Celebrating 20 years of the UK Dermatology Clinical Trials Network. Part 1: Developing and delivering high-quality independent clinical trials.

The UK Dermatology Clinical Trials Network (UK DCTN) was formed in 2002 with the aim of developing and supporting high-quality independent national clinical trials that address prioritized research questions for people with skin disease. Its philosophy is to democratize UK dermatological clinical research and to tackle important clinical questions that industry has no incentive to answer. The network also plays a key role in training and capacity development. Its membership of over 1000 individuals includes dermatology consultants, trainees, dermatology nurses, general practitioners, methodologists and patients. Its organizational structures are lean and include a co-ordinating team based at the Centre of Evidence-Based Dermatology in Nottingham, and an executive with independent members to ensure probity and business progression. A prioritization panel and steering group enable a pipeline of projects to be prioritized and refined for external funding from independent sources. The UK DCTN has supported and completed 12 national clinical trials, attracting investment of over £15 million into UK clinical dermatology research. Trials have covered a range of interventions from drugs such as doxycycline (BLISTER), silk clothing for eczema (CLOTHES) and surgical interventions for hidradenitis suppurativa (THESEUS). Trial results are published in prestigious journals and have global impact. Genuine partnership with patients and carers has been a strong feature of the network since its inception. The UK DCTN is proud of its first 20 years of collaborative work, and aims to remain at the forefront of independent dermatological health technology assessment, as well as expanding into areas including diagnostics, artificial intelligence, efficient studies and innovative designs.

Celebrating 20 years of the UK Dermatology Clinical Trials Network. Part 2: education, training and capacity building.

In Part 1 of this 2-part review of the 20th anniversary of the UK Dermatology Clinical Trials Network (UK DCTN), we described its role in developing and supporting clinical trial proposals, elaborating on structure, process and clinical trials activity. This review describes the diverse educational and training activities that the UK DCTN supports. Although not primarily set up as an educational organization, an education and training function emerged organically as the network grew. Education and training also embodies the democratization principle that drove the formation of the UK DCTN, allowing participation from a much wider group of individuals than just senior academics. Far from being a sideline, education and training has now become a major component of the UK DCTN that evolves constantly through changing training curricula and trial methodology developments. Formal UK DCTN training opportunities started in 2007 with competitively awarded annual fellowships for dermatology trainees, followed by similar schemes for general practitioners, Staff and Associate Specialist clinicians and dermatology nurses. These were followed in 2013 by larger groups of trainees who work up specific trial proposals with senior mentors. Finally, a virtual journal club emerged during the pandemic in 2020 in order to reach trainees with little access to academic training. Focused activities with dermatological nurses and patients/carers also take place. Such activities require considerable organization and volunteerism from the co-ordinating centre and former fellows. Education and training has become an essential component for capacity building to develop clinical trials and succession planning for the UK DCTN.

Hypothermia is associated with a low ETCO2 and low pH-stat PaCO2 in refractory cardiac arrest.

AIMS: The end-tidal carbon dioxide (ETCO2) is frequently measured in cardiac arrest (CA) patients, for management and for predicting survival. Our goal was to study the PaCO2 and ETCO2 in hypothermic cardiac arrest patients. METHODS: We included patients with refractory CA assessed for extracorporeal cardiopulmonary resuscitation. Hypothermic patients were identified from previously prospectively collected data from Poland, France and Switzerland. The non-hypothermic CA patients were identified from two French cohort studies. The primary parameters of interest were ETCO2 and PaCO2 at hospital admission. We analysed the data according to both alpha-stat and pH-stat strategies. RESULTS: We included 131 CA patients (39 hypothermic and 92 non-hypothermic). Both ETCO2 (p < 0.001) and pH-stat PaCO2 (p < 0.001) were significantly lower in hypothermic compared to non-hypothermic patients, which was not the case for alpha-stat PaCO2 (p = 0.15). The median PaCO2-ETCO2 gradient was greater for hypothermic compared to non-hypothermic patients when using the alpha-stat method (46 mmHg vs 30 mmHg, p = 0.007), but not when using the pH-stat method (p = 0.10). Temperature was positively correlated with ETCO2 (p < 0.01) and pH-stat PaCO2 (p < 0.01) but not with alpha-stat PaCO2 (p = 0.5). The ETCO2 decreased by 0.5 mmHg and the pH-stat PaCO2 by 1.1 mmHg for every decrease of 1° C of the temperature. The proportion of survivors with an ETCO2 ≤ 10 mmHg at hospital admission was 45% (9/25) for hypothermic and 12% (2/17) for non-hypothermic CA patients. CONCLUSIONS: Hypothermic CA is associated with a decrease of the ETCO2 and pH-stat PaCO2 compared with non-hypothermic CA. ETCO2 should not be used in hypothermic CA for predicting outcome.

