Machine learning enables pan-cancer identification of mutational hotspots at persistent CTCF binding sites.

CCCTC-binding factor (CTCF) is an insulator protein that binds to a highly conserved DNA motif and facilitates regulation of three-dimensional (3D) nuclear architecture and transcription. CTCF binding sites (CTCF-BSs) reside in non-coding DNA and are frequently mutated in cancer. Our previous study identified a small subclass of CTCF-BSs that are resistant to CTCF knock down, termed persistent CTCF binding sites (P-CTCF-BSs). P-CTCF-BSs show high binding conservation and potentially regulate cell-type constitutive 3D chromatin architecture. Here, using ICGC sequencing data we made the striking observation that P-CTCF-BSs display a highly elevated mutation rate in breast and prostate cancer when compared to all CTCF-BSs. To address whether P-CTCF-BS mutations are also enriched in other cell-types, we developed CTCF-INSITE-a tool utilising machine learning to predict persistence based on genetic and epigenetic features of experimentally-determined P-CTCF-BSs. Notably, predicted P-CTCF-BSs also show a significantly elevated mutational burden in all 12 cancer-types tested. Enrichment was even stronger for P-CTCF-BS mutations with predicted functional impact to CTCF binding and chromatin looping. Using in vitro binding assays we validated that P-CTCF-BS cancer mutations, predicted to be disruptive, indeed reduced CTCF binding. Together this study reveals a new subclass of cancer specific CTCF-BS DNA mutations and provides insights into their importance in genome organization in a pan-cancer setting.

Expanding access to fracture liaison services in Australia for people with minimal trauma fractures: a system dynamics modelling study.

OBJECTIVES: To project how many minimal trauma fractures could be averted in Australia by expanding the number and changing the operational characteristics of fracture liaison services (FLS). STUDY DESIGN: System dynamics modelling. SETTING, PARTICIPANTS: People aged 50 years or more who present to hospitals with minimal trauma fractures, Australia, 2020-31. MAIN OUTCOME MEASURES: Numbers of all minimal trauma fractures and of hip fractures averted by increasing the FLS number (from 29 to 58 or 100), patient screening rate (from 30% to 60%), and capacity for accepting new patients (from 40 to 80 per service per month), and reducing the proportion of eligible patients who do not attend FLS (from 30% to 15%); cost per fracture averted. RESULTS: Our model projected a total of 2 441 320 minimal trauma fractures (258 680 hip fractures; 2 182 640 non-hip fractures) in people aged 50 years or older during 2020-31, including 1 211 646 second or later fractures. Increasing the FLS number to 100 averted a projected 5405 fractures (0.22%; $39 510 per fracture averted); doubling FLS capacity averted a projected 3674 fractures (0.15%; $35 835 per fracture averted). Our model projected that neither doubling the screening rate nor reducing by half the proportion of eligible patients who did not attend FLS alone would reduce the number of fractures. Increasing the FLS number to 100, the screening rate to 60%, and capacity to 80 new patients per service per month would together avert a projected 13 672 fractures (0.56%) at a cost of $42 828 per fracture averted. CONCLUSION: Our modelling indicates that increasing the number of hospital-based FLS and changing key operational characteristics would achieve only moderate reductions in the number of minimal trauma fractures among people aged 50 years or more, and the cost would be relatively high. Alternatives to specialist-led, hospital-based FLS should be explored.

Young children experience both regret and relief in a gain-or-loss context.

Recent research has provided compelling evidence that children experience the negative counterfactual emotion of regret, by manipulating the presence of a counterfactual action that would have led to participants receiving a better outcome. However, it remains unclear if children similarly experience regret's positive counterpart, relief. The current study examined children's negative and positive counterfactual emotions in a novel gain-or-loss context. Four- to 9-year-old children (N = 136) were presented with two opaque boxes concealing information that would lead to a gain or loss of stickers, respectively. Half of the children chose between two keys that matched each box, whereas the other half were compelled to select one box because only one of the two keys matched. After seeing inside the alternative, non-chosen box, children were significantly more likely to report a change in emotion when they could have opened that box than when they could not have. The effects were similar for children who lost stickers and won stickers, and neither effect varied with age. These findings suggest that children may become capable of experiencing regret and relief around the same time, although their expression of these counterfactual emotions may vary with actual and counterfactual gains and losses.

