He Looks Like My Father.

Social media has kept us connected in many ways but for Black adults, it can be a harrowing reminder of the treatment of Black bodies. This poem was crafted from focus group data on a study of the effects of vicarious racism on the mental health of Black adults in the wake of George Floyd's death in 2020. This poem uses elements of found poetry and incorporates texts from the narrative (re)telling of Black adults' emotional impact of seeing racially and police-involved killings of Black men. Participants expressed feelings of anger, powerlessness, and sadness and how watching these videos has led to avoidance behavior for the sake of coping. In this poem titled "He Looks like My Father," the participant shares a memory of the last video that they watched on social media in 2014 and why they continue to avoid this type of content. It's traumatizing. It is important to fully reflect on these stories as Black Americans struggle with staying informed and preserving their mental health while being inundated by a continuous feedback loop of Black death. The elements of this poem incorporate repetition and the bolded words are verbatim text from the participant transcript. I acknowledge that my positionality being a Black American woman, with a Black father, and having shared the embodied experience of witnessing Black death via social media influenced the meaning of this poem. As we continue to see a focus on naming racism as a public health threat, this form of vicarious racism is salient and should be explored as health professionals dig deeper into understanding the many ways racism permeates the lives of Black, is a daily stressor, and is a social determinant of mental health equity. These are the narratives from muted lips to unveil your eyes. To view the original version of this poem, see the supplemental material section of this article online.

Cost-conscious generation of multiplexed short-read DNA libraries for whole-genome sequencing.

Massively parallel, second-generation short-read DNA sequencing has become an integral tool in biology for genomic studies. Offering highly accurate base-pair resolution at the most competitive price, the technology has become widespread. However, high-throughput generation of multiplexed DNA libraries can be costly and cumbersome. Here, we present a cost-conscious protocol for generating multiplexed short-read DNA libraries using a bead-linked transposome from Illumina. We prepare libraries in high-throughput with small reaction volumes that use 1/50th the amount of transposome compared to Illumina DNA Prep tagmentation protocols. By reducing transposome usage and optimising the protocol to circumvent magnetic bead-based clean-ups between steps, we reduce costs, labour time and DNA input requirements. Developing our own dual index primers further reduced costs and enables up to nine 96-well microplate combinations. This facilitates efficient usage of large-scale sequencing platforms, such as the Illumina NovaSeq 6000, which offers up to three terabases of sequencing per S4 flow cell. The protocol presented substantially reduces the cost per library by approximately 1/20th compared to conventional Illumina methods.

Assessment of Natural Language Processing Methods for Ascertaining the Expanded Disability Status Scale Score From the Electronic Health Records of Patients With Multiple Sclerosis: Algorithm Development and Validation Study.

BACKGROUND: The Expanded Disability Status Scale (EDSS) score is a widely used measure to monitor disability progression in people with multiple sclerosis (MS). However, extracting and deriving the EDSS score from unstructured electronic health records can be time-consuming. OBJECTIVE: We aimed to compare rule-based and deep learning natural language processing algorithms for detecting and predicting the total EDSS score and EDSS functional system subscores from the electronic health records of patients with MS. METHODS: We studied 17,452 electronic health records of 4906 MS patients followed at one of Canada's largest MS clinics between June 2015 and July 2019. We randomly divided the records into training (80%) and test (20%) data sets, and compared the performance characteristics of 3 natural language processing models. First, we applied a rule-based approach, extracting the EDSS score from sentences containing the keyword "EDSS." Next, we trained a convolutional neural network (CNN) model to predict the 19 half-step increments of the EDSS score. Finally, we used a combined rule-based-CNN model. For each approach, we determined the accuracy, precision, recall, and F-score compared with the reference standard, which was manually labeled EDSS scores in the clinic database. RESULTS: Overall, the combined keyword-CNN model demonstrated the best performance, with accuracy, precision, recall, and an F-score of 0.90, 0.83, 0.83, and 0.83 respectively. Respective figures for the rule-based and CNN models individually were 0.57, 0.91, 0.65, and 0.70, and 0.86, 0.70, 0.70, and 0.70. Because of missing data, the model performance for EDSS subscores was lower than that for the total EDSS score. Performance improved when considering notes with known values of the EDSS subscores. CONCLUSIONS: A combined keyword-CNN natural language processing model can extract and accurately predict EDSS scores from patient records. This approach can be automated for efficient information extraction in clinical and research settings.

An assessment of bioinformatics tools for the detection of human endogenous retroviral insertions in short-read genome sequencing data.

There is a growing interest in the study of human endogenous retroviruses (HERVs) given the substantial body of evidence that implicates them in many human diseases. Although their genomic characterization presents numerous technical challenges, next-generation sequencing (NGS) has shown potential to detect HERV insertions and their polymorphisms in humans. Currently, a number of computational tools to detect them in short-read NGS data exist. In order to design optimal analysis pipelines, an independent evaluation of the available tools is required. We evaluated the performance of a set of such tools using a variety of experimental designs and datasets. These included 50 human short-read whole-genome sequencing samples, matching long and short-read sequencing data, and simulated short-read NGS data. Our results highlight a great performance variability of the tools across the datasets and suggest that different tools might be suitable for different study designs. However, specialized tools designed to detect exclusively human endogenous retroviruses consistently outperformed generalist tools that detect a wider range of transposable elements. We suggest that, if sufficient computing resources are available, using multiple HERV detection tools to obtain a consensus set of insertion loci may be ideal. Furthermore, given that the false positive discovery rate of the tools varied between 8% and 55% across tools and datasets, we recommend the wet lab validation of predicted insertions if DNA samples are available.

Intravenous or oral antibiotic treatment in adults and children with cystic fibrosis and Pseudomonas aeruginosa infection: the TORPEDO-CF RCT.

