Determinants of successful clinical networks : The conceptual framework and study protocol

Background Clinical networks are increasingly being viewed as an important strategy for increasing evidence-based practice and improving models of care, but success is variable and characteristics of networks with high impact are uncertain. This study takes advantage of the variability in the functioning and outcomes of networks supported by the Australian New South Wales (NSW) Agency for Clinical Innovation's non-mandatory model of clinical networks to investigate the factors that contribute to the success of clinical networks. Methods/Design The objective of this retrospective study is to examine the association between external support, organisational and program factors, and indicators of success among 19 clinical networks over a three-year period (2006-2008). The outcomes (health impact, system impact, programs implemented, engagement, user perception, and financial leverage) and explanatory factors will be collected using a web-based survey, interviews, and record review. An independent expert panel will provide judgements about the impact or extent of each network's initiatives on health and system impacts. The ratings of the expert panel will be the outcome used in multivariable analyses. Following the rating of network success, a qualitative study will be conducted to provide a more in-depth examination of the most successful networks. Discussion This is the first study to combine quantitative and qualitative methods to examine the factors that contribute to the success of clinical networks and, more generally, is the largest study of clinical networks undertaken. The adaptation of expert panel methods to rate the impacts of networks is the methodological innovation of this study. The proposed project will identify the conditions that should be established or encouraged by agencies developing clinical networks and will be of immediate use in forming strategies and programs to maximise the effectiveness of such networks

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all &gt;0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

Recombinant Haplotypes Narrow the ARMS2/HTRA1 Association Signal for Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness in ageing societies, triggered by both environmental and genetic factors. The strongest genetic signal for AMD with odds ratios of up to 2.8 per adverse allele was found previously over a chromosomal region in 10q26 harboring two genes, ARMS2 and HTRA1, although with little knowledge as to which gene or genetic variation is functionally relevant to AMD pathology. In this study, we analyzed rare recombinant haplotypes in 16,144 AMD cases and 17,832 controls from the International AMD Genomics Consortium and identified variants in ARMS2 but not HTRA1 to exclusively carry the AMD risk with P-values between 1.0 x 10(-773) and 6.7 x 10(-5). This now allows prioritization of the gene of interest for subsequent functional studies

Somnolence syndrome in patients receiving radical radiotherapy for primary brain tumours: A prospective study

Background and purpose: To characterise the incidence, pattern and severity of post cranial radiotherapy somnolence and to identify factors predictive of frequency and severity. Materials and methods: Seventy consecutive patients receiving radical cranial irradiation were prospectively assessed for somnolence at baseline, during and up to 10 weeks following radiotherapy using five variables scored on a visual analogue scale (VAS) and the Littman scale. Fatigue was measured using the FACT-G score and quality of life using the EORTC QLQC30+3 with the brain tumour module questionnaire. Results: Ninety percent of patients experienced grade 1 somnolence (Littman score) and this correlated with VAS scores (r = 0.456, p < 0.001). The score increased from 3 to 12 weeks (p < 0.001) with a peak at the end of treatment and improvement 6 weeks later. None of the patient, disease or treatment characteristics analysed were predictive for the development or the severity of somnolence. Conclusions: The majority of patients experience some degree of somnolence following radical radiotherapy for primary brain tumour and this follows a clear pattern during and after treatment. While there are no clear predictors of severity, the pattern described allows for provision of information for patients and carers to minimise the distress the syndrome may cause. (c) 2011 Published by Elsevier Ireland Ltd. Radiotherapy and Oncology 100 (2011) 131-13

The Application of Genetic Risk Scores in Age-Related Macular Degeneration: A Review

Age-related macular degeneration (AMD), a highly prevalent and impactful disease of aging, is inarguably influenced by complex interactions between genetic and environmental factors. Various risk scores have been tested that assess measurable genetic and environmental contributions to disease. We herein summarize and review the ability and utility of these numerous models for prediction of AMD and suggest additional risk factors to be incorporated into clinically useful predictive models of AMD

Fractionated stereotactic conformal radiotherapy following conservative surgery in the control of craniopharyngiomas

Purpose: To describe the technique and results of stereotactically guided conformal radiotherapy (SCRT) in patients with craniopharyngioma after conservative surgery. Methods and materials: Thirty-nine patients with craniopharyngioma aged 3-68 years (median age 18 years) were treated with SCRT between June 1994 and January 2003. All patients were referred for radiotherapy after undergoing one or more surgical procedures. Treatment was delivered in 30-33 daily fractions over 6-6.5 weeks to a total dose of 50 Gy using 6 MV photons. Outcome was assessed prospectively. Results: At a median follow-up of 40 months (range 3-88 months) the 3- and 5-year progression-free survival (PFS) was 97% and 92%, and 3- and 5-year survival 100%. Two patients required further debulking surgery for progressive disease 8 and 41 months after radiotherapy. Twelve patients (30%) had acute clinical deterioration due to cystic enlargement of craniopharyngioma following SCRT and required cyst aspiration. One patient with severe visual impairment prior to radiotherapy had visual deterioration following SCRT. Seven out of 10 patients with a normal pituitary function before SCRT had no endocrine deficits following treatment. Conclusion: SCRT as a high-precision technique of localized RT is suitable for the treatment of incompletely excised craniopharyngioma. The local control, toxicity and survival outcomes are comparable to results reported following conventional external beam RT. Longer follow-up is required to assess long-term efficacy and toxicity, particularly in terms of potential reduction in treatment related late toxicity. © 2006 Elsevier Ireland Ltd. All rights reserved