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Background and purposeA subset of patients with Alzheimer's disease (AD) present with early and prominent language deficits. It is unclear whether the burden of underlying β‐amyloid pathology is associated with language or general cognitive impairment in these subjects.MethodsThe relationship between cortical β‐amyloid burden on [11C]Pittsburgh compound B (PiB) positron emission tomography (PET) and performance on the Montreal Cognitive Assessment (MoCA), the Wechsler Memory Scale − Third Edition (WMS‐III), the Boston Naming Test (BNT) and the Western Aphasia Battery (WAB) was assessed using regression and correlation analyses in subjects presenting with aphasia who showed β‐amyloid deposition on PiB PET.ResultsThe global PiB ratio was inversely correlated with MoCA (P = 0.02) and the WMS‐III Visual Reproduction (VR) subtest (VR I, P = 0.02; VR II, P = 0.04). However, the correlations between PiB ratio, BNT (P = 0.13), WAB aphasia quotient (P = 0.11) and WAB repetition scores (P = 0.34) were not significant.ConclusionThis study demonstrates that an increased cortical β‐amyloid burden is associated with cognitive impairment, but not language deficits, in AD subjects presenting with aphasia. The results suggest that β‐amyloid deposition could be partly contributing to impaired cognition in such patients whilst language dysfunction may be more influenced by other pathological mechanisms, perhaps downstream pathways of β‐amyloid deposition.

Bridging for antiplatelet therapy remains a subject of debate with data favoring GP blockers but at a risk of bleeding. This Conversation in Cardiology addresses a key and often asked question about use of alternatives to P2Y12 agents in patients requiring surgery within 6 months after drug eluting stent implantation. © 2013 Wiley Periodicals, Inc.

Objectives To model renal function after radical nephroureterectomy ( RNU ) for upper tract urothelial carcinoma ( UTUC ). To identify predictors of renal function decline after surgery, thereby allowing the identification of patients likely to be ineligible for cisplatin‐based chemotherapy in the adjuvant setting. Patients and Methods We retrospectively identified 374 patients treated with RNU for UTUC at three centres between 1995 and 2010. Estimated glomerular filtration rate ( eGFR ) was calculated using Chronic Kidney Disease Epidemiology Collaboration equation before RNU and at early (1–5 months after RNU ) and late (>5 months) time points after RNU . Only patients deemed eligible for cisplatin‐based chemotherapy before RNU (preoperative glomerular filtration rate [ GFR ] ≥60 mL/min/1.73 m 2 ) were included. Multivariable analysis identified the preoperative predictors of eGFR after RNU at early postoperative and late postoperative time points. Results A total of 163 patients had an eligible early post‐ RNU eGFR measurement and 172 had an eligible late eGFR measurement. The median eGFR declined by 32% and did not show a significant trend toward recovery over time ( P = 0.4). On multivariable analysis preoperative eGFR and patient age were significantly associated with early and late postoperative eGFR , while C harlson comorbidity index score was significantly associated with late postoperative eGFR alone. Conclusions In patients with normal preoperative eGFR (≥60 mL/min/1.73 m 2 ), renal function decreases by one‐third after RNU and does not show evidence of recovery over time. Elderly patients and those with pre‐ RNU eGFR closer to 60 mL/min/1.73 m 2 (lower eGFR in the present cohort) are more likely to be ineligible for adjuvant cisplatin‐based chemotherapy regimens because of renal function loss after RNU .

Abstract BACKGROUND Urine albumin is the primary biomarker for detection and monitoring of kidney damage. Because fixed decision criteria are used to identify patients with increased values, we investigated if commonly used routine measurement procedures gave comparable results. METHODS Results from 17 commercially available urine albumin measurement procedures were investigated vs an isotope dilution mass spectrometry (IDMS) procedure. Nonfrozen aliquots of freshly collected urine from 332 patients with chronic kidney disease, diabetes, cardiovascular disease, and hypertension were distributed to manufacturers to perform urine albumin measurements according to the respective instructions for use for each procedure. Frozen aliquots were used for measurements by the IDMS procedure. An error model was used to determine imprecision and bias components. RESULTS Median differences between the largest positive and negative biases vs IDMS were 45%, 37%, and 42% in the concentration intervals of 12–30 mg/L, 31–200 mg/L, and 201–1064 mg/L, respectively. Biases varied with concentration for most procedures and exceeded ±10% over the concentration interval for 14 of 16 quantitative procedures. Mean biases ranged from −35% to 34% at 15 mg/L. Dilution of samples with high concentrations introduced bias for 4 procedures. The combined CV was >10% for 5 procedures. It was not possible to estimate total error due to dependence of bias on concentration. CVs for sample-specific influences were 0% to 15.2%. CONCLUSIONS Bias was the dominant source of disagreement among routine measurement procedures. Consequently, standardization efforts will improve agreement among results. Variation of bias with concentration needs to be addressed by manufacturers.

