Strategies for containing Ebola in West Africa.

The ongoing Ebola outbreak poses an alarming risk to the countries of West Africa and beyond. To assess the effectiveness of containment strategies, we developed a stochastic model of Ebola transmission between and within the general community, hospitals, and funerals, calibrated to incidence data from Liberia. We find that a combined approach of case isolation, contact-tracing with quarantine, and sanitary funeral practices must be implemented with utmost urgency in order to reverse the growth of the outbreak.

Effect of Ebola progression on transmission and control in Liberia.

Background: The Ebola outbreak that is sweeping across West Africa is the largest, most volatile, and deadliest Ebola epidemic ever recorded. Liberia is the most profoundly affected country, with more than 3500 infections and 2000 deaths recorded in the past 3 months.

Objective: To evaluate the contribution of disease progression and case fatality on transmission and to examine the potential for targeted interventions to eliminate the disease.

Impact of Schistosoma mansoni on malaria transmission in Sub-Saharan Africa.

Background: Sub-Saharan Africa harbors the majority of the global burden of malaria and schistosomiasis infections. The co-endemicity of these two tropical diseases has prompted investigation into the mechanisms of coinfection, particularly the competing immunological responses associated with each disease. Epidemiological studies have shown that infection with Schistosoma mansoni is associated with a greater malaria incidence among school-age children.

Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors.

We report herein the discovery, structure guided design, synthesis and biological evaluation of a novel class of JAK2 inhibitors. Optimization of the series led to the identification of the potent and orally bioavailable JAK2 inhibitor 28 (NMS-P953). Compound 28 displayed significant tumour growth inhibition in SET-2 xenograft tumour model, with a mechanism of action confirmed in vivo by typical modulation of known biomarkers, and with a favourable pharmacokinetic and safety profile.

Fragment-based hit discovery and structure-based optimization of aminotriazoloquinazolines as novel Hsp90 inhibitors.

In the last decade the heat shock protein 90 (Hsp90) has emerged as a major therapeutic target and many efforts have been dedicated to the discovery of Hsp90 inhibitors as new potent anticancer agents. Here we report the identification of a novel class of Hsp90 inhibitors by means of a biophysical FAXS-NMR based screening of a library of fragments. The use of X-ray structure information combined with modeling studies enabled the fragment evolution of the initial triazoloquinazoline hit to a class of compounds with nanomolar potency and drug-like properties suited for further lead optimization.

The TPM3-NTRK1 rearrangement is a recurring event in colorectal carcinoma and is associated with tumor sensitivity to TRKA kinase inhibition.

The NTRK1 gene encodes Tropomyosin-related kinase A (TRKA), the high-affinity Nerve Growth Factor Receptor. NTRK1 was originally isolated from a colorectal carcinoma (CRC) sample as component of a somatic rearrangement (TPM3-NTRK1) resulting in expression of the oncogenic chimeric protein TPM3-TRKA, but there has been no subsequent report regarding the relevance of this oncogene in CRC. The KM12 human CRC cell line expresses the chimeric TPM3-TRKA protein and is hypersensitive to TRKA kinase inhibition.

Cost-effectiveness of influenza vaccination in prior pneumonia patients in Israel.

Pneumonia is a common complication of influenza infection, and accounts for the majority of influenza mortality. Both the WHO and the Ministry of Health in Israel prioritize seasonal influenza vaccination primarily on the basis of age and specific co-morbidities. Here we consider whether the targeting of individuals previously infected with pneumonia for influenza vaccination would be a cost-effective addition to the current policy.

Evaluating the potential impact of mass praziquantel administration for HIV prevention in Schistosoma haematobium high-risk communities.

Genital infection with Schistosoma haematobium is prevalent in sub-Saharan Africa. Epidemiological studies have observed that genital schistosomiasis is associated with an increased odd of HIV infection among women. We used mathematical modeling to explore the potential impact of mass preventive chemotherapy against schistosomiasis on HIV transmission in three sub-Saharan Africa countries: Angola, Kenya, and Zambia.

An innovative influenza vaccination policy: targeting last season's patients.

Influenza vaccination is the primary approach to prevent influenza annually. WHO/CDC recommendations prioritize vaccinations mainly on the basis of age and co-morbidities, but have never considered influenza infection history of individuals for vaccination targeting. We evaluated such influenza vaccination policies through small-world contact networks simulations.

A marginal benefit approach for vaccinating influenza "superspreaders".

Background: There is widespread recognition that interventions targeting "superspreaders" are more effective at containing epidemics than strategies aimed at the broader

Population: However, little attention has been devoted to determining optimal levels of coverage for targeted vaccination strategies, given the nonlinear relationship between program scale and the costs and benefits of identifying and successfully administering vaccination to potential superspreaders.