Vibration assisted rehabilitation in patients with Pompe disease: A case series.

The results of three cases with infantile-onset Pompe disease participating in a rehabilitation program with home-based vibration training will be presented. In this retrospective observational case study, the cases participated in the neuromuscular training program "Auf die Beine", which combines two blocks of intensive, goal directed training with 6 months of home-based whole body vibration (WBV). Assessments by the means of a dual-energy X-ray absorptiometry and grip strength were applied at multiple points throughout the program. Two cases showed an increase in lean mass index of +0.319 kg/m2, +0.721 kg/m2 and bone mineral content of +0.028 kg/m2, +0.031 kg/m2 over one year. Additionally physiotherapeutic therapy goals could be achieved. In the remaining child lean mass index did not change, bone mineral content decreased by -0.03 kg. The neuromuscular rehabilitation program "Auf die Beine" has shown to be safe and effective in two of three cases for muscle and bone mass gain as well as in achievement of physiotherapeutic goals. To summarize, WBV is an innovative therapy in a rehabilitation concept, which might be helpful in Pompe disease, but further studies with larger cohorts are needed.

Dual Energy X-ray Absorptiometry Reports Fail to Adhere to International Guidelines.

INTRODUCTION: Bone mineral density, measured by dual X-ray absorptiometry (DXA), is the gold standard for diagnosis of osteoporosis. The utility of DXA relies on the accuracy of scan acquisition, interpretation of data, and the adequacy of reports. The International Society for Clinical Densitometry (ISCD) has published guidelines regarding minimum reporting guidelines. This study assessed whether DXA reports for patients receiving care at an academic teaching hospital adhere to these reporting standards, and determine whether differences exist depending on patient factors and the imaging service. METHODS: Patients aged ≥18 years, receiving care at specialist outpatient clinics between January 1, 2018 and December 31, 2019, with a DXA report available, were eligible for inclusion. DXA reports were manually reviewed for adherence to ISCD guidelines, with each criterion scored as one point, giving a total score of 14 for baseline DXA scans and 18 for repeat DXA scans. The score was then converted to a percentage. RESULTS: Of 459 DXA scans included, 214 were performed internally at our hospital and 245 performed at 23 external imaging services. Mean (SD) patient age was 60 (16.3) years, and 75.8% were female. The overall median (IQR) report score was 57.1% (42.9, 82.4). ISCD criteria with the lowest scores were recommendation and timing of future DXA scans (included in 1.1% of reports) and investigation for secondary causes of osteoporosis (included in 1.2% of reports). Reports performed internally had significantly higher scores than those performed externally, after adjusting for age, sex, indication, and type of scan (incidence rate ratio 1.83, 95% confidence interval 1.77, 1.89). Baseline DXA reports had slightly higher scores than repeat DXA scans, and, among external imaging services, rural services had higher scores than metropolitan services. CONCLUSION: This study, the largest comprehensive evaluation of DXA reports, highlights significant deficiencies and variation in report standards between imaging services. This has potential implications for osteoporosis diagnosis and management.

Circular permutation profiling by deep sequencing libraries created using transposon mutagenesis.

Deep mutational scanning has been used to create high-resolution DNA sequence maps that illustrate the functional consequences of large numbers of point mutations. However, this approach has not yet been applied to libraries of genes created by random circular permutation, an engineering strategy that is used to create open reading frames that express proteins with altered contact order. We describe a new method, termed circular permutation profiling with DNA sequencing (CPP-seq), which combines a one-step transposon mutagenesis protocol for creating libraries with a functional selection, deep sequencing and computational analysis to obtain unbiased insight into a protein's tolerance to circular permutation. Application of this method to an adenylate kinase revealed that CPP-seq creates two types of vectors encoding each circularly permuted gene, which differ in their ability to express proteins. Functional selection of this library revealed that >65% of the sampled vectors that express proteins are enriched relative to those that cannot translate proteins. Mapping enriched sequences onto structure revealed that the mobile AMP binding and rigid core domains display greater tolerance to backbone fragmentation than the mobile lid domain, illustrating how CPP-seq can be used to relate a protein's biophysical characteristics to the retention of activity upon permutation.

A 4-d Water Intake Intervention Increases Hydration and Cognitive Flexibility among Preadolescent Children.

