Detection of primary melanoma in individuals at extreme high risk: a prospective 5-year follow-up study

IMPORTANCE: The clinical phenotype and certain predisposing genetic mutations that confer increased melanoma risk are established; however, no consensus exists regarding optimal screening for such individuals. Early identification remains the most important intervention in reducing melanoma mortality. OBJECTIVE: To evaluate the impact of full-body examinations every 6 months supported by dermoscopy and total-body photography (TBP) on all patients and sequential digital dermoscopy imaging (SDDI), when indicated, on detecting primary melanoma in an extreme-risk population. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational study from February 2006 to February 2011, with patients recruited from Sydney Melanoma Diagnostic Centre and Melanoma Institute Australia who had a history of invasive melanoma and dysplastic nevus syndrome, history of invasive melanoma and at least 3 first-degree or second-degree relatives with prior melanoma, history of at least 2 primary invasive melanomas, or a CDKN2A or CDK4 gene mutation. EXPOSURES: Six-month full-body examination compared with TBP. For equivocal lesions, SDDI short term (approximately 3 months) or long term (≥6 months), following established criteria, was performed. Atypical lesions were excised. MAIN OUTCOMES AND MEASURES: New primary melanoma numbers, characteristics, and cumulative incidence in each patient subgroup; effect of diagnostic aids on new melanoma identification. RESULTS: In 311 patients with a median (interquartile range [IQR]) follow-up of 3.5 (2.4-4.2) years, 75 primary melanomas were detected, 14 at baseline visit. Median (IQR) Breslow thickness of postbaseline incident melanomas was in situ (in situ to 0.60 mm). Thirty-eight percent were detected using TBP and 39% with SDDI. Five melanomas were greater than 1 mm Breslow thickness, 3 of which were histologically desmoplastic; the other 2 had nodular components. The benign to malignant excision ratio was 1.6:1 for all lesions excised and 4.4:1 for melanocytic lesions. Cumulative risk of developing a novel primary melanoma was 12.7% by year 2, with new primary melanoma incidence during the final 3 years of follow-up half of that observed during the first 2 years (incidence density ratio, 0.43 [95% CI, 0.25-0.74]; P = .002). CONCLUSIONS AND RELEVANCE: Monitoring patients at extreme risk with TBP and SDDI assisted with early diagnosis of primary melanoma. Hypervigilance for difficult-to-detect thick melanoma subtypes is crucial. Copyright 2014 American Medical Association. All rights reserved

Rates and predictors of risk of stroke and its subtypes in diabetes: a prospective observational study

Background Small vessel disease is reported to be a more common cause of ischaemic stroke in people with diabetes than in others. However, population based studies have shown no difference between those with and those without diabetes in the subtypes of stroke. We determined the rates and predictors of risk of stroke and its subtypes in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial. Methods 9795 patients aged 50–75 years with type 2 diabetes were followed up for a median of 5 years. Annual rates were derived by the Kaplan–Meier method and independent predictors of risk by Cox proportional hazards regression analyses. Results The annual rate of stroke was 6.7 per 1000 person years; 82% were ischaemic and caused by small artery disease (36%), large artery disease (17%) and embolism from the heart (13%); 10% were haemorrhagic. Among the strongest baseline predictors of ischaemic or unknown stroke were age (60–65 years, HR 1.98; >65 years, HR 2.35) and a history of stroke or transient ischaemic attack (TIA) (HR 2.06). Other independent baseline predictors were male sex, smoking, history of hypertension, ischaemic heart disease, nephropathy, systolic blood pressure and blood low density lipoprotein (LDL) cholesterol, HbA1c and fibrinogen. A history of peripheral vascular disease, low high density lipoprotein, age and history of hypertension were associated with large artery ischaemic stroke. A history of diabetic retinopathy, LDL cholesterol, male sex, systolic blood pressure, smoking, diabetes duration and a history of stroke or TIA were associated with small artery ischaemic stroke. Conclusions Older people with a history of stroke were at highest risk of stroke, but the prognosis and prognostic factors of subtypes were heterogeneous. The results will help clinicians quantify the absolute risk of stroke and its subtypes for typical diabetes patients.FIELD trial sponsored by Laboratoires Fournier SA, Dijon, France (part of Abbott

Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study

Abstract Aims/hypothesis Fenofibrate caused an acute, sustained plasma creatinine increase in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies. We assessed fenofibrate’s renal effects in a FIELD washout sub-study. Methods Type 2 diabetic patients (n=9795) aged 50 to 75 years were randomly assigned to fenofibrate (n=4895) or placebo (n=4900) for 5 years, after 6 weeks fenofibrate run-in. Albuminuria (urinary albumin:creatinine ratio) measured at baseline, year 2 and close-out) and estimated GFR, measured 4 to 6 monthly according to the Modification of Diet in Renal Disease study, were pre-specified endpoints. Plasma creatinine was re-measured 8 weeks after treatment cessation at close-out (washout sub-study, n=661). Analysis was by intention-to-treat. Results During fenofibrate run-in, plasma creatinine increased by 10.0 µmol/l (p<0.001), but quickly reversed on placebo assignment. It remained higher on fenofibrate than on placebo, but the chronic rise was slower (1.62 µmol/l vs 1.89 µmol/l annually, p=0.01), with less estimated GFR loss (1.19 vs 2.03 ml min−1 1.73 m−2 annually, p<0.001). After washout, estimated GFR had fallen less from baseline on fenofibrate (1.9 ml min−1 1.73 m−2, p=0.065) than on placebo (6.9 ml min−1 1.73 m−2, p<0.001), sparing 5.0 ml min−1 1.73 m−2 (95% CI 2.3-7.7, p<0.001). Greater preservation of estimated GFR with fenofibrate was observed during greater reduction over the active run-in period (pre-randomisation) of triacylglycerol (n=186 vs 170) and baseline hypertriacylglycerolaemia (n=89 vs 80) alone, or combined with low HDL-cholesterol (n=71 vs 60). Fenofibrate reduced urine albumin concentrations and hence albumin:creatinine ratio by 24% vs 12% (p<0.001; mean difference 14% [95% CI 9-18]; p<0.001), with 14% less progression and 18% more albuminuria regression (p<0.001) than in participants on placebo. End-stage renal event frequency was similar (n=21 vs 26, p=0.48). Conclusions/interpretation Fenofibrate reduced albuminuria and slowed estimated GFR loss over 5 years, despite initially and reversibly increasing plasma creatinine. Fenofibrate may delay albuminuria and GFR impairment in type 2 diabetes patients. Confirmatory studies are merited. Trial registration: ISRCTN64783481 Funding: The study was funded by grants from Laboratoires Fournier, Dijon, France (now part of Solvay and Abbott Pharmaceuticals) and the NHMRC of Australia.Laboratoires Fournier, Dijon, France (now part of Solvay and Abbott Pharmaceuticals

Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study

Abstract Aims/hypothesis Fenofibrate caused an acute, sustained plasma creatinine increase in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies. We assessed fenofibrate’s renal effects in a FIELD washout sub-study. Methods Type 2 diabetic patients (n=9795) aged 50 to 75 years were randomly assigned to fenofibrate (n=4895) or placebo (n=4900) for 5 years, after 6 weeks fenofibrate run-in. Albuminuria (urinary albumin:creatinine ratio) measured at baseline, year 2 and close-out) and estimated GFR, measured 4 to 6 monthly according to the Modification of Diet in Renal Disease study, were pre-specified endpoints. Plasma creatinine was re-measured 8 weeks after treatment cessation at close-out (washout sub-study, n=661). Analysis was by intention-to-treat. Results During fenofibrate run-in, plasma creatinine increased by 10.0 µmol/l (p<0.001), but quickly reversed on placebo assignment. It remained higher on fenofibrate than on placebo, but the chronic rise was slower (1.62 µmol/l vs 1.89 µmol/l annually, p=0.01), with less estimated GFR loss (1.19 vs 2.03 ml min−1 1.73 m−2 annually, p<0.001). After washout, estimated GFR had fallen less from baseline on fenofibrate (1.9 ml min−1 1.73 m−2, p=0.065) than on placebo (6.9 ml min−1 1.73 m−2, p<0.001), sparing 5.0 ml min−1 1.73 m−2 (95% CI 2.3-7.7, p<0.001). Greater preservation of estimated GFR with fenofibrate was observed during greater reduction over the active run-in period (pre-randomisation) of triacylglycerol (n=186 vs 170) and baseline hypertriacylglycerolaemia (n=89 vs 80) alone, or combined with low HDL-cholesterol (n=71 vs 60). Fenofibrate reduced urine albumin concentrations and hence albumin:creatinine ratio by 24% vs 12% (p<0.001; mean difference 14% [95% CI 9-18]; p<0.001), with 14% less progression and 18% more albuminuria regression (p<0.001) than in participants on placebo. End-stage renal event frequency was similar (n=21 vs 26, p=0.48). Conclusions/interpretation Fenofibrate reduced albuminuria and slowed estimated GFR loss over 5 years, despite initially and reversibly increasing plasma creatinine. Fenofibrate may delay albuminuria and GFR impairment in type 2 diabetes patients. Confirmatory studies are merited. Trial registration: ISRCTN64783481 Funding: The study was funded by grants from Laboratoires Fournier, Dijon, France (now part of Solvay and Abbott Pharmaceuticals) and the NHMRC of Australia.Laboratoires Fournier, Dijon, France (now part of Solvay and Abbott Pharmaceuticals

Eosinophils Are Important for Protection, Immunoregulation and Pathology during Infection with Nematode Microfilariae

Eosinophil responses typify both allergic and parasitic helminth disease. In helminthic disease, the role of eosinophils can be both protective in immune responses and destructive in pathological responses. To investigate whether eosinophils are involved in both protection and pathology during filarial nematode infection, we explored the role of eosinophils and their granule proteins, eosinophil peroxidase (EPO) and major basic protein-1 (MBP-1), during infection with Brugia malayi microfilariae. Using eosinophil-deficient mice (PHIL), we further clarify the role of eosinophils in clearance of microfilariae during primary, but not challenge infection in vivo. Deletion of EPO or MBP-1 alone was insufficient to abrogate parasite clearance suggesting that either these molecules are redundant or eosinophils act indirectly in parasite clearance via augmentation of other protective responses. Absence of eosinophils increased mast cell recruitment, but not other cell types, into the broncho-alveolar lavage fluid during challenge infection. In addition absence of eosinophils or EPO alone, augmented parasite-induced IgE responses, as measured by ELISA, demonstrating that eosinophils are involved in regulation of IgE. Whole body plethysmography indicated that nematode-induced changes in airway physiology were reduced in challenge infection in the absence of eosinophils and also during primary infection in the absence of EPO alone. However lack of eosinophils or MBP-1 actually increased goblet cell mucus production. We did not find any major differences in cytokine responses in the absence of eosinophils, EPO or MBP-1. These results reveal that eosinophils actively participate in regulation of IgE and goblet cell mucus production via granule secretion during nematode-induced pathology and highlight their importance both as effector cells, as damage-inducing cells and as supervisory cells that shape both innate and adaptive immunity

The Eighth Data Release of the Sloan Digital Sky Survey: First Data from SDSS-III

