Citations

ABSTRACT Objectives: The aim of the study was to describe changes in intestinal permeability in early childhood in diverse epidemiologic settings. Methods: In a birth cohort study, the lactulose:mannitol (L:M) test was administered to 1980 children at 4 time points in the first 24 months of life in 8 countries. Data from the Brazil site with an incidence of diarrhea similar to that seen in the United States and no growth faltering was used as an internal study reference to derive age‐ and sex‐specific z scores for mannitol and lactulose recoveries and the L:M ratio. Results: A total of 6602 tests demonstrated mannitol recovery, lactulose recovery, and the L:M ratio were associated with country, sex, and age. There was heterogeneity in the recovery of both probes between sites with mean mannitol recovery ranging for 1.34% to 5.88%, lactulose recovery of 0.19% to 0.58%, and L:M ratios 0.10 to 0.17 in boys of 3 months of age across different sites. We observed strong sex‐specific differences in both mannitol and lactulose recovery, with boys having higher recovery of both probes. Alterations in intestinal barrier function increased in most sites from 3 to 9 months of age and plateaued or diminished from 9 to 15 months of age. Conclusions: Alterations in recovery of the probes differ markedly in different epidemiologic contexts in children living in the developing world. The rate of change in the L:M‐ z ratio was most rapid and consistently disparate from the reference standard in the period between 6 and 9 months of age, suggesting that this is a critical period of physiologic impact of enteropathy in these populations.

BACKGROUND. Adrenal aldosterone excess is the most common cause of secondary hypertension and is associated with increased cardiovascular morbidity. However, adverse metabolic risk in primary aldosteronism extends beyond hypertension, with increased rates of insulin resistance, type 2 diabetes, and osteoporosis, which cannot be easily explained by aldosterone excess. METHODS. We performed mass spectrometry–based analysis of a 24-hour urine steroid metabolome in 174 newly diagnosed patients with primary aldosteronism (103 unilateral adenomas, 71 bilateral adrenal hyperplasias) in comparison to 162 healthy controls, 56 patients with endocrine inactive adrenal adenoma, 104 patients with mild subclinical, and 47 with clinically overt adrenal cortisol excess. We also analyzed the expression of cortisol-producing CYP11B1 and aldosterone-producing CYP11B2 enzymes in adenoma tissue from 57 patients with aldosterone-producing adenoma, employing immunohistochemistry with digital image analysis. RESULTS. Primary aldosteronism patients had significantly increased cortisol and total glucocorticoid metabolite excretion (all P < 0.001), only exceeded by glucocorticoid output in patients with clinically overt adrenal Cushing syndrome. Several surrogate parameters of metabolic risk correlated significantly with glucocorticoid but not mineralocorticoid output. Intratumoral CYP11B1 expression was significantly associated with the corresponding in vivo glucocorticoid excretion. Unilateral adrenalectomy resolved both mineralocorticoid and glucocorticoid excess. Postoperative evidence of adrenal insufficiency was found in 13 (29%) of 45 consecutively tested patients. CONCLUSION. Our data indicate that glucocorticoid cosecretion is frequently found in primary aldosteronism and contributes to associated metabolic risk. Mineralocorticoid receptor antagonist therapy alone may not be sufficient to counteract adverse metabolic risk in medically treated patients with primary aldosteronism. FUNDING. Medical Research Council UK, Wellcome Trust, European Commission.

