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Naked mole-rats are among the most hypoxia-tolerant mammals. During hypoxia, their body temperature (Tb) decreases via unknown mechanisms to conserve energy. In small mammals, non-shivering thermogenesis in brown adipose tissue (BAT) is critical to Tb regulation; therefore, we hypothesize that hypoxia decreases naked mole-rat BAT thermogenesis. To test this, we measure changes in Tb during normoxia and hypoxia (7% O2; 1–3 h). We report that interscapular thermogenesis is high in normoxia but ceases during hypoxia, and Tb decreases. Furthermore, in BAT from animals treated in hypoxia, UCP1 and mitochondrial complexes I-V protein expression rapidly decrease, while mitochondria undergo fission, and apoptosis and mitophagy are inhibited. Finally, UCP1 expression decreases in hypoxia in three other social African mole-rat species, but not a solitary species. These findings suggest that the ability to rapidly down-regulate thermogenesis to conserve oxygen in hypoxia may have evolved preferentially in social species., Naked mole-rats are hypoxia-tolerant mammals, and during hypoxia their body temperature decreases via unknown mechanisms. Here the authors report that the hypoxia-induced body temperature decrease in naked mole rats occurs through decreased brown adipose tissue thermogenesis via decreases in a key thermogenic mitochondrial protein: UCP1.

Background\ud \ud Although non-invasive central and peripheral stimulations are accruing support as promising treatments in different neurological conditions, their effects on dysarthria have not been systematically investigated.\ud \ud \ud \ud Objective\ud \ud The purpose of this review was to examine the evidence base of non-invasive stimulation for treating dysarthria, identify which stimulation parameters have the most potential for treatment and determine safety risks.\ud \ud \ud \ud Methods\ud \ud A systematic review with meta-analysis, when possible, involving publications indexed in MEDLINE, PsychINFO, EMBASE CINHAL the Linguistics and Language Behavioral Abstracts, Web of Science, Cochrane Register of Control Trials and 2 trial registries was completed. Articles were searched in December 2018 and updated in June 2021 using keywords related to brain and electrical stimulation, dysarthria and research design. We included trials with randomised, cross-over or quasi-experimental designs; involving a control group; and investigating treatment of neurogenic dysarthria with non-invasive stimulation. Methodological quality was determined with the Cochrane's Risk of Bias-2 tool.\ud \ud \ud \ud Results\ud \ud In total, 6186 studies were identified; 10 studies (6 randomised controlled trials and 4 cross-over studies) fulfilled the inclusion criteria. All 10 trials (268 adults with Parkinson's disease, stroke and neurodegenerative cerebellar ataxia) focused on brain stimulation (6 repetitive transcranial magnetic stimulation; 3 transcranial direct current stimulation; and 1 repetitive transorbital alternating current stimulation). Adjunct speech-language therapy was delivered in 2 trials. Most trials reported one or more positive effects of stimulation on dysarthria-related features; however, given the overall high risk of bias and heterogeneity in participant, trial and outcome measurement characteristics, no conclusions can be drawn. Post-treatment size effects for 2 stroke trials demonstrated no statistically significant differences between active and sham stimulation across 3 dysarthria outcomes.\ud \ud \ud \ud Conclusions\ud \ud Evidence for use of non-invasive brain stimulation in treating dysarthria remains inconclusive. Research trials that provide reliable and replicable findings are required.

We assessed the validity of coded healthcare data to identify cases of haemophagocytic lymphohistiocytosis (HLH). Hospital Episode Statistics (HES) identified 127 cases within five hospital Trusts 2013-2018 using ICD-10 codes D76.1, D76.2 and D76.3. Hospital records were reviewed to validate diagnoses. Out of 74 patients, 73 were coded D76.1 or D76.2 (positive predictive value 89·0% [95% Confidence Interval {CI} 80·2-94·9%]) with confirmed/probable HLH. For cases considered not HLH, 44/53 were coded D76.3 (negative predictive value 97·8% [95% CI 88·2-99·9%]). D76.1 or D76.2 had 68% sensitivity in detecting HLH compared to an established active case-finding HLH register in Sheffield. Office for National Statistics (ONS) mortality data (2003-2018) identified 698 patients coded D76.1, D76.2 and D76.3 on death certificates. Five hundred and forty-one were coded D76.1 or D76.2 of whom 524 (96·9%) had HLH in the free-text cause of death. Of 157 coded D76.3, 66 (42·0%) had HLH in free text. D76.1 and D76.2 codes reliably identify HLH cases, and provide a lower bound on incidence. Non-concordance between D76.3 and HLH excludes D76.3 as an ascertainment source from HES. Our results suggest electronic healthcare data in England can enable population-wide registration and analysis of HLH for future research.

Forced vital capacity (FVC) is an essential respiratory measurement for assessment and monitoring of patients with Amyotrophic Lateral Sclerosis (ALS). Our clinic rapidly implemented remote assessment of FVC after COVID-19 related restrictions on respiratory testing were imposed, using mini-spirometers and video consultation. We sought to evaluate the patient's experiences of performing remote respiratory assessments to guide future development and optimisation of the service. Twenty-five patients completed surveys. The mean age was 65.2 years and average time from diagnosis was 17.04 (2-99) months. Seventy-two percent (n = 18) required help from a caregiver to perform the tests. Ninety-two percent (n = 23) of patients reported that overall, they were satisfied and were happy to continue with remote respiratory assessment. Reducing the number of clinic visits for review and assessment was valued by 92% (n = 23) and reducing the risk associated with COVID-19 was valued by 96% (n = 24). The highest frequency reported as acceptable for performing the remote breathing assessments was monthly (60%, n = 15), followed by every second month (28%, n = 7). Remote respiratory testing is viewed positively by patients. These technologies used in combination with video-consultations and other novel forms of remote monitoring implemented in response to the COVID-19 crisis will continue to be valuable tools for clinical care in future. However, further evaluation of the validity of remote respiratory assessment is required.

Background and Aim Immune checkpoint inhibitor (ICI) colitis is an increasingly common problem encountered as the use of checkpoint inhibitors (CPIs) grows in the management of cancers. Corticosteroids and tumour necrosis factor (TNF)‐alpha inhibitors are widely recommended in the management of ICI colitis; however, the experience is limited when patients are refractory. Different authors have reported success with vedolizumab, mycophenolate, and cyclosporine. This case series describes our experience with calcineurin inhibitors in the management of corticosteroid and anti‐TNF‐alpha refractory ICI colitis. Methods Data from electronic medical records were identified and reviewed retrospectively from a cohort of patients treated at a single oncology center. All patients who were identified between March 2018 and May 2020 with ICI colitis refractory to treatment with infliximab and corticosteroids were included. Results There were 11 patients who developed ICI colitis after receiving CPIs for advanced melanoma and required rescue therapy with either cyclosporine or tacrolimus after treatment failure of infliximab. Median age was 53 (±8.48) years, with nine patients (81%) receiving combination Cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) / programmed cell death protein 1 (PD‐1) immunotherapy. Median time after first CPI infusion to ICI colitis was 4.43 (±19.53) weeks. The median time from onset of symptoms to commencement of rescue therapy with calcineurin inhibitors was 70 days (±66.06). Eight of the 11 patients (72.7%) responded to calcineurin inhibition. In patients who responded, calcineurin inhibitors were continued for a median of 54 (±28.96) days. Conclusion The calcineurin inhibitors cyclosporine and tacrolimus appear to be a safe and effective option for the management of patients with infliximab‐refractory ICI colitis. The therapeutic benefit is observed rapidly, and adverse effects appear to be limited with close monitoring., Immune checkpoint inhibitor (ICI) colitis is an increasingly common and often challenging management problem. In addition to battling prolonged symptoms, colitis may pose a significant interruption to treatment options for malignancy. This case series describes our experience with calcineurin inhibitors in the management of corticosteroid and anti‐TNF‐alpha refractory ICI.

Current risk stratification strategies do not fully explain cardiovascular disease (CVD) risk. We aimed to evaluate the association of low-density lipoprotein (LDL-P) and high-density lipoprotein (HDL-P) particles with progression of coronary artery calcium and carotid wall injury. All participants in the Multi-Ethnic Study Atherosclerosis (MESA) with LDL-P and HDL-P measured by ion mobility, coronary artery calcium score (CAC), carotid intima-media thickness (IMT), and carotid plaque data available at Exam 1 and 5 were included in the study. CAC progression was annualized and treated as a categorical or continuous variable. Carotid IMT and plaque progression were treated as continuous variables. Fully adjusted regression models included established CVD risk factors, as well as traditional lipids. Mean (±SD) follow-up duration was 9.6 ± 0.6 years. All LDL-P subclasses as well as large HDL-P at baseline were positively and significantly associated with annualized CAC progression, however, after adjustment for established risk factors and traditional lipids, only the association with medium and very small LDL-P remained significant (β -0.02, p = 0.019 and β 0.01, p = 0.003, per 1 nmol/l increase, respectively). Carotid plaque score progression was positively associated with small and very small LDL-P (p

Introduction In relation to wrist imaging, the accepted requirement is two orthogonal projections obtained at 90°, each with the wrist in neutral position. However, the literature and anecdotal experience suggests that this principle is not universally applied. Method This multiphase study was undertaken across eight different hospitals sites. Compliance with standard UK technique was confirmed if there was a change in ulna orientation between the dorsi-palmar (DP) and lateral wrist projections. A baseline evaluation for three days was randomly identified from the preceding three months. An educational intervention was implemented using a poster to demonstrate standard positioning. To measure the impact of the intervention, further evaluation took place at two weeks (early) and three months (late). Results Across the study phases, only a minority of radiographs demonstrated compliance with the standard technique, with an identical anatomical appearance of the distal ulna across the projections. Initial compliance was 16.8% ( n = 40/238), and this improved to 47.8% ( n = 77/161) post-intervention, but declined to 32.8% ( n = 41/125) within three months. The presence of pathology appeared to influence practice, with a greater proportion of those with an abnormal radiographic examination demonstrating a change in ulna appearances in the baseline cohort ( p Conclusion Assessment of image quality is critical for diagnosis and treatment monitoring. Yet poor compliance with standard anatomical principles was evident. A simple educational intervention resulted in a transient improvement in wrist positioning, but the impact was not sustained over time.

