Limited proliferation capacity of aortic intima resident macrophages requires monocyte recruitment for atherosclerotic plaque progression.

Early atherosclerosis depends upon responses by immune cells resident in the intimal aortic wall. Specifically, the healthy intima is thought to be populated by vascular dendritic cells (DCs) that, during hypercholesterolemia, initiate atherosclerosis by being the first to accumulate cholesterol. Whether these cells remain key players in later stages of disease is unknown. Using murine lineage-tracing models and gene expression profiling, we reveal that myeloid cells present in the intima of the aortic arch are not DCs but instead specialized aortic intima resident macrophages (MacAIR) that depend upon colony-stimulating factor 1 and are sustained by local proliferation. Although MacAIR comprise the earliest foam cells in plaques, their proliferation during plaque progression is limited. After months of hypercholesterolemia, their presence in plaques is overtaken by recruited monocytes, which induce MacAIR-defining genes. These data redefine the lineage of intimal phagocytes and suggest that proliferation is insufficient to sustain generations of macrophages during plaque progression.

Ileitis-associated tertiary lymphoid organs arise at lymphatic valves and impede mesenteric lymph flow in response to tumor necrosis factor.

Lymphangitis and the formation of tertiary lymphoid organs (TLOs) in the mesentery are features of Crohn's disease. Here, we examined the genesis of these TLOs and their impact on disease progression. Whole-mount and intravital imaging of the ileum and ileum-draining collecting lymphatic vessels (CLVs) draining to mesenteric lymph nodes from TNFΔARE mice, a model of ileitis, revealed TLO formation at valves of CLVs. TLOs obstructed cellular and molecular outflow from the gut and were sites of lymph leakage and backflow. Tumor necrosis factor (TNF) neutralization begun at early stages of TLO formation restored lymph transport. However, robustly developed, chronic TLOs resisted regression and restoration of flow after TNF neutralization. TNF stimulation of cultured lymphatic endothelial cells reprogrammed responses to oscillatory shear stress, preventing the induction of valve-associated genes. Disrupted transport of immune cells, driven by loss of valve integrity and TLO formation, may contribute to the pathology of Crohn's disease.

The impact of endoscopist performance and patient factors on distal adenoma detection and colorectal cancer incidence.

BACKGROUND: High quality endoscopy is key for detecting and removing precursor lesions to colorectal cancer (CRC). Adenoma detection rates (ADRs) measure endoscopist performance. Improving other components of examinations could increase adenoma detection. AIMS: To investigate how endoscopist performance at flexible sigmoidoscopy (FS) affects adenoma detection and CRC incidence. METHODS: Among 34,139 participants receiving FS screening by the main endoscopist at one of 13 centres in the UK FS Screening Trial, median follow-up was 17 years. Factors examined included family history of CRC, bowel preparation quality, insertion and withdrawal time, bowel segment reached, patient pain and ADR. Odds ratios (OR) for distal adenoma detection were estimated by logistic regression. Hazard ratios (HR) for distal CRC incidence were estimated by Cox regression. RESULTS: At screening, 4,104 participants had distal adenomas detected and 168 participants developed distal CRC during follow-up. In multivariable models, a family history of CRC (yes vs. no: OR 1.40, 95%CI 1.21-1.62), good or adequate bowel preparation quality (vs. excellent: OR 0.84, 95%CI 0.74-0.95; OR 0.56, 95%CI 0.49-0.65, respectively) and longer insertion and withdrawal times (≥ 4.00 vs. < 2.00 min: OR 1.96, 95%CI 1.68-2.29; OR 32.79, 95%CI 28.22-38.11, respectively) were associated with adenoma detection. Being screened by endoscopists with low or intermediate ADRs, compared to high ADRs, was positively associated with CRC incidence (multivariable: HR 4.71, 95%CI 2.65-8.38; HR 2.16, 95%CI 1.22-3.81, respectively). CONCLUSIONS: Bowel preparation quality and longer insertion and withdrawal time are key for improving distal adenoma detection. Higher ADRs were associated with a lower risk of distal CRC.

Actigraphy measures show sleep improvement after parathyroidectomy for primary hyperparathyroidism.

