Frequency of pathogenic germline variants in BRCA1, BRCA2, PALB2, CHEK2 and TP53 in ductal carcinoma in situ diagnosed in women under the age of 50 years.

INTRODUCTION: Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive ductal breast cancer, and approximately 20% of screen-detected tumours are pure DCIS. Most risk factors for breast cancer have similar associations with DCIS and IDC; however, there is limited data on the prevalence of the known high and moderate penetrance breast cancer predisposition genes in DCIS and which women with DCIS should be referred for genetic screening. The aim of this study was to assess the frequency of germline variants in BRCA2, BRCA1, CHEK2, PALB2 and TP53 in DCIS in women aged less than 50 years of age. METHODS: After DNA extraction from the peripheral blood, Access Array technology (Fluidigm) was used to amplify all exons of these five known breast cancer predisposition genes using a custom made targeted sequencing panel in 655 cases of pure DCIS presenting in women under the age of 50 years together with 1611 controls. RESULTS: Case-control analysis revealed an excess of pathogenic variants in BRCA2 (OR = 27.96, 95%CI 6.56-119.26, P = 2.0 × 10-10) and CHEK2 (OR = 8.04, 95%CI 2.93-22.05, P = 9.0 × 10-6), with weaker associations with PALB2 (P = 0.003), BRCA1 (P = 0.007) and TP53 (P = 0.02). For oestrogen receptor (ER)-positive DCIS the frequency of pathogenic variants was 9% under the age of 50 (14% with a family history of breast cancer) and 29% under the age of 40 (42% with a family history of breast cancer). For ER-negative DCIS, the frequency was 9% (16% with a family history of breast cancer) and 8% (11% with a family history of breast cancer) under the ages of 50 and 40, respectively. CONCLUSIONS: This study has shown that breast tumourigenesis in women with pathogenic variants in BRCA2, CHEK2, PALB2, BRCA1 and TP53 can involve a DCIS precursor stage and that the focus of genetic testing in DCIS should be on women under the age of 40 with ER-positive DCIS.

Association between fish consumption and risk of dementia: a new study from China and a systematic literature review and meta-analysis.

OBJECTIVE: To assess the association of fish consumption with risk of dementia and its dose-response relationship, and investigate variations in the association among low-, middle- and high-income countries. DESIGN: A new community-based cross-sectional study and a systematic literature review.SettingsUrban and rural communities in China; population-based studies systematically searched from worldwide literature. SUBJECTS: Chinese adults aged ≥60 years in six provinces (n 6981) took part in a household health survey of dementia prevalence and risk factors. In addition, 33 964 participants from eleven published and eligible studies were included in the systematic review and meta-analysis. RESULTS: In the new study in China, 326 participants were diagnosed with dementia (4·7 %); those who consumed any amount of fish in the past two years v. those who consumed no fish had reduced risk of dementia (adjusted OR=0·73, 95 % CI 0·64, 0·99), but the dose-response relationship was not statistically significant. The meta-analysis of available data from the literature and the new study showed relative risk (RR) of dementia of 0·80 (95 % CI 0·74, 0·87) for people with fish consumption; the impact was similar among countries with different levels of income. Pooled dose-response data revealed RR (95 % CI) of 0·84 (0·72, 0·98), 0·78 (0·68, 0·90) and 0·77 (0·61, 0·98) in people with low, middle and high consumption of fish, respectively. Corresponding figures for Alzheimer's disease were 0·88 (0·74, 1·04), 0·79 (0·65, 0·96) and 0·67 (0·58, 0·78), respectively. CONCLUSIONS: Greater consumption of fish is associated with a lower risk of dementia. Increasing fish consumption may help prevent dementia worldwide regardless of income level.

Exposure to air pollution and cognitive functioning across the life course--A systematic literature review.

