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Purpose The purpose of this paper is to discuss financial fraud and exploitation against seniors relating to wills, trusts and guardianship. The paper describes how this fraud affects its victims, points out red flags and makes recommendations that may help control this pervasive type of fraud. Design/methodology/approach Information from a range of different sources, such as journal publications, law textbooks, law enforcement websites and estate planning cases are used as a basis to provide information about how fraudsters are committing this type of fraud, which red flags to watch out for and how to prevent this fraud from occurring. Findings Fraud relating to wills, trusts and guardianship is oftentimes difficult to detect and continues to be a grave threat to its victims. While this fraud will likely never be eradicated, specific efforts have been put into place to track financial exploitation. Further steps presented in this paper can be deployed to help rein in these fraud schemes. Practical implications The paper provides useful information about frauds related to wills, trusts and guardianship for stakeholders. This includes, but is not limited to, anyone whose work is related to seniors, such as accountants, lawyers, regulators, bankers, financial planners, law enforcement personnel, academics, medical professionals, caregivers, family members and ethicists. These stakeholders can use this information to help combat this fraud and prevent not only financial losses of seniors but physical harm as well. Social implications Decreasing financial exploitation of seniors will not only improve their financial position and may reduce their reliance on Medicaid but will also improve their mental and physical well-being and save lives. Originality/value Research in the area of maltreatment and exploitation of older adults is still in its early stages, as knowledge of effective prevention, intervention and remediation practices are limited. This paper adds to the research in this arena by drawing on a unique set of resources that shed light on financial fraud commonly committed against seniors. This study also makes much needed recommendations that are aimed to prevent this threat related to wills, trusts and guardianship.

Background Radiotherapy (RT) following breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) reduces ipsilateral breast event rates in clinical trials. This study assessed the impact of DCIS treatment on a 20-year risk of ipsilateral DCIS (iDCIS) and ipsilateral invasive breast cancer (iIBC) in a population-based cohort. Methods The cohort comprised all women diagnosed with DCIS in the Netherlands during 1989–2004 with follow-up until 2017. Cumulative incidence of iDCIS and iIBC following BCS and BCS + RT were assessed. Associations of DCIS treatment with iDCIS and iIBC risk were estimated in multivariable Cox models. Results The 20-year cumulative incidence of any ipsilateral breast event was 30.6% (95% confidence interval (CI): 28.9–32.6) after BCS compared to 18.2% (95% CI 16.3–20.3) following BCS + RT. Women treated with BCS compared to BCS + RT had higher risk of developing iDCIS and iIBC within 5 years after DCIS diagnosis (for iDCIS: hazard ratio (HR)age 3.2 (95% CI 1.6–6.6); HRage ≥ 50 3.6 (95% CI 2.6–4.8) and for iIBC: HRage 2.1 (95% CI 1.4–3.2); HRage ≥ 50 4.3 (95% CI 3.0–6.0)). After 10 years, the risk of iDCIS and iIBC no longer differed for BCS versus BCS + RT (for iDCIS: HRage 0.7 (95% CI 0.3–1.5); HRage ≥ 50 0.7 (95% CI 0.4–1.3) and for iIBC: HRage 0.6 (95% CI 0.4–0.9); HRage ≥ 50 1.2 (95% CI 0.9–1.6)). Conclusion RT is associated with lower iDCIS and iIBC risk up to 10 years after BCS, but this effect wanes thereafter.

Globally we are experiencing a decline in aggregate natural capital. Many primary industries and enterprises are highly dependent on renewable and non-renewable natural capital, but there has been little focus on measuring and monitoring the flows benefits from natural capital. Natural capital accounting can help by potentially enabling the enterprise to better adapt and respond to risks in the future. To assist future implementation of natural capital accounting we assess the value proposition perceived by primary industry stakeholders. We use three primary industries in Australia as case studies (cotton, forestry and fisheries), and surveyed 140 stakeholders across the three industries. Interviewees generally suggested natural capital accounting is of public benefit by improving environmental outcomes. Private benefits are obtained through industry gaining social licence, greater market access and better business models. Although there was general agreement over improved environmental outcomes and access to premium markets, there were differences between industries and stakeholders. There were some concerns across the industries about the potential costs natural capital accounting may add to normal business operations and the lack of consistency in practices. Mainstreaming natural capital accounting across primary industries will mean that the value propositions and the implementation barriers need to be addressed. Overall the value proposition of implementing natural capital accounts at the enterprise level must stack up favourably against its costs.

Sexuality education (SE) for individuals with intellectual and developmental disabilities is needed, but is sparse. Seven individuals with intellectual and developmental disabilities and two educat...

Background The onset of the COVID-19 pandemic forced the Dutch national screening program to a halt and increased the burden on health care services, necessitating the introduction of specific breast cancer treatment recommendations from week 12 of 2020. We aimed to investigate the impact of COVID-19 on the diagnosis, stage and initial treatment of breast cancer. Methods Women included in the Netherlands Cancer Registry and diagnosed during four periods in weeks 2–17 of 2020 were compared with reference data from 2018/2019 (averaged). Weekly incidence was calculated by age group and tumor stage. The number of women receiving initial treatment within 3 months of diagnosis was calculated by period, initial treatment, age, and stage. Initial treatment, stratified by tumor behavior (ductal carcinoma in situ [DCIS] or invasive), was analyzed by logistic regression and adjusted for age, socioeconomic status, stage, subtype, and region. Factors influencing time to treatment were analyzed by Cox regression. Results Incidence declined across all age groups and tumor stages (except stage IV) from 2018/2019 to 2020, particularly for DCIS and stage I disease (p wks2–8: 2.04, ORwks9–11: 2.18). Invasive tumors were less likely to be treated initially by mastectomy with immediate reconstruction (ORwks12–13: 0.52) or by breast conserving surgery (ORwks14–17: 0.75). Chemotherapy was less likely for tumors diagnosed in the beginning of the study period (ORwks9–11: 0.59, ORwks12–13: 0.66), but more likely for those diagnosed at the end (ORwks14–17: 1.31). Primary hormonal treatment was more common (ORwks2–8: 1.23, ORwks9–11: 1.92, ORwks12–13: 3.01). Only women diagnosed in weeks 2–8 of 2020 experienced treatment delays. Conclusion The incidence of breast cancer fell in early 2020, and treatment approaches adapted rapidly. Clarification is needed on how this has affected stage migration and outcomes.

Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer–specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype. Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (Padj > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5–25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06–1.34)]; current versus never smoking [1.37 (1.27–1.47)], high versus low physical activity [0.43 (0.21–0.86)], age ≥30 years versus 0– Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.

