A multi-professional survey of UK practice in the use of intra-articular corticosteroid injection for symptomatic first metatarsophalangeal joint osteoarthritis.

BACKGROUND: The first metatarsophalangeal joint is the most common site of osteoarthritis (OA) in the foot and ankle. Intra-articular corticosteroid injections are widely used for this condition, but little is known about their use in practice. This study explored current practice within the UK National Health Service (NHS) relating to the administration of intra-articular corticosteroids for people with painful first metatarsophalangeal joint (MTPJ) OA. METHODS: A cross-sectional survey using Qualtrics online survey platform (Qualtrics, Provo, UT, USA), distributed through professional bodies, special interest groups, and social media. RESULTS: One hundred forty-four healthcare professionals responded, including podiatrists (53/144; 39%), orthopaedic surgeons (28/144; 19%), podiatric surgeons (26/144; 17%) and physiotherapists (24/144; 16%). Half of respondents administered up to 25 corticosteroid injections per year (67/136; 49%) but some administered more than fifty (21/136; 15%). Injections were administered across the healthcare system but were most common in hospital settings (64/136; 44%) followed by community (38/136; 26%), with less delivered in primary care (11/136; 8%). Half of respondents routinely used image-guidance, either ultrasound or x-ray/fluoroscopy (65/136; 48%) although over one third used none (52/136; 38%). Imaging guidance was more common amongst medical professionals (21/31; 68%) compared to non-medical health professionals (45/105; 43%). Overall, methylprednisolone acetate was the most common corticosteroid used. Medical professionals mostly injected methylprednisolone acetate (n = 15/27; 56%) or triamcinolone acetonide (n = 11/27; 41%), whereas premixed methylprednisolone acetate with lidocaine hydrochloride was the most common preparation used by non-medical health professionals (41/85; 48%). When injecting non premixed steroid, lidocaine hydrochloride (15/35; 43%) was the most common choice of local anaesthetic for non-medical health professionals but medical professionals showed more variation between lidocaine hydrochloride (8/23; 35%) levobupivacaine hydrochloride (9/23; 39%) and bupivacaine hydrochloride (5/23; 22%). CONCLUSIONS: Multiple professional groups regularly administer intra-articular corticosteroids for symptomatic first MTPJ OA across a range of NHS healthcare settings. Overall, methylprednisolone acetate was the most commonly administered steroid and lidocaine hydrochloride the most common local anaesthetic. There was large variation in the use of imaging guidance, type and dose of steroid, local anaesthetic, and clinical pathways used in the intra-articular injection of corticosteroids for people with first MTPJ OA.

Overcoming challenges in conducting systematic reviews in implementation science: a methods commentary.

Consolidation of the literature using systematic reviews is a critical way to advance a discipline and support evidence-based decision-making in healthcare. However, unique challenges exist that impact the conduct of systematic reviews in implementation science. In this commentary, we reflect on our combined experience to describe five key challenges unique to systematic reviews of primary implementation research. These challenges include (1) descriptors used in implementation science publications, (2) distinction between evidence-based interventions and implementation strategies, (3) assessment of external validity, (4) synthesis of implementation studies with substantial clinical and methodological diversity, and (5) variability in defining implementation 'success'. We outline possible solutions and highlight resources that can be used by authors of primary implementation research, as well as systematic review and editorial teams, to overcome the identified challenges and optimise the utility of future systematic reviews in implementation science.

Clinical evaluation of the Immulite® 1000 chemiluminescent immunoassay for measurement of equine serum insulin.

Introduction: Accurate quantitative analysis of equine insulin in blood samples is critical for assessing hyperinsulinemia in horses. Although there are various laboratory methods for evaluating equine serum insulin, different immunoassays show significant discrepancies between the determined insulin concentrations and are often not comparable. The aim of this study was to evaluate the Immulite® 1000 chemiluminescent immunoassay (CLIA) to establish independent laboratory and assay-specific cut values to provide an accurate diagnosis of hyperinsulinemia in horses. Thus, the analytical and clinical performance of Immulite® 1000 CLIA in terms of precision (intra- and inter-assay coefficient of variance, CV) and recovery upon dilution were evaluated and compared with radioimmunoassay (RIA), which has been previously validated for use in horses. Material and methods: Archived serum samples (n = 106) from six Quarter horse mares enrolled in the glucose phase of a Frequently Sampled Insulin and Glucose Test (FSIGT) study were used to measure blood insulin. Results: The Immulite® 1000 CLIA had good precision with acceptable intra- and inter-assay CVs, adequate recovery on dilution, and a strong correlation with the RIA (r = 0.974, P < 0.0001), with constant bias resulting in consistently lower values. Discussion: On this basis, the Immulite® 1000 Insulin Assay is valid for measuring equine serum insulin for diagnostic and monitoring purposes when cut values are appropriately adjusted.

