Clinical validity assessment of a breast cancer risk model combining genetic and clinical information

_Background:_ The extent to which common genetic variation can assist in breast cancer (BCa) risk assessment is unclear. We assessed the addition of risk information from a panel of BCa-associated single nucleotide polymorphisms (SNPs) on risk stratification offered by the Gail Model.

_Methods:_ We selected 7 validated SNPs from the literature and genotyped them among white women in a nested case-control study within the Women’s Health Initiative Clinical Trial. To model SNP risk, previously published odds ratios were combined multiplicatively. To produce a combined clinical/genetic risk, Gail Model risk estimates were multiplied by combined SNP odds ratios. We assessed classification performance using reclassification tables and receiver operating characteristic (ROC) curves. 

_Results:_ The SNP risk score was well calibrated and nearly independent of Gail risk, and the combined predictor was more predictive than either Gail risk or SNP risk alone. In ROC curve analysis, the combined score had an area under the curve (AUC) of 0.594 compared to 0.557 for Gail risk alone. For reclassification with 5-year risk thresholds at 1.5% and 2%, the net reclassification index (NRI) was 0.085 (Z = 4.3, P = 1.0×10^-5^). Focusing on women with Gail 5-year risk of 1.5-2% results in an NRI of 0.195 (Z = 3.8, P = 8.6×10^−5^).

_Conclusions:_ Combining clinical risk factors and validated common genetic risk factors results in improvement in classification of BCa risks in white, postmenopausal women. This may have implications for informing primary prevention and/or screening strategies. Future research should assess the clinical utility of such strategies.
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Efficient Replication of Over 180 Genetic Associations with Self-Reported Medical Data

While the cost and speed of generating genomic data have come down dramatically in recent years, the slow pace of collecting medical data for large cohorts continues to hamper genetic research. Here we evaluate a novel online framework for amassing large amounts of medical information in a recontactable cohort by assessing our ability to replicate genetic associations using these data. Using web-based questionnaires, we gathered self-reported data on 50 medical phenotypes from a generally unselected cohort of over 20,000 genotyped individuals. Of a list of genetic associations curated by NHGRI, we successfully replicated about 75% of the associations that we expected to (based on the number of cases in our cohort and reported odds ratios, and excluding a set of associations with contradictory published evidence). Altogether we replicated over 180 previously reported associations, including many for type 2 diabetes, prostate cancer, cholesterol levels, and multiple sclerosis. We found significant variation across categories of conditions in the percentage of expected associations that we were able to replicate, which may reflect systematic inflation of the effects in some initial reports, or differences across diseases in the likelihood of misdiagnosis or misreport. We also demonstrated that we could improve replication success by taking advantage of our recontactable cohort, offering more in-depth questions to refine self-reported diagnoses. Our data suggests that online collection of self-reported data in a recontactable cohort may be a viable method for both broad and deep phenotyping in large populations

Public housing and healthcare use: Determining whether public housing functions as an intervention using linked population-based administrative data

Introduction Public housing is a form of subsidized housing that is owned and/or managed by government. Previous research suggests that public housing has a positive impact on personal finances and education outcomes, but less is known about if/how it impacts health and healthcare use. Objectives and Approach Using linked administrative health and social data, we tested for changes in healthcare use among a cohort who moved into public housing in 2012 and 2013 in Manitoba, Canada, and compared utilization to a matched general population cohort who did not move into public housing. Generalized linear models with generalized estimating equations tested for differences in numbers of healthcare contacts in the years before and after the move-in date, adjusted for economic, residential mobility, and health characteristics. The data were modeled using a Poisson (rate ratio, RR), negative binomial (incident rate ratio, IRR), or a binomial (odds ratio, OR) distribution. Results There were 2619 residents in the public housing cohort; 99.7% were matched to the general population. The cohort by time interaction was statistically significant for inpatient days (p Conclusion/Implications Public housing residents were more likely to use healthcare services than the matched population, but changes in use were similar in the two cohorts. There is little evidence that public housing impacts healthcare use, but it serves an important function of meeting basic needs for a vulnerable population group

Covid Sex Lives: How the Pandemic Impacted the Sex Lives of Men Who Have Sex With Men

