Uric acid predicts long-term cardiovascular risk in type 2 diabetes but does not mediate the benefits of fenofibrate: The FIELD study.

AIM: To explore the relationship between baseline uric acid (UA) levels and long-term cardiovascular events in adults with type 2 diabetes (T2D) and to determine whether the cardioprotective effects of fenofibrate are partly mediated through its UA-lowering effects. METHODS: Data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial were utilized, comprising 9795 adults with T2D randomly allocated to treatment with fenofibrate or matching placebo. Plasma UA was measured before and after a 6-week, active fenofibrate run-in phase in all participants. Cox proportional hazards models were used to explore the relationships between baseline UA, pre-to-post run-in reductions in UA and long-term cardiovascular outcomes. RESULTS: Mean baseline plasma UA was 0.33 mmol/L (SD 0.08). Baseline UA was a significant predictor of long-term cardiovascular events, with every 0.1 mmol/L higher UA conferring a 21% increase in event rate (HR 1.21, 95% CI 1.13-1.29, P < .001). This remained significant after adjustment for treatment allocation, cardiovascular risk factors and renal function. The extent of UA reduction during fenofibrate run-in was also a significant predictor of long-term cardiovascular events, with every 0.1 mmol/L greater reduction conferring a 14% lower long-term risk (HR 0.86, 95% CI 0.76-0.97, P = .015). This effect was not modified by treatment allocation (Pinteraction = .77). CONCLUSIONS: UA is a strong independent predictor of long-term cardiovascular risk in adults with T2D. Although greater reduction in UA on fenofibrate is predictive of lower cardiovascular risk, this does not appear to mediate the cardioprotective effects of fenofibrate.

An evaluation of two novel capillaroscopy techniques in suspected scleroderma-spectrum disorders: A single-centre cross-sectional study.

OBJECTIVES: The primary aim was to evaluate the diagnostic performance of digital photographs taken with a smartphone camera using both a lens attachment and, separately, a dermatoscope. The secondary aims were to assess the influence of prior capillaroscopy experience and familiarity with the novel techniques on diagnostic accuracy. METHODS: All patients referred for capillaroscopy between May 2016 and January 2017 were eligible for inclusion. Nailfolds were classified by widefield microscopy before proceeding double-blinded to nailfold photography using both novel techniques. Randomised photographs were assessed by three independent investigators and results were compared to widefield microscopy. Sensitivity, specificity, inter- and intra-observer variability were calculated. RESULTS: Sixty-five participants contributed over 1000 digital photographs for assessment. The 'smartphone-lens' technique performed with moderate sensitivity (65%; 58-72) and high specificity (90%; 84-96). The 'smartphone-dermatoscope' technique performed with higher sensitivity (74%; 66-82) and excellent specificity (95%; 88-100) and was used more accurately by a novice. Prior assessor experience with nailfold capillaroscopy in general and prior experience with the novel techniques positively modulated the diagnostic accuracy. CONCLUSION: New technologies, in this case utilising a smartphone camera, could help to improve accessibility to nailfold capillaroscopy, an important diagnostic tool and putative biomarker in scleroderma-spectrum disorders, whilst retaining accurate results.

Percutaneous cryoablation of renal tumours: outcomes from 171 tumours in 147 patients.

OBJECTIVE: To evaluate the technical and oncological efficacy of an image-guided cryoablation programme for renal tumours. PATIENTS AND METHODS: A prospective analysis of technical and radiological outcomes was undertaken after treatment of 171 consecutive tumours in 147 patients. Oncological efficacy in a subset of 125 tumours in 104 patients with >6 months' radiological follow-up and a further subset of 62 patients with solitary, biopsy-proven renal carcinoma was also analysed. Factors influencing technical success, as determined by imaging follow-up, and complication rates were statistically analysed using a statistics software package and logistic regression analyses. RESULTS: No variables were found to predict subtotal treatment, although gender (P = 0.08), tumour size of >4 cm (P = 0.09) and central location of tumour (P = 0.07) approached significance. Upper pole location was the single variable that was found to predict complications (P = 0.006). Among the 104 patients (125 tumours), radiologically assessed at ≥6 months and with a mean radiological follow-up of 20.1 months, we found a single case of unexpected late local recurrence. CONCLUSION: Percutaneous image-guided cryoablation, at a mean of 20.1 months' follow-up, appears to provide a safe and effective treatment option with a low complication rate. Anteriorly sited tumours should not be considered a contraindication for percutaneous image-guided cryoablation.

