Integration of Water,Sanitation, and Hygiene for the Prevention and Control of Neglected Tropical Diseases: A Rationale for Inter-Sectoral Collaboration

Improvements of water, sanitation, and hygiene (WASH) infrastructure and appropriate health-seeking behavior are necessary for achieving sustained control, elimination, or eradication of many neglected tropical diseases (NTDs). Indeed, the global strategies to fight NTDs include provision of WASH, but few programs have specific WASH targets and approaches. Collaboration between disease control programs and stakeholders in WASH is a critical next step. A group of stakeholders from the NTD control, child health, and WASH sectors convened in late 2012 to discuss opportunities for, and barriers to, collaboration. The group agreed on a common vision, namely “Disease-free communities that have adequate and equitable access to water and sanitation, and that practice good hygiene.” Four key areas of collaboration were identified, including (i) advocacy, policy, and communication; (ii) capacity building and training; (iii) mapping, data collection, and monitoring; and (iv) research. We discuss strategic opportunities and ways forward for enhanced collaboration between the WASH and the NTD sectors.     

An Innovative Lab-Based Training Program to Help Patient Groups Understand Their Disease and the Research Process

Genuine partnership between patient groups and medical experts is important but challenging. Our training program meets this challenge by organizing hands-on, lab-based training sessions for members of patient groups. These sessions allow “trainees” to better understand their disease and the biomedical research process, and strengthen links between patients and local researchers. Over the past decade, we and our partner institutes have received more than 900 French patients, with the participation of over 60 researchers and clinicians.

This Community Page is part of the "Public Engagement in Science" Series.

     

Dietary Factors Associated with Faecal Consistency and Other Indicators of Gastrointestinal Health in the Captive Cheetah (Acinonyx jubatus)

Gastrointestinal diseases pose significant risks to captive cheetah survival and welfare. Multiple factors are thought to be associated with these diseases, but to date a comprehensive epidemiological survey of disease risk factors has not been conducted. A survey of diet and health parameters was completed for 184 captive cheetahs in 86 international facilities. Comparisons were made among dietary factors with respect to disease status and observed faecal consistency, incidence of vomiting and diarrhoea in the past 4 weeks. Extremely dry faeces were most common in cheetahs fed carcasses, but was still of low incidence (15%). Contrastingly, cheetahs fed commercially prepared diets had the highest prevalence of liquid faeces “always” or “often” (9%). Cheetahs fed raw meat diets had the highest prevalence of soft faeces with no shape (22%), as well as of firm and dry faeces (40%). No broad category of diet exerted any influence on the health parameters investigated. However, feeding of ribs at least once per week reduced the odds of diarrhoea (P = 0.020) and feeding of long bones (limbs) at least once per week was associated with a lower odds of vomiting (P = 0.008). Cheetahs fed muscle meat at least once per week had reduced odds of suffering from chronic gastritis (P = 0.005) or non-specific gastrointestinal disease (P < 0.001). The only factor identified as increasing the odds of chronic gastritis was feeding of horse “often” or “always” (P = 0.023). The findings of the current study build on existing empirical research to support a recommendation towards a greater inclusion of skeletal components. Current husbandry guidelines advocating the use of supplemented raw meat diets are likewise supported, but the use of horse meat, as well as commercially prepared diets for captive cheetahs, warrants caution until further research is conducted.     

A Universal Trend among Proteomes Indicates an Oily Last Common Ancestor

Despite progresses in ancestral protein sequence reconstruction, much needs to be unraveled about the nature of the putative last common ancestral proteome that served as the prototype of all extant lifeforms. Here, we present data that indicate a steady decline (oil escape) in proteome hydrophobicity over species evolvedness (node number) evident in 272 diverse proteomes, which indicates a highly hydrophobic (oily) last common ancestor (LCA). This trend, obtained from simple considerations (free from sequence reconstruction methods), was corroborated by regression studies within homologous and orthologous protein clusters as well as phylogenetic estimates of the ancestral oil content. While indicating an inherent irreversibility in molecular evolution, oil escape also serves as a rare and universal reaction-coordinate for evolution (reinforcing Darwin''s principle of Common Descent), and may prove important in matters such as (i) explaining the emergence of intrinsically disordered proteins, (ii) developing composition- and speciation-based “global” molecular clocks, and (iii) improving the statistical methods for ancestral sequence reconstruction.     

