Quality of care and survival of haemodialysed patients in western Switzerland

Background. Many factors affect survival in haemodialysis (HD) patients. Our aim was to study whether quality of clinical care may affect survival in this population, when adjusted for demographic characteristics and co-morbidities. Methods. We studied survival in 553 patients treated by chronic HD during March 2001 in 21 dialysis facilities in western Switzerland. Indicators of quality of care were established for anaemia control, calcium and phosphate product, serum albumin, pre-dialysis blood pressure (BP), type of vascular access and dialysis adequacy (spKt/V) and their baseline values were related to 3-year survival. The modified Charlson co-morbidity index (including age) and transplantation status were also considered as a predictor of survival. Results. Three-year survival was obtained for 96% of the patients; 39% (211/541) of these patients had died. The 3-year survival was 50, 62 and 69%, respectively, in patients who had 0-2, 3 and ≥4 fulfilled indicators of quality of care (test for linear trend, P < 0.001). In a Cox multivariate analysis model, the absence of transplantation, a higher modified Charlson's score, decreased fulfilment of indicators of good clinical care and low pre-dialysis systolic BP were independent predictors of death. Conclusion. Good clinical care improves survival in HD patients, even after adjustment for availability of transplantation and co-morbiditie

Defining adenoma detection rate benchmarks in average-risk male veterans

Background and Aims Veterans have higher prevalence of colorectal neoplasia than non-veterans; however, it is not known whether specific Veterans Affairs (VA) adenoma detection rate (ADR) benchmarks are required. We compared ADRs of a group of endoscopists for colonoscopies performed at a VA to their ADRs at a non-VA academic medical center. Methods This was a retrospective review of screening colonoscopies performed by endoscopists who practice at the Indianapolis VA and Indiana University (IU). Patients were average-risk males aged 50 years or older. ADR, proximal adenoma detection rate, advanced adenoma detection rate, and adenomas per colonoscopy were compared between IU and the VA groups. Results Six endoscopists performed screening colonoscopies at both locations during the study period (470 at IU vs 608 at the VA). The overall ADR was not significantly different between IU and the VA (58% vs 61%; p =0.21). Advanced neoplasia detection rate (13% vs 17%; p=0.46), proximal adenoma detection rate (46% vs 47%; p=0.31), and adenoma per colonoscopy (1.59 vs 1.84; p=0.24) were not significantly different. There were no significant differences in cecal intubation rate (100% vs 99%; p=0.13) or withdrawal time (10.9 vs 11.1 min; p=0.28). In regression analysis, there was significant correlation between the attending-specific ADRs at IU and the VA (p=0.041, r-square=0.69). Conclusions In this study of average-risk males undergoing screening colonoscopies by the same group of endoscopists, the ADRs of VA and non-VA colonoscopies were not significantly different. This suggests that a VA-specific ADR target is not required for endoscopists with high ADR

The effect of prior androgen synthesis inhibition on outcomes of subsequent therapy with docetaxel in patients with metastatic castrate-resistant prostate cancer: results from a retrospective analysis of a randomized phase 3 clinical trial (CALGB 90401) (Alliance).

BACKGROUND: Preliminary data suggest a potential decreased benefit of docetaxel in patients with metastatic, castration-resistant prostate cancer (mCRPC) who previously received abiraterone acetate, a novel androgen synthesis inhibitor (ASI). Cancer and Leukemia Group B (CALGB) trial 90401 (Alliance), a phase 3 trial in patients with mCRPC who received docetaxel-based chemotherapy, offered the opportunity to evaluate effect of prior ketoconazole, an earlier generation ASI, on clinical outcomes after docetaxel. METHODS: In CALGB trial 90401, 1050 men with chemotherapy-naive mCRPC were randomized to receive treatment with docetaxel and prednisone that included either bevacizumab or placebo. In total, 1005 men (96%) had data available regarding prior ketoconazole therapy. The observed effects of prior ketoconazole on overall survival (OS), progression-free survival (PFS), prostate-specific antigen (PSA) decline, and the objective response rate (ORR) were assessed using proportional hazards and Poisson regression methods adjusted for validated prognostic factors and treatment arm. RESULTS: Baseline characteristics between patients who did (N=277) and did not (N=728) receive prior ketoconazole therapy were similar. There were no statistically significant differences between patients who did and those who did not receive prior ketoconazole therapy with respect to OS (median OS, 21.1 months vs 22.3 months, respectively; stratified log-rank P=.635), PFS (median PFS, 8.1 months vs 8.6 months, respectively; stratified log-rank P=.342), the proportion achieving a decline ≥ 50% in PSA (61% vs 66%, respectively; relative risk, 1.09; adjusted P=.129), or ORR (39% vs 43%, respectively; relative risk, 1.11; adjusted P=.366). CONCLUSIONS: As measured by OS, PFS, PSA, and the ORR, there was no evidence that prior treatment with ketoconazole had an impact on the clinical outcomes of patients with mCRPC who received subsequent docetaxel-based therapy. The current results highlight the need for prospective studies to assess for potential cross-resistance with novel ASIs and to define the optimal sequence of therapy in mCRPC

