Cancer health awareness through screening and education: A community approach to healthy equity.

BACKGROUND: The Cancer Health Awareness through screeNinG and Education (CHANGE) initiative delivers cancer awareness education with an emphasis on modifiable risk factors and navigation to screening for prostate, breast, and colorectal cancers to residents of public housing communities who experience significant negative social determinants of health. METHODS: Residents of five communities participated. Community advisory board members were recruited and provided feedback to local environmental change projects, recruitment, and community engagement at each site. At each site, four education sessions were provided by trained facilitators on cancer risk factors and etiology, racial disparities, eligibility for cancer screening, and participation in clinical trials. Attendance, knowledge, attitudes and beliefs about cancer, and height, weight, and waist circumference were measured at baseline and 1-week post-CHANGE sessions. RESULTS: 90 residents (60% 65 and older years old, 33% male, 60% High School education, 93% AA) participated in the program. 95% completed post-intervention evaluation. Participants were eligible for breast (n = 12), prostate (n = 15), and colorectal screening (n = 25) based on American Cancer Society guidelines, and 22 for tobacco cessation; 21 participants accepted navigation assistance for these services. At post-test, participants significantly increased in knowledge and behaviors around obesity/overweight risk for cancer, nutrition, and physical activity. Colorectal, prostate, and breast cancer knowledge scores also increased, but were not significant. CONCLUSIONS: CHANGE participants demonstrated improved health knowledge and intentions to improve their modifiable health behaviors. Participants reported being motivated and confident in seeking preventive care and satisfaction with community engagement efforts. Replication of this project in similar communities may improve knowledge and health equity among underserved populations.

AAV9:PKP2 improves heart function and survival in a Pkp2-deficient mouse model of arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease associated with ventricular arrhythmias and an increased risk of sudden cardiac death. Currently, there are no approved treatments that address the underlying genetic cause of this disease, representing a significant unmet need. Mutations in Plakophilin-2 (PKP2), encoding a desmosomal protein, account for approximately 40% of ARVC cases and result in reduced gene expression. METHODS: Our goal is to examine the feasibility and the efficacy of adeno-associated virus 9 (AAV9)-mediated restoration of PKP2 expression in a cardiac specific knock-out mouse model of Pkp2. RESULTS: We show that a single dose of AAV9:PKP2 gene delivery prevents disease development before the onset of cardiomyopathy and attenuates disease progression after overt cardiomyopathy. Restoration of PKP2 expression leads to a significant extension of lifespan by restoring cellular structures of desmosomes and gap junctions, preventing or halting decline in left ventricular ejection fraction, preventing or reversing dilation of the right ventricle, ameliorating ventricular arrhythmia event frequency and severity, and preventing adverse fibrotic remodeling. RNA sequencing analyses show that restoration of PKP2 expression leads to highly coordinated and durable correction of PKP2-associated transcriptional networks beyond desmosomes, revealing a broad spectrum of biological perturbances behind ARVC disease etiology. CONCLUSIONS: We identify fundamental mechanisms of PKP2-associated ARVC beyond disruption of desmosome function. The observed PKP2 dose-function relationship indicates that cardiac-selective AAV9:PKP2 gene therapy may be a promising therapeutic approach to treat ARVC patients with PKP2 mutations.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart disease that leads to abnormal heartbeats and a higher risk of sudden cardiac death. ARVC is often caused by changes in a gene called PKP2, that then makes less PKP2 protein. PKP2 protein is important for the normal structure and function of the heart. Human ARVC characteristics can be mimicked in a mouse model missing this gene. Given no therapeutic option, our goal was to test if adding a working copy of PKP2 gene in the heart of this mouse model, using a technique called gene therapy that can deliver genes to cells, could improve heart function. Here, we show that a single dose of PKP2 gene therapy can improve heart function and heartbeats as well as extend lifespan in mice. PKP2 gene therapy may be a promising approach to treat ARVC patients with PKP2 mutations.

