A randomized controlled trial of efficacy and safety of Fecal Microbiota Transplant for preventing recurrent Clostridioides difficile infection.

BACKGROUND: Clostridioides difficile infection (CDI) is the most common cause of healthcare-associated infections in US hospitals with 15%-30% of patients experiencing recurrence. The aim of our randomized, double-blind clinical trial was to assess the efficacy of capsule-delivered fecal microbiota transplantation (FMT) versus placebo in reducing recurrent diarrhea and CDI recurrence. The secondary aim was FMT safety assessment. METHODS: Between 2018 and 2022, Veterans across the Veterans Health Administration system with recurrent CDI who responded to antibiotic treatment were randomized in a 1:1 ratio to oral FMT or placebo capsules. Randomization was stratified by number of prior CDI recurrences (1 or ≥2). The primary endpoint was clinical recurrence by day 56, defined as >3 unformed stools daily for ≥2 days with or without laboratory confirmation of C. difficile, or death within 56 days. RESULTS: The study was stopped due to futility after meeting pre-specified criteria. Of 153 participants (76 FMT, 77 placebo) with an average age of 66.5 years, 25 participants (32.9%) in the FMT arm and 23 (29.9%) in the placebo arm experienced the primary endpoint of diarrhea and possible or definite CDI recurrence or death within 56 days of capsule administration (absolute difference 3.0%; 95% CI [-11.7%, 17.7%]). Stratification by number of recurrences revealed no statistically significant differences. There were no clinically important differences in adverse events. CONCLUSIONS: FMT therapy vs. placebo did not reduce CDI recurrence or death at 56 days. There were no meaningful differences in adverse events between treatment groups.

Risk Factors for Development of Incisional Hernia after Aortic Aneurysm Repair: Secondary Analysis of the OVER Randomized Controlled Trial.

BACKGROUND: Since the risk of mortality from rupture is elevated, elective repair of abdominal aortic aneurysms (AAAs) is often recommended. Currently, over 80% of elective repairs are carried out using an endovascular approach. While open repair has similar late survival and fewer reintervention outcomes when compared to endovascular repair, incisional hernia is a frequent complication with morbidity and cost implications. The Open versus Endovascular Repair (OVER) trial was the largest randomized trial of endovascular versus open repair of AAA in the United States. The purpose of this study was to determine risk factors associated with incisional hernia development following AAA repair via secondary analysis of the OVER data. METHODS: This was a multisite trial conducted within the Veterans Affairs health-care system. Study participants (N = 881) were enrolled from 2002 to 2008 and followed until 2011 with additional administrative data collection until 2016. Eligible patients had AAA for which elective repair was planned and randomized 1:1 to either open or endovascular repair. Incisional hernia was a prespecified end point in the OVER protocol, specifically assessed at each protocol follow-up visit. Technical details were extracted from each operative report, repair case report form(s), and adverse event form(s). Patient demographics, comorbid conditions, reported preoperative activity level, and operative details including initial approach, blood loss, and closure methods were analyzed using Bayesian hierarchical Weibull survival regression modeling. RESULTS: Incisional hernias were recorded among 46 participants (5.2%). The average time to hernia diagnosis was 3.5 years. Of the 437 participants randomized to open treatment, 427 received an open repair including crossovers from endovascular treatment assignment. Transperitoneal repair was performed in 81%, running suture in 96%, and absorbable suture in 71% of cases. Randomization to endovascular repair was associated with reduced risk of hernia (hazard ratio [HR] 0.70, 95% credible interval [CI] 0.49-0.94). Higher activity level was associated with increased hernia risk (HR 1.39, 95% CI 1.06-1.84). Approach, suture closure techniques, body mass index, diabetes, and smoking status were not associated with increased risk of hernia development. CONCLUSIONS: Incisional hernia is a frequent complication associated with open repair of abdominal aortic aneurysm and commonly required reintervention. Endovascular repair was associated with reduced risk of hernia. Patients with increased activity experienced a higher incidence of hernia. However, no other modifiable patient, operative, or technical factors were found to be associated with hernia development.

The effect of a fermented soy beverage among patients with localized prostate cancer prior to radical prostatectomy.