Background: The inclusion of mental health issues in the evaluation of multimorbidity generally has been as the presence or absence of the condition rather than severity, complexity, or stage. The hypothesis for this study was that clinical outcome of the depression 6 months after enrollment into collaborative care management would have a role in predicting future complexity of care tier. Methods: This study was a retrospective chart review of 1894 primary care patients who were diagnosed with major depressive disorder or dysthymia as of December 2012. Multiple logistic regression analysis was used to test the independent associations between each variable and the odds of being included in the higher tiers (HT) group. Results: Age (odds ratio [OR] = 1.022, confidence interval [CI] = 1.013-1.030, P < .001), female gender (OR = 1.380, CI = 1.020-1.868, P = .037), being married (OR = 0.730, CI = 0.563-0.947, P = .018), and the presence of comorbidities (1, OR = 1.986, CI = 1.485-2.656, P < .001; ≥2, OR = 4.678, CI = 3.242-6.750, P < .001) were independently associated with future HT levels. The presence of persistent depressive symptoms (PHQ-9 ≥10) at 6 months conferred 2.280 (CI = 1.673-3.107, P < .001) times likely odds of HT level compared with clinical remission at 6 months. Conclusion: Patients with the diagnosis of major depression or dysthymia had greater odds of complex tier levels in the future, if depression was not treated to remission by 6 months. This study demonstrated the importance of the goal of significant improvement (ie, remission) of depression symptoms by 6 months (especially those older patients with more comorbidity) from entering into the higher complexity tiers.

Abstract A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76–0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75–0.95; P = 0.006). Considering a multiple-testing–corrected significance threshold of P &lt; 2.5 × 10−5, only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79–0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted. Cancer Res; 74(3); 852–61. ©2013 AACR.

Key PointsMGUS patients have significantly increased cortical bone porosity and reduced bone strength relative to matched controls.

Abstract A Saskatchewan multi-incident family was clinically characterized with Parkinson disease (PD) and Lewy body pathology. PD segregates as an autosomal-dominant trait, which could not be ascribed to any known mutation. DNA from three affected members was subjected to exome sequencing. Genome alignment, variant annotation and comparative analyses were used to identify shared coding mutations. Sanger sequencing was performed within the extended family and ethnically matched controls. Subsequent genotyping was performed in a multi-ethnic case–control series consisting of 2928 patients and 2676 control subjects from Canada, Norway, Taiwan, Tunisia, and the USA. A novel mutation in receptor-mediated endocytosis 8/RME-8 (DNAJC13 p.Asn855Ser) was found to segregate with disease. Screening of cases and controls identified four additional patients with the mutation, of which two had familial parkinsonism. All carriers shared an ancestral DNAJC13 p.Asn855Ser haplotype and claimed Dutch–German–Russian Mennonite heritage. DNAJC13 regulates the dynamics of clathrin coats on early endosomes. Cellular analysis shows that the mutation confers a toxic gain-of-function and impairs endosomal transport. DNAJC13 immunoreactivity was also noted within Lewy body inclusions. In late-onset disease which is most reminiscent of idiopathic PD subtle deficits in endosomal receptor-sorting/recycling are highlighted by the discovery of pathogenic mutations VPS35, LRRK2 and now DNAJC13. With this latest discovery, and from a neuronal perspective, a temporal and functional ecology is emerging that connects synaptic exo- and endocytosis, vesicular trafficking, endosomal recycling and the endo-lysosomal degradative pathway. Molecular deficits in these processes are genetically linked to the phenotypic spectrum of parkinsonism associated with Lewy body pathology.