OBJECTIVES: Air pollution is associated with increased risk of respiratory, cardiovascular and cerebrovascular disease, but its association with cognitive functioning and impairment is unclear. The aim of this systematic review was to examine whether a relationship exists between these variables across the life course. METHODS: We searched Web of Knowledge, Pubmed, SciVerse Scopus, CINAHL, PsychInfo and Science Direct up to October 2015 to identify studies that investigated the association between air pollution and performance on neurocognitive tests. RESULTS: Variations in exposure assessment and outcome measures make meta-analysis impossible. Thirty one studies published between 2006 and 2015, from the Americas (n=15), Asia (n=5) and Europe (n=11), met the criteria for inclusion. Many showed weak but quantified relationships between various air pollutants and cognitive function. Pollution exposure in utero has been associated with increased risk of neuro-developmental delay. Exposure in childhood has been inversely associated with neuro-developmental outcomes in younger children and with academic achievement and neurocognitive performance in older children. In older adults, air pollution has been associated with accelerated cognitive decline. CONCLUSIONS: The evidence to date is coherent in that exposure to a range of largely traffic-related pollutants has been associated with quantifiable impairment of brain development in the young and cognitive decline in the elderly. There is insufficient evidence at present to comment on consistency, in view of the different indices of pollution and end-points measured, the limited number of studies, and the probability at this stage of publication bias. However, plausible toxicological mechanisms have been demonstrated and the evidence as a whole suggests that vehicular pollution, at least, contributes to cognitive impairment, adding to pressure on governments and individuals to continue to reduce air pollution.

Assessing CSF ctDNA to Improve Diagnostic Accuracy and Therapeutic Monitoring in Breast Cancer Leptomeningeal Metastasis.

PURPOSE: Cerebrospinal fluid (CSF) cytology is the gold standard diagnostic test for breast cancer leptomeningeal metastasis (BCLM), but has impaired sensitivity, often necessitating repeated lumbar puncture to confirm or refute diagnosis. Further, there is no quantitative response tool to assess response or progression during BCLM treatment. EXPERIMENTAL DESIGN: Facing the challenge of working with small-volume samples and the lack of common recurrent mutations in breast cancers, cell-free DNA was extracted from the CSF and plasma of patients undergoing investigation for BCLM (n = 30). ctDNA fraction was assessed by ultra-low-pass whole genome sequencing (ulpWGS), which does not require prior tumor sequencing. RESULTS: In this proof-of-concept study, ctDNA was detected (fraction ≥0.10) in the CSF of all 24 patients with BCLM+ (median ctDNA fraction, 0.57), regardless of negative cytology or borderline MRI imaging, whereas CSF ctDNA was not detected in the six patients with BCLM- (median ctDNA fraction 0.03, P < 0.0001). Plasma ctDNA was only detected in patients with extracranial disease progression or who had previously received whole brain radiotherapy. ctDNA fraction was highly concordant with mutant allele fraction measured by tumor mutation-specific ddPCR assays (r = 0.852; P < 0.0001). During intrathecal treatment, serial monitoring (n = 12 patients) showed that suppression of CSF ctDNA fraction was associated with longer BCLM survival (P = 0.034), and rising ctDNA fraction was detectable up to 12 weeks before clinical progression. CONCLUSIONS: Measuring ctDNA fraction by ulpWGS is a quantitative marker demonstrating potential for timely and accurate BCLM diagnosis and therapy response monitoring, with the ultimate aim to improve management of this poor-prognosis patient group.

Associations of coping styles with nonsuicidal self-injury in adolescents: Do they vary with gender and adverse childhood experiences?

BACKGROUND: The impact of positive coping style on non-suicidal self-injury in adolescents remains unclear, while negative coping style increases the risk of non-suicidal self-injury (NSSI). There is less investigation on gender differences in the impacts of positive coping style and negative coping style on NSSI. It is unknown whether the impacts vary with different levels of adverse childhood experiences (ACEs). AIMS: To identify gender differences in the impacts of positive coping style and negative coping style on NSSI, and investigate the impacts at different levels of ACEs. METHOD: An adolescent health survey was conducted in 15 schools in China between November 2013 and January 2014. 9704 students aged 11-19 years completed standard questionnaires to record the details of coping style, NSSI and ACEs. RESULTS: 38.5 % of adolescents had ≥1 NSSI over the past 12 months. NSSI was significantly increased with the low positive coping style in girls with ≥3 ACEs, but not with 0 and 1-2 ACEs, and not in boys with any levels of ACEs. NSSI was increased with high negative coping style in both girls and boys across all ACEs. The negative coping style impact was stronger in girls than in boys (odds ratio 1.66, p < 0.05), especially in those with 1-2 ACEs. CONCLUSIONS: Adolescents at high risk of NSSI in relation to coping styles should be targeted accordingly. Reducing negative coping style in girls and boys and improving positive coping style in girls who have high ACEs could help prevent NSSI in adolescents.

