Increased Lifetime Risk Research Articles

Bicuspid aortic valve interventions in Texas—2009–2019

Background: Bicuspid aortic valve (BAV) is a common congenital heart defect occurring in 0.5–2% of adults. It is associated with increased lifetime risk of aortic valve intervention (AVI). Different AVI options include surgical replacement [surgical aortic valve replacement (SAVR)], repair, the Ross procedure, and transcatheter replacement [transcatheter aortic valve replacement (TAVR)]. This study seeks to evaluate statewide trends in BAV AVI and compare in-hospital outcomes over 11 years period.

Development and initial testing of a multi-stakeholder intervention for Lynch syndrome cascade screening: an intervention mapping approach

BackgroundLynch syndrome is an underdiagnosed hereditary condition carrying an increased lifetime risk for colorectal and endometrial cancer and affecting nearly 1 million people in the United States. Cascade screening, systematic screening through family members of affected patients, could improve identification of Lynch syndrome, but this strategy is underused due to multi-level barriers including low knowledge about Lynch syndrome, low access to genetics services, and challenging family dynamics.MethodsWe used intervention mapping, a 6-step methodology to create stakeholder-driven interventions that meet the needs of a target population, to develop an intervention to improve cascade screening for Lynch syndrome. The intervention development process was guided by input from key stakeholders in Lynch syndrome care and patients. We conducted usability testing on the intervention with Lynch syndrome patients using qualitative semi-structured interviewing and rapid qualitative analysis.ResultsWe developed a workbook intervention named Let’s Talk that addresses gaps in knowledge, skills, self-efficacy, outcome expectancy and other perceived barriers to cascade screening for Lynch syndrome. Let’s Talk contained educational content, goal setting activities, communication planning prompts and supplemental resources for patients to plan family communication. Evidence-based methods used in the workbook included information chunking, guided practice, goal setting and gain-framing. We conducted usability testing focused on the complexity and relative advantage of the intervention through 45-min virtual interviews with 10 adult patients with Lynch syndrome recruited from a national advocacy organization in the United States. Usability testing results suggested the intervention was acceptable in terms of complexity and relative advantage to other available resources, but additional information for communication with young or distant family members and a web-based platform could enhance the intervention’s usability.ConclusionsIntervention mapping provided a framework for intervention development that addressed the unique needs of Lynch syndrome patients in overcoming barriers to cascade screening. Future work is needed to transform Let’s Talk into a web-based tool and evaluate the effectiveness of the intervention in clinical practice with patients and genetic counselors. Intervention mapping can be useful to researchers as an evidence-based technique to develop stakeholder-centered interventions for addressing the needs of other unique populations.

Diagnostic activity impacts lifetime risk of prostate cancer diagnosis more strongly than life expectancy.

The main aim of the study was to determine the impact of diagnostic activity and life expectancy on the lifetime risk of a prostate cancer diagnosis. We used a state transition simulation model based on Swedish population-based data to simulate life trajectories for 2,000,000 men from age 40 to 100 in order to estimate the lifetime risk of a prostate cancer diagnosis. Risk estimates were determined by the level of diagnostic activity and estimated life expectancy. Higher exposure to diagnostic activity resulted in more prostate cancer diagnoses. This was especially true for men diagnosed with low or intermediate grade disease. Men exposed to high diagnostic compared to low diagnostic activity had a five-fold increased lifetime risk (22% vs. 5%) of being diagnosed with a low or intermediate-risk prostate cancer and half the risk of being diagnosed with a high-risk prostate cancer (6% vs. 13%). Men with a long life expectancy had a higher lifetime risk of a prostate cancer diagnosis both overall (21% vs. 15%) and in all risk categories when compared to men with a short life expectancy. The lifetime risk of a prostate cancer diagnosis is strongly influenced by diagnostic activity and to a lesser degree by life expectancy.

Patterns of DNA mismatch repair protein expression for primary and recurrent colorectal cancer at an advanced surgical unit: A retrospective audit.