Iron-sulfur cluster biosynthesis in bacteria: Mechanisms of cluster assembly and transfer

Iron-sulfur [Fe-S] clusters are ubiquitous ancient prosthetic groups that are required to sustain fundamental life processes. Formation of intracellular [Fe-S] clusters does not occur spontaneously but requires a complex biosynthetic machinery. Different types of [Fe-S] cluster assembly systems have been discovered. All of them have in common the requirement of a cysteine desulfurase and the participation of [Fe-S] scaffold proteins. The purpose of this review is to discuss various aspects of the molecular mechanisms of [Fe-S] cluster assembly in living organisms: (i) mechanism of sulfur donor enzymes, namely the cysteine desulfurases; (ii) mechanism by which clusters are preassembled on scaffold proteins and (iii) mechanism of [Fe-S] cluster transfer from scaffold to target proteins.     

What Guidance Are Researchers Given on How to Present Network Meta-Analyses to End-Users such as Policymakers and Clinicians? A Systematic Review

Introduction

Network meta-analyses (NMAs) are complex methodological approaches that may be challenging for non-technical end-users, such as policymakers and clinicians, to understand. Consideration should be given to identifying optimal approaches to presenting NMAs that help clarify analyses. It is unclear what guidance researchers currently have on how to present and tailor NMAs to different end-users.

Methods

A systematic review of NMA guidelines was conducted to identify guidance on how to present NMAs. Electronic databases and supplementary sources were searched for NMA guidelines. Presentation format details related to sample formats, target audiences, data sources, analysis methods and results were extracted and frequencies tabulated. Guideline quality was assessed following criteria developed for clinical practice guidelines.

Results

Seven guidelines were included. Current guidelines focus on how to conduct NMAs but provide limited guidance to researchers on how to best present analyses to different end-users. None of the guidelines provided reporting templates. Few guidelines provided advice on tailoring presentations to different end-users, such as policymakers. Available guidance on presentation formats focused on evidence networks, characteristics of individual trials, comparisons between direct and indirect estimates and assumptions of heterogeneity and/or inconsistency. Some guidelines also provided examples of figures and tables that could be used to present information.

Conclusions

Limited guidance exists for researchers on how best to present NMAs in an accessible format, especially for non-technical end-users such as policymakers and clinicians. NMA guidelines may require further integration with end-users'' needs, when NMAs are used to support healthcare policy and practice decisions. Developing presentation formats that enhance understanding and accessibility of NMAs could also enhance the transparency and legitimacy of decisions informed by NMAs.     

Ensemble-based computational approach discriminates functional activity of p53 cancer and rescue mutants

The tumor suppressor protein p53 can lose its function upon single-point missense mutations in the core DNA-binding domain (“cancer mutants”). Activity can be restored by second-site suppressor mutations (“rescue mutants”). This paper relates the functional activity of p53 cancer and rescue mutants to their overall molecular dynamics (MD), without focusing on local structural details. A novel global measure of protein flexibility for the p53 core DNA-binding domain, the number of clusters at a certain RMSD cutoff, was computed by clustering over 0.7 µs of explicitly solvated all-atom MD simulations. For wild-type p53 and a sample of p53 cancer or rescue mutants, the number of clusters was a good predictor of in vivo p53 functional activity in cell-based assays. This number-of-clusters (NOC) metric was strongly correlated (r² = 0.77) with reported values of experimentally measured ΔΔG protein thermodynamic stability. Interpreting the number of clusters as a measure of protein flexibility: (i) p53 cancer mutants were more flexible than wild-type protein, (ii) second-site rescue mutations decreased the flexibility of cancer mutants, and (iii) negative controls of non-rescue second-site mutants did not. This new method reflects the overall stability of the p53 core domain and can discriminate which second-site mutations restore activity to p53 cancer mutants.     

