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Background Severe early-onset intrauterine growth restriction is associated with stillbirth, neonatal death and neurodevelopmental impairment. There is no treatment for intrauterine growth restriction with timely delivery being the only management option. Placentas from intrauterine growth restriction pregnancies often show failure to remodel maternal spiral arteries leading to a persistent vasoactive responsiveness. Sildenafil, a phosphodiesterase type 5 inhibitor, potentiates naturally occurring nitrous oxide, encouraging vasodilation of vasoactive vessels. Previous studies in animal models and humans show recovery of placental function and improvement in fetal growth. The STRIDER trial aimed to address whether treatment with sildenafil is beneficial to fetal growth and perinatal and toddler outcomes. Methods The STRIDER trial was a superiority, randomised double-blind placebo-controlled trial that was carried out in 19 fetal medicine units in the United Kingdom. Women with a singleton pregnancy between 22+0 and 29+6 weeks’ gestation, with severe early-onset intrauterine growth restriction, were asked to participate. Women were randomised (1 : 1) to receive either sildenafil 25-mg three times daily or placebo until 31+6 weeks’ gestation or delivery. Women were stratified by site and their gestational age at randomisation (before 26+0 or at 26+0 weeks or later). Severe intrauterine growth restriction was defined as a combination of estimated fetal weight or abdominal circumference below the 10th percentile and absent or reversed end-diastolic blood flow in the umbilical artery on Doppler velocimetry. The primary outcome was the time from randomisation to delivery, measured in days with a 1-week difference deemed to be clinically significant. The phase 2 study followed up all babies alive at discharge to assess for cardiovascular function and neurodevelopment at 2 years of age. Results Between 21 November 2014 and 6 July 2016, a total number of 135 women were recruited to the study, of these 70 were assigned to sildenafil and 65 to the placebo. No difference was found in the median randomisation to delivery interval between sildenafil [17 days (interquartile range 7–24)] and placebo [18 days (8–28), p = 0.23]. Live births [relative risk 1.06, 95% confidence interval 0.84 to 1.33; p = 0.62], fetal deaths (relative risk 0.89, 95% confidence interval 0.54 to 1.45; p = 0.64), neonatal deaths (relative risk 1.33, 95% confidence interval 0.54 to 3.28; p = 0.53), and birthweight [mean difference −14 g (95% confidence interval −100 to 126); p = 0.81] did not differ between the treatment arms and no differences were found for other maternal or perinatal secondary outcomes. Eight serious adverse events were reported during the study (six in the placebo group and two in the sildenafil group); none of these were attributed to sildenafil. Seventy-five babies were discharged alive from the neonatal unit and of those 61 were available for follow-up with 32 treated with sildenafil and 29 with placebo. Of those that did not have a follow-up 1 baby died (placebo) and 3 declined follow-up and 10 were uncontactable. There was no difference in neurodevelopment, or blood pressure for infants treated with sildenafil versus placebo. Infants who received sildenafil had a greater head circumference compared to those who received placebo (median difference 49.25 cm, interquartile range 46.4–50.26 vs. 47.17 cm, 95% confidence interval 44.71 to 48.95). Conclusion Sildenafil did not prolong pregnancy or improve pregnancy outcomes. There was no effect from sildenafil treatment on infant neurodevelopment. Our data show that sildenafil should not be prescribed for fetal growth restriction. Trial registration This trial is registered as ISRCTN39133303. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/62/109) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 18. See the NIHR Funding and Awards website for further award information. Plain language summary Babies that are very small in the womb are at greater risk of a poor outcome to the pregnancy such as stillbirth and learning difficulties in surviving children. Usually, a baby grows small because the placenta, which feeds the baby, is poorly formed. The study wanted to know whether using a medication, which improves the blood supply to the placenta, will give the baby more nutrition and allow better growth. This would allow doctors to keep the baby inside the womb for longer. The study used a medication called sildenafil to improve the blood supply. To be sure if it worked, the study wanted to compare this drug against an identical looking blank tablet (placebo) so women and their healthcare professionals would not know what medication was being given. Women with very small babies and who were pregnant between 22 weeks and 0 days to 29 weeks and 6 days were asked to take part in the study. Treatment was three times a day and continued until delivery or 31 weeks and 6 days. A total of 135 women agreed to take part in the study. Seventy were given sildenafil and 65 were given placebo. A computer decided which medication would be given to which women with a 50 : 50 chance of each. Women were kept in the study until discharge of their baby from hospital. Surviving babies were seen with their mothers at 2 years of age to test for brain injury and problems with thinking, speech and language, or movement (neurodevelopment). The study showed no benefit of sildenafil when compared to placebo in helping the baby grow or in preventing early delivery. In surviving babies there was no benefit for neurodevelopment 2 years after treatment with sildenafil. The findings of our study mean that sildenafil should not be used for the treatment of small babies. Scientific summary Background Severe early-onset intrauterine growth restriction (IUGR) is associated with stillbirth, neonatal death and neurodevelopmental impairment. There is currently no treatment for IUGR with timely delivery being the only management option available. The researchers know from human placentas from IUGR pregnancies that there is often a failure to remodel the maternal spiral arteries within the uterus and myometrium. This inadequate remodelling leads to the persistence of a vasoactive responsiveness within these vessels. Sildenafil, a phosphodiesterase type 5 inhibitor, potentiates naturally occurring nitrous oxide (NO), encouraging vasodilation of vasoactive vessels. Previous studies in animal models and human ex vivo samples have shown recovery of placental function and improvement in fetal growth. Small numbers of clinical trials have also shown an increase in fetal growth or vascular flow (Doppler studies) from maternal use of sildenafil. The STRIDER trial aims to address whether maternal treatment with sildenafil is beneficial to fetal growth and perinatal and toddler outcomes. Objectives The STRIDER United Kingdom (UK) study was designed to answer the following objectives in two phases; phase 1 – recruitment to a randomised controlled trial of sildenafil versus placebo for the treatment of early-onset intrauterine fetal growth restriction, and phase 2 – follow-up at 2 years of age to assess cardiovascular and neurodevelopmental outcomes effect the surviving infants. The primary objective of the phase 1 study was to determine whether sildenafil, compared to placebo therapy, delays the need to deliver a severely growth-restricted fetus by a minimum of 1 week. The secondary objectives were as follows: To investigate impact on fetal growth and fetal well‐being by comparing differential effect on vascular resistance in the uterine arteries, umbilical, fetal middle cerebral artery and fetal ductus venosus and differences in birthweight centiles in infants treated in utero with sildenafil and placebo. To examine, through collaboration with an international consortium, the hypothesis that sildenafil therapy compared to placebo therapy increases the rate of infant survival free of major neurodisability. To report frequency of adverse and serious adverse events (SAEs) associated with sildenafil use. To investigate the impact on maternal cardiovascular parameters by measurements of maternal heart rate and peripheral blood pressure (BP) before and after administration of study medication. To elucidate the precise mechanism and location of action of sildenafil in pregnancy by investigating the effects of sildenafil therapy on omental (representative of the wider maternal systemic vasculature), myometrial (uterine vasculature) and chorionic plate artery (placental vasculature) reactivity. The objective of the phase 2 follow-up study was to examine neurodevelopmental and cardiovascular outcomes at 2 years of age in children born to mothers who received sildenafil compared with placebo during pregnancy. It was hypothesised that: STRIDER UK children whose mothers received sildenafil will have improved neurodevelopmental outcomes at age 2–3 years (corrected) compared with controls exposed to placebo. There will be no difference in BP at 2–3 years (corrected) between STRIDER UK children whose mothers received sildenafil compared with controls exposed to placebo. Methods The STRIDER study was a Phase III clinical trial to quantify the effects of administration of sildenafil on pregnancy outcome in severe early‐onset IUGR. The study was designed as a randomised double-blind, placebo-controlled trial with sildenafil or placebo prescribed orally at a dose of 25 mg three times per day. All participants recruited had a singleton pregnancy between 22+0 weeks’ gestation and 29+6 weeks’ gestation with a diagnosis of IUGR and had agreed to expectant management. For the purpose of the study, IUGR was defined as a fetus with an estimated fetal weight or abdominal circumference below the 10th centile using local charts and absent or reversed end-diastolic flow in the umbilical artery on Doppler velocimetry. All participants were recruited from one of the 19 STRIDER research sites located in the UK. All sites were leading obstetric units within the UK with a high level of fetal medicine and neonatal services provided. Gestational age was confirmed by first trimester ultrasound and in each case, the diagnosis of severe early-onset IUGR was confirmed by a fetal medicine expert having excluded fetal anatomical abnormalities. Following diagnosis and informed consent, a full history, measurements of maternal cardiovascular parameters (BP and pulse rate), fetal biometry and Doppler velocimetry were taken. Maternal venepuncture for angiogenic biomarkers was also performed. All