The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With BRCA1 or BRCA2 Mutations

Background: Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers. Methods: Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort. Results: For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] ¼ 0.99, 95% confidence interval [CI] ¼ 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc¼ 0.79, 95% CI ¼ 0.69 to 0.91; HRc¼ 0.70, 95% CI ¼ 0.59 to 0.82; HRc¼ 0.50, 95% CI ¼ 0.40 to 0.63, for 2, 3, and 4 FTPs, respectively, Ptrend < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort Ptrend ¼ .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] ¼ 1.69, 95% CI ¼ 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc ¼ 1.33, 95% CI ¼ 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc¼ 0.72, 95% CI ¼ 0.54 to 0.98). Conclusions: These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers

Modelling heterogeneity in viral-tumour dynamics: The effects of gene-attenuation on viral characteristics

The use of viruses as a cancer treatment is becoming increasingly more robust; however, there is still a long way to go before a completely successful treatment is formulated. One major challenge in the field is to select which virus, out of a burgeoning number of oncolytic viruses and engineered derivatives, can maximise both treatment spread and anticancer cytotoxicity. To assist in solving this problem, an in-depth understanding of the virus-tumour interaction is crucial. In this article, we present a novel integro-differential system with distributed delays embodying the dynamics of an oncolytic adenovirus with a fixed population of tumour cells in vitro, allowing for heterogeneity to exist in the virus and cell populations. The parameters of the model are optimised in a hierarchical manner, the purpose of which is not to obtain a perfect representation of the data. Instead, we place our parameter values in the correct region of the parameter space. Due to the sparse nature of the data it is not possible to obtain the parameter values with any certainty, but rather we demonstrate the suitability of the model. Using our model we quantify how modifications to the viral genome alter the viral characteristics, specifically how the attenuation of the E1B 19 and E1B 55 gene affect the system performance, and identify the dominant processes altered by the mutations. From our analysis, we conclude that the deletion of the E1B 55 gene significantly reduces the replication rate of the virus in comparison to the deletion of the E1B 19 gene. We also found that the deletion of both the E1B 19 and E1B 55 genes resulted in a long delay in the average replication start time of the virus. This leads us to propose the use of E1B 19 gene-attenuated adenovirus for cancer therapy, as opposed to E1B 55 gene-attenuated adenoviruses.</p

Health, Burnout and Wellbeing of UK Cardiology Trainees: Insights from the British Junior Cardiologists’ Association Survey

Background: Cardiology training is demanding and associated with high workloads. Poor lifestyle and health among clinicians may stretch workforces and impact patient care. It has not been established what impact training in cardiology has on the doctors undertaking it. We aimed to establish the prevalence of physical and mental illness, burnout and the ability to maintain a healthy lifestyle among cardiology trainees in the United Kingdom (UK). Methods: The 2023 British Junior Cardiologists’ Association training survey included questions on ill health, burnout, healthy living and invited responders to complete screening questionnaires for depression (Patient Health Questionnaire 9; PHQ-9) and anxiety (Generalised Anxiety Disorder 7; GAD-7). Significant anxiety and depression were defined as scoring within the moderate or severe range (PHQ-9≥10; GAD-7≥10). Burnout was a self-reported outcome. Poisson regression was used to determine prevalence ratios (PR) between univariate predictors of anxiety, depression and burnout. Results: Of 398 responders, 212 consented to answer health and well-being questions. Prior physical and mental health conditions were reported by 9% and 7% of trainees, respectively. Significant depression and anxiety symptoms were reported by 25% and 18% of trainees, respectively. Burnout was reported by 76% of trainees. Less than full-time trainees reported greater anxiety (PR 2.92, 95% CI 1.39 to 6.16, p<0.01) and depression (PR 3.66, 95% CI 2.24 to 5.98, p<0.01), while trainees with dependents reported less burnout (PR 0.77, 95% CI 0.65 to 0.92, p<0.01). Exercise, good sleep quality and maintaining a healthy diet were associated with less burnout and depressive symptoms (p<0.05). Half of trainees reported training having a negative impact on well-being, driven by the amount of service provision, curriculum requirements and lack of training opportunities. Conclusions: The prevalence of anxiety, depression and burnout is high among UK cardiology trainees. Further work should establish the impact of cardiology trainee health on the quality of patient care. Training bodies should consider how occupational factors may contribute to health