Iron Is Critical for Mucosal-Associated Invariant T Cell Metabolism and Effector Functions.

Mucosal-Associated Invariant T (MAIT) cells are a population of innate T cells that play a critical role in host protection against bacterial and viral pathogens. Upon activation, MAIT cells can rapidly respond via both TCR-dependent and -independent mechanisms, resulting in robust cytokine production. The metabolic and nutritional requirements for optimal MAIT cell effector responses are still emerging. Iron is an important micronutrient and is essential for cellular fitness, in particular cellular metabolism. Iron is also critical for many pathogenic microbes, including those that activate MAIT cells. However, iron has not been investigated with respect to MAIT cell metabolic or functional responses. In this study, we show that human MAIT cells require exogenous iron, transported via CD71 for optimal metabolic activity in MAIT cells, including their production of ATP. We demonstrate that restricting iron availability by either chelating environmental iron or blocking CD71 on MAIT cells results in impaired cytokine production and proliferation. These data collectively highlight the importance of a CD71-iron axis for human MAIT cell metabolism and functionality, an axis that may have implications in conditions where iron availability is limited.

Circulating microRNAs can predict chemotherapy-induced toxicities in patients being treated for primary breast cancer.

PURPOSE: Prescribing NAC for breast cancer is a pragmatic treatment strategy for several reasons; however, certain patients suffer chemotherapy-induced toxicities. Unfortunately, identifying patients at risk of toxicity often proves challenging. MiRNAs are small non-coding RNA molecules which modulate genetic expression. The aim of this study was to determine whether circulating miRNAs are sensitive biomarkers that can identify the patients likely to suffer treatment-related toxicities to neoadjuvant chemotherapy (NAC) for primary breast cancer. METHODS: This secondary exploratory from the prospective, multicentre translational research trial (CTRIAL ICORG10/11-NCT01722851) recruited 101 patients treated with NAC for breast cancer, from eight treatment sites across Ireland. A predetermined five miRNAs panel was quantified using RQ-PCR from patient bloods at diagnosis. MiRNA expression was correlated with chemotherapy-induced toxicities. Regression analyses was performed using SPSS v26.0. RESULTS: One hundred and one patients with median age of 55 years were recruited (range: 25-76). The mean tumour size was 36 mm and 60.4% had nodal involvement (n = 61) Overall, 33.7% of patients developed peripheral neuropathies (n = 34), 28.7% developed neutropenia (n = 29), and 5.9% developed anaemia (n = 6). Reduced miR-195 predicted patients likely to develop neutropenia (P = 0.048), while increased miR-10b predicted those likely to develop anaemia (P = 0.049). Increased miR-145 predicted those experiencing nausea and vomiting (P = 0.019), while decreased miR-21 predicted the development of mucositis (P = 0.008). CONCLUSION: This is the first study which illustrates the value of measuring circulatory miRNA to predict patient-specific toxicities to NAC. These results support the ideology that circulatory miRNAs are biomarkers with utility in predicting chemotherapy toxicity as well as treatment response.

Evaluating the Role of Circulating MicroRNAs to Aid Therapeutic Decision Making for Neoadjuvant Chemotherapy in Breast Cancer: A Prospective, Multicenter Clinical Trial.