BACKGROUND: Fermented soy products have shown to possess inhibitory effects on prostate cancer (PCa). We evaluated the effect of a fermented soy beverage (Q-Can®), containing medium-chain triglycerides, ketones and soy isoflavones, among men with localized PCa prior to radical prostatectomy. METHODS: We conducted a placebo-controlled, double-blind randomized trial of Q-Can®. Stratified randomization (Cancer of the Prostate Risk Assessment (CAPRA) score at diagnosis) was used to assign patients to receive Q-Can® or placebo for 2-5 weeks before RP. Primary endpoint was change in serum PSA from baseline to end-of-study. We assessed changes in other clinical and pathologic endpoints. The primary ITT analysis compared PSA at end-of-study between randomization arms using repeated measures linear mixed model incorporating baseline CAPRA risk strata. RESULTS: We randomized 19 patients, 16 were eligible for analysis of the primary outcome. Mean age at enrollment was 61, 9(56.2%) were classified as low and intermediate risk, and 7(43.8%) high CAPRA risk. Among patients who received Q-Can®, mean PSA at baseline and end-of-study was 8.98(standard deviation, SD 4.07) and 8.02ng/mL(SD 3.99) compared with 8.66(SD 2.71) to 9.53ng/mL(SD 3.03), respectively, (Difference baseline - end-of-study, p = 0.36). There were no significant differences in Gleason score, clinical stage, surgical margin status, or CAPRA score between treatment arms (p > 0.05), and no significant differences between treatment arms in end-of-study or change in lipids, testosterone and FACT-P scores (p > 0.05). CONCLUSIONS: Short exposure to Q-Can® among patients with localized PCa was not associated with changes in PSA levels, PCa characteristics including grade and stage or serum testosterone. Due to early termination from inability to recruit, study power, was not achieved.

Serum Neutralizing Antibody Titers 12 Months After Coronavirus Disease 2019 Messenger RNA Vaccination: Correlation to Clinical Variables in an Adult, US Population.

BACKGROUND: We studied whether comorbid conditions affect strength and duration of immune responses after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA vaccination in a US-based, adult population. METHODS: Sera (before and after BNT162b2 vaccination) were tested serially up to 12 months after 2 doses of vaccine for SARS-CoV-2-anti-Spike neutralizing capacity by pseudotyping assay in 124 individuals; neutralizing titers were correlated to clinical variables with multivariate regression. Postbooster (third dose) effect was measured at 1 and 3 months in 72 and 88 subjects, respectively. RESULTS: After completion of primary vaccine series, neutralizing antibody half maximal inhibitory concentration (IC50) values were high at 1 month (14-fold increase from prevaccination), declined at 6 months (3.3-fold increase), and increased at 1 month postbooster (41.5-fold increase). Three months postbooster, IC50 decreased in coronavirus disease (COVID)-naïve individuals (18-fold increase) and increased in prior COVID 2019 (COVID-19+) individuals (132-fold increase). Age >65 years (ß = -0.94, P = .001) and malignancy (ß = -0.88, P = .002) reduced strength of response at 1 month. Both neutralization strength and durability at 6 months, respectively, were negatively affected by end-stage renal disease ([ß = -1.10, P = .004]; [ß = -0.66, P = .014]), diabetes mellitus ([ß = -0.57, P = .032]; [ß = -0.44, P = .028]), and systemic steroid use ([ß = -0.066, P = .032]; [ß = -0.55, P = .037]). Postbooster IC50 was robust against WA-1 and B.1.617.2. Postbooster neutralization increased with prior COVID-19 (ß = 2.9, P < .0001), and malignancy reduced neutralization response (ß = -0.68, P = .03), regardless of infection status. CONCLUSIONS: Multiple clinical factors affect the strength and duration of neutralization response after primary series vaccination, but not the postbooster dose strength. Malignancy was associated with lower booster-dose response regardless of prior COVID infection, suggesting a need for clinically guided vaccine regimens.

Scientific evidence supporting the newly developed one-health labeling tool "Med-Index": an umbrella systematic review on health benefits of mediterranean diet principles and adherence in a planeterranean perspective.