Clinical characteristics and haemodynamic state of patients undergoing interhospital transfer for postpartum haemorrhage: A study of a single-centre helicopter emergency medical service.

OBJECTIVE: Uterine artery embolization is an attractive option for the management of postpartum haemorrhage, however it is not available in every hospital. We compared the clinical characteristics and haemodynamic state of patients with postpartum haemorrhage, before and after helicopter transfer to a tertiary hospital for possible uterine artery embolization. We also analysed whether the type of treatment could modify the outcome. STUDY DESIGN: Between 1999 and 2019 in Switzerland, we retrospectively found 82 consecutive patients with postpartum haemorrhage who were transferred by a physician-staffed helicopter emergency medical service to the tertiary hospital for potential uterine artery embolization. The collected data included the type of delivery, estimated blood loss, shock index and blood lactate levels before transfer and at destination, uterine artery embolization rate and hospital mortality rate. Our primary outcome was to describe the clinical characteristics, outcomes and haemodynamic state of the patients with postpartum haemorrhage before and after helicopter transfer. Our secondary outcome was to report the treatments performed at the tertiary hospital. The collected data were analysed with Stata version 14 (Stata Corporation, College Station, TX, USA). Continuous data are compared by using the Student's t-test or the Mann-Whitney U test, as appropriate. RESULTS: We included 69 patients. Postpartum haemorrhage occurred after vaginal delivery in 38 cases (55%). Blood loss prior to transfer exceeded 2 L in 34% of cases. The median shock index was 1 (IQR 0.8-1.1) before transfer and 0.9 (IQR 0.8-1.1) after transfer (p = 0.41). The median lactate level was 2.9 mmol/L (IQR 2.1-6.8) before, and 2.1 mmol/L (IQR 1.55-3.5) after transfer (p = 0.90). Forty-four patients underwent uterine artery embolization (64%), with an overall success rate of 93%. One patient died (1.4%), from a haemorrhagic shock of abdominal origin. CONCLUSIONS: Interhospital helicopter transfer of patients with postpartum haemorrhage to a tertiary hospital seems to be safe in our setting, despite a significant proportion of patients exhibiting signs of haemodynamic instability. Decision criteria would be helpful to better guide choices regarding the transfer of patients with postpartum haemorrhage.

An evaluation of the Swiss staging model for hypothermia using hospital cases and case reports from the literature.

BACKGROUND: The Swiss staging model for hypothermia uses clinical indicators to stage hypothermia and guide the management of hypothermic patients. The proposed temperature range for clinical stage 1 is < 35-32 °C, for stage 2 is < 32-28 °C, for stage 3 is < 28-24 °C, and for stage 4 is below 24 °C. Our previous study using 183 case reports from the literature showed that the measured temperature only corresponded to the clinical stage in the Swiss staging model in approximately 50% of cases. This study, however, included few patients with moderate hypothermia. We aimed to expand this database by adding cases of hypothermic patients admitted to hospital to perform a more comprehensive evaluation of the staging model. METHODS: We retrospectively included patients aged ≥18 y admitted to hospital between 1.1.1994 and 15.7.2016 with a core temperature below 35 °C. We added the cases identified through our previously published literature review to estimate the percentage of those patients who were correctly classified and compare the theoretical with the observed temperature ranges for each clinical stage. RESULTS: We included 305 cases (122 patients from the hospital sampling and the 183 previously published). Using the theoretically derived temperature ranges for clinical stages resulted in 185/305 (61%) patients being assigned to the correct temperature range. Temperature was overestimated using the clinical stage in 55/305 cases (18%) and underestimated in 65/305 cases (21%); important overlaps in temperature existed among the four stage groups. The optimal temperature thresholds for discriminating between the four stages (32.1 °C, 27.5 °C, and 24.1 °C) were close to those proposed historically (32 °C, 28 °C, and 24 °C). CONCLUSIONS: Our results provide further evidence of the relationship between the clinical state of patients and their temperature. The historical proposed temperature thresholds were almost optimal for discriminating between the different stages. Adding overlapping temperature ranges for each clinical stage might help clinicians to make appropriate decisions when using clinical signs to infer temperature. An update of the Swiss staging model for hypothermia including our methodology and findings could positively impact clinical care and future research.

