Genomic structures and regulation patterns at HPV integration sites in cervical cancer.

Human papillomavirus (HPV) integration has been implicated in transforming HPV infection into cancer, but its genomic consequences have been difficult to study using short-read technologies. To resolve the dysregulation associated with HPV integration, we performed long-read sequencing on 63 cervical cancer genomes. We identified six categories of integration events based on HPV-human genomic structures. Of all HPV integrants, defined as two HPV-human breakpoints bridged by an HPV sequence, 24% contained variable copies of HPV between the breakpoints, a phenomenon we termed heterologous integration. Analysis of DNA methylation within and in proximity to the HPV genome at individual integration events revealed relationships between methylation status of the integrant and its orientation and structure. Dysregulation of the human epigenome and neighboring gene expression in cis with the HPV-integrated allele was observed over megabase-ranges of the genome. By elucidating the structural, epigenetic, and allele-specific impacts of HPV integration, we provide insight into the role of integrated HPV in cervical cancer.

Clinical characteristics of patients undergoing primary bariatric surgery in the United Kingdom based on the National Bariatric Surgery Registry.

Baseline demographic characteristics and operations undertaken for patients having bariatric surgery in the United Kingdom are largely unknown. This study aimed to describe the profile of patients having primary bariatric surgery in the National Health Service (NHS) or by self-pay, and associated operations performed for both pathways. The National Bariatric Surgery Registry dataset for 5 years between January 2015 and December 2019 was used. 34 580 patients underwent primary bariatric surgery, of which 75.9% were NHS patients. Mean patient age and initial body mass index were significantly higher for NHS compared to self-pay patients (mean age 45.8 ± 11.3 [SD] vs. 43.0 ± 12.0 years and initial body mass index 48.0 ± 7.9 vs. 42.9 ± 7.3 kg/m2 , p < .001). NHS patients were more likely to have obesity-related complications compared to self-pay patients: prevalence of Type 2 diabetes mellitus 27.7% versus 8.3%, hypertension 37.1% versus 20.1%, obstructive sleep apnoea 27.4% versus 8.9%, severely impaired functional status 19.3% versus 13.9%, musculoskeletal pain 32.5% versus 20.1% and being on medication for depression 31.0% versus 25.9%, respectively (all p < .001). Gastric bypass was the most commonly performed primary NHS bariatric operation 57.2%, but sleeve gastrectomy predominated in self-pay patients 48.7% (both p < .001). In contrast to self-pay patients, NHS patients are receiving bariatric surgery only once they are older and at a much more advanced stage of obesity-related disease complications.

Prognostic Value of 18 F-Fluoro-Deoxyglucose-Positron Emission Tomography Volumetric Parameters in Human Papillomavirus-Related Oropharyngeal Squamous Cell Carcinoma.

BACKGROUND: This study evaluates and compares the prognostic significance of 18 F-fluoro-deoxyglucose-positron emission tomography (18 F-FDG PET) volumetric parameters in human papillomavirus-related oropharyngeal squamous cell carcinoma (OPSCC). METHODS: A retrospective review of all patients treated for OPSCC with curative intent between 2012 and 2018 was performed. Volumetric parameters analyzed included the maximum standardized uptake value (SUVmax ), SUVpeak , metabolic tumor volume (MTV), and total lesion glycolysis (TLG) in both the primary tumor and nodal metastases. Prognostic significance was determined using Cox proportional hazards models for disease-free survival (DFS) and overall survival (OS). RESULTS: Primary tumor MTV and TLG significantly correlated with both DFS and OS however the commonly reported SUVmax was not found to be predictive. Nodal measures of SUVmax , MTV, and TLG were not significant predictors of survival outcomes. CONCLUSION: A higher burden of metabolically active primary tumor as measured on volumetric 18 F-FDG PET parameters is associated with poorer DFS and OS. This improved prognostication may be used to counsel patients and select those appropriate for treatment de-escalation in the future. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:1667-1672, 2023.

The first board examination in pediatric surgery.

