Sema K. Sgaier

Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture

Genes associated with human microcephaly, a condition characterized by a small brain, include critical regulators of proliferation, cell fate and DNA repair. We describe a syndrome of congenital microcephaly and diverse defects in cerebral cortical architecture. Genome-wide linkage analysis in two families identified a 7.5-Mb locus on chromosome 19q13.12 containing 148 genes. Targeted high throughput sequence analysis of linked genes in each family yielded > 4,000 DNA variants and implicated a single gene, WDR62, as harboring potentially deleterious changes. We subsequently identified additional WDR62 mutations in four other families. Magnetic resonance imaging and postmortem brain analysis supports important roles for WDR62 in the proliferation and migration of neuronal precursors. WDR62 is a WD40 repeat–containing protein expressed in neuronal precursors as well as in postmitotic neurons in the developing brain and localizes to the spindle poles of dividing cells. The diverse phenotypes of WDR62 suggest it has central roles in many aspects of cerebral cortical development.

Morphogenetic and cellular movements that shape the mouse cerebellum; insights from genetic fate mapping.

We used the cerebellum as a model to study the morphogenetic and cellular processes underlying the formation of elaborate brain structures from a simple neural tube, using an inducible genetic fate mapping approach in mouse. We demonstrate how a 90 degrees rotation between embryonic days 9 and 12 converts the rostral-caudal axis of dorsal rhombomere 1 into the medial-lateral axis of the wing-like bilateral cerebellar primordium. With the appropriate use of promoters, we marked specific medial-lateral domains of the cerebellar primordium and derived a positional fate map of the murine cerebellum. We show that the adult medial cerebellum is produced by expansion, rather than fusion, of the thin medial primordium. Furthermore, ventricular-derived cells maintain their original medial-lateral coordinates into the adult, whereas rhombic lip-derived granule cells undergo lateral to medial posterior transverse migrations during foliation. Thus, we show that progressive changes in the axes of the cerebellum underlie its genesis.

The Engrailed homeobox genes determine the different foliation patterns in the vermis and hemispheres of the mammalian cerebellum.

Little is known about the genetic pathways and cellular processes responsible for regional differences in cerebellum foliation, which interestingly are accompanied by regionally distinct afferent circuitry. We have identified the Engrailed (En) homeobox genes as being crucial to producing the distinct medial vermis and lateral hemisphere foliation patterns in mammalian cerebella. By producing a series of temporal conditional mutants in En1 and/or En2, we demonstrate that both En genes are required to ensure that folia exclusive to the vermis or hemispheres form in the appropriate mediolateral position. Furthermore, En1/En2 continue to regulate foliation after embryonic day 14, at which time Fgf8 isthmic organizer activity is complete and the major output cells of the cerebellar cortex have been specified. Changes in spatially restricted gene expression occur prior to foliation in mutants, and foliation is altered from the onset and is accompanied by changes in the thickness of the layer of proliferating granule cell precursors. In addition, the positioning and timing of fissure formation are altered. Thus, the En genes represent a new class of genes that are fundamental to patterning cerebellum foliation throughout the mediolateral axis and that act late in development.

Learning about scale, measurement and community mobilisation: reflections on the implementation of the Avahan HIV/AIDS initiative in India

Debates have raged in development for decades about the appropriateness of participatory approaches and the degree to which they can be managed, scaled and measured. The Avahan programme confronted these issues over the last 7 years and concludes that it is advantageous to manage scaled community mobilisation processes so that participation evolves and programming on the ground is shaped by what is learnt through implementation. The donor (Bill & Melinda Gates Foundation) and its partners determined a standard set of programme activities that were implemented programme-wide but evolved with input from communities on the ground. Difficulties faced in monitoring and measurement in Avahan may be characteristic of similar efforts to measure community mobilisation in a scaled programme, and ultimately these challenges informed methods that were useful. The approach the programme undertook for learning and changing, the activities it built into the HIV prevention programme, and its logic model and measurement tools, may be relevant in other public health settings seeking to integrate community mobilisation.

