Search

Rationale: Chronic lung diseases (CLDs) have been variably associated with a risk for more severe manifestations and death with coronavirus disease (COVID-19). Objectives: To determine the risk overall and by type of CLD for severity of COVID-19 outcomes in a U.S. national cohort. Methods: Using data from the Veterans Health Administration, we determined the risk associated with CLDs, including chronic obstructive pulmonary disease (COPD) (mild or severe), asthma (mild, active, or severe), idiopathic pulmonary fibrosis (IPF), sarcoidosis, and other interstitial lung diseases (ILDs) for outcomes among veterans with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive tests between March 1, 2020 and April 30, 2021. We used multinomial regression to estimate risk of four mutually exclusive COVID-19 outcomes within 30 days: outpatient management, hospitalization, hospitalization with indicators of critical illness, or death. We calculated the overall proportion with each outcome, the absolute risk difference, and risk ratios for each outcome between those with and without CLD. We also describe clinical and laboratory abnormalities by CLD in those hospitalized. Results: We included 208,283 veterans with COVID-19; 35,587 (17%) had CLD. Compared with no CLD, veterans with CLD were older and had more comorbidities. Hospitalized veterans with CLD were more likely to have low temperature, mean arterial pressure, oxygen saturation, and leukopenia and thrombocytopenia and were more likely to receive oxygen, mechanical ventilation, and vasopressors. Veterans with CLD were significantly less likely to have mild COVID-19 (-4.5%; adjusted risk ratio [aRR], 0.94; 95% confidence interval [CI], 0.94-0.95), and more likely to have a moderate (+2.5%; aRR, 1.21; 95% CI, 1.18-1.24), critical (+1.4%; aRR, 1.38; 95% CI, 1.32-1.45), or fatal (+0.7%; aRR, 1.15; 95% CI, 1.10-1.20) outcome. IPF was most strongly associated with COVID-19 severity, especially mortality (+3.2%; aRR, 1.69; 95% CI, 1.46-1.96), followed by other ILDs and COPD, whereas asthma was less likely to be associated with severity of COVID-19. In veterans younger than age 65 years, worse COVID-19 outcomes were generally more likely with IPF, sarcoidosis, and other ILDs. Conclusions: Veterans who had CLD, particularly IPF, other ILDs, and COPD, had an increased probability of more severe 30-day outcomes with COVID-19. These results provide insight into the absolute and relative risk of different CLDs with severity of COVID-19 outcomes and can help inform considerations of healthcare utilization and prognosis. Observational clinical epidemiology study registered with www.clinicaltrials.gov (NCT04628039).

Chronic obstructive pulmonary disease (COPD) is one of the most common comorbid diseases among aging people with HIV (PWH) and is often mismanaged. To address this gap, we are conducting the study, "Advancing care for COPD in people living with HIV by Implementing Evidence-based management through proactive E-consults (ACHIEVE)." This intervention optimizes COPD management by promoting effective, evidence-based care and de-implementing inappropriate therapies for COPD in PWH receiving care at Veteran Affairs (VA) medical centers. Study pulmonologists are proactively supporting ID providers managing a population of PWH who have COPD, offering real-time evidence-based recommendations tailored to each patient. We are leveraging VA clinical and informatics infrastructures to communicate recommendations between the study team and clinical providers through the electronic health record (EHR) as an E-consult. If effective, ACHIEVE could serve as a model of effective, efficient COPD management among PWH receiving care in VA. This paper outlines the rationale and methodology of the ACHIEVE trial, one of a series of studies funded by the National Heart, Lung, and Blood Institute (NHLBI) within the ImPlementation REsearCh to DEvelop Interventions for People Living with HIV (PRECluDE) consortium to study chronic disease comorbidities in HIV populations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS), yet the viral genetic factors that lead to the development of KS in KSHV-infected individuals have not been fully elucidated. Nearly, all previous analyses of KSHV genomic evolution and diversity have excluded the three major internal repeat regions: the two origins of lytic replication, internal repeats 1 and 2 (IR1 and IR2), and the latency-associated nuclear antigen (LANA) repeat domain (LANAr). These regions encode protein domains that are essential to the KSHV infection cycle but have been rarely sequenced due to their extended repetitive nature and high guanine and cytosine (GC) content. The limited data available suggest that their sequences and repeat lengths are more heterogeneous across individuals than in the remainder of the KSHV genome. To assess their diversity, the full-length IR1, IR2, and LANAr sequences, tagged with unique molecular identifiers (UMIs), were obtained by Pacific Biosciences' single-molecule real-time sequencing (SMRT-UMI) from twenty-four tumors and six matching oral swabs from sixteen adults in Uganda with advanced KS. Intra-host single-nucleotide variation involved an average of 0.16 per cent of base positions in the repeat regions compared to a nearly identical average of 0.17 per cent of base positions in the remainder of the genome. Tandem repeat unit (TRU) counts varied by only one from the intra-host consensus in a majority of individuals. Including the TRU indels, the average intra-host pairwise identity was 98.3 per cent for IR1, 99.6 per cent for IR2 and 98.9 per cent for LANAr. More individuals had mismatches and variable TRU counts in IR1 (twelve/sixteen) than in IR2 (two/sixteen). There were no open reading frames in the Kaposin coding sequence inside IR2 in at least fifty-five of ninety-six sequences. In summary, the KSHV major internal repeats, like the rest of the genome in individuals with KS, have low diversity. IR1 was the most variable among the repeats, and no intact Kaposin reading frames were present in IR2 of the majority of genomes sampled., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press.)

