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Women at high inherited risk of ovarian cancer are offered risk-reducing salpingo-oophorectomy (RRSO) from age 35 to 45 years. Although potentially life-saving, RRSO may induce symptoms that negatively affect quality of life and impair long-term health. Clinical care following RRSO is often suboptimal. This scoping review describes how RRSO affects short- and long-term health and provides evidence-based international consensus recommendations for care from preoperative counselling to long-term disease prevention. This includes the efficacy and safety of hormonal and non-hormonal treatments for vasomotor symptoms, sleep disturbance and sexual dysfunction and effective approaches to prevent bone and cardiovascular disease.

Pathways associated with G9a copy number in the Leeds melanoma cohort

Epigenetic regulators, when genomically altered, may become driver oncogenes that mediate otherwise unexplained pro-oncogenic changes lacking a clear genetic stimulus, such as activation of the WNT/β-catenin pathway in melanoma. This study identifies previously unrecognized recurrent activating mutations in the G9a histone methyltransferase gene, as well as G9a genomic copy gains in approximately 26% of human melanomas, which collectively drive tumor growth and an immunologically sterile microenvironment beyond melanoma. Furthermore, the WNT pathway is identified as a key tumorigenic target of G9a gain-of-function, via suppression of the WNT antagonist DKK1. Importantly, genetic or pharmacologic suppression of mutated or amplified G9a using multiple in vitro and in vivo models demonstrates that G9a is a druggable target for therapeutic intervention in melanoma and other cancers harboring G9a genomic aberrations.Significance:Oncogenic G9a abnormalities drive tumorigenesis and the “cold” immune microenvironment by activating WNT signaling through DKK1 repression. These results reveal a key druggable mechanism for tumor development and identify strategies to restore “hot” tumor immune microenvironments.This article is highlighted in the In This Issue feature, p. 890

Supplementary Table 1 - PDF file 57K, Supplementary Table 1. Details of platinum sensitivity and best response to olaparib and post-PARPi chemotherapy of the six patients whose tumor samples were analyzed by massively parallel sequencing. (NE: not evaluable)

Purpose: Preclinical data suggest that exposure to PARP inhibitors (PARPi) may compromise benefit to subsequent chemotherapy, particularly platinum-based regimens, in patients with BRCA1/2 mutation carrier ovarian cancer (PBMCOC), possibly through the acquisition of secondary BRCA1/2 mutations. The efficacy of chemotherapy in the PARPi-resistant setting was therefore investigated.Experimental Design: We conducted a retrospective review of PBMCOC who received chemotherapy following disease progression on olaparib, administered at ≥200 mg twice daily for one month or more. Tumor samples were obtained in the post-olaparib setting where feasible and analyzed by massively parallel sequencing.Results: Data were collected from 89 patients who received a median of 3 (range 1–11) lines of pre-olaparib chemotherapy. The overall objective response rate (ORR) to post-olaparib chemotherapy was 36% (24 of 67 patients) by Response Evaluation Criteria in Solid Tumors (RECIST) and 45% (35 of 78) by RECIST and/or Gynecologic Cancer InterGroup (GCIG) CA125 criteria with median progression-free survival (PFS) and overall survival (OS) of 17 weeks [95% confidence interval (CI), 13–21] and 34 weeks (95% CI, 26–42), respectively. For patients receiving platinum-based chemotherapy, ORRs were 40% (19 of 48) and 49% (26/53), respectively, with a median PFS of 22 weeks (95% CI, 15–29) and OS of 45 weeks (95% CI, 15–75). An increased platinum-to-platinum interval was associated with an increased OS and likelihood of response following post-olaparib platinum. No evidence of secondary BRCA1/2 mutation was detected in tumor samples of six PARPi-resistant patients [estimated frequency of such mutations adjusted for sample size: 0.125 (95%-CI: 0–0.375)].Conclusions: Heavily pretreated PBMCOC who are PARPi-resistant retain the potential to respond to subsequent chemotherapy, including platinum-based agents. These data support the further development of PARPi in PBMCOC. Clin Cancer Res; 19(19); 5485–93. ©2013 AACR.

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Family history screening to identify individuals at increased risk for hereditary cancers could be a powerful strategy to prevent cancer but is used inconsistently in primary care. The objective was to improve identification of women with at-risk family histories using a point-of-care family history screening tool administered on an electronic tablet device during well-woman appointments. A total of 288 women were invited to participate and 136 women (47.2%) completed the electronic family history screening tool. Significantly more women were identified and referred to the genetics department with the electronic family history screening tool than the standard-of-care paper questionnaire (11.8% versus 0.8%, P < 0.001). There were no statistically significant differences in the proportion of referred women who were evaluated by the genetic counselors, and no pathogenic variants were found with either family history screening method. Implementing innovative self-reporting tools may improve inherited cancer risk detection.

