An enhanced CRISPR repressor for targeted mammalian gene regulation.

The RNA-guided endonuclease Cas9 can be converted into a programmable transcriptional repressor, but inefficiencies in target-gene silencing have limited its utility. Here we describe an improved Cas9 repressor based on the C-terminal fusion of a rationally designed bipartite repressor domain, KRAB-MeCP2, to nuclease-dead Cas9. We demonstrate the system's superiority in silencing coding and noncoding genes, simultaneously repressing a series of target genes, improving the results of single and dual guide RNA library screens, and enabling new architectures of synthetic genetic circuits

Information Communication Technology as Instrumental Activities of Daily Living for Aging-in-Place in Chinese Older Adults With and Without Cognitive Impairment: The Validation Study of Advanced Instrumental Activities of Daily Living Scale

Background: The capability in applying information communication technology (ICT) is crucial to the functional independence of older peoples of community living nowadays. The proper assessment of individuals' capability of ICT application is the corner stone for the future development of telemedicine in our aging population. Methods: With the recruitment of 300 participants of different functional and social background in home-living, hostel-living, and care-and-attention home living; and through assessing the ability of individuals in instrumental activities of daily living and cognitive assessments, this study aimed at capturing the content validity and construct validity of the Advanced Instrumental Activities of Daily Living (AIADL scale). In addition, this study assess the ability of older peoples in applying ICT and how the functional and social background affects their independence in aging-in-place. Results: The AIADL scale showed good test-retest reliability and good-to-excellent internal consistency. To determine if items of the AIADL scale measure various aspects of community living, exploratory factor analysis revealed a two-factor structure with “home living and management” and “community living”. Validity analysis with the known-groups method showed a high overall accuracy of prediction of individuals' capability of independent living in the community. Conclusions: The AIADL scale is a valid and reliable instrument to assess the ability of older adults in handling ICT as part of their instrumental activities in daily living. The scale can reflect capability of older peoples in applying ICT. This instrument can serve as a reference in measuring readiness of individuals in receiving telemedicine and their ability of aging-in-place

Shared medical appointments and mindfulness for Type 2 diabetes : a mixed-methods feasibility study

Introduction: Type 2 diabetes (T2DM) is a major health concern with significant personal and healthcare system costs. There is growing interest in using shared medical appointments (SMAs) for management of T2DM. We hypothesize that adding mindfulness to SMAs may be beneficial. This study aimed to assess the feasibility and acceptability of SMAs with mindfulness for T2DM within primary care in Australia. Materials and Methods: We conducted a single-blind randomized controlled feasibility study of SMAs within primary care for people with T2DM living in Western Sydney, Australia. People with T2DM, age 21 years and over, with HbA1c > 6.5% or fasting glucose >7.00 mmol/L within the past 3 months were eligible to enroll. The intervention group attended six 2-h programmed SMAs (pSMAs) which were held fortnightly. pSMAs included a structured education program and mindfulness component. The control group received usual care from their healthcare providers. We collected quantitative and qualitative data on acceptability as well as glycemic control (glycated hemoglobin and continuous glucose monitoring), lipids, anthropometric measures, blood pressure, selfreported psychological outcomes, quality of life, diet, and physical activity using an ActiGraph accelerometer. Results: Over a 2-month period, we enrolled 18 participants (10 females, 8 males) with a mean age of 58 years (standard deviation 9.8). We had 94.4% retention. All participants in the intervention group completed at least four pSMAs. Participants reported that attending pSMAs had been a positive experience that allowed them to accept their diagnosis and empowered them to make changes, which led to beneficial effects including weight loss and better glycemic control. Four pSMA participants found the mindfulness component helpful while two did not. All of the seven participants who contributed to qualitative evaluation reported improved psychosocial wellbeing and found the group setting beneficial. There was a significant difference in total cholesterol levels at 12 weeks between groups (3.86 mmol/L in intervention group vs. 4.15 mmol/L in the control group; p = 0.025) as well as pain intensity levels as measured by the PROMIS-29 (2.11 vs. 2.38; p = 0.034). Conclusion: pSMAs are feasible and acceptable to people with T2DM and may result in clinical improvement. A follow-up fully-powered randomized controlled trial is warranted. Clinical Trial Registration: Australia and New Zealand Clinical Trial Registry, identifier ACTRN12619000892112

Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis

Adoption and Handling Information Communication Technology as Instrumental Activities of Daily Living for Aging-in-Place in Chinese Older Adults

(Background) The use of information communication technology and smartphone application are crucial to individuals’ functional independence of community living. Previous studies did not reveal how older adults’ in applying the information communication technology will affect their aging-in-place in our contemporary community. (Methods) This study aimed at developing the psychometric properties of the instrument named Advanced Instrumental Activities of Daily Living (AIADL), and to explore the adoption and handling information communication technology in instrumental activities of daily living for aging-in-place of older adults. 100 home-living participants who are functionally and socially independent, 100 hostel-living participants who are functionally independent but need social assistance, and 100 care-and-attention home living participants who need environment support and assistance in daily functioning were recruited for this study. (Results) AIADL showed good test-retest reliability and good-to-excellent internal consistency. Exploratory factor analysis revealed a two-factor structure with “home living and management” and “community living”. Validity analysis with the known-groups method showed a high overall accuracy of prediction of individuals’ capability of independent living in the community. (Conclusions) AIADL is a valid and reliable instrument to assess older adults’ ability in handling contemporary instrumental activities in their daily life. This instrument can serve as a reference in measuring individuals’ ability of aging-in-place

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Shared genetic variants suggest common pathways in allergy and autoimmune diseases.

BACKGROUND: The relationship between allergy and autoimmune disorders is complex and poorly understood. OBJECTIVE: To investigate commonalities in genetic loci and pathways between allergy and autoimmune diseases to elucidate shared disease mechanisms. METHODS: We meta-analyzed two GWAS on self-reported allergy and sensitization comprising a total of 62,330 individuals. These results were used to calculate enrichment for SNPs previously associated with autoimmune diseases. Furthermore, we probed for enrichment within genetic pathways and of transcription factor binding sites, and characterized commonalities in the variant burden on tissue-specific regulatory sites by calculating the enrichment of allergy SNPs falling in gene regulatory regions in various cells using Encode Roadmap DHS data, and compared the allergy data with all known diseases. RESULTS: Among 290 loci previously associated with 16 autoimmune diseases, we found a significant enrichment of loci also associated with allergy (p=1.4e-17) encompassing 29 loci at a false discovery rate<0.05. Such enrichment seemed to be a general characteristic for all autoimmune diseases. Among the common loci, 48% had the same direction of effect for allergy and autoimmune diseases. Additionally, we observed an enrichment of allergy SNPs falling within immune pathways and regions of chromatin accessible in immune cells that was also represented in autoimmune diseases, but not in other diseases. CONCLUSION: We identified shared susceptibility loci and commonalities in pathways between allergy and autoimmune diseases, suggesting shared diseases mechanisms. Further studies of these shared genetic mechanisms might help understanding the complex relationship between these diseases, including the parallel increase in disease prevalence

Transcription factor NRF2 as a therapeutic target for chronic diseases: a systems medicine approach

Systems medicine has a mechanism-based rather than a symptom- or organ-based approach to disease and identifies therapeutic targets in a nonhypothesis-driven manner. In this work, we apply this to transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) by cross-validating its position in a protein-protein interaction network (the NRF2 interactome) functionally linked to cytoprotection in low-grade stress, chronic inflammation, metabolic alterations, and reactive oxygen species formation. Multiscale network analysis of these molecular profiles suggests alterations of NRF2 expression and activity as a common mechanism in a subnetwork of diseases (the NRF2 diseasome). This network joins apparently heterogeneous phenotypes such as autoimmune, respiratory, digestive, cardiovascular, metabolic, and neurodegenerative diseases, along with cancer. Importantly, this approach matches and confirms in silico several applications for NRF2-modulating drugs validated in vivo at different phases of clinical development. Pharmacologically, their profile is as diverse as electrophilic dimethyl fumarate, synthetic triterpenoids like bardoxolone methyl and sulforaphane, protein-protein or DNA-protein interaction inhibitors, and even registered drugs such as metformin and statins, which activate NRF2 and may be repurposed for indications within the NRF2 cluster of disease phenotypes. Thus, NRF2 represents one of the first targets fully embraced by classic and systems medicine approaches to facilitate both drug development and drug repurposing by focusing on a set of disease phenotypes that appear to be mechanistically linked. The resulting NRF2 drugome may therefore rapidly advance several surprising clinical options for this subset of chronic diseases