participants had further BP and pulse rate measurements and blood sampling 2 hours after receiving the first dose of the study drug. Subsequently, participants were followed up within 3–4 days and at weekly intervals thereafter, or earlier if clinically indicated. The remainder of clinical care was at the discretion of the local fetal medicine experts and included regular ultrasound assessment of growth and Doppler blood flow and antenatal cardiotocography. Study medication was over encapsulated (Sharp Clinical Services, Crickhowell, UK) to ensure that participants, clinicians and pharmacists were masked to the study drug. Medication was dispensed in 10-day supplies with a new supply being provided weekly to ensure there was no period where medication was missed. Treatment ended at 31+6 weeks’ gestation or delivery, whichever came first. All participants were advised of the potential side effects. Data on pregnancy outcome were collected prospectively from clinical maternity notes and entered onto a secure electronic case report form (eCRF) platform at research sites. Data quality and protocol compliance were monitored regularly by central and on-site monitoring methods. All surviving infants of mothers recruited to the STRIDER study were eligible and invited for follow-up. A study invitation pack was sent to all parents/carers of surviving children. This included an invitation letter, participant information sheet and informed consent form. Participants who did not contact the research team within 2 weeks were contacted by a member of the research team. Assessments took place in a clinical research setting or in the child’s home. Informed written consent was obtained before the assessment began. All assessments were performed by a single senior research psychologist with expertise in developmental assessment techniques. This researcher was blinded to treatment allocation. Assessments included the Cognitive, Language and Motor Subscales of the Bayley Scales of Infant and Toddler Development – III (BSID-III); Hempel’s Neurological Examination for Toddler Age to identify major neurological impairment (cerebral palsy; CP) and subtle deviations from typical neurological and neuromotor function. In addition, a cardiovascular assessment was undertaken, which included brachial systolic BP and diastolic BP and arterial stiffness, assessed as aortic (central) augmentation index (AIx). Where potential participants cancelled or failed to attend follow-up appointments on more than three occasions, they were invited to participate remotely. All such participants received a Follow-up questionnaire pack, which included participant information sheet, consent form and all questionnaires detailed as part of the main study in addition to the Ages and Stages Questionnaire-3 (in place of the BSID-III, neurodevelopmental assessment). The health status classification system – preschool version (HSCS-PS) is a parental (or clinician) proxy measurement of the health status of a child. The overall health status is described as a 10-element vector consisting of one level for each domain. In this study, to facilitate comparisons between groups, a total ‘disability score’ for the overall health state of a child was calculated as the sum of the level codes for the original domains. Therefore, the range of the disability score varied from 10 (no disability on any domain) to 41 (maximum disability on all 10 domains). The child behaviour checklist (CBCL) 1.5–5 was used to assess emotional and behavioural difficulties. Raw scores are normalised into T-scores [mean: 50, standard deviation (SD): 10]. Higher T-scores represent more problematic behaviour. T-scores below 60 are in the normal range, T-scores of 60–63 (84th to 90th percentile) are in the borderline range, and T-scores above 63 (above 90th percentile) are in the clinical range. The T-scores are dichotomised into typical (scores in the normal range) and atypical (scores in the borderline and clinical range). The behaviour rating inventory of executive function – preschool version (BRIEF-P) is a parent questionnaire for early assessment of executive function to assess severity of executive dysfunction in day-to-day situations. Age-based T-scores are computed for each subscale and index, and a score of 65 or higher is considered a clinically significant problem. Results The study recruited 135 participants between 21 November 2014 and 6 July 2016. A number of 75 participants were recruited before 26+0 weeks’ gestation and 60 between 26+0 and 29+6 weeks’ gestation. A total of 70 participants were randomly assigned to receive sildenafil and 65 to placebo. None of the participants withdrew their consent nor were lost to follow-up prior to delivery, therefore, additional ‘per-protocol’ analysis was not performed. Differences at baseline were not clinically important between the sildenafil group and the placebo group. The median gestation at randomisation was 24.4 weeks [interquartile range (IQR) 24.0–27.5]. Two babies were postnatally diagnosed with Down syndrome (one sildenafil and one placebo) and two had confirmed cytomegalovirus infection (one sildenafil and one placebo); all four babies were included in the intention to treat (ITT) analysis. There was no beneficial effect on maternal cardiovascular function from treatment with sildenafil. The follow-up phase was delayed due to the impact of the COVID-19 pandemic on research staff’s availability and access to patients. Out of the 75 babies who were discharged alive from the neonatal unit, 61 babies (81.3%) were included in the follow-up phase. Of those not followed up, 1 baby died (placebo), 3 declined follow-up and 10 were uncontactable. By the nature of follow-up participants were not randomised by treatment leaving 32 mothers who had received sildenafil and 29 had received placebo. There was no difference in the sex, birthweight, gestation at delivery (median 29.2 weeks vs. 29.9 weeks), mode of delivery, or oxygen usage. The physical characteristics of the population available for follow-up showed no difference in height or weight. Head circumference was slightly larger in those treated with sildenafil (49.25, 46.43–50.26) versus placebo (47.18, 44.71–48.95). There was no difference between systolic and diastolic BP between those children treated with sildenafil or placebo. Median values were appropriate for children aged 2 years. The Bayley assessment showed no significant differences in cognitive, language (including receptive and expressive language), or motor (including fine and gross motor) subscales between children of sildenafil-and placebo-treated mothers. Total scores were somewhat lower than expected across all three domains compared with standard population norms (i.e. 100, SD = 15); however, the difference was neither clinically nor statistically significant. There was no difference between the sildenafil and placebo groups for the presence of CP reported by parents. Functional assessment with the BRIEF-P demonstrated no difference in adjusted T-scores between sildenafil and placebo for any of the assessed domains. Likewise, the median total CBCL scores and adjusted T-scores also showed no difference between babies whose mothers were treated with sildenafil versus placebo for any of the assessed domains. The HSCS scores are shown as a total score by domain and as individual components. There was no difference between infants who had received sildenafil to those who had received placebo for any of the domains assessed. It was not possible to record the HEMPEL assessments and as such neurology could not be assessed. Unfortunately, no children were able to tolerate the NICOM (Non-invasive Cardiac Output Monitor)cardiovascular test, leaving BP as the sole assessment of infant cardiovascular status. Conclusions The results of the STRIDER study demonstrated that sildenafil did not result in prolongation of pregnancy, improvements in fetal growth, or perinatal outcome when administered to pregnant women with a severely-growth restricted fetus. These results have subsequently been confirmed in a number of other studies. Our study demonstrated a lack of benefit on any neurodevelopmental, emotional or behavioural assessment from treatment with sildenafil. This study represents the first study to report to the impact of antenatal treatment of women with severe early-onset FGR on their infants’ well-being at 2 years of age. Along with the findings of no benefit on prolongation of pregnancy or perinatal outcome this study it confirms the ineffectiveness of this treatment to improve outcomes in babies with severe early-onset FGR. Further to this lack of benefit there were concerns raised during the Dutch STRIDER trial of increased perinatal mortality in the sildenafil group. Further assessment deemed this excess mortality to be predominantly due to persistent pulmonary hypertension of the neonates (PPHN), which has been proposed to be a pathophysiological mechanism of ‘rebound’ vasoconstriction after cessation of sildenafil. Both the UK and the New Zealand/Australia STRIDER Trials reviewed their data using the same criteria for PPHN as the Dutch STRIDER trial and did not find an increased mortality. The international STRIDER studies are committed to combine the study data in a prospective individual participant data (IPD) meta-analysis to look for any possible long-term effect of sildenafil, particularly on neurodevelopmental and cardiovascular outcome. On current evidence, the researchers do not believe that there is likely to be any beneficial effect on fetal growth, perinatal outcomes or neurodevelopment in this patient group and would advise that further use of sildenafil in this population should be stopped. Prior to any further studies using PDE5 inhibitors to treat FGR being performed, pharmacokinetic and pharmacodynamic experiments specific to pregnancy should be performed to establish an efficacious therapeutic dose. Therefore, the STRIDER study showed no beneficial effect for any perinatal outcome for mother or baby from treatment with 25 mg sildenafil TDS for severe early-onset FGR. The follow-up study confirmed that there was no beneficial effect from maternal treatment with sildenafil on behavioural assessment performed at 2 years of age in the surviving infants. There was also no effect on infant BP from treatment with sildenafil. Trial registration This trial is registered as ISRCTN39133303. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/62/109) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 18. See the NIHR Funding and Awards website for further award information.