Investigating the association between educational attainment and allostatic load with risk of cancer mortality among African American women.

BACKGROUND: African American (AA) women navigate the world with multiple intersecting marginalized identities. Accordingly, AA women have higher cumulative stress burden or allostatic load (AL) compared to other women. Studies suggest that AA women with a college degree or higher have lower AL than AA women with less than a high school diploma. We examined the joint effect of educational attainment and AL status with long-term risk of cancer mortality, and whether education moderated the association between AL and cancer mortality. METHODS: We performed a retrospective analysis among 4,677 AA women within the National Health and Nutrition Examination Survey (NHANES) from 1988 to 2010 with follow-up data through December 31, 2019. We fit weighted Cox proportional hazards models to estimate adjusted hazard ratios (aHRs) of cancer death between educational attainment/AL (adjusted for age, income, and smoking status). RESULTS: AA women with less than a high school diploma living with high AL had nearly a 3-fold increased risk (unadjusted HR: 2.98; 95%C CI: 1.24-7.15) of cancer death compared to AA college graduates living with low AL. However, after adjusting for age, this effect attenuated (age-adjusted HR: 1.11; 95% CI: 0.45-2.74). AA women with high AL had 2.3-fold increased risk of cancer death (fully adjusted HR: 2.26; 95% CI: 1.10-4.57) when compared to AA with low AL, specifically among women with high school diploma or equivalent and without history of cancer. CONCLUSIONS: Our findings suggest that high allostatic load is associated with a higher risk of cancer mortality among AA women with lower educational attainment, while no such association was observed among AA women with higher educational attainment. Thus, educational attainment plays a modifying role in the relationship between allostatic load and the risk of cancer death for AA women. Higher education can bring several benefits, including improved access to medical care and enhanced medical literacy, which in turn may help mitigate the adverse impact of AL and the heightened risk of cancer mortality among AA women.

Improved Cardiac Function in Postischemic Rats Using an Optimized Cardiac Reprogramming Cocktail Delivered in a Single Novel Adeno-Associated Virus.

BACKGROUND: Cardiac reprogramming is a technique to directly convert nonmyocytes into myocardial cells using genes or small molecules. This intervention provides functional benefit to the rodent heart when delivered at the time of myocardial infarction or activated transgenically up to 4 weeks after myocardial infarction. Yet, several hurdles have prevented the advancement of cardiac reprogramming for clinical use. METHODS: Through a combination of screening and rational design, we identified a cardiac reprogramming cocktail that can be encoded in a single adeno-associated virus. We also created a novel adeno-associated virus capsid that can transduce cardiac fibroblasts more efficiently than available parental serotypes by mutating posttranslationally modified capsid residues. Because a constitutive promoter was needed to drive high expression of these cell fate-altering reprogramming factors, we included binding sites to a cardiomyocyte-restricted microRNA within the 3' untranslated region of the expression cassette that limits expression to nonmyocytes. After optimizing this expression cassette to reprogram human cardiac fibroblasts into induced cardiomyocyte-like cells in vitro, we also tested the ability of this capsid/cassette combination to confer functional benefit in acute mouse myocardial infarction and chronic rat myocardial infarction models. RESULTS: We demonstrated sustained, dose-dependent improvement in cardiac function when treating a rat model 2 weeks after myocardial infarction, showing that cardiac reprogramming, when delivered in a single, clinically relevant adeno-associated virus vector, can support functional improvement in the postremodeled heart. This benefit was not observed with GFP (green fluorescent protein) or a hepatocyte reprogramming cocktail and was achieved even in the presence of immunosuppression, supporting myocyte formation as the underlying mechanism. CONCLUSIONS: Collectively, these results advance the application of cardiac reprogramming gene therapy as a viable therapeutic approach to treat chronic heart failure resulting from ischemic injury.

Gene and pathway based burden analyses in familial lymphoid cancer cases: Rare variants in immune pathway genes.