BACKGROUND: People with cystic fibrosis are susceptible to pulmonary infection with Pseudomonas aeruginosa. This may become chronic and lead to increased mortality and morbidity. If treatment is commenced promptly, infection may be eradicated through prolonged antibiotic treatment. OBJECTIVE: To compare the clinical effectiveness, cost-effectiveness and safety of two eradication regimens. DESIGN: This was a Phase IV, multicentre, parallel-group, randomised controlled trial. SETTING: Seventy UK and two Italian cystic fibrosis centres. PARTICIPANTS: Participants were individuals with cystic fibrosis aged > 28 days old who had never had a P. aeruginosa infection or who had been infection free for 1 year. INTERVENTIONS: Fourteen days of intravenous ceftazidime and tobramycin or 3 months of oral ciprofloxacin. Inhaled colistimethate sodium was included in both regimens over 3 months. Consenting patients were randomly allocated to either treatment arm in a 1 : 1 ratio using simple block randomisation with random variable block length. MAIN OUTCOME MEASURES: The primary outcome was eradication of P. aeruginosa at 3 months and remaining free of infection to 15 months. Secondary outcomes included time to reoccurrence, spirometry, anthropometrics, pulmonary exacerbations and hospitalisations. Primary analysis used intention to treat (powered for superiority). Safety analysis included patients who had received at least one dose of any of the study drugs. Cost-effectiveness analysis explored the cost per successful eradication and the cost per quality-adjusted life-year. RESULTS: Between 5 October 2010 and 27 January 2017, 286 patients were randomised: 137 patients to intravenous antibiotics and 149 patients to oral antibiotics. The numbers of participants achieving the primary outcome were 55 out of 125 (44%) in the intravenous group and 68 out of 130 (52%) in the oral group. Participants randomised to the intravenous group were less likely to achieve the primary outcome; although the difference between groups was not statistically significant, the clinically important difference that the trial aimed to detect was not contained within the confidence interval (relative risk 0.84, 95% confidence interval 0.65 to 1.09; p = 0.184). Significantly fewer patients in the intravenous group (40/129, 31%) than in the oral group (61/136, 44.9%) were hospitalised in the 12 months following eradication treatment (relative risk 0.69, 95% confidence interval 0.5 to 0.95; p = 0.02). There were no clinically important differences in other secondary outcomes. There were 32 serious adverse events in 24 participants [intravenous: 10/126 (7.9%); oral: 14/146 (9.6%)]. Oral therapy led to reductions in costs compared with intravenous therapy (-£5938.50, 95% confidence interval -£7190.30 to -£4686.70). Intravenous therapy usually necessitated hospital admission, which accounted for a large part of this cost. LIMITATIONS: Only 15 out of the 286 participants recruited were adults - partly because of the smaller number of adult centres participating in the trial. The possibility that the trial participants may be different from the rest of the cystic fibrosis population and may have had a better clinical status, and so be more likely to agree to the uncertainty of trial participation, cannot be ruled out. CONCLUSIONS: Intravenous antibiotics did not achieve sustained eradication of P. aeruginosa in a greater proportion of cystic fibrosis patients. Although there were fewer hospitalisations in the intravenous group during follow-up, this confers no advantage over the oral therapy group, as intravenous eradication frequently requires hospitalisation. These results do not support the use of intravenous antibiotics to eradicate P. aeruginosa in cystic fibrosis. FUTURE WORK: Future research studies should combine long-term follow-up with regimens to reduce reoccurrence after eradication. TRIAL REGISTRATION: Current Controlled Trials ISRCTN02734162 and EudraCT 2009-012575-10. 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. 25, No. 65. See the NIHR Journals Library website for further project information.

Cystic fibrosis is a genetic condition that affects mucous glands, causing sticky mucus in the lungs and digestive system. People with cystic fibrosis are prone to lung infection with a bacterium called Pseudomonas aeruginosa, which can lead to serious long-term complications and death. It is possible to eradicate P. aeruginosa if antibiotics are started promptly and taken for several months. The Trial of Optimal TheRapy for Pseudomonas EraDicatiOn in Cystic Fibrosis (TORPEDO-CF) was designed to find out if intravenous ceftazidime and tobramycin were better at eradicating P. aeruginosa than oral ciprofloxacin. A total of 286 children, young people and adults with cystic fibrosis joined the study from 70 UK and two Italian centres. Approximately half of the participants received treatment with intravenous antibiotics and half with oral antibiotics. All participants received inhaled colistin for 3 months and were followed up for a minimum of 15 months. We studied whether or not either treatment eradicated P. aeruginosa, and if reinfection happened during follow-up. We also collected data on lung function, other chest infections and hospital admissions, and examined whether or not one treatment was more cost-effective than the other. In total, 15 adults joined TORPEDO-CF, so the study population may not totally match the wider cystic fibrosis population; however, in TORPEDO-CF, we found that intravenous antibiotics did not achieve persistent eradication of P. aeruginosa in a greater proportion of cystic fibrosis patients. We also found that oral antibiotics were more cost-effective than intravenous antibiotics. The intravenous antibiotics group had fewer hospital admissions during follow-up, but, as they were usually admitted for their initial treatment, this was not considered an advantage over the oral antibiotics group. The TORPEDO-CF results do not support the use of intravenous antibiotics to eradicate P. aeruginosa in cystic fibrosis and, when the findings of this trial are applied in routine clinical practice in the NHS, patients will most likely receive oral treatment as an outpatient, avoiding the need for hospital admission.

Intravenous versus oral antibiotics for eradication of Pseudomonas aeruginosa in cystic fibrosis (TORPEDO-CF): a randomised controlled trial.

