Role of Diffusion Tensor Imaging in Prognostication and Treatment Monitoring in Niemann-Pick Disease Type C1

Niemann-Pick Disease, type C1 (NPC1) is a rapidly progressive neurodegenerative disorder characterized by cholesterol sequestration within late endosomes and lysosomes, for which no reliable imaging marker exists for prognostication and management. Cerebellar volume deficits are found to correlate with disease severity and diffusion tensor imaging (DTI) of the corpus callosum and brainstem, which has shown that microstructural disorganization is associated with NPC1 severity. This study investigates the utility of cerebellar DTI in clinical severity assessment. We hypothesize that cerebellar volume, fractional anisotropy (FA) and mean diffusivity (MD) negatively correlate with NIH NPC neurological severity score (NNSS) and motor severity subscores. Magnetic resonance imaging (MRI) was obtained for thirty-nine NPC1 subjects, ages 1–21.9 years (mean = 11.1, SD = 6.1). Using an atlas-based automated approach, the cerebellum of each patient was measured for FA, MD and volume. Additionally, each patient was given an NNSS. Decreased cerebellar FA and volume, and elevated MD correlate with higher NNSS. The cognition subscore and motor subscores for eye movement, ambulation, speech, swallowing, and fine motor skills were also statistically significant. Microstructural disorganization negatively correlated with motor severity in subjects. Additionally, Miglustat therapy correlated with lower severity scores across ranges of FA, MD and volume in all regions except the inferior peduncle, where a paradoxical effect was observed at high FA values. These findings suggest that DTI is a promising prognostication tool

A genome guided evaluation of the Lab4 probiotic consortium

In this study, we present the draft genome sequences of the Lab4 probiotic consortium using whole genome sequencing. Draft genome sequences were retrieved and deposited for each of the organisms; PRJNA559984 for B. bifidum CUL20, PRJNA482335 for Lactobacillus acidophilus CUL60, PRJNA482434 for Lactobacillus acid. Probiogenomic in silico analyses confirmed existing taxonomies and identified the presence putative gene sequences that were functionally related to the performance of each organism during in vitro assessments of bile and acid tolerability, adherence to enterocytes and susceptibility to antibiotics. Predictions of genomic stability identified no significant risk of horizontal gene transfer in any of the Lab4 strains and the absence of both antibiotic resistance and virulence genes. These observations were supported by the outcomes of acute phase and repeat dose tolerability studies in Wistar rats where challenge with high doses of Lab4 did not result in any mortalities, clinical/histopathological abnormalities nor indications of systemic toxicity. Detection of increased numbers of lactobacilli and bifidobacteria in the faeces of supplemented rats implied an ability to survive transit through the gastrointestinal tract and/or impact upon the intestinal microbiota composition. In summary, this study provides in silico, in vitro and in vivo support for probiotic functionality and the safety of the Lab4 consortium

Extending Delivery of Seasonal Malaria Chemoprevention to Children Aged 5-10 Years in Chad: A Mixed-Methods Study.

BACKGROUND: To prevent malaria among children aged 3-59 months in areas with high seasonal transmission, seasonal malaria chemoprevention (SMC) is recommended. In Chad, there is evidence of SMC administration to children aged older than 5 years (referred to as "leakage"). This study aimed to understand the reasons for leakage and explore the feasibility and acceptability of extending the delivery of SMC to children aged 5-10 years in Chad. METHODS: We conducted a mixed-methods study in Massaguet health district with a cross-sectional survey to determine SMC coverage for children aged up to 10 years after SMC cycles 1 and 3 (n=90 and n=100 caregivers surveyed, respectively) and at the end of cycle 4 (n=101 caregivers surveyed). We conducted 14 key informant interviews at the national and district level and 8 focus group discussions with community distributors and caregivers. RESULTS: In the compounds surveyed, there were no children aged 5-10 years in cycle 1. In cycles 3 (n=1 children) and 4 (n=16 children), there was 100% (95% confidence interval [CI]=2.5, 100.0) and 62.5% (95% CI=35.4, 84.8) coverage of SMC in children aged 5-10 years, respectively. Extension of SMC to older children was considered acceptable, but there were concerns about feasibility and ensuring the sustainability of the current program in children aged 3-59 months. Key informants acknowledged the need to secure additional funding to pilot SMC in older age groups and were uncertain about the impact of the current SMC program at scale. CONCLUSION: Key informants considered extending SMC to children aged 5-10 years acceptable but did not deem it a current priority. They expressed an urgent need to address leakage and reinforce both the sustainability and quality of the current SMC program

