Arylsulfatase A Overexpressing Human iPSC-derived Neural Cells Reduce CNS Sulfatide Storage in a Mouse Model of Metachromatic Leukodystrophy.

Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disorder resulting from a functional deficiency of arylsulfatase A (ARSA), an enzyme that catalyzes desulfation of 3-O-sulfogalactosylceramide (sulfatide). Lack of active ARSA leads to the accumulation of sulfatide in oligodendrocytes, Schwann cells and some neurons and triggers progressive demyelination, the neuropathological hallmark of MLD. Several therapeutic approaches have been explored, including enzyme replacement, autologous hematopoietic stem cell-based gene therapy, intracerebral gene therapy or cell-based gene delivery into the central nervous system (CNS). However, long-term treatment of the blood-brain-barrier protected CNS remains challenging. Here we used MLD patient-derived induced pluripotent stem cells (iPSCs) to generate long-term self-renewing neuroepithelial stem cells and astroglial progenitors for cell-based ARSA replacement. Following transplantation of ARSA-overexpressing precursors into ARSA-deficient mice we observed a significant reduction of sulfatide storage up to a distance of 300 µm from grafted cells. Our data indicate that neural precursors generated via reprogramming from MLD patients can be engineered to ameliorate sulfatide accumulation and may thus serve as autologous cell-based vehicle for continuous ARSA supply in MLD-affected brain tissue.

Does Patient Preference for Mode of Intervention Delivery Impact Intervention Efficacy and Attrition?

PURPOSE: To explore whether there was a difference in objectively measured physical activity and study participation between people who received their preferred study group allocation (matched) and those who did not receive their preferred study group (mismatched). DESIGN: Secondary data from the NewCOACH randomized controlled trial. SETTING: Insufficiently active patients in the primary care settings in Sydney and Newcastle, Australia. PARTICIPANTS: One hundred seventy-two adults aged 20 to 81 years. INTERVENTION: Participants indicated their intervention preference at baseline for (1) five face-to-face visits with an exercise specialist, (2) one face-to-face visit and 4 telephone follow-ups with an exercise specialist, (3) written material, or (4) slight-to-no preference. Participants were then allocated to an intervention group and categorized as either "matched" or "mismatched" based on their indications. Participants who reported a slight-to-no preference was categorized as "matched." MEASURES: Daily step count as measured by pedometers and study participation. ANALYSIS: Mean differences between groups in daily step count at 3 and 12 months (multiple linear regression models) and study participation at baseline, 3 months, and 12 months (χ2 tests). RESULTS: Preference for an intervention group prior to randomization did not significantly (all P's > .05 using 95% confidence interval) impact step counts (differences of <600 steps/day between groups) or study participation. CONCLUSION: Future research should continue to address whether the strength of preferences influence study outcome and participation and whether the study preferences change over time.

Daily steps and diet, but not sleep, are related to mortality in older Australians.

OBJECTIVES: Supporting healthy ageing is a key priority worldwide. Physical activity, diet quality and sleep are all associated with health outcomes, but few studies have explored their independent associations with all-cause mortality in an older population in the same model. The study aim was to examine associations between step-count, self-reported diet quality, restless sleep, and all-cause mortality in adults aged 55-85 years. DESIGN: A prospective cohort study of adults in Newcastle, New South Wales, Australia. METHOD: Data were from 1697 participants (49.3% women; baseline mean age 65.4 ±â€¯7.1 years). Daily steps (measured by pedometer), diet quality (from a modified Australian Recommended Food Score), and frequency of restless sleep (by self-report) were assessed in relation to all-cause mortality using Cox proportional hazard regression with adjustment for sex, age, household income and smoking. Baseline data were collected between January 2005 and April 2008, and last follow-up was in March 2017 (median follow-up 9.6 years). RESULTS: Higher step count (HR: 0.93, 95%CI: 0.88-0.98 per 1000-step increment) and higher diet quality (HR: 0.86, 95%CI: 0.74-0.99 per 8-point increment in diet quality score) were associated with reduced mortality risk. Restless sleep for ≥3 nights/week was not associated with mortality risk (HR: 1.03, 95%CI: 0.78-1.39). Sensitivity analyses, adjusting for chronic disease and excluding deaths <1 year after baseline, did not change these estimates. CONCLUSIONS: Increased daily steps and consumption of a greater variety of nutrient-dense foods every week would result in substantial health benefits for older people. Future research should include a greater variety of sleep measures.

