ES8 COST-EFFECTIVENESS OF DARUNAVIR/R IN HIGHLY TREATMENT-EXPERIENCED HIV/AIDS PATIENTS IN DIFFERENT EUROPEAN HEALTH CARE SETTINGS

Large-scale molecular interaction data sets have the potential to provide a comprehensive, system-wide understanding of biological function. Although individual molecules can be promiscuous in terms of their contribution to function, molecular functions emerge from the specific interactions of molecules giving rise to modular organisation. As functions often derive from a range of mechanisms, we demonstrate that they are best studied using networks derived from different sources. Implementing a graph partitioning algorithm we identify subnetworks in yeast protein-protein interaction (PPI), genetic interaction and gene co-regulation networks. Among these subnetworks we identify cohesive subgraphs that we expect to represent functional modules in the different data types. We demonstrate significant overlap between the subgraphs generated from the different data types and show these overlaps can represent related functions as represented by the Gene Ontology (GO). Next, we investigate the correspondence between our subgraphs and the Gene Ontology. This revealed varying degrees of coverage of the biological process, molecular function and cellular component ontologies, dependent on the data type. For example, subgraphs from the PPI show enrichment for 84%, 58% and 93% of annotated GO terms, respectively. Integrating the interaction data into a combined network increases the coverage of GO. Furthermore, the different annotation types of GO are not predominantly associated with one of the interaction data types. Collectively our results demonstrate that successful capture of functional relationships by network data depends on both the specific biological function being characterised and the type of network data being used. We identify functions that require integrated information to be accurately represented, demonstrating the limitations of individual data types. Combining interaction subnetworks across data types is therefore essential for fully understanding the complex and emergent nature of biological function

Effects of information, education, and communication campaign on a community-based health insurance scheme in Burkina Faso

Objective : The study analysed the effect of Information, Education, and Communication (IEC) campaign activities on the adoption of a community-based health insurance (CHI) scheme in Nouna, Burkina Faso. It also identified the factors that enhanced or limited the campaign's effectiveness. Design : Complementary data collection approaches were used. A survey was conducted with 250 randomly selected household heads, followed by in-depth interviews with 22 purposively selected community leaders, group discussions with the project management team, and field observations. Bivariate analysis and multivariate logistic regression models were used to assess the association between household exposure to campaign and acquisition of knowledge as well as household exposure to campaign and enrolment. Results : The IEC campaign had a positive effect on households’ knowledge about the CHI and to a lesser extent on household enrolment in the scheme. The effectiveness of the IEC strategy was mainly influenced by: 1 frequent and consistent IEC messages from multiple media channels (mass and interpersonal channels), including the radio, a mobile information van, and CHI team, and 2 community heads’ participation in the CHI scheme promotion. Education was the only significantly influential socio-demographic determinant of knowledge and enrolment among household heads. The relatively low effects of the IEC campaign on CHI enrolment are indicative of other important IEC mediating factors, which should be taken into account in future CHI campaign evaluation. Conclusion : The study concludes that an IEC campaign is crucial to improving the understanding of the CHI scheme concept, which is an enabler to enrolment, and should be integrated into scheme designs and evaluations

Localization of a gene for nonsyndromic renal hypodysplasia to chromosome 1p32-33.

Nonsyndromic defects in the urinary tract are the most common cause of end-stage renal failure in children and account for a significant proportion of adult nephropathy. The genetic basis of these disorders is not fully understood. We studied seven multiplex kindreds ascertained via an index case with a nonsyndromic solitary kidney or renal hypodysplasia. Systematic ultrasonographic screening revealed that many family members harbor malformations, such as solitary kidneys, hypodysplasia, or ureteric abnormalities (in a total of 29 affected individuals). A genomewide scan identified significant linkage to a 6.9-Mb segment on chromosome 1p32-33 under an autosomal dominant model with reduced penetrance (peak LOD score 3.5 at D1S2652 in the largest kindred). Altogether, three of the seven families showed positive LOD scores at this interval, demonstrating heterogeneity of the trait (peak HLOD 3.9, with 45% of families linked). The chromosome 1p32-33 interval contains 52 transcription units, and at least 23 of these are expressed at stage E12.5 in the murine ureteric bud and/or metanephric mesenchyme. These data show that autosomal dominant nonsyndromic renal hypodysplasia and associated urinary tract malformations are genetically heterogeneous and identify a locus for this common cause of human kidney failure