Support for a patient in the aftermath of a potentially traumatic event is enhanced when clinicians understand the normal reactions that may occur during the traumatization process. This article discusses recommendations from international and national guidelines as well as best practices from the medical and psychiatric literature to help guide clinicians providing care for acutely traumatized patients.

Background: Although exposure to potentially traumatic events (PTEs) for Black and Latinx may be comparable or lower than their White counterparts, type of trauma experiences differ such as more interpersonal trauma and violence reported by Black people, who also experience higher rates of PTSD. In this retrospective study, we examined the association between use of particular substances and various PTEs and the race/ethnicity-group differences for this association. Methods: One-hundred seventy-nine participants recruited from an outpatient substance use disorder program from February 2018 to October 2020 completed measures on lifetime trauma history and current/past cocaine, cannabis, and alcohol misuse. Bayesian generalized linear modeling with horseshoe prior was used to predict substance misuse using 17 PTEs, then PTEs were ranked and examined by racial/ethnic group. Results: No PTEs were associated with substance misuse across all four r/e groups. Transportation accident, natural disaster, war exposure, and other stressful events were associated with substance misuse across two or three r/e groups. Notably, the three PTEs involving interpersonal violence in our study (weapon assault, physical assault, and sexual assault) were only associated with substance misuse (posterior probability ≥70%) for Latinx participants. Conclusion: The relational nature of interpersonal/violent traumas may make them particularly salient for Latinx people where interpersonal relationships are prioritized. These types of traumas may also be viewed as an extension of discrimination and exclusion, two longstanding, intractable issues for people of color in the US, making them even more damaging. Furthermore, lack of resources may limit options for coping, resulting in substance use problems.

An overview is given of inelastic electron scattering in solids with an emphasis on calculations and measurements of electron inelastic mean free paths (IMFPs). There is generally good agreement between IMFPs calculated from optical data and IMFPs measured by elastic-peak electron spectroscopy for electron energies greater than 100 eV. For lower energies, however, there are significant differences between these calculated IMFPs and IMFPs determined from X-ray absorption fine structure experiments., International Tables for Crystallography, Vol. I, X-ray Absorption Spectroscopy and Related Techniques

Background Heart failure (HF) is a leading cause of hospital admission. However, prompt identification of worsening HF using implantable device data and proactive intervention may reduce hospitalizations. The validated TriageHF algorithm in enabled ICD/CRT devices uses sensor data to risk stratify patients for HF hospitalization in the next 30 days. TriageHF Plus is a novel device-based HF care pathway (DHFP) that uses “high” risk status as the trigger for remote intervention (see Figure 1 for pathway overview). Outcomes after DHFP implementation in a clinical setting have not been examined. Purpose To evaluate the impact of TriageHF Plus clinical pathway on hospitalisation rates. Methods A prospective, multi-center evaluation comparing monthly hospitalization rates for patients enrolled in a DHFP with a concurrent standard of care (SoC) cohort and characterizing staffing resources necessary to implement the DHFP. The DHFP cohort received telephonic assessment and guideline-directed clinical care upon transition to high-risk status. Propensity scores (PS) were applied to DHFP and SoC cohorts to allow unbiased comparison. A negative binomial model was fitted to the monthly number of all-cause hospitalizations with treatment group (DHFP vs. SoC) as a covariate, using PS as weights. Results Between 09/11/2019 and 06/24/2021, 758 patients were included in the study (443 DHFP, 315 SoC). Proportion CRT 76%/ 89% and LVEF 196 high risk transmissions prompted telephone assessment, with successful contact in 182; of which, 79 (43%) identified an explanatory acute medical issue. A secondary intervention was undertaken in 44/79 (56%). High risk transmissions took on average 19 minutes per clinical assessment (initial telephone triage and 30 day follow up). The rate of hospitalizations was 58% lower in the DHFP group, compared with SoC, after PS adjustment (IRR 0.42, 95% CI: 0.23, 0.76, p=0.004), see Figure 2. Sensitivity analyses showed Covid-19 had little effect on results. Conclusions This is the first prospective, real-world evaluation of a device-based HF care pathway to report a reduction in hospitalizations and does so with minimal staffing time. Integrated into existing HF services, device-based remote monitoring of HF patients can improve outcomes. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Medtronic

