Identification of PKD1L1 Gene Variants in Children with the Biliary Atresia Splenic Malformation Syndrome

Biliary atresia (BA) is the most common cause of end‐stage liver disease in children and the primary indication for pediatric liver transplantation, yet underlying etiologies remain unknown. Approximately 10% of infants affected by BA exhibit various laterality defects (heterotaxy) including splenic abnormalities and complex cardiac malformations — a distinctive subgroup commonly referred to as the biliary atresia splenic malformation (BASM) syndrome. We hypothesized that genetic factors linking laterality features with the etiopathogenesis of BA in BASM patients could be identified through whole exome sequencing (WES) of an affected cohort. DNA specimens from 67 BASM subjects, including 58 patient‐parent trios, from the NIDDK‐supported Childhood Liver Disease Research Network (ChiLDReN) underwent WES. Candidate gene variants derived from a pre‐specified set of 2,016 genes associated with ciliary dysgenesis and/or dysfunction or cholestasis were prioritized according to pathogenicity, population frequency, and mode of inheritance. Five BASM subjects harbored rare and potentially deleterious bi‐allelic variants in polycystin 1‐like 1, PKD1L1, a gene associated with ciliary calcium signaling and embryonic laterality determination in fish, mice and humans. Heterozygous PKD1L1 variants were found in 3 additional subjects. Immunohistochemical analysis of liver from the one BASM subject available revealed decreased PKD1L1 expression in bile duct epithelium when compared to normal livers and livers affected by other non‐cholestatic diseases. Conclusion WES identified bi‐allelic and heterozygous PKD1L1 variants of interest in 8 BASM subjects from the ChiLDReN dataset. The dual roles for PKD1L1 in laterality determination and ciliary function suggest that PKD1L1 is a new, biologically plausible, cholangiocyte‐expressed candidate gene for the BASM syndrome

Participation in adherence clubs and on-time drug pickup among HIV-infected adults in Zambia: a matched-pair cluster randomized trial

Background: Current models of HIV service delivery, with frequent facility visits, have led to facility congestion, patient and healthcare provider dissatisfaction, and suboptimal quality of services and retention in care. The Zambian urban adherence club (AC) is a health service innovation designed to improve on-time drug pickup and retention in HIV care through off-hours facility access and pharmacist-led group drug distribution. Similar models of differentiated service delivery (DSD) have shown promise in South Africa, but observational analyses of these models are prone to bias and confounding. We sought to evaluate the effectiveness and implementation of ACs in Zambia using a more rigorous study design. Methods and findings: Using a matched-pair cluster randomized study design (ClinicalTrials.gov: NCT02776254), 10 clinics were randomized to intervention (5 clinics) or control (5 clinics). At each clinic, between May 19 and October 27, 2016, a systematic random sample was assessed for eligibility (HIV+, age ≥ 14 years, on ART >6 months, not acutely ill, CD4 count not 7 days late). Intervention effect was estimated using unadjusted Kaplan–Meier survival curves and a Cox proportional hazards model to derive an adjusted hazard ratio (aHR). Medication possession ratio (MPR) and implementation outcomes (adoption, acceptability, appropriateness, feasibility, and fidelity) were additionally evaluated as secondary outcomes. Baseline characteristics were similar between 571 intervention and 489 control participants with respect to median age (42 versus 41 years), sex (62% versus 66% female), median time since ART initiation (4.8 versus 5.0 years), median CD4 count at study enrollment (506 versus 533 cells/mm3), and baseline retention (53% versus 55% with at least 1 late drug pickup in previous 12 months). The rate of late drug pickup was lower in intervention participants compared to control participants (aHR 0.26, 95% CI 0.15–0.45, p < 0.001). Median MPR was 100% in intervention participants compared to 96% in control participants (p < 0.001). Although 18% (683/3,734) of AC group meeting visits were missed, on-time drug pickup (within 7 days) still occurred in 51% (350/683) of these missed visits through alternate means (use of buddy pickup or early return to the facility). Qualitative evaluation suggests that the intervention was acceptable to both patients and providers. While patients embraced the convenience and patient-centeredness of the model, preference for traditional adherence counseling and need for greater human resources influenced intervention appropriateness and feasibility from the provider perspective. The main limitations of this study were the small number of clusters, lack of viral load data, and relatively short follow-up period. Conclusions: ACs were found to be an effective model of service delivery for reducing late ART drug pickup among HIV-infected adults in Zambia. Drug pickup outside of group meetings was relatively common and underscores the need for DSD models to be flexible and patient-centered if they are to be effective

Differentiated care preferences of stable patients on ART in Zambia: a discrete choice experiment