Objective: Improved understanding of the effect of HIV infection on Kaposi sarcoma (KS) presentation and outcomes will guide development of more effective KS staging and therapeutic approaches. We enrolled a prospective cohort of epidemic (HIV-positive; HIV + KS) and endemic (HIV-negative; HIV - KS) KS patients in Uganda to identify factors associated with survival and response., Methods: Adults with newly diagnosed KS presenting for care at the Uganda Cancer Institute (UCI) in Kampala, Uganda, between October 2012 and December 2019 were evaluated. Participants received chemotherapy per standard guidelines and were followed over 1 year to assess overall survival (OS) and treatment response., Results: Two hundred participants were enrolled; 166 (83%) had HIV + KS, and 176 (88%) were poor-risk tumor (T1) stage. One-year OS was 64% (95% confidence interval [CI] 57-71%), with the hazard of death nearly threefold higher for HIV + KS (hazard ratio [HR] = 2.93; P  = 0.023). Among HIV + KS, abnormal chest X-ray (HR = 2.81; P  = 0.007), lower CD4 + T-cell count (HR = 0.68 per 100 cells/μl; P  = 0.027), higher HIV viral load (HR = 2.22 per log 10  copies/ml; P  = 0.026), and higher plasma Kaposi sarcoma-associated herpesvirus (KSHV) copy number (HR = 1.79 per log 10  copies/ml; P  = 0.028) were associated with increased mortality. Among HIV - KS, factors associated with mortality included Karnofsky score <70 (HR = 9.17; P  = 0.045), abnormal chest X-ray (HR = 8.41; P  = 0.025), and higher plasma KSHV copy number (HR = 6.21 per log 10  copies/ml; P  < 0.001)., Conclusions: Although survival rates were better for HIV - KS than HIV + KS, the high mortality rate seen in both groups underscores the urgent need to identify new staging and therapeutic approaches. Factors associated with mortality, including high plasma KSHV, may serve as important targets of therapy., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Kaposi sarcoma (KS), a common HIV-associated malignancy, presents a range of clinicopathological features. Kaposi sarcoma-associated herpesvirus (KSHV) is its etiologic agent, but the contribution of viral genomic variation to KS development is poorly understood. To identify potentially influential viral polymorphisms, we characterized KSHV genetic variation in 67 tumors from 1-4 distinct sites from 29 adults with advanced KS in Kampala, Uganda. Whole KSHV genomes were sequenced from 20 tumors with the highest viral load, whereas only polymorphic genes were screened by PCR and sequenced from 47 other tumors. Nine individuals harbored ≥1 tumors with a median 6-fold over-coverage of a region centering on K5 and K6 genes. K8.1 gene was inactivated in 8 individuals, while 5 had mutations in the miR-K10 microRNA coding sequence. Recurring inter-host polymorphisms were detected in K4.2 and K11.2. The K5-K6 region rearrangement breakpoints and K8.1 mutations were all unique, indicating that they arise frequently de novo. Rearrangement breakpoints were associated with potential G-quadruplex and Z-DNA forming sequences. Exploratory evaluations of viral mutations with clinical and tumor traits were conducted by logistic regression without multiple test corrections. K5-K6 over-coverage and K8.1 inactivation were tentatively correlated (p<0.001 and p = 0.005, respectively) with nodular rather than macular tumors, and with individuals that had lesions in ≤4 anatomic areas (both p≤0.01). Additionally, a trend was noted for miR-K10 point mutations and lower survival rates (HR = 4.11, p = 0.053). Two instances were found of distinct tumors within an individual sharing the same viral mutation, suggesting metastases or transmission of the aberrant viruses within the host. To summarize, KSHV genomes in tumors frequently have over-representation of the K5-K6 region, as well as K8.1 and miR-K10 mutations, and each might be associated with clinical phenotypes. Studying their possible effects may be useful for understanding KS tumorigenesis and disease progression., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Santiago et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Cervical cancer mortality remains high in sub-Saharan Africa, especially among women living with HIV (WLWH). Characterization of prevalent high-risk human papillomavirus (hrHPV) types and immune function in WLWH with cervical abnormalities despite antiretroviral therapy (ART) can inform prevention strategies., Setting: Kampala, Uganda., Methods: From 2017 to 2020, we enrolled Ugandan women with cervical dysplasia detected with visual inspection with acetic acid (VIA). WLWH were required to be on ART >3 months with plasma HIV RNA <1000 copies/mL. Biopsies from VIA-positive lesions underwent histopathologic grading and cervical swab specimens were tested for hrHPV. Clinical correlations were evaluated with Poisson regression to estimate adjusted prevalence ratios (aPR)., Results: One hundred eighty-eight WLWH and 116 HIV-seronegative women participated. Among WLWH, median ART duration was 6 years and median CD4 667 cells/µL. Cervical intraepithelial neoplasia (CIN) grade 2/3 was found in 29% of WLWH versus 9% of HIV-seronegative women. In women with CIN1 or without histopathology-confirmed dysplasia, hrHPV (aPR [95% confidence interval]: 2.17 [1.43 to 3.29]) and multiple hrHPV (aPR 3.73 [1.07 to 13.1]) were more common in WLWH, as were vaccine-targeted and vaccine-untargeted hrHPVtypes. Differences in hrHPV prevalence by HIV serostatus were not observed in women with CIN2/3 (interaction P < 0.01). Among WLWH, low CD4/8 ratio was associated with hrHPV while detectable plasma HIV RNA (20-1000 copies/mL) was associated with CIN2/3 or invasive cancer., Conclusion: Despite ART, WLWH with cervical VIA abnormalities remain at elevated risk for multiple hrHPV and high-grade dysplasia. Cervical cancer prevention and research tailored for WLWH are warranted in the ART era., Competing Interests: S.V.A., A.T., J.O. and T.S.U. received support from Hoffman LaRoche for investigator-initiated research. T.S.U. received research support from Merck and Celgene/BMS for investigator-initiated research and consults for AbbVie and Seattle Genetics. T.S.U. is currently an employee at Regeneron. C.C. is a member of the scientific advisory boards of Viracta Therapeutics and Curevo Vaccines, receives research support from Celularity, Inc., and is a consultant for EUSA Pharma. The remaining authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

In people living with HIV (PLWH) on antiretroviral therapy (ART), virus persists in a latent form where there is minimal transcription or protein expression. Latently infected cells are a major barrier to curing HIV. Increasing HIV transcription and viral production in latently infected cells could facilitate immune recognition and reduce the pool of infected cells that persist on ART. Given that programmed cell death protein 1 (PD-1) expressing CD4 + T cells are preferentially infected with HIV in PLWH on ART, we aimed to determine whether administration of antibodies targeting PD-1 would reverse HIV latency in vivo. We therefore evaluated the impact of intravenous administration of pembrolizumab every 3 weeks on HIV latency in 32 PLWH and cancer on ART. After the first infusion of anti-PD-1, we observed a median 1.32-fold increase in unspliced HIV RNA and 1.61-fold increase in unspliced RNA:DNA ratio in sorted blood CD4 + T cells compared to baseline. We also observed a 1.65-fold increase in plasma HIV RNA. The frequency of CD4 + T cells with inducible virus evaluated using the tat/rev limiting dilution assay was higher after 6 cycles compared to baseline. Phylogenetic analyses of HIV env sequences in a participant who developed low concentrations of HIV viremia after 6 cycles of pembrolizumab did not demonstrate clonal expansion of HIV-infected cells. These data are consistent with anti-PD-1 being able to reverse HIV latency in vivo and support the rationale for combining anti-PD-1 with other interventions to reduce the HIV reservoir.

Introduction: Chronic kidney disease-mineral and bone disorders (CKD-MBD) are prevalent in patients undergoing maintenance dialysis. Yet, there are limited and mixed evidence on the effects of different dialysis modalities involving longer treatment times or higher frequencies on CKD-MBD markers., Methods: This cohort study used data from 132,523 incident dialysis patients treated with any of the following modalities: conventional thrice-weekly in-center hemodialysis, nocturnal in-center hemodialysis (NICHD), home hemodialysis (HHD), or peritoneal dialysis (PD) from 2007 to 2011. We used marginal structural models fitted with inverse probability weights to adjust for fixed and time-varying confounding and informative censoring. We estimated the average effects of treatments with different dialysis modalities on time-varying serum concentrations of CKD-MBD markers: albumin-corrected calcium, phosphate, parathyroid hormone (PTH), and alkaline phosphatase (ALP) using pooled linear regression., Results: Most of the cohort were exclusively treated with conventional in-center hemodialysis, while few were ever treated with NICHD or HHD. At the baseline, PD patients had the lowest mean and median values of PTH, while NICHD patients had the highest median values. During follow-up, compared to hemodialysis patients, patients treated with NICHD had lower mean serum PTH (19.8 pg/mL [95% confidence interval: 2.8, 36.8] lower), whereas PD and HHD patients had higher mean PTH (39.7 pg/mL [31.6, 47.8] and 51.2 pg/mL [33.0, 69.3] higher, respectively). Compared to hemodialysis patients, phosphate levels were lower for patients treated with NICHD (0.44 mg/dL [0.37, 0.52] lower), PD (0.15 mg/dL [0.12, 0.19] lower), or HHD (0.33 mg/dL [0.27, 0.40] lower). There were no clinically meaningful associations between dialysis modalities and concentrations of calcium or ALP., Conclusion: In incident dialysis patients, compared to treatment with conventional in-center hemodialysis, treatments with other dialysis modalities with longer treatment times or higher frequency were associated with different patterns of serum phosphate and PTH. Given the recent growth in the use of dialysis modalities other than hemodialysis, the associations between the treatment and the CKD-MBD markers warrant additional study., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Background: Neutropenic fever (NF) is associated with significant morbidity and mortality for patients receiving cancer treatment in sub-Saharan Africa (sSA). However, the antibiotic management of NF in sub-Saharan Africa has not been well described. We evaluated the timing and selection of antibiotics for patients with NF at the Uganda Cancer Institute (UCI)., Methods: We conducted a retrospective chart review of adults with acute leukemia admitted to UCI from 1 January 2016 to 31 May 2017, who developed NF. For each NF event, we evaluated the association of clinical presentation and demographics with antibiotic selection as well as time to both initial and guideline-recommended antibiotics. We also evaluated the association between ordered antibiotics and the in-hospital case fatality ratio (CFR)., Results: Forty-nine NF events occurred among 39 patients. The time to initial antibiotic order was <1 day. Guideline-recommended antibiotics were ordered for 37 (75%) NF events. The median time to guideline-recommended antibiotics was 3 days. Fever at admission, a documented physical examination, and abdominal abnormalities were associated with a shorter time to initial and guideline-recommended antibiotics. The in-hospital CFR was 43%. There was no difference in in-hospital mortality when guideline-recommended antibiotics were ordered as compared to when non-guideline or no antibiotics were ordered (hazard ratio, 0.51 [95% confidence interval {CI}, .10-2.64] and 0.78 [95% CI, .20-2.96], respectively)., Conclusions: Patients with acute leukemia and NF had delayed initiation of guideline-recommended antibiotics and a high CFR. Prospective studies are needed to determine optimal NF management in sub-Saharan Africa, including choice of antibiotics and timing of antibiotic initiation., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The most mature aspect of applying artificial intelligence (AI)/machine learning (ML) to problems in the atmospheric sciences is likely post-processing of model output. This article provides some history and current state of the science of post-processing with AI for weather and climate models. Deriving from the discussion at the 2019 Oxford workshop on Machine Learning for Weather and Climate, this paper also presents thoughts on medium-term goals to advance such use of AI, which include assuring that algorithms are trustworthy and interpretable, adherence to FAIR data practices to promote usability, and development of techniques that leverage our physical knowledge of the atmosphere. The coauthors propose several actionable items and have initiated one of those: a repository for datasets from various real weather and climate problems that can be addressed using AI. Five such datasets are presented and permanently archived, together with Jupyter notebooks to process them and assess the results in comparison with a baseline technique. The coauthors invite the readers to test their own algorithms in comparison with the baseline and to archive their results. This article is part of the theme issue 'Machine learning for weather and climate modelling'.