The inaugural certifying examination for special competence in pediatric surgery in North America was given by the American Board of Surgery (ABS) in April 1975, the day before the sixth meeting of the American Pediatric Surgical Association at a resort near San Juan, PR. The event came after failed applications before the ABS and the Advisory Board for Medical Specialties in 1957, 1961, and 1967. The specialty had matured with a scholarly publication devoted to the field (Journal of Pediatric Surgery, 1965), the establishment of standards for training and training programs (1966), and a society independent of pediatrics and devoted solely to pediatric surgery (American Pediatric Surgical Association, first meeting 1970). Harvey Beardmore had guided the successful campaign for a certificate for pediatric surgery under the aegis of the ABS that was approved in June 1972. Pediatric surgery had thus gained full recognition as a specialty of surgery. A group photograph of its participants became one of the iconic images in our specialty. Thanks to Jim and Nancy Hopkins of Windsor Heights, IA, and to their many friends and colleagues, nearly half (71 of 151) of the pediatric surgeons in the photo were identified, marking their places in the history of pediatric surgery.

Effect of Preoperative Weight Loss and Baseline Comorbidity on Short-Term Complications and Reoperations After Laparoscopic Roux-en-Y Gastric Bypass in 2,067 Patients.

PURPOSE: Decreasing popularity of Roux-en-Y gastric bypass (RYGB) in bariatric-metabolic surgery may be due to higher perceived peri-operative complications. There are few studies on whether preoperative weight loss can reduce complications or reoperations following RYGB. We investigated this using a standardised operative technique. MATERIALS AND METHODS: Retrospective single-centre study of RYGB from 2004 to 2019 using a prospective database. Preoperative behavioural management included intentional weight loss. Maximum preoperative weight, weight on the day of operation, and Obesity-Surgery Mortality Risk Score (OS-MRS) class were recorded. Short-term outcomes (post-operative stay, 30-day complication and reoperation rates) were analysed. RESULTS: In 2,067 RYGB patients (1,901 primary and 166 revisional), median preoperative total body weight loss (TWL) was 6.2% (IQR: 2.5-10.7%). The median age was 46 (interquartile range (IQR) 38-54) and 80.4% were female (n=1,661). For primary surgery, the median body mass index (BMI) was 47.6 kg/m2 (IQR: 43.1-53.3). Excluding the 100-procedure learning curve, the complication rate for primary cases was 4.4% and reoperation rate of 2.8% and one peri-operative mortality (0.06%). OS-MRS ≥2 (class B or C) predicted higher risk of complications (6.1%) compared to those with a score <2 (class A) (3.8%, p=0.021), but not reoperations. Five percent preoperative TWL did not decrease complications compared to <5% TWL. Patients with ≥10% TWL had greater baseline risk and had an increased risk of complications (6.6% vs 3.7%, p=0.017) and reoperations (4.5% vs 2.7%, p<0.001). CONCLUSIONS: RYGB performed using a standardised technique has low overall risk. The influence of preoperative weight loss on outcomes was inconsistent.

Regulation of CEACAM5 and Therapeutic Efficacy of an Anti-CEACAM5-SN38 Antibody-drug Conjugate in Neuroendocrine Prostate Cancer.

