Faculty Bibliography

The prognosis of chronic lymphocytic leukemia (CLL) depends on different markers, including cytogenetic aberrations, oncogenic mutations, and mutational status of the immunoglobulin (Ig) heavy-chain variable (IGHV) gene. The number of IGHV mutations distinguishes mutated (M) CLL with a markedly superior prognosis from unmutated (UM) CLL cases. In addition, B cell antigen receptor (BCR) stereotypes as defined by IGHV usage and complementarity-determining regions (CDRs) classify ∼30% of CLL cases into prognostically important subsets. Subset 2 expresses a BCR with the combination of IGHV3-21-derived heavy chains (HCs) with IGLV3-21-derived light chains (LCs), and is associated with an unfavorable prognosis. Importantly, the subset 2 LC carries a single-point mutation, termed R110, at the junction between the variable and constant LC regions. By analyzing 4 independent clinical cohorts through BCR sequencing and by immunophenotyping with antibodies specifically recognizing wild-type IGLV3-21 and R110-mutated IGLV3-21 (IGLV3-21^R110), we show that IGLV3-21^R110-expressing CLL represents a distinct subset with poor prognosis independent of IGHV mutations. Compared with other alleles, only IGLV3-21*01 facilitates effective homotypic BCR-BCR interaction that results in autonomous, oncogenic BCR signaling after acquiring R110 as a single-point mutation. Presumably, this mutation acts as a standalone driver that transforms IGLV3-21*01-expressing B cells to develop CLL. Thus, we propose to expand the conventional definition of CLL subset 2 to subset 2L by including all IGLV3-21^R110-expressing CLL cases regardless of IGHV mutational status. Moreover, the generation of monoclonal antibodies recognizing IGLV3-21 or mutated IGLV3-21^R110 facilitates the recognition of B cells carrying this mutation in CLL patients or healthy donors.

Higher exposure to tenofovir (TFV) increases the risk for kidney function decline, but the impact of genetic factors on TFV exposure is largely unknown. We investigated whether single-nucleotide polymorphisms (SNPs, n=211) in 12 genes are potentially involved in TFV exposure. Participants (n=91) from the Women's Interagency HIV Study, underwent a 24 h intensive pharmacokinetic sampling of TFV after witnessed dose and TFV area under the time-concentration curves (AUCs) were calculated for each participant. SNPs were assayed using a combination of array genotyping and Sanger sequencing. Linear regression models were applied to logarithmically transformed AUC. Those SNPs that met an a priori threshold of P<0.001 were considered statistically associated with TFV AUC. ABCG2 SNP rs2231142 was associated with TFV AUC with rare allele carriers displaying 1.51-fold increase in TFV AUC (95% confidence interval: 1.26, 1.81; P=1.7 x 10-5). We present evidence of a moderately strong effect of the rs2231142 SNP in ABCG2 on a 24 h TFV AUC.The Pharmacogenomics Journal advance online publication, 2 May 2017; doi:10.1038/tpj.2017.3.

INTRODUCTION: Integration of HIV into child survival platforms is an evolving territory with multiple connotations. Most literature on integration of HIV into other health services focuses on adults; however promising practices for children are emerging. These include the Double Dividend (DD) framework, a new programming approach with dual goal of improving paediatric HIV care and child survival. In this commentary, the authors discuss why integrating HIV testing, treatment and care into child survival platforms is important, as well as its potential to advance progress towards global targets that call for, by 2020, 90% of children living with HIV to know their status, 90% of those diagnosed to be on treatment and 90% of those on treatment to be virally suppressed (90-90-90). DISCUSSION: Integration is critical in improving health outcomes and efficiency gains. In children, integration of HIV in programmes such as immunization and nutrition has been associated with an increased uptake of HIV infant testing. Integration is increasingly recognized as a case-finding strategy for children missed from prevention of mother-to-child transmission programmes and as a platform for diffusing emerging technologies such as point-of-care diagnostics. These support progress towards the 90-90-90 targets by providing a pathway for early identification of HIV-infected children with co-morbidities, prompt initiation of treatment and improved survival. There are various promising practices that have demonstrated HIV outcomes; however, few have documented the benefits of integration on child survival interventions. The DD framework is well positioned to address the bidirectional impacts for both programmes. CONCLUSIONS: Integration provides an important programmatic pathway for accelerated progress towards the 90-90-90 targets. Despite this encouraging information, there are still challenges to be addressed in order to maximize the benefits of integration.

Abstract. We describe community health workers (CHWs) in government community case management (CCM) programs for child survival across sub-Saharan Africa. In sub-Saharan Africa, 91% of 44 United Nations Children's Fund (UNICEF) offices responded to a cross-sectional survey in 2010. Frequencies describe CHW profiles and activities in government CCM programs (N = 29). Although a few programs paid CHWs a salary or conversely, rewarded CHWs purely on a non-financial basis, most programs combined financial and non-financial incentives and had training for 1 week. Not all programs allowed CHWs to provide zinc, use timers, dispense antibiotics, or use rapid diagnostic tests. Many CHWs undertake health promotion, but fewer CHWs provide soap, water treatment products, indoor residual spraying, or ready-to-use therapeutic foods. For newborn care, very few promote kangaroo care, and they do not provide antibiotics or resuscitation. Even if CHWs are as varied as the health systems in which they work, more work must be done in terms of the design and implementation of the CHW programs for them to realize their potential.