Clinical characteristics and outcomes of witnessed hypothermic cardiac arrest: A systematic review on rescue collapse.

AIMS: Cardiac arrest related to accidental hypothermia may occur at temperatures below 32 °C. Our goal was to describe the clinical characteristics and outcomes of patients who suffered from witnessed hypothermic cardiac arrest (CA) and assess the occurrence of hypothermic CA as a function of patient body temperature. METHODS: We conducted a systematic review of the literature on cases of hypothermic CA due to rescue collapse. Patient information data from hypothermic CA patients were collected and combined with additional unpublished data to assess the clinical characteristics and outcome of hypothermic CA patients. RESULTS: A total of 214 patients was included in this systematic review. Of the 206 witnessed hypothermic CA patients with a recorded body temperature, the average body temperature was 23.9 ± 2.7 °C with five patients (2.4%) having a core body temperature of >28 °C. The highest temperature of a patient surviving hypothermic witnessed cardiac arrest without other associated risk factors for cardiac arrest was 29.4 °C. The first recorded cardiac rhythm was asystole in 33 of the 112 patients (30%) for whom this information was available. The survival rate at hospital discharge of these hypothermic cardiac arrest patients was 73% (153 of 210 patients) and most survivors had favourable neurological outcome (89%; 102 of 105 patients). CONCLUSIONS: CA that is solely caused by hypothermia did not occurs for patients with a body temperature >30 °C. Our findings provide valuable new information that can be incorporated into the international clinical management guidelines of accidental hypothermia.

Use of rituximab as an induction therapy in anti-glomerular basement-membrane disease.

BACKGROUND: Anti-glomerular basement-membrane (anti-GBM) disease (or Goodpasture disease) is characterized by severe kidney and lung involvement. Prognoses have improved with treatments that combine plasma exchange and immunosuppressive drugs. However, patients with severe renal involvement can have poor renal outcomes and cyclophosphamide can cause significant complications. Anti-GBM antibodies have a direct pathogenic effect on the disease: thus, therapeutics that can decrease their production, such as rituximab, could be a good alternative. METHODS: The medical files of five patients that had received rituximab as a first-line therapy (instead of cyclophosphamide), plus plasma exchange and steroids, were reviewed. All patients had severe disease manifestations. RESULTS: Four patients required dialysis at diagnosis and remained dialysis-dependent over the mean follow-up of 15 months. Three patients had pulmonary involvement, but recovered even though mechanical ventilation was required. Anti-GBM antibodies became rapidly undetectable in all patients. One infectious and two hematological complications were observed. CONCLUSIONS: We report the outcomes of five patients with Goodpasture disease and treated with rituximab as a first-line treatment. This strategy was effective at treating pulmonary manifestations and was associated with a good biological response with no major serious adverse events. However, renal outcomes were not significantly improved.

Effect of double-filtration plasmapheresis for antibody-mediated rejection on hemostasis parameters and thrombin generation.

