Optimising Strategies for Plasmodium falciparum Malaria Elimination in Cambodia: Primaquine, Mass Drug Administration and Artemisinin Resistance

Malaria elimination requires a variety of approaches individually optimized for different transmission settings. A recent field study in an area of low seasonal transmission in South West Cambodia demonstrated dramatic reductions in malaria parasite prevalence following both mass drug administration (MDA) and high treatment coverage of symptomatic patients with artemisinin-piperaquine plus primaquine. This study employed multiple combined strategies and it was unclear what contribution each made to the reductions in malaria.A mathematical model fitted to the trial results was used to assess the effects of the various components of these interventions, design optimal elimination strategies, and explore their interactions with artemisinin resistance, which has recently been discovered in Western Cambodia. The modelling indicated that most of the initial reduction of P. falciparum malaria resulted from MDA with artemisinin-piperaquine. The subsequent continued decline and near elimination resulted mainly from high coverage with artemisinin-piperaquine treatment. Both these strategies were more effective with the addition of primaquine. MDA with artemisinin combination therapy (ACT) increased the proportion of artemisinin resistant infections, although much less than treatment of symptomatic cases with ACT, and this increase was slowed by adding primaquine. Artemisinin resistance reduced the effectiveness of interventions using ACT when the prevalence of resistance was very high. The main results were robust to assumptions about primaquine action, and immunity.The key messages of these modelling results for policy makers were: high coverage with ACT treatment can produce a long-term reduction in malaria whereas the impact of MDA is generally only short-term; primaquine enhances the effect of ACT in eliminating malaria and reduces the increase in proportion of artemisinin resistant infections; parasite prevalence is a better surveillance measure for elimination programmes than numbers of symptomatic cases; combinations of interventions are most effective and sustained efforts are crucial for successful elimination

Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer.

BackgroundT cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s.MethodsPatients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells). In trial C-9701 and C-9702, CART72 cells were administered in escalating doses up to 1010 total cells; in trial C-9701 CART72 cells were administered by intravenous infusion. In trial C-9702, CART72 cells were administered via direct hepatic artery infusion in patients with colorectal liver metastases. In both trials, a brief course of interferon-alpha (IFN-α) was given with each CART72 infusion to upregulate expression of TAG-72.ResultsFourteen patients were enrolled in C-9701 and nine in C-9702. CART72 manufacturing success rate was 100% with an average transduction efficiency of 38%. Ten patients were treated in CC-9701 and 6 in CC-9702. Symptoms consistent with low-grade, cytokine release syndrome were observed in both trials without clear evidence of on target/off tumor toxicity. Detectable, but mostly short-term (≤14 weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48 weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had 111Indium-labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum; there was a precipitous decline of TAG-72, but not CEA, in some patients due to induction of an interfering antibody to the TAG-72 binding domain of humanized CC49, reflecting an anti-CAR immune response. No radiologic tumor responses were observed.ConclusionThese findings demonstrate the relative safety of CART72 cells. The limited persistence supports the incorporation of co-stimulatory domains in the CAR design and the use of fully human CAR constructs to mitigate immunogenicity

Exploring dietitians' salient beliefs about shared decision-making behaviors

<p>Abstract</p> <p>Background</p> <p>Shared decision making (SDM), a process by which health professionals and patients go through the decision-making process together to agree on treatment, is a promising strategy for promoting diet-related decisions that are informed and value based and to which patients adhere well. The objective of the present study was to identify dietitians' salient beliefs regarding their exercise of two behaviors during the clinical encounter, both of which have been deemed essential for SDM to take place: (1) presenting patients with all dietary treatment options for a given health condition and (2) helping patients clarify their values and preferences regarding the options.</p> <p>Methods</p> <p>Twenty-one dietitians were allocated to four focus groups. Facilitators conducted the focus groups using a semistructured interview guide based on the Theory of Planned Behavior. Discussions were audiotaped, transcribed verbatim, coded, and analyzed with NVivo8 (QSR International, Cambridge, MA) software.</p> <p>Results</p> <p>Most participants stated that better patient adherence to treatment was an advantage of adopting the two SDM behaviors. Dietitians identified patients, physicians, and the multidisciplinary team as normative referents who would approve or disapprove of their adoption of the SDM behaviors. The most often reported barriers and facilitators for the behaviors concerned patients' characteristics, patients' clinical situation, and time.</p> <p>Conclusions</p> <p>The implementation of SDM in nutrition clinical practice can be guided by addressing dietitians' salient beliefs. Identifying these beliefs also provides the theoretical framework needed for developing a quantitative survey questionnaire to further study the determinants of dietitians' adoption of SDM behaviors.</p

