Novel Renal Autologous Cell Therapy for Type 2 Diabetes Mellitus Chronic Diabetic Kidney Disease: Clinical Trial Design.

BACKGROUND: Cell therapies explore unmet clinical needs of patients with chronic kidney disease with the potential to alter the pathway toward end-stage kidney disease. We describe the design and baseline patient characteristics of a phase II multicenter clinical trial utilizing the novel renal autologous cell therapy (REACT), by direct kidney parenchymal injection via the percutaneous approach in adults with type 2 diabetic kidney disease (T2DKD), to delay or potentially avoid renal replacement therapy. DESIGN: The study conducted a prospective, multicenter, randomized control, open-label, phase II clinical trial between an active treatment group (ATG) receiving REACT from the beginning of the trial and a contemporaneous deferred treatment group (DTG) receiving standard of care for 12 months before crossing over to receive REACT. OBJECTIVES: The objective of this study was to establish the safety and efficacy of 2 REACT injections with computed tomography guidance, into the renal cortex of patients with T2DKD administered 6 months apart, and to compare the longitudinal change in renal function between the ATG and the DTG. SETTING: This was a multicenter study conducted in major US hospitals. PATIENTS: We enrolled eighty-three adult patients with T2DKD, who have estimated glomerular filtration rates (eGFRs) between 20 and 50 mL/min/1.73 m2. METHODS: All patients undergo an image-guided percutaneous kidney biopsy to obtain epithelial phenotype selective renal cells isolated from the kidney tissue that is then expanded ex vivo over 4-6 weeks, resulting in the REACT biologic product. Patients are randomized 1:1 into the ATG or the DTG. Primary efficacy endpoints for both study groups include eGFR measurements at baseline and at 3-month intervals, through 24 months after the last REACT injection. Safety analyses include biopsy-related complications, REACT injection, and cellular-related adverse events. The study utilizes Good Clinical and Manufacturing Practices and a Data and Safety Monitoring Board. The sample size confers a statistical power of 80% to detect an eGFR change in the ATG compared to the DTG at 24 months with an α = 0.05. LIMITATIONS: Blinding cannot occur due to the intent to treat procedure, biopsy in both groups, and open trial design. CONCLUSION: This multicenter phase II randomized clinical trial is designed to determine the efficacy and safety of REACT in improving or stabilizing renal function among patients with T2DKD stages 3a-4.

Protocol and Baseline Data on Renal Autologous Cell Therapy Injection in Adults with Chronic Kidney Disease Secondary to Congenital Anomalies of the Kidney and Urinary Tract.

BACKGROUND: Advanced cell therapies with autologous, homologous cells show promise to affect reparative and restorative changes in the chronic kidney disease (CKD) nephron. We present our protocol and preliminary analysis of an IRB-approved, phase I single-group, open-label trial that tests the safety and efficacy of Renal Autologous Cell Therapy (REACT; NCT04115345) in adults with congenital anomalies of the kidney and urinary tract (CAKUT). METHODS: Adults with surgically corrected CAKUT and CKD stages 3 and 4 signed an informed consent and served as their "own" baseline control. REACT is an active biological ingredient acquired from a percutaneous tissue acquisition from the patient's kidney cortex. The specimen undergoes a GMP-compliant manufacturing process that harvests the selected renal cells composed of progenitors for renal repair, followed by image-guided locoregional reinjection into the patient's renal cortex. Participants receive 2 doses at 6-month intervals. Primary outcomes are stable renal function and stable/improved quality of life. Additional exploratory endpoints include the impact of REACT on blood pressure, vitamin D levels, hemoglobin, hematocrit and kidney volume by MRI analysis. RESULTS: Four men and 1 woman were enrolled and underwent 5 cell injections. Their characteristics were as follows: mean 52.8 years (SD 17.7 years), 1 Hispanic, 4 non-Hispanic, and 5 white. There were no renal tissue acquisition, cell injection, or cell product-related complications at baseline. CONCLUSION: REACT is demonstrating feasibility and patient safety in preliminary analysis. Autologous cell therapy treatment has the potential to stabilize or improve renal function in CAKUT-associated CKD to delay or avert dialysis. Patient enrollment and follow-up are underway.

