Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer.

Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.

Reducing overdose deaths among persons with opioid use disorder in connecticut.

BACKGROUND: People in Connecticut are now more likely to die of a drug-related overdose than a traffic accident. While Connecticut has had some success in slowing the rise in overdose death rates, substantial additional progress is necessary. METHODS: We developed, verified, and calibrated a mechanistic simulation of alternative overdose prevention policy options, including scaling up naloxone (NLX) distribution in the community and medications for opioid use disorder (OUD) among people who are incarcerated (MOUD-INC) and in the community (MOUD-COM) in a simulated cohort of people with OUD in Connecticut. We estimated how maximally scaling up each option individually and in combinations would impact 5-year overdose deaths, life-years, and quality-adjusted life-years. All costs were assessed in 2021 USD, employing a health sector perspective in base-case analyses and a societal perspective in sensitivity analyses, using a 3% discount rate and 5-year and lifetime time horizons. RESULTS: Maximally scaling NLX alone reduces overdose deaths 20% in the next 5 years at a favorable incremental cost-effectiveness ratio (ICER); if injectable rather than intranasal NLX was distributed, 240 additional overdose deaths could be prevented. Maximally scaling MOUD-COM and MOUD-INC alone reduce overdose deaths by 14% and 6% respectively at favorable ICERS. Considering all permutations of scaling up policies, scaling NLX and MOUD-COM together is the cost-effective choice, reducing overdose deaths 32% at ICER $19,000/QALY. In sensitivity analyses using a societal perspective, all policy options were cost saving and overdose deaths reduced 33% over 5 years while saving society $338,000 per capita over the simulated cohort lifetime. CONCLUSIONS: Maximally scaling access to naloxone and MOUD in the community can reduce 5-year overdose deaths by 32% among people with OUD in Connecticut under realistic budget scenarios. If societal cost savings due to increased productivity and reduced crime costs are considered, one-third of overdose deaths can be reduced by maximally scaling all three policy options, while saving money.

Use of Deep Learning to Evaluate Tumor Microenvironmental Features for Prediction of Colon Cancer Recurrence.

Deep learning may detect biologically important signals embedded in tumor morphologic features that confer distinct prognoses. Tumor morphologic features were quantified to enhance patient risk stratification within DNA mismatch repair (MMR) groups using deep learning. Using a quantitative segmentation algorithm (QuantCRC) that identifies 15 distinct morphologic features, we analyzed 402 resected stage III colon carcinomas [191 deficient (d)-MMR; 189 proficient (p)-MMR] from participants in a phase III trial of FOLFOX-based adjuvant chemotherapy. Results were validated in an independent cohort (176 d-MMR; 1,094 p-MMR). Association of morphologic features with clinicopathologic variables, MMR, KRAS, BRAFV600E, and time-to-recurrence (TTR) was determined. Multivariable Cox proportional hazards models were developed to predict TTR. Tumor morphologic features differed significantly by MMR status. Cancers with p-MMR had more immature desmoplastic stroma. Tumors with d-MMR had increased inflammatory stroma, epithelial tumor-infiltrating lymphocytes (TIL), high-grade histology, mucin, and signet ring cells. Stromal subtype did not differ by BRAFV600E or KRAS status. In p-MMR tumors, multivariable analysis identified tumor-stroma ratio (TSR) as the strongest feature associated with TTR [HRadj 2.02; 95% confidence interval (CI), 1.14-3.57; P = 0.018; 3-year recurrence: 40.2% vs. 20.4%; Q1 vs. Q2-4]. Among d-MMR tumors, extent of inflammatory stroma (continuous HRadj 0.98; 95% CI, 0.96-0.99; P = 0.028; 3-year recurrence: 13.3% vs. 33.4%, Q4 vs. Q1) and N stage were the most robust prognostically. Association of TSR with TTR was independently validated. In conclusion, QuantCRC can quantify morphologic differences within MMR groups in routine tumor sections to determine their relative contributions to patient prognosis, and may elucidate relevant pathophysiologic mechanisms driving prognosis. SIGNIFICANCE: A deep learning algorithm can quantify tumor morphologic features that may reflect underlying mechanisms driving prognosis within MMR groups. TSR was the most robust morphologic feature associated with TTR in p-MMR colon cancers. Extent of inflammatory stroma and N stage were the strongest prognostic features in d-MMR tumors. TIL density was not independently prognostic in either MMR group.

