Higher incidence of childhood-onset type 1 diabetes mellitus in remote areas: a UK regional small-area analysis

Aims/hypothesis: We investigated the association between the incidence of type 1 diabetes mellitus and remoteness (a proxy measure for exposure to infections) using recently developed techniques for statistical analysis of small-area data.

Subjects, materials and methods: New cases in children aged 0 to 14 years in Northern Ireland were prospectively registered from 1989 to 2003. Ecological analysis was conducted using small geographical units (582 electoral wards) and area characteristics including remoteness, deprivation and child population density. Analysis was conducted using Poisson regression models and Bayesian
hierarchical models to allow for spatially correlated risks that were potentially caused by unmeasured explanatory variables.

Results: In Northern Ireland between 1989 and 2003, there were 1,433 new cases of type 1 diabetes, giving a directly standardised incidence rate of 24.7 per 100,000 personyears. Areas in the most remote fifth of all areas had a significantly (p=0.0006) higher incidence of type 1 diabetes mellitus (incidence rate ratio=1.27 [95% CI 1.07, 1.50]) than those in the most accessible fifth of all areas. There was also a higher incidence rate in areas that were less deprived (p<0.0001) and less densely populated (p=0.002). After adjustment for deprivation and additional adjustment for child population density the association between diabetes and remoteness remained significant (p=0.01 and p=0.03, respectively).

Conclusions/interpretation: In Northern Ireland, there is evidence that remote areas experience higher rates of type 1 diabetes mellitus. This could reflect a reduced or delayed exposure to infections, particularly early in life, in these areas.

Association of Caveolin-1 gene polymorphism with kidney transplant fibrosis and allograft failure

Context: Caveolin-1 (CAV1) is an inhibitor of tissue fibrosis.
Objective: To study the association of CAV1 gene variation with kidney transplant outcome, using kidney transplantation as a model of accelerated fibrosis.
Design, Setting, and Patients: Candidate gene association and validation study. Genomic DNA from 785 white kidney transplant donors and their respective recipients (transplantations in Birmingham, England, between 1996 and 2006; median followup, 81 months) were analyzed for common variation in CAV1 using a singlenucleotide polymorphism (SNP) tagging approach. Validation of positive findings was sought in an independent kidney transplant donor-recipient cohort (transplantations in Belfast, Northern Ireland, between 1986 and 2005; n=697; median follow-up, 69 months). Association between genotype and allograft failure was initially assessed by Kaplan-Meier analysis, then in an adjusted Cox model.
Main Outcome Measure: Death-censored allograft failure, defined as a return to dialysis or retransplantation.
Results: The presence of donor AA genotype for the CAV1 rs4730751 SNP was associated with increased risk of allograft failure in the Birmingham group (donor AA vs non-AA genotype in adjusted Cox model, hazard ratio [HR], 1.97; 95% confidence interval [CI], 1.29-3.16; P=.002). No other tag SNPs showed a significant association. This finding was validated in the Belfast cohort (in adjusted Cox model, HR, 1.56; 95% CI, 1.07-2.27; P=.02). Overall graft failure rates were as follows: for the Birmingham cohort, donor genotype AA, 22 of 57 (38.6%); genotype CC, 96 of 431 (22.3%); and genotype AC, 66 of 297 (22.2%); and for the Belfast cohort, donor genotype AA, 32 of 48 (67%); genotype CC, 150 of 358 (42%); and genotype AC, 119 of 273 (44%).
Conclusion: Among kidney transplant donors, the CAV1 rs4730751 SNP was significantly associated with allograft failure in 2 independent cohorts.

