Development and validation of a virtual teaching method for minimally invasive surgery skills: a prospective cohort study.

INTRODUCTION: The COVID-19 pandemic led to a significant reduction in operative exposure for surgical trainees, necessitating alternative training methods to mitigate the impact on surgical education. This study sought to evaluate whether minimally invasive surgery (MIS) skills could be taught remotely using widely available technology with objective assessments of proficiency. METHODS: This was a pilot observational study with comparative assessment of face-to-face (F2F) and virtual training of novice learners in MIS skills. Performance and objective cognitive workload parameters (Surgical Task Load Index (SURG-TLX) score, heart rate and pupil metrics) were evaluated. The assessments were peg transfer (McGill Inanimate System for Training and Evaluation of Laparoscopic Skills (MISTELS)) and suturing (Suturing Training and Testing (SUTT)) tasks performed using box trainers. Virtual teaching was conducted by expert trainers using a web-based streaming platform. RESULTS: Technical challenges of delivering a virtual MIS skills course were addressed after a pilot course. Participants (n = 20) in the final course had similar baseline characteristics and were randomly allocated to F2F (n = 8) and virtual (n = 12) teaching groups. Participants in the online group completed the peg transfer task faster than the F2F group (11.25 minutes vs. 16.88 minutes; P = 0.015). There were no significant differences in all other MISTELS and SUTT performance measures between groups. Cognitive workload parameters (SURG-TLX score, heart rate and pupil metrics) were also similar between groups. CONCLUSION: This study has demonstrated that virtual teaching of MIS skills using a web-based streaming platform is feasible and effective, providing the foundation for low-cost, effective, and scalable MIS skills programs in the future.

Development and Evaluation of a Quality Assessment Tool for Laparoscopic Sleeve Gastrectomy Videos: A Review and Comparison of Academic and Online Video Resources.

BACKGROUND: Video recording of surgical procedures is increasing in popularity. They are presented in various platforms, many of which are not peer-reviewed. Laparoscopic sleeve gastrectomy (LSG) videos are widely available; however, there is limited evidence supporting the use of reporting guidelines when uploading LSG videos to create a valuable educational video. We aimed to determine the variations and establish the quality of published LSG videos, in both peer-reviewed literature and on YouTube, using a newly designed checklist to improve the quality and enhance the transparency of video reporting. METHODS: A quality assessment tool was designed by using existing research and society guidelines, such as the Bariatric Metabolic Surgery Standardization (BMSS). A systematic review using PRISMA guidelines was performed on MEDLINE and EMBASE databases to identify video case reports (academic videos) and a similar search was performed on the commercial YouTube platform (commercial videos) simultaneously. All videos displaying LSG were reviewed and scored using the quality assessment tool. Academic and commercial videos were subsequently compared and an evidence-based checklist was created. RESULTS: A total of 93 LSG recordings including 26 academic and 67 commercial videos were reviewed. Mean score of the checklist was 5/11 and 4/11 for videos published in articles and YouTube, respectively. Academic videos had higher rates of describing instruments used, such as orogastric tube (P < 0.001) and stapler information (P = 0.04). Fifty-four percent of academic videos described short-term patient outcomes, while not reported in commercial videos (P < 0.001). Sleeve resection status was not universally reported. CONCLUSIONS: Videos published in the academic literature are describing steps in greater detail with more emphasis on specific technical elements and patient outcomes and thus have a higher educational value. A new quality assessment tool has been proposed for video reporting guidelines to improve the reliability and value of published video research.

Bone health following paediatric and adolescent bariatric surgery: a systematic review and meta-analysis.