OBJECTIVE: To evaluate whether circulating micro ribonucleic acids (miRNAs) predict response to neoadjuvant chemotherapy (NAC) and inform decision-making in breast cancer patients. INTRODUCTION: Deciphering response to NAC remains a challenge. Those unlikely to respond may benefit from NAC de-escalation before completion, while "responders" should complete treatment. Establishing biomarkers which identify response to NAC is imperative to personalize treatment strategies. miRNAs are small noncoding RNA molecules which modulate genetic expression. miRNAs are believed to inform response to NAC. METHODS: This prospective, multicenter trial (NCT01722851) recruited 120 patients treated with NAC across 8 Irish treatment sites. Predetermined miRNAs were quantified from patient whole bloods using relative quantification polymerase chain reactiond. Venous sampling was performed at diagnosis and midway during NAC. Trends in miRNA expression between timepoints were correlated with treatment response. Data analysis was performed using R 3.2.3. RESULTS: A total of 120 patients were included (median age: 55 years). Overall, 49.2% had luminal breast cancers (59/120), 17.5% luminal B (L/HER2) (21/120), 12.5% human epidermal growth factor receptor-2 positive (HER2+) (15/120), and 20.8% triple negative disease (25/120). In total, 46.7% of patients responded to NAC (56/125) and 26.7% achieved a pathological complete response (pCR) (32/120). For patients with L/HER2, increased Let-7a predicted response to NAC ( P =0.049), while decreased miR-145 predicted response to NAC in HER2+ ( P =0.033). For patients with luminal breast cancers, reduced Let-7a predicted achieving a pCR ( P =0.037) and reduced miR-145 predicted achieving a pCR to NAC in HER2+ ( P =0.027). CONCLUSIONS: This study illustrates the potential value of circulatory miRNA measurement in predicting response to NAC. Further interrogation of these findings may see miRNAs personalize therapeutic decision-making for patients undergoing NAC for early breast cancer.

Segmental versus extended colectomy for tumours of the transverse colon: a systematic review and meta-analysis.

AIM: There is no consensus on the appropriate extent of oncological resection for tumours of the transverse colon. Concerns regarding tumour factors such as pattern of lymph node spread and technical factors such as anastomotic perfusion lead to a variety of procedures being performed. METHODS: A comprehensive search for published studies examining outcomes following segmental versus extended colectomy for transverse colon tumours was performed adhering to PRISMA (Preferred Reporting Items in Systematic Reviews and Meta-analyses) guidelines. Random effects methods were used to combine data. RESULTS: Seven comparative series examining outcomes in 3395 patients were identified. Segmental colectomy results in shorter operating times (mean difference 15.80 min, 95% CI -20.98 to -10.62, P < 0.001) and less ileus (OR 0.52, 95% CI 0.33-0.81, P = 0.004). There was no difference in length of hospital stay (mean difference 1.53 days, 95% CI -3.79 to 0.73, P = 0.18). Extended colectomy results in a lower rate of anastomotic leak (OR 0.62, 95% CI 0.40-0.97, P = 0.04). There are fewer nodes retrieved in segmental colectomy (mean difference 7.60 nodes, 95% CI -9.60 to -5.61, P < 0.001) but no difference in disease recurrence (OR 0.88, 95% CI 0.59-1.34, P = 0.56) or overall survival (OR 0.98, 95% CI 0.68-1.4, P = 0.9). CONCLUSIONS: Available data are limited due to a lack of randomized controlled trials. However, based on current evidence, segmental resection for transverse colon tumours is associated with less ileus but lower lymph node yields and higher anastomotic leak rates. Length of stay is similar. Oncological outcomes are equivalent.

Can CT-PET and Endoscopic Assessment Post-Neoadjuvant Chemoradiotherapy Predict Residual Disease in Esophageal Cancer?

OBJECTIVE: The aim of this study is to assess CT-PET and endoscopic assessment postneoadjuvant chemoradiotherapy (nCRT) in predicting complete pathologic response (pCR) in locally advanced esophageal cancer (LAEC). DESIGN: A prospective cohort study. BACKGROUND: nCRT is increasingly standard of care in LAEC, with pCR a surrogate for excellent outcome. Predicting pCR before surgery, with metabolic imaging and endoscopy, may spare patients' operative intervention. METHODS: One hundred thirty-eight consecutive patients [mean age 61 ±â€Š8, 99 male (72%), 103 (75%) adenocarcinoma] underwent nCRT with CT-PET and endoscopy 4 to 6 weeks later, and surgery subsequently. A complete metabolic response (cMR) was defined as SUVmax of <4. A complete endoscopic response (cER) was no residual mucosal abnormality. The association of pCR with cMR and cER was analyzed. RESULTS: pCR was achieved in 30 patients (22%); 37% SCC and 17% adenocarcinoma. A cMR was evident in 63 (46%), of whom 17 (27%) had a pCR and 17(27%) were ypN+. A cER was observed in 45 (33%). The Spearman correlation for cER and cMR was 0.066 (P = 0.479), for cER and pCR was 0.004 (P = 0.969), and cMR and pCR -0.120 (P = 0.160). The sensitivity, specificity, positive predictive value, and negative predictive value of cMR was 57%, 57%, 27%, and 82%, respectively, and for combined cMR and cER was 24%, 83%, 28%, and 79%, respectively. CONCLUSIONS: The prediction of pCR through CT-PET and endoscopy independently or combined is limited by low sensitivity and poor positive predictive value. Protocols to avoid surgery in patients with apparent complete clinical complete based on these criteria should be adopted with considerable caution.