Effects of Eimeria acervulina infection on the luminal and mucosal microbiota of the cecum and ileum in broiler chickens.

Coccidiosis, an intestinal disease caused by Eimeria parasites, is responsible for major losses in the poultry industry by impacting chicken health. The gut microbiota is associated with health factors, such as nutrient exchange and immune system modulation, requiring understanding on the effects of Eimeria infection on the gut microbiota. This study aimed to determine the effects of Eimeria acervulina infection on the luminal and mucosal microbiota of the cecum (CeL and CeM) and ileum (IlL and IlM) at multiple time points (days 3, 5, 7, 10, and 14) post-infection. E. acervulina infection decreased evenness in CeL microbiota at day 10, increased richness in CeM microbiota at day 3 before decreasing richness at day 14, and decreased richness in IlL microbiota from day 3 to 10. CeL, CeM, and IlL microbiota differed between infected and control birds based on beta diversity at varying time points. Infection reduced relative abundance of bacterial taxa and some predicted metabolic pathways known for short-chain fatty acid production in CeL, CeM, and IlL microbiota, but further understanding of metabolic function is required. Despite E. acervulina primarily targeting the duodenum, our findings demonstrate the infection can impact bacterial diversity and abundance in the cecal and ileal microbiota.

Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk.

BACKGROUND: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk. METHODS: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated. RESULTS: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10-8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%-4.0%) vs 6.1% (5.7%-6.5%) (difference 2.4%, P-value = 1.83 × 10-14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%-1.8%) vs 2.2% (1.9%-2.4%) (difference 0.6%, P-value = 1.01 × 10-3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk. CONCLUSIONS: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.

Sex hormones and risk of lung and colorectal cancers in women: a Mendelian randomization study.

The roles of sex hormones such as estradiol, testosterone, and sex hormone-binding globulin (SHBG) in the etiology of lung and colorectal cancers in women, among the most common cancers after breast cancer, are unclear. This Mendelian randomization (MR) study evaluated such potential causal associations in women of European ancestry. We used summary statistics data from genome-wide association studies (GWASs) on sex hormones and from the Trøndelag Health (HUNT) Study and large consortia on cancers. There was suggestive evidence of genetically predicted 1-standard deviation increase in total testosterone levels being associated with a lower risk of lung non-adenocarcinoma (hazard ratio (HR) 0.60, 95% CI 0.37-0.98) in the HUNT Study. However, this was not confirmed by using data from a larger consortium. In general, we did not find convincing evidence to support a causal role of sex hormones on risk of lung and colorectal cancers in women of European ancestry.

Associations between pathological features and risk of metachronous colorectal cancer.

Survivors of colorectal cancer (CRC) are at risk of developing another primary colorectal cancer - metachronous CRC. Understanding which pathological features of the first tumour are associated with risk of metachronous CRC might help tailor existing surveillance guidelines. Population-based CRC cases were recruited from the United States, Canada and Australia between 1997 and 2012 and followed prospectively until 2022 by the Colon Cancer Family Registry. Metachronous CRC was defined as a new primary CRC diagnosed at least 1 year after the initial CRC. Those with the genetic cancer predisposition Lynch syndrome or MUTYH mutation carriers were excluded. Cox regression models were fitted to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the associations. Of 6085 CRC cases, 138 (2.3%) were diagnosed with a metachronous CRC over a median follow-up time of 12 years (incidence: 2.0 per 1000 person-years). CRC cases with a synchronous CRC were 3.4-fold more likely to develop a metachronous CRC (adjusted HR: 3.36, 95% CI: 1.89-5.98) than those without a synchronous tumour. CRC cases with MMR-deficient tumours had a 72% increased risk of metachronous CRC (adjusted HR: 1.72, 95% CI: 1.11-2.64) compared to those with MMR-proficient tumours. Compared to cases who had an adenocarcinoma histologic type, those with an undifferentiated histologic type were 77% less likely to develop a metachronous CRC (adjusted HR: 0.23, 95% CI: 0.06-0.94). Existing surveillance guidelines for CRC survivors could be updated to include increased surveillance for those whose first CRC was diagnosed with a synchronous CRC or was MMR-deficient.

