Screening for Tuberculosis With Xpert MTB/RIF Assay Versus Fluorescent Microscopy Among Adults Newly Diagnosed With Human Immunodeficiency Virus in Rural Malawi: A Cluster Randomized Trial (Chepetsa).

BACKGROUND: Tuberculosis (TB) remains the leading cause of death among human immunodeficiency virus (HIV)-infected individuals globally. Screening for TB at the point of HIV diagnosis with a high-sensitivity assay presents an opportunity to reduce mortality. METHODS: We performed a cluster randomized trial of TB screening among adults newly diagnosed with HIV in 12 primary health clinics in rural Thyolo, Malawi. Clinics were allocated in a 1:1 ratio to perform either point-of-care Xpert MTB/RIF assay (Xpert) or point-of-care light-emitting diode fluorescence microscopy (LED-FM) for individuals screening positive for TB symptoms. Asymptomatic participants were offered isoniazid preventive therapy in both arms. Investigators, but not clinic staff or participants, were masked to allocation. Our primary outcome was the incidence rate ratio (RR) of all-cause mortality within 12 months of HIV diagnosis. RESULTS: Prevalent TB was diagnosed in 24 of 1001 (2.4%) individuals enrolled in clinics randomized to Xpert, compared with 10 of 841 (1.2%) in clinics randomized to LED-FM. All-cause mortality was 22% lower in the Xpert arm than in the LED-FM arm (6.7 vs 8.6 per 100 person-years; RR, 0.78 [95% confidence interval {CI}, .58-1.06]). A planned subgroup analysis suggested that participants with more advanced HIV (World Health Organization clinical stage 3 or 4) disease had lower mortality in clinics randomized to Xpert than to LED-FM (RR, 0.43 [95% CI, .22-.87]). CONCLUSIONS: In rural Malawi, using point-of-care Xpert MTB/RIF to test symptomatic patients for TB at the time of HIV diagnosis reduced all-cause 12-month mortality among individuals with advanced HIV. CLINICAL TRIALS REGISTRATION: NCT01450085

Anti-Allergic Cromones Inhibit Histamine and Eicosanoid Release from Activated Human and Murine Mast Cells by Releasing Annexin A1

PMCID: PMC3601088This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations.

Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies of asthma in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent (P = 3.9 × 10(-9)). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma

Moving interdisciplinary science forward: integrating participatory modelling with mathematical modelling of zoonotic disease in Africa

This review outlines the benefits of using multiple approaches to improve model design and facilitate multidisciplinary research into infectious diseases, as well as showing and proposing practical examples of effective integration. It looks particularly at the benefits of using participatory research in conjunction with traditional modelling methods to potentially improve disease research, control and management. Integrated approaches can lead to more realistic mathematical models which in turn can assist with making policy decisions that reduce disease and benefit local people. The emergence, risk, spread and control of diseases are affected by many complex bio-physical, environmental and socio-economic factors. These include climate and environmental change, land-use variation, changes in population and people’s behaviour. The evidence base for this scoping review comes from the work of a consortium, with the aim of integrating modelling approaches traditionally used in epidemiological, ecological and development research. A total of five examples of the impacts of participatory research on the choice of model structure are presented. Example 1 focused on using participatory research as a tool to structure a model. Example 2 looks at identifying the most relevant parameters of the system. Example 3 concentrates on identifying the most relevant regime of the system (e.g., temporal stability or otherwise), Example 4 examines the feedbacks from mathematical models to guide participatory research and Example 5 goes beyond the so-far described two-way interplay between participatory and mathematical approaches to look at the integration of multiple methods and frameworks. This scoping review describes examples of best practice in the use of participatory methods, illustrating their potential to overcome disciplinary hurdles and promote multidisciplinary collaboration, with the aim of making models and their predictions more useful for decision-making and policy formulation

Response shift in patient-reported outcomes:definition, theory, and a revised model

International audiencePurpose The extant response shift definitions and theoretical response shift models, while helpful, also introduce predicaments and theoretical debates continue. To address these predicaments and stimulate empirical research, we propose a more specific formal definition of response shift and a revised theoretical model. Methods This work is an international collaborative effort and involved a critical assessment of the literature. Results Three main predicaments were identified. First, the formal definitions of response shift need further specification and clarification. Second, previous models were focused on explaining change in the construct intended to be measured rather than explaining the construct at multiple time points and neglected the importance of using at least two time points to investigate response shift. Third, extant models do not explicitly distinguish the measure from the construct. Here we define response shift as an effect occurring whenever observed change (e.g., change in patient-reported outcome measures (PROM) scores) is not fully explained by target change (i.e., change in the construct intended to be measured). The revised model distinguishes the measure (e.g., PROM) from the underlying target construct (e.g., quality of life) at two time points. The major plausible paths are delineated, and the underlying assumptions of this model are explicated. Conclusion It is our hope that this refined definition and model are useful in the further development of response shift theory. The model with its explicit list of assumptions and hypothesized relationships lends itself for critical, empirical examination. Future studies are needed to empirically test the assumptions and hypothesized relationships

Comparative Therapeutic Effects of Velaglucerase Alfa and Imiglucerase in a Gaucher Disease Mouse Model

Gaucher disease type 1 is caused by the defective activity of the lysosomal enzyme, acid β-glucosidase (GCase). Regular infusions of purified recombinant GCase are the standard of care for reversing hematologic, hepatic, splenic, and bony manifestations. Here, similar in vitro enzymatic properties, and in vivo pharmacokinetics and pharmacodynamics (PK/PD) and therapeutic efficacy of GCase were found with two human GCases, recombinant GCase (CHO cell, imiglucerase, Imig) and gene-activated GCase (human fibrosarcoma cells, velaglucerase alfa, Vela), in a Gaucher mouse, D409V/null. About 80+% of either enzyme localized to the liver interstitial cells and <5% was recovered in spleens and lungs after bolus i.v. injections. Glucosylceramide (GC) levels and storage cell numbers were reduced in a dose (5, 15 or 60 U/kg/wk) dependent manner in livers (60–95%) and in spleens (∼10–30%). Compared to Vela, Imig (60 U/kg/wk) had lesser effects at reducing hepatic GC (p = 0.0199) by 4 wks; this difference disappeared by 8 wks when nearly WT levels were achieved by Imig. Anti-GCase IgG was detected in GCase treated mice at 60 U/kg/wk, and IgE mediated acute hypersensitivity and death occurred after several injections of 60 U/kg/wk (21% with Vela and 34% with Imig). The responses of GC levels and storage cell numbers in Vela- and Imig-treated Gaucher mice at various doses provide a backdrop for clinical applications and decisions

Method for Quantitative Study of Airway Functional Microanatomy Using Micro-Optical Coherence Tomography

We demonstrate the use of a high resolution form of optical coherence tomography, termed micro-OCT (μOCT), for investigating the functional microanatomy of airway epithelia. μOCT captures several key parameters governing the function of the airway surface (airway surface liquid depth, periciliary liquid depth, ciliary function including beat frequency, and mucociliary transport rate) from the same series of images and without exogenous particles or labels, enabling non-invasive study of dynamic phenomena. Additionally, the high resolution of μOCT reveals distinguishable phases of the ciliary stroke pattern and glandular extrusion. Images and functional measurements from primary human bronchial epithelial cell cultures and excised tissue are presented and compared with measurements using existing gold standard methods. Active secretion from mucus glands in tissue, a key parameter of epithelial function, was also observed and quantified