Breast-feeding and childhood-onset type 1 diabetes:A pooled analysis of individual participant data from 43 observational studies

OBJECTIVE: To investigate if there is a reduced risk of type 1 diabetes in children breastfed or exclusively breastfed by performing a pooled analysis with adjustment for recognized confounders.
RESEARCH DESIGN AND METHODS: Relevant studies were identified from literature searches using MEDLINE, Web of Science, and EMBASE. Authors of relevant studies were asked to provide individual participant data or conduct prespecified analyses. Meta-analysis techniques were used to combine odds ratios (ORs) and investigate heterogeneity between studies.
RESULTS: Data were available from 43 studies including 9,874 patients with type 1 diabetes. Overall, there was a reduction in the risk of diabetes after exclusive breast-feeding for >2 weeks (20 studies; OR = 0.75, 95% CI 0.64-0.88), the association after exclusive breast-feeding for >3 months was weaker (30 studies; OR = 0.87, 95% CI 0.75-1.00), and no association was observed after (nonexclusive) breast-feeding for >2 weeks (28 studies; OR = 0.93, 95% CI 0.81-1.07) or >3 months (29 studies; OR = 0.88, 95% CI 0.78-1.00). These associations were all subject to marked heterogeneity (I(2) = 58, 76, 54, and 68%, respectively). In studies with lower risk of bias, the reduced risk after exclusive breast-feeding for >2 weeks remained (12 studies; OR = 0.86, 95% CI 0.75-0.99), and heterogeneity was reduced (I(2) = 0%). Adjustments for potential confounders altered these estimates very little.
CONCLUSIONS: The pooled analysis suggests weak protective associations between exclusive breast-feeding and type 1 diabetes risk. However, these findings are difficult to interpret because of the marked variation in effect and possible biases (particularly recall bias) inherent in the included studies.

Excess mortality in Type 1 diabetes diagnosed in childhood and adolescence: a systematic review of population-based cohorts

Aims: Systematic review of mortality in childhood-/adolescent-diagnosed Type 1 diabetes and examination of factors explaining the mortality variation between studies. 
Methods: Relevant studies were identified from systematic searches of MEDLINE and EMBASE. Observed and expected numbers of deaths were extracted, and standardised mortality ratios (SMRs) and 95 % confidence intervals (CIs) were calculated. Negative binomial regression was used to investigate association between mortality and study/country characteristics.
Results: Thirteen relevant publications with mortality data were identified describing 23 independent studies. SMRs varied markedly ranging from 0 to 854 (chi-squared = 70.68,df = 21, p<0.0001). Significant associations were observed between SMR and mid-year of follow-up [incidence rate ratio (IRR) 0.95, 95 % CI 0.91–0.99 equivalent to a 5 % decrease per year], between SMR and infant mortality rate (IRR 1.07, 95 % CI 1.02–1.12, a 7 % increase for each death per 1,000 live births) and, after omitting an outlier, between SMR and health expenditure as a percentage of gross domestic product (GDP) (IRR 0.79, 95 % CI 0.68–0.93, a 21 % decrease for each one percent increase in GDP). No relationship was detected between SMR and a country’s childhood diabetes incidence rate or GDP.
Conclusions: Excess mortality in childhood-/adolescent diagnosed Type 1 diabetes is apparent across countries worldwide. Excesses were less marked in more recent studies and in countries with lower infant mortality and higher health expenditure.

Multicenter Randomized Controlled Trial of Withdrawal of Inhaled Corticosteroids in Cystic Fibrosis

Rationale: Lung inflammation and injury is critical in cystic fibrosis. An ideal antiinflammatory agent has not been identified but inhaled corticosteroids are widely used despite lack of evidence.

Objectives: To test the safety of withdrawal of inhaled corticosteroids with the hypothesis this would not be associated with an earlier onset of acute chest exacerbations.

Methods: Multicenter randomized double-blind placebo-controlled trial in 18 pediatric and adult UK centers. Eligibility criteria included age > 6.0 yr, FEV1 ? 40% predicted, and corticosteroid use > 3 mo. During the 2-mo run-in period, all patients received fluticasone; they then took either fluticasone or placebo for 6 mo.