Background: Co-infection with hepatitis B virus (HBV) and human immunodeficiency virus (HIV) is common in sub-Saharan Africa (SSA) and can rapidly progress to cirrhosis and hepatocellular carcinoma. Recent data demonstrate ongoing HBV transmission among HIV-infected adults in SSA, suggesting that complications of HIV/HBV co-infection could be prevented with HBV vaccination. Because HBV vaccine efficacy is poorly understood among HIV-infected persons in SSA, we sought to characterize the humoral response to the HBV vaccine in HIV-seropositive Ugandan adults., Methods: We enrolled HIV-infected adults in Kampala, Uganda without serologic evidence of prior HBV infection. Three HBV vaccine doses were administered at 0, 1 and 6 months. Anti-HBs levels were measured 4 weeks after the third vaccine dose. "Response" to vaccination was defined as anti-HBs levels ≥ 10 IU/L and "high response" as ≥ 100 IU/L. Regression analysis was used to determine predictors of response., Results: Of 251 HIV-positive adults screened, 132 (53%) had no prior HBV infection or immunity and were enrolled. Most participants were women [89 (67%)]; median (IQR) age was 32 years (27-41), and 68 (52%) had received antiretroviral therapy (ART) for > 3 months. Median (IQR) CD4 count was 426 (261-583), and 64 (94%) of the 68 receiving ART had undetectable plasma HIV RNA. Overall, 117 (92%) participants seroconverted to the vaccine (anti-HBs ≥ 10 IU/L), with 109 (86%) participants having high-level response (anti-HBs ≥ 100 IU/L). In multivariate analysis, only baseline CD4 > 200 cells/mm3 was associated with response [OR = 6.97 (1.34-34.71), p = 0.02] and high-level response [OR = 4.25 (1.15-15.69)], p = 0.03]., Conclusion: HBV vaccination was effective in eliciting a protective humoral response, particularly among those with higher CD4 counts. Half of the screened patients did not have immunity to HBV infection, suggesting a large at-risk population for HBV infection among HIV-positive adults in Uganda. Our findings support including HBV vaccination as part of routine care among HIV-positive adults., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Cadmium production has risen 1000-fold in the past 100 years, from under 20 to over 20,000 tons per year, causing anthropogenically-mobilized Cd to overwhelm natural sources in global cycling. Cadmium has no known biological function in humans, yet has biochemical behaviors similar to zinc and manganese, making exposure detrimental to human health. Identifying and quantifying the sources of Cd for human sub-populations is key to reducing exposures. Cadmium stable isotopes may provide a method for tracing Cd sources throughout the environment and the human body, but at present the limited database for high precision Cd isotopic compositions is inadequate to support such an analysis. Here, we provide new Cd isotope data on dietary sources, cigarette smoking components, and environmentally relevant standard reference materials. Results indicated that minor but significant variations are observed in food products (e.g., peanuts, sunflower seeds, spinach, kale, lettuce, cocoa powder; ~0.9‰ at 4 amu) that may be useful for tracing contamination in agricultural soils. In contrast, Cd isotope fractionation during smoking is larger (~6‰ at 4 amu) and has implications for tracing cadmium sources from tobacco combustion in the environment and throughout the human body. The primary inhaled component of cigarette smoke contains highest delta values (δ 116/112 Cd or δ 114/110 Cd ~5.2‰), while the second-hand smoke and cigarette ash have the lowest delta values (δ 116/112 Cd or δ 114/110 Cd ~-0.9‰). Used cigarette butts have δ 114/110 Cd ~2.4‰, in between the values measured in ash/s hand smoke and the inhaled smoke components. The high delta values of the inhaled smoke indicate that Cd isotopes may be used to determine the extent of Cd exposure due to smoking in human biological samples. This study provides new data for previously uncharacterized isotopic reservoirs that can be included in future studies of Cd source-exposure tracing., (Published by Elsevier B.V.)

Purpose: "Endemic" Burkitt lymphoma (BL) is a common childhood cancer in Africa. Social and treatment factors may contribute to poor survival. With the aim of improving BL outcomes in Uganda, we undertook a comprehensive project (BL Project) that provided diagnostic support, access to standard chemotherapy, nutritional evaluations, and case management. We evaluated survival of children with BL in the context of the project., Patients and Methods: Patients followed by the BL Project who consented to research were enrolled in this study. Children with a pathology diagnosis consistent with BL were eligible. Data were collected prospectively. First-line chemotherapy generally consisted of six cycles of cyclophosphamide, vincristine, low-dose methotrexate (COM). We used Kaplan-Meier and Cox regression analyses to evaluate factors associated with overall survival (OS)., Results: Between July 2012 and June 2017, 341 patients with suspected BL presented to the BL Project. One hundred eighty patients with a pathology-based diagnosis were included in this study. The median age was seven years (interquartile range, 5-9), 74% lived ≥100 km from the Uganda Cancer Institute, 61% had late-stage disease, 84% had ECOG performance status < 3, 63% reported B-symptoms, and 22% showed neurologic symptoms. Fewer than 10% abandoned therapy. The four-year OS rate was 44% (95% CI, 36%-53%). In a multivariate model, ECOG status was significantly associated with mortality., Conclusion: The BL Project reduced effects of lacking supportive care and oncology resources, and allowed patients from Uganda to receive curative intent therapy with minimal loss to follow-up. Nonetheless, OS remains unacceptably low. Improved therapeutic approaches to endemic BL are urgently needed in Africa., (© 2019 Wiley Periodicals, Inc.)

Purpose: Interactive clinical video telemedicine (CVT) has the potential to benefit health care systems and patients by improving access, lowering costs, and more efficiently distributing providers. However, there is a gap in current knowledge around the demand for and potential uses of CVT in large integrated health care systems., Methods: We conducted an observational study using Veterans Health Administration (VHA) administrative databases to analyze trends in CVT utilization, and types of care received, among 7.65 million veterans during fiscal years (FY) 2009-2015 (October 1, 2008-September 30, 2015). Trends were stratified by veteran rurality and analyzed using linear regression. Among 4.95 million veterans in FY2015, we used logistic regression to identify characteristics associated with CVT utilization for any care, mental health care, and major specialties., Findings: Over 6 years, the annual CVT utilization grew from 30 to 124 encounters per 1,000 veterans (>300% increase), with faster growth among rural veterans than urban veterans. Over the study period, ≥50% of all CVT-delivered care was mental health care. In FY2015, 3.2% of urban and 7.2% of rural veterans utilized CVT for nearly 725,000 clinical encounters. Rural residence, younger age, longer driving distance to VHA facilities, one or more comorbidities, and higher rates of traditional, non-video utilization were independently associated with higher odds of CVT use., Conclusions: CVT utilization in VHA has increased quickly and exceeds published rates in the private health care market. The availability of CVT has likely increased access to VHA care for rural veterans, especially for mental health care., (© 2018 National Rural Health Association.)

