Stress is a major risk factor for the development of mood and anxiety disorders; elucidation of novel approaches to mitigate the deleterious effects of stress could have broad clinical applications. ...Pharmacological augmentation of central endogenous cannabinoid (eCB) signaling may be an effective therapeutic strategy to mitigate the adverse behavioral and physiological consequences of stress. Here we show that acute foot-shock stress induces a transient anxiety state measured 24 h later using the light-dark box assay and novelty-induced hypophagia test. Acute pharmacological inhibition of the anandamide-degrading enzyme, fatty acid amide hydrolase (FAAH), reverses the stress-induced anxiety state in a cannabinoid receptor-dependent manner. FAAH inhibition does not significantly affect anxiety-like behaviors in non-stressed mice. Moreover, whole brain anandamide levels are reduced 24 h after acute foot-shock stress and are negatively correlated with anxiety-like behavioral measures in the light-dark box test. These data indicate that central anandamide levels predict acute stress-induced anxiety, and that reversal of stress-induced anandamide deficiency is a key mechanism subserving the therapeutic effects of FAAH inhibition. These studies provide further support that eCB-augmentation is a viable pharmacological strategy for the treatment of stress-related neuropsychiatric disorders.
Almost 70% of breast cancers are estrogen receptor α (ERα) positive. Tamoxifen, a selective estrogen receptor modulator (SERM), represents the standard of care for many patients; however, 30–50% ...develop resistance, underlining the need for alternative therapeutics. Paradoxically, agonists at ERα such as estradiol (E2) have demonstrated clinical efficacy in patients with heavily treated breast cancer, although side effects in gynecological tissues are unacceptable. A drug that selectively mimics the actions of E2 in breast cancer therapy but minimizes estrogenic effects in other tissues is a novel, therapeutic alternative. We hypothesized that a selective human estrogen receptor partial agonist (ShERPA) at ERα would provide such an agent. Novel benzothiophene derivatives with nanomolar potency in breast cancer cell cultures were designed. Several showed partial agonist activity, with potency of 0.8–76 nM, mimicking E2 in inhibiting growth of tamoxifen-resistant breast cancer cell lines. Three ShERPAs were tested and validated in xenograft models of endocrine-independent and tamoxifen-resistant breast cancer, and in contrast to E2, ShERPAs did not cause significant uterine growth.
Summary
Cardiac arrest in the peri‐operative period is rare but associated with significant morbidity and mortality. Current reporting systems do not capture many such events, so there is an ...incomplete understanding of incidence and outcomes. As peri‐operative cardiac arrest is rare, many hospitals may only see a small number of cases over long periods, and anaesthetists may not be involved in such cases for years. Therefore, a large‐scale prospective cohort is needed to gain a deep understanding of events leading up to cardiac arrest, management of the arrest itself and patient outcomes. Consequently, the Royal College of Anaesthetists chose peri‐operative cardiac arrest as the 7th National Audit Project topic. The study was open to all UK hospitals offering anaesthetic services and had a three‐part design. First, baseline surveys of all anaesthetic departments and anaesthetists in the UK, examining respondents' prior peri‐operative cardiac arrest experience, resuscitation training and local departmental preparedness. Second, an activity survey to record anonymised details of all anaesthetic activity in each site over 4 days, enabling national estimates of annual anaesthetic activity, complexity and complication rates. Third, a case registry of all instances of peri‐operative cardiac arrest in the UK, reported confidentially and anonymously, over 1 year starting 16 June 2021, followed by expert review using a structured process to minimise bias. The definition of peri‐operative cardiac arrest was the delivery of five or more chest compressions and/or defibrillation in a patient having a procedure under the care of an anaesthetist. The peri‐operative period began with the World Health Organization ‘sign‐in’ checklist or first hands‐on contact with the patient and ended either 24 h after the patient handover (e.g. to the recovery room or intensive care unit) or at discharge if this occured earlier than 24 h. These components described the epidemiology of peri‐operative cardiac arrest in the UK and provide a basis for developing guidelines and interventional studies.
