Oleoylethanolamine and palmitoylethanolamine modulate intestinal permeability in vitro via TRPV1 and PPARα

Cannabinoids modulate intestinal permeability through cannabinoid receptor 1 (CB1). The endocannabinoid-like compounds oleoylethanolamine (OEA) and palmitoylethanolamine (PEA) play an important role in digestive regulation, and we hypothesized they would also modulate intestinal permeability. Transepithelial electrical resistance (TEER) was measured in human Caco-2 cells to assess permeability after application of OEA and PEA and relevant antagonists. Cells treated with OEA and PEA were stained for cytoskeletal F-actin changes and lysed for immunoassay. OEA and PEA were measured by liquid chromatography–tandem mass spectrometry. OEA (applied apically, logEC50 −5.4) and PEA (basolaterally, logEC50 −4.9; apically logEC50 −5.3) increased Caco-2 resistance by 20–30% via transient receptor potential vanilloid (TRPV)-1 and peroxisome proliferator-activated receptor (PPAR)-α. Preventing their degradation (by inhibiting fatty acid amide hydrolase) enhanced the effects of OEA and PEA. OEA and PEA induced cytoskeletal changes and activated focal adhesion kinase and ERKs 1/2, and decreased Src kinases and aquaporins 3 and 4. In Caco-2 cells treated with IFNγ and TNFα, OEA (via TRPV1) and PEA (via PPARα) prevented or reversed the cytokine-induced increased permeability compared to vehicle (0.1% ethanol). PEA (basolateral) also reversed increased permeability when added 48 or 72 h after cytokines (P < 0.001, via PPARα). Cellular and secreted levels of OEA and PEA (P < 0.001–0.001) were increased in response to inflammatory mediators. OEA and PEA have endogenous roles and potential therapeutic applications in conditions of intestinal hyperpermeability and inflammation

Opioid prescription at postoperative discharge: a retrospective observational cohort study

Opioid misuse is now considered a major public health epidemic in North America, with substantial social and financial consequences. As well as socio-economic and commercial drivers, modifiable risk-factors that have resulted in this crisis have been identified. The purpose of this study was to identify whether, within England, modifiable drivers for persistent postoperative opioid use were present. This was a retrospective cohort study of practice at 14 National Health Service hospitals across England. Data were collected retrospectively and validated for adult patients undergoing elective intermediate and major or complex major general surgical procedures between 1 and 31 March 2019. Of the 509 patients enrolled from 14 centres, 499 were included in the data analysis. In total, 31.5% (157/499) patients were in the intermediate surgery cohort and 68.5% (342/499) were in the major or complex major surgery cohort, with 21.0% (33/157) and 21.6% (74/342) discharged with opioid medicines to be taken at regular intervals, respectively. There were similar median oral morphine equivalent doses prescribed at discharge. Of patients prescribed regular opioid medicines, 76.6% (82/107) had a specified duration at discharge. However, 72.9% (78/107) had no written deprescribing advice on discharge. Similarly, of patients prescribed ‘when required’ opioids, 59.6% (93/156) had a specified duration of their prescription and 33.3% (52/156) were given written deprescribing advice. This study has identified a pattern of poor prescribing practices, a lack of guidance and formal training at individual institutions and highlights opportunities for improvement in opioid-prescribing practices within England

Identification of surgeon burnout via a single-item measure

Background Burnout is endemic in surgeons in the UK and linked with poor patient safety and quality of care, mental health problems, and workforce sustainability. Mechanisms are required to facilitate the efficient identification of burnout in this population. Multi-item measures of burnout may be unsuitable for this purpose owing to assessment burden, expertise required for analysis, and cost. Aims To determine whether surgeons in the UK reporting burnout on the 22-item Maslach Burnout Inventory (MBI) can be reliably identified by a single-item measure of burnout. Methods Consultant (n = 333) and trainee (n = 217) surgeons completed the MBI and a single-item measure of burnout. We applied tests of discriminatory power to assess whether a report of high burnout on the single-item measure correctly classified MBI cases and non-cases. Results The single-item measure demonstrated high discriminatory power on the emotional exhaustion burnout domain: the area under the curve was excellent for consultants and trainees (0.86 and 0.80), indicating high sensitivity and specificity. On the depersonalisation domain, discrimination was acceptable for consultants (0.76) and poor for trainees (0.69). In contrast, discrimination was acceptable for trainees (0.71) and poor for consultants (0.62) on the personal accomplishment domain. Conclusions A single-item measure of burnout is suitable for the efficient assessment of emotional exhaustion in consultant and trainee surgeons in the UK. Administered regularly, such a measure would facilitate the early identification of at-risk surgeons and swift intervention, as well as the monitoring of group-level temporal trends to inform resource allocation to coincide with peak periods

Burnout among surgeons in the United Kingdom during the COVID-19 pandemic: A cohort study