Prospective Study of Malabsorption and Malnutrition After Esophageal and Gastric Cancer Surgery.

OBJECTIVE: To study malabsorption and malnutrition after curative resection of esophageal and gastric cancer. DESIGN: Prospective cohort study. BACKGROUND: Improved cure rates for esophageal and gastric cancer have increased focus on health-related quality of life (HR-QL) in survivorship. Although malnutrition is well described in long-term follow-up, and gastrointestinal symptoms are common, data on gut and pancreatic-related malabsorption are scant. METHODS: Disease-free patients at least 18 months after esophageal or gastric oncologic resections represented the study cohort. A modified Gastrointestinal Symptom Rating Scale questionnaire was completed, and weight, fecal elastase (FE), albumin, vitamins, and micronutrients measured preoperatively and at 1, 6, and 18 to 24 months postoperatively. Small intestinal bacterial overgrowth (SIBO) and changes in body composition were also evaluated postoperatively. RESULTS: At a median follow-up of 23 months, 45 of 66 patients in a consecutive series were disease-free. Mean weight (78 ±â€Š19 vs 67 ±â€Š16 kg), body mass index (27 ±â€Š5 vs 24 ±â€Š5 kg/m), Vitamin A (1.7 ±â€Š0.6 vs 1.2 ±â€Š0.4 umol/L), and Vitamin E (28 ±â€Š7 vs 20 ±â€Š7 umol/L) were significantly decreased (P < 0.01) at last follow-up compared with preoperatively. Malabsorption was evident in 73% of patients, of whom 44% had FE < 200 µg/g and 38% had evidence of SIBO. Total body fat-free mass (175 ±â€Š96 vs 84 ±â€Š71, P < 0.001) and skeletal muscle index (44 ±â€Š8 vs 39 ±â€Š8, P = 0.007) were significantly decreased at 18 to 24 months. CONCLUSIONS: Malabsorption and malnutrition are prevalent in survivorship of esophageal and stomach cancer. This may be underappreciated, and both gut and pancreatic insufficiency represent modifiable targets in the interdisciplinary approach to recovery of HR-QL.

Evaluating the Impact of Enhanced Recovery After Surgery Protocols on Surgical Outcomes Following Bariatric Surgery-A Systematic Review and Meta-analysis of Randomised Clinical Trials.

BACKGROUND: Enhanced recovery after surgery (ERAS) programmes are evidence-based care improvement processes for surgical patients, which are designed to decrease the impact the anticipated negative physiological cascades following surgery. AIM: To perform a systematic review and meta-analysis of randomised clinical trials (RCTs) to evaluate the impact of ERAS protocols on outcomes following bariatric surgery compared to standard care (SC). METHODS: A systematic review was performed in accordance with PRISMA guidelines. Meta-analysis was performed using Review Manager version 5.4 RESULTS: Six RCTs including 740 patients were included. The mean age was 40.2 years, and mean body mass index was 44.1 kg/m2. Overall, 54.1% underwent Roux-en-Y gastric bypass surgery (400/740) and 45.9% sleeve gastrectomy (340/700). Overall, patients randomised to ERAS programmes had a significant reduction in nausea and vomiting (odds ratio (OR): 0.42, 95% confidence interval (CI): 0.19-0.95, P = 0.040), intraoperative time (mean difference (MD): 5.40, 95% CI: 3.05-7.77, P < 0.001), time to mobilisation (MD: - 7.78, 95% CI: - 5.46 to - 2.10, P < 0.001), intensive care unit stay (ICUS) (MD: 0.70, 95% CI: 0.13-1.27, P = 0.020), total hospital stay (THS) (MD: - 0.42, 95% CI: - 0.69 to - 0.16, P = 0.002), and functional hospital stay (FHS) (MD: - 0.60, 95% CI: - 0.98 to - 0.22, P = 0.002) compared to those who received SC. CONCLUSION: ERAS programmes reduce postoperative nausea and vomiting, intraoperative time, time to mobilisation, ICUS, THS, and FHS compared to those who received SC. Accordingly, ERAS should be implemented, where feasible, for patients indicated to undergo bariatric surgery. Trial registration International Prospective Register of Systematic Reviews (PROSPERO - CRD42023434492.

