Engraftment of engineered ES cell–derived cardiomyocytes but not BM cells restores contractile function to the infarcted myocardium

Cellular cardiomyoplasty is an attractive option for the treatment of severe heart failure. It is, however, still unclear and controversial which is the most promising cell source. Therefore, we investigated and examined the fate and functional impact of bone marrow (BM) cells and embryonic stem cell (ES cell)–derived cardiomyocytes after transplantation into the infarcted mouse heart. This proved particularly challenging for the ES cells, as their enrichment into cardiomyocytes and their long-term engraftment and tumorigenicity are still poorly understood. We generated transgenic ES cells expressing puromycin resistance and enhanced green fluorescent protein cassettes under control of a cardiac-specific promoter. Puromycin selection resulted in a highly purified (>99%) cardiomyocyte population, and the yield of cardiomyocytes increased 6–10-fold because of induction of proliferation on purification. Long-term engraftment (4–5 months) was observed when co-transplanting selected ES cell–derived cardiomyocytes and fibroblasts into the injured heart of syngeneic mice, and no teratoma formation was found (n = 60). Although transplantation of ES cell–derived cardiomyocytes improved heart function, BM cells had no positive effects. Furthermore, no contribution of BM cells to cardiac, endothelial, or smooth muscle neogenesis was detected. Hence, our results demonstrate that ES-based cell therapy is a promising approach for the treatment of impaired myocardial function and provides better results than BM-derived cells

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

User Participation in Coproduction of Health Innovation : Proposal for a Synergy Project

Background: This project concerns advancing knowledge, methods, and logic for user participation in coproduction of health innovations. Such advancement is vital for several reasons. From a user perspective, participation in coproduction provides an opportunity to gain real influence over goal definition, design, and implementation of health innovations, ensuring that the solution developed solves real problems in right ways. From a societal perspective, it's a mean to improve the efficiency of health care and the implementation of the Patient Act. As for industry, frameworks and knowledge of coproduction offer tools to operate in a complex sector, with great potential for innovation of services and products. Objective: The fundamental objective of this project is to advance knowledge and methods of how user participation in the coproduction of health innovations can be applied in order to benefit users, industry, and public sector. Methods: This project is a synergy project, which means that the objective will be accomplished through collaboration and meta-analysis between three subprojects that address different user groups, apply different strategies to promote human health, and relate to different parts of the health sector. Furthermore, subprojects focus on distinctive stages in the spectrum of innovation, with the objective to generate knowledge of the innovation process as a whole. The project is organized around three work packages related to three challenges-coproduction, positioning, and realization. Each subproject is designed such that it has its own field of study with clearly identified objectives but also targets work packages to contribute to the project as a whole. The work on the work packages will use case methodology for data collection and analysis based on the subprojects as data sources. More concretely, logic of multiple case studies will be applied with each subproject representing a separate case which is similar to each other in its attention to user participation in coproduction, but different regarding, for example, context and target groups. At the synergy level, the framework methodology will be used to handle and analyze the vast amount of information generated within the subprojects. Results: The project period is from July 1, 2018 to June 30, 2022. Conclusions: By addressing the objective of this project, we will create new knowledge on how to manage challenges to health innovation associated with the coproduction process, the positioning of solutions, and realization. © Jens Nygren, Elena Zukauskaite, Niklas Westberg

Smartphone-Based Measurement Systems for Road Vehicle Traffic Monitoring and Usage-Based Insurance

