Somatic mutation rates scale with lifespan across mammals.

The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans1-7. Comparative analyses can shed light on the diversity of mutagenesis across species, and on long-standing hypotheses about the evolution of somatic mutation rates and their role in cancer and ageing. Here we performed whole-genome sequencing of 208 intestinal crypts from 56 individuals to study the landscape of somatic mutation across 16 mammalian species. We found that somatic mutagenesis was dominated by seemingly endogenous mutational processes in all species, including 5-methylcytosine deamination and oxidative damage. With some differences, mutational signatures in other species resembled those described in humans8, although the relative contribution of each signature varied across species. Notably, the somatic mutation rate per year varied greatly across species and exhibited a strong inverse relationship with species lifespan, with no other life-history trait studied showing a comparable association. Despite widely different life histories among the species we examined-including variation of around 30-fold in lifespan and around 40,000-fold in body mass-the somatic mutation burden at the end of lifespan varied only by a factor of around 3. These data unveil common mutational processes across mammals, and suggest that somatic mutation rates are evolutionarily constrained and may be a contributing factor in ageing.

Somatic mutation landscapes at single-molecule resolution.

Somatic mutations drive the development of cancer and may contribute to ageing and other diseases1,2. Despite their importance, the difficulty of detecting mutations that are only present in single cells or small clones has limited our knowledge of somatic mutagenesis to a minority of tissues. Here, to overcome these limitations, we developed nanorate sequencing (NanoSeq), a duplex sequencing protocol with error rates of less than five errors per billion base pairs in single DNA molecules from cell populations. This rate is two orders of magnitude lower than typical somatic mutation loads, enabling the study of somatic mutations in any tissue independently of clonality. We used this single-molecule sensitivity to study somatic mutations in non-dividing cells across several tissues, comparing stem cells to differentiated cells and studying mutagenesis in the absence of cell division. Differentiated cells in blood and colon displayed remarkably similar mutation loads and signatures to their corresponding stem cells, despite mature blood cells having undergone considerably more divisions. We then characterized the mutational landscape of post-mitotic neurons and polyclonal smooth muscle, confirming that neurons accumulate somatic mutations at a constant rate throughout life without cell division, with similar rates to mitotically active tissues. Together, our results suggest that mutational processes that are independent of cell division are important contributors to somatic mutagenesis. We anticipate that the ability to reliably detect mutations in single DNA molecules could transform our understanding of somatic mutagenesis and enable non-invasive studies on large-scale cohorts.

Partnering With Food Pantries to Disseminate and Implement Eating Disorder Interventions.

OBJECTIVE: Food insecurity is associated with eating disorder psychopathology. This Spotlight describes why food pantries could be promising partners for disseminating and implementing eating disorder interventions. METHOD: Researchers are increasingly collaborating with community-based organizations to improve access to health interventions, because community-based organizations overcome structural barriers to traditional healthcare by being embedded physically in the communities they serve, convenient to visit, regularly frequented, and led by trusted community members. RESULTS: We describe strategies we have identified with our partner to disseminate and implement our digital intervention for binge eating; we also discuss ways we support the pantry's needs to improve the mutuality of the partnership. DISCUSSION: The potential benefits of partnerships with food pantries make this an area to explore further. Future research directions include deeply engaging with food pantries to determine how pantries benefit from disseminating and implementing eating disorder interventions and how to intervene in non-stigmatizing ways, what resources they need to sustainably support these efforts, what eating disorder intervention modalities guests are willing and able to engage with, what intervention adaptations are needed so individuals with food insecurity can meaningfully engage in eating disorder intervention, and what implementation strategies facilitate uptake to intervention sustainably over time.

Evolution and lineage dynamics of a transmissible cancer in Tasmanian devils.