Identifying mechanisms for facilitating knowledge to action strategies targeting the built environment.

BACKGROUND: In recent years, obesity-related diseases have been on the rise globally resulting in major challenges for health systems and society as a whole. Emerging research in population health suggests that interventions targeting the built environment may help reduce the burden of obesity and type 2 diabetes. However, translation of the evidence on the built environment into effective policy and planning changes requires engagement and collaboration between multiple sectors and government agencies for designing neighborhoods that are more conducive to healthy and active living. In this study, we identified knowledge gaps and other barriers to evidence-based decision-making and policy development related to the built environment; as well as the infrastructure, processes, and mechanisms needed to drive policy changes in this area. METHODS: We conducted a qualitative thematic analysis of data collected through consultations with a broad group of stakeholders (N = 42) from Southern Ontario, Canada, within various sectors (public health, urban planning, and transportation) and levels of government (federal, provincial, and municipalities). Relevant themes were classified based on the specific phase of the knowledge-to-action cycle (research, translation, and implementation) in which they were most closely aligned. RESULTS: We identified 5 themes including: 1) the need for policy-informed and actionable research (e.g. health economic analyses and policy evaluations); 2) impactful messaging that targets all relevant sectors to create the political will necessary to drive policy change; 3) common measures and tools to increase capacity for monitoring and surveillance of built environment changes; (4) intersectoral collaboration and alignment within and between levels of government to enable collective actions and provide mechanisms for sharing of resources and expertise, (5) aligning public and private sector priorities to generate public demand and support for community action; and, (6) solution-focused implementation of research that will be tailored to meet the needs of policymakers and planners. Additional research priorities and key policy and planning actions were also noted. CONCLUSION: Our research highlights the necessity of involving stakeholders in identifying inter-sectoral solutions to develop and translate actionable research on the built environment into effective policy and planning initiatives.

Association of Neighborhood Walkability With Change in Overweight, Obesity, and Diabetes.

IMPORTANCE: Rates of obesity and diabetes have increased substantially in recent decades; however, the potential role of the built environment in mitigating these trends is unclear. OBJECTIVE: To examine whether walkable urban neighborhoods are associated with a slower increase in overweight, obesity, and diabetes than less walkable ones. DESIGN, SETTING, AND PARTICIPANTS: Time-series analysis (2001-2012) using annual provincial health care (N ≈ 3 million per year) and biennial Canadian Community Health Survey (N ≈ 5500 per cycle) data for adults (30-64 years) living in Southern Ontario cities. EXPOSURES: Neighborhood walkability derived from a validated index, with standardized scores ranging from 0 to 100, with higher scores indicating more walkability. Neighborhoods were ranked and classified into quintiles from lowest (quintile 1) to highest (quintile 5) walkability. MAIN OUTCOMES AND MEASURES: Annual prevalence of overweight, obesity, and diabetes incidence, adjusted for age, sex, area income, and ethnicity. RESULTS: Among the 8777 neighborhoods included in this study, the median walkability index was 16.8, ranging from 10.1 in quintile 1 to 35.2 in quintile 5. Resident characteristics were generally similar across neighborhoods; however, poverty rates were higher in high- vs low-walkability areas. In 2001, the adjusted prevalence of overweight and obesity was lower in quintile 5 vs quintile 1 (43.3% vs 53.5%; P < .001). Between 2001 and 2012, the prevalence increased in less walkable neighborhoods (absolute change, 5.4% [95% CI, 2.1%-8.8%] in quintile 1, 6.7% [95% CI, 2.3%-11.1%] in quintile 2, and 9.2% [95% CI, 6.2%-12.1%] in quintile 3). The prevalence of overweight and obesity did not significantly change in areas of higher walkability (2.8% [95% CI, -1.4% to 7.0%] in quintile 4 and 2.1% [95% CI, -1.4% to 5.5%] in quintile 5). In 2001, the adjusted diabetes incidence was lower in quintile 5 than other quintiles and declined by 2012 from 7.7 to 6.2 per 1000 persons in quintile 5 (absolute change, -1.5 [95% CI, -2.6 to -0.4]) and 8.7 to 7.6 in quintile 4 (absolute change, -1.1 [95% CI, -2.2 to -0.05]). In contrast, diabetes incidence did not change significantly in less walkable areas (change, -0.65 in quintile 1 [95% CI, -1.65 to 0.39], -0.5 in quintile 2 [95% CI, -1.5 to 0.5], and -0.9 in quintile 3 [95% CI, -1.9 to 0.02]). Rates of walking or cycling and public transit use were significantly higher and that of car use lower in quintile 5 vs quintile 1 at each time point, although daily walking and cycling frequencies increased only modestly from 2001 to 2011 in highly walkable areas. Leisure-time physical activity, diet, and smoking patterns did not vary by walkability (P > .05 for quintile 1 vs quintile 5 for each outcome) and were relatively stable over time. CONCLUSIONS AND RELEVANCE: In Ontario, Canada, higher neighborhood walkability was associated with decreased prevalence of overweight and obesity and decreased incidence of diabetes between 2001 and 2012. However, the ecologic nature of these findings and the lack of evidence that more walkable urban neighborhood design was associated with increased physical activity suggest that further research is necessary to assess whether the observed associations are causal.