Genome-wide association studies have revealed common genetic variants with small effect sizes associated with diverse lymphoid cancers. Family studies have uncovered rare variants with high effect sizes. However, these variants explain only a portion of the heritability of these cancers. Some of the missing heritability may be attributable to rare variants with small effect sizes. We aim to identify rare germline variants associated with familial lymphoid cancers using exome sequencing. One case per family was selected from 39 lymphoid cancer families based on early onset of disease or rarity of subtype. Control data was from Non-Finnish Europeans in gnomAD exomes (N = 56,885) or ExAC (N = 33,370). Gene and pathway-based burden tests for rare variants were performed using TRAPD. Five putatively pathogenic germline variants were found in four genes: INTU, PEX7, EHHADH, and ASXL1. Pathway-based association tests identified the innate and adaptive immune systems, peroxisomal pathway and olfactory receptor pathway as associated with lymphoid cancers in familial cases. Our results suggest that rare inherited defects in the genes involved in immune system and peroxisomal pathway may predispose individuals to lymphoid cancers.

Association of Food Deserts and Food Swamps With Obesity-Related Cancer Mortality in the US.

Importance: Obesity-related cancers account for 40% of all cancers in the US. Healthy food consumption is a modifiable factor shown to reduce obesity-related cancer mortality, but residing in areas with less access to grocery stores (food deserts) or higher access to fast food (food swamps) reduces healthy food access and has been understudied. Objective: To analyze the association of food deserts and food swamps with obesity-related cancer mortality in the US. Design, Setting, and Participants: This cross-sectional ecologic study used US Department of Agriculture Food Environment Atlas data from 2012, 2014, 2015, 2017, and 2020 and Centers for Disease Control and Prevention mortality data from 2010 to 2020. A total of 3038 US counties or county equivalents with complete information on food environment scores and obesity-related cancer mortality data were included. An age-adjusted, generalized, mixed-effects regression model was performed for the association of food desert and food swamp scores with obesity-related cancer mortality rates. Data were analyzed from September 9, 2022, to September 30, 2022. Exposures: Food swamp score was calculated as the ratio of fast-food and convenience stores to grocery stores and farmers markets. Higher food swamp and food desert scores (20.0 to ≥58.0) indicated counties with fewer healthy food resources. Main Outcomes and Measures: Obesity-related cancer (based on the International Agency for Research on Cancer evidence between obesity and 13 types of cancer) mortality rates were categorized as high (≥71.8 per 100 000 population) vs low (<71.8 per 100 000 population) per county. Results: A total of 3038 counties or county equivalents with high obesity-related cancer mortality rates had a higher percentage of non-Hispanic Black residents (3.26% [IQR, 0.47%-26.35%] vs 1.77% [IQR, 0.43%-8.48%]), higher percentage of persons older than 65 years (15.71% [IQR, 13.73%-18.00%] vs 15.40% [IQR, 12.82%-18.09%]), higher poverty rates (19.00% [IQR, 14.20%-23.70%] vs 14.40% [IQR, 11.00%-18.50%]), higher adult obesity rates (33.00% [IQR, 32.00%-35.00%] vs 32.10% [IQR, 29.30%-33.20%]), and higher adult diabetes rates (12.50% [IQR, 11.00%-14.20%] vs 10.70% [IQR, 9.30%-12.40%]) compared with counties or county equivalents with low obesity-related cancer mortality. There was a 77% increased odds of having high obesity-related cancer mortality rates among US counties or county equivalents with high food swamp scores (adjusted odds ratio, 1.77; 95% CI, 1.43-2.19). A positive dose-response relationship among 3 levels of food desert and food swamp scores and obesity-related cancer mortality was also observed. Conclusions and Relevance: The findings of this cross-sectional ecologic study suggest that policy makers, funding agencies, and community stakeholders should implement sustainable approaches to combating obesity and cancer and establishing access to healthier food, such as creating more walkable neighborhoods and community gardens.