Background and Objectives: Whether patients with monoclonal protein are at a higher risk for progression of kidney disease is not known. The goal of this study was to measure the association of monoclonal protein with progression to ESKD., Design, Setting, Participants, & Measurements: This was a retrospective cohort study of 2,156,317 patients who underwent serum creatinine testing between October 1, 2000 and September 30, 2001 at a Department of Veterans Affairs medical center, among whom 21,898 had paraprotein testing within 1 year before or after cohort entry. Progression to ESKD was measured using linked data from the US Renal Data System., Results: Overall, 1,741,707 cohort members had an eGFR≥60 ml/min per 1.73 m 2 , 283,988 had an eGFR of 45-59 ml/min per 1.73 m 2 , 103,123 had an eGFR of 30-44 ml/min per 1.73 m 2 and 27,499 had an eGFR of 15-29 ml/min per 1.73 m 2 . The crude incidence of ESKD ranged from 0.7 to 80 per 1000 person-years from the highest to lowest eGFR category. Patients with low versus preserved eGFR were more likely to be tested for monoclonal protein but no more likely to have a positive test result. In adjusted analyses, a positive versus negative test result was associated with a higher risk of ESKD among patients with an eGFR≥60 ml/min per 1.73 m 2 (hazard ratio, 1.67; 95% confidence interval, 1.22 to 2.29) and those with an eGFR of 15-29 ml/min per 1.73 m 2 (hazard ratio, 1.38; 95% confidence interval, 1.07 to 1.77), but not among those with an eGFR of 30-59 ml/min per 1.73 m 2 . Progression to ESKD was attributed to a monoclonal process in 21 out of 76 versus seven out of 174 patients with monoclonal protein and preserved versus severely reduced eGFR at cohort entry., Conclusions: The detection of monoclonal protein provides little information on ESKD risk for most patients with a low eGFR. Further study is required to better understand factors contributing to a positive association of monoclonal protein with ESKD risk in patients with preserved and severely reduced levels of eGFR., (Copyright © 2018 by the American Society of Nephrology.)

We present here a learning system using the iCub humanoid robot and the SpiNNaker neuromorphic chip to solve the real-world task of object-specific attention. Integrating spiking neural networks with robots introduces considerable complexity for questionable benefit if the objective is simply task performance. But, we suggest, in a cognitive robotics context, where the goal is understanding how to compute, such an approach may yield useful insights to neural architecture as well as learned behavior, especially if dedicated neural hardware is available. Recent advances in cognitive robotics and neuromorphic processing now make such systems possible. Using a scalable, structured, modular approach, we build a spiking neural network where the effects and impact of learning can be predicted and tested, and the network can be scaled or extended to new tasks automatically. We introduce several enhancements to a basic network and show how they can be used to direct performance toward behaviorally relevant goals. Results show that using a simple classical spike-timing-dependent plasticity (STDP) rule on selected connections, we can get the robot (and network) to progress from poor task-specific performance to good performance. Behaviorally relevant STDP appears to contribute strongly to positive learning: "do this" but less to negative learning: "don't do that." In addition, we observe that the effect of structural enhancements tends to be cumulative. The overall system suggests that it is by being able to exploit combinations of effects, rather than any one effect or property in isolation, that spiking networks can achieve compelling, task-relevant behavior.

Purpose: Heavy metals and other elements may act as breast carcinogens due to estrogenic activity. We investigated associations between urine concentrations of a panel of elements and breast density., Methods: Mammographic density categories were abstracted from radiology reports of 725 women aged 40-65 yr in the Avon Army of Women. A panel of 27 elements was quantified in urine using high resolution magnetic sector inductively coupled plasma mass spectrometry. We applied LASSO (least absolute shrinkage and selection operator) logistic regression to the 27 elements and calculated odds ratios (OR) and 95% confidence intervals (CI) for dense vs. nondense breasts, adjusting for potential confounders., Results: Of the 27 elements, only magnesium (Mg) was selected into the optimal regression model. The odds ratio for dense breasts associated with doubling the Mg concentration was 1.24 (95% CI 1.03-1.49). Doubling the calcium-to-magnesium ratio was inversely associated with dense breasts (OR 0.83, 95% CI 0.70-0.98)., Conclusions: Our cross-sectional study found that higher levels of urinary magnesium were associated with greater breast density. Prospective studies are needed to confirm whether magnesium as evaluated in urine is prospectively associated with breast density and, more importantly, breast cancer.

Background: Postmenopausal bone fracture's have been proposed as a marker of lifetime estrogen exposure and have been associated with decreased risk of breast and endometrial cancer. It is plausible that prediagnostic fractures may be related to survival of estrogen-sensitive cancers., Methods: We evaluated a cohort of breast (n = 6411), endometrial (n = 1127), and ovarian (n = 658) cancer cases diagnosed between 1992 and 2010 while participating in the Women's Health Initiative. Postmenopausal fracture history was assessed from baseline reports of fractures after age 55 years and incident fractures that occurred at least one year prior to cancer diagnosis during study follow-up. Using Cox regression, we compared women with and without a history of fractures with respect to overall and cancer-specific survival. Estimates were adjusted for participant factors, including hormone therapy use; hormone receptor status was not included in our analysis., Results: Among women with breast cancer, a history of prediagnostic fractures at any site was associated with poorer overall survival (hazard ratio [HR] = 1.22, 95% confidence interval [CI] = 1.05 to 1.43). A history of hip, forearm, or spine fractures, or hip fracture alone, was associated with increased risk of mortality (HR = 1.26, 95% CI = 1.01 to 1.58, and HR = 2.05, 95% CI = 1.27 to 3.32, respectively). Fracture history was associated neither with cancer-specific survival among breast cancer survivors, nor with overall or disease-specific mortality among endometrial and ovarian cancer survivors., Conclusions: Postmenopausal breast cancer patients with a history of fractures, especially of the hip, are more likely to die of any cause than breast cancer survivors without a fracture history. Identifying and intervening in fracture risk factors should be standard of care for all women diagnosed with breast cancer.

Purpose: We aimed to determine whether the association between late-stage cancer and American Indian/Alaska Native (AI/AN) race differed by enrollment in the Indian Health Service Care System (IHSCS)., Methods: We used Surveillance, Epidemiology, and End Results (SEER) data linked to Medicare files to compare the odds of late-stage breast, colorectal, lung, or prostate cancer between non-Hispanic Whites (NHWs) (n=285,993) and AI/ANs with (n=581) and without (n=543) IHSCS enrollment., Results: For AI/ANs without IHSCS enrollment, the odds of late-stage disease were higher in AI/ANs compared with NHWs for breast (OR=3.17, 95%CI: 1.82-5.53) and for prostate (OR=2.59, 95%CI:1.55-4.32) cancer, but not for colorectal or lung cancers. Among AI/ANs with IHSCS enrollment, there was not a significant association between late-stage disease and AI/AN race for any of the four cancers evaluated., Conclusion: Our results suggest that enrollment in the IHSCS reduced the disparity between AI/ANs and NHWs with respect to late-stage cancer diagnoses.