IMPORTANCE: The symptoms of primary hyperparathyroidism are often subtle, such as fatigue, mood changes, and sleep disturbances. After parathyroidectomy, patients often report improvement in sleep and mood; however, objective data supporting these improvements is lacking. OBJECTIVE: This prospective study uses standard measures to objectively and subjectively assess sleep in patients with primary hyperparathyroidism before and after parathyroidectomy. DESIGN: A longitudinal prospective study was conducted over three one-week-long periods: pre-parathyroidectomy, 1-week post-parathyroidectomy, and three months post-parathyroidectomy. During each time point, patients wore an actigraphy device, recorded a sleep diary, and completed the Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), and Depression Anxiety Stress Scale (DASS). Statistical analysis was performed using repeated measures models to compare the average measures among the three time points and test for trends over time. SETTING: Single institution, tertiary care center. PARTICIPANTS: Patients with primary hyperparathyroidism from ages 18 to 89 years old. EXPOSURE: Parathyroidectomy between September 2020 and January 2024. MAIN OUTCOMES AND MEASURES: Actigraphy data, consensus sleep diary, Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), Depression Anxiety Stress Scales - 21 Items (DASS). RESULTS: Thirty-six patients were enrolled, and 34 patients completed the study. Actigraphy data showed a significant negative trend in average sleep latency (p = 0.045) and average time in bed (p = 0.046). Sleep diary data showed additional differences in the number of awakenings (p = 0.002), wake after sleep onset (p < 0.001), sleep quality (p < 0.001), and sleep efficiency (p = 0.02) among the three time points and/or as a significant negative trend. PSQI and ISI scores were significantly different among the three time points (p = 0.002 and p < 0.001, respectively) and also declined significantly over time (p = 0.008 and p = 0.007, respectively). DASS depression, anxiety, and stress scores were significantly different among the three time points (p < 0.001, p = 0.01, and p < 0.001, respectively), and stress also declined significantly over time (p = 0.005). CONCLUSION AND RELEVANCE: This study represents the most extensive prospective study demonstrating objective and subjective sleep and mood improvement in patients with primary hyperparathyroidism after parathyroidectomy.

Economic impact of implementing optical diagnosis with a "resect and discard" strategy within the English Bowel Cancer Screening Programme: findings from the DISCARD3 study.

BACKGROUND AND AIMS: Advances in endoscopic technology, such as narrow-band imaging and high-definition colonoscopes, offer the potential for optical diagnosis (OD) with a "resect and discard" (RD) strategy for diminutive (≤5 mm) and small (6-9 mm) colorectal polyps. This could help alleviate the huge cost and time burden required for histopathology. The aim of this study was to conduct an economic analysis of an RD strategy within the English Bowel Cancer Screening Programme (BCSP). METHODS: A decision tree was designed to compare an RD strategy with standard histopathology for patients included in the DISCARD3 study (Detect InSpect ChAracterise Resect and Discard 3) and was extrapolated to a national BCSP patient cohort. RESULTS: Of the 525 patients in the DISCARD3 study, 354 were assessed for surveillance intervals (after excluding cases with colorectal cancer and at least 1 polyp >10 mm). Of 354 patients, 269 had polyps, of which 182 had only diminutive polyps, 77 had both small and diminutive polyps, and 10 had only small polyps. Surveillance interval concordance was 97.9% in patients with at least 1 diminutive polyp and 98.7% in patients with at least 1 diminutive or small polyp. In DISCARD3, an RD approach was found to reduce overall direct healthcare costs by $44,285.63 (-72.3%) for patients with diminutive polyps or by $66,129.13 (-75.0%) for patients with diminutive or small polyps. When extrapolated to the entire English BCSP, the annual savings were almost $3 million for patients with diminutive polyps or $4.3 million for patients with diminutive or small polyps, after adjusting for the costs of an OD quality assurance process. CONCLUSIONS: OD with an RD strategy for diminutive and small polyps during BCSP colonoscopy would offer substantial cost savings without adversely affecting surveillance interval concordance.

NBI International Colorectal Endoscopic-derived high-confidence optical diagnosis of small polyps compared with histology: understanding errors to improve diagnostic accuracy.

BACKGROUND AND AIMS: Developments in image-enhancing endoscopy and polyp classification systems have led to a number of gastroenterology societies endorsing an optical diagnosis (OD) approach for small polyps at colonoscopy. In this study we performed a root-cause analysis of ODs to determine the most likely causes of OD error. METHODS: As part of a prospective feasibility study, DISCARD3 (Detect InSpect ChAracterise Resect and Discard 3), evaluating implementation and quality assurance of a "resect and discard" strategy for consecutive small polyps <10 mm, a root-cause analysis of 184 cases of high-confidence OD error was performed. In all cases, histopathology underwent a second blinded review and, where discrepancy persisted, further review with deeper levels. RESULTS: After a root-cause analysis, 133 of 184 true OD errors were identified and classified into 4 types: A (OD, adenoma; histology, serrated), 45/133 (33.8%); B (OD, serrated; histology, adenoma), 55/133 (41.4%); C (OD, adenoma; histology, normal), 19/133 (14.3%); and D (OD, serrated; histology, normal), 14/133 (10.5%). The remaining 51 of 184 errors were because of a pathology error requiring deeper levels (43/184), pathology observer or laboratory error (7/184), or other error (1/184). CONCLUSIONS: OD errors can be related to endoscopist-related factors such as poor photodocumentation, failures of current classification systems, and incomplete histology. We identified a subset of serrated polyps frequently misdiagnosed as adenomas ("pseudoadenomas") using the NBI International Colorectal Endoscopic (NICE) classification. An enhanced algorithm for OD is proposed based on the NICE classification including morphologic and adjunct polyp features.