Should I Take Aspirin? (SITA): RCT of a decision aid for cancer chemoprevention.

Background Australian guidelines recommend that all people aged 50-70 years old consider taking low-dose aspirin to reduce the risk of colorectal cancer (CRC). Aim To determine the effect of a consultation with a researcher in general practice using a decision aid about taking low-dose aspirin to prevent CRC on informed decision-making and low-dose aspirin uptake compared to a general CRC prevention brochure. Design and Setting Individually randomised controlled trial in six general practices in Victoria, Australia, from October 2020 to March 2021. Method Patients aged 50-70 years attending a general practitioner (GP) were recruited consecutively. The intervention was a consultation using a decision aid to discuss taking aspirin to reduce CRC risk; control consultations discussed reducing CRC risk generally. The self-reported co-primary outcomes were informed choices about taking aspirin at one month and low-dose aspirin uptake at six months. Results 261 participants (86% of eligible patients) were randomised into trial arms (129 intervention, 132 control). 17.7% (20/113) of intervention and 7.6% (9/118) control participants reported making an informed choice at one month, an estimated 9.1% (95% CI 0.29% to 18.5) between-arm difference in proportions [odds ratio (OR) 2.47 (97.5% CI:0.94 to 6.52) p=0.074]. The proportions of individuals who reported using aspirin at six months were: 10.2% (12/118) intervention vs 13.8% (16/116) control (estimated between-arm difference: -4.0% (95% CI: -13.5 to 5.5); [OR= 0.68 (97.5% CI:0.27 to 1.70), p= 0.692]. Conclusion The decision aid improved informed decision-making; but has little effect on long-term regular use of aspirin to reduce CRC risk.

Breast and bowel cancers diagnosed in people 'too young to have cancer': A blueprint for research using family and twin studies.

Young breast and bowel cancers (e.g., those diagnosed before age 40 or 50 years) have far greater morbidity and mortality in terms of years of life lost, and are increasing in incidence, but have been less studied. For breast and bowel cancers, the familial relative risks, and therefore the familial variances in age-specific log(incidence), are much greater at younger ages, but little of these familial variances has been explained. Studies of families and twins can address questions not easily answered by studies of unrelated individuals alone. We describe existing and emerging family and twin data that can provide special opportunities for discovery. We present designs and statistical analyses, including novel ideas such as the VALID (Variance in Age-specific Log Incidence Decomposition) model for causes of variation in risk, the DEPTH (DEPendency of association on the number of Top Hits) and other approaches to analyse genome-wide association study data, and the within-pair, ICE FALCON (Inference about Causation from Examining FAmiliaL CONfounding) and ICE CRISTAL (Inference about Causation from Examining Changes in Regression coefficients and Innovative STatistical AnaLysis) approaches to causation and familial confounding. Example applications to breast and colorectal cancer are presented. Motivated by the availability of the resources of the Breast and Colon Cancer Family Registries, we also present some ideas for future studies that could be applied to, and compared with, cancers diagnosed at older ages and address the challenges posed by young breast and bowel cancers.

Aqueous Ozone Exposure Inhibits Sporulation in the Cyclospora cayetanensis Surrogate Eimeria acervulina.