Simulations show that the orbits of planets are readily disrupted in dense star-forming regions; planets can be exchanged between stars, become free-floating and then be captured by other stars. However, dense star-forming regions also tend to be populous, containing massive stars that emit photoionising radiation, which can evaporate the gas in protoplanetary discs. We analyse N-body simulations of star-forming regions containing Jovian-mass planets and determine the times when their orbits are altered, when they become free-floating, and when they are stolen or captured. Simultaneously, we perform calculations of the evolution of protoplanetary discs when exposed to FUV radiation fields from massive stars in the same star-forming regions. In almost half (44 per cent) of the planetary systems that are disrupted - either altered, captured, stolen or become free-floating, we find that the radius of the protoplanetary disc evolves inwards, or the gas in the disc is completely evaporated, before the planets' orbits are disrupted. This implies that planets that are disrupted in dense, populous star-forming regions are more likely to be super Earths or mini Neptunes, as Jovian mass planets would not be able to form due to mass loss from photoevaporation. Furthermore, the recent discoveries of distant Jovian mass planets around tightly-packed terrestrial planets argue against their formation in populous star-forming regions, as photoevaporation would preclude gas giant planet formation at distances of more than a few au., 8 pages, 6 figures, accepted for publication in MNRAS

This study aimed to examine coping strategies used by advanced colorectal cancer (CRC-A) survivors to manage death anxiety and fear of cancer progression, and links between these strategies and quality of life (QoL), distress, and death acceptance. Qualitative semi-structured interviews of 38 CRC-A survivors (22 female) were analysed via framework analysis. QoL and distress were assessed through the FACT-C and Distress Thermometer. Eleven themes were identified and mapped to active avoidance (keeping busy and distracted), passive avoidance (hoping for a cure), active confrontation (managing negative emotions; reaching out to others; focusing on the present; staying resilient), meaning-making (redefining one’s identity; contributing to society; gaining perspective; remaining spiritual), and acceptance (accepting one’s situation). Active confrontation (specifically utilising informal support networks) and meaning-making appeared beneficial coping strategies; more research is needed to develop and evaluate interventions which increase CRC-A survivors’ use of these strategies to manage and cope with their death anxiety.

To describe breast and ovarian cancer risk reduction strategies in the clinical management of women who test positive for non-BRCA hereditary breast and ovarian cancer (HBOC) pathogenic variants compared to those who test positive for pathogenic BRCA variants or have negative germline panel testing.Examination of imaging and preventive surgeries in women undergoing HBOC genetic testing from 1/1/2015 to 12/31/2018, with follow up to 03/31/2020 in Kaiser Permanente Northern California.A total of 13,271 tests which included HBOC genes were identified. Rate of bilateral salpingo-oophorectomy after genetic testing were similar for BRCA and the non-BRCA moderate risk ovarian pathogenic variants (PVs) (47.4% vs 54%, p = 0.25). Rates were lower for low risk or unknownrisk non-BRCA PVs (12.8%, p0.001, 5.3% (p0.001). Rates of surveillance for ovarian cancer with ultrasound and CA 125 in the first year was 63.3% and 64.7% for BRCA PV, 37.5% and 27.1%, for non-BRCA moderate risk PVs and 13.7% and 4.6%, for low-risk PVs. Bilateral mastectomy rates were 19.7% for BRCA PV, 10.1% (p = 0.028) for non-BRCA breast high risk PVs, for moderate risk PVs 7.7% (p0.001) and for unknown risk 0.4% (p0.001). MRI surveillance rates in the first year similarly were 47.4% for non-BRCA BRCA PV, 43% for breast high risk PV, 39.4% for moderate risk and 4.9% for unknown risk PV.Surgical and surveillance strategies are underutilized for HBOC PV, however there is concordance of uptake of preventive strategies with specific risk associated with non-BRCA PVs.

Objective To develop a longitudinal algorithm combining two biomarkers, CA125 and HE4, for early detection of ovarian cancer in women with BRCA mutations. Methods Women with BRCA mutations and intact ovaries were invited to participate in a novel ovarian cancer early detection prospective study. The Risk of Ovarian Cancer Algorithm (ROCA) identifying significant increases above each woman's baseline in serum CA125 and HE4 was performed every four months; abnormal risks triggered a subsequent ultrasound. The study first used a risk algorithm for only CA125, a second algorithm was developed for HE4 and finally a risk algorithm combining the two biomarkers was implemented. The ROCA strategy was compared to Standard of Care (SOC) surveillance strategy. Results A total of 149 women enrolled in the ROCA arm while 43 women enrolled in the SOC arm. Abnormal scores were found in 24% of ROCA CA125 tests, 16% if ROCA CA125 or the novel ROCA HE4 were used independently and reduced to 8% using the new two-marker ROCA, significantly lower than the 15% of abnormal tests seen in the SOC arm (p = 0.042). The average false positive rate among women without ovarian cancer for two-marker ROCA for referral to ultrasound was 6.6% (specificity 93.4%), and for the two-marker ROCA plus ultrasound for referral to surgical consultation was 1.7% (specificity 98.3%). Conclusion A newly developed two-marker ROCA administered every 4 months had lower call-back rates than SOC surveillance. Having established high specificity, the two-marker ROCA score deserves further evaluation for sensitivity in a larger trial.