Objectives:\ud Health technology assessment aims to inform and support healthcare decision making, and trials are part of that process. The purpose of this study was to measure the impact of a sample of trials in a meaningful but robust fashion.\ud \ud Methods:\ud All randomized controlled trials funded and published by the UK National Institute of Health Research in the Health Technology Assessment journal series and other peer-reviewed journals were identified for 2006 to 2015. Citation analysis was performed for all trials, and quantitative content analysis was undertaken on a purposive sample to determine whether impact could be categorized as “instrumental” (ie, having a clear influence on key research and policy publications).\ud \ud Results:\ud The search identified 133 relevant trials. The citation rate per trial was 102.97. Of the 133 trials, 129 (98%) were cited in 1 or more systematic reviews or meta-analyses (mean per trial = 7.18, range = 0-44). Where they were cited, the trials were used in some form of synthesis 63% of the time. Ninety-one of the 133 (68%) trials were found to be cited in 1 or more guidance or policy document (mean per trial = 2.75, range = 0-26) and had an instrumental influence 41% of the time. The publication of these trials’ results in journals other than the Health Technology Assessment journal appears to enhance the discoverability of the trial data. Altmetric.com proved to be very useful in identifying unique policy and guidance documents.\ud \ud Conclusion:\ud These trials have impressive citation rates, and a sizeable proportion are certainly being used in key publications in a genuinely instrumental manner.

Background Relative enlargement of the pulmonary artery (PA) on chest CT imaging is associated with respiratory exacerbations in patients with COPD or cystic fibrosis. We sought to determine whether similar findings were present in patients with asthma and whether these findings were explained by differences in ventricular size. Methods We measured the PA and aorta diameters in 233 individuals from the Severe Asthma Research Program III cohort. We also estimated right, left, and total epicardial cardiac ventricular volume indices (eERVVI, eELVVI, and eETVVI, respectively). Associations between the cardiac and PA measures (PA-to-aorta [PA/A] ratio, eERVVI-to-eELVVI [eRV/eLV] ratio, eERVVI, eELVVI, eETVVI) and clinical measures of asthma severity were assessed by Pearson correlation, and associations with asthma severity and exacerbation rate were evaluated by multivariable linear and zero-inflated negative binomial regression. Results Asthma severity was associated with smaller ventricular volumes. For example, those with severe asthma had 36.1 mL/m2 smaller eETVVI than healthy control subjects (P = .003) and 14.1 mL/m2 smaller eETVVI than those with mild/moderate disease (P = .011). Smaller ventricular volumes were also associated with a higher rate of asthma exacerbations, both retrospectively and prospectively. For example, those with an eETVVI less than the median had a 57% higher rate of exacerbations during follow-up than those with eETVVI greater than the median (P = .020). Neither PA/A nor eRV/eLV was associated with asthma severity or exacerbations. Conclusions In patients with asthma, smaller cardiac ventricular size may be associated with more severe disease and a higher rate of asthma exacerbations. Trial Registry ClinicalTrials.gov; No.: NCT01761630; URL: www.clinicaltrials.gov

Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. Acurrent challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma.

Background Multisystem Inflammatory Syndrome in Adults (MIS-A) is a recently emerging condition that occurs as a delayed complication of COVID-19 infection. It involves inflammation of multiple extra-pulmonary organ systems. Diagnostic criteria and treatment recommendations have yet to be clearly defined. We present a case of a young adult with suspected MIS-A who initially displayed symptoms and radiological findings of colitis. Case: A 22-year-old male with no past medical history suffered a minor respiratory illness for a few days and tested positive on SARS-CoV-2 RT-PCR. Approximately 6 weeks later, he presents after 3 days of right-sided abdominal pain, diarrhoea and fever. He is initially admitted with a working diagnosis of gastroenteritis. Sustained fever and escalating blood markers of illness led to abdominal CT; showing inflammation of ascending colon as well as some loops of small bowel. Hypotension becomes increasingly pronounced and on the fourth day of admission he developed type 1 respiratory failure with evidence of fluid overload. He was transferred to critical care for vasopressor and respiratory support. All microbiological and autoimmune screens performed return negative results but inflammatory markers were significantly elevated, he was diagnosed as MIS-A. IVIg was added to the antibiotics on day 4. His clinical condition dramatically improved and he was discharged home after 10 days in hospital. His blood tests have returned to normal and he has no lasting complications from his illness. Discussion This case displays the potential for MIS-A to present in various ways, with this example a primarily gastroenterological illness. It therefore highlights the importance of physicians in different fields having an awareness of the condition, in order to identify when MDT input is required to guide treatment. We review the current literature on various presentations and treatments of MIS-A, and discuss the need for clear case definition.

ObjectivesCOVIDTrach is a UK multicentre prospective cohort study project that aims to evaluate the outcomes of tracheostomy in patients with COVID-19 receiving mechanical ventilation and record the incidence of SARS-CoV-2 infection among healthcare workers involved in the procedure.DesignData on patient demographic, clinical history and outcomes were entered prospectively and updated over time via an online database (REDCap). Clinical variables were compared with outcomes, with logistic regression used to develop a model for mortality. Participants recorded whether any operators tested positive for SARS-CoV-2 within 2 weeks of the procedure.SettingUK National Health Service departments involved in treating patients with COVID-19 receiving mechanical ventilation.ParticipantsThe cohort comprised 1605 tracheostomy cases from 126 UK hospitals collected between 6 April and 26 August 2020.Main outcome measuresMortality following tracheostomy, successful wean from mechanical ventilation and length of time from tracheostomy to wean, discharge from hospital, complications from tracheostomy, reported SARS-CoV-2 infection among operators.ResultsThe median time from intubation to tracheostomy was 15 days (IQR 11, 21). 285 (18%) patients died following the procedure. 1229 (93%) of the survivors had been successfully weaned from mechanical ventilation at censoring and 1049 (81%) had been discharged from hospital. Age, inspired oxygen concentration, positive end-expiratory pressure setting, fever, number of days of ventilation before tracheostomy, C reactive protein and the use of anticoagulation and inotropic support independently predicted mortality. Six reports were received of operators testing positive for SARS-CoV-2 within 2 weeks of the procedure.ConclusionsTracheostomy appears to be safe in mechanically ventilated patients with COVID-19 and to operators performing the procedure and we identified clinical parameters that are predictive of mortality.Trial registration numberThe study is registered with ClinicalTrials.Gov (NCT04572438).

Objective: Sniff nasal inspiratory pressure (SNIP) is a commonly used clinical measure of respiratory impairment in amyotrophic lateral sclerosis (ALS), which is used to guide the initiation of noninvasive ventilation (NIV). SNIP can be completed with either an occluded or an un-occluded contralateral nostril. The aim of this study was to compare occluded and un-occluded SNIP measurements and to examine the decline in occluded SNIP over time compared to the ALSFRS-R respiratory subscore. Methods: This was a prospective longitudinal study examining occluded and un-occluded SNIP scores in ALS and PLS patients recorded between 2001 and 2018. Bland and Altman graphs were plotted for occluded vs. un-occluded SNIP measurements taking account of the repeated measures nature of the data. Longitudinal models were constructed as linear mixed effects multi-level models with follow-up in ALS limited to 6 years. Results: SNIP measured with an occluded contralateral nostril was systematically higher than with an un-occluded nostril. SNIP measured using both methods declined non-linearly, particularly after 2-3 years. The best fit model for decline in occluded SNIP included a main effect and interaction between site of onset and time, with age and diagnostic delay as independent variables. This showed a linear decline in spinal onset with a floor effect in bulbar-onset ALS. Conclusion: SNIP measured with an occluded and un-occluded contralateral nostril is not interchangeable, which is relevant in interpreting thresholds for initiation of NIV. SNIP declines non-linearly, which is explained in spinal onset ALS by age and diagnostic delay, but an apparent floor effect remains in bulbar onset.

Background There is little evidence to guide surgical management of biopsies yielding the histologic descriptor atypical intraepidermal melanocytic proliferation (AIMP). Objective Determine frequency of and factors associated with melanoma and melanoma in-situ (MIS) diagnoses after excision of AIMP and evaluate margins used to completely excise AIMP. Methods Retrospective, cross-sectional study of 1127 biopsies reported as AIMP and subsequently excised within one academic institution. Results Melanoma (in situ, stage 1A) was diagnosed after excision in 8.2% (92/1127) of AIMP samples. Characteristics associated with melanoma/MIS diagnosis included age 60-79 years (odds ratio [OR] 8.1, 95% confidence interval [CI] 2.5-26.2), age ≥80 years (OR 7.2, 95% CI 1.7-31.5), head/neck location (OR 4.9, 95% CI 3.1-7.7), clinical lesion partially biopsied (OR 11.0, 95% CI 6.7-18.1), and lesion extending to deep biopsy margin (OR 15.1, 95% CI 1.7-136.0). Average ± standard deviation surgical margin used to excise AIMP lesions was 4.5 ± 1.8 mm. Limitations Single-site, retrospective, observational study; interobserver variability across dermatopathologists. Conclusion Dermatologists and pathologists can endeavor to avoid ambiguous melanocytic designations whenever possible through excisional biopsy technique, interdisciplinary communication, and ancillary studies. In the event of AIMP biopsy, physicians should consider the term a histologic description rather than a diagnosis, and, during surgical planning, use clinicopathologic correlation while bearing in mind factors that might predict true melanoma/MIS.