227 Background: The objective of this work was to develop a reliable and valid survey measuring aspects of cancer care important to patients to be used in both inpatient and outpatient settings, and that allows comparisons of patient experiences across treatment centers and treatment modalities (medical oncology, radiation, surgery). Other objectives included testing various modes of data collection and developing a standardized sampling methodology based on ICD diagnosis and procedure codes. Methods: We conducted focus groups with patients who had received cancer treatment and with family members of cancer patients. We convened a panel of experts representing quality improvement, oncology, shared decision-making, patient safety, and patient advocacy to obtain feedback on the development of the survey. We interviewed stakeholder groups representing oncology associations to obtain feedback on focal provider, attribution and sampling. We then conducted a field test of the survey among six cancer centers around the country, conducted psychometric analyses, revised the survey, conducted a second field test among four community oncology practices in CA, re-analyzed the data, and finalized the survey. Results: Final survey content was determined using results of the formative research, psychometric analyses, and input from the CAHPS Consortium. The core survey includes 56 questions, 23 of which map to eight composites: Provider Communication, Enabling Patient Self-management, Team Available to Provide Information, Access to Care, Care Coordination, and Office Staff. Supplemental item sets include seven items assessing Shared Decision Making, four items measuring Keeping Patients Informed, and two additional Access to Care items. Mail-only, mail-telephone mixed-mode, and web-mail mixed-mode are recommended methods of data collection. The survey and all recruiting materials are available in English and Spanish. Conclusions: The CAHPS Cancer Care Survey is a rigorously developed, well-tested, reliable and valid survey of patient experiences with their cancer care. The survey and supporting materials are available free of charge on the CAHPS website (www.ahrq.gov/cahps).

ABSTRACT To our knowledge, fecal microbiota collection methods have not been evaluated in low- and middle-income countries. Therefore, we evaluated five different fecal sample collection methods for technical reproducibility, stability, and accuracy within the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh. Fifty participants from the HEALS provided fecal samples in the clinic which were aliquoted into no solution, 95% ethanol, RNAlater, postdevelopment fecal occult blood test (FOBT) cards, and fecal immunochemical test (FIT) tubes. Half of the aliquots were frozen immediately at −80°C (day 0) and the remaining samples were left at ambient temperature for 96 h and then frozen (day 4). Intraclass correlation coefficients (ICC) were calculated for the relative abundances of the top three phyla, for two alpha diversity measures, and for four beta diversity measures. The duplicate samples had relatively high ICCs for technical reproducibility at day 0 and day 4 (range, 0.79 to 0.99). The FOBT card and samples preserved in RNAlater and 95% ethanol had the highest ICCs for stability over 4 days. The FIT tube had lower stability measures overall. In comparison to the “gold standard” method using immediately frozen fecal samples with no solution, the ICCs for many of the microbial metrics were low, but the rank order appeared to be preserved as seen by the Spearman correlation. The FOBT cards, 95% ethanol, and RNAlater were effective fecal preservatives. These fecal collection methods are optimal for future cohort studies, particularly in low- and middle-income countries. IMPORTANCE The collection of fecal samples in prospective cohort studies is essential to provide the opportunity to study the effect of the human microbiota on numerous health conditions. However, these collection methods have not been adequately tested in low- and middle-income countries. We present estimates of technical reproducibility, stability at ambient temperature for 4 days, and accuracy comparing a “gold standard” for fecal samples in no solution, 95% ethanol, RNAlater, postdevelopment fecal occult blood test cards, and fecal immunochemical test tubes in a study conducted in Bangladesh. Fecal occult blood test cards and fecal samples stored in 95% ethanol or RNAlater adequately preserve fecal samples in this setting. Therefore, new studies in low- and middle-income countries should include collection of fecal samples using fecal occult blood test cards, 95% ethanol, or RNAlater for prospective cohort studies.

Abstract Introduction We sought to determine whether a systems biology approach may identify novel late‐onset Alzheimer's disease (LOAD) loci. Methods We performed gene‐wide association analyses and integrated results with human protein‐protein interaction data using network analyses. We performed functional validation on novel genes using a transgenic Caenorhabditis elegans Aβ proteotoxicity model and evaluated novel genes using brain expression data from people with LOAD and other neurodegenerative conditions. Results We identified 13 novel candidate LOAD genes outside chromosome 19. Of those, RNA interference knockdowns of the C. elegans orthologs of UBC, NDUFS3, EGR1 , and ATP5H were associated with Aβ toxicity, and NDUFS3, SLC25A11, ATP5H , and APP were differentially expressed in the temporal cortex. Discussion Network analyses identified novel LOAD candidate genes. We demonstrated a functional role for four of these in a C. elegans model and found enrichment of differentially expressed genes in the temporal cortex.