Planar silver nanowire, carbon nanotube and PEDOT:PSS nanocomposite transparent electrodes.

Highly conductive, transparent and flexible planar electrodes were fabricated using interwoven silver nanowires and single-walled carbon nanotubes (AgNW:SWCNT) in a PEDOT:PSS matrix via an epoxy transfer method from a silicon template. The planar electrodes achieved a sheet resistance of 6.6 ± 0.0 Ω/□ and an average transmission of 86% between 400 and 800 nm. A high figure of merit of 367 Ω-1 is reported for the electrodes, which is much higher than that measured for indium tin oxide and reported for other AgNW composites. The AgNW:SWCNT:PEDOT:PSS electrode was used to fabricate low temperature (annealing free) devices demonstrating their potential to function with a range of organic semiconducting polymer:fullerene bulk heterojunction blend systems.

Base-specific ionization of deprotonated nucleotides by resonance enhanced two-photon detachment.

The intrinsic ionization energy of a base in DNA plays a critical role in determining the energies at which damage mechanisms may emerge. Here, a two-photon resonance-enhanced ionization scheme is presented that utilizes the (1)ππ* transition, localized on the DNA base, to elucidate the base-specific ionization in a deprotonated nucleotide. In contrast to previous reports, the scheme is insensitive to competing ionization channels arising from the sugar-phosphate backbone. Using this approach, we demonstrate that for all bases except guanine, the lowest electron detachment energy corresponds to detachment from the sugar-phosphate backbone and allows us to determine the lowest adiabatic ionization energy for the other three bases for the first time in an isolated nucleotide.

A qualitative examination of the impact of the COVID-19 pandemic on children and adolescents with autism and their parents.

BACKGROUND: The unprecedented challenges introduced by the Coronavirus disease 2019 (COVID-19) pandemic may be amplified for children with autism spectrum disorder (ASD) and their families. AIMS: The current study aimed to describe the experiences of children with ASD and their families during the pandemic and to identify the needs of this community during emergency situations. METHODS AND PROCEDURES: Participants were 122 parents of 122 children and adolescents (aged 3-18 years; one parent per family participated) with ASD living in Arizona, USA who participated in the first time point (July/August 2020) of a larger longitudinal survey study. A qualitative approach based in grounded theory methodology was used to analyze six open-ended survey questions. OUTCOMES AND RESULTS: The resulting conceptual model included a core category, Longing for Stability, and four main categories: Public Health Measures Yielding New Challenges and Unexpected Gains, Experiencing Abrupt Changes across Developmental Domains, Changing Family Dynamics, and Protective Factors. CONCLUSIONS: Findings add to limited research examining whether, and how, emergency events uniquely impact the ASD community, identifying potential methods by which services can be proactively adapted to best support the needs of children with ASD.