Multiscale deep learning framework captures systemic immune features in lymph nodes predictive of triple negative breast cancer outcome in large-scale studies.

The suggestion that the systemic immune response in lymph nodes (LNs) conveys prognostic value for triple-negative breast cancer (TNBC) patients has not previously been investigated in large cohorts. We used a deep learning (DL) framework to quantify morphological features in haematoxylin and eosin-stained LNs on digitised whole slide images. From 345 breast cancer patients, 5,228 axillary LNs, cancer-free and involved, were assessed. Generalisable multiscale DL frameworks were developed to capture and quantify germinal centres (GCs) and sinuses. Cox regression proportional hazard models tested the association between smuLymphNet-captured GC and sinus quantifications and distant metastasis-free survival (DMFS). smuLymphNet achieved a Dice coefficient of 0.86 and 0.74 for capturing GCs and sinuses, respectively, and was comparable to an interpathologist Dice coefficient of 0.66 (GC) and 0.60 (sinus). smuLymphNet-captured sinuses were increased in LNs harbouring GCs (p < 0.001). smuLymphNet-captured GCs retained clinical relevance in LN-positive TNBC patients whose cancer-free LNs had on average ≥2 GCs, had longer DMFS (hazard ratio [HR] = 0.28, p = 0.02) and extended GCs' prognostic value to LN-negative TNBC patients (HR = 0.14, p = 0.002). Enlarged smuLymphNet-captured sinuses in involved LNs were associated with superior DMFS in LN-positive TNBC patients in a cohort from Guy's Hospital (multivariate HR = 0.39, p = 0.039) and with distant recurrence-free survival in 95 LN-positive TNBC patients of the Dutch-N4plus trial (HR = 0.44, p = 0.024). Heuristic scoring of subcapsular sinuses in LNs of LN-positive Tianjin TNBC patients (n = 85) cross-validated the association of enlarged sinuses with shorter DMFS (involved LNs: HR = 0.33, p = 0.029 and cancer-free LNs: HR = 0.21 p = 0.01). Morphological LN features reflective of cancer-associated responses are robustly quantifiable by smuLymphNet. Our findings further strengthen the value of assessment of LN properties beyond the detection of metastatic deposits for prognostication of TNBC patients. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Investigating the Association between Educational Attainment and Allostatic Load with Risk of Cancer Mortality among African American Women.

Background African American (AA) women navigate the world with multiple intersecting marginalized identities. Accordingly, AA women have higher cumulative stress burden or allostatic load (AL) compared to other women. AL correlates with poorer health outcomes and increased risk of cancer death. However, research indicates AA women with a college degree or higher have lower AL than AA women with less than a high school diploma. We examined whether educational attainment differences and AL status in AA women are associated with long-term risk of cancer mortality. Methods We performed a retrospective analysis among 4,677 AA women respondents using National Health and Nutrition Examination Survey (NHANES) data from 1988 through 2010 with follow up data through December 31, 2019. We fit Cox proportional hazards models to estimate adjusted hazard ratios (aHRs) of cancer death between educational attainment/AL (adjusted for age, sociodemographic, and health factors). Results AA women with less than a high school diploma living with high AL had nearly a 3-fold increased risk (unadjusted HR: 2.98; 95%C CI: 1.24â€"7.15) of cancer death compared to AA college graduates living with low AL. However, after adjusting for age, the increased risk of cancer death in those with less than a high school diploma and high AL attenuated (age-adjusted HR: 1.11; 95% CI: .45-2.74). Conclusions Differences in educational attainment and AL in AA women were not associated with increased risk of cancer mortality when adjusted for age. Previous studies have shown that increased allostatic load is associated with increased risk of cancer death. However, for African American women, higher educational attainment does not modify the risk of cancer mortality. The benefits that may come along with higher education such as increased access to medical care and better medical literacy do not change the risk of cancer mortality in AA women.