Health management information system (HMIS) data quality and associated factors in Massaguet district, Chad

Background Quality data from Health Management Information Systems (HMIS) are important for tracking the effectiveness of malaria control interventions. However, HMIS data in many resource-limited settings do not currently meet standards set by the World Health Organization (WHO). We aimed to assess HMIS data quality and associated factors in Chad. Methods A cross-sectional study was conducted in 14 health facilities in Massaguet district. Data on children under 15 years were obtained from the HMIS and from the external patient register covering the period January-December 2018. An additional questionnaire was administered to 16 health centre managers to collect data on contextual variables. Patient registry data were aggregated and compared with the HMIS database at district and health centre level. Completeness and accuracy indicators were calculated as per WHO guidelines. Multivariate logistic regressions were performed on the Verification Factor for attendance, suspected and confirmed malaria cases for three age groups (1 to < 12 months, 1 to < 5 years and 5 to < 15 years) to identify associations between health centre characteristics and data accuracy. Results Health centres achieved a high level of data completeness in HMIS. Malaria data were over-reported in HMIS for children aged under 15 years. There was an association between workload and higher odds of inaccuracy in reporting of attendance among children aged 1 to < 5 years (Odds ratio [OR]: 10.57, 95% CI 2.32-48.19) and 5- < 15 years (OR: 6.64, 95% CI 1.38-32.04). Similar association was found between workload and stock-outs in register books, and inaccuracy in reporting of malaria confirmed cases. Meanwhile, we found that presence of a health technician, and of dedicated staff for data management, were associated with lower inaccuracy in reporting of clinic attendance in children aged under five years. Conclusion Data completeness was high while the accuracy was low. Factors associated with data inaccuracy included high workload and the unavailability of required data collection tools. The results suggest that improvement in working conditions for clinic personnel may improve HMIS data quality. Upgrading from paper-based forms to a web-based HMIS may provide a solution for improving data accuracy and its utility for future evaluations of health interventions. Results from this study can inform the Ministry of Health and it partners on the precautions to be taken in the use of HMIS data and inform initiatives for improving its quality

The relevance of model-driven engineering thirty years from now

International audienceAlthough model-driven engineering (MDE) is now an established approach for developing complex software systems, it has not been universally adopted by the software industry. In order to better understand the reasons for this, as well as to identify future opportunities for MDE, we carried out a week-long design thinking experiment with 15 MDE experts. Participants were facilitated to identify the biggest problems with current MDE technologies, to identify grand challenges for society in the near future, and to identify ways that MDE could help to address these challenges. The outcome is a reflection of the current strengths of MDE, an outlook of the most pressing challenges for society at large over the next three decades, and an analysis of key future MDE research opportunities

Extending seasonal malaria chemoprevention to five cycles: a pilot study of feasibility and acceptability in Mangodara district, Burkina Faso.