Development of antidrug antibodies against adalimumab maps to variation within the HLA-DR peptide-binding groove.

Targeted biologic therapies can elicit an undesirable host immune response characterized by the development of antidrug antibodies (ADA), an important cause of treatment failure. The most widely used biologic across immune-mediated diseases is adalimumab, a tumor necrosis factor inhibitor. This study aimed to identify genetic variants that contribute to the development of ADA against adalimumab, thereby influencing treatment failure. In patients with psoriasis on their first course of adalimumab, in whom serum ADA had been evaluated 6-36 months after starting treatment, we observed a genome-wide association with ADA against adalimumab within the major histocompatibility complex (MHC). The association signal mapped to the presence of tryptophan at position 9 and lysine at position 71 of the HLA-DR peptide-binding groove, with both residues conferring protection against ADA. Underscoring their clinical relevance, these residues were also protective against treatment failure. Our findings highlight antigenic peptide presentation via MHC class II as a critical mechanism in the development of ADA against biologic therapies and downstream treatment response.

Effects of a Supplement Containing Cannabidiol (CBD) on Sedation and Ataxia Scores and Health.

Supplements containing Cannabidiol (CBD) are available for horses, however, few studies have been published on their effects on behavior and health parameters. The purpose of this study was to determine if a daily oral supplement containing CBD would cause sedation, ataxia or alterations in other health parameters during administration for 56 days. Twenty clinically healthy adult Thoroughbred horses were housed in stalls. Before treatment was initiated, a complete physical examination, complete blood count (CBC) and biochemical panel were evaluated. In addition, horses were examined for sedation and ataxia using standard scoring systems. Horses were randomly divided into two treatment groups, treated (supplement pellets containing CBD as Hemp Extract, 150 mg) or control (supplement pellets without CBD). Horses were treated daily and sedation and ataxia scores were assigned by two masked observers once weekly for 56 days. Horses were monitored daily for clinical signs or adverse events and body weights were recorded weekly. A CBC and biochemical panel were repeated on days 28 and 56, two hours after administration of the supplement. The supplement was readily consumed by the horses and no adverse effects were seen over the treatment period. Sedation and ataxia scores ranged from zero to two for all horses during the weekly examinations and there was no statistical difference between treatment groups. There were no treatment effects on blood values, including indicators of anemia and blood proteins, liver enzymes, kidney values, electrolytes or calcium. Body weight significantly increased in all horses, by Day 56 compared to Day zero but no treatment by day effect was noted. The CBD supplement (150 mg) was readily consumed and safe and did not result in changes in mentation, gait, or other health parameters, and no adverse clinical signs were observed during 56 days of oral administration.

Evaluating telehealth lifestyle therapy versus telehealth psychotherapy for reducing depression in adults with COVID-19 related distress: the curbing anxiety and depression using lifestyle medicine (CALM) randomised non-inferiority trial protocol.