Devil facial tumour 1 (DFT1) is a transmissible cancer clone endangering the Tasmanian devil. The expansion of DFT1 across Tasmania has been documented, but little is known of its evolutionary history. We analysed genomes of 648 DFT1 tumours collected throughout the disease range between 2003 and 2018. DFT1 diverged early into five clades, three spreading widely and two failing to persist. One clade has replaced others at several sites, and rates of DFT1 coinfection are high. DFT1 gradually accumulates copy number variants (CNVs), and its telomere lengths are short but constant. Recurrent CNVs reveal genes under positive selection, sites of genome instability, and repeated loss of a small derived chromosome. Cultured DFT1 cell lines have increased CNV frequency and undergo highly reproducible convergent evolution. Overall, DFT1 is a remarkably stable lineage whose genome illustrates how cancer cells adapt to diverse environments and persist in a parasitic niche.

Searching for transmissible cancers among the mussels of Europe.

Transmissible cancers are infectious malignant cell clones that spread among individuals through transfer of living cancer cells. Several such clones have been identified in various species of marine bivalve molluscs, including mussels, clams and cockles. These parasitic cell lineages cause a leukaemia-like disease called disseminated neoplasia, and are presumed to pass between hosts by ingestion of water-borne cancer cells during filter feeding. Although occasional cases of transmissible cancer had previously been identified in mussels of the genus Mytilus in Europe, the number of distinct clones affecting these animals, and their prevalence, was unknown. In this issue of Molecular Ecology, Hammel et al. (2021) present findings from a large-scale screen for transmissible cancer across 5907 European Mytilus mussels. Using a genotyping approach, Hammel et al. searched for signal of genetic chimerism, which can arise due to infection by transmissible cancer cells. The screen detected a previously identified globally distributed mussel transmissible cancer at very low prevalence, and found no evidence of additional contagious clones. A parallel histological screen additionally revealed low prevalence of a nontransmissible form of disseminated neoplasia. By quantifying the burden of disseminated neoplasia in European mussel populations, this study provides strong foundations for future work investigating the origins, evolution and impacts of transmissible cancers in mussels.

Location-specific psychosocial and environmental correlates of physical activity and sedentary time in young adolescents: preliminary evidence for location-specific approaches from a cross-sectional observational study.

BACKGROUND: A better understanding of the extent to which psychosocial and environmental correlates of physical activity are specific to locations would inform intervention optimization. PURPOSE: To investigate cross-sectional associations of location-general and location-specific variables with physical activity and sedentary time in three common locations adolescents spend time. METHODS: Adolescents (N = 472,Mage = 14.1,SD = 1.5) wore an accelerometer and global positioning systems (GPS) tracker and self-reported on psychosocial (e.g., self-efficacy) and environmental (e.g., equipment) factors relevant to physical activity and sedentary time. We categorized each survey item based on whether it was specific to a location to generate psychosocial and environmental indices that were location-general or specific to either school, non-school, or home location. Physical activity (MVPA) and sedentary time were based on time/location match to home, school, or all "other" locations. Mixed-effects models investigated the relation of each index with location-specific activity. RESULTS: The location-general and non-school physical activity psychosocial indices were related to greater MVPA at school and "other" locations. The school physical activity environment index was related to greater MVPA and less sedentary time at school. The home activity environment index was related to greater MVPA at home. The non-school sedentary psychosocial index was related to less sedentary time at home. Interactions among indices revealed adolescents with low support on one index benefited (i.e., exhibited more optimal behavior) from high support on another index (e.g., higher scores on the location-general PA psychosocial index moderated lower scores on the home PA environment index). Concurrent high support on two indices did not provide additional benefit. CONCLUSIONS: No psychosocial or environment indices, including location-general indices, were related to activity in all locations. Most of the location-specific indices were associated with activity in the matching location(s). These findings provide preliminary evidence that psychosocial and environmental correlates of activity are location specific. Future studies should further develop location-specific measures and evaluate these constructs and whether interventions may be optimized by targeting location-specific psychosocial and environmental variables across multiple locations.

Computational approaches for discovery of mutational signatures in cancer.

The accumulation of somatic mutations in a genome is the result of the activity of one or more mutagenic processes, each of which leaves its own imprint. The study of these DNA fingerprints, termed mutational signatures, holds important potential for furthering our understanding of the causes and evolution of cancer, and can provide insights of relevance for cancer prevention and treatment. In this review, we focus our attention on the mathematical models and computational techniques that have driven recent advances in the field.