Lynch syndrome is an inherited cancer syndrome associated with an increased lifetime risk of colorectal cancer (CRC) and characterized by germline mutations to one of four DNA mismatch repair (MMR) genes. Immunohistochemical (IHC) testing is used to screen for Lynch syndrome; however, despite routine completion following resection of primary CRC, it is only variably completed following resection of recurrent disease. This may be significant, as MMR protein expression can change from primary to recurrent CRC. The primary aim of this study is to investigate how MMR profiles change from primary to recurrent CRC; the secondary aim is to assess rates of MMR testing of primary and recurrent disease. We conducted a retrospective analysis of patients undergoing surgery for recurrent CRC from 2018-19 at a high-volume institution. MMR profiles were obtained following both primary and recurrent resection of CRC, and MMR protein expression was evaluated from both time points. A total of 107 patients met the inclusion criteria and IHC results were obtained for both primary and recurrent resections in 85 cases. MMR profiles changed in nine patients (10.6%), with a loss of staining from primary to recurrent disease in six (7.1%) and a gain of staining in three (3.5%). IHC testing was completed following 88.7% of primary and 39.3% of recurrent resections. MMR profiles can change from primary to recurrent CRC and repeat MMR testing for recurrent CRC is completed in only a minority of cases.

Lessons learnt from the implementation of a colorectal cancer screening programme for lynch syndrome in a tertiary public hospital

BackgroundLynch syndrome (LS) is the first cause of inherited colorectal cancer (CRC), being responsible for 2–4% of all diagnoses. Identification of affected individuals is important as they have an increased lifetime risk of multiple CRC and other neoplasms, however, LS is consistently underdiagnosed at the population level. We aimed to evaluate the yield of LS screening in CRC in a single-referral centre and to identify the barriers to its effective implementation. MethodsLS screening programme included individuals with CRC < 70 years, multiple CRC, or endometrial cancer at any age. Mismatch repair (MMR) protein immunohistochemistry (IHC) analysis was performed in routine practice on the surgical specimen and, if MLH1 IHC was altered, MLH1 gene promoter methylation was analysed. Results were collected in the CRC multidisciplinary board database. LS suspected individuals (altered MMR IHC without MLH1 promoter methylation) were referred to the Cancer Genetic Counselling Unit (CGCU). If accepted, a genetic study was performed. Two checkpoints were included: review of the pathology data and verification of patient referral by a genetic counsellor. ResultsBetween 2016 and 2019, 381 individuals were included. MMR IHC analysis was performed in 374/381 (98.2 %) CRC cases and MLH1 promoter methylation in 18/21 (85.7 %). Seventeen of the 20 LS suspected individuals were invited for referral at the CGCU. Two cases were not invited and the remaining patient died of cancer before completion of tumour screening. Fifteen individuals attended and a genetic analysis was performed in 15/20 (75 %) LS suspected individuals. Ten individuals were diagnosed with LS, in concordance with the IHC profile (2.7 % of the total cohort). This led to cascade testing in 58/75 (77.3 %) of the available adult relatives at risk, identifying 26 individuals with LS. ConclusionsEstablishing a standardized institutional LS screening programme with checkpoints in the workflow is key to increasing the yield of LS identification.

Abstract 12556: Prevalence of Hypertension and Left Ventricular Hypertrophy in Adolescents Following Left Ventricular Outflow Tract Obstruction Repair

