Proglumide Reverses Nonalcoholic Steatohepatitis by Interaction with the Farnesoid X Receptor and Altering the Microbiome.

Nonalcoholic steatohepatitis (NASH) is associated with obesity, metabolic syndrome, and dysbiosis of the gut microbiome. Cholecystokinin (CCK) is released by saturated fats and plays an important role in bile acid secretion. CCK receptors are expressed on cholangiocytes, and CCK-B receptor expression increases in the livers of mice with NASH. The farnesoid X receptor (FXR) is involved in bile acid transport and is a target for novel therapeutics for NASH. The aim of this study was to examine the role of proglumide, a CCK receptor inhibitor, in a murine model of NASH and its interaction at FXR. Mice were fed a choline deficient ethionine (CDE) diet to induce NASH. Some CDE-fed mice received proglumide-treated drinking water. Blood was collected and liver tissues were examined histologically. Proglumide's interaction at FXR was evaluated by computer modeling, a luciferase reporter assay, and tissue FXR expression. Stool microbiome was analyzed by RNA-Sequencing. CDE-fed mice developed NASH and the effect was prevented by proglumide. Computer modeling demonstrated specific binding of proglumide to FXR. Proglumide binding in the reporter assay was consistent with a partial agonist at the FXR with a mean binding affinity of 215 nM. FXR expression was significantly decreased in livers of CDE-fed mice compared to control livers, and proglumide restored FXR expression to normal levels. Proglumide therapy altered the microbiome signature by increasing beneficial and decreasing harmful bacteria. These data highlight the potential novel mechanisms by which proglumide therapy may improve NASH through interaction with the FXR and consequent alteration of the gut microbiome.

Corneal collagen cross-linking for bacterial infectious keratitis.

BACKGROUND: Infectious keratitis is an infection of the cornea that can be caused by bacteria, viruses, fungi, protozoa, or parasites. It may be associated with ocular surgery, trauma, contact lens wear, or conditions that cause deficiency or loss of corneal sensation, or suppression of the immune system, such as diabetes, chronic use of topical steroids, or immunomodulatory therapies. Photoactivated chromophore for collagen cross-linking (PACK-CXL) of the cornea is a therapy that has been successful in treating eye conditions such as keratoconus and corneal ectasia. More recently, PACK-CXL has been explored as a treatment option for infectious keratitis. OBJECTIVES: To determine the comparative effectiveness and safety of PACK-CXL with standard therapy versus standard therapy alone for the treatment of bacterial keratitis. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2019, Issue 7); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Science Information database (LILACS); ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 8 July 2019. SELECTION CRITERIA: We included randomized controlled trials (RCTs), quasi-RCTs, and controlled clinical trials (CCTs) of PACK-CXL for bacterial keratitis. We included quasi-RCTs and CCTs as we anticipated that there would not be many RCTs eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors working independently selected studies for inclusion in the review, assessed trials for risk of bias, and extracted data. The primary outcome was proportion of participants with complete healing at four to eight weeks. Secondary outcomes included visual acuity, morphology, adverse events, and treatment failure at four to eight weeks. MAIN RESULTS: We included three trials (two RCTs and one quasi-RCT) in this review for a total of 59 participants (59 eyes) with bacterial keratitis. Trials were all single-center and were conducted in Egypt, Iran, and Thailand between 2010 and 2014. It is very uncertain whether PACK-CXL with standard antibiotic therapy is more effective than standard antibiotic therapy alone for re-epithelialization and complete healing (risk ratio (RR) 1.53, 95% confidence interval (CI) 0.88 to 2.66; participants = 15). We judged the certainty of the evidence to be very low due to the small sample size and high risk of selection and performance bias. The high risk of selection bias reflects the overall review. Masking of participants was not possible for the surgical arm. No participant had a best-corrected visual acuity of 20/100 or better at eight weeks (very low certainty evidence). There is also no evidence that use of PACK-CXL with standard therapy results in fewer instances of treatment failure than standard therapy alone (RR 0.50, 95% CI 0.05 to 4.98; participants = 32). We judged the certainty of evidence to be low due to the small sample size and high risk of selection bias. There were no adverse events reported at 14 days (low certainty evidence). Data on other outcomes, such as visual acuity and morphological characteristics, could not be compared because of variable time points and specific metrics. AUTHORS' CONCLUSIONS: The current evidence on the effectiveness of PACK-CXL for bacterial keratitis is of low certainty and clinically heterogenous in regard to outcomes. There are five ongoing RCTs enrolling 1136 participants that may provide better answers in the next update of this review. Any future research should include subgroup analyses based on etiology. A core outcomes set would benefit healthcare decision-makers in comparing and understanding study data.