Background: Body weight is associated with colorectal cancer (CRC) risk and survival, but to the authors' knowledge, the impact of long-term postdiagnostic weight change is unclear. Herein, the authors investigated whether weight change over the 5 years after a diagnosis of CRC is associated with survival., Methods: CRC cases diagnosed from 1997 to 2008 were identified through 4 population-based cancer registry sites. Participants enrolled within 2 years of diagnosis and reported their height and weight 2 years prior. Follow-up questionnaires were administered approximately 5 years after diagnosis. Associations between change in weight (in kg) or body mass index (BMI) with overall and CRC-specific survival were estimated using Cox regression analysis adjusted for age, sex, American Joint Committee on Cancer stage of disease, baseline BMI, nonsteroidal anti-inflammatory drug use, smoking, time between diagnosis and enrollment, and study site., Results: At the 5-year postdiagnostic survey, 2049 participants reported higher (53%; median plus 5 kg), unchanged (12%), or lower (35%; median -4 kg) weight. Over a median of 5.1 years of subsequent follow-up (range, 0.3-9.9 years), 344 participants died (91 of CRC). Long-term weight loss (per 5 kg) was found to be associated with poorer overall survival (hazard ratio, 1.13; 95% confidence interval, 1.07-1.21) and CRC-specific survival (hazard ratio, 1.25; 95% confidence interval, 1.13-1.39). Significantly lower survival was similarly observed for relative weight loss (>5% vs ≤5% change), BMI reduction (per 1 unit), or BMI category change (overweight to normal vs remaining overweight)., Conclusions: Weight loss 5 years after a diagnosis of CRC was found to be significantly associated with decreased long-term survival, suggesting the importance of avoiding weight loss in survivors of CRC. Future research should attempt to further evaluate this association, accounting for whether this weight change was intentional or represents a marker of declining health. Cancer 2017;123:4701-4708. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Background: Plasma microRNAs (miRNAs) are promising non-invasive biomarkers for colorectal cancer (CRC) prognosis. However, the published studies to date have yielded conflicting and inconsistent results for specific plasma miRNAs., Methods: We have conducted a study using robust assays to assess a panel of nine miRNAs for CRC prognosis and early detection of recurrence. Plasma samples from 144 patients in a prospective CRC cohort study were collected at diagnosis, 6, 12, and 24 months after diagnosis. miRNAs were assayed by Taqman qRT-PCR to generate miRNA normalised copy numbers., Results: Preoperative high plasma miRNA levels were associated with increased recurrence risk for miR-200b (HR [95% CI]=2.04 [1.00, 4.16], P=0.05), miR-203 (HR=4.2 [1.48, 11.93], P=0.007), miR-29a (HR=2.61 [1.34,5.07], P=0.005), and miR-31 (HR=4.03 [1.76, 9.24], P=0.001). Both plasma miR-31 (AUC: 0.717) and miR-29a (AUC: 0.703) could discriminate recurrence from these patients without recurrence. In addition, high levels of miR-31 during surveillance was associated with a three-fold increased risk of recurrence across all time points. Dynamic postoperative plasma miR-141 and 16 levels correlated with recurrence in the surveillance samples., Conclusions: Pre-operative plasma miR-29a, 200b, 203, and 31 are potential CRC prognosis biomarkers. In addition, dynamic postoperative miR-31, 141 and 16 levels are potential biomarkers for the early detection of recurrence during CRC surveillance.

Hospitalization is a major source of morbidity among patients with ESRD undergoing maintenance hemodialysis and is a significant contributor to health care costs. To identify subgroups at the highest risk of hospitalization, we analyzed by sex, age, and race, adjusting for demographic and clinical characteristics, the hospitalization rates, and 30-day readmissions for 333,756 hospitalizations among 111,653 patients undergoing maintenance hemodialysis in facilities operated by a large dialysis organization in the United States (2007-2011). The overall hospitalization rate was 1.85 hospitalizations per person-year and was much higher among women than among men (2.08 versus 1.68 hospitalizations per year for women versus men, P <0.001). Age group-specific hospitalization rates were consistently higher for women than for men of the same race, and the differences were greatest in younger age groups (for example, women aged 18-34 years and ≥75 years had 54% [95% confidence interval, 42% to 67%] and 14% [95% confidence interval, 11% to 18%] higher hospitalization rates, respectively, than did men of respective ages). Women also had substantially higher risk for 30-day readmission, with the largest differences at younger ages. Women had a significantly lower serum albumin level than men, and stratification by serum albumin level attenuated sex differences in the age group-specific hospitalization and 30-day readmission rates. These findings suggest that women undergoing maintenance hemodialysis have substantially higher risks for hospitalization and 30-day readmission than men. In this cohort, the sex differences were greatest in the younger age groups and were attenuated by accounting for differences in health status reflected by serum albumin level., (Copyright © 2017 by the American Society of Nephrology.)

Purpose Regular use of aspirin is associated with improved survival for patients with colorectal cancer (CRC). However, the timing of and the subtype of CRC that would benefit the most from using aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) in relation to survival is unclear. Patients and Methods In all, 2,419 patients age 18 to 74 years with incident invasive CRC who were diagnosed from 1997 to 2008 were identified from population-based cancer registries in the United States, Canada, and Australia. Detailed epidemiologic questionnaires were administered at study enrollment and at 5-year follow-up. Survival outcomes were completed through linkage to national death registries. BRAF- and KRAS-mutation status, microsatellite instability, and CpG island methylator phenotype were also evaluated. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for overall survival (OS) and CRC-specific survival. Results After a median of 10.8 years of follow-up since diagnosis, 381 deaths (100 as a result of CRC) were observed. Compared with nonusers, postdiagnostic aspirin-only users had more favorable OS (HR, 0.75; 95% CI, 0.59 to 0.95) and CRC-specific survival (HR, 0.44; 95% CI, 0.25 to 0.71), especially among those who initiated aspirin use (OS: HR, 0.64; 95% CI, 0.47 to 0.86; CRC-specific survival: HR, 0.40; 95% CI, 0.20 to 0.80). The association between any NSAID use after diagnosis and OS differed significantly by KRAS-mutation status ( P interaction = .01). Use of any NSAID after diagnosis was associated with improved OS only among participants with KRAS wild-type tumors (HR, 0.60; 95% CI, 0.46 to 0.80) but not among those with KRAS-mutant tumors (HR, 1.24; 95% CI, 0.78 to 1.96). Conclusion Among long-term CRC survivors, regular use of NSAIDs after CRC diagnosis was significantly associated with improved survival in individuals with KRAS wild-type tumors.

To assess whether timing of initial post-diagnosis cancer care differs between American Indian and Alaska Native (AI/AN) and non-Hispanic White (NHW) patients, we accessed SEER-Medicare data for breast, colorectal, lung, and prostate cancers (2001-2007). Medicare claims data were examined for initiation of cancer-directed treatment. Overall, AI/ANs experienced longer median times to starting treatment than NHWs (45 and 39 days, p &lt; .001) and lower rates of treatment initiation (HR[95%CI]: 0.86[0.79-0.93]). Differences were largest for prostate (HR: 0.80[0.71-0.89]) and smallest for breast cancer (HR: 0.96[0.83-1.11]). American Indians / Alaska Natives also had elevated odds of greater than 10 weeks between diagnosis and treatment compared with NHWs (OR[95% CI]: 1.37[1.16-1.63]), especially for prostate cancer (OR: 1.41[1.14-1.76]). Adjustment for comorbidity and socio-demographic factors attenuated associations except for prostate cancer. In this insured population, we observed evidence that AI/ANs start cancer therapy later than NHWs. The modest magnitude of delays suggests that they are unlikely to be a determinant of survival disparities.

Extended-hours hemodialysis offers substantially longer treatment time compared to conventional hemodialysis schedules and is associated with improved fluid and electrolyte control and favorable cardiac remodeling. However, whether extended-hours hemodialysis improves survival remains unclear. Therefore, we determined the association between extended-hours compared to conventional hemodialysis and the risk of all-cause mortality in a nationally representative cohort of patients initiating maintenance dialysis in the United States from 2007 to 2011. Survival analyses using causal inference modeling with marginal structural models were performed to compare mortality risk among 1206 individuals undergoing thrice weekly extended-hours hemodialysis or 111,707 patients receiving conventional hemodialysis treatments. The average treatment time per session for extended-hours hemodialysis was 399 minutes compared to 211 minutes for conventional therapy. The crude mortality rate with extended-hours hemodialysis was 6.4 deaths per 100 patient-years compared with 14.7 deaths per 100 patient-years for conventional hemodialysis. In the primary analysis, patients treated with extended-hours hemodialysis had a 33% lower adjusted risk of death compared to those who were treated with a conventional regimen (95% confidence interval: 7% to 51%). Additional analyses accounting for analytical assumptions regarding exposure and outcome, facility-level confounders, and prior modality history were similar. Thus, in this large nationally representative cohort, treatment with extended-hours hemodialysis was associated with a lower risk for mortality compared to treatment with conventional in-center therapy. Adequately powered randomized clinical trials comparing extended-hours to conventional hemodialysis are required to confirm these findings., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Exposure to As, Cd, Pb, and U among older Hispanic adults residing in underserved communities in southern New Mexico was investigated. Personal information was obtained by standardized interview from 188 adults aged 40-85 years. Urinary metal concentrations were measured and compared to results from the National Health and Nutritional Examination Survey (NHANES). Urinary As and U in study participants significantly (p < .05) exceeded NHANES reference values. Elevated urinary As concentration was significantly associated with older age, Latin American birthplace, clinic site, private-well drinking water, higher self-rated health, and diabetes. Higher urinary Cd was significantly associated with older age, clinic site, female sex, agricultural work, and current cigarette smoking. No personal characteristics were significantly associated with urinary Pb or U. Our results suggest elevated levels of As and U in this population.