Perceived Benefits of Bariatric Surgery: Patient Perspectives.

BACKGROUND: Obesity is a chronic and complex disease characterized by the excessive accumulation of adipose tissue, which has detrimental effects on health. Evaluating the changes in quality of life (QoL) after bariatric surgery complements the medical benefits which are documented by healthcare professionals. PURPOSE: To study the perceived health benefits 1 year after substantial weight loss induced by bariatric surgery. METHODS: This pilot study evaluated patients 1 year after bariatric surgery using 13 questions related to the health domains of the KOSS: airway, body mass, cardiovascular risk, diabetes, economic impact, functional, gonadal impact, health status perceived, image, junction of the gastro-esophagus, kidney, liver, and medication. In addition, the patients were asked to score the most significant benefit as "1," while the least beneficial benefit was scored as "13." RESULTS: One hundred fourteen consecutive patients were evaluated (men = 37 and women = 77). The responses were divided into functional, metabolic, and mental/social benefits. Patients ranked the functional question, "I became more active, and I can do more things" as the most important (average score of 3.7 ± 0.2), followed by a question related to metabolic status: "I am less worried about my risk of heart disease" (4.5 ± 0.3), and then a social/mental question, "My clothes fit better" (5.4 ± 0.3). The three least valuable benefits for the cohort were sexual life improvements (8.9 ± 0.3), heartburn improvements (9.0 ± 0.3), and urinary incontinence improvements (9.8 ± 0.3). CONCLUSIONS: Our observational pilot study demonstrated that patients value functional benefits after substantial weight loss the most, but that metabolic benefits and social/mental health benefits are also considered important.

Obesity and outcomes in trauma - a systematic review and meta-analysis.

BACKGROUND: The physiological abnormalities relating to obesity and metabolic syndrome can contribute to worse outcomes following trauma especially in class 2 and 3 obesity. The aim of this systematic review was to determine whether patients with a higher class of obesity who suffer traumatic injury have a higher risk of worse outcomes including in-hospital mortality than normal-weight patients. METHODS: A systematic search of MEDLINE, EMBASE, CENTRAL, Web of Science and CINAHL was performed for studies that reported a comparison of in-hospital obesity-related outcomes against normal-weight individuals aged 15 years and older following trauma. Single or multiple injuries from either blunt and/or penetrating trauma were included. Burn-related injuries, isolated head injury and studies focusing on orthopaedic related perioperative complications were excluded. RESULTS: The search yielded 7405 articles; 26 were included in this systematic review. 945,511 patients had a BMI>30. A random-effects meta-analysis was performed for analysis of all four outcomes. Patients with class 3 obesity (BMI>40) have significantly higher odds of in-hospital mortality than normal-BMI individuals following blunt and penetrating trauma (OR, 1.75; 95% CI, 1.39-2.19, p=<0.00001), significantly longer hospital LOS (SMD, 0.23; 95% CI, 0.21-0.25; p<0.00001) and significantly longer ICU LOS (SMD, 0.19; 95% CI, 0.12-0.26; p<0.0001). In contrast, studies that examined blunt and penetrating trauma and classified obesity with a threshold of BMI>30 found no significant difference in the odds of in-hospital mortality (OR, 0.94; 95% CI, 0.86-1.02, p=0.13). CONCLUSIONS: There is a higher risk of in-hospital mortality in patients living with class 3 obesity following trauma when compared with individuals with normal BMI. The management of patients with obesity is complex and trauma systems should develop specific weight related pathways to manage and anticipate the complications that arise in these patients. Systematic review registration number PROSPERO registration: CRD42021234482 Level of Evidence: Level 3.