LigaSure™ haemorrhoidectomy and the risk of postoperative bleeding.

AIM: LigaSure™ is an electro-surgical device that has increasingly been utilized in haemorrhoid surgery. However, recent literature has highlighted a possible increased risk of delayed postoperative bleeding following LigaSure haemorrhoidectomy (LH). We aim to evaluate the rates of postoperative bleeding following LigaSure compared to Ferguson (closed) haemorrhoidectomy (FH). METHODS: A retrospective cohort study was undertaken at our single academic safety-net county hospital from August 2016 through July 2019 evaluating patients who received FH or LH. Patient demographics, surgical data, postoperative emergency department visit for pain or bleeding within 30 days and resulting transfusion requirement, and rates of readmission and interventions within 30 days were collected. RESULTS: Sixty-one FH and 66 LH patients were identified. The groups had no difference in demographics. The LH group and FH group had similar rates of postoperative emergency department visits (29% vs. 23%, P = 0.454), as well as visits for bleeding (20% vs. 11%, P = 0.204). The average operating time was also significantly shorter with LH (14.5 min vs. 24.9 min, P ≤ 0.001). On multivariate analysis, male sex (OR 7.28, 95% CI 1.88-28.25) and haemorrhoid grade ≤2 (OR 4.64, 95% CI 1.31-16.49) were significantly associated with postoperative bleeding on multivariate analysis. Use of LH was not independently associated with postoperative bleeding risk (OR 1.89, 95% CI 0.70-5.11). CONCLUSIONS: LH and FH have similar risks for postoperative bleeding and other complications. Male sex and haemorrhoid Grades 1 or 2 may be associated with increased postoperative bleeding risk. Excisional haemorrhoidectomy should be undertaken with caution for male patients with lower internal haemorrhoid grades.

Outcomes of colostomy takedown following Hartmann's procedure: successful restoration of continuity comes with a high risk of morbidity.

AIM: Restoration of bowel continuity following a Hartmann's procedure is a major surgical undertaking associated with significant morbidity. The aim of this study was to review the authors' experience with Hartmann's reversal. METHOD: This was a retrospective review of consecutive patients from institutional databases who were selected to undergo open or laparoscopic Hartmann's reversal at two tertiary academic referral centres and a public safety net hospital (2010-2019). The main outcome measure was the rate of successful stoma reversal. Secondary outcomes included 30-day postoperative outcomes and procedural details. RESULTS: One hundred and fifty patients underwent attempted reversal during the study period, which was successful in all but three patients (98%). Patients were 59% Hispanic and 73% male, with a mean age of 48.7 ± 14.1 years, mean American Society of Anesthesiologists classification of 2.2 ± 0.6 and mean body mass index (BMI) of 28.6 ± 5.3 kg/m2 , with 39% of patients having a BMI > 30 kg/m2 . The mean time interval between the index procedure and reversal was 14.4 months, 53% of the index cases were performed at outside institutions and the most common index diagnoses were diverticulitis (54%), abdominal trauma (16%) and colorectal malignancy (15%). In 22% of cases a laparoscopic approach was used, with 42% of these requiring conversion to open. Proximal diverting stomas were created in 32 patients (21%), of which 94% were reversed. The overall morbidity rate was 54%, comprising ileus (32%), wound infection (15%) and anastomotic leak (6%), with a major morbidity rate (Clavien-Dindo ≥ 3) of 23%. CONCLUSION: Hartmann's reversal remains a highly morbid procedure. Our results suggest that operative candidates can be successfully reversed, but there is significant morbidity associated with restoration of intestinal continuity, particularly in obese patients. A laparoscopic approach may decrease morbidity in selected patients but such cases have a high conversion rate.

Meta-Analysis of Adherence Promotion Interventions in Pediatric Asthma.

