Assessing risk for HIV infection among adolescent girls in South Africa: an evaluation of the VOICE risk score (HPTN 068)

INTRODUCTION: To maximize impact and minimize costs, antiretroviral pre-exposure prophylaxis (PrEP) interventions should be offered to those at highest risk for HIV infection. The risk score derived from the VOICE trial is one tool currently being utilized to determine eligibility in adolescent PrEP trials in sub-Saharan Africa. This study is aimed at evaluating the utility of the risk score in predicting HIV incidence among a cohort of adolescent girls in rural South Africa. METHODS: We utilized data from HIV Prevention Trials Network (HPTN) 068, a phase III randomized controlled trial conducted in rural Mpumalanga province, South Africa. School-attending young women aged 13 to 20 years were enrolled into the trial from 2011 to 2012 and followed for up to three years. A risk score based on individual-level risk factors measured at enrolment was calculated for HPTN 068 participants who completed a one-year follow-up visit and were HIV seronegative at enrolment. Possible scores ranged from 0 to 10. A proportional hazards model was then used to determine if risk score at enrolment was predictive of incident HIV infection at follow-up and an area under the curve analysis was used to examine the predictive ability of the score. RESULTS AND DISCUSSION: The risk score had limited variability in the HPTN 068 sample. Scores ≥5 identified 85% of incident infections from 94% of the sample, compared to the VOICE sample in which scores ≥5 identified 91% of incident infections from only 64% of participants. The risk score did not predict HIV incidence after one year of follow-up (hazard ratio = 1.029; 95% confidence interval (CI): 0.704, 1.503, p = .884) and showed poor predictive ability (area under the curve = 0.55; 95% CI: 0.44, 0.65). Certain individual risk factors that comprise the risk score may be context specific or not relevant for adolescent populations. Additional factors should be considered when assessing risk for the purposes of determining PrEP eligibility. CONCLUSIONS: The VOICE risk score demonstrated low utility to predict HIV incidence in the HPTN 068 sample. Findings highlight the need for an age and developmentally appropriate tool for assessing risk for HIV infection among adolescents. Use of the VOICE risk score for determining PrEP eligibility in younger populations should be carefully considered

A forward genetic screen with a thalamocortical axon reporter mouse yields novel neurodevelopment mutants and a distinct emx2 mutant phenotype

<p>Abstract</p> <p>Background</p> <p>The dorsal thalamus acts as a gateway and modulator for information going to and from the cerebral cortex. This activity requires the formation of reciprocal topographic axon connections between thalamus and cortex. The axons grow along a complex multistep pathway, making sharp turns, crossing expression boundaries, and encountering intermediate targets. However, the cellular and molecular components mediating these steps remain poorly understood.</p> <p>Results</p> <p>To further elucidate the development of the thalamocortical system, we first created a thalamocortical axon reporter line to use as a genetic tool for sensitive analysis of mutant mouse phenotypes. The TCA-<it>tau-lacZ </it>reporter mouse shows specific, robust, and reproducible labeling of thalamocortical axons (TCAs), but not the overlapping corticothalamic axons, during development. Moreover, it readily reveals TCA pathfinding abnormalities in known cortical mutants such as <it>reeler</it>. Next, we performed an unbiased screen for genes involved in thalamocortical development using random mutagenesis with the TCA reporter. Six independent mutant lines show aberrant TCA phenotypes at different steps of the pathway. These include ventral misrouting, overfasciculation, stalling at the corticostriatal boundary, and invasion of ectopic cortical cell clusters. An outcross breeding strategy coupled with a genomic panel of single nucleotide polymorphisms facilitated genetic mapping with small numbers of mutant mice. We mapped a ventral misrouting mutant to the <it>Emx2 </it>gene, and discovered that some TCAs extend to the olfactory bulbs in this mutant. Mapping data suggest that other lines carry mutations in genes not previously known for roles in thalamocortical development.</p> <p>Conclusions</p> <p>These data demonstrate the feasibility of a forward genetic approach to understanding mammalian brain morphogenesis and wiring. A robust axonal reporter enabled sensitive analysis of a specific axon tract inside the mouse brain, identifying mutant phenotypes at multiple steps of the pathway, and revealing a new aspect of the <it>Emx2 </it>mutant. The phenotypes highlight vulnerable choice points and latent tendencies of TCAs, and will lead to a refined understanding of the elements and interactions required to form the thalamocortical system.</p> <p>See Commentary: <url>http://www.biomedcentral.com/1741-7007/9/1</url></p

Post-Acute Care Payment Reform Demonstration: Final Report Volume 4 of 4

This is the Final Report for the Post-Acute Care Payment Reform Demonstration (PAC-PRD), authorized by section 5008 of the Deficit Reduction Act of 2005, Public Law 109-171. The report has 12 sections, which are divided into four volumes: Volume 1: Executive Summary. Volume 2: Sections 1-4 (Section 1: Introduction; Section 2: Underlying Issues of the PAC-PRD Initiating Legislation; Section 3: Developing Standardized Measurement Approaches: The Continuity Assessment Record and Evaluation (CARE); Section 4: Demonstration Methods and Data Collection) Volume 3: Sections 5-6 (Section 5: Framework for Analysis; Section 6: Factors Associated with Hospital Discharge Destination) Volume 4: Sections 7-12; References (Section 7: Outcomes: Hospital Readmissions; Section 8: Outcomes: Functional Status; Section 9: Determinants of Resource Intensity: Methods and Analytic Sample Description; Section 10: Determinants of Resource Intensity: Lessons from the CART Analysis; Section 11: Determinants of Resource Intensity: Multivariate Regression Results; Section 12: Conclusions and Review of Findings; References