PURPOSE: Neuroendocrine prostate cancer (NEPC) is an aggressive form of castration-resistant prostate cancer (CRPC) for which effective therapies are lacking. We previously identified carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) as a promising NEPC cell surface antigen. Here we investigated the scope of CEACAM5 expression in end-stage prostate cancer, the basis for CEACAM5 enrichment in NEPC, and the therapeutic potential of the CEACAM5 antibody-drug conjugate labetuzumab govitecan in prostate cancer. EXPERIMENTAL DESIGN: The expression of CEACAM5 and other clinically relevant antigens was characterized by multiplex immunofluorescence of a tissue microarray comprising metastatic tumors from 34 lethal metastatic CRPC (mCRPC) cases. A genetically defined neuroendocrine transdifferentiation assay of prostate cancer was developed to evaluate mechanisms of CEACAM5 regulation in NEPC. The specificity and efficacy of labetuzumab govitecan was determined in CEACAM5+ prostate cancer cell lines and patient-derived xenografts models. RESULTS: CEACAM5 expression was enriched in NEPC compared with other mCRPC subtypes and minimally overlapped with prostate-specific membrane antigen, prostate stem cell antigen, and trophoblast cell surface antigen 2 expression. We focused on a correlation between the expression of the pioneer transcription factor ASCL1 and CEACAM5 to determine that ASCL1 can drive neuroendocrine reprogramming of prostate cancer which is associated with increased chromatin accessibility of the CEACAM5 core promoter and CEACAM5 expression. Labetuzumab govitecan induced DNA damage in CEACAM5+ prostate cancer cell lines and marked antitumor responses in CEACAM5+ CRPC xenograft models including chemotherapy-resistant NEPC. CONCLUSIONS: Our findings provide insights into the scope and regulation of CEACAM5 expression in prostate cancer and strong support for clinical studies of labetuzumab govitecan for NEPC.

Bariatric surgery for patients with type 2 diabetes mellitus requiring insulin: Clinical outcome and cost-effectiveness analyses.

BACKGROUND: Although bariatric surgery is well established as an effective treatment for patients with obesity and type 2 diabetes mellitus (T2DM), there exists reluctance to increase its availability for patients with severe T2DM. The aims of this study were to examine the impact of bariatric surgery on T2DM resolution in patients with obesity and T2DM requiring insulin (T2DM-Ins) using data from a national database and to develop a health economic model to evaluate the cost-effectiveness of surgery in this cohort when compared to best medical treatment (BMT). METHODS AND FINDINGS: Clinical data from the National Bariatric Surgical Registry (NBSR), a comprehensive database of bariatric surgery in the United Kingdom, were extracted to analyse outcomes of patients with obesity and T2DM-Ins who underwent primary bariatric surgery between 2009 and 2017. Outcomes for this group were combined with data sourced from a comprehensive literature review in order to develop a state-transition microsimulation model to evaluate cost-effectiveness of bariatric surgery versus BMT for patients over a 5-year time horizon. The main outcome measure for the clinical study was insulin cessation at 1-year post-surgery: relative risks (RR) summarising predictive factors were determined, unadjusted, and after adjusting for variables including age, initial body mass index (BMI), duration of T2DM, and weight loss. Main outcome measures for the economic evaluation were total costs, total quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) at willingness-to-pay threshold of GBP£20,000. A total of 2,484 patients were eligible for inclusion, of which 1,847 had 1-year follow-up data (mean age of 51 years, mean initial BMI 47.2 kg/m2, and 64% female). 67% of patients no longer required insulin at 1-year postoperatively: these rates persisted for 4 years. Roux-en-Y gastric bypass (RYGB) was associated with a higher rate of insulin cessation (71.7%) than sleeve gastrectomy (SG; 64.5%; RR 0.92, confidence interval (CI) 0.86-0.99) and adjustable gastric band (AGB; 33.6%; RR 0.45, CI 0.34-0.60; p < 0.001). When adjusted for percentage total weight loss and demographic variables, insulin cessation following surgery was comparable for RYGB and SG (RR 0.97, CI 0.90-1.04), with AGB having the lowest cessation rates (RR 0.55, CI 0.40-0.74; p < 0.001). Over 5 years, bariatric surgery was cost saving compared to BMT (total cost GBP£22,057 versus GBP£26,286 respectively, incremental difference GBP£4,229). This was due to lower treatment costs as well as reduced diabetes-related complications costs and increased health benefits. Limitations of this study include loss to follow-up of patients within the NBSR dataset and that the time horizon for the economic analysis is limited to 5 years. In addition, the study reflects current medical and surgical treatment regimens for this cohort of patients, which may change. CONCLUSIONS: In this study, we observed that in patients with obesity and T2DM-Ins, bariatric surgery was associated with high rates of postoperative cessation of insulin therapy, which is, in turn, a major driver of overall reductions in direct healthcare cost. Our findings suggest that a strategy utilising bariatric surgery for patients with obesity and T2DM-Ins is cost saving to the national healthcare provider (National Health Service (NHS)) over a 5-year time horizon.