INTRODUCTION: Donor-specific alloantibodies (DSAs) cause kidney-allograft loss in chronic antibody-mediated rejection (CAMR). Treatment relies on blocking antibody-producing cells and removing DSAs by apheresis: e.g., double-filtration plasmapheresis (DFPP). MATERIALS AND METHODS: To determine the impact of DFPP (6 or 8 sessions/patient) on clotting factors and natural anticoagulants, and on thrombin generation, we performed a prospective and observational study in five CAMR kidney-transplant patients who received DFPP plus rituximab therapy. Thrombin generation was performed in poor platelet plasma (PPP) with 5 pM tissue factor without and with 2 nM recombinant human thrombomodulin. RESULTS: After the first DFPP session, median levels of high molecular-weight proteins (fibrinogen, FV, FVIII, FXI, FXIII, von Willebrand factors and α2-MG) decreased significantly to <50% of baseline values, whereas levels of low molecular-weight factors (<100 kDa) were not significantly modified, except for protein S and TFPI. Of note, binding-protein (BP) S, i.e., C4BP, was significantly decreased. Over the course of successive DFPP sessions, both high and lower molecular-weight proteins (<100 kDa) with longer half-lives (>2 days, prothrombin and factor XII) were significantly decreased. DFPP also highly affected thrombin generation in the absence of thrombomodulin but not significantly in the presence of thrombomodulin. After the first DFPP session, mean endogenous thrombin potential (ETP) and peak thrombin (PH) significantly decreased when the thrombin generation assay was performed without thrombomodulin (respectively, 1084 nM·min for ETP and 210 nM for PH after the first DFPP session compared to 1616 nM·min and 264 nM at baseline). In the presence of thrombomodulin, there was only a slight decrease in ETP and PH (respectively 748 nM·min, and 172 nM after the first DFPP session compared to 822 nM·min and 179 nM at baseline). After the last session, median ETP and PH decreased respectively to 646 nM·min and 143 nM without thrombomodulin, and, to 490 nM·min and 117 nM with thrombomodulin. CONCLUSIONS: DFPP significantly removed high molecular-weight proteins from the haemostatic system and profoundly decreased levels of protein S and TFPI. Overall thrombin-generation balance was only moderately affected in the presence of thrombomodulin. Nevertheless, high depletion of fibrinogen, FXIII and Von Willebrand Factor may expose patients to an increased risk of bleeding.

A retrospective study of complaint letters sent to a Swiss Emergency Department between 2009 and 2014.

OBJECTIVE: Patient complaints are a valuable resource for monitoring and improving patient safety and quality of care. The purpose of this study was to analyze the complaint letters received at a Swiss academic emergency department (ED) over six years. METHODS: A retrospective study of all complaint letters sent to a Swiss academic ED between 2009 and 2014 was conducted. The following data were extracted: epidemiology items, reasons for complaints, hospital responses, follow-up, and severity of the events mentioned in the complaints. All complaint letters related to adult patients evaluated in the ED between 2009 and 2014 were included and a qualitative evaluation was performed based on a systematic taxonomy. Context, patient characteristics, mode of resolution and clinical severity of the related adverse event were evaluated. RESULTS: A total number of 156 complaints were recorded, corresponding to an annual complaint rate of 5.5 to 8.8 per 10,000 visits. The complaints concerned mostly three domains (clinical care, management and patient or caregiver relationship) with a slight predominance for organisation and logistics (39%) compared with 31.4% for standard of care and 29.6% for communication/relational complaints. The majority of complaints were sent within one month of the ED visit. Most complaints were resolved with written apologies or explanations. The consequences of 73.5% of the events in question were considered minor or negligible, 19% moderate, and 6.5% major. Only 1% (two cases) was related to situations with catastrophic consequences. CONCLUSION: Complaint incidence in our ED was low and remained stable over the six-year observation period. Most of the complaints pertained to incidents that entailed negligible or minor consequences. As most complaints were due to inadequate communication, interventions targeting improvement of the doctor/patient communication are required.

An induction or flare of arthritis and/or sacroiliitis by vedolizumab in inflammatory bowel disease: a case series.

BACKGROUND: In inflammatory bowel disease (IBD), a new biological therapy has recently been approved. Vedolizumab is a humanised IgG1 monoclonal antibody to α4ß7 integrin that modulates gut lymphocyte trafficking. Although an exclusively local effect of vedolizumab could be expected based on the restricted presence of the α4ß7-mucosal vascular addressin cell adhesion molecule 1 complex in the gut, past combined success with anti-tumour necrosis factor, and previous demonstration of α4ß7 integrin in the joint, led to the expectation of a therapeutic efficacy in spondyloarthritis. Nonetheless, the effect of vedolizumab on extraintestinal manifestations-and especially the joint-has not been reported so far. CASE REPORT: A series of five patients with IBD who were treated with vedolizumab and promptly developed new onset or exacerbation of sacroiliitis or arthritis are reported. CONCLUSIONS: Vedolizumab therapy does not seem to show any efficacy in and might even induce arthritis and/or sacroiliitis. However, larger cohort studies are needed to provide information on the prevalence, the evolution and underlying mechanism.