Compare detection of Lynch syndrome in endometrial cancer between regions of a health care system with different screening strategies.A retrospective study of endometrial cancer (EC) cases from 2 regions of an integrated health care system (Kaiser Permanente Northern (KPNC) and Southern (KPSC) California). Within KPNC, immunohistochemistry tumor screening (IHC) was physician ordered and risk-based; within KPSC, IHC was universal and automated. Clinical risk factors associated with abnormal IHC and Lynch Syndrome (LS) were identified.During the study, there were 2045 endometrial cancers: 1399 in the physician-order group and 646 in the universal testing group. In the physician-order group: among womenage 60, 34% underwent IHC; 9.6% were abnormal, and 3% were possible LS after methylation testing; among women ≥60, 11% underwent IHC, 3% were abnormal and1% were possible LS. In the universal group, 87% of women age60 had IHC, 19.4% were abnormal, and 6% were possible LS; Among women age ≥60, 82% underwent IHC, 26% were abnormal, and 2% were possible LS. There were no differences in LS cases between the physician-order group and the universal group in either age strata (60: 3% vs. 3.6%, p=0.62; ≥60:1% vs. 1%, p=0.63) Factors associated with LS were younger age (odds ratio (OR) 0.11, 95% confidence interval (CI) 0.04-0.29) and lower body mass index (BMI), (OR 0.38 95% CI 0.18-0.80).Universal IHC screening did not result in increased LS detection in EC.

Exosomes are secreted extracellular vesicles with lipid bilayer membranes. They are emerging as a new category of messengers that facilitate cross-talk between cells, tissues, and organs. Thus, a critical demand arises for the development of a sensitive and non-invasive tracking system for endogenous exosomes. We have generated a genetic mouse model that meets this goal. The Nano-luciferase (NanoLuc) reporter was fused with the exosome surface marker CD63 for exosome labeling. The cardiomyocyte-specific αMHC promoter followed by the loxP-STOP-loxP cassette was engineered for temporal and spatial labeling of exosomes originated from cardiomyocytes. The transgenic mouse was bred with a tamoxifen-inducible Cre mouse (Rosa26Cre-ERT2) to achieve inducible expression of CD63NanoLuc reporter. The specific labeling and tissue distribution of endogenous exosomes released from cardiomyocytes were demonstrated by luciferase assay and non-invasive bioluminescent live imaging. This endogenous exosome tracking mouse provides a useful tool for a range of research applications., Using nano-luciferase-CD63, Weijia Luo et al. develop transgenic mice where cardiac exosomes can be tracked with non-invasive bioluminescent live imaging in a tamoxifen-inducible manner. These mice serve as a valuable tool that allow researchers to track cardiac exosomes in a defined time window.

The Q-parameter is used extensively to quantify the spatial distributions of stars and gas in star-forming regions as well as older clusters and associations. It quantifies the amount of structure using the ratio of the average length of a minimum spanning tree, mbar, to the average length within the complete graph, sbar. The interpretation of the Q-parameter often relies on comparing observed values of Q, mbar and sbar to idealised synthetic geometries, where there is little or no match between the observed star-forming regions and the synthetic regions. We measure Q, mbar, and sbar over 10 Myr in N-body simulations which are compared to IC 348, NGC 1333, and the ONC. For each star-forming region we set up simulations that approximate their initial conditions for a combination of different virial rations and fractal dimensions. We find that dynamical evolution of idealised fractal geometries can account for the observed Q, mbar, and sbar values in nearby star-forming regions. In general, an initially fractal star-forming region will tend to evolve to become more smooth and centrally concentrated. However, we show that initial conditions, as well as where the edge of the region is defined, can cause significant differences in the path that a star-forming region takes across the mbar-sbar plot as it evolves. We caution that the observed Q-parameter should not be directly compared to idealised geometries. Instead, it should be used to determine the degree to which a star-forming region is either spatially substructured or smooth and centrally concentrated., 12 pages, 10 figures, acccepted for publication in MNRAS