Introduction: Left ventricular outflow tract obstructions predispose patients to increased lifetime risk of cardiovascular events even after successful repair (rLVOTO). Left ventricular hypertrophy (LVH) is an adaptive response to elevated afterload and is a predictor of cardiovascular events in adulthood. The prevalence of elevated blood pressure (SBP) and LVH in youths with rLVOTO is limited. Methods: Retrospective analysis of rLVOTO patients between 2012-2019, age 13-17 years with documented body mass index (BMI), SBP, LVOT velocity and left ventricular mass indexed to height (LVMi). Moderate LVOTO was defined as peak velocity ≥ 3 m/s. Patients categorized into normotensive (NT, SBP &lt; 120 mm Hg), elevated (E-BP, 120 ≤ SBP &lt; 130 mm Hg), Stage 1 HTN (HTN-1, 130 ≤ SBP &lt; 140 mm Hg) and Stage 2 HTN (HTN-2, SBP ≥ 140 mm Hg). Prevalence of LVH was reported in each group (pediatric cutoff of LVMi-HT 2.7 ≥ 38.6 g/ht 2.7 ). Results: A total of 193 patients met criteria (age 15.6 ± 1.4 years), 135/193 (70%) male, SBP 120±13 mm Hg, and LVMi-HT 2.7 36.2±9.8 g/ht 2.7 . Half were in the NT group (93/193 (48%)), 55/193 (28%) in E-BP, 32/193 (17%) in HTN-1, and 13/193 (7%) in HTN-2 with no difference in BMI. Prevalence of LVH increased with higher SBP with 24/93 (26%) in NT, 21/55 (38%) in E-BP, 14/32 (43%) in HTN-1, and 4/13 (31%) in HTN-2. 124/193 (64%) had no residual LVOT gradient, 69/193 (36%) with residual LVOT gradient. 52/69 (75%) had LVOT &lt; 3 m/s, of these 12/52 (23%) had ≥ HTN-1. 17/69 (25%) had residual LVOTO ≥ 3 m/s, of these 6/17 (35%) had ≥ HTN-1. No difference in LVMi found between no or mild LVOTO groups (35.9±13 vs 35.6±10 g/ht 2.7 , p = NS). Higher LVMi was found in the LVOTO ≥ 3 m/s group (41.5±13 g/ht 2.7 , p = 0.01 compared to both no or mild LVOTO). Conclusions: Youths with rLVOTO have a high prevalence of elevated BP, HTN, and LVH. When stratified by LVOTO severity, presence of ≥ HTN-1 was common with increased LVMi. No difference in BMI was observed among abnormal SBP groups suggesting BMI is not solely responsible for the increased LVMi. Longitudinal studies are needed to define the impact of rLVOTO and HTN on LVH over time. Our findings support early surveillance and management of hypertension in patients following LVOTO repair to help minimize the risk of future cardiovascular events related to LVH.

266 (PB-090) Poster - Imaging features of malignant lesions in women with PTEN Hamartoma Tumor Syndrome

Background: Women with PTEN Hamartoma Tumor Syndrome (PHTS) have an increased lifetime risk (67–85%) for breast cancer (BC) and are offered breast cancer surveillance. In order to allow for the early diagnosis of BC, knowledge of imaging features of malignant lesions is important. In this study, we thus evaluated the types of malignant lesions encountered and the associated imaging characteristics in women with PHTS who underwent breast cancer surveillance.

High-Risk Lesion Management

High-risk lesions or lesions of uncertain malignant potential are frequent findings on image-guided needle biopsy of the breast and comprise a number of distinct entities. These lesions are known for having risk of underlying malignancy and are usually associated with an increased lifetime risk for breast cancer. Surgical excision was traditionally recommended for all high-risk lesions but recent studies have demonstrated that vacuum-assisted excision or surveillance may be adequate for some lesions. While management of high-risk lesion varies among institutions, this chapter describes the management recommendations based on recent literature of the most frequent types of lesions.

Contemporary Therapies and Future Directions in the Management of Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a genetic disorder caused by pathogenic variants in sarcomeric genes, leading to left ventricular hypertrophy and complex phenotypic heterogeneity. While HCM is the most common inherited cardiomyopathy, pharmacological treatment options have previously been limited and were predominantly directed towards symptom control owing to left ventricular outflow obstruction. These therapies, including beta blockers, calcium channel blockers, and disopyramide, have not been shown to affect the natural history of the disease, which is of particular concern for younger patients who have an increased lifetime risk of experiencing arrhythmias, heart failure, and sudden cardiac death. Increased knowledge of the genetic mechanisms underlying this disease in recent years has led to the development of targeted, potentially disease-modifying therapies for both obstructive and nonobstructive phenotypes that may help to prevent or ameliorate left ventricular hypertrophy. In this review article, we will define the etiology and clinical phenotypes of HCM, summarize the conventional therapies for obstructive HCM, discuss the emerging targeted therapies as well as novel invasive approaches for obstructive HCM, describe the therapeutic advances for nonobstructive HCM, and outline the future directions for the treatment of HCM.