BACKGROUND: Med-Index is a one-health front-of-pack (FOP) label, based on Mediterranean diet (MedDiet) principles, developed to summarize information about the nutritional properties and related-health benefits of any food as well as its sustainable production processes, and the associated food company's social responsibility parameters in a new "Planeterranean" perspective. Thus, Med-Index can be adopted in and by any European region and authority as well as worldwide; this is achieved by consumption and cooking of locally available and sourced foods that respect MedDiet principles, both in terms of healthy nutrition and sustainable production. The huge body of scientific evidence about the health benefits of the MedDiet model and principles requires a comprehensive framework to encompass the scientific reliability and robustness of this tool. A systematic review was carried out to examine the association between human health and adherence to MedDiet patterns upon which the "Med-Index" tool was subsequently developed. METHODS: MEDLINE and PubMed databases were searched for eligible publications from 1990 to April 2023. Systematic literature reviews, with or without meta-analysis, of clinical trials and observational studies were screened by two independent investigators for eligibility, data extraction, and quality assessment. English language and the time interval 1990-2023 were applied. A registry code CRD42023464807 was generated on PROSPERO and approved for this search protocol. The corrected covered area (CCA), calculated to quantify the degree of overlap between reviews, gave a slight overlap (CCA = 4%). RESULTS: A total of 84 systematic reviews out of 6681 screened records were selected. Eligible reviews included studies with predominantly observational designs (61/84, 72.6%%), of which 26/61 referenced studies of mixed observational and RCT designs, while 23/84 (27.4%) were RCT-only systematic reviews. Seventy-nine different entries were identified for health outcomes, clustered into 10 macro-categories, each reporting a statistically significant association with exposure to the MedDiet. Adherence to MedDiet was found to strongly benefit age-related chronic diseases (21.5%), neurological disorders (19%), and obesity-related metabolic features (12.65), followed by CVDs (11.4%), cancer (10.1%), diabetes (7.5%), liver health (6.3%), inflammation (5%), mortality (5%), and renal health (1.2%). The quality of the studies was moderate to high. CONCLUSION: In the context of a "Planeterranean" framework and perspective that can be adopted in any European region and worldwide, MedDiet represents a healthy and sustainable lifestyle model, able to prevent several diseases and reduce premature mortality. In addition, the availability of a FOP, such as Med-Index, might foster more conscious food choices among consumers, paying attention both to human and planetary health.

Effect of preservation of antegrade hypogastric flow on development of claudication following aortoiliac aneurysm repair.

OBJECTIVE: The objective of this study was to compare the rate of development of buttock claudication in patients undergoing aortoiliac aneurysm repair with and without exclusion of antegrade hypogastric arterial flow. In the absence of convincing data, questions remain regarding the best management of hypogastric arterial flow to prevent the theoretical risk of buttock claudication. METHODS: The Veterans' Affairs Open Versus Endovascular Repair (OVER) Cooperative Study prospectively collected information on buttock claudication. Trial participants were specifically prompted both pre- and postoperatively to report the development of claudication symptoms at several anatomic levels. Of note, trial investigators were specifically trained to occlude the trunk hypogastric arterial, preserving the anterior and posterior divisions. Bayesian survival models were created to evaluate time to development of left, right, or bilateral buttock claudication according to the presence/absence of antegrade hypogastric perfusion. RESULTS: A total of 881 patients from the OVER trial with information regarding status of hypogastric flow were included in the analysis. Of these, 788 patients maintained bilateral antegrade hypogastric arterial perfusion, 63 had right hypogastric coverage/occlusion, and 27 had left hypogastric coverage/occlusion, whereas 3 patients had bilateral hypogastric coverage/occlusion. Just under 5% of all patients (n = 41) developed buttock claudication. After adjustment for smoking, chronic obstructive pulmonary disease, medications, study arm, preoperative activity level, body mass index, age, and diabetes, intervention-related changes to hypogastric perfusion had no effect on time to development of buttock claudication. A Maximum A Posteriori Kullback- Leibler misfit χ2 was 14.45 with 24 degrees of freedom, resulting in a goodness of fit P-value of P = .94, indicative of a good fit. CONCLUSIONS: OVER is the largest aneurysm treatment study to prospectively collect data related to the development of claudication as well as hypogastric preservation status. Despite this, we were unable to find evidence to support the assertion that preservation of antegrade hypogastric flow decreases the rate of development of buttock claudication symptoms. The low rate of development of buttock claudication overall and in the subgroups is striking.

Analysis of Repair Type and Hypogastric Artery Antegrade Perfusion and Erectile Function following Repair of Abdominal Aortic Aneurysms.

