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Clinical trial designs often include multiple levels of clustering in which patients are nested within clinical sites and recurrent outcomes are nested within patients who may also experience a semi-competing risk. Traditional survival methods that analyze these processes separately may lead to erroneous inferences as they ignore possible dependencies. To account for the association between recurrent events and a semi-competing risk in the presence of two levels of clustering, we developed a semi-parametric joint model. The Gaussian quadrature with a piecewise constant baseline hazard was used to estimate the unspecified baseline hazards and the likelihood. Simulations showed that the proposed joint model has good statistical properties (i.e. <5% bias and 95% coverage) compared to the shared frailty and joint frailty models when informative censoring and multiple levels of clustering were present. The proposed method was applied to data from an AIDS clinical trial to investigate the impact of antiretroviral treatment on recurrent AIDS-defining events in the presence of a semi-competing risk of death and multi-level clustering and showed a significant dependency between AIDS-defining events and death at the patient level but not at the clinic level. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 HIVinfected 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 timeto- 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%). [ABSTRACT FROM AUTHOR]

Importance: Posttraumatic stress disorder (PTSD) often interferes with a person's ability to obtain or sustain employment, which leads to premature exit from the labor force and reduced income.Objective: To determine whether individual placement and support (IPS)-supported employment is more effective than stepwise vocational rehabilitation involving transitional work assignments at helping veterans with PTSD attain steady, competitive employment.Design, Setting, and Participants: The Veterans Individual Placement and Support Toward Advancing Recovery (VIP-STAR) study was a prospective, multisite, randomized clinical trial that included 541 unemployed veterans with PTSD at 12 Veterans Affairs medical centers. Data were collected from December 23, 2013, to May 3, 2017. Intent-to-treat analysis was performed.Interventions: Individual placement and support is a supported employment intervention that rapidly engages people with disabilities in community job development to obtain work based on their individual job preferences. Transitional work is a stepwise vocational rehabilitation intervention that assigns people temporarily to noncompetitive jobs as preparation for competitive employment in the community.Main Outcomes and Measures: A priori hypotheses were that, compared with those in transitional work, more participants in the IPS group would become steady workers (primary) and earn more income from competitive jobs (secondary) over 18 months. Steady worker was defined as holding a competitive job for at least 50% of the 18-month follow-up period.Results: A total of 541 participants (n = 271 IPS; n = 270 transitional work) were randomized. Mean (SD) age was 42.2 (11) years; 99 (18.3%) were women, 274 (50.6%) were white, 225 (41.6%) were African American, and 90 (16.6%) were of Hispanic, Spanish, or Latino ethnicity. More participants in the IPS group achieved steady employment than in the transitional work group (105 [38.7%] vs 63 [23.3%]; odds ratio, 2.14; 95% CI, 1.46-3.14). A higher proportion of IPS participants attained any competitive job (186 [68.6%] vs 154 [57.0%]; P = .005) and had higher cumulative earnings from competitive jobs (median [interquartile range] $7290 [$23 174] in IPS vs $1886 [$17 167] in transitional work; P = .004).Conclusions and Relevance: This multisite trial demonstrated significantly greater effectiveness of IPS-supported employment over stepwise transitional work vocational rehabilitation for veterans living with chronic PTSD. The results provide supporting evidence for increasing access to IPS for veterans living with PTSD.Trial Registration: clinicaltrials.gov Identifier: NCT01817712. [ABSTRACT FROM AUTHOR]

Objective: Very-low-level viremia (VLLV) is a relatively new concept in the realm of human immunodeficiency virus (HIV) care. Newer generation assays are now able to detect plasma HIV RNA Viral Load (VL) levels as low as 20 copies/mL. The authors characterized patients with VLLV (VL between 20 and 50 copies/mL) in order to identify possible risk factors associated with virologic failure and poor clinical outcomes.Methods: The authors reviewed 119 consecutive charts of patients with VLLV. Sociodemographic data were extracted and viral load and CD4 counts were trended over a 12 month period (February 2013-February 2014). Regression analysis was used to assess the role of different factors on virologic failure at 1 year.Results: Of the study participants with evaluable data (n = 100), the median age was 53 years (interquartile range: 43-57.5), 67% were nonwhite, 34% were women, 58% were smokers, 47% were alcoholics, 58% had a history of intravenous drug use, and 40% were coinfected with hepatitis C virus. More than half of the participants had 3 or more comorbidities and their HIV pill burden was high (more than 2 pills daily). After 12 months, 65 participants achieved undetectable viral load levels, whereas 15 experienced virologic failure (2 consecutive viral loads > 50 copies/mL) and the remaining 20 had persistent VLLV. In the virologic failure group, there was a predominance of white males (66%) with a significant number of comorbidities and pill burden. Univariate logistic regression suggested that there was a difference between the failure versus nonfailure groups in terms of race, ethnicity, and alcohol use. Multivariate regression with virological failure as the outcome suggested a trend only in terms of participant's alcohol use.Conclusion: Most patients with initial VLLV (70%) achieved virologic suppression at 1 year with no antiretroviral therapy changes. Thus, VLLV does not necessarily predict virologic failure and should not prompt more frequent clinic visits or antiretroviral regimen changes. Further research is needed in order to determine the predictors of virologic failure in this subset of patients and the clinicians' attitude toward VLLV. [ABSTRACT FROM AUTHOR]

Heterozygosity for CYP21A2 mutations in females is possibly related to increased risk of developing clinical hyperandrogenism. The present study was designed to seek evidence on the phenotype-genotype correlation in female children, adolescents, and women with CYP21A2 mutations and variants in the 3′UTR region of the gene. Sixty-six patients out of the 169 were identified as carriers of CYP21A2 mutations. Higher values of stimulated 17 hydroxyprogesterone (17-OHP) levels were found in the carriers of the p.Val281Leu mutation compared to the carriers of other mutations (mean: 24.7 nmol/l versus 15.6 nmol/l). The haplotype of the ∗52C>T, ∗440C>T, and ∗443T>C in the 3′UTR was identical in all heterozygous patients with p.Val281Leu and the haplotype of the ∗12C>T and ∗52C>T was identical in all heterozygous patients with the p.Gln318∗. In conclusion, hyperandrogenaemic females are likely to bear heterozygous CYP21A2 mutations. Carriers of the mild p.Val281Leu mutation are at higher risk of developing hyperandrogenism than the carriers of more severe mutations. The identification of variants in the 3′UTR of CYP21A2 in combination with the heterozygous mutation may be associated with the mild form of nonclassic congenital adrenal hyperplasia and reveal the importance of analyzing the CYP21A2 untranslated regions for the appropriate management of this category of patients. [ABSTRACT FROM AUTHOR]