Lifetime lung function trajectories and COPD: when the train derails

Increasing recognition that chronic respiratory disease originates in early life has shifted the paradigm away from traditional concepts of chronic obstructive pulmonary disease (COPD) as solely a smoker's disease. 1 Martinez FD Early-life origins of chronic obstructive pulmonary disease. N Engl J Med. 2016; 375: 871-878 Crossref PubMed Scopus (277) Google Scholar Building on Fletcher and Peto's landmark publication highlighting smoking-related decline of FEV1, 2 Fletcher C Peto R The natural history of chronic airflow obstruction. BMJ. 1977; 1: 1645-1648 Crossref PubMed Scopus (1800) Google Scholar multiple cohort studies have since implicated altered lung function trajectories originating in childhood in the accelerated development of lung disease. 3 Berry CE Billheimer D Jenkins IC et al. A distinct low lung function trajectory from childhood to the fourth decade of life. Am J Respir Crit Care Med. 2016; 194: 607-612 Crossref PubMed Scopus (114) Google Scholar , 4 Lange P Celli B Agustí A et al. Lung-function trajectories leading to chronic obstructive pulmonary disease. N Engl J Med. 2015; 373: 111-122 Crossref PubMed Scopus (346) Google Scholar , 5 McGeachie MJ Yates KP Zhou X et al. Patterns of growth and decline in lung function in persistent childhood asthma. N Engl J Med. 2016; 374: 1842-1852 Crossref PubMed Scopus (350) Google Scholar , 6 Stern DA Morgan WJ Wright AL Guerra S Martinez FD Poor airway function in early infancy and lung function by age 22 years: a non-selective longitudinal cohort study. Lancet. 2007; 370: 758-764 Summary Full Text Full Text PDF PubMed Scopus (429) Google Scholar This work has revealed that many individuals tend to track along a lung function percentile established in childhood, such that those who begin life at a lower lung function percentile because of adverse perinatal or chronic childhood respiratory conditions are hindered from reaching maximal peak lung function as young adults. Even with the normal age-related rate of lung function decline, these individuals stay on a path with an increased lifetime risk for COPD. Importantly, multiple identified early-life risk factors—including those experienced in utero—alter developmental programming, affecting the timing and course of progression to chronic lung disease. 7 Postma DS Bush A van den Berge M Risk factors and early origins of chronic obstructive pulmonary disease. Lancet. 2015; 385: 899-909 Summary Full Text Full Text PDF PubMed Scopus (318) Google Scholar Lifetime spirometry patterns of obstruction and restriction, and their risk factors and outcomes: a prospective cohort studyTo our knowledge, this is the first study to characterise lifetime phenotypes of obstruction and restriction simultaneously using objective data-driven techniques and unique life course spirometry measures of FEV1/FVC ratio and FVC from childhood to middle age. Mixed and obstructive-only patterns indicate those who might benefit from early COPD interventions. Those with the restrictive-only pattern had evidence of true lung restriction and were at increased risk of multimorbidity by middle age. Full-Text PDF

Posttranslational modifications in pathogenesis of PCOS.

Polycystic ovary syndrome (PCOS) is a lifelong reproductive, metabolic, and psychiatric disorder that affects 5-18% of women, which is associated with a significantly increased lifetime risk of concomitant diseases, including type 2 diabetes, psychiatric disorders, and gynecological cancers. Posttranslational modifications (PTMs) play an important role in changes in protein function and are necessary to maintain cellular viability and biological processes, thus their maladjustment can lead to disease. Growing evidence suggests the association between PCOS and posttranslational modifications. This article mainly reviews the research status of phosphorylation, methylation, acetylation, and ubiquitination, as well as their roles and molecular mechanisms in the development of PCOS. In addition, we briefly summarize research and clinical trials of PCOS therapy to advance our understanding of agents that can be used to target phosphorylated, methylated, acetylated, and ubiquitinated PTM types. It provides not only ideas for future research on the mechanism of PCOS but also ideas for PCOS treatments with therapeutic potential.

Population genomic screening: Ethical considerations to guide age at implementation.