Background While biologic therapy, typically with infliximab or Roferon, was used for Behçet syndrome after first-line immunosuppressants, no high-quality randomised trials or predictive biomarkers were available. Objective To undertake a randomised controlled clinical trial of infliximab versus Roferon in Behçet syndrome and identify potential biomarkers for response. Design Pragmatic, standard of care, single-masked, randomised, two-arm, parallel head-to-head trial, with exploratory study on potential role of interferon lambda 3 and interferon lambda 4 single nucleotide polymorphisms and urinary metabolomics biomarkers. Setting Three national UK Behçet syndrome centres and allied clinics. Participants Patients with active Behçet syndrome, fulfilling International Study Group 1990 criteria, with inadequate response to or intolerance of first-line treatment. Intervention Randomisation to infliximab (5 mg/kg intravenous infusion) or Roferon (subcutaneous injection), utilising the UK Behçet syndrome drug pathway protocol. Outcomes Primary outcome: modified Behçet’s disease activity index at 12 weeks of therapy. Secondary outcomes: (1) modified Behçet’s disease activity index score at 24 weeks and (2) significant improvement at 12 and 24 weeks from baseline in vitreous haze and best corrected visual acuity change, oral ulcer severity score, number of genital ulcers, arthritis pain, adverse events, reduction in dose of glucocorticoid, quality-of-life scores and Physician’s Global Assessment of disease activity. Sample size Utilising a Bayesian analysis of covariance model (80% credible interval), initial sample size was 45/arm (Bayesian power 90%). With an anticipated 10% dropout rate, 100 patients were to be recruited. Following recommendations to reduce the overall length of the trial, this was revised down to 80 patients (36 in each arm, allowing for 10% dropout): 80% equi-tailed credibility interval, Bayesian power 88%. In total, 79 patients were eventually recruited for the study. Methods Patients with refractory active Behçet syndrome underwent stratified block randomisation, based on randomly permuted blocks with random block sizes of two and four, allocating treatment to either infliximab or Roferon. Follow up with symptom-directed examination at weeks 12 and 24 according to standard of care. Analysis of the primary end point was undertaken using a Bayesian analysis of covariance approach. Informative priors for the anticipated treatment effect were derived from a cohort of six international experts prior to the start of the study. Results In this first prospective head-to-head randomised controlled clinical trial of two biologic drugs in Behçet syndrome, both infliximab and Roferon were equally effective [mean difference (80% credibility interval) = 0.13 (–0.19 to 0.46)], with a trend for minor benefit in favour of infliximab in terms of tolerability and treatment persistence. Genetic data suggested a potential association between patient outcome and carriage of either rs4803221 or rs7248668 variants in the interferon lambda 3 (interleukin 28B) gene locus in the Roferon-treated arm. However, with the relatively small sample size, statistical significance of the association was lost when correcting for multiple tests. Metabolomic analysis identified potential markers of a metabolic response to treatment with infliximab. Limitations Single-masked design. Slow recruitment with fewer patients recruited in total, limiting the strength of analysis for secondary outcomes and mechanistic studies. Conclusion We report clinical efficacy in both infliximab and Roferon in refractory active Behçet syndrome, together with the potential for a novel metabolomic biomarker identifying response to infliximab. Future work Further work will characterise the appropriate metabolite(s) from existing samples to inform future prospective trials to study this in more detail clinically. The efficacy of Roferon in Behçet syndrome may support future manufacture of this drug. Trial registration This trial is registered as EudraCT Number: 2014-005390-36; ISRCTN49793874. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/205/46) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 17. See the NIHR Funding and Awards website for further award information. Plain language summary Behçet syndrome, a very rare disease in the UK, causes major illness. Yet without high-quality, randomised, controlled trials, choosing treatment is somewhat hit and miss. We set up a randomised controlled clinical trial to study the two most widely used biologic drugs in Behçet syndrome, infliximab and Roferon, head-to-head and searched for potential blood and urinary markers for response. Patients with active Behçet syndrome, in the United Kingdom national Behçet syndrome centres and allied clinics, who had not responded to or could not tolerate first-line treatment were randomised to either infliximab infusions or Roferon injections. The primary outcome was modified Behçet’s disease activity index at 12 weeks of therapy. Secondary outcomes included modified Behçet’s disease activity index at 24 weeks and significant improvements in individual organs, quality of life and Physician’s Global Assessments of activity at 12 and 24 weeks. Initial assessment suggested 100 patients were required for a statistically meaningful outcome but was revised down to 80 following recommendations to shorten the trial. In this first prospective head-to-head randomised controlled clinical trial of two biologics in Behçet syndrome, both drugs worked equally well. There was a non-significant trend for minor benefits of infliximab in terms of tolerability and treatment persistence. Genetic data suggested a potential association between patient outcome and carriage of either rs4803221 or rs7248668 variants in the interferon lambda 3 (interleukin 28B) gene locus in the Roferon arm, but statistical significance was lost with the relatively small sample size. Metabolomics analysis identified potential markers of a metabolic response to infliximab. The limitations of the study included the single-masked design: patients (but not clinicians) were aware of their treatment, and fewer patients were studied than planned. This limited the strength of analysis for secondary outcomes and mechanistic studies. We now plan to characterise the metabolite(s) from existing samples to design future trials to study if there can be effective targeting of treatment in Behçet syndrome. Scientific summary Background Behçet syndrome (BS), a multisystem inflammatory vasculitis, is infrequent in the UK, but it has the potential to cause significant morbidity and mortality. The evidence base supporting biologic treatment, which is used for active disease after failure of standard immunosuppression or when prognosis is poor, is largely based on uncontrolled studies. At the time of the trial, the UK National guideline for therapy of Behçet’s indicated that either the tumour necrosis factor alpha inhibitor infliximab or the interferon alpha drug Roferon could be employed as treatment for patients following failure of first-line treatment with standard immunomodulators. The Bio Behçet’s trial was conceived to exploit the opportunity of the three UK National Centres of Excellence for Behçet’s and associated satellite centres to undertake the first randomised clinical trial to compare infliximab and Roferon as treatment for BS, together with an exploratory analysis of potential genomic and metabolomic biomarkers of therapeutic response. Methods The Bio Behçet’s trial is a pragmatic, standard of care, single-masked, randomised, two-arm, parallel trial comparing the efficacies of infliximab and Roferon employed after failure of first-line therapy in BS. Patients with BS, diagnosed according to the International Study Group 1990 criteria, with active disease who had failed to respond to, or were intolerant of, first-line treatment of BS with topical steroids or small-molecule immunosuppressants were randomised to treatment with either infliximab (Remicade) 5 mg/kg intravenous infusions or Roferon subcutaneous injection (in variable dose), utilising the treatment protocol for each of these drugs in normal clinical care as detailed in the BS drugs pathway for England. The trial utilised a Bayesian design utilising priors informed by a small survey of international experts in BS. Utilising a Bayesian analysis of covariance model, with an 80% credible interval, a sample size of 45 patients per arm was deemed appropriate and gave a Bayesian power of 90%. Allowing for an anticipated 10% dropout rate, 100 patients were planned to be recruited but reduced to 80 following recommendations to reduce the overall length of the trial. Allowing for a 10% dropout rate, estimates of study power based on 72 evaluable patients (36 on each arm) and an 80% credible interval a Bayesian power of 88% was obtained. Between June 2016 and February 2020, 161 patients were screened, and 79 patients were randomised. The intention-to-treat analysis was restricted to 37 subjects allocated to infliximab and 37 to Roferon. Based on previous work with hepatitis C infection and response to interferon therapy and given the role of the innate immune system in the pathogenesis of BS, we examined interferon lambda 3 (IFNL3) and interferon lambda 4 (IFNL4) single nucleotide polymorphisms (SNPs) as biomarkers of response to treatment with alpha interferon and/or infliximab in BS. We also examined the potential for urine metabolomics to act as biomarkers for drug response. The primary outcome was a modified version of the Behçet’s disease activity index (mBDAI) after 3 months of therapy. Secondary outcomes comprised mBDAI score after 6 months of therapy and significant improvement in organ systems after 3 and 6 months (week 12 and week 24 visits) assessed by: reduction in vitreous haze using the SUN consensus group grading scale and best corrected visual acuity change [using the logarithm of the minimal angle of resolution (LogMAR) chart at 4 m] from baseline; change in oral ulcer severity score; change in number of genital ulcers; arthritis pain (10 cm Likert scale); adverse events (AEs) in each group; reduction in dose of prednisolone (or equivalent glucocorticoid) at 3 months (week 12 visit); reduction in dose of prednisolone (or equivalent glucocorticoid) at 6 months (week 24 visit); quality-of-life (QoL) scores at 3 and 6 months (week 12 and week 24 visits) and Physician’s Global Assessment of disease activity at 3 and 6 months (week 12 and week 24 visits). Results Baseline characteristics of the two treatment arms did not differ significantly by sex, ethnic profile, baseline disease characteristics and steroid use. For the primary outcome measure, change in mBDAI between baseline and 3 months (and as a secondary outcome between baseline and 6 months) did not differ significantly between the two treatments [mean difference (80% CrI) = 0.13 (–0.19 to 0.46)]. A significantly higher proportion of patients randomised to Roferon swapped away from their randomised treatment compared to those randomised to infliximab treatment (Roferon 11 of 37, infliximab 3 of 37; p = 0.0104). The clinician’s overall perception of disease activity indicated a reduction in disease activity for most patients between baseline and 3 months and between baseline and 6 months, with a median reduction of −2.0 (infliximab) and −1.0 (Roferon) at 3 months and −3.0 (infliximab) and −2.0 (alpha interferon) at 6 months. There was a small but significant difference in favour of infliximab compared to Roferon at both 3 and 6 months (p