Background: Prior studies have shown the association of low serum magnesium levels with adverse health outcomes in patients undergoing hemodialysis. There is a paucity of such studies in patients undergoing peritoneal dialysis (PD)., Study Design: Cohort study., Setting & Participants: 10,692 patients treated with PD from January 1, 2007, through December 31, 2011, in facilities operated by a single large dialysis organization in the United States., Predictor: Baseline serum magnesium levels, examined as 5 categories (<1.8, 1.8-<2.0, 2.0-<2.2 [reference], 2.2-<2.4, and ≥2.4mg/dL)., Outcomes: Time to first hospitalization and time to death using competing-risks regression models., Results: The distribution of baseline serum magnesium levels in the cohort was <1.8mg/dL, 1,928 (18%); 1.8 to <2.0mg/dL, 2,204 (21%); 2.0 to <2.2mg/dL, 2,765 (26%); 2.2 to <2.4mg/dL, 1,765 (16%); and ≥2.4mg/dL, 2,030 (19%). Of 10,692 patients, 6,465 (60%) were hospitalized at least once and 1,392 (13%) died during follow-up (median, 13; IQR, 7-23 months). Baseline serum magnesium level < 1.8mg/dL was associated with higher risk for hospitalization and all-cause mortality after adjustment for demographic and clinical characteristics (adjusted HRs of 1.23 [95% CI, 1.14-1.33] and 1.21 [95% CI, 1.03-1.42], respectively). The higher risk for hospitalization persisted upon adjustment for laboratory variables, whereas that for all-cause mortality was attenuated to a nonsignificant level. The greatest risk for hospitalization was in patients with low serum albumin levels (<3.5g/dL; P for interaction < 0.001)., Limitations: Possibility of residual confounding by unmeasured variables cannot be excluded., Conclusions: Lower serum magnesium levels may be associated with higher risk for hospitalization in incident PD patients, particularly those with hypoalbuminemia. Additional studies are needed to confirm these findings and investigate whether correction of hypomagnesemia reduces these risks., (Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: Nationally, a greater proportion of American Indians and Alaska Natives (AI/ANs) are diagnosed with advanced-stage cancers compared with non-Hispanic whites. The reasons for observed differences in stage at diagnosis between AI/ANs and non-Hispanic whites remain unclear., Methods: Medicaid, Indian Health Service Care Systems, and state cancer registry data for California, Oregon, and Washington (2001-2008, analyzed in 2014-2015) were linked to identify AI/ANs and non-Hispanic whites diagnosed with invasive breast, cervical, colorectal, lung, or prostate cancer. Logistic regression was used to estimate ORs and 95% CIs for distant disease versus local or regional disease, in AI/ANs compared with non-Hispanic white case patients., Results: A similar proportion of AI/AN (31.2%) and non-Hispanic white (35.5%) patients were diagnosed with distant-stage cancer in this population (AOR=1.03, 95% CI=0.88, 1.20). No significant differences in stage at diagnosis were found for any individual cancer site. Among AI/ANs, Indian Health Service Care Systems eligibility was not associated with stage at diagnosis., Conclusions: In contrast to the general population of the U.S., among Medicaid enrollees, AI/AN race is not associated with later stage at diagnosis. Cancer survival disparities associated with AI/AN race that have been observed in the broader population may be driven by factors associated with income and health insurance that are also associated with race, as income and insurance status are more homogenous within the Medicaid population than within the broader population., (Copyright © 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Background and Aim: Because most colorectal cancer patients survive beyond five years, understanding quality of life among these long-term survivors is essential to providing comprehensive survivor care. We sought to identify personal characteristics associated with reported quality of life in colorectal cancer survivors, and sub-groups of survivors potentially vulnerable to very low quality of life., Methods: We assessed quality of life using the Veterans RAND 12-item Health Survey within a population-based sample of 1,021 colorectal cancer survivors in the Seattle Colorectal Cancer Family Registry, approximately 5 years post-diagnosis. In this case-only study, mean physical component summary scores and mental component summary scores were examined with linear regression. To identify survivors with substantially reduced ability to complete daily tasks, logistic regression was used to estimate odds ratios for "very low" summary scores, defined as a score in the lowest decile of the reference US population. All cases were followed for vital status following QoL assessment, and mortality was analyzed with Cox proportional hazards regression., Results: Lower mean physical component summary score was associated with older age, female sex, obesity, smoking, and diabetes or other co-morbidity; lower mean mental component summary score was associated with younger age and female sex. Higher odds of very low physical component summary score was associated with older age, obesity, less education, smoking, co-morbidities, and later stage at diagnosis; smoking was associated with higher odds of very low mental component summary score. A very low physical component score was associated with higher risk of mortality (hazard ratio (95% confidence interval): 3.97 (2.95-5.34))., Conclusions: Our results suggest that identifiable sub-groups of survivors are vulnerable to very low physical components of quality of life, decrements that may represent meaningful impairment in completing everyday tasks and are associated with higher risk of death.

Cadmium, a heavy metal dispersed in the environment as a result of industrial and agricultural applications, has been implicated in several human diseases including renal disease, cancers, and compromised bone health. In the general population, the predominant sources of cadmium exposure are tobacco and diet. Urinary cadmium (uCd) reflects long-term exposure and has been frequently used to assess cadmium exposure in epidemiological studies; estimated dietary intake of cadmium (dCd) has also been used in several studies. The validity of dCd in comparison with uCd is unclear. This study aimed to compare dCd, estimated from food frequency questionnaires, to uCd measured in spot urine samples from 1,002 participants of the Women's Health Initiative. Using linear regression, we found that dCd was not statistically significantly associated with uCd (β=0.006, P-value=0.14). When stratified by smoking status, dCd was not significantly associated with uCd both in never smokers (β=0.006, P-value=0.09) and in ever smokers (β=0.003, P-value=0.67). Our results suggest that because of the lack of association between estimated dCd and measured uCd, dietary estimation of cadmium exposure should be used with caution in epidemiologic studies., Competing Interests: The authors declare no conflict of interest.

Cadmium is a widespread heavy metal pollutant that may act as an exogenous estrogenic hormone. Environmental cadmium exposure has been associated with risk of breast cancer in retrospective studies. We prospectively assessed the relationship between cadmium exposure, evaluated by creatinine-normalized urinary cadmium concentration, and invasive breast cancer among 12,701 postmenopausal women aged ≥50 years in a Women's Health Initiative study of bone mineral density. After a median of 13.2 years of follow-up (1993-2010), 508 cases of invasive breast cancer and 1,050 comparison women were identified for a case-cohort analysis. Multivariable Cox regression was used to calculate hazard ratios and 95% confidence intervals. Risk of breast cancer was not associated with urinary cadmium parameterized either in quartiles (comparing highest quartile with lowest, hazard ratio = 0.80, 95% confidence interval: 0.56, 1.14; P for trend = 0.20) or as a log-transformed continuous variable (per 2-fold higher urinary cadmium concentration, hazard ratio = 0.94, 95% confidence interval: 0.86, 1.03). We did not observe an association between urinary cadmium and breast cancer risk in any subgroup examined, including never smokers and women with body mass index (weight (kg)/height (m)(2)) less than 25. Results were consistent in both estrogen receptor-positive and estrogen receptor-negative tumors. Our results do not support the hypothesis that environmental cadmium exposure is associated with risk of postmenopausal breast cancer., (© The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: To compare incidence and survival of peripheral T-cell lymphoma (PTCL) subtypes among US racial/ethnic groups., Methods: Patients with PTCL (age ≥ 15 years; 2000 to 2012) were identified in the Surveillance, Epidemiology, and End Results (SEER) registries. Race/ethnicity was categorized as non-Hispanic white, black, Asian/Pacific Islander, Hispanic white, or American Indian/Alaskan native. Age-standardized annual incidence rates and incidence rate ratios were estimated with 95% CIs, and case-case odds ratios were estimated by race/ethnicity using polytomous regression. Survival was estimated from SEER follow-up data with Cox regression., Results: Thirteen thousand one hundred seven patients with PTCL were identified. Annual PTCL incidence was highest in blacks and lowest in Native Americans. Compared with non-Hispanic whites, blacks had a higher incidence of PTCL not otherwise specified (PTCL-NOS), anaplastic large-cell lymphoma, and adult T-cell leukemia/lymphoma (ATLL) and a lower incidence of angioimmunoblastic T-cell lymphoma (AITL); Asians/Pacific Islanders had a higher incidence of AITL, extranodal nasal-type natural killer/T-cell lymphoma and NK-cell leukemia (ENKCL), and ATLL and a lower incidence of anaplastic large-cell lymphoma; Hispanics had a higher incidence of AITL and ENKCL; and Native Americans had a lower incidence of PTCL-NOS (all P < .05). The ratio of ENKCL to PCTL-NOS among Native Americans, Asians/Pacific Islanders, and Hispanic whites was approximately three- to four-fold the same ratio among non-Hispanic whites. Survival varied significantly by race/ethnicity (P < .001), with blacks in particular experiencing shorter survival for most subtypes., Conclusion: Striking variation in incidence, proportions of PTCL subtypes, and survival was observed. Aspects of these PTCL subtype patterns, such as for ENKCL and ATLL, were similar to corresponding global populations. Despite the small population size and limited number of Native American patients, PTCL subtype frequencies in this group were distinct but most similar to Hispanic whites. Survival disparities were evident, especially for blacks compared with non-Hispanic whites., Competing Interests: Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article., (© 2016 by American Society of Clinical Oncology.)