Association between socioeconomic status and incident stroke in China.

BACKGROUND: Little is known about the impact of socioeconomic status (SES) on incidence of stroke in China. This study aimed to examine the association of SES, which was measured by different indicators, with incidence of stroke and gender differences in the association. METHODS AND RESULTS: Two prospective cohort studies were conducted including 2852 participants aged ≥60 years in Anhui province and 3016 participants in four other provinces in China. During a median follow-up of 7.1 years, 211 incident stroke cases occurred in the Anhui cohort. The risk of stroke increased with living in rural areas (adjusted HR 2.49, 95% CI 1.19 to 5.22; women 3.64, 95% CI 1.17 to 11.32, men 2.23, 95% CI 0.81 to 6.19), but not significantly with educational level, occupational class, satisfactory income and financial problems (except for women with low education). The four-province cohort had 113 incident stroke cases over the 3.1 years' follow-up. The five SES indicators were not significantly associated with incident stroke (except for increased risk in men with high occupation), but additional measurement for actual income showed that incident stroke increased in women with low personal income and in men with high family income. Pooled data from the two cohorts demonstrated the impacts of rural living (1.66, 95% CI 1.08 to 2.57) and having high occupational class (1.56, 95% CI 1.01 to 2.38), and gender differences for women with low education (2.26, 95% CI 1.19 to 4.27). CONCLUSIONS: Rural living and being female with low SES are associated with increased stroke risk in China. Strategies to improve public health in the rural communities and gender-specific targets for health inequality should be an integral component of stroke interventions.

Association of Internet Addiction With Nonsuicidal Self-injury Among Adolescents in China.

Importance: Both nonsuicidal self-injury (NSSI), defined as the direct, deliberate damage of one's body tissue without suicidal intent, and internet addiction among adolescents are public health concerns. However, the possible association of NSSI with internet addiction is not well understood. Objective: To examine the occurrence of internet addiction with NSSI and any sex differences among Chinese adolescents. Design, Setting, and Participants: A multicenter, cross-sectional, survey study was conducted from February 18 to October 15, 2015, among adolescents aged 11 to 20 years from 343 classes in 45 public high schools across 5 provinces of China. Data analysis was performed from August 1, 2018, to March 1, 2019. Exposures: Possible internet addiction and internet addiction. Main Outcomes and Measures: Less-frequent (1-4 times) NSSI and more-frequent (≥5 times) NSSI were surveyed using the Chinese version of the Functional Assessment of Self-Mutilation. Results: A total of 15 623 students (8043 male [51.5%] and 7580 female [48.5%]) aged 11 to 20 years (mean [SD] age, 15.1 [1.8] years) participated. Of these, 4670 participants (29.9%) met the criteria for possible internet addiction and 509 participants (3.3%) met the criteria for internet addiction. A total of 2667 students (17.1%) engaged in less-frequent NSSI, while 1798 students (11.5%) engaged in more-frequent NSSI in the 12 months preceding the survey. Both possible internet addiction and internet addiction were associated with less-frequent or more-frequent NSSI. The adjusted odds ratios were 1.29 (95% CI, 1.17-1.42) for possible internet addiction and 1.41 (95% CI, 1.11-1.80) for internet addiction for less-frequent NSSI; for more-frequent NSSI, the adjusted odds ratios were 1.75 (95% CI, 1.56-1.96) for possible internet addiction and 2.66 (95% CI, 2.10-3.38) for internet addiction. These associations were similarly observed among age groups of 11 to 14, 15 to 17, and 18 to 20 years. No sex disparities were found in the associations of internet addiction with NSSI, except among adolescents aged 11 to 14 years, where the odds ratios for possible internet addiction with less-frequent NSSI were higher in male adolescents (1.53; 95% CI, 1.25-1.88) than female adolescents (1.13; 95% CI, 0.90-1.47). Conclusion and Relevance: Internet addiction appears to be associated with NSSI, and the findings of this study suggest that the association was similar between male adolescents and female adolescents. These data suggest that evaluation of the risk of NSSI for adolescents in association with internet addiction may help health care professionals in developing preventive interventions for NSSI.