Single cell transcriptomes of normal endometrial derived organoids uncover novel cell type markers and cryptic differentiation of primary tumours.

Endometrial carcinoma, the most common gynaecological cancer, develops from endometrial epithelium which is composed of secretory and ciliated cells. Pathologic classification is unreliable and there is a need for prognostic tools. We used single cell sequencing to study organoid model systems derived from normal endometrial endometrium to discover novel markers specific for endometrial ciliated or secretory cells. A marker of secretory cells (MPST) and several markers of ciliated cells (FAM92B, WDR16, and DYDC2) were validated by immunohistochemistry on organoids and tissue sections. We performed single cell sequencing on endometrial and ovarian tumours and found both secretory-like and ciliated-like tumour cells. We found that ciliated cell markers (DYDC2, CTH, FOXJ1, and p73) and the secretory cell marker MPST were expressed in endometrial tumours and positively correlated with disease-specific and overall survival of endometrial cancer patients. These findings suggest that expression of differentiation markers in tumours correlates with less aggressive disease, as would be expected for tumours that retain differentiation capacity, albeit cryptic in the case of ciliated cells. These markers could be used to improve the risk stratification of endometrial cancer patients, thereby improving their management. We further assessed whether consideration of MPST expression could refine the ProMiSE molecular classification system for endometrial tumours. We found that higher expression levels of MPST could be used to refine stratification of three of the four ProMiSE molecular subgroups, and that any level of MPST expression was able to significantly refine risk stratification of the copy number high subgroup which has the worst prognosis. Taken together, this shows that single cell sequencing of putative cells of origin has the potential to uncover novel biomarkers that could be used to guide management of cancers. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Dissociation of solid tumor tissues with cold active protease for single-cell RNA-seq minimizes conserved collagenase-associated stress responses.

BACKGROUND: Single-cell RNA sequencing (scRNA-seq) is a powerful tool for studying complex biological systems, such as tumor heterogeneity and tissue microenvironments. However, the sources of technical and biological variation in primary solid tumor tissues and patient-derived mouse xenografts for scRNA-seq are not well understood. RESULTS: We use low temperature (6 °C) protease and collagenase (37 °C) to identify the transcriptional signatures associated with tissue dissociation across a diverse scRNA-seq dataset comprising 155,165 cells from patient cancer tissues, patient-derived breast cancer xenografts, and cancer cell lines. We observe substantial variation in standard quality control metrics of cell viability across conditions and tissues. From the contrast between tissue protease dissociation at 37 °C or 6 °C, we observe that collagenase digestion results in a stress response. We derive a core gene set of 512 heat shock and stress response genes, including FOS and JUN, induced by collagenase (37 °C), which are minimized by dissociation with a cold active protease (6 °C). While induction of these genes was highly conserved across all cell types, cell type-specific responses to collagenase digestion were observed in patient tissues. CONCLUSIONS: The method and conditions of tumor dissociation influence cell yield and transcriptome state and are both tissue- and cell-type dependent. Interpretation of stress pathway expression differences in cancer single-cell studies, including components of surface immune recognition such as MHC class I, may be especially confounded. We define a core set of 512 genes that can assist with the identification of such effects in dissociated scRNA-seq experiments.

Diagnostic conundrum: simultaneous gallstone ileus and a gas-filled inguinal hernia in a patient with lower abdominal pain.

Gallstone ileus and small bowel diverticulosis are uncommon pathologies. However, the simultaneous presentation of both in this patient provided a diagnostic puzzle for the surgical and radiological teams at our institution. The imaging also demonstrated several typical features for the pathologies in question. Ultimately the management of the patient was not compromised by the diagnostic dilemma, but the imaging findings represent a useful learning opportunity for all radiologists and general surgeons.

Drug-encapsulated carbon (DECON): A novel platform for enhanced drug delivery.

