Assessing micro- vs macro-costing approaches for treating appendicitis in children with appendicectomy or non-operatively

OBJECTIVES: We conducted a health economic sub-study within a feasibility RCT comparing a non-operative treatment pathway as an alternative to appendicectomy for the treatment of uncomplicated acute appendicitis in children. The objectives were to understand and assess data collection tools and methods and to determine indicative costs and benefits assessing the feasibility of conducting a full economic evaluation within the definitive trial. METHODS: We compared different methods of estimating treatment costs including micro-costing, hospital administrative data (PLICS) and health system (NHS) reference costs. We compared two different HRQoL instruments (CHU-9D and EQ-5D-5L) in terms of data completeness and sensitivity to change over time, including potential ceiling effects. We also explored how the timing of data collection and duration of the analysis could affect QALYs (Quality Adjusted Life Years) and the results of the cost-utility analysis (CUA) within the future RCT. RESULTS: Using a micro-costing approach, the total per treatment costs were in alignment with hospital administrative data (PLICS). Average health system reference cost data (macro-costing using NHS costs) could potentially underestimate these treatment costs, particularly for non-operative treatment. Costs incurred following hospital discharge in the primary care setting were minimal, and limited family borne costs were reported by parents/carers. While both HRQoL instruments performed relatively well, our results highlight the problem of ceiling effect and the importance of the timing of data collection and the duration of the analysis in any future assessment using QALYs and CUA. CONCLUSIONS: We highlighted the importance of obtaining accurate individual-patient cost data when conducting economic evaluations. Our results suggest that timing of data collection and duration of the assessment are important considerations when evaluating cost-effectiveness and reporting cost per QALY. CLINICAL TRIAL REGISTRATION: Current Controlled Trials ISRCTN15830435

Investigating SSH Research and Publication Practices in Disciplinary and Institutional Contexts. A Survey-Based Comparative Approach in Two Universities

In this paper, we comparatively analyze, present and discuss the results from a survey on increasing the visibility of research achievements in the social sciences and humanities (SSH) that was carried out at the University of Vienna (Austria) and the University of Navarra (Spain) in 2016 and 2017. Covering four major topics—searching and finding literature, publishing, the visibility of research, and the assessment of research outputs—we ask the following questions: are there disciplinary differences to be identified, and how do they present themselves in the two institutional contexts? Discussing the results, we showcase how disciplinary and institutional traditions and contexts are important factors that influence research and publication practices in the SSH. Our results indicate that the practices of searching and finding literature as well as publication practices and behavior are shaped by disciplinary traditions and epistemic cultures. On the contrary, assessment and valuation of research outputs are influenced by institutional and national contexts in which SSH research is organized and carried out

Accuracy of High-Speed Video Analysis to Diagnose Primary Ciliary Dyskinesia

Background: primary ciliary dyskinesia (PCD) is a rare genetic disease that impairs motility of cilia. Diagnosis relies on a combination of tests and final decision by multidisciplinary team (MDT). High-speed video microscopy (HSVM) is an important contribution to diagnostic testing, and is the only test that examines cilia motility on the day of patients’ appointment. No study has assessed the accuracy of HSVM. We hypothesised that scientists experienced in cilia assessment by HSVM would accurately diagnose PCD using HSVM alone compared to MDT diagnosis.Methods: we used 720 archived videos from 120 patients referred to three UK PCD diagnostic services in 2015-17. One scientist from each PCD centre reviewed videos, blinded to diagnostic and clinical data, and scored them for final diagnosis using a standardised proforma. We compared the final scoring for each scientist to: a) a report containing final diagnosis from the MDT decision, and b) diagnostic criteria provided in the 2017 ERS PCD diagnostic guidelines.Results: sensitivity and specificity were: a) 96.1% and 100% respectively when compared to MDT decision, and b) 95.7% and 100% respectively when compared to ERS guidelines criteria. Inter-rater reliability between the three scientists was substantial (k=0.7) for ‘PCD positive’, and moderate (k=0.44) for ‘PCD highly unlikely’.Conclusions: specialist scientists accurately diagnosed PCD using HSVM analysis, with high inter-observer agreement. HSVM can be used to reliably counsel patients on their likely diagnosis on the same day as clinic appointment and inform clinicians on initiation of treatment while confirmatory investigations are conducted