Impacts of Overweight and Obesity in Older Age on the Risk of Dementia: A Systematic Literature Review and a Meta-Analysis.

BACKGROUND: It is unclear whether overweight and obesity in older age reduces or increases the risk of incident dementia. OBJECTIVE: To assess the impacts of overweight and obesity in older age on incident dementia. METHODS: We searched cohort studies reporting body weight measured in older age and dementia through PubMed, Embase, Medline, PyschInfo, and Cochrane library until July 2016. Sixteen articles were identified for the review. We pooled data from them and a new unpublished study from China, to calculate relative risk (RR) of incident dementia in relation to body mass index (BMI) and waist circumference (WC). RESULTS: All 16 cohort studies were undertaken in high income countries, with follow-up periods ranging between 3 to 18 years. Thirteen studies showed an inverse association between BMI and dementia, and three studies demonstrated a positive association. Pooled RR of dementia in relation to continuous BMI from 14 studied populations, including the new Chinese data, was 0.97 (95% CI 0.95-1.00); in those followed up <9 years it was 0.95 (0.93-0.96) while in ≥9 years follow-up it was 1.03 (0.96-1.11). In five studied populations examining categorical BMI, RR of dementia in older people classified as overweight and obese was 0.98 (0.54-1.77) and 1.17 (0.65-2.10) respectively, in comparison with other weights. The pooled WC data showed no association between increased WC and reduced risk of dementia. CONCLUSION: The current evidence did not support a paradox on beneficial impacts of overweight and obesity in older age on incident dementia. More studies with long term follow up are needed to clarify the association of body weight in older age with dementia risk.

Frequency of Pathogenic Germline Variants in CDH1, BRCA2, CHEK2, PALB2, BRCA1, and TP53 in Sporadic Lobular Breast Cancer.

BACKGROUND: Invasive lobular breast cancer (ILC) accounts for approximately 15% of invasive breast carcinomas and is commonly associated with lobular carcinoma in situ (LCIS). Both have been shown to have higher familial risks than the more common ductal cancers. However, there are little data on the prevalence of the known high and moderate penetrance breast cancer predisposition genes in ILC. The aim of this study was to assess the frequency of germline variants in CDH1, BRCA2, BRCA1, CHEK2, PALB2, and TP53 in sporadic ILC and LCIS diagnosed in women ages ≤60 years. METHODS: Access Array technology (Fluidigm) was used to amplify all exons of CDH1, BRCA2, BRCA1, TP53, CHEK2, and PALB2 using a custom-made targeted sequencing panel in 1,434 cases of ILC and 368 cases of pure LCIS together with 1,611 controls. RESULTS: Case-control analysis revealed an excess of pathogenic variants in BRCA2, CHEK2, PALB2, and CDH1 in women with ILC. CHEK2 was the only gene that showed an association with pure LCIS [OR = 9.90; 95% confidence interval (CI), 3.42-28.66, P = 1.4 × 10-5] with a larger effect size seen in LCIS compared with ILC (OR = 4.31; 95% CI, 1.61-11.58, P = 1.7 × 10-3). CONCLUSIONS: Eleven percent of patients with ILC ages ≤40 years carried germline variants in known breast cancer susceptibility genes. IMPACT: Women with ILC ages ≤40 years should be offered genetic screening using a panel of genes that includes BRCA2, CHEK2, PALB2, and CDH1.

Anti-Folate Receptor Alpha-Directed Antibody Therapies Restrict the Growth of Triple-negative Breast Cancer.

