Intra-colony venom diversity contributes to maintaining eusociality in a cooperatively breeding ant.

BACKGROUND: Eusociality is widely considered to evolve through kin selection, where the reproductive success of an individual's close relative is favored at the expense of its own. High genetic relatedness is thus considered a prerequisite for eusociality. While ants are textbook examples of eusocial animals, not all ants form colonies of closely related individuals. One such example is the ectatommine ant Rhytidoponera metallica, which predominantly forms queen-less colonies that have such a low intra-colony relatedness that they have been proposed to represent a transient, unstable form of eusociality. However, R. metallica is among the most abundant and widespread ants on the Australian continent. This apparent contradiction provides an example of how inclusive fitness may not by itself explain the maintenance of eusociality and raises the question of what other selective advantages maintain the eusocial lifestyle of this species. RESULTS: We provide a comprehensive portrait of the venom of R. metallica and show that the colony-wide venom consists of an exceptionally high diversity of functionally distinct toxins for an ant. These toxins have evolved under strong positive selection, which is normally expected to reduce genetic variance. Yet, R. metallica exhibits remarkable intra-colony variation, with workers sharing only a relatively small proportion of toxins in their venoms. This variation is not due to the presence of chemical castes, but has a genetic foundation that is at least in part explained by toxin allelic diversity. CONCLUSIONS: Taken together, our results suggest that the toxin diversity contained in R. metallica colonies may be maintained by a form of group selection that selects for colonies that can exploit more resources and defend against a wider range of predators. We propose that increased intra-colony genetic variance resulting from low kinship may itself provide a selective advantage in the form of an expanded pharmacological venom repertoire. These findings provide an example of how group selection on adaptive phenotypes may contribute to maintaining eusociality where a prerequisite for kin selection is diminished.

Population-Based Prevalence of Gastrointestinal Abnormalities at Colon Capsule Endoscopy.

BACKGROUND & AIMS: The population prevalence of gastrointestinal (GI) disease is unclear and difficult to assess in an asymptomatic population. The aim of this study was to determine prevalence of GI lesions in a largely asymptomatic population undergoing colon capsule endoscopy (CCE). METHODS: Participants aged between 50-75 years were retrieved from the Rotterdam Study, a longitudinal epidemiological study, between 2017-2019. Participants received CCE with bowel preparation. Abnormalities defined as clinically relevant were Barrett segment >3cm, severe ulceration, polyp >10 mm or ≥3 polyps in small bowel (SB) or colon, and cancer. RESULTS: Of 2800 invited subjects, 462 (16.5%) participants (mean age 66.8 years, female 53.5%) ingested the colon capsule. A total of 451 videos were analyzed, and in 94.7% the capsule reached the descending colon. At least 1 abnormal finding was seen in 448 (99.3%) participants. The prevalence of abnormalities per GI segment, and the most common type of abnormality, were as follows: Esophageal 14.8% (Barrett's esophagus <3 cm in 8.3%), gastric 27.9% (fundic gland polyps in 18.1%), SB abnormalities 33.9% (erosions in 23.8%), colon 93.3% (diverticula in 81.2%). A total of 54 participants (12%) had clinically relevant abnormalities, 3 (0.7%) in esophagus/stomach (reflux esophagitis grade D, Mallory Weiss lesion and severe gastritis), 5 (1.1%) in SB (polyps > 10 mm; n = 4, severe ulcer n = 1,) and 46 (10.2%) in colon (polyp > 10 mm or ≥3 polyps n = 46, colorectal cancer n = 1). CONCLUSIONS: GI lesions are very common in a mostly asymptomatic Western population, and clinically relevant lesions were found in 12% at CCE. These findings provide a frame of reference for the prevalence rates of GI lesions in the general population.

Colon capsule endoscopy in colorectal cancer screening: a systematic review.