BACKGROUND: Published reports suggest that exclusion of antegrade hypogastric artery flow may have deleterious effects on erectile function after abdominal aortic aneurysm (AAA) repair. Off-label and open surgical hybrid procedures and, more recently, purpose-built branched devices have been developed to maintain antegrade pelvic perfusion in patients undergoing endovascular repair. Maintaining antegrade perfusion may reduce a spectrum of risks, including buttock claudication, colorectal ischemia, and spinal cord ischemia when patients undergo subsequent thoracic aortic procedures, as well as erectile dysfunction (ED). This project specifically focuses on erectile function, and analyzes baseline associations and relationships of hypogastric artery exclusion on changes in erectile function following aneurysm repair. METHODS: Male patients in the Veterans Affairs Open Versus Endovascular Repair (CSP#498; OVER) Trial had erectile function assessed preoperatively and postoperatively by administration of the International Index of Erectile Function-5 questionnaire. Bayesian mixed-effects regression models were created with the outcome variable (erectile function) treated as a latent variable. Primary effects of differences in erectile function between groups with and without preservation of bilateral antegrade hypogastric flow were compared. RESULTS: 876 men (442 randomized to endovascular repair) were enrolled in the trial and included in the analysis comparing treatment assignment. There is significant ED in elderly men with aortic aneurysm at baseline. Over 5 years of follow-up, there is modest decrease in erectile function and the endovascular group has improved function compared to open repair (0.082; 95% credible interval (CI) 0.008 and 0.155). A fifth of patients did not have bilateral preservation of antegrade hypogastric artery perfusion, with no difference in erectile function by univariate analysis. A more detailed regression analysis was applied--and after adjustment for baseline score, age, beta blocker use, diabetes, activity level, ejection fraction, preoperative ankle-brachial indices and time--preservation of both antegrade hypogastric arteries' perfusion showed transient improvement in survey scores compared to occlusion of at least 1 hypogastric artery at 6 months and 12 months after treatment, although this was not sustained at 60 months (score change: 0.046; 95% CI: -0.123, 0.215). Retesting this model in the cohort with complete data as a sensitivity analysis did not meaningfully change the conclusions. CONCLUSIONS: In this large prospective aneurysm treatment trial with systematic measurement of erectile function with a validated instrument, endovascular repair is associated with improved erectile function. Preservation of antegrade hypogastric flow with any repair is associated with early improved erectile function; however, it is not a sustained benefit. There is limited benefit of maintaining bilateral hypogastric artery perfusion for this specific indication in unselected men undergoing AAA repair.

Open versus Endovascular Repair of Abdominal Aortic Aneurysm.

BACKGROUND: Elective endovascular repair of an abdominal aortic aneurysm results in lower perioperative mortality than traditional open repair, but after 4 years this survival advantage is not seen; in addition, results of two European trials have shown worse long-term outcomes with endovascular repair than with open repair. Long-term results of a study we conducted more than a decade ago to compare endovascular repair with open repair are unknown. METHODS: We randomly assigned patients with asymptomatic abdominal aortic aneurysms to either endovascular repair or open repair of the aneurysm. All the patients were candidates for either procedure. Patients were followed for up to 14 years. RESULTS: A total of 881 patients underwent randomization: 444 were assigned to endovascular repair and 437 to open repair. The primary outcome was all-cause mortality. A total of 302 patients (68.0%) in the endovascular-repair group and 306 (70.0%) in the open-repair group died (hazard ratio, 0.96; 95% confidence interval [CI], 0.82 to 1.13). During the first 4 years of follow-up, overall survival appeared to be higher with endovascular repair than with open repair; from year 4 through year 8, overall survival was higher in the open-repair group; and after 8 years, overall survival was once again higher in the endovascular-repair group (hazard ratio for death, 0.94; 95% CI, 0.74 to 1.18). None of these trends were significant. There were 12 aneurysm-related deaths (2.7%) in the endovascular-repair group and 16 (3.7%) in the open-repair group (between-group difference, -1.0 percentage point; 95% CI, -3.3 to 1.4); most deaths occurred during the perioperative period. Aneurysm rupture occurred in 7 patients (1.6%) in the endovascular-repair group, and rupture of a thoracic aneurysm occurred in 1 patient (0.2%) in the open-repair group (between-group difference, 1.3 percentage points; 95% CI, 0.1 to 2.6). Death from chronic obstructive lung disease was just over 50% more common with open repair (5.4% of patients in the endovascular-repair group and 8.2% in the open-repair group died from chronic obstructive lung disease; between-group difference, -2.8 percentage points; 95% CI, -6.2 to 0.5). More patients in the endovascular-repair group underwent secondary procedures. CONCLUSIONS: Long-term overall survival was similar among patients who underwent endovascular repair and those who underwent open repair. A difference between groups was noted in the number of patients who underwent secondary therapeutic procedures. Our results were not consistent with the findings of worse performance of endovascular repair with respect to long-term survival that was seen in the two European trials. (Funded by the Department of Veteran Affairs Office of Research and Development; OVER ClinicalTrials.gov number, NCT00094575.).

Cost-Effectiveness of Individual Placement and Support Compared to Transitional Work Program for Veterans with Post-traumatic Stress Disorder.