Using Patients' Social Network to Improve Compliance to Outpatient Screening Colonoscopy Appointments Among Blacks: A Randomized Clinical Trial.

OBJECTIVES: Patient navigation improves colorectal cancer screening among underserved populations, but limited resources preclude widespread adoption in minority-serving institutions. We evaluated whether a patient's self-selected social contact person can effectively facilitate outpatient screening colonoscopy. METHODS: From September 2014 to March 2017 in an urban tertiary center, 399 black participants scheduled for outpatient screening colonoscopy self-selected a social contact person to be a facilitator and provided the person's phone number. Of these, 201 participants (50.4%) were randomly assigned to the intervention arm for their social contact persons to be engaged by phone. The study was explained to the social contact person with details about colonoscopy screening and bowel preparation process. The social contacts were asked to assist the participants, provide support, and encourage compliance with the procedures. The social contact person was not contacted in the usual care arm, n = 198 (49.6%). We evaluated attendance to the scheduled outpatient colonoscopy and adequacy of bowel preparation. Analysis was performed by intention to treat. RESULTS: The social contact person was reached and agreed to be involved for 130 of the 201 participants (64.7%). No differences were found in the proportion of participants who underwent screening colonoscopy (77.3% vs 77.2%; relative risk = 1.01; 95% confidence interval: 0.91-1.12), but there was a modest increase in the proportion with adequate bowel preparation with social contact involvement (89.1% vs 80.9%; relative risk = 1.10; 95% confidence interval: 1.00-1.21). DISCUSSION: Engaging a patient's social network to serve in the role of a patient navigator did not improve compliance to outpatient screening colonoscopy but modestly improved the adequacy of bowel preparation.

Impact of a multicomponent screening, brief intervention, and referral to treatment (SBIRT) training curriculum on a medical residency program.

BACKGROUND: Substance-related disorders are a growing problem in the United States. The patient-provider setting can serve as a crucial environment to detect and prevent at-risk substance use. Screening, brief intervention, and referral to treatment (SBIRT) is an integrated approach to deliver early intervention and treatment services for persons who have or are at risk for substance-related disorders. SBIRT training components can include online modules, in-person instruction, practical experience, and clinical skills assessment. This paper will evaluate the impact of multiple modes of training on acquisition of SBIRT skills as observed in a clinical skills assessment. METHODS: Residents were part of an SBIRT training program, from 2009 through 2013, consisting of lecture, role-play, online modules, patient encounters, and clinical skills assessment (CSA). Differences were assessed across satisfactory and unsatisfactory CSA performance. RESULTS: Seventy percent of the residents satisfactorily completed CSA. Demographics, type of components completed, and number of components completed were similar among residents who demonstrated satisfactory clinical skills compared with those who did not. All components of the training program were accepted equally across specialties and resident matriculation cohorts. CONCLUSION: The authors conclude that the components employed in SBIRT training do not have to be numerous or of a particular mode of training in order to see observable demonstration of SBIRT skills among medical residents. Thus, residency educators who have limited time or resources may utilize as few as 1 mode of training to effectually disseminate SBIRT skills among health care providers. As SBIRT continues to evolve as a promising tool to address at-risk substance-related disorders, it is critical to train medical residents and other health professionals.

Obesity and Cardiovascular Diseases in a High-Risk Population: Evidence-Based Approach to CHD Risk Reduction.