PurposeContinuing employment or returning to work (RTW) as a cancer survivor can be meaningful and financially necessary, yet challenging. However, there is a lack of qualitative research on RTW experiences and financial wellbeing of people with advanced colorectal cancer (CRC-A). This study aimed to fill this gap.MethodsAdults treated for CRC-A were recruited 0.5-2 years post-surgery (or post-diagnosis of CRC-A for palliative chemotherapy participants). Semi-structured telephone interviews, exploring RTW and finances, were subjected to framework analysis. Demographic, clinical, and quality of life data (FACT-C, Distress Thermometer, COST measure) were collected to characterise the sample and inform the framework analysis.ResultsAnalysis of 38 interviews revealed five overarching themes: work as a struggle; work as my identity; work as my saviour; work as a financial necessity; and employer and colleague response. Many survivors with CRC-A desired to, and had the capacity to, continue work or RTW, yet faced unique challenges from compounded stigma of both cancer and toileting issues. Inability to RTW negatively impacted financial and psychosocial wellbeing. Workplace support was an important facilitator of RTW.ConclusionFor survivors with CRC-A, continuing or RTW is fraught with challenges, including physical functioning challenges, financial anxiety, and unsupportive workplace environments. Survivors require psychosocial, financial, and employer support to manage these difficulties. This paper recommends a multiprong approach, including education programs (facilitated through workers’ union groups, human resource institutions, and/or large consumer CRC groups) and policies, to support workers and for employers to understand the unique challenges of employees with CRC-A.

Continuing employment or returning to work (RTW) as a cancer survivor can be meaningful and financially necessary, yet challenging. However, there is a lack of qualitative research on RTW experiences and financial wellbeing of people with advanced colorectal cancer (CRC-A). This study aimed to fill this gap.Adults treated for CRC-A were recruited 0.5-2 years post-surgery (or post-diagnosis of CRC-A for palliative chemotherapy participants). Semi-structured telephone interviews, exploring RTW and finances, were subjected to framework analysis. Demographic, clinical, and quality of life data (FACT-C, Distress Thermometer, COST measure) were collected to characterise the sample and inform the framework analysis.Analysis of 38 interviews revealed five overarching themes: work as a struggle, work as my identity, work as my saviour, work as a financial necessity, and employer and colleague response. Many survivors with CRC-A desired to, and had the capacity to, continue work or RTW, yet faced unique challenges from compounded stigma of both cancer and toileting issues. Inability to RTW negatively impacted financial and psychosocial wellbeing. Workplace support was an important facilitator of RTW.For survivors with CRC-A, continuing or RTW is fraught with challenges, including physical functioning challenges, financial anxiety, and unsupportive workplace environments. Survivors require psychosocial, financial, and employer support to manage these difficulties. This paper recommends a multiprong approach, including education programmes (facilitated through workers' union groups, human resource institutions, and/or large consumer CRC groups) and policies, to support workers and for employers to understand the unique challenges of employees with CRC-A.

Objective: Evaluate the incidence and characteristics of breast cancers (BC) diagnosed following an epithelial ovarian cancer (EOC) diagnosis in women with pathogenic BRCA mutations. Methods: Retrospective cohort study of all women in an integrated healthcare system with BRCA mutations diagnosed with EOC from 1/1/1997–12/31/2018. Primary outcome was rate of subsequent BC diagnosis. Secondary outcomes included risk factors associated with development of BC, median time to detection following EOC, and method of detection. Results: There were 284 women with BRCA-associated EOC identified. Fifty-two women had risk-reducing mastectomy and were excluded. Of the 232 eligible women with a median follow-up of 5.6 years, 33 (14%) women were diagnosed with BC following EOC: 27 (11%) new cases and 6 (3%) recurrences. Twelve (36%) cases of BC were detected on screening mammogram, 4 (12%) on screening MRI, and 9 (27%) on work-up after presenting with a palpable lump. Twenty-nine (87%) were early stage (0-II) disease. Median interval from EOC to BC diagnosis was 80 months (IQR 32, 134) for new and 63 months (IQR 21, 94) for recurrent BCs. There was one death from breast cancer while 12 women died of ovarian cancer. Conclusions: Most BC following BRCA-associated EOC is early stage and not associated with mortality. Given BC rate similar to general population and median diagnosis at 6.6 years following ovarian cancer, increased BC screening may not be warranted in the early years after EOC diagnosis.

