Faculty Bibliography

Thermoanaerobacter thermohydrosulfuricus BSB-33 is a thermophilic gram positive obligate anaerobe isolated from a hot spring in West Bengal, India. Unlike other T. thermohydrosulfuricus strains, BSB-33 is able to anaerobically reduce Fe(III) and Cr(VI) optimally at 60 degrees C. BSB-33 is the first Cr(VI) reducing T. thermohydrosulfuricus genome sequenced and of particular interest for bioremediation of environmental chromium contaminations. Here we discuss features of T. thermohydrosulfuricus BSB-33 and the unique genetic elements that may account for the peculiar metal reducing properties of this organism. The T. thermohydrosulfuricus BSB-33 genome comprises 2597606 bp encoding 2581 protein genes, 12 rRNA, 193 pseudogenes and has a G + C content of 34.20 %. Putative chromate reductases were identified by comparative analyses with other Thermoanaerobacter and chromate-reducing bacteria.

The sarcoplasmic reticulum (SR) calcium pump (SERCA) and its regulator phospholamban are required for cardiovascular function. Phospholamban alters the apparent calcium affinity of SERCA in a process that is modulated by phosphorylation via the beta-adrenergic pathway. This regulatory axis allows for the dynamic control of SR calcium stores and cardiac contractility. Herein we focus on hereditary mutants of phospholamban that are associated with heart failure, such as Arg(9)-Cys, Arg(9)-Leu, Arg(9)-His, and Arg(14)-deletion. Each mutant has a distinct effect on PLN function and SR calcium homeostasis. Arg(9)-Cys and Arg(9)-Leu do not inhibit SERCA, Arg(14)-deletion is a partial inhibitor, and Arg(9)-His is comparable to wild-type. While the mutants have distinct functional effects on SERCA, they have in common that they cannot be phosphorylated by protein kinase A (PKA). Arg(9) and Arg(14) are required for PKA recognition and phosphorylation of PLN. Thus, mutations at these positions eliminate beta-adrenergic control and dynamic cardiac contractility. Hydrophobic mutations of Arg(9) cause more complex changes in function, including loss of PLN function and dominant negative interaction with SERCA in heterozygous individuals. In addition, aberrant interaction with PKA may prevent phosphorylation of wild-type PLN and sequester PKA from other local subcellular targets. Herein we consider what is known about each mutant and how the synergistic changes in SR calcium homeostasis lead to impaired cardiac contractility and dilated cardiomyopathy.

The sarcoplasmic reticulum calcium pump (SERCA) is regulated by the small integral membrane proteins phospholamban (PLN) and sarcolipin (SLN). These regulators have homologous transmembrane regions, yet they differ in their cytoplasmic and luminal domains. Although the sequences of PLN and SLN are practically invariant among mammals, they vary in fish. Zebrafish (zf) appear to harbor multiple PLN isoforms, one of which contains 18 sequence variations and a unique luminal extension. Characterization of this isoform (zfPLN) revealed that SERCA inhibition and reversal by phosphorylation were comparable with human PLN. To understand the sequence variations in zfPLN, chimeras were created by transferring the N terminus, linker, and C terminus of zfPLN onto human PLN. A chimera containing the N-terminal domain resulted in a mild loss of function, whereas a chimera containing the linker domain resulted in a gain of function. This latter effect was due to changes in basic residues in the linker region of PLN. Removing the unique luminal domain of zfPLN ((53)SFHGM) resulted in loss of function, whereas adding this domain to human PLN had a minimal effect on SERCA inhibition. We conclude that the luminal extension contributes to SERCA inhibition but only in the context of zfPLN. Although this domain is distinct from the SLN luminal tail, zfPLN appears to use a hybrid PLN-SLN inhibitory mechanism. Importantly, the different zebrafish PLN isoforms raise the interesting possibility that sarcoplasmic reticulum calcium handling and cardiac contractility may be regulated by the differential expression of PLN functional variants.

By the end of 2014, an estimated 8.5 million men had undergone voluntary medical male circumcision (VMMC) for HIV prevention in 14 priority countries in eastern and southern Africa, representing more than 40% of the global target. However, demand, especially among men most at risk for HIV infection, remains a barrier to realizing the program's full scale and potential impact. We analyzed current demand generation interventions for VMMC by reviewing the available literature and reporting on field visits to programs in 7 priority countries. We present our findings and recommendations using a framework with 4 components: insight development; intervention design; implementation and coordination to achieve scale; and measurement, learning, and evaluation. Most program strategies lacked comprehensive insight development; formative research usually comprised general acceptability studies. Demand generation interventions varied across the countries, from advocacy with community leaders and community mobilization to use of interpersonal communication, mid- and mass media, and new technologies. Some shortcomings in intervention design included using general instead of tailored messaging, focusing solely on the HIV preventive benefits of VMMC, and rolling out individual interventions to address specific barriers rather than a holistic package. Interventions have often been scaled-up without first being evaluated for effectiveness and cost-effectiveness. We recommend national programs create coordinated demand generation interventions, based on insights from multiple disciplines, tailored to the needs and aspirations of defined subsets of the target population, rather than focused exclusively on HIV prevention goals. Programs should implement a comprehensive intervention package with multiple messages and channels, strengthened through continuous monitoring. These insights may be broadly applicable to other programs where voluntary behavior change is essential to achieving public health benefits.