Evaluation of a real-time computer-aided polyp detection system during screening colonoscopy: AI-DETECT study.

BACKGROUND: Polyp detection and resection during colonoscopy significantly reduce long-term colorectal cancer risk. Computer-aided detection (CADe) may increase polyp identification but has undergone limited clinical evaluation. Our aim was to assess the effectiveness of CADe at colonoscopy within a bowel cancer screening program (BCSP). METHODS: This prospective, randomized controlled trial involved all eight screening-accredited colonoscopists at an English National Health Service (NHS) BCSP center (February 2020 to December 2021). Patients were randomized to CADe or standard colonoscopy. Patients meeting NHS criteria for bowel cancer screening were included. The primary outcome of interest was polyp detection rate (PDR). RESULTS: 658 patients were invited and 44 were excluded. A total of 614 patients were randomized to CADe (n = 308) or standard colonoscopy (n = 306); 35 cases were excluded from the per-protocol analysis due to poor bowel preparation (n = 10), an incomplete procedure (n = 24), or a data issue (n = 1). Endocuff Vision was frequently used and evenly distributed (71.7 % CADe and 69.2 % standard). On intention-to-treat (ITT) analysis, there was a borderline significant difference in PDR (85.7 % vs. 79.7 %; P = 0.05) but no significant difference in adenoma detection rate (ADR; 71.4 % vs. 65.0 %; P = 0.09) for CADe vs. standard groups, respectively. On per-protocol analysis, no significant difference was observed in these rates. There was no significant difference in procedure times. CONCLUSIONS: In high-performing colonoscopists in a BCSP who routinely used Endocuff Vision, CADe improved PDR but not ADR. CADe appeared to have limited benefit in a BCSP setting where procedures are performed by experienced colonoscopists.

Injectable Colloidal Hydrogels of N-Vinylformamide Microgels Dispersed in Covalently Interlinked pH-Responsive Methacrylic Acid-Based Microgels.

Injectable hydrogels offer great potential to augment damaged or degenerated soft tissues. A key criterion for such gels is that their modulus is as close as possible to that of the target tissue. The majority of synthetic hydrogels have used low molecular weight polymer chains which may cause problems if they diffuse away from the injection site and/or increase the local osmotic pressure. We previously introduced a different approach of injecting preformed ultra-high molecular weight pH-responsive microgels (MGs) that interlink to form hydrogels. MGs are crosslinked polymer colloid particles that swell when the pH approaches the particle pKa. These colloidal hydrogels are termed doubly crosslinked microgels (DX MGs). The gel moduli of previous DX MGs were much greater than that reported for human nucleus pulposus (NP) tissue of the spinal intervertebral disk. Here, we replace some of the pH-responsive poly(ethyl acrylate-co-methacrylic acid) (PEA-MAA) MGs with hydrophilic non-ionic MGs based on poly(N-vinylformamide) (NVF). We investigate the morphology and mechanical properties of these new injectable composite DX MGs and show that the mechanical properties can be tuned by systematically varying the NVF MG content. Using this approach, the gel moduli close to that for NP tissue are achieved. These injectable new pH-responsive gels exhibit low cytotoxicity. Our work provides a potential new system for minimally invasive intervertebral disk augmentation.

Evaluating the Implementation of a Medical Student's Handoff Curriculum During the Surgery Clerkship.

INTRODUCTION: Early introduction to essential communication skills is important. We sought to determine if a handoff curriculum (HC) would improve confidence, decrease anxiety, and increase participation in clinical handoffs during the surgical clerkship. METHODS: A multi-center prospective cohort study was performed at two medical schools. Training in the intervention group (HC) consisted of a didactic lecture, video review, and practice session. Students completed a pre-clerkship knowledge test and confidence/anxiety/handoff experience questionnaire pre- and post-clerkship. RESULTS: There were no significant differences in pre-clerkship handoff experiences between institutions except having previously witnessed a verbal handoff (School A 96.4% versus School B 76.2%, P = 0.01). While there were no significant differences in post-clerkship confidence or anxiety, HC students were significantly more involved with written sign-outs (52.9% versus 18.2%, P = 0.02) and verbal handoffs (29.4% versus 4.6%, P = 0.03). CONCLUSIONS: Medical students exposed to handoff training shared similar confidence and anxiety scores compared to those that were not, however, they were more involved in handoff experiences during their surgical clerkship. Early introduction to handoff skills may encourage greater participation during subsequent clinical experiences.