Ozone is a potent disinfecting agent used to treat potable water and wastewater, effectively clearing protozoa such as Giardia and Cryptosporidium spp. It is unclear whether ozone treatment of water or fresh produce can reduce the spread of the emerging parasite Cyclospora cayetanensis, which causes cyclosporiasis in humans. Obtaining viable C. cayetanensis oocysts to evaluate inactivation methods is challenging because we lack the means to propagate them in vitro, because of delays in case reporting, and because health departments typically add inactivating fixatives to clinical specimens. Research in various surrogate organisms has sought to bolster understanding of the biology of C. cayetanensis. Among these surrogates is the poultry parasite Eimeria acervulina, a closely related and easily cultured parasite of economic significance. We used this surrogate to evaluate the consequences of ozone treatment, using the sporulation state as an indicator of infectious potential. Treating with ozonated water acidified with citric acid reduced sporulation ability in a dose-dependent manner; treatment with up to 4.93 mg/L initial concentration of ozone resulted in a 93% inactivation of sporulation by 7 days posttreatment. This developmental arrest was accompanied by transcriptional changes in genes involved in regulating the response to reactive oxygen species (ROS) in a time course that is consistent with the production of oxygen free radicals. This study shows that ozone is highly effective in preventing sporulation of E. acervulina, a model coccidian used as a surrogate for Cyclospora. Furthermore, ozone exposure induced molecular responses to general oxidative stress, documented with several well-characterized antioxidant enzymes.

Young Children and the Creation of a Digital Identity on Social Networking Sites: Scoping Review.

BACKGROUND: There is limited understanding of the concept of the digital identity of young children created through engagement on social networking sites. OBJECTIVE: The objective of this scoping review was to identify key characteristics of the concept of digital identity for children from conception to the age of 8 years on social networking sites. METHODS: This scoping review was conducted using the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines. The key databases searched were EBSCO, Web of Science, ProQuest ERIC, and Scopus. Gray literature sources (National Grey Literature Collection, ProQuest Dissertations and Theses, and Google Scholar) were also searched to identify unpublished studies. Articles were selected if they were published in English and reported data on the digital identity of children in relation to social networking sites. RESULTS: The key terms used in the literature were sharenting, followed by digital footprints and children's identities. Our study revealed 2 approaches to the creation of digital identity: social digital identity and performative digital identity. The articles in this review most commonly used the term sharenting to describe the behavior parents engage in to create digital identities for children on social networking sites. Motivations to post information about children differed among parents; however, the most common reasons were to share with friends and family and create digital archives of childhood photos, termed social digital identity. The second motivation was categorized as performative digital identity. The risk of digital kidnapping and identity theft associated with the creation of digital identities also influenced parents' behaviors. CONCLUSIONS: The creation of a digital identity for children is an emerging concept. Our review develops a deeper understanding of sharenting behaviors that can be used to better support parents and their children in creating a digital identity with children and awareness of the potential future impact. We recommend that future studies explore the perspectives of children as key stakeholders in the creation of their digital identity.

Body size and risk of colorectal cancer molecular defined subtypes and pathways: Mendelian randomization analyses.

BACKGROUND: Obesity has been positively associated with most molecular subtypes of colorectal cancer (CRC); however, the magnitude and the causality of these associations is uncertain. METHODS: We used Mendelian randomization (MR) to examine potential causal relationships between body size traits (body mass index [BMI], waist circumference, and body fat percentage) with risks of Jass classification types and individual subtypes of CRC (microsatellite instability [MSI] status, CpG island methylator phenotype [CIMP] status, BRAF and KRAS mutations). Summary data on tumour markers were obtained from two genetic consortia (CCFR, GECCO). FINDINGS: A 1-standard deviation (SD:5.1 kg/m2) increment in BMI levels was found to increase risks of Jass type 1MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype (odds ratio [OR]: 2.14, 95% confidence interval [CI]: 1.46, 3.13; p-value = 9 × 10-5) and Jass type 2non-MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype CRC (OR: 2.20, 95% CI: 1.26, 3.86; p-value = 0.005). The magnitude of these associations was stronger compared with Jass type 4non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-wildtype CRC (p-differences: 0.03 and 0.04, respectively). A 1-SD (SD:13.4 cm) increment in waist circumference increased risk of Jass type 3non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-mutated (OR 1.73, 95% CI: 1.34, 2.25; p-value = 9 × 10-5) that was stronger compared with Jass type 4 CRC (p-difference: 0.03). A higher body fat percentage (SD:8.5%) increased risk of Jass type 1 CRC (OR: 2.59, 95% CI: 1.49, 4.48; p-value = 0.001), which was greater than Jass type 4 CRC (p-difference: 0.03). INTERPRETATION: Body size was more strongly linked to the serrated (Jass types 1 and 2) and alternate (Jass type 3) pathways of colorectal carcinogenesis in comparison to the traditional pathway (Jass type 4). FUNDING: Cancer Research UK, National Institute for Health Research, Medical Research Council, National Institutes of Health, National Cancer Institute, American Institute for Cancer Research, Brigham and Women's Hospital, Prevent Cancer Foundation, Victorian Cancer Agency, Swedish Research Council, Swedish Cancer Society, Region Västerbotten, Knut and Alice Wallenberg Foundation, Lion's Cancer Research Foundation, Insamlingsstiftelsen, Umeå University. Full funding details are provided in acknowledgements.