BACKGROUND: Obesity is becoming a worldwide public health problem and it is expected to worsen as its prevalence is increasing in children and adolescents. This report examined the distribution of major cardiovascular disease (CVD) risk factors and the effect of life-style changes on coronary heart disease (CHD) risk prediction in a high risk obese African Americans. METHODS: We examined the baseline distribution of CVD risk factors in 515 obese African Americans, with mean BMI of 42.9 ± 6.8 kg/m2, and prospectively the effect of a 6-month low-salt, low-fat diet and aerobic-exercise intervention program on risk reduction. RESULTS: Prevalence of hypertension, dyslipidemia, and diabetes mellitus were 57%, 27% and 24% respectively. Metabolic syndrome was present in 36% and 39% met two features of the syndrome. The 10-year risk prediction for developing CHD ranged from 4% to 17% for women and 6% to 29% for men. After 6 months of life-style changes, many of the risk factors improved, and the CHD risk scores decreased from 6% to 4% in the women and 16% to 13% in the men. CONCLUSION: The high prevalence and increasing incidence of obesity and associated cardiovascular risk emphasizes the need to focus on obesity reduction in this high risk population.

Evaluation of the influence of alcohol dehydrogenase polymorphisms on alcohol elimination rates in African Americans.

INTRODUCTION: The relationship between alcohol dehydrogenase (ADH) polymorphisms and alcohol use disorders in populations of African descent has not been clearly established. This study examined the effect of ADH1B polymorphisms on alcohol metabolism and subjective response, following intravenous (IV) alcohol administration, and the influence of gender, recent drinking history, and family history of alcoholism (FHA), in nondependent African American drinkers. MATERIALS: The sample included eighty-seven 21- to 35-year-old, light social drinkers of African descent. Participants included 39 sib pairs, 2 sibships with 3 siblings each, and 3 individuals who were not part of a sibship. Participants received infusions via the use of the clamp method that refers to the goal of controlling breath alcohol concentration in 2 randomized sessions at 0.06 g% ethanol and 0 mg% (placebo), and a battery of subjective scales at predefined time points. Dependent measures included alcohol elimination rates (AERs), alcohol disappearance rates (ADRs), subjective measures peak scores, and area under the curve. General linear model and mixed models were performed to examine the relationship between ADH1B genotype, dependent measures, and influence of covariates. RESULTS: Participants with ADH1B1/1 genotypes showed higher number of drinks (p = 0.023) and drinks per drinking day (p = 0.009) compared with the persons with ADH1B1/3 genotype. AER (adjusted for body weight) was higher in ADH1B*1 homozygotes (p = 0.045) compared with ADH1B1/3 heterozygotes. ADR differed significantly between males and females (p = 0.002), regardless of body weight (p = 0.004) and lean body mass (p < 0.001) adjustments. Although a few subjective measures differed across genotype, all measures were higher in alcohol sessions compared with placebo sessions (p < 0.001). These observations were mediated by drinks per drinking day, gender, and FHA. CONCLUSIONS: ADH1B polymorphism had a marginal effect on alcohol pharmacokinetics following IV alcohol administration in nondependent drinkers of African descent. Session (alcohol vs. placebo) and ADH1B genotype did, however, influence subjective response to alcohol with some variation by gender, FHA, and drinks per drinking day.

Factors associated with attendance to scheduled outpatient endoscopy.

BACKGROUND: Non-attendance of 42% has been reported for outpatient colonoscopy among persons with low socioeconomic status (SES) in an open access system in the USA. OBJECTIVES: To evaluate attendance to outpatient endoscopy among populations with low SES after inperson consultations with endoscopists prior to scheduling. METHODS: Retrospectively, we reviewed the endoscopy schedule from September 2009 to August 2010 in an inner city teaching hospital in Washington, DC. We identified patients who came for their procedures. We defined non-attendance as when patients did not notify the facility up to 24 h prior to their scheduled procedures and did not show up. RESULTS: A total of 3304 patients were scheduled for outpatient endoscopy (mean age 55.2 years; 59.5% women). Only 36 (1.1%) patients were uninsured. 716 (21.7%) patients did not show up for their procedures. There were no differences in attendance by age, sex and race. Patients seen in a private endoscopist's office (OR=1.47; 95% CI 1.07 to 2.04) were more likely to attend when compared with patients seen in trainees' continuity clinic. Married patients (OR=1.40; 95% CI 1.11 to 1.78) were also more likely to attend. Conversely, Medicaid and uninsured patients were less likely to attend. Restricting our analysis to patients scheduled for only colonoscopy yielded similar results except that patients aged 50 years and older were more likely to attend. CONCLUSIONS: Our study suggests improved attendance to endoscopy when populations with lower SES undergo prior consultation with an endoscopist. There is a potential to further improve attendance to outpatient endoscopy by directly involving the social support of the patients.

Applicants' choice of an ophthalmology residency program.