Higher Adenoma Detection Rates at Screening Associated With Lower Long-Term Colorectal Cancer Incidence and Mortality.

BACKGROUND & AIMS: Detection and removal of adenomas reduces colorectal cancer (CRC) risk. The impact of adenoma detection rates (ADRs) on long-term CRC incidence and mortality is unknown. We investigated this using data from the UK Flexible Sigmoidoscopy Screening Trial. METHODS: Of 167,882 UK Flexible Sigmoidoscopy Screening Trial participants, 40,085 were in the intervention arm and underwent flexible sigmoidoscopy screening at 13 trial centers. The median follow-up time was 17 years. At each center, 1 endoscopist performed most flexible sigmoidoscopies. Multivariable logistic regression was used to classify centers into high-, intermediate-, and low-detector groups based on their main endoscopist's ADR. We calculated the incidence and mortality of distal and all-site CRC, and estimated hazard ratios (HRs) with 95% CIs using Cox regression. RESULTS: Five, 4, and 4 centers, respectively, were classified into the high-detector, intermediate-detector, and low-detector groups. The average ADRs in each respective group were 15%, 12%, and 9%. Distal CRC incidence and mortality were reduced among those screened compared with controls in all groups, and effects of screening varied significantly by detector ranking, with larger reductions in incidence and mortality seen in the high-detector group (incidence: HR, 0.34; 95% CI, 0.27-0.42; mortality: HR, 0.22, 95% CI, 0.13-0.37) than in the low-detector group (incidence: HR, 0.55; 95% CI, 0.44-0.68; mortality: HR, 0.54; 95% CI, 0.34-0.86). Similar results were observed for all-site CRC, with larger effects seen in the high-detector (incidence: HR, 0.58; 95% CI, 0.50-0.67; mortality: HR, 0.52; 95% CI, 0.39-0.69) than in the low-detector group (incidence: HR, 0.72; 95% CI, 0.61-0.85; mortality: HR, 0.68; 95% CI, 0.51-0.92), although the heterogeneity was not statistically significant. CONCLUSIONS: Higher ADRs at screening provide greater long-term protection against CRC incidence and mortality. Isrctn.org, number: ISRCTN28352761.

Implementation of optical diagnosis with a "resect and discard" strategy in clinical practice: DISCARD3 study.

BACKGROUND AND AIMS: Optical diagnosis (OD) of polyps can be performed with advanced endoscopic imaging. For high-confidence diagnoses, a "resect and discard" strategy could offer significant histopathology time and cost savings. The implementation threshold is a ≥90% OD-histology surveillance interval concordance. Here we assessed the OD learning curve and feasibility of a resect and discard strategy for ≤5-mm and <10-mm polyps in a bowel cancer screening setting. METHODS: In this prospective feasibility study, 8 bowel cancer screening endoscopists completed a validated OD training module and performed procedures. All <10-mm consecutive polyps had white-light and narrow-band images taken and were given high- or low-confidence diagnoses until 120 high-confidence ≤5-mm polyp diagnoses had been performed. All polyps had standard histology. High-confidence OD errors underwent root-cause analysis. Histology and OD-derived surveillance intervals were calculated. RESULTS: Of 565 invited patients, 525 patients were included. A total of 1560 <10-mm polyps underwent OD and were resected and retrieved (1329 ≤5 mm and 231 6-9 mm). There were no <10-mm polyp cancers. High-confidence OD was accurate in 81.5% of ≤5-mm and 92.8% of 6-9-mm polyps. Sensitivity for OD of a ≤5-mm adenoma was 93.0% with a positive predictive value of 90.8%. OD-histology surveillance interval concordance for ≤5-mm OD was 91.3% (209/229) for U.S. Multi-Society Task Force, 98.3% (225/229) for European Society of Gastrointestinal Endoscopy, and 98.7% (226/229) for British Society of Gastroenterology guidelines, respectively. CONCLUSIONS: A resect and discard strategy for high-confidence ≤5-mm polyp OD in a group of bowel cancer screening colonoscopists is feasible and safe, with performance exceeding the 90% surveillance interval concordance required for implementation in clinical practice. (Clinical trial registration number: NCT04710693.).

Post-polypectomy surveillance interval and advanced neoplasia detection rates: a multicenter, retrospective cohort study.