Current drug-delivery systems are designed primarily for parenteral applications and are either lipid or polymer drug conjugates. In our quest to inhibit herpes simplex virus infection via the compounds found in commonly used cosmetic products, we found that activated carbon particles inhibit infection and, in addition, substantially improve topical delivery and, hence, the efficacy of a common antiviral drug, acyclovir (ACV). Our in vitro studies demonstrate that highly porous carbon structures trapped virions, blocked infection and substantially improved efficacy when ACV was loaded onto them. Also, using murine models of corneal and genital herpes infections, we show that the topical use of drug-encapsulated carbon (DECON) reduced dosing frequency, shortened treatment duration, and exhibited higher therapeutic efficacy than currently approved topical or systemic antivirals alone. DECON is a nontoxic, cost-effective and nonimmunogenic alternative to current topical drug-delivery systems that is uniquely triggered for drug release by virus trapping.

Effects of 'pre-fracking' operations on ambient air quality at a shale gas exploration site in rural North Yorkshire, England.

Rural observations of air quality and meteorological parameters (NOx, O3, NMHCs, SO2, PM) were made over a 2.5-year period (2016-2018) before, during and after preparations for hydraulic fracturing (fracking) at a shale gas exploration site near Kirby Misperton, North Yorkshire, England. As one of the first sites to apply for permits to carry out hydraulic fracturing, it has been subject to extensive regulatory and public scrutiny, as well as the focus for a major programme of long-term environmental monitoring. A baseline period of air quality monitoring (starting 2016) established the annual climatology of atmospheric composition against which a 20-week period of intensive activity on the site in preparation for hydraulic fracturing could be compared. During this 'pre-operational phase' of work in late 2017, the most significant effect was an increase in ambient NO (3-fold) and NOx (2-fold), arising from a combination of increased vehicle activity and operation of equipment on site. Although ambient NOx increased, air quality limit values for NO2 were not exceeded, even close to the well-site. Local ozone concentrations during the pre-operational period were slightly lower than the baseline phase due to titration with primary emitted NO. The activity on site did not lead to significant changes in airborne particulate matter or non-methane hydrocarbons. Hydraulic fracturing of the well did not subsequently take place and the on-site equipment was decommissioned and removed. Air quality parameters then returned to the original (baseline) climatological conditions. This work highlights the need to characterise the full annual climatology of air quality parameters against which short-term local activity changes can be compared. Based on this study, changes to ambient NOx appear to be the most significant air quality ahead of hydraulic fracturing. However, in rural locations, concentrations at individual sites are expected to be below ambient air quality limit thresholds.

Single-stage conversions from failed gastric band to sleeve gastrectomy versus Roux-en-Y gastric bypass: results from the United Kingdom National Bariatric Surgical Registry.

BACKGROUND: For patients in whom laparoscopic adjustable gastric band has failed, conversion to Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy are both options for further surgical treatment. There are limited data comparing these 2 procedures. The National Bariatric Surgery Registry is a comprehensive United Kingdom-wide database of bariatric procedures, in which preoperative demographic characteristics and clinical outcomes are prospectively recorded. OBJECTIVES: To compare perioperative complication rate and short-term outcomes of patients undergoing single-stage conversion of gastric band to Roux-en-Y gastric bypass or laparoscopic sleeve gastrectomy. SETTING: United Kingdom national bariatric surgery database. METHODS: From the National Bariatric Surgical Registry data set, we identified 141 patients undergoing single-stage conversion from gastric band to either gastric bypass (113) or sleeve gastrectomy (28) between 2009 and 2014, and analyzed their clinical outcomes. RESULTS: With respect to perioperative outcomes gastric bypass was associated with a higher incidence of readmission or reintervention postoperatively (16 versus 0; P = .04). There was no difference in percentage excess weight loss between sleeve gastrectomy and gastric bypass at final follow-up at 1 year (52.1% versus 57.1% respectively; P = .4). CONCLUSIONS: Conversion from band to sleeve or bypass give comparable good early excess weight loss; however, conversion to sleeve is associated with a better perioperative safety profile.

Herpes Simplex Virus 1 Infection Promotes the Growth of a Subpopulation of Tumor Cells in Three-Dimensional Uveal Melanoma Cultures.