BACKGROUND: Youth with asthma commonly have suboptimal adherence to inhaled corticosteroids (ICS). It is critical to systematically evaluate the effectiveness of ICS adherence promotion interventions and discern which techniques are most effective. OBJECTIVE: This study aims to (1) quantify the extent to which interventions improve ICS adherence in pediatric asthma, (2) explore differences in effect size estimates based on intervention and study characteristics, and (3) characterize the risk of bias across interventions. METHODS: We conducted literature searches across five databases. Included studies quantitatively measured ICS adherence as an intervention outcome among youth (<18 years old) diagnosed with asthma and were published after 1997. We analyzed aggregate effect sizes and moderator variables using random-effects models and characterized risk of bias using the Cochrane Collaboration tool. RESULTS: Thirty-three unique studies met inclusion criteria. At post-intervention, the aggregate effect size for pediatric ICS adherence promotion interventions was small but significant (n = 33, g = 0.39, 95% confidence interval [CI] = 0.24-0.54); however, the aggregate effect size at follow-up was not statistically significant (n = 6, g = 0.38, 95% CI = -0.08 to 0.83). Method of adherence measurement and intervention format were significant moderators. Most interventions had a high risk of performance bias and an unclear risk of bias in one or more domains. CONCLUSIONS: ICS adherence promotion interventions are effective among youth with asthma. Additional longitudinal research is needed to quantify a more precise measure of intervention effectiveness over time, and moderators of intervention effectiveness should be reassessed as the literature base expands.

Adaptive mHealth Intervention for Adolescent Physical Activity Promotion.

OBJECTIVE: The present nonrandomized controlled trial aimed to evaluate feasibility, acceptability, and preliminary efficacy of a tailored text message intervention for increasing adolescent physical activity, as compared with passive monitoring. METHODS: Forty adolescents (13-18 years old) received either a tailored text messaging intervention (Network Underwritten Dynamic Goals Engine [NUDGE]; N = 20), or participated in an attention-control condition (N = 20), for 20 days. Physical activity was measured for all participants via continuous accelerometry. Frequency analyses were conducted on program usage and satisfaction ratings to evaluate feasibility and acceptability, and multilevel models were used to evaluate the efficacy hypotheses. RESULTS: The vast majority of participants (90%) reported being very or mostly satisfied with the NUDGE program and rated their enjoyment as above average. The intervention group was estimated to spend an average of 20.84 more minutes per day in moderate-to-vigorous physical activity relative to the attention-control group (ß = 20.84, SE = 8.19). Exploratory analyses revealed that the intervention group also engaged in 82 fewer minutes of sedentary time per day on average, although this effect was not significant due to the large variability in sedentary time (ß = -81.98, SE = 46.86). CONCLUSIONS: The NUDGE tailored text messaging intervention was feasible, acceptable, and efficacious in increasing physical activity in this sample. Findings warrant additional evaluation of NUDGE as both a standalone physical activity intervention or as part of a multicomponent package.

Differences in adolescent activity and dietary behaviors across home, school, and other locations warrant location-specific intervention approaches.

BACKGROUND: Investigation of physical activity and dietary behaviors across locations can inform "setting-specific" health behavior interventions and improve understanding of contextual vulnerabilities to poor health. This study examined how physical activity, sedentary time, and dietary behaviors differed across home, school, and other locations in young adolescents. METHODS: Participants were adolescents aged 12-16 years from the Baltimore-Washington, DC and the Seattle areas from a larger cross-sectional study. Participants (n = 472) wore an accelerometer and Global Positioning Systems (GPS) tracker (Mean days = 5.12, SD = 1.62) to collect location-based physical activity and sedentary data. Participants (n = 789) completed 24-h dietary recalls to assess dietary behaviors and eating locations. Spatial analyses were performed to classify daily physical activity, sedentary time patterns, and dietary behaviors by location, categorized as home, school, and "other" locations. RESULTS: Adolescents were least physically active at home (2.5 min/hour of wear time) and school (2.9 min/hour of wear time) compared to "other" locations (5.9 min/hour of wear time). Participants spent a slightly greater proportion of wear time in sedentary time when at school (41 min/hour of wear time) than at home (39 min/hour of wear time), and time in bouts lasting ≥30 min (10 min/hour of wear time) and mean sedentary bout duration (5 min) were highest at school. About 61% of daily energy intake occurred at home, 25% at school, and 14% at "other" locations. Proportionately to energy intake, daily added sugar intake (5 g/100 kcal), fruits and vegetables (0.16 servings/100 kcal), high calorie beverages (0.09 beverages/100 kcal), whole grains (0.04 servings/100 kcal), grams of fiber (0.65 g/100 kcal), and calories of fat (33 kcal/100 kcal) and saturated fat (12 kcal/100 kcal) consumed were nutritionally least favorable at "other" locations. Daily sweet and savory snacks consumed was highest at school (0.14 snacks/100 kcal). CONCLUSIONS: Adolescents' health behaviors differed based on the location/environment they were in. Although dietary behaviors were generally more favorable in the home and school locations, physical activity was generally low and sedentary time was higher in these locations. Health behavior interventions that address the multiple locations in which adolescents spend time and use location-specific behavior change strategies should be explored to optimize health behaviors in each location.