Background: Although differentiated service delivery (DSD) models for stable patients on antiretroviral therapy (ART) offer a range of health systems innovations, their comparative desirability to patients remains unknown. We conducted a discrete choice experiment to quantify service attributes most desired by patients to inform model prioritization Methods: Between July and December 2016 a sample of HIV-positive adults on ART at 12 clinics in Zambia were asked to choose between two hypothetical facilities which differed across six DSD attributes. We used mixed logit models to explore preferences, heterogeneity and trade-offs Results: Of 486 respondents, 59% were female and 85% resided in urban locations. Patients strongly preferred infrequent clinic visits (3 vs. 1-month visits: β (i.e. relative utility) =2.84; p <0.001). Milder preferences were observed for: waiting time for ART pick-up (1 vs. 6 hrs.; β=-0.67; p<0.001) or provider (1 vs. 3 hrs.; β=-0.41; p=0.002); ‘buddy’ ART collection (β=0.84; p <0.001); and ART pick-up location (clinic vs. community: β=0.35; p=0.028). Urban patients demonstrated a preference for collecting ART at a clinic (β=1.32, p<0.001), and although the majority of rural patients preferred community ART pick-up (β=-0.74, p=0.049), 40% of rural patients still preferred facility ART collection. Conclusions: Stable patients on ART primarily want to attend clinic infrequently, supporting a focus in Zambia on optimizing multi-month prescribing over other DSD features - particularly in urban areas. Substantial preference heterogeneity highlights the need for DSD models to be flexible, and accommodate both setting features and patient choice in their design

Immediate and early engagement of same-day antiretroviral therapy initiation among newly diagnosed people living with HIV in urban Zambia: a retrospective cohort study

Introduction: as Zambia moves towards attaining human immunodeficiency virus (HIV) epidemic control, it is clear significant efforts are required to facilitate achievement of UNAIDS treatment targets by 2030. To accelerate progress towards global target of 95% of people living with HIV (PLHIV) knowing their status, country is promoting community-based HIV testing and same-day antiretroviral therapy (ART) initiation. However, there are uncertainties of how this strategy affects immediate and early engagement in program settings. To address this research gap, we analysed R programme data of PLHIV newly diagnosed and initiated on ART in community and health facility settings. Study objectives were; to estimate the proportion of immediate engagement, to estimate early engagement among newly diagnosed PLHIV and to examine factors independently associated with immediate and early engagement in care among newly diagnosed PLHIV offered same-day ART initiation. Methods: we included all newly diagnosed PLHIV aged 18 years or older and provided same-day ART initiation between October 2018 and January 2019 in Lusaka District. Immediate engagement was estimated as proportion of newly diagnosed PLHIV who visited the health facility at least once within 14 days after same-day ART initiation, whereas early engagement as proportion of newly diagnosed PLHIV active 6 months after same-day ART initiation. Pearson's chi-squared test was used to assess association of outcomes with key background characteristics. Results: of 12,777 newly diagnosed PLHIV who initiated same day ART 7,943 (62%) were tested and initiated in the community. Overall, 6,257 (49%) engaged within 14 days (median 15, IQR: 13-37). Older individuals (36-49 years) were more likely to be engaged at 14 days (aRR 1.29; 95%CI 1.06-1.18; p<0.001) and retained at 6 months (aRR1.27;95%CI 1.21-1.34P<0.001) whilst risk of attrition at 6 months was highest in younger ages (18-24 years) (aRR 0.79;95 %CI 0.76-0.82; p<0.001). Conclusion: to adequately address the HIV epidemic targeted engagement approaches are required particularly in the younger ages

Putting Youth on the Map: A Pilot Instrument for Assessing Youth Well-Being

Extant measures of adolescent well-being in the United States typically focus on negative indicators of youth outcomes. Indices comprised of such measures paint bleak views of youth and orient action toward the prevention of problems over the promotion of protective factors. Their tendency to focus analyses at a state or county geographic scale produces limited information about localized outcome patterns that could inform policymakers, practitioners and advocacy networks. We discuss the construction of a new geo-referenced index of youth well-being based on positive indicators of youth development. In demonstrating the index for the greater Sacramento, California region of the United States, we find that overall youth well-being falls far short of an optimal outcome, and geographic disparities in well-being appear to exist across school districts at all levels of our analysis. Despite its limitations, the sub-county geographic scale of this index provides needed data to facilitate local and regional interventions

Neurodevelopmental Outcome of Young Children with Biliary Atresia and Native Liver: Results from the ChiLDReN Study

