Genomic changes in Kaposi Sarcoma-associated Herpesvirus and their clinical correlates.

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.

Comparative Effectiveness of Dialysis Modality on Laboratory Parameters of Mineral Metabolism.

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.

Survival of children with endemic Burkitt lymphoma in a prospective clinical care project in Uganda.

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.

Urinary Magnesium and Other Elements in Relation to Mammographic Breast Density, a Measure of Breast Cancer Risk.

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.

Sex Differences in Hospitalizations with Maintenance Hemodialysis.

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.

Long-term weight loss after colorectal cancer diagnosis is associated with lower survival: The Colon Cancer Family Registry.

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.

Dynamic plasma microRNAs are biomarkers for prognosis and early detection of recurrence in colorectal cancer.

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.

Urinary Cadmium and Risk of Invasive Breast Cancer in the Women's Health Initiative.

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.

Extended-hours hemodialysis is associated with lower mortality risk in patients with end-stage renal disease.

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.

Serum Magnesium Levels and Hospitalization and Mortality in Incident Peritoneal Dialysis Patients: A Cohort Study.

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.

Genetic variation in metallothionein and metal-regulatory transcription factor 1 in relation to urinary cadmium, copper, and zinc.

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.

COVID-19 Severity and Mortality in Veterans with Chronic Lung Disease.

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).

Differences in epidemiologic risk factors for colorectal adenomas and serrated polyps by lesion severity and anatomical site.

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.

Variation within major internal repeats of KSHV in vivo.

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.

A prospective study of clinical outcomes of HIV-associated and HIV-negative Kaposi sarcoma in Uganda.

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.

Design and methods of a randomized trial testing "Advancing care for COPD in people living with HIV by implementing evidence-based management through proactive E-consults (ACHIEVE)".

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.

Dietary cadmium and risk of invasive postmenopausal breast cancer in the VITAL cohort.

PURPOSE: The aim of the study was to estimate the association between dietary intake of cadmium, a carcinogenic heavy metal, and risk of invasive postmenopausal breast cancer. METHODS: Study subjects were 30,543 postmenopausal women in the VITamins And Lifestyle (VITAL) cohort who completed a food frequency questionnaire (FFQ) at baseline (2000-2002). Dietary cadmium consumption was estimated by combining FFQ responses with US Food and Drug Administration data on food cadmium content. Incidence of invasive breast cancer was ascertained through linkage of the cohort to the western Washington Surveillance, Epidemiology, and End Results cancer registry through 31 December 2009. Cox regression was applied to estimate adjusted hazard ratios (aHRs) and 95 % confidence intervals (CIs) for breast cancer with increasing dietary cadmium intake, adjusted for total energy intake, smoking history, consumption of vegetables, potatoes, and whole grains, multivitamin use, education, race, body mass index, physical activity, age at first birth, postmenopausal hormone use, and mammography. RESULTS: Vegetables and grains together contributed an average of 66 % of estimated dietary cadmium. During a mean of 7.5 years of follow-up, 1,026 invasive postmenopausal breast cancers were identified. Among 899 cases with complete covariate information, no evidence of an association between dietary cadmium intake and breast cancer risk was observed (aHR (95 % CI), highest to lowest quartile cadmium: 1.00 (0.72-1.41), p (trend) = 0.95). No evidence was found for interactions between dietary cadmium and breast cancer risk factors, smoking habits, or total intake of calcium, iron, or zinc from diet, supplements, and multivitamins. CONCLUSIONS: This study does not support the hypothesis that dietary cadmium intake is a risk factor for breast cancer. However, non-differential measurement error in the estimate of cadmium intake is likely the most important factor that could have obscured an association.

Cadmium exposure and cancer mortality in the Third National Health and Nutrition Examination Survey cohort.

OBJECTIVE: This study examined prospective data from the Third National Health and Nutrition Examination Survey (NHANES III) cohort to investigate the relationship between cadmium exposure and cancer mortality, and the specific cancers associated with cadmium exposure, in the general population. METHODS: Vital status and cause of death through 31 December 2006 were obtained by the National Center for Health Statistics for NHANES III participants. The cadmium concentration of spot urine samples was measured and corrected for urine creatinine (uCd). Weighted Cox proportional hazards regression with age as the time metric was applied to estimate sex-specific adjusted HRs (aHRs) of mortality associated with uCd for all cancers and the cancers responsible for the most deaths in the USA. Estimates were stratified by smoking history and adjusted for education, body mass index and race. RESULTS: uCd was associated with cancer mortality (aHR per twofold higher uCd (95% CI), men: 1.26 (1.07 to 1.48); women: 1.21 (1.04 to 1.42)). In men, mortality from lung cancer, pancreatic cancer and non-Hodgkin lymphoma was associated with uCd; an association with leukaemia mortality was suggested. In women, associations were suggested with mortality due to lung cancer, leukaemia, ovarian and uterine cancer, but evidence was weaker than in men. CONCLUSIONS: Cadmium appears to be associated with overall cancer mortality in men and women, but the specific cancers associated differ between men and women, suggesting avenues for future research. Limitations of the study include the possibility of uncontrolled confounding by cigarette smoking or other factors, and the limited number of deaths due to some cancers.

Prediagnostic non-steroidal anti-inflammatory drug use and survival after diagnosis of colorectal cancer.

OBJECTIVE: Non-steroidal anti-inflammatory drug (NSAID) use decreases both the incidence of colorectal cancer and recurrence of adenomas among patients with prior colorectal neoplasia. However, few studies have investigated the association between NSAID use and colorectal cancer-specific survival. The role of prediagnostic NSAID use was therefore examined in relation to colorectal cancer-specific survival among cases from the Seattle Colon Cancer Family Registry (Seattle Colon CFR). METHODS: This was a follow-up study that included incident cases of colorectal cancer from the Seattle Colon CFR. Cases were aged 20-74, diagnosed from 1997 to 2002, and were identified using the population-based Puget Sound SEER registry. Detailed information on history of NSAID use, including type, recency and duration, was collected through an interviewer-administered questionnaire. Follow-up for mortality was completed through linkages to the National Death Index. The main outcome measure was death due to colorectal cancer after diagnosis. Cox proportional hazards regression was used to investigate the relationship between prediagnostic NSAID use and colorectal cancer-specific mortality among cases. RESULTS: NSAID use prior to colorectal cancer diagnosis was associated with an ~20% lower rate of colorectal cancer mortality after diagnosis compared with never use (HR 0.79; 95% CI 0.65 to 0.97). This relationship appeared to be duration dependent, with longer reported use prior to diagnosis associated with lower rates of colorectal cancer mortality among cases. The most pronounced reductions in mortality were observed among cases diagnosed with proximal disease (HR 0.55; 95% CI 0.37 to 0.82), whereas no association was observed between NSAID use prior to diagnosis and colorectal cancer-specific mortality among cases diagnosed with distal or rectal disease. CONCLUSIONS: The findings suggest that regular use of NSAIDs prior to diagnosis is associated with improved colorectal cancer survival, particularly among cases diagnosed with proximal disease and in longer term NSAID users.