BACKGROUND: There is increasing recognition of the substantial burden of mental health disorders at an individual and population level, including consequent demand on mental health services. Lifestyle-based mental healthcare offers an additional approach to existing services with potential to help alleviate system burden. Despite the latest Royal Australian New Zealand College of Psychiatrists guidelines recommending that lifestyle is a 'first-line', 'non-negotiable' treatment for mood disorders, few such programs exist within clinical practice. Additionally, there are limited data to determine whether lifestyle approaches are equivalent to established treatments. Using an individually randomised group treatment design, we aim to address this gap by evaluating an integrated lifestyle program (CALM) compared to an established therapy (psychotherapy), both delivered via telehealth. It is hypothesised that the CALM program will not be inferior to psychotherapy with respect to depressive symptoms at 8 weeks. METHODS: The study is being conducted in partnership with Barwon Health's Mental Health, Drugs & Alcohol Service (Geelong, Victoria), from which 184 participants from its service and surrounding regions are being recruited. Eligible participants with elevated psychological distress are being randomised to CALM or psychotherapy. Each takes a trans-diagnostic approach, and comprises four weekly (weeks 1-4) and two fortnightly (weeks 6 and 8) 90-min, group-based sessions delivered via Zoom (digital video conferencing platform). CALM focuses on enhancing knowledge, behavioural skills and support for improving dietary and physical activity behaviours, delivered by an Accredited Exercise Physiologist and Accredited Practising Dietitian. Psychotherapy uses cognitive behavioural therapy (CBT) delivered by a Psychologist or Clinical Psychologist, and Provisional Psychologist. Data collection occurs at baseline and 8 weeks. The primary outcome is depressive symptoms (assessed via the Patient Health Questionnaire-9) at 8 weeks. Societal and healthcare costs will be estimated to determine the cost-effectiveness of the CALM program. A process evaluation will determine its reach, adoption, implementation and maintenance. DISCUSSION: If the CALM program is non-inferior to psychotherapy, this study will provide the first evidence to support lifestyle-based mental healthcare as an additional care model to support individuals experiencing psychological distress. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12621000387820 , Registered 8 April 2021.

Profiling the risk factors associated with falls in older people with diabetes receiving at-home nursing care: Retrospective analysis of an Australian aged care provider database.

Falls among older people with diabetes mellitus (DM) are a major health concern. Preventive measures can be implemented to reduce the likelihood of falls. The aim of this study was to determine the factors most strongly associated with falls in older people living with DM who receive at-home care support services. This will inform home-visiting nurses to prioritise falls prevention strategies in the care of clients who are at high risk of falls. A retrospective analysis of routinely collected data from a large not-for-profit community aged care service provider was undertaken. The sample comprised adults aged ≥65 years residing in Victoria, Australia, with a recorded diagnosis of DM, and who received at least one episode of care by the aged care provider during July 1, 2014 and June 30, 2015. Self-reported data on falls in previous 6 months was obtained via the Comprehensive Health Assessment Tool (CHAT). Selection of factors associated with falls was guided by the Falls Risk for Older People in the Community (FROP-Com) assessment tool. For the study population, data for these factors were obtained from clients' self-reported CHAT data, and from International Classification of Disease codes obtained from medical records. Descriptive statistics were used to identify the demographic and clinical profile; logistic regression was used to assess the strength of association between various factors and the occurrence of a fall. Data were obtained for 1,574 older adults; overall prevalence of falls was 30.6% (n = 482). Significant factors displaying the highest odds of falling were gait issues (OR: 2.11, p = 0.002); needing help to walk (OR: 1.91, p = <0.001); and cognitive dysfunction (OR: 1.55, p = 0.001). Interpreted with caution, several factors contribute to an increased odds of falling in older people with DM. Home-visiting nurses are uniquely placed to introduce preventive interventions to reduce the likelihood of debilitating falls in this population.

Enhanced NF-κB signaling in type-2 dendritic cells at baseline predicts non-response to adalimumab in psoriasis.

Biologic therapies have transformed the management of psoriasis, but clinical outcome is variable leaving an unmet clinical need for predictive biomarkers of response. Here we perform in-depth immunomonitoring of blood immune cells of 67 patients with psoriasis, before and during therapy with the anti-TNF drug adalimumab, to identify immune mediators of clinical response and evaluate their predictive value. Enhanced NF-κBp65 phosphorylation, induced by TNF and LPS in type-2 dendritic cells (DC) before therapy, significantly correlates with lack of clinical response after 12 weeks of treatment. The heightened NF-κB activation is linked to increased DC maturation in vitro and frequency of IL-17+ T cells in the blood of non-responders before therapy. Moreover, lesional skin of non-responders contains higher numbers of dermal DC expressing the maturation marker CD83 and producing IL-23, and increased numbers of IL-17+ T cells. Finally, we identify and clinically validate LPS-induced NF-κBp65 phosphorylation before therapy as a predictive biomarker of non-response to adalimumab, with 100% sensitivity and 90.1% specificity in an independent cohort. Our study uncovers important molecular and cellular mediators underpinning adalimumab mechanisms of action in psoriasis and we propose a blood biomarker for predicting clinical outcome.