BACKGROUND: Chronic pulmonary infection with Pseudomonas aeruginosa is one of the most important causes of mortality and morbidity in cystic fibrosis. If antibiotics are commenced promptly, infection can be eradicated. The aim of the trial was to compare the effectiveness and safety of intravenous ceftazidime and tobramycin versus oral ciprofloxacin in the eradication of P aeruginosa. METHODS: We did a multicentre, parallel group, open-label, randomised controlled trial in 72 cystic fibrosis centres (70 in the UK and two in Italy). Eligible participants were older than 28 days with an isolate of P aeruginosa (either the first ever isolate or a new isolate after at least 1 year free of infection). Participants were excluded if the P aeruginosa was resistant to, or they had a contraindication to, one or more of the trial antibiotics; if they were already receiving P aeruginosa suppressive therapy; if they had received any P aeruginosa eradication therapy within the previous 9 months; or if they were pregnant or breastfeeding. We used web-based randomisation to assign patients to 14 days intravenous ceftazidime and tobramycin or 12 weeks oral ciprofloxacin. Both were combined with 12 weeks inhaled colistimethate sodium. Randomisation lists were generated by a statistician, who had no involvement in the trial, using a computer-generated list. Randomisation was stratified by centre and because of the nature of the interventions, blinding was not possible. Our primary outcome was eradication of P aeruginosa at 3 months and remaining free of infection to 15 months. Primary analysis used intention to treat (powered for superiority). Safety analysis included patients who received at least one dose of study drug. TORPEDO-CF was registered on the ISRCTN register, ISRCTN02734162, and EudraCT, 2009-012575-10. FINDINGS: Between Oct 5, 2010, and Jan 27, 2017, 286 patients were randomly assigned to treatment: 137 to intravenous antibiotics and 149 to oral antibiotics. 55 (44%) of 125 participants in the intravenous group and 68 (52%) of 130 participants in the oral group achieved the primary outcome. Participants randomly assigned to the intravenous group were less likely to achieve the primary outcome, although the difference between groups was not statistically significant (relative risk 0·84, 95% CI 0·65-1·09; p=0·18). 11 serious adverse events occurred in ten (8%) of 126 participants in the intravenous antibiotics group and 17 serious adverse events in 12 (8%) of 146 participants in the oral antibiotics group. INTERPRETATION: Compared with oral therapy, intravenous antibiotics did not achieve sustained eradication of P aeruginosa in a greater proportion of patients with cystic fibrosis and was more expensive. Although there were fewer hospitalisations in the intravenous group than the oral group during follow-up, this confers no advantage over oral treatment because intravenous eradication frequently requires hospitalisation. These results do not support the use of intravenous antibiotics to eradicate P aeruginosa in cystic fibrosis. FUNDING: National Institute for Health Research Health Technology Assessment Programme.

Different corticosteroid induction regimens in children and young people with juvenile idiopathic arthritis: the SIRJIA mixed-methods feasibility study.

BACKGROUND: In the UK, juvenile idiopathic arthritis is the most common inflammatory disorder in childhood, affecting 10 : 100,000 children and young people aged < 16 years each year, with a population prevalence of around 1 : 1000. Corticosteroids are commonly used to treat juvenile idiopathic arthritis; however, there is currently a lack of consensus as to which corticosteroid induction regimen should be used with various disease subtypes and severities of juvenile idiopathic arthritis. OBJECTIVE: The main study objective was to determine the feasibility of conducting a randomised controlled trial to compare the different corticosteroid induction regimens in children and young people with juvenile idiopathic arthritis. DESIGN: This was a mixed-methods study. Work packages included a literature review; qualitative interviews with children and young people with juvenile idiopathic arthritis and their families; a questionnaire survey and screening log to establish current UK practice; a consensus meeting with health-care professionals, children and young people with juvenile idiopathic arthritis, and their families to establish the primary outcome; a feasibility study to pilot data capture and to collect data for future sample size calculations; and a final consensus meeting to establish the final protocol. SETTING: The setting was rheumatology clinics across the UK. PARTICIPANTS: Children, young people and their families who attended clinics and health-care professionals took part in this mixed-methods study. INTERVENTIONS: This study observed methods of prescribing corticosteroids across the UK. MAIN OUTCOME MEASURES: The main study outcomes were the acceptability of a future trial for children, young people, their families and health-care professionals, and the feasibility of delivering such a trial. RESULTS: Qualitative interviews identified differences in the views of children, young people and their families on a randomised controlled trial and potential barriers to recruitment. A total of 297 participants were screened from 13 centres in just less than 6 months. In practice, all routes of corticosteroid administration were used, and in all subtypes of juvenile idiopathic arthritis. Intra-articular corticosteroid injection was the most common treatment. The questionnaire surveys showed the varying clinical practice across the UK, but established intra-articular corticosteroids as the treatment control for a future trial. The primary outcome of choice for children, young people, their families and health-care professionals was the Juvenile Arthritis Disease Activity Score, 71-joint count. However, results from the feasibility study showed that, owing to missing blood test data, the clinical Juvenile Arthritis Disease Activity Score should be used. The Juvenile Arthritis Disease Activity Score, 71-joint count, and the clinical Juvenile Arthritis Disease Activity Score are composite disease activity scoring systems for juvenile arthritis. Two final trial protocols were established for a future randomised controlled trial. LIMITATIONS: Fewer clinics were included in this feasibility study than originally planned, limiting the ability to draw strong conclusions about these units to take part in future research. CONCLUSIONS: A definitive randomised controlled trial is likely to be feasible based on the findings from this study; however, important recommendations should be taken into account when planning such a trial. FUTURE WORK: This mixed-methods study has laid down the foundations to develop the evidence base in this area and conducting a randomised control trial to compare different corticosteroid induction regimens in children and young people with juvenile idiopathic arthritis is likely to be feasible. STUDY REGISTRATION: Current Controlled Trials ISRCTN16649996. 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. 36. See the NIHR Journals Library website for further project information.