Methods: We developed a framework for such an assessment derived from a transmission model of seasonal influenza parameterized to emulate typical seasonal influenza epidemics in the US. We used this framework to estimate how the marginal benefit of expanded targeted vaccination changes with the proportion of the target population already vaccinated.

Probabilistic uncertainty analysis of epidemiological modeling to guide public health intervention policy.

Mathematical modeling of disease transmission has provided quantitative predictions for health policy, facilitating the evaluation of epidemiological outcomes and the cost-effectiveness of interventions. However, typical sensitivity analyses of deterministic dynamic infectious disease models focus on model architecture and the relative importance of parameters but neglect parameter uncertainty when reporting model predictions. Consequently, model results that identify point estimates of intervention levels necessary to terminate transmission yield limited insight into the probability of success.

Cost-effectiveness of canine vaccination to prevent human rabies in rural Tanzania.

Background: The annual mortality rate of human rabies in rural Africa is 3.6 deaths per 100 000 persons. Rabies can be prevented with prompt postexposure prophylaxis, but this is costly and often inaccessible in rural Africa.

Free-riding behavior in vaccination decisions: an experimental study.

Individual decision-making regarding vaccination may be affected by the vaccination choices of others. As vaccination produces externalities reducing transmission of a disease, it can provide an incentive for individuals to be free-riders who benefit from the vaccination of others while avoiding the cost of vaccination. This study examined an individual's decision about vaccination in a group setting for a hypothetical disease that is called "influenza" using a computerized experimental game.

Economic epidemiology of avian influenza on smallholder poultry farms.

Highly pathogenic avian influenza (HPAI) is often controlled through culling of poultry. Compensating farmers for culled chickens or ducks facilitates effective culling and control of HPAI. However, ensuing price shifts can create incentives that alter the disease dynamics of HPAI.

Country- and age-specific optimal allocation of dengue vaccines.

Several dengue vaccines are under development, and some are expected to become available imminently. Concomitant with the anticipated release of these vaccines, vaccine allocation strategies for dengue-endemic countries in Southeast Asia and Latin America are currently under development. We developed a model of dengue transmission that incorporates the age-specific distributions of dengue burden corresponding to those in Thailand and Brazil, respectively, to determine vaccine allocations that minimize the incidence of dengue hemorrhagic fever, taking into account limited availability of vaccine doses in the initial phase of production.

Discovery and optimization of pyrrolo[1,2-a]pyrazinones leads to novel and selective inhibitors of PIM kinases.

A novel series of PIM inhibitors was derived from a combined effort in natural product-inspired library generation and screening. The novel pyrrolo[1,2-a]pyrazinones initial hits are inhibitors of PIM isoforms with IC50 values in the low micromolar range. The application of a rational optimization strategy, guided by the determination of the crystal structure of the complex in the kinase domain of PIM1 with compound 1, led to the discovery of compound 15a, which is a potent PIM kinases inhibitor exhibiting excellent selectivity against a large panel of kinases, representative of each family.

Epidemiology. Social factors in epidemiology.

The coupling of social and biological contagion in human populations can have positive or negative outcomes.

Evaluating paratransgenesis as a potential control strategy for African trypanosomiasis.

Genetic-modification strategies are currently being developed to reduce the transmission of vector-borne diseases, including African trypanosomiasis. For tsetse, the vector of African trypanosomiasis, a paratransgenic strategy is being considered: this approach involves modification of the commensal symbiotic bacteria Sodalis to express trypanosome-resistance-conferring products. Modified Sodalis can then be driven into the tsetse population by cytoplasmic incompatibility (CI) from Wolbachia bacteria.

HIV and Schistosoma haematobium prevalences correlate in sub-Saharan Africa.

Objective: Epidemiological studies have observed that genital schistosomiasis increases the risk of HIV infection in Africa. We analysed the correlation between Schistosoma haematobium prevalence and HIV prevalence across sub-Saharan African countries.

Design: Regression analysis of prevalence of HIV and S.

Potential cost-effectiveness of schistosomiasis treatment for reducing HIV transmission in Africa--the case of Zimbabwean women.

Background: Epidemiological data from Zimbabwe suggests that genital infection with Schistosoma haematobium may increase the risk of HIV infection in young women. Therefore, the treatment of Schistosoma haematobium with praziquantel could be a potential strategy for reducing HIV infection. Here we assess the potential cost-effectiveness of praziquantel as a novel intervention strategy against HIV infection.

Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell death.

VCP (also known as p97 or Cdc48p in yeast) is an AAA(+) ATPase regulating endoplasmic reticulum-associated degradation. After high-throughput screening, we developed compounds that inhibit VCP via different mechanisms, including covalent modification of an active site cysteine and a new allosteric mechanism. Using photoaffinity labeling, structural analysis and mutagenesis, we mapped the binding site of allosteric inhibitors to a region spanning the D1 and D2 domains of adjacent protomers encompassing elements important for nucleotide-state sensing and ATP hydrolysis.