Ranking Malaria Risk Factors to Guide Malaria Control Efforts in African Highlands

Introduction

Malaria is re-emerging in most of the African highlands exposing the non immune population to deadly epidemics. A better understanding of the factors impacting transmission in the highlands is crucial to improve well targeted malaria control strategies.

Methods and Findings

A conceptual model of potential malaria risk factors in the highlands was built based on the available literature. Furthermore, the relative importance of these factors on malaria can be estimated through “classification and regression trees”, an unexploited statistical method in the malaria field. This CART method was used to analyse the malaria risk factors in the Burundi highlands. The results showed that Anopheles density was the best predictor for high malaria prevalence. Then lower rainfall, no vector control, higher minimum temperature and houses near breeding sites were associated by order of importance to higher Anopheles density.

Conclusions

In Burundi highlands monitoring Anopheles densities when rainfall is low may be able to predict epidemics. The conceptual model combined with the CART analysis is a decision support tool that could provide an important contribution toward the prevention and control of malaria by identifying major risk factors.     

Brain Insulin Signaling and Alzheimer's Disease: Current Evidence and Future Directions

Insulin receptors in the brain are found in high densities in the hippocampus, a region that is fundamentally involved in the acquisition, consolidation, and recollection of new information. Using the intranasal method, which effectively bypasses the blood-brain barrier to deliver and target insulin directly from the nose to the brain, a series of experiments involving healthy humans has shown that increased central nervous system (CNS) insulin action enhances learning and memory processes associated with the hippocampus. Since Alzheimer's disease (AD) is linked to CNS insulin resistance, decreased expression of insulin and insulin receptor genes and attenuated permeation of blood-borne insulin across the blood-brain barrier, impaired brain insulin signaling could partially account for the cognitive deficits associated with this disease. Considering that insulin mitigates hippocampal synapse vulnerability to amyloid beta and inhibits the phosphorylation of tau, pharmacological strategies bolstering brain insulin signaling, such as intranasal insulin, could have significant therapeutic potential to deter AD pathogenesis.     

River Restoration in the Twenty-First Century: Data and Experiential Knowledge to Inform Future Efforts

Despite some highly visible projects that have resulted in environmental benefits, recent efforts to quantify the number and distribution of river restoration projects revealed a paucity of written records documenting restoration outcomes. Improving restoration designs and setting watershed priorities rely on collecting and making accessible this critical information. Information within the unpublished notes of restoration project managers is useful but rarely documents ecological improvements. This special section of Restoration Ecology is devoted to the current state of knowledge on river restoration. We provide an overview of the section’s articles, reflecting on lessons learned, which have implications for the implementation, legal, and financing frameworks for restoration. Our reflections are informed by two databases developed under the auspices of the National River Restoration Science Synthesis project and by extensive interactions with those who fund, implement, and permit restoration. Requiring measurable ecological success criteria, comprehensive watershed plans, and tracking of when and where restoration projects are implemented are critical to improving the health of U.S. waters. Documenting that a project was put in the ground and stayed intact cannot be equated with ecological improvements. However, because significant ecological improvements can come with well‐designed and ‐implemented stream and river restorations, a small investment in documenting the factors contributing to success will lead to very large returns in the health of our nation’s waterways. Even projects that may appear to be failures initially can be turned into success stories by applying the knowledge gained from monitoring the project in an adaptive restoration approach.     

Elimination of schistosomiasis in China: Current status and future prospects

Elimination of schistosomiasis as a public health problem among all disease-endemic countries in 2030 is an ambitious goal. Recent achievements resulting from mass drug administration (MDA) with praziquantel is promising but may need to be complemented with also other means. Schistosomiasis was highly prevalent in China before the initiation of the national schistosomiasis control program in the mid-1950s, and, at that time, the country bore the world’s highest burden of schistosomiasis. The concerted control efforts, upheld without interruption for more than a half century, have resulted in elimination of the disease as a public health problem in China as of 2015. Here, we describe the current status of schistosomiasis in China, analyze the potential challenges affecting schistosomiasis elimination, and propose the future research needs and priorities for the country, aiming to provide more universal insights into the structures needed for a global schistosomiasis elimination encompassing also other endemic regions.     