Epidemiologic Factors in Relation to Colorectal Cancer Risk and Survival by Genotoxic Colibactin Mutational Signature.

BACKGROUND: The genotoxin colibactin causes a tumor single-base substitution (SBS) mutational signature, SBS88. It is unknown whether epidemiologic factors' association with colorectal cancer risk and survival differs by SBS88. METHODS: Within the Genetic Epidemiology of Colorectal Cancer Consortium and Colon Cancer Family Registry, we measured SBS88 in 4,308 microsatellite stable/microsatellite instability low tumors. Associations of epidemiologic factors with colorectal cancer risk by SBS88 were assessed using multinomial regression (N = 4,308 cases, 14,192 controls; cohort-only cases N = 1,911), and with colorectal cancer-specific survival using Cox proportional hazards regression (N = 3,465 cases). RESULTS: 392 (9%) tumors were SBS88 positive. Among all cases, the highest quartile of fruit intake was associated with lower risk of SBS88-positive colorectal cancer than SBS88-negative colorectal cancer [odds ratio (OR) = 0.53, 95% confidence interval (CI) 0.37-0.76; OR = 0.75, 95% CI 0.66-0.85, respectively, Pheterogeneity = 0.047]. Among cohort studies, associations of body mass index (BMI), alcohol, and fruit intake with colorectal cancer risk differed by SBS88. BMI ≥30 kg/m2 was associated with worse colorectal cancer-specific survival among those SBS88-positive [hazard ratio (HR) = 3.40, 95% CI 1.47-7.84], but not among those SBS88-negative (HR = 0.97, 95% CI 0.78-1.21, Pheterogeneity = 0.066). CONCLUSIONS: Most epidemiologic factors did not differ by SBS88 for colorectal cancer risk or survival. Higher BMI may be associated with worse colorectal cancer-specific survival among those SBS88-positive; however, validation is needed in samples with whole-genome or whole-exome sequencing available. IMPACT: This study highlights the importance of identification of tumor phenotypes related to colorectal cancer and understanding potential heterogeneity for risk and survival.

Increasing bowel cancer screening using SMS in general practice: the SMARTscreen cluster randomised trial.

BACKGROUND: Australia has one of the highest incidences of colorectal cancer (CRC) worldwide. The Australian National Bowel Cancer Screening Program (NBCSP) is a best-practice, organised screening programme, but uptake is low (40.9%) and increasing participation could reduce morbidity and mortality associated with CRC. Endorsement by GPs is strongly associated with increasing screening uptake. AIM: This study (SMARTscreen) aimed to test whether a multi-intervention short message service (SMS) sent by general practices to 50-60-year-old patients who were due to receive the NBCSP kit would increase NBCSP uptake, by comparing it with usual care. DESIGN AND SETTING: A stratified cluster randomised controlled trial was undertaken, involving 21 Australian general practices in Western Victoria, Australia. METHOD: For intervention practices, people due to receive the NBCSP kit within a 6-month study period were sent an SMS just before receiving the kit. The SMS included a personalised message from the person's general practice endorsing the kit, a motivational narrative video, an instructional video, and a link to more information. Control practices continued with usual care, comprising at-home testing with a faecal immunochemical test (FIT) through the NBCSP. The primary outcome was the between-arm percentage difference in uptake of FIT screening within 12 months from randomisation, which was estimated using generalised linear model regression. RESULTS: In total, 39.2% (1143/2914) of people in 11 intervention practices and 23.0% (583/2537) of people in 10 control practices had a FIT result in their electronic health records - a difference of 16.5% (95% confidence interval = 2.02 to 30.9). CONCLUSION: The SMS intervention increased NBCSP kit return in 50-60-year-old patients in general practice. This finding informed a larger trial - SMARTERscreen - to test this intervention in a broader Australian population.