Locally Transmitted Trypanosoma cruzi in a Domestic Llama (Lama glama) in a Rural Area of Greater New Orleans, Louisiana, USA.

Trypanosoma cruzi-associated megaesophagus was diagnosed in a domestic Louisiana-born llama with no significant travel history. The llama resided in the same rural area of greater New Orleans, Louisiana, where the first human autochthonous case of Chagas disease was identified in the state. Venous blood from the llama tested positive for T. cruzi kinetoplastid DNA by conventional PCR. The cardiac evaluation was unremarkable, while thoracic radiographs revealed generalized megaesophagus. The llama received supportive care, but was ultimately humanely euthanized. The esophagus was severely distended throughout its length on necropsy, and histologic evaluation showed no microscopic changes in esophageal tissue and minimal to mild lymphoplasmacytic inflammation in cardiac tissue. T. cruzi DNA was detected by conventional PCR in the esophagus, small intestine, and blood despite no protozoan organisms being observed in multiple tissue sections examined. This report contributes to the growing body of evidence of local transmission of T. cruzi in the southern United States, and Chagas disease should be considered a differential diagnosis when evaluating llamas and other large animal species for esophageal dysfunction. There is little research describing megaesophagus or Chagas disease in llamas, and this report aims to increase awareness about this zoonotic disease that is becoming more frequently reported in the southern United States.

Analysis of Tools Used in Assessing Technical Skills and Operative Competence in Trauma and Orthopaedic Surgical Training: A Systematic Review.

BACKGROUND: Robust assessment of skills acquisition and surgical performance during training is vital to ensuring operative competence among orthopaedic surgeons. A move to competency-based surgical training requires the use of tools that can assess surgical skills objectively and systematically. The aim of this systematic review was to describe the evidence for the utility of assessment tools used in evaluating operative performance in trauma and orthopaedic surgical training. METHODS: We performed a comprehensive literature search of MEDLINE, Embase, and Google Scholar databases to June 2019. From eligible studies we abstracted data on study aim, assessment format (live theater or simulated setting), skills assessed, and tools or metrics used to assess surgical performance. The strengths, limitations, and psychometric properties of the assessment tools are reported on the basis of previously defined utility criteria. RESULTS: One hundred and five studies published between 1990 and 2019 were included. Forty-two studies involved open orthopaedic surgical procedures, and 63 involved arthroscopy. The majority (85%) were used in the simulated environment. There was wide variation in the type of assessment tools in used, the strengths and weaknesses of which are assessor and setting-dependent. CONCLUSIONS: Current technical skills-assessment tools in trauma and orthopaedic surgery are largely procedure-specific and limited to research use in the simulated environment. An objective technical skills-assessment tool that is suitable for use in the live operative theater requires development and validation, to ensure proper competency-based assessment of surgical performance and readiness for unsupervised clinical practice. CLINICAL RELEVANCE: Trainers and trainees can gain further insight into the technical skills assessment tools that they use in practice through the utility evidence provided.

Use of an audit with feedback implementation strategy to promote medication error reporting by nurses.

AIMS AND OBJECTIVES: To outline the development and effect of an audit with feedback implementation strategy that intended to increase the rate of voluntary medication error reporting by nurses. BACKGROUND: Medication errors are a serious global health issue. Audit with feedback is a widely used implementation strategy that has potential to modify nurses' reporting behaviour and improve medication error reporting rates. DESIGN: Quasi-experimental implementation study (fulfilling the TIDieR checklist) with two pairs of matched wards at a private hospital in Australia was conducted from March 2015-September 2016. One ward from each pair was randomised to either the intervention or control group. METHOD: Nurses within intervention wards received audit with feedback on a quarterly basis over a 12-month implementation period. Control wards underwent quarterly audits only (without feedback). Feedback consisted of a one-page infographic poster, with content based on medication error data obtained from audits and the hospitals' risk management system (RiskMan). The primary outcome-rate of medication errors reported per month-was determined in both groups at pre-implementation, implementation and postimplementation phases. Differences between groups were compared using generalised linear mixed models with Poisson distribution and log link. RESULTS: A nonsignificant intervention effect was found for rate of medication errors reported per month. Interestingly, when combining data from both groups, a significant increasing time trend was observed for medication errors reported per month across pre-implementation and implementation phases (80% increase). CONCLUSIONS: The audit with feedback strategy developed in the present study did not effectively influence the voluntary reporting of medication errors by nurses. RELEVANCE TO CLINICAL PRACTICE: Despite the lack of intervention effects, the use of a published checklist to optimise the reporting quality of this study will contribute to the field by furthering the understanding of how to enhance audit with feedback implementation strategies for nurses.