BACKGROUND: Longer post-polypectomy surveillance intervals are associated with increased colorectal neoplasia detection at surveillance in some studies. We investigated this association to inform optimal surveillance intervals. METHODS: Patients who underwent colonoscopy and post-polypectomy surveillance at 17 UK hospitals were classified as low/high risk by baseline findings. We compared detection rates of advanced adenomas (≥ 10 mm, tubulovillous/villous, high grade dysplasia), high risk findings (HRFs: ≥ 2 serrated polyps/[adenomas] of which ≥ 1 is ≥ 10 mm or has [high grade] dysplasia; ≥ 5 serrated polyps/adenomas; or ≥ 1 nonpedunculated polyp ≥ 20 mm), or colorectal cancer (CRC) at surveillance colonoscopy by surveillance interval (< 18 months, 2, 3, 4, 5, 6 years). Risk ratios (RRs) were estimated using multivariable regression. RESULTS: Of 11 214 patients, 7216 (64 %) were low risk and 3998 (36 %) were high risk. Among low risk patients, advanced adenoma, HRF, and CRC detection rates at first surveillance were 7.8 %, 3.7 %, and 1.1 %, respectively. Advanced adenoma detection increased with increasing surveillance interval, reaching 9.8 % with a 6-year interval (P trend < 0.001). Among high risk patients, advanced adenoma, HRF, and CRC detection rates at first surveillance were 15.3 %, 10.0 %, and 1.5 %, respectively. Advanced adenoma and CRC detection rates (P trends < 0.001) increased with increasing surveillance interval; RRs (95 % confidence intervals) for CRC were 1.54 (0.68-3.48), 4.44 (1.95-10.08), and 5.80 (2.51-13.40) with 3-, 4-, and 5-year intervals, respectively, versus an interval of < 18 months. CONCLUSIONS: Metachronous neoplasia was uncommon among low risk patients, even with long surveillance intervals, supporting recommendations for no surveillance in these patients. For high risk patients, a 3-year surveillance interval would ensure timely CRC detection.

Definition of competence standards for optical diagnosis of diminutive colorectal polyps: European Society of Gastrointestinal Endoscopy (ESGE) Position Statement.

BACKGROUND : The European Society of Gastrointestinal Endoscopy (ESGE) has developed a core curriculum for high quality optical diagnosis training for practice across Europe. The development of easy-to-measure competence standards for optical diagnosis can optimize clinical decision-making in endoscopy. This manuscript represents an official Position Statement of the ESGE aiming to define simple, safe, and easy-to-measure competence standards for endoscopists and artificial intelligence systems performing optical diagnosis of diminutive colorectal polyps (1 - 5 mm). METHODS : A panel of European experts in optical diagnosis participated in a modified Delphi process to reach consensus on Simple Optical Diagnosis Accuracy (SODA) competence standards for implementation of the optical diagnosis strategy for diminutive colorectal polyps. In order to assess the clinical benefits and harms of implementing optical diagnosis with different competence standards, a systematic literature search was performed. This was complemented with the results from a recently performed simulation study that provides guidance for setting alternative competence standards for optical diagnosis. Proposed competence standards were based on literature search and simulation study results. Competence standards were accepted if at least 80 % agreement was reached after a maximum of three voting rounds. RECOMMENDATION 1: In order to implement the leave-in-situ strategy for diminutive colorectal lesions (1-5 mm), it is clinically acceptable if, during real-time colonoscopy, at least 90 % sensitivity and 80 % specificity is achieved for high confidence endoscopic characterization of colorectal neoplasia of 1-5 mm in the rectosigmoid. Histopathology is used as the gold standard.Level of agreement 95 %. RECOMMENDATION 2: In order to implement the resect-and-discard strategy for diminutive colorectal lesions (1-5 mm), it is clinically acceptable if, during real-time colonoscopy, at least 80 % sensitivity and 80 % specificity is achieved for high confidence endoscopic characterization of colorectal neoplasia of 1-5 mm. Histopathology is used as the gold standard.Level of agreement 100 %. CONCLUSION : The developed SODA competence standards define diagnostic performance thresholds in relation to clinical consequences, for training and for use when auditing the optical diagnosis of diminutive colorectal polyps.

Highly Stretchable Conductive Covalent Coacervate Gels for Electronic Skin.