Background: Childhood obesity is a pressing health crisis of epidemic proportions. Bariatric surgery (BS) is an effective weight loss solution however its role in the paediatric population is contentious owing to the paucity of weight specific and generalised health outcomes. This systematic review and meta-analysis aimed to assess the impact of paediatric BS on bone health. Methods: This prospectively registered systematic review (PROSPERO ID: CRD42023432035) was performed in accordance with PRISMA guidelines. We searched MEDLINE (1946-1928 September 2023), EMBASE (1947-1928 September 2023) via the Ovid platform, and the Cochrane Review Library to identify scientific publications reporting bone outcome measures in patients under the age of 18 years who underwent BS. Meta-analysis was undertaken on post-operative weight and bone parameters in paediatric patients following BS. Outcomes were reported as weighted or standardized mean difference with 95 percent confidence intervals. Subgroup analysis by intervention, quality scoring and risk of bias were assessed. Findings: Twelve studies with 681 patients across 5 countries (mean age 17 ± 0.57 years) were included. The quality of included studies was rated as high and there was substantial between-study heterogeneity for most factors included in the meta-analysis (I2 from 0% to 99.1%). Patients underwent Roux-en-Y gastric bypass (RYGB, n = 216), sleeve gastrectomy (SG, n = 257), gastric band (n = 184) or intragastric balloon placement (n = 24). BS was associated with significant weight reduction, body mass index (BMI) -12.7 kg/m2 (95% CI -14.5 to -10.9, p < 0.001), with RYGB being most effective, BMI -16.58 kg/m2 (95% CI -19.6 to -13.6, p < 0.001). Patients who underwent SG or RYGB had significantly lower lumbar bone mineral density, -0.96 g/cm2 (95% CI -0.1 to -0.03, p < 0.001), Z score, -1.132 (95% CI -1.8 to -0.45, p < 0.001) and subtotal body bone mineral density, -0.7 g/cm2 (95% CI -1.2 to -0.2, p < 0.001) following surgery. This was accompanied with higher markers of bone resorption, C-terminal telopeptide of type 1 collagen 0.22 ng/ml (95% CI 0.12-0.32, p < 0.001) and osteocalcin, 10.83 ng/ml (95% CI 6.01-15.67, p < 0.001). There was a significant reduction in calcium levels following BS, -3.78 mg/dl (95% CI -6.1 to -1.5, p < 0.001) but no difference in 25-hydroxyvitamin D, phosphate, bone alkaline phosphatase, procollagen type 1 N propeptide or parathyroid hormone. Interpretation: BS effectively reduces weight in paediatric patients, but RYGB and SG may have adverse effects on bone health in the medium term. It is crucial to monitor and support bone health through appropriate nutritional supplementation and judicious follow-up. Long-term data is needed to fully understand the clinical implications of these findings on bone outcomes. Funding: Medical Research Council (MRC), United Kingdom.

Outcomes of One-Anastomosis Gastric Bypass Conversion to Roux-en-Y Gastric Bypass for Severe Obesity: A Systematic Review and Meta-analysis.

One-anastomosis gastric bypass (OAGB) is an effective procedure to treat severe obesity. However, conversion to Roux-en-Y gastric bypass (RYGB) is increasing. We therefore conducted a systematic review to determine the safety and efficacy associated with OAGB-RYGB conversion. A systematic search was conducted by three independent reviewers using Medline, Embase, and the Cochrane library following PRISMA guidelines. Six studies including 134 patients were selected who were undergoing OAGB-RYGB conversion. The most common indications were reflux (47.8%), malnutrition (31.3%), and inadequate weight loss (8.2%). Study outcomes demonstrated 100% resolution of bile reflux. Overall, there was medium-term weight gain of 0.61 BMI. OAGB to RYGB conversion leads to resolution of reflux symptoms. However, it is associated with weight regain, albeit this may be acceptable to patients to treat biliary reflux.