ABOUT JUVENILE IDIOPATHIC ARTHRITIS: Juvenile idiopathic arthritis refers to a group of conditions that cause inflammation and damage of the joints, starting in children and young people aged < 16 years. Treatments include anti-inflammatory medicines, disease-modifying/biologic medicines and corticosteroids. Young people often require corticosteroids at the start of their treatment, or in a flare with worsening inflammation, to get their juvenile idiopathic arthritis under control. A short course of corticosteroids can help and can be given by injection into the joint, through a drip into a vein, by injection into the muscle or in the form of tablets or liquid to be taken orally. Although they have been used for decades, there is no research to show the best way(s) of giving corticosteroids. STUDY AIMS: The study aimed to (1) agree on what corticosteroid treatments to compare in a treatment trial and the best way to measure changes in juvenile idiopathic arthritis to evaluate a quick-acting treatment and (2) find out if there are enough young people with active juvenile idiopathic arthritis in the UK to be included in such a study. METHODS: Published research on corticosteroids in juvenile idiopathic arthritis was reviewed. Health-care professionals were asked how they choose which corticosteroids to use and which method of administration to use. Interviews were carried out with children and young people and their families to (1) consider the design of a study comparing corticosteroid routes, (2) identify outcomes important to them and (3) determine whether or not they would be willing to take part in a future study. A 3-month feasibility study was carried out to collect details of children and young people with active juvenile idiopathic arthritis before and after corticosteroid treatment to measure improvements in juvenile idiopathic arthritis activity, and to see whether or not a larger study would be possible. FINDINGS: This study showed that corticosteroids are used in different ways across the UK. The views of children, young people and their families must be taken into account when designing a future study. This study calculated the number of young people who would be needed to take part in the future, showing that it would be possible to do a larger study that compared different corticosteroid treatments, which would help everyone to understand the best way to use corticosteroids.

Routine gastric residual volume measurement to guide enteral feeding in mechanically ventilated infants and children: the GASTRIC feasibility study.

BACKGROUND: The routine measurement of gastric residual volume to guide the initiation and delivery of enteral feeding is widespread in paediatric intensive care and neonatal units, but has little underlying evidence to support it. OBJECTIVE: To answer the question: is a trial of no gastric residual volume measurement feasible in UK paediatric intensive care units and neonatal units? DESIGN: A mixed-methods study involving five linked work packages in two parallel arms: neonatal units and paediatric intensive care units. Work package 1: a survey of units to establish current UK practice. Work package 2: qualitative interviews with health-care professionals and caregivers of children admitted to either setting. Work package 3: a modified two-round e-Delphi survey to investigate health-care professionals' opinions on trial design issues and to obtain consensus on outcomes. Work package 4: examination of national databases to determine the potential eligible populations. Work package 5: two consensus meetings of health-care professionals and parents to review the data and agree consensus on outcomes that had not reached consensus in the e-Delphi study. PARTICIPANTS AND SETTING: Parents of children with experience of ventilation and tube feeding in both neonatal units and paediatric intensive care units, and health-care professionals working in neonatal units and paediatric intensive care units. RESULTS: Baseline surveys showed that the practice of gastric residual volume measurement was very common (96% in paediatric intensive care units and 65% in neonatal units). Ninety per cent of parents from both neonatal units and paediatric intensive care units supported a future trial, while highlighting concerns around possible delays in detecting complications. Health-care professionals also indicated that a trial was feasible, with 84% of staff willing to participate in a trial. Concerns expressed by junior nurses about the intervention arm of not measuring gastric residual volumes were addressed by developing a simple flow chart and education package. The trial design survey and e-Delphi study gained consensus on 12 paediatric intensive care unit and nine neonatal unit outcome measures, and identified acceptable inclusion and exclusion criteria. Given the differences in physiology, disease processes, environments, staffing and outcomes of interest, two different trials are required in the two settings. Database analyses subsequently showed that trials were feasible in both settings in terms of patient numbers. Of 16,222 children who met the inclusion criteria in paediatric intensive care units, 12,629 stayed for > 3 days. In neonatal units, 15,375 neonates < 32 weeks of age met the inclusion criteria. Finally, the two consensus meetings demonstrated 'buy-in' from the wider UK neonatal communities and paediatric intensive care units, and enabled us to discuss and vote on the outcomes that did not achieve consensus in the e-Delphi study. CONCLUSIONS AND FUTURE WORK: Two separate UK trials (one in neonatal units and one in paediatric intensive care units) are feasible to conduct, but they cannot be combined as a result of differences in outcome measures and treatment protocols, reflecting the distinctness of the two specialties. TRIAL REGISTRATION: Current Controlled Trials ISRCTN42110505. 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. 23. See the NIHR Journals Library website for further project information.