Cytokines as Mediators of Chemotherapy-Associated Cognitive Changes: Current Evidence,Limitations and Directions for Future Research

Objectives

While various clinical and pharmacological determinants for chemotherapy-associated cognitive impairment have been identified, conflicting evidence suggests that cytokines might play an intermediary role. The objective of this systematic review was to evaluate the current evidence pertaining to the associations among chemotherapy, cytokines induction and cognitive impairment in cancer patients.

Methods

A literature search with PubMed and SciVerse Scopus was conducted in March 2013 to gather relevant articles and abstracts that fulfilled the inclusion and exclusion criteria. This review included studies that had performed objective and/or subjective cognitive assessments and cytokine measurements on defined populations of cancer patients who received chemotherapy.

Results

High methodological heterogeneity existed among the selected studies which differed in cancer populations, subject characteristics, cognitive endpoints, types of cytokines tested and their measurement methods. Weak to moderate correlations were observed between IL-1β, IL-6, TNF-α levels, and different degrees of cognitive impairment. Different types of chemotherapy treatments might lead to varying presentations and severities of cytokine-induced cognitive impairment. Notably, the time concordance between the onset of cytokine induction and occurrence of cognitive impairment was not well elucidated. A number of confounding factors was identified to interfere with the expression levels of cytokines; these confounders included subjects'' cancer types, ages, genders, genetics and psychosocial characteristics such as anxiety, depression and fatigue.

Conclusion

Although existing studies observed cognitive impairment and cytokine dysregulation in patients who receive chemotherapy, our results suggest that the intermediary role of cytokines in post-chemotherapy cognitive impairment is still controversial and requires further evaluation. A list of methodological recommendations is proposed to harmonize future studies of this subject matter.     

Measles Contributes to Rheumatoid Arthritis: Evidence from Pathway and Network Analyses of Genome-Wide Association Studies

Growing evidence from epidemiological studies indicates the association between rheumatoid arthritis (RA) and measles. However, the exact mechanism for this association is still unclear now. We consider that the strong association between both diseases may be caused by shared genetic pathways. We performed a pathway analysis of large-scale RA genome-wide association studies (GWAS) dataset with 5,539 cases and 20,169 controls of European descent. Meanwhile, we evaluated our findings using previously identified RA loci, protein-protein interaction network and previous results from pathway analysis of RA and other autoimmune diseases GWAS. We confirmed four pathways including Cytokine-cytokine receptor interaction, Jak-STAT signaling, T cell receptor signaling and Cell adhesion molecules. Meanwhile, we highlighted for the first time the involvement of Measles and Intestinal immune network for IgA production pathways in RA. Our results may explain the strong association between RA and measles, which may be caused by the shared genetic pathway. We believe that our results will be helpful for future genetic studies in RA pathogenesis and may significantly assist in the development of therapeutic strategies.     

Phylogeny of Cyperaceae Based on DNA Sequence Data: Current Progress and Future Prospects

In the last decade, efforts to reconstruct suprageneric phylogeny of the Cyperaceae have intensified. We present an analysis of 262 taxa representing 93 genera in 15 tribes, sequenced for the plastid rbcL and trnL-F (intron and intergenic spacer). Cyperaceae are monophyletic and resolved into two clades, here recognised as Mapanioideae and Cyperoideae, and the overall topology is similar to results from previous studies. Within Cyperoideae, Trilepideae are sister to rest of taxa whereas Cryptangieae, Bisboeckelerieae and Sclerieae are resolved within Schoeneae. Cladium and Rhynchospora (and Pleurostachys) are resolved into clades sister to the rest of Schoeneae, lending support to the recognition of these taxa in separate tribes. However, we retain these taxa in Schoeneae pending broader sampling of the group. The phylogenetic position of 40 species in 21 genera is presented in this study for the first time, elucidating their position in Abildgaardieae (Trachystylis), Cryptangieae (Didymiandrum, Exochogyne), Cypereae (Androtrichum, Volkiella), Eleocharideae (Chillania), and Schoeneae (Calyptrocarya, Morelotia). More sampling effort (more taxa and the use of more rapidly evolving markers) is needed to resolve relationships in Fuireneae and Schoeneae.     