Highly stretchable electrically conductive hydrogels have been extensively researched in recent years, especially for applications in strain and pressure sensing, electronic skin, and implantable bioelectronic devices. Herein, we present a new cross-linked complex coacervate approach to prepare conductive hydrogels that are both highly stretchable and compressive. The gels involve a complex coacervate between carboxylated nanogels and branched poly(ethylene imine), whereby the latter is covalently cross-linked by poly(ethylene glycol) diglycidyl ether (PEGDGE). Inclusion of graphene nanoplatelets (Gnp) provides electrical conductivity as well as tensile and compressive strain-sensing capability to the hydrogels. We demonstrate that judicious selection of the molecular weight of the PEGDGE cross-linker enables the mechanical properties of these hydrogels to be tuned. Indeed, the gels prepared with a PEGDGE molecular weight of 6000 g/mol defy the general rule that toughness decreases as strength increases. The conductive hydrogels achieve a compressive strength of 25 MPa and a stretchability of up to 1500%. These new gels are both adhesive and conformal. They provide a self-healable electronic circuit, respond rapidly to human motion, and can act as strain-dependent sensors while exhibiting low cytotoxicity. Our new approach to conductive gel preparation is efficient, involves only preformed components, and is scalable.

Polysaccharide Capsules Equip the Human Symbiont Bacteroides thetaiotaomicron to Modulate Immune Responses to a Dominant Antigen in the Intestine.

Bacteria express multiple diverse capsular polysaccharides (CPSs) for protection against environmental and host factors, including the host immune system. Using a mouse TCR transgenic CD4+ T cell, BθOM, that is specific for B. thetaiotaomicron and a complete set of single CPS-expressing B. thetaiotaomicron strains, we ask whether CPSs can modify the immune responses to specific bacterial Ags. Acapsular B. thetaiotaomicron, which lacks all B. thetaiotaomicron CPSs, stimulated BθOM T cells more strongly than wild-type B. thetaiotaomicron Despite similar levels of BθOM Ag expression, many single CPS-expressing B. thetaiotaomicron strains were antistimulatory and weakly activated BθOM T cells, but a few strains were prostimulatory and strongly activated BθOM T cells just as well or better than an acapsular strain. B. thetaiotaomicron strains that expressed an antistimulatory CPS blocked Ag delivery to the immune system, which could be rescued by Fc receptor-dependent Ab opsonization. All single CPS-expressing B. thetaiotaomicron strains stimulated the innate immune system to skew toward M1 macrophages and release inflammatory cytokines in an MyD88-dependent manner, with antistimulatory CPS activating the innate immune system in a weaker manner than prostimulatory CPS. The expression of antistimulatory versus prostimulatory CPSs on outer membrane vesicles also regulated immune responses. Moreover, antistimulatory and prostimulatory single CPS-expressing B. thetaiotaomicron strains regulated the activation of Ag-specific and polyclonal T cells as well as clearance of dominant Ag in vivo. These studies establish that the immune responses to specific bacterial Ags can be modulated by a diverse set of CPSs.

Colorectal cancer risk following polypectomy in a multicentre, retrospective, cohort study: an evaluation of the 2020 UK post-polypectomy surveillance guidelines.

OBJECTIVE: Colonoscopy surveillance aims to reduce colorectal cancer (CRC) incidence after polypectomy. The 2020 UK guidelines recommend surveillance at 3 years for 'high-risk' patients with ≥2 premalignant polyps (PMPs), of which ≥1 is 'advanced' (serrated polyp (or adenoma) ≥10 mm or with (high-grade) dysplasia); ≥5 PMPs; or ≥1 non-pedunculated polyp ≥20 mm; 'low-risk' patients without these findings are instead encouraged to participate in population-based CRC screening. We examined the appropriateness of these risk classification criteria and recommendations. DESIGN: Retrospective analysis of patients who underwent colonoscopy and polypectomy mostly between 2000 and 2010 at 17 UK hospitals, followed-up through 2017. We examined CRC incidence by baseline characteristics, risk group and number of surveillance visits using Cox regression, and compared incidence with that in the general population using standardised incidence ratios (SIRs). RESULTS: Among 21 318 patients, 368 CRCs occurred during follow-up (median: 10.1 years). Baseline CRC risk factors included age ≥55 years, ≥2 PMPs, adenomas with tubulovillous/villous/unknown histology or high-grade dysplasia, proximal polyps and a baseline visit spanning 2-90 days. Compared with the general population, CRC incidence without surveillance was higher among those with adenomas with high-grade dysplasia (SIR 1.74, 95% CI 1.21 to 2.42) or ≥2 PMPs, of which ≥1 was advanced (1.39, 1.09 to 1.75). For low-risk (71%) and high-risk (29%) patients, SIRs without surveillance were 0.75 (95% CI 0.63 to 0.88) and 1.30 (1.03 to 1.62), respectively; for high-risk patients after first surveillance, the SIR was 1.22 (0.91 to 1.60). CONCLUSION: These guidelines accurately classify post-polypectomy patients into those at high risk, for whom one surveillance colonoscopy appears appropriate, and those at low risk who can be managed by non-invasive screening.

WASh multicentre randomised controlled trial: water-assisted sigmoidoscopy in English NHS bowel scope screening.