Herpes simplex virus 1 (HSV-1)-mediated oncolytic therapy is an emerging cancer treatment modality with potential effectiveness against a variety of malignancies. To better understand the interaction of HSV-1 with neoplastic cells, we inoculated three-dimensional (3D) cultures of human uveal melanoma cells with HSV-1. 3D melanoma cultures were established by placing tumor cells on the surface of a Matrigel matrix, which was followed by the growth of tumor cells on the matrix surface and invasion of the Matrigel matrix by some tumor cells to form multicellular tumor spheroids within the matrix. When established 3D melanoma cultures were inoculated with HSV-1 by placing virus on the surface of cultures, virus infection caused extensive death of melanoma cells growing on the surface of the 3D matrix and significantly decreased the number of tumor cell spheroids within the matrix. However, HSV-1 infection did not lead to a complete destruction of tumor cells in the 3D cultures during a 17-day observation period and, surprisingly, HSV-1 infection promoted the growth of some melanoma cells within the matrix as determined by the significantly increased size of residual viable multicellular tumor spheroids in virus-inoculated 3D cultures at 17 days after virus inoculation. Acyclovir treatment inhibited HSV-1-induced tumor cell killing but did not block the virus infection-induced increase in spheroid size. These findings suggest that although HSV-1 oncolytic virotherapy may cause extensive tumor cell killing, it may also be associated with the unintended promotion of the growth of some tumor cells.IMPORTANCE Cancer cells are exposed to HSV-1 during oncolytic virotherapy with the intention of killing tumor cells. Our observations reported here suggest that potential dangers of HSV-1 oncolytic therapy include promotion of growth of some tumor cells. Furthermore, our findings raise the possibility that HSV-1 infection of neoplastic cells during natural infections or vaccinations may promote the growth of tumors. Our study indicates that HSV-1 infection of 3D tumor cell cultures provides an experimental platform in which mechanisms of HSV-1-mediated promotion of tumor cell growth can be effectively studied.

Obesity surgery makes patients healthier and more functional: real world results from the United Kingdom National Bariatric Surgery Registry.

BACKGROUND: The National Bariatric Surgery Registry (NBSR) is the largest bespoke database in the field in the United Kingdom. OBJECTIVES: Our aim was to analyze the NBSR to determine whether the effects of obesity surgery on associated co-morbidities observed in small randomized controlled clinical trials could be replicated in a "real life" setting within U.K. healthcare. SETTING: United Kingdom. METHODS: All NBSR entries for operations between 2000 and 2015 with associated demographic and co-morbidity data were analyzed retrospectively. RESULTS: A total of 50,782 entries were analyzed. The patients were predominantly female (78%) and white European with a mean age of 45 ± 11 years and a mean body mass index of 48 ± 8 kg/m2. Over 5 years of follow-up, statistically significant reductions in the prevalence of type 2 diabetes, hypertension, dyslipidemia, sleep apnea, asthma, functional impairment, arthritis, and gastroesophageal reflux disease were observed. The "remission" of these co-morbidities was evident 1 year postoperatively and reached a plateau 2 to 5 years after surgery. Obesity surgery was particularly effective on functional impairment and diabetes, almost doubling the proportion of patients able to climb 3 flights of stairs and halving the proportion of patients with diabetes related hyperglycemia compared with preoperatively. Surgery was safe with a morbidity of 3.1% and in-hospital mortality of .07% and a reduced median inpatient stay of 2 days, despite an increasingly sick patient population. CONCLUSIONS: Obesity surgery in the U.K. results not only in weight loss, but also in substantial improvements in obesity-related co-morbidities. Appropriate support and funding will help improve the quality of the NBSR data set even further, thus enabling its use to inform healthcare policy.

EndoBarrier®: a Safe and Effective Novel Treatment for Obesity and Type 2 Diabetes?