Intratumoral presence of the genotoxic gut bacteria pks+ E. coli, Enterotoxigenic Bacteroides fragilis, and Fusobacterium nucleatum and their association with clinicopathological and molecular features of colorectal cancer.

BACKGROUND: This study aimed to investigate clinicopathological and molecular tumour features associated with intratumoral pks+ Escherichia coli (pks+E.coli+), pks+E.coli- (non-E.coli bacteria harbouring the pks island), Enterotoxigenic Bacteroides fragilis (ETBF) and Fusobacterium nucleatum (F. nucleatum). METHODS: We screened 1697 tumour-derived DNA samples from the Australasian Colorectal Cancer Family Registry, Melbourne Collaborative Cohort Study and the ANGELS study using targeted PCR. RESULTS: Pks+E.coli+ was associated with male sex (P < 0.01) and APC:c.835-8 A > G somatic mutation (P = 0.03). The association between pks+E.coli+ and APC:c.835-8 A > G was specific to early-onset CRCs (diagnosed<45years, P = 0.02). The APC:c.835-A > G was not associated with pks+E.coli- (P = 0.36). F. nucleatum was associated with DNA mismatch repair deficiency (MMRd), BRAF:c.1799T>A p.V600E mutation, CpG island methylator phenotype, proximal tumour location, and high levels of tumour infiltrating lymphocytes (Ps < 0.01). In the stratified analysis by MMRd subgroups, F. nucleatum was associated with Lynch syndrome, MLH1 methylated and double MMR somatic mutated MMRd subgroups (Ps < 0.01). CONCLUSION: Intratumoral pks+E.coli+ but not pks+E.coli- are associated with CRCs harbouring the APC:c.835-8 A > G somatic mutation, suggesting that this mutation is specifically related to DNA damage from colibactin-producing E.coli exposures. F. nucleatum was associated with both hereditary and sporadic MMRd subtypes, suggesting the MMRd tumour microenvironment is important for F. nucleatum colonisation irrespective of its cause.

A Study of Cross-Protection between Eimeria maxima Immunovariants.

For reasons unknown, Eimeria maxima is unique among Eimeria species infecting chickens in the immunovariability it displays among isolates from different geographical areas. Eimeria maxima oocysts (named EmaxAPU3) were isolated late in grow-out (6 weeks) from litter in a commercial broiler operation that was using Eimeria vaccination as the coccidiosis control program. Cross-protection studies (n = 4) were conducted in immunologically naïve chickens between EmaxAPU3 and two E. maxima lab strains (EmaxAPU1, EmaxAPU2) by immunizing with one E. maxima strain and challenging with either the homologous or heterologous E. maxima. As measured by oocyst output, immunization with EmaxAPU1 protected against homologous challenge (EmaxAPU1) and against heterologous challenge with EmaxAPU3, but not against EmaxAPU2. Similarly, immunization with EmaxAPU3 protected against homologous challenge (EmaxAPU3) and against heterologous challenge with EmaxAPU1, but not against EmaxAPU2. Immunization of chickens with EmaxAPU2 elicited a protective response against homologous challenge (EmaxAPU2), but not against EmaxAPU1 nor EmaxAPU3. The most plausible explanation for the appearance of this immunovariant late in grow-out is that E. maxima APU3 escaped immunity directed to E. maxima antigenic types in the commercial vaccine.

The Report of Access and Engagement With Digital Health Interventions Among Children and Young People: Systematic Review.