Maternity service organisational interventions that aim to reduce caesarean section: a systematic review and meta-analyses.

BACKGROUND: Caesarean sections (CSs) are associated with increased maternal and perinatal morbidity, yet rates continue to increase within most countries. Effective interventions are required to reduce the number of non-medically indicated CSs and improve outcomes for women and infants. This paper reports findings of a systematic review of literature related to maternity service organisational interventions that have a primary intention of improving CS rates. METHOD: A three-phase search strategy was implemented to identify studies utilising organisational interventions to improve CS rates in maternity services. The database search (including Cochrane CENTRAL, CINAHL, MEDLINE, Maternity and Infant Care, EMBASE and SCOPUS) was restricted to peer-reviewed journal articles published from 1 January 1980 to 31 December 2017. Reference lists of relevant reviews and included studies were also searched. Primary outcomes were overall, planned, and unplanned CS rates. Secondary outcomes included a suite of birth outcomes. A series of meta-analyses were performed in RevMan, separated by type of organisational intervention and outcome of interest. Summary risk ratios with 95% confidence intervals were presented as the effect measure. Effect sizes were pooled using a random-effects model. RESULTS: Fifteen articles were included in the systematic review, nine of which were included in at least one meta-analysis. Results indicated that, compared with women allocated to usual care, women allocated to midwife-led models of care implemented across pregnancy, labour and birth, and the postnatal period were, on average, less likely to experience CS (overall) (average RR 0.83, 95% CI 0.73 to 0.96), planned CS (average RR 0.75, 95% CI 0.61 to 0.93), and episiotomy (average RR 0.84, 95% CI 0.74 to 0.95). Narratively, audit and feedback, and a hospital policy of mandatory second opinion for CS, were identified as interventions that have potential to reduce CS rates. CONCLUSION: Maternity service leaders should consider the adoption of midwife-led models of care across the maternity episode within their organisations, particularly for women classified as low-risk. Additional studies are required that utilise either audit and feedback, or a hospital policy of mandatory second opinion for CS, to facilitate the quantification of intervention effects within future reviews. PROSPERO REGISTRATION: CRD42016039458 ; prospectively registered.

Global synergies and trade-offs between multiple dimensions of biodiversity and ecosystem services.

Ensuring the persistence of biodiversity and ecosystem services represents a global challenge that need to be addressed with high urgency. Global priority areas can only be identified by means of an integrated prioritization approach that would not only preserve species numbers and ecosystem services, but also the evolutionary and functional components of diversity. In this study we combine global datasets on the distribution of mammals and birds with species traits and phylogenetic data and we identify conservation priorities for taxonomic, functional and phylogenetic diversity, as well as for three ecosystem services, including potential for carbon sequestration, pollination potential and groundwater recharge. We show that, when priority areas are identified based only on individual, e.g. functional diversity, or any combination of the three biodiversity components, these areas do not allow a sufficient protection of the three ecosystem services. However, an integrated approach whereby prioritization is based on all biodiversity components and ecosystem services would allow to identify areas that maximize protection of all ecosystem services with a minimal loss in biodiversity coverage. Our results highlight the need for an integrated conservation planning framework in order to optimally allocate resources and achieve the long-term preservation of the multiple dimensions of biodiversity and ecosystems services.

Effect of a Health Coach Intervention for the Management of Individuals With Type 2 Diabetes Mellitus in China: A Pragmatic Cluster Randomized Controlled Trial.