Nurses looking after babies and children on intensive care units in the UK usually pass a tube and aspirate whatever food or fluid is in the baby's stomach before they give a feed. The idea is to ensure that the stomach is not overdistended with food and prevent the baby vomiting or, worse, aspirating food into the lungs. However, there is little justification for this practice. It is rarely done in many other countries. It may not be pleasant for the child and perhaps is unnecessary. Some experts have suggested that the policy should be evaluated in a randomised controlled trial. This would mean allocating a large number of children at random to either have the stomach aspirated before feeds, or not. Such a trial would be a major undertaking and we are unsure if parents or staff would be willing to allow children to participate. The aim of this study was to see if it is possible to conduct such a large trial in the UK. Two surveys (of 119 units) showed us that regularly measuring the stomach contents when starting and increasing feeds is common practice for both newborn and older children in UK intensive care units. However, in some countries, such as France, this practice is rarely done. We asked 31 parents and 51 health-care professionals about a future study. Overall, parents were supportive of a trial if it was explained to them well by a knowledgeable and caring professional, and if they were approached at the right time. Some concerns were expressed about not picking up complications early if gastric residual volume was not measured. Health-care professionals were also mainly positive about a future trial, but mentioned similar concerns about not picking up complications early and the difficulty of changing a long-standing routine practice. Parents suggested study outcomes that were important to them. These, along with other outcomes, were voted on in a further survey of 106 professionals and at face-to-face meetings involving 41 participants. Overall, our findings suggest that a trial is feasible to perform and acceptable to parents. However, because of differences in both treatments and important outcomes between children's intensive care units and newborn baby intensive care units, two trials would be needed, one in each type of intensive care unit. These two trials will test whether or not the benefits of not measuring gastric residual volume (e.g. improved calorie intake) outweigh the potential harms (e.g. delayed diagnosis of complications).

Opposing effects of bacterial endophytes on biomass allocation of a wild donor and agricultural recipient.

Root endophytes are a promising tool for increasing plant growth, but it is unclear whether they perform consistently across plant hosts. We characterized the blue grama (Bouteloua gracilis) root microbiome using two sequencing methods, quantified the effects of root endophytes in the original host (blue grama) and an agricultural recipient, corn (Zea mays), under drought and well-watered conditions and examined in vitro mechanisms for plant growth promotion. 16S rRNA amplicon sequencing revealed that the blue grama root microbiome was similar across an elevation gradient, with the exception of four genera. Culturing and Sanger sequencing revealed eight unique endophytes belonging to the genera Bacillus, Lysinibacillus and Pseudomonas. All eight endophytes colonized corn roots, but had opposing effects on aboveground and belowground biomass in each plant species: they increased blue grama shoot mass by 45% (19) (mean +/- SE) while decreasing corn shoot mass by 10% (19), and increased corn root:shoot by 44% (7), while decreasing blue grama root:shoot by 17% (7). Furthermore, contrary to our expectations, endophytes had stronger effects on plant growth under well-watered conditions rather than drought conditions. Collectively, these results suggest that ecological features, including host identity, bacterial traits, climate conditions and morphological outcomes, should be carefully considered in the design and implementation of agricultural inocula.

Use of routinely collected data in a UK cohort of publicly funded randomised clinical trials.

Routinely collected data about health in medical records, registries and hospital activity statistics is now routinely collected in an electronic form. The extent to which such sources of data are now being routinely accessed to deliver efficient clinical trials, is unclear. The aim of this study was to ascertain current practice amongst a United Kingdom (UK) cohort of recently funded and ongoing randomised controlled trials (RCTs) in relation to sources and use of routinely collected outcome data. Recently funded and ongoing RCTs were identified for inclusion by searching the National Institute for Health Research journals library. Trials that have a protocol available were assessed for inclusion and those that use or plan to use routinely collected health data (RCHD) for at least one outcome were included. RCHD sources and outcome information were extracted. Of 216 RCTs, 102 (47%) planned to use RCHD. A RCHD source was the sole source of outcome data for at least one outcome in 46 (45%) of those 102 trials. The most frequent sources are Hospital Episode Statistics (HES) and Office for National Statistics (ONS), with the most common outcome data to be extracted being on mortality, hospital admission, and health service resource use. Our study has found that around half of publicly funded trials in a UK cohort (NIHR HTA funded trials that had a protocol available) plan to collect outcome data from routinely collected data sources.

Adalimumab in combination with methotrexate for refractory uveitis associated with juvenile idiopathic arthritis: a RCT.

BACKGROUND: Children with juvenile idiopathic arthritis (JIA) are at risk of uveitis. The role of adalimumab (Humira®; AbbVie Inc., Ludwigshafen, Germany) in the management of uveitis in children needs to be determined. OBJECTIVE: To compare the efficacy, safety and cost-effectiveness of adalimumab in combination with methotrexate (MTX) versus placebo with MTX alone, with regard to controlling disease activity in refractory uveitis associated with JIA. DESIGN: This was a randomised (applying a ratio of 2 : 1 in favour of adalimumab), double-blind, placebo-controlled, multicentre parallel-group trial with an integrated economic evaluation. A central web-based system used computer-generated tables to allocate treatments. A cost-utility analysis based on visual acuity was conducted and a 10-year extrapolation by Markov modelling was also carried out. SETTING: The setting was tertiary care centres throughout the UK. PARTICIPANTS: Patients aged 2-18 years inclusive, with persistently active JIA-associated uveitis (despite optimised MTX treatment for at least 12 weeks). INTERVENTIONS: All participants received a stable dose of MTX and either adalimumab (20 mg/0.8 ml for patients weighing < 30 kg or 40 mg/0.8 ml for patients weighing ≥ 30 kg by subcutaneous injection every 2 weeks based on body weight) or a placebo (0.8 ml as appropriate according to body weight by subcutaneous injection every 2 weeks) for up to 18 months. A follow-up appointment was arranged at 6 months. MAIN OUTCOME MEASURES: Primary outcome - time to treatment failure [multicomponent score as defined by set criteria based on the Standardisation of Uveitis Nomenclature (SUN) criteria]. Economic outcome - incremental cost per quality-adjusted life-year (QALY) gained from the perspective of the NHS in England and Personal Social Services providers. Full details of secondary outcomes are provided in the study protocol. RESULTS: A total of 90 participants were randomised (adalimumab, n = 60; placebo, n = 30). There were 14 (23%) treatment failures in the adalimumab group and 17 (57%) in the placebo group. The analysis of the data from the double-blind phase of the trial showed that the hazard risk (HR) of treatment failure was significantly reduced, by 75%, for participants in the adalimumab group (HR 0.25, 95% confidence interval 0.12 to 0.51; p < 0.0001 from log-rank test). The cost-effectiveness of adalimumab plus MTX was £129,025 per QALY gained. Adalimumab-treated participants had a much higher incidence of adverse and serious adverse events. CONCLUSIONS: Adalimumab in combination with MTX is safe and effective in the management of JIA-associated uveitis. However, the likelihood of cost-effectiveness is < 1% at the £30,000-per-QALY threshold. FUTURE WORK: A clinical trial is required to define the most effective time to stop therapy. Prognostic biomarkers of early and complete response should also be identified. TRIAL REGISTRATION: Current Controlled Trials ISRCTN10065623 and European Clinical Trials Database number 2010-021141-41. 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. 23, No. 15. See the NIHR Journals Library website for further project information. This trial was also funded by Arthritis Research UK (grant reference number 19612). Two strengths of adalimumab (20 mg/0.8 ml and 40 mg/0.8 ml) and a matching placebo were manufactured by AbbVie Inc. (the Marketing Authorisation holder) and supplied in bulk to the contracted distributor (Sharp Clinical Services, Crickhowell, UK) for distribution to trial centres.