Dynamic Biobanking for Advancing Breast Cancer Research.

Longitudinal patient biospecimens and data advance breast cancer research through enabling precision medicine approaches for identifying risk, early diagnosis, improved disease management and targeted therapy. Cancer biobanks must evolve to provide not only access to high-quality annotated biospecimens and rich associated data, but also the tools required to harness these data. We present the Breast Cancer Now Tissue Bank centre at the Barts Cancer Institute as an exemplar of a dynamic biobanking ecosystem that hosts and links longitudinal biospecimens and multimodal data including electronic health records, genomic and imaging data, offered alongside integrated data sharing and analytics tools. We demonstrate how such an ecosystem can inform precision medicine efforts in breast cancer research.

Exploring the intersectionality of race/ethnicity with rurality on breast cancer outcomes: SEER analysis, 2000-2016.

PURPOSE: Disparities in breast cancer survival have been observed within marginalized racial/ethnic groups and within the rural-urban continuum for decades. We examined whether there were differences among the intersectionality of race/ethnicity and rural residence on breast cancer outcomes. METHODS: We performed a retrospective analysis among 739,448 breast cancer patients using Surveillance Epidemiology and End Results (SEER) 18 registries years 2000 through 2016. We conducted multilevel logistic-regression and Cox proportional hazards models to estimate adjusted odds ratios (AORs) and hazard ratios (AHRs), respectively, for breast cancer outcomes including surgical treatment, radiation therapy, chemotherapy, late-stage disease, and risk of breast cancer death. Rural was defined as 2013 Rural-Urban Continuum Codes (RUCC) of 4 or greater. RESULTS: Compared with non-Hispanic white-urban (NH-white-U) women, NH-black-U, NH-black-rural (R), Hispanic-U, and Hispanic-R women, respectively, were at increased odds of no receipt of surgical treatment (NH-black-U, AOR = 1.98, 95% CI 1.91-2.05; NH-black-R, AOR = 1.72, 95% CI 1.52-1.94; Hispanic-U, AOR = 1.58, 95% CI 1.52-1.65; and Hispanic-R, AOR = 1.40, 95% CI 1.18-1.67), late-stage diagnosis (NH-black-U, AOR = 1.32, 95% CI 1.29-1.34; NH-black-R, AOR = 1.29, 95% CI 1.22-1.36; Hispanic-U, AOR = 1.25, 95% CI 1.23-1.27; and Hispanic-R, AOR = 1.17, 95% CI 1.08-1.27), and increased risks for breast cancer death (NH-black-U, AHR = 1.46, 95% CI 1.43-1.50; NH-black-R, AHR = 1.42, 95% CI 1.32-1.53; and Hispanic-U, AHR = 1.10, 95% CI 1.07-1.13). CONCLUSION: Regardless of rurality, NH-black and Hispanic women had significantly increased odds of late-stage diagnosis, no receipt of treatment, and risk of breast cancer death.

Home-based rehabilitation following anterior cruciate ligament reconstruction in the Kurdistan region of Iraq: epidemiology and outcomes.

PURPOSE: This study, set in in the Kurdistan region of Iraq, describes the epidemiology and outcomes of anterior cruciate ligament reconstruction (ACLR) followed by home-based rehabilitation alone. METHODS: A cohort observational study of patients aged ≥ 16 years with an ACL rupture who underwent an ACLR under a single surgeon. Followed by a home-based rehabilitation programme of appropriate simplicity for completion in the home setting; consisting of stretching, range of motion and strengthening exercises. Demographics, mechanism of injury, operative findings, and outcome data (Lysholm, Tegner Activity Scale (TAS), and revision rates) were collected from 2016 to 2021. Data were analysed using descriptive statistics. RESULTS: The cohort consisted of 545 patients (547 knees), 99.6% were male with a mean age of 27.8 years (SD 6.18 years). The mean time from diagnosis to surgery was 40.6 months (SD 40.3). Despite data attrition Lysholm scores improved over the 15-month follow-up period, matched data showed the most improvement occurred within the first 2 months post-operatively. Post-operative TAS results showed an improvement in level of function, but did not reach pre-injury levels by final follow-up. At final follow-up, six (1.1%) patients required an ACLR revision. CONCLUSION: Patients who completed a home-based rehabilitation programme in Kurdistan had low revision rates and improved Lysholm scores 15 months post-operatively. To optimise resources, further research should investigate the efficacy of home-based rehabilitation for trauma and elective surgery in low- to middle-income countries and the developed world.

