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Barrett's esophagus and esophageal adenocarcinoma diagnoses have increased markedly in recent decades. Recent research with patients diagnosed with Barrett's esophagus (the only known precursor for esophageal adenocarcinoma) and esophageal adenocarcinoma has identified several modifiable and nonmodifiable potential risk factors. Consistent risk factors for both disorders include increasing age, male sex, white non-Hispanic race/ethnicity, gastroesophageal reflux disease, lack of infection with Helicobacter pylori, smoking, abdominal obesity, and a Western diet. The authors present detailed discussions of these risk factors along with possible explanations for some apparent discrepancies and ideas for future study., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Development of unwanted immune responses against therapeutic proteins is a major clinical complication. Recently, we have shown that exposure of Factor VIII in the presence of phosphatidylserine (PS) induces antigen-specific hyporesponsiveness to Factor VIII rechallenge, suggesting that PS is not immune suppressive, but rather immune regulatory in that PS converts an immunogen to a tolerogen. Since PS is exposed in the outer leaflet during apoptosis, we hypothesize that PS imparts tolerogenic activity to this natural process. Thus, immunization with PS containing liposomes would mimic this natural process. Here, we investigate the immune regulatory effects of PS in inducing tolerance toward recombinant human acid alpha-glucosidase (rhGAA). rhGAA was found to complex with PS liposomes through hydrophobic interactions, and incubation PS-rhGAA with dendritic cells resulted in the increased secretion of transforming growth factor-β. Immunization with PS-rhGAA or O-phospho-L-serine-rhGAA led to a reduction in anti-rhGAA antibody response which persisted despite rechallenge with free rhGAA. Importantly, the titer levels in a majority of these animals remained unchanged after rechallenge and can be considered nonresponders. These data provide evidence that PS liposomes can be used to induce tolerance toward therapeutic proteins, in general., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Background: Reports on associations between azole antifungal medications and acute liver injury are inconsistent and have not been based on liver-related laboratory tests. We evaluated incidence rates of acute liver injury associated with oral azole antifungals., Methods: We conducted a cohort study among Kaiser Permanente Northern California members who initiated an oral azole antifungal in an outpatient setting during 2004-2010. We determined development of: (1) liver aminotransferases >200 U/L, (2) severe acute liver injury (coagulopathy with hyperbilirubinemia), and (3) acute liver failure. We calculated incidence rates of endpoints. Cox regression was used to determine whether chronic liver disease was a risk factor for outcomes., Results: Among 195,334 azole initiators (178,879 fluconazole; 14,296 ketoconazole; 1653 itraconazole; 478 voriconazole; 28 posaconazole), incidence rates (events/1000 person-years [95% confidence intervals (CIs)]) of liver aminotransferases >200 U/L were similarly low with fluconazole (13.0 [11.4-14.6]), ketoconazole (19.3 [13.8-26.3]), and itraconazole (24.5 [10.6-48.2]). Rates were higher with voriconazole (181.9 [112.6-278.0]) and posaconazole (191.1 [23.1-690.4]), but comparable. Severe acute liver injury was uncommon with fluconazole (2.0 [1.4-2.7]), ketoconazole (2.9 [1.1-6.3]), and itraconazole (0.0 [0.0-11.2]), but more frequent with voriconazole (16.7 [2.0-60.2]) and posaconazole (93.4 [2.4-520.6]). One patient developed acute liver failure due to ketoconazole. Pre-existing chronic liver disease increased risks of aminotransferases >200 U/L (hazard ratio 4.68 [95% CI, 3.68-5.94]) and severe acute liver injury (hazard ratio 5.62 [95% CI, 2.56-12.35])., Conclusions: Rates of acute liver injury were similarly low for fluconazole, ketoconazole, and itraconazole. Events were more common among voriconazole and posaconazole users but were comparable. Pre-existing chronic liver disease increased risk of azole-induced liver injury., (Copyright © 2016 Elsevier Inc. All rights reserved.)

