Policy Recommendations From Transmission Modeling for the Elimination of Visceral Leishmaniasis in the Indian Subcontinent.

Background: Visceral leishmaniasis (VL) has been targeted by the World Health Organization (WHO) and 5 countries in the Indian subcontinent for elimination as a public health problem. To achieve this target, the WHO has developed guidelines consisting of 4 phases of different levels of interventions, based on vector control through indoor residual spraying of insecticide (IRS) and active case detection (ACD). Mathematical transmission models of VL are increasingly used for planning and assessing the efficacy of interventions and evaluating the intensity and timescale required to achieve the elimination target. Methods: This paper draws together the key policy-relevant conclusions from recent transmission modeling of VL, and presents new predictions for VL incidence under the interventions recommended by the WHO using the latest transmission models. Results: The model predictions suggest that the current WHO guidelines should be sufficient to reach the elimination target in areas that had medium VL endemicities (up to 5 VL cases per 10000 population per year) prior to the start of interventions. However, additional interventions, such as extending the WHO attack phase (intensive IRS and ACD), may be required to bring forward elimination in regions with high precontrol endemicities, depending on the relative infectiousness of different disease stages. Conclusions: The potential hurdle that asymptomatic and, in particular, post-kala-azar dermal leishmaniasis cases may pose to reaching and sustaining the target needs to be addressed. As VL incidence decreases, the pool of immunologically naive individuals will grow, creating the potential for new outbreaks

Sialic Acid Glycobiology Unveils Trypanosoma cruzi Trypomastigote Membrane Physiology.

Trypanosoma cruzi, the flagellate protozoan agent of Chagas disease or American trypanosomiasis, is unable to synthesize sialic acids de novo. Mucins and trans-sialidase (TS) are substrate and enzyme, respectively, of the glycobiological system that scavenges sialic acid from the host in a crucial interplay for T. cruzi life cycle. The acquisition of the sialyl residue allows the parasite to avoid lysis by serum factors and to interact with the host cell. A major drawback to studying the sialylation kinetics and turnover of the trypomastigote glycoconjugates is the difficulty to identify and follow the recently acquired sialyl residues. To tackle this issue, we followed an unnatural sugar approach as bioorthogonal chemical reporters, where the use of azidosialyl residues allowed identifying the acquired sugar. Advanced microscopy techniques, together with biochemical methods, were used to study the trypomastigote membrane from its glycobiological perspective. Main sialyl acceptors were identified as mucins by biochemical procedures and protein markers. Together with determining their shedding and turnover rates, we also report that several membrane proteins, including TS and its substrates, both glycosylphosphatidylinositol-anchored proteins, are separately distributed on parasite surface and contained in different and highly stable membrane microdomains. Notably, labeling for α(1,3)Galactosyl residues only partially colocalize with sialylated mucins, indicating that two species of glycosylated mucins do exist, which are segregated at the parasite surface. Moreover, sialylated mucins were included in lipid-raft-domains, whereas TS molecules are not. The location of the surface-anchored TS resulted too far off as to be capable to sialylate mucins, a role played by the shed TS instead. Phosphatidylinositol-phospholipase-C activity is actually not present in trypomastigotes. Therefore, shedding of TS occurs via microvesicles instead of as a fully soluble form

Policy Recommendations From Transmission Modeling for the Elimination of Visceral Leishmaniasis in the Indian Subcontinent.

Background: Visceral leishmaniasis (VL) has been targeted by the World Health Organization (WHO) and 5 countries in the Indian subcontinent for elimination as a public health problem. To achieve this target, the WHO has developed guidelines consisting of 4 phases of different levels of interventions, based on vector control through indoor residual spraying of insecticide (IRS) and active case detection (ACD). Mathematical transmission models of VL are increasingly used for planning and assessing the efficacy of interventions and evaluating the intensity and timescale required to achieve the elimination target. Methods: This paper draws together the key policy-relevant conclusions from recent transmission modeling of VL, and presents new predictions for VL incidence under the interventions recommended by the WHO using the latest transmission models. Results: The model predictions suggest that the current WHO guidelines should be sufficient to reach the elimination target in areas that had medium VL endemicities (up to 5 VL cases per 10000 population per year) prior to the start of interventions. However, additional interventions, such as extending the WHO attack phase (intensive IRS and ACD), may be required to bring forward elimination in regions with high precontrol endemicities, depending on the relative infectiousness of different disease stages. Conclusions: The potential hurdle that asymptomatic and, in particular, post-kala-azar dermal leishmaniasis cases may pose to reaching and sustaining the target needs to be addressed. As VL incidence decreases, the pool of immunologically naive individuals will grow, creating the potential for new outbreaks

Moonlighting Proteins Hal3 and Vhs3 Form a Heteromeric PPCDC with Ykl088w in Yeast CoA Biosynthesis

Premi a l'excel·lència investigadora. 2010Unlike most other organisms, the essential five-step Coenzyme A biosynthetic pathway has not been fully resolved in yeast. Specifically, the gene(s) encoding the phosphopantothenoylcysteine decarboxylase (PPCDC) activity still remains unidentified. Sequence homology analyses suggest three candidates, namely Ykl088w, Hal3 and Vhs3, as putative PPCDC enzymes in Saccharomyces cerevisiae. Interestingly, Hal3 and Vhs3 have been characterized as negative regulatory subunits of the Ppz1 protein phosphatase. Here we show that YKL088w does not encode a third Ppz1 regulatory subunit, and that the essential roles of Ykl088w and the Hal3/Vhs3 pair are complementary, cannot be interchanged and can be attributed to PPCDC-related functions. We demonstrate that while known eukaryotic PPCDCs are homotrimers, the active yeast enzyme is a heterotrimer which consists of Ykl088w and Hal3/Vhs3 monomers that separately provides two essential catalytic residues. Our results unveil Hal3/Vhs3 as moonlighting proteins, involved in both CoA biosynthesis and protein phosphatase regulation