BACKGROUND AND AIMS: Obesity associated with diabetes mellitus is a significant worldwide problem associated with considerable health care costs. Whilst surgical intervention is effective, it is invasive, costly and associated with complications. This study aims to evaluate the safety and efficacy of the EndoBarrier®, a duodenal-jejunal sleeve bypass as an alternative treatment of diabetes mellitus in obese patients. MATERIALS AND METHODS: This was a multi-centre, non-randomised trial recruiting obese patients with type 2 diabetes from three sites in the UK. Eligible participants had a BMI of 30-50 kg/m2 and HbA1c levels of 7.5-10%. The study comprised a 12-month period with the EndoBarrier® inserted and a 6-month follow-up period after it had been explanted. The primary study outcomes were weight, BMI, HbA1c levels and fasting insulin and glucose levels. RESULTS: Forty-five patients were recruited and 31 patients (69%) completed the 12-month study period. Significant reductions in weight (95%CI 0.62-29.38; p < 0.05) and BMI (95%CI 1.1-8.7; p < 0.005) were documented 12 months after device insertion. The mean HbA1c was significantly reduced (95%CI 0.1-1.6; p < 0.05) after the device insertion period and reductions in metabolic parameters (fasting insulin and glucose levels) were also documented during the study. Adverse events were also assessed in all patients, the vast majority of which were reported as mild. CONCLUSIONS: The EndoBarrier® appears to be a safe and effective treatment strategy in overweight patients with poor glycaemic control despite medical therapy, or in those who are eligible but decline bariatric surgery.

ANRIL Promoter DNA Methylation: A Perinatal Marker for Later Adiposity.

Experimental studies show a substantial contribution of early life environment to obesity risk through epigenetic processes. We examined inter-individual DNA methylation differences in human birth tissues associated with child's adiposity. We identified a novel association between the level of CpG methylation at birth within the promoter of the long non-coding RNA ANRIL (encoded at CDKN2A) and childhood adiposity at age 6-years. An association between ANRIL methylation and adiposity was also observed in three additional populations; in birth tissues from ethnically diverse neonates, in peripheral blood from adolescents, and in adipose tissue from adults. Additionally, CpG methylation was associated with ANRIL expression in vivo, and CpG mutagenesis in vitro inhibited ANRIL promoter activity. Furthermore, CpG methylation enhanced binding to an Estrogen Response Element within the ANRIL promoter. Our findings demonstrate that perinatal methylation at loci relevant to gene function may be a robust marker of later adiposity, providing substantial support for epigenetic processes in mediating long-term consequences of early life environment on human health.

A Core Outcome Set for the Benefits and Adverse Events of Bariatric and Metabolic Surgery: The BARIACT Project.

BACKGROUND: Bariatric and metabolic surgery is used as a treatment for patients with severe and complex obesity. However, there is a need to improve outcome selection and reporting in bariatric surgery trials. A Core Outcome Set (COS), an agreed minimum set of outcomes reported in all studies of a specific condition, may achieve this. Here, we present the development of a COS for BARIAtric and metabolic surgery Clinical Trials-the BARIACT Study. METHODS AND FINDINGS: Outcomes identified from systematic reviews and patient interviews informed a questionnaire survey. Patients and health professionals were surveyed three times and asked to rate the importance of each item on a 1-9 scale. Delphi methods provided anonymised feedback to participants. Items not meeting predefined criteria were discarded between rounds. Remaining items were discussed at consensus meetings, held separately with patients and professionals, where the COS was agreed. Data sources identified 2,990 outcomes, which were used to develop a 130-item questionnaire. Round 1 response rates were moderate but subsequently improved to above 75% for other rounds. After rounds 2 and 3, 81 and 14 items were discarded, respectively, leaving 35 items for discussion at consensus meetings. The final COS included nine items: "weight," "diabetes status," "cardiovascular risk," "overall quality of life (QOL)," "mortality," "technical complications of the specific operation," "any re-operation/re-intervention," "dysphagia/regurgitation," and "micronutrient status." The main limitation of this study was that it was based in the United Kingdom only. CONCLUSIONS: The COS is recommended to be used as a minimum in all trials of bariatric and metabolic surgery. Adoption of the COS will improve data synthesis and the value of research data. Future work will establish methods for the measurement of the outcomes in the COS.