Understanding geographic and racial/ethnic disparities in mortality from four major cancers in the state of Georgia: a spatial epidemiologic analysis, 1999-2019.

We examined geographic and racial variation in cancer mortality within the state of Georgia, and investigated the correlation between the observed spatial differences and county-level characteristics. We analyzed county-level cancer mortality data collected by the Centers for Disease Control and Prevention on breast, colorectal, lung, and prostate cancer mortality among adults (aged ≥ 18 years) in 159 Georgia counties from years 1999 through 2019. Geospatial methods were applied, and we identified hot spot counties based on cancer mortality rates overall and stratified by non-Hispanic white (NH-white) and NH-black race/ethnicity. Among all adults, 5.0% (8 of 159), 8.2% (13 of 159), 5.0% (8 of 159), and 6.9% (11 of 159) of Georgia counties were estimated hot spots for breast cancer, colorectal, lung, and prostate cancer mortality, respectively. Cancer mortality hot spots were heavily concentrated in three major areas: (1) eastern Piedmont to Coastal Plain regions, (2) southwestern rural Georgia area, or (3) northern-most rural Georgia. Overall, hot spot counties generally had higher proportion of NH-black adults, older adult population, greater poverty, and more rurality. In Georgia, targeted cancer prevention strategies and allocation of health resources are needed in counties with elevated cancer mortality rates, focusing on interventions suitable for NH-black race/ethnicity, low-income, and rural residents.

Exploring racial disparities on the association between allostatic load and cancer mortality: A retrospective cohort analysis of NHANES, 1988 through 2019.

Background: Several studies suggest that chronic stress may be associated with increased risk of cancer mortality. Our study sought to determine the association between allostatic load (AL), a measure of cumulative stress, and risk of cancer death; and whether these associations varied by race/ethnicity. Methods: We performed retrospective analysis using National Health and Nutrition Examination Survey (NHANES) years 1988 through 2010 linked with the National Death Index through December 31, 2019. We fit Fine & Gray Cox proportional hazards models to estimate sub-distribution hazard ratios (SHRs) of cancer death between high and low AL status (models adjusted for age, sociodemographics, and comorbidities). Results: In fully adjusted models, high AL was associated with a 14% increased risk of cancer death (adjusted (SHR): 1.14, 95% CI: 1.04-1.26) among all participants and a 18% increased risk of cancer death (SHR:1.18, 95% CI: 1.03-1.34) among Non-Hispanic White (NH-White) adults. When further stratified by age (participants aged <40 years), high AL was associated with a 80% increased risk (SHR: 1.80, 95% CI: 1.35-2.41) among all participants; a 95% increased risk (SHR: 1.95, 95% CI: 1.22-3.12) among NH-White adults; a 2-fold (SHR: 2.06, 95% CI: 1.27-3.34) increased risk among Non-Hispanic Black (NH-Black) adults; and a 36% increased risk among Hispanic adults (SHR: 1.36, 95% CI: 0.70-2.62). Conclusions: Overall, the risk of cancer death was associated with high AL; however, when stratified among NH-Black and Hispanic adults this association was slightly attenuated. Impact: High AL is associated with increased risk of overall cancer death, and future studies should delineate the association between AL and cancer-specific mortality to better understand the causal mechanisms between cumulative stress and cancer.

The Role of Mitochondrial DNA Variation in Drug Response: A Systematic Review.