Objectives The Modern Innovative Solutions to Improve Outcomes in Asthma, Breathlessness and Chronic Obstructive Pulmonary Disease (COPD) (MABC) service aimed to enhance disease management for chronic respiratory conditions through specialist multidisciplinary clinics, predominantly in the community. This study assesses the outcomes of these clinics.Design This study used a prospective, longitudinal, participatory action research approach.Setting The study was conducted in primary care practices across Hampshire, UK.Participants Adults aged 16 years and above with poorly controlled asthma or COPD, as well as those with undifferentiated breathlessness not under specialist care, were included.Interventions Participants received care through the multidisciplinary, specialist-led MABC clinics.Primary and secondary outcome measures Primary outcomes included disease activity, quality of life and healthcare utilisation. Secondary outcomes encompassed clinic attendance, diagnostic changes, patient activation, participant and healthcare professional experiences and cost-effectiveness.Results A total of 441 participants from 11 general practitioner practices were recruited. Ninety-six per cent of participants would recommend MABC clinics. MABC assessments led to diagnosis changes for 64 (17%) participants with asthma and COPD and treatment adjustments for 252 participants (57%). Exacerbations decreased significantly from 236 to 30 after attending the clinics (p

Abstract Background Renal colic is the pain experienced by a patient when a renal calculus (kidney stone) causes partial or complete obstruction of part of the renal outflow tract. The standard analgesic regimes for renal colic are often ineffective; in some studies, less than half of patients achieve complete pain relief, and a large proportion of patients require rescue analgesia within 4 h. Current analgesic regimes are also associated with significant side effects including nausea, vomiting, drowsiness and respiratory depression. It has been hypothesised that beta adrenoreceptor agonists, such as salbutamol, may reduce the pain of renal colic. They have been shown to impact a number of factors that target the physiological causes of pain in renal colic (ureteric spasm and increased peristalsis, increased pressure at the renal pelvis and prostaglandin release with inflammation). There is biological plausibility and a body of evidence sufficient to suggest that this novel treatment for the pain of renal colic should be taken to a phase II clinical trial. The aim of this trial is to test whether salbutamol is an efficacious analgesic adjunct when added to the standard analgesic regime for patients presenting to the ED with subsequently confirmed renal colic. Methods A phase II, randomised, placebo-controlled trial will be performed in an acute NHS Trust in the East Midlands. Patients presenting to the emergency department with pain requiring IV analgesia and working diagnosis of renal colic will be randomised to receive standard analgesia ± a single intravenous injection of Salbutamol. Secondary study objectives will explore the feasibility of conducting a larger, phase III trial. Discussion The trial will provide important information about the efficacy of salbutamol as an analgesic adjunct in renal colic. It will also guide the development of a definitive phase III trial to test the cost and clinical effectiveness of salbutamol as an analgesic adjunct in renal colic. Salbutamol benefits from widespread use across the health service for multiple indications, extensive staff familiarity and a good side effect profile; therefore, its potential use for pain relief may have significant benefits for patient care. Trial registration ISRCTN Registry ISRCTN14552440 . Registered on 22 July 2019

Abstract Background Outcomes from studies employing nitisinone 10 mg and 2 mg in alkaptonuria were compared. Patients and methods Sixty‐nine patients in each of the nitisinone (10 mg daily) and controls of suitability of nitisinone in alkaptonuria 2 (SONIA 2), as well as 37 and 23 in nitisinone (2 mg daily) and control cohorts at the National Alkaptonuria Centre (NAC), respectively, were followed up for 4 years. Severity of alkaptonuria (AKU) was assessed by the AKU Severity Score Index (AKUSSI). 24‐h urine homogentisic acid (uHGA24), serum HGA (sHGA), serum tyrosine (sTYR) and serum nitisinone (sNIT) were also analysed at each time point. Dietetic support was used in the NAC, but not in SONIA 2. Safety outcomes were also compared. All statistical analyses were post hoc. Results The slope of the AKUSSI was 0.55, 0.19, 0.30, and 0.06 per month in the control NAC, nitisinone NAC, control SONIA 2, and nitisinone SONIA 2 cohorts, respectively. The intersection of the slopes on the x‐axis was −132, −411, −295, and − 1460 months, respectively. The control and nitisinone slope comparisons were statistically significant both in the NAC (p

Background: Glioblastoma is a high-grade aggressive neoplasm whose outcomes have not changed in decades. In the current treatment pathway, tumour growth continues and remains untreated for several weeks post-diagnosis. Intensified upfront therapy could target otherwise untreated tumour cells and improve the treatment outcome. POBIG will evaluate the safety and feasibility of single-fraction preoperative radiotherapy for newly diagnosed glioblastoma, assessed by the maximum tolerated dose (MTD) and maximum tolerated irradiation volume (MTIV). Methods: POBIG is an open-label, dual-centre phase I dose and volume escalation trial that has received ethical approval. Patients with a new radiological diagnosis of glioblastoma will be screened for eligibility. This is deemed sufficient due to the high accuracy of imaging and to avoid treatment delay. Eligible patients will receive a single fraction of preoperative radiotherapy ranging from 6 to 14 Gy followed by their standard of care treatment comprising maximal safe resection and postoperative chemoradiotherapy (60 Gy/30 fr) with concurrent and adjuvant temozolomide). Preoperative radiotherapy will be directed to the part of the tumour that is highest risk for remaining as postoperative residual disease (hot spot). Part of the tumour will remain unirradiated (cold spot) and sampled separately for diagnostic purposes. Dose/volume escalation will be guided by a Continual Reassessment Method (CRM) model. Translational opportunities will be afforded through comparison of irradiated and unirradiated primary glioblastoma tissue. Discussion: POBIG will help establish the role of radiotherapy in preoperative modalities for glioblastoma. Trial registration: NCT03582514 (clinicaltrials.gov).

Objectives Ochronotic spondyloarthropathy represents one of the main clinical manifestations of alkaptonuria (AKU); however, prospective data and description of the effect of nitisinone treatment are lacking.Methods Patients with AKU aged 25 years or older were randomly assigned to receive either oral nitisinone 10 mg/day (N=69) or no treatment (N=69). Spine radiographs were recorded yearly at baseline, 12, 24, 36 and 48 months, and the images were scored for the presence of intervertebral space narrowing, soft tissue calcifications, vacuum phenomena, osteophytes/hyperostosis and spinal fusion in the cervical, thoracic and lumbosacral segment at each of the time points.Results At baseline, narrowing of the intervertebral spaces, the presence of osteophytes/hyperostosis and calcifications were the three most frequent radiographic features in AKU. The rate of progression of the five main features during the 4 years, ranked from the highest to lowest was as follows: intervertebral spaces narrowing, calcifications, vacuum phenomena, osteophytes/hyperostosis and fusions. The rate of progression did not differ between the treated and untreated groups in any of the five radiographic parameters except for a slower rate of progression (sum of all five features) in the treatment group compared with the control group (0.45 (1.11) nitisinone vs 0.74 (1.11) controls, p=0.049) in the thoracic segment.Conclusion The present study shows a relatively slow but significant worsening of radiographic features in patients with AKU over 4 years. Our results demonstrate a modest beneficial effect of 10 mg/day of nitisinone on the slowly progressing spondylosis in AKU during the relatively limited follow-up time.Trial registration number NCT01916382.