OBJECTIVE: To determine the factors most important to applicants when selecting an ophthalmology residency program. DESIGN: Cross-sectional survey. PARTICIPANTS: All 595 applicants who submitted a rank list to the Ophthalmology Residency Matching Program for the 2012 match. METHODS: Participants anonymously completed a 25-item questionnaire after the submission of their rank lists. A multiple-choice format and ordinal scale were used to query applicants on demographics, career plans, and the importance of factors related to program characteristics. One question allowed a free text response to identify factors that caused the applicant to rank a program lower than other programs or not at all (i.e., "red flag"). MAIN OUTCOME MEASURES: Factors important to applicants when creating their rank lists. RESULTS: The response rate was 37% (218/595). The 3 most important factors affecting rank lists were resident-faculty relationships, clinical and surgical volume, and diversity of training. The fourth most important was the interview experience with faculty; poor interview experience was the most frequently cited "red flag." Age, gender, and marital status did not affect how applicants rated factors. Applicants planning a post-residency fellowship or an academic career placed greater importance on opportunities for resident research and a program's prestige (P<0.0001). Female and ethnic minority applicants placed greater importance on the diversity of faculty and residents by gender or ethnicity (P<0.0001). CONCLUSIONS: Applicants rated educational and interpersonal factors as more important than geographic factors when selecting an ophthalmology residency program. Future career plans and demographic factors influenced the rating of specific factors. The results of this study provide a useful resource to programs preparing for the match.

Alcohol dependence and health care utilization in African Americans.

OBJECTIVE: Ethnic and cultural differences in patterns of alcohol use disorders must be understood in order to address improvement in prevention of such disorders and accessibility to health care services. The purpose of this study was to evaluate factors that influence the utilization of medical and mental health services among alcohol-dependent and non-alcohol-dependent African Americans. METHOD: A cohort of 454 African Americans was evaluated. Alcohol-dependent participants were recruited from various inpatient treatment facilities in the Washington, DC, metropolitan area and through advertisement and word of mouth. Non-alcohol-dependent participants were recruited by advertisements. Each participant was administered the Semi-Structured Assessment for the Genetics of Alcoholism to assess alcohol dependency and the Family History Assessment module to access family history of alcoholism. Xl Test and analysis of variance were used to analyze the data. RESULTS: Alcohol dependence was more prevalent among men, those with lower income, those with less education, and they utilized mental health counseling as opposed to medical-based therapy. Increased reports of medical conditions such as migraine (p<.001), loss of consciousness (p=.001), and sexually transmitted diseases: (p<.001) were also associated with alcohol dependency. Other factors, including visits to inpatient treatment programs, were directly related to incidence of alcohol dependency regardless of gender status (p<.001). CONCLUSIONS: This study suggests an association exists among alcohol dependence, medical conditions, health care, and mental care utilization among African Americans. Future research may benefit from investigating if an association exists between alcohol use disorders and health care utilization for other ethnic groups.

Erratum: Virtual Ophthalmology Rotation for Visiting Medical Students: An Opportunity to Enhance Diversity in the Workforce.

[This corrects the article DOI: 10.1055/s-0043-1760831.].

Virtual Ophthalmology Rotation for Visiting Medical Students: An Opportunity to Enhance Diversity in the Workforce.

Introduction We created a virtual rotation to facilitate the exposure of ophthalmology to medical students and serve as a pilot program to help attract students from under-represented in medicine (URM) backgrounds. In addition to the rotation eliminating the financial burdens associated with in-person away rotations, we offered a not-for-credit (i.e., drop-in) option that included sessions outside the typical clinic hours. This option reduced scheduling conflicts as a barrier to enrollment and allowed junior medical students and postgraduates to participate and hopefully further develop an interest in ophthalmology. Methods Before the rotation, participants completed a pre-test and a survey to collect data on learners' backgrounds and interest in applying for ophthalmology residency. The rotation included live lectures, case-based discussions, chart reviews, and guided self-study. Following the rotation, participants completed a post-test and a survey to query applicants on the online rotation's utility and delivery. Results Eleven learners enrolled in the course and completed the prerotation survey and test. Approximately one-third (4/11; 36%) were URM students and two-thirds (7/11; 64%) were female. All responded they were planning to apply for ophthalmology residency. All responded they strongly agreed that the rotation increased their general knowledge in ophthalmology, and 89% (9/11) strongly agreed that it improved their ability to diagnose and manage actual patients. Nearly all (7/8; 87.5%) strongly agreed the rotation provided the opportunity to seek support for the residency application process, and all found the online platform reliable and easy to access. Exam scores improved significantly from pre- to post-tests (60 vs. 79%; p < 0.01). Conclusions The rotation attracted a substantial proportion of URM students. Learners reported that the virtual rotation effectively taught and supported their endeavors to become ophthalmologists. Virtual rotations for visiting students can reduce barriers such as travel, financial costs, and time constraints that might otherwise hinder exposure to specialty training that is not offered or is underrepresented at students' home institutions. Increasing exposure and offering mentorship through this novel platform deserves further study to enhance diversity and inclusion in medicine.