CONservative TReatment of Appendicitis in Children – a randomised controlled feasibility Trial (CONTRACT)

Objective To establish the feasibility of a multicentre randomised controlled trial to assess the effectiveness and cost-effectiveness of a non-operative treatment pathway compared with appendicectomy in children with uncomplicated acute appendicitis.Design Feasibility randomised controlled trial with embedded qualitative study to inform recruiter training to optimise recruitment and the design of a future definitive trial.Setting Three specialist paediatric surgery centres in the UK.Patients Children (aged 4–15 years) with a clinical diagnosis of uncomplicated acute appendicitis.Interventions Appendicectomy or a non-operative treatment pathway (comprising broad-spectrum antibiotics and active observation).Main outcome measures Primary outcome measure was the proportion of eligible patients recruited. Secondary outcomes evaluated adherence to interventions, data collection during follow-up, safety of treatment pathways and clinical course.Results Fifty per cent of eligible participants (95% CI 40 to 59) approached about the trial agreed to participate and were randomised. Repeated bespoke recruiter training was associated with an increase in recruitment rate over the course of the trial from 38% to 72%. There was high acceptance of randomisation, good patient and surgeon adherence to trial procedures and satisfactory completion of follow-up. Although more participants had perforated appendicitis than had been anticipated, treatment pathways were found to be safe and adverse event profiles acceptable.Conclusion Recruitment to a randomised controlled trial examining the effectiveness and cost-effectiveness of a non-operative treatment pathway compared with appendicectomy for the treatment of uncomplicated acute appendicitis in children is feasible.Trial registration number ISRCTN15830435

Conservative treatment for uncomplicated appendicitis in children:the CONTRACT feasibility study, including feasibility RCT

Background Whilst non-operative treatment is known to be effective for the treatment of uncomplicated acute appendicitis in children, comparative randomised trial data reporting important outcomes compared to appendicectomy are lacking.ObjectivesTo ascertain the feasibility of conducting a multi-centre randomised controlled trial (RCT) testing the effectiveness and cost-effectiveness of a non-operative treatment pathway compared to appendicectomy for the treatment of uncomplicated acute appendicitis in children.•DesignMixed methods study including: a feasibility RCT; embedded and parallel qualitative and survey studies; parallel health economic feasibility study; development of a core outcome set.Setting Three specialist NHS Paediatric Surgical Units in EnglandParticipants Children (aged 4-15 years) clinically diagnosed with uncomplicated acute appendicitis participated in the feasibility RCT. Children, their families, recruiting clinicians and other healthcare professionals involved in caring for children with appendicitis took part in the qualitative study. UK Specialist Paediatric Surgeons took part in the survey. Specialist Paediatric Surgeons, Adult General Surgeons who treat children, and children and young people who previously had appendicitis along with their families took part in the core outcomes set development.Interventions Participants in the feasibility RCT were randomised to a non-operative treatment pathway (broad-spectrum antibiotics and active observation) or appendicectomy.Main outcome measures Primary outcome measure was the proportion of eligible patients recruited to the feasibility trial.Data sourcesNHS casenotes, questionnaire responses, transcribed audio recordings of recruitment discussions and qualitative interviewsResults Overall, 50% (95%CI 40-59) of 115 eligible participants approached about the trial agreed to participate and were randomised. There was high acceptance of randomisation and good adherence to trial procedures and follow-up (follow rates of 89%, 85% and 85% at six weeks, three months and six months respectively). More participants had perforated appendicitis than had been anticipated.Qualitative work enabled us to: communicate about the trial effectively with patients and families; design and deliver bespoke training to optimise recruitment; and understand how to optimise design and delivery of a future trial.The health economic study, indicated that the main cost drivers are the ward stay cost and the cost of the operation, and has informed quality of life assessment methods for future work.A core outcome set for the treatment of uncomplicated acute appendicitis in children and young people was developed, containing 14 outcomes.There is adequate surgeon interest to justify proceeding to an effectiveness trial with 51% of those surveyed expressing a willingness to recruit with an unchanged trial protocol.LimitationsSince the feasibility RCT was only performed in three centres we cannot guarantee successful recruitment across a larger number of sites. However, our qualitative work has informed a bespoke training package to facilitate this. Although survey results suggest adequate clinician interest to make a larger trial possible, actual participation may differ, and equipoise may have moved over time.Conclusions A future effectiveness trial is feasible following limited additional preparation to establish appropriate outcome measures and case identification. We recommend a limited package of qualitative work be included to optimise recruitment at new centres in particular.Future work Prior to proceeding to an effectiveness trial we need to: develop a robust method for distinguishing children with uncomplicated acute appendicitis from those with more advanced appendicitis; reach agreement on a primary outcome measure and effect size that is acceptable to all stakeholder groups involved.Study registration ISRCTN15830435.Funding detailsNIHR HTA programm