SummaryWe assessed the validity of coded health care data to identify cases of haemophagocytic lymphohistiocytosis (HLH). Hospital Episode Statistics (HES) identified 127 cases within five hospital Trusts 2013-2018 using ICD-10 codes D76.1, D76.2 and D76.3. Hospital records were reviewed to validate diagnoses. 73/74 patients with confirmed/probable HLH were coded D76.1 or D76.2 (positive predictive value 89.0% [95% CI 80.2-94.9%]). For cases considered not HLH, 44/53 were coded D76.3 (negative predictive value 97.8% [95% CI 88.2%-99.9%]). D76.1 or D76.2 had 68% sensitivity in detecting HLH compared to an established active case finding HLH register in Sheffield. Office for National Statistics (ONS) mortality data (2003-2018) identified 698 patients coded D76.1, D76.2 and D76.3 on death certificates. 541 were coded D76.1 or D76.2 of whom 524(96.9%) had HLH in the free text cause of death. Of 157 coded D76.3, 66(42.0%) had HLH in free text.D76.1 and D76.2 codes reliably identify HLH cases, and provide a lower bound on incidence. Non-concordance between D76.3 and HLH excludes D76.3 as an ascertainment source from HES. Our results suggest electronic health care data in England can enable population wide registration and analysis of HLH for future research.

Background/Aims Juvenile idiopathic arthritis (JIA) is a heterogenous, childhood-onset condition persisting into adulthood in over 50% of people. Recognition of JIA-specific features is poor in adult services, there are no validated disease activity scores for adults with JIA and specialist adult JIA clinics are rare; this leads to under-treatment of adults with JIA. Sheffield Teaching Hospitals (STH) has a mature transition service and well-established young adult clinic (YAC) for 16-25 year olds and older adults with JIA. Here, we evaluate the proportion of our adult rheumatology workload attributable to JIA, the prevalence of JIA subtypes and therapies utilised. Methods Outpatient attendances in STH rheumatology are coded by diagnosis. The evaluation period was 1.12.2018 to 27.2.2020. We evaluated the number and characteristics of patients in the JIA cohort, producing a database from coded diagnoses and patient records, and analysed this using Microsoft Excel. Local permission was granted. Results 11,520 patients were seen in adult rheumatology in the evaluation period; 9,422 had a coded diagnosis of which 4,915 (52%) had inflammatory arthritis (IA). Assuming a proportional number of the 2,098 non-coded patients had IA (1,090), the adult IA cohort is estimated at 6,005. 304 patients (aged 17-72) with JIA were seen in adult rheumatology, accounting for 5% of the adult IA cohort. 280 (92%) were in the YAC, and 24 (8%) in general rheumatology. 31 (10%) patients had evidence of uveitis. The commonest subtypes of JIA were: 75 polyarticular (25%), 38 enthesitis related (13%) and 37 extended oligoarticular (12%). 64 (21%) patients had no subtype specified. Of the 233 (77%) JIA patients ever treated with methotrexate, 132 (57%) had discontinued due to inefficacy or adverse effects. 175 (58%) patients were on biologic treatment: the commonest therapies were adalimumab (40%, 70 patients) and etanercept (27%, 47 patients). There is evidence of diagnostic relabelling from JIA to other IA to access biologics not approved by NICE. Conclusion This evaluation uses real-world data, with some data loss due to absent coding, but shows JIA is a small proportion of adult rheumatology. This is a complex group with high biologic use, poor methotrexate tolerance and heterogenous disease phenotypes. Young adults experience specific challenges in adult services and require developmentally appropriate care, for which best evidence confirms young adult clinics are ideal. The majority of people with JIA are in a dedicated young adult service at STH. Biologics are used within NICE guidance, except for a minority where JIA is relabelled as IA to access additional biologics or due to independent funding requests. NICE guidance for JIA is outdated and restrictive. JIA is an adult disease in > 50% and requires specialist services, further research to elucidate validated adult disease activity scores and wider education amongst adult rheumatologists. Disclosure R.J. Nock: None. J.R. Maxwell: Other; JRM has served on advisory boards for Abbvie, Pfizer, BMS and Lilly and has received speaking honoraria from Pfizer, BMS, Novartis and Lilly. R.S. Tattersall: Other; RST has received speaker fees and educational grants to attend meetings from UCB, AbbVie, Pfizer and Janssen.

Background/Aims Alemtuzumab is an efficacious therapy for relapsing remitting multiple sclerosis (RRMS) preventing neural damage and reducing relapse rate by up to 74%. Administered in 2 treatment cycles 12 months apart and authorised for use in > 40 countries, it is a humanized monoclonal antibody selectively directed against the CD52 antigen of T- and B-Lymphocytes. Significant autoimmune effects of Alemtuzumab are reported 6-60 months post-treatment including secondary autoimmunity (40%), thyroid disease (18-26%), idiopathic thrombocytopenic purpura (1-3%) and anti-glomerular basement membrane disease (1%). There are 2 case reports of haemophagocytic lymphohistiocytosis(HLH) in people with MS triggered by Alemtuzumab. HLH is a clinical syndrome of dysregulated, pathological overactivation of innate immunity leading to cytokine storm, multi-organ failure and a very high mortality rate. Clinical features are difficult to distinguish from, and may coexist with, other syndromes such as sepsis. Recognition requires a high index of clinical suspicion and management through multidisciplinary teams (MDT) using immune suppression. Early recognition and treatment improve outcome. Methods We report a case of HLH in a 30-year-old female 1 year after her first cycle of alemtuzumab (second cycle delayed due to COVID-19 pandemic) for treatment of RRMS. She was well until presentation 2 days post gadolinium-contrasted routine MRI head scan with headache, fever, bacterial pneumonia/empyema and acute kidney injury. Febrile episodes persisted despite antibiotics. Results Investigations revealed hepatosplenomegaly, pancytopenia (Haemoglobin: 80g/L, WBC: 0.9x109/L, neutrophils: 0.67x109/L, lymphocytes: 0.14 X109/L, platelets: 82x109/L), hypertriglyceridaemia (5.5mmol/L) and hyperferritinaemia (94023ng/ml). She fulfilled the Histiocyte Society HLH-2004 diagnostic criteria for HLH (H-score: 238). Initial treatment was IV methylprednisolone (1g) and intravenous immunoglobulin (IVIG) 2g/kg. Ferritin levels initially decreased (66933ng/ml) but re-escalated (93912ng/ml) with clinical deterioration, necessitating additional treatment with subcutaneous Anakinra 4mg/kg(recombinant interleukin-1 receptor antagonist) alongside oral prednisolone 1mg/kg. There was rapid, sustained improvement with resolution of fever but ferritin levels remained highly elevated (45000ng/ml) and cytopaenia was slow to resolve. Marker T cell subsets showed significant T cell depression presumably post-alemtuzumab. MDT discussion locally and nationally through the HLH Across Speciality Collaboration (HASC) led to discharge with careful outpatient monitoring. Further IVIG 2g/kg was administered which led to complete resolution of HLH and treatment wean. Conclusion HLH is an under-recognised complication of alemtuzumab therapy. Severe HLH requires both cytokine storm-directed treatment and identification/treatment of the trigger. Here, HLH was refractory to first line therapy (steroids and IVIG) and required immune modulation. The combination of alemtuzumab-induced immune dysregulation and sepsis were likely triggers, rather than Gadolinium. Supportive regional and national MDT input were required to guide therapy, especially as the patient wished to avoid etoposide (a standard refractory-HLH therapy) to preserve fertility. MDT working enabled early discharge with close monitoring in ambulatory care - a preferred outcome in the coronavirus pandemic. Disclosure N.L. Wong: Grants/research support; In the last 5 years NLW has received educational grant to attend meetings from Eli Lilly. N.J. Morley: Grants/research support; In the last 5 years NJM has received speaker fees and educational grants to attend meetings from ROCHE, AMGEN, AbbVie, TAKEDA, Kite Gilead and Janssen. D.J. Paling: Grants/research support; DJP has recieved speaker fees and educational grants to attend meetings from Biogen, Novartis, Genzyme and Teva. R.S. Tattersall: Grants/research support; In the last 5 years RST has received speaker fees and educational grants to attend meetings from UCB, AbbVie, Pfizer and Janssen.

Background: Absence of coronary artery calcium (CAC) identifies asymptomatic individuals at low cardiovascular disease risk. Carotid artery plaque is a marker of increased risk, but its association with cardiovascular risk and incident CAC in people without CAC is unclear. Methods: Multi-Ethnic Study of Atherosclerosis participants with CAC score of 0 at enrollment who also underwent carotid plaque measurement using B-mode ultrasonography were prospectively followed for incident coronary heart disease, stroke, and cardiovascular disease events, and CAC (score >0 on up to 3 serial computed tomography scans). The association of carotid plaque presence and plaque score (Ln[score+1]) at baseline with cardiovascular events and incident CAC was evaluated with Cox proportional hazards regression models adjusted for demographics, risk factors, and statin use. Results: Among these 2673 participants (58 years, 64% women, 34% White, 30% Black, 24% Hispanic, and 12% Chinese), carotid plaque at baseline was observed in 973 (36%) and the median plaque score (range, 1–12) among those with plaque was 1. A total of 79 coronary heart disease, 80 stroke, and 151 cardiovascular disease events were observed during 16.1 years of follow-up. Carotid plaque presence and plaque score were independently associated with coronary heart disease risk (HRs, 1.66 [95% CI, 1.04–2.66]; and 1.48 [95% CI, 1.01–2.17], respectively) but not with stroke and cardiovascular disease risk. A total of 973 (36.4%) participants developed CAC over the evaluation period (median 9.3 years). Carotid plaque presence and plaque score were independently associated with incident CAC (HRs, 1.34 [95% CI, 1.18–1.54]; and 1.37 [95% CI, 1.21–1.54]), respectively. Conclusions: The presence and extent of carotid plaque are associated with long-term coronary heart disease risk and incident CAC among middle-aged asymptomatic individuals with an initial CAC score of 0.