INTRODUCTION: Primary colonoscopy and fecal immunochemical test (FIT) are the most commonly used colorectal cancer (CRC) screening modalities. Colon capsule endoscopy (CCE) might be an alternative. Data on the performance of CCE as a CRC screening tool in a screening population remain scarce. This is the first systematic review to provide an overview of the applicability of CCE as a CRC screening tool. METHODS: A systematic search was conducted of literature published up to September 2020. Studies reporting on CRC screening by second-generation CCE in an average-risk screening population were included. RESULTS: 582 studies were identified and 13 were included, comprising 2485 patients. Eight studies used CCE as a filter test after a positive FIT result and five studies used CCE for primary screening. The polyp detection rate of CCE was 24 % - 74 %. For polyps > 6 mm, sensitivity of CCE was 79 % - 96 % and specificity was 66 % - 97 %. For polyps ≥ 10 mm, sensitivity of CCE was 84 % - 97 %, which was superior to computed tomographic colonography (CTC). The CRC detection rate for completed CCEs was 93 % (25/27). Bowel preparation was adequate in 70 % - 92 % of examinations, and completion rates varied from 57 % to 92 %, depending on the booster used. No CCE-related complications were described. CONCLUSION: CCE appeared to be a safe and effective tool for the detection of CRC and polyps in a screening setting. Accuracy was comparable to colonoscopy and superior to CTC, making CCE a good alternative to colonoscopy in CRC screening programs, although completion rates require improvement.

Metachronous colorectal cancer risk according to Lynch syndrome pathogenic variant after extensive versus partial colectomy in the Netherlands: a retrospective cohort study.

BACKGROUND: Extensive colectomy (subtotal or total colectomy) is often advised for carriers of Lynch syndrome with colorectal cancer. However, the risk of metachronous colorectal cancer might differ by Lynch syndrome variant, meaning that partial colectomy, which has better functional outcomes, might be adequate for some patients with low-risk variants. We aimed to assess the risk of metachronous colorectal cancer after partial colectomy and extensive colectomy in carriers of Lynch syndrome with different pathogenic variants. METHODS: For this retrospective cohort study, carriers of Lynch syndrome with colorectal cancer in the Netherlands were identified by linkage of the Dutch Foundation for the Detection of Hereditary Tumors (StOET) database and the Dutch Nationwide Network and Registry of Histopathology and Cytopathology (PALGA) database. Data on demographics, Lynch syndrome variants, colorectal cancers, surgery types, mortality, and surveillance colonoscopies were extracted. Data on colorectal cancer and surveillance colonoscopies were updated until Feb 28, 2022. Data on survival status was updated until Feb 7, 2022. MLH1, MSH2, and EPCAM were classified as high-risk variants and MSH6 and PMS2 as low-risk variants. Patients for whom the type of surgery was unknown were excluded. Cox regression time-to-event analyses were done to assess the risk of metachronous colorectal cancer in four subgroups based on pathogenic variant (high-risk vs low-risk variants) and the extent of surgery (extensive colectomy vs partial colectomy). Sex, age at the time of primary colorectal cancer, primary colorectal cancer stage, performance of surveillance colonoscopies, adherence to the surveillance guidelines, and time period of primary colorectal cancer diagnosis were added to the model as possible confounders. Metachronous colorectal cancer was defined as colorectal cancer diagnosed more than 6 months after the primary colorectal cancer. Patients were censored at time of death or assembly of the database. FINDINGS: Of 1908 carriers of Lynch syndrome registered in StOET, 532 with a history of colorectal cancer were identified after linkage with PALGA. Five carriers were excluded because of an unknown surgery type, leaving 527 in our sample (mean age at primary colorectal cancer 48·7 years [SD 12·1]; 274 [52%] male and 253 [48%] female). 121 (23%) patients developed metachronous colorectal cancer (median time from primary colorectal cancer to metachronous colorectal cancer 11·0 years [IQR 2·1-17·8]). Metachronous colorectal cancer occurred in 12 (12%) of 97 patients with high-risk variants and extensive colectomy, in 85 (32%) of 267 patients with high-risk variants and partial colectomy, in zero (0%) of 11 patients with low-risk variants and extensive colectomy, and in 24 (16%) of 152 patients with low-risk variants and partial colectomy. Partial colectomy was associated with a higher risk of metachronous colorectal cancer than extensive colectomy in the high-risk variant group (hazard ratio 1·97, 95% CI 1·04-3·73; p=0·039). The risk of metachronous colorectal cancer did not differ between carriers of low-risk variants who had partial colectomy and those of high-risk variants who had extensive colectomy (1·14, 0·55-2·36; p=0·72). INTERPRETATION: The risk of metachronous colorectal cancer after partial colectomy in carriers of low-risk variants is similar to the risk after extensive colectomy in carriers of high-risk variants. This finding suggests that partial colectomy followed by endoscopic surveillance is an appropriate management approach to treat colorectal cancer in carriers of low-risk Lynch syndrome variants. FUNDING: None.