Brief Report: Six-Week Treatment of Axial Spondyloarthritis Patients With an Optimal Dose of Nonsteroidal Antiinflammatory Drugs: Early Response to Treatment in Signal Intensity on Magnetic Resonance Imaging of the Sacroiliac Joints.

OBJECTIVE: To evaluate the early effect of full-dose nonsteroidal antiinflammatory drugs (NSAIDs) on the extent and intensity of bone marrow edema of the sacroiliac (SI) joints on magnetic resonance imaging (MRI) in axial spondyloarthritis (SpA). METHODS: A single-center, 6-week study of a cohort of consecutive patients with clinically suspected axial SpA was conducted. A total of 117 patients were screened. Forty patients who were diagnosed as having axial SpA and had presented with a positive MRI of the SI joints as defined by the Assessment of SpondyloArthritis international Society (ASAS) criteria were considered for a followup MRI after 6 weeks of an optimal dose of NSAIDs. Twenty patients completed the study. Disease activity was monitored by determining the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score every 2 weeks and the Bath Ankylosing Spondylitis Functional Index score at baseline and week 6. NSAID intake was assessed by the ASAS NSAID index. Primary end points were improvement in bone marrow edema of the SI joints on MRI and BASDAI response at week 6. RESULTS: Approximately one-third of eligible patients newly diagnosed as having axial SpA were unable to continue the full-dose NSAID schedule. The median NSAID index was 97% in patients who completed the study. There was a reduction of 1.1 units (10.5%) in mean Spondyloarthritis Research Consortium of Canada (SPARCC) scores at week 6 in comparison to baseline (P = 0.032). Overall, only 30% of the patients (6 of 20) had a minimal clinically important difference of ≥2.5 in SPARCC score. However, 80% of the patients displayed high-intensity lesions on STIR images at baseline, which decreased significantly at week 6 (P = 0.011). There was a significant decrease in the relative intensity of the region of interest (P = 0.007) and a mean decrease of 0.6 in the BASDAI score per 2 weeks of therapy (P = 0.001). Only 29.4% of the patients met the BASDAI criteria for 50% improvement (BASDAI50) at week 6. CONCLUSION: Our findings indicate a high level of dropout among patients receiving full-dose NSAID therapy in daily practice. In those who tolerated NSAID therapy, there was no clinically relevant decrease in SPARCC scores and low BASDAI50 response. However, we found a decrease in signal intensity of bone marrow edema of the SI joints as an early response to 6 weeks of optimal NSAID therapy in patients newly presenting with axial SpA.

Diagnostic value of pelvic enthesitis on MRI of the sacroiliac joints in spondyloarthritis.

OBJECTIVE: To determine the prevalence and diagnostic value of pelvic enthesitis on MRI of the sacroiliac (SI) joints in spondyloarthritis (SpA). MATERIALS AND METHODS: A retrospective study in 444 patients aged 17-45 years old with MRI of the SI joints and with clinically suspected sacroiliitis was performed. Patients were classified as having SpA if they fulfilled the Assessment of Spondyloarthritis International Society (ASAS) criteria. Pelvic enthesitis on MRI was correlated with the final diagnosis. Sensitivity, specificity, positive and negative likelihood ratio (LR) and predictive values (PV) of pelvic enthesitis for the diagnosis of SpA were calculated. RESULTS: MRI showed pelvic enthesitis in 24.4 % of patients with SpA and in 7.1 % of patients without SpA. Presence of any enthesitis had sensitivity, specificity, LR+, LR-, PPV and NPV of 24.4 %, 92.9 %, 3.45, 0.81, 69.4 % and 65.2 % for the diagnosis of SpA, respectively. The most commonly affected entheses were the longitudinal ligament insertion (4.5 %), the retroarticular ligaments (4.1 %) and the pubic symphysis (4.1 %). The sites of enthesitis with the highest PPV for SpA were the iliac crest/wing (85.7 %) and the retroarticular ligaments (81.3 %). CONCLUSION: Nearly one fourth of SpA patients with suspected sacroiliitis showed pelvic enthesitis on MRI. Such pelvic enthesitis has a high specificity for the diagnosis of spondyloarthritis. KEY POINTS: • Enthesitis is the primary clinical feature of spondyloarthritis. • Magnetic resonance imaging of the sacroiliac joints can demonstrate pelvic enthesitis. • Pelvic enthesitis has a high specificity for the diagnosis of spondyloarthritis.

