Ending preventable child deaths in South Africa: What role can ward-based outreach teams play?

South Africa (SA) has emerged from the Millennium Development Goal era with a  mixture of success and failure. The successful national scale-up of prevention of  mother-to-child transmission of HIV services with increasingly efficacious   antiretroviral regimens has reduced the mother-to-child transmission rate dramatically; however, over the same period there appears to have been no progress in coverage of high-impact interventions for pneumonia and diarrhoea, which are now leading causes of under-5 mortality. SA embarked on a strategy to re-engineer the primary healthcare system in 2011, which included the creation of ward-based outreach teams consisting of community health workers (CHWs). In this article we argue that the proposed ratio of CHWs to population is too low for public health impact and that the role and scope of CHWs should be extended beyond giving of health information to include assessment and treatment of childhood illnesses (particularly diarrhoea and suspected pneumonia). Evidence and experience amply demonstrate that CHWs in sufficient density can have a rapid and positive impact on neonatal and young child mortality, especially when they are allowed to treat common acute conditions. SA’s mediocre performance in child survival could be dramatically improved if there were more CHWs who were allowed to do more

Coarse-grained model of entropic allostery

Many signaling functions in molecular biology require proteins to bind to substrates such as DNA in response to environmental signals such as the simultaneous binding to a small molecule. Examples are repressor proteins which may transmit information via a conformational change in response to the ligand binding. An alternative entropic mechanism of "allostery" suggests that the inducer ligand changes the intramolecular vibrational entropy, not just the mean static structure. We present a quantitative, coarse-grained model of entropic allostery, which suggests design rules for internal cohesive potentials in proteins employing this effect. It also addresses the issue of how the signal information to bind or unbind is transmitted through the protein. The model may be applicable to a wide range of repressors and also to signaling in trans-membrane proteins

Genetic Correlates of Brain Aging on MRI and Cognitive Test Measures: A Genome-Wide Association and Linkage Analysis in the Framingham Study

BACKGROUND: Brain magnetic resonance imaging (MRI) and cognitive tests can identify heritable endophenotypes associated with an increased risk of developing stroke, dementia and Alzheimer's disease (AD). We conducted a genome-wide association (GWA) and linkage analysis exploring the genetic basis of these endophenotypes in a community-based sample. METHODS: A total of 705 stroke- and dementia-free Framingham participants (age 62 +9 yrs, 50% male) who underwent volumetric brain MRI and cognitive testing (1999–2002) were genotyped. We used linear models adjusting for first degree relationships via generalized estimating equations (GEE) and family based association tests (FBAT) in additive models to relate qualifying single nucleotide polymorphisms (SNPs, 70,987 autosomal on Affymetrix 100K Human Gene Chip with minor allele frequency ≥ 0.10, genotypic call rate ≥ 0.80, and Hardy-Weinberg equilibrium p-value ≥ 0.001) to multivariable-adjusted residuals of 9 MRI measures including total cerebral brain (TCBV), lobar, ventricular and white matter hyperintensity (WMH) volumes, and 6 cognitive factors/tests assessing verbal and visuospatial memory, visual scanning and motor speed, reading, abstract reasoning and naming. We determined multipoint identity-by-descent utilizing 10,592 informative SNPs and 613 short tandem repeats and used variance component analyses to compute LOD scores. RESULTS: The strongest gene-phenotype association in FBAT analyses was between SORL1 (rs1131497; p = 3.2 × 10-6) and abstract reasoning, and in GEE analyses between CDH4 (rs1970546; p = 3.7 × 10-8) and TCBV. SORL1 plays a role in amyloid precursor protein processing and has been associated with the risk of AD. Among the 50 strongest associations (25 each by GEE and FBAT) were other biologically interesting genes. Polymorphisms within 28 of 163 candidate genes for stroke, AD and memory impairment were associated with the endophenotypes studied at p < 0.001. We confirmed our previously reported linkage of WMH on chromosome 4 and describe linkage of reading performance to a marker on chromosome 18 (GATA11A06), previously linked to dyslexia (LOD scores = 2.2 and 5.1). CONCLUSION: Our results suggest that genes associated with clinical neurological disease also have detectable effects on subclinical phenotypes. These hypothesis generating data illustrate the use of an unbiased approach to discover novel pathways that may be involved in brain aging, and could be used to replicate observations made in other studies.National Institutes of Health National Center for Research Resources Shared Instrumentation grant (ISI0RR163736-01A1); National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC-25195); National Institute of Aging (5R01-AG08122, 5R01-AG16495); National Institute of Neurological Disorders and Stroke (5R01-NS17950

