collaborators for final comment. The participants of the expert consensus group will be asked to draw together these comments, ratify and ‘sign off’ the final minimal dataset. Discussion An internationally agreed minimal dataset has the potential to significantly enhance collaboration, allow effective communication between groups, provide a minimal standard of care and enable analysis of the largest possible number of JDM patients to provide a greater understanding of this disease. The final approved minimum core dataset could be rapidly incorporated into national and international collaborative efforts, including existing prospective databases, and be available for use in randomised controlled trials and for treatment/protocol comparisons in cohort studies.

We report a case of Kingella kingae endocarditis in a patient with a history of recent respiratory tract infection and dental extraction. This case is remarkable for embolic and vasculitic phenomena in association with a large valve vegetation and valve perforation. Kingella kingae is an organism known to cause endocarditis, however early major complications are uncommon. Our case of Kingella endocarditis behaved in a virulent fashion necessitating a combined approach of intravenous antibiotic therapy and a valve replacement. It highlights the importance of expedited investigation for endocarditis in patients with Kingella bacteraemia.

Existing packages that allow plate scale reconstruction deal with a host of individual objects, abstracted from geological and geophysical data. The typical approach is to show existing continental outlines and to represent their movement through a few hundred million years of history, providing a reconstruction based on rigid plate motion. This work presents the release of a new reconstruction package, PlatyPlusPlus, designed to provide a new way to carry out tectonic reconstruction. Based on the first version of PlatyPlus, PlatyPlusPlus has been designed with a client-server architecture, allowing reconstructions to present a degree of complexity not reached before. In this paper we will present (1) the architectural complexity of the software; (2) some of the new features; (3) analyse their merits in comparison with classical reconstruction (4) the first results of this new technology.

The GREAT spectrometer is designed to measure the decay properties of reaction products transported to the focal plane of a recoil separator. GREAT comprises a system of silicon, germanium and gas detectors optimised for detecting the arrival of the reaction products and correlating with any subsequent radioactive decay involving the emission of protons, α particles, β particles, γ rays, X-rays or conversion electrons. GREAT can either be employed as a sensitive stand-alone device for decay measurements at the focal plane, or used to provide a selective tag for prompt conversion electrons or γ rays measured with arrays of detectors deployed at the target position. A new concept of triggerless data acquisition (total data readout) has also been developed as part of the GREAT project, which circumvents the problems and limitations of common dead time in conventional data acquisition systems.

Summary: A patent arteriovenous fistula (AVF) in stable renal transplant recipients may be viewed as ‘insurance’ against late graft failure and a return to haemodialysis. A patent AVF may, however, exert significant chronic demands on cardiac output (CO) which may in turn adversely affect the prognosis of patients already at risk of cardiac disease. Doppler echocardiography and anaerobic threshold (AT) assessment were used to measure the CO and the work capacity of nine stable renal transplant recipients > 15 months post transplantation who had patent AVF. Cardiac output fell from 6.9 ± 1.48L/min with the AVF open to 6.0 ± 0.97L/min with the AVF closed (P < 0.002). the AT rose from 14.1 ± 5.67 with the AVF open to 16.5 ± 6.72 with the AVF closed (P < 0.002). the work capacity to reach the AT improved from 68.7 ± 30.8 watts with the AVF open to 84.6 ± 38.0 watts with the AVF closed (P < 0.004). This study suggests that a significant and chronic increase in left ventricular work-load accompanies a patent AVF resulting in a markedly reduced exercise efficiency. A patent AVF is ideal where graft survival is doubtful but, where long-term graft function is expected, the adverse effects of AVF patency, a chronic elevation in CO and reduced exercise capacity make a strong case for considering AVF closure. the prognostic advantage for left ventricular function may outweigh AVF preservation in stable renal transplant recipients.

Applications programming for high-performance computing is notoriously difficult. Al-though parallel programming is intrinsically complex, the principal reason why high-performance computing is difficult is the lack of effective software tools. We believe that the lack of tools in turn is largely due to market forces rather than our inability to design and build such tools. Unfortunately, the poor availability and utilization of parallel tools hurt the entire supercomputing industry and the U.S. high performance computing initiative which is focused on applications. A disproportionate amount of resources is being spent on faster hardware and architectures, while tools are being neglected. This article introduces a taxonomy of tools, analyzes the major factors that contribute to this situation, and suggests ways that the imbalance could be redressed and the likely evolution of tools.