Aim: To determine the effect of a health coach intervention for the management of glycemic control, as well as physiological, psychological and self-care outcomes of patients with type 2 diabetes mellitus (T2DM), compared with usual care. Methods: This pragmatic cluster RCT was conducted in the Fengtai district of Beijing from August 2011 to December 2013. Forty-one community health stations (CHSs) were cluster randomized (stratified geographically, 1:1 ratio) and eligible, randomly selected T2DM patients were sequentially contacted by CHSs. Control participants received usual care according to the Chinese Guideline for Diabetes Prevention and Management. Intervention participants received 18-months of health coaching based on principles of Motivational Interviewing (MI) plus usual care. Medical and pathology fees were waived for both groups. Outcome assessment was performed at baseline, 6, 12, and 18-months. The primary outcome was glycated hemoglobin (HbA1c); secondary outcomes encompassed a suite of physiological, psychological and self-care measures. Results: No differential treatment effect was found at 18-months for HbA1c (adj. difference -0.07, 95% CI -0.53 to 0.39, p = 0.769) or any specified secondary outcomes. Interestingly, both groups displayed a statistically and clinically significant within-group improvement of the same magnitude at 18-months for HbA1c (intervention: mean change -3.65, 95% CI -3.92 to -3.37; control: mean change -3.38, 95% CI -3.67 to -3.08). Conclusions: The lack of differential treatment effects observed indicate that it may be premature to recommend the routine delivery of health coach interventions based on MI principles for the management of T2DM in China. However, the large, comparable within-group improvement in mean HbA1c promotes the establishment of free, regular clinical health assessments for individuals with T2DM in China. TRIAL REGISTRATION: ISRCTN registry - ISRCTN01010526 (https://doi.org/10.1186/ISRCTN01010526).

Attending away from the body predicts increased physical symptom reports at six months in primary care patients.

OBJECTIVE: High symptom reporting (HSR) and medically unexplained symptoms (MUS) are associated with considerable distress, disability, healthcare utilization and costs, but are poorly understood, and current treatments are of limited benefit. Most models of HSR and MUS implicate cognitive-perceptual factors, such as increased body-focused attention, reduced perceptual thresholds and a tendency to experience somatic misperception, but little is known about the causal role of these variables. We investigated this issue by studying whether there is a longitudinal relationship between perceptual-attentional variables and later clinical outcomes in primary care patients. METHOD: Primary care patients (N = 102) completed clinical (physical symptom reporting, health anxiety and healthcare utilization) and perceptual-attentional (body-focused attention, perceptual threshold, somatic misperception) measures at baseline and then again six months later (N = 72). Hierarchical regression was used to examine cross-lagged relationships between baseline and follow-up scores. RESULTS: Contrary to expectation, attending away from the body at baseline predicted increased not decreased symptom reporting six months later. Neither perceptual threshold nor somatic misperception predicted clinical outcomes at six months. CONCLUSIONS: These findings suggest that body avoidance, rather than increased body focus, contribute to the development of HSR. Future studies should consider the potential clinical benefits of reducing bodily avoidance, via techniques that promote adaptive engagement with bodily sensations.

Neutrophil granule proteins generate bactericidal ammonia chloramine on reaction with hydrogen peroxide.

The neutrophil enzyme, myeloperoxidase, by converting hydrogen peroxide (H2O2) and chloride to hypochlorous acid (HOCl), provides important defense against ingested micro-organisms. However, there is debate about how efficiently HOCl is produced within the phagosome and whether its reactions with phagosomal constituents influence the killing mechanism. The phagosome is a small space surrounding the ingested organism, into which superoxide, H2O2 and high concentrations of proteins from cytoplasmic granules are released. Previous studies imply that HOCl is produced in the phagosome, but a large proportion should react with proteins before reaching the microbe. To mimic these conditions, we subjected neutrophil granule extract to sequential doses of H2O2. Myeloperoxidase in the extract converted all the H2O2 to HOCl, which reacted with the granule proteins. 3-Chlorotyrosine, protein carbonyls and large amounts of chloramines were produced. At higher doses of H2O2, the extract developed potent bactericidal activity against Staphylococcus aureus. This activity was due to ammonia monochloramine, formed as a secondary product from protein chloramines and dichloramines. Isolated myeloperoxidase and elastase also became bactericidal when modified with HOCl and antibacterial activity was seen with a range of species. Comparison of levels of protein modification in the extract and in phagosomes implies that a relatively low proportion of phagosomal H2O2 would be converted to HOCl, but there should be sufficient for substantial protein chloramine formation and some breakdown to ammonia monochloramine. It is possible that HOCl could kill ingested bacteria by an indirect mechanism involving protein oxidation and monochloramine formation.