Performance of InterVA for assigning causes of death to verbal autopsies: multisite validation study using clinical diagnostic gold standards

Background: InterVA is a widely disseminated tool for cause of death attribution using information from verbal autopsies. Several studies have attempted to validate the concordance and accuracy of the tool, but the main limitation of these studies is that they compare cause of death as ascertained through hospital record review or hospital discharge diagnosis with the results of InterVA. This study provides a unique opportunity to assess the performance of InterVA compared to physician-certified verbal autopsies (PCVA) and alternative automated methods for analysis.Methods: Using clinical diagnostic gold standards to select 12,542 verbal autopsy cases, we assessed the performance of InterVA on both an individual and population level and compared the results to PCVA, conducting analyses separately for adults, children, and neonates. Following the recommendation of Murray et al., we randomly varied the cause composition over 500 test datasets to understand the performance of the tool in different settings. We also contrasted InterVA with an alternative Bayesian method, Simplified Symptom Pattern (SSP), to understand the strengths and weaknesses of the tool.Results: Across all age groups, InterVA performs worse than PCVA, both on an individual and population level. On an individual level, InterVA achieved a chance-corrected concordance of 24.2% for adults, 24.9% for children, and 6.3% for neonates (excluding free text, considering one cause selection). On a population level, InterVA achieved a cause-specific mortality fraction accuracy of 0.546 for adults, 0.504 for children, and 0.404 for neonates. The comparison to SSP revealed four specific characteristics that lead to superior performance of SSP. Increases in chance-corrected concordance are attained by developing cause-by-cause models (2%), using all items as opposed to only the ones that mapped to InterVA items (7%), assigning probabilities to clusters of symptoms (6%), and using empirical as opposed to expert probabilities (up to 8%).Conclusions: Given the widespread use of verbal autopsy for understanding the burden of disease and for setting health intervention priorities in areas that lack reliable vital registrations systems, accurate analysis of verbal autopsies is essential. While InterVA is an affordable and available mechanism for assigning causes of death using verbal autopsies, users should be aware of its suboptimal performance relative to other methods

Robust metrics for assessing the performance of different verbal autopsy cause assignment methods in validation studies

<p>Abstract</p> <p>Background</p> <p>Verbal autopsy (VA) is an important method for obtaining cause of death information in settings without vital registration and medical certification of causes of death. An array of methods, including physician review and computer-automated methods, have been proposed and used. Choosing the best method for VA requires the appropriate metrics for assessing performance. Currently used metrics such as sensitivity, specificity, and cause-specific mortality fraction (CSMF) errors do not provide a robust basis for comparison.</p> <p>Methods</p> <p>We use simple simulations of populations with three causes of death to demonstrate that most metrics used in VA validation studies are extremely sensitive to the CSMF composition of the test dataset. Simulations also demonstrate that an inferior method can appear to have better performance than an alternative due strictly to the CSMF composition of the test set.</p> <p>Results</p> <p>VA methods need to be evaluated across a set of test datasets with widely varying CSMF compositions. We propose two metrics for assessing the performance of a proposed VA method. For assessing how well a method does at individual cause of death assignment, we recommend the average chance-corrected concordance across causes. This metric is insensitive to the CSMF composition of the test sets and corrects for the degree to which a method will get the cause correct due strictly to chance. For the evaluation of CSMF estimation, we propose CSMF accuracy. CSMF accuracy is defined as one minus the sum of all absolute CSMF errors across causes divided by the maximum total error. It is scaled from zero to one and can generalize a method's CSMF estimation capability regardless of the number of causes. Performance of a VA method for CSMF estimation by cause can be assessed by examining the relationship across test datasets between the estimated CSMF and the true CSMF.</p> <p>Conclusions</p> <p>With an increasing range of VA methods available, it will be critical to objectively assess their performance in assigning cause of death. Chance-corrected concordance and CSMF accuracy assessed across a large number of test datasets with widely varying CSMF composition provide a robust strategy for this assessment.</p

Genetic identification of cytomegaloviruses in a rural population of Côte d'Ivoire.

