Modeling heterogeneity for count data: A study of maternal mortality in health facilities in Mozambique

Count data are very common in health services research, and very commonly the basic Poisson regression model has to be extended in several ways to accommodate several sources of heterogeneity: (i) an excess number of zeros relative to a Poisson distribution, (ii) hierarchical structures, and correlated data, (iii) remaining “unexplained” sources of overdispersion. In this paper, we propose hierarchical zero‐inflated and overdispersed models with independent, correlated, and shared random effects for both components of the mixture model. We show that all different extensions of the Poisson model can be based on the concept of mixture models, and that they can be combined to account for all different sources of heterogeneity. Expressions for the first two moments are derived and discussed. The models are applied to data on maternal deaths and related risk factors within health facilities in Mozambique. The final model shows that the maternal mortality rate mainly depends on the geographical location of the health facility, the percentage of women admitted with HIV and the percentage of referrals from the health facility.     

High prevalence and mortality due to Histoplasma capsulatum in the Brazilian Amazon: An autopsy study

BackgroundHistoplasmosis is acquired by inhalation of spores of the dimorphic fungus Histoplasma spp. Although this pathogen is distributed worldwide, it is more prevalent in the Americas. However, the real burden of histoplasmosis remains undefined in many endemic regions.MethodologyWe conducted a series of 61 autopsies to individuals who died in a hospital in the Brazilian Amazon focused on infectious diseases. We performed a detailed histological and microbiological evaluation with genetic characterization of Histoplasma strains with the aim to evaluate the contribution of histoplasmosis to morbidity and mortality. Additionally, we assessed the clinicopathological correlation.Principal findingsEvidence of Histoplasma infection was detected in 21 patients (34%). Eight cases were disseminated infections, all of them occurred in HIV-positive patients. Six cases were localized histoplasmosis, limited to the lungs. In seven patients Histoplasma DNA was detected by PCR in patients with no histological lesions. Histoplasma infection was detected in 38% of HIV-positive patients and was a major contributor to death in 22% of them. Lungs, liver and spleen were affected in all cases of disseminated histoplasmosis. Phylogenetic analysis of the strains suggested a high diversity of Histoplasma species circulating in the Brazilian Amazon. Histoplasmosis was clinically missed in 75% of the disseminated infections.ConclusionsThe high incidence of histoplasmosis, the low index of clinical suspicion, and the severity of the disseminated disease highlight the need of proactively implementing sensitive routine screening methods for this pathogen in endemic areas. Antifungal prophylaxis against Histoplasma should be encouraged in the severely immunocompromised HIV patients in these areas. In conclusion, substantial mortality is associated with disseminated histoplasmosis among HIV-positive patients in the Brazilian Amazon.     

An appraisal of the maternal mortality decline in Nepal

Background

A decline in the national maternal mortality ratio in Nepal has been observed from surveys conducted between 1996 and 2008. This paper aims to assess the plausibility of the decline and to identify drivers of change.

Methods

National and sub-national trends in mortality data were investigated using existing demographic and health surveys and maternal mortality and morbidity surveys. Potential drivers of the variation in maternal mortality between districts were identified by regressing district-level indicators from the Nepal demographic health surveys against maternal mortality estimates.

Results

A statistically significant decline of the maternal mortality ratio from 539 maternal deaths to 281 per 100,000 (95% CI 91,507) live births between 1993 and 2003 was demonstrated. The sub-national changes are of similar magnitude and direction to those observed nationally, and in the terai region (plains) the differences are statistically significant with a reduction of 361 per 100,000 live births (95% CI 36,686) during the same time period.The reduction in fertility, changes in education and wealth, improvements in components of the human development index, gender empowerment and anaemia each explained more than 10% of the district variation in maternal mortality. A number of limitations in each of the data sources used were identified. Of these, the most important relate to the underestimation of numbers of deaths.

Conclusion

It is likely that there has been a decline in Nepal''s maternal mortality since 1993. This is good news for the country''s sustained commitments in this area. Conclusions on the magnitude, pattern of the change and drivers of the decline are constrained by lack of data. We recommend close tracking of maternal mortality and its determinants in Nepal, attention to the communication of future estimates, and various options for bridging data gaps.     