Background: Metallothionein (MT) proteins play critical roles in the physiological handling of both essential (Cu and Zn) and toxic (Cd) metals. MT expression is regulated by metal-regulatory transcription factor 1 (MTF1). Hence, genetic variation in the MT gene family and MTF1 might influence excretion of these metals., Methods: 321 women were recruited in Seattle, WA and Las Cruces, NM and provided demographic information, urine samples for measurement of metal concentrations by mass spectrometry and creatinine, and blood or saliva for extraction of DNA. Forty-one single nucleotide polymorphisms (SNPs) within the MTF1 gene region and the region of chromosome 16 encoding the MT gene family were selected for genotyping in addition to an ancestry informative marker panel. Linear regression was used to estimate the association of SNPs with urinary Cd, Cu, and Zn, adjusted for age, urinary creatinine, smoking history, study site, and ancestry., Results: Minor alleles of rs28366003 and rs10636 near the MT2A gene were associated with lower urinary Cd, Cu, and Zn. Minor alleles of rs8044719 and rs1599823, near MT1A and MT1B, were associated with lower urinary Cd and Zn, respectively. Minor alleles of rs4653329 in MTF1 were associated with lower urinary Cd., Conclusions: These results suggest that genetic variation in the MT gene region and MTF1 influences urinary Cd, Cu, and Zn excretion., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background and Objectives: Although a peritoneal equilibration test yields data on three parameters (4-hour dialysate/plasma creatinine, 4- to 0-hour dialysate glucose, and 4-hour ultrafiltration volume), all studies have focused on the prognostic value of dialysate/plasma creatinine for patients undergoing peritoneal dialysis. Because dialysate 4- to 0-hour glucose and ultrafiltration volume may be superior in predicting daily ultrafiltration, the likely mechanism for the association of peritoneal equilibration test results with outcomes, we hypothesized that they are superior to dialysate/plasma creatinine for risk prediction., Design, Setting, Participants, & Measurements: We examined unadjusted and adjusted associations of three peritoneal equilibration test parameters with all-cause mortality, technique failure, and hospitalization rate in 10,142 patients on peritoneal dialysis treated between January 1, 2007 and December 31, 2011 in 764 dialysis facilities operated by a single large dialysis organization in the United States, with a median follow-up period of 15.8 months; 87% were treated with automated peritoneal dialysis., Results: Demographic and clinical parameters explained only 8% of the variability in dialysate/plasma creatinine. There was a linear association between dialysate/plasma creatinine and mortality (adjusted hazards ratio per 0.1 unit higher, 1.07; 95% confidence interval, 1.02 to 1.13) and hospitalization rate (adjusted incidence rate ratio per 0.1 unit higher, 1.05; 95% confidence interval, 1.03 to 1.06). Dialysate/plasma creatinine and dialysate glucose were highly correlated (r=-0.84) and yielded similar risk prediction. Ultrafiltration volume was inversely related with hospitalization rate but not with all-cause mortality. None of the parameters were associated with technique failure. Adding 4- to 0-hour dialysate glucose, ultrafiltration volume, or both did not result in any improvement in risk prediction with dialysate/plasma creatinine alone., Conclusions: This analysis from a large contemporary cohort treated primarily with automated peritoneal dialysis validates dialysate/plasma creatinine as a robust predictor of outcomes in patients treated with peritoneal dialysis., (Copyright © 2015 by the American Society of Nephrology.)

The mammalian visual system has been extensively studied since Hubel and Wiesel's work on cortical feature maps in the 1960s. Feature maps representing the cortical neurons' ocular dominance, orientation and direction preferences have been well explored experimentally and computationally. The predominant view has been that direction selectivity (DS) in particular, is a feature entirely dependent upon visual experience and as such does not exist prior to eye opening (EO). However, recent experimental work has shown that there is in fact a DS bias already present at EO. In the current work we use a computational model to reproduce the main results of this experimental work and show that the DS bias present at EO could arise purely from the cortical architecture without any explicit coding for DS and prior to any self-organising process facilitated by spontaneous activity or training. We explore how this latent DS (and its corresponding cortical map) is refined by training and that the time-course of development exhibits similar features to those seen in the experimental study. In particular we show that the specific cortical connectivity or 'proto-architecture' is required for DS to mature rapidly and correctly with visual experience.

Background: Little has been reported regarding patterns of oncologic care in American Indian/Alaska Natives (AI/AN). Observed worse survival has been attributed to later-stage presentation. We aimed to evaluate racial differences in cancer-directed therapy and hospice care utilization in AI/ANs and non-Hispanic whites (NHW) with metastatic cancer., Methods: The linked Surveillance, Epidemiology, and End Results (SEER)-Medicare claims database was accessed for AI/AN and NHW metastatic-cancer cases diagnosed between 2001 and 2007. Utilization of cancer-directed therapy (surgery, radiation, and/or chemotherapy) and/or hospice services was compared between AI/ANs and NHWs. Minimally adjusted (age, sex, diagnosis year) and fully-adjusted (also Klabunde comorbidity score, sociodemographic factors) regression models were used to estimate odds (OR) and hazard ratios (HR) for receipt of care., Results: AI/ANs were younger, more likely to reside in the West, be unmarried, have lower income, and live in a nonurban setting than NHWs. Fewer AI/ANs received any cancer-directed therapy (57% vs. 61% NHWs) within 3 months of diagnosis; sociodemographic factors accounted for much of this difference [fully-adjusted HR, 0.94; 95% confidence interval (CI), 0.83-1.08]. We noted differences in hospice utilization between AI/ANs (52%) and NHWs (61%). A significant difference in hospice utilization remained after adjustment for sociodemographics (OR, 0.78; 95% CI, 0.61-0.99)., Conclusion: Observed absolute differences in care for AI/ANs and NHWs with metastatic cancer were largely accounted for by adjusting for socioeconomics, comorbidities, and demographic factors. A significant association between race and hospice utilization was noted., Impact: Efforts to improve metastatic-cancer care should focus on socioeconomic barriers and investigate the observed disparity in receipt of hospice services., (©2015 American Association for Cancer Research.)

Background: MicroRNAs (miRNAs) are regulatory RNAs, stable in circulation, and implicated in colorectal cancer (CRC) etiology and progression. Therefore they are promising as early detection biomarkers of colorectal neoplasia. However, many circulating miRNAs are highly expressed in blood cells, and therefore may not be specific to colorectal neoplasia., Methods: We selected 7 miRNA candidates with previously reported elevated expression in adenoma tissue but low expression in blood cells ("rare" miRNAs), 2 previously proposed as adenoma biomarkers, and 3 implicated in CRC. We conducted a colonoscopy-based case-control study including 48 polyp-free controls, 43 advanced adenomas, 73 non-advanced adenomas, and 8 CRC cases. miRNAs from plasma were quantified by qRT-PCR. Correlations between miRNA expression levels, adjusted for age and sex, were assessed. We used polytomous logistic regression to estimate odds ratios (ORs) and 95% confidence intervals quantifying the association between expression levels of miRNAs and case groups. We also conducted nonparametric receiver operating characteristic (ROC) analyses and estimated area under the curve (AUC)., Results: miRNAs with high expression levels were statistically significantly correlated with one another. No miRNAs were significantly associated with non-advanced or advanced adenomas. Strong (ORs >5) and significant associations with CRC were observed for 6 miRNA candidates, with corresponding AUCs significantly >0.5., Conclusions: These candidate miRNAs, assayed by qRT-PCR, are probably unsuitable as blood-based adenoma biomarkers. Strong associations between miRNAs and CRC were observed, but primarily with miRNAs highly expressed in blood cells. These results suggest that rare miRNAs will require new detection methods to serve as circulating biomarkers of adenomas.