MRI of the SI joints commonly shows non-inflammatory disease in patients clinically suspected of sacroiliitis.

PURPOSE: To determine the prevalence of clinically relevant non-inflammatory disease on MRI of the sacroiliac (SI) joints in patients suspected of sacroiliitis. To assess the added value of axial imaging of the pelvis in these patients. METHODS: In a retrospective study of 691 patients undergoing MRI of the SI joints from January 2006 to December 2012 for inflammatory back pain the prevalence of sacroiliitis and non-inflammatory disease was recorded. RESULTS: In 285 (41%) patients MRI did not show any abnormal findings. In 36% of patients MRI features of sacroiliitis were present. Spinal degenerative changes were the most common non-inflammatory finding in 305 patients (44.1%) and consisted of disc degeneration in 222 (32%) patients, facet joint arthrosis in 58 (8.4%) patients and disc herniation in 25 (3.6%) patients. Hip joint disease in 44 (6.4%) patients, lumbosacral transitional anomaly in 41 (5.9%) patients, SI joint degenerative changes in 25 (3.6%) patients and diffuse idiopathic skeletal hyperostosis in 24 (3.5%) patients were also common. Osteitis condensans ilii in 17 (2.5%) patients, tumour in 11 (1.6%) patients, fracture in 8 (1.2%) patients, infection in 4 (0.6%) patients and acute spondylolysis in 2 patients (0.3%) were less frequently seen. CONCLUSION: Our study shows that non-inflammatory disease is more common than true sacroiliitis on MRI of the SI joints in patients with inflammatory type back pain. Axial pulse sequences may demonstrate unexpected findings that remain undetected if only coronal images are obtained. Clinical relevance statement:, MRI of the SI joints may demonstrate conditions that clinically mimic sacroiliitis. Axial imaging of the pelvis may help detect these unexpected findings.

How sensitive and specific are MRI features of sacroiliitis for diagnosis of spondyloarthritis in patients with inflammatory back pain?

OBJECTIVE: To determine the sensitivity and specificity of MRI features of sacroiliitis in spondyloarthritis (SpA). MATERIALS AND METHODS: A retrospective study reviewed MRI of the sacroiliac (SI) joints in 517 patients with inflammatory back pain. Sensitivity, specificity, positive and negative likelihood ratios of active and structural lesions of sacroiliitis with final clinical diagnosis as golden standard was calculated. RESULTS: MRI showed active inflammation in 42% of patients (bone marrow oedema (BMO) (41.5%), capsulitis (3.3%), enthesitis (2.5%)) and structural changes in 48.8% of patients (erosion (25%), fat infiltration (31.6%), sclerosis (32%) and ankylosis (7.6%)). BMO was the MRI feature with the highest sensitivity (65.1%) for diagnosis of SpA. Capsulitis (99%), enthesitis (98.4%), ankylosis (97.4%) and erosion (94.8%) had a high specificity for diagnosis of SpA, whereas BMO (74.3%), sclerosis (75.8%) and fat infiltration (84.0%) were less specific. BMO concomitant with enthesitis, capsulitis or erosions increased the specificity. Concomitant presence of BMO and sclerosis or fat infiltration decreased the specificity. CONCLUSION: BMO is moderately sensitive and specific for diagnosis of SpA in patients with inflammatory back pain. BMO concomitant with enthesitis, capsulitis, ankylosis or erosion increases the specificity. Concomitant fat infiltration or sclerosis decreases the specificity for diagnosis of SpA. Of all lesions, erosion had by far the highest positive likelihood ratio for diagnosis of SpA.

[Mushroom poisoning]. / Intoxication par les champignons.

Mushroom poisoning is a regular complaint for consultation in emergency facilities. These situations are usually benign and symptomatic treatment is sufficient. However, severe damage can occur, potentially life-threatening. We review the various syndromes associated with the toxins involved, their management and the major signs that are suggestive of serious injury and requiring hospitalization.