AAV2-Mediated Combined Subretinal Delivery of IFN-α and IL-4 Reduces the Severity of Experimental Autoimmune Uveoretinitis

We previously showed that adeno-associated virus 2 (AAV2) mediated subretinal delivery of human interferon-alpha (IFN-α) could effectively inhibit experimental autoimmune uveoretinitis (EAU). In this study we investigated whether subretinal injection of both AVV2.IFN-α and AAV2.IL-4 had a stronger inhibition on EAU activity. B10RIII mice were subretinally injected with AAV2.IFN-α alone (1.5×107 vg), AAV2.IL-4 alone (3.55×107 vg), and AAV2.IFN-α combined with AAV2.IL-4. PBS, AAV2 vector encoding green fluorescent protein (AAV2.GFP) (5×107 vg) was subretinally injected as a control. IFN-α and IL-4 were effectively expressed in the eyes from three weeks to three months following subretinal injection of AAV2 vectors either alone or following combined administration and significantly attenuated EAU activity clinically and histopathologically. AAV2.IL-4 showed a better therapeutic effect as compared to AAV2.IFN-α. The combination of AAV2.IL-4 and AAV2.IFN-α was not significantly different as compared to AAV2.IL-4 alone. There was no difference concerning DTH (delayed-type hypersensitivity) reaction, lymphocyte proliferation and IL-17 production among the investigated treatment groups, suggesting that local retinal gene delivery did not affect the systemic immune response

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error

Abstract: Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia

Development of an objectively measured walkability index for the Netherlands

Background: Walkability indices have been developed and linked to behavioural and health outcomes elsewhere in the world, but not comprehensively for Europe. We aimed to 1) develop a theory-based and evidence-informed Dutch walkability index, 2) examine its cross-sectional associations with total and purpose-specific walking behaviours of adults across socioeconomic (SES) and urbanisation strata, 3) explore which walkability components drive these associations. Methods: Components of the index included: population density, retail and service density, land use mix, street connectivity, green space, sidewalk density and public transport density. Each of the seven components was calculated for three Euclidean buffers: 150 m, 500 m and 1000 m around every 6-digit postal code location and for every administrative neighbourhood in GIS. Componential z-scores were averaged, and final indices normalized between 0 and 100. Data on self-reported demographic characteristics and walking behaviours of 16,055 adult respondents (aged 18–65) were extracted from the Dutch National Travel Survey 2017. Using Tobit regression modelling adjusted for individual- and household-level confounders, we assessed the associations between walkability and minutes walking in total, for non-discretionary and discretionary purposes. By assessing the attenuation in associations between partial indices and walking outcomes, we identified which of the seven components drive these associations. We also tested for effect modification by urbanization degree, SES, age and sex. Results: In fully adjusted models, a 10% increase in walkability was associated with a maximum increase of 8.5 min of total walking per day (95%CI: 7.1–9.9). This association was consistent across buffer sizes and purposes of walking. Public transport density was driving the index’s association with walking outcomes. Stratified results showed that associations with minutes of non-discretionary walking were stronger in rural compared to very urban areas, in neighbourhoods with low SES compared to high SES, and in middle-aged (36–49 years) compared to young (18–35 years old) and older adults (50–65 years old). Conclusions: The walkability index was cross-sectionally associated with Dutch adult’s walking behaviours, indicating its validity for further use in research

A positive neighborhood walkability is associated with a higher magnitude of leisure walking in adults upon COVID-19 restrictions: a longitudinal cohort study

Abstract Background Previous cross-sectional and longitudinal observational studies revealed positive relationships between contextual built environment components and walking behavior. Due to severe restrictions during COVID-19 pandemic lockdowns, physical activity was primarily performed within the immediate living area. Using this unique opportunity, we evaluated whether built environment components were associated with the magnitude of change in walking activity in adults during COVID-19 restrictions. Methods Data on self-reported demographic characteristics and walking behaviour were extracted from the prospective longitudinal Lifelines Cohort Study in the Netherlands of participants ≥ 18 years. For our analyses, we made use of the data acquired between 2014–2017 (n = 100,285). A fifth of the participants completed the questionnaires during COVID-19 restrictive policies in July 2021 (n = 20,806). Seven spatial components were calculated for a 500m and 1650m Euclidean buffer per postal code area in GIS: population density, retail and service destination density, land use mix, street connectivity, green space density, sidewalk density, and public transport stops. Additionally, the walkability index (WI) of these seven components was calculated. Using multivariable linear regression analyses, we analyzed the association between the WI (and separate components) and the change in leisure walking minutes/week. Included demographic variables were age, gender, BMI, education, net income, occupation status, household composition and the season in which the questionnaire was filled in. Results The average leisure walking time strongly increased by 127 min/week upon COVID-19 restrictions. All seven spatial components of the WI were significantly associated with an increase in leisure walking time; a 10% higher score in the individual spatial component was associated with 5 to 8 more minutes of leisure walking/week. Green space density at the 500m Euclidean buffer and side-walk density at the 1650m Euclidean buffer were associated with the highest increase in leisure walking time/week. Subgroup analysis revealed that the built environment showed its strongest impact on leisure walking time in participants not engaging in leisure walking before the COVID-19 pandemic, compared to participants who already engaged in leisure walking before the COVID-19 pandemic. Conclusions These results provide strong evidence that the built environment, corrected for individual-level characteristics, directly links to changes observed in leisure walking time during COVID-19 restrictions. Since this relation was strongest in those who did not engage in leisure walking before the COVID-19 pandemic, our results encourage new perspectives in health promotion and urban planning