Gene-Gene and Gene-Environment Interactions in Meta-Analysis of Genetic Association Studies

Extensive genetic studies have identified a large number of causal genetic variations in many human phenotypes; however, these could not completely explain heritability in complex diseases. Some researchers have proposed that the “missing heritability” may be attributable to gene–gene and gene–environment interactions. Because there are billions of potential interaction combinations, the statistical power of a single study is often ineffective in detecting these interactions. Meta-analysis is a common method of increasing detection power; however, accessing individual data could be difficult. This study presents a simple method that employs aggregated summary values from a “case” group to detect these specific interactions that based on rare disease and independence assumptions. However, these assumptions, particularly the rare disease assumption, may be violated in real situations; therefore, this study further investigated the robustness of our proposed method when it violates the assumptions. In conclusion, we observed that the rare disease assumption is relatively nonessential, whereas the independence assumption is an essential component. Because single nucleotide polymorphisms (SNPs) are often unrelated to environmental factors and SNPs on other chromosomes, researchers should use this method to investigate gene–gene and gene–environment interactions when they are unable to obtain detailed individual patient data.     

Caloric restriction mimetics: natural/physiological pharmacological autophagy inducers

Nutrient depletion, which is one of the physiological triggers of autophagy, results in the depletion of intracellular acetyl coenzyme A (AcCoA) coupled to the deacetylation of cellular proteins. We surmise that there are 3 possibilities to mimic these effects, namely (i) the depletion of cytosolic AcCoA by interfering with its biosynthesis, (ii) the inhibition of acetyltransferases, which are enzymes that transfer acetyl groups from AcCoA to other molecules, mostly leucine residues in cellular proteins, or (iii) the stimulation of deacetylases, which catalyze the removal of acetyl groups from leucine residues. There are several examples of rather nontoxic natural compounds that act as AcCoA depleting agents (e.g., hydroxycitrate), acetyltransferase inhibitors (e.g., anacardic acid, curcumin, epigallocatechin-3-gallate, garcinol, spermidine) or deacetylase activators (e.g., nicotinamide, resveratrol), and that are highly efficient inducers of autophagy in vitro and in vivo, in rodents. Another common characteristic of these agents is their capacity to reduce aging-associated diseases and to confer protective responses against ischemia-induced organ damage. Hence, we classify them as “caloric restriction mimetics” (CRM). Here, we speculate that CRM may mediate their broad health-improving effects by triggering the same molecular pathways that usually are elicited by long-term caloric restriction or short-term starvation and that imply the induction of autophagy as an obligatory event conferring organismal, organ- or cytoprotection.     

The Effect of Comorbidity on Glycemic Control and Systolic Blood Pressure in Type 2 Diabetes: A Cohort Study with 5 Year Follow-Up in Primary Care

Aims

To explore the longitudinal effect of chronic comorbid diseases on glycemic control (HbA₁C) and systolic blood pressure (SBP) in type 2 diabetes patients.

Methods

In a representative primary care cohort of patients with newly diagnosed type 2 diabetes in The Netherlands (n = 610), we tested differences in the five year trend of HbA₁C and SBP according to comorbidity profiles. In a mixed model analysis technique we corrected for relevant covariates. Influence of comorbidity (a chronic disease already present when diabetes was diagnosed) was tested as total number of comorbid diseases, and as presence of specific disease groups, i.e. cardiovascular, mental, and musculoskeletal disease, malignancies, and COPD. In subgroup effect analyses we tested if potential differences were modified by age, sex, socioeconomic status, and BMI.

Results

The number of comorbid diseases significantly influenced the SBP trend, with highest values after five years for diabetes patients without comorbidity (p = 0.005). The number of diseases did not influence the HbA₁C trend (p = 0.075). Comorbid musculoskeletal disease resulted in lower HbA₁C at the time of diabetes diagnosis, but in higher values after five years (p = 0.044). Patients with cardiovascular diseases had sustained elevated levels of SBP (p = 0.014). Effect modification by socioeconomic status was observed in some comorbidity subgroups.