Purpose: Highly aggressive triple-negative breast cancers (TNBCs) lack validated therapeutic targets and have high risk of metastatic disease. Folate receptor alpha (FRα) is a central mediator of cell growth regulation that could serve as an important target for cancer therapy.Experimental Design: We evaluated FRα expression in breast cancers by genomic (n = 3,414) and IHC (n = 323) analyses and its association with clinical parameters and outcomes. We measured the functional contributions of FRα in TNBC biology by RNA interference and the antitumor functions of an antibody recognizing FRα (MOv18-IgG1), in vitro, and in human TNBC xenograft models.Results: FRα is overexpressed in significant proportions of aggressive basal like/TNBC tumors, and in postneoadjuvant chemotherapy-residual disease associated with a high risk of relapse. Expression is associated with worse overall survival. TNBCs show dysregulated expression of thymidylate synthase, folate hydrolase 1, and methylenetetrahydrofolate reductase, involved in folate metabolism. RNA interference to deplete FRα decreased Src and ERK signaling and resulted in reduction of cell growth. An anti-FRα antibody (MOv18-IgG1) conjugated with a Src inhibitor significantly restricted TNBC xenograft growth. Moreover, MOv18-IgG1 triggered immune-dependent cancer cell death in vitro by human volunteer and breast cancer patient immune cells, and significantly restricted orthotopic and patient-derived xenograft growth.Conclusions: FRα is overexpressed in high-grade TNBC and postchemotherapy residual tumors. It participates in cancer cell signaling and presents a promising target for therapeutic strategies such as ADCs, or passive immunotherapy priming Fc-mediated antitumor immune cell responses. Clin Cancer Res; 24(20); 5098-111. ©2018 AACR.

Prevalence and determinants of undetected dementia in the community: a systematic literature review and a meta-analysis.

OBJECTIVES: Detection of dementia is essential for improving the lives of patients but the extent of underdetection worldwide and its causes are not known. This study aimed to quantify the prevalence of undetected dementia and to examine its correlates. METHODS/SETTING/PARTICIPANTS: A systematic search was conducted until October 2016 for studies reporting the proportion of undetected dementia and/or its determinants in either the community or in residential care settings worldwide. Random-effects models calculated the pooled rate of undetected dementia and subgroup analyses were conducted to identify determinants of the variation. PRIMARY AND SECONDARY OUTCOME MEASURES: The outcome measures of interest were the prevalence and determinants of undetected dementia. RESULTS: 23 studies were eligible for inclusion in this review. The pooled rate of undetected dementia was 61.7% (95% CI 55.0% to 68.0%). The rate of underdetection was higher in China and India (vs Europe and North America), in the community setting (vs residential/nursing care), age of <70 years, male gender and diagnosis by general practitioner. However, it was lower in the studies using Mini-Mental State Examination (MMSE) diagnosis criteria. CONCLUSIONS: The prevalence of undetected dementia is high globally. Wide variations in detecting dementia need to be urgently examined, particularly in populations with low socioeconomic status. Efforts are required to reduce diagnostic inequality and to improve early diagnosis in the community.

Demographic and socio-economic influences on community-based care and caregivers of people with dementia in China.

BACKGROUND: Dementia is a major public health challenge and China has the largest population with dementia in the world. However, dementia care and caregivers for Chinese are less investigated. OBJECTIVES AND DESIGN: To evaluate demographic and socio-economic influences on dementia care, management patterns and caregiver burden in a household community-dwelling-based survey, using participants' care receipts and Zarit scale. SETTING AND PARTICIPANTS: Rural and urban communities across six provinces of China comprising 4837 residents aged ≥60 years, in whom 398 had dementia and 1312 non-dementia diseases. RESULTS: People with dementia were less likely to receive care if they were living in rural compared to urban areas (Odd ratio (OR) = 0.20; 95%CI: 0.10-0.41), having education level below compared to above secondary school (OR = 0.24; 95%CI: 0.08-0.70), manual labourer compared to non-manual workers (OR = 0.27; 95%CI: 0.13-0.55), having personal annual income below RMB 10,000 yuan (£1000) compared to above (OR = 0.37; 95%CI: 0.13-0.74) or having four or more than compared to less four children (OR = 0.52; 95%CI: 0.27-1.00). Caregivers for dementia compared with those for non-dementia diseases were younger and more likely to be patients' children or children in-law, had lower education and spent more caring time. Caregiver burden increased with low education, cutback on work and caring for patients who were younger or living in rural areas, and this caregiver burden was three-fold greater than that for non-dementia diseases. CONCLUSIONS: There are a number of inequalities in dementia care and caregiver burden in China. Reducing the socio-economic gap and increasing education may improve community care for people with dementia and preserve caregivers' well-being.