Prognostic and Predictive Utility of GPD1L in Human Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths worldwide. GPD1L, a member of the glycerol-3-phosphate dehydrogenase family, has emerged as a potential tumour suppressor gene, with high expression associated with a favourable prognosis in various cancers. Despite an intriguing inverse relationship observed with HCC, the precise role and underlying function of GPD1L in HCC remain poorly understood. Here, we aimed to investigate the prognostic significance, molecular characteristics, and predictive potential of GPD1L overexpression in HCC. Analysis of independent datasets revealed a significant correlation between high GPD1L expression and poor survival in HCC patients. Spatial and single cell transcriptome datasets confirmed elevated GDP1L expression in tumour tissue compared to adjacent normal tissue. GPD1L exhibited increased expression and promoter demethylation with advancing tumour stage, confirming positive selection during tumorigeneses. GPD1L overexpression was associated with metabolic dysregulation and enrichment of gene sets related to cell cycle control, epithelial-mesenchymal transition, and E2F targets. Moreover, we demonstrated an inverse correlation between GPD1L expression and therapeutic response for three therapeutic agents (PF-562271, Linsitinib, and BMS-754807), highlighting its potential as a predictive biomarker for HCC treatment outcomes. These data provide insights into the prognostic significance, molecular characteristics, and predictive potential of GPD1L in HCC.

Medium-Term Weight Loss and Remission of Comorbidities Following Endoscopic Sleeve Gastroplasty: a Systematic Review and Meta-analysis.

This systematic review and meta-analysis aimed to determine the short- and medium-term weight loss outcomes and comorbidity resolution following endoscopic sleeve gastroplasty. Our search identified 35 relevant studies containing data from 7525 patients. Overall, pooled short-term (12 months) total weight loss (TWL) was 16.2% (95% CI 13.1-19.4%) in 23 studies (n = 5659). Pooled medium-term TWL was 15.4% (95% CI 13.7-17.2%) in 10 studies (n = 4040). Diabetes resolution was 55.4% (95% CI 46-64%), hypertension resolution was 62.8% (95% CI 43-82%), dyslipidaemia resolution was 56.3% (95% CI 49-63%), and obstructive sleep apnoea resolution was 51.7% (95% CI 16.2-87.3%) in four studies (n = 480). This pooled analysis demonstrates that ESG can induce durable weight loss and resolution of obesity-associated comorbidities in patients with moderate obesity.

Vagal Nerve Therapy in the Management of Obesity: A Systematic Review and Meta-Analysis.

INTRODUCTION: The vagus nerve has an important role in satiety, metabolism, and autonomic control in upper gastrointestinal function. However, the role and effects of vagal nerve therapy on weight loss remain controversial. This systematic review and meta-analysis assessed the effects of vagal nerve therapy on weight loss, body mass index (BMI), and obesity-related conditions. METHODS: MEDLINE, EMBASE, and CINAHL databases were searched for studies up to April 2022 that reported on percentage excess weight loss (%EWL) or BMI at 12 months or remission of obesity-related conditions following vagal nerve therapy from January 2000 to April 2022. Weighted mean difference (WMD) was calculated, meta-analysis was performed using random-effects models, and between-study heterogeneity was assessed. RESULTS: Fifteen studies, of which nine were randomised controlled trials, of 1,447 patients were included. Vagal nerve therapy led to some improvement in %EWL (WMD 17.19%; 95% confidence interval [CI]: 10.94-23.44; p < 0.001) and BMI (WMD -2.24 kg/m2; 95% CI: -4.07 to -0.42; p = 0.016). There was a general improvement found in HbA1c following vagal nerve therapy when compared to no treatment given. No major complications were reported. CONCLUSIONS: Vagal nerve therapy can safely result in a mild-to-moderate improvement in weight loss. However, further clinical trials are required to confirm these results and investigate the possibility of the long-term benefit of vagal nerve therapy as a dual therapy combined with standard surgical bariatric interventions.

Gastrojejunostomy Closure Technique and Risk of Leak: an Evaluation in Ex Vivo Porcine Models.