A randomised controlled trial to compare the safety, effectiveness and cost-effectiveness of doxycycline (200 mg/day) with that of oral prednisolone (0.5 mg/kg/day) for initial treatment of bullous pemphigoid: the Bullous Pemphigoid Steroids and Tetracyclines (BLISTER) trial.

BACKGROUND: Bullous pemphigoid (BP) is an autoimmune blistering skin disorder with increased morbidity and mortality in the elderly. OBJECTIVES: To evaluate the effectiveness, safety and cost-effectiveness of a strategy of initiating BP treatment with oral doxycycline or oral prednisolone. We hypothesised that starting treatment with doxycycline gives acceptable short-term blister control while conferring long-term safety advantages over starting treatment with oral prednisolone. DESIGN: Pragmatic multicentre two-armed parallel-group randomised controlled trial with an economic evaluation. SETTING: A total of 54 dermatology secondary care centres in the UK and seven in Germany. PARTICIPANTS: Adults with BP [three or more blisters at two sites and positive direct and/or indirect immunofluorescence (immunoglobulin G and/or complement component 3 immunofluorescence at the dermal-epidermal junction)] and able to give informed consent. INTERVENTIONS: Participants were allocated using online randomisation to initial doxycycline treatment (200 mg/day) or prednisolone (0.5 mg/kg/day). Up to 30 g/week of potent topical corticosteroids was permitted for weeks 1-3. After 6 weeks, clinicians could switch treatments or alter the prednisolone dose as per normal practice. MAIN OUTCOME MEASURES: Primary outcomes: (1) the proportion of participants with three or fewer blisters at 6 weeks (investigator blinded) and (2) the proportion with severe, life-threatening and fatal treatment-related events at 52 weeks. A regression model was used in the analysis adjusting for baseline disease severity, age and Karnofsky score, with missing data imputed. Secondary outcomes included the effectiveness of blister control after 6 weeks, relapses, related adverse events and quality of life. The economic evaluation involved bivariate regression of costs and quality-adjusted life-years (QALYs) from a NHS perspective. RESULTS: In total, 132 patients were randomised to doxycycline and 121 to prednisolone. The mean patient age was 77.7 years and baseline severity was as follows: mild 31.6% (three to nine blisters), moderate 39.1% (10-30 blisters) and severe 29.3% (> 30 blisters). For those starting on doxycycline, 83 out of 112 (74.1%) had three or fewer blisters at 6 weeks, whereas for those starting on prednisolone 92 out of 101 (91.1%) had three or fewer blisters at 6 weeks, an adjusted difference of 18.6% in favour of prednisolone [90% confidence interval (CI) 11.1% to 26.1%], using a modified intention-to-treat (mITT) analysis. Per-protocol analysis showed similar results: 74.4% compared with 92.3%, an adjusted difference of 18.7% (90% CI 9.8% to 27.6%). The rate of related severe, life-threatening and fatal events at 52 weeks was 18.2% for those started on doxycycline and 36.6% for those started on prednisolone (mITT analysis), an adjusted difference of 19.0% (95% CI 7.9% to 30.1%; p = 0.001) in favour of doxycycline. Secondary outcomes showed consistent findings. There was no significant difference in costs or QALYs per patient at 1 year between doxycycline-initiated therapy and prednisolone-initiated therapy (incremental cost of doxycycline-initiated therapy £959, 95% CI -£24 to £1941; incremental QALYs of doxycycline-initiated therapy -0.024, 95% CI -0.088 to 0.041). Using a willingness-to-pay criterion of < £20,000 per QALY gained, the net monetary benefit associated with doxycycline-initiated therapy was negative but imprecise (-£1432, 95% CI -£3094 to £230). CONCLUSIONS: A strategy of starting BP patients on doxycycline is non-inferior to standard treatment with oral prednisolone for short-term blister control and considerably safer in the long term. The limitations of the trial were the wide non-inferiority margin, the moderate dropout rate and that serious adverse event collection was unblinded. Future work might include inducing remission with topical or oral corticosteroids and then randomising to doxycycline or prednisolone for maintenance. TRIAL REGISTRATION: Current Controlled Trials ISRCTN13704604. 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. 21, No. 10. See the NIHR Journals Library website for further project information.