Metformin has anti-inflammatory effects and induces immunometabolic reprogramming via multiple mechanisms in hidradenitis suppurativa.

BACKGROUND: Targeting immunometabolism has shown promise in treating autoimmune and inflammatory conditions. Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease involving painful lesions in apocrine gland-bearing skin. Therapeutic options for HS are limited and often ineffective; thus, there is a pressing need for improved treatments. To date, metabolic dysregulation has not been investigated in HS. As HS is highly inflammatory, we hypothesized that energy metabolism is dysregulated in these patients. Metformin, an antidiabetic drug, which is known to impact on cellular metabolic and signalling pathways, has been shown to have anti-inflammatory effects in cancer and arthritis. While metformin is not licensed for use in HS, patients with HS taking metformin show improved clinical symptoms. OBJECTIVE: To assess the effect and mechanism of action of metformin in HS. METHODS: To assess the effect of metformin in vivo, we compared the immune and metabolic profiles of peripheral blood mononuclear cells (PBMCs) of patients with HS taking metformin vs. those not taking metformin. To examine the effect of metformin treatment ex vivo, we employed a skin explant model on skin biopsies from patients with HS not taking metformin, which we cultured with metformin overnight. We used enzyme-linked immunosorbent assays, multiplex cytokine assays and quantitative real-time polymerase chain reaction (RT-PCR) to measure inflammatory markers, and Seahorse flux technology and quantitative RT-PCR to assess glucose metabolism. RESULTS: We showed that metabolic pathways are dysregulated in the PBMCs of patients with HS vs. healthy individuals. In metformin-treated patients, these metabolic pathways were restored and their PBMCs had reduced inflammatory markers following long-term metformin treatment. In the skin explant model, we found that overnight culture with metformin reduced inflammatory cytokines and chemokines and glycolytic genes in lesions and tracts of patients with HS. Using in vitro assays, we found that metformin may induce these changes via the NLR family pyrin domain containing 3 (NLRP3) inflammasome and the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway, which is linked to glycolysis and protein synthesis. CONCLUSIONS: Our study provides insight into the mechanisms of action of metformin in HS. The anti-inflammatory effects of metformin support its use as a therapeutic agent in HS, while its effects on immunometabolism suggest that targeting metabolism is a promising therapeutic option in inflammatory diseases, including HS.

Frailty and emergency abdominal surgery: A systematic review and meta-analysis.

INTRODUCTION: Patients aged ≥65 years currently account for approximately 55% of all emergent operations. However, these patients account for 75% of post-operative mortality. Older age has long been associated with adverse outcomes from emergency surgery. However, old age is a heterogenous state. Recent studies have indicated that frailty may more accurately reflect true biological age and perioperative risk than chronological age alone in patients undergoing elective surgery. Few studies have evaluated the impact of frailty on post-operative outcomes in this setting. METHODS: A systematic, electronic search for relevant publications was performed in November 2019 using Pubmed and Embase from 2009 to 2019. The latest search for articles was performed on February 16th, 2020. Articles were excluded if frailty was not measured using a frailty tool, or if patients did not undergo emergency general surgery (EGS). RESULTS: The prevalence of frailty amongst patients undergoing emergency abdominal surgery was 30.8%. The all-cause mortality rate was 15.68%. The mortality rate amongst the frail undergoing EGS was 24.7%. Frailty was associated with an increased mortality rate compared with the non-frail (odds ratio (OR) 4.3, 95% CI 2.25-8.19%, p < 0.05, I2 = 80%). CONCLUSIONS: There is strong evidence to suggest that frailty in the older population predicts post-operative mortality, complications, prolonged length of stay and the loss of independence. Collaborative working with medicine for the elderly physicians to target modifiable aspects of the frailty syndrome in the perioperative pathway may improve outcomes. Frailty scoring should be integrated into acute surgical assessment practice to aid decision-making and development of novel postoperative strategies.

The impact of ursodeoxycholic acid on gallstone disease after bariatric surgery: a meta-analysis of randomized control trials.

BACKGROUND: Ursodeoxycholic acid (UDCA) is a bile acid that has been shown to reduce the formation of gallstones after significant weight loss. OBJECTIVE: This study aimed to evaluate the impact of UDCA on the incidence of gallstones after bariatric surgery. SETTINGS: An electronic search of PubMed (Medline), Cochrane Central Register of Controlled Studies (CENTRAL), Scopus (Elsevier) databases, EMBASE, CINAHL, Clinicaltrials.gov, and Web of Science. METHODS: A meta-analysis of randomized control trials was performed. The primary outcome was the incidence of gallstones after bariatric surgery. Secondary outcomes included type of operation and time interval to and characteristics associated with gallstone formation. RESULTS: Ten randomized control trials including 2583 patients were included, 1772 patients (68.6%) receiving UDCA and 811 (31.4%) receiving placebo. There was a significant reduction in gallstone formation in patients who received UDCA postoperatively (risk ratio [RR] .36, 95% confidence interval [CI] .22-.41, P < .00001). The overall prevalence of gallstone formation was 24.7% in the control group compared to 7.3% in the UDCA group. A dose of ≤600 mg/day had a significantly reduced risk of gallstone formation compared to the placebo group (risk ratio .35; 95% CI .24-.53; P < .001). The risk reduction was not significant for the higher dose (>600 mg/day) group (risk ratio .30; 95% CI, .09-1.01, P = .05). CONCLUSIONS: UDCA significantly reduces the risk of both asymptomatic and symptomatic gallstones after bariatric surgery. A dose of 600 mg/day is associated with improved compliance and better outcomes regardless of type of surgery. UDCA should be considered part of a standard postoperative care bundle after bariatric surgery.

Segmental arterial mediolysis: a rare cause of an acute abdomen.

Segmental arterial mediolysis (SAM) is a nonatherosclerotic, noninflammatory and nonimmune arteriopathy of unknown aetiology. We present the case of a 43-year-old male who presented to the emergency department with abdominal pain. A computed tomography of abdomen and pelvis showed a narrow, hypodense superior mesenteric artery after the origin, raising the possibility of thrombus or vasculitis. He was commenced on rivaroxaban and steroids. He subsequently presented with an acute abdomen in a collapsed state. Repeat imaging of his abdomen and pelvis revealed an ischaemic ileal segment and caecum. He required an emergency laparotomy with resection of the ischaemic segment and formation of a double-barrelled stoma. SAM is an important diagnosis for clinicians and radiologists to be aware of, given the risks of life-threatening haemorrhage and acute organ ischaemia. This is a commonly overlooked cause of abdominal pain, where an early diagnosis with lifestyle modifications may prevent disease progression and subsequent development of life-threatening complications.