Post-traumatic stress disorder (PTSD) leads to significant disability, unemployment, and substantial healthcare costs. The cost-effectiveness of vocational rehabilitation (VR) interventions is important to consider when determining which services to offer. This study assesses the cost-effectiveness and return on investment of Individual Placement and Support (IPS) compared to transitional work (TW) programs. Employment outcomes from a multisite randomized trial comparing IPS to TW in military veterans with PTSD (n = 541) were linked to Veterans Health Administration (VHA) archival medical record databases to examine the comparative cost-effectiveness and return on investment. Effectiveness was defined as hours worked and income earned in competitive jobs. Costs for VR, mental health, and medical care and income earned from competitive sources were annualized and adjusted to 2019 US dollars. The annualized mean cost per person of outpatient (including vocational services) were $3970 higher for IPS compared to TW ($23,245 vs. $19,276, respectively; P = 0.004). When TW income was included in costs, mean grand total costs per person per year were similar between groups ($29,828 IPS vs. $26,772 TW; P = 0.17). The incremental cost-effectiveness analysis showed that while IPS is more costly, it is also more effective. The return on investment (excluding TW income) was 32.9% for IPS ($9762 mean income/$29,691 mean total costs) and 29.6% for TW ($7326 mean income/$24,781 mean total costs). IPS significantly improves employment outcomes for individuals with PTSD with negligible increase in healthcare costs and yields very good return on investment compared to non-IPS VR services.

Microbiota or placebo after antimicrobial therapy for recurrent Clostridioides difficile at home: A clinical trial with novel home-based enrollment.

INTRODUCTION: Clostridiodes difficile infection is the leading cause of infectious diarrhea in the United States, with substantial morbidity and mortality. Recurrent infection is especially challenging, with each recurrence increasing the likelihood of a successive recurrence, leading to cycles of prolonged symptoms, frequent antimicrobial use, and decreased quality of life. Fecal microbiota transplantation to prevent recurrent infection is a promising intervention with a large effect size in observational studies, but with conflicting results from randomized controlled trials. We are conducting a Veterans Affairs-wide randomized controlled trial utilizing centralized case identification, with enrollment and fecal microbiota transplant administration occurring at the participant's home. This type of trial design significantly improves trial efficiency, greatly decreases trial cost, increases consistency of trial administration, and most importantly makes nationwide clinical trials in less-common diseases possible. METHODS: This is a randomized comparison of capsule-delivered fecal microbiota transplant for the prevention of recurrent Clostridiodes difficile infection, administered after successful initial treatment of recurrent C. difficile infection with standard therapy. The primary endpoint is the incidence of recurrent C. difficile infection or death. Cases are identified by searching the Veterans Affairs Corporate Data Warehouse, with central study coordinators then reaching out to potential participants. Individuals meeting inclusion criteria and interested in participation are scheduled for in-home consent, randomization, and capsule administration, followed by telephone follow-up for 6 months. To mitigate risks of COVID-19, enrollment via video visits has been implemented. RESULTS: A total of 102 participants have been enrolled through January 2021. Centralized case identification and in-home enrollment has facilitated enrollment from 34 unique states, with 38% being from rural or highly rural areas. DISCUSSION: Centralized case identification and in-home enrollment is a feasible and innovative method of conducting randomized controlled trials in the Veterans Affairs system, improving access to clinical research for populations who may have difficulty engaging with the traditional model of clinical trials where enrollment is based at large hospitals in major metropolitan areas.

Identification of exosomal muscle-specific miRNAs in serum of myotonic dystrophy patients relating to muscle disease progress.

Myotonic dystrophy type 1 (DM1) is the most common form of adult-onset muscular dystrophy, which is characterised by progressive muscle wasting and the discovery of reliable blood-based biomarkers could be useful for the disease progress monitoring. There have been some reports showing that the presence of specific miRNAs in blood correlates with DM1. In one of these, our group identified four muscle-specific miRNAs, miR-1, miR-133a, miR-133b and miR-206, which correlated with the progression of muscle wasting observed in DM1 patients. The levels of the four muscle-specific miRNAs were elevated in the serum of DM1 patients compared to healthy participants and were also elevated in the serum of progressive muscle wasting DM1 patients compared to disease-stable DM1 patients. The aim of this work was to characterise the ontology of these four muscle-specific miRNAs in the blood circulation of DM1 patients. Here we show that the four muscle-specific miRNAs are encapsulated within exosomes isolated from DM1 patients. Our results show for the first time, the presence of miRNAs encapsulated within exosomes in blood circulation of DM1 patients. More interestingly, the levels of the four exosomal muscle-specific miRNAs are associated with the progression of muscle wasting in DM1 patients. We propose that exosomal muscle-specific miRNAs may be useful molecular biomarkers for monitoring the progress of muscle wasting in DM1 patients. There has been a growing interest regarding the clinical applications of exosomes and their role in prognosis and therapy of various diseases and the above results contribute towards this way.

The Spectrum of Genetic Defects in Congenital Adrenal Hyperplasia in the Population of Cyprus: A Retrospective Analysis.