As genome sequencing technology advances, research is needed to guide decision-making about what results can or should be offered to patients in different clinical settings. We conducted three focus groups with individuals who had prior preconception genetic testing experience to explore perceived advantages and disadvantages of genome sequencing for preconception carrier screening, compared to usual care. Using a discussion guide, a trained qualitative moderator facilitated the audio-recorded focus groups. Sixteen individuals participated. Thematic analysis of transcripts started with a grounded approach and subsequently focused on participants' perceptions of the value of genetic information. Analysis uncovered two orientations toward genomic preconception carrier screening: "certain" individuals desiring all possible screening information; and "hesitant" individuals who were more cautious about its value. Participants revealed valuable information about barriers to screening: fear/anxiety about results; concerns about the method of returning results; concerns about screening necessity; and concerns about partner participation. All participants recommended offering choice to patients to enhance the value of screening and reduce barriers. Overall, two groups of likely users of genome sequencing for preconception carrier screening demonstrated different perceptions of the advantages or disadvantages of screening, suggesting tailored approaches to education, consent, and counseling may be warranted with each group.

Background & Aims: Few studies have evaluated the ability of laboratory tests to predict risk of acute liver failure (ALF) among patients with drug-induced liver injury (DILI). We aimed to develop a highly sensitive model to identify DILI patients at increased risk of ALF. We compared its performance with that of Hy's Law, which predicts severity of DILI based on levels of alanine aminotransferase or aspartate aminotransferase and total bilirubin, and validated the model in a separate sample., Methods: We conducted a retrospective cohort study of 15,353 Kaiser Permanente Northern California members diagnosed with DILI from 2004 through 2010, liver aminotransferase levels above the upper limit of normal, and no pre-existing liver disease. Thirty ALF events were confirmed by medical record review. Logistic regression was used to develop prognostic models for ALF based on laboratory results measured at DILI diagnosis. External validation was performed in a sample of 76 patients with DILI at the University of Pennsylvania., Results: Hy's Law identified patients that developed ALF with a high level of specificity (0.92) and negative predictive value (0.99), but low level of sensitivity (0.68) and positive predictive value (0.02). The model we developed, comprising data on platelet count and total bilirubin level, identified patients with ALF with a C statistic of 0.87 (95% confidence interval [CI], 0.76-0.96) and enabled calculation of a risk score (Drug-Induced Liver Toxicity ALF Score). We found a cut-off score that identified patients at high risk patients for ALF with a sensitivity value of 0.91 (95% CI, 0.71-0.99) and a specificity value of 0.76 (95% CI, 0.75-0.77). This cut-off score identified patients at high risk for ALF with a high level of sensitivity (0.89; 95% CI, 0.52-1.00) in the validation analysis., Conclusions: Hy's Law identifies patients with DILI at high risk for ALF with low sensitivity but high specificity. We developed a model (the Drug-Induced Liver Toxicity ALF Score) based on platelet count and total bilirubin level that identifies patients at increased risk for ALF with high sensitivity., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Funding agencies and researchers increasingly recognize the importance of patient stakeholder engagement in research. Despite calls for greater patient engagement, few studies have engaged a broad-based online community of patient stakeholders in the early stages of the research development process., Objective: The objective of our study was to inform a research priority-setting agenda by using a Web-based survey to gather perceptions of important and difficult aspects of diabetes care from patient members of a social networking site-based community., Methods: Invitations to participate in a Web-based survey were sent by email to members of the PatientsLikeMe online diabetes community. The survey asked both quantitative and qualitative questions addressing individuals' level of difficulty with diabetes care, provider communication, medication management, diet and exercise, and relationships with others. Qualitative responses were analyzed using content analysis., Results: Of 6219 PatientsLikeMe members with diabetes who were sent survey invitations, 1044 (16.79%) opened the invitation and 320 (5.15% of 6219; 30.65% of 1044) completed the survey within 23 days. Of the 320 respondents, 33 (10.3%) reported having Type 1 diabetes; 107 (33.4%), Type 2 diabetes and taking insulin; and 180 (56.3%), Type 2 diabetes and taking oral agents or controlling their diabetes with lifestyle modifications. Compared to 2005-2010 National Health and Nutrition Examination Survey data for individuals with diabetes, our respondents were younger (mean age 55.8 years, SD 9.9 vs 59.4 years, SE 0.5); less likely to be male (111/320, 34.6% vs 48.4%); and less likely to be a racial or ethnic minority (40/312, 12.8% vs 37.5%). Of 29 potential challenges in diabetes care, 19 were categorized as difficult by 20% or more of respondents. Both quantitative and qualitative results indicated that top patient challenges were lifestyle concerns (diet, physical activity, weight, and stress) and interpersonal concerns (trying not to be a burden to others, getting support from family/friends). In our quantitative analysis, similar concerns were expressed across patient subgroups., Conclusions: Lifestyle and interpersonal factors were particularly challenging for our online sample of adults with Type 1 or Type 2 diabetes. Our study demonstrates the innovative use of social networking sites and online communities to gather rapid, meaningful, and relevant patient perspectives that can be used to inform the development of research agendas.