The Sloan Digital Sky Survey (SDSS) started a new phase in August 2008, with new instrumentation and new surveys focused on Galactic structure and chemical evolution, measurements of the baryon oscillation feature in the clustering of galaxies and the quasar Ly alpha forest, and a radial velocity search for planets around ~8000 stars. This paper describes the first data release of SDSS-III (and the eighth counting from the beginning of the SDSS). The release includes five-band imaging of roughly 5200 deg^2 in the Southern Galactic Cap, bringing the total footprint of the SDSS imaging to 14,555 deg^2, or over a third of the Celestial Sphere. All the imaging data have been reprocessed with an improved sky-subtraction algorithm and a final, self-consistent photometric recalibration and flat-field determination. This release also includes all data from the second phase of the Sloan Extension for Galactic Understanding and Evolution (SEGUE-2), consisting of spectroscopy of approximately 118,000 stars at both high and low Galactic latitudes. All the more than half a million stellar spectra obtained with the SDSS spectrograph have been reprocessed through an improved stellar parameters pipeline, which has better determination of metallicity for high metallicity stars.Comment: Astrophysical Journal Supplements, in press (minor updates from submitted version

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Predicting the capability of carboxylated cellulose nanowhiskers for the remediation of copper from water using response surface methodology (RSM) and artificial neural network (ANN) models

This study observed the influence of temperature, initial Cu(II) ion concentration, and sorbent dosage on the Cu(II) removal from the water matrix using surface-oxidized cellulose nanowhiskers (CNWs) bearing carboxylate functionalities. In addition, this study focused on the actual conditions in a wastewater treatment plant. Conductometric titration of CNWs suspensions showed a surface charge of 54 and 410 mmol/kg for the unmodified and modified CNWs, respectively, which indicated that the modified CNWs provide a relatively high surface area per unit mass than the unmodified CNWs. In addition, the stability of the modified CNWs was tested under different conditions and proved that the functional groups were permanent and not degraded. Response surface methodology (RSM) and artificial neural network (ANN) models were employed in order to optimize the system and to create a predictive model to evaluate the Cu(II) removal performance of the modified CNWs. The performance of the ANN and RSM models were statistically evaluated in terms of the coefficient of determination (R2), absolute average deviation (AAD), and the root mean squared error (RMSE) on predicted experiment outcomes. Moreover, to confirm the model suitability, unseen experiments were conducted for 14 new trials not belonging to the training data set and located both inside and outside of the training set boundaries. Result showed that the ANN model (R2 = 0.9925, AAD = 1.15%, RMSE = 1.66) outperformed the RSM model (R2 = 0.9541, AAD = 7.07%, RMSE = 3.99) in terms of the R2, AAD, and RMSE when predicting the Cu(II) removal and is thus more reliable. The Langmuir and Freundlich isotherm models were applied to the equilibrium data and the results revealed that Langmuir isotherm (R2 = 0.9998) had better correlation than the Freundlich isotherm (R2 = 0.9461). Experimental data were also tested in terms of kinetics studies using pseudo-first order and pseudo-second order kinetic models. The results showed that the pseudo-second-order model accurately described the kinetics of adsorption

Development and validation of a targeted gene sequencing panel for application to disparate cancers

Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour’s molecular profile. We aimed to develop a targeted gene sequencing panel for application to disparate cancer types with particular focus on tumours of the head and neck, plus test for utility in liquid biopsy. The final panel designed through Roche/Nimblegen combined 451 cancer-associated genes (2.01 Mb target region). 136 patient DNA samples were collected for performance and application testing. Panel sensitivity and precision were measured using well-characterised DNA controls (n = 47), and specificity by Sanger sequencing of the Aryl Hydrocarbon Receptor Interacting Protein (AIP) gene in 89 patients. Assessment of liquid biopsy application employed a pool of synthetic circulating tumour DNA (ctDNA). Library preparation and sequencing were conducted on Illumina-based platforms prior to analysis with our accredited (ISO15189) bioinformatics pipeline. We achieved a mean coverage of 395x, with sensitivity and specificity of >99% and precision of >97%. Liquid biopsy revealed detection to 1.25% variant allele frequency. Application to head and neck tumours/cancers resulted in detection of mutations aligned to published databases. In conclusion, we have developed an analytically-validated panel for application to cancers of disparate types with utility in liquid biopsy