Summary Background Radical surgery via total mesorectal excision might not be the optimal first-line treatment for early-stage rectal cancer. An organ-preserving strategy with selective total mesorectal excision could reduce the adverse effects of treatment without substantially compromising oncological outcomes. We investigated the feasibility of recruiting patients to a randomised trial comparing an organ-preserving strategy with total mesorectal excision. Methods TREC was a randomised, open-label feasibility study done at 21 tertiary referral centres in the UK. Eligible participants were aged 18 years or older with rectal adenocarcinoma, staged T2 or lower, with a maximum diameter of 30 mm or less; patients with lymph node involvement or metastases were excluded. Patients were randomly allocated (1:1) by use of a computer-based randomisation service to undergo organ preservation with short-course radiotherapy followed by transanal endoscopic microsurgery after 8–10 weeks, or total mesorectal excision. Where the transanal endoscopic microsurgery specimen showed histopathological features associated with an increased risk of local recurrence, patients were considered for planned early conversion to total mesorectal excision. A non-randomised prospective registry captured patients for whom randomisation was considered inappropriate, because of a strong clinical indication for one treatment group. The primary endpoint was cumulative randomisation at 12, 18, and 24 months. Secondary outcomes evaluated safety, efficacy, and health-related quality of life assessed with the European Organisation for Research and Treatment of Cancer (EORTC) QLQ C30 and CR29 in the intention-to-treat population. This trial is registered with the ISRCTN Registry, ISRCTN14422743. Findings Between Feb 22, 2012, and Dec 19, 2014, 55 patients were randomly assigned at 15 sites; 27 to organ preservation and 28 to radical surgery. Cumulatively, 18 patients had been randomly assigned at 12 months, 31 at 18 months, and 39 at 24 months. No patients died within 30 days of initial treatment, but one patient randomly assigned to organ preservation died within 6 months following conversion to total mesorectal excision with anastomotic leakage. Eight (30%) of 27 patients randomly assigned to organ preservation were converted to total mesorectal excision. Serious adverse events were reported in four (15%) of 27 patients randomly assigned to organ preservation versus 11 (39%) of 28 randomly assigned to total mesorectal excision (p=0·04, χ2 test). Serious adverse events associated with organ preservation were most commonly due to rectal bleeding or pain following transanal endoscopic microsurgery (reported in three cases). Radical total mesorectal excision was associated with medical and surgical complications including anastomotic leakage (two patients), kidney injury (two patients), cardiac arrest (one patient), and pneumonia (two patients). Histopathological features that would be considered to be associated with increased risk of tumour recurrence if observed after transanal endoscopic microsurgery alone were present in 16 (59%) of 27 patients randomly assigned to organ preservation, versus 24 (86%) of 28 randomly assigned to total mesorectal excision (p=0·03, χ2 test). Eight (30%) of 27 patients assigned to organ preservation achieved a complete response to radiotherapy. Patients who were randomly assigned to organ preservation showed improvements in patient-reported bowel toxicities and quality of life and function scores in multiple items compared to those who were randomly assigned to total mesorectal excision, which were sustained over 36 months’ follow-up. The non-randomised registry comprised 61 patients who underwent organ preservation and seven who underwent radical surgery. Non-randomised patients who underwent organ preservation were older than randomised patients and more likely to have life-limiting comorbidities. Serious adverse events occurred in ten (16%) of 61 non-randomised patients who underwent organ preservation versus one (14%) of seven who underwent total mesorectal excision. 24 (39%) of 61 non-randomised patients who underwent organ preservation had high-risk histopathological features, while 25 (41%) of 61 achieved a complete response. Overall, organ preservation was achieved in 19 (70%) of 27 randomised patients and 56 (92%) of 61 non-randomised patients. Interpretation Short-course radiotherapy followed by transanal endoscopic microsurgery achieves high levels of organ preservation, with relatively low morbidity and indications of improved quality of life. These data support the use of organ preservation for patients considered unsuitable for primary total mesorectal excision due to the short-term risks associated with this surgery, and support further evaluation of short-course radiotherapy to achieve organ preservation in patients considered fit for total mesorectal excision. Larger randomised studies, such as the ongoing STAR-TREC study, are needed to more precisely determine oncological outcomes following different organ preservation treatment schedules. Funding Cancer Research UK.

Background: An ongoing longitudinal study in six European sites includes a 3-monthly assessment of forced vital capacity (FVC), slow vital capacity (SVC), peak cough flow (PCF), and Sniff nasal inspiratory pressure (SNIP). The aim of this interim analysis was to assess the potential for SNIP to be a surrogate for aerosol generating procedures given COVID-19 related restrictions. Methods: This was a prospective observational study. Patients attending six study sites with King's Stage 2 or 3 ALS completed baseline FVC/SVC/SNIP/PCF and repeated assessments 3 monthly. Data were collected from March 2018 to March 2020, after which a COVID-19 related study suspension was imposed. Correlations between the measures were calculated. A Bayesian multiple outcomes random-effects model was constructed to investigate rates of decline across measures. Results: In total, 270 cases and 828 assessments were included (Mean age 65.2 ± 15.4 years; 32.6% Female; 60% Kings stage 2; 81.1% spinal onset). FVC and SVC were the most closely correlated outcomes (0.95). SNIP showed the least correlation with other metrics 0.53 (FVC), 0.54 (SVC), 0.60 (PCF). All four measures significantly declined over time. SNIP in the bulbar onset group showed the fastest rate of decline. Discussion: SNIP was not well correlated with FVC and SVC, probably because it examines a different aspect of respiratory function. Respiratory measures declined over time, but differentially according to the site of onset. SNIP is not a surrogate for FVC and SVC, but is a complementary measure, declining linearly and differentiating spinal and bulbar onset patients.

Background Ustekinumab was approved by NICE in 2016 for adults with moderate to severe CD. Real world data are required to establish effectiveness of therapy where restrictive inclusion and exclusion criteria from trials are not routinely applied. Methods This retrospective audit of clinical data included all patients treated with Ustekinumab for CD at 8 North West England and Yorkshire hospitals that form the Cross Pennine IBD Initiative. The dataset included medical history, treatment history, phenotype and disease activity (at 3 and 12 months). Remission was defined as Physician Global Assessment (PGA) of 0 and response by PGA of 1. Results The cohort comprised of 259 patients (160 females, mean age 39.99, mean disease duration 11.78 years) with active Crohn’s Disease. The majority (n=137) had ileocolonic, 65 colonic and 57 ileal disease distribution. Eighty six (33.2%) had inflammatory, 78 (30.1%) stricturing and 95 (36.7%) penetrating disease behaviour. Perianal disease was noted in 32.1% and 46% had had a previous bowel resection. Previous treatment history included Infliximab in 73%, Adalimumab in 80.7% and Vedolizumab in 30.1% with 35.5% having been exposed to 1, 40.5% to 2 and 22.4% to 3 previous biologics. Steroid exposure at baseline was 36.7%. At 3 months 89 (34.4%) had achieved remission and 84 (32.4%) had a clinical response. By 12 months 65 (25%) patients had discontinued Ustekinumab, 63 (24.3%) were in remission and 34 (13.1%) in response (outcomes not available for 37.6%). Bowel resections were required in 20 and perianal surgery in 6 cases. 84% of patients were given 8-weekly sc ustekinumab. Adverse events included headaches (8), joint pains/arthralgia (8), body rashes/urticaria (6) and flu type symptoms (5). Serious adverse events included hospitalisations with infection (17), gastrointestinal operations (26), CD flare (46), abdominal pain (6), medical admissions (8). There was one death from a pre-existing primary malignant melanoma, 3 cases of newly diagnosed cancers (1 small bowel adenocarcinoma, 1 breast cancer, 1 hepatocellular carcinoma), and 2 recurrences of previous known cancers (1 basal cell carcinoma of the skin, 1 bladder transitional cell carcinoma). Conclusion In this large real-world study of patients with long disease duration and highly refractory CD we found that Ustekinumab was clinically effective and safe in line with expectations from clinical trials. Further analysis of predictors of response may help clinicians’ decision making on biologic choices for CD.

Background Primary mesenteric soft tissue sarcomas (STS) are rare and limited evidence is available to inform management. Surgical resection is challenging due to the proximity of vital structures and a need to preserve enteric function. Objectives To determine the overall survival (OS) and recurrence-free survival (RFS) for patients undergoing primary resection for mesenteric STS. Methods The Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) is an intercontinental collaborative comprising specialist sarcoma centers. Data were collected retrospectively for all patients with mesenteric STS undergoing primary resection between 2000 and 2019. Results Fifty-six cases from 15 institutions were included. The spectrum of pathology was similar to the retroperitoneum, although of a higher grade. R0/R1 resection was achieved in 87%. Median OS was 56 months. OS was significantly shorter in higher-grade tumors (p = .018) and extensive resection (p < .001). No significant association between OS and resection margin or tumor size was detected. Rates of local recurrence (LR) and distant metastases (DM) at 5 years were 60% and 41%, respectively. Liver metastases were common (60%), reflecting portal drainage of the mesentery. Conclusion Primary mesenteric sarcoma is rare, with a modest survival rate. LR and DM are frequent events. Liver metastases are common, highlighting the need for surveillance imaging.

Chronic kidney disease (CKD) causes substantial global morbidity and increases cardiovascular and all-cause mortality. Unlike other chronic diseases with established strategies for screening, there has been no consensus on whether health systems and governments should prioritize early identification and intervention for CKD. Guidelines on evaluating and managing early CKD are available but have not been universally adopted in the absence of incentives or quality measures for prioritizing CKD care. The burden of CKD falls disproportionately upon persons with lower socioeconomic status, who have a higher prevalence of CKD, limited access to treatment, and poorer outcomes. Therefore, identifying and treating CKD at the earliest stages is an equity imperative. In 2019, Kidney Disease: Improving Global Outcomes (KDIGO) held a controversies conference entitled "Early Identification and Intervention in CKD." Participants identified strategies for screening, risk stratification, and treatment for early CKD and the key health system and economic factors for implementing these processes. A consensus emerged that CKD screening coupled with risk stratification and treatment should be implemented immediately for high-risk persons and that this should ideally occur in primary or community care settings with tailoring to the local context.