Background & Aims: Reliable estimates of adenoma detection rates (ADRs) are needed to inform colonoscopy quality standards, yet little is known about the contributions of patient demographics to variation in ADRs. We evaluated the effects of adjusting for patient age, race/ethnicity, and family history of colorectal cancer on variations in ADRs and the relative rank order of physicians., Methods: In a retrospective cohort study, we collected data from Kaiser Permanente Northern California members who were ≥ 50 years old who received colonoscopies from 2006 through 2008. We evaluated ADRs (before and after adjustment for age, sex, race/ethnicity, and family history of colorectal cancer) for 102 endoscopists who performed 108,662 total colonoscopies and 20,792 screening colonoscopies. Adenomas were identified from the pathology database, and cancers were detected by using the Kaiser Permanente Northern California cancer registry., Results: About two-thirds of examiners had unadjusted ADRs for screening exams that met gastroenterology society guidelines (>25% for men and >15% for women), although rates of detection varied widely (7.7%-61.5% for male patients and 1.7%-45.6% for female patients). Adjusting for case mix reduced the variation in detection rates (from 8-fold to 3-fold for male patients and from 27-fold to 5-fold for female patients), but the median change in physician order by detection rate was just 2 ranks, and few physicians changed quartiles of detection. For example, only 3 of 102 endoscopists moved into and 3 out of the lowest quartile of ADR., Conclusions: In a community-based setting, most endoscopists met the ADR standards, although there was wide variation in ADRs, which was similar to that reported from academic and referral settings. Case-mix adjustment reduced variability but had only small effects on differences in ADRs between physicians, and only a small percentage of physicians changed quartiles of detection. Adjustments to ADRs are therefore likely only needed in settings in which physicians have very different patient demographics, such as in sex or age. Moderate differences in patient demographics between physicians are unlikely to substantially change rates of adenoma detection., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

While the incidence rates of many cancers have decreased in past decades, the incidence of oesophageal adenocarcinoma continues to increase. The only known precursor for oesophageal adenocarcinoma is Barrett's oesophagus. Studies conducted have identified white race, male sex, GORD, cigarette smoking, obesity, and the absence of Helicobacter pylori status as risk factors for oesophageal adenocarcinoma. Other potential associations include dietary factors and the absence of non-steroidal anti-inflammatory drug use. Many individual studies have been limited by sample size and several meta-analyses have pooled data from studies to address this limitation. In this review we present a synthesis of these studies and summarize current knowledge of risk factors for both oesophageal adenocarcinoma and Barrett's oesophagus., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objectives: Evaluate the utility of 2 electronic medical record (EMR)-linked, automated phone reminder interventions for improving adherence to cardiovascular disease medications., Study Design: A 1-year, parallel arm, pragmatic clinical trial in which 21,752 adults were randomized to receive either usual care (UC) or 1 of 2 interventions in the form of interactive voice recognition calls-regular (IVR) or enhanced (IVR+). The interventions used automated phone reminders to increase adherence to cardiovascular disease medications. The primary outcome was medication adherence; blood pressure and lipid levels were secondary outcomes., Methods: The study took place in 3 large health maintenance organizations. We enrolled participants who were 40 years or older, had diabetes mellitus or atherosclerotic cardiovascular disease, and were suboptimally adherent. IVR participants received automated phone calls when they were due or overdue for a refill. IVR+ participants received these phone calls, plus personalized reminder letters, live outreach calls, EMR-based feedback to their primary care providers, and additional mailed materials., Results: Both interventions significantly increased adherence to statins and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs) compared with UC (1.6 to 3.7 percentage points). Adherence to ACEIs/ARBs was also significantly higher for IVR+ relative to IVR participants. These differences persisted across subgroups. Among statin users, IVR+ participants had significantly lower low-density lipoprotein (LDL) levels at follow-up compared with UC (Δ = -1.5; 95% CI, -2.7 to -0.2 mg/dL); this effect was seen mainly in those with baseline LDL levels ≥ 100 mg/dL (Δ = -3.6; 95% CI, -5.9 to -1.3 mg/dL)., Conclusions: Technology-based tools, in conjunction with an EMR, can improve adherence to chronic disease medications and measured cardiovascular disease risk factors.

