In response to bacteria, neutrophils release extracellular vesicles capable of initiating thrombin generation through DNA-dependent and independent pathways.

Neutrophils release extracellular vesicles (EVs) and some subsets of neutrophil-derived EVs are procoagulant. In response to S. aureus, neutrophils produce EVs that associate electrostatically with neutrophil extracellular traps (NETs). DNA in NETs is procoagulant, but whether neutrophil EVs produced during bacterial challenge have similar activity is unknown. Given that EV activity is agonist- and cell-type dependent and coagulation contributes to sepsis, we hypothesized that sepsis-causing bacteria increase production of neutrophil-derived EVs, as well as EV-associated DNA, and intact EVs and DNA cause coagulation. We recovered EVs from neutrophils challenged with S. aureus (SA), S. epidermidis (SE), E. coli (EC), and P. aeruginosa (PA), and measured associated DNA and procoagulant activity. EVs from SA-challenged neutrophils (SA-EVs), which were previously characterized, displayed dose-dependent procoagulant activity as measured by thrombin generation (TG) in platelet-poor plasma. EV lysis and DNase treatment reduced TG by 90% and 37%, respectively. SE, EC, and PA also increased EV production and EV-associated extracellular DNA, and these EVs were also procoagulant. Compared to spontaneously released EVs, which demonstrated some ability to amplify Factor XII-dependent coagulation in the presence of an activator, only EVs produced in response to bacteria could initiate the pathway. SA-EVs and SE-EVs had more surface-associated DNA than EC-EVs and PA-EVs, and SA-EVs and SE-EVs contributed to initiation and amplification of TG in a DNA-dependent manner. However, DNA on EC- or PA-EVs played no role, suggesting that neutrophils release procoagulant EVs which can activate the coagulation cascade through both DNA-dependent and independent mechanisms.

The impact of psychedelics on patients with alcohol use disorder: a systematic review with meta-analysis.

OBJECTIVES: Critique the available systematic review and de novo assessment of the role of psychedelics in the treatment of alcohol use disorder. METHODS: A systematic literature search of PubMed was completed from 1960 to 9/9/2023. We pooled randomized controlled trials comparing psychedelics to control therapy for the treatment of alcohol use disorder. RESULTS: At the first recorded follow-up, LSD [n = 3, Odds Ratio (OR) 1.99 (95% Confidence interval (CI): 1.10 to 3.61)] and any psychedelic [n = 4, OR 2.16 (95%CI: 1.26 to 3.69)] enhanced the odds of patients achieving abstinence or a substantial reduction in drinking alcohol versus placebo in randomized, double-blind, placebo-controlled trials. When the inclusion criteria were relaxed to include controlled trials without double-blinding or placebo control, LSD [n = 5, OR 1.79 (95%CI: 1.36 to 2.34)] and any psychedelic therapy [n = 6, OR 1.89 (95%CI: 1.42 to 2.50)] still enhanced the odds of patients achieving abstinence or a substantial reduction in drinking alcohol. Four of 6 trials had high risk of bias and other methodological issues. One trial found an instance of suicidal ideation as well as transient increases in blood pressure that requires further exploration before the balance of benefits to harms can be determined. CONCLUSIONS: The use of psychedelics to treat alcohol use disorder is promising, but the weaknesses in the literature base preclude making definitive statements about its value. Future trials with greater methodological rigor are needed.

Lysergic acid diethylamine (LSD) and psilocybin (hallucinogenic mushrooms) are psychedelics that have been studied in patients with alcohol use disorder (chronic issue with heavy or problem drinking). When all the studies are pooled together in a meta-analysis, the odds of being able to refrain from drinking alcohol or to substantially reduce the amount of alcohol consumed was enhanced by 89%. This is a promising finding that if bore out in additional studies, especially those with higher study quality, would be a major advance in patients with alcohol use disorder. We cannot make more definitive conclusions because all the LSD studies were published between 1966 and 1970 which may not reflect contemporary practice and most of the studies had methodological weaknesses that reduce confidence in the studies to prove the benefits. It is heartening that the single psilocybin trial from 2022 was of higher methodological quality, reflected contemporary practice, and still showed positive effects.

Biodegradable piezoelectric skin-wound scaffold.

Electrical stimulation (ES) induces wound healing and skin regeneration. Combining ES with the tissue-engineering approach, which relies on biomaterials to construct a replacement tissue graft, could offer a self-stimulated scaffold to heal skin-wounds without using potentially toxic growth factors and exogenous cells. Unfortunately, current ES technologies are either ineffective (external stimulations) or unsafe (implanted electrical devices using toxic batteries). Hence, we propose a novel wound-healing strategy that integrates ES with tissue engineering techniques by utilizing a biodegradable self-charged piezoelectric PLLA (Poly (l-lactic acid)) nanofiber matrix. This unique, safe, and stable piezoelectric scaffold can be activated by an external ultrasound (US) to produce well-controlled surface-charges with different polarities, thus serving multiple functions to suppress bacterial growth (negative surface charge) and promote skin regeneration (positive surface charge) at the same time. We demonstrate that the scaffold activated by low intensity/low frequency US can facilitate the proliferation of fibroblast/epithelial cells, enhance expression of genes (collagen I, III, and fibronectin) typical for the wound healing process, and suppress the growth of S. aureus and P. aeruginosa bacteria in vitro simultaneously. This approach induces rapid skin regeneration in a critical-sized skin wound mouse model in vivo. The piezoelectric PLLA skin scaffold thus assumes the role of a multi-tasking, biodegradable, battery-free electrical stimulator which is important for skin-wound healing and bacterial infection prevention simultaneuosly.

Morbidity and mortality audits: "How to"for family practice.

PROBLEM BEING ADDRESSED: While professions hold their members responsible for self-regulation, many physicians have insufficient information about outcome measures in their practices to judge performance and are inexperienced in performing audits to gather the information they need to judge performance. OBJECTIVE OF PROGRAM: To develop a structure and process to support family doctors with little experience in doing quality improvement studies to conduct morbidity and mortality (M&M) audits. PROGRAM DESCRIPTION: A family medicine teaching group provides members on a rotating basis to an M&M review committee. The committee meets eight times a year and has done four audits, the most comprehensive on the topic of preventable hospital admissions. Both implicit and explicit criteria were incorporated into decision making. Strengths and limitations of the audit process and practice changes that resulted from the audit are discussed. CONCLUSION: Morbidity and mortality audits can vary in rigour. To promote physicians' interest in and commitment to audits, factors considered should reflect the goals, needs, skills, and time available of the physicians involved. Practical learning often results from simple projects.