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is caused by mutations in the CYP21A2 gene. The study refers to CAH patients of Greek-Cypriot ancestry between years 2007 and 2018. One hundred and twenty patients with various degrees of CAH were categorized and genotyped. The patients were categorized in 4 mutation groups based on their clinical and biochemical findings. The majority of patients (85.0%) belonged to the non-classic (NC)-CAH form and the disorder was more often diagnosed in females (71.7%). The most severe classic salt-wasting (SW) form was identified in 11 neonates (9.2%). Seven (5.8%) children were also identified with the simple virilizing (SV) form and a median presentation age of 5 years [interquartile range (IQR) 3.2-6.5]. In the 240 nonrelated alleles, the most frequent mutation was p.Val281Leu (60.0%) followed by c.655 A/C>G (IVS2-13A/C>G) (8.8%), p.Pro453Ser (5.8%), DelEx1-3 (4.6%), p.Val304Met (4.6%), and p.Gln318stop (4.2%). Other less frequent mutations including rare deletions were also identified. Following our recent report that the true carrier frequency of CYP21A2 in Greek-Cypriots is 1:10, this study reports that the CAH prevalence is predicted around 1.7 cases per 10 000 people. Therefore, the up-to-date 120 CAH patients identified by our group make only the 6.9% of the ones estimated (approximately 1750) to exist in the Greek Cypriot population. The compiled data from a coherent population such as the Greek-Cypriot could be valuable for the antenatal diagnosis, management and genetic counselling of the existing and prospect families with CAH.

Efficacy of Extended-Release Naltrexone on HIV-Related and Drinking Outcomes Among HIV-Positive Patients: A Randomized-Controlled Trial.

We sought to test the efficacy of extended-release naltrexone (XR-NTX) on HIV-related and drinking outcomes. From April 2011-February 2015, we conducted a 4-site randomized double-blind placebo controlled clinical trial involving 51 HIV-positive patients with heavy drinking and < 95% antiretroviral (ART) adherence. All participants received counseling. The primary outcome was proportion with ≥ 95% ART adherence. Secondary outcomes included HIV biomarkers, VACS Index score, and past 30-day heavy drinking days. Based on receipt of ≥ 5 injections, 23 participants were retained at 24 weeks. We did not detect an effect of XR-NTX on ART adherence (p = 0.38); undetectable HIV viral load (p = 0.26); CD4 cell count (p = 0.75) or VACS Index score (p = 0.70). XR-NTX was associated with fewer heavy drinking days (p = 0.03). While XR-NTX decreases heavy drinking days, we did not detect improvements in ART adherence or HIV outcomes. Strategies to improve retention in alcohol treatment and HIV-related outcomes among heavy drinking HIV-positive patients are needed.

High prevalence of non-adherence to antiretroviral therapy among undisclosed HIV-infected children in Ghana.

Adherence to antiretroviral therapy (ART) remains one of the greatest obstacles in pediatric HIV care. We sought to determine the prevalence of adherence to ART among undisclosed HIV-infected children and adolescents in Ghana. We analyzed baseline data from HIV-infected children and adolescents aged 7-18 years old enrolled in the SANKOFA Pediatric HIV disclosure intervention study in Ghana. Antiretroviral medication adherence was measured using caregiver 3-day recall; child 3-day recall; and pharmacy records for antiretroviral time-to-refill. Four hundred and twenty child-caregiver dyads were enrolled from January 2013 to June 2016. The median adherence (interquartile range), as measured by time-to-refill, was 93.2% (68.0%-100.0%). However, only 47.5% of children had ≥95% adherence ("good adherence") using time-to-refill data. Children of caregivers who had received secondary or higher level of education versus no school (aOR, 2.90, 95% Confidence Interval, CI 1.29-6.56), p = 0.010) or elementary education only (aOR, 2.20, CI, 1.24-3.88, p = 0.007) were more likely to have "good adherence" (≥95%). In this cohort of children unaware of their HIV positive status, median ART adherence rate was sub-optimal (by World Health Organization definition) while 38% had poor adherence (<85%).

Prevalence and correlates of depression among caregivers of children living with HIV in Ghana: findings from the Sankofa pediatric disclosure study.