Objectives: Examine association of comprehensiveness of colorectal cancer (CRC) screening discussion by primary care physicians (PCPs) with completion of CRC screening., Study Design: Observational study in Kaiser Permanente Northwest, a group-model health maintenance organization., Methods: A total of 883 participants overdue for CRC screening received an automated telephone call (ATC) between April and June 2009 encouraging CRC screening. Between January and March 2010, participants completed a survey on PCPs' discussion of CRC screening and patient beliefs regarding screening., Primary Outcome Measure: receipt of CRC screening (assessed by electronic medical record [EMR], 9 months after ATC). Primary independent variable: comprehensiveness of CRC screening discussion by PCPs (7-item scale). Secondary independent variables: perceived benefits of screening (4-item scale assessing respondents' agreement with benefits of timely screening) and primary care utilization (EMR; 9 months after ATC). The independent association of variables with CRC screening was assessed with logistic regression., Results: Average scores for comprehensiveness of CRC discussion and perceived benefits were 0.4 (range 0-1) and 4.0 (range 1-5), respectively. A total of 28.2% (n = 249) completed screening, 84% of whom had survey assessments after their screening date. Of screeners, 95.2% completed the fecal immunochemical test. More comprehensive discussion of CRC screening was associated with increased screening (odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.03-2.21). Higher perceived benefits (OR = 1.46, 95% CI = 1.13-1.90) and 1 or more PCP visits (OR = 5.82, 95% CI = 3.87-8.74) were also associated with increased screening., Conclusions: More comprehensive discussion of CRC screening was independently associated with increased CRC screening. Primary care utilization was even more strongly associated with CRC screening, irrespective of discussion of CRC screening.

Objectives: To estimate the cost-effectiveness of an automated telephone intervention for colorectal cancer screening from a managed care perspective, using data from a pragmatic randomized controlled trial., Methods: Intervention patients received calls for fecal occult blood testing (FOBT) screening. We searched patients' electronic medical records for any screening (defined as FOBT, flexible sigmoidoscopy, double-contrast barium enema, or colonoscopy) during follow-up. Intervention costs included project implementation and management, telephone calls, patient identification, and tracking. Screening costs included FOBT (kits, mailing, and processing) and any completed screening tests during follow-up. We estimated the incremental cost-effectiveness ratio (ICER) of the cost per additional screen., Results: At 6 months, average costs for intervention and control patients were $37 (25% screened) and $34 (19% screened), respectively. The ICER at 6 months was $42 per additional screen, less than half what other studies have reported. Cost-effectiveness probability was 0.49, 0.84, and 0.99 for willingness-to-pay thresholds of $40, $100, and $200, respectively. Similar results were seen at 9 months. A greater increase in FOBT testing was seen for patients aged >70 years (45/100 intervention, 33/100 control) compared with younger patients (25/100 intervention, 21/100 control). The intervention was dominant for patients aged >70 years and was $73 per additional screen for younger patients. It increased screening rates by about 6% and costs by $3 per patient., Conclusions: At willingness to pay of $100 or more per additional screening test, an automated telephone reminder intervention can be an optimal use of resources.