In this digital age, how easily accessible is pharmacist vaccination information? The case of New Zealand.

Background: Pharmacist-led vaccination that has the potential to ease the vaccination burden from general practitioners, is comparatively a newer service in New Zealand. However, to reap the maximum benefits out of this service, a consistent and effective promotion approach using various online platforms is indispensable. Objective: To identify what online information the general public can find about which pharmacies across NZ provide vaccination services. Methods: Every pharmacy in NZ was reviewed online to determine what vaccination information they advertised, then a sample of pharmacies were randomly selected from six District Health Boards (DHBs) to be called and confirm if the information they stated online was accurate. Results: Whilst the majority (more than 70%) of pharmacies did provide information about their services online, only 31% of the pharmacies had vaccination information on their websites, 20% on Healthpoint, and 13% had the information on social media. The telephonic survey revealed various information discrepancies in more than a quarter of the sample. Conclusions: A lack of online presence across multiple pharmacies is a pressing issue. Also, currently, NZ pharmacies do not have a very high online presence advertising vaccination services. Improving the amount and quality of this information is pertinent at this time as when COVID-19 vaccination drive may commence anytime, and the pharmacy sector will be well placed to conduct vaccinations on a large scale.

Universal Drug Coverage and Socioeconomic Disparities in Health Care Costs Among Persons With Diabetes.

OBJECTIVE: To examine whether neighborhood socioeconomic status (SES) is a predictor of non-drug-related health care costs among Canadian adults with diabetes and, if so, whether SES disparities in costs are reduced after age 65 years, when universal drug coverage commences as an insurable benefit. RESEARCH DESIGN AND METHODS: Administrative health databases were used to examine publicly funded health care expenditures among 698,113 younger (20-64 years) and older (≥65 years) adults with diabetes in Ontario from April 2004 to March 2014. Generalized linear models were constructed to examine relative and absolute differences in health care costs (total and non-drug-related costs) across neighborhood SES quintiles, by age, with adjustment for differences in age, sex, diabetes duration, and comorbidity. RESULTS: Unadjusted costs per person-year in the lowest SES quintile (Q1) versus the highest (Q5) were 39% higher among younger adults ($5,954 vs. $4,270 [Canadian dollars]) but only 9% higher among older adults ($10,917 vs. $9,993). Adjusted non-drug costs (primarily for hospitalizations and physician visits) were $1,569 per person-year higher among younger adults in Q1 vs. Q5 (modeled relative cost difference: 35.7% higher) and $139.3 million per year among all individuals in Q1. Scenarios in which these excess costs per person-year were decreased by ≥10% or matched the relative difference among seniors suggested a potential for savings in the range of $26.0-$128.2 million per year among all lower-SES adults under age 65 years (Q1-Q4). CONCLUSIONS: SES is a predictor of diabetes-related health care costs in our setting, more so among adults under age 65 years, a group that lacks universal drug coverage under Ontario's health care system. Non-drug-related health care costs were more than one-third higher in younger, lower-SES adults, translating to >$1 billion more in health care expenditures over 10 years.

Neighbourhood walkability and the incidence of diabetes: an inverse probability of treatment weighting analysis.