Atherosclerotic vascular disease is a leading cause of death worldwide. Atherosclerotic stenosis of the internal carotid or intracranial arteries causes up to 15% of strokes. Peripheral artery disease affects up to one in five people in the United States who are 60 years and older and nearly one-half of those who are 85 years and older. Renal artery stenosis may affect up to 5% of people with isolated hypertension and up to 40% of people with other atherosclerotic diseases. All patients with atherosclerotic vascular disease should receive a comprehensive program of guideline-directed medical therapy, including structured physical activity and lifestyle modification, an antiplatelet agent, a statin, antihypertensive therapy, and smoking cessation counseling. The U.S. Preventive Services Task Force recommends one-time screening for abdominal aortic aneurysm with ultrasonography in men 65 to 75 years of age who have smoked at least 100 cigarettes, but screening is not recommended for carotid, peripheral, and renal disease. Surgical revascularization decreases adverse outcomes and mortality in selected patients with advanced vascular disease. Endovascular repair has become more common for patients younger than 70 years because of decreased short-term mortality. Carotid revascularization with carotid endarterectomy or carotid artery stenting is recommended for symptomatic patients with greater than 50% internal carotid artery stenosis. Carotid artery stenting is preferred in patients with multiple comorbidities, tracheostomy, or previous neck radiation or dissection. In patients older than 70 years, carotid endarterectomy is associated with a lower risk of periprocedural stroke or death than carotid artery stenting. Revascularization is a reasonable treatment option for patients with lifestyle-limiting claudication and an inadequate response to guideline-directed therapies. Revascularization is indicated for patients with critical limb ischemia and is emergently indicated for acute limb ischemia. Renal artery revascularization offers no proven clinical benefit when added to optimal medical therapy.

Exoplanets display incredible diversity, from planetary system architectures around Sun-like stars that are very different to our Solar System, to planets orbiting post-main sequence stars or stellar remnants. Recently the B-star Exoplanet Abundance STudy (BEAST) reported the discovery of at least two super-Jovian planets orbiting massive stars in the Sco Cen OB association. Whilst such massive stars do have Keplerian discs, it is hard to envisage gas giant planets being able to form in such hostile environments. We use N-body simulations of star-forming regions to show that these systems can instead form from the capture of a free-floating planet, or the direct theft of a planet from one star to another, more massive star. We find that this occurs on average once in the first 10Myr of an association's evolution, and that the semimajor axes of the hitherto confirmed BEAST planets (290 and 556au) are more consistent with capture than theft. Our results lend further credence to the notion that planets on more distant (>100au) orbits may not be orbiting their parent star., 5 pages, 4 figures, published in MNRAS Letters

Gravitational interactions in star-forming regions are capable of disrupting and destroying planetary systems, as well as creating new ones. In particular, a planet can be stolen, where it is directly exchanged between passing stars during an interaction; or captured, where a planet is first ejected from its birth system and is free-floating for a period of time, before being captured by a passing star. We perform sets of direct N-body simulations of young, substructured star-forming regions, and follow their evolution for 10 Myr in order to determine how many planets are stolen and captured, and their respective orbital properties. We show that in high density star-forming regions, stolen and captured planets have distinct properties. The semimajor axis distribution of captured planets is significantly skewed to wider orbits compared to the semimajor axis distribution of stolen planets and planets that are still orbiting their parent star (preserved planets). However, the eccentricity and inclination distributions of captured and stolen planets are similar, but in turn very different to the inclination and eccentricity distributions of preserved planets. In low-density star-forming regions these differences are not as distinct but could still, in principle, be used to determine whether observed exoplanets have likely formed in situ or have been stolen or captured. We find that the initial degree of spatial and kinematic substructure in a star-forming region is as important a factor as the stellar density in determining whether a planetary system will be altered, disrupted, captured or stolen., Comment: 15 pages, 10 figures, 1 appendix, accepted for publication in MNRAS

Highlights • Clinical decision support system to automatically assess radiographic changes in foot collapse. • Fully automatic generation of Meary's angle, calcaneal tilt, and cuboid height. • Good manual measurement agreement among clinical experts for all three measurements. • Automatically generated measurements in agreement with clinical expert measurements. • First software system to automatically generate measurements in acquired foot collapse., Background Foot collapse is primarily diagnosed and monitored using lateral weight-bearing foot x-ray images. There are several well-validated measurements which aid assessment. However, these are subject to inter- and intra-user variability. Objective To develop and validate a software system for the fully automatic assessment of radiographic changes associated with foot collapse; automatically generating measurements for calcaneal tilt, cuboid height and Meary's angle. Methods This retrospective study was approved by the Health Research Authority (IRAS 244852). The system was developed using lateral weight-bearing foot x-ray images, and evaluated against manual measurements from five clinical experts. The system has two main components: (i) a Random Forest-based point-finder to outline the bones of interest; and (ii) a geometry-calculator to generate the measurements based on the point positions from the point-finder. The performance of the point-finder was assessed using the point-to-point error (i.e. the mean absolute distance between each found point and the equivalent ground truth point, averaged over all points per image). For assessing the performance of the geometry-calculator, linear mixed models were fitted to estimate clinical inter-observer agreement and to compare the performance of the software system to that of the clinical experts. Results A total of 200 images were collected from 79 subjects (mean age: 56.4 years ±12.9 SD, 30/49 females/males). There was good agreement among all clinical experts with intraclass correlation estimates between 0.78 and 0.86. The point-finder achieved a median point-to-point error of 2.2 mm. There was no significant difference between the clinical and automatically generated measurements using the point-finder points, suggesting that the fully automatically obtained measurements are in agreement with the manually obtained measurements. Conclusions The proposed system can be used to support and automate radiographic image assessment for diagnosing and managing foot collapse, saving clinician time, and improving patient outcomes.

