Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer's Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein.

Developing effective therapeutics for complex diseases such as late-onset, sporadic Alzheimer's disease (SAD) is difficult due to genetic and environmental heterogeneity in the human population and the limitations of existing animal models. Here, we used hiPSC-derived neurons to test a compound that stabilizes the retromer, a highly conserved multiprotein assembly that plays a pivotal role in trafficking molecules through the endosomal network. Using this human-specific system, we have confirmed previous data generated in murine models and show that retromer stabilization has a potentially beneficial effect on amyloid beta generation from human stem cell-derived neurons. We further demonstrate that manipulation of retromer complex levels within neurons affects pathogenic TAU phosphorylation in an amyloid-independent manner. Taken together, our work demonstrates that retromer stabilization is a promising candidate for therapeutic development in AD and highlights the advantages of testing novel compounds in a human-specific, neuronal system

Predicting Joint Replacement Waiting Times

Currently, the median waiting time for total hip and knee replacement in Ontario is greater than 6 months. Waiting longer than 6 months is not recommended and may result in lower post-operative benefits. We developed a simulation model to estimate the proportion of patients who would receive surgery within the recommended waiting time for surgery over a 10-year period considering a wide range of demand projections and varying the number of available surgeries. Using an estimate that demand will grow by approximately 8.7% each year for 10 years, we determined that increasing available supply by 10% each year was unable to maintain the status quo for 10 years. Reducing waiting times within 10 years required that the annual supply of surgeries increased by 12% or greater. Allocating surgeries across regions in proportion to each region’s waiting time resulted in a more efficient distribution of surgeries and a greater reduction in waiting times in the long-term compared to allocation strategies based only on the region’s population size

An Evaluation of Strategies to Reduce Waiting Times for Total Joint Replacement in Ontario

Background: In 2005, the median waiting time for total hip and knee joint replacements in Ontario was greater than 6 months, which is considered longer than clinically appropriate. Demand is expected to increase and exacerbate already long waiting times. Solutions are needed to reduce waiting times and improve waiting list management. Methods: We developed a discrete event simulation model of the Ontario total joint replacement system to evaluate the effects of 4 management strategies on waiting times: (1) reductions in surgical demand; (2) formal clinical prioritization; (3) waiting time guarantees; and (4) common waiting list management. Results: If the number of surgeries performed increases by less than 10% each year, then demand must be reduced by at least 15% to ensure that, within 10 years, 90% of patients receive surgery within their maximum recommended waiting time. Clinically prioritizing patients reduced waiting times for high-priority patients and increased the number of patients at all priority levels who received surgery each year within recommended maximum waiting times by 9.3%. A waiting time guarantee for all patients provided fewer surgeries within recommended waiting times. Common waiting list management improved efficiency and increased equity in waiting across regions. Discussion: Dramatically increasing the supply of joint replacement surgeries or diverting demand for surgeries to other jurisdictions will reduce waiting times for total joint replacement surgery. Introducing a strictly adhered to patient prioritization scheme will ensure that more patients receive surgery within severity-specific waiting time targets. Implementing a waiting time guarantee for all patients will not reduce waiting times—it will only shuffle waiting times from some patients to others. To reduce waiting times to clinically acceptable levels within 10 years, increases in the number of surgeries provided greater than those observed historically or reductions in demand are needed

College completion predicts lower depression but higher metabolic syndrome among disadvantaged minorities in young adulthood

College graduates enjoy healthier, longer lives compared with individuals who do not graduate from college. However, the health benefit of educational attainment is not as great for blacks as it is for whites. Moreover, college completion may not erase the detrimental effects of early-life disadvantage for blacks and Hispanics. We use nationally representative data on young adults to test whether American minorities experience differential returns to educational attainment. We find that college completion predicts lower rates of depression for all racial groups. It also predicts lower metabolic syndrome among whites. However, college completion predicts higher metabolic syndrome among black and Hispanic adults from disadvantaged backgrounds, suggesting upward mobility may come at a health cost to young minorities in America