INTRODUCTION: Roux-en-Y gastric bypass (RYGB) is one of the most commonly performed bariatric operations worldwide. Leaks following RYGB are rare, but the consequences can be devastating. Although most leaks occur at the gastrojejunostomy (GJ) anastomosis, there is a lack of data on modifiable technical factors that can reduce the risk of leaks. Therefore, we evaluated whether the leak pressure of a GJ linear stapled anastomosis is dependent on the closure technique. METHODS: Two expert surgeons constructed gastric pouches and GJ anastomoses on ex vivo porcine models in a laparoscopic simulator using 30-mm and 45-mm endoscopic staplers. The GJ anastomosis was closed using either a single layer suture, double layer suture or stapler. The endpoints were leak pressure to air insufflation, measured by two independent observers, site of leak and internal circumference of the GJ anastomosis. RESULTS: In total, 30 GJ anastomoses were constructed (30 mm, n = 15; 45 mm, n = 15). The GJ anastomosis was closed using single layer (n = 9), double layer (n = 9) and stapled techniques (n = 12). Inter-observer agreement was high. Stapled and double layer closures were more resilient than a single layer closure, with 75% (9/12) stapled closures remaining intact at < 70 mmHg. GJ stoma circumference was lower using a 30-mm stapler (64.8 mm vs 80.2 mm; p < 0.05) but independent of closure technique. The most common leak site was the corner of the closure (67%). CONCLUSION: In summary, the GJ anastomosis closure technique may be a modifiable factor to prevent anastomotic leak.

Weight loss specific to indication, remission of diabetes, and short-term complications after sleeve gastrectomy conversion to Roux-en-Y gastric bypass: a systematic review and meta-analysis.

Laparoscopic sleeve gastrectomy (SG) is the most frequently performed bariatric procedure worldwide. Long-term complications such as insufficient weight loss (IWL) and gastroesophageal reflux disease (GERD) may necessitate SG conversion to Roux-en-Y gastric bypass (RYGB). The aim of this review was to determine the indication-specific weight loss and diabetes remission after SG conversion to RYGB (STOBY). Our objective was to extract all available published data on indication for conversion, weight loss, remission of diabetes, and short-term complications after STOBY. A systematic literature search was conducted to identify studies reporting outcomes following STOBY. A random effects model was used for meta-analysis. The search identified 44 relevant studies. Overall short-term (12-mo) excess weight loss (EWL) was 54.6% (95% confidence interval [CI], 46%-63%) in 23 studies (n = 712) and total weight loss (TWL) was 19.9% (95% CI, 14%-25%) in 21 studies (n = 740). For IWL, short-term (12-mo) pooled weight loss outcomes were 53.9% EWL (95% CI, 48%-59%) in 14 studies (n = 295) and 22.7% TWL (95% CI, 17%-28%) in 12 studies (n = 219), and medium-term (2-5 yr) outcomes were 45.8% EWL (95% CI, 38%-53%) in 7 studies (n = 154) and 20.6% TWL (95% CI, 15%-26%) in 9 studies (n = 206). Overall diabetes remission was 53% (95% CI, 33%-72%), and the perioperative complication rate was 8.2% (95% CI, 7.6%-8.7%). Revisional SG conversion to RYGB for IWL can achieve good weight loss outcomes and diabetes remission.

Pancreaticoduodenectomy with right hemicolectomy for advanced malignancy: a single UK hepatopancreaticobiliary centre experience.

AIM: Locally advanced intestinal neoplasms including colon cancer may require radical en bloc pancreaticoduodenectomy and right hemicolectomy (PD-RC) to achieve curative, margin-negative resection, but the safety and benefit of this uncommon procedure has not been established. The Association of Coloproctology of Great Britain and Ireland IMPACT initiative has also highlighted a lack of awareness about current services available within the UK for patients with advanced colorectal cancer and concerns about low-volume centres managing complex cases. Thus, we aimed to review the feasibility, safety and long-term outcomes of this procedure at a single high-volume hepatopancreaticobiliary surgery unit in the UK. METHOD: A retrospective cohort study was performed using a database of all consecutive patients with intestinal cancer who had been referred to our regional advanced multidisciplinary team and undergone PD-RC in a 7-year period (2013-2020). Clinico-pathological and outcome data were reviewed. RESULTS: Ten patients (mean age 54 ± 13, 8/10 men) were identified. Final histology revealed the primary tumour sites were colon (n = 7) and duodenum (n = 3). R0 resection was achieved in all cases. The major complication rate (Clavien-Dindo ≥ 3) was 10% (1/10) with no deaths within 90 days of surgery. The Kaplan-Meier estimated 5-year overall survival was 83.3% (95% CI 58.3%-100%). Univariate survival analysis identified perineural invasion and extra-colonic origin as predictors of poor survival (log-rank P < 0.05). CONCLUSION: En bloc PD-RC for locally advanced intestinal cancer can be performed safely with a high proportion of margin-negative resections and resultant long-term survival in carefully selected patients.