BACKGROUND: Hydration effects on cognition remain understudied in children. This is concerning since a large proportion of US children exhibit insufficient hydration. OBJECTIVE: This study investigated the effects of water intake on urinary markers of hydration and cognition among preadolescents. METHODS: A 3-intervention crossover design was used among 9- to 11-y-olds [n = 75 (43 males, 32 females); 58.2 ± 28.5 BMI percentile]. Participants maintained their water intake [ad libitum (AL)] or consumed high (2.5 L/d) or low (0.5 L/d) water for 4 d. The primary outcomes were performance on cognitive tasks requiring inhibition, working memory, and cognitive flexibility assessed using a modified flanker, go/no-go, and color-shape switch tasks, respectively. Secondary outcomes included urine hydration indices [i.e., color, urine specific gravity (USG), osmolality] assessed using 24-h urine collected during day 4 of each intervention. Repeated-measures ANOVAs were used to assess intervention effects. RESULTS: There was a significant difference in hydration across all 3 interventions. Urine color during the low intervention [median (IQR): 6 (2)] was greater than during AL [5 (2)], and both were greater than during the high intervention [18 (0)] (all P ≤ 0.01). Similarly, osmolality [low (mean ± SD): 912 ± 199 mOsmol/kg, AL: 790 ± 257.0 mOsmol/kg, high: 260 ± 115 mOsmol/kg] and USG [low (mean ± SD): 1.023 ± 0.005, AL: 1.020 ± 0.007, high: 1.005 ± 0.004] during the low intervention were greater during AL, and both were greater than during the high intervention (all P ≤ 0.01). USG and osmolality AL values were related to switch task measures (ß: 0.21 to -0.31, P < 0.05). Benefits of the high intervention were observed during the switch task, whereby participants exhibited 34% lower working memory cost relative to the low intervention. No significant changes in cognition were observed for the flanker and go/no-go tasks. CONCLUSIONS: The water intervention improved urinary markers of hydration and had selective benefits during task switching. Furthermore, children's cognitive flexibility selectively benefits from greater habitual hydration and water intake. This study is registered at clinicaltrials.gov as NCT02816450.

A cross-cultural analysis of the Test of Memory Malingering among Latin American Spanish-speaking adults.

Cognitive efforts tests, such as the Test of Memory Malingering (TOMM; Tombaugh, 1997), are widely used internationally, yet there is a dearth of research that has assessed the utility of these measures in different cultures, countries, and languages. This study evaluated the specificity of the TOMM Trial 2 among a sample of 3,590 Spanish-speaking adults residing in 8 Latin American countries (Argentina, Bolivia, Chile, Colombia, Mexico, Paraguay, Peru, and Puerto Rico). Trial 2 TOMM scores were negatively associated with participants' age and positively associated with level of education. Country development, as measured by the United Nations Human Development Index, was also positively associated with TOMM scores. With the widespread use of cognitive efforts tests, this study offers useful insights into the utility of the TOMM in the assessment of Spanish speakers and highlights potential cultural biases that may impact test performance. Furthermore, this study raises concerns about the cross-cultural applicability of the TOMM, particularly when using cut scores established and evaluated primarily on North American, English-speaking samples. Forensic psychologists should be cautious when interpreting TOMM performance with Spanish-speaking adults from Latin American countries because it appears that there are cross-cultural differences that influence test performance. (PsycINFO Database Record

Determining when to conduct a violence risk assessment: Development and initial validation of the Fordham Risk Screening Tool (FRST).

Techniques to assess violence risk are increasingly common, but no systematic approach exists to help clinicians decide which psychiatric patients are most in need of a violence risk assessment. The Fordham Risk Screening Tool (FRST) was designed to fill this void, providing a structured, systematic approach to screening psychiatric patients and determining the need for further, more thorough violence risk assessment. The FRST was administered to a sample of 210 consecutive admissions to the civil psychiatric units of an urban medical center, 159 of whom were subsequently evaluated using the Historical Clinical Risk Management-20, version 3, to determine violence risk. The FRST showed a high degree of sensitivity (93%) in identifying patients subsequently deemed to be at high risk for violence (based on the Case Prioritization risk rating). The FRST also identified all of the patients (100%) rated high in potential for severe violence (based on the Serious Physical Harm Historical Clinical Risk Management-20, version 3, summary risk rating). Sensitivity was more modest when individuals rated as moderate risk were included as the criterion (rather than only those identified as high risk). Specificity was also moderate, screening out approximately half of all participants as not needing further risk assessment. A systematic approach to risk screening is clearly needed to prioritize psychiatric admissions for thorough risk assessment, and the FRST appears to be a potentially valuable step in that process. (PsycINFO Database Record

Bone density assessment in a tertiary paediatric centre over 13 years: Referral patterns and limitations.