Investigate whether disparities and other factors influence referral to genetic counseling and testing for hereditary breast and ovarian cancer syndrome (HBOC) in a large health care system. Examination of clinical, demographic, and socioeconomic factors from electronic health records associated with genetic referral and testing within 12 months after a new cancer diagnosed between August 1, 2013 and December 31, 2018. For patients meeting institutional criteria for HBOC testing, 60.6% were referred for genetic counseling, 88% of whom underwent germline testing; at least one pathogenic variant was found in 15.3%. Referral rates for patients with breast (69%) or ovarian cancer (65.7%) were much higher than for metastatic prostate (11.1%, p 0.0001) or pancreatic cancer (22.3%, p 0.0001); referral criteria were implemented more recently for the latter two cancers. Younger age, family history, and chemotherapy were associated with referral. Higher Elixhauser comorbidity score and prior cancer were associated with non-referral. No other factors were associated with genetic referral for all eligible cancers combined, although differences were seen in specific cancers. Race was a significant factor only for breast cancer, with fewer Asians than Whites referred. Health disparities in referral to genetics for HBOC cancers are mitigated in a comprehensive integrated health care system.

Highlights • Rate of breast cancer diagnosis after ovarian cancer in women with BRCA pathogenic mutations was 14.5%. • The majority of breast cancers, 87%, were diagnosed at stage 0-II. • Median times from ovarian cancer to breast cancer diagnosis was 80 months., Objective Evaluate the incidence and characteristics of breast cancers (BC) diagnosed following an epithelial ovarian cancer (EOC) diagnosis in women with pathogenic BRCA mutations. Methods Retrospective cohort study of all women in an integrated healthcare system with BRCA mutations diagnosed with EOC from 1/1/1997–12/31/2018. Primary outcome was rate of subsequent BC diagnosis. Secondary outcomes included risk factors associated with development of BC, median time to detection following EOC, and method of detection. Results There were 284 women with BRCA-associated EOC identified. Fifty-two women had risk-reducing mastectomy and were excluded. Of the 232 eligible women with a median follow-up of 5.6 years, 33 (14%) women were diagnosed with BC following EOC: 27 (11%) new cases and 6 (3%) recurrences. Twelve (36%) cases of BC were detected on screening mammogram, 4 (12%) on screening MRI, and 9 (27%) on work-up after presenting with a palpable lump. Twenty-nine (87%) were early stage (0-II) disease. Median interval from EOC to BC diagnosis was 80 months (IQR 32, 134) for new and 63 months (IQR 21, 94) for recurrent BCs. There was one death from breast cancer while 12 women died of ovarian cancer. Conclusions Most BC following BRCA-associated EOC is early stage and not associated with mortality. Given BC rate similar to general population and median diagnosis at 6.6 years following ovarian cancer, increased BC screening may not be warranted in the early years after EOC diagnosis.

Scanning electron microscopy-based energy dispersive X-ray spectroscopy (SEM-EDS) is proposed as a versatile tool for quantifying surface area coverage (SAC) by magnesium stearate (MgSt) on pharmaceutical tablets and particles. Our approach involved fast elemental mapping and subsequent SAC quantitation by image analysis. The study was conducted using a multi-component system, but the particle-level mapping was limited to active pharmaceutical ingredient (API) crystals. For both tablets and API particles, the calculated SAC against MgSt loading afforded a positive linear correlation over the range of MgSt levels examined in this work. On the tablet surface, MgSt was found to be preferentially concentrated at or in the close vicinity of grain boundaries, supporting the idea of compression-driven migration and relocation of MgSt within the tablet. On the particle surface, only discrete aggregates of MgSt were observed, as opposed to the widely accepted phenomenon of the formation of a thin lubricant film around host particles. The selection of proper SEM-EDS operating conditions and the challenges confronted in particle surface mapping are discussed in detail.