Introduction The COVID-19 pandemic led to a significant drop in the incidence of cancer diagnoses in the Netherlands, partially due to the suspension of all national cancer screening programs on 16th March 2020 (week 12). Hospitals were forced to focus on care for COVID-19 patients resulting in limited capacity and down scaling of health care for non-COVID-19 patients. Specific recommendations for breast cancer treatment strategies, such as alterations in sequence, type, and/or frequency, were temporarily implemented from week 12 onwards. The aim of this study was to investigate the impact of the first outbreak on the initial treatment of breast cancer patients. Methods Women older than 18 years, treated within three months following their breast cancer diagnosis during weeks 2-17 2018-2019 (reference period) or weeks 2-17 2020 (COVID-19 period), were selected from the Netherlands Cancer Registry. Weeks 2-17 2020 were split up in four periods, based on the number of breast cancer diagnoses: weeks 2-8, weeks 9-11, weeks 12-13, and weeks 14-17. Average number of breast conserving surgeries (BCS), mastectomies with direct reconstruction (DR), mastectomies without DR, chemotherapy, endocrine therapy or other therapies, given as initial treatment per week, were calculated, stratified by period and by tumor stage. Treatments given to patients diagnosed in the reference period were compared with treatments given to patients diagnosed in the COVID-19 period, using a Mantel-Haenszel test, adjusting for age. Results A total of 16,553 patients were included in the current study. Of these patients 5,504 received their initial treatment in weeks 2-17 2018, 5,641 in weeks 2-17 2019 and 5,408 in weeks 2-17 2020. An increase in the use of endocrine therapy was seen in weeks 12-13 and 14-17 2020 compared to weeks 2-17 2018/2019, especially for patients with stage I cancer (12.3% and 7.7% vs 4.8%) and stage II cancer (25.4% and 17.4% vs 13.4%). In addition, a lower proportion of patients with stage II breast cancer received chemotherapy as first treatment in weeks 12-13 (21.1%) and 14-17 2020 (20.1%) compared to weeks 2-17 2018/2019 (29.8%) (Table). Discussion The COVID-19 pandemic led to a major increase in the use of endocrine therapy following the recommendations, which was mainly used to enable postponing surgery. The lower use of chemotherapy was probably related to the thought to limit hospital visits and the expected higher risk of developing COVID-19 complications due to chemotherapy. Possible long-term effects of changes in initial treatments will be monitored. Foodnote by table: Weeks 2-17 2020 (the COVID-19 period) were compared to the same weeks in 2018-2019, adjusted for age (74). A statistically significant: ↑ higher proportion of patients received this therapy, corrected for age; ↓ lower proportion of patients received this therapy, corrected for age; a: lower proportion of patients aged between 50 and 64 years received BCS; b: higher proportion of patients aged 39 or younger received mastectomy without DR; c: higher proportion of patients aged 39 or younger, or aged between 50 and 75 years received endocrine therapy; d: higher proportion of patients aged between 40 and 74 years received endocrine therapy; e: higher proportion of patients aged 74 or younger received endocrine therapy; f: higher proportion of patients aged 39 or younger received chemotherapy; g: higher proportion of patients aged 75 years or older received BCS Average number (percentage) initial treatments per week, stratified by stage and periodTotalBreast conserving surgeryMastectomy with direct reconstructionMastectomy without direct reconstructionChemotherapyEndocrine therapyTotalDCISWeek 2-17 2018/201940.629.5 (72.7)4.9 (12.0)5.7 (13.9)0.1 (0.2)0.3 (0.8)0.1 (0.2)Week 2-8 202043.730.9 (70.6)5.0 (11.4)7.3 (16.7)0.4 (1.0)0.1 (0.3)0.0 (0.0)Week 9-11 202038.027.0 (71.1)4.0 (10.5)7.0 (18.4)0.0 (0.0)0.0 (0.0)0.0 (0.0)Week 12-13 202048.031.5 (65.6)7.0 (14.6)7.0 (14.6)0.0 (0.0)2.5 (5.2) ↑0.0 (0.0)Week 14-17 202028.319.0 (67.3)3.0 (10.6)5.8 (20.4) ↑0.0 (0.0)0.5 (1.8)0.0 (0.0)Stage IWeek 2-17 2018/2019146.2104.5 (71.5)10.0 (6.8)17.8 (12.2)6.2 (4.3)7.0 (4.8)0.7 (0.5)Week 2-8 2020148.4107.9 (72.7)7.0 (4.7) ↓15.3 (10.3)10.0 (6.7) ↑7.4 (5.0)0.9 (0.6)Week 9-11 2020131.793.7 (71.1)8.0 (6.1)14.3 (10.9)6.3 (4.8)8.0 (6.1)1.3 (1.0)Week 12-13 2020163.0107.5 (66.0)a10.0 (6.1)20.0 (12.3)b4.5 (2.8)20.0 (12.3)c1.0 (0.6)Week 14-17 2020117.377.0 (65.7) ↓10.8 (9.2)16.8 (14.3)3.3 (2.8)9.0 (7.7) ↑0.5 (0.4)Stage IIWeek 2-17 2018/2019114.937.0 (32.2)5.0 (4.3)20.8 (18.1)34.3 (29.8)15.4 (13.4)2.5 (2.2)Week 2-8 2020116.133.4 (28.8) ↓4.1 (3.6)18.4 (15.9)38.4 (33.1) ↑18.3 (15.7)3.4 (3.0)Week 9-11 2020118.735.7 (30.1)5.7 (4.8)19.0 (16.0)36.0 (30.3)20.0 (16.9)2.3 (2.0)Week 12-13 2020142.042.5 (29.9)5.5 (3.9)26.5 (18.7)30.0 (21.1) ↓36.0 (25.4)d1.5 (1.1)Week 14-17 202083.327.5 (33.0)5.5 (6.6)16.0 (19.2)16.8 (20.1) ↓14.5 (17.4)e3.0 (3.6)Stage IIIWeek 2-17 2018/201931.12.0 (6.3)0.5 (1.7)5.8 (18.5)16.0 (51.5)5.3 (17.0)1.6 (5.0)Week 2-8 202027.92.4 (8.7)0.6 (2.1)5.0 (17.9)14.3 (51.3)4.7 (16.9)0.9 (3.1)Week 9-11 202026.72.0 (7.5)0.3 (1.3)5.7 (21.3)12.7 (47.5)f5.7 (21.3)0.3 (1.3)Week 12-13 202038.52.0 (5.2)0.5 (1.3)7.5 (19.5)19.0 (49.4)8.5 (22.1)1.0 (2.6)Week 14-17 202020.81.5 (7.2)1.3 (6.0) ↑4.5 (21.7)8.0 (38.6)4.5 (21.7)1.0 (4.8)Stage IVWeek 2-17 2018/201915.00.3 (2.3)0.0 (0.2)0.6 (4.0)5.3 (34.9)6.8 (44.9)2.1 (13.7)Week 2-8 202014.60.6 (3.9)0.0 (0.0)0.4 (2.9)4.7 (32.4)6.7 (46.1)2.1 (14.7)Week 9-11 202012.00.0 (0.0)0.0 (0.0)0.0 (0.0)3.3 (27.8)7.0 (58.3)1.3 (11.1)Week 12-13 202019.51.5 (7.7)0.0 (0.0)2.5 (12.8) ↑6.0 (30.8)7.5 (38.5)2.0 (10.3)Week 14-17 202013.80.3 (1.8)g0.0 (0.0)0.3 (1.8)3.8 (27.3)8.3 (60.0) ↑1.3 (9.1) Citation Format: Anouk H Eijkelboom, Linda de Munck, Marie-Jeanne Vrancken Peeters, Marjolein Smidt, Mireille Broeders, Monique Bos, Marjanka K Schmidt, Maud Bessems, Luc Strobbe, Desirée van den Bongard, Aafke Honkoop, Janneke Verloop, Cristina Guerrero Paez, Marc Lobbes, Sabine Linn, Pieter Westenend, Catharina W Menke-van der Houven van Oordt, Jelle Wesseling, Vivianne Tjan Heijnen, Sabine Siesling, On behalve of the NABON COVID-19 consortium. Effect of the COVID-19 pandemic on the initial treatment of breast cancer in the Netherlands: A population-based study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-88.