Objectives: To compare completion rates of colorectal cancer screening tests within a health maintenance organization before and after widespread adoption of the fecal immunochemical test (FIT)., Study Design: Retrospective cohort study., Methods: Using electronic medical records of 113,901 patients eligible for colorectal cancer screening, we examined test completion during 2 successive time periods among those who received an automated screening outreach call. The time periods were: 1) the "guaiac fecal occult blood test (gFOBT) era," a 15-month period during which only gFOBT was routinely offered, and 2) a 9-month "FIT era," when only a new FIT was routinely offered. In addition to analyzing completion rates, we analyzed the impact of practice-level variables and patient-level variables on overall screening completion during the 2 different observation periods., Results: The change from gFOBT to FIT in an integrated care delivery system increased the likelihood of screening completion by 7.7% overall, and the likelihood of screening with a fecal test by 8.9%. The greatest gains in screening completion using FIT were among women and elderly patients. Completion of FIT was not as strongly associated with medical office visits or with having a primary care provider as was screening with gFOBT., Conclusions: Adoption of FIT within an integrated care system increased completion of colon cancer screening tests within a 9-month assessment period, compared with a previous 15-month gFOBT era. Higher completion rates of the FIT may allow for more effective dissemination of programs to increase colorectal cancer screening through centralized outreach programs.

Objectives: To evaluate the effectiveness of an intervention based on health information technology (HIT) that used speech recognition software to promote adherence to inhaled corticosteroids (ICS) among individuals with asthma who were members of a large health maintenance organization., Study Design: Pragmatic randomized clinical trial., Methods: Adults with asthma enrolled in a large managed care organization (N = 8517) were randomized to receive either usual care or an interactive voice recognition (IVR) intervention designed to prompt medication refills and improve ICS adherence. The primary outcome was ICS adherence as measured by modified medication possession ratio calculated from the electronic medical record (EMR). Secondary measures included survey- and EMR-based measures of asthma morbidity., Results: Our primary analyses found that ICS adherence increased modestly but significantly for participants in the intervention group relative to those in the usual care group ( Δ= 0.02, 95% confidence interval 0.01-0.03), with a baseline adherence of 0.42 in both groups. No difference was observed in asthma morbidity measures. In post hoc analyses of participants receiving 2 or more direct IVR contacts or detailed messages, the intervention effect was more marked. The overall effect was triple that observed in the primary analyses (0.06 vs 0.02), and significant differences were observed between groups in asthma control., Conclusions: An HIT-based adherence intervention shows potential for supporting medication adherence in patients with chronic diseases such as asthma. However, additional research is needed to determine how best to enhance the reach and effectiveness of such interventions.

Background: Our purpose was to determine whether type 2 diabetes is associated with altered bone mineral density (BMD) and whether fasting serum insulin levels are correlated with BMD., Methods: In a population-based family study of Mexican-Americans, we obtained measurements of BMD, diabetes status (by 2-h oral glucose tolerance test), obesity, and serum insulin concentrations in 600 subjects from 34 families. Analyses were stratified by sex and conditioned on the pedigree structure to account for residual correlations among related individuals., Results: Women with diabetes had significantly higher BMD at hip than women without diabetes (p=0.03) even after adjustment for age, body mass index (BMI), and menopause status. BMD at spine was also higher in diabetic women than in nondiabetic women, although the association was no longer statistically significant after adjustment for BMI. Diabetes was not associated with BMD in men. In nondiabetic men and women, insulin levels were significantly correlated with BMD after adjustment for age and other lifestyle covariates, but correlations were diminished and were no longer statistically significant after further adjustment for body mass index., Conclusions: These results suggest that Mexican-American women with type 2 diabetes have higher BMD compared to their nondiabetic counterparts, with the association independent of obesity at hip, although not at spine or forearm. Increased BMD was also correlated with serum insulin levels, although this association was not independent of obesity. Longitudinal studies may be required to better define the mechanisms underlying the observed association between BMD and diabetes.