Background: The triad of drug efficacy, toxicity and resistance underpins the risk-benefit balance of all therapeutics. The application of pharmacogenomics has the potential to improve the risk-benefit balance of a given therapeutic via the stratification of patient populations based on DNA variants. A growth in the understanding of the particulars of the mitochondrial genome, alongside the availability of techniques for its interrogation has resulted in a growing body of literature examining the impact of mitochondrial DNA (mtDNA) variation upon drug response. Objective: To critically evaluate and summarize the available literature, across a defined period, in a systematic fashion in order to map out the current landscape of the subject area and identify how the field may continue to advance. Methods: A systematic review of the literature published between January 2009 and December 2020 was conducted using the PubMed database with the following key inclusion criteria: reference to specific mtDNA polymorphisms or haplogroups, a core objective to examine associations between mtDNA variants and drug response, and research performed using human subjects or human in vitro models. Results: Review of the literature identified 24 articles reporting an investigation of the association between mtDNA variant(s) and drug efficacy, toxicity or resistance that met the key inclusion criteria. This included 10 articles examining mtDNA variations associated with antiretroviral therapy response, 4 articles examining mtDNA variants associated with anticancer agent response and 4 articles examining mtDNA variants associated with antimicrobial agent response. The remaining articles covered a wide breadth of medications and were therefore grouped together and referred to as "other." Conclusions: Investigation of the impact of mtDNA variation upon drug response has been sporadic to-date. Collective assessment of the associations identified in the articles was inconclusive due to heterogeneous methods and outcomes, limited racial/ethnic groups, lack of replication and inadequate statistical power. There remains a high degree of idiosyncrasy in drug response and this area has the potential to explain variation in drug response in a clinical setting, therefore further research is likely to be of clinical benefit.

Faecal immunochemical tests for haemoglobin: Analytical challenges and potential solutions.

Quantitative faecal immunochemical tests for haemoglobin (FIT) are being used increasingly around the world in colorectal cancer screening programmes, and in patients presenting with lower bowel symptoms to determine who should proceed to further bowel visualisation investigations, usually colonoscopy. The clinical utility of FIT is well reported. There are a number of analytical challenges including pre-analytical variation, difficulty setting up external quality assessment schemes, access to third party internal quality control material and a lack of standardisation or harmonisation of FIT methods. Here we report the work of the International Federation of Clinical Chemistry FIT Working Group. We provide an overview of the main pre-analytical variables; discuss different approaches to external quality assurance of FIT; propose a solution to third party internal quality assurance materials and summarise the challenges of standardisation and harmonisation of FIT.

Investigating dihydroorotate dehydrogenase inhibitor mediated mitochondrial dysfunction in hepatic in vitro models.

Inhibition of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzymatic step in de novo pyrimidine synthesis, has broad immunosuppressive effects in vivo and shows promise as a therapeutic target for the treatment of malignancies, viral infections and auto-immune diseases. Whilst there are numerous DHODH inhibitors under development, leflunomide and teriflunomide are the only FDA approved compounds on the market, each of which have been issued with black-box warnings for hepatotoxicity. Mitochondrial dysfunction is a putative mechanism by which teriflunomide and leflunomide elicit their hepatotoxic effects, however it is as yet unclear whether this is shared by other nascent DHODH inhibitors. The present study aimed to evaluate the propensity for DHODH inhibitors to mediate mitochondrial dysfunction in two hepatic in vitro models. Initial comparisons of cytotoxicity and ATP content in HepaRG® cells primed for oxidative metabolism, in tandem with mechanistic evaluations by extracellular flux analysis identified multifactorial toxicity and moderate indications of respiratory chain dysfunction or uncoupling. Further investigations using HepG2 cells, a hepatic line with limited capability for phase I xenobiotic metabolism, identified leflunomide and brequinar as positive mitochondrial toxicants. Taken together, biotransformation of some DHODH inhibitor species may play a role in mediating or masking hepatic mitochondrial liabilities.