iTRAQ-based quantitative protein expression profiling and MRM verification of markers in type 2 diabetes.

The pathogenesis of Type 2 diabetes mellitus (T2DM) is complex owing to molecular heterogeneity in the afflicted population. Current diagnostic methods rely on blood glucose measurements, which are noninformative with respect to progression of the disease to other associated pathologies. Thus, predicting the risk and development of T2DM-related complications, such as cardiovascular disease, remains a major challenge. We have used a combination of quantitative methods for characterization of circulating serum biomarkers of T2DM using a cohort of nondiabetic control subjects (n = 76) and patients diagnosed with T2DM (n = 106). In this case-control study, the samples were randomly divided as training and validation data sets. In the first step, iTRAQ (isobaric tagging for relative and absolute quantification) based protein expression profiling was performed for identification of proteins displaying a significant differential expression in the two study groups. Five of these protein markers were selected for validation using multiple reaction-monitoring mass spectrometry (MRM-MS) and further confirmed with Western blot and QPCR analysis. Functional pathway analysis identified perturbations in lipid and small molecule metabolism as well as pathways that lead to disruption of glucose homeostasis and blood coagulation. These putative biomarkers may be clinically useful for subset stratification of T2DM patients as well as for the development of novel therapeutics targeting the specific pathology.

Screening, brief intervention, and referral to treatment: public health training for primary care.

OBJECTIVES: The purpose of this study was to elucidate changes in attitudes, experiences, readiness, and confidence levels of medical residents to perform screening, brief intervention, and referral to treatment (SBIRT) and factors that moderate these changes. METHODS: A cohort of 121 medical residents received an educational intervention. Self-reported experience, readiness, attitude, and confidence toward SBIRT-related skills were measured at baseline and at follow-up. Analyses were conducted to evaluate the effects of medical specialization. RESULTS: The intervention significantly increased experience (P<.001), attitude (P<.05), readiness (P<.001), and confidence (P<.001). Residents were more likely to report that their involvement influenced patients' substance use. However, experience applying SBIRT skills varied by country of birth, specialty, and baseline scores. CONCLUSIONS: This study suggested that SBIRT training was an effective educational tool that increased residents' sense of responsibility. However, application of skills might differ by specialization and other variables. Future studies are needed to explore and evaluate SBIRT knowledge obtained, within the context of cultural awareness and clinical skills.

Community-based Versus Traditional Research Among Older Minority Women With Urinary Incontinence.

OBJECTIVE: The aim of this study was to evaluate research retention of older minority women with urinary incontinence (UI) using a community-based participatory research (CBPR) versus a traditional research approach. METHODS: An ancillary prospective study was conducted within an ongoing pilot randomized clinical trial to treat UI. Participants were recruited using CBPR in collaboration with a local community versus a traditional research approach at an academic center. Inclusion criteria were women 65 years and older and symptomatic UI. The primary outcome was the randomization rate defined as the proportion of women randomized into the randomized clinical trial out of screened participants. Screening and consent rates were also evaluated. Pearson χ2, Fisher exact, and t tests were used. The effect of CBPR on research retention rates was expressed as odds ratio (OR) with 95% confidence intervals (CI). RESULTS: There were 10 and 88 women screened in the CBPR and traditional research groups, respectively. The CBPR participants were Hispanic (n = 10, 100%) and older (78.4 ± 8.3 years; P < 0.01). Most of the traditional research participants were non-Hispanic Black (n = 55, 62.5%) and younger (71.0 ± 4.9 years). The CBPR group had higher rates of screening (76.9% vs 40.6%; P = 0.01), consent (80% vs 44.3%; P = 0.045), and randomization (50.0% vs 14.8%; P < 0.01) compared with the traditional research group. Community-based participatory research increased the odds of research retention during screening (OR, 4.9; 95% CI, 1.3-18.2), consent (OR, 5.0; 95% CI, 1.0-25.0), and randomization (OR, 5.8; 95% CI, 1.5-22.7). CONCLUSION: Compared with traditional research, CBPR yielded higher research retention among older minority women with UI in a clinical study.

