Implementing and evaluating the comprehensive integration of physical activity into a major health system: study design and protocol.

Introduction: The healthcare sector has great potential for promoting physical activity (PA) for chronic disease prevention, treatment and management; however, multiple adoption and implementation barriers exist, ranging from practice integration to information flow. In 2016, Exercise is Medicine Greenville (EIMG), a comprehensive clinic-to-community approach that involves PA assessment, recommendation and/or prescription and provider-based referral of patients to community-based PA programmes, was launched by Prisma Health in Greenville, South Carolina, USA. Since inception, variability has emerged in adoption and implementation, impacting patient reach, referral rates and engagement in the community-based PA programmes, highlighting the need for closer evaluation and refinement of strategies to maximise programme impact.

Highly Diastereoselective Access to Densely Functionalized Piperidine Cores of Influenza Endonuclease Inhibitors via a Metal-Free S1 Approach.

A novel, highly diastereoselective, and metal-free synthesis of multisubstituted piperidines via an S1 approach is reported in this study. The method allows for the preparation of highly functionalized compounds with exceptional diastereomeric selectivities and consistently reproducible yields. These compounds are of significant interest due to their remarkable biological activities toward influenza endonuclease.

Microglia cannibalism during neurodevelopment results in necroptotic cell death.

Clearance of dying neurons by microglia is critical to healthy neurodevelopment, but what else do microglia eat? A new study in PLOS Biology demonstrates that microglia not only eat neurons but each other, and that this "microglia cannibalism" causes necroptotic cell death.

Role of Microglia in Central Nervous System Development and Plasticity.

The nervous system comprises a remarkably diverse and complex network of cell types, which must communicate with one another with speed, reliability, and precision. Thus, the developmental patterning and maintenance of these cell populations and their connections with one another pose a rather formidable task. Emerging data implicate microglia, the resident myeloid-derived cells of the central nervous system (CNS), in spatial patterning and synaptic wiring throughout the healthy, developing, and adult CNS.

Microglia replacement by ER-Hoxb8 conditionally immortalized macrophages provides insight into Aicardi-Goutières Syndrome neuropathology.

Microglia, the brain's resident macrophages, can be reconstituted by surrogate cells - a process termed "microglia replacement." To expand the microglia replacement toolkit, we here introduce estrogen-regulated (ER) homeobox B8 (Hoxb8) conditionally immortalized macrophages, a cell model for generation of immune cells from murine bone marrow, as a versatile model for microglia replacement. We find that ER-Hoxb8 macrophages are highly comparable to primary bone marrow-derived (BMD) macrophages in vitro, and, when transplanted into a microglia-free brain, engraft the parenchyma and differentiate into microglia-like cells.

Attachment classification and early adversity predict perinatal partial hospital treatment response.

Background: Depression and anxiety are common in the perinatal period. While most of those affected respond well to treatment, a subpopulation is more resistant. Understanding more about individuals who do not respond well to available treatments may improve care for this group.

A Review of the Indications, Outcomes, and Postoperative Management After Total and Completion Pancreatectomy for Pancreatic Cancer: More Is Not Necessarily Better.

With improvements in surgical technique and advances in pancreatic endocrine and exocrine replacement therapy, the indications for, and threshold to perform, total or completion pancreatectomy in the modern surgical era are ever evolving. The following review will evaluate such indications for pancreatic cancer including pancreatic ductal adenocarcinoma and intraductal papillary mucinous neoplasms. The authors also review the literature on oncologic outcomes of total and completion pancreatectomy for pancreatic cancer.

Incidence and burden of 671 injuries in professional women footballers: time to focus on context-specific injury risk reduction strategies.

This study investigated the extent of injury incidence and burden in a professional women football team of the Scottish Women's Premier League during two seasons. All injuries causing time-loss or required medical attention were recorded prospectively. A total of 671 injuries, 570 requiring medical attention and 101 causing time-loss were recorded in 41 players.

Senescent glia link mitochondrial dysfunction and lipid accumulation.

Senescence is a cellular state linked to ageing and age-onset disease across many mammalian species. Acutely, senescent cells promote wound healing and prevent tumour formation; but they are also pro-inflammatory, thus chronically exacerbate tissue decline. Whereas senescent cells are active targets for anti-ageing therapy, why these cells form in vivo, how they affect tissue ageing and the effect of their elimination remain unclear.

Structure Guided Discovery of Novel Pan Metallo-β-Lactamase Inhibitors with Improved Gram-Negative Bacterial Cell Penetration.

The use of β-lactam (BL) and β-lactamase inhibitor combination to overcome BL antibiotic resistance has been validated through clinically approved drug products. However, unmet medical needs still exist for the treatment of infections caused by Gram-negative (GN) bacteria expressing metallo-β-lactamases. Previously, we reported our effort to discover pan inhibitors of three main families in this class: IMP, VIM, and NDM.

Biomarker Qualification for Neurofilament Light Chain in Amyotrophic Lateral Sclerosis: Theory and Practice.

Objective: To explore whether the utility of neurofilament light chain (NfL), as a biomarker to aid amyotrophic lateral sclerosis (ALS) therapy development, would be enhanced by obtaining formal qualification from the US Food and Drug Administration for a defined context-of-use.

Methods: Consensus discussion among academic, industry, and patient advocacy group representatives.

Results: A wealth of scientific evidence supports the use of NfL as a prognostic, response, and potential safety biomarker in the broad ALS population, and as a risk/susceptibility biomarker among the subset of SOD1 pathogenic variant carriers.

GC targeting antisense oligonucleotides potently mitigate TDP-43 dysfunction in human C9orf72 ALS/FTD induced pluripotent stem cell derived neurons.

The GC repeat expansion in the C9orf72 gene is the most common genetic cause of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Many studies suggest that dipeptide repeat proteins produced from this repeat are toxic, yet, the contribution of repeat RNA toxicity is under investigated and even less is known regarding the pathogenicity of antisense repeat RNA. Recently, two clinical trials targeting GC (sense) repeat RNA via antisense oligonucleotide failed despite a robust decrease in sense-encoded dipeptide repeat proteins demonstrating target engagement.

Human OPRM1 and murine Oprm1 promoter driven viral constructs for genetic access to μ-opioidergic cell types.

With concurrent global epidemics of chronic pain and opioid use disorders, there is a critical need to identify, target and manipulate specific cell populations expressing the mu-opioid receptor (MOR). However, available tools and transgenic models for gaining long-term genetic access to MOR+ neural cell types and circuits involved in modulating pain, analgesia and addiction across species are limited. To address this, we developed a catalog of MOR promoter (MORp) based constructs packaged into adeno-associated viral vectors that drive transgene expression in MOR+ cells.

Cross-talk between B cells, microglia and macrophages, and implications to central nervous system compartmentalized inflammation and progressive multiple sclerosis.

Background: B cells can be enriched within meningeal immune-cell aggregates of multiple sclerosis (MS) patients, adjacent to subpial cortical demyelinating lesions now recognized as important contributors to progressive disease. This subpial demyelination is notable for a 'surface-in' gradient of neuronal loss and microglial activation, potentially reflecting the effects of soluble factors secreted into the CSF. We previously demonstrated that MS B-cell secreted products are toxic to oligodendrocytes and neurons.

CRISPR generation of CSF1R-G795A human microglia for robust microglia replacement in a chimeric mouse model.

Chimeric mouse models have recently been developed to study human microglia in vivo. However, widespread engraftment of donor microglia within the adult brain has been challenging. Here, we present a protocol to introduce the G795A point mutation using CRISPR-Cas9 into the CSF1R locus of human pluripotent stem cells.