Conclusions

Presence of comorbidity in type 2 diabetes patients affected the long-term course of HbA₁C and SBP in this primary care cohort. Numbers and types of comorbidity showed differential effects: not the simple sum of diseases, but specific types of comorbid disease had a negative influence on long-term diabetes control parameters. The complex interactions between comorbidity, diabetes control and effect modifiers require further investigation and may help to personalize treatment goals.     

The syndrome of inappropriate antidiuretic hormone secretion

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the commonest form of normovolaemic or dilutional hyponatraemia. The diagnosis of SIADH should be considered if the five cardinal criteria are fulfilled (hypotonic hyponatraemia, natriuresis, urine osmolality in excess of plasma osmolality, absence of oedema and volume depletion, normal renal and adrenal function). The clinical features are principally neuro-muscular and gastro-intestinal, the severity of which is related to both the absolute serum sodium concentration and its rate of fall, particularly if greater than 0.5 mmol/1/h. The dilutional hyponatraemia of SIADH develops due to persistent detectable or elevated plasma arginine vasopressin (AVP) concentrations in the presence of continued fluid intake. Osmoregulated inhibition of thirst failures to curb fluid intake. The major groups of causes of SIADH are: (i) neoplasia, (ii) neurological diseases, (iii) lung diseases and (iv) a wide variety of drugs. Inappropriate infusion of hypotonic fluids in the post-operative state remains a common cause. Four categories of osmoregulated AVP secretion have been described: (i) erratic AVP release, (ii) reset osmostat, (iii) persistent AVP release at low plasma osmolality and (iv) normal osmoregulated AVP secretion. For symptomatic patients with chronic SIADH, the mainstay of therapy remains fluid restriction. New antagonists to the antidiuretic action of AVP offer a new therapeutic approach.     

SCA10 and ATTCT repeat expansion: clinical features and molecular aspects

Analysis of the horse genome is proceeding at a rapid pace. Within a short span of 6-7 years, approximately 1,500 markers have been mapped in horse, of which at least half are genes/ESTs. Health, performance and phenotypic characteristic are of major concern/interest to horse breeders and owners. Current efforts to analyze the equine genome are primarily aimed at developing critical resources (including an advanced gene map) that could readily be used in the near future to i) identify genes and mutations responsible for inherited equine diseases/disorders and to formulate approaches for accurate diagnostics, therapeutics and prevention, ii) discover genes associated with various other traits of significance, e.g. fertility, disease resistance, coat color and athletic performance etc., and iii) use functional genomic approaches to identify gene regulatory events involved in the manifestation of various diseases.     

Caribbean coral diseases: primary transmission or secondary infection?

Over the last 40 years, disease outbreaks have significantly reduced coral populations throughout the Caribbean. Most coral‐disease models assume that coral diseases are contagious and that pathogens are transmitted from infected to susceptible hosts. However, this assumption has not been rigorously tested. We used spatial epidemiology to examine disease clustering, at scales ranging from meters to tens of kilometers, to determine whether three of the most common Caribbean coral diseases, (i) yellow‐band disease, (ii) dark‐spot syndrome, and (iii) white‐plague disease, were spatially clustered. For all three diseases, we found no consistent evidence of disease clustering and, therefore, these diseases did not follow a contagious‐disease model. We suggest that the expression of some coral diseases is instead a two‐step process. First, environmental thresholds are exceeded. Second, these environmental conditions either weaken the corals, which are then more susceptible to infection, or the conditions increase the virulence or abundance of pathogens. Exceeding such environmental thresholds will most likely become increasingly common in rapidly warming oceans, leading to more frequent coral‐disease outbreaks.     