Background Sarcomas represent 10%–15% of cancers in adolescent and young adult (AYA) patients, and survival for those with metastatic disease or relapse is poor. Immunotherapy with checkpoint inhibition has improved outcomes in multiple tumor types, but data in advanced sarcomas, particularly within the AYA population, are limited. Aim We aim to evaluate response and toxicity for AYA patients with sarcoma treated with pembrolizumab. Methods and results We retrospectively reviewed AYA patients with advanced bone and soft tissue sarcoma who received self‐funded pembrolizumab between May 2015 and January 2019. Eighteen patients were identified. One patient with Ewing sarcoma had a sustained complete response to therapy. Two patients with alveolar soft part sarcoma received a clinical benefit from pembrolizumab: one had a radiological partial response with an excellent clinical response and one patient achieved stable disease. Four patients died of disease prior to first scheduled assessment and thus were not evaluable. The remaining eleven patients had progressive disease. Conclusion The role of immunotherapy in AYA sarcoma warrants further investigation. Biomarkers of response need to be further evaluated in order to guide patient selection.

Background: Statin therapy may alter arterial stiffness by decreasing the low density lipoprotein cholesterol (LDL-C) content within blood vessel walls and reducing inflammation. Progression of arterial stiffness with prolonged statin treatment is not clear. Methods: The subset of MESA participants (n=1,225) with comprehensive data on statin use who underwent B-mode carotid ultrasound at baseline (visit 1) and after (mean ± SD) 9.3±0.7 years (visit 5) was analyzed. Arterial stiffness was measured using carotid distensibility coefficient (DC) and Young’s elastic modulus (YEM) at MESA exam 1 and 5. Linear regression models evaluated associations of ten-year change in DC and YEM with statin treatment duration and intensity during visits 1-4. Models were adjusted for age, sex, ethnicity, systolic blood pressure (SBP), diabetes status, alcohol use, smoking, and lipid profiles. Results: At baseline, participants were 66.5±8.1 years of age, 41% female, 36% Caucasian, 30% African American, 13.7% Asian American, and 20.0% Hispanic, with LDL-C of 149.5±14.5 mg/dL; DC was 2.88×10-3±1.28×10-3 mmHg-1, YEM was 1659±1056 mmHg. Participants not on statin therapy at any visit had greater baseline arterial stiffness measures compared to participants who were treated at all visits (YEM: 1,724 ±993 mmHg vs 1,457 ±776 mmHg; p=0.0003; DC: 2.72 ±1.22×10-3 mmHg-1 vs 3.22 ±1.33×10-3 mmHg-1; p Conclusions: Statin therapy was not associated with progression of carotid artery distensibility and elasticity over nearly a decade of follow up regardless of treatment duration or dose intensity.

BackgroundColitis is one of the common immune-related adverse events that leads to morbidity and treatment discontinuation of immunotherapy. The clinical presentation, endoscopic and histopathological features and best management of this toxicity are not well defined.Patients and methodsPatients with metastatic melanoma who received immunotherapy (programmed cell death protein 1 (PD1) antibodies, alone or in combination with a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody (PD1 +CTLA-4)) and who developed clinically significant colitis (requiring systemic corticosteroids) were identified retrospectively from two academic centers. Clinical data were collected for all patients; endoscopic and histopathological data were examined in a subset.ResultsFrom May 2013 to May 2019, 118/1507 (7.8%) patients developed significant colitis; 80/553 (14.5%) after PD1+CTLA-4, 35/1000 (3.5%) PD1 alone, and three patients after Ipilimumab (IPI) alone. Combination therapy-induced colitis was more frequent (14.5% vs 3.5% in PD1 alone, p=ConclusionClinically significant colitis varies in presentation, response to immunosuppression, and endoscopic/histologic features depending on the immunotherapy type. Infliximab-refractory colitis occurs early, is often high grade, and has adverse endoscopic and histopathologic features

Case report - Introduction Childhood-onset mixed connective tissue disease (MCTD) is rare and heterogeneous presenting both diagnostic and treatment challenges. Symptoms often present sequentially over an extended period of time, requiring a high index of suspicion and careful clinical evaluation to diagnose. We present the cases of two young women which demonstrate the evolution of this disease and the diagnostic and management challenges. Summarising these two cases from childhood, through adolescence and into adult life will highlight the importance of integrated clinical pathways and effective transition in managing their disease. Case report - Case description Case 1: Twenty-year-old female presented in 2016, age 15 years with polyarthritis, Raynaud’s phenomenon, fatigue, and headaches – rheumatoid-factor (RF) positive, anti-RNP antibody positive, Smith antibody positive at diagnosis. Initially treated with methotrexate, prednisolone, and hydroxychloroquine. Due to methotrexate-associated nausea, she switched to sulfasalazine but remained steroid dependent requiring several doses of methyl prednisolone. Treatment was escalated, and transfer delayed, and in 2017 (age 16) she had rituximab with good efficacy. She transferred into adult rheumatology with careful monitoring for symptom evolution. Her arthritis flared in November 2019, associated with fatigue and malaise, and she developed immune thrombocytopenia (ITP) in April 2020. The combination of arthritis, ITP, malaise, and activation of complement (without other features of lupus) necessitated a further pulse of rituximab with resolution of symptoms and normalisation of complement. Case 2: Twenty-two-year-old female presented in 2006, age 9 with fatigue, polyarthritis, leucopoenia, and positive ANA. Managed as JIA with prednisolone, methotrexate and etanercept then switched to infliximab as features of juvenile dermatomyositis developed. Arthritis and muscle weakness worsened with Raynaud’s phenomenon developing and new sclerodactyly. Serology evolved with positive ANA, anti-RNP antibodies and positive RF leading to diagnosis of MCTD. Treatment included azathioprine and mycophenolate mofetil (MMF). Disease escalated and cyclophosphamide/rituximab administered. Remission was reached in 2011, age 13, and maintained with rituximab, methotrexate, and hydroxychloroquine. Transition into adult services was carefully planned and transfer occurred in a period of remission age 17. In adult services she is stable on azathioprine and hydroxychloroquine and sclerodactyly has completely regressed. Treatment complications are evident -panhypogammaglobulinaemia secondary to rituximab treatment and steroid induced osteoporosis/fracture. Case report - Discussion MCTD was first suggested as a distinct entity in 1972 by Sharp and colleagues. There is a lack of consensus over the four published diagnostic criteria (Kasukawa’s, Alarcon-Segovia, Kahn and Sharp), none of which have been validated for use in children. Heterogeneity of clinical features and the rarity of childhood-onset MCTD makes diagnosis a challenge. Raynaud’s phenomenon and polyarthritis are the most common presenting features. It was only with time that the clinical picture of MCTD emerged. There is limited evidence available to guide treatment but emerging evidence of benefit from rituximab. Management aims to minimise active inflammation and treatment toxicity balancing the evolving clinical picture with side effects from treatments used, as exemplified in these two cases. Given potential evolution to SLE anti-TNF drugs are usually avoided but in case 2 when this appeared phenotypically to be JIA/JDM both etanercept and infliximab were used. In Sheffield transfer usually occurs around the end of school year 11 but for case 1 this was the time of maximum clinical instability. Transition was delayed enabling treatment with rituximab in a familiar environment and transfer only occurred when disease was stable. In case 2 with such intensive treatment in paediatric rheumatology transition planning carefully emphasised the clinical features and medicines used which has been of great benefit in adult services to maintain disease control and quiescence and avoid risks of over treatment. An integrated transition pathway from paediatric to adult services has ensured a safety net to the evolving nature of these inflammatory diseases and allowed a joint approach to the diagnosis and management. Case report - Key learning points: Evolution of disease Paediatric-onset MCTD is rare. As paediatric and adolescent rheumatologists we will be seeing patients early in the disease course. We need an awareness of the potential for our inflammatory patients’ symptoms to evolve and to re-assess the diagnosis when this happens. Respect anti-RNP antibodies anti-RNP antibodies, either at disease outset (case 1) or occurring later in disease course (case 2) help distinguish evolving MCTD, presenting with polyarthritis with or without Raynaud’s phenomenon, from ‘straightforward’ polyarticular JIA. Children and young people who have anti-RNP antibodies need to be watched carefully for evolution of MCTD symptoms. Integrated Transition As MCTD may evolve over several years, a close partnership between paediatric and adult rheumatology (whether part of an integrated adolescent transition service or not) helps deliver developmentally appropriate health care. Expect complications Paediatric onset MCTD tends to have a milder disease course than in adults, although complete remission is rare. The most common causes of death are linked to pulmonary hypertension and interstitial lung disease. However, these complications are less seen in children. Clinical vigilance and proactive screening in watching for development of the disease and trying to anticipate potential problems are important. This requires multi-disciplinary team working. This is just as important when managing treatment effects such as panhypogammaglobulinaemia and liaison with immunology team or steroid side effects and liaison with endocrinology team. Individualised Approach There is no one specific treatment for MCTD. The heterogeneity of the condition dictates an individualised approach using best available evidence. It is particularly important to review treatment strategies as new symptoms emerge, or side-effects emerge from treatments being used.