Prior studies show an association between caregiver depression and child health outcomes. There has been little examination of depression among caregivers of HIV-infected children in sub-Saharan countries where pediatric HIV is concentrated. Using baseline data collected in the pediatric HIV disclosure intervention trial, Sankofa, we examined the prevalence and factors associated with depression among caregivers (N = 446) of children infected with HIV in Ghana. Data were analyzed with descriptive and regression analyses. The mean age of the caregivers was 42.2 ± 10.4 years. Eighty percent of the caregivers were female and 59% were HIV-infected. Twenty-eight percent (n = 126) of the caregivers were found to have mild to severe depression. In the adjusted model, factors significantly associated with caregiver depression included: HIV-positive caregiver status (P = 0.04), low income (P = 0.02), lower social support, (P = 0.01), lower HIV knowledge, (P = 0.01), worse HIV illness perceptions (P≤0.001), and greater perceived HIV stigma (P≤0.001). Although we found a high prevalence of depression among our study participants, several of the risks factors identified are modifiable and amenable to interventions that are locally available and affordable.

Automated safety event monitoring using electronic medical records in a clinical trial setting: Validation study using the VA NEPHRON-D trial.

BACKGROUND/AIMS: Electronic medical records are now frequently used for capturing patient-level data in clinical trials. Within the Veterans Affairs health care system, electronic medical record data have been widely used in clinical trials to assess eligibility, facilitate referrals for recruitment, and conduct follow-up and safety monitoring. Despite the potential for increased efficiency in using electronic medical records to capture safety data via a centralized algorithm, it is important to evaluate the integrity and accuracy of electronic medical record-captured data. To this end, this investigation assesses data collection, both for general and study-specific safety endpoints, by comparing electronic medical record-based safety monitoring versus safety data collected during the course of the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) clinical trial. METHODS: The VA NEPHRON-D study was a multicenter, double-blind, randomized clinical trial designed to compare the effect of combination therapy (losartan plus lisinopril) versus monotherapy (losartan) on the progression of kidney disease in individuals with diabetes and proteinuria. The trial's safety outcomes included serious adverse events, hyperkalemia, and acute kidney injury. A subset of the participants (~62%, n = 895) enrolled in the trial's long-term follow-up sub-study and consented to electronic medical record data collection. We applied an automated algorithm to search and capture safety data using the VA Corporate Data Warehouse which houses electronic medical record data. Using study safety data reported during the trial as the gold standard, we evaluated the sensitivity and precision of electronic medical record-based safety data and related treatment effects. RESULTS: The sensitivity of the electronic medical record-based safety for hospitalizations was 65.3% without non-VA hospitalization events and 92.3% with the non-VA hospitalization events included. The sensitivity was only 54.3% for acute kidney injury and 87.3% for hyperkalemia. The precision of electronic medical record-based safety data was 89.4%, 38%, and 63.2% for hospitalization, acute kidney injury, and hyperkalemia, respectively. Relative treatment differences under the study and electronic medical record settings were 15% and 3% for hospitalization, 123% and 29% for acute kidney injury, and 238% and 140% for hyperkalemia, respectively. CONCLUSION: The accuracy of using automated electronic medical record safety data depends on the events of interest. Identification of all-cause hospitalizations would be reliable if search methods could, in addition to VA hospitalizations, also capture non-VA hospitalizations. However, hospitalization is different from a cause-specific serious adverse event that could be more sensitive to treatment effects. In addition, some study-specific safety events were not easily identified using the electronic medical records. This limits the effectiveness of the automated central database search for purposes of safety monitoring. Hence, this data captured approach should be carefully considered when implementing endpoint data collection in future pragmatic trials.

Video Game Intervention for Sexual Risk Reduction in Minority Adolescents: Randomized Controlled Trial.

BACKGROUND: Human immunodeficiency virus (HIV) disproportionately impacts minority youth. Interventions to decrease HIV sexual risk are needed. OBJECTIVE: We hypothesized that an engaging theory-based digital health intervention in the form of an interactive video game would improve sexual health outcomes in adolescents. METHODS: Participants aged 11 to 14 years from 12 community afterschool, school, and summer programs were randomized 1:1 to play up to 16 hours of an experimental video game or control video games over 6 weeks. Assessments were conducted at 6 weeks and at 3, 6, and 12 months. Primary outcome was delay of initiation of vaginal/anal intercourse. Secondary outcomes included sexual health attitudes, knowledge, and intentions. We examined outcomes by gender and age. RESULTS: A total of 333 participants were randomized to play the intervention (n=166) or control games (n=167): 295 (88.6%) were racial/ethnic minorities, 177 (53.2%) were boys, and the mean age was 12.9 (1.1) years. At 12 months, for the 258 (84.6%) participants with available data, 94.6% (122/129) in the intervention group versus 95.4% (123/129) in the control group delayed initiation of intercourse (relative risk=0.99, 95% CI 0.94-1.05, P=.77). Over 12 months, the intervention group demonstrated improved sexual health attitudes overall compared to the control group (least squares means [LS means] difference 0.37, 95% CI 0.01-0.72, P=.04). This improvement was observed in boys (LS means difference 0.67, P=.008), but not girls (LS means difference 0.06, P=.81), and in younger (LS means difference 0.71, P=.005), but not older participants (LS means difference 0.03, P=.92). The intervention group also demonstrated increased sexual health knowledge overall (LS means difference 1.13, 95% CI 0.64-1.61, P<.001), in girls (LS means difference 1.16, P=.001), boys (LS means difference 1.10, P=.001), younger (LS means difference 1.18, P=.001), and older (LS means difference=1.08, P=.002) participants. There were no differences in intentions to delay the initiation of intercourse between the two groups (LS means difference 0.10, P=.56). CONCLUSIONS: An interactive video game intervention improves sexual health attitudes and knowledge in minority adolescents for at least 12 months. TRIAL REGISTRATION: Clinicaltrials.gov NCT01666496; https://clinicaltrials.gov/ct2/show/NCT01666496 (Archived by WebCite at http://www.webcitation.org/6syumc9C0).