BACKGROUND: Digital health interventions are increasingly used to deliver health-related interventions for children and young people to change health behaviors and improve health outcomes. Digital health interventions have the potential to enhance access to and engagement with children and young people; however, they may also increase the divide between those who can access technology and are supported to engage and those who are not. This review included studies that reported on the access to or engagement with digital health interventions among children and young people. OBJECTIVE: This review aims to identify and report on access and engagement in studies involving digital health interventions among children and young people. METHODS: A systematic review following the Joanna Briggs Institute methods for conducting systematic reviews was conducted. An electronic literature search was conducted for all studies published between January 1, 2010, and August 2022, across sources, including MEDLINE, CINAHL, and PsycINFO. Studies were included if they examined any aspect of access or engagement in relation to interventions among children and young people. The quality of the included papers was assessed, and data were extracted. Data were considered for meta-analysis, where possible. RESULTS: A total of 3292 references were identified using search terms. Following the exclusion of duplicates and review by inclusion criteria, 40 studies were independently appraised for their methodological quality. A total of 16 studies were excluded owing to their low assessed quality and flawed critical elements in the study design. The studies focused on a variety of health conditions; type 1 diabetes, weight management and obesity, mental health issues, and sexual health were the predominant conditions. Most studies were conducted in developed countries, with most of them being conducted in the United States. Two studies reported data related to access and considered ethnicity and social determinants. No studies used strategies to enhance or increase access. All studies included in the review reported on at least 1 aspect of engagement. Engagement with interventions was measured in relation to frequency of engagement, with no reference to the concept of effective engagement. CONCLUSIONS: Most digital health interventions do not consider the factors that can affect access and engagement. Of those studies that measured either access or engagement or both, few sought to implement strategies to improve access or engagement to address potential disparities between groups. Although the literature to date provides some insight into access and engagement and how these are addressed in digital health interventions, there are major limitations in understanding how both can be enhanced to promote equity. Consideration of both access and engagement is vital to ensure that children and young people have the ability to participate in studies. TRIAL REGISTRATION: PROSPERO CRD42020170874; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=170874.

Inherited BRCA1 and RNF43 pathogenic variants in a familial colorectal cancer type X family.

Genetic susceptibility to familial colorectal cancer (CRC), including for individuals classified as Familial Colorectal Cancer Type X (FCCTX), remains poorly understood. We describe a multi-generation CRC-affected family segregating pathogenic variants in both BRCA1, a gene associated with breast and ovarian cancer and RNF43, a gene associated with Serrated Polyposis Syndrome (SPS). A single family out of 105 families meeting the criteria for FCCTX (Amsterdam I family history criteria with mismatch repair (MMR)-proficient CRCs) recruited to the Australasian Colorectal Cancer Family Registry (ACCFR; 1998-2008) that underwent whole exome sequencing (WES), was selected for further testing. CRC and polyp tissue from four carriers were molecularly characterized including a single CRC that underwent WES to determine tumor mutational signatures and loss of heterozygosity (LOH) events. Ten carriers of a germline pathogenic variant BRCA1:c.2681_2682delAA p.Lys894ThrfsTer8 and eight carriers of a germline pathogenic variant RNF43:c.988 C > T p.Arg330Ter were identified in this family. Seven members carried both variants, four of which developed CRC. A single carrier of the RNF43 variant met the 2019 World Health Organization (WHO2019) criteria for SPS, developing a BRAF p.V600 wildtype CRC. Loss of the wildtype allele for both BRCA1 and RNF43 variants was observed in three CRC tumors while a LOH event across chromosome 17q encompassing both genes was observed in a CRC. Tumor mutational signature analysis identified the homologous recombination deficiency (HRD)-associated COSMIC signatures SBS3 and ID6 in a CRC for a carrier of both variants. Our findings show digenic inheritance of pathogenic variants in BRCA1 and RNF43 segregating with CRC in a FCCTX family. LOH and evidence of BRCA1-associated HRD supports the importance of both these tumor suppressor genes in CRC tumorigenesis.

