Evidence-based restructuring of health and social care

In this Perspective, Aziz Sheikh discusses research to evaluate health policy changes in the provision of care, commenting on a study by James Lopez Bernal and colleagues that examined specialist-dominated hospital care versus community-based care in the United Kingdom

A systematic review on health resilience to economic crises

Background The health effects of recent economic crises differ markedly by population group. The objective of this systematic review is to examine evidence from longitudinal studies on factors influencing resilience for any health outcome or health behaviour among the general population living in countries exposed to financial crises. Methods We systematically reviewed studies from six electronic databases (EMBASE, Global Health, MEDLINE, PsycINFO, Scopus, Web of Science) which used quantitative longitudinal study designs and included: (i) exposure to an economic crisis; (ii) changes in health outcomes/behaviours over time; (iii) statistical tests of associations of health risk and/or protective factors with health outcomes/behaviours. The quality of the selected studies was appraised using the Quality Assessment Tool for Quantitative Studies. PRISMA reporting guidelines were followed. Results From 14,584 retrieved records, 22 studies met the eligibility criteria. These studies were conducted across 10 countries in Asia, Europe and North America over the past two decades. Ten socio-demographic factors that increased or protected against health risk were identified: gender, age, education, marital status, household size, employment/occupation, income/ financial constraints, personal beliefs, health status, area of residence, and social relations. These studies addressed physical health, mortality, suicide and suicide attempts, mental health, and health behaviours. Women’s mental health appeared more susceptible to crises than men’s. Lower income levels were associated with greater increases in cardiovascular disease, mortality and worse mental health. Employment status was associated with changes in mental health. Associations with age, marital status, and education were less consistent, although higher education was associated with healthier behaviours. Conclusions Despite widespread rhetoric about the importance of resilience, there was a dearth of studies which operationalised resilience factors. Future conceptual and empirical research is needed to develop the epidemiology of resilience

Explaining why simple liquids are quasi-universal

It has been known for a long time that many simple liquids have surprisingly similar structure as quantified, e.g., by the radial distribution function. A much more recent realization is that the dynamics are also very similar for a number of systems with quite different pair potentials. Systems with such non-trivial similarities are generally referred to as "quasi-universal". From the fact that the exponentially repulsive pair potential has strong virial potential-energy correlations in the low-temperature part of its thermodynamic phase diagram, we here show that a liquid is quasi-universal if its pair potential can be written approximately as a sum of exponential terms with numerically large prefactors. Based on evidence from the literature we moreover conjecture the converse, i.e., that quasi-universality only applies for systems with this property

The Interaction of Canine Plasminogen with Streptococcus pyogenes Enolase: They Bind to One Another but What Is the Nature of the Structures Involved?

For years it has been clear that plasminogen from different sources and enolase from different sources interact strongly. What is less clear is the nature of the structures required for them to interact. This work examines the interaction between canine plasminogen (dPgn) and Streptococcus pyogenes enolase (Str enolase) using analytical ultracentrifugation (AUC), surface plasmon resonance (SPR), fluorescence polarization, dynamic light scattering (DLS), isothermal titration calorimetry (ITC), and simple pull-down reactions. Overall, our data indicate that a non-native structure of the octameric Str enolase (monomers or multimers) is an important determinant of its surface-mediated interaction with host plasminogen. Interestingly, a non-native structure of plasminogen is capable of interacting with native enolase. As far as we can tell, the native structures resist forming stable mixed complexes

Identification of Candidate Parkinson Disease Genes by Integrating Genome-Wide Association Study, Expression, and Epigenetic Data Sets

Importance Substantial genome-wide association study (GWAS) work in Parkinson disease (PD) has led to the discovery of an increasing number of loci shown reliably to be associated with increased risk of disease. Improved understanding of the underlying genes and mechanisms at these loci will be key to understanding the pathogenesis of PD. / Objective To investigate what genes and genomic processes underlie the risk of sporadic PD. / Design and Setting This genetic association study used the bioinformatic tools Coloc and transcriptome-wide association study (TWAS) to integrate PD case-control GWAS data published in 2017 with expression data (from Braineac, the Genotype-Tissue Expression [GTEx], and CommonMind) and methylation data (derived from UK Parkinson brain samples) to uncover putative gene expression and splicing mechanisms associated with PD GWAS signals. Candidate genes were further characterized using cell-type specificity, weighted gene coexpression networks, and weighted protein-protein interaction networks. / Main Outcomes and Measures It was hypothesized a priori that some genes underlying PD loci would alter PD risk through changes to expression, splicing, or methylation. Candidate genes are presented whose change in expression, splicing, or methylation are associated with risk of PD as well as the functional pathways and cell types in which these genes have an important role. / Results Gene-level analysis of expression revealed 5 genes (WDR6 [OMIM 606031], CD38 [OMIM 107270], GPNMB [OMIM 604368], RAB29 [OMIM 603949], and TMEM163 [OMIM 618978]) that replicated using both Coloc and TWAS analyses in both the GTEx and Braineac expression data sets. A further 6 genes (ZRANB3 [OMIM 615655], PCGF3 [OMIM 617543], NEK1 [OMIM 604588], NUPL2 [NCBI 11097], GALC [OMIM 606890], and CTSB [OMIM 116810]) showed evidence of disease-associated splicing effects. Cell-type specificity analysis revealed that gene expression was overall more prevalent in glial cell types compared with neurons. The weighted gene coexpression performed on the GTEx data set showed that NUPL2 is a key gene in 3 modules implicated in catabolic processes associated with protein ubiquitination and in the ubiquitin-dependent protein catabolic process in the nucleus accumbens, caudate, and putamen. TMEM163 and ZRANB3 were both important in modules in the frontal cortex and caudate, respectively, indicating regulation of signaling and cell communication. Protein interactor analysis and simulations using random networks demonstrated that the candidate genes interact significantly more with known mendelian PD and parkinsonism proteins than would be expected by chance. / Conclusions and Relevance Together, these results suggest that several candidate genes and pathways are associated with the findings observed in PD GWAS studies

