Charlotte McDonald

BACKGROUND: Statin-related myalgia is difficult to distinguish from other conditions causing myalgia and may often lead to statin discontinuation. OBJECTIVE: To compare the effect of statin rechallenge with placebo in patients with prior statin-related myalgia and to determine whether patients resumed statin therapy after evaluating the results. DESIGN: N-of-1 trial with 3 double-blind, crossover comparisons separated by 3-week washout periods. (Clinicaltrials.gov: NCT01259791) SETTING: Tertiary care lipid clinic. PATIENTS: Patients with prior statin-related myalgia with or without mild elevation of creatine kinase levels. INTERVENTION: Rechallenge with the statin that was previously associated with myalgia within 3 weeks of open-label use versus matching placebo. MEASUREMENTS: Weekly visual analogue scale (VAS) scores for myalgia and specific symptoms (VAS myalgia score and symptom-specific VAS score, respectively), pain interference scores, and pain severity scores were recorded during the 3-week periods when patients were receiving placebo or statin. The primary outcome was the VAS myalgia score (range, 0 to 100 mm). RESULTS: Eight patients (mean age, 66 years [SD, 8 years]; 88% women, all with high 10-year Framingham cardiovascular risk) participated in n-of-1 trials. Seven patients completed 3 treatment pairs, and 1 completed 2 treatment pairs. For each n-of-1 trial, no statistically significant differences were seen between statin and placebo in the VAS myalgia score, symptom-specific VAS score, pain interference score, and pain severity score. Five patients resumed open-label statin treatment, with a median posttrial follow-up of 10 months. LIMITATION: Results are limited by the small sample size and cannot be extended to patients with longer onset of myalgia after statin initiation. CONCLUSION: In selected patients with a history of statin-related myalgia whose symptoms are difficult to evaluate, n-of-1 trials may be a useful method for determining statin tolerability. PRIMARY FUNDING SOURCE: Western University, London, Ontario, Canada.

Bruton's tyrosine kinase (BTK) is a TEC kinase with a multifaceted role in B-cell biology and function, highlighted by its position as a critical component of the B-cell receptor signalling pathway. Due to its role as a therapeutic target in several haematological malignancies including chronic lymphocytic leukaemia, BTK has been gaining tremendous momentum in recent years. Within the immune system, BTK plays a part in numerous pathways and cells beyond B cells (i.e. T cells, macrophages). Not surprisingly, BTK has been elucidated to be a driving factor not only in lymphoproliferative disorders but also in autoimmune diseases and response to infection. To extort this role, BTK inhibitors such as ibrutinib have been developed to target BTK in other diseases. However, due to rising levels of resistance, the urgency to develop new inhibitors with alternative modes of targeting BTK is high. To meet this demand, an expanding list of BTK inhibitors is currently being trialled. In this review, we synopsize recent discoveries regarding BTK and its role within different immune cells and pathways. Additionally, we discuss the broad significance and relevance of BTK for various diseases ranging from haematology and rheumatology to the COVID-19 pandemic. Overall, BTK signalling and its targetable nature have emerged as immensely important for a wide range of clinical applications. The development of novel, more specific and less toxic BTK inhibitors could be revolutionary for a significant number of diseases with yet unmet treatment needs.

BACKGROUND: Clinical islet transplantation (ITx) shows insulin independence with adequate metabolic control in patients with type 1 diabetes. The aim of this study was to characterize the pattern of elevation in liver enzymes observed after ITx and to investigate any correlation between these elevations and graft characteristics or graft functional outcome. METHODS: Eighty-four consecutive ITx procedures were performed in 42 recipients. Liver function tests (LFT) were assessed during the first 40 days posttransplant. LFT elevated greater than or equal to 2.5 times above the upper limit of normal (ULN) were considered relevant. RESULTS: In 54% of the transplants, the aspartate aminotransferase (AST) increased by more than 2.5 times above ULN. A 5-fold increase in AST was observed in 27% of the procedures. The highest AST levels were observed after the first ITx. AST for all transplants peaked at 7+/-0.5 days at a value of 162+/-23 U/L (P<0.001, compared with the pretransplant values). Changes in alanine aminotransferase were similar to AST. Alkaline phosphatase increased more than 2-fold above ULN in 12% of the procedures. LFT normalized in 90% of the recipients within 4 weeks posttransplant. The remaining 10% normalized within 2 months after ITx. Graft characteristics and graft function were not significantly different when comparing LFT with greater than 5-fold versus less than 2.5-fold increase above ULN. The mean bilirubin remained within the normal range. CONCLUSIONS: After intraportal ITx, a significant increase in LFT levels was noticed in more than 50% of the procedures. These levels normalized spontaneously in 90% of the recipients within 4 weeks. No correlation between the increase in LFT and graft characteristics or graft function was found.

AIM: The International Continence Society (ICS) has standardized quality control and interpretation of uroflowmetry and urodynamics. We evaluated traces from two large studies of male lower urinary tract symptoms (UPSTREAM and UNBLOCS) against ICS standards of urodynamic equipment and practice. METHODS: Ten percent of uroflowmetry and urodynamics traces were selected at random from hospital sites. A data capture template was designed from the ICS Fundamentals of Urodynamic Practice checklist. Two pretrained blinded assessors extracted the data, with a third assessor to arbitrate. Departmental records of calibration checks and equipment maintenance were scrutinized. RESULTS: Seven out of twenty-five (28%) departments reported no calibration checks. Four sites (16%) could not provide annual service records. In 32 out of 296 (10.8%) uroflowmetry traces, findings were affected by artifact. One hundred ten urodynamic study traces were reviewed; in 11 records (10%), key pressure traces were incompletely displayed. In 30 (27.2%), reference zero was not set to atmospheric pressure. Resting pressures were outside the expected range for 36 (32.7%). Pressure drift was seen in 18 traces (16.4%). At pressure-flow study commencement, permission to void was omitted in 15 (13.6%). Cough testing after voiding was done in 71.2%, but the resulting cough spikes were significantly different in 16.5%. Erroneous diagnosis of bladder outlet obstruction (BOO) was identified in six cases (5.5%). CONCLUSIONS: Erroneous diagnosis of BOO is a serious error of interpretation, as it could lead to unnecessary surgery. Other errors of standardization, testing, and interpretation were identified with lower risk of adverse implications. Inconsistent documentation of service records mean equipment accuracy is uncertain.