The Impact of Bariatric Surgery on the Incidence of Colorectal Cancer in Patients with Obesity-a Systematic Review and Meta-analysis of Registry Data.

PURPOSE: Cancer and obesity represent two of the most significant global health concerns. The risk of malignancy, including colorectal cancer (CRC), increases with obesity. The aim of this study was to perform a systematic review and meta-analysis to determine the value of bariatric surgery in reducing CRC risk in patients with obesity using registry data. MATERIALS AND METHODS: A systematic review and meta-analysis were performed as per PRISMA guidelines. The risk of CRC was expressed as a dichotomous variable and reported as odds ratios (OR) with 95% confidence intervals (CIs) using the Mantel-Haenszel method. A multi-treatment comparison was performed, examining the risk reduction associated with existing bariatric surgery techniques. Analysis was performed using RevMan, R packages, and Shiny. RESULTS: Data from 11 registries including 6,214,682 patients with obesity were analyzed. Of these, 14.0% underwent bariatric surgery (872,499/6,214,682), and 86.0% did not undergo surgery (5,432,183/6,214,682). The mean age was 49.8 years, and mean follow-up was 5.1 years. In total, 0.6% of patients who underwent bariatric surgery developed CRC (4,843/872,499), as did 1.0% of unoperated patients with obesity (54,721/5,432,183). Patients with obesity who underwent bariatric surgery were less likely to develop CRC (OR: 0.53, 95% CI: 0.36-0.77, P < 0.001, I2 = 99%). Patients with obesity undergoing gastric bypass surgery (GB) (OR: 0.513, 95% CI: 0.336-0.818) and sleeve gastrectomy (SG) (OR: 0.484, 95% CI: 0.307-0.763) were less likely to develop CRC than unoperated patients. CONCLUSION: At a population level, bariatric surgery is associated with reduced CRC risk in patients with obesity. GB and SG are associated with the most significant reduction in CRC risk. PROSPERO REGISTRATION: CRD42022313280.

Evaluating the Role of Circulating MicroRNAs in Predicting Long-Term Survival Outcomes in Breast Cancer: A Prospective, Multicenter Clinical Trial.

BACKGROUND: While long-term outcomes have improved for patients with breast cancer, 20% to 30% will still develop recurrence, and identifying these patients remains a challenge. MicroRNAs (miRNAs) are small, noncoding molecules that modulate genetic expression and affect oncogenesis. STUDY DESIGN: This prospective, multicenter trial (ICORG10/11-NCT01722851) recruited patients undergoing neoadjuvant chemotherapy across 8 Irish centers. Predetermined miRNAs were quantified from patient whole blood using quantitative reverse transcriptase polymerase chain reaction. Venous sampling was performed at diagnosis (timepoint 1) and midway during neoadjuvant chemotherapy (timepoint 2 [T2]). miRNA expression profiles were correlated with recurrence-free survival (RFS), disease-free survival (DFS), and overall survival. Data analysis was performed using R v3.2.3. RESULTS: A total of 124 patients were recruited with a median age of 55.0 years. The median follow-up was 103.1 months. Increased miR-145 expression at T2 was associated with improved RFS (hazard ratio 0.00; 95% confidence interval [CI] 0.00 to 0.99; p = 0.050). Using survival regression tree analysis, a relative cutoff of increased miR-145 expression greater than 0.222 was associated with improved RFS (p = 0.041). Increased miR-145 expression at T2 trended towards significance in predicting improved DFS (hazard ratio 0.00; 95% CI 0.00 to 1.42; p = 0.067). Using survival regression tree analysis, a relative cutoff of increased miR-145 expression greater than 0.222 was associated with improved DFS (p = 0.012). No miRNAs correlated with overall survival. CONCLUSIONS: ICORG10/11 is the first Irish multicenter, translational research trial evaluating circulatory miRNAs as biomarkers predictive of long-term survival and correlated increased miR-145 expression with enhanced outcomes in early-stage breast cancer. Validation of these findings is required in the next generation of translational research trials.

The effects of normalizing hyperhomocysteinemia on clinical and operative outcomes in patients with critical limb ischemia.