Phage display in the study of infectious diseases

Microbial infections are dependent on the panoply of interactions between pathogen and host and identifying the molecular basis of such interactions is necessary to understand and control infection. Phage display is a simple functional genomic methodology for screening and identifying protein-ligand interactions and is widely used in epitope mapping, antibody engineering and screening for receptor agonists or antagonists. Phage display is also used widely in various forms, including the use of fragment libraries of whole microbial genomes, to identify peptide-ligand and protein-ligand interactions that are of importance in infection. In particular, this technique has proved successful in identifying microbial adhesins that are vital for colonization.     

DNA microarrays in the clinic: infectious diseases

We argue that the most-promising area of clinical application of microarrays in the foreseeable future is the diagnostics and monitoring of infectious diseases. Microarrays for the detection and characterization of human pathogens have already found their way into clinical practice in some countries. After discussing the persistent, yet often underestimated, importance of infectious diseases for public health, we consider the technologies that are best suited for the detection and clinical investigation of pathogens. Clinical application of microarray technologies for the detection of mycobacteria, Bacillus anthracis, HIV, hepatitis and influenza viruses, and other major pathogens, as well as the analysis of their drug-resistance patterns, illustrate our main thesis.     

Applications of bioluminescence imaging to the study of infectious diseases

Bioluminescence imaging (BLI) has emerged as a powerful new method to analyse infectious diseases in animal models. BLI offers real-time monitoring of spatial and temporal progression of infection in the same animal, as opposed to euthanizing a cohort of animals and quantifying colony or plaque forming units at multiple time points. Pathogens or mice are engineered to express genetically encoded luciferase enzymes from bacteria, insects, or the sea pansy. The seminal study showing the feasibility of detecting microbially generated luminescence within a living mouse was published by Contag and colleagues in 1995, using Salmonella typhimurium transformed with the lux operon from Photorhabdus luminescens. Following this, they and others performed many studies of infection by bioluminescent Gram-negative and Gram-positive bacteria. Viruses can also be engineered to encode luciferase. Our laboratory has used bioluminescent reporter viruses to follow HSV and vaccinia pathogenesis; others have used an alphavirus or novirhabdovirus. Recently, even eukaryotic parasites Plasmodium, Leishmania and Toxoplasma have been transformed with luciferase and yielded unique insights into their in vivo behaviour. We expect that both the range of organisms and the molecular events able to be studied by BLI will continue to expand, yielding important insights into mechanisms of pathogenesis.     

微生物组与动物疫病防控

微生物组研究的发展推动了人类不断探索人体微生物群与疾病之间的相关性。然而,微生物组学在动物疫病防控中的研究尚处于起步阶段。本文对动物疫病防控领域中微生物组研究所发挥的6个作用进行了阐述：揭示疾病与菌群的相关性,鉴定新发病原体,确立有益于维持机体健康生长的菌群,筛选疾病防控的新药物和新制剂,开发新疫苗或改进疫苗的使用效果,提出更简单有效的防控措施。     

Lurking in the shadows: emerging rodent infectious diseases

Rodent parvoviruses, Helicobacter spp., murine norovirus, and several other previously unknown infectious agents have emerged in laboratory rodents relatively recently. These agents have been discovered serendipitously or through active investigation of atypical serology results, cell culture contamination, unexpected histopathology, or previously unrecognized clinical disease syndromes. The potential research impact of these agents is not fully known. Infected rodents have demonstrated immunomodulation, tumor suppression, clinical disease (particularly in immunodeficient rodents), and histopathology. Perturbations of organismal and cellular physiology also likely occur. These agents posed unique challenges to laboratory animal resource programs once discovered; it was necessary to develop specific diagnostic assays and an understanding of their epidemiology and transmission routes before attempting eradication, and then evaluate eradication methods for efficacy. Even then management approaches varied significantly, from apathy to total exclusion, and such inconsistency has hindered the sharing and transfer of rodents among institutions, particularly for genetically modified rodent models that may not be readily available. As additional infectious agents are discovered in laboratory rodents in coming years, much of what researchers have learned from experiences with the recently identified pathogens will be applicable. This article provides an overview of the discovery, detection, and research impact of infectious agents recently identified in laboratory rodents. We also discuss emerging syndromes for which there is a suspected infectious etiology, and the unique challenges of managing newly emerging infectious agents.     