Background Breast cancer follow-up aims at early detection of locoregional recurrences (LRR) and second primary breast cancer (SP). Predicting a patient’s time-dependent risk for such an event may improve follow-up strategies. Furthermore, many clinicians and patients are interested in the risk of distant metastasis (DM) as well, as it provides additional information on prognosis. The existing INFLUENCE nomogram predicts the yearly risk of LRR up to five years from diagnosis using logistic regression analyses. However, this model was based on patients diagnosed between 2003 and 2006 and lacked information on HER2 status, which is nowadays an important prognostic variable. In this population-based study, we aimed to improve the INFLUENCE model with more flexible predictions over time, more recent information and additional outcomes - risk of LRR, distant metastasis (DM) and SP - using different underlying models. Methods Patient-, tumor- and treatment-related characteristics of all female patients diagnosed with invasive adenocarcinoma of the breast in 2007, 2008 and 2012, of who active 5-year follow-up was performed, were selected from the Netherlands Cancer Registry. Models were developed for LRR, DM and SP as a first event separately, and for each three-monthly time interval to predict time-dependent risks as accurately as possible. Follow-up was calculated from date of definite surgery to date of event or last observation. We compared three different models to estimate the three outcomes: a Cox regression model, a flexible parametric spline model and a random survival forest (RF) model. To assess calibration of each outcome, three-monthly risk predictions during the 5-year follow-up period were compared to corresponding observed event rates. To assess discrimination, the areas under the curves (AUC) were calculated for each timeframe in the 5-year period and averaged to one combined measure (average 5-year AUC). To correct for optimism we performed bootstrapping on the entire cohort with 200 replicates and updated the calibration measures and AUCs accordingly. Results In total, 13,494 patients were included. LRR, DM and SP within five years were experienced by 2.8%, 6.3% and 3.1% of the patients, respectively. The following variables were included in the final models: age, tumor grade, tumor stage, nodal stage, multifocality, HER2 status, hormonal receptor status, type of surgery, chemotherapy, radiotherapy, hormonal therapy, anti-HER2 therapy. The optimism-corrected mean time-dependent prediction errors for individual risk predictions ranged between 0.12% and 0.46% for all three models and all three month timeframes. The average 5-year AUCs for LRR, SP and DM using the Cox model were 0.71, 0.63 and 0.77, respectively. The average 5-year AUCs for LRR, SP and DM using the parametric spline model were 0.71, 0.63 and 0.78, respectively. When using the RF model, the average 5-year AUCs were 0.74, 0.68 and 0.77 for LRR, SP and DM, respectively (Table). Conclusion Although differences were very small, the RF model had the best performance overall. This INFLUENCE 2.0 model provides us with updated information on the individual time-dependent risks of LRR, DM and SP within five years following surgery. This model is freely accessible at https://tinyurl.com/influence-2 and can be used as an instrument to improve follow-up strategies and to give patients better insights in their prognosis. Table. Optimism-corrected average AUCs over the 5-year follow-up periodModel typeLRDMSPCox regression0.710.770.63Flexible parametric spline0.710.780.63Random survival forest0.740.770.68 Citation Format: Sabine Siesling, Vinzenz Völkel, Tom Hueting, Teresa Draeger, Marissa C van Maaren, Luc JA Strobbe, Marjanka K Schmidt, Gabe S Sonke, Marjan van Hezewijk, Catharina GM Groothuis-Oudshoorn. Risk estimation of locoregional recurrence, distant metastasis and second primary breast cancer in early stage breast cancer patients: The INFLUENCE 2.0 nomogram [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-10.

To investigate the prevalence of burnout among Danish and American urologists.An email invitation was sent with 2 reminders spaced by 14 days intervals to members of the Danish Urological Association and urologists at the University of Michigan to participate in a survey consisting of the 2 item Maslach Burnout Inventory. Burnout was defined as reporting "once a week," "a few times a week," or "everyday" on either the emotional exhaustion or depersonalization domains of the Maslach Burnout Inventory. Two open-ended questions were added to the survey for the Danish urologists, these were then qualitatively analyzed using thematic analysis. Categorial variables were compared using Chi square analysis.The response rate was 193 of 387 (49.9%) for the Danish urologists and 43 of 64 (67.1%) among American urologists. The prevalence of burnout for the American and Danish cohorts was identified in 4 (44.4%) of the American residents and 10 (32.3%) of the American attendings compared to 2 (3%) of Danish residents and 16 (12.7%) of Danish attendings. The difference in rate of burnout between Danish residents and attendings was statistically significant (P= .03). Burnout was statistically significantly different between American and Danish residents (P.01) and attendings (P.01). There was a statistically significant difference in rates of burnout between American and the Danish female urologists (P = .02) and similarly among male urologists (P.01).This study demonstrated low rates of burnout among Danish urologists and a significant difference in burnout between residents and attendings from Michigan compared to Danish residents and attendings.

Sexual and reproductive health is an important aspect of human development, but discussions with adolescents and young adults on this topic are often challenging for health-care providers. As a result, many adolescents and young adults do not receive appropriate, comprehensive sexual education, despite recognition from WHO and the UN that access to this education is a human right. Adolescents and young adults with mild to moderate intellectual or developmental disability, or both, are just as likely to be sexually active as are their peers without disability; however, these individuals are less likely to receive comprehensive sexual education. To ensure adequate comprehensive sexual education for adolescents and young adults with intellectual and developmental disabilities, sexual health educators should facilitate conversations about sexual and reproductive health that are non-judgmental and sexually inclusive. Such initiatives should use an educational framework grounded in universal design for learning, including use of multiple media types with clear, concise language and images.

Introduction: Hormone replacement therapy can diminish hormone depletion -related complaints in postmenopausal women, but is contraindicated for postmenopausal breast cancer (BC) patients. Re- covery of menstruation after chemotherapy -induced amenorrhea in young hormone receptor -negative BC patients however, is accepted. To determine the safety of this strategy, we investigated the effect of recovery of menstruation on disease -free survival (DFS) and overall survival (OS) in young hormone receptor -negative BC patients treated with (neo)adjuvant chemotherapy. Methods: We selected 636 patients from a single -center cohort with early stage hormone receptor - negative BC and under the age of 50 years when treated with chemotherapy. Suf ficient data on course of menstruation in medical records was retrospectively found for 397 patients, of whom 299 patients (75%) had a recovery of menstruation after chemotherapy. We used Cox proportional hazards models to estimate hazard ratios (HR) for the effect of recovery of menstruation on DFS and OS. Results: Patients with recovery of menstruation after chemotherapy less frequently had lymph node involvement at diagnosis (45% vs 66%, p = 0.001). After a median follow-up of 6.7 years, the adjusted hazard ratios were 1.45 (95% CI: 0.83-2.54) for DFS and 1.19 (95% CI: 0.71-1.98) for OS. Conclusion: No signi ficantly increased recurrence risk was found for hormone receptor -negative BC patients with recovery of menstruation after chemotherapy. However, the outcome of the multivariable model is not reassuring and a potentially increased recurrence risk cannot be excluded. The results need to be validated in a larger prospective study for a more de finitive answer. (c) 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Three flutter-suppression designs for a flexible flying-wing research drone are discussed, along with the modeling and flight-test results. The drone, with wing span of 10 feet, aspect ratio of alm...

As of 10 April 2020, New York State had 180,458 cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and 9,385 reported deaths. Patients with cancer comprised 8.4% of deceased individuals1. Population-based studies from China and Italy suggested a higher coronavirus disease 2019 (COVID-19) death rate in patients with cancer2,3, although there is a knowledge gap as to which aspects of cancer and its treatment confer risk of severe COVID-194. This information is critical to balance the competing safety considerations of reducing SARS-CoV-2 exposure and cancer treatment continuation. From 10 March to 7 April 2020, 423 cases of symptomatic COVID-19 were diagnosed at Memorial Sloan Kettering Cancer Center (from a total of 2,035 patients with cancer tested). Of these, 40% were hospitalized for COVID-19, 20% developed severe respiratory illness (including 9% who required mechanical ventilation) and 12% died within 30 d. Age older than 65 years and treatment with immune checkpoint inhibitors (ICIs) were predictors for hospitalization and severe disease, whereas receipt of chemotherapy and major surgery were not. Overall, COVID-19 in patients with cancer is marked by substantial rates of hospitalization and severe outcomes. The association observed between ICI and COVID-19 outcomes in our study will need further interrogation in tumor-specific cohorts.