AIM: This study aims to examine the referral practices for the Royal Children's Hospital (RCH) bone density service over the past 13 years and to demonstrate referral patterns and possible limitations to accessing paediatric bone densitometry. METHODS: All patients attending the RCH Healthy Bones Unit for bone densitometry from 1 July 1999 to 30 June 2012, aged under 18 years of age, were included. Densitometry results were downloaded directly from the Hologic scanner into an Excel document. However, the referring unit and indication for referral were collected manually from either the referral card or the hospital's scanned medical records system. RESULTS: A total of 5767 bone densitometry scans were performed over the study period on 3004 patients. The majority of referrals were made by the Endocrinology department, followed by Adolescent Medicine, Gastroenterology and Neurology. Relatively few referrals were made by general paediatrics. The most common indication for bone density test overall was eating disorders, followed by steroid use, osteogenesis imperfecta and other collagen disorders and inflammatory bowel disease. The lowest lumbar spine z-scores by indication were for cerebral palsy and other causes of immobility. CONCLUSIONS: Multiple childhood diseases predispose to low bone density; however, paediatric bone densitometry is still underutilised and not appropriately supported by subsidies.

Using social bonding theory to examine 'recovery' in a forensic mental health hospital: A qualitative study.

BACKGROUND: For people living with mental illness, recovery involves learning to overcome and manage their symptoms and striving to live fulfilling lives. The literature on achieving recovery emphasises the importance of social connections and positive role models. Hirschi's social bonding theory posits that an individual's attachment to others, belief in social norms, and their commitment and involvement in conventional activities are the major contributors to normalising social behaviour. AIMS: The aim of this study is to understand the qualities of service identified by patients in a forensic hospital as being important and meaningful to recovery. METHODS: Semi-structured interviews with 30 inpatients in a forensic mental health hospital in British Columbia, Canada, were audio recorded, and the transcriptions were analysed using thematic analysis. RESULTS: Five themes emerged: involvement in programmes, belief in rules and social norms, attachment to supportive individuals, commitment to work-related activities and concern about indeterminacy of stay. CONCLUSIONS: The first four themes map closely onto Hirschi's criminologically derived social bonding theory; however, indeterminacy of stay also arose as a common theme. In addition, the theory was too simple in its separation of elements; our data suggested the complex integration of themes. Our findings may be useful for informing evaluation of forensic mental health services.

Characteristics associated with criminal responsibility assessment outcomes among women in Central Canada.

The number of women involved with forensic mental health systems internationally is rising, however, limited research has explored the characteristics of those assessed for criminal responsibility. We investigated the demographic, psychiatric, and criminological characteristics of women recommended as eligible or ineligible for the defence of Not Criminally Responsible (NCR) on account of mental disorder following a criminal responsibility assessment in Central Canada. Data were collected through retrospective chart reviews of court-ordered criminal responsibility assessments for 109 women referred for evaluations between 2003 and 2019. Accused were an average age of 34.55 years, predominately identified as Indigenous (37.7%) or Caucasian (20.8%), and had often been charged with assault (47.7%). Women identified in the reports as NCR-eligible were significantly more likely to be employed, experience delusions during the index offence, and have expert reports linking their mental health symptoms to NCR legal criteria. They were also significantly less likely to have a personality disorder, substance-related diagnosis, or have used substances during the index offence. Delusions during the index offence significantly predicted assessment recommendations when controlling for age at assessment order, current substance-related diagnosis, and whether the expert report linked mental health symptoms to NCR legal criteria. Findings indicate the key factors considered by forensic mental health professionals when conducting criminal responsibility assessments with women. Meaningful differences exist between women identified as NCR-eligible and ineligible, with findings illustrating who may be more likely to receive services within the Canadian forensic mental health system.

Geographic Variation in Osteoporosis Treatment in Postmenopausal Women: A 15-Year Longitudinal Analysis.