Currently, most genetic testing involves next generation sequencing or panel testing, indicating future population-based screening will involve simultaneous testing for multiple disease risks (called here “panel testing”). Genomic screening typically focuses on single or groups of related disorders, with little utilization of panel testing. Furthermore, the optimal age for test ordering is rarely addressed in terms of whether it should coincide with the age of majority (18 years old) or after the age of majority (26 years old). We conducted an ethical analysis utilizing a hypothetical “narrow” panel test comprised of the CDC Tier 1 Genomic Applications: Familial Hypercholesterolemia (FH), increases individuals’ cardiovascular risk due to elevated low-density lipoprotein (LDL) cholesterol levels; Hereditary Breast and Ovarian Cancer (HBOC), increases lifetime risk of developing cancer; and Lynch Syndrome (LS), increases lifetime risk of developing colorectal cancer. We conducted a utilitarian analysis, on the assumption that health systems seek to maximize utility for patients. Screening at the “age of majority” is preferred for FH due to lowering FH patients’ cholesterol levels via statins providing high lifetime benefits and low risks. Screening “after the age of majority” is preferred for HBOC and LS due to availability of effective surveillance, the recommendation for screening activities to begin at age 26, and prophylactic interventions connected to surveillance. We also utilized a supplemental principlist-based approach that identified relevant concerns and trade-offs. Consideration of clinical, non-clinical, and family planning implications suggests narrow panel testing would be best deployed after 26 (rather than at 18) years of age.

Cardiometabolic multimorbidity and lifetime risk of atrial fibrillation among men and women

Abstract Background Atrial fibrillation (AF) is the most common cardiac arrythmia worldwide, with an increased risk of comorbidity, and significant sex differences in pathophysiology and prognosis. Cardiometabolic disorders, including obesity, hypertension, diabetes mellitus, coronary heart disease, stroke, and heart failure commonly coexist with AF. However, the sex-specific patterns and (combined) impact of cardiometabolic disorders on the risk of new-onset AF remains largely unknown. Purpose To examine the association between patterns of cardiometabolic multimorbidity and new-onset AF and lifetime risk of AF incidence among men and women. Methods 4,113 men and 5,432 women free of prevalent AF at baseline (from 1996 to 2008) from the Rotterdam Study were included. AF incidents were assessed by electrocardiograms and general practitioners' and hospital records, and followed up to January 1st, 2014. Sex-specific Cox proportional hazards regression models were used to assess the association between the amount of cardiometabolic disorders and risks of new-onset AF. Models were adjusted for traditional cardiovascular risk factors. Remaining lifetime risk for AF was estimated across the cardiometabolic multimorbidity groups at index ages of 55, 65, and ≥75 years up to age 108. Results Mean age at baseline was 65.5±9.4 years. Median follow-up time was 10.8 years. In the fully-adjusted model, a significant association was found between the amount of cardiometabolic disorders and incident AF among women but not men. Compared to women without cardiometabolic disorders, women with 3 (hazard ratios, 95% conference intervals: 2.17 (1.24–3.79)) and ≥4 comorbidities (4.58 (2.22–9.48)) had higher AF risks. The lifetime risk for AF was significantly increased with the number of cardiometabolic disorders among both men and women. At index age of 55 years, the lifetime risks (95% confidence interval) for AF were 25.2% (17.1–33.4), 24.2% (20.0–28.9), 27.1% (23.2–31.0), 30.0% (24.3–35.7) and 34.1% (22.4–45.7), for 0, 1, 2, 3, and ≥4 comorbid cardiometabolic disorders among men, respectively. Corresponding risks were 16.3% (6.68–25.9), 20.3% (16.3–24.3), 27.6% (24.1–31.2), 23.6% (17.8–29.4) and 33.3% (16.0–50.2) among women. Conclusions We observed a significant combined impact of cardiometabolic disorders on AF risk, most evidently among women. Participants with cardiometabolic multimorbidity had a significantly increased lifetime risk of AF, especially at a young index age. Funding Acknowledgement Type of funding sources: None.

Prenatal programming of developmental trajectories for obesity risk and early pubertal timing.

