Prone positioning of patients with moderate hypoxaemia due to covid-19: multicentre pragmatic randomised trial (COVID-PRONE).

OBJECTIVES: To assess the effectiveness of prone positioning to reduce the risk of death or respiratory failure in non-critically ill patients admitted to hospital with covid-19. DESIGN: Multicentre pragmatic randomised clinical trial. SETTING: 15 hospitals in Canada and the United States from May 2020 until May 2021. PARTICIPANTS: Eligible patients had a laboratory confirmed or a clinically highly suspected diagnosis of covid-19, needed supplemental oxygen (up to 50% fraction of inspired oxygen), and were able to independently lie prone with verbal instruction. Of the 570 patients who were assessed for eligibility, 257 were randomised and 248 were included in the analysis. INTERVENTION: Patients were randomised 1:1 to prone positioning (that is, instructing a patient to lie on their stomach while they are in bed) or standard of care (that is, no instruction to adopt prone position). MAIN OUTCOME MEASURES: The primary outcome was a composite of in-hospital death, mechanical ventilation, or worsening respiratory failure defined as needing at least 60% fraction of inspired oxygen for at least 24 hours. Secondary outcomes included the change in the ratio of oxygen saturation to fraction of inspired oxygen. RESULTS: The trial was stopped early on the basis of futility for the pre-specified primary outcome. The median time from hospital admission until randomisation was 1 day, the median age of patients was 56 (interquartile range 45-65) years, 89 (36%) patients were female, and 222 (90%) were receiving oxygen via nasal prongs at the time of randomisation. The median time spent prone in the first 72 hours was 6 (1.5-12.8) hours in total for the prone arm compared with 0 (0-2) hours in the control arm. The risk of the primary outcome was similar between the prone group (18 (14%) events) and the standard care group (17 (14%) events) (odds ratio 0.92, 95% confidence interval 0.44 to 1.92). The change in the ratio of oxygen saturation to fraction of inspired oxygen after 72 hours was similar for patients randomised to prone positioning and standard of care. CONCLUSION: Among non-critically ill patients with hypoxaemia who were admitted to hospital with covid-19, a multifaceted intervention to increase prone positioning did not improve outcomes. However, wide confidence intervals preclude definitively ruling out benefit or harm. Adherence to prone positioning was poor, despite multiple efforts to increase it. Subsequent trials of prone positioning should aim to develop strategies to improve adherence to awake prone positioning. STUDY REGISTRATION: ClinicalTrials.gov NCT04383613.

Reducing Disparities in Cancer Screening and Prevention through Community-Based Participatory Research Partnerships with Local Libraries: A Comprehensive Dynamic Trial.

Reduction of cancer-related disparities requires strategies that link medically underserved communities to preventive care. In this community-based participatory research project, a public library system brought together stakeholders to plan and undertake programs to address cancer screening and risk behavior. This study was implemented over 48 months in 20 large urban neighborhoods, selected to reach diverse communities disconnected from care. In each neighborhood, Cancer Action Councils were organized to conduct a comprehensive dynamic trial, an iterative process of program planning, implementation and evaluation. This process was phased into neighborhoods in random, stepped-wedge sequence. Population-level outcomes included self-reported screening adherence and smoking cessation, based on street intercept interviews. Event-history regressions (n = 9374) demonstrated that adherence outcomes were associated with program implementation, as were mediators such as awareness of screening programs and cancer information seeking. Findings varied by ethnicity, and were strongest among respondents born outside the U.S. or least engaged in care. This intervention impacted health behavior in diverse, underserved and vulnerable neighborhoods. It has been sustained as a routine library system program for several years after conclusion of grant support. In sum, participatory research with the public library system offers a flexible, scalable approach to reduce cancer health disparities.

The Genetic Intersection of Neurodevelopmental Disorders and Shared Medical Comorbidities - Relations that Translate from Bench to Bedside.