Purpose The majority of ‘low-risk’ (grade I/II) Ductal Carcinoma In Situ (DCIS) lesions do not progress to invasive breast cancer during a woman’s lifetime. Therefore, the safety of active surveillance versus standard surgical treatment for grade I/II DCIS is being evaluated in several clinical trials. If active surveillance is proven safe and implemented in clinical practice, a significant group of women with low-risk DCIS may forego surgery and radiotherapy. To further reduce their risks, there is an urgent need to identify potentially modifiable risk factors. Nonetheless, non-modifiable risk factors are also of great importance to gain clear understanding of the overall risk for developing a subsequent event (invasive breast cancer, in situ recurrences, distant metastases) following untreated DCIS. A systematic literature review was performed to evaluate the impact of established breast cancer risk factors on the risk of developing in situ or invasive disease after treatment of primary pure DCIS. Methods A systematic literature search was performed in PUBMED, EMBASE and Web of Science. PRISMA methodology was applied for the selection of studies. We only included studies that were published after the review by Shamliyan et al in 2010. Results Nine out of the 3,852 articles retrieved were included for final data extraction and evaluation. These nine studies included a total of 11,602 patients with primary pure DCIS. The sample size of these studies ranged from 50 to 4,131 patients. Across the studies, a total of 979 (range: 2-239) subsequent events, such as ipsilateral invasive, ipsilateral in situ events, and distant metastases, were reported. The median follow-up varied between four and nine years. There was limited information published and limited evidence in the selected studies especially on modifiable factors; and all studies except one, were in women of European-descent. Of the modifiable factors only a high BMI (≥25) in mainly postmenopausal women seemed to be associated with a lower risk of a subsequent event. There was some evidence for several non-modifiable predictors, i.e. younger age at diagnosis of DCIS, positive family history of breast cancer, premenopausal status, and high breast density. Age was associated with a two to threefold risk for experiencing a subsequent event. A positive family history had an almost two-fold increased risk, and pre-menopausal status increased the risk for a subsequent event between 46 to 89%. Furthermore, the highest quintile for breast density was associated with a 70% increase in risk for a subsequent event. See table 1 for effect sizes with 95% confidence intervals. Conclusion There is a limited number of studies published on the impact of risk factors on subsequent events after pure DCIS. Moreover, the available evidence is insufficient to identify potential targets for risk reduction strategies, due to the relatively small numbers and the lack of long term follow-up in a low-event disease such as DCIS. Traditional risk factors for primary invasive breast cancer showed, in general, also to be associated with the risk for a subsequent event after primary pure DCIS. The single study that reported on BMI showed a direction of association that was contrary to expectations. In conclusion large scale, well-designed, studies with specific attention to lifestyle factors are necessary to enable identification of DCIS who are at low and high risk for a subsequent event after primary pure DCIS. Table 1. Overview of published effect sizes of risk of a subsequent event after pure DCISIncluded articlesVariableHR/OR (95% CI)Moran et al. 2017 Age (≥50 vs < 50 years) HR(Multivariate) 0.54 (0.41-0.71)Alvarado et al. 2012Age (2 relatives with Breast Cancer)OR(Multivariate) 1.78 (1.02–3.10)De Lorenzi et al. 2018BMI (high ≥ 25 vs low)HR(Multivariate)0.48(0.26-0.90)De Lorenzi et al. 2018Menopausal state (pre vs post)HR(Multivariate)1.89 (0.37-0.77)Shurell et al. 2017Menopausal state (post vs pre)HR(Multivariate)0.54 (0.37-0.77)Habel et al. 2010Breast density (highest quintile)HR(Multivariate)1.70 (1.00–2.39) Citation Format: Sena Alaeikhanehshir, Ellen G Engelhardt, Frederieke H van Duijnhoven, Maartje van Seijen, Patrick A Bhairosing, Donna Pinto, Deborah Collyar, Jelle Wesseling, Esther H Lips, Marjanka K Schmidt. The impact of patient characteristics and lifestyle factors on the risk of an ipsilateral event after a primary DCIS: A systematic review [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-08-15.

Cellular micromotors are attractive for locally delivering high concentrations of drug, and targeting hard-to-reach disease sites such as cervical cancer and early ovarian cancer lesions by non-invasive means. Spermatozoa are highly efficient micromotors perfectly adapted to traveling up the female reproductive system. Indeed, bovine sperm-based micromotors have shown potential to carry drugs toward gynecological cancers. However, due to major differences in the molecular make-up of bovine and human sperm, a key translational bottleneck for bringing this technology closer to the clinic is to transfer this concept to human material. Here, we successfully load human sperm with Doxorubicin (DOX) and perform treatment of 3D cervical cancer and patient-representative ovarian cancer cell cultures, resulting in strong anticancer cell effects. Additionally, we define the subcellular localization of the chemotherapeutic drug within human sperm, using high-resolution optical microscopy. We also assess drug effects on sperm motility and viability over time, employing sperm samples from healthy donors as well as assisted reproduction patients. Finally, we demonstrate guidance and release of human drug-loaded sperm onto cancer tissues using magnetic microcaps, and show the sperm microcap loaded with a second anticancer drug, camptothecin (CPT), which unlike DOX is not suitable for directly loading into sperm due to its hydrophobic nature. This co-drug delivery approach opens up novel targeted combinatorial drug therapies for future applications. © 2020 The Royal Society of Chemistry.

Purpose We evaluated the performance of the recently extended Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA version 5) in a Dutch prospective cohort, using a polygenic risk score (PRS) based on 313 breast cancer (BC)-associated variants (PRS313) and other, nongenetic risk factors. Methods Since 1989, 6522 women without BC aged 45 or older of European descent have been included in the Rotterdam Study. The PRS(313)was calculated per 1 SD in controls from the Breast Cancer Association Consortium (BCAC). Cox regression analysis was performed to estimate the association between the PRS(313)and incident BC risk. Cumulative 10-year risks were calculated with BOADICEA including different sets of variables (age, risk factors and PRS313). C-statistics were used to evaluate discriminative ability. Results In total, 320 women developed BC. The PRS(313)was significantly associated with BC (hazard ratio [HR] per SD of 1.56, 95% confidence interval [CI] [1.40-1.73]). Using 10-year risk estimates including age and the PRS313, other risk factors improved the discriminatory ability of the BOADICEA model marginally, from a C-statistic of 0.636 to 0.653. Conclusions The effect size of the PRS(313)is highly reproducible in the Dutch population. Our results validate the BOADICEA v5 model for BC risk assessment in the Dutch general population.

Residual biospecimens that are stored in hospitals' diagnostic specimen archives can be used for scientific research under strict legal and ethical regulations. In the Netherlands, a Code of Conduct governs responsible secondary use of residual biospecimens. However, implementation of this Code seems to be challenging. This study aims to explore the most important factors that facilitate or hinder the implementation of the Code. In addition, it investigates what is needed to further foster the responsible use of residual biospecimens. A mixed-methods design was used. Questionnaires were sent out to pathologists, patient information centers, physicians, researchers, data protection officers (DPOs), members of research ethics committees, and members of the boards of directors of all hospitals in the Netherlands (81 hospitals). To further investigate the barriers and facilitators, interviews were conducted with pathologists, patient information centers, physician-researchers, DPOs, review boards, research coordinators, and quality managers of pathology departments. In total, 246 respondents filled out the questionnaire and 36 interviews were conducted. Major barriers for implementing were a lack of resources (time, money), a lack of attention for responsible use, and a lack of practical knowledge (knowing what to do, where to go with questions). In contrast, the perception that implementing the Code was necessary, either by the respondent or by colleagues, was considered "a driver"for implementation. Practical instruments such as checklists and roadmaps were considered necessary to foster implementation; however, the creation of such instruments was hindered by a lack of clear-cut answers regarding legal aspects. Therefore, more clarity and harmonization on how to interpret both the Code and legislation regarding secondary use were considered necessary.

Background Conventional epidemiologic studies have evaluated associations between circulating lipid levels and breast cancer risk, but results have been inconsistent. As Mendelian randomization analyses may provide evidence for causal inference, we sought to evaluate potentially unbiased associations between breast cancer risk and four genetically predicted lipid traits. Methods Previous genome-wide association studies (GWAS) have identified 164 discrete variants associated with high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), triglycerides and total cholesterol. We used 162 of these unique variants to construct weighted genetic scores (wGSs) for a total of 101 424 breast cancer cases and 80 253 controls of European ancestry from the Breast Cancer Association Consortium (BCAC). Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between per standard deviation increase in genetically predicted lipid traits and breast cancer risk. Additional Mendelian randomization analysis approaches and sensitivity analyses were conducted to assess pleiotropy and instrument validity. Results Corresponding to approximately 15 mg/dL, one standard deviation increase in genetically predicted HDL-C was associated with a 12% increased breast cancer risk (OR: 1.12, 95% CI: 1.08–1.16). Findings were consistent after adjustment for breast cancer risk factors and were robust in several sensitivity analyses. Associations with genetically predicted triglycerides and total cholesterol were inconsistent, and no association for genetically predicted LDL-C was observed. Conclusions This study provides strong evidence that circulating HDL-C may be associated with an increased risk of breast cancer, whereas LDL-C may not be related to breast cancer risk.