Trends in future health financing and coverage: future health spending and universal health coverage in 188 countries, 2016–40

Background: Achieving universal health coverage (UHC) requires health financing systems that provide prepaid pooled resources for key health services without placing undue financial stress on households. Understanding current and future trajectories of health financing is vital for progress towards UHC. We used historical health financing data for 188 countries from 1995 to 2015 to estimate future scenarios of health spending and pooled health spending through to 2040. Methods: We extracted historical data on gross domestic product (GDP) and health spending for 188 countries from 1995 to 2015, and projected annual GDP, development assistance for health, and government, out-of-pocket, and prepaid private health spending from 2015 through to 2040 as a reference scenario. These estimates were generated using an ensemble of models that varied key demographic and socioeconomic determinants. We generated better and worse alternative future scenarios based on the global distribution of historic health spending growth rates. Last, we used stochastic frontier analysis to investigate the association between pooled health resources and UHC index, a measure of a country's UHC service coverage. Finally, we estimated future UHC performance and the number of people covered under the three future scenarios. Findings: In the reference scenario, global health spending was projected to increase from US$10 trillion (95$20 trillion (18 trillion to 22 trillion) in 2040. Per capita health spending was projected to increase fastest in upper-middle-income countries, at 4·2% (3·4–5·1) per year, followed by lower-middle-income countries (4·0%, 3·6–4·5) and low-income countries (2·2%, 1·7–2·8). Despite global growth, per capita health spending was projected to range from only $40 (24–65) to$413 (263–668) in 2040 in low-income countries, and from $140 (90–200) to$1699 (711–3423) in lower-middle-income countries. Globally, the share of health spending covered by pooled resources would range widely, from 19·8% (10·3–38·6) in Nigeria to 97·9% (96·4–98·5) in Seychelles. Historical performance on the UHC index was significantly associated with pooled resources per capita. Across the alternative scenarios, we estimate UHC reaching between 5·1 billion (4·9 billion to 5·3 billion) and 5·6 billion (5·3 billion to 5·8 billion) lives in 2030. Interpretation: We chart future scenarios for health spending and its relationship with UHC. Ensuring that all countries have sustainable pooled health resources is crucial to the achievement of UHC. Funding: The Bill & Melinda Gates Foundation

Versailles project on advanced materials and standards (VAMAS) interlaboratory study on measuring the number concentration of colloidal gold nanoparticles

We describe the outcome of a large international interlaboratory study of the measurement of particle number concentration of colloidal nanoparticles, project 10 of the technical working area 34, "Nanoparticle Populations" of the Versailles Project on Advanced Materials and Standards (VAMAS). A total of 50 laboratories delivered results for the number concentration of 30 nm gold colloidal nanoparticles measured using particle tracking analysis (PTA), single particle inductively coupled plasma mass spectrometry (spICP-MS), ultraviolet-visible (UV-Vis) light spectroscopy, centrifugal liquid sedimentation (CLS) and small angle X-ray scattering (SAXS). The study provides quantitative data to evaluate the repeatability of these methods and their reproducibility in the measurement of number concentration of model nanoparticle systems following a common measurement protocol. We find that the population-averaging methods of SAXS, CLS and UV-Vis have high measurement repeatability and reproducibility, with between-labs variability of 2.6%, 11% and 1.4% respectively. However, results may be significantly biased for reasons including inaccurate material properties whose values are used to compute the number concentration. Particle-counting method results are less reproducibile than population-averaging methods, with measured between-labs variability of 68% and 46% for PTA and spICP-MS respectively. This study provides the stakeholder community with important comparative data to underpin measurement reproducibility and method validation for number concentration of nanoparticles