Progress with Metabolomic Blood Tests for Gastrointestinal Cancer Diagnosis-An Assessment of Biomarker Translation.

There is an urgent need for cost-effective, non-invasive tools to detect early stages of gastrointestinal cancer (colorectal, gastric, and esophageal cancers). Despite many publications suggesting circulating metabolites acting as accurate cancer biomarkers, few have reached the clinic. In upper gastrointestinal cancer this is critically important, as there is no test to complement gold-standard endoscopic evaluation in patients with mild symptoms that do not meet referral criteria. Therefore, this study aimed to describe and solve this translational gap. Studies reporting diagnostic accuracy of metabolomic blood-based gastrointestinal cancer biomarkers from 2007 to 2020 were systematically reviewed and progress of each biomarker along the discovery-validation-adoption pathway was mapped. Successful biomarker translation was defined as a composite endpoint, including patent protection/FDA approval/recommendation in national guidelines. The review found 77 biomarker panels of gastrointestinal cancer, including 25 with an AUROC >0.9. All but one was stalled at the discovery phase, 9.09% were patented and none were clinically approved, confirming the extent of biomarker translational gap. In addition, there were numerous "re-discoveries," including histidine, discovered in 7 colorectal studies. Finally, this study quantitatively supports the presence of a translational gap between discovery and clinical adoption, despite clear evidence of highly performing biomarkers with significant potential clinical value.

Clinical outcomes of single-stage versus two-stage laparoscopic Roux-en-y gastric bypass in the management of obesity (BMI ≥ 50 kg/m2): a retrospective cohort study.

BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (LRYGB) in patients with obesity, BMI ≥ 50 kg/m2, can be a challenging operation. Weight loss with intra-gastric balloon (IGB) insertion prior to LRYGB may improve operative outcomes. METHODS: Between June 2000 and June 2020, patients with a BMI ≥ 50 kg/m2 underwent either IGB insertion followed by LRYGB (two-stage group), or LRYGB as the definitive bariatric procedure (single-stage group) in our institution. The two-stage procedure was adopted for high risk individuals. Primary outcome measures were percentage total weight loss (%TWL) at 24 months, length of stay and postoperative morbidity. Propensity score analysis was used to account for differences between groups. RESULTS: A total of 155 (mean age 42.9 years ± 10.60; mean BMI 54.6 kg/m2 ± 4.53) underwent either the two-stage (n = 30) or single-stage procedure (n = 125) depending on preoperative fitness. At 6 months following LRYGB, there was a significant difference in %TWL between the groups in a matched analysis (11.9% vs 23.7%, p < 0.001). At 24 months, there was no difference in %TWL (32.0% vs 34.7%, p = 0.13). Median hospital stay following LRYGB was 2.0 (1-4) days with the two-stage vs 2.0 (0-14) days for the single-stage approach (p = 0.75). There was also no significant difference in complication rates (p = 0.058) between the two groups. CONCLUSIONS: There was no difference in weight loss after one or two-stage procedures in the treatment of patients with a BMI ≥ 50 kg/m2 super obesity in a propensity score weighted analysis at 24 months. Length of stay and perioperative complications were similar for high risk patients; however, the two-stage approach was associated with delayed weight loss. Single-stage management is recommended for moderate risk patients, particularly with significant metabolic disorders, whilst two-stage approach is a safe and feasible pathway for high risk individuals.