Measurements and Main Results: Fluticasone group: n = 84, median age 14.6 yr, mean (SD) FEV1 76% (18); placebo group: n = 87, median age 15.8 yr, mean (SD) FEV1 76% (18). There was no difference in time to first exacerbation (primary outcome) with hazard ratio (95% confidence interval) of 1.07 (0.68 to 1.70) for fluticasone versus placebo. There was no effect of age, atopy, corticosteroid dose, FEV1, or Pseudomonas aeruginosa status. There was no change in lung function or differences in antibiotic or rescue bronchodilator use. Fewer patients in the fluticasone group withdrew from the study due to lung-related adverse events (9 vs. 15%); with a relative risk (95% confidence interval) of 0.59 (0.23–1.48) fluticasone versus placebo.

Conclusions: In this study population (applicable to 40% of patients with cystic fibrosis in the UK), it appears safe to consider stopping inhaled corticosteroids. Potential advantages will be to reduce the drug burden on patients, reduce adverse effects, and make financial savings.

Response of surface horizons in an oak forest to prescribed burning

The reduction of forest floor ground cover and litter layers by prescribed fires may alter the morphology (field and micro) and physical properties of surface horizons. This study determined long-term (35 yr) changes in surface horizon bulk density, organic matter concentration and content, and morphology in response to periodic (5 yr) and annual (1 yr) prescribed fires. Soils were fine-silty, siliceous, thermic Glossic Fragiuldults, supporting mixed oak vegetation in middle Tennessee. Upper mineral soils (0- to 2-cm and 0- to 7.6-cm depths) were sampled and detailed field descriptions made. Periodic and control plots had a thin layer of Oi, Oe, and Oa horizons 5 yr after the 1993 burn, whereas on annual burn plots a 1- to 2-cm charred layer was present. Significant reductions in organic matter concentration and mean thickness of the A horizon were found from burning (A horizons thicknesses were 6.4, 4.6, and 2.9 cm in control, periodic, and annual plots, respectively). Periodic burns did not significantly alter the organic matter and bulk density of the upper 7.6 cm of mineral soil; however, annual burns did result in significantly higher bulk densities (1.01, 1.07, and 1.29 Mg m-3 in control, periodic, and annual plots, respectively) and lower organic matter concentrations and contents. Microscopic investigations confirmed that compaction was increased from annual burning. Thin sections also revealed that the granular structure of the A horizons in control and periodic plots resulted from bioterbation of macro and mesofauna, fungi, and roots. Long-term annual burning greatly affected surface soil properties, whereas periodic burning on a 5-yr cycle had only limited effects.

Exposure to oral bisphosphonates and risk of esophageal cancer

Context: Use of oral bisphosphonates has increased dramatically in the United States and elsewhere. Esophagitis is a known adverse effect of bisphosphonate use, and recent reports suggest a link between bisphosphonate use and esophageal cancer, but this has not been robustly investigated.
Objective: To investigate the association between bisphosphonate use and esophageal cancer.
Design, Setting, and Participants: Data were extracted from the UK General Practice Research Database to compare the incidence of esophageal and gastric cancer in a cohort of patients treated with oral bisphosphonates between January 1996 and December 2006 with incidence in a control cohort. Cancers were identified from relevant Read/Oxford Medical Information System codes in the patient's clinical files. Cox proportional hazards modeling was used to calculate hazard ratios and 95% confidence intervals for risk of esophageal and gastric cancer in bisphosphonate users compared with nonusers, with adjustment for potential confounders.
Main Outcome Measure: Hazard ratio for the risk of esophageal and gastric cancer in the bisphosphonate users compared with the bisphosphonate nonusers. Results: Mean follow-up time was 4.5 and 4.4 years in the bisphosphonate and control cohorts, respectively. Excluding patients with less than 6 months' follow-up, there were 41 826 members in each cohort (81% women; mean age, 70.0 (SD, 11.4) years). One hundred sixteen esophageal or gastric cancers (79 esophageal) occurred in the bisphosphonate cohort and 115 (72 esophageal) in the control cohort. The incidence of esophageal and gastric cancer combined was 0.7 per 1000 person-years of risk in both the bisphosphonate and control cohorts; the incidence of esophageal cancer alone in the bisphosphonate and control cohorts was 0.48 and 0.44 per 1000 person-years of risk, respectively. There was no difference in risk of esophageal and gastric cancer combined between the cohorts for any bisphosphonate use (adjusted hazard ratio, 0.96 [95% confidence interval, 0.74-1.25]) or risk of esophageal cancer only (adjusted hazard ratio, 1.07 [95% confidence interval, 0.77-1.49]). There also was no difference in risk of esophageal or gastric cancer by duration of bisphosphonate intake.
Conclusion: Among patients in the UK General Practice Research Database, the use of oral bisphosphonates was not significantly associated with incident esophageal or gastric cancer.