Is exposure to secondhand smoke associated with cognitive parameters of children and adolescents?--a systematic literature review.

PURPOSE: Despite the known association of second hand smoke (SHS) with increased risk of ill health and mortality, the effects of SHS exposure on cognitive functioning in children and adolescents are unclear. Through a critical review of the literature we sought to determine whether a relationship exists between these variables. METHODS: The authors systematically reviewed articles (dated 1989-2012) that investigated the association between SHS exposure (including in utero due to SHS exposure by pregnant women) and performance on neurocognitive and academic tests. Eligible studies were identified from searches of Web of Knowledge, MEDLINE, Science Direct, Google Scholar, CINAHL, EMBASE, Zetoc, and Clinicaltrials.gov. RESULTS: Fifteen articles were identified, of which 12 showed inverse relationships between SHS and cognitive parameters. Prenatal SHS exposure was inversely associated with neurodevelopmental outcomes in young children, whereas postnatal SHS exposure was associated with poor academic achievement and neurocognitive performance in older children and adolescents. Furthermore, SHS exposure was associated with an increased risk of neurodevelopmental delay. CONCLUSIONS: Recommendations should be made to the public to avoid sources of SHS and future research should investigate interactions between SHS exposure and other risk factors for delayed neurodevelopment and poor cognitive performance.

Effects of maternal cigarette smoking during pregnancy on cognitive parameters of children and young adults: a literature review.

The long term effects of maternal smoking during pregnancy on the cognitive development of the child are not well understood due to conflicting findings in past research. The aim of this paper was to provide an up to date, critical review of the literature to determine whether there is evidence of a relationship between tobacco smoke exposure in utero and cognitive functioning. We systematically reviewed observational studies (dated 2000-2011) that examined associations between tobacco smoke exposure in utero due to maternal smoking and performance on cognitive, intelligence, neurodevelopmental and academic tests. Eligible studies were identified through searches of Web of Knowledge, Medline, Science Direct, Google Scholar, CINAHL, EMBASE, Zetoc and Clinicaltrials.gov databases. The review found evidence of a relationship between tobacco smoke exposure in utero and reduced academic achievement and cognitive abilities independent of other variables. Maternal smoking during pregnancy may therefore be a modifiable risk factor for reduced cognitive abilities later in the life of the child. Giving up smoking during pregnancy should be initiated as early as possible to reduce the impact on the child's cognitive development.

Doing, seeing, or both: effects of learning condition on subsequent action perception.

It has been proposed that common codes for vision and action emerge from associations between an individual's production and simultaneous observation of actions. This typically first-person view of one's own action subsequently transfers to the third-person view when observing another individual. We tested vision-action associations and the transfer from first-person to third-person perspective by comparing novel hand-action sequences that were learned under three conditions: first, by being performed and simultaneously viewed from a first-person perspective; second, by being performed but not seen; and third, by being seen from a first-person view without being executed. We then used functional magnetic resonance imaging (fMRI) to compare the response to these three types of learned action sequences when they were presented from a third-person perspective. Visuomotor areas responded most strongly to sequences that were learned by simultaneously producing and observing the action sequences. We also note an important asymmetry between vision and action: Action sequences learned by performance alone, in the absence of vision, facilitated the emergence of visuomotor responses, whereas action sequences learned by viewing alone had comparably little effect. This dominance of action over vision supports the notion of forward/predictive models of visuomotor systems.