Juvenile idiopathic arthritis (JIA) is one of the most common rheumatic diseases in children and young people, who are at risk of developing inflammation in an area of the eye called the uvea (called uveitis). The purpose of the study was to look at how effective the use of adalimumab in combination with methotrexate (MTX) is compared with using MTX alone to treat JIA-associated uveitis. A total of 90 children (aged 2­18 years) taking MTX with JIA-associated uveitis took part in the study. If the inflammation in a patient's eye or eyes was not getting better during the 18 months, the patient was told to stop taking the study drug. It was found that those patients who were taking placebo and MTX in the trial stopped taking the study drug sooner than those who were taking adalimumab and MTX. This means that adalimumab and MTX was better at treating uveitis than MTX alone. It was found that more patients taking adalimumab and MTX together either reduced or stopped taking topical steroids than the patients taking placebo and MTX. It was found that patients taking adalimumab and MTX together experienced more side effects than those taking placebo with MTX. However, these were expected based on what was already known about adalimumab's side effects. An economic evaluation was conducted to estimate whether or not adalimumab would represent value for money for the NHS for this condition. This included long-term effects based on information about patients' clarity of vision. The analysis showed that adalimumab may not be cost-effective, as the additional costs of treatment may not be justified by the benefits. The final results show that although adalimumab used in combination with MTX does help to treat patients with JIA and uveitis, it may not represent good value for the NHS.

Cost-Effectiveness Analysis of Adalimumab for the Treatment of Uveitis Associated with Juvenile Idiopathic Arthritis.

PURPOSE: To investigate the cost effectiveness of adalimumab in combination with methotrexate, compared with methotrexate alone, for the management of uveitis associated with juvenile idiopathic arthritis (JIA). DESIGN: A cost-utility analysis based on a clinical trial and decision analytic model. PARTICIPANTS: Children and adolescents 2 to 18 years of age with persistently active uveitis associated with JIA, despite optimized methotrexate treatment for at least 12 weeks. METHODS: The SYCAMORE (Randomised controlled trial of the clinical effectiveness, SafetY and Cost effectiveness of Adalimumab in combination with MethOtRExate for the treatment of juvenile idiopathic arthritis associated uveitis) trial (identifier, ISRCTN10065623) of methotrexate (up to 25 mg weekly) with or without fortnightly administered adalimumab (20 or 40 mg, according to body weight) provided data on resource use (based on patient self-report and electronic records) and health utilities (from the Health Utilities Index questionnaire). Surgical event rates and long-term outcomes were based on data from a 10-year longitudinal cohort. A Markov model was used to extrapolate the effects of treatment based on visual impairment. MAIN OUTCOME MEASURES: Medical costs to the National Health Service in the United Kingdom, utility of defined health states, quality-adjusted life-years (QALYs), and incremental cost per QALY. RESULTS: Adalimumab in combination with methotrexate resulted in additional costs of £39 316, with a 0.30 QALY gain compared with methotrexate alone, resulting in an incremental cost-effectiveness ratio of £129 025 per QALY gained. The probability of cost effectiveness at a threshold of £30 000 per QALY was less than 1%. Based on a threshold analysis, a price reduction of 84% would be necessary for adalimumab to be cost effective. CONCLUSIONS: Adalimumab is clinically effective in uveitis associated with JIA; however, its cost effectiveness is not demonstrated compared with methotrexate alone in the United Kingdom setting.

Beyond fall risk assessment: A case-control study in an Urban Medical Center.

AIMS AND OBJECTIVES: To examine the characteristics of patients that fell and compare them with patients that did not fall and to seek differences between the two groups that might help better predict falls in future patients. BACKGROUND: It has been estimated that between 700,000 and one million inpatient falls occur yearly in hospitals in the United States, which results in an increase in healthcare costs of over $19 billion dollars per year. DESIGN: This was a case-control study employing a retrospective analysis of inpatient electronic health records. It includes records from 160 patients who experienced a fall after the implementation of the Johns Hopkins Fall Risk Assessment Tool, and 160 records of patient with similar fall risk scores that did not fall. METHODS: All fall and nonfall patient data for the database were obtained by one research team member, while systematic random selection of nonfall patient records was performed by three research team members as described below. Each patient was assigned a unique study code number which was entered into the research database. The final sample size was 302 patients. RESULTS: Patients who did not receive lorazepam within 12 hr of the fall risk assessment were less likely to fall than patients who did receive lorazepam. A statistical relationship was also found between toileting at the time of the fall and age. CONCLUSIONS: Better stratification of patient populations combined with astute nursing awareness may result in a further reduction in falls. RELEVANCE TO CLINICAL PRACTICE: The results indicate that the nursing assessment with respect to falls is critical to identifying fall-prone individuals who may score as a low-to-moderate fall risk. In addition, the administration of lorazepam should cue the nurse that fall precautions be implemented regardless of scored risk.