WASP-21b: a hot-Saturn exoplanet transiting a thick disc star

We report the discovery of WASP-21b, a new transiting exoplanet discovered by the Wide Angle Search for Planets (WASP) Consortium and established and characterized with the FIES, SOPHIE, CORALIE and HARPS fiber-fed echelle spectrographs. A 4.3-d period, 1.1% transit depth and 3.4-h duration are derived for WASP-21b using SuperWASP-North and high precision photometric observations at the Liverpool Telescope. Simultaneous fitting to the photometric and radial velocity data with a Markov Chain Monte Carlo procedure leads to a planet in the mass regime of Saturn. With a radius of 1.07 RJup and mass of 0.30 MJup, WASP-21b has a density close to 0.24 ?Jup corresponding to the distribution peak at low density of transiting gaseous giant planets. With a host star metallicity [Fe/H] of -0.46, WASP-21b strengthens the correlation between planetary density and host star metallicity for the five known Saturn-like transiting planets. Furthermore there are clear indications that WASP-21b is the first transiting planet belonging to the thick disc.

Blood pressure lowering in patients without prior cerebrovascular disease for prevention of cognitive impairment and dementia

Background: This is an update of a previous review (McGuinness 2006). Hypertension and cognitive impairment are prevalent in older people. Hypertension is a direct risk factor for vascular dementia (VaD) and recent studies have suggested hypertension impacts upon prevalence of Alzheimer's disease (AD). Therefore does treatment of hypertension prevent cognitive decline?
Objectives: To assess the effects of blood pressure lowering treatments for the prevention of dementia and cognitive decline in patients with hypertension but no history of cerebrovascular disease.
Search strategy: The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group, The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS as well as many trials databases and grey literature sources were searched on 13 February 2008 using the terms: hypertens$ OR anti-hypertens$. Selection criteria: Randomized, double-blind, placebo controlled trials in which pharmacological or non-pharmacological interventions to lower blood pressure were given for at least six months.
Data collection and analysis: Two independent reviewers assessed trial quality and extracted data. The following outcomes were assessed: incidence of dementia, cognitive change from baseline, blood pressure level, incidence and severity of side effects and quality of life.
Main results: Four trials including 15,936 hypertensive subjects were identified. Average age was 75.4 years. Mean blood pressure at entry across the studies was 171/86 mmHg. The combined result of the four trials reporting incidence of dementia indicated no significant difference between treatment and placebo (236/7767 versus 259/7660, Odds Ratio (OR) = 0.89, 95% CI 0.74, 1.07) and there was considerable heterogeneity between the trials. The combined results from the three trials reporting change in Mini Mental State Examination (MMSE) did not indicate a benefit from treatment (Weighted Mean Difference (WMD) = 0.42, 95%CI 0.30, 0.53). Both systolic and diastolic blood pressure levels were reduced significantly in the three trials assessing this outcome (WMD = -10.22, 95% CI -10.78, -9.66 for systolic blood pressure, WMD = -4.28, 95% CI -4.58, -3.98 for diastolic blood pressure). Three trials reported adverse effects requiring discontinuation of treatment and the combined results indicated no significant difference (OR = 1.01, 95% CI 0.92, 1.11). When analysed separately, however, more patients on placebo in Syst Eur 1997 were likely to discontinue treatment due to side effects; the converse was true in SHEP 1991. Quality of life data could not be analysed in the four studies. Analysis of the included studies in this review was problematic as many of the control subjects received antihypertensive treatment because their blood pressures exceeded pre-set values. In most cases the study became a comparison between the study drug against a usual antihypertensive regimen.
Authors' conclusions: There is no convincing evidence fromthe trials identified that blood pressure lowering in late-life prevents the development of dementia or cognitive impairment in hypertensive patients with no apparent prior cerebrovascular disease. There were significant problems identified with analysing the data, however, due to the number of patients lost to follow-up and the number of placebo patients who received active treatment. This introduced bias. More robust results may be obtained by conducting a meta-analysis using individual patient data.