The thrifty phenotype and fetal overnutrition hypotheses are two developmental hypotheses that originated from the developmental origins of health and disease (DOHaD) perspective. The DOHaD posits that exposures experienced prenatally and early in life may influence health outcomes through altering form and function of internal organs related to metabolic processes. Obesity risk and early pubertal timing might be influenced by similar mechanisms. The thrifty phenotype hypothesis is primarily characterized by experiencing a deprivation of nutrients during gestation paired with an energy rich postnatal environment. The fetal overnutrition hypothesis says that obesity experienced prenatally will be associated with increased lifetime risk of obesity in the offspring. Both hypotheses were tested by examining developmental pathways from genetic and prenatal risk through early growth trajectories (birth to 7 years) to pubertal timing at age 11 years. Participants included 361 children adopted at birth (57% male; 57% non-Hispanic White, 11% Black, 9% Hispanic; adoptive family income Mdn = $70,000-$100,000, birth family income Mdn = < $15,000). Associations between boys' childhood body mass index (BMI) and pubertal timing were confounded by genetics, prenatal risk, and early growth. The thrifty phenotype hypothesis was partially supported for boys' childhood BMI (at ages 4 to 7 years). Both hypotheses were partially supported for girls' childhood BMI but not pubertal timing. A novel Gene × Prenatal Risk interaction showed that genetic risk predicted girls' childhood BMI most strongly at adequate compared with at excessive levels of gestational weight gain. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Frequent cleft lip and palate in families with pathogenic germline CDH1 variants.

Pathogenic and likely pathogenic (P/LP) germline variants in the tumor suppressor gene CDH1 (E-cadherin) result in increased lifetime risk of diffuse-type gastric cancer and lobular breast cancer. CDH1 variants are also associated with hereditary cleft lip and palate (CLP), the mechanism of which is not well understood. We sought to determine the prevalence of CLP in families who carry P/LP CDH1 variants. Patients with P/LP CDH1 variants who were enrolled in a prospective clinical trial were reviewed (NCT03030404). The cohort included 299 individuals from 153 families that had 80 unique P/LP variants in CDH1. The rate of CLP was 19% (29/153) in families reporting CLP in at least one family member, and 2.7% (8/299) among individuals with confirmed germline CDH1 P/LP variants. There were 22 unique variants in CDH1 among the 29 families that reported CLP, or a CLP rate of 27.5% per variant (22/80). 10 of the variants were not previously reported to be associated with CLP. We observed that 24% (7/29) of CLP-associated gene variants involved large-scale (≥1 exon) deletions. Among families with CLP, 69% (20/29) had a member diagnosed with gastric cancer, and 79% (23/29) had a member with breast cancer, which were similar to rates observed in non-CLP families (p >0.3 for both). Our analysis suggests that the prevalence of CLP in families with germline CDH1 P/LP variants was high in this large cohort, and there was no genotype-phenotype pattern. Genetic testing for CDH1 variants should be considered in families with CLP and history of either diffuse-type gastric or lobular breast cancer.

Hereditary Ovarian Cancer: Towards a Cost-Effective Prevention Strategy.

Ovarian cancer (OC) is the most lethal gynaecological malignancy. The search for a widely affordable and accessible screening strategy to reduce mortality from OC is still ongoing. This coupled with the late-stage presentation and poor prognosis harbours significant health-economic implications. OC is also the most heritable of all cancers, with an estimated 25% of cases having a hereditary predisposition. Advancements in technology have detected multiple mutations, with the majority affecting the BRCA1 and/or BRCA2 genes. Women with BRCA mutations are at a significantly increased lifetime risk of developing OC, often presenting with a high-grade serous pathology, which is associated with higher mortality due to its aggressive characteristic. Therefore, a targeted, cost-effective approach to prevention is paramount to improve clinical outcomes and mortality. Current guidelines offer multiple preventive strategies for individuals with hereditary OC (HOC), including genetic counselling to identify the high-risk women and risk-reducing interventions (RRI), such as surgical management or chemoprophylaxis through contraceptive medications. Evidence for sporadic OC is abundant as compared to the existing dearth in the hereditary subgroup. Hence, our review article narrates an overview of HOC and explores the RRI developed over the years. It attempts to compare the cost effectiveness of these strategies with women of the general population in order to answer the crucial question: what is the most prudent clinically and economically effective strategy for prevention amongst high-risk women?