Most psychiatric disorders are considered neurodevelopmental, and the associated genes often are expressed in tissues outside of the brain. This suggests a biological relatedness with medical co-occurrences that could have broad clinical implications for diagnosis and patient management over a lifetime. A qualitative integration of public data from genetic consortia of psychiatric disorders and medical comorbidities explores the question of whether genetically associated psychiatric illnesses present with co-occurring disturbances can be used to define specific mental-physical health relations. Novel patterns of gene-disorder relations appear with approximately one-third of conservatively defined, consortia-generated candidate risk genes with multiple psychiatric diagnoses. Moreover, nearly as many genes overlap with non-psychiatric phenotypes, including cardiovascular, renal, respiratory, and metabolic disturbances. While the landscape of genetic risk will change as study populations are expanded and biological confirmations accrue, the current relationships suggest that a mostly siloed perspective of gene relatedness to one categorical psychiatric diagnosis is not clinically useful. The future holds the promise that once candidates are fully validated, genome screening and mutation identification will bring more precision for predicting the risk for complex health conditions. Our view is that as genetic data are refined, continuing to decipher a shared pattern of genetic risk for brain and peripheral organ pathophysiology is not simply an academic exercise. Rather, determining relatedness will impact predictions of multifaceted health risks, patient treatment, and management.

Peroxynitrite donor SIN-1 alters high-affinity choline transporter activity by modifying its intracellular trafficking.

Sodium-coupled, high-affinity choline transporters (CHTs) are inhibited by 3-morpholinosydnonimine (SIN-1) [peroxynitrite (ONOO⁻) donor]; ONOO⁻ can be produced from nitric oxide and reactive oxygen species during neurodegeneration. SIN-1 rapidly increases CHT internalization from the cell surface, and this correlates with decreased choline uptake. This study addresses mechanisms by which SIN-1 inhibits CHT function in human neuronal SH-SY5Y cells. Thus, mutant L531A-CHT, which does not constitutively internalize into cells by a clathrin-mediated process, is resistant to SIN-1 effects. This suggests that CHT inhibition is not due to oxidative-nitrosative inactivation of the protein and that decreased levels of cell surface CHT in SIN-1-treated cells is related to alterations in its trafficking and subcellular disposition. Dominant-negative proteins AP180C and dynamin-K44A, which interfere with clathrin-mediated and dynamin-dependent endocytosis, respectively, attenuate CHT inhibition by SIN-1. CHT in both vehicle- and SIN-1-treated cells colocalizes with Rab7, Rab9, and Lamp-1 in late endosomes and lysosomes to a similar extent. Lysosome inhibitors increase choline uptake, suggesting that CHT proteins are normally degraded by lysosomes, and this is not altered by oxidative stress. Unexpectedly, inhibitors of proteasomes, but not lysosomes, attenuate SIN-1-mediated inhibition of choline uptake, indicating that proteasomal degradation plays a role in regulating CHT disposition in SIN-1-treated cells. SIN-1 treatment also enhances CHT ubiquitination. Thus, CHT inhibition in SIN-1-treated cells is mediated by proteasomal degradation, which differs from inhibitory mechanisms for some neurotransmitter transporters under similar conditions. Increased oxidative-nitrosative stress in the microenvironment of cholinergic nerve terminals would diminish cholinergic transmission by reducing choline availability for ACh synthesis.

Regulated recycling and plasma membrane recruitment of the high-affinity choline transporter.

The high-affinity choline transporter (CHT1) is responsible for uptake of choline from the synaptic cleft and supplying choline for acetylcholine synthesis. CHT1 internalization by clathrin-coated vesicles is proposed to represent a mechanism by which high-affinity choline uptake can be modulated. We show here that internalized CHT1 is rapidly recycled back to the cell surface in both human embryonic kidney cells (HEK 293 cells) and SH-SY5Y neuroblastoma cells. This rapidly recycling pool of CHT1 comprises about 10% of total CHT1 protein. In the SH-SY5Y neuroblastoma cell line K(+)-depolarization promotes Ca(2+)-dependent increase in the rate of CHT1 recycling to the plasma membrane without affecting the rate of CHT1 internalization. K(+)-depolarization also increases the size of the pool of CHT1 protein that can be mobilized to the plasma membrane. Thus, the activity-dependent increase in plasma membrane CHT1 localization appears to be regulated by two mechanisms: (i) an increase in the rate of externalization of the intracellular CHT1 pool; and (ii) the recruitment of additional intracellular transporters to the recycling pool.