How The Avahan HIV Prevention Program Transitioned From The Gates Foundation To The Government Of India

Developing countries face diminishing development aid and time-limited donor commitments that challenge the long-term sustainability of donor-funded programs to improve the health of local populations. Increasing country ownership of the programs is one solution. Transitioning managerial and financial responsibility for donor-funded programs to governments and local stakeholders represents a highly advanced form of country ownership, but there are few successful examples among large-scale programs. We present a transition framework and describe how it was used to transfer the Bill & Melinda Gates Foundations HIV/AIDS prevention program, the Avahan program, to the Government of India. Essential features recommended for the transition of donor-funded programs to governments include early planning with the government, aligning donor program components with government structures and funding models prior to transition, building government capacity through active technical and management support, budgeting for adequate support during and after the transition, and dividing the transition into phases to allow time for adjustments and corrections. The transition of programs to governments is an important sustainability strategy for efforts to scale up HIV prevention programs to reach the populations most at risk.

Body mass index, sexual behaviour, and sexually transmitted infections : an analysis using the NHANES 1999–2000 data

BackgroundFactors determining human sexual behaviour are not completely understood, but are important in the context of sexually transmitted disease epidemiology and prevention. Being obese is commonly associated with a reduced physical attractiveness but the associations between body mass index, sexual behaviour and the risk of acquiring sexually transmitted infections has never been studied.MethodsThe National Health and Nutrition Examination Survey (NHANES) files of 1999–2000 were used. Linear regression was used to relate the reported number of sex partners in the last year and lifetime to Body Mass Index (BMI). Logistic regression was used to relate Herpes Simplex Virus type II (HSV-2) antibodies to BMI and other variables.ResultsData on 979 men and 1250 women were available for analysis. Obese (mean number of partners for men:1.12, women: 0.93) and overweight (mean for men: 1.38, women: 1.03) individuals reported fewer partners than individuals of normal BMI (mean for men:2.00, women: 1.15) in the last year (p < .0.01 & p < 0.05 for men, p < 0.05 & n.s. for women). The same relationship held for lifetime partners in men (mean 11.94, 18.80, and 22.08 for obese, overweight and normal BMI respectively (p < 0.05 & n.s. for obese and overweight vs normal respectively), but not in women (mean 7.96, 4.77, and 5.24 respectively). HSV-2 antibodies were significantly correlated with the number of lifetime partners in both men and women, with the odds of being HSV-2 positive increasing by 0.6% (p < 0.01) and 2.7% (p < 0.01) for men and women respectively. HSV-2 antibodies increased with age, even after adjustment for lifetime partners (p < 0.01). Being obese (HSV-2 prevalence 15.9 and 34.9% for men and women respectively) or overweight (HSV-2 prevalence 16.7 and 29.3 for men and women respectively) was not associated with HSV-2 antibodies (HSV-2 prevalence for normal BMI: 15.6 and 23.2% respectively), independent of whether the association was adjusted for life time sexual partners or not. There was evidence of substantial misreporting of sexual behaviour.ConclusionObese and overweight individuals, especially men, self report fewer sex partners than individuals of normal weight, but surprisingly this is not reflected in their risk of HSV-2 infection. HSV-2 antibodies provide information not contained in self-reported number of partners and may better estimate sexual risk than self-reported behaviour.

Lessons learned from scale-up of voluntary medical male circumcision focusing on adolescents: benefits, challenges, and potential opportunities for linkages with adolescent HIV, sexual, and reproductive health services.

Background and Methods:By December 2013, it was estimated that close to 6 million men had been circumcised in the 14 priority countries for scaling up voluntary medical male circumcision (VMMC), the majority being adolescents (10–19 years). This article discusses why efforts to scale up VMMC should prioritize adolescent men, drawing from new evidence and experiences at the international, country, and service delivery levels. Furthermore, we review the extent to which VMMC programs have reached adolescents, addressed their specific needs, and can be linked to their sexual and reproductive health and other key services. Results and Discussion:In priority countries, adolescents represent 34%–55% of the target population to be circumcised, whereas program data from these countries show that adolescents represent between 35% and 74% of the circumcised men. VMMC for adolescents has several advantages: uptake of services among adolescents is culturally and socially more acceptable than for adults; there are fewer barriers regarding sexual abstinence during healing or female partner pressures; VMMC performed before the age of sexual debut has maximum long-term impact on reducing HIV risk at the individual level and consequently reduces the risk of transmission in the population. Offered as a comprehensive package, adolescent VMMC can potentially increase public health benefits and offers opportunities for addressing gender norms. Additional research is needed to assess whether current VMMC services address the specific needs of adolescent clients, to test adapted tools, and to assess linkages between VMMC and other adolescent-focused HIV, health, and social services.