The measurement of the QT and QTc on the neonatal and infant electrocardiogram: a comprehensive reliability assessment.

BACKGROUND: An electrocardiogram has been proposed to screen for prolonged QT interval that may predispose infants to sudden death in the first year of life. Understanding the reliability of QT interval measurement will inform the design of a screening program. METHODS: Three pediatric cardiologists measured the QT/RR intervals on 60 infant electrocardiograms (median age 46 days), from leads II, V5 and V6 on three separate occasions, 7 days apart, according to a standard protocol. The QTc was corrected by Bazett's (QTcB), Fridericia's (QT(CFrid)), and Hodges' (QTcH) formulae. Intraobserver and interobserver reliability were assessed by intraclass correlation coefficients (ICC), limits of agreement and repeatability coefficients for single, average of two and average of three measures. Agreement for QTc prolongation (> 440 msec) was assessed by kappa coefficients. RESULTS: QT interval intraobserver ICC was 0.86 and repeatability coefficient was 25.9 msec; interobserver ICC increased from 0.88 for single observations to 0.94 for the average of 3 measurements and repeatability coefficients decreased from 22.5 to 16.7 msec. For QTcB, intraobserver ICC was 0.67, and repeatability was 39.6 msec. Best interobserver reliability for QTcB was for the average of three measurements (ICC 0.83, reproducibility coefficient 25.8 msec), with further improvement for QTcH (ICC 0.92, reproducibility coefficient 16.69 msec). Maximum interobserver kappa for prolonged QTc was 0.77. Misclassification around specific cut points occurs because of the repeatability coefficients. CONCLUSIONS: Uncorrected QT measures are more reliable than QTcB and QT(CFrid). An average of three independent measures provides the most reliable QT and QTc measurements, with QTcH better than QTcB.

Air Quality in Association With Rural Coal Mining and Combustion in New South Wales Australia.

PURPOSE: Rural areas may face under-recognized threats to air quality. We tested 2 hypotheses that 1) rural areas in New South Wales, Australia, would have better air quality than metropolitan Sydney, and that 2) the rural Upper Hunter region characterized by coal mining and coal combustion would have worse air quality than other rural areas of the state. METHODS: We analyzed 2017 daily mean values for New South Wales, Australia, for particulate matter (PM2.5 and PM10), sulfur dioxide (SO2 ), nitric oxide (NO), nitrogen dioxide (NO2 ), and NOx (sum of NO and NO2 ). Forty-six air monitoring stations were grouped into 6 rural and urban regional areas. Linear regression models examined pollution levels in association with rural and urban regions and meteorological covariates. RESULTS: Findings show that daily mean pollutant levels in the rural Upper Hunter were the highest of all regions, and were significantly higher than metropolitan Sydney, with and without control for weather conditions, for every pollutant. For example, daily mean PM2.5 was 8.64 µg/m3 in the rural Upper Hunter, compared to 7.23 µg/m3 in metropolitan Sydney. CONCLUSIONS: Results highlight the need to consider both urban and rural sources of pollution in air quality studies, and appropriate policy steps to address likely rural air pollution from coal mining.

One Health in South Asia and its challenges in implementation from stakeholder perspective.

One Health is a concept which fosters collaborative relationships between human health, animal health and environmental health partners. Diseases are emerging and re-emerging in South Asia due to poor sanitation, close proximity of people to livestock, deforestation, porous borders, climate change, changes in human behaviour and unhygienic food preparation and consumption practices. This review was completed in two stages. First, we conducted a review of peer-reviewed literature and grey literature available in Google search engine related to One Health in four countries (Bangladesh, Bhutan, India and Nepal). Second, we used a structured questionnaire completed by the key stakeholders working on One Health for the collection of information related to the challenges in implementing One Health. Most of the One Health activities in South Asia are determined by donor preferences. Bangladesh and India did considerable work in advancing One Health with limited support from the government agencies. Weak surveillance mechanisms, uncertain cost-effectiveness of One Health compared with the existing approach, human resources and laboratory capacity are some of the factors hindering implementation of the One Health concept. Implementation of One Health is growing in the South Asia region with limited or no government acceptance. To institutionalise it, there is a need for leadership, government support and funding.