The preservation of synovial fluid using dimethyl sulfoxide.

BACKGROUND: The Royal College of Pathologists of Australasia Quality Assurance Programs runs a Quality Assurance Program for the assessment of synovial fluid crystals. It provides aliquots of synovial fluid to various laboratories. The quality of specimens can deteriorate prior to being examined. We aimed to assess whether the addition of dimethyl sulfoxide (DMSO) to synovial fluid specimens helps maintain cellular morphology. METHODS: Synovial fluid specimens were obtained from 15 patients. Each specimen was aliquoted into 24 samples, with half having DMSO added at a concentration of 10%. For each specimen, six samples containing DMSO and six samples not containing DMSO were stored at-80°C and room temperature. Samples from each group were examined at 1, 2, 3, 6, 7 and 8 weeks. Comparative Analysis: For each specimen, the final remaining aliquoted samples containing DMSO and not containing DMSO, which were stored at-80°C, were directly compared. Quantitative Analysis: A system for grading cellular morphology and assessing for artefacts and cellular clumping was applied by two independent assessors. RESULTS: Comparative Analysis: A significant difference was found between samples containing DMSO and not containing DMSO which were stored at -80°C (p = .000), in favour of those containing DMSO. Quantitative Analysis: Regarding the combined findings of Assessors 1 and 2 and the grading of cellular morphology, a significant difference was found according to "groups" (p = .000), in favour of those containing DMSO and stored at-80°C. CONCLUSIONS: DMSO contributes to the maintenance of cellular morphology in synovial fluid when stored in frozen conditions.

Blood conservation and pain control in scoliosis corrective surgery: an online survey of UK practice.

BACKGROUND: Discussion at local meetings led to the realization of the diversity in anaesthetic practice for pediatric and adolescent scoliosis surgery. This diversity was assessed using an online survey, the aim being to provoke discussion and highlight areas of future research. METHODS: Of the 24 centers practicing pediatric and adolescent scoliosis surgery, 21 completed questionnaires, a response rate of 88%. RESULTS: Blood conservation; the area of greatest clinical variability was seen in dosing regimes for Tranexamic acid. Thromboprophylaxis; both mechanical and pharmacological regimes showed wide range in both application and timing. Pain control; eight different types of postoperative pain relief were utilized across the centres, some in isolation but many in combination. CONCLUSIONS: The results from our survey show wide variation nationally and hopefully will provoke discussion and ultimately national multi-centred research to define best practice.

Nailfold capillaroscopy by smartphone-dermatoscope for connective tissue disease diagnosis in interstitial lung disease: a prospective observational study.

Nailfold capillaroscopy (NFC) is a non-invasive tool validated for systemic sclerosis diagnosis. The role and interpretation of NFC in interstitial lung disease (ILD) patients for the diagnosis of connective tissue disease associated ILD (CTD-ILD) remains undefined. In a prospective study, quantitative and qualitative NFC by smartphone-dermatoscope (3M Dermlite-DL4ΤΜ attached to iPhone-6plusΤΜ) was performed in 96 patients with well-defined CTD-ILD (n=27) and non-CTD ILD (n=69; idiopathic interstitial pneumonia n=42, interstitial pneumonia with autoimmune features n=27) by ILD-multidisciplinary meeting. NFC scoring was performed by two independent, blinded specialist rheumatologists. Comprehensive baseline clinical, serological, physiological and radiological data were included. Multivariable models for CTD diagnosis in ILD, comprising nailfold characteristics at empirical thresholds determined by receiver operating characteristic curve analysis and clinical variables, were explored. In 94 patients with complete NFC data (total 687 images, median eight images per patient from eight digits), low capillary density (<6 capillaries/millimetre), increased giant capillaries (≥3), avascular areas (≥2) and microhaemorrhages all strongly enhanced the discrimination of CTD-ILD from non-CTD ILD (OR 5.00-7.47) independent of clinical covariates. In multivariable analysis, low capillary density and microhaemorrhages were independent predictors of CTD in ILD additional to the risk conferred by serology and radiology. Microhaemorrhages were also a strong predictor of CTD (adjusted OR 13.45, p=0.006) independent of clinical manifestations. All pre-specified qualitative NFC classification schemes identified CTD-ILD (OR range 3.27-8.47). NFC performed by smartphone-dermatoscope is an accessible, clinically feasible tool that may improve the identification of CTD further to routine clinical assessment of the ILD patient.