Adalimumab plus Methotrexate for Uveitis in Juvenile Idiopathic Arthritis.

BACKGROUND: Adalimumab, a fully human anti-tumor necrosis factor α monoclonal antibody, is effective in the treatment of juvenile idiopathic arthritis (JIA). We tested the efficacy of adalimumab in the treatment of JIA-associated uveitis. METHODS: In this multicenter, double-blind, randomized, placebo-controlled trial, we assessed the efficacy and safety of adalimumab in children and adolescents 2 years of age or older who had active JIA-associated uveitis. Patients who were taking a stable dose of methotrexate were randomly assigned in a 2:1 ratio to receive either adalimumab (at a dose of 20 mg or 40 mg, according to body weight) or placebo, administered subcutaneously every 2 weeks. Patients continued the trial regimen until treatment failure or until 18 months had elapsed. They were followed for up to 2 years after randomization. The primary end point was the time to treatment failure, defined according to a multicomponent intraocular inflammation score that was based on the Standardization of Uveitis Nomenclature criteria. RESULTS: The prespecified stopping criteria were met after the enrollment of 90 of 114 patients. We observed 16 treatment failures in 60 patients (27%) in the adalimumab group versus 18 treatment failures in 30 patients (60%) in the placebo group (hazard ratio, 0.25; 95% confidence interval [CI], 0.12 to 0.49; P<0.0001 [the prespecified stopping boundary]). Adverse events were reported more frequently in patients receiving adalimumab than in those receiving placebo (10.07 events per patient-year [95% CI, 9.26 to 10.89] vs. 6.51 events per patient-year [95% CI, 5.26 to 7.77]), as were serious adverse events (0.29 events per patient-year [95% CI, 0.15 to 0.43] vs. 0.19 events per patient-year [95% CI, 0.00 to 0.40]). CONCLUSIONS: Adalimumab therapy controlled inflammation and was associated with a lower rate of treatment failure than placebo among children and adolescents with active JIA-associated uveitis who were taking a stable dose of methotrexate. Patients who received adalimumab had a much higher incidence of adverse events and serious adverse events than those who received placebo. (Funded by the NIHR Health Technology Assessment Programme and Arthritis Research UK; SYCAMORE EudraCT number, 2010-021141-41 .).

Life Space Assessment in Spinal Cord Injury.

Objectives: To examine the Life Space Assessment (LSA) in persons with spinal cord injury (SCI), exploring its psychometric properties, differences between persons with cervical versus thoracolumbar injuries, and cutoff score differentiating a restricted from an unrestricted life space. Method: We conducted a test-retest reliability study in a community setting involving 50 persons with SCI (25 injured above C7, 25 injured below T1). Data were collected in 2 phone interviews approximately 9 days apart using the LSA. Results: Mean LSA scores were 66 ± 25 (n = 50): 62 ± 23 for the cervical group, and 70 ± 25 for the thoracolumbar group. Scores were not significantly different between phone interviews [t(49) = 0.379, p = .706] or between groups [t(48) = -1.214, p = .231]. Test-retest reliability intraclass correlation coefficient (ICC) was 0.876 (95% CI, 0.792-0.928). Spearman's rho correlations between the LSA and Reintegration to Normal Living Index total and subscores ranged from .509 to .538 (p < .001). LSA scores were normally distributed. The minimum detectable change was approximately 23 points. A cutoff score of 78.5 (sensitivity 76.9%, specificity 81.1%) differentiated between persons with a restricted from an unrestricted life space if equipment and personal assistance were not needed for mobility. If equipment was needed, the cutoff score was found to be 49 (sensitivity of 90%, specificity of 90%). Conclusions: The LSA is a reliable and valid measure of life space in persons with SCI and can be used to identify persons with a restricted life space who may be at increased risk of mobility disability.

Investigation of next-generation sequencing technologies as a diagnostic tool for amyotrophic lateral sclerosis.

The future of genetic diagnostics will see a move toward massively parallel next-generation sequencing of a patient's DNA. Amyotrophic lateral sclerosis (ALS) is one of the diseases that would benefit from this prospect. Exploring this idea, we designed a screening panel to sequence 25 ALS-linked genes and examined samples from 95 patients with both familial and sporadic ALS. Forty-three rare polymorphisms were detected in this cohort. A third of these have already been reported with respect to ALS, leaving 28 novel variants all open for further investigation. This study highlights the potential benefits of next-generation sequencing as a reliable, cost and time efficient, diagnostic, and research tool for ALS.

Effects of a culturally informed intervention on abused, suicidal African American women.

This study examined (a) the relative efficacy of a culturally sensitive empowerment group intervention (Nia) aimed at increasing 3 protective factors-self-esteem, hopefulness, and effectiveness of obtaining resources-versus treatment as usual (TAU) for low-income, abused African American women who recently had attempted suicide and (b) the impact of participants' readiness to change with regard to their abusive relationship and suicidal behavior on their levels of each protective factor in the 2 conditions. The sample included 89 African American women who reported intimate partner violence (IPV) exposure and a recent suicide attempt. Multivariate general linear modeling revealed that those in Nia showed greater improvements in self-esteem, but not in hopefulness or effectiveness of obtaining resources. However, significant interactions emerged in which participants who were "less ready to change" (i.e., earlier in the stages of change process) their IPV situation and suicidal behavior endorsed greater levels of hopefulness and perceived effectiveness of obtaining resources, respectively, following Nia. Findings suggest that abused, suicidal African American women who are more reluctant initially to changing their abusive situation and suicidal behavior may benefit from even a brief, culturally informed intervention.