Current Advances in Colorectal Surgery in Latin America: Insights on the 2019 Latin American Association of Coloproctology Congress.

The Latin American Association of Coloproctology (ALACP) held its 26 biennial congress in conjunction with the 44 annual meeting of the Mexican Society of Surgeons of the Rectum, Colon, and Anus (SMCRCA). The meeting took place October 2 to 5, 2019, in Cancun, Mexico. Twenty-eight international professors from North America, Europe, and Asia participated alongside 62 speakers from all of Latin America and the Caribbean. More than 400 participants converged from North, Central, and South America; the Caribbean; Europe; and Asia. Participants included 63 residents from Latin America, Europe, and Asia who contributed an unprecedented number of poster presentations. The meeting was highly interactive, consisting of 1 day of 5 highly dynamic workshops and 3 days of plenary sessions covering a broad spectrum of topics within colorectal surgery. Authoritative lectures by world leaders were punctuated by debates, panel discussions, and presentations of problem cases that delighted the audience. ALACP accomplished transformative changes in its general assembling meetings set into motion by its 26 presidency. These accomplishments included the first reformation of its bylaws in over a quarter century, an official affiliation with Diseases of the Colon & Rectum, and the relocation of the ALACP Secretariat General from Rio de Janeiro to Mexico City.

Idiopathic Pruritus Ani and Acute Perianal Dermatitis.

This article reviews the etiologies, pathophysiology, clinical evaluation, and treatment of idiopathic pruritus ani and perianal dermatitis. It underscores a practical approach to each of these common proctologic conditions.

Mycotic and Bacterial Infections.

This article reviews the salient clinical features, evaluation, and treatment of mycotic and bacterial infections of the perianal and contiguous zones of the human body.

Systemic and Autoimmune Diseases.

This article reviews the clinical features of systemic and autoimmune diseases affecting the perianal region and its surrounding integumentary structures.

Selected Techniques of Anal Fistula Surgery from Antiquity Through the Early 20th Century Illustrated.

This article highlights surgical approaches to the surgical treatment of anal fistula from antiquity to the early 20th century. Primary translations and other authoritative commentaries on the subject are included. Selected surgical techniques have been reconstructed and illustrated in contemporary interpreted images.

IonGAP: integrative bacterial genome analysis for Ion Torrent sequence data.

UNLABELLED: We introduce IonGAP, a publicly available Web platform designed for the analysis of whole bacterial genomes using Ion Torrent sequence data. Besides assembly, it integrates a variety of comparative genomics, annotation and bacterial classification routines, based on the widely used FASTQ, BAM and SRA file formats. Benchmarking with different datasets evidenced that IonGAP is a fast, powerful and simple-to-use bioinformatics tool. By releasing this platform, we aim to translate low-cost bacterial genome analysis for microbiological prevention and control in healthcare, agroalimentary and pharmaceutical industry applications. AVAILABILITY AND IMPLEMENTATION: IonGAP is hosted by the ITER's Teide-HPC supercomputer and is freely available on the Web for non-commercial use at http://iongap.hpc.iter.es. CONTACT: mcolesan@ull.edu.es or cflores@ull.edu.es SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.