Abstract Background Sodium valproate (VPA) has been associated with a reduced risk of head and neck cancer development. The potential protective mechanism of action is believed to be via inhibition of histone deacetylase and subsequent epigenetic reprogramming. SAVER is a phase IIb open-label, randomised control trial of VPA as a chemopreventive agent in patients with high-risk oral epithelial dysplasia (OED). The aim of the trial is to gather preliminary evidence of the clinical and biological effects of VPA upon OED and assess the feasibility and acceptability of such a trial, with a view to inform a future definitive phase III study. Methods One hundred and ten patients with high-risk OED will be recruited from up to 10 secondary care sites in the UK and randomised into either VPA or observation only for 4 months. Women of childbearing potential will be excluded due to the teratogenic properties of VPA. Tissue and blood samples will be collected prior to randomisation and on the last day of the intervention/observation-only period (end of 4 months). Clinical measurement and additional safety bloods will be taken at multiple time points during the trial. The primary outcome will be a composite, surrogate endpoint of change in lesion size, change in grade of dysplasia and change in LOH profile at 8 key microsatellite regions. Feasibility outcomes will include recruitment targets, compliance with the study protocol and adverse effects. A qualitative sub-study will explore patient experience and perception of the trial. Discussion The current management options for patients with high-risk OED are limited and mostly include surgical resection and clinical surveillance. However, there remains little evidence whether surgery can effectively lead to a notable reduction in the risk of oral cancer development. Similarly, surveillance is associated with concerns regarding delayed diagnosis of OED progressing to malignancy. The SAVER trial provides an opportunity to investigate the effects of a repurposed, inexpensive and well-tolerated medication as a potential chemopreventive strategy for patients with high-risk OED. The clinical and biological findings of SAVER will inform the appropriateness, design and feasibility of a definitive phase III trial. Trial registration The trial is registered with the European Clinical Trials Database ( Eudra-CT 2018-000197-30 ). ( http://www.isrctn.com/ISRCTN12448611 ). The trial was prospectively registered on 24/04/2018.

Objective:. Whether a Blumgart anastomosis (BA) is superior to Cattell-Warren anastomosis (CWA) in terms of postoperative pancreatic fistula (POPF) following pancreatoduodenectomy. Importance:. Complications driven by POPF following pancreatic cancer resection may hinder adjuvant therapy, shortening survival. BA may reduce complications compared to CWA, improving the use of adjuvant therapy and prolonging survival. Methods:. A multicenter double-blind, controlled trial of patients undergoing resection for suspected pancreatic head cancer, randomized during surgery to a BA or CWA, stratified by pancreatic consistency and duct diameter. The primary end point was POPF, and secondary outcome measures were adjuvant therapy use, specified surgical complications, quality of life, and survival from the date of randomization. For a 10% POPF reduction, 416 patients were required, 208 per arm (two-sided α = 0·05; power = 80%). Results:. Z-score at planned interim analysis was 0.474 so recruitment was held to 238 patients; 236 patients were analyzed (112 BA and 124 CWA). No significant differences in POPF were observed between BA and CWA, odds ratio (95% confidence interval [CI]) 1·04 (0.58–1.88), P = 0.887, nor in serious adverse events. Adjuvant therapy was delivered to 98 (62%) of 159 eligible patients with any malignancy; statistically unrelated to arm or postoperative complications. Twelve-month overall survival, hazard ratio (95% CI), did not differ between anastomoses; BA 0.787 (0.713–0.868) and CWA 0.854 (0.792–0.921), P = 0.266, nor for the 58 patients with complications, median (IQR), 0.83 (0.74–0.91) compared to 101 patients without complications 0.82 (0.76–0.89) (P = 0.977). Conclusions:. PANasta represents the most robust analysis of BA versus CWA to date.

BackgroundDespite high levels of psychological distress experienced by many patients with cancer, previous research has identified several barriers to accessing traditional face-to-face psychological support. Web-based psychosocial interventions have emerged as a promising alternative. ObjectiveThis meta-review aimed to synthesize evidence on recruitment challenges and enablers, factors that promote engagement and adherence to web-based intervention content, and factors that promote the efficacy of web-based psychosocial interventions for patients with cancer and cancer survivors. MethodsWe conducted a systematic search of previous reviews that investigated the recruitment, engagement, and efficacy of web-based and app-based psychosocial interventions in adult patients with cancer and cancer survivors. We searched PubMed, CINAHL, PsycINFO, and the Cochrane Library database for relevant literature. The search terms focused on a combination of topics pertaining to neoplasms and telemedicine. Two independent authors conducted abstract screening, full text screening, and data extraction for each identified article. ResultsA total of 20 articles met eligibility criteria. There was inconsistency in the reporting of uptake and engagement data; however, anxiety about technology and perceived time burden were identified as 2 key barriers. Web-based psychosocial oncology interventions demonstrated efficacy in reducing depression and stress but reported weak to mixed findings for distress, anxiety, quality of life, and well-being. Although no factors consistently moderated intervention efficacy, preliminary evidence indicated that multicomponent interventions and greater communication with a health care professional were preferred by participants and were associated with superior effects. ConclusionsSeveral consistently cited barriers to intervention uptake and recruitment have emerged, which we recommend future intervention studies address. Preliminary evidence also supports the superior efficacy of multicomponent interventions and interventions that facilitate communication with a health care professional. However, a greater number of appropriately powered clinical trials, including randomized trials with head-to-head comparisons, are needed to enable more confident conclusions regarding which web-based psychosocial oncology interventions work best and for whom. Trial RegistrationPROSPERO CRD42020202633; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=202633

Abstract Background Stillbirth remains a major concern across the globe and in some high-resource countries, such as the UK; efforts to reduce the rate have achieved only modest reductions. One third of stillborn babies are small for gestational age (SGA), and these pregnancies are also at risk of neonatal adverse outcomes and lifelong health problems, especially when delivered preterm. Current UK clinical guidance advocates regular monitoring and early term delivery of the SGA fetus; however, the most appropriate regimen for surveillance of these babies remains unclear and often leads to increased intervention for a large number of these women. This pilot trial will determine the feasibility of a large-scale trial refining the risk of adverse pregnancy outcome in SGA pregnancies using biomarkers of placental function sFlt-1/PlGF, identifying and intervening in only those deemed at highest risk of stillbirth. Methods PLANES is a randomised controlled feasibility study of women with an SGA fetus that will be conducted at two tertiary care hospitals in the UK. Once identified on ultrasound, women will be randomised into two groups in a 3:1 ratio in favour of sFlt-1/PlGF ratio led management vs standard care. Women with an SGA fetus and a normal sFlt-1/PlGF ratio will have a repeat ultrasound and sFlt-1/PlGF ratio every 2 weeks with planned birth delayed until 40 weeks. In those women with an SGA fetus and an abnormal sFlt-1/PlGF ratio, we will offer birth from 37 weeks or sooner if there are other concerning features on ultrasound. Women assigned to standard care will have an sFlt-1/PlGF ratio taken, but the results will be concealed from the clinical team, and the woman’s pregnancy will be managed as per the local NHS hospital policy. This integrated mixed method study will also involve a health economic analysis and a perspective work package exploring trial feasibility through interviews and questionnaires with participants, their partners, and clinicians. Discussion Our aim is to determine feasibility through the assessment of our ability to recruit and retain participants to the study. Results from this pilot study will inform the design of a future large randomised controlled trial that will be adequately powered for adverse pregnancy outcome. Such a study would provide the evidence needed to guide future management of the SGA fetus. Trial registration ISRCTN58254381 . Registered on 4 July 2019

Abstract Background Complications after major surgery are a significant cause of morbidity and mortality. Neck dissection is one of the most commonly performed major operations in Head and Neck Surgical Oncology. Significant surgical complications occur in approximately 10–20% of all patients, increasing to 40% in patients who have had previous treatment to the area or have multiple co-morbidities and/or polypharmacy. Current evidence suggests that fibrin sealants (FS) may have potential clinical advantages in Head and Neck Surgery through the reduction of complications, volume of wound drainage and retention time of the drains. However, a paucity of high-quality trial-based evidence means that a surgical trial to determine the effectiveness of FS in reducing the rate and severity of complications in patients undergoing lateral neck dissection is warranted. The DEFeND randomised external pilot trial will address critical questions on how well key components of the proposed study design work together as well as the feasibility of a future phase III trial. Methods The study design that is being piloted is that of a two-arm, parallel group, superiority trial with block randomisation in a 1:1 allocation ratio. The interventional arm will constitute the application of FS (Artiss, Baxter Healthcare Ltd.) to the surgical wound following completion of a neck dissection procedure, in addition to standard of care (SOC). The control arm will constitute SOC alone. Eligible patients will include patients who require a lateral neck dissection with a minimum of three cervical nodal levels. Patients who require bilateral neck procedures or undergoing immediate reconstruction with free or regional flaps will be excluded. The outcomes being assessed will be recruitment rate, screened to randomisation rate, fidelity of blinding process using blinding indices, number of missing or incomplete data entries, number of protocol deviations and number of losses to follow-up. Suitability of the outcome measures proposed for the future phase III trial will also be assessed. Discussion The anticipated challenges for this study will be recruitment, complexity of the intervention and adherence to the protocol. The outcomes will inform the design, feasibility and conduct of a future phase III surgical trial. Trial registration First participant randomised: November 06, 2018; UKCRN Portfolio ID: 37896; ISRCTN99181100 .