Gene Signatures in Breast Cancer: Current and Future Uses

Gene signatures have been developed for estrogen receptor-positive breast cancer to complement pathological factors in providing prognostic information. The 70-gene and the 21-gene signatures identify patients who may not require adjuvant chemotherapy. Gene signatures in triple-negative disease and HER2-positive disease have not been fully developed yet, although studies demonstrate heterogeneity within these subgroups. Further research is needed before genotyping will help in making clinical decisions in triple-negative and HER2-positive disease. Molecular subtyping of breast cancer led to define luminal, basal, and HER2-enriched subtypes, which have specific clinical behavior. This approach may lead to identify new subgroups requiring specific therapies. Standardization of techniques will be required to translate investigations to the clinic.     

Current and Future Immunomodulation Strategies to Restore Tolerance in Autoimmune Diseases

Autoimmune diseases reflect a breakdown in self-tolerance that results from defects in thymic deletion of potentially autoreactive T cells (central tolerance) and in T-cell intrinsic and extrinsic mechanisms that normally control potentially autoreactive T cells in the periphery (peripheral tolerance). The mechanisms leading to autoimmune diseases are multifactorial and depend on a complex combination of genetic, epigenetic, molecular, and cellular elements that result in pathogenic inflammatory responses in peripheral tissues driven by self-antigen-specific T cells. In this article, we describe the different checkpoints of tolerance that are defective in autoimmune diseases as well as specific events in the autoimmune response which represent therapeutic opportunities to restore long-term tolerance in autoimmune diseases. We present evidence for the role of different pathways in animal models and the therapeutic strategies targeting these pathways in clinical trials in autoimmune diseases.Autoimmune diseases are debilitating conditions that affect a large and growing portion of the population (∼3%–5% in the United States) (Jacobson et al. 1997). Autoimmune diseases take a devastating toll on affected families and have a considerable economic impact. Thus, improving the understanding of autoimmune diseases and developing novel therapies have been significant goals in public health. The development of autoimmune diseases reflects a loss of tolerance of the immune system for self-antigens. With the exception of a few rare monogenic diseases such as immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome, the development of autoimmunity is a complex and multifactorial process. This process usually involves genetic predispositions and poorly defined environmental factors that result in slight alterations in many different checkpoints, which in turn tilts the balance toward autoreactivity and away from immunoregulation. Although clearly there are key roles for B cells, antigen-presenting cells (APCs), and the innate immune response in the development and progression of autoimmune diseases, this article will focus on autoreactive T cells and potential targets of tolerogenic treatments (Fig. 1). In addition, we will discuss selected strategies currently available or being developed in the clinic as well as future opportunities to prevent and treat these diseases. Finally, current clinical strategies available as the standard of care for autoimmune diseases rely on immunosuppressive and anti-inflammatory treatments that curtail the pathological events, alleviate symptoms, and provide short-term relief in some patients. Thus, we will focus for the most part on immunotherapies aimed at reestablishing long-term tolerance.Open in a separate windowFigure 1.Development of the pathogenic autoimmune response and targets for immunotherapy. Autoreactive T cells that escape thymic negative selection are usually controlled by intrinsic (inhibitory receptors) and extrinsic (regulatory cell populations) mechanisms of tolerance in the periphery. In individuals genetically prone to autoimmunity, one or several of these checkpoints are defective, resulting in expansion of autoreactive T cells that cannot be controlled by Tregs (red, autoreactive effector T cells; green, Tregs; gray, polyclonal conventional T cells). Autoreactive T cells migrate to their targeted tissue where cytotoxic mechanisms and uncontrolled inflammation mediated by soluble mediators released by T cells and innate cells result in tissue damage. Various immunotherapeutic strategies target different steps in this process. (A) The ultimate goal of immunotherapy is to alter the balance of pathogenic versus regulatory T cells to restore tolerance, as detailed in Figure 2. (B) Anti-CD3 mAbs, antigen-specific therapies, and costimulation blockade alter the interactions between autoreactive T cells and antigen-presenting cells (APCs) and/or the signaling pathways resulting from productive T-cell receptor (TCR) ligation after presentation of cognate self-peptide/MHC (major histocompatibility complexes) in the presence of costimulatory signals, leading to deletion, anergy, immune deviation, or induction of Tregs. (C) Many strategies aim at boosting Tregs, either by concomitantly deleting Teff and promoting Tregs, and thus resetting the immune system to various degrees, such as antithymocyte globulin (ATG), rapamycin plus IL-2, and autologous hematopoietic stem cell transplantation (HSCT), or directly providing Tregs through cellular therapy. (D,E) Some therapies target populations of APCs, such as depletion of B cells by rituximab or the promotion of self-antigen presentation specifically by tolerogenic dendritic cells (DCs). (F) The migration of autoreactive T cells to their target tissue is being altered by inhibitors of leukocyte trafficking such as natalizumab and fingolimod. These drugs may further promote tolerance by keeping autoreactive T cells in the lymph nodes (LN) during immunosuppression, a prerequisite for efficient immunomodulation in some cases. (G) Anti-inflammatory therapies such as tumor necrosis factor (TNF) antagonists reduce tissue damage but also create an immunological environment more favorable to the induction of Tregs and restoration of tolerance.     