Objective To assess CA 125 and transvaginal ultrasound surveillance in women with BRCA1 or BRCA2 pathogenic variants in a pragmatic clinical setting with>1 year follow up. Methods Retrospective cohort study in a large integrated health care system of women identified from 1/1/2003 to 12/31/2017 with a BRCA1 or BRCA2 pathogenic variant with at least one intact ovary. Demographic and clinical data were collected from date of genetic testing until oophorectomy, an ovarian cancer diagnosis, or 7/1/2019. Primary outcome was frequency and findings of CA 125 tests and ultrasounds performed; secondary outcome was epithelial ovarian cancers diagnosed. Results There were 1418 women, age ≥ 30 years with a BRCA1 or BRCA2 pathogenic variant with at least one intact ovary. Of the total of 1683 ultrasounds and 2437 CA 125 tests done, 1022 ultrasounds and 1709 CA 125 tests were performed for surveillance in 771 women followed >1 year. Of these women 241 (31%) women had no surveillance, and 530 (69%) women underwent any surveillance. Only 108 (20%) underwent regular surveillance. The number who underwent regular surveillance declined each year. Twenty-one women underwent surveillance indicated surgery with only 2 ovarian cancers found by surveillance. Conclusions Many women with BRCA1 or BRCA2 pathogenic variants undergo ultrasound and CA 125 surveillance testing but abnormal surveillance testing led to diagnosis of ovarian cancer in only two cases. These findings question the use of CA 125 and ultrasound surveillance in the clinical setting for ovarian cancer detection in women with BRCA1 or BRCA2 pathogenic variants.

Referral to Genetics for pre-testing counseling may be inefficient for women with ovarian cancer. This study assesses feasibility of gynecologic oncologists directly offering genetic testing.A prospective pilot study was conducted at two gynecologic oncology hubs in an integrated healthcare system from May 1 to November 6, 2019. Gynecologic oncologists offered multigene panel testing to women with newly diagnosed ovarian cancer, followed by selective genetic counseling. Outcomes were compared between study participants and women from other hubs in the health system.Of ovarian cancer patients at study sites, 40 participated and all underwent genetic testing. Of 101 patients diagnosed at other sites, 85% were referred to genetics (p = .0061 compared to pilot participants) and 67% completed testing (p .0001). The time from diagnosis to blood draw and notification of result was 18.5 and 34 days for the pilot group compared to 25.5 and 53 days at other sites. Panel testing detected 9 (22.5%) and 7 (10.3%, p = .08) pathogenic mutations in each group, respectively. Patients and providers were highly satisfied with the streamlined process.Genetic testing performed at the gynecologic oncology point of care for patients with ovarian cancer is feasible, increases uptake of testing, and improves time to results.

Heart failure is a leading cause of hospital admissions and death in the United States and worldwide. In 2016, the American Heart Association, the American College of Cardiology, and the Heart Failure Society of America released a joint focused guideline update for the management of patients with Stage C heart failure with reduced ejection fraction. An additional update released in 2017 reinforces the 2016 update's strong recommendation for substituting angiotensin-converting enzyme inhibitors or angiotensin receptor blockers with an angiotensin receptor-neprilysin inhibitor to reduce morbidity and mortality in selected patients. The 2017 and 2016 updates also support adding a sinoatrial node modulator to further reduce heart rates in patients already maximized on beta-blocker therapy. These innovative therapies can significantly improve patients' quality of life and reduce the healthcare costs associated with managing heart failure.

Epigenetic regulators, when genomically altered, may become driver oncogenes that mediate otherwise unexplained pro-oncogenic changes lacking a clear genetic stimulus, such as activation of the WNT/β-catenin pathway in melanoma. This study identifies previously unrecognized recurrent activating mutations in the G9a histone methyltransferase gene, as well as G9a genomic copy gains in approximately 26% of human melanomas, which collectively drive tumor growth and an immunologically sterile microenvironment beyond melanoma. Furthermore, the WNT pathway is identified as a key tumorigenic target of G9a gain-of-function, via suppression of the WNT antagonist DKK1. Importantly, genetic or pharmacologic suppression of mutated or amplified G9a using multiple in vitro and in vivo models demonstrates that G9a is a druggable target for therapeutic intervention in melanoma and other cancers harboring G9a genomic aberrations. Significance: Oncogenic G9a abnormalities drive tumorigenesis and the “cold” immune microenvironment by activating WNT signaling through DKK1 repression. These results reveal a key druggable mechanism for tumor development and identify strategies to restore “hot” tumor immune microenvironments. This article is highlighted in the In This Issue feature, p. 890

The surgical management of advanced symptomatic atherosclerotic disease in multiple distributions including the coronary circulation presents unique challenges due to the high risk of perioperative ischemic complications in the setting of coronary artery bypass grafting. We present a novel case of the combined surgical management of symptomatic carotid, coronary and mesenteric ischemic disease. The patient underwent carotid endarterectomy followed by combined coronary and mesenteric revascularization using cardiopulmonary bypass during the same hospital admission. He had an uncomplicated post-operative course and was discharged to home on post-operative day 7 after the combined procedure. Ninety-day follow-up was also unremarkable with the patient having no recurrent symptoms of ischemia. This case demonstrates the feasibility and safety of our approach for this rare clinical presentation.