Methods to increase response to postal and electronic questionnaires

Background: Postal and electronic questionnaires are widely used for data collection in epidemiological studies but non-response reduces the effective sample size and can introduce bias. Finding ways to increase response to postal and electronic questionnaires would improve the quality of health research. Objectives: To identify effective strategies to increase response to postal and electronic questionnaires. Search strategy: We searched 14 electronic databases to February 2008 and manually searched the reference lists of relevant trials and reviews, and all issues of two journals. We contacted the authors of all trials or reviews to ask about unpublished trials. Where necessary, we also contacted authors to confirm methods of allocation used and to clarify results presented. We assessed the eligibility of each trial using pre-defined criteria. Selection criteria: Randomised controlled trials of methods to increase response to postal or electronic questionnaires. Data collection and analysis: We extracted data on the trial participants, the intervention, the number randomised to intervention and comparison groups and allocation concealment. For each strategy, we estimated pooled odds ratios (OR) and 95% confidence intervals (CI) in a random-effects model. We assessed evidence for selection bias using Egger's weighted regression method and Begg's rank correlation test and funnel plot. We assessed heterogeneity among trial odds ratios using a Chi 2 test and the degree of inconsistency between trial results was quantified using the I 2 statistic. Main results: Postal We found 481 eligible trials.The trials evaluated 110 different ways of increasing response to postal questionnaires.We found substantial heterogeneity among trial results in half of the strategies. The odds of response were at least doubled using monetary incentives (odds ratio 1.87; 95% CI 1.73 to 2.04; heterogeneity P < 0.00001, I 2 = 84%), recorded delivery (1.76; 95% CI 1.43 to 2.18; P = 0.0001, I 2 = 71%), a teaser on the envelope - e.g. a comment suggesting to participants that they may benefit if they open it (3.08; 95% CI 1.27 to 7.44) and a more interesting questionnaire topic (2.00; 95% CI 1.32 to 3.04; P = 0.06, I 2 = 80%). The odds of response were substantially higher with pre-notification (1.45; 95% CI 1.29 to 1.63; P < 0.00001, I 2 = 89%), follow-up contact (1.35; 95% CI 1.18 to 1.55; P < 0.00001, I 2 = 76%), unconditional incentives (1.61; 1.36 to 1.89; P < 0.00001, I 2 = 88%), shorter questionnaires (1.64; 95%CI 1.43 to 1.87; P < 0.00001, I 2 = 91%), providing a second copy of the questionnaire at follow up (1.46; 95% CI 1.13 to 1.90; P < 0.00001, I 2 = 82%), mentioning an obligation to respond (1.61; 95% CI 1.16 to 2.22; P = 0.98, I 2 = 0%) and university sponsorship (1.32; 95% CI 1.13 to 1.54; P < 0.00001, I 2 = 83%). The odds of response were also increased with non-monetary incentives (1.15; 95% CI 1.08 to 1.22; P < 0.00001, I 2 = 79%), personalised questionnaires (1.14; 95% CI 1.07 to 1.22; P < 0.00001, I 2 = 63%), use of hand-written addresses (1.25; 95% CI 1.08 to 1.45; P = 0.32, I 2 = 14%), use of stamped return envelopes as opposed to franked return envelopes (1.24; 95% CI 1.14 to 1.35; P < 0.00001, I 2 = 69%), an assurance of confidentiality (1.33; 95% CI 1.24 to 1.42) and first class outward mailing (1.11; 95% CI 1.02 to 1.21; P = 0.78, I 2 = 0%). The odds of response were reduced when the questionnaire included questions of a sensitive nature (0.94; 95% CI 0.88 to 1.00; P = 0.51, I 2 = 0%). Electronic: We found 32 eligible trials. The trials evaluated 27 different ways of increasing response to electronic questionnaires. We found substantial heterogeneity among trial results in half of the strategies. The odds of response were increased by more than a half using non-monetary incentives (1.72; 95% CI 1.09 to 2.72; heterogeneity P < 0.00001, I 2 = 95%), shorter e-questionnaires (1.73; 1.40 to 2.13; P = 0.08, I 2 = 68%), including a statement that others had responded (1.52; 95% CI 1.36 to 1.70), and a more interesting topic (1.85; 95% CI 1.52 to 2.26). The odds of response increased by a third using a lottery with immediate notification of results (1.37; 95% CI 1.13 to 1.65), an offer of survey results (1.36; 95% CI 1.15 to 1.61), and using a white background (1.31; 95% CI 1.10 to 1.56). The odds of response were also increased with personalised e-questionnaires (1.24; 95% CI 1.17 to 1.32; P = 0.07, I 2 = 41%), using a simple header (1.23; 95% CI 1.03 to 1.48), using textual representation of response categories (1.19; 95% CI 1.05 to 1.36), and giving a deadline (1.18; 95% CI 1.03 to 1.34). The odds of response tripled when a picture was included in an e-mail (3.05; 95% CI 1.84 to 5.06; P = 0.27, I 2 = 19%). The odds of response were reduced when "Survey" was mentioned in the e-mail subject line (0.81; 95% CI 0.67 to 0.97; P = 0.33, I 2 = 0%), and when the e-mail included a male signature (0.55; 95% CI 0.38 to 0.80; P = 0.96, I 2 = 0%). Authors' conclusions: Health researchers using postal and electronic questionnaires can increase response using the strategies shown to be effective in this systematic review. Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.