Keeping children safe: a multicentre programme of research to increase the evidence base for preventing unintentional injuries in the home in the under-fives

Background: Unintentional injuries among 0- to 4-year-olds are a major public health problem incurring substantial NHS, individual and societal costs. However, evidence on the effectiveness and cost-effectiveness of preventative interventions is lacking. Aim: To increase the evidence base for thermal injury, falls and poisoning prevention for the under-fives. Methods: Six work streams comprising five multicentre case–control studies assessing risk and protective factors, a study measuring quality of life and injury costs, national surveys of children’s centres, interviews with children’s centre staff and parents, a systematic review of barriers to, and facilitators of, prevention and systematic overviews, meta-analyses and decision analyses of home safety interventions. Evidence from these studies informed the design of an injury prevention briefing (IPB) for children’s centres for preventing fire-related injuries and implementation support (training and facilitation). This was evaluated by a three-arm cluster randomised controlled trial comparing IPB and support (IPB+), IPB only (no support) and usual care. The primary outcome was parent-reported possession of a fire escape plan. Evidence from all work streams subsequently informed the design of an IPB for preventing thermal injuries, falls and poisoning. Results: Modifiable risk factors for falls, poisoning and scalds were found. Most injured children and their families incurred small to moderate health-care and non-health-care costs, with a few incurring more substantial costs. Meta-analyses and decision analyses found that home safety interventions increased the use of smoke alarms and stair gates, promoted safe hot tap water temperatures, fire escape planning and storage of medicines and household products, and reduced baby walker use. Generally, more intensive interventions were the most effective, but these were not always the most cost-effective interventions. Children’s centre and parental barriers to, and facilitators of, injury prevention were identified. Children’s centres were interested in preventing injuries, and believed that they could prevent them, but few had an evidence-based strategic approach and they needed support to develop this. The IPB was implemented by children’s centres in both intervention arms, with greater implementation in the IPB+ arm. Compared with usual care, more IPB+ arm families received advice on key safety messages, and more families in each intervention arm attended fire safety sessions. The intervention did not increase the prevalence of fire escape plans [adjusted odds ratio (AOR) IPB only vs. usual care 0.93, 95% confidence interval (CI) 0.58 to 1.49; AOR IPB+ vs. usual care 1.41, 95% CI 0.91 to 2.20] but did increase the proportion of families reporting more fire escape behaviours (AOR IPB only vs. usual care 2.56, 95% CI 1.38 to 4.76; AOR IPB+ vs. usual care 1.78, 95% CI 1.01 to 3.15). IPB-only families were less likely to report match play by children (AOR 0.27, 95% CI 0.08 to 0.94) and reported more bedtime fire safety routines (AOR for a 1-unit increase in the number of routines 1.59, 95% CI 1.09 to 2.31) than usual-care families. The IPB-only intervention was less costly and marginally more effective than usual care. The IPB+ intervention was more costly and marginally more effective than usual care. Limitations: Our case–control studies demonstrate associations between modifiable risk factors and injuries but not causality. Some injury cost estimates are imprecise because of small numbers. Systematic reviews and meta-analyses were limited by the quality of the included studies, the small numbers of studies reporting outcomes and significant heterogeneity, partly explained by differences in interventions. Network meta-analysis (NMA) categorised interventions more finely, but some variation remained. Decision analyses are likely to underestimate cost-effectiveness for a number of reasons. IPB implementation varied between children’s centres. Greater implementation may have resulted in changes in more fire safety behaviours. Conclusions: Our studies provide new evidence about the effectiveness of, as well as economic evaluation of, home safety interventions. Evidence-based resources for preventing thermal injuries, falls and scalds were developed. Providing such resources to children’s centres increases their injury prevention activity and some parental safety behaviours. Future work: Further randomised controlled trials, meta-analyses and NMAs are needed to evaluate the effectiveness and cost-effectiveness of home safety interventions. Further work is required to measure NHS, family and societal costs and utility decrements for childhood home injuries and to evaluate complex multicomponent interventions such as home safety schemes using a single analytical model. Trial registration: Current Controlled Trials ISRCTN65067450 and ClinicalTrials.gov NCT01452191. Funding: The National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 5, No. 14. See the NIHR Journals Library website for further project information