Mitochondria function associated genes contribute to Parkinson's Disease risk and later age at onset

Mitochondrial dysfunction has been implicated in the etiology of monogenic Parkinson’s disease (PD). Yet the role that mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here, we comprehensively assessed the role of mitochondrial function-associated genes in sporadic PD by leveraging improvements in the scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. We calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our primary and secondary gene lists are significantly associated with increased PD risk. We further reported that the PRS of the secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional genomic associations we implemented Mendelian randomization, which showed that 14 of these mitochondrial functionassociated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes are not only involved in mitophagy, but implicate new mitochondrial processes. Our data suggests that therapeutics targeting mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early stage of PD

Adopting a high-polyphenolic diet is associated with an improved glucose profile: prospective analysis within the PREDIMED-plus trial

Previous studies suggested that dietary polyphenols could reduce the incidence and complications of type-2 diabetes (T2D); although the evidence is still limited and inconsistent. This work analyzes whether changing to a diet with a higher polyphenolic content is associated with an improved glucose profile. At baseline, and at 1 year of follow-up visits, 5921 participants (mean age 65.0 ± 4.9, 48.2% women) who had overweight/obesity and metabolic syndrome filled out a validated 143-item semi-quantitative food frequency questionnaire (FFQ), from which polyphenol intakes were calculated. Energy-adjusted total polyphenols and subclasses were categorized in tertiles of changes. Linear mixed-effect models with random intercepts (the recruitment centers) were used to assess associations between changes in polyphenol subclasses intake and 1-year plasma glucose or glycosylated hemoglobin (HbA1c) levels. Increments in total polyphenol intake and some classes were inversely associated with better glucose levels and HbA1c after one year of follow-up. These associations were modified when the analyses were run considering diabetes status separately. To our knowledge, this is the first study to assess the relationship between changes in the intake of all polyphenolic groups and T2D-related parameters in a senior population with T2D or at high-risk of developing T2D

Immunological aspects in chronic lymphocytic leukemia (CLL) development

Chronic lymphocytic leukemia (CLL) is unique among B cell malignancies in that the malignant clones can be featured either somatically mutated or unmutated IGVH genes. CLL cells that express unmutated immunoglobulin variable domains likely underwent final development prior to their entry into the germinal center, whereas those that express mutated variable domains likely transited through the germinal center and then underwent final development. Regardless, the cellular origin of CLL remains unknown. The aim of this review is to summarize immunological aspects involved in this process and to provide insights about the complex biology and pathogenesis of this disease. We propose a mechanistic hypothesis to explain the origin of B-CLL clones into our current picture of normal B cell development. In particular, we suggest that unmutated CLL arises from normal B cells with self-reactivity for apoptotic bodies that have undergone receptor editing, CD5 expression, and anergic processes in the bone marrow. Similarly, mutated CLL would arise from cells that, while acquiring self-reactivity for autoantigens—including apoptotic bodies—in germinal centers, are also still subject to tolerization mechanisms, including receptor editing and anergy. We believe that CLL is a proliferation of B lymphocytes selected during clonal expansion through multiple encounters with (auto)antigens, despite the fact that they differ in their state of activation and maturation. Autoantigens and microbial pathogens activate BCR signaling and promote tolerogenic mechanisms such as receptor editing/revision, anergy, CD5+ expression, and somatic hypermutation in CLL B cells. The result of these tolerogenic mechanisms is the survival of CLL B cell clones with similar surface markers and homogeneous gene expression signatures. We suggest that both immunophenotypic surface markers and homogenous gene expression might represent the evidence of several attempts to re-educate self-reactive B cells