Unique structure and positive selection promote the rapid divergence of Drosophila Y chromosomes

Y chromosomes across diverse species convergently evolve a gene-poor, heterochromatic organization enriched for duplicated genes, LTR retrotransposons, and satellite DNA. Sexual antagonism and a loss of recombination play major roles in the degeneration of young Y chromosomes. However, the processes shaping the evolution of mature, already degenerated Y chromosomes are less well-understood. Because Y chromosomes evolve rapidly, comparisons between closely related species are particularly useful. We generated de novo long-read assemblies complemented with cytological validation to reveal Y chromosome organization in three closely related species of the Drosophila simulans complex, which diverged only 250,000 years ago and share \u3e98% sequence identity. We find these Y chromosomes are divergent in their organization and repetitive DNA composition and discover new Y-linked gene families whose evolution is driven by both positive selection and gene conversion. These Y chromosomes are also enriched for large deletions, suggesting that the repair of double-strand breaks on Y chromosomes may be biased toward microhomology-mediated end joining over canonical non-homologous end-joining. We propose that this repair mechanism contributes to the convergent evolution of Y chromosome organization across organisms

Promoting Teamwork in Translational Medical Teams: Insights and Recommendations from Science and Practice

Translational medical teams are transdisciplinary, highly collaborative, and operate within dynamic environments to solve time-sensitive and complex problems. These teams are tasked with turning observations in the laboratory and clinic into effective interventions that improve the health of individuals and the public. The nature of the problems they seek to solve requires coordination among clinicians, scientists, and experts from various scientific disciplines. Characteristically, translational medical teams have complex compositions, structure, and pluralistic goals, which pose significant challenges and barriers to enacting effective teamwork, compromising team performance. Given these challenges, it is imperative to glean insights from teams research and the science of team science on how to execute efficacious teamwork. Consequently, the purpose of this paper is to discuss specific teamwork processes (i.e., trust, communication, self-correction, backup behavior, shared mental models, and conflict management) that are critical to translational medical team performance and offer mechanisms to better equip such teams. Utilizing a theoretical framework of transdisciplinary teamwork adapted from the science of team science and tailored to translational medical teams, we describe each of these processes, their relation to translational medical team outcomes, and how they can be leveraged to improve teamwork. Such a discussion aims to provide practical guidance for conceptualizing and enhancing teamwork in translational medical teams

Preconditioning Human Adipose-Derived Stromal Cells on Decellularized Adipose Tissue Scaffolds Within a Perfusion Bioreactor Modulates Cell Phenotype and Promotes a Pro-regenerative Host Response

Cell-based therapies involving the delivery of adipose-derived stromal cells (ASCs) on decellularized adipose tissue (DAT) scaffolds are a promising approach for soft tissue augmentation and reconstruction. Our lab has recently shown that culturing human ASCs on DAT scaffolds within a perfusion bioreactor prior to implantation can enhance their capacity to stimulate in vivo adipose tissue regeneration. Building from this previous work, the current study investigated the effects of bioreactor preconditioning on the ASC phenotype and secretory profile in vitro, as well as host cell recruitment following implantation in an athymic nude mouse model. Immunohistochemical analyses indicated that culturing within the bioreactor increased the percentage of ASCs co-expressing inducible nitric oxide synthase (iNOS) and arginase-1 (Arg-1), as well as tumor necrosis factor-alpha (TNF-α) and interleukin-10 (IL-10), within the peripheral regions of the DAT relative to statically cultured controls. In addition, bioreactor culture altered the expression levels of a range of immunomodulatory factors in the ASC-seeded DAT. In vivo testing revealed that culturing the ASCs on the DAT within the perfusion bioreactor prior to implantation enhanced the infiltration of host CD31+ endothelial cells and CD26+ cells into the DAT implants, but did not alter CD45+F4/80+CD68+ macrophage recruitment. However, a higher fraction of the CD45+ cell population expressed the pro-regenerative macrophage marker CD163 in the bioreactor group, which may have contributed to enhanced remodeling of the scaffolds into host-derived adipose tissue. Overall, the findings support that bioreactor preconditioning can augment the capacity of human ASCs to stimulate regeneration through paracrine-mediated mechanisms