BACKGROUND: The voluntary medical male circumcision (VMMC) program in Zimbabwe aims to circumcise 80% of males aged 13-29 by 2017. We assessed the impact of actual VMMC scale-up to date and evaluated the impact of potential alterations to the program to enhance program efficiency, through prioritization of subpopulations. METHODS AND FINDINGS: We implemented a recently developed analytical approach: the age-structured mathematical (ASM) model and accompanying three-level conceptual framework to assess the impact of VMMC as an intervention. By September 2014, 364,185 males were circumcised, an initiative that is estimated to avert 40,301 HIV infections by 2025. Through age-group prioritization, the number of VMMCs needed to avert one infection (effectiveness) ranged between ten (20-24 age-group) and 53 (45-49 age-group). The cost per infection averted ranged between $811 (20-24 age-group) and $5,518 (45-49 age-group). By 2025, the largest reductions in HIV incidence rate (up to 27%) were achieved by prioritizing 10-14, 15-19, or 20-24 year old. The greatest program efficiency was achieved by prioritizing 15-24, 15-29, or 15-34 year old. Prioritizing males 13-29 year old was programmatically efficient, but slightly inferior to the 15-24, 15-29, or 15-34 age groups. Through geographic prioritization, effectiveness varied from 9-12 VMMCs per infection averted across provinces. Through risk-group prioritization, effectiveness ranged from one (highest sexual risk-group) to 60 (lowest sexual risk-group) VMMCs per infection averted. CONCLUSION: The current VMMC program plan in Zimbabwe is targeting an efficient and impactful age bracket (13-29 year old), but program efficiency can be improved by prioritizing a subset of males for demand creation and service availability. The greatest program efficiency can be attained by prioritizing young sexually active males and males whose sexual behavior puts them at higher risk for acquiring HIV.

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 $1,089 and 306,000 infections were averted. Through age-group prioritization, effectiveness ranged from 11 (20-24 age-group) to 36 (45-49 age-group); cost-effectiveness ranged from $888 (20-24 age-group) to $3,300 (45-49 age-group). Circumcising 10-14, 15-19, or 20-24 year old achieved the largest incidence rate reduction; prioritizing 15-24, 15-29, or 15-34 year old achieved the greatest program efficiency. Through geographic prioritization, effectiveness ranged from 9-12. Prioritizing Lusaka achieved the highest effectiveness. Through risk-group prioritization, prioritizing the highest risk group achieved the highest effectiveness, with only one VMMC needed per infection averted; the lowest risk group required 80 times more VMMCs. CONCLUSION: Epidemic impact and efficiency of VMMC programs can be improved by prioritizing young males (sexually active or just before sexual debut), geographic areas with higher HIV prevalence than the national, and high sexual-risk groups.

BACKGROUND: Male circumcision (MC) has been demonstrated to be effective and cost-effective for HIV/AIDS prevention. Global guidance to adopt this intervention was announced in 2007 for countries with high HIV/AIDS prevalence and low MC prevalence. However, scale up of voluntary medical male circumcision (VMMC) programs in MC priority countries have been slow. Many of these countries have particular cultural barriers that impede uptake of this effective intervention. This analysis explored correlates of MC status among men and their socio-economic, health and sexual behaviour factors using DHS data (2006-2011) from 11 MC priority countries. METHODS: Our analysis included univariate unadjusted analyses for individual countries and the region (by combining all countries into one dataset) and a multiple logistic regression model. RESULTS: Individual country results vary widely but alignment was mostly found between unadjusted analyses and multiple logistic regression model. The model found that men who are of the Muslim faith, reside in urban areas, have higher or secondary education attainment, hold professional occupations, and be in the richest wealth quintile are more likely to be circumcised. Circumcision is also positively correlated with lower reports of STIs, safe sexual behaviour, and HIV/AIDS prevention knowledge. CONCLUSIONS: Since the data collected predate VMMC program launch in these countries, results can only indicate baseline associations. However, characteristics of these existing circumcision practices may be utilized for better population targeting and program management to achieve higher impact with this effective prevention strategy.

BACKGROUND: Shellfish allergy in Singapore is highly prevalent, and shrimp allergy is the most common. OBJECTIVE: This study aims to evaluate the clinical characteristics and immunological phenotype of shellfish allergy in this population. METHODS: Patients with self-reported shellfish allergy were recruited from outpatient clinics of three large hospitals and from a population survey. Open oral food challenges (OFC) to glass prawn (Litopenaeus vannamei) and tiger prawn (Penaeus monodon) were carried out on all patients except for those who had a history of severe anaphylaxis. Skin prick tests (SPT) and specific IgE to crude and recombinant allergens were carried out to evaluate shrimp and dust mite sensitization. Immunoblots were used to assess IgE-binding proteins. RESULTS: The 104 patients recruited were categorized into shellfish allergic (SA) when OFC was positive or had a history of severe anaphylaxis (n = 39), shellfish tolerant (ST) when OFC was negative (n = 27), and house dust mite positive controls (HDM(+) ) who were ST (n = 38). Oral symptoms (87.1%) were the predominant clinical manifestation. Positive challenge doses ranged from 2 to 80 g of cooked shrimp, with 25/52 patients reacting to either one or both shrimps challenged. The presence of specific IgE to shrimp either by SPT and/or ImmunoCAP((R)) assay provided diagnostic test sensitivity of 82% and specificity of 22.2%. The inclusion of specific IgE to shrimp tropomyosin and IgE immunoblots with shrimp extracts did not improve the diagnostic proficiency substantially. CONCLUSIONS AND CLINICAL RELEVANCE: This study highlights the predominance of oral symptoms in shrimp allergy in tropical Asia and that a high provocation dose may be necessary to reveal shrimp allergy. Furthermore, specific IgE diagnostic tests and immunoblots were of limited use in this population.