Process Evaluation in Action: Lessons Learned from Alabama REACH 2010

The CDC-funded Alabama Racial and Ethnic Approaches to Community Health (REACH 2010) project is designed to reduce and eliminate disparities in breast and cervical cancer between African American and white women in six rural and three urban counties in Alabama. In this manuscript, we report on the development, implementation, results, and lessons learned from a process evaluation plan initiated during the Phase I planning period of the Alabama REACH 2010 program. The process evaluation plan for Alabama REACH 2010 focused on four main areas of activity that coincided with program objectives: assessing coalition development, building community capacity, conducting a needs assessment, and developing a community action plan. Process evaluation findings indicated that progress made by Alabama REACH 2010 was due, in part, to evaluative feedback. We conclude that process evaluation can be a powerful tool for monitoring and measuring the administrative aspect of a complex, community-based health intervention

Selective Inhibition of p300 HAT Blocks Cell Cycle Progression, Induces Cellular Senescence, and Inhibits the DNA Damage Response in Melanoma Cells

Epigenetic events, including covalent post-translational modifications of histones, have been demonstrated to have critical roles in tumor development and progression. The transcriptional coactivator p300/CBP possesses both histone acetyltransferase (HAT) activity and scaffolding properties that directly influence the transcriptional activation of targeted genes. We have used a potent and specific inhibitor of p300/CBP HAT activity, C646, in order to evaluate the functional contributions of p300/CBP HAT to tumor development and progression. Here we report that C646 inhibits the growth of human melanoma and other tumor cells and promotes cellular senescence. Global assessment of the p300 HAT transcriptome in human melanoma identified functional roles in promoting cell cycle progression, chromatin assembly, and activation of DNA repair pathways through direct transcriptional regulatory mechanisms. In addition, C646 is shown to promote sensitivity to DNA damaging agents, leading to the enhanced apoptosis of melanoma cells after combination treatment with cisplatin. Together, our data suggest that p300 HAT activity mediates critical growth regulatory pathways in tumor cells and may serve as a potential therapeutic target for melanoma and other malignancies by promoting cellular responses to DNA damaging agents that are currently ineffective against specific cancers

Pentaalkoxytriphenylene monoesters and their dyads; structural factors influencing columnar and nematic mesophase behaviour

Ester linkages are frequently employed in the design of discotic liquid crystals, and indeed the first examples of discotic liquid crystals reported by Chandrasekhar, Sadashiva and Suresh were hexaesters of benzene. Within the wide range of liquid crystalline triphenylene systems so far reported, the symmetrical hexa(aryl) esters are particularly noteworthy because they form the relatively rare and technologically important discotic nematic mesophase. An alternative strategy for inducing nematogenic behaviour is to build linked and twinned structures, and here we report examples of materials that combine the two design features. Pentahexyloxy triphenylenes bearing a single aryl ester retain the columnar mesophase. Linked dyad structures promote nematic phase formation and stability is influenced by the link type and bonding arrangement within isomeric series (phthalates) and related constructs

Building capacity for HIV/AIDS program leadership and management in Uganda through mentored Fellowships

Background: Around the world, health professionals and program managers are leading and managing public and private health organizations with little or no formal management and leadership training and experience. Objective: To describe an innovative 2-year, long-term apprenticeship Fellowship training program implemented by Makerere University School of Public Health (MakSPH) to strengthen capacity for leadership and management of HIV/AIDS programs in Uganda. Implementation process: The program, which began in 2002, is a 2-year, full-time, non-degree Fellowship. It is open to Ugandan nationals with postgraduate training in health-related disciplines. Enrolled Fellows are attached to host institutions implementing HIV/AIDS programs and placed under the supervision of host institution and academic mentors. Fellows spend 75% of their apprenticeship at the host institutions while the remaining 25% is dedicated to didactic short courses conducted at MakSPH to enhance their knowledge base. Achievements: Overall, 77 Fellows have been enrolled since 2002. Of the 57 Fellows who were admitted between 2002 and 2008, 94.7% (54) completed the Fellowship successfully and 50 (92.3%) are employed in senior leadership and management positions in Uganda and internationally. Eighty-eight percent of those employed (44/54) work in institutions registered in Uganda, indicating a high level of in-country retention. Nineteen of the 20 Fellows who were admitted between 2009 and 2010 are still undergoing training. A total of 67 institutions have hosted Fellows since 2002. The host institutions have benefited through staff training and technical expertise from the Fellows as well as through grant support to Fellows to develop and implement innovative pilot projects. The success of the program hinges on support from mentors, stakeholder involvement, and the hands-on approach employed in training. Conclusion: The Fellowship Program offers a unique opportunity for hands-on training in HIV/AIDS program leadership and management for both Fellows and host institutions