Impairments in fear extinction are thought to be central to the psychopathology of posttraumatic stress disorder, and endocannabinoid (eCB) signaling has been strongly implicated in extinction ...learning. Here we utilized the monoacylglycerol lipase inhibitor JZL184 to selectively augment brain 2-AG levels combined with an auditory cue fear-conditioning paradigm to test the hypothesis that 2-AG-mediated eCB signaling modulates short-term fear extinction learning in mice. We show that systemic JZL184 impairs short-term extinction learning in a CB1 receptor-dependent manner without affecting non-specific freezing behavior or the acquisition of conditioned fear. This effect was also observed in over-conditioned mice environmentally manipulated to re-acquire fear extinction. Cumulatively, the effects of JZL184 appear to be partly due to augmentation of 2-AG signaling in the basolateral nucleus of the amygdala (BLA), as direct microinfusion of JZL184 into the BLA produced similar results. Moreover, we elucidate a short ~3-day temporal window during which 2-AG augmentation impairs extinction behavior, suggesting a preferential role for 2-AG-mediated eCB signaling in the modulation of short-term behavioral sequelae to acute traumatic stress exposure.
Emerging evidence suggests electronic health record (EHR)-related information overload is a risk to patient safety. In the US Department of Veterans Affairs (VA), EHR-based 'inbox' notifications ...originally intended for communicating important clinical information are now cited by 70% of primary care practitioners (PCPs) to be of unmanageable volume. We evaluated the impact of a national, multicomponent, quality improvement (QI) programme to reduce low-value EHR notifications.
The programme involved three steps: (1) accessing daily PCP notification load data at all 148 facilities operated nationally by the VA; (2) standardising and restricting mandatory notification types at all facilities to a recommended list; and (3) hands-on training for all PCPs on customising and processing notifications more effectively. Designated leaders at each of VA's 18 regional networks led programme implementation using a nationally developed toolkit. Each network supervised technical requirements and data collection, ensuring consistency. Coaching calls and emails allowed the national team to address implementation challenges and monitor effects. We analysed notification load and mandatory notifications preintervention (March 2017) and immediately postintervention (June-July 2017) to assess programme impact.
Median number of mandatory notification types at each facility decreased significantly from 15 (IQR: 13-19) to 10 (IQR: 10-11) preintervention to postintervention, respectively (P<0.001). Mean daily notifications per PCP decreased significantly from 128 (SEM=4) to 116 (SEM=4; P<0.001). Heterogeneity in implementation across sites led to differences in observed programme impact, including potentially beneficial carryover effects.
Based on prior estimates on time to process notifications, a national QI programme potentially saved 1.5 hours per week per PCP to enable higher value work. The number of daily notifications remained high, suggesting the need for additional multifaceted interventions and protected clinical time to help manage them. Nevertheless, our project suggests feasibility of using large-scale 'de-implementation' interventions to reduce unintended safety or efficiency consequences of well-intended electronic communication systems.
Hydrodynamic instabilities can cause capsule defects and other perturbations to grow and degrade implosion performance in ignition experiments at the National Ignition Facility (NIF). Here, we show ...the first experimental demonstration that a strong unsupported first shock in indirect drive implosions at the NIF reduces ablation front instability growth leading to a 3 to 10 times higher yield with fuel ρR>1 g/cm(2). This work shows the importance of ablation front instability growth during the National Ignition Campaign and may provide a path to improved performance at the high compression necessary for ignition.
The 7th National Audit Project of the Royal College of Anaesthetists studied peri-operative cardiac arrest in the UK, a topic of importance to patients, anaesthetists and surgeons. Here we report the ...results of the 12-month registry, from 16 June 2021 to 15 June 2022, focusing on epidemiology and clinical features. We reviewed 881 cases of peri-operative cardiac arrest, giving an incidence of 3 in 10,000 anaesthetics (95%CI 3.0-3.5 per 10,000). Incidence varied with patient and surgical factors. Compared with denominator survey activity, patients with cardiac arrest: included more males (56% vs. 42%); were older (median (IQR) age 60.5 (40.5-80.5) vs. 50.5 (30.5-70.5) y), although the age distribution was bimodal, with infants and patients aged > 66 y overrepresented; and were notably more comorbid (73% ASA physical status 3-5 vs. 27% ASA physical status 1-2). The surgical case-mix included more weekend (14% vs. 11%), out-of-hours (19% vs. 10%), non-elective (65% vs. 30%) and major/complex cases (60% vs. 28%). Cardiac arrest was most prevalent in orthopaedic trauma (12%), lower gastrointestinal surgery (10%), cardiac surgery (9%), vascular surgery (8%) and interventional cardiology (6%). Specialities with the highest proportion of cases relative to denominator activity were: cardiac surgery (9% vs. 1%); cardiology (8% vs. 1%); and vascular surgery (8% vs. 2%). The most common causes of cardiac arrest were: major haemorrhage (17%); bradyarrhythmia (9%); and cardiac ischaemia (7%). Patient factors were judged a key cause of cardiac arrest in 82% of cases, anaesthesia in 40% and surgery in 35%.
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