Design, development, testing at ISO standards and in vivo feasibility study of a novel polymeric heart valve prosthesis.

Clinically available prosthetic heart valves are life-saving, but imperfect: mechanical valves requiring anticoagulation therapy, whilst bioprosthetic valves have limited durability. Polymer valves offer the prospect of good durability without the need for anticoagulation. We report the design and development of a polymeric heart valve, its bench-testing at ISO standards, and preliminary extra-vivo and in vivo short-term feasibility. Prototypes were manufactured by injection moulding of styrenic block copolymers to achieve anisotropic mechanical properties. Design was by finite element stress-strain modelling, which has been reported previously, combined with feedback from bench and surgery-based testing using various combinations of materials, valve geometry and processing conditions. Bench testing was according to ISO 5840:2015 standards using an in vitro cardiovascular hydrodynamic testing system and an accelerated fatigue tester. Bench comparisons were made with a best-in-class bio-prosthesis. Preliminary clinical feasibility evaluations included extra-vivo and short-term (1-24 hours) in vivo testing in a sheep model. The optimised final prototype met the requirements of ISO standards with hydrodynamic performance equivalent to the best-in-class bioprosthesis. Bench durability of greater than 1.2 billion cycles (30 years equivalent) was achieved (still ongoing). Extra-vivo sequential testing (n = 8) allowed refinement of external diameter, 3D shape, a low profile, flexibility, suturability, and testing of compatibility to magnetic resonance imaging and clinical sterilisation. In vivo short-term (1-24 hours) feasibility (n = 3) confirmed good suturability, no mechanical failure, no trans-valvular regurgitation, competitive trans-valvular gradients, and good biocompatibility at histopathology. We have developed and tested at ISO standards a novel prosthetic heart valve featuring competitive bench-based hydrodynamics and durability, well beyond the ISO requirements and comparable to a best-in-class bioprosthesis. In vivo short-term feasibility testing confirmed preliminary safety, functionality and biocompatibility, supporting progression to a long-term efficacy trial.

Birth Order, Sibship Size, Childhood Environment and Immune-Related Disorders, and Risk of Lymphoma in Lymphoid Cancer Families.

BACKGROUND: Familial aggregation of lymphoid cancers and immune-related disorders suggests a role for genetic susceptibility; however, few studies examine environmental factors. According to the hygiene hypothesis, adult-onset immune-related diseases may be a consequence of reduced childhood infectious exposures and aberrant immune development. In a cohort of 196 multiple-case lymphoid cancer families, we analyzed environmental factors related to the hygiene hypothesis. METHODS: Family structure, childhood environment, and immune-related disorders were examined among 196 lymphoid cancer families, in relation to risk of lymphoid cancer. We report on 450 lymphoid cancer cases and 1,018 unaffected siblings using logistic regression models with generalized estimating equations to estimate ORs and 95% confidence intervals (CI) for association. RESULTS: The risk of lymphoma tended to decrease with later birth order (OR = 0.83; 95% CI, 0.78-0.89) and larger sibship size (OR = 0.82; 95% CI, 0.79-0.85). High maternal education, above average family income during childhood, allergies (OR = 2.25; 95% CI, 1.44-3.51), and tonsillectomy (OR = 1.78; 95% CI, 1.14-2.78) were independent risk factors for lymphoma. Familial lymphoid cancer cases were more likely to report environment (OR = 1.90; 95% CI, 1.21-2.98) and drug (OR = 2.30; 95% CI, 1.41-3.73) allergies. CONCLUSIONS: These associations underscore the complex etiology of familial lymphoma. To our knowledge, this is the largest multiple-case family-based study that supports the hygiene hypothesis contributing to lymphoid cancer risk. IMPACT: Understanding the mechanism by which environmental and lifestyle factors affect lymphoid cancer risk may advance cancer prevention, even in the familial context.