Background Breast cancer survivors are at risk for contralateral breast cancer (CBC), with the consequent burden of further treatment and potentially less favorable prognosis. We aimed to develop and validate a CBC risk prediction model and evaluate its applicability for clinical decision-making. Methods We included data of 132,756 invasive non-metastatic breast cancer patients from 20 studies with 4682 CBC events and a median follow-up of 8.8 years. We developed a multivariable Fine and Gray prediction model (PredictCBC-1A) including patient, primary tumor, and treatment characteristics and BRCA1/2 germline mutation status, accounting for the competing risks of death and distant metastasis. We also developed a model without BRCA1/2 mutation status (PredictCBC-1B) since this information was available for only 6% of patients and is routinely unavailable in the general breast cancer population. Prediction performance was evaluated using calibration and discrimination, calculated by a time-dependent area under the curve (AUC) at 5 and 10 years after diagnosis of primary breast cancer, and an internal-external cross-validation procedure. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility. Results In the multivariable model, BRCA1/2 germline mutation status, family history, and systemic adjuvant treatment showed the strongest associations with CBC risk. The AUC of PredictCBC-1A was 0.63 (95% prediction interval (PI) at 5 years, 0.52–0.74; at 10 years, 0.53–0.72). Calibration-in-the-large was -0.13 (95% PI: -1.62–1.37), and the calibration slope was 0.90 (95% PI: 0.73–1.08). The AUC of Predict-1B at 10 years was 0.59 (95% PI: 0.52–0.66); calibration was slightly lower. Decision curve analysis for preventive contralateral mastectomy showed potential clinical utility of PredictCBC-1A between thresholds of 4–10% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. Conclusions We developed a reasonably calibrated model to predict the risk of CBC in women of European-descent; however, prediction accuracy was moderate. Our model shows potential for improved risk counseling, but decision-making regarding contralateral preventive mastectomy, especially in the general breast cancer population where limited information of the mutation status in BRCA1/2 is available, remains challenging.

We theoretically and numerically study the efficiency of Brillouin-based opto-acoustic data storage in a photonic waveguide in the presence of thermal noise and laser phase noise. We compare the physics of the noise processes and how they affect different storage techniques, examining both amplitude and phase storage schemes. We investigate the effects of storage time and pulse properties on the quality of the retrieved signal, and find that phase storage is less sensitive to thermal noise than amplitude storage., Comment: 12 pages, 9 figures

Importance: People with intellectual and developmental disabilities (IDD) express a clear interest in intimate relationships but face many barriers to receiving sex education (SE) that would support their engagement in these relationships. Objective: To understand barriers to, the context of, and recommendations for SE for people with IDD. Design: Qualitative study design with interviews and focus groups with four key stakeholder groups. Data were analyzed using a constant comparative approach. Participants: Participants were 8 youths with IDD, 9 parents, 12 health care providers, and 8 educators. Results: Four barriers to SE were identified: (1) values and cultural issues, (2) parental attitudes toward their child’s sexuality, (3) a lack of organizational policies and standards, and (4) limited professional education or societal biases. These barriers contribute to a SE context primarily initiated by people with IDD or provided reactively. The participants recommended proactive, formal SE provided by multiple stakeholders throughout adulthood. Conclusions and Relevance: Stakeholders should advocate for policies, standards, and additional training for parents, educators, and health care providers to support SE for people with IDD throughout adulthood. What This Article Adds: Barriers to SE contribute to the current context in which SE is shared with people with IDD. Stakeholders can advocate for policies, standards, and training to overcome these barriers and support recommendations for proactive, formal SE provided by multiple stakeholders through adulthood.

Postpartum breast cancer (PPBC) - which according to new data, can extend to 5-10 years after the birth - are estimated to represent 35-55% of all cases of breast cancer in women younger than 45 years. Increasing clinical evidence indicates that PPBC represents a high-risk form of breast cancer in young women with an approximately 2-fold increased risk for metastasis and death. Yet, the exact mechanisms that underlay this poor prognosis are incompletely understood and, hence, it is unknown why postpartum breast cancer has an enhanced risk for metastasis or how it should be effectively targeted for improved survival. This article is an accompanying resource of the original article entitled "Breast cancer diagnosed in the post-weaning period is indicative for a poor outcome" and present epidemiological data that compare standard prognostic parameters, first site of metastatic disease and survival and metastatic rates in young women with primary invasive breast cancer diagnosed within two years postpartum (PP-BC), in young women diagnosed during pregnancy (Pr-BC) and nulliparous women (NP-BC). Via an international collaboration of 13 centres participating in the International Network on Cancer, Infertility and Pregnancy (INCIP), retrospective data of 1180 patients with primary invasive breast cancer, aged 25-40 years and diagnosed between January 1995 and December 2017 were collected. In particular, tumour-, patient, and therapy-related characteristics were collected. Furthermore, patient files were reviewed thoroughly to assess, for each parity, if and for how long breastfeeding was given. For PP-BC patients, breastfeeding history was used to differentiate breast cancers identified during lactation (PP-BCDL) from those diagnosed post-weaning (PP-BCPW). Primary exposures were prior childbirth or no childbirth, time between most recent childbirth and breast cancer diagnosis, time between cessation of lactation and breast cancer diagnosis and time between breast cancer diagnosis and metastasis or death. Distribution of standard prognostic parameters and first site of distant metastasis among study groups was determined applying fisher's exact, chi-squared, One-Way ANOVA or Kruskal-Wallis tests or logistic regression models, where applicable. The risks for metastasis and death were assessed using Cox proportional hazards models. A subgroup analysis was performed in PP-BCPW patients that never lactated (PP-BCPW/NL), lactated ≤3 months (PP-BCPW/Lshort) or lactated >3 months (PP-BCPW/Llong). ispartof: DATA IN BRIEF vol:38 ispartof: location:Netherlands status: published

Purpose To extend the functionality of the existing INFLUENCE nomogram for locoregional recurrence (LRR) of breast cancer toward the prediction of secondary primary tumors (SP) and distant metastases (DM) using updated follow-up data and the best suitable statistical approaches. Methods Data on women diagnosed with non-metastatic invasive breast cancer were derived from the Netherlands Cancer Registry (n = 13,494). To provide flexible time-dependent individual risk predictions for LRR, SP, and DM, three statistical approaches were assessed; a Cox proportional hazard approach (COX), a parametric spline approach (PAR), and a random survival forest (RSF). These approaches were evaluated on their discrimination using the Area Under the Curve (AUC) statistic and on calibration using the Integrated Calibration Index (ICI). To correct for optimism, the performance measures were assessed by drawing 200 bootstrap samples. Results Age, tumor grade, pT, pN, multifocality, type of surgery, hormonal receptor status, HER2-status, and adjuvant therapy were included as predictors. While all three approaches showed adequate calibration, the RSF approach offers the best optimism-corrected 5-year AUC for LRR (0.75, 95%CI: 0.74–0.76) and SP (0.67, 95%CI: 0.65–0.68). For the prediction of DM, all three approaches showed equivalent discrimination (5-year AUC: 0.77–0.78), while COX seems to have an advantage concerning calibration (ICI Conclusions INFLUENCE 2.0 is a flexible model to predict time-dependent individual risks of LRR, SP and DM at a 5-year scale; it can support clinical decision-making regarding personalized follow-up strategies for curatively treated non-metastatic breast cancer patients.