Immune Toxicity with Checkpoint Inhibition for Metastatic Melanoma: Case Series and Clinical Management.

Immune checkpoint inhibitors (anti-PD-1 and anti-CTLA-4 antibodies) are a standard of care for advanced melanoma. Novel toxicities comprise immune-related adverse events (irAE). With increasing use, irAE require recognition, practical management strategies, and multidisciplinary care. We retrospectively evaluated the incidence, kinetics, and management of irAE in 41 patients receiving anti-PD-1 antibody therapy (pembrolizumab) for advanced melanoma. 63% received prior anti-CTLA-4 antibody therapy (ipilimumab). IrAE occurred in 54%, most commonly dermatological (24%), rheumatological (22%), and thyroid dysfunction (12%). Thyroiditis was characterised by a brief asymptomatic hyperthyroid phase followed by a symptomatic hypothyroid phase requiring thyroxine replacement. Transplant rejection doses of methylprednisolone were necessary to manage refractory hepatotoxicity. A bullous pemphigoid-like skin reaction with refractory pruritus responded to corticosteroids and neuropathic analgesia. Disabling grade 3-4 oligoarthritis required sulfasalazine therapy in combination with steroids. The median interval between the last dose of anti-CTLA-4 antibody and the first dose of anti-PD-1 therapy was 2.0 months (range: 0.4 to 22.4). Toxicities may occur late; this requires vigilance and multidisciplinary management which may allow effective anticancer therapy to continue. Management algorithms for thyroiditis, hypophysitis, arthralgia/arthritis, colitis, steroid-refractory hepatitis, and skin toxicity are discussed.

Effect of fenofibrate on uric acid and gout in type 2 diabetes: a post-hoc analysis of the randomised, controlled FIELD study.

BACKGROUND: Gout is a painful disorder and is common in type 2 diabetes. Fenofibrate lowers uric acid and reduces gout attacks in small, short-term studies. Whether fenofibrate produces sustained reductions in uric acid and gout attacks is unknown. METHODS: In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial, participants aged 50-75 years with type 2 diabetes were randomly assigned to receive either co-micronised fenofibrate 200 mg once per day or matching placebo for a median of 5 years follow-up. We did a post-hoc analysis of recorded on-study gout attacks and plasma uric acid concentrations according to treatment allocation. The outcomes of this analysis were change in uric acid concentrations and risk of on-study gout attacks. The FIELD study is registered with ISRCTN, number ISRCTN64783481. FINDINGS: Between Feb 23, 1998, and Nov 3, 2000, 9795 patients were randomly assigned to fenofibrate (n=4895) or placebo (n=4900) in the FIELD study. Uric acid concentrations fell by 20·2% (95% CI 19·9-20·5) during the 6-week active fenofibrate run-in period immediately pre-randomisation (a reduction of 0·06 mmol/L or 1 mg/dL) and remained -20·1% (18·5-21·7, p<0·0001) lower in patients taking fenofibrate than in those on placebo in a random subset re-measured at 1 year. With placebo allocation, there were 151 (3%) first gout events over 5 years, compared with 81 (2%) among those allocated fenofibrate (HR with treatment 0·54, 95% CI 0·41-0·70; p<0·0001). In the placebo group, the cumulative proportion of patients with first gout events was 7·7% in patients with baseline uric acid concentration higher than 0·36 mmol/L and 13·9% in those with baseline uric acid concentration higher than 0·42 mmol/L, compared with 3·4% and 5·7%, respectively, in the fenofibrate group. Risk reductions were similar among men and women and those with dyslipidaemia, on diuretics, and with elevated uric acid concentrations. For participants with elevated baseline uric acid concentrations despite taking allopurinol at study entry, there was no heterogeneity of the treatment effect of fenofibrate on gout risk. Taking account of all gout events, fenofibrate treatment halved the risk (HR 0·48, 95% CI 0·37-0·60; p<0·0001) compared with placebo. INTERPRETATION: Fenofibrate lowered uric acid concentrations by 20%, and almost halved first on-study gout events over 5 years of treatment. Fenofibrate could be a useful adjunct for preventing gout in diabetes. FUNDING: None.