Self-organizing artificial neural networks are a popular tool for studying visual system development, in particular the cortical feature maps present in real systems that represent properties such as ocular dominance (OD), orientation-selectivity (OR) and direction selectivity (DS). They are also potentially useful in artificial systems, for example robotics, where the ability to extract and learn features from the environment in an unsupervised way is important. In this computational study we explore a DS map that is already latent in a simple artificial network. This latent selectivity arises purely from the cortical architecture without any explicit coding for DS and prior to any self-organising process facilitated by spontaneous activity or training. We find DS maps with local patchy regions that exhibit features similar to maps derived experimentally and from previous modeling studies. We explore the consequences of changes to the afferent and lateral connectivity to establish the key features of this proto-architecture that support DS.

Background: In vitro and animal data suggest that cadmium, a heavy metal that contaminates some foods and tobacco plants, is an estrogenic endocrine disruptor. Elevated estrogen exposure is associated with breast, endometrial, and ovarian cancer risk., Objectives: We examined the association between dietary cadmium intake and risk of these cancers in the large, well-characterized Women's Health Initiative (WHI)., Methods: A total of 155,069 postmenopausal women, 50-79 years of age, who were enrolled in the WHI clinical trials or observational study, participated in this study. We estimated dietary cadmium consumption by combining baseline food frequency questionnaire responses with U.S. Food and Drug Administration data on food cadmium content. Participants reported incident invasive breast, endometrial, or ovarian cancer, and WHI centrally adjudicated all cases through August 2009. We applied Cox regression to estimate adjusted hazard ratios (HRs) and 95% CIs for each cancer, comparing quintiles of energy-adjusted dietary cadmium intake., Results: Over an average of 10.5 years, 6,658 invasive breast cancers, 1,198 endometrial cancers, and 735 ovarian cancers were reported. We observed no statistically significant associations between dietary cadmium and risk of any of these cancers after adjustment for potential confounders including total dietary energy intake. Results did not differ in any subgroup of women examined., Conclusions: We found little evidence that dietary cadmium is a risk factor for breast, endometrial, or ovarian cancers in postmenopausal women. Misclassification in dietary cadmium assessment may have attenuated observed associations.

Exposure to cadmium, a heavy metal present in cigarettes, can be assessed in both urine and blood. Few studies have compared the properties of concurrent measurements of urine cadmium (uCd) and blood cadmium (bCd) in relation to the duration and timing of a known exposure. In this study, bCd and uCd were modeled with data from the National Health and Nutrition Examination Survey (1999-2010). Adjusted geometric mean bCd and uCd were estimated from regression results. Each 1% higher geometric mean uCd was associated with 0.50% (95% confidence interval: 0.47%-0.54%; R(2)=0.30) higher bCd. In male never-smokers, bCd was 69% (59%-81%) and uCd was 200% (166%-234%) higher at age ≥70 years versus 20-29 years. Ten pack-years (py) of smoking were associated with 13.7% (10.0%-17.4%) higher bCd and 16.8% (12.6%-21.1%) higher uCd in male smokers. The first year after smoking cessation was associated with 53% (48%-58%) lower bCd and 23% (14%-33%) lower uCd in representative males aged 55 years with 20 py smoking. Smoking in the previous 5 days was associated with 55% (40%-71%) higher bCd and 7% (-3%-18%) higher uCd. Results were similar for women. uCd mainly measures long-term exposure and bCd recent exposure, but with noticeable overlap. Epidemiological studies should base the choice of uCd or bCd on the timing of cadmium exposure relevant to the disease under study.

This work investigates self-organising cortical feature maps (SOFMs) based upon the Kohonen Self-Organising Map (SOM) but implemented with spiking neural networks. In future work, the feature maps are intended as the basis for a sensorimotor controller for an autonomous humanoid robot. Traditional SOM methods require some modifications to be useful for autonomous robotic applications. Ideally the map training process should be self-regulating and not require predefined training files or the usual SOM parameter reduction schedules. It would also be desirable if the organised map had some flexibility to accommodate new information whilst preserving previous learnt patterns. Here methods are described which have been used to develop a cortical motor map training system which goes some way towards addressing these issues. The work is presented under the general term 'Adaptive Plasticity' and the main contribution is the development of a 'plasticity resource' (PR) which is modelled as a global parameter which expresses the rate of map development and is related directly to learning on the afferent (input) connections. The PR is used to control map training in place of a traditional learning rate parameter. In conjunction with the PR, random generation of inputs from a set of exemplar patterns is used rather than predefined datasets and enables maps to be trained without deciding in advance how much data is required. An added benefit of the PR is that, unlike a traditional learning rate, it can increase as well as decrease in response to the demands of the input and so allows the map to accommodate new information when the inputs are changed during training., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Aim: To investigate the survival of individuals with colorectal cancer (CRC) with inflammatory bowel disease (IBD-associated CRC) compared to that of individuals without IBD diagnosed with CRC., Methods: Epidemiologic, clinical, and follow-up data were obtained from the Colon Cancer Family Registry (Colon CFR). IBD-associated cases were identified from self-report of physician diagnosis. For a subset of participants, medical records were examined to confirm self-report of IBD. Cox proportional hazards regression was applied to estimate adjusted hazard ratios (aHR) and 95%CI of mortality, comparing IBD-associated to non-IBD-associated CRC, adjusted for age at CRC diagnosis, sex, Colon CFR phase, and number of prior endoscopies. Following imputation to complete CRC stage information, adjustment for CRC stage was examined., Results: A total of 7202 CRC cases, including 250 cases of IBD-associated CRC, were analyzed. Over a twelve year follow-up period following CRC diagnosis, 2013 and 74 deaths occurred among non-IBD associated CRC and IBD-associated CRC patients, respectively. The difference in survival between IBD-associated and non-IBD CRC cases was not statistically significant (aHR = 1.08; 95%CI: 0.85-1.36). However, the assumption of proportional hazards necessary for valid inference from Cox regression was not met over the entire follow-up period, and we therefore limited analyses to within five years after CRC diagnosis when the assumption of proportional hazards was met. Over this period, there was evidence of worse prognosis for IBD-associated CRC (aHR = 1.36; 95%CI: 1.05-1.76). Results were similar when adjusted for CRC stage, or restricted to IBD confirmed in medical records., Conclusion: These results support the hypothesis that IBD-associated CRC has a worse prognosis than non-IBD-associated CRC.

Using a case-control design, we evaluated differences in risk factors for colorectal polyps according to histological type, anatomical site, and severity. Participants were enrollees in the Group Health Cooperative aged 20-79 years who underwent colonoscopy in Seattle, Washington, between 1998 and 2007 and comprised 628 adenoma cases, 594 serrated polyp cases, 247 cases with both types of polyps, and 1,037 polyp-free controls. Participants completed a structured interview, and polyps were evaluated via standardized pathology review. We used multivariable polytomous logistic regression to compare case groups with controls and with the other case groups. Factors for which the strength of the association varied significantly between adenomas and serrated polyps were sex (P < 0.001), use of estrogen-only postmenopausal hormone therapy (P = 0.01), and smoking status (P < 0.001). For lesion severity, prior endoscopy (P < 0.001) and age (P = 0.05) had significantly stronger associations with advanced adenomas than with nonadvanced adenomas; and higher education was positively correlated with sessile serrated polyps but not with other serrated polyps (P = 0.02). Statistically significant, site-specific associations were observed for current cigarette smoking (P = 0.05 among adenomas and P < 0.001 among serrated polyps), postmenopausal estrogen-only therapy (P = 0.01 among adenomas), and obesity (P = 0.01 among serrated polyps). These findings further illustrate the epidemiologic heterogeneity of colorectal neoplasia and may help elucidate carcinogenic mechanisms for distinct pathways.