Case report - Introduction Juvenile Idiopathic Arthritis (JIA) is a lifelong condition in over 50% but there is limited knowledge of JIA in adulthood. We discuss C, who presented in childhood with polyarticular JIA which evolved into systemic lupus erythematosus (SLE). After careful transition she defaulted on care and had a life-threatening SLE flare. In adult services axial symptoms became dominant. Adult rheumatologists queried a third diagnosis of axial spondyloarthropathy, not recognising axial disease as a feature of JIA. This case highlights that knowledge sharing is needed to improve care of adults with JIA and reminds us that transfer can be a risky time. Case report - Case description C presented age 11 with pain and swelling in the small joints of her hands and feet. She was treated for polyarticular JIA with methotrexate and etanercept. At the point of transfer and having had early, detailed transition planning, C developed mouth ulcers, and Raynaud’s with lymphopenia, positive ANA, DsDNA, Ro, Sm, and RNP antibodies, low C4 and an elevated ESR, resulting in a diagnosis of evolving SLE/JIA. Treatment with methotrexate and etanercept continued but C’s adherence became poor. She stopped taking methotrexate due to nausea and ceased etanercept some months previously. C had extra transition support to enhance adherence and transferred into the young adult clinic (YAC) re-established on treatment. After transfer, her SLE became more complex so there was further transition into the adult connective tissue disease (CTD) service. Azathioprine was prescribed but failed to control symptoms and was stopped, although adherence was a significant issue again. C was admitted to hospital with an SLE flare causing rash, inflammatory arthritis, and nephritis with strongly positive DsDNA and low C3 and C4. She also had hyperferritinaemia, anaemia, leucopoenia, neutropenia, a raised CRP, and haemophagocytosis on bone marrow trephine due to haemophagocytic lymphohistiocytosis (HLH). This flare was a life-threatening culmination of poor adherence. C commenced mycophenolate and rituximab during this admission. Engagement improved significantly but C developed back pain associated with a raised CRP. An MRI scan revealed evidence of bilateral sacroiliitis, interpreted by the adult SLE team as possible axial spondyloarthropathy, as she has a history of psoriasis. Referral back to the adolescent team highlighted that axial disease is a feature of polyarticular JIA. Close liaison between the two led to a revision of her diagnosis away from SLE to polyarticular JIA/SLE crossover syndrome with axial disease. C is currently managed with tocilizumab and mycophenolate. Case report - Discussion Paediatric and adolescent rheumatologists recognise that inflammatory disease in young people may evolve: C went from a diagnosis of polyarticular JIA to SLE to possible axial spondyloarthropathy to polyarticular JIA/SLE crossover. C transitioned into the YAC and then into the adult CTD service. There may have been a conflict here between focusing on generic young adult care, as opposed to specialist disease-related care. Defaulting on medical care is a normal phenomenon in adolescent development. For C this resulted in a life-threatening SLE flare. In adolescents, it is crucial to recognise transfer as a high-risk time, to remain alert to potential non-adherence and to chase up non-attendance especially immediately after seemingly successful transfer. Therefore, extra appointments and support may be needed in adult services. JIA is a small yet significant part of general adult rheumatology workload. In Sheffield, JIA comprises 4% of the adult inflammatory arthritis service (compared with 39% for rheumatoid arthritis (RA), the commonest adult inflammatory arthritis). There is little in the literature about the phenotype or treatment of JIA in adults leading to the relative invisibility of JIA in adult rheumatology and relabelling of JIA as RA. Management of adolescent and adult JIA is further complicated by the differing definition and distributions of active joints between JIA and adult inflammatory arthritis. Both recognise tender and swollen joints as active, but in paediatrics, restricted joints are also ‘active’. Paediatric joint counts include all joints, not just selected joints as in, for example, DAS28 in RA. The burden of adolescent and adult JIA may be under-recognised and under-treated. For C this led to delayed recognition of axial disease in adult services, but early and close working of adolescent and adult specialists led to the correct diagnosis and reinforces the importance of taking a life course approach to JIA. Case report - Key learning points C was managed in a seamless service where child-to-adult pathways are well developed. Despite this, she had significant non-adherence to medication, causing a life-threatening disease flare. The period immediately after transfer may be one of particular vulnerability and should be a target for extra support in adult services.Adult rheumatology is often super-specialised and just as transition from child to adult services may risk information being lost and a failure of developmentally appropriate care, transition within adult services (here from the YAC to the specialist CTD clinic) may also be challenging for patients and professionals alike. What worked well here was referral back to the YAC when axial disease was recognised and the shared approach to diagnosis and appropriate management.The optimum way to assess JIA activity in adults is not established. There is evidence that using scores for rheumatoid arthritis such as DAS28 risks underestimating JIA activity and denying young people access to treatment but there are no validated scores for adult JIA. This is a key area for future research.JIA persists into adult life in at least half of those with childhood onset disease.It is important that all rheumatologists appreciate the course, impact, and phenotypes of JIA in adults, to ensure the best outcomes and treatment. Young adult clinics are an ideal way to ensure developmentally appropriate care, but may not be feasible in all services, making education about JIA for adult rheumatologists (which paediatric and adolescent rheumatologists are ideally placed to deliver) all the more necessary.Young people with JIA need to be continually educated about their disease especially at transfer to adult services so they can remind adult rheumatologists that they have JIA.Good collaboration across all areas of rheumatology improves care for children, adolescents, and adults with rheumatic disease

Background A 7 month old boy was referred to paediatric admissions with ‘simple bronchiolitis’. During his admission, however, mum mentioned that something was not right. Case Presentation His bronchiolitis made feeding difficult and he tired easily. Admission was required for feeding support, with a nasogastric tube inserted. Ward review noted that he had not met gross motor milestones and was hypotonic. He was unable to sit, even when supported, had some head lag and only a few anti-gravity movements. Faltering growth was demonstrated, dropping from the 91st to the 9th centile in the past few months. He was otherwise well, with a normal examination and no dysmorphic features. Investigations were arranged, including a genetic and hypotonia screen. Prader-Willi and spinal muscular atrophy, in particular, were considered. Bloods showed a raised ALT at 222 and CK at 908. After discussion with the metabolic team, further tests were requested, including an echocardiogram. The echocardiogram showed septal and left ventricular hypertrophy with mild diastolic dysfunction. Pompe’s disease was, therefore, considered. Alpha-glucosidase levels were checked, confirming this diagnosis. He is now under follow-up at the tertiary centre, with multidisciplinary care locally, and has started life-long enzyme replacement therapy. Pompe’s disease is an autosomal recessive glycogen storage disorder that has variable rates of progression and time of onset. An earlier age of onset usually confers a worse prognosis. Mobility problems characterise the disease due to skeletal muscle weakness and subsequent wasting. Infantile onset Pompe’s presents with hypertrophic cardiomyopathy, an enlarged liver from cardiac failure and respiratory problems due to wasting of the skeletal muscles. Conclusion This case highlights the importance of ensuring a thorough history and examination for every child that comes to child health, even when the diagnosis seems clear and relatively benign. In the midst of the bronchiolitis season, doctors can be tempted to make assumptions to save time. However, ensuring each patient is reviewed properly enables rare diagnoses to be considered, confirmed and ensures children are started on the treatment they need. Not just a case of ‘simple bronchiolitis’ after all!

Summary Background A subset of patients with severe COVID-19 develop a hyperinflammatory syndrome, which might contribute to morbidity and mortality. This study explores a specific phenotype of COVID-19-associated hyperinflammation (COV-HI), and its associations with escalation of respiratory support and survival. Methods In this retrospective cohort study, we enrolled consecutive inpatients (aged ≥18 years) admitted to University College London Hospitals and Newcastle upon Tyne Hospitals in the UK with PCR-confirmed COVID-19 during the first wave of community-acquired infection. Demographic data, laboratory tests, and clinical status were recorded from the day of admission until death or discharge, with a minimum follow-up time of 28 days. We defined COV-HI as a C-reactive protein concentration greater than 150 mg/L or doubling within 24 h from greater than 50 mg/L, or a ferritin concentration greater than 1500 μg/L. Respiratory support was categorised as oxygen only, non-invasive ventilation, and intubation. Initial and repeated measures of hyperinflammation were evaluated in relation to the next-day risk of death or need for escalation of respiratory support (as a combined endpoint), using a multi-level logistic regression model. Findings We included 269 patients admitted to one of the study hospitals between March 1 and March 31, 2020, among whom 178 (66%) were eligible for escalation of respiratory support and 91 (34%) patients were not eligible. Of the whole cohort, 90 (33%) patients met the COV-HI criteria at admission. Despite having a younger median age and lower median Charlson Comorbidity Index scores, a higher proportion of patients with COV-HI on admission died during follow-up (36 [40%] of 90 patients) compared with the patients without COV-HI on admission (46 [26%] of 179). Among the 178 patients who were eligible for full respiratory support, 65 (37%) met the definition for COV-HI at admission, and 67 (74%) of the 90 patients whose respiratory care was escalated met the criteria by the day of escalation. Meeting the COV-HI criteria was significantly associated with the risk of next-day escalation of respiratory support or death (hazard ratio 2·24 [95% CI 1·62–2·87]) after adjustment for age, sex, and comorbidity. Interpretation Associations between elevated inflammatory markers, escalation of respiratory support, and survival in people with COVID-19 indicate the existence of a high-risk inflammatory phenotype. COV-HI might be useful to stratify patient groups in trial design. Funding None.

Transition from paediatric to adult services is a challenging process and developing rare, life-threatening, lifelong illness around this time adds significant complexity. Sheffield has a seamless adolescent rheumatology service spanning both paediatric and adult hospitals, aiming to provide developmentally appropriate healthcare (DAH). To exemplify the benefits of this approach, we present two adolescents with the rare combination of large vessel vasculitis and inflammatory bowel disease. Case A was diagnosed in the Children’s hospital and B in adult services, within 1 month of each other. Within the seamless service we were able to coordinate a patient-centred approach both for complex medicines management and ongoing clinical care. A: 17 year-old male with complex inflammatory bowel disease since age 2. Treated with oral steroids with poor response to multiple DMARDs, biologics and elemental nutrition. Health professionals doubted good adherence and he needed extensive input. Vedolizumab was started in 2019 with improvement of gut symptoms but subsequent investigation of neck pain revealed stenotic large vessel vasculitis (LVV) and a diagnosis of Takayasu arteritis was made. B: 17 year-old male with ulcerative colitis, diagnosed aged 14. Treated with infliximab and azathioprine when transferred to adult gastroenterology services. Atypical symptoms developed in 2019 and chest CT/PET-CT confirmed LVV (Takayasu arteritis). LVV is a rare, life-threatening condition. Well-established team working enabled sharing of paediatric and adult rheumatology and gastroenterology experience. This enabled rational, tailored treatment plans to be devised through shared professional expertise – A has stopped vedolizumab and started tocilizumab, B has started adalimumab and both started methotrexate. LVV needs lifetime monitoring. Planning for that monitoring (imaging, serology, biopsychosocial care) in adult services is therefore an important part of initial management. A and B are at different developmental stages. Our service enables DAH with A remaining in paediatrics, but with care planned to facilitate transition and ongoing management in adult services, B continues in adult services with the benefit of paediatric experience in managing Takayasu arteritis. ‘Adolescent responsive services’ are key in developmentally appropriate healthcarecare. The Sheffield Seamless Adolescent Rheumatology service is an example of this in practice.