During the COVID-19 pandemic, messages from the government and public health organizations aimed at stopping the spread of the coronavirus were turned into media campaigns targeting different groups. The COVID Sex Lives project sought to understand how these messages affected the experiences Men Who Have Sex with Men (MSM) in the United Kingdom when it came to their sex lives and using digital platforms for sexual purposes. Over the past two decades, dating and hookup apps have become popular ways for people to meet and connect, even during the pandemic, and MSM have been early adopters of these technologies for dating, hooking up, and combating loneliness. The research project, a collaboration between the University of Salford, Newcastle University, King's College London, and Birmingham City University, was funded by the Arts and Humanities Research Council and aimed to understand how health messages during the pandemic affected the sex lives of MSM, their sexual health and overall well-being during and after this challenging time.The research team conducted four online surveys between April 2021 and January 2022 with a total of 1,409 responses from MSM, as well as analysis of relevant topics in the media, on health organisation websites and on Twitter. In the surveys, participants gave brutally honest and vibrant answers about their experiences, these were sometimeshilarious and sometimes heart-breaking. This zine aims to show some of the key themes that came from the research, whilst giving space to the variety of voices of UK MSM thatappeared in our data. They demonstrate the frustration, challenges, and spirit of a community navigating an unprecedented period of global uncertainty in their personal and intimate lives

The Covid Sex Lives Project: Health Messaging, Hooking Up And Dating Among Men Who Have Sex With Men During The UK COVID-19 Pandemic

In the context of the pandemic, government and public health measures to mitigate the spread of coronavirus have been translated into media messaging by organisations that target the health of different groups. Engaging experiences of the minority group, men who have sex with men (MSM), we provide evidence on the approaches and responses to these messages in relation to using digital platforms to connect for sexual purposes.Dating and hookup applications, or apps, are a key area where sex and romance has been negotiated over the past two decades, a trend which continued during the pandemic. MSM are an ideal group to look atthe challenges posed here as they have been early adopters of these technologies for a variety of purposes, including the obvious ones related to dating and hooking up as well as for increasing more general sociality and reducing loneliness.Due to this culture of engagement with digital media by MSM, and whatis known about their sexual cultures, digital platforms have been engaged by health educators in an attempt to improve the sexual health and wellbeing of this group. The question in the context of a pandemic therefore becomes: how are these sexual cultures affected, and how might health messaging be engaged with, or not

An open electromagnetic tracking framework applied to targeted liver tumour ablation

Purpose: Electromagnetic tracking is a core platform technology in the navigation and visualisation of image-guided procedures. The technology provides high tracking accuracy in non-line-of-sight environments, allowing instrument navigation in locations where optical tracking is not feasible. EMT can be beneficial in applications such as percutaneous radiofrequency ablation for the treatment of hepatic lesions where the needle tip may be obscured due to difficult liver environments (e.g subcutaneous fat or ablation artefacts). Advances in the field of EMT include novel methods of improving tracking system accuracy, precision and error compensation capabilities, though such system-level improvements cannot be readily incorporated in current therapy applications due to the ‘blackbox’ nature of commercial tracking solving algorithms. Methods: This paper defines a software framework to allow novel EMT designs, and improvements become part of the global design process for image-guided interventions. An exemplary framework is implemented in the Python programming language and demonstrated with the open-source Anser EMT system. The framework is applied in the preclinical setting though targeted liver ablation therapy on an animal model. Results: The developed framework was tested with the Anser EMT electromagnetic tracking platform. Liver tumour targeting was performed using the tracking framework with the CustusX navigation platform using commercially available electromagnetically tracked needles. Ablation of two tumours was performed with a commercially available ablation system. Necropsy of the tumours indicated ablations within 5 mm of the tumours. Conclusions: An open-source framework for electromagnetic tracking was presented and effectively demonstrated in the preclinical setting. We believe that this framework provides a structure for future advancement in EMT system in and customised instrument design

Neurofibromin Deficient Myeloid Cells are Critical Mediators of Aneurysm Formation In Vivo

Background Neurofibromatosis Type 1 (NF1) is a genetic disorder resulting from mutations in the NF1 tumor suppressor gene. Neurofibromin, the protein product of NF1, functions as a negative regulator of Ras activity in circulating hematopoietic and vascular wall cells, which are critical for maintaining vessel wall homeostasis. NF1 patients have evidence of chronic inflammation resulting in development of premature cardiovascular disease, including arterial aneurysms, which may manifest as sudden death. However, the molecular pathogenesis of NF1 aneurysm formation is unknown. Method and Results Utilizing an angiotensin II-induced aneurysm model, we demonstrate that heterozygous inactivation of Nf1 (Nf1+/−) enhanced aneurysm formation with myeloid cell infiltration and increased oxidative stress in the vessel wall. Using lineage-restricted transgenic mice, we show loss of a single Nf1 allele in myeloid cells is sufficient to recapitulate the Nf1+/− aneurysm phenotype in vivo. Finally, oral administration of simvastatin or the antioxidant apocynin, reduced aneurysm formation in Nf1+/− mice. Conclusion These data provide genetic and pharmacologic evidence that Nf1+/− myeloid cells are the cellular triggers for aneurysm formation in a novel model of NF1 vasculopathy and provide a potential therapeutic target