In a recent article [5], Shaw puts forth the argument that a process control paradigm for structuring software is more natural, and hence most appropriate for process control applications. However, we believe that there are other considerations, such as scalability and maintainability, that need to be addressed when choosing a design paradigm. Our experience, and a re-examination of Shaw's models, suggests that object modeling is more appropriate for large scale process control applications.

BackgroundGas chromatography–mass spectrometry (GC-MS) is a technique frequently used in targeted and non-targeted measurements of metabolites. Most existing software tools for processing of raw instrument GC-MS data tightly integrate data processing methods with graphical user interface facilitating interactive data processing. While interactive processing remains critically important in GC-MS applications, high-throughput studies increasingly dictate the need for command line tools, suitable for scripting of high-throughput, customized processing pipelines.ResultsPyMS comprises a library of functions for processing of instrument GC-MS data developed in Python. PyMS currently provides a complete set of GC-MS processing functions, including reading of standard data formats (ANDI- MS/NetCDF and JCAMP-DX), noise smoothing, baseline correction, peak detection, peak deconvolution, peak integration, and peak alignment by dynamic programming. A novel common ion single quantitation algorithm allows automated, accurate quantitation of GC-MS electron impact (EI) fragmentation spectra when a large number of experiments are being analyzed. PyMS implements parallel processing for by-row and by-column data processing tasks based on Message Passing Interface (MPI), allowing processing to scale on multiple CPUs in distributed computing environments. A set of specifically designed experiments was performed in-house and used to comparatively evaluate the performance of PyMS and three widely used software packages for GC-MS data processing (AMDIS, AnalyzerPro, and XCMS).ConclusionsPyMS is a novel software package for the processing of raw GC-MS data, particularly suitable for scripting of customized processing pipelines and for data processing in batch mode. PyMS provides limited graphical capabilities and can be used both for routine data processing and interactive/exploratory data analysis. In real-life GC-MS data processing scenarios PyMS performs as well or better than leading software packages. We demonstrate data processing scenarios simple to implement in PyMS, yet difficult to achieve with many conventional GC-MS data processing software. Automated sample processing and quantitation with PyMS can provide substantial time savings compared to more traditional interactive software systems that tightly integrate data processing with the graphical user interface.

Cobaltism related to athroplasty implants has been anecdotally documented in at least six cases presenting with a combination of neurological, endocrine and cardiac symptoms with improvement in most symptoms after revision. Causality however has not been well established. This report documents the case of a 75 year-old male farmer who presents with possible cobalt cardiomyopathy from severe cobalt poisoning in the setting of arthroprosthetic cobaltism with symptomatic improvement upon revision of the hip.

We encountered and treated two cases of Prevotella bivia in mixed aerobic/anaerobic paronychia within a period of 1 year. Upon reviewing the literature, we found a dearth of both experimental and anecdotal evidence of this specific bacterial infection, with only one case of P. bivia in the hand having been reported [1]. The most prevalent pathogen in acute paronychia is Staphylococcus aureus, which is the causative bacterium in 50 to 80% of cases [2–4]. However, anaerobic infections, especially mixed aerobic/anaerobic infections, are becoming increasingly common [1, 5–7]. Mixed infections, not uncommon in paronychia, provide a fertile environment for the exchange of genetic material, thus increasing both the severity of infection and the chance of developing bacterial resistance [8–10]. Gram-negative anaerobes, which have been proven to induce a pro-inflammatory response, are normally the anaerobes involved in these mixed infections [2, 5, 7, 10, 11]. P. bivia is an anaerobic, non-pigmented, Gram-negative bacillus species which naturally thrives in the human female vaginal tract and occasionally is found in the oral flora [1, 5, 12, 13]. Due to its ability to grow abundantly in the presence of estrogen, P. bivia is traditionally implicated in vaginal tract infections such as endometritis and pelvic inflammatory disease [5, 13]. However, P. bivia has also been found in rare locations such as the nail bed, chest wall, intervertebral discs, and even the hip and knee joints [5, 10, 14–16]. If left untreated, it may lead to more serious conditions, including necrotizing fasciitis, osteomyelitis, or septic arthritis [12, 17–20]. In recent reports, the general consensus for treating paronychial infections has been broad spectrum antibiotics such as oral amoxicillin/clavulanate or oral clindamycin [2, 11, 21]. These choices are intended to provide broad coverage of both aerobic and anaerobic species, regardless of susceptibility testing. The challenging aspect of mixed infections is that susceptibility testing for anaerobes is not well standardized [22]. Also, some P. bivia strains have actually shown resistance to broad spectrum antibiotics such as clindamycin [9]. Thus, confusion still exists over how to treat these infections. The following cases shed some light on how the aerobic pathogen may be a new target for treating these mixed infections.