COVIDTrach is a UK multidisciplinary collaborative project that aims to evaluate the outcomes of tracheostomy in COVID-19 patients. It also examines the implementation of national guidance in COVID-19 tracheostomies and the incidence of COVID-19 infections amongst those health care workers involved in the procedure. An invitation to participate in an online survey tool (REDCap) was disseminated to all UK NHS departments involved in tracheostomy in mechanically ventilated COVID-19 patients via the Federation of Surgical Specialty Associations, it’s subsidiary organisations and the Intensive Care Society. To date 78 hospitals have submitted 564 COVID-19 tracheostomy cases. Fifty-two percent (n=219/465) of patients who had undergone tracheostomy and were still alive had been successfully weaned from mechanical ventilation at the point of completing the survey. The all cause in-hospital mortality following tracheostomy was 12% (n=62/530), with 3% of these (n=2/62) due to tracheostomy related complications and the remaining deaths due to COVID-19 related complications. Amongst 400 cases submitting data two weeks after the tracheostomy, no instance of COVID-19 infection amongst operators was recorded. FFP3 masks or Powered Air Purifying Respirators were used by operators in 100% of tracheostomies and a face visor or hood with face shield was available in 99% of cases. This interim report highlights early outcomes following tracheostomy in mechanically ventilated COVID-19 patients. Future reporting from COVIDTrach will include more detailed analysis at later timepoints using comparator groups in order to provide a more comprehensive assessment of tracheostomy in COVID-19.

Summary The term cytokine storm syndromes describes conditions characterised by a life-threatening, fulminant hypercytokinaemia with high mortality. Cytokine storm syndromes can be genetic or a secondary complication of autoimmune or autoinflammatory disorders, infections, and haematological malignancies. These syndromes represent a key area of interface between rheumatology and general medicine. Rheumatologists often lead in management, in view of their experience using intensive immunosuppressive regimens and managing cytokine storm syndromes in the context of rheumatic disorders or infection (known as secondary haemophagocytic lymphohistiocytosis or macrophage activation syndrome [sHLH/MAS]). Interleukin (IL)-1 is pivotal in hyperinflammation. Anakinra, a recombinant humanised IL-1 receptor antagonist, is licenced at a dose of 100 mg once daily by subcutaneous injection for rheumatoid arthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, and cryopyrin-associated periodic syndromes. In cytokine storm syndromes, the subcutaneous route is often problematic, as absorption can be unreliable in patients with critical illness, and multiple injections are needed to achieve the high doses required. As a result, intravenous anakinra is used in clinical practice for sHLH/MAS, despite this being an off-licence indication and route of administration. Among 46 patients admitted to our three international, tertiary centres for sHLH/MAS and treated with anakinra over 12 months, the intravenous route of delivery was used in 18 (39%) patients. In this Viewpoint, we describe current challenges in the management of cytokine storm syndromes and review the pharmacokinetic and safety profile of intravenous anakinra. There is accumulating evidence to support the rationale for, and safety of, intravenous anakinra as a first-line treatment in patients with sHLH/MAS. Intravenous anakinra has important clinical relevance when high doses of drug are required or if patients have subcutaneous oedema, severe thrombocytopenia, or neurological involvement. Cross-speciality management and collaboration, with the generation of international, multi-centre registries and biobanks, are needed to better understand the aetiopathogenesis and improve the poor prognosis of cytokine storm syndromes.

Background Vasculitis can present in many ways and large vessel vascultis is reported rarely to co-present with inflammatory bowel disease. We would like to present two adolescent patients who presented in very similar ways via the gastroenterology team with a seemingly clear diagnosis of inflammatory bowel disease but who were found to have large vessel vasculitis later in their disease journey. The presentation is to raise awareness of this rare co-presentation and to discuss treatment challenges in particular those apparent in adolescent patients crossing the transition bridge. Methods Patient A is a 17 year old boy who has had a long and rocky road to control of his inflammatory bowel disease which presented when he was 2 years old. Histologically it fitted a Crohn’s classification. His journey included moderate response to oral steroids and little to no response to a range of DMARDs, biologics (including infliximab and adalimumab which both had secondary failure) and elemental nutrition, over a period of 12 years. Vedolizumab was introduced this year with almost immediate improvement of gut symptoms, but with ongoing raised inflammatory markers (CRP 79, ESR 86). Incidental investigations of neck pain following the start of vedolizumab revealed significant abnormality in the external carotids, with 70% stenosis. MR angiography confirmed a typical pattern of stenotic large vessel vasculitis. The second patient, B is also 17 and was diagnosed with histological ulcerative colitis aged 14. He has an older brother with IBD but has recently been found to have small bowel disease and is likely therefore to have Crohn’s disease. He is on infliximab 10mg/kg 4 weekly but presented with a 3-month history of high inflammatory markers, malaise towards the end of the 4 week infliximab cycle and drenching night sweats. CT Chest confirmed vasculitis in the thoracic aorta, subclavians and carotids. On PET CT there is mural thickening and no stenosis. Results Patient A presented in paediatric care and B in adult care but because of the seamless rheumatology service and combined MDT with gastroenterology both patients’ care has been widely discussed amongst relevant adult and paediatric teams. Conclusion Large vessel vasculitis might be driving the inflammatory bowel disease in both patients as such the life threatening element of the disease ought to be managed immediately, while ensuring safe transition to between paediatric and adult care. Disclosures S. Rasul None. M. Dockery None. R. Tattersall None. D. Hawley None. S. Maltby None. A. McMahon None.

Introduction: Secondary haemophagocytic lymphohistiocytosis (sHLH) or Macrophage Activation Syndrome (MAS) is a life-threatening hyperinflammatory syndrome that can occur in patients with severe infections, malignancy or autoimmune diseases. It is also a rare complication of haematopoetic stem cell transplantation (HSCT), with a high mortality. It may be associated with graft vs. host disease in the allogeneic HSCT setting. It is also reported following CAR-T cell therapy, but differentiation from cytokine release syndrome (CRS) is challenging. Here, we summarise the literature and present results of a survey of current awareness and practice in EBMT-affiliated centres of sHLH/MAS following HSCT and CAR-T cell therapy. Methods: An online questionnaire was sent to the principal investigators of all EBMT member transplant centres treating adult patients (18 years and over) inviting them to provide information regarding: number of cases of sHLH/MAS seen in their centre over 3 years (2016-2018 inclusive); screening strategies and use of existing diagnostic/classification criteria and treatment protocols. Results: 114/472 centres from 24 different countries responded (24%). We report estimated rates of sHLH/MAS of 1.09% (95% CI = 0.89-1.30) following allogeneic HSCT, 0.15% (95% CI = 0.09-5.89) following autologous HSCT and 3.48% (95% CI = 0.95-6.01) following CAR-T cell therapy. A majority of centres (70%) did not use a standard screening protocol. Serum ferritin was the most commonly used screening marker at 78% of centres, followed by soluble IL-2 receptor (24%), triglycerides (15%), and fibrinogen (11%). There was significant variation in definition of "clinically significant" serum ferritin levels ranging from 500 to 10,000 μg/mL. The most commonly used criteria to support diagnosis were HLH-2004 (43%) and the H score (15%). Eighty percent of responders reported using no standard management protocol, but reported using combinations of corticosteroids, chemotherapeutic agents, cytokine blockade, and monoclonal antibodies. Conclusions: There is a remarkable lack of consistency between EBMT centres in the approach to screening, diagnosis and management. Further research in this field is needed to raise awareness of and inform harmonised, evidence-based approaches to the recognition and treatment of sHLH/MAS following HSCT/CAR-T cell therapy. ispartof: FRONTIERS IN IMMUNOLOGY vol:11 ispartof: location:Switzerland status: published

Background: Asthma and atrial fibrillation (AF) share an underlying inflammatory pathophysiology. We hypothesized that persistent asthmatics are at higher risk for developing AF and that this association would be attenuated by adjustment for baseline markers of systemic inflammation. Methods: The MESA (Multi-Ethnic Study of Atherosclerosis) is a prospective longitudinal study of adults free of cardiovascular disease at baseline. Presence of asthma was determined at exam 1. Persistent asthma was defined as asthma requiring use of controller medications. Intermittent asthma was defined as asthma without use of controller medications. Participants were followed for a median of 12.9 (interquartile range, 10–13.6) years for incident AF. Multivariable Cox regression models were used to assess associations of asthma subtype and AF. Results: The 6615 participants were a mean (SD) 62.0 (10.2) years old (47% male, 27% black, 12% Chinese, and 22% Hispanic). AF incidence rates were 0.11 (95% CI, 0.01–0.12) events/10 person-years for nonasthmatics, 0.11 (95% CI, 0.08–0.14) events/10 person-years for intermittent asthmatics, and 0.19 (95% CI, 0.120.49) events/10 person-years for persistent asthmatics (log-rank P =0.008). In risk-factor adjusted models, persistent asthmatics had a greater risk of incident AF (hazard ratio, 1.49 [95% CI, 1.03–2.14], P =0.03). IL (Interleukin)-6 (hazard ratio, 1.26 [95% CI, 1.13–1.42]), TNF (tumor necrosis factor)-α receptor 1 (hazard ratio, 1.09 [95% CI, 1.08–1.11]) and D-dimer (hazard ratio, 1.10 [95% CI, 1.02–1.20]) predicted incident AF, but the relationship between asthma and incident AF was not attenuated by adjustment for any inflammation marker (IL-6, CRP [C-reactive protein], TNF-α R1, D-dimer, and fibrinogen). Conclusions: In a large multiethnic cohort with nearly 13 years follow-up, persistent asthma was associated with increased risk for incident AF. This association was not attenuated by adjustment for baseline inflammatory biomarkers.