Achieving serum urate targets in gout: an audit in a gout-oriented rheumatology practice.

AIM: To assess the proportion of patients with gout who achieve target serum urate levels, the drug regime required and the reasons for failing to do so. METHODS: We reviewed the files of all patients with gout who presented to a gout-oriented rheumatology practice between January 2010 and September 2014. RESULTS: Two hundred and thirty patients agreed to commence urate lowering therapy (ULT); 73% achieved their urate target, including 74% with non-tophaceous gout (target ≤ 0.36 mmol/L) and 71% with tophi (target ≤ 0.30 mmol/L). Of the 62 who failed to reach target, in 61 it was due to non-adherence and in one due to inefficacy. CONCLUSION: Adherence remains the major challenge to successful long-term gout management.

Immunotherapy-induced sarcoidosis in patients with melanoma treated with PD-1 checkpoint inhibitors: Case series and immunophenotypic analysis.

AIM: Sarcoidosis is a multisystem granulomatous disease. This condition has a documented association with the diagnosis of melanoma and can be induced in melanoma patients receiving anti-neoplastic therapy. We evaluated a case series of melanoma patients who developed immunotherapy-induced sarcoidosis. METHODS: Three patients with melanoma (n = 1 resected Stage III, n = 2 metastatic) treated with anti-programmed cell death (PD)-1 antibody therapy at two institutions developed biopsy-proven sarcoidosis. We used mass cytometry to determine expression of the relevant chemokine receptors (CR) by peripheral blood mononuclear cells for two of the three patients who developed sarcoidosis and 13 melanoma patients who did not. Blood samples were collected before receiving PD-1 checkpoint inhibitor therapy. RESULTS: Immunophenotypic analysis demonstrated abnormally high numbers of circulating Th17.1 (CCR6+ CCR4- CXCR3+ CCR10- ) cells prior to commencing PD-1 checkpoint inhibitor therapy in five of 15 melanoma patients, including both the patients who developed sarcoidosis during the course of therapy. CONCLUSION: Our findings support prior literature implicating Th17.1 cells in the pathogenesis of sarcoidosis. However, we demonstrate these findings in patients with melanoma prior to administration of checkpoint therapy and before the onset of clinically symptomatic sarcoidosis. The identification of elevated Th17.1 cells in melanoma patients who have not developed sarcoidosis may reflect the established association between melanoma and sarcoidosis. With some patients receiving these agents over a prolonged period, the clinical course of immunotherapy-induced sarcoidosis is uncertain.

Lemierre disease in the pediatric intensive care unit, clinical course, and the use of high-frequency oscillatory ventilation.

OBJECTIVE: To highlight that cavitating pneumonias may be part of Lemierre disease, caused by Fusobacterium necrophorum. Also to report on the use of high-frequency oscillatory ventilation (HFOV) among other strategies, in the treatment of such a cavitating pneumonia. DESIGN: Case study. SETTING: Tertiary pediatric intensive care unit in a university teaching hospital. PATIENT: A 45-kg, 14-yr old girl. INTERVENTIONS: Ventilation with a HFOV for 12 days, conventional ventilation for 24 days, and the concomitant use of nitric oxide. MEASUREMENTS AND MAIN RESULTS: Oxygenation improved markedly following institution of HFOV and nitric oxide, the PaO2/FIO2 ratio increasing from 10.7 kPa on conventional ventilation to 24 kPa on HFOV and nitric oxide after an initial period of respiratory unit recruitment. Mean airway pressure decreased from 26 cm H2O to 22 cm H2O during this period, while amplitude was 80 cm H2O. After 12 days of gradual improvement on HFOV, the PaO2/FIO2 ratio increased to 27 kPa, mean airway pressure decreased to 17 cm H2O, and amplitude decreased to 65 cm H2O. Multiple chest drains for loculated pneumothoraces were required during the periods of conventional ventilation and HFOV. CONCLUSIONS: HFOV and nitric oxide improved oxygenation through the critical period of this disease when conventional ventilation variables were considered maximal. There were eight occurrences of loculated pneumothoraces during the period of HFOV and five occurrences during conventional ventilation. We would like to remind fellow clinicians that Lemierre disease may be the cause of cavitating pneumonias.