A general piecewise multi-state survival model: Application to breast cancer

Multi-state models are considered in the field of survival analysis for modelling illnesses that evolve through several stages over time. Multi-state models can be developed by applying several techniques, such as non-parametric, semi-parametric and stochastic processes, particularly Markov processes. When the development of an illness is being analysed, its progression is tracked periodically. Medical reviews take place at discrete times, and a panel data analysis can be formed. In this paper, a discrete-time piecewise non-homogeneous Markov process is constructed for modelling and analysing a multi-state illness with a general number of states. The model is built, and relevant measures, such as survival function, transition probabilities, mean total times spent in a group of states and the conditional probability of state change, are determined. A likelihood function is built to estimate the parameters and the general number of cut-points included in the model. Time-dependent covariates are introduced, the results are obtained in a matrix algebraic form and the algorithms are shown. The model is applied to analyse the behaviour of breast cancer. A study of the relapse and survival times of 300 breast cancer patients who have undergone mastectomy is developed. The results of this paper are implemented computationally with MATLAB and R.Ministerio de Economía y Competitividad FQM-307European Regional Development Fund (ERDF) MTM2017-88708-PUniversity of Milano-Bicocca 2014-ATE-022

Coarse graining ππ scattering

We carry out an analysis of ππ scattering in the I J = 00, 11 and 20 channels in configuration space up to a maximal center-of-mass energy √ s = 1.4 GeV. We separate the interaction into two regions marked by an elementarity radius of the system; namely, a long distance region above which pions can be assumed to interact as elementary particles and a short distance region where many physical effects cannot be disentangled. The long distance interaction is described by chiral dynamics, where a two-pionexchange potential is identified, computed and compared to lattice calculations. The short distance piece corresponds to a coarse grained description exemplified by a superposition of delta-shell potentials sampling the interaction with the minimal wavelength. We show how the so constructed nonperturbative scattering amplitude complies with the proper analytic structure, allowing for an explicit N/D type decomposition in terms of the corresponding Jost functions and fulfilling dispersion relations without subtractions. We also address renormalization issues in coordinate space and investigate the role of crossing when fitting the scattering amplitudes above and below threshold to Roy-equation results. At higher energies, we show how inelasticities can be described by one single complex and energy dependent parameter. A successful description of the data can be achieved with a minimal number of fitting parameters, suggesting that coarse graining is a viable approach to analyze hadronic processes.Work partially supported by Spanish MINEICO and European FEDER funds (grants FIS2014-59386-P, FIS2017-85053-C2-1-P and FPA2015- 64041-C2-1-P), Junta de Andalucía (grant FQM-225) and the Swiss National Science Foundation

Decline in Diarrhea Mortality and Admissions after Routine Childhood Rotavirus Immunization in Brazil: A Time-Series Analysis

A time series analysis by Manish Patel and colleagues shows that the introduction of rotavirus vaccination in Brazil is associated with reduced diarrhea-related deaths and hospital admissions in children under 5 years of age

The C-terminal region of Trypanosoma cruzi MASPs is antigenic and secreted via exovesicles.

Trypanosoma cruzi is the etiological agent of Chagas disease, a neglected and emerging tropical disease, endemic to South America and present in non-endemic regions due to human migration. The MASP multigene family is specific to T. cruzi, accounting for 6% of the parasite's genome and plays a key role in immune evasion. A common feature of MASPs is the presence of two conserved regions: an N-terminal region codifying for signal peptide and a C-terminal (C-term) region, which potentially acts as GPI-addition signal peptide. Our aim was the analysis of the presence of an immune response against the MASP C-term region. We found that this region is highly conserved, released via exovesicles (EVs) and has an associated immune response as revealed by epitope affinity mapping, IFA and inhibition of the complement lysis assays. We also demonstrate the presence of a fast IgM response in Balb/c mice infected with T. cruzi. Our results reveal the presence of non-canonical secreted peptides in EVs, which can subsequently be exposed to the immune system with a potential role in evading immune system targets in the parasite

How protective is cervical cancer screening against cervical cancer mortality in developing countries? The Colombian case

<p>Abstract</p> <p>Background</p> <p>Cervical cancer is one of the top causes of cancer morbidity and mortality in Colombia despite the existence of a national preventive program. Screening coverage with cervical cytology does not explain the lack of success of the program in reducing incidence and mortality rates by cervical cancer. To address this problem an ecological analysis, at department level, was carried out in Colombia to assess the relationship between cervical screening characteristics and cervical cancer mortality rates.</p> <p>Methods</p> <p>Mortality rates by cervical cancer were estimated at the department level for the period 2000-2005. Levels of mortality rates were compared to cervical screening coverage and other characteristics of the program. A Poisson regression was used to estimate the effect of different dimensions of program performance on mortality by cervical cancer.</p> <p>Results</p> <p>Screening coverage ranged from 28.7% to 65.6% by department but increases on this variable were not related to decreases in mortality rates. A significant reduction in mortality was found in departments where a higher proportion of women looked for medical advice when abnormal findings were reported in Pap smears. Geographic areas where a higher proportion of women lack health insurance had higher rates of mortality by cervical cancer.</p> <p>Conclusions</p> <p>These results suggest that coverage is not adequate to prevent mortality due to cervical cancer if women with abnormal results are not provided with adequate follow up and treatment. The role of different dimensions of health care such as insurance coverage, quality of care, and barriers for accessing health care needs to be evaluated and addressed in future studies.</p