A framework is presented to deploy a smartphone-based measurement system for road vehicle traffic monitoring and usage-based insurance (UBI). Through the aid of a hierarchical model to modularize the description, the functionality is described as spanning from sensor-level functionality and technical specification to the topmost business model. The designer of a complex measurement system has to consider the full picture from low-level sensing, actuating, and wireless data transfer to the topmost level, including enticements for the individual smartphone owners, i.e., the end users who are the actual measurement probes. The measurement system provides two data streams: a primary stream to support road vehicle traffic monitoring and a secondary stream to support the UBI program. The former activity has a clear value for a society and its inhabitants, as it may reduce congestion and environmental impacts. The latter data stream drives the business model and parts of the revenue streams, which ensure the funding of the total measurement system and create value for the end users, the service provider, and the insurance company. In addition to the presented framework, outcome from a measurement campaign is presented, including road vehicle traffic monitoring (primary data stream) and a commercial pilot of UBI based on the driver profiles (secondary data stream). The measurement system is believed to be sustainable due to the incitements offered to the individual end users, in terms of favorable pricing for the insurance premium. The measurement campaign itself is believed to have an interest in its own right, as it includes smartphone probing of road traffic with a number of probes in the vicinity of the current state of the art, given by the Berkeley Mobile Millennium Project. During the ten-month run of the project, some 4500 driving h/250 000 km of road vehicle traffic data were collected.QC 20150113</p

Resilience in children of parents with mental illness, alcohol or substance misuse—An integrative review

Abstract Aim The aim of this integrative review was to investigate how resilience has been researched and explore experiences of resilience, in children of parents with mental illness or alcohol or substance misuse. Design An integrative review. Method The search included three major electronic databases, PubMed, Scopus and PsycINFO with the aim of identifying peer‐reviewed studies where the concept of resilience was explored as resilience, coping, adaptation or protective factors. Results Out of 4016 studies, 14 were included after meeting predetermined criteria and methodological quality evaluation. The findings are presented in five categories: characteristics of the studies, operationalization and interpretation of resilience, individual resources, family resources and resources outside the family. Patient or public contribution Resilience in children of parents with mental illness or substance misuse refers to coping strategies, protective factors and absence of symptoms or risk behaviour despite being exposed to risk. We suggest a three‐level approach for mapping of resilience resources in the target group: the individual level, family level and outside of the family that includes both non‐professionals and professionals. The use of disengagement or avoidance strategies implies poor resilience but may be necessary in absence of support, as acts of self‐preservation during chaotic periods or harmful situations

Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes distinct from physiological stem cell aging.

Somatic stem cells mediate tissue maintenance for the lifetime of an organism. Despite the well-established longevity that is a prerequisite for such function, accumulating data argue for compromised stem cell function with age. Identifying the mechanisms underlying age-dependent stem cell dysfunction is therefore key to understanding the aging process. Here, using a model carrying a proofreading-defective mitochondrial DNA polymerase, we demonstrate hematopoietic defects reminiscent of premature HSC aging, including anemia, lymphopenia, and myeloid lineage skewing. However, in contrast to physiological stem cell aging, rapidly accumulating mitochondrial DNA mutations had little functional effect on the hematopoietic stem cell pool, and instead caused distinct differentiation blocks and/or disappearance of downstream progenitors. These results show that intact mitochondrial function is required for appropriate multilineage stem cell differentiation, but argue against mitochondrial DNA mutations per se being a primary driver of somatic stem cell aging

Potential risks of bone marrow cell transplantation into infarcted hearts

Cellular replacement therapy has emerged as a novel strategy for the treatment of heart failure. The aim of our study was to determine the fate of injected mesenchymal stem cells (MSCs) and whole bone marrow (BM) cells in the infarcted heart. MSCs were purified from BM of transgenic mice and characterized using flow cytometry and in vitro differentiation assays. Myocardial infarctions were generated in mice and different cell populations including transgenic MSCs, unfractionated BM cells, or purified hematopoietic progenitors were injected. Encapsulated structures were found in the infarcted areas of a large fraction of hearts after injecting MSCs (22 of 43, 51.2%) and unfractionated BM cells (6 of 46, 13.0%). These formations contained calcifications and/or ossifications. In contrast, no pathological abnormalities were found after injection of purified hematopoietic progenitors (0 of 5, 0.0%), fibroblasts (0 of 5, 0.0%), vehicle only (0 of 30, 0.0%), or cytokine-induced mobilization of BM cells (0 of 35, 0.0%). We conclude that the developmental fate of BM-derived cells is not restricted by the surrounding tissue after myocardial infarction and that the MSC fraction underlies the extended bone formation in the infarcted myocardium. These findings seriously question the biologic basis and clinical safety of using whole BM and in particular MSCs to treat nonhematopoietic disorders