BACKGROUND: Cytomegaloviruses (CMVs) are herpesviruses that infect many mammalian species, including humans. Infection generally passes undetected, but the virus can cause serious disease in individuals with impaired immune function. Human CMV (HCMV) is circulating with high seroprevalence (60-100 %) on all continents. However, little information is available on HCMV genoprevalence and genetic diversity in subsaharan Africa, especially in rural areas of West Africa that are at high risk of human-to-human HCMV transmission. In addition, there is a potential for zoonotic spillover of pathogens through bushmeat hunting and handling in these areas as shown for various retroviruses. Although HCMV and nonhuman CMVs are regarded as species-specific, potential human infection with CMVs of non-human primate (NHP) origin, shown to circulate in the local NHP population, has not been studied. FINDINGS: Analysis of 657 human oral swabs and fecal samples collected from 518 individuals living in 8 villages of Côte d'Ivoire with generic PCR for identification of human and NHP CMVs revealed shedding of HCMV in 2.5 % of the individuals. Determination of glycoprotein B sequences showed identity with strains Towne, AD169 and Toledo, respectively. NHP CMV sequences were not detected. CONCLUSIONS: HCMV is actively circulating in a proportion of the rural Côte d'Ivoire human population with circulating strains being closely related to those previously identified in non-African countries. The lack of NHP CMVs in human populations in an environment conducive to cross-species infection supports zoonotic transmission of CMVs to humans being at most a rare event

The Potential Contribution of Mass Treatment to the Control of Plasmodium falciparum Malaria

Mass treatment as a means to reducing P. falciparum malaria transmission was used during the first global malaria eradication campaign and is increasingly being considered for current control programmes. We used a previously developed mathematical transmission model to explore both the short and long-term impact of possible mass treatment strategies in different scenarios of endemic transmission. Mass treatment is predicted to provide a longer-term benefit in areas with lower malaria transmission, with reduced transmission levels for at least 2 years after mass treatment is ended in a scenario where the baseline slide-prevalence is 5%, compared to less than one year in a scenario with baseline slide-prevalence at 50%. However, repeated annual mass treatment at 80% coverage could achieve around 25% reduction in infectious bites in moderate-to-high transmission settings if sustained. Using vector control could reduce transmission to levels at which mass treatment has a longer-term impact. In a limited number of settings (which have isolated transmission in small populations of 1000–10,000 with low-to-medium levels of baseline transmission) we find that five closely spaced rounds of mass treatment combined with vector control could make at least temporary elimination a feasible goal. We also estimate the effects of using gametocytocidal treatments such as primaquine and of restricting treatment to parasite-positive individuals. In conclusion, mass treatment needs to be repeated or combined with other interventions for long-term impact in many endemic settings. The benefits of mass treatment need to be carefully weighed against the risks of increasing drug selection pressure

Genome-Wide Association Studies in an Isolated Founder Population from the Pacific Island of Kosrae

It has been argued that the limited genetic diversity and reduced allelic heterogeneity observed in isolated founder populations facilitates discovery of loci contributing to both Mendelian and complex disease. A strong founder effect, severe isolation, and substantial inbreeding have dramatically reduced genetic diversity in natives from the island of Kosrae, Federated States of Micronesia, who exhibit a high prevalence of obesity and other metabolic disorders. We hypothesized that genetic drift and possibly natural selection on Kosrae might have increased the frequency of previously rare genetic variants with relatively large effects, making these alleles readily detectable in genome-wide association analysis. However, mapping in large, inbred cohorts introduces analytic challenges, as extensive relatedness between subjects violates the assumptions of independence upon which traditional association test statistics are based. We performed genome-wide association analysis for 15 quantitative traits in 2,906 members of the Kosrae population, using novel approaches to manage the extreme relatedness in the sample. As positive controls, we observe association to known loci for plasma cholesterol, triglycerides, and C-reactive protein and to a compelling candidate loci for thyroid stimulating hormone and fasting plasma glucose. We show that our study is well powered to detect common alleles explaining ≥5% phenotypic variance. However, no such large effects were observed with genome-wide significance, arguing that even in such a severely inbred population, common alleles typically have modest effects. Finally, we show that a majority of common variants discovered in Caucasians have indistinguishable effect sizes on Kosrae, despite the major differences in population genetics and environment

Systematic evaluation of immune regulation and modulation

Cancer immunotherapies are showing promising clinical results in a variety of malignancies. Monitoring the immune as well as the tumor response following these therapies has led to significant advancements in the field. Moreover, the identification and assessment of both predictive and prognostic biomarkers has become a key component to advancing these therapies. Thus, it is critical to develop systematic approaches to monitor the immune response and to interpret the data obtained from these assays. In order to address these issues and make recommendations to the field, the Society for Immunotherapy of Cancer reconvened the Immune Biomarkers Task Force. As a part of this Task Force, Working Group 3 (WG3) consisting of multidisciplinary experts from industry, academia, and government focused on the systematic assessment of immune regulation and modulation. In this review, the tumor microenvironment, microbiome, bone marrow, and adoptively transferred T cells will be used as examples to discuss the type and timing of sample collection. In addition, potential types of measurements, assays, and analyses will be discussed for each sample. Specifically, these recommendations will focus on the unique collection and assay requirements for the analysis of various samples as well as the high-throughput assays to evaluate potential biomarkers