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Concomitant and antecedent deep venous thrombosis and cancer survival in male US veterans

Survival is reportedly worse in patients with cancer concurrently diagnosed with deep venous thrombosis. However, information on specific malignancies is limited. From a cohort study of male US veterans we identified incident cancer cases (n aEuroS== aEuroS412 008) and compared survival patterns among those with versus without a history of deep venous thrombosis. Using Cox proportional hazard models, we estimated hazard ratios (HRs) and 95%% confidence intervals as measures of the relative risk of dying. Individuals with (versus without) a concomitant deep venous thrombosis and cancer diagnosis had a higher risk of dying (HR aEuroS== aEuroS1.38; 1.28--1.49). The most prominent excess mortality (HR aEuroS== aEuroS1.29--2.55) was observed among patients diagnosed with deep venous thrombosis at the time of diagnosis of lung, gastric, prostate, bladder, or kidney cancer. Increased risk of dying was also found among cancer patients diagnosed with deep venous thrombosis 1 year (HR aEuroS== aEuroS1.14; 1.07--1.22), 1--5 years (HR aEuroS== aEuroS1.14; 1.10--1.19), and > 5 years (HR aEuroS== aEuroS1.27; 1.23--1.31) before cancer; this was true for most cancer sites (HR aEuroS== aEuroS1.17--1.64). In summary, antecedent deep venous thrombosis confers a worse prognosis upon cancer patients. Advanced stage at diagnosis, treatment effects, lifestyle factors, and comorbidity could explain differences by cancer site and time frame between a prior deep venous thrombosis diagnosis and cancer outcome.