Post-Acute Care Payment Reform Demonstration: Final Report Volume 3 of 4

This is the Final Report for the Post-Acute Care Payment Reform Demonstration (PAC-PRD), authorized by section 5008 of the Deficit Reduction Act of 2005, Public Law 109-171. The report has 12 sections, which are divided into four volumes: Volume 1: Executive Summary. Volume 2: Sections 1-4 (Section 1: Introduction; Section 2: Underlying Issues of the PAC-PRD Initiating Legislation; Section 3: Developing Standardized Measurement Approaches: The Continuity Assessment Record and Evaluation (CARE); Section 4: Demonstration Methods and Data Collection) Volume 3: Sections 5-6 (Section 5: Framework for Analysis; Section 6: Factors Associated with Hospital Discharge Destination) Volume 4: Sections 7-12; References (Section 7: Outcomes: Hospital Readmissions; Section 8: Outcomes: Functional Status; Section 9: Determinants of Resource Intensity: Methods and Analytic Sample Description; Section 10: Determinants of Resource Intensity: Lessons from the CART Analysis; Section 11: Determinants of Resource Intensity: Multivariate Regression Results; Section 12: Conclusions and Review of Findings; References

Post-Acute Care Payment Reform Demonstration: Final Report Volume 2 of 4

This is the Final Report for the Post-Acute Care Payment Reform Demonstration (PAC-PRD), authorized by section 5008 of the Deficit Reduction Act of 2005, Public Law 109-171. The report has 12 sections, which are divided into four volumes: Volume 1: Executive Summary. Volume 2: Sections 1-4 (Section 1: Introduction; Section 2: Underlying Issues of the PAC-PRD Initiating Legislation; Section 3: Developing Standardized Measurement Approaches: The Continuity Assessment Record and Evaluation (CARE); Section 4: Demonstration Methods and Data Collection) Volume 3: Sections 5-6 (Section 5: Framework for Analysis; Section 6: Factors Associated with Hospital Discharge Destination) Volume 4: Sections 7-12; References (Section 7: Outcomes: Hospital Readmissions; Section 8: Outcomes: Functional Status; Section 9: Determinants of Resource Intensity: Methods and Analytic Sample Description; Section 10: Determinants of Resource Intensity: Lessons from the CART Analysis; Section 11: Determinants of Resource Intensity: Multivariate Regression Results; Section 12: Conclusions and Review of Findings; References

Post-Acute Care Payment Reform Demonstration: Final Report Volume 1 of 4

This is the Final Report for the Post-Acute Care Payment Reform Demonstration (PAC-PRD), authorized by section 5008 of the Deficit Reduction Act of 2005, Public Law 109-171. The report has 12 sections, which are divided into four volumes: Volume 1: Executive Summary. Volume 2: Sections 1-4 (Section 1: Introduction; Section 2: Underlying Issues of the PAC-PRD Initiating Legislation; Section 3: Developing Standardized Measurement Approaches: The Continuity Assessment Record and Evaluation (CARE); Section 4: Demonstration Methods and Data Collection) Volume 3: Sections 5-6 (Section 5: Framework for Analysis; Section 6: Factors Associated with Hospital Discharge Destination) Volume 4: Sections 7-12; References (Section 7: Outcomes: Hospital Readmissions; Section 8: Outcomes: Functional Status; Section 9: Determinants of Resource Intensity: Methods and Analytic Sample Description; Section 10: Determinants of Resource Intensity: Lessons from the CART Analysis; Section 11: Determinants of Resource Intensity: Multivariate Regression Results; Section 12: Conclusions and Review of Findings; References

A Cystine-Rich Whey Supplement (Immunocal®) Provides Neuroprotection from Diverse Oxidative Stress-Inducing Agents In Vitro

Oxidative stress is a principal mechanism underlying the pathophysiology of neurodegeneration. Therefore, nutritional enhancement of endogenous antioxidant defenses may represent a viable treatment option. We investigated the neuroprotective properties of a unique whey protein supplement (Immunocal®) that provides an essential precursor (cystine) for synthesis of the endogenous antioxidant, glutathione (GSH). Primary cultures of rat cerebellar granule neurons (CGNs), NSC34 motor neuronal cells, or HT22 hippocampal cells were preincubated in medium containing Immunocal and then subsequently treated with agents known to induce oxidative stress. Immunocal protected CGNs against neurotoxicity induced by the Bcl-2 inhibitor, HA14-1, the nitric oxide donor, sodium nitroprusside, CuCl2, and AlCl3. Immunocal also significantly reduced NSC34 cell death due to either H2O2 or glutamate and mitigated toxicity in HT22 cells overexpressing β-amyloid1-42. The neuroprotective effects of Immunocal were blocked by inhibition of γ-glutamyl-cysteine ligase, demonstrating dependence on de novo GSH synthesis. These findings indicate that sustaining GSH with Immunocal significantly protects neurons against diverse inducers of oxidative stress. Thus, Immunocal is a nutritional supplement worthy of testing in preclinical animal models of neurodegeneration and in future clinical trials of patients afflicted by these diseases