Unexplained mismatch repair deficiency: Case closed.

To identify Lynch syndrome (LS) carriers, DNA mismatch repair (MMR) immunohistochemistry (IHC) is performed on colorectal cancers (CRCs). Upon subsequent LS diagnostics, MMR deficiency (MMRd) sometimes remains unexplained (UMMRd). Recently, the importance of complete LS diagnostics to explain UMMRd, involving MMR methylation, germline, and somatic analyses, was stressed. To explore why some MMRd CRCs remain unsolved, we performed a systematic review of the literature and mapped patients with UMMRd diagnosed in our center. A systematic literature search was performed in Ovid Medline, Embase, Web of Science, Cochrane CENTRAL, and Google Scholar for articles on UMMRd CRCs after complete LS diagnostics published until December 15, 2021. Additionally, UMMRd CRCs diagnosed in our center since 1993 were mapped. Of 754 identified articles, 17 were included, covering 74 patients with UMMRd. Five CRCs were microsatellite stable. Upon complete diagnostics, 39 patients had single somatic MMR hits, and six an MMR germline variant of unknown significance (VUS). Ten had somatic pathogenic variants (PVs) in POLD1, MLH3, MSH3, and APC. The remaining 14 patients were the only identifiable cases in the literature without a plausible identified cause of the UMMRd. Of those, nine were suspected to have LS. In our center, complete LS diagnostics in approximately 5,000 CRCs left seven MMRd CRCs unexplained. All had a somatic MMR hit or MMR germline VUS, indicative of a missed second MMR hit. In vitually all patients with UMMRd, complete LS diagnostics suggest MMR gene involvement. Optimizing detection of currently undetectable PVs and VUS interpretation might explain all UMMRd CRCs, considering UMMRd a case closed.

Predictors of Gastrointestinal Transit Times in Colon Capsule Endoscopy.

INTRODUCTION: Optimizing the accuracy of colon capsule endoscopy (CCE) requires high completion rates. To prevent incomplete CCE, we aimed to identify predictors associated with slow CCE transit times. METHODS: In this population-based study, participants received CCE with a split-dose polyethylene glycol bowel preparation and booster regimen (0.5 L oral sulfate solution and 10 mg metoclopramide if capsule remained in stomach for > 1 hour). The following predictors were assessed: age, sex, body mass index (BMI), smoking, coffee and fiber intake, diet quality, physical activity, dyspeptic complaints, stool pattern, history of abdominal surgery, medication use, and CCE findings. Multivariable logistic and linear regressions with backward elimination were performed. RESULTS: We analyzed 451 CCE procedures with a completion rate of 51.9%. The completion rate was higher among older participants (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.04-2.28, P = 0.03) and participants with a changed stool pattern (OR 2.27, 95% CI 1.20-4.30, P = 0.01). Participants with a history of abdominal surgery had a lower completion rate (OR 0.54, 95% CI 0.36-0.80, P = 0.003). Participants with higher BMI had faster stomach, small bowel, and total transit times (ß = -0.10, P = 0.01; ß = -0.14, P = 0.001; ß = -0.12, P = 0.01). A faster small bowel transit was found in participants with a changed stool pattern (ß = -0.08, P = 0.049) and the use of metoclopramide (ß = -0.14, P = 0.001). Participants with high fiber intake had a slower colonic transit (ß = 0.11, P = 0.03). DISCUSSION: Younger age, unchanged stool pattern, history of abdominal surgery, low BMI, and high fiber intake resulted in slower CCE transit times and lower completion rates. In future practice, these factors can be considered to adjust preparation protocols.