Health utility decreases with increasing clinical stage in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease typically causing death within three years. Understanding the impact of disease on patients using health utility at different stages of ALS would allow meaningful cost-benefit analysis of new potential therapies. A common health-related quality of life measurement, developed and validated for the UK, is the EQ-5D. Using clinical trial data from the LiCALS study, we calculated health utility using the EQ-5D for each King's ALS clinical stage from 214 patients. We analysed whether health utility, and other health-related measures, significantly changed between each of the clinical stages. Results showed that mean health utility decreased by 0.487 (the scale runs from 1 to - 0.594) between clinical stages 2A and 4. Emotional states, measured using the Hospital Anxiety and Depression Scale (HADS), showed worsening depression and anxiety scores as ALS progressed. Age of onset, disease onset, gender and treatment group were not predictors of EQ-5D, depression or anxiety. In conclusion, increasing severity of King's ALS Clinical Stage is associated with a progressive decrease in EQ-5D health utility. This is useful for cost-benefit analysis of new therapies and validates this ALS clinical staging system.

A randomised controlled trial of the clinical effectiveness, safety and cost-effectiveness of adalimumab in combination with methotrexate for the treatment of juvenile idiopathic arthritis associated uveitis (SYCAMORE Trial).

BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. Children with JIA are at risk of inflammation of the uvea in the eye (uveitis). Overall, 20% to 25% of paediatric uveitis is associated with JIA. Major risk factors for development of uveitis in JIA are oligoarticular pattern of arthritis, an age at onset of arthritis of less than seven years of age, and antinuclear antibody positivity. In the initial stages of mild to moderate inflammation the uveitis is asymptomatic. This has led to current practice of screening all children with JIA for uveitis. Approximately 12% to 38% of patients with JIA develop uveitis in seven years following onset of arthritis. In 30% to 50% of children with JIA-associated uveitis structural complications are present at diagnosis. Furthermore about 50% to 75% of those with severe uveitis will eventually develop visual impairment secondary to ocular complications such as cataract and glaucoma. Defining the severity of inflammation and structural complications in uveitis patients is now possible following Standardised Uveitis Nomenclature (SUN) guidelines, and modified to incorporate the consensus of end point and outcome criteria into the design of randomised trials. Despite current screening and therapeutic options (pre-biologics) 10% to 15% of children with JIA-associated uveitis may develop bilateral visual impairment and certified legally blind. To date, there remains no controlled trial evidence of benefits of biologic therapy. METHODS/DESIGN: This study will randomise 154 patients aged 2 to 18 years with active JIA-associated uveitis (despite methotrexate (MTX) treatment for at least 12 weeks). All participants will be treated for 18 months, with follow up of 3 years from randomisation (continuing on MTX throughout). All participants will receive a stable dose of MTX and in addition either adalimumab (20 mg/0.8 ml for patients<30 kg or 40 mg/0.8 ml for patients weighing 30 kg or more, subcutaneous (s/c) injection every 2 weeks based on body weight), or placebo (0.8 ml as appropriate according to body weight) s/c injection every 2 weeks. DISCUSSION: This is the first randomised controlled trial that will assess the clinical effectiveness, safety and cost effectiveness of adalimumab in combination with methotrexate for the treatment of juvenile idiopathic arthritis associated uveitis. TRIAL REGISTRATION: ISRCTN10065623.

The use of systematic reviews in the planning, design and conduct of randomised trials: a retrospective cohort of NIHR HTA funded trials.

BACKGROUND: A systematic review, with or without a meta-analysis, should be undertaken to determine if the research question of interest has already been answered before a new trial begins. There has been limited research on how systematic reviews are used within the design of new trials, the aims of this study were to investigate how systematic reviews of earlier trials are used in the planning and design of new randomised trials. METHODS: Documentation from the application process for all randomised trials funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) between 2006 and 2008 were obtained. This included the: commissioning brief (if appropriate), outline application, minutes of the Board meeting in which the outline application was discussed, full application, detailed project description, referee comments, investigator response to referee comments, Board minutes on the full application and the trial protocol. Data were extracted on references to systematic reviews and how any such reviews had been used in the planning and design of the trial. RESULTS: 50 randomised trials were funded by NIHR HTA during this period and documentation was available for 48 of these. The cohort was predominately individually randomised parallel trials aiming to detect superiority between two treatments for a single primary outcome. 37 trials (77.1%) referenced a systematic review within the application and 20 of these (i.e. 41.7% of the total) used information contained in the systematic review in the design or planning of the new trial. The main areas in which systematic reviews were used were in the selection or definition of an outcome to be measured in the trial (7 of 37, 18.9%), the sample size calculation (7, 18.9%), the duration of follow up (8, 21.6%) and the approach to describing adverse events (9, 24.3%). Boards did not comment on the presence/absence or use of systematic reviews in any application. CONCLUSIONS: Systematic reviews were referenced in most funded applications but just over half of these used the review to inform the design. There is an expectation from funders that applicants will use a systematic review to justify the need for a new trial but no expectation regarding further use of a systematic review to aid planning and design of the trial. Guidelines for applicants and funders should be developed to promote the use of systematic reviews in the design and planning of randomised trials, to optimise delivery of new studies informed by the most up-to-date evidence base and to minimise waste in research.