Background: Surgeon burnout has implications for patient safety and workforce sustainability. The aim of this study was to establish the prevalence of burnout among surgeons in the UK during the COVID-19 pandemic. Methods: This cross-sectional online survey was set in the UK National Health Service and involved 601 surgeons across the United Kingdom of all specialities and grades. Participants completed of the Maslach Burnout Inventory and bespoke questionnaire. Outcome measures included emotional exhaustion, depersonalisation and personal accomplishment, as measured by the Maslach Burnout Inventory-Human Services Survey (MBI-HSS). Results: 142 surgeons reported having contracted COVID-19. Burnout prevalence was particularly high in the emotional exhaustion (57%) and depersonalisation (50%) domains, while lower on the personal accomplishment domain (15%). Burnout prevalence was unrelated to COVID-19 status; however, the greater the perceived impact of COVID-19 on work, the higher the prevalence of emotional exhaustion and depersonalisation. Degree of worry about contracting COVID-19 oneself and degree of worry about family and friends contacting COVID-19 was positively associated with prevalence on all three burnout domains. Across all three domains burnout prevalence was exceptionally high in the Core Trainee 1-2 and Specialty Trainee 1-2 grades. Conclusions: These findings highlight potential undesirable implications for patient safety arising from surgeon burnout. Moreover, there is a need for ongoing monitoring in addition to an enhanced focus on mental health self-care in surgeon training and the provision of accessible and confidential support for practising surgeons

The role of CB1 in intestinal permeability and inflammation

The endocannabinoid system has previously been shown to play a role in the permeability and inflammatory response of the human gut. The goal of our study was to determine the effects of endogenous anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) on the permeability and inflammatory response of intestinal epithelium under normal, inflammatory, and hypoxic conditions. Human intestinal mucosa was modeled using Caco-2 cells. Human tissue was collected from planned colorectal resections. Accumulation of AEA and 2-AG was achieved by inhibiting their metabolizing enzymes URB597 (a fatty acid amide hydrolase inhibitor) and JZL184 (a monoacylglycerol lipase inhibitor). Inflammation and ischemia were simulated with TNF-a and IFN-g and oxygen deprivation. Permeability changes were measured by transepithelial electrical resistance. The role of the CB1 receptor was explored using CB1-knockdown (CB1Kd) intestinal epithelial cells. Endocannabinoid levels were measured using liquid chromatography–mass spectrometry. Cytokine secretion was measured using multiplex and ELISA. URB597 and JZL184 caused a concentration-dependent increase in permeability via CB1 (P < 0.0001) and decreased cytokine production. Basolateral application of JZL184 decreased permeability via CB1 (P < 0.0001). URB597 and JZL184 increased the enhanced (worsened) permeability caused by inflammation and hypoxia (

The impact of pre‐operative intravenous iron on quality of life after colorectal cancer surgery: outcomes from the intravenous iron in colorectal cancer‐associated anaemia (IVICA) trial

Anaemia is associated with a reduction in quality of life, and is common in patients with colorectal cancer . Werecently reported thefindings of the intravenous iron in colorectal cancer-associated anaemia (IVICA) trialcomparing haemoglobin levels and transfusion requirements following intravenous or oral iron replacement inanaemic colorectal cancer patients undergoing elective surgery. In this follow-up study, we compared theefficacy of intravenous and oral iron at improving quality of life in this patient group. We conducted amulticentre, open-label randomised controlled trial. Anaemic colorectal cancer patients were randomlyallocated at least two weeks pre-operatively, to receive either oral (ferrous sulphate) or intravenous (ferriccarboxymaltose) iron. We assessed haemoglobin and quality of life scores at recruitment, immediately beforesurgery and at outpatient review approximately three months postoperatively, using the Short Form 36,EuroQoL 5-dimension 5-level and Functional Assessment of Cancer Therapy–Anaemia questionnaires. Werecruited 116 anaemic patients across seven UK centres (oral iron n=61 (53%), and intravenous iron n=55(47%)). Eleven quality of life components increased by a clinically significant margin in the intravenous irongroup between recruitment and surgery compared with one component for oral iron. Median (IQR [range])visual analogue scores were significantly higher with intravenous iron at a three month outpatient review (oraliron 70, (60–85 [20–95]); intravenous iron 90 (80–90 [50–100]), p=0.001). The Functional Assessment ofCancer Therapy–Anaemia score comprises of subscales related to cancer, fatigue and non-fatigue itemsrelevant to anaemia. Median outpatient scores were higher, and hence favourable, for intravenous iron on theFunctional Assessment of Cancer Therapy–Anaemia subscale (oral iron 66 (55–72 [23–80]); intravenous iron 71(66–77 [46–80]); p=0.002), Functional Assessment of Cancer Therapy–Anaemia trial outcome index (oral iron108 (90–123 [35–135]); intravenous iron 121 (113–124 [81–135]); p=0.003) and Functional Assessment ofCancer Therapy–Anaemia total score (oral iron 151 (132–170 [69–183]); intravenous iron 168 (160–174 [125–186]); p=0.005). Thesefindings indicate that intravenous iron is more efficacious at improving quality of lifescores than oral iron in anaemic colorectal cancer patients