HIV Epidemic Appraisals for Assisting in the Design of Effective Prevention Programmes: Shifting the Paradigm Back to Basics

Background To design HIV prevention programmes, it is critical to understand the temporal and geographic aspects of the local epidemic and to address the key behaviours that drive HIV transmission. Two methods have been developed to appraise HIV epidemics and guide prevention strategies. The numerical proxy method classifies epidemics based on current HIV prevalence thresholds. The Modes of Transmission (MOT) model estimates the distribution of incidence over one year among risk-groups. Both methods focus on the current state of an epidemic and provide short-term metrics which may not capture the epidemiologic drivers. Through a detailed analysis of country and sub-national data, we explore the limitations of the two traditional methods and propose an alternative approach. Methods and Findings We compared outputs of the traditional methods in five countries for which results were published, and applied the numeric and MOT model to India and six districts within India. We discovered three limitations of the current methods for epidemic appraisal: (1) their results failed to identify the key behaviours that drive the epidemic; (2) they were difficult to apply to local epidemics with heterogeneity across district-level administrative units; and (3) the MOT model was highly sensitive to input parameters, many of which required extraction from non-regional sources. We developed an alternative decision-tree framework for HIV epidemic appraisals, based on a qualitative understanding of epidemiologic drivers, and demonstrated its applicability in India. The alternative framework offered a logical algorithm to characterize epidemics; it required minimal but key data. Conclusions Traditional appraisals that utilize the distribution of prevalent and incident HIV infections in the short-term could misguide prevention priorities and potentially impede efforts to halt the trajectory of the HIV epidemic. An approach that characterizes local transmission dynamics provides a potentially more effective tool with which policy makers can design intervention programmes.

Knowing your HIV/AIDS epidemic and tailoring an effective response: how did India do it?

Tremendous global efforts have been made to collect data on the HIV/AIDS epidemic. Yet, significant challenges remain for generating and analysing evidence to allocate resources efficiently and implement an effective AIDS response. India offers important lessons and a model for intelligent and integrated use of data on HIV/AIDS for an evidence-based response. Over the past 15 years, the number of data sources has expanded and the geographical unit of data generation, analysis and use for planning has shifted from the national to the state, district and now subdistrict level. The authors describe and critically analyse the evolution of data sets in India and how they have been utilised to better understand the epidemic, advance policy, and plan and implement an increasingly effective, well-targeted and decentralised national response to HIV and AIDS. The authors argue that India is an example of how ‘know your epidemic, know your response’ message can effectively be implemented at scale and presents important lessons to help other countries design their evidence generation systems.

Investigating Voluntary Medical Male Circumcision Program Efficiency Gains through Subpopulation Prioritization: Insights from Application to Zambia.

Background Countries in sub-Saharan Africa are scaling-up voluntary male medical circumcision (VMMC) as an HIV intervention. Emerging challenges in these programs call for increased focus on program efficiency (optimizing program impact while minimizing cost). A novel analytic approach was developed to determine how subpopulation prioritization can increase program efficiency using an illustrative application for Zambia. Methods and Findings A population-level mathematical model was constructed describing the heterosexual HIV epidemic and impact of VMMC programs (age-structured mathematical (ASM) model). The model stratified the population according to sex, circumcision status, age group, sexual-risk behavior, HIV status, and stage of infection. A three-level conceptual framework was also developed to determine maximum epidemic impact and program efficiency through subpopulation prioritization, based on age, geography, and risk profile. In the baseline scenario, achieving 80% VMMC coverage by 2017 among males 15–49 year old, 12 VMMCs were needed per HIV infection averted (effectiveness). The cost per infection averted (cost-effectiveness) was USD