Discordant and heterogeneous clinically relevant genomic alterations in circulating tumor cells vs plasma DNA from men with metastatic castration resistant prostate cancer

Circulating tumor cell (CTC) and cellâ free (cf) DNAâ based genomic alterations are increasingly being used for clinical decisionâ making in oncology. However, the concordance and discordance between paired CTC and cfDNA genomic profiles remain largely unknown. We performed comparative genomic hybridization (CGH) on CTCs and cfDNA, and lowâ pass whole genome sequencing (lpWGS) on cfDNA to characterize genomic alterations (CNA) and tumor content in two independent prospective studies of 93 men with mCRPC treated with enzalutamide/abiraterone, or radiumâ 223. Comprehensive analysis of 69 patient CTCs and 72 cfDNA samples from 93 men with mCRPC, including 64 paired samples, identified common concordant gains in FOXA1, AR, and MYC, and losses in BRCA1, PTEN, and RB1 between CTCs and cfDNA. Concordant PTEN loss and discordant BRCA2 gain were associated with significantly worse outcomes in Epic ARâ V7 negative men with mCRPC treated with abiraterone/enzalutamide. We identified and externally validated CTCâ specific genomic alternations that were discordant in paired cfDNA, even in samples with high tumor content. These CTC/cfDNAâ discordant regions included key genomic regulators of lineage plasticity, osteomimicry, and cellular differentiation, including MYCN gain in CTCs (31%) that was rarely detected in cfDNA. CTC MYCN gain was associated with poor clinical outcomes in ARâ V7 negative men and small cell transformation. In conclusion, we demonstrated concordance of multiple genomic alterations across CTC and cfDNA platforms; however, some genomic alterations displayed substantial discordance between CTC DNA and cfDNA despite the use of identical copy number analysis methods, suggesting tumor heterogeneity and divergent evolution associated with poor clinical outcomes.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153751/1/gcc22824.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153751/2/gcc22824_am.pd

A Closed-Loop Control Traffic Engineering System for the Dynamic Load Balancing of Inter-AS Traffic

Inter-AS outbound traffic engineering (TE) is a set of techniques for controlling inter-AS traffic exiting an autonomous system (AS) by assigning the traffic to the best egress points (i.e. routers or links) from which the traffic is forwarded to adjacent ASes towards the destinations. In practice, changing network conditions such as inter-AS traffic demand variation, link failures and inter-AS routing changes occur dynamically. These changes can make fixed outbound TE solutions inadequate and may subsequently cause inter-AS links to become congested. In order to overcome this problem, we propose the deployment of a closed-loop control traffic engineering system that makes outbound traffic robust to inter-AS link failures and adaptive to changing network conditions. The objective is to keep the inter-AS link utilization balanced under unexpected events while reducing service disruptions and reconfiguration overheads. Our evaluation results show that the proposed system can successfully achieve better load balancing with less service disruption and re-configuration overhead in comparison to alternative approaches

Endothelial ether lipids link the vasculature to blood pressure, behavior, and neurodegeneration