Burnout as a predictor of all-cause mortality among industrial employees: A 10-year prospective register-linkage study

Objective: Burnout, a psychological consequence of prolonged work stress, has been shown to coexist with physical and mental disorders. The aim of this study was to investigate whether burnout is related to all-cause mortality among employees. Methods: In 1996, of 15,466 Finnish forest industry employees, 9705 participated in the 'Still Working' study and 8371 were subsequently identified from the National Population Register. Those who had been treated in a hospital for the most common causes of death prior to the assessment of burnout were excluded on the basis of the Hospital Discharge Register, resulting in a final study population of 7396 people. Burnout was measured using the Maslach Burnout Inventory-General Survey. Dates of death from 1996 to 2006 were extracted from the National Mortality Register. Mortality was predicted with Cox hazard regression models, controlling for baseline sociodemographic factors and register-based health status according to entitled medical reimbursement and prescribed medication for mental health problems, cardiac risk factors, and pain problems. Results: During the 10-year 10-month follow-up, a total of 199 employees had died. The risk of mortality per one-unit increase in burnout was 35% higher (95% CI 1.07-1.71) for total score and 26% higher (0.99-1.60) for exhaustion, 29% higher for cynicism (1.03-1.62), and 22% higher for diminished professional efficacy (0.96-1.55) in participants who had been under 45 at baseline. After adjustments, only the associations regarding burnout and exhaustion were statistically significant. Burnout was not related to mortality among the older employees. Conclusion: Burnout, especially work-related exhaustion, may be a risk for overall survival. (C) 2010 Elsevier Inc. All rights reserved.

Confirmatory method for the determination of various acetylgestagens in animal kidney fat using liquid chromatography-tandem mass spectrometry

A confirmatory method has been developed and validated that allows for the simultaneous detection of medroxyprogesterone acetate (MPA), megestrol acetate (MGA), melengestrol acetate (MLA), chlormadinone acetate (CMA) and delmadinone acetate (DMA) in animal kidney fat using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The compounds were extracted from kidney fat using acetonitrile, defatted using a hexane wash and subsequent saponification. Extracts were then purified on Isolute CN solid-phase extraction cartridges and analysed by LC-MS/MS. The method was validated in animal kidney fat in accordance with the criteria defined in Commission Decision 2002/657/EC. The decision limit (CC) was calculated to be 0.12, 0.48, 0.40, 0.63 and 0.54 g kg-1, respectively, for MPA, MGA, MLA, DMA and CMA, with respective detection capability (CC) values of 0.20, 0.81, 0.68, 1.07 and 0.92 g kg-1. The measurement uncertainty of the method was estimated at 16, 16, 19, 27 and 26% for MPA, MGA, MLA, DMA and CMA, respectively. Fortifying kidney fat samples (n = 18) in three separate assays showed the accuracy of the method to be between 98 and 100%. The precision of the method, expressed as % RSD, for within-laboratory reproducibility at three levels of fortification (1, 1.5 and 2 g kg-1 for MPA, 5, 7.5 and 10 g kg-1 for MGA, MLA, DMA and CMA) was less than 5% for all analytes.

Ranibizumab versus Bevacizumab to Treat Neovascular Age-related Macular Degeneration: One-Year Findings from the IVAN Randomized Trial.

Purpose
To compare the efficacy and safety of ranibizumab and bevacizumab intravitreal injections to treat neovascular age-related macular degeneration (nAMD).

Design
Multicenter, noninferiority factorial trial with equal allocation to groups. The noninferiority limit was 3.5 letters. This trial is registered (ISRCTN92166560).