Studying complex interventions : reflections from the FEMHealth project on evaluating fee exemption policies in West Africa and Morocco

Peer reviewedPublisher PD

Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease

Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer's disease. Longitudinal, within-person analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini-Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer's disease, which supports its potential utility as a clinically useful biomarker

BDNF Val66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer’s disease

The brain-derived neurotrophic factor ( BDNF ) Val66Met polymorphism is implicated in synaptic excitation and neuronal integrity, and has previously been shown to moderate amyloid-β-related memory decline and hippocampal atrophy in preclinical sporadic Alzheimer’s disease. However, the effect of BDNF in autosomal dominant Alzheimer’s disease is unknown. We aimed to determine the effect of BDNF Val66Met on cognitive function, hippocampal function, tau and amyloid-β in preclinical autosomal dominant Alzheimer’s disease. We explored effects of apolipoprotein E ( APOE ) ε4 on these relationships. The Dominantly Inherited Alzheimer Network conducted clinical, neuropsychological, genetic, biomarker and neuroimaging measures at baseline in 131 mutation non-carriers and 143 preclinical autosomal dominant Alzheimer’s disease mutation carriers on average 12 years before clinical symptom onset. BDNF genotype data were obtained for mutation carriers (95 Val 66 homozygotes, 48 Met 66 carriers). Among preclinical mutation carriers, Met 66 carriers had worse memory performance, lower hippocampal glucose metabolism and increased levels of cerebrospinal fluid tau and phosphorylated tau (p-tau) than Val 66 homozygotes. Cortical amyloid-β and cerebrospinal fluid amyloid-β 42 levels were significantly different from non-carriers but did not differ between preclinical mutation carrier Val 66 homozygotes and Met 66 carriers. There was an effect of APOE on amyloid-β levels, but not cognitive function, glucose metabolism or tau. As in sporadic Alzheimer’s disease, the deleterious effects of amyloid-β on memory, hippocampal function, and tau in preclinical autosomal dominant Alzheimer’s disease mutation carriers are greater in Met 66 carriers. To date, this is the only genetic factor found to moderate downstream effects of amyloid-β in autosomal dominant Alzheimer’s disease

Dihydrotanshinone I exhibits antitumor effects via β-catenin downregulation in papillary thyroid cancer cell lines

Thyroid cancer is the most common endocrine carcinoma and, among its different subtypes, the papillary subtype (PTC) is the most frequent. Generally, PTCs are well differentiated, but a minor percentage of PTCs are characterized by a worse prognosis and more aggressive behavior. Phytochemicals, naturally found in plant products, represent a heterogeneous group of bioactive compounds that can interfere with cell proliferation and the regulation of the cell cycle, taking part in multiple signaling pathways that are often disrupted in tumor initiation, proliferation, and progression. In this work, we focused on 15,16-dihydrotanshinone I (DHT), a tanshinone isolated from Salvia miltiorrhiza Bunge (Danshen). We first evaluated DHT biological effect on PTC cells regarding cell viability, colony formation ability, and migration capacity. All of these parameters were downregulated by DHT treatment. We then investigated gene expression changes after DHT treatment by performing RNA-seq. The analysis revealed that DHT significantly reduced the Wnt signaling pathway, which plays a role in various diseases, including cancer. Finally, we demonstrate that DHT treatment decreases protein levels of β-catenin, a final effector of canonical Wnt signaling pathway. Overall, our data suggest a possible use of this nutraceutical as an adjuvant in the treatment of aggressive papillary thyroid carcinoma