Summary of Year-One Effort of the RCMI Consortium to Enhance Research Capacity and Diversity with Data Science.

Despite being disproportionately impacted by health disparities, Black, Hispanic, Indigenous, and other underrepresented populations account for a significant minority of graduates in biomedical data science-related disciplines. Given their commitment to educating underrepresented students and trainees, minority serving institutions (MSIs) can play a significant role in enhancing diversity in the biomedical data science workforce. Little has been published about the reach, curricular breadth, and best practices for delivering these data science training programs. The purpose of this paper is to summarize six Research Centers in Minority Institutions (RCMIs) awarded funding from the National Institute of Minority Health Disparities (NIMHD) to develop new data science training programs. A cross-sectional survey was conducted to better understand the demographics of learners served, curricular topics covered, methods of instruction and assessment, challenges, and recommendations by program directors. Programs demonstrated overall success in reach and curricular diversity, serving a broad range of students and faculty, while also covering a broad range of topics. The main challenges highlighted were a lack of resources and infrastructure and teaching learners with varying levels of experience and knowledge. Further investments in MSIs are needed to sustain training efforts and develop pathways for diversifying the biomedical data science workforce.

Diagnostic accuracy of a rapid diagnostic test for the early detection of COVID-19.

OBJECTIVES: This study was undertaken to evaluate the diagnostic performance of the BinaxNOW COVID-19 Ag Card rapid antigen assay (Abbott; Chicago, IL, USA) in the detection of COVID-19 infection compared to the reference standard of PCR testing. METHODS: We evaluated the BinaxNOW COVID-19 Ag Card rapid antigen assay relative to a standard reference PCR test. We tested 3810 nasal swabs from symptomatic and asymptomatic adults undergoing surveillance COVID-19 testing at Howard University using one swab for each nostril. One swab was tested using the rapid antigen assay and the other using the PCR test. RESULTS: The sensitivity of the BinaxNOW COVID-19 Ag Card rapid antigen assay was 91.84% (95% confidence interval (CI): 80.40-97.73%) and the specificity was 99.95% (95% CI: 99.81-99.99%). The range of Ct values for the N gene was 10.74-34.90 (M = 26.88, SD=4.86). Fourteen (28.6%) samples had an N gene Ct value > 30. The average N gene Ct value for rapid test negative (i.e. false negative) samples was 31.92. CONCLUSIONS: The sensitivity of the test in our symptomatic and asymptomatic cohort was lower than the manufacturer's reported sensitivity in a symptomatic cohort (97.1%). Despite their relatively lower sensitivity (especially in asymptomatic individuals), rapid tests have undeniable benefits (i.e., ease of use and rapid results) that make them a helpful tool in the control of the SARS-CoV-2 pandemic. Given the diagnostic accuracy of these tests as evidenced by this study, rapid tests can be thoughtfully employed in situations where swift results are critical.

Safety and Dosing Study of a Cholecystokinin Receptor Antagonist in Non-alcoholic Steatohepatitis.