PURPOSE: To assess the outcome of patients with medically treated hyperhomocysteinemia (HHC) requiring intervention for critical limb ischemia (CLI). METHODS: A parallel observational study was conducted to compare the clinical and revascularization outcomes of CLI patients who received standardized treatment for HHC preoperatively (folic acid and vitamin B12) vs. contemporaneous patients with normal homocysteine levels. The threshold for HHC diagnosis was 13.0 µmol/L. From 2009 to 2011, 169 patients underwent revascularization procedures for CLI. Of these, all 66 patients (40 men; mean age 69.6 ± 11.2 years) with HHC (mean 17.3 µmol/L, range 13.5-34.9) were treated to normalize the homocysteine level prior to lower limb revascularization. The remaining 103 patients (58 men; mean age 72.7±8.1 years) had normal homocysteine levels (8.2 µmol/L, range 5-12.3) before revascularization. The primary endpoint was symptomatic and hemodynamic improvement in the treated HHC group. The secondary endpoints were all-cause survival, binary restenosis, reintervention, amputation-free survival, and major adverse events. The treated HHC cohort was compared to an age/sex-matched historical group of patients with untreated HHC from 2002 to 2006 before HHC pretreatment became routine. All interventions (endovascular, hybrid, and open) were performed by the same surgeon, and the groups were evenly matched. RESULTS: Patients with HHC were treated for a mean 12.2 days, which significantly reduced their mean homocysteine level after 3 weeks to 10.1 µmol/L (range 6.2-14.4, p<0.05). After revascularization, immediate clinical improvement was similar between normal homocysteine and medically corrected HHC groups. There was no significant difference in time to binary restenosis (p=0.822). Secondary endpoints and all-cause mortality were similar. Multivariate logistic regression showed that untreated HHC was a significant factor for graft occlusion and limb loss (p<0.0001), but medically corrected HHC was no longer predictive of adverse operative outcome. CONCLUSION: Patients with medically corrected HHC have similar outcomes compared to those with normal homocysteine levels. Thus, aggressively treating HHC with folic acid and vitamin B12 may help enhance the clinical outcome of CLI patients undergoing revascularization.

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.

Innate PD-L1 limits T cell-mediated adipose tissue inflammation and ameliorates diet-induced obesity.

Obesity has become a major health problem in the industrialized world. Immune regulation plays an important role in adipose tissue homeostasis; however, the initial events that shift the balance from a noninflammatory homeostatic environment toward inflammation leading to obesity are poorly understood. Here, we report a role for the costimulatory molecule programmed death-ligand 1 (PD-L1) in the limitation of diet-induced obesity. Functional ablation of PD-L1 on dendritic cells (DCs) using conditional knockout mice increased weight gain and metabolic syndrome during diet-induced obesity, whereas PD-L1 expression on type 2 innate lymphoid cells (ILC2s), T cells, and macrophages was dispensable for obesity control. Using in vitro cocultures, DCs interacted with T cells and ILC2s via the PD-L1:PD-1 axis to inhibit T helper type 1 proliferation and promote type 2 polarization, respectively. A role for PD-L1 in adipose tissue regulation was also shown in humans, with a positive correlation between PD-L1 expression in visceral fat of people with obesity and elevated body weight. Thus, we define a mechanism of adipose tissue homeostasis controlled by the expression of PD-L1 by DCs, which may be a clinically relevant finding with regard to immune-related adverse events during immune checkpoint inhibitor therapy.

The therapeutic potential of microRNAs: disease modulators and drug targets.

MiRNAs are a class of small, naturally occurring RNA molecules that play critical roles in modulating numerous biological pathways by regulating gene expression. The knowledge that miRNA expression is dysregulated in many pathological disease processes, including cancer, has led to a rapidly expanding body of literature as we try to unveil their mechanism of action. Their putative role as oncogenes or tumour suppressor genes presents a wonderful opportunity to provide targeted cancer treatment strategies. Additionally, their documented function in a host of benign diseases broadens the potential market for miRNA-based therapeutics. The present review outlines the underlying rationales for considering mi(cro)RNAs as therapeutic agents or targets. We highlight the potential of manipulating miRNAs for the treatment of many common diseases, particularly cancers. Finally, we summarize the challenges that need to be overcome to fully harness the potential of miRNA-based therapies so they become the next generation of pharmaceutical products.