140 Background: High-risk prostate cancer (HRPC) is a challenging disease and the role of surgery is often considered in the context of a multimodal approach but patients with positive section margins (R1) disease have not always the same cancer-specific survival (CSS). The current study aims to analyze current postoperative pathological features in order to predict CSS of HRPC patients with R1, but with negative lymph nodes (pN0), treated with surgery. Methods: From a multi-institutional retrospective cohort of 5,876 HRPC patients treated by radical prostatectomy and pelvic lymph node dissection, 1541 patients with pN0 and R1 were selected. Following surgery, adjuvant EBRT and/or ADT were delivered according to institutional protocols. Patients were subdivided into four groups according to pT stage (pT≥3 and pT<3) and p-Gleason score (pGS≥8 and pGS<8). Kaplan-Meier plots with log-rank tests and a Cox proportional hazards model were applied to study CSS. All significance levels were set at 0.05. MedCalc was used for all statistical analyses. Results: Median age at surgery was 66 years (42-89). Of all patients, 399 (25.9%) had GS≥8 and 999 (64.8%) had pT≥3 at definitive histopathology. Patients were classified as COMBO groups: C1 (423; 27.4%; GS<8,pT<3), C2 (674; 43.7%; GS<8, pT≥3), C3 (83; 5.4%; GS≥8, pT<3), C4 (362; 23.5%; GS≥8, pT≥3). Adjuvant EBRT and ADT, respectively, were delivered in C1 3%/5%, C2 15%/21%, C3 21%/20%, C4 28%/40%. Kaplan-Meier plots demonstrated statistically different 10-yr CSS between groups: C1 97%, C2 93.8%, C3 85.1% and C4 77.3% (p<0.0001). COMBO groups were also compared using a Cox model and results are shown in the Table. Conclusions: COMBO groups demonstrated to be able to subdivide margin-positive, pN0 HRPC into 4 demarcated groups with significantly different CSS. This subdivision could be considered an easy-to-use tool which can help for counseling patients for adjuvant treatment strategies. [Table: see text]

114 Background: High-risk prostate cancer (HRPC) is a challenging disease and the role of surgery is often considered in the context of a multimodal approach. The indication for adjuvant therapy after surgery for HRPC patients who have specimen-confined disease (R0, pN0, <pT3b) is still difficult. The current study aims to analyze postoperative pathological features which help to predict CSS in specimen-confined HRPC and thus may aid in the decision to administer adjuvant EBRT or ADT. Methods: From a multi-institutional retrospective cohort of 5876 HRPC patients treated by radical prostatectomy and pelvic lymph node dissection, 1391 patients with specimen-confined disease were selected. Following surgery, adjuvant EBRT and/or ADT were delivered according to institutional protocols. Patients were subdivided into four groups according to pT stage (pT≥3 and pT<3) and final Gleason score (GS≥8 and GS<8). Kaplan-Meier plots with log-rank tests and a Cox proportional hazards model were applied to study CSS. All significance levels were set at 0.05. MedCalc was used for all statistical analyses. Results: Median age was 65 years (43-84). Of all patients, 346 (24.9%) had GS≥8 and 794 (57.1%) had pT≥3 at definitive histopathology. Patients were classified into COMBO groups: C1 (478; 34.4%; GS<8,pT<3), C2 (567; 40.8%; GS<8, pT≥3), C3 (119; 8.6%; GS≥8, pT<3), C4 (227; 16.3%; GS≥8, pT≥3). Adjuvant EBRT and ADT, respectively, were delivered in C1 2%/2%, C2 15%/22%, C3 3%/10%, C4 18%/25%. Kaplan Meier plots demonstrated statistically different 10-yr CSS between groups: C1 97.4%, C2 95.2%, C3 89.9% and C4 84.4% (p<0.0001). COMBO groups were also compared using a Cox model and results are shown in the Table. Conclusions: COMBO groups demonstrated to be able to subdivide specimen-confined HRPC into 4 demarcated groups with significantly different CSS. This subdivision could be considered an easy-to-use tool which can help for counseling patients for adjuvant treatment strategies. [Table: see text]