Exploring computational approaches to design mRNA Vaccine against vaccinia and Mpox viruses

Background: Messenger RNA (mRNA) vaccines emerged as a powerful tool in the fight against infections. Unlike traditional vaccines, this unique type of vaccine elicits robust and persistent innate and humoral immune response with a unique host cell‐mediated pathogen gene expression and antigen presentation. Methods: This offers a novel approach to combat poxviridae infections. From the genome of vaccinia and Mpox viruses, three key genes (E8L, E7R, and H3L) responsible for virus attachment and virulence were selected and employed for designing the candidate mRNA vaccine against vaccinia and Mpox viral infection. Various bioinformatics tools were employed to generate (B cell, CTL, and HTL) epitopes, of which 28 antigenic and immunogenic epitopes were selected and are linked to form the mRNA vaccine construct. Additional components, including a 5′ cap, 5′ UTR, adjuvant, 3′ UTR, and poly(A) tail, were incorporated to enhance stability and effectiveness. Safety measures such as testing for human homology and in silico immune simulations were implemented to avoid autoimmunity and to mimics the immune response of human host to the designed mRNA vaccine, respectively. The mRNA vaccine's binding affinity was evaluated by docking it with TLR‐2, TLR‐3, TLR‐4, and TLR‐9 receptors which are subsequently followed by molecular dynamics simulations for the highest binding one to predict the stability of the binding complex. Results: With a 73% population coverage, the mRNA vaccine looks promising, boasting a molecular weight of 198 kDa and a molecular formula of C8901H13609N2431O2611S48 and it is said to be antigenic, nontoxic and nonallergic, making it safe and effective in preventing infections with Mpox and vaccinia viruses, in comparison with other insilico‐designed vaccine for vaccinia and Mpox viruses. Conclusions: However, further validation through in vivo and in vitro techniques is underway to fully assess its potential

Consuming cassava as a staple food places children 2-5 years old at risk for inadequate protein intake, an observational study in Kenya and Nigeria

<p>Abstract</p> <p>Background</p> <p>Inadequate protein intake is known to be deleterious in animals. Using WHO consensus documents for human nutrient requirements, the protein:energy ratio (P:E) of an adequate diet is > 5%. Cassava has a very low protein content. This study tested the hypothesis that Nigerian and Kenyan children consuming cassava as their staple food are at greater risk for inadequate dietary protein intake than those children who consume less cassava.</p> <p>Methods</p> <p>A 24 hour dietary recall was used to determine the food and nutrient intake of 656 Nigerian and 449 Kenyan children aged 2-5 years residing in areas where cassava is a staple food. Anthropometric measurements were conducted. Diets were scored for diversity using a 12 point score. Pearson's Correlation Coefficients were calculated to relate the fraction of dietary energy obtained from cassava with protein intake, P:E, and dietary diversity.</p> <p>Results</p> <p>The fraction of dietary energy obtained from cassava was > 25% in 35% of Nigerian children and 89% of Kenyan children. The mean dietary diversity score was 4.0 in Nigerian children and 4.5 in Kenyan children, although the mean number of different foods consumed on the survey day in Nigeria was greater than Kenya, 7.0 compared to 4.6. 13% of Nigerian and 53% of Kenyan children surveyed had inadequate protein intake. The fraction of dietary energy derived from cassava was negatively correlated with protein intake, P:E, and dietary diversity. Height-for age z score was directly associated with protein intake and negatively associated with cassava consumption using regression modeling that controlled for energy and zinc intake.</p> <p>Conclusions</p> <p>Inadequate protein intake was found in the diets of Nigerian and Kenyan children consuming cassava as a staple food. Inadequate dietary protein intake is associated with stunting in this population. Interventions to increase protein intake in this vulnerable population should be the focus of future work.</p