The epidemiology and treatment of gout.

The development and expression of gout depends on three key steps: (1) chronic hyperuricemia, (2) the growth of monosodium urate (MSU) crystals, and (3) interaction between MSU crystals and the inflammatory system. Epidemiological studies have continued to improve our understanding of the environmental and genetic factors which influence chronic hyperuricemia and gout. The influence of obesity, alcohol, race, sex, age, and specific dietary components will be discussed below. The primary mechanism of hyperuricemia is insufficient renal clearance of uric acid which in turn is dependent on transport of uric acid in the proximal renal tubule. Knowledge of the transport mechanisms has improved understanding of the genetic influences on gout and is relevant to understanding of the effects of drugs which can increase or decrease renal uric acid clearance. The application of established principles of management including diagnosis through crystal identification, the gradual introduction of hypouricemic therapy with the use of prophylaxis to reduce the risk of flares, identification of a suitably low target of plasma urate, a progressive increase in therapy to achieve the target and taking steps to encourage good compliance, has the potential to improve outcomes for patients with this very common affliction. The potential role for new therapies will also be discussed.

Hepatobiliary scintigraphy in vasculitis of the gallbladder as a manifestation of polyarteritis nodosa: a case report.

INTRODUCTION: Polyarteritis nodosa can on rare occasions manifest itself as vasculitis of the gallbladder. Patients typically present with right upper quadrant pain and are initially worked up for cholecystitis. The definitive diagnosis is then usually based on surgical and histopathological findings. CASE PRESENTATION: In this case a 23-year-old Caucasian female presented with a 3 week history of right upper quadrant pain and fevers. CONCLUSION: The clinical pathway and imaging findings of a rare case of gallbladder vasculitis as a manifestation of polyarteritis nodosa are demonstrated.

Mechanical methods of reducing blood transfusion in cardiac surgery: randomised controlled trial.

OBJECTIVE: To assess the effectiveness of two mechanical methods of blood conservation in reducing the need for allogeneic red blood cells or coagulation products during cardiac surgery. DESIGN: Randomised controlled trial. SETTING: Regional cardiac centre in a teaching hospital in Southampton. PARTICIPANTS: 263 adults aged 18-80 years undergoing elective coronary artery bypass surgery entered the study, of whom 252 completed the trial. All patients received routine perioperative care. Patients were allocated to one of three treatment groups: intraoperative cell salvage, intraoperative cell salvage with acute perioperative normovolaemic haemodilution, or no mechanical blood conservation. There were 84 patients in each group. MAIN OUTCOME MEASURES: Numbers of patients who received allogeneic blood or coagulation products, and the mean number of units of blood transfused per patient. RESULTS: Of the patients in the intraoperative cell salvage group, 26 were given a transfusion of allogeneic blood, compared with 43 in the control group (odds ratio 0.43 (95% confidence interval 0.23 to 0.80)). The mean number of units of allogeneic blood transfused per patient in the intraoperative cell salvage group was 0.68 units (SD=1.55), compared with 1.07 (1.56) units in the control group. 32 of the patients in the intraoperative cell salvage group were given any blood product, compared with 47 in the control group (odds ratio 0.47 (0.25 to 0.89); P=0.019). Combining acute perioperative normovolaemic haemodilution with intraoperative cell salvage conferred no additional benefits. CONCLUSIONS: An intraoperative cell salvage device should be used in elective coronary artery bypass grafting. Pharmacological strategies may achieve further reductions in blood transfusions. Yet further reductions in blood transfusions could be achieved if the lower safe limit of haemoglobin concentration in patients undergoing cardiac surgery were known.