Association of self-rated health with multimorbidity, chronic disease and psychosocial factors in a large middle-aged and older cohort from general practice: a cross-sectional study.

BACKGROUND: The prevalence of coexisting chronic conditions (multimorbidity) is rising. Disease labels, however, give little information about impact on subjective health and personal illness experience. We aim to examine the strength of association of single and multimorbid physical chronic diseases with self-rated health in a middle-aged and older population in England, and to determine whether any association is mediated by depression and other psychosocial factors. METHODS: 25 268 individuals aged 39 to 79 years recruited from general practice registers in the European Prospective Investigation of Cancer (EPIC-Norfolk) study, completed a survey including self-rated health, psychosocial function and presence of common physical chronic conditions (cancer, stroke, heart attack, diabetes, asthma/bronchitis and arthritis). Logistic regression models determined odds of "moderate/poor" compared to "good/excellent" health by condition and number of conditions adjusting for psychosocial measures. RESULTS: One-third (8252) reported one, around 7.5% (1899) two, and around 1% (194) three or more conditions. Odds of "moderate/poor" self-rated health worsened with increasing number of conditions (one (OR = 1.3(1.2-1.4)) versus three or more (OR = 3.4(2.3-5.1)), and were highest where there was comorbidity with stroke (OR = 8.7(4.6-16.7)) or heart attack (OR = 8.5(5.3-13.6)). Psychosocial measures did not explain the association between chronic diseases and multimorbidity with self-rated health.The relationship of multimorbidity with self-rated health was particularly strong in men compared to women (three or more conditions: men (OR = 5.2(3.0-8.9)), women OR = 2.1(1.1-3.9)). CONCLUSIONS: Self-rated health provides a simple, integrative patient-centred assessment for evaluation of illness in the context of multiple chronic disease diagnoses. Those registering in general practice in particular men with three or more diseases or those with cardiovascular comorbidities and with poorer self-rated health may warrant further assessment and intervention to improve their physical and subjective health.EPIC-Norfolk is supported by programme grants from Medical Research Council UK (G9502233, G0300128) and Cancer Research UK (C865/A2883), with additional support from the European Union, Stroke Association, Research into Ageing, British Heart Foundation, Department of Health and Wellcome Trust.This is the final version. It was first published by BioMed Central at http://www.biomedcentral.com/1471-2296/15/18

Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk:an international prospective cohort of BRCA1 and BRCA2 mutation carriers

Background The effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer risk for BRCA1 and BRCA2 mutation carriers is uncertain. Retrospective analyses have suggested a protective effect but may be substantially biased. Prospective studies have had limited power, particularly for BRCA2 mutation carriers. Further, previous studies have not considered the effect of RRSO in the context of natural menopause. Methods A multi-centre prospective cohort of 2272 BRCA1 and 1605 BRCA2 mutation carriers was followed for a mean of 5.4 and 4.9 years, respectively; 426 women developed incident breast cancer. RRSO was modelled as a time-dependent covariate in Cox regression, and its effect assessed in premenopausal and postmenopausal women. Results There was no association between RRSO and breast cancer for BRCA1 (HR = 1.23; 95% CI 0.94-1.61) or BRCA2 (HR = 0.88; 95% CI 0.62-1.24) mutation carriers. For BRCA2 mutation carriers, HRs were 0.68 (95% CI 0.40-1.15) and 1.07 (95% CI 0.69-1.64) for RRSO carried out before or after age 45 years, respectively. The HR for BRCA2 mutation carriers decreased with increasing time since RRSO (HR = 0.51; 95% CI 0.26-0.99 for 5 years or longer after RRSO). Estimates for premenopausal women were similar. Conclusion We found no evidence that RRSO reduces breast cancer risk for BRCA1 mutation carriers. A potentially beneficial effect for BRCA2 mutation carriers was observed, particularly after 5 years following RRSO. These results may inform counselling and management of carriers with respect to RRSO.</p

What determines the self-rated health of older individuals with stroke compared to other older individuals? A cross-sectional analysis of the Medical Research Council Cognitive Function and Aging Study.