Objective To identify factors predictive of relapse risk and disability in myelin oligodendrocyte glycoprotein associated disease (MOGAD).Setting Patients were seen by the neuromyelitis optica spectrum disorders (NMOSD) service in Liverpool, UK, a national referral centre for adult patients with MOGAD, NMOSD and related conditions.Participants Patients with MOGAD=76 from England, Northern Ireland and Scotland were included in this cohort study.Results Relapsing disease was observed in 55% (42/76) of cases. Steroid treatment >1 month (OR 0.2, 95% CI 0.05 to 0.80; p=0.022), transverse myelitis (TM) at first attack (OR 0.03, 95% CI 0.004 to 0.23; p=0.001) and male sex (OR 0.16, 95% CI 0.04 to 0.68; p=0.014) were associated with monophasic disease (area under the curve=0.85). Male sex (HR 0.46, 95% CI 0.24 to 0.89; p=0.011) and TM at disease onset (HR 0.42, 95% CI 0.22 to 0.82; p=0.011) were also associated with an increased latency to first relapse. 45% (32/71) of patients became MOG-antibody negative and in relapsing patients negative seroconversion was associated with a lower relapse risk (relative risk 0.11 95% CI 0.05 to 0.26; p

Nitisinone (NTBC) was recently approved to treat alkaptonuria (AKU), but there is no information on its impact on oxidative stress and inflammation, which are observed in AKU. Therefore, serum samples collected during the clinical studies SONIA1 (40 AKU patients) and SONIA2 (138 AKU patients) were tested for Serum Amyloid A (SAA), CRP and IL-8 by ELISA; Advanced Oxidation Protein Products (AOPP) by spectrophotometry; and protein carbonyls by Western blot. Our results show that NTBC had no significant effects on the tested markers except for a slight but statistically significant effect for NTBC, but not for the combination of time and NTBC, on SAA levels in SONIA2 patients. Notably, the majority of SONIA2 patients presented with SAA > 10 mg/L, and 30 patients in the control group (43.5%) and 40 patients (58.0%) in the NTBC-treated group showed persistently elevated SAA > 10 mg/L at each visit during SONIA2. Higher serum SAA correlated with lower quality of life and higher morbidity. Despite no quantitative differences in AOPP, the preliminary analysis of protein carbonyls highlighted patterns that deserve further investigation. Overall, our results suggest that NTBC cannot control the sub-clinical inflammation due to increased SAA observed in AKU, which is also a risk factor for developing secondary amyloidosis.

BackgroundCancer survivors frequently report a range of unmet psychological and supportive care needs; these often continue after treatment has finished and are predictive of psychological distress and poor health-related quality of life. Web-based interventions demonstrate good efficacy in addressing these concerns and are more accessible than face-to-face interventions. Finding My Way (FMW) is a web-based, psycho-educational, and cognitive behavioral therapy intervention for cancer survivors developed in Australia. Previous trials have demonstrated that FMW is acceptable, highly adhered to, and effective in reducing the impact of distress on quality of life while leading to cost savings through health resource use reduction. ObjectiveThis study aims to adapt the Australian FMW website for a UK cancer care context and then undertake a single-blinded, randomized controlled trial of FMW UK against a treatment-as-usual waitlist control. MethodsTo an extent, our trial design replicates the existing Australian randomized controlled trial of FMW. Following a comprehensive adaptation of the web resource, we will recruit 294 participants (147 per study arm) from across clinical sites in North West England and North Wales. Participants will have been diagnosed with cancer of any type in the last 6 months, have received anticancer treatment with curative intent, be aged ≥16 years, be proficient in English, and have access to the internet and an active email address. Participants will be identified and recruited through the National Institute for Health Research clinical research network. Measures of distress, quality of life, and health economic outcomes will be collected using a self-report web-based questionnaire at baseline, midtreatment, posttreatment, and both 3- and 6-month follow-up. Quantitative data will be analyzed using intention-to-treat mixed model repeated measures analysis. Embedded semistructured qualitative interviews will probe engagement with, and experiences of using, FMW UK and suggestions for future improvements. ResultsThe website adaptation work was completed in January 2021. A panel of cancer survivors and health care professionals provided feedback on the test version of FMW UK. Feedback was positive overall, although minor updates were made to website navigation, inclusivity, terminology, and the wording of the Improving Communication and Sexuality and Intimacy content. Recruitment for the clinical trial commenced in April 2021. We aim to report on findings from mid-2023. ConclusionsReplication studies are an important aspect of the scientific process, particularly in psychological and clinical trial literature, especially in different geographical settings. Before replicating the FMW trial in the UK setting, content updating was required. If FMW UK now replicates Australian findings, we will have identified a novel and cost-effective method of psychosocial care delivery for cancer survivors in the United Kingdom. Trial RegistrationInternational Standard Randomized Controlled Trial Number (ISRCTN) 14317248; https://www.isrctn.com/ISRCTN14317248 International Registered Report Identifier (IRRID)DERR1-10.2196/31976

Abstract Obsessive and Compulsive Symptoms (OCS) or Obsessive Compulsive Disorder (OCD) in the context of schizophrenia or related disorders are of clinical importance as these are associated with a range of adverse outcomes. Natural Language Processing (NLP) applied to Electronic Health Records (EHRs) presents an opportunity to create large datasets to facilitate research in this area. This is a challenging endeavour however, because of the wide range of ways in which these symptoms are recorded, and the overlap of terms used to describe OCS with those used to describe other conditions. We developed an NLP algorithm to extract OCS information from a large mental healthcare EHR data resource at the South London and Maudsley NHS Foundation Trust using its Clinical Record Interactive Search (CRIS) facility. We extracted documents from individuals who had received a diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder. These text documents, annotated by human coders, were used for developing and refining the NLP algorithm (600 documents) with an additional set reserved for final validation (300 documents). The developed NLP algorithm utilized a rules-based approach to identify each of symptoms associated with OCS, and then combined them to determine the overall number of instances of OCS. After its implementation, the algorithm was shown to identify OCS with a precision and recall (with 95% confidence intervals) of 0.77 (0.65–0.86) and 0.67 (0.55–0.77) respectively. The development of this application demonstrated the potential to extract complex symptomatic data from mental healthcare EHRs using NLP to facilitate further analyses of these clinical symptoms and their relevance for prognosis and intervention response.

Net fluid balance in the Alberta Basin has been negative over the last 60 years because extensive fluid production has consistently exceeded injection during this period. However, future gigaton-scale carbon sequestration, among other activities, can result in future cumulative fluid injection exceeding extraction (i.e., a positive net fluid balance). The in-situ net fluid balance (i.e., total fluids produced minus total fluids injected) in this basin over the period 1960–2020 shows that a liquids deficit of 4.53 × 109 m3 and a gas deficit of 6.05 × 1012 m3 currently exist. However, fluid deficits are more significant in the upper stratigraphic intervals (located more than 1 km above the Precambrian Basement) than in the stratigraphic intervals located within 1 km of the Precambrian Basement in most geographic regions. This observation indicates that greater sustainable injection capacity for large-scale fluid injection may exist in the upper stratigraphic intervals (located at more than 1 km above the Precambrian Basement), reducing the potential for generating induced seismicity of concern. Additionally, while fluid depletion rates consistently increased over most of the last 60 years in the Alberta Basin, this trend appears to have changed over the past few years. Such analysis of regional net fluid balance and trends may be useful in assessing regional sustainable fluid storage capacity and managing induced seismicity hazards.

Abstract Background Traditional health information systems are generally devised to support clinical data collection at the point of care. However, as the significance of the modern information economy expands in scope and permeates the healthcare domain, there is an increasing urgency for healthcare organisations to offer information systems that address the expectations of clinicians, researchers and the business intelligence community alike. Amongst other emergent requirements, the principal unmet need might be defined as the 3R principle (right data, right place, right time) to address deficiencies in organisational data flow while retaining the strict information governance policies that apply within the UK National Health Service (NHS). Here, we describe our work on creating and deploying a low cost structured and unstructured information retrieval and extraction architecture within King’s College Hospital, the management of governance concerns and the associated use cases and cost saving opportunities that such components present. Results To date, our CogStack architecture has processed over 300 million lines of clinical data, making it available for internal service improvement projects at King’s College London. On generated data designed to simulate real world clinical text, our de-identification algorithm achieved up to 94% precision and up to 96% recall. Conclusion We describe a toolkit which we feel is of huge value to the UK (and beyond) healthcare community. It is the only open source, easily deployable solution designed for the UK healthcare environment, in a landscape populated by expensive proprietary systems. Solutions such as these provide a crucial foundation for the genomic revolution in medicine.