Can surgical skills be taught using technological advances online? A comparative study of online and face-to-face surgical skills training.

INTRODUCTION: Online teaching has rapidly emerged as a viable alternative to traditional face-to-face education. How to teach surgical skills in the online environment, however, has not yet been fully established nor evaluated. METHODS: An international 1-day online surgical skills course consisting of lectures, pre-recorded virtual workshops, live demonstrations and along with surgical skills teaching in breakout rooms was organised. Based on existing learning theories, new methods were developed to deliver skills teaching online. Simultaneously, traditional in-person surgical skills teaching was also conducted and used as a benchmark. Skills development was assessed by trained demonstrators and self-reported competency scores were compared between the online and face-to-face event. RESULTS: 553 delegates from 20 different countries attended the online course. Of these, 64 were trained in breakout rooms with a 1:5 demonstrator-to-delegate ratio whilst the remaining 489 delegates participated in didactic skills development sessions. In a separate face-to-face course, 20 delegates were trained with traditional methods. Demonstrators rated the competency of delegates for suturing, tendon repair and vascular anastomosis. There was no significant difference in the competency ratings of delegates receiving online teaching or face-to-face teaching (p = 0.253, p = 0.084, p = 1.00, respectively). The development of the same skills to "articulation" were not different between formats (p = 0.841, p = 0.792, p = 1.00, respectively). Post course self-rated competency scores improved for all technical skills (p < 0.001). Small group sessions, both online and face-to-face, received higher satisfaction ratings compared to large group sessions in terms of clarity of instructions, answers to questions and demonstrator feedback. Overall feedback on teaching quality, however, was equivalent across both groups. DISCUSSION: Online teaching of surgical skills for early training years is an appropriate alternative to face-to-face teaching.

The myths of obesity.

Despite an epidemic of obesity, the availability of bariatric surgery is limited. Negative beliefs about obesity and bariatric surgery are one of the barriers to access. In this article, we address and dispel some of the common myths surrounding obesity and bariatric surgery.

The Utility of Routine Ultrasound Imaging after Elective Transplant Ureteric Stent Removal.

Background. Ureteric stent insertion during kidney transplantation reduces the incidence of major urological complications (MUCs). We evaluated whether routine poststent removal graft ultrasonography (PSRGU) was useful in detecting MUCs before they became clinically or biochemically apparent. Methods. A retrospective analysis was undertaken of clinical outcomes following elective stent removals from adult single renal transplant recipients (sRTRs) at our centre between 1 January 2011 and 31 December 2013. Results. Elective stent removal was performed for 338 sRTRs. Of these patients, 222 had routine PSRGU (median (IQR) days after stent removal = 18 (11-31)), 79 had urgent PSRGU due to clinical or biochemical indications, 12 had CT imaging, and 25 had no further renal imaging. Of the 222 sRTRs who underwent routine PSRGU, 210 (94.6%) had no change of management, three (1.4%) required repeat imaging only, and eight patients (3.6%) had incidental (nonureteric) findings. One patient (0.5%) had nephrostomy insertion as a result of routine PSRGU findings, but no ureteric stenosis was identified. Of 79 patients having urgent PSRGU after elective stent removal, three patients required transplant ureteric reimplantation. Conclusions. This analysis found no evidence that routine PSRGU at two to three weeks after elective stent removal provides any added value beyond standard clinical and biochemical monitoring.

Is the Stretta procedure as effective as the best medical and surgical treatments for gastro-oesophageal reflux disease? A best evidence topic.