BACKGROUND: People living in highly walkable neighbourhoods tend to be more physically active and less likely to be obese. Whether walkable urban design reduces the future risk of diabetes is less clear. METHODS: We used inverse probability of treatment weighting to compare 10-year diabetes incidence between residents living in high-walkability and low-walkability neighbourhoods within five urban regions in Ontario, Canada. Adults (aged 30-85 years) who were diabetes-free on 1 April 2002 were identified from administrative health databases and followed until 31 March 2012 (n=958 567). Within each region, weights reflecting the propensity to live in each neighbourhood type were created based on sociodemographic characteristics, comorbidities and healthcare utilisation and incorporated into region-specific Cox proportional hazards models. RESULTS: Low-walkability areas were more affluent and had more South Asian residents (6.4%vs3.6%, p<0.001) but fewer residents from other minority groups (16.6%vs21.7%, p<0.001). Baseline characteristics were well balanced between low-walkability and high-walkability neighbourhoods after applying individual weights (standardised differences all <0.1). In each region, high walkability was associated with lower diabetes incidence among adults aged <65 years (overall weighted incidence: 8.2vs9.2 per 1000; HR 0.85, 95% CI 0.78 to 0.93), but not among adults aged ≥65 years (weighted incidence: 20.7vs19.5 per 1000; HR 1.01, 95% CI 0.91 to 1.12). Findings were consistent regardless of income and immigration status. CONCLUSIONS: Younger adults living in high-walkability neighbourhoods had a lower 10-year incidence of diabetes than similarly aged adults living in low-walkability neighbourhoods. Urban designs that support walking may have important benefits for diabetes prevention.

Evolving Trends in the Epidemiology, Risk Factors, and Prevention of Type 2 Diabetes: A Review.

Currently, the global prevalence of diabetes is 8.8%. This figure is expected to increase worldwide, with the largest changes projected to occur in low- and middle-income countries. The aging of the world's population and substantial increases in obesity have contributed to the rise in diabetes. Global shifts in lifestyles have led to the adoption of unhealthy behaviours such as physical inactivity and poorer-quality diets. Correspondingly, diabetes is a rapidly-increasing problem in higher- as well as lower-income countries. In Canada, the prevalence of diabetes increased approximately 70% in the past decade. Although diabetes-related mortality rates have decreased in Canada, the number of people affected by diabetes has continued to grow because of a surge in the number of new diabetes cases. Non-European ethnic groups and individuals of lower socioeconomic status have been disproportionately affected by diabetes and its risk factors. Clinical trials have proven efficacy in reducing the onset of diabetes in high-risk populations through diet and physical activity interventions. However, these findings have not been broadly implemented into the Canadian health care context. In this article we review the evolving epidemiology of type 2 diabetes, with regard to trends in occurrence rates and prevalence; the role of risk factors including those related to ethnicity, obesity, diet, physical activity, socioeconomic status, prediabetes, and pregnancy; and the identification of critical windows for lifestyle intervention. Identifying high-risk populations and addressing the upstream determinants and risk factors of diabetes might prove to be effective diabetes prevention strategies to curb the current diabetes epidemic.

Ink-Jet Printing of High-Molecular-Weight Polymers in Oil-in-Water Emulsions.

Ink-jet printing of high-molecular-weight polymers is inhibited by the extensional elasticity of the polymer chains. This article describes how emulsions can be used to print high-molecular-weight polymers at much higher concentrations than is possible in a binary solution. The polymers are dissolved in the dispersed phase of an oil-in-water emulsion. The surface tension of the oil-water interface opposes deformation of the oil droplets during ejection from the nozzle and leads to the extensional strain occurring in the polymer-free continuous phase. We show that a solution of polystyrene (PS) (Mn = 419 kDa, polydispersity index = 1.21) can be printed at an overall concentration of 3.8 wt % in a sodium dodecyl sulfate-stabilized emulsion of methyl benzoate in water, an order of magnitude higher in concentration than previously reported for PS dissolved in binary solutions [ Hoath , S. D. , Harlen , O. G. , and Hutchings , I. M. J. Rheol. 2012 , 56 ( 5 ), 1109 - 1127 ]. Factors influencing the formulation of emulsions for ink-jet printing of polymers are discussed.