Context: Osteoporosis affects more than half of older women, but many are not treated. Whether treatment differs between rural and urban areas is unknown. Objective: To examine differences in osteoporosis treatment among postmenopausal women living in urban and rural areas of Australia. Methods: Women participating in the Australian Longitudinal Study on Women's Health, a prospective longitudinal cohort study, born between 1946-1951, and with osteoporosis or fractures, were included. Surveys from 2004 to 2019 were linked to the Pharmaceutical Benefits Scheme (government-subsidized medications) to assess osteoporosis treatment and adherence, comparing geographical areas. Results: Of the 4259 women included (mean age, 55.6 years), 1703 lived in major cities, 1629 inner regional, 794 outer regional, and 133 remote areas. Over the 15-year follow-up, 1401 (32.9%) women received treatment, including 47.4% of women with osteoporosis and 29.9% with fractures. Women in outer regional and remote areas were less likely to use antiosteoporosis treatment than those in major cities on univariable analysis (outer regional odds ratio, 0.83; 95% CI, 0.72-0.95; remote, 0.65; 0.49-0.86), but this did not remain significant on multivariable analysis. Median duration of use was 10 to 36 months, adherence varied by treatment type (34%-100%) but was not related to incident fractures, and of the women who stopped denosumab, 85% did not receive another consolidating treatment. Conclusions: One-third of women with osteoporosis/fractures received treatment, and adherence was low. There was no difference in treatment use between urban and rural areas after adjusting for risk factors, although the specific treatment used, and adherence, differed.

Supporting recovery by improving patient engagement in a forensic mental health hospital: results from a demonstration project.

BACKGROUND: Mental health services are shifting toward approaches that promote patients' choices and acknowledge the value of their lived experiences. OBJECTIVE: To support patients' recovery and improve their experiences of care in a Canadian forensic mental health hospital, an intervention was launched to increase patient engagement by establishing a peer support program, strengthening a patient advisory committee, and creating a patient-led research team. DESIGN: The effect of the intervention on patient- and system-level outcomes was studied using a naturalistic, prospective, longitudinal approach. Quantitative and qualitative data were gathered from inpatients and service providers twice during the 19-month intervention. RESULTS: Despite succeeding in supporting patients' participation, the intervention had minimal impacts on internalized stigma, personal recovery, personal empowerment, service engagement, therapeutic milieu, and the recovery orientation of services. Peer support demonstrated positive effects on internalized stigma and personal recovery. CONCLUSIONS: Strengthening patient engagement contributes toward improving experiences of care in a forensic hospital, but it may have limited effects on outcomes.

Bone health in rural Australia: a mixed methods study of consumer needs.

This mixed methods study explores osteoporosis among adults living in a regional area of Victoria, Australia. Three major themes emerged from interviews, which reflected the findings of surveys, concerns regarding the adequacy of care in rural areas, a desire for tailored, local care, and a desire for hybrid telemedicine or in-person services. PURPOSE: Osteoporosis or osteopenia affects over half of adults aged over 50 years. People living outside major cities in Australia have higher hip fracture rates than people living in cities, along with reduced access to bone densitometry and osteoporosis specialists. This study explores osteoporosis risk factors, knowledge, experiences of and preferences for care in people living in a regional area, to inform development of osteoporosis care programs. METHODS: Adults living in a large non-metropolitan region of Australia were invited to participate in a mixed methods study: a survey (phase 1) followed by semi-structured interviews (phase 2) with triangulation of results. Data collected included osteoporosis diagnosis, risk factors, management, knowledge, preferences for care and experience using telemedicine. Surveys were analysed quantitatively, with linear and logistic regression used to assess factors related to osteoporosis knowledge or satisfaction with telemedicine. Interview transcripts were analysed using thematic analysis by two researchers, with in-depth discussion to identify themes. RESULTS: Sixty-two participants completed the survey, and 15 completed interviews. The mean (SD) age of survey participants was 62.2 (14.1) years, 57% had a screening test for osteoporosis, and 12 (19%) had a diagnosis of osteoporosis. The mean osteoporosis knowledge score was 8.4 / 19 and did not differ with age, education, or history of osteoporosis. The majority wanted access to more information about osteoporosis but preferred method differed, and the majority preferred in-person medical consultations to telemedicine. Interview participants were aged between 57 and 87 years, and included 8 with osteoporosis or osteopenia. Three major themes emerged: concerns regarding the adequacy of care in rural areas, a desire for tailored local car and a desire for hybrid telemedicine or in-person services. CONCLUSION: Gaps exist in rural osteoporosis care, including knowledge, screening and management. People have differing experiences of care, access to services and preferences for care. High-quality care, tailored to their needs, was preferred. Improving osteoporosis services for regional Australia will require a flexible, multi-faceted approach, addressing needs of the local community and providers.