Lithium protects against anaesthesia neurotoxicity in the infant primate brain

Exposure of infant animals, including non-human primates (NHPs), to anaesthetic drugs causes apoptotic death of neurons and oligodendrocytes (oligos) and results in long-term neurodevelopmental impairment (NDI). Moreover, retrospective clinical studies document an association between anaesthesia exposure of human infants and significant increase in NDI. These findings pose a potentially serious dilemma because millions of human infants are exposed to anaesthetic drugs every year as part of routine medical care. Lithium (Li) at clinically established doses is neuroprotective in various cerebral injury models. We therefore investigated whether Li also protects against anaesthesia neurotoxicity in infant NHPs. On postnatal day 6 NHPs were anaesthetized with the widely used anaesthetic isoflurane (ISO) for 5 h employing the same standards as in a human pediatric surgery setting. Co-administration of Li completely prevented the acute ISO-induced neuroapoptosis and significantly reduced ISO-induced apoptosis of oligodendroglia. Our findings are highly encouraging as they suggest that a relatively simple pharmacological manipulation might protect the developing primate brain against the neurotoxic action of anaesthetic drugs while not interfering with the beneficial actions of these drugs. Further research is needed to determine Li’s potential to prevent long-term NDI resulting from ISO anaesthesia, and to establish its safety in human infants

Identification of a transporter complex responsible for the cytosolic entry of nitrogen-containing bisphosphonates

Nitrogen-containing-bisphosphonates (N-BPs) are widely prescribed to treat osteoporosis and other bone-related diseases. Although previous studies established that N-BPs function by inhibiting the mevalonate pathway in osteoclasts, the mechanism by which N-BPs enter the cytosol from the extracellular space to reach their molecular target is not understood. Here we implemented a CRISPRi-mediated genome-wide screen and identified SLC37A3 (solute carrier family 37 member A3) as a gene required for the action of N-BPs in mammalian cells. We observed that SLC37A3 forms a complex with ATRAID (all-trans retinoic acid-induced differentiation factor), a previously identified genetic target of N-BPs. SLC37A3 and ATRAID localize to lysosomes and are required for releasing N-BP molecules that have trafficked to lysosomes through fluid-phase endocytosis into the cytosol. Our results elucidate the route by which N-BPs are delivered to their molecular target, addressing a key aspect of the mechanism of action of N-BPs that may have significant clinical relevance

When will I get my paper back? A replication study of publication timelines for health professions education research.

INTRODUCTION: Biomedical researchers have lamented the lengthy timelines from manuscript submission to publication and highlighted potential detrimental effects on scientific progress and scientists\u27 careers. In 2015, Himmelstein identified the mean time from manuscript submission to acceptance in biomedicine as approximately 100 days. The length of publication timelines in health professions education (HPE) is currently unknown. METHODS: This study replicates Himmelstein\u27s work with a sample of 14 HPE journals published between 2008-2018. Using PubMed, 19,182 article citations were retrieved. Open metadata for each were downloaded, including the date the article was received by the journal, date the authors resubmitted revisions, date the journal accepted the article, and date of entry into PubMed. Journals without publication history metadata were excluded. RESULTS: Publication history data were available for 55% (n = 8) of the journals sampled. The publication histories of 4,735 (25%) articles were analyzed. Mean time from: (1) author submission to journal acceptance was 180.93 days (SD = 103.89), (2) author submission to posting on PubMed was 263.55 days (SD = 157.61), and (3) journal acceptance to posting on PubMed was 83.15 days (SD = 135.72). DISCUSSION: This study presents publication metadata for journals that openly provide it-a first step towards understanding publication timelines in HPE. Findings confirm the replicability of the original study, and the limited data suggest that, in comparison to biomedical scientists broadly, medical educators may experience longer wait times for article acceptance and publication. Reasons for these delays are currently unknown and deserve further study; such work would be facilitated by increased public access to journal metadata