Endoscopic findings and outcomes of revisional procedures for patients with weight recidivism after gastric bypass.

BACKGROUND: Significant weight regain occurs for 10% to 20% of patients after Roux-en-Y gastric bypass (RYGB). Potential causative factors include anatomic abnormalities such as enlargement of the gastric pouch and gastrojejunostomy (GJ). This report describes endoscopic findings for patients referred for investigation of weight regain and presents the outcomes of revisional therapy for patients with abnormal anatomy. METHODS: To evaluate gastric pouch and stoma size, RYGB patients referred for weight regain underwent upper endoscopy. A GJ was defined as enlarged if it had a diameter greater than 2 cm in any dimension, and a pouch was defined as enlarged if its length exceeded 6 cm long or its width exceeded 5 cm. Patients with abnormal anatomy who subsequently underwent revisional procedures were arbitrarily categorized into three groups based on the interval from RYGB to endoscopic evaluation: less than 5 years (group 1), 5 to 10 years (group 2), longer than 10 years (group 3). The percentage of regained weight lost (%RWL) after revision was compared between the groups. RESULTS: In this study, 205 RYGB patients (176 women with a mean age of 47 ± 10 years and a current body mass index [BMI] of 43.4 ± 8.4 kg/m(2)) were evaluated. The mean time from primary RYGB was 6.9 ± 3.7 years, and the increase in BMI from its nadir was 9.78 ± 5.80 kg/m(2). Abnormal endoscopic findings (n = 146, 71.2%) included large GJ (n = 86, 58.9%), large pouch (n = 42, 28.8%), or both (n = 18, 12.3%). Of the 205 patients, 51 (24.9%) underwent a revisional surgical or endoluminal procedure. At a mean follow-up assessment 13 months after revision, group 1 (n = 12) had a mean %RWL of 103% ± 89.3%, and 62% of these patients lost all their regained weight. The mean %RWL was 45% ± 12.6% in group 2 (n = 30) and 40% ± 13.6% in group 3 (n = 9). CONCLUSION: Endoscopy is a valuable tool for evaluating weight regain after bariatric surgery that can identify abnormal post-RYGB anatomy in a majority of patients. Revisional procedures to restore normal RYGB anatomy appear to be most successful if performed within 5 years after the primary procedure.

Early effects of gastric bypass on endothelial function, inflammation, and cardiovascular risk in obese patients.

BACKGROUND: Obesity is associated with a chronic low-grade inflammatory state, insulin resistance, and endothelial dysfunction, all of which contribute to increased risk of cardiovascular disease. We hypothesized that gastric bypass would produce rapid improvements in endothelial function, reduce inflammation, and lead to a decrease in cardiovascular risk. METHODS: We performed a prospective study of morbidly obese patients who underwent laparoscopic Roux-en-Y gastric bypass (RYGB). Clinical data, biochemical markers of inflammation, and parameters indicative of cardiovascular risk were collected preoperatively and at 3 and 6 months postoperatively. Metabolic and inflammatory mediators that were quantified included C-reactive protein, fibrinogen, PAI-1, IL-6, IL-10, IL-1Ra, adiponectin, leptin, triglycerides, total cholesterol, HDL, LDL, glucose, insulin, and HbA1c. Brachial artery reactivity testing (BART) was performed to assess peripheral arterial endothelial function, and Framingham cardiovascular risk score (FRS) was calculated on all study participants pre- and postoperatively. RESULTS: Fifteen patients (11 female) were enrolled (age = 49.2 ± 10.4 years; BMI = 48.1 ± 5.3 kg/m(2)). Six months post RYGB, mean BMI decreased to 35.4 ± 4.5, corresponding to 51.7% excess weight loss (P < 0.001). Mean waist circumference decreased significantly from 132 cm at baseline to 110 cm at 3 months (P = 0.003) and 107 cm at 6 months (P < 0.001). Six months after RYGB, weight loss led to significant improvements in clinical parameters indicative of cardiovascular disease or risk, including brachial artery diameter, endothelial independent vasodilation, and FRS. Favorable improvements in the proinflammatory markers CRP (P = 0.01) and leptin (P = 0.005), the anti-inflammatory mediator adiponectin (P = 0.002), and insulin sensitivity (HOMA-IR, P = 0.007) were evident at 3 months. At 6 months, improvements in CRP, leptin, and fasting insulin were maintained and fibrinogen levels also decreased (P = 0.047). Adiponectin continued to increase at 6 months (P = 0.004). CONCLUSION: Gastric bypass is associated with early reversal of endothelial dysfunction, a more favorable inflammatory milieu, and, most importantly, a reduction in cardiovascular risk.