Role of Alanine Racemase Mutations in Mycobacterium tuberculosis d-Cycloserine Resistance.

A screening of more than 1,500 drug-resistant strains of Mycobacterium tuberculosis revealed evolutionary patterns characteristic of positive selection for three alanine racemase (Alr) mutations. We investigated these mutations using molecular modeling, in vitro MIC testing, as well as direct measurements of enzymatic activity, which demonstrated that these mutations likely confer resistance to d-cycloserine

CONTRACT Study - CONservative TReatment of Appendicitis in Children (feasibility):study protocol for a randomised controlled Trial

BackgroundCurrently, the routine treatment for acute appendicitis in the United Kingdom is an appendicectomy. However, there is increasing scientific interest and research into non-operative treatment of appendicitis in adults and children. While a number of studies have investigated non-operative treatment of appendicitis in adults, this research cannot be applied to the paediatric population. Ultimately, we aim to perform a UK-based multicentre randomised controlled trial (RCT) to test the clinical and cost effectiveness of non-operative treatment of acute uncomplicated appendicitis in children, as compared with appendicectomy. First, we will undertake a feasibility study to assess the feasibility of performing such a trial.Methods/designThe study involves a feasibility RCT with a nested qualitative research to optimise recruitment as well as a health economic substudy. Children (aged 4–15 years inclusive) diagnosed with acute uncomplicated appendicitis that would normally be treated with an appendicectomy are eligible for the RCT. Exclusion criteria include clinical/radiological suspicion of perforated appendicitis, appendix mass or previous non-operative treatment of appendicitis. Participants will be randomised into one of two arms. Participants in the intervention arm are treated with antibiotics and regular clinical assessment to ensure clinical improvement. Participants in the control arm will receive appendicectomy. Randomisation will be minimised by age, sex, duration of symptoms and centre. Children and families who are approached for the RCT will be invited to participate in the embedded qualitative substudy, which includes recording of recruitment consultants and subsequent interviews with participants and non-participants and their families and recruiters. Analyses of these will inform interventions to optimise recruitment. The main study outcomes include recruitment rate (primary outcome), identification of strategies to optimise recruitment, performance of trial treatment pathways, clinical outcomes and safety of non-operative treatment. We have involved children, young people and parents in study design and delivery.DiscussionIn this study we will explore the feasibility of performing a full efficacy RCT comparing non-operative treatment with appendicectomy in children with acute uncomplicated appendicitis. Factors determining success of the present study include recruitment rate, safety of non-operative treatment and adequate interest in the future RCT. Ultimately this feasibility study will form the foundation of the main RCT and reinforce its design.Trial registrationISRCTN15830435. Registered on 8 February 2017

Prevention of Morbidity in Sickle Cell Disease (POMS2a)-overnight auto-adjusting continuous positive airway pressure compared with nocturnal oxygen therapy: a randomised crossover pilot study examining patient preference and safety in adults and children.