Participants
People >50 years of age with untreated nAMD in the study eye who read =25 letters on the Early Treatment Diabetic Retinopathy Study chart.

Methods
We randomized participants to 4 groups: ranibizumab or bevacizumab, given either every month (continuous) or as needed (discontinuous), with monthly review.

Main Outcome Measures
The primary outcome is at 2 years; this paper reports a prespecified interim analysis at 1 year. The primary efficacy and safety outcome measures are distance visual acuity and arteriothrombotic events or heart failure. Other outcome measures are health-related quality of life, contrast sensitivity, near visual acuity, reading index, lesion morphology, serum vascular endothelial growth factor (VEGF) levels, and costs.

Results
Between March 27, 2008 and October 15, 2010, we randomized and treated 610 participants. One year after randomization, the comparison between bevacizumab and ranibizumab was inconclusive (bevacizumab minus ranibizumab -1.99 letters, 95% confidence interval [CI], -4.04 to 0.06). Discontinuous treatment was equivalent to continuous treatment (discontinuous minus continuous -0.35 letters; 95% CI, -2.40 to 1.70). Foveal total thickness did not differ by drug, but was 9% less with continuous treatment (geometric mean ratio [GMR], 0.91; 95% CI, 0.86 to 0.97; P = 0.005). Fewer participants receiving bevacizumab had an arteriothrombotic event or heart failure (odds ratio [OR], 0.23; 95% CI, 0.05 to 1.07; P = 0.03). There was no difference between drugs in the proportion experiencing a serious systemic adverse event (OR, 1.35; 95% CI, 0.80 to 2.27; P = 0.25). Serum VEGF was lower with bevacizumab (GMR, 0.47; 95% CI, 0.41 to 0.54; P<0.0001) and higher with discontinuous treatment (GMR, 1.23; 95% CI, 1.07 to 1.42; P = 0.004). Continuous and discontinuous treatment costs were £9656 and £6398 per patient per year for ranibizumab and £1654 and £1509 for bevacizumab; bevacizumab was less costly for both treatment regimens (P<0.0001).

Conclusions
The comparison of visual acuity at 1 year between bevacizumab and ranibizumab was inconclusive. Visual acuities with continuous and discontinuous treatment were equivalent. Other outcomes are consistent with the drugs and treatment regimens having similar efficacy and safety.

Financial Disclosure(s)
Proprietary or commercial disclosures may be found after the references.

In vivo safety of trypan blue use in vitreoretinal surgery

Purpose: The purpose of this study was to evaluate "in vivo" safety of trypan blue (TB) in patients undergoing TB-assisted internal limiting membrane or epiretinal membrane peeling. Methods: Prospective study including 21 patients (21 eyes) with full-thickness macular hole and/or epiretinal membrane undergoing TB-assisted internal limiting membrane/epiretinal membrane peeling. Main outcome measures included distance visual acuity, near visual acuity, amplitude of P50 and N95 of the pattern electroretinogram, and fundus autofluorescence; these were assessed preoperatively, at 6 months (n = 21) and 12 months (n = 10) postoperatively. Results: There was a statistically significant improvement in distance visual acuity, near visual acuity, P50, and N95 amplitude at 6 months and 12 months postoperatively. The mean logarithm of the minimum angle of resolution distance visual acuity and near visual acuity improved from baseline by 0.31 (SD 0.37) and 0.17 (SD 0.31) at 6 months, respectively, and by 0.4 (SD 0.25) and 0.35 (SD 0.28) at 12 months, respectively. The mean P50 and N95 component amplitudes improved by 28% compared with baseline at 6 months (P50 0.4 [SD 0.8]; N95 0.53 [SD 1.07]) and by 63% at 12 months (P50 0.9 [0.85]; N95 1.04 [1.34]). Autofluorescence did not demonstrate damage to the retinal pigment epithelium attributable to TB. Conclusion: No deleterious effects of TB were observed in this study. Copyright © 2011 Lippincott Williams &Wilkins.