Heterogeneity in host susceptibility is a key determinant of infectious disease dynamics but is rarely accounted for in assessment of disease control measures. Understanding how susceptibility is distributed in populations, and how control measures change this distribution, is integral to predicting the course of epidemics with and without interventions. Using multiple experimental and modeling approaches, we show that rainbow trout have relatively homogeneous susceptibility to infection with infectious hematopoietic necrosis virus and that vaccination increases heterogeneity in susceptibility in a nearly all-or-nothing fashion. In a simple transmission model with an R0 of 2, the highly heterogeneous vaccine protection would cause a 35 percentage-point reduction in outbreak size over an intervention inducing homogenous protection at the same mean level. More broadly, these findings provide validation of methodology that can help to reduce biases in predictions of vaccine impact in natural settings and provide insight into how vaccination shapes population susceptibility.

BackgroundDespite approval of immunotherapy for a wide range of cancers, the majority of patients fail to respond to immunotherapy or relapse following initial response. These failures may be attributed to immunosuppressive mechanisms co-opted by tumor cells. However, it is challenging to use conventional methods to systematically evaluate the potential of tumor intrinsic factors to act as immune regulators in patients with cancer.MethodsTo identify immunosuppressive mechanisms in non-responders to cancer immunotherapy in an unbiased manner, we performed genome-wide CRISPR immune screens and integrated our results with multi-omics clinical data to evaluate the role of tumor intrinsic factors in regulating two rate-limiting steps of cancer immunotherapy, namely, T cell tumor infiltration and T cell-mediated tumor killing.ResultsOur studies revealed two distinct types of immune resistance regulators and demonstrated their potential as therapeutic targets to improve the efficacy of immunotherapy. Among them, PRMT1 and RIPK1 were identified as a dual immune resistance regulator and a cytotoxicity resistance regulator, respectively. Although the magnitude varied between different types of immunotherapy, genetically targeting PRMT1 and RIPK1 sensitized tumors to T-cell killing and anti-PD-1/OX40 treatment. Interestingly, a RIPK1-specific inhibitor enhanced the antitumor activity of T cell-based and anti-OX40 therapy, despite limited impact on T cell tumor infiltration.ConclusionsCollectively, the data provide a rich resource of novel targets for rational immuno-oncology combinations.

Objective Examine patterns of contraceptive use and contraceptive transitions over time among an Australian cohort of women through their later reproductive years. Study design Latent Transition Analysis was performed using data on 8,197 women from the Australian Longitudinal Study on Women’s Health’s 1973–78 cohort to identify distinct patterns of contraceptive use across 2006, 2012 and 2018. Women were excluded from the analysis at time points where they were not at risk of an unintended pregnancy. Latent status membership probabilities, item-response probabilities, transitions probabilities and the effect of predictors on latent status membership were estimated and reported. Results Patterns of contraceptive use were relatively consistent over time, particularly for high efficacy contraceptive methods with 71% of women using long-acting reversible contraceptives in 2012 also using long-acting reversible contraceptives in 2018. Multiple contraceptive use was highest in 2006 when women were aged 28–33 years (19.3%) but declined over time to 14.3% in 2018 when women were aged 40–45 years. Overall, contraceptive patterns stabilised as the women moved into their late 30s and early 40s. Conclusions Although fertility declines with age, the stability of contraceptive choice and continued use of short-acting contraception among some women suggests that a contraceptive review may be helpful for women during perimenopause so that they are provided with contraceptive options most appropriate to their specific circumstances.

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Background Chronic disease represents an ongoing public health challenge in Australia with women disproportionately affected and at younger ages compared to men. Accurate prevalence and ascertainment of chronic disease among women of reproductive age at the population level is essential for meeting the family planning and reproductive health challenges that chronic diseases pose. This study estimated the prevalence of chronic disease among younger Australian women of reproductive age, in order to ascertain key conditions that would benefit from targeted family planning support strategies. Methods and findings Population-level survey data from the 1973–78 and 1989–95 cohorts of the Australian Longitudinal Study on Women’s Health were linked to health service use, pharmaceutical, cancer and cause of death data to ascertain the prevalence and chronic disease trends for ten chronic health conditions associated with poor maternal and foetal outcomes. Individual chronic disease algorithms were developed for each chronic disease of interest using the available linked datasets. Lifetime prevalence of chronic disease varied substantially based on each individual data source for each of the conditions of interest. When all data sources were considered, all conditions with the exception of mental health conditions were higher among women in the 1973–78 cohort. However, when focused on point prevalence at similar ages (approximately 25–30 years), the chronic disease trend for women in the 1989–95 cohort was substantially higher, particularly for mental health conditions (70.4% vs 23.6%), diabetes (4.5% vs 1.3%) and multimorbidity (17.9% vs 9.1%). Conclusions Given the low concordance between individual data sources, the use of multiple data sources are recommended for chronic disease research focused on women of reproductive age. In order to reduce the increasing chronic disease and multimorbidity trend among women, strategic chronic disease interventions are required to be implemented in childhood and adolescence to ensure the long-term health of not only current but also future generations.