OBJECTIVES: The English Bowel Cancer Screening Programme invites 55 year olds for a sigmoidoscopy (Bowel Scope Screening (BSS)), aiming to resect premalignant polyps, thus reducing cancer incidence. A national patient survey indicated higher procedural pain than anticipated, potentially impacting on screening compliance and effectiveness. We aimed to assess whether water-assisted sigmoidoscopy (WAS), as opposed to standard CO2 technique, improved procedural pain and detection of adenomatous polyps. DESIGN: The WASh (Water-Assisted Sigmoidoscopy) trial was a multicentre, single-blind, randomised control trial for people undergoing BSS. Participants were randomised to either receive WAS or CO2 from five sites across England. The primary outcome measure was patient-reported moderate/severe pain, as assessed by patients on a standard Likert scale post procedure prior to discharge. The key secondary outcome was adenoma detection rate (ADR). The costs of each technique were also measured. RESULTS: 1123 participants (50% women, mean age 55) were randomised (561 WAS, 562 CO2). We found no difference in patient-reported moderate/severe pain between WAS and CO2 (14% in WAS, 15% in CO2; p=0.47). ADR was 15% in the CO2 arm and 11% in the WAS arm (p=0.03); however, it remained above the minimum national performance standard in both arms. There was no statistical difference in mean number of adenomas nor overall polyp detection rate. There was negligible cost difference between the two techniques. CONCLUSION: In the context of enema-prepared unsedated screening sigmoidoscopies performed by screening-accredited endoscopists, no difference in patient-reported pain was seen when using either a CO2 or WAS intubation technique. TRIAL REGISTRATION NUMBER: ISRCTN81466870.

Site-Directed Differentiation of Human Adipose-Derived Mesenchymal Stem Cells to Nucleus Pulposus Cells Using an Injectable Hydroxyl-Functional Diblock Copolymer Worm Gel.

Adipose-derived mesenchymal stem cells (ASCs) have been identified for their promising therapeutic potential to regenerate and repopulate the degenerate intervertebral disk (IVD), which is a major cause of lower back pain. The optimal cell delivery system remains elusive but encapsulation of cells within scaffolds is likely to offer a decisive advantage over the delivery of cells in solution by ensuring successful retention within the tissue. Herein, we evaluate the use of a fully synthetic, thermoresponsive poly(glycerol monomethacrylate)-poly(2-hydroxypropyl methacrylate) (PGMA-PHPMA) diblock copolymer worm gel that mimics the structure of hydrophilic glycosaminoglycans. The objective was to use this gel to direct differentiation of human ASCs toward a nucleus pulposus (NP) phenotype, with or without the addition of discogenic growth factors TGFß or GDF6. Accordingly, human ASCs were incorporated into a cold, free-flowing aqueous dispersion of the diblock copolymer, gelation induced by warming to 37 °C and cell culture was conducted for 14 days with or without such growth factors to assess the expression of characteristic NP markers compared to those produced when using collagen gels. In principle, the shear-thinning nature of the biocompatible worm gel enables encapsulated human ASCs to be injected into the IVD using a 21G needle. Moreover, we find significantly higher gene expression levels of ACAN, SOX-9, KRT8, and KR18 for ASCs encapsulated within worm gels compared to collagen scaffolds, regardless of the growth factors employed. In summary, such wholly synthetic worm gels offer considerable potential as an injectable cell delivery scaffold for the treatment of degenerate disk disease by promoting the transition of ASCs toward an NP-phenotype.

Including fluorescent nanoparticle probes within injectable gels for remote strain measurements and discrimination between compression and tension.

The ability to remotely and non-invasively monitor and measure the strain within injectable gels used to augment soft tissue is highly desirable. Such information could enable real-time monitoring of gel performance and bespoke gel design. We report progress towards this goal using two fluorescent particle probe systems included within two different injectable gels. The two injectable gels have been previously studied in the contexts of intervertebral disc repair and stretchable gels for cartilage repair. The two fluorophore particle probes are blue or near-infrared (NIR) emitting and are present at very low concentrations. The normalised photoluminescence (PL) intensity from the blue emitting probe is shown to equal the compressive deformation ratio of the gels. Furthermore, the normalised ratio of the PL intensities for the blue and NIR probes varies linearly with deformation ratio over a wide range (from 0.2 to 3.0) with a seamless transition from compression to tension. Hence, PL can discriminate between compression and tension. The new approach established here should apply to other gels and enable remote detection of whether a gel is being compressed or stretched as well as the extent. This study may provide an important step towards remotely and minimally invasively measuring the strain experienced by load-supporting gels in vivo.

Low Referral Rates for Genetic Assessment of Patients With Multiple Adenomas in United Kingdom Bowel Cancer Screening Programs.