BACKGROUND: Seasonal malaria chemoprevention (SMC) involves administering antimalarial drugs at monthly intervals during the high malaria transmission period to children aged 3 to 59 months as recommended by the World Health Organization. Typically, a full SMC course is administered over four monthly cycles from July to October, coinciding with the rainy season. However, an analysis of rainfall patterns suggest that the malaria transmission season is longer and starting as early as June in the south of Burkina Faso, leading to a rise in cases prior to the first cycle. This study assessed the acceptability and feasibility of extending SMC from four to five cycles to coincide with the earlier rainy season in Mangodara health district. METHODS: The mixed-methods study was conducted between July and November 2019. Quantitative data were collected through end-of-cycle and end-of-round household surveys to determine the effect of the additional cycle on the coverage of SMC in Mangodara. The data were then compared with 22 other districts where SMC was implemented by Malaria Consortium. Eight focus group discussions were conducted with caregivers and community distributors and 11 key informant interviews with community, programme and national-level stakeholders. These aimed to determine perceptions of the acceptability and feasibility of extending SMC to five cycles. RESULTS: The extension was perceived as acceptable by caregivers, community distributors and stakeholders due to the positive impact on the health of children under five. However, many community distributors expressed concern over the feasibility, mainly due to the clash with farming activities in June. Stakeholders highlighted the need for more evidence on the impact of the additional cycle on parasite resistance prior to scale-up. End-of-cycle survey data showed no difference in coverage between five SMC cycles in Mangodara and four cycles in the 22 comparison districts. CONCLUSIONS: The additional cycle should begin early in the day in order to not coincide with the agricultural activities of community distributors. Continuous sensitisation at community level is critical for the sustainability of SMC and acceptance of an additional cycle, which should actively engage male caregivers. Providing additional support in proportion to the increased workload from a fifth cycle, including timely remuneration, is critical to avoid the demotivation of community distributors. Further studies are required to understand the effectiveness, including cost-effectiveness, of tailoring SMC according to the rainy season. Understanding the impact of an additional cycle on parasite resistance to SPAQ is critical to address key informants' concerns around the deviation from the current four-cycle policy recommendation

A Combinatorial Approach to Detect Coevolved Amino Acid Networks in Protein Families of Variable Divergence

Communication between distant sites often defines the biological role of a protein: amino acid long-range interactions are as important in binding specificity, allosteric regulation and conformational change as residues directly contacting the substrate. The maintaining of functional and structural coupling of long-range interacting residues requires coevolution of these residues. Networks of interaction between coevolved residues can be reconstructed, and from the networks, one can possibly derive insights into functional mechanisms for the protein family. We propose a combinatorial method for mapping conserved networks of amino acid interactions in a protein which is based on the analysis of a set of aligned sequences, the associated distance tree and the combinatorics of its subtrees. The degree of coevolution of all pairs of coevolved residues is identified numerically, and networks are reconstructed with a dedicated clustering algorithm. The method drops the constraints on high sequence divergence limiting the range of applicability of the statistical approaches previously proposed. We apply the method to four protein families where we show an accurate detection of functional networks and the possibility to treat sets of protein sequences of variable divergence

Emission line gas ionisation in young radio galaxies

This paper is the second in a series in which we present intermediate-resolution spectra for a complete sample of 14 compact radio sources, taken with the aim of investigating the impact of the nuclear activity on the cirumnuclear interstellar medium (ISM) in the early stages of radio source evolution. In the first paper we presented the kinematic results from the line modelling and reported fast outflows in the circumnuclear gas. Here, we use the line fluxes to investigate the physical conditions and dominant ionisation mechanisms of the emission line gas. We find evidence for large electron densities and high reddening in the nuclear regions, particularly in the broader, blueshifted components. These results are consistent with the idea that the young, recently triggered radio sources still reside in dense and dusty cocoons deposited by the recent activity triggering event. In addition, we find that the quiescent nuclear and extended narrow components are consistent with AGN photoionisation. For the nuclear broader and shifted components the results are less clear. Whilst there are suggestions that the broader components may be closer to shock plus precursor models on the diagnostic diagrams (with high electron temperatures and densities), we are unable to unambiguously distinguish the dominant ionisation mechanism using the optical emission line ratios. This is surprising given the strong evidence for jet-cloud interactions (broad emission lines, large outflow velocities and strong radio-optical alignments), which favours the idea that the warm gas has been accelerated in shocks driven by the radio lobes expanding through a dense cocoon of gas deposited during the triggering event.Comment: Accepted for publication in MNRAS - Full paper (including Appendices) available at http://www.astron.nl/~morganti/Papers/Holt_MNRAS2009.p