Identifying positive impression management using the MMPI-2 and the MMPI-2-RF: A meta-analysis.

Objective:Individuals may be motivated to conceal or minimize psychological symptoms and engage in positive impression management (PIM) in order to achieve desired outcomes across high stakes contexts (e.g. fitness for duty evaluations, pre-sentencing assessments, medical procedure evaluations, civil commitment). Despite the importance of this topic, the most recent meta-analysis of the MMPI-2, a widely used instrument for detecting PIM, was conducted more than two decades ago. Method:Using a Robust Variance Estimation method, this meta-analysis synthesized the results of 27 studies that examined the MMPI-2 (k = 22) and MMPI-2-RF (k = 5) validity scales' ability to discriminate individuals who engage in PIM from genuine responders, with a particular focus on the L, K, and S scales. Results:The MMPI-2 L scale produced the largest effect size (g = 1.30), whereas the MMPI-2-RF L-r scale effect size was moderate (g = 1.16). Moderate effect sizes were also found for the K (g = 1.01) and K-r (g = 1.21) scales, and for the MMPI-2 S scale (g = 1.23). Conclusions: Effect sizes did not significantly vary between the two versions of the MMPI. Findings suggest that both versions of the MMPI have demonstrated utility in identifying PIM, but clinicians should interpret T scores conservatively to account for the modest elevations associated with defensiveness. Findings are discussed in the context of the recently released MMPI-3.

Comparing the Ability of MMPI-2 and MMPI-2-RF Validity Scales to Detect Feigning: A Meta-Analysis.

Several meta-analyses of the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) and Minnesota Multiphasic Personality Inventory-2 Restructured Form (MMPI-2-RF) have examined these instruments' ability to detect symptom exaggeration or feigning. However, limited research has directly compared whether the scales across these two instruments are equally effective. This study used a moderated meta-analysis to compare 109 MMPI-2 and 41 MMPI-2-RF feigning studies, 83 (56.46%) of which were not included in previous meta-analyses. Although there were differences between the two test versions, with most MMPI-2 validity scales generating larger effect sizes than the corresponding MMPI-2-RF scales, these differences were not significant after controlling for study design and type of symptoms being feigned. Additional analyses showed that the F and Fp-r scales generated the largest effect sizes in identifying feigned psychiatric symptoms, while the FBS and RBS were better at detecting exaggerated medical symptoms. The findings indicate that the MMPI-2 validity scales and their MMPI-2-RF counterparts were similarly effective in differentiating genuine responders from those exaggerating or feigning psychiatric and medical symptoms. These results provide reassurance for the use of both the MMPI-2 and MMPI-2-RF in settings where symptom exaggeration or feigning is likely. Findings are discussed in the context of the recently released MMPI-3.

The mutational landscape of the adult healthy parous and nulliparous human breast.

The accumulation of somatic mutations in healthy human tissues has been extensively characterized, but the mutational landscape of the healthy breast is still poorly understood. Our analysis of whole-genome sequencing shows that in line with other healthy organs, the healthy breast during the reproduction years accumulates mutations with age, with the rate of accumulation in the epithelium of 15.24 ± 5 mutations/year. Both epithelial and stromal compartments contain mutations in breast-specific driver genes, indicative of subsequent positive selection. Parity- and age-associated differences are evident in the mammary epithelium, partly explaining the observed difference in breast cancer risk amongst women of different childbearing age. Parity is associated with an age-dependent increase in the clone size of mutated epithelial cells, suggesting that older first-time mothers have a higher probability of accumulating oncogenic events in the epithelium compared to younger mothers or nulliparous women. In conclusion, we describe the reference genome of the healthy female human breast during reproductive years and provide evidence of how parity affects the genomic landscape of the mammary gland.