OBJECTIVES: To assess neurodevelopmental outcomes among participants with biliary atresia with their native liver at ages 12 months (group 1) and 24 months (group 2), and to evaluate variables predictive of neurodevelopmental impairment. STUDY DESIGN: Participants enrolled in a prospective, longitudinal, multicenter study underwent neurodevelopmental testing with either the Bayley Scales of Infant Development, 2nd edition, or Bayley Scales of Infant and Toddler Development, 3rd edition. Scores (normative mean = 100 ± 15) were categorized as ≥100, 85-99, and <85 for χ2 analysis. Risk for neurodevelopmental impairment (defined as ≥1 score of <85 on the Bayley Scales of Infant Development, 2nd edition, or Bayley Scales of Infant and Toddler Development, 3rd edition, scales) was analyzed using logistic regression. RESULTS: There were 148 children who completed 217 Bayley Scales of Infant and Toddler Development, 3rd edition, examinations (group 1, n = 132; group 2, n = 85). Neurodevelopmental score distributions significantly shifted downward compared with test norms at 1 and 2 years of age. Multivariate analysis identified ascites (OR, 3.17; P = .01) and low length z-scores at time of testing (OR, 0.70; P < .04) as risk factors for physical/motor impairment; low weight z-score (OR, 0.57; P = .001) and ascites (OR, 2.89; P = .01) for mental/cognitive/language impairment at 1 year of age. An unsuccessful hepatoportoenterostomy was predictive of both physical/motor (OR, 4.88; P < .02) and mental/cognitive/language impairment (OR, 4.76; P = .02) at 2 years of age. CONCLUSION: Participants with biliary atresia surviving with native livers after hepatoportoenterostomy are at increased risk for neurodevelopmental delays at 12 and 24 months of age. Those with unsuccessful hepatoportoenterostomy are >4 times more likely to have neurodevelopmental impairment compared with those with successful hepatoportoenterostomy. Growth delays and/or complications indicating advanced liver disease should alert clinicians to the risk for neurodevelopmental delays, and expedite appropriate interventions

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Participation in adherence clubs and on-time drug pickup among HIV-infected adults in Zambia: A matched-pair cluster randomized trial.

BackgroundCurrent models of HIV service delivery, with frequent facility visits, have led to facility congestion, patient and healthcare provider dissatisfaction, and suboptimal quality of services and retention in care. The Zambian urban adherence club (AC) is a health service innovation designed to improve on-time drug pickup and retention in HIV care through off-hours facility access and pharmacist-led group drug distribution. Similar models of differentiated service delivery (DSD) have shown promise in South Africa, but observational analyses of these models are prone to bias and confounding. We sought to evaluate the effectiveness and implementation of ACs in Zambia using a more rigorous study design.Methods and findingsUsing a matched-pair cluster randomized study design (ClinicalTrials.gov: NCT02776254), 10 clinics were randomized to intervention (5 clinics) or control (5 clinics). At each clinic, between May 19 and October 27, 2016, a systematic random sample was assessed for eligibility (HIV+, age ≥ 14 years, on ART &gt;6 months, not acutely ill, CD4 count not &lt;200 cells/mm3) and willingness to participate in an AC. Clinical and antiretroviral drug pickup data were obtained through the existing electronic medical record. AC meeting attendance data were collected at intervention facilities prospectively through October 28, 2017. The primary outcome was time to first late drug pickup (&gt;7 days late). Intervention effect was estimated using unadjusted Kaplan-Meier survival curves and a Cox proportional hazards model to derive an adjusted hazard ratio (aHR). Medication possession ratio (MPR) and implementation outcomes (adoption, acceptability, appropriateness, feasibility, and fidelity) were additionally evaluated as secondary outcomes. Baseline characteristics were similar between 571 intervention and 489 control participants with respect to median age (42 versus 41 years), sex (62% versus 66% female), median time since ART initiation (4.8 versus 5.0 years), median CD4 count at study enrollment (506 versus 533 cells/mm3), and baseline retention (53% versus 55% with at least 1 late drug pickup in previous 12 months). The rate of late drug pickup was lower in intervention participants compared to control participants (aHR 0.26, 95% CI 0.15-0.45, p &lt; 0.001). Median MPR was 100% in intervention participants compared to 96% in control participants (p &lt; 0.001). Although 18% (683/3,734) of AC group meeting visits were missed, on-time drug pickup (within 7 days) still occurred in 51% (350/683) of these missed visits through alternate means (use of buddy pickup or early return to the facility). Qualitative evaluation suggests that the intervention was acceptable to both patients and providers. While patients embraced the convenience and patient-centeredness of the model, preference for traditional adherence counseling and need for greater human resources influenced intervention appropriateness and feasibility from the provider perspective. The main limitations of this study were the small number of clusters, lack of viral load data, and relatively short follow-up period.ConclusionsACs were found to be an effective model of service delivery for reducing late ART drug pickup among HIV-infected adults in Zambia. Drug pickup outside of group meetings was relatively common and underscores the need for DSD models to be flexible and patient-centered if they are to be effective.Trial registrationClinicalTrials.gov NCT02776254