There is a growing need for flexible stretch sensors to monitor real time stress and strain in wearable technology. However, developing stretch sensors with linear responses is difficult due to viscoelastic and strain rate dependent effects. Instead of trying to engineer the perfect linear sensor we take a deep learning approach which can cope with non-linearity and yet still deliver reliable results. We present a general method for calibrating highly hysteretic resistive stretch sensors. We show results for textile and elastomeric stretch sensors however we believe the method is directly applicable to any physical choice of sensor material and fabrication, and easily adaptable to other sensing methods, such as those based on capacitance. Our algorithm does not require any a priori knowledge of the physical attributes or geometry of the sensor to be calibrated, which is a key advantage as stretchable sensors are generally applicable to highly complex geometries with integrated electronics requiring bespoke manufacture. The method involves three-stages. The first stage requires a calibration step in which the strain of the sensor material is measured using a webcam while the electrical response is measured via a set of arduino-based electronics. During this data collection stage, the strain is applied manually by pulling the sensor over a range of strains and strain rates corresponding to the realistic in-use strain and strain rates. The correlated data between electrical resistance and measured strain and strain rate are stored. In the second stage the data is passed to a Long Short Term Memory Neural Network (LSTM) which is trained using part of the data set. The ability of the LSTM to predict the strain state given a stream of unseen electrical resistance data is then assessed and the maximum errors established. In the third stage the sensor is removed from the webcam calibration set-up and embedded in the wearable application where the live stream of electrical resistance is the only measure of strain-this corresponds to the proposed use case. Highly accurate stretch topology mapping is achieved for the three commercially available flexible sensor materials tested.

Aunque actualmente pueda considerarse un tópico, aún es sorprendente cómo, desde los dramáticos eventos del 11 de septiembre de 2001, el “terrorismo” —o, mejor dicho, las respuestas a actos terroristas encerradas bajo el concepto de “lucha contra el terrorismo”— ha llegado a ser virtualmente central a todos los aspectos de la vida moderna. A nivel doméstico, por lo menos en la mayoría de los países occidentales, las medidas contra el terrorismo han pasado a ser una parte aparentemente permanente y completamente normalizada, entre otros aspectos, de los viajes, las actividades bancarias, los eventos deportivos, la seguridad, la vigilancia policial, las políticas, el derecho, las organizaciones benéficas, los medios de comunicación, el entretenimiento, las comunicaciones, la religión y la educación. En un periodo de tiempo relativamente corto, también ha pasado a ser común el hecho de que, en algunas jurisdicciones, los maestros de las escuelas primarias tengan que buscar y denunciar señales de “radicalización” en los niños. De hecho, tantas son las esferas de la vida privada y social que han pasado a estar sujetas a las medidas contra el terrorismo diseñadas a fin de controlar el riesgo de ataques, que algunos han definido este proceso como una gobernanza a través del terrorismo.

Introduction: With the globalization of higher education through online training, opportunities exist for collaboration between institutions to promote ongoing advancement of healthcare professionals in resource-limited countries. The success of these programs is dependent on the ability of the program to meet the educational needs of the student and assist with implementation of the new information into practice. A post graduate residency program for physical therapists was introduced to Kenya to promote the development of the profession of physical therapy. This study sought to explore barriers that affected participation in the residency program, and how participants perceived the residency program fostered the use of new skills in the clinical environment, as well as the limitations they faced in applying the skills gained through the residency program in a clinical setting.Methods and Materials: The participants in this study were in the third and fourth cohorts of the residency program (n = 27). One-on-one interviews were performed with the residents following completion of the program. A qualitative phenomenology research design was used to describe the manner in which the residency was experienced within the context of the environment in which the experience took place. Descriptions and narratives were obtained from the residents to provide a window into their lived experience.Results: Four themes were discovered: (1) The ongoing challenge to balance often conflicting responsibilities: family, work and education, (2) A need to educate patients and colleagues on newly acquired skills to gain acceptance, (3) Success in the program requires reliance on support networks, and (4) Increased confidence gained in delivery of patient care.Discussion: Although the residents faced obstacles for completing the residency and integrating newly acquired knowledge and skills into clinical practice, they were able to formulate strategies to meet these challenges. Understanding the barriers and facilitators that affect participants in international collaborative efforts may ultimately assist residency and other educational programs in designing new models of education, which will advance the physical therapy profession globally.

Background: Deep Phenotyping is the precise and comprehensive analysis of phenotypic features in which the individual components of the phenotype are observed and described. In UK mental health clinical practice, most clinically relevant information is recorded as free text in the Electronic Health Record, and offers a granularity of information beyond what is expressed in most medical knowledge bases. The SNOMED CT nomenclature potentially offers the means to model such information at scale, yet given a sufficiently large body of clinical text collected over many years, it is difficult to identify the language that clinicians favour to express concepts. Methods: By utilising a large corpus of healthcare data, we sought to make use of semantic modelling and clustering techniques to represent the relationship between the clinical vocabulary of internationally recognised SMI symptoms and the preferred language used by clinicians within a care setting. We explore how such models can be used for discovering novel vocabulary relevant to the task of phenotyping Serious Mental Illness (SMI) with only a small amount of prior knowledge. Results: 20 403 terms were derived and curated via a two stage methodology. The list was reduced to 557 putative concepts based on eliminating redundant information content. These were then organised into 9 distinct categories pertaining to different aspects of psychiatric assessment. 235 concepts were found to be expressions of putative clinical significance. Of these, 53 were identified having novel synonymy with existing SNOMED CT concepts. 106 had no mapping to SNOMED CT. Conclusions: We demonstrate a scalable approach to discovering new concepts of SMI symptomatology based on real-world clinical observation. Such approaches may offer the opportunity to consider broader manifestations of SMI symptomatology than is typically assessed via current diagnostic frameworks, and create the potential for enhancing nomenclatures such as SNOMED CT based on real-world expressions.

In this paper, the authors present research into adaptive architectural envelopes that adapt to environmental changes using active materials, as a result of application of biomimetic principles from plants to architecture. Buildings use large amounts of energy in order to maintain their internal comfort, because conventional buildings are designed to provide a static design solution. Most of the current solutions for facades are not designed for optimum adaptation to contextual issues and needs, while biological solutions to adaptation are often complex, multi-functional and highly responsive. We focus on plant adaptations to the environment, as, due to their immobility, they have developed special means of protection against weather changing conditions. Furthermore, recent developments in new technologies are allowing the possibility to transfer these plant adaptation strategies to technical implementation. These technologies include: multi-material 3D printing, advances in materials science and new capabilities in simulation software. Unlike traditional mechanical activation used for dynamic systems in kinetic facades, adaptive architectural envelopes require no complex electronics, sensors, or actuators. The paper proposes a research of the relationship that can be developed between active materials and environmental issues in order to propose innovative and low-tech design strategies to achieve living envelopes according to plant adaptation principles.

IntroductionThere are very few opportunities for long-term, comprehensive postgraduate education in developing countries because of fiscal and human resource constraints. Therefore, physiotherapists have little opportunity following graduation to advance their skills through the improvement of clinical reasoning and treatment planning and application.BackgroundTo address the need for sustainable advanced instruction in physiotherapy within the country, a postgraduate Residency program was initiated in Nairobi, Kenya in 2012. The mission of the program is to graduate advanced orthopedic practitioners who can lead their communities and local profession in the advancement of clinical care and education. Since its inception, six cohorts have been initiated for a total of 90 resident participants. In addition, six program graduates are being trained to continue the Residency program and are serving as teaching assistants for the on campus modules. This training will result in a self-sustaining program by 2020.DiscussionThe manual therapy Residency education model allowed for advancement of the participating physiotherapists professional development utilizing evidence-based practice. This was done without altering the current education system within the country, or accessing expensive equipment.Concluding remarksThe Residency program was developed and established with the cooperation of a local education institution and a non-profit corporation in the United States. This collaboration has facilitated the advancement of orthopedic clinical standards in the country and will, hopefully, one day serve an as a template for future programs.

ABSTRACT Objectives Electronic health records (EHRs) contain rich information for understanding health conditions and their treatment. A large proportion of clinical information in EHRs is stored in narrative free text. This text is currently under-utilised due to privacy concerns, as it is harder to remove patient identifiers from text than from structured data. Automated de-identification of clinical text is now possible using heuristic or machine-learning-based systems. We conducted a review of the literature on patient and public understanding and attitudes towards the use of patients’ medical data for research, particularly seeking views on free text. The aim was to inform and develop a governance framework for the de-identification and use of medical free text for research, and to instigate a wider discussion on the topic. Approach We undertook a systematic search in Web of Science and ScienceDirect with terms such as “public attitudes” and “electronic health records”. 3480 results were sifted by title, abstract and full text. Forty-two articles were retained for review, these reported on studies of patient and public perceptions, understanding and attitudes towards the use of patients’ medical data in research. Results Research participants were positively inclined towards information in records being used in research “for the greater good”. However, no clear patterns by age, ethnicity, education level or SES emerged as to who was more favourable to data use. Participants generally trusted health care professionals and public sector researchers with de-identified medical data, whereas government health agencies and commercial entities were not trusted. No explicitly feared harms associated with data use were articulated. However the general objections appeared to be a dislike of personal data being exploited for commercial gain, and a dislike of personal data being moved around and used without personal knowledge or consent. Notably the use of EHR medical text for research did not emerge as a specific patient/public concern. De-identification was important to participants but text was not identified as a distinct privacy risk. Conclusion This review demonstrates that transparency about data usage, and working “for the greater good” rather than financial gain, appear to be the most important public concerns to be addressed when using patients’ medical data. Governance frameworks for using EHRs must now be enhanced to provide for the use of medical text. This will involve informing both regulators and the public about the current capabilities of automated de-identification, and developing other assurances to safeguard patients’ privacy.