DESIGN: This randomised crossover trial compared nocturnal auto-adjusting continuous positive airway pressure (APAP) and nocturnal oxygen therapy (NOT) in adults and children with sickle cell anaemia, with patient acceptability as the primary outcome. Secondary outcomes included pulmonary physiology (adults), safety, and daily pain during interventions and washout documented using tablet technology. METHODS: Inclusion criteria were age > 8 years and the ability to use an iPad to collect daily pain data. Trial participation was 4 weeks; week 1 involved baseline data collection and week 3 was a washout between interventions, which were administered for 7 days each during weeks 2 and 4 in a randomised order. Qualitative interviews were transcribed verbatim and analysed for content using a funnelling technique, starting generally and then gaining more detailed information on the experience of both interventions. Safety data included routine haematology and median pain days between each period. Missing pain day values were replaced using multiple imputation. RESULTS: Ten adults (three female, median age 30.2 years, range 18-51.5 years) and eleven children (five female, median age 12 years, range 8.7-16.9 years) enrolled. Nine adults and seven children completed interviews. Qualitative data revealed that the APAP machine was smaller, easier to handle, and less noisy. Of 16 participants, 10 preferred APAP (62.5%, 95% confidence interval (CI) 38.6-81.5%). Haemoglobin decreased from baseline on APAP and NOT (mean difference -3.2 g/L (95% CI -6.0 to -0.2 g/L) and -2.5 g/L (95% CI -4.6 to 0.3 g/L), respectively), but there was no significant difference between interventions (NOT versus APAP, 1.1 (-1.2 to 3.6)). Pulmonary function changed little. Compared with baseline, there were significant decreases in the median number of pain days (1.58 for APAP and 1.71 for NOT) but no significant difference comparing washout with baseline. After adjustment for carry-over and period effects, there was a non-significant median difference of 0.143 (95% CI -0.116 to 0.401) days additional pain with APAP compared with NOT. CONCLUSION: In view of the point estimate of patient preference for APAP, and no difference in haematology or pulmonary function or evidence that pain was worse during or in washout after APAP, it was decided to proceed with a Phase II trial of 6 months APAP versus standard care with further safety monitoring for bone marrow suppression and pain. TRIAL REGISTRATION: ISRCTN46078697 . Registered on 18 July 2014

Virulence in Murine Model Shows the Existence of Two Distinct Populations of Brazilian Vaccinia virus Strains

Brazilian Vaccinia virus had been isolated from sentinel mice, rodents and recently from humans, cows and calves during outbreaks on dairy farms in several rural areas in Brazil, leading to high economic and social impact. Some phylogenetic studies have demonstrated the existence of two different populations of Brazilian Vaccinia virus strains circulating in nature, but little is known about their biological characteristics. Therefore, our goal was to study the virulence pattern of seven Brazilian Vaccinia virus strains. Infected BALB/c mice were monitored for morbidity, mortality and viral replication in organs as trachea, lungs, heart, kidneys, liver, brain and spleen. Based on the virulence potential, the Brazilian Vaccinia virus strains were grouped into two groups. One group contained GP1V, VBH, SAV and BAV which caused disease and death in infected mice and the second one included ARAV, GP2V and PSTV which did not cause any clinical signals or death in infected BALB/c mice. The subdivision of Brazilian Vaccinia virus strains into two groups is in agreement with previous genetic studies. Those data reinforce the existence of different populations circulating in Brazil regarding the genetic and virulence characteristics