BACKGROUND: Approximately 1 in 20 cases of colorectal cancer are caused by monogenic syndromes. Published guidelines recommend that patients with 10 or more adenomas be referred for genetic testing, based on evidence that colorectal cancer risk is associated with adenoma multiplicity. OBJECTIVE: The aim of this study was to determine adherence to guidelines on referral for genetic screening in patients with 10 or more adenomas. DESIGN: A cross-sectional study was performed of prospectively collected data from the UK Bowel Cancer Screening Programme between May 2007 and June 2018. Only histologically confirmed adenomas were included. Clinicopathological data were recorded from patient records, and referrals to clinical genetics services were ascertained. SETTING: Data were obtained from 3 centers in London, United Kingdom. PATIENTS: A total of 17,450 subjects underwent colonoscopy following an abnormal fecal occult blood test. MAIN OUTCOME MEASURES: We quantified patients with 10 or more adenomas and the proportion referred for genetic screening. RESULTS: The adenoma detection rate was 50.6% among 17,450 patients who underwent colonoscopy (8831 had 1 or more adenomas). Three hundred forty-seven patients (2.0%) had 10 or more adenomas. Patients with 10 or more adenomas were more likely to be male than those with fewer than 10 adenomas (76.9% vs 53.4%; p < 0.0001). A family history was collected in 37.8% of the multiple adenoma population. Of 347 patients with 10 or more adenomas, 28 (8.1%) were referred for genetic assessment. LIMITATIONS: All 3 screening centers were in a single city. No genetic outcome data were available to permit analysis of actual rates of inherited cancer syndromes in this population. CONCLUSIONS: In this study, almost 1 in 50 patients had 10 or more adenomas. Despite guidelines advising genetic testing in this group, referral rates are low. A referral pathway and management strategies should be established to address this patient population. See Video Abstract at http://links.lww.com/DCR/B630. TASAS BAJAS DE DERIVACIN PARA LA EVALUACIN GENTICA DE PACIENTES CON ADENOMAS MLTIPLES EN LOS PROGRAMAS DE DETECCIN DEL CNCER DE INTESTINO DEL REINO UNIDO: ANTECEDENTES:Aproximadamente uno de cada veinte casos de cáncer colorrectal son causados por síndromes monogénicos. Las pautas publicadas recomiendan que los pacientes con diez o más adenomas sean derivados para pruebas genéticas, basándose en la evidencia de que el riesgo de cáncer colorrectal está asociado con la multiplicidad de adenomas.OBJETIVO:El objetivo de este estudio fue determinar la adherencia a las guías de derivación para cribado genético en pacientes con diez o más adenomas.DISEÑO:Se realizó un estudio transversal de datos recolectados prospectivamente del Programa de Detección de Cáncer de Intestino del Reino Unido entre mayo de 2007 y junio de 2018. Solo se incluyeron los adenomas confirmados histológicamente. Los datos clínico-patológicos se registraron a partir de los registros de los pacientes y se determinaron las derivaciones a los servicios de genética clínica.AJUSTE ENTORNO CLINICO:Los datos se obtuvieron de tres centros en Londres, Reino Unido.PACIENTES:Un total de 17.450 17450 sujetos pacientes se sometieron a una colonoscopia después de una prueba de sangre oculta en heces anormal positiva.PRINCIPALES MEDIDAS DE RESULTADO VOLARACION:cuantificamos los pacientes con diez o más adenomas y la proporción remitida para cribado genético.RESULTADOS:La tasa de detección de adenomas fue del 50,6% entre 17.450 17450 pacientes que se sometieron a colonoscopia (8.831 8831 tenían uno o más adenomas). 347 pacientes (2,0%) tenían 10 o más adenomas. Los pacientes con 10 o más adenomas tenían más probabilidades de ser hombres que aquellos con menos de 10 adenomas (76,9% frente versus a 53,4%; p <0,0001). Se recogieron antecedentes familiares en el 37,8% de la población de adenomas múltiples. De 347 pacientes con 10 o más adenomas, 28 (8,1%) fueron remitidos para evaluación genética.LIMITACIONES:Los tres centros de detección se encontraban en una sola ciudad. No se disponía de datos de resultados genéticos que permitieran el análisis de las tasas reales de síndromes de cáncer hereditario en esta población.CONCLUSIONES:En este estudio, casi uno de cada cincuenta pacientes tenía diez o más adenomas. A pesar de las pautas que recomiendan las pruebas genéticas en este grupo, las tasas de derivación son bajas. Se debe establecer una vía de derivación y estrategias de manejo para abordar esta población de pacientes. Consulte Video Resumen en http://links.lww.com/DCR/B630.