Predictors of retention among men attending STI clinics in HIV prevention programs and research: a case control study in Pune, India

Background

Retention is critical in HIV prevention programs and clinical research. We studied retention in the three modeled scenarios of primary prevention programs, cohort studies and clinical trials to identify predictors of retention.

Methodology/Principal Findings

Men attending Sexually Transmitted Infection (STI) clinics (n = 10, 801) were followed in a cohort study spanning over a ten year period (1993–2002) in Pune, India. Using pre-set definitions, cases with optimal retention in prevention program (n = 1286), cohort study (n = 940) and clinical trial (n = 896) were identified from this cohort. Equal number of controls matched for age and period of enrollment were selected. A case control analysis using conditional logistic regression was performed.Being employed was a predictor of lower retention in all the three modeled scenarios. Presence of genital ulcer disease (GUD), history of commercial sex work and living away from the family were predictors of lower retention in primary prevention, cohort study and clinical trial models respectively. Alcohol consumption predicted lower retention in cohort study and clinical trial models. Married monogamous men were less likely to be retained in the primary prevention and cohort study models.

Conclusions/Significance

Predicting potential drop-outs among the beneficiaries or research participants at entry point in the prevention programs and research respectively is possible. Suitable interventions might help in optimizing retention. Customized counseling to prepare the clients properly may help in their retention.     

Galactomannan-Based and PCR-Based Assays in Bronchoalveolar Lavage to Diagnose Invasive Aspergillosis: Current Status and Future Prospects

Invasive pulmonary aspergillosis (IPA) is a life-threatening complication in patients receiving chemotherapy or undergoing allogeneic haematopoietic stem cell transplantation for acute leukemia. The existing tools to diagnose IPA lack specificity or sensitivity, or both; the search for improved diagnostic tools for IPA has focused on novel serologic and molecular methods. Aspergillus Galactomannan enzyme-linked immunosorbent assay (GM) analyses showed sensitivity rates in serum samples ranging in a wide span; testing GM in bronchoalveolar lavage (BAL) originated from the primary site of the infection seems to be more sensitive in patients with IPA. Other novel diagnostic markers to detect fungal DNA directly in clinical samples, rapidly, early, sensitively and specifically, are provided by polymerase chain reaction (PCR) based assays; higher sensitivity and specificity rates have been observed for BAL samples in IPA, even under antifungal treatment. The clinical place value of a diagnostic approach combining PCR and GM in BAL is unclear.