Eating the enemy within: autophagy in infectious diseases

Autophagy is emerging as a central component of antimicrobial host defense against diverse viral, bacterial, and parasitic infections. In addition to pathogen degradation, autophagy has other functions during infection such as innate and adaptive immune activation. As an important host defense pathway, microbes have also evolved mechanisms to evade, subvert, or exploit autophagy. Additionally, some fungal pathogens harness autophagy within their own cells to promote pathogenesis. This review will highlight our current understanding of autophagy in infection, focusing on the most recent advances in the field, and will discuss the potential implications of these studies in the design of anti-infective therapeutics.     

线粒体自噬在感染性疾病中的作用机制研究进展

线粒体自噬作为一种选择性自噬方式是近年研究的热点.细胞通过自噬机制选择性清除受损伤或不必需的线粒体,从而维持其功能稳态.近年来,越来越多的研究聚焦于病原体通过胁迫线粒体自噬在机体感染过程中调节先天免疫信号通路,从而影响感染性疾病的进程.本文分别从线粒体自噬在病毒、细菌和真菌感染性疾病中的作用机制研究进展进行综述,以期为...     

Leprosy: a paradigm for the study of human genetic susceptibility to infectious diseases

Fifty years ago, the first identification of a non Mendelian genetic contribution to the development of a common infectious disease, i.e. the association between malaria and sickle-cell trait, was shown using a supervised approach which tests a limited number of candidate genes selected by hypothesis. Since then, the few genes that were convincingly associated with susceptibility to human infectious diseases were identified following the same strategy. The study of leprosy has contributed to modifying this way of thinking. In the absence of a satisfying experimental model and because of the impossibility to grow the causative agent in vitro, the candidate gene approach has turned out to be of limited interest. Conversely, positional cloning led to the identification of two major genes involved in the control of the disease, establishing for the first time the oligogenic nature of a human genetic contribution to an infectious disease. It is likely that these major results obtained in leprosy and the recent burst of genomic tools will make the genome-wide screening (functional or positional) the main strategy of dissection of the genetic susceptibility to many common infectious diseases.     

Modelling infectious diseases with relapse: a case study of HSV-2

Background

Herpes Simplex Virus Type 2 (HSV-2) is one of the most common sexually transmitted diseases. Although there is still no licensed vaccine for HSV-2, a theoretical investigation of the potential effects of a vaccine is considered important and has recently been conducted by several researchers. Although compartmental mathematical models were considered for each special case in the previous studies, as yet there are few global stability results.

Results

In this paper, we formulate a multi-group SVIRI epidemic model for HSV-2, which enables us to consider the effects of vaccination, of waning vaccine immunity, and of infection relapse. Since the number of groups is arbitrary, our model can be applied to various structures such as risk, sex, and age group structures. For our model, we define the basic reproduction number ?₀ and prove that if ?₀≤1, then the disease-free equilibrium is globally asymptotically stable, whereas if ?₀>1, then the endemic equilibrium is so. Based on this global stability result, we estimate ?₀ for HSV-2 by applying our model to the risk group structure and using US data from 2001 to 2014. Through sensitivity analysis, we find that ?₀ is approximately in the range of 2-3. Moreover, using the estimated parameters, we discuss the optimal vaccination strategy for the eradication of HSV-2.

Conclusions

Through discussion of the optimal vaccination strategy, we come to the following conclusions. (1) Improving vaccine efficacy is more effective than increasing the number of vaccines. (2) Although the transmission risk in female individuals is higher than that in male individuals, distributing the available vaccines almost equally between female and male individuals is more effective than concentrating them within the female population.