BACKGROUND: Poor self-rated health has been associated with poorer objective health outcomes across a range of conditions including stroke. Identification of factors associated with poor self-rated health in stroke survivors has received little attention compared to that in other older individuals. This study identifies determinants of self-rated health in older individuals with or without a history of stroke participating in the population-representative MRC Cognitive Function and Aging Study (MRC CFAS). METHODS: The MRC CFAS is a multicentred longitudinal survey of a population representative sample of people in their 65th year and older at baseline. Baseline interview included questions about functional disability, psychiatric history, independent living status, social interactions, and cognitive function. Multiple logistic regression was used to determine associations between demographic, physical, cognitive, psychological and social factors with poor self-rated health among those with and without stroke. RESULTS: After excluding those with impaired cognitive function, 776 individuals out of 11,957 reported a stroke. Factors associated with self-rated health were similar between those with or without a stroke in older individuals. Poorer self-rated health in those who had suffered a stroke was associated predominantly with the presence of comorbidity with diabetes (OR 3.5; 95% CI 1.5-8.1) and not "getting out and about" (OR 2.6; 95% CI 1.7-4.1) even after adjustment for disability levels and for depression. In those without a stroke the most important determinants were disability (OR 3.9; 95% CI 3.2-4.8) and not "getting out and about" (OR 2.9; 95% CI 2.5-3.3). The presence of disability was less strongly associated with poor self-rated health in those with a history of stroke than those without due to a substantially higher reporting of poor self-rated health in the non-disabled stroke group than the non-disabled stroke-free group, while those with disabilities reported poor self-rated health irrespective of stroke status. CONCLUSIONS: Self-rated health is determined by a range of psychological and social factors in addition to disability in older patients with stroke. Addressing social integration and mobility out of the home is an important element of rehabilitation for older people with stroke as well as those without

Polygenic risk score is associated with increased disease risk in 52 Finnish breast cancer families

The risk of developing breast cancer is increased in women with family history of breast cancer and particularly in families with multiple cases of breast or ovarian cancer. Nevertheless, many women with a positive family history never develop the disease. Polygenic risk scores (PRSs) based on the risk effects of multiple common genetic variants have been proposed for individual risk assessment on a population level. We investigate the applicability of the PRS for risk prediction within breast cancer families. We studied the association between breast cancer risk and a PRS based on 75 common genetic variants in 52 Finnish breast cancer families including 427 genotyped women and pedigree information on similar to 4000 additional individuals by comparing the affected to healthy family members, as well as in a case-control dataset comprising 1272 healthy population controls and 1681 breast cancer cases with information on family history. Family structure was summarized using the BOADICEA risk prediction model. The PRS was associated with increased disease risk in women with family history of breast cancer as well as in women within the breast cancer families. The odds ratio (OR) for breast cancer within the family dataset was 1.55 [95 % CI 1.26-1.91] per unit increase in the PRS, similar to OR in unselected breast cancer cases of the case-control dataset (1.49 [1.38-1.62]). High PRS-values were informative for risk prediction in breast cancer families, whereas for the low PRS-categories the results were inconclusive. The PRS is informative in women with family history of breast cancer and should be incorporated within pedigree-based clinical risk assessment.Peer reviewe

Compliance with Australian stroke guideline recommendations for outdoor mobility and transport training by post-inpatient rehabilitation services: an observational cohort study

Background: Community participation is often restricted after stroke, due to reduced confidence and outdoor mobility. Australian clinical guidelines recommend that specific evidence-based interventions be delivered to target these restrictions, such as multiple escorted outdoor journeys. The aim of this study was to describe post-inpatient outdoor mobility and transport training delivered to stroke survivors in New South Wales, Australia and whether therapy differed according to type, sector or location of service provider. Methods: Using an observational retrospective cohort study design, 24 rehabilitation service providers were audited. Provider types included outpatient (n = 8), day therapy (n = 9), home-based rehabilitation (n = 5) and transitional aged care services (TAC, n = 2). Records of 15 stroke survivors who had received post-hospital rehabilitation were audited per service, for wait time, duration, amount of therapy and outdoor-related therapy. Results: A total of 311 records were audited. Median wait time for post-hospital therapy was 13 days (IQR, 5–35). Median duration of therapy was 68 days (IQR, 35–109), consisting of 11 sessions (IQR 4–19). Overall, a median of one session (IQR 0–3) was conducted outdoors per person. Outdoor-related therapy was similar across service providers,except that TAC delivered an average of 5.4 more outdoor-related sessions (95 % CI 4.4 to 6.4), and 3.5 more outings into public streets (95 % CI 2.8 to 4.3) per person, compared to outpatient services. Conclusion: The majority of service providers in the sample delivered little evidence-based outdoor mobility and travel training per stroke participant, as recommended in national stroke guidelines

Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers

$\textbf{Background:}$ Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes $\textit{BRCA1}$ or $\textit{BRCA2}$. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. $\textbf{Methods:}$ We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through populationbased GWAS: for BC (overall, estrogen receptor [ER]–positive, and ER-negative) and for OC. Using data from 15 252 female $\textit{BRCA1}$ and 8211 $\textit{BRCA2}$ carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. $\textbf{Results:}$ The PRS for ER-negative BC displayed the strongest association with BC risk in $\textit{BRCA1}$ carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, $P$ = 8.2 $\times$ 10$^{-53}$). In $\textit{BRCA2}$ carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, $P$ = 7.2 $\times$ 10$^{-20}$). The OC PRS was strongly associated with OC risk for both $\textit{BRCA1}$ and $\textit{BRCA2}$ carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom AR deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for $\textit{BRCA2}$ carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. $\textbf{Conclusions:}$ BC and OC PRS are predictive of cancer risk in $\textit{BRCA1}$ and $\textit{BRCA2}$ carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.Cancer Research U

Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management

Health Humanities curriculum and evaluation in health professions education: a scoping review

Background The articulation of learning goals, processes and outcomes related to health humanities teaching currently lacks comparability of curricula and outcomes, and requires synthesis to provide a basis for developing a curriculum and evaluation framework for health humanities teaching and learning. This scoping review sought to answer how and why the health humanities are used in health professions education. It also sought to explore how health humanities curricula are evaluated and whether the programme evaluation aligns with the desired learning outcomes. Methods A focused scoping review of qualitative and mixed-methods studies that included the influence of integrated health humanities curricula in pre-registration health professions education with programme evaluate of outcomes was completed. Studies of students not enrolled in a pre-registration course, with only ad-hoc health humanities learning experiences that were not assessed or evaluated were excluded. Four databases were searched (CINAHL), (ERIC), PubMed, and Medline. Results The search over a 5 year period, identified 8621 publications. Title and abstract screening, followed by full-text screening, resulted in 24 articles selected for inclusion. Learning outcomes, learning activities and evaluation data were extracted from each included publication. Discussion Reported health humanities curricula focused on developing students’ capacity for perspective, reflexivity, self- reflection and person-centred approaches to communication. However, the learning outcomes were not consistently described, identifying a limited capacity to compare health humanities curricula across programmes. A set of clearly stated generic capabilities or outcomes from learning in health humanities would be a helpful next step for benchmarking, clarification and comparison of evaluation strategy

Incorporating Alternative Polygenic Risk Scores into the BOADICEA Breast Cancer Risk Prediction Model

Background: The multifactorial risk prediction model BOADI-CEA enables identification of women at higher or lower risk of developing breast cancer. BOADICEA models genetic susceptibility in terms of the effects of rare variants in breast cancer susceptibility genes and a polygenic component, decomposed into an unmeasured and a measured component -the polygenic risk score (PRS). The current version was developed using a 313 SNP PRS. Here, we evaluated approaches to incorporating this PRS and alternative PRS in BOADICEA.Methods: The mean, SD, and proportion of the overall polygenic component explained by the PRS (a2) need to be estimated. a was estimated using logistic regression, where the age-specific log-OR is constrained to be a function of the age-dependent polygenic relative risk in BOADICEA; and using a retrospective likelihood (RL) approach that models, in addition, the unmeasured polygenic component.Results: Parameters were computed for 11 PRS, including 6 variations of the 313 SNP PRS used in clinical trials and imple-mentation studies. The logistic regression approach underestimates a, as compared with the RL estimates. The RL a estimates were very close to those obtained by assuming proportionality to the OR per 1 SD, with the constant of proportionality estimated using the 313 SNP PRS. Small variations in the SNPs included in the PRS can lead to large differences in the mean.Conclusions: BOADICEA can be readily adapted to different PRS in a manner that maintains consistency of the model.Impact : The methods described facilitate comprehensive breast cancer risk assessment

An insulator loop resides between the synthetically interacting elements of the human/rat conserved breast cancer susceptibility locus MCS5A/Mcs5a

Many low-penetrance breast cancer susceptibility loci are found to be located in non-protein-coding regions, suggesting their involvement in gene expression regulation. We identified the human/rat-conserved breast cancer susceptibility locus MCS5A/Mcs5a. This locus has been shown to act in a non-mammary cell-autonomous fashion through the immune system. The resistant Mcs5a allele from the Wistar–Kyoto (WKy) rat strain consists of two non-protein-coding genetic elements that must be located on the same chromosome to elicit the phenotype. In this study, we show the presence of a conserved higher order chromatin structure in MCS5A/Mcs5a located in between the synthetically interacting genetic elements. The looped elements are shown to be bound by CTCF and cohesin. We identify the downregulation of Fbxo10 expression in T cells as a strong candidate mechanism through which the interacting genetic elements of the resistant Mcs5a allele modulate mammary carcinoma susceptibility. Finally, we show that the human MCS5A polymorphisms associated with breast cancer risk are located at both sides of the looped structure and functionally interact to downregulate transcriptional activity, similar to rat Mcs5a. We propose a mechanistic model for MCS5a/Mcs5a in which a CTCF-mediated insulator loop encompassing the TOMM5/Tomm5 gene, resides in between and brings into closer physical proximity the synthetically and functionally interacting resistant genetic variants