The design and implementation of a randomized controlled trial of a risk reduction and human immunodeficiency virus prevention videogame intervention in minority adolescents: PlayForward: Elm City Stories.

BACKGROUND: To address the need for risk behavior reduction and human immunodeficiency virus prevention interventions that capture adolescents "where they live," we created a tablet-based videogame to teach skills and knowledge and influence psychosocial antecedents for decreasing risk and preventing human immunodeficiency virus infection in minority youth in schools, after-school programs, and summer camps. METHODS: We developed PlayForward: Elm City Stories over a 2-year period, working with researchers, commercial game designers, and staff and teens from community programs. The videogame PlayForward provides an interactive world where players, using an avatar, "travel" through time, facing challenges such as peer pressure to drink alcohol or engage in risky sexual behaviors. Players experience how their choices affect their future and then are able to go back in time and change their choices, creating different outcomes. A randomized controlled trial was designed to evaluate the efficacy of PlayForward. Participants were randomly assigned to play PlayForward or a set of attention/time control games on a tablet at their community-based program. Assessment data were collected during face-to-face study visits and entered into a web-based platform and unique real-time "in-game" PlayForward data were collected as players engaged in the game. The innovative methods of this randomized controlled trial are described. We highlight the logistical issues of conducting a large-scale trial using mobile technology such as the iPad(®), and collecting, transferring, and storing large amounts of in-game data. We outline the methods used to analyze the in-game data alone and in conjunction with standardized assessment data to establish correlations between behaviors during gameplay and those reported in real life. We also describe the use of the in-game data as a measure of fidelity to the intervention. RESULTS: In total, 333 boys and girls, aged 11-14 years, were randomized over a 14-month period: 166 were assigned to play PlayForward and 167 to play the control games. To date (as of 1 March 2016), 18 have withdrawn from the study; the following have completed the protocol-defined assessments: 6 weeks: 271 (83%), 3 months: 269 (84%), 6 months: 254 (79%), 12 months: 259 (82%), and 24 months: is ongoing with 152 having completed out of the 199 participants (76%) who were eligible to date (assessment windows were still open). CONCLUSION: Videogames can be developed to address complex behaviors and can be subject to empiric testing using community-based randomized controlled trials. Although mobile technologies pose challenges in their use as interventions and in the collection and storage of data they produce, they provide unique opportunities as new sources of potentially valid data and novel methods to measure the fidelity of digitally delivered behavioral interventions.

Familial Mediterranean fever associated with MEFV mutations in a large cohort of Cypriot patients.

Familial Mediterranean fever (FMF) is caused by mutations in the MEFV gene and the spectrum of mutations among Greek-Cypriots with FMF-related symptoms was examined. Sequence analysis for exons 2, 3, 5, and 10 of the MEFV gene was performed in a cohort of 593 patients. A total of 70 patients carried mutations in the homozygote or compound heterozygote state, 128 were identified with one MEFV mutation and 395 had no mutations. Of the 268 identified alleles, p.Val726Ala (27.61%) was the most frequent followed by p.Met694Val (19.40%). The missense mutations p.Arg761His (3.73%) and p.Ala744Ser (2.24%) were identified as the rarest. An interesting finding is the high frequency (18.28%) of the complex p.Phe479Leu-p.Glu167Asp that was identified in 49 of the mutated alleles. The MEFV genotypes did not follow a binomial distribution and proved not to satisfy the HWE (P < 0.001). The high percentage (66.61%) of patients with unidentified mutations could be due to mutations in the rest of the coding or noncoding MEFV gene or due to mutations in other genes that are also causing Hereditary Recurrent Fevers. Results from this work indicate the high incidence of FMF in Cyprus and describe the spectrum of the mutations which occur in the country.