Background Caries (dental decay) is a disease of the hard tissues of the teeth caused by an imbalance, over time, in the interactions between cariogenic bacteria in dental plaque and fermentable carbohydrates (mainly sugars). The use of fluoride toothpaste is the primary intervention for the prevention of caries. Objectives To determine the relative effectiveness of fluoride toothpastes of different concentrations in preventing dental caries in children and adolescents, and to examine the potentially modifying effects of baseline caries level and supervised toothbrushing. Search methods A search was undertaken on Cochrane Oral Health Group's Trials Register, CENTRAL, MEDLINE and several other databases. Reference lists of articles were also searched. Date of the most recent searches: 8 June 2009. Selection criteria Randomised controlled trials and cluster-randomised controlled trials comparing fluoride toothpaste with placebo or fluoride toothpaste of a different concentration in children up to 16 years of age with a follow-up period of at least 1 year. The primary outcome was caries increment in the permanent or deciduous dentition as measured by the change in decayed, (missing), filled tooth surfaces (D(M)FS/d(m)fs) from baseline. Data collection and analysis Inclusion of studies, data extraction and quality assessment were undertaken independently and in duplicate by two members of the review team. Disagreements were resolved by discussion and consensus or by a third party. The primary effect measure was the prevented fraction (PF), the caries increment of the control group minus the caries increment of the treatment group, expressed as a proportion of the caries increment in the control group. Where it was appropriate to pool data, network meta-analysis, network meta-regression or meta-analysis models were used. Potential sources of heterogeneity were specified a priori and examined through random-effects meta-regression analysis where appropriate. Main results 75 studies were included, of which 71 studies comprising 79 trials contributed data to the network meta-analysis, network meta-regression or meta-analysis. For the 66 studies (74 trials) that contributed to the network meta-analysis of D(M)FS in the mixed or permanent dentition, the caries preventive effect of fluoride toothpaste increased significantly with higher fluoride concentrations (D(M)FS PF compared to placebo was 23% (95% credible interval (CrI) 19% to 27%) for 1000/1055/1100/1250 parts per million (ppm) concentrations rising to 36% (95% CrI 27% to 44%) for toothpastes with a concentration of 2400/2500/2800 ppm), but concentrations of 440/500/550 ppm and below showed no statistically significant effect when compared to placebo. There is some evidence of a dose response relationship in that the PF increased as the fluoride concentration increased from the baseline although this was not always statistically significant. The effect of fluoride toothpaste also increased with baseline level of D(M)FS and supervised brushing, though this did not reach statistical significance. Six studies assessed the effects of fluoride concentrations on the deciduous dentition with equivocal results dependent upon the fluoride concentrations compared and the outcome measure. Compliance with treatment regimen and unwanted effects was assessed in only a minority of studies. When reported, no differential compliance was observed and unwanted effects such as soft tissue damage and tooth staining were minimal. Authors' conclusions This review confirms the benefits of using fluoride toothpaste in preventing caries in children and adolescents when compared to placebo, but only significantly for fluoride concentrations of 1000 ppm and above. The relative caries preventive effects of fluoride toothpastes of different concentrations increase with higher fluoride concentration. The decision of what fluoride levels to use for children under 6 years should be balanced with the risk of fluorosis.