Risk‐reducing mastectomy decisions among women with mutations in high‐ and moderate‐ penetrance breast cancer susceptibility genes

BackgroundWomen harboring mutations in breast cancer susceptibility genes are at increased lifetime risk of developing breast cancer and are faced with decisions about risk management, including whether to undergo high‐risk screening or risk‐reducing mastectomy (RRM). National guidelines recommend BRCA1 or BRCA2 mutation carriers consider RRM, but that carriers of moderate penetrance mutations (e.g., ATM or CHEK2) should be managed based on family history. We aimed to investigate determinants of decision for RRM, and hypothesized that mutation status, age, family history, partner status, and breast cancer would impact RRM decision making.MethodsWe performed a retrospective study assessing RRM decisions for 279 women.ResultsWomen with BRCA and moderate penetrance gene mutations, a personal history of breast cancer, or a first degree relative with a history of breast cancer were more likely to undergo RRM. Breast cancer status and age showed an interaction effect such that women with breast cancer were less likely to undergo RRM with increasing age.ConclusionAlthough national guidelines do not recommend RRM for moderate penetrance carriers, the rates of RRM for this population approached those for BRCA mutation carriers. Further insights are needed to better support RRM decision‐making in this population.

Does Dose Matter? Ionizing Radiation Exposure of the Veterinary Patient From Computed Tomography: A Discussion

Advanced imaging techniques such as computed tomography are commonplace in human medicine and increasingly, are being utilized by the veterinary profession as scanners become more available and affordable. The benefit of computed tomography imaging is the provision of detailed cross-sectional imaging and 3D reconstruction, but this incurs higher doses of ionizing radiation to the patient. This paper reviews risks and effects associated with ionizing radiation, making comparisons to human models, and a hypothetical scenario is discussed using the human risk model for age at time of exposure and increased lifetime risk of cancer with a dog to human year's formula. Various issues are considered with respect to dose reduction, training, equipment and the reported “greater need for guidance and the establishment of best practice” which may lead to future guidance from the International Commission on Radiological Protection.

Childhood exposure to war and adult onset of cardiometabolic disorders among older Europeans

Childhood exposure to contexts of war is a common occurrence among current and recent cohorts of children in various parts of the world. It was also common among older cohorts across Europe. Utilizing the Survey of Health, Ageing, and Retirement in Europe (SHARE) the present study links early life course residential histories with detailed information on the timing and location of hostilities during WWII to address three questions: 1) is childhood exposure to war associated with earlier onset of cardiometabolic disease (cardiovascular disease, hypertension, high cholesterol, and diabetes)? 2) did this additional risk vary depending on the timing of first exposure? 3) did this additional risk manifest via different life course pathways depending on exposure timing? Results demonstrate that exposure to war is associated with increased lifetime risk of cardiovascular disease, diabetes, high cholesterol, and hypertension and that this association is strongly concentrated among cohorts exposed in utero or during early childhood (e.g., before age 8). The results also suggest that the impact of war exposure on cardiometabolic disorders are likely to be direct, operating through latent biological processes rather than through childhood hardship, stunting of adult socioeconomic attainment, or elevated risk-taking behaviors.

Functional assessment of missense variants of uncertain significance in the cancer susceptibility gene PALB2

Germline PALB2 pathogenic variants are associated with an increased lifetime risk for breast, pancreatic, and ovarian cancer. However, the interpretation of the pathogenicity of numerous PALB2 missense variants of uncertain significance (VUSs) identified in germline genetic testing remains a challenge. Here we selected ten potentially pathogenic PALB2 VUSs identified in 2279 Chinese patients with breast cancer and evaluated their impacts on PALB2 function by systematic functional assays. We showed that three PALB2 VUSs p.K16M [c.47 A > T], p.L24F [c.72 G > C], and p.L35F [c.103 C > T] in the coiled-coil domain impaired PALB2-mediated homologous recombination. The p.L24F and p.L35F variants partially disrupted BRCA1-PALB2 interactions, reduced RAD51 foci formation in response to DNA damage, abrogated ionizing radiation-induced G2/M checkpoint maintenance, and conferred increased sensitivity to olaparib and cisplatin. The p.K16M variant presented mild effects on BRCA1-PALB2 interactions and RAD51 foci formation. Altogether, we identify two novel PALB2 VUSs, p.L24F and p.L35F, that compromise PALB2 function and may increase cancer risk. These two variants display marked olaparib and cisplatin sensitivity and may help predict response to targeted therapy in the clinical treatment of patients with these variants.