Vascular disease contributes to neurodegeneration, which is associated with decreased blood pressure in older humans. Plasmalogens, ether phospholipids produced by peroxisomes, are decreased in Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders. However, the mechanistic links between ether phospholipids, blood pressure, and neurodegeneration are not fully understood. Here, we show that endothelium-derived ether phospholipids affect blood pressure, behavior, and neurodegeneration in mice. In young adult mice, inducible endothelial-specific disruption of PexRAP, a peroxisomal enzyme required for ether lipid synthesis, unexpectedly decreased circulating plasmalogens. PexRAP endothelial knockout (PEKO) mice responded normally to hindlimb ischemia but had lower blood pressure and increased plasma renin activity. In PEKO as compared with control mice, tyrosine hydroxylase was decreased in the locus coeruleus, which maintains blood pressure and arousal. PEKO mice moved less, slept more, and had impaired attention to and recall of environmental events as well as mild spatial memory deficits. In PEKO hippocampus, gliosis was increased, and a plasmalogen associated with memory was decreased. Despite lower blood pressure, PEKO mice had generally normal homotopic functional connectivity by optical neuroimaging of the cerebral cortex. Decreased glycogen synthase kinase-3 phosphorylation, a marker of neurodegeneration, was detected in PEKO cerebral cortex. In a co-culture system, PexRAP knockdown in brain endothelial cells decreased glycogen synthase kinase-3 phosphorylation in co-cultured astrocytes that was rescued by incubation with the ether lipid alkylglycerol. Taken together, our findings suggest that endothelium-derived ether lipids mediate several biological processes and may also confer neuroprotection in mice

Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3

Evolving treatments, disease phenotypes, and biology, together with a changing drug development environment, have created the need to revise castration-resistant prostate cancer (CRPC) clinical trial recommendations to succeed those from prior Prostate Cancer Clinical Trials Working Groups

Tissue based biomarkers in non-clear cell RCC: Correlative analysis from the ASPEN clinical trial

Biomarkers are needed in patients with non-clear cell renal cell carcinomas (NC-RCC), particularly papillary renal cell carcinoma, in order to inform on initial treatment selection and identify potentially novel targets for therapy. We enrolled 108 patients in ASPEN, an international randomized open-label phase 2 trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC treated with the mTOR inhibitor everolimus (n=57) or the vascular endothelial growth factor (VEGF) receptor inhibitor sunitinib (n=51), stratified by MSKCC risk and histology. The primary endpoint was overall survival (OS) and secondary efficacy endpoints for this exploratory biomarker analysis were radiographic progression-free survival (rPFS) defined by intentionto- treat using the RECIST 1.1 criteria and radiographic response rates. Tissue biomarkers (n=78) of mTOR pathway activation (phospho-S6 and -Akt, c-kit) and VEGF pathway activation (HIF-1, c-MET) were prospectively explored in tumor tissue by immunohistochemistry prior to treatment and associated with clinical outcomes. We found that S6 activation was more common in poor-risk NC-RCC tumors and S6/Akt activation was associated with worse PFS and OS outcomes with both everolimus and sunitinib, while c-kit was commonly expressed in chromophobe tumors and associated with improved outcomes with both agents. C-MET was commonly expressed in papillary tumors and was associated with lower rates of radiographic response but did not predict PFS for either agent. In multivariable analysis, both pAkt and c-kit were statistically significant prognostic biomarkers of OS. No predictive biomarkers of treatment response were identified for clinical outcomes. Most biomarker subgroups had improved outcomes with sunitinib as compared to everolimus

Education as a Predictor of Chronic Periodontitis: A Systematic Review with Meta-Analysis Population-Based Studies

The impact of socioeconomic inequalities on health is well-documented. Despite the links of periodontal disease with cardiovascular diseases, adverse pregnancy outcomes and diabetes, no meta-analysis of socioeconomic variations in periodontal disease exists. This meta-analytic review was conducted to determine the extent to which education attainment influences risk of periodontitis in adults aged 35+ years in the general population.The authors searched studies published until November 2010 using EMBASE and MEDLINE databases. References listed were then scrutinised, our own files were checked, and, finally, we contacted experts in the field. The authors included only general population-based studies conducted in adults aged 35 years and more. All articles were blind reviewed by two investigators. In the case of disagreement, a third investigator arbitrated. Using PRISMA statement, two reviewers independently extracted papers of interest.Relative to the higher education group, people with low education attainment experience a greater risk of periodontitis (OR: 1.86 [1.66–2.10]; p<0.00001). The association was partially attenuated after adjustment for covariates (OR: 1.55 [1.30–1.86]; p<0.00001). Sensitivity analyses showed that methods used to assess periodontitis, definition of cases, study country and categorization of education are largely responsible for the heterogeneity between studies. No significant bias of publication was shown using both the Egger (p = 0.16) and rank correlation tests (p = 0.35).In the studies reviewed, low educational attainment was associated with an increased risk of periodontitis. Although this evidence should be cautiously interpreted due to methodological problems in selected studies, efforts to eliminate educational inequalities in periodontitis should focus on early life interventions