A best evidence topic in surgery was written according to a structured protocol. The question addressed whether the Stretta(®) procedure is as effective as the best medical and surgical treatments for patients with symptoms of gastro-oesophageal reflux disease (GORD). One hundred and forty Stretta-related papers were identified using the reported search, of which five represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group, study type, relevant outcomes and results of these papers are tabulated. One study was a randomised controlled trial comparing Stretta with proton pump inhibitors (PPIs), and four were prospective observational studies that compared Stretta with laparoscopic fundoplication. These studies provide limited evidence that Stretta is as effective as medical therapy at controlling symptoms of GORD and may allow some patients to reduce their PPI use, but laparoscopic fundoplication appears to be more effective than Stretta though with a higher rate of adverse events. Further studies are required to determine the long-term efficacy of Stretta compared to the current best medical and surgical treatments.

Role of late gadolinium enhancement cardiovascular magnetic resonance in the risk stratification of hypertrophic cardiomyopathy.

OBJECTIVE: Myocardial fibrosis identified by late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) in patients with hypertrophic cardiomyopathy (HCM) is associated with adverse cardiovascular events, but its value as an independent risk factor for sudden cardiac death (SCD) is unknown. We investigated the role of LGE-CMR in the risk stratification of HCM. METHODS: We conducted a prospective cohort study in a tertiary referral centre. Consecutive patients with HCM (n=711, median age 56.3 years, IQR 46.7-66.6; 70.0% male) underwent LGE-CMR and were followed for a median 3.5 years. The primary end point was SCD or aborted SCD. RESULTS: Overall, 471 patients (66.2%) had myocardial fibrosis (median 5.9% of left ventricular mass, IQR: 2.2-13.3). Twenty-two (3.1%) reached the primary end point. The extent but not the presence of fibrosis was a significant univariable predictor of the primary end point (HR per 5% LGE: 1.24, 95% CI 1.06 to 1.45; p=0.007 and HR for LGE: 2.69, 95% CI 0.91 to 7.97; p=0.073, respectively). However, on multivariable analysis, only LV-EF remained statistically significant (HR: 0.92, 95% CI 0.89 to 0.95; p<0.001). For the secondary outcome of cardiovascular mortality/aborted SCD, the presence and the amount of fibrosis were significant predictors on univariable but not multivariable analysis after adjusting for LV-EF and non-sustained ventricular tachycardia. CONCLUSIONS: The amount of myocardial fibrosis was a strong univariable predictor of SCD risk. However, this effect was not maintained after adjusting for LV-EF. Further work is required to elucidate the interrelationship between fibrosis and traditional predictors of outcome in HCM.

Lineage tracing reveals multipotent stem cells maintain human adenomas and the pattern of clonal expansion in tumor evolution.

The genetic and morphological development of colorectal cancer is a paradigm for tumorigenesis. However, the dynamics of clonal evolution underpinning carcinogenesis remain poorly understood. Here we identify multipotential stem cells within human colorectal adenomas and use methylation patterns of nonexpressed genes to characterize clonal evolution. Numerous individual crypts from six colonic adenomas and a hyperplastic polyp were microdissected and characterized for genetic lesions. Clones deficient in cytochrome c oxidase (CCO(-)) were identified by histochemical staining followed by mtDNA sequencing. Topographical maps of clone locations were constructed using a combination of these data. Multilineage differentiation within clones was demonstrated by immunofluorescence. Methylation patterns of adenomatous crypts were determined by clonal bisulphite sequencing; methylation pattern diversity was compared with a mathematical model to infer to clonal dynamics. Individual adenomatous crypts were clonal for mtDNA mutations and contained both mucin-secreting and neuroendocrine cells, demonstrating that the crypt contained a multipotent stem cell. The intracrypt methylation pattern was consistent with the crypts containing multiple competing stem cells. Adenomas were epigenetically diverse populations, suggesting that they were relatively mitotically old populations. Intratumor clones typically showed less diversity in methylation pattern than the tumor as a whole. Mathematical modeling suggested that recent clonal sweeps encompassing the whole adenoma had not occurred. Adenomatous crypts within human tumors contain actively dividing stem cells. Adenomas appeared to be relatively mitotically old populations, pocketed with occasional newly generated subclones that were the result of recent rapid clonal expansion. Relative stasis and occasional rapid subclone growth may characterize colorectal tumorigenesis.