High saturated fat diets have been shown to raise blood levels of cholecystokinin (CCK) and induce nonalcoholic steatohepatitis (NASH). CCK receptors are expressed on stellate cells and are responsible for hepatic fibrosis when activated. The purpose of this study was to test the safety and dose of a CCK receptor antagonist, proglumide, in human participants with NASH. An open-label single ascending dose study was conducted in 18 participants with clinical NASH based upon steatosis by liver ultrasound, elevated hepatic transaminases, and a component of the metabolic syndrome. Three separate cohorts (N = 6 each) were treated with oral proglumide for 12 weeks in a sequential ascending fashion with 800 (Cohort 1), 1,200 (Cohort 2), and 1,600 (Cohort 3) mg/day, respectively. Blood hematology, chemistries, proglumide levels, a biomarker panel for fibrosis, and symptom surveys were determined at baseline and every 4 weeks. Abdominal ultrasounds and transient elastography utilizing FibroScan were obtained at baseline and at Week 12. Proglumide was well tolerated at all doses without any serious adverse events. There was no change in body weight from baseline to Week 12. For Cohorts 1, 2, and 3, the median percent change in alanine aminotransferase was 8.42, -5.05, and -22.23 and median percent change in fibrosis score by FibroScan was 8.13, -5.44, and -28.87 (kPa), respectively. Hepatic steatosis as measured by controlled attenuation parameter score significantly decreased with proglumide, (P < 0.05). Blood microRNA biomarkers and serum 4-hydroxyproline were consistent with decreased fibrosis at Week 12 compared with baseline. These findings suggest proglumide exhibits anti-inflammatory and anti-fibrotic properties and this compound is well tolerated in participants with NASH.

Ethnic and geographic variation in stroke mortality trends.

BACKGROUND AND PURPOSE: Magnitude, geographic, and ethnic variation in trends in stroke within the United States require updating for health services and health disparities research. METHODS: Data for stroke were analyzed from the US mortality files for 1999 to 2007. Age-adjusted death rates were computed for non-Hispanic African Americans and European Americans aged ≥45 years. RESULTS: Between 1999 and 2007, the age-adjusted death rate per 100,000 for stroke declined both in African Americans and in European Americans of both genders. Among African American females, European American females, and European American males, rates declined by at least 2% annually in every division. Among African American males, rates declined little in the East and West South Central divisions where disparities in trends by urbanization level were found. CONCLUSIONS: Between 1999 and 2007, the rate of decline in stroke mortality varied by geographic region and ethnic group.

Aerobic Exercise Training-Induced Changes on DNA Methylation in Mild Cognitively Impaired Elderly African Americans: Gene, Exercise, and Memory Study - GEMS-I.

BACKGROUND: DNA methylation at CpG sites is a vital epigenetic modification of the human genome affecting gene expression, and potentially, health outcomes. However, evidence is just budding on the effects of aerobic exercise-induced adaptation on DNA methylation in older mild cognitively impaired (MCI) elderly African American (AAs). Therefore, we examined the effects of a 6-month aerobic exercise-intervention on genome-wide DNA methylation in elderly AA MCI volunteers. DESIGN: Elderly AA volunteers confirmed MCI assigned into a 6-month program of aerobic exercise (eleven participants) underwent a 40-min supervised-training 3-times/week and controls (eight participants) performed stretch training. Participants had maximal oxygen consumption (VO2max) test and Genome-wide methylation levels at CpG sites using the Infinium HumanMethylation450 BeadChip assay at baseline and after a 6-month exercise program. We computed false discovery rates (FDR) using Sidak to account for multiplicity of tests and performed quantitative real-time polymerase chain-reaction (qRT-PCR) to confirm the effects of DNA methylations on expression levels of the top 5 genes among the aerobic participants. CpG sites identified from aerobic-exercise participants were similarly analyzed by the stretch group to quantify the effects of exercise-induced methylation changes among the group of stretch participants. RESULTS: Eleven MCI participants (aerobic: 73% females; mean age 72.3 ± 6.6 years) and eight MCI participants (stretch: 75% female; mean age 70.6 ± 6.7 years) completed the training. Aerobic exercise-training was associated with increases in VO2max and with global hypo- and hypermethylation changes. The most notable finding was CpG hypomethylation within the body of the VPS52 gene (P = 5.4 × 10-26), a Golgi-associated protein, involved in intracellular protein trafficking including amyloid precursor protein. qRT-PCR confirmed a nearly twofold increased expression of VPS52. Other top findings with FDR q-value < 10-5, include hypomethylations of SCARB1 (8.8 × 10-25), ARTN (6.1 × 10-25), NR1H2 (2.1 × 10-18) and PPP2R5D (9.8 × 10-18). CONCLUSION: We conclude that genome-wide DNA methylation patterns is associated with exercise training-induced methylation changes. Identification of methylation changes around genes previously shown to interact with amyloid biology, intracellular protein trafficking, and lipoprotein regulations provide further support to the likely protective effect of exercise in MCI. Future studies in larger samples are needed to confirm our findings.