Background We modified and evaluated an advance care planning (ACP) intervention, which had been shown to improve compliance with patient’s end of life (EoL) wishes, in a different patient population. Methods Patients with incurable cancer, and a Family Member (FM), were randomised one-to-one to usual care or usual care plus an ACP intervention, between April 2014 and January 2017. Oncologists and participants were non-blinded. ACP was based on the Respecting Patient Choices model, with an offer to provide individualised ranges for typical, best-case and worst-case scenarios for survival time. Seven facilitators (two oncology nurses, two nurses and three allied health professionals) delivered the intervention within 2 weeks of study enrolment. The primary outcome measure, assessed by interviewing the FM 3 months after patient death, was the FM perception that the patient’s wishes were discussed, and met. Results Six hundred and sixty-five patients from seven Australian metropolitan oncology centres were referred for consideration by their oncologists, 444 (67%) met the study inclusion criteria and were approached by a study researcher. Two hundred and eight patients (47%) and their FM entered the trial as dyads. Fifty-three (46%) dyads in the ACP group and 63 (54%) dyads in the usual-care group had complete primary outcome data (p = 0.16). Seventy-nine patients and 53 FMs attended an ACP discussion. Mean length of discussion was 57 min. FMs from 23 (43%) dyads allocated to ACP and 21 (33%) dyads allocated usual care reported the patient’s EoL wishes were discussed and met (difference 10%, 95% CI: −2 to 8, p = 0.27). There were no differences in EoL care received, patient satisfaction with care; FM satisfaction with care or with death; or FM well being. Rates of palliative care referral were high in both groups (97% vs 96%). Conclusions A formal ACP intervention did not increase the likelihood that EoL care was consistent with patients’ preferences.

Incremental haemodialysis has the potential to allow better preservation of renal function, is less invasive to the patient and has lower cost. Despite these advantages, it is not commonly applied. This may be due to uncertainty about how to account for renal function in the prescription of dialysis and measurement of dose. In this issue, Vartia describes the practical basis for including the effect of renal function in the prescription and quantification of dialysis. He uses a well-known and validated urea kinetic model to calculate time average urea concentrations and the equivalent renal clearance (EKR) from dialysis. The effect of renal function is amplified by a weighting factor to account for the relatively greater effect of renal function compared with dialysis with the same urea clearance. In that way, patients on differing dialysis regimens can be dialysed with the same target dose. A further step would be to use a downward adjusting factor for dialysis to convert the urea clearance by dialysis (as EKR) to a glomerular filtration rate (GFR) equivalent. A factor of 0.75 is suggested. In that way, dialysis dose can be reported as GFR equivalent in mL/min/1.73 m2, comparable between different types of dialysis and also to renal function without dialysis.

Objective— HDL-C (high-density lipoprotein cholesterol) may not always be cardioprotective in postmenopausal women. HDL particles (HDL-P) via ion-mobility may better reflect the antiatherogenicity of HDL. Objectives were (1) to evaluate associations of HDL-C and ion-mobility HDL-P with carotid intima-media thickness (cIMT) and carotid plaque separately and jointly in women; and (2) to assess interactions by age at and time since menopause. Approach and Results— Analysis included 1380 females from the MESA (Multi-Ethnic Study of Atherosclerosis; age: 61.8±10.3; 61% natural-, 21% surgical-, and 18% peri-menopause). Women with unknown or early menopause (age at nonsurgical menopause ≤45 years) were excluded. Adjusting for each other, higher HDL-P but not HDL-C was associated with lower cIMT ( P =0.001), whereas higher HDL-C but not HDL-P was associated with greater risk of carotid plaque presence ( P =0.04). Time since menopause significantly modified the association of large but not small HDL-P with cIMT; higher large HDL-P was associated with higher cIMT close to menopause but with lower cIMT later in life. The proatherogenic association reported for HDL-C with carotid plaque was most evident in women with later age at menopause who were >10 years postmenopausal. Conclusions— Elevated HDL-C may not always be cardioprotective in postmenopausal women. The cardioprotective capacity of large HDL-P may adversely compromise close to menopause supporting the importance of assessing how the menopause transition might impact HDL quality and related cardiovascular disease risk later in life.

To document the effect of a cancer specific question prompt list (QPL) on patients question asking and shared decision-making (SDM), and to evaluate the combined effect of the QPL and consultation audio recording (CAR) on patient outcomes.This exploratory study compared two groups of patients receiving either a QPL or combined QPL/CAR, to a control group. Measurements included number/types of questions asked, and physician SDM behavior (OPTION score). Questionnaire data included anxiety/depression and quality of life (QoL).A total of 93 patients participated (31 Control, 30 QPL and 32 Combined). Patients in the intervention groups asked more questions concerning prognosis (p .0001), the disease (p = .006) and quality of treatment (p .001) than patients in the control group, but no impact was found on the OPTION score. An increase in mean consultation length was observed in the intervention groups compared to the control group (44 vs. 36 min; p = .028). Patients rated both interventions positively.Provision of the QPL facilitates patients to ask a broader range of questions, but does not increase physician SDM behavior.The combination of QPL and CAR seems feasible and should be tested in an implementation study following the disease trajectory.

BACKGROUND: Inflammation is intimately involved in the pathogenesis of atherosclerosis and is accurately measured by high sensitivity C-reactive protein (hs-CRP), a sensitive marker for future risk of cardiovascular disease. The Correlation between Oral Health and Systemic Inflammation (COHESION) trial was designed to test the hypothesis that PlaqueHD, a plaque identifying toothpaste, reduces hs-CRP. METHODS: COHESION was designed initially to enroll 132 subjects with hs-CRP between 2.0 and 10.0 milligrams per liter but randomized 112 between 0.5 and 10.0, of which 103 had baseline and follow up data and comprise the intention to treat sample. Of these, a pre-specified subgroup analysis included 40 with baseline hs-CRP > 2.0 and all hs-CRP < 10. Since the distribution of hs-CRP was skewed toward higher values, to achieve normality assumptions, the significance of changes in hs-CRP between groups over time was tested on log-transformed data using a mixed effects analysis of variance. RESULTS: The intention-to-treat analysis showed no significant differences between the PlaqueHD and placebo group (p=0.615). The pre-specified subgroup analysis showed a significant difference between the PlaqueHD and placebo group (p=0.047). This finding resulted from a reduction in hs-CRP at follow up of 0.58 in the PlaqueHD and an increase of 0.55 in the placebo group. CONCLUSIONS: These findings are compatible with those of a prior pilot trial which also suggested benefits only in subjects with baseline elevations. These findings suggest that future trials targeting reductions of hs-CRP levels should randomize subjects with baseline hs-CRP between 2.0 and 10.0.

Objective: The rates of decline in respiratory measurements, including Peak Cough Flow (PCF) have not been established in Amyotrophic Lateral Sclerosis (ALS). Additionally, optimal prescription of ...

In this White Paper, we discuss the current state of microbial cancer therapy. This paper resulted from a meeting (‘Microbial Based Cancer Therapy’) at the US National Cancer Institute in the summer of 2017. Here, we define ‘Microbial Therapy’ to include both oncolytic viral therapy and bacterial anticancer therapy. Both of these fields exploit tumor-specific infectious microbes to treat cancer, have similar mechanisms of action, and are facing similar challenges to commercialization. We designed this paper to nucleate this growing field of microbial therapeutics and increase interactions between researchers in it and related fields. The authors of this paper include many primary researchers in this field. In this paper, we discuss the potential, status and opportunities for microbial therapy as well as strategies attempted to date and important questions that need to be addressed. The main areas that we think will have the greatest impact are immune stimulation, control of efficacy, control of delivery, and safety. There is much excitement about the potential of this field to treat currently intractable cancer. Much of the potential exists because these therapies utilize unique mechanisms of action, difficult to achieve with other biological or small molecule drugs. By better understanding and controlling these mechanisms, we will create new therapies that will become integral components of cancer care.

Current guidelines for dialysis specify a minimum Kt/V. For haemodialysis (HD) patients, minimum treatment time and frequency is also specified. The guidelines allow for modification to take account of renal function. The guidelines are not specifically aimed at the elderly and may not be appropriate for all patients in this group. Increasing age is accompanied by physiological and pathological changes that may modify the patient's response to uraemia and dialysis. Frailty and multi-morbidity are likely, but to a variable extent. Elderly patients could be more susceptible to the effects of uraemia and require a higher dose of dialysis. Conversely, the generation rate of uraemic toxins is lower in elderly patients, potentially reducing the need for dialysis. In the elderly, quality of life may be more adversely affected by multimorbidity than uraemic symptoms, thus the dose of dialysis may be less relevant. Higher doses of dialysis may be more difficult to achieve in the elderly and may be less well tolerated. We conclude that the prescription of dialysis in the elderly should be individualized, taking multiple factors into account. An individualized Kt/V may be useful in controlling dialysis dose and detecting problems in delivery. However, achievement of a specified Kt/V may not result in any benefit to an elderly patient and could be counterproductive.

Haemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome, which if not promptly treated, can lead rapidly to critical illness and death. HLH is termed macrophage activation syndrome (MAS) when associated with rheumatic disease (where it is best characterized in systemic JIA) and secondary HLH (sHLH) when associated with other triggers including malignancy and infection. MAS/sHLH is rare and coupled with its mimicry of other conditions, is underrecognized. These inherent challenges can lead to diagnostic and management challenges in multiple medical specialties including haematology, infectious diseases, critical care and rheumatology. In this review we highlight the pathogenesis of MAS/sHLH including its underlying triggers, key clinical features and diagnostic challenges, prognostic factors and current treatments in adults.

Germline genomic testing is increasingly used in research to identify genetic causes of disease, including cancer. However, there is evidence that individuals who are notified of clinically actionable research findings have difficulty making informed decisions regarding uptake of genetic counseling for these findings. This study aimed to produce and pilot test a decision aid to assist participants in genomic research studies who are notified of clinically actionable research findings to make informed choices regarding uptake of genetic counseling. Development was guided by published literature, the International Patient Decision Aid Standards, and the expertise of a steering committee of clinicians, researchers, and consumers. Decision aid acceptability was assessed by self-report questionnaire. All 19 participants stated that the decision aid was easy to read, clearly presented, increased their understanding of the implications of taking up research findings, and would be helpful in decision-making. While low to moderate levels of distress/worry were reported after reading the booklet, a majority of participants also reported feeling reassured. All participants would recommend the booklet to others considering uptake of clinically actionable research findings. Results indicate the decision aid is acceptable to the target audience, with potential as a useful decision support tool for genomic research participants.