Artificial Intelligence in Colon Capsule Endoscopy-A Systematic Review.

Background and aims: The applicability of colon capsule endoscopy in daily practice is limited by the accompanying labor-intensive reviewing time and the risk of inter-observer variability. Automated reviewing of colon capsule endoscopy images using artificial intelligence could be timesaving while providing an objective and reproducible outcome. This systematic review aims to provide an overview of the available literature on artificial intelligence for reviewing colonic mucosa by colon capsule endoscopy and to assess the necessary action points for its use in clinical practice. Methods: A systematic literature search of literature published up to January 2022 was conducted using Embase, Web of Science, OVID MEDLINE and Cochrane CENTRAL. Studies reporting on the use of artificial intelligence to review second-generation colon capsule endoscopy colonic images were included. Results: 1017 studies were evaluated for eligibility, of which nine were included. Two studies reported on computed bowel cleansing assessment, five studies reported on computed polyp or colorectal neoplasia detection and two studies reported on other implications. Overall, the sensitivity of the proposed artificial intelligence models were 86.5-95.5% for bowel cleansing and 47.4-98.1% for the detection of polyps and colorectal neoplasia. Two studies performed per-lesion analysis, in addition to per-frame analysis, which improved the sensitivity of polyp or colorectal neoplasia detection to 81.3-98.1%. By applying a convolutional neural network, the highest sensitivity of 98.1% for polyp detection was found. Conclusion: The use of artificial intelligence for reviewing second-generation colon capsule endoscopy images is promising. The highest sensitivity of 98.1% for polyp detection was achieved by deep learning with a convolutional neural network. Convolutional neural network algorithms should be optimized and tested with more data, possibly requiring the set-up of a large international colon capsule endoscopy database. Finally, the accuracy of the optimized convolutional neural network models need to be confirmed in a prospective setting.

Applicability of colon capsule endoscopy as pan-endoscopy: From bowel preparation, transit, and rating times to completion rate and patient acceptance.

Background and study aims Colon capsule endoscopy (CCE) has the potential to explore the entire gastrointestinal tract. The aim of this study was to assess the applicability of CCE as pan-endoscopy. Patients and methods Healthy participants received CCE with bowel preparation (bisacodyl, polyethylene electrolyte glycol (PEG) + ascorbic acid) and booster regimen (metoclopramide, oral sulfate solution (OSS)). For each segment of the gastrointestinal tract, the following quality parameters were assessed: cleanliness, transit times, reading times, patient acceptance and safety of the procedure. When all gastrointestinal segments had cleansing score good or excellent, cleanliness of the whole gastrointestinal tract was assessed as good. Participants' expected and perceived burden was assessed by questionnaires and participants were asked to grade the procedure (scale 0-10). All serious adverse events (SAEs) were documented. Results A total of 451 CCE procedures were analyzed. A good cleansing score was achieved in the stomach in 69.6%, in the SB in 99.1 % and in the colon in 76.6 %. Cleanliness of the whole gastrointestinal tract was good in 52.8 % of the participants. CCE median transit time of the whole gastrointestinal tract was 583 minutes IQR 303-659). The capsule reached the descending colon in 94.7 %. Median reading time per procedure was 70 minutes (IQR 57-83). Participants graded the procedure with a 7.8. There were no procedure-related SAEs. Conclusions CCE as pan-endoscopy has shown to be a safe procedure with good patient acceptance. When cleanliness of all gastrointestinal segments per patient, completion rate and reading time will be improved, CCE can be applied as a good non-invasive alternative to evaluate the gastrointestinal tract.