Realities and hopes in the application of microbial tools in agriculture

The use of microbial tools to sustainably increase agricultural production has received significant attention from researchers, industries and policymakers. Over the past decade, the market access and development of microbial products have been accelerated by (i) the recent advances in plant-associated microbiome science, (ii) the pressure from consumers and policymakers for increasing crop productivity and reducing the use of agrochemicals, (iii) the rising threats of biotic and abiotic stresses, (iv) the loss of efficacy of some agrochemicals and plant breeding programs and (v) the calls for agriculture to contribute towards mitigating climate change. Although the sector is still in its infancy, the path towards effective microbial products is taking shape and the global market of these products has increased faster than that of agrochemicals. Promising results from using microbes either as biofertilizers or biopesticides have been continually reported, fuelling optimism and high expectations for the sector. However, some limitations, often related to low efficacy and inconsistent performance in field conditions, urgently need to be addressed to promote a wider use of microbial tools. We propose that advances in in situ microbiome manipulation approaches, such as the use of products containing synthetic microbial communities and novel prebiotics, have great potential to overcome some of these current constraints. Much more progress is expected in the development of microbial inoculants as areas such as synthetic biology and nano-biotechnology advance. If key technical, translational and regulatory issues are addressed, microbial tools will not only play an important role in sustainably boosting agricultural production over the next few decades but also contribute towards other sustainable development goals, including job creation and mitigation of the impacts of climate change.     

Classification and analysis of regulatory pathways using graph property, biochemical and physicochemical property, and functional property

Given a regulatory pathway system consisting of a set of proteins, can we predict which pathway class it belongs to? Such a problem is closely related to the biological function of the pathway in cells and hence is quite fundamental and essential in systems biology and proteomics. This is also an extremely difficult and challenging problem due to its complexity. To address this problem, a novel approach was developed that can be used to predict query pathways among the following six functional categories: (i) “Metabolism”, (ii) “Genetic Information Processing”, (iii) “Environmental Information Processing”, (iv) “Cellular Processes”, (v) “Organismal Systems”, and (vi) “Human Diseases”. The prediction method was established trough the following procedures: (i) according to the general form of pseudo amino acid composition (PseAAC), each of the pathways concerned is formulated as a 5570-D (dimensional) vector; (ii) each of components in the 5570-D vector was derived by a series of feature extractions from the pathway system according to its graphic property, biochemical and physicochemical property, as well as functional property; (iii) the minimum redundancy maximum relevance (mRMR) method was adopted to operate the prediction. A cross-validation by the jackknife test on a benchmark dataset consisting of 146 regulatory pathways indicated that an overall success rate of 78.8% was achieved by our method in identifying query pathways among the above six classes, indicating the outcome is quite promising and encouraging. To the best of our knowledge, the current study represents the first effort in attempting to identity the type of a pathway system or its biological function. It is anticipated that our report may stimulate a series of follow-up investigations in this new and challenging area.     

Transmission of infectious diseases en route to habitat hotspots

Background

The spread of infectious diseases in wildlife populations is influenced by patterns of between-host contacts. Habitat “hotspots” - places attracting a large numbers of individuals or social groups - can significantly alter contact patterns and, hence, disease propagation. Research on the importance of habitat hotspots in wildlife epidemiology has primarily focused on how inter-individual contacts occurring at the hotspot itself increase disease transmission. However, in territorial animals, epidemiologically important contacts may primarily occur as animals cross through territories of conspecifics en route to habitat hotspots. So far, the phenomenon has received little attention. Here, we investigate the importance of these contacts in the case where infectious individuals keep visiting the hotspots and in the case where these individuals are not able to travel to the hotspot any more.

Methodology and Principal Findings

We developed a simulation epidemiological model to investigate both cases in a scenario when transmission at the hotspot does not occur. We find that (i) hotspots still exacerbate epidemics, (ii) when infectious individuals do not travel to the hotspot, the most vulnerable individuals are those residing at intermediate distances from the hotspot rather than nearby, and (iii) the epidemiological vulnerability of a population is the highest when the number of hotspots is intermediate.

Conclusions and Significance

By altering animal movements in their vicinity, habitat hotspots can thus strongly increase the spread of infectious diseases, even when disease transmission does not occur at the hotspot itself. Interestingly, when animals only visit the nearest hotspot, creating additional artificial hotspots, rather than reducing their number, may be an efficient disease control measure.