ABSTRACT Objectives Clinical text de-identification is a common requirement of the ‘enclave’ governance model of ethical EHR research. However, there is often little consideration of the engineering task that is required to scale these approaches across the hundreds of millions of clinical documents containing personal identifiers that are resident in the data repositories of a typical NHS Trust. Similarly, natural language processing is an increasingly important field of clinical data science, yet it requires fault tolerant approaches to data processing. This work concerns the development of “turbo-laser” - a distributed document processing architecture based upon the popular ‘battle hardened’ Spring Batch framework - an industry standard for large scale processing tasks. Approach Using Spring Batch, we developed a highly scalable unstructured data processing framework, using the concept of remote partitioning. Remote partitioning allows us to offload processing tasks to any and all computers in a network. With this approach, it is possible to harness the entire compute available of an organisation, whether it be an office of 15 desktop PCs that go unused overnight, or a compute cluster of a thousand processors. This method is especially valuable in the NHS, where the provision of sufficient compute to make large scale analytics possible are often hindered by the lack of available hardware, or difficulties in navigating technical governance policies ill equipped for the demands of modern data science. Results Turbo-laser was developed in consideration of the processing challenges common in the NHS. Currently, four types of ‘job’ are available - De-identification, using the Cognition algorithm, generic GATE output, text extraction from binary files such as MS Office, PDF and scanned documents, and a document re-compiler to deal with EHR legacy issues. Examples of turbo-laser usage include processing 9 million binary documents on modest hardware, within 48 hours. Conclusion Turbo-laser is an enterprise grade processing tool, in keeping with the software engineering pattern of ‘batch processing’ that has been at the forefront of the informatics movement. An open source project, it is hoped that others may contribute and extend its principles, lowering the barrier of large scale data processing throughout the NHS.

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Aunque los medios tienen un impacto significativo sobre las emociones, las actitudes, el comportamiento, y las medidas fisiológicas, ninguna investigación ha examinado un hecho muy usual como lo es el citar renglones cinematográficos en conversaciones cotidianas. La meta principal de la investigación actual fue medir las emociones, razones, y el comportamiento asociado a la citación de los renglones cinematográficos, y para comparar la exactitud predicha con la verdadera exactitud. Se administraron 478 cuestionarios a una muestra de estudiantes universitarios adultos jóvenes. Los resultados mostraron que el100% de los mismos citaron renglones cinematográficos, principalmente provenientes de comedias (70%) tanto para divertirse como para divertir a otros. Refirieron que recordar los renglones les requería poco o ningún esfuerzo y citaron a los mismos textualmente o casi textualmente en aproximadamente 90% de los casos. Quienes recepcionaban los mensajes habían visto la película y quienes los citaban no se mostraron sorprendidos por la respuesta de los receptores. Los resultados fueron interpretados a la luz de la Teoría de Bandura (2002) sobre el Aprendizaje Observacional y sus cuatro componentes.

Bipolar disorder is a significant cause of morbidity and mortality. Although existing treatments are effective, there is often a substantial delay before diagnosis and treatment initiation. We sought to investigate factors associated with the delay before diagnosis of bipolar disorder and the onset of treatment in secondary mental healthcare.Retrospective cohort study using anonymised electronic mental health record data from the South London and Maudsley NHS Foundation Trust (SLaM) Biomedical Research Centre (BRC) Case Register on 1364 adults diagnosed with bipolar disorder between 2007 and 2012. The following predictor variables were analysed in a multivariable Cox regression analysis: age, gender, ethnicity, compulsory admission to hospital under the UK Mental Health Act, marital status and other diagnoses prior to bipolar disorder. The outcomes were time to recorded diagnosis from first presentation to specialist mental health services (the diagnostic delay), and time to the start of appropriate therapy (treatment delay).The median diagnostic delay was 62 days (interquartile range: 17-243) and median treatment delay was 31 days (4-122). Compulsory hospital admission was associated with a significant reduction in both diagnostic delay (hazard ratio 2.58, 95% CI 2.18-3.06) and treatment delay (4.40, 3.63-5.62). Prior diagnoses of other psychiatric disorders were associated with increased diagnostic delay, particularly alcohol (0.48, 0.33-0.41) and substance misuse disorders (0.44, 0.31-0.61). Prior diagnosis of schizophrenia and psychotic depression were associated with reduced treatment delay.Some individuals experience a significant delay in diagnosis and treatment of bipolar disorder after initiation of specialist mental healthcare, particularly those who have prior diagnoses of alcohol and substance misuse disorders. These findings highlight a need for further study on strategies to better identify underlying symptoms and offer appropriate treatment sooner in order to facilitate improved clinical outcomes, such as developing specialist early intervention services to identify and treat people with bipolar disorder.

The sexually dimorphic expression of genes across 26 somatic rat tissues was using Affymetrix RAE-230 genechips. We considered probesets to be sexually dimorphically expressed (SDE) if they were measurably expressed above background in at least one sex, there was at least a two-fold difference in expression (dimorphism) between the sexes, and the differences were statistically significant after correcting for false discovery. 14.5% of expressed probesets were SDE in at least one tissue, with higher expression nearly twice as prevalent in males compared to females. Most were SDE in a single tissue. Surprisingly, nearly half of the probesets that were (SDE) in multiple tissues were oppositely sex biased in different tissues, and most SDE probesets were also expressed without sex bias in other tissues. Two genes were widely SDE: Xist (female-only) and Eif2s3y (male-only). The frequency of SDE probesets varied widely between tissues, and was highest in the duodenum (6.2%), whilst less than 0.05% in over half of the surveyed tissues. The occurrence of SDE probesets was not strongly correlated between tissues. Within individual tissues, however, relational networks of SDE genes were identified. In the liver, networks relating to differential metabolism between the sexes were seen. The estrogen receptor was implicated in differential gene expression in the duodenum. To conclude, sexually dimorphic gene expression is common, but highly tissue-dependent. Sexually dimorphic gene expression may provide insights into mechanisms underlying phenotypic sex differences. Online data are provided as a resource for further analyses (GEO reference GSE63362).

BACKGROUND:High smoking prevalence is a major public health concern for people with mental disorders. Improved monitoring could be facilitated through electronic health record (EHR) databases. We evaluated whether EHR information held in structured fields might be usefully supplemented by open-text information. The prevalence and correlates of EHR-derived current smoking in people with severe mental illness were also investigated. METHODS:All cases had been referred to a secondary mental health service between 2008-2011 and received a diagnosis of schizophreniform or bipolar disorder. The study focused on those aged over 15 years who had received active care from the mental health service for at least a year (N=1,555). The 'CRIS-IE-Smoking' application used General Architecture for Text Engineering (GATE) natural language processing software to extract smoking status information from open-text fields. A combination of CRIS-IE-Smoking with data from structured fields was evaluated for coverage and the prevalence and demographic correlates of current smoking were analysed. RESULTS:Proportions of patients with recorded smoking status increased from 11.6% to 64.0% through supplementing structured fields with CRIS-IE-Smoking data. The prevalence of current smoking was 59.6% in these 995 cases for whom this information was available. After adjustment, younger age (below 65 years), male sex, and non-cohabiting status were associated with current smoking status. CONCLUSIONS:A natural language processing application substantially improved routine EHR data on smoking status above structured fields alone and could thus be helpful in improving monitoring of this lifestyle behaviour. However, limited information on smoking status remained a challenge.

The present studies examined the effects of varying degrees of unfamiliar vocabulary within written discourse on individuals' abilities to use linguistic context for the purposes of translation and comprehension (i.e., lexical inferencing). Prose varied in the number of foreign words introduced into each sentence (e.g., 0 through 7 content words per sentence). Furthermore, Krashen's Input Hypothesis and the Evaluation component of the Involvement Load Hypothesis were tested to determine the degree at which non-comprehensible input hinders the ability of a learner to successfully use linguistic context for translation and comprehension. Results indicated that, as the number of foreign words per sentence, i.e., non-comprehensible input, increased the ability to successfully translate foreign words and create situational models for comprehension begins to decrease especially beyond five unfamiliar words per sentence. This result suggests that there is an optimal level of effectiveness in the use of a linguistic context strategy for learning foreign language vocabulary, but also that there is a limit to the strategy's effectiveness. Implications and applications to the field of foreign language learning are discussed.