Circulating white blood cell traits and colorectal cancer risk: A Mendelian randomisation study.

Observational studies have suggested a protective role for eosinophils in colorectal cancer (CRC) development and implicated neutrophils, but the causal relationships remain unclear. Here, we aimed to estimate the causal effect of circulating white blood cell (WBC) counts (N = ~550 000) for basophils, eosinophils, monocytes, lymphocytes and neutrophils on CRC risk (N = 52 775 cases and 45 940 controls) using Mendelian randomisation (MR). For comparison, we also examined this relationship using individual-level data from UK Biobank (4043 incident CRC cases and 332 773 controls) in a longitudinal cohort analysis. The inverse-variance weighted (IVW) MR analysis suggested a protective effect of increased basophil count and eosinophil count on CRC risk [OR per 1-SD increase: 0.88, 95% CI: 0.78-0.99, P = .04; OR: 0.93, 95% CI: 0.88-0.98, P = .01]. The protective effect of eosinophils remained [OR per 1-SD increase: 0.88, 95% CI: 0.80-0.97, P = .01] following adjustments for all other WBC subtypes, to account for genetic correlation between the traits, using multivariable MR. A protective effect of increased lymphocyte count on CRC risk was also found [OR: 0.84, 95% CI: 0.76-0.93, P = 6.70e-4] following adjustment. Consistent with MR results, a protective effect for eosinophils in the cohort analysis in the fully adjusted model [RR per 1-SD increase: 0.96, 95% CI: 0.93-0.99, P = .02] and following adjustment for the other WBC subtypes [RR: 0.96, 95% CI: 0.93-0.99, P = .001] was observed. Our study implicates peripheral blood immune cells, in particular eosinophils and lymphocytes, in CRC development, highlighting a need for mechanistic studies to interrogate these relationships.

Risk factors for metachronous colorectal cancer and advanced neoplasia following primary colorectal cancer: a systematic review and meta-analysis.

BACKGROUND: Identifying risk factors for metachronous colorectal cancer (CRC) and metachronous advanced neoplasia could be useful for guiding surveillance. We conducted a systematic review and meta-analysis to investigate risk factors for metachronous CRC and advanced neoplasia. METHODS: Searches were conducted in MEDLINE, Embase, Web of Science and Cochrane Central Registry of Controlled Trials for articles (searching period: 1945 to Feburary, 2021) that reported the results of an association between any factor and metachronous advanced neoplasia or metachronous CRC. There were no restrictions on the publication date or language. Random effects models were fitted to estimate the combined association between the risk factors and metachronous CRC or advanced neoplasia. The Risk of Bias In Non-Randomised Studies of Interventions tool (ROBINS-I) was used to assess the risk of bias of included studies. RESULTS: In total, 22 observational studies with 625,208 participants were included in the systematic review and meta-analysis. Of these, 13 studies investigated risk factors for metachronous CRC and 9 for advanced neoplasia. The risks of metachronous CRC or advanced neoplasia were higher if the first CRC was diagnosed in the presence of a synchronous advanced lesion (pooled risk ratio (RR) from 3 studies: 3.61, 95% confidence interval (CI): 1.44-9.05; and pooled RR from 8 studies: 2.77, 95% CI: 2.23-3.43, respectively). The risk of metachronous CRC was lower, but the risk of metachronous advanced neoplasia was higher if the first CRC was distal (compared with proximal) (pooled RR from 3 studies: 0.48, 95% CI: 0.23-0.98; and pooled RR from 2 studies: 2.99, 95% CI: 1.60-5.58 respectively). The risk of metachronous advanced neoplasia increased with age (pooled RR from 3 studies: 1.07 per year of age, 95% CI: 1.03-1.11). There was no evidence that any lifestyle risk factors studied were associated with the risk of metachronous CRC or advanced neoplasia. CONCLUSIONS: The identified risk factors for metachronous CRC and advanced neoplasia might be useful to tailor the existing surveillance guidelines after the first CRC. There were potential limitations due to possible misclassification of the outcome, confounding and risk of bias, and the findings cannot be generalised to high-risk genetic syndrome cases.