Terminal osteoblast differentiation, mediated by runx2 and p27KIP1, is disrupted in osteosarcoma

The molecular basis for the inverse relationship between differentiation and tumorigenesis is unknown. The function of runx2, a master regulator of osteoblast differentiation belonging to the runt family of tumor suppressor genes, is consistently disrupted in osteosarcoma cell lines. Ectopic expression of runx2 induces p27KIP1, thereby inhibiting the activity of S-phase cyclin complexes and leading to the dephosphorylation of the retinoblastoma tumor suppressor protein (pRb) and a G1 cell cycle arrest. Runx2 physically interacts with the hypophosphorylated form of pRb, a known coactivator of runx2, thereby completing a feed-forward loop in which progressive cell cycle exit promotes increased expression of the osteoblast phenotype. Loss of p27KIP1 perturbs transient and terminal cell cycle exit in osteoblasts. Consistent with the incompatibility of malignant transformation and permanent cell cycle exit, loss of p27KIP1 expression correlates with dedifferentiation in high-grade human osteosarcomas. Physiologic coupling of osteoblast differentiation to cell cycle withdrawal is mediated through runx2 and p27KIP1, and these processes are disrupted in osteosarcoma

A cluster-randomised, non-inferiority trial of the impact of a two-dose compared to three-dose schedule of pneumococcal conjugate vaccination in rural Gambia: the PVS trial.

BACKGROUND: Pneumococcal conjugate vaccines (PCV) effectively prevent pneumococcal disease but the global impact of pneumococcal vaccination is hampered by the cost of PCV. The relevance and feasibility of trials of reduced dose schedules is greatest in middle- and low-income countries, such as The Gambia, where PCV has been introduced with good disease control but where transmission of vaccine-type pneumococci persists. We are conducting a large cluster-randomised, non-inferiority, field trial of an alternative reduced dose schedule of PCV compared to the standard schedule, the PVS trial. METHODS: PVS is a prospective, cluster-randomised, non-inferiority, real-world field trial of an alternative schedule of one dose of PCV scheduled at age 6 weeks with a booster dose at age 9 months (i.e. the alternative '1 + 1' schedule) compared to the standard schedule of three primary doses scheduled at 6, 10, and 14 weeks of age (i.e. the standard '3 + 0' schedule). The intervention will be delivered for 4 years. The primary endpoint is the population-level prevalence of nasopharyngeal vaccine-type pneumococcal carriage in children aged 2 weeks to 59 months with clinical pneumonia in year 4 of the trial. Participants and field staff are not masked to group allocation while measurement of the laboratory endpoint will be masked. Sixty-eight geographic population clusters have been randomly allocated, in a 1:1 ratio, to each schedule and all resident infants are eligible for enrolment. All resident children less than 5 years of age are under continuous surveillance for clinical safety endpoints measured at 11 health facilities; invasive pneumococcal disease, radiological pneumonia, clinical pneumonia, and hospitalisations. Secondary endpoints include the population-level prevalence of nasopharyngeal vaccine-type pneumococcal carriage in years 2 and 4 and vaccine-type carriage prevalence in unimmunised infants aged 6-12 weeks in year 4. The trial includes components of mathematical modelling, health economics, and health systems research. DISCUSSION: Analysis will account for potential non-independence of measurements by cluster, comparing the population-level impact of the two schedules with interpretation at the individual level. The non-inferiority margin is informed by the 'acceptable loss of effect' of the alternative compared to the standard schedule. The secondary endpoints will provide substantial evidence to support the interpretation of the primary endpoint. PVS will evaluate the effect of transition from a standard 3+ 0 schedule to an alternative 1 + 1 schedule in a setting of high pneumococcal transmission. The results of PVS will inform global decision-making concerning the use of reduced-dose PCV schedules. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number 15056916 . Registered on 15 November 2018