BACKGROUND: In young women, a breast cancer diagnosis after childbirth increases the risk for metastasis and death. Studies in rodents suggest that post-weaning mammary gland involution contributes to the poor prognosis of postpartum breast cancers. However, this association has not been investigated in humans, mainly because of missing information on the patient's lactation status at diagnosis. PATIENTS AND METHODS: Clinicopathological data of 1180 young women with primary invasive breast cancer, diagnosed within 2 years postpartum (PP-BC), during pregnancy (Pr-BC), or nulliparous (NP-BC), were collected. For PP-BC patients, breastfeeding history was retrieved to differentiate breast cancers identified during lactation (PP-BCDL) from those diagnosed post-weaning (PP-BCPW). Differences in prognostic parameters, first site of distant metastasis, and risks for metastasis and death were determined between patient groups. RESULTS: Cox proportional hazard models pointed to a twofold increased the risk of metastasis and death in PP-BCPW patients compared with PP-BCDL (hazard ratio [HR] 2.1 [PDRS = 0.021] and 2.9 [POS = 0.004]), Pr-BC (HR 2.1 [PDRS

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease. Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.

We present a numerical method for modelling noise in Stimulated Brillouin Scattering (SBS). The model applies to dynamic cases such as optical pulses, and accounts for both thermal noise and phase noise from the input lasers. Using this model, we compute the statistical properties of the optical and acoustic power in the pulsed spontaneous and stimulated Brillouin cases, and investigate the effects of gain and pulse width on noise levels. We find that thermal noise plays an important role in the statistical properties of the fields, and that laser phase noise impacts the SBS interaction when the laser coherence time is close to the time-scale of the optical pulses. This algorithm is applicable to arbitrary waveguide geometries and material properties, and thus presents a versatile way of performing noise-based SBS numerical simulations, which are important in signal processing, sensing, microwave photonics and opto-acoustic memory storage., Comment: 10 pages, 12 figures

Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is a serious infectious disease with diverse clinical manifestations. The morbidity and mortality of melioidosis is high in Southeast Asia and no licensed vaccines currently exist. This study was aimed at evaluating human cellular and humoral immune responses in Thai adults against four melioidosis vaccine candidate antigens. Blood samples from 91 melioidosis patients and 100 healthy donors from northeast Thailand were examined for immune responses against B. pseudomallei Hcp1, AhpC, TssM and LolC using a variety of cellular and humoral immune assays including IFN-γ ELISpot assays, flow cytometry and ELISA. PHA and a CPI peptide pool were also used as control stimuli in the ELISpot assays. Hcp1 and TssM stimulated strong IFN-γ secreting T cell responses in acute melioidosis patients which correlated with survival. High IFN-γ secreting CD4+ T cell responses were observed during acute melioidosis. Interestingly, while T cell responses of melioidosis patients against the CPI peptide pool were low at the time of enrollment, the levels increased to the same as in healthy donors by day 28. Although high IgG levels against Hcp1 and AhpC were detected in acute melioidosis patients, no significant differences between survivors and non-survivors were observed. Collectively, these studies help to further our understanding of immunity against disease following natural exposure of humans to B. pseudomallei as well as provide important insights for the selection of candidate antigens for use in the development of safe and effective melioidosis subunit vaccines.

Liver impairment is frequently reported in Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) infected patients and contributes to increased morbidity and mortality in critically ill Coronavirus disease-2019 (COVID-19) patients. We report of a 44-year-old male patient with hypoxic and cholestatic liver failure after an initially complicated course of COVID-19 pneumonia with moderate Acute Respiratory Distress Syndrome (ARDS), Acute Kidney Injury (AKI) stage 3 with Kidney Replacement Therapy (KRT), thromboembolic intestinal ischemia with subtotal colectomy and partial resection of the small intestine and septic shock. After considerable clinical improvement we initiated extracorporeal liver support due to progressive hyperbilirubinemia up to 25,3 mg/dl. Within 17 days we conducted 11 sessions of extracorporeal liver support by Fractionated Plasma Separation and Adsorption (FPSA; Prometheus®) until stabilization of liver function occurred. After 52 days of intensive care treatment and successful weaning from ventilation and KRT, the patient was transferred to an Intermediate Care (IMC) unit. To the best of our knowledge, this is the first report of a COVID-19 patient successfully treated with prolonged extracorporeal liver support. Extracorporeal procedures that support liver function should be considered as bridging to recovery in selected COVID-19 patients if liver failure presents a dominant organ dysfunction.

Background: Breast cancer survivors are at risk for contralateral breast cancer (CBC), with the consequent burden of further treatment and potentially less favorable prognosis. We aimed to develop and validate a CBC risk prediction model, and evaluate its applicability for clinical decision-making. Methods: We included data of 132,756 invasive non-metastatic breast cancer patients from 20 studies with 4,682 CBC events and a median follow-up of 8.8 years. We developed a multivariable Fine and Gray prediction model (PredictCBC-1A) including patient, primary tumor, and treatment characteristics, and BRCA1/2 germline mutation status, accounting for the competing risks of death and distant metastasis. We also developed a model without BRCA1/2 mutation status (PredictCBC-1B). Prediction performance was evaluated using calibration and discrimination, calculated by a time-dependent Area-Under-the-Curve (AUC) at 5 and 10 years after diagnosis of primary breast cancer, and an internal-external cross-validation procedure. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility. Results: In the multivariable model, BRCA1/2 germline mutation status, family history and systemic adjuvant treatment showed the strongest associations with CBC risk. The AUC of PredictCBC-1A was 0.63 (95% prediction interval (PI) at 5 years: 0.52–0.74; at 10 years: 0.53–0.72). Calibration in-the-large was -0.13 (95%PI: -1.62–1.37) and the calibration slope was 0.90 (95%PI: 0.73–1.08). The AUC of Predict-1B at 10 years was 0.59 (95% PI: 0.52–0.66); calibration was slightly lower. Decision curve analysis for preventive contralateral mastectomy showed potential clinical utility of PredictCBC-1A between thresholds of 4-10% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. Conclusions: We developed a reasonably calibrated model to predict the risk of CBC in women of European-descent, however, prediction accuracy was moderate. Our model shows potential for improved risk counseling, but decision regarding contralateral preventive mastectomy, especially in the general breast cancer population, remains challenging. Citation Format: Daniele Giardiello, Ewout W Steyerberg, Michael Hauptmann, Muriel A Adank, Agnes Jager, Hester OA Oldenburg, Maartje J Hooning, Marjanka K Schmidt, Breast Cancer Association Consortium. Prediction and clinical utility of a contralateral breast cancer risk model [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-07-12.

Ductal carcinoma in situ (DCIS) is considered a potential precursor of invasive breast carcinoma (IBC). Studies aiming to find markers involved in DCIS progression generally have compared characteristics of IBC lesions with those of adjacent synchronous DCIS lesions. The question remains whether synchronous DCIS and IBC comparisons are a good surrogate for primary DCIS and subsequent IBC. In this study, we compared both primary DCIS and synchronous DCIS with the associated IBC lesion, on the basis of immunohistochemical marker expression. Immunohistochemical analysis of ER, PR, HER2, p53, and cyclo-oxygenase 2 (COX-2) was performed for 143 primary DCIS and subsequent IBC lesions, including 81 IBC lesions with synchronous DCIS. Agreement between DCIS and IBC was assessed using kappa, and symmetry tests were performed to assess the pattern in marker conversion. The primary DCIS and subsequent IBC more often showed discordant marker expression than synchronous DCIS and IBC. Strikingly, 18 of 49 (36%) women with HER2-positive primary DCIS developed an HER2-negative IBC. Such a difference in HER2 expression was not observed when comparing synchronous DCIS and IBC. The frequency of discordant marker expression did not increase with longer time between primary DCIS and IBC. In conclusion, comparison of primary DCIS and subsequent IBC yields different results than a comparison of synchronous DCIS and IBC, in particular with regard to HER2 status. To gain more insight into the progression of DCIS to IBC, it is essential to focus on the relationship between primary DCIS and subsequent IBC, rather than comparing IBC with synchronous DCIS.