Enhanced Recovery After Bariatric Surgery: Feasibility and Outcomes in a National Bariatric Centre.

PURPOSE: This study aimed to assess outcomes of bariatric surgical procedures after the implementation of an enhanced recovery after bariatric surgery protocol in the National Bariatric Centre in Ireland. MATERIALS AND METHODS: Data on consecutive bariatric procedures performed over a 36-month period was prospectively recorded. ERABS interventions utilized included preoperative counselling, shortened preoperative fasts, specific anaesthetic protocols, early postop mobilization and feeding, and extended post-discharge thromboprophylaxis. RESULTS: A total of 280 primary bariatric procedures were performed over a 36-month period. The primary procedures were laparoscopic sleeve gastrectomy (57.5%), laparoscopic one anastomosis gastric bypass (33.2%) and laparoscopic Roux-en-Y gastric bypass (9.3%). Mean (SD) age was 48 (± 10) years, mean (SD) preoperative BMI 49.5 (± 9) kg/m2 and 68% were female. Median ASA score was 3, and median OSMRS also 3. Over 50% of patients had a diagnosis of hypertension or OSA, and over one-third had a diagnosis of type 2 diabetes mellitus or dyslipidemia. All procedures were completed laparoscopically and 29 patients underwent a simultaneous procedure. The mean (SD) length of stay was 2.3 (± 1.4) days (median 2 days, range 2-47 days). Overall postoperative morbidity rate was 10.0% (n = 29). The 30-day readmission and reoperation rates were 3.6% and 2.5% respectively. There was no mortality recorded in this series. CONCLUSION: Implementing an ERABS protocol was feasible, safe, associated with low morbidity, no mortality, acceptable LOS and low readmission and reoperation rates. Although patients with obesity have a spectrum of disease-related complications, this should not preclude the use of an ERABS protocol in bariatric surgery.

Assessment of baseline rates of functional and absolute iron deficiency in bariatric surgery candidates: a retrospective study.

BACKGROUND: Preoperative optimization of iron status is a priority in candidates for bariatric surgery. Inflammation is strongly associated with obesity, and as a consequence, functional iron deficiency (ID) is potentially an underreported issue in surgical candidates. OBJECTIVES: In light of updated practice guidelines, to retrospectively review preoperative iron status in an Irish cohort of bariatric surgery candidates, taking account of the relative incidence rate of functional ID. SETTING: A tertiary care obesity service with bariatric surgery referral in Ireland. METHODS: Baseline nutritional biochemistry records were reviewed between February 2017 and February 2020 in a hospital, Dublin, Ireland. Absolute ID was defined as serum ferritin <30 µg/L; functional ID was defined as ferritin, 30 to 100 µg/L, in the presence of C-reactive protein >5 mg/L. Anemia was indexed with reference to hemoglobin and qualified by vitamin B12 and folate status to rule out anemia unrelated to primary ID. RESULTS: The analysis included 120 patients, 68% female, 49.6 ± 9.3 years, and body mass index, 52.0 ± 9.6 kg/m2. The prevalence of absolute and functional ID was 11.7% and 30.8%, respectively (P = .0003). Anemia was associated with absolute ID and functional ID in 14.3% and 10.8% of patients (P = .29). Folate and vitamin B12 deficiency occurred in <5% of patients. CONCLUSION: In patients seeking bariatric surgery for severe obesity, the prevalence of baseline functional ID is substantial and can be associated with anemia. These findings raise queries with regard to how best to optimize preoperative iron status in the context of ongoing inflammation.