Individuals with intellectual and developmental disabilities (I/DD) may experience greater risk of sexually transmitted infections, higher rates of sexual abuse, and decreased sexual health knowledge, emphasizing the need for accessible, comprehensive sexual health education. The purpose of this scoping review was to identify the extent and nature of sexual health education interventions among individuals with I/DD ages 15–24 years. Six studies were included in the review. They investigated sexual health interventions for individuals with autism spectrum disorder and mild I/DD, covered a wide range of topics (e.g. puberty, healthy relationships), included multiple learning activities (e.g. illustrations, activity-based learning), and measured behavior and sexual health knowledge outcomes. Future research is needed in this area to assess intervention effectiveness.

BackgroundAn increasing number of breast cancer (BC) survivors are at risk of developing contralateral breast cancer (CBC). We aimed to investigate the influence of various adjuvant systemic regimens on, subtype-specific, risk of CBC.MethodsThis population-based cohort study included female patients diagnosed with first invasive BC between 2003 and 2010; follow-up was complete until 2016. Clinico-pathological data were obtained from the Netherlands Cancer Registry and additional data on receptor status through linkage with PALGA: the Dutch Pathology Registry. Cumulative incidences (death and distant metastases as competing risk) and hazard ratios (HRs) were estimated for all invasive metachronous CBC and CBC subtypes.ResultsOf 83 144 BC patients, 2816 developed a CBC; the 10-year cumulative incidence was 3.8% (95% confidence interval [CI] = 3.7% to 4.0%). Overall, adjuvant chemotherapy (HR = 0.70, 95% CI = 0.62 to 0.80), endocrine therapy (HR = 0.46, 95% CI = 0.41 to 0.52), and trastuzumab with chemotherapy (HR = 0.57, 95% CI = 0.45 to 0.73) were strongly associated with a reduced CBC risk. Specifically, taxane-containing chemotherapy (HR = 0.48, 95% CI = 0.36 to 0.62) and aromatase inhibitors (HR = 0.32, 95% CI = 0.23 to 0.44) were associated with a large CBC risk reduction. More detailed analyses showed that endocrine therapy statistically significantly decreased the risk of estrogen receptor (ER)-positive CBC (HR = 0.41, 95% CI = 0.36 to 0.47) but not ER-negative CBC (HR = 1.32, 95% CI = 0.90 to 1.93) compared with no endocrine therapy. Patients receiving chemotherapy for ER-negative first BC had a higher risk of ER-negative CBC from 5 years of follow-up (HR = 2.84, 95% CI = 1.62 to 4.99) compared with patients not receiving chemotherapy for ER-negative first BC.ConclusionEndocrine therapy, chemotherapy, as well as trastuzumab with chemotherapy reduce CBC risk. However, each adjuvant therapy regimen had a different impact on the CBC subtype distribution. Taxane-containing chemotherapy and aromatase inhibitors were associated with the largest CBC risk reduction.

Objective Although mu-opioid receptor agonists have been the mainstay of analgesic regimens for moderate to severe pain, they are associated with serious side effects, risks, and limitations. We evaluate the most serious risks associated with conventional opioids and compare these with the pharmacology of CYT-1010, a prototypical endomorphin and mu-opioid receptor agonist. Results Addiction and respiratory depression are serious risks of traditional mu-opioid analgesics. Mitigation strategies have been inadequate at addressing the opioid crisis and may interfere with the effective treatment of pain. Improved understanding of mu-opioid receptor biology and the discovery in 1997 of an additional and unique family of endogenous opioid peptides (endomorphins) have provided a pathway for dissociating analgesia from opioid-related adverse events and developing new classes of mu-opioid receptor agonists that use biased signaling and/or target novel sites to produce analgesia with reduced side effect liability. Endomorphin-1 and -2 are endogenous opioid peptides highly selective for mu-opioid receptors that exhibit potent analgesia with reduced side effects. CYT-1010 is a cyclized, D-lysine-containing analog of endomorphin-1 with a novel mechanism of action targeting traditional mu- and exon 11/truncated mu-opioid receptor 6TM variants. CYT-1010 preclinical data have demonstrated reduced abuse potential and analgesic potency exceeding that of morphine. In an initial phase 1 clinical study, CYT-1010 demonstrated significant analgesia vs baseline and no respiratory depression at the dose levels tested. Conclusions CYT-1010 and other novel mu-opioid receptor agonists in clinical development are promising alternatives to conventional opioids that may offer the possibility of safer treatment of moderate to severe pain.

The relevant content changes for pathologists in the updated interdisciplinary S3 guideline "Early detection, diagnosis, therapy and aftercare of breast cancer" are explained and discussed in the context of the most recent evidence. These include recommendations for risk assessment using Ki-67 and the use of multigene tests in the decision for or against adjuvant chemotherapy in estrogen receptor(ER)‑/progesterone receptor(PR)-positive and human epidermal growth factor receptor 2 (HER2)-negative invasive breast cancer. In addition, the assessment of HER2 status is explained. It is described which threshold distance or resection margin status is considered sufficient for resection of ductal carcinoma in situ (DCIS) and invasive breast carcinoma. Finally, recommendations concerning the clinical consequences to be drawn from the detection of a risk lesion in a core needle or vacuum biopsy or at the resection margin of a breast surgical specimen are discussed.

Protein prenylation by farnesyltransferase (FTase) is often described as the targeting of a cysteine-containing motif (CaaX) that is enriched for aliphatic amino acids at the a1 and a2 positions, while quite flexible at the X position. Prenylation prediction methods often rely on these features despite emerging evidence that FTase has broader target specificity than previously considered. Using a machine learning approach and training sets based on canonical (prenylated, proteolyzed, and carboxymethylated) and recently identified shunted motifs (prenylation only), this study aims to improve prenylation predictions with the goal of determining the full scope of prenylation potential among the 8000 possible Cxxx sequence combinations. Further, this study aims to subdivide the prenylated sequences as either shunted (i.e., uncleaved) or cleaved (i.e., canonical). Predictions were determined for Saccharomyces cerevisiae FTase and compared to results derived using currently available prenylation prediction methods. In silico predictions were further evaluated using in vivo methods coupled to two yeast reporters, the yeast mating pheromone a-factor and Hsp40 Ydj1p, that represent proteins with canonical and shunted CaaX motifs, respectively. Our machine learning based approach expands the repertoire of predicted FTase targets and provides a framework for functional classification.

Our study aimed to provide a comprehensive overview of trends in incidence, survival, mortality and treatment of first primary invasive breast cancer (BC), according to age, stage and receptor subtype in the Netherlands between 1989 and 2017. Data from all women diagnosed with first primary stage I to IV BC (N = 320 249) were obtained from the Netherlands Cancer Registry. BC mortality and general population data were retrieved from Statistics Netherlands. Age‐standardised incidence and mortality rates were calculated with annual percentage change (APC) and average annual percentage change (AAPC) statistics. The relative survival (RS) was used as estimator for disease‐specific survival. The BC incidence for all BC patients combined significantly increased until 2013 from 126 to 158 per 100 000 person‐years, after which a declining trend was observed. Surgery became less extensive, but (neo‐)adjuvant systemic treatments and their combinations were given more frequently. The RS improved for all age groups and for most stages and receptor subtypes, but remained stable for all subtypes since 2012 to 2013 and since 2000 to 2009 for Stage IV BC at 15 years of follow‐up. Overall, the 5‐ and 10‐year RS increased from 76.8% (95% confidence interval [CI]: 76.1, 77.4) and 55.9% (95% CI: 54.7, 57.1) in 1989 to 1999 to 91.0% (95% CI: 90.5, 91.5) and 82.9% (95% CI: 82.2, 83.5), respectively, in 2010 to 2016. BC mortality improved regardless of age and overall decreased from 57 to 35 per 100 000 person‐years between 1989 and 2017. In conclusion, the BC incidence in the Netherlands has steadily increased since 1989, but the latest trends show promising declines. Survival improved markedly for most patients and the mortality decreased regardless of age., What's new? Studies that simultaneously capture incidence, survival, and mortality trends in breast cancer are scarce, and receptor subtype‐specific trends have remained largely unexplored. This study provides an up‐to‐date and comprehensive overview of first primary invasive breast cancer trends in the Netherlands in 1989 to 2017. Breast cancer incidence increased for all breast cancer patients combined until 2013, but the latest trends show a promising decline. Treatment strategies became more complex. Relative survival improved for all age groups and for most stages and receptor subtypes, and mortality decreased overall. The results may be useful in supporting healthcare management and informing current clinical practice.

IntroductionDirect-to-family clinical trials efficiently provide data while reducing the participation burden for children and their families. Although these trials can offer significant advantages over traditional clinical trials, the process of designing and implementing direct-to-family studies is poorly defined, especially in children with rheumatic disease. This paper provides lessons learnt from the design and implementation of a self-controlled, direct-to-family pilot trial aimed to evaluate the effects of a medication management device on adherence to hydroxychloroquine in paediatric SLE.MethodsSeveral design features accommodate a direct-to-family approach. Participants meeting eligibility criteria from across the USA were identified a priori through a disease registry, and all outcome data are collected remotely. The primary outcome (medication adherence) is evaluated using electronic medication event-monitoring, plasma drug levels, patient questionnaires and pill counts. Secondary and exploratory endpoints include (1) lupus disease activity measured by a remote SLE Disease Activity Index examination and the Systemic Lupus Activity Questionnaire; and (2) hydroxychloroquine pharmacokinetics and pharmacodynamics. Recruitment of the initial target of 20 participants was achieved within 10 days. Due to initial recruitment success, enrolment was increased to 26 participants. Additional participants who were interested were placed on a waiting list in case of dropouts during the study.Discussion and disseminationDirect-to-family trials offer several advantages but present unique challenges. Lessons learnt from the protocol development, design, and implementation of this trial will inform future direct-to-family trials for children and adults with rheumatic diseases. Additionally, the data collected remotely in this trial will provide critical information regarding the accuracy of teleresearch in lupus, the impact of adherence to hydroxychloroquine on disease activity and a pharmacokinetic analysis to inform paediatric-specific dosing of hydroxychloroquine.Trial registration numberClinicalTrials.gov Registry (NCT04358302).

The properties of laser-accelerated ion bunches are demanding and require development of suitable beam diagnostics. In particular, the short and intense particle bunches with a broad energy spectrum emitted in conjunction with a strong electromagnetic pulse (EMP) are challenging for conventional and well established monitoring systems. An approach based on measuring the acoustic signals of particles depositing their energy in water, referred to as ionoacoustics [https://doi.org/10.1118/1.4905047] was recently developed into Ion-Bunch Energy Acoustic Tracing (I-BEAT)\cite{haffa_i-beat:_2019}. I-BEAT allows online detection of single proton bunches while being cost effective and EMP resistant. A simple water phantom equipped with only one ultrasound transducer positioned on the ion axis allows for reconstructing a rather complex energy spectrum that is typical for (manipulated) laser-accelerated ion bunches. To deduce the lateral bunch properties, additional transducers can be added, for example perpendicular to the ion beam axis. This established setup has been adapted for use closely behind the laser target and tested at the PHELIX laser at GSI. The capability of the system to retrieve information about the broad proton spectrum close to the source despite the harsh conditions has been demonstrated. Future improvements are required, most importantly the increase of dynamic range. Nevertheless, I-BEAT holds promise to evolve into an online diagnostic tool particularly suited for laser-driven source development and optimization at high repetition rates.

Bi-allelic loss-of-function (LoF) variants in the base excision repair (BER) gene NTHL1 cause a high-risk hereditary multi-tumor syndrome that includes breast cancer, but the contribution of heterozygous variants to hereditary breast cancer is unknown. An analysis of 4985 women with breast cancer, enriched for familial features, and 4786 cancer-free women revealed significant enrichment for NTHL1 LoF variants. Immunohistochemistry confirmed reduced NTHL1 expression in tumors from heterozygous carriers but the NTHL1 bi-allelic loss characteristic mutational signature (SBS 30) was not present. The analysis was extended to 27,421 breast cancer cases and 19,759 controls from 10 international studies revealing 138 cases and 93 controls with a heterozygous LoF variant (OR 1.06, 95% CI: 0.82–1.39) and 316 cases and 179 controls with a missense variant (OR 1.31, 95% CI: 1.09–1.57). Missense variants selected for deleterious features by a number of in silico bioinformatic prediction tools or located within the endonuclease III functional domain showed a stronger association with breast cancer. Somatic sequencing of breast cancers from carriers indicated that the risk associated with NTHL1 appears to operate through haploinsufficiency, consistent with other described low-penetrance breast cancer genes. Data from this very large international multicenter study suggests that heterozygous pathogenic germline coding variants in NTHL1 may be associated with low- to moderate- increased risk of breast cancer.

Pure ductal carcinoma in situ (DCIS) is being diagnosed more frequently through breast screening programmes and is associated with an increased risk of developing invasive breast cancer. We assessed the clonal relatedness of 143 cases of pure DCIS and their subsequent events using a combination of whole exome, targeted and copy number sequencing, supplemented by single cell analysis. Unexpectedly, 18% of all invasive events after DCIS were clonally unrelated to the primary DCIS. Single cell sequencing of selected pairs confirmed our findings. In contrast, synchronous DCIS and invasive disease (n=44) were almost always (93%) clonally related. This challenges the dogma that almost all invasive events after DCIS represent invasive transformation of the initial DCIS and suggests that DCIS could be an independent risk factor for developing invasive disease as well as a precursor lesion. Our findings support a paradigm shift that confirms a more complex role for DCIS than previously recognized, and that the future management of DCIS should take into account both the precursor and risk factor implications of this diagnosis.

Background Mutations in certain genes are known to increase breast cancer risk. We study the relevance of rare protein-truncating variants (PTVs) that may result in loss-of-function in breast cancer susceptibility genes on tumor characteristics and survival in 8852 breast cancer patients of Asian descent. Methods Gene panel sequencing was performed for 34 known or suspected breast cancer predisposition genes, of which nine genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, and TP53) were associated with breast cancer risk. Associations between PTV carriership in one or more genes and tumor characteristics were examined using multinomial logistic regression. Ten-year overall survival was estimated using Cox regression models in 6477 breast cancer patients after excluding older patients (≥75years) and stage 0 and IV disease. Results PTV9genes carriership (n = 690) was significantly associated (p < 0.001) with more aggressive tumor characteristics including high grade (poorly vs well-differentiated, odds ratio [95% confidence interval] 3.48 [2.35–5.17], moderately vs well-differentiated 2.33 [1.56–3.49]), as well as luminal B [HER−] and triple-negative subtypes (vs luminal A 2.15 [1.58–2.92] and 2.85 [2.17–3.73], respectively), adjusted for age at diagnosis, study, and ethnicity. Associations with grade and luminal B [HER2−] subtype remained significant after excluding BRCA1/2 carriers. PTV25genes carriership (n = 289, excluding carriers of the nine genes associated with breast cancer) was not associated with tumor characteristics. However, PTV25genes carriership, but not PTV9genes carriership, was suggested to be associated with worse 10-year overall survival (hazard ratio [CI] 1.63 [1.16–2.28]). Conclusions PTV9genes carriership is associated with more aggressive tumors. Variants in other genes might be associated with the survival of breast cancer patients. The finding that PTV carriership is not just associated with higher breast cancer risk, but also more severe and fatal forms of the disease, suggests that genetic testing has the potential to provide additional health information and help healthy individuals make screening decisions.

Recent experiments demonstrating storage of optical pulses in acoustic phonons based on stimulated Brillouin scattering raise a number of questions about the spectral and temporal capacities of such protocols and the limitations of the theoretical frameworks routinely used to describe them. In this work, we consider the dynamics of photon-phonon scattering induced by optical pulses with temporal widths comparable to the period of acoustic oscillations. We revisit the widely adopted classical formalism of coupled modes and demonstrate its breakdown. We propose a simple extension to generalise the formulation and find potentially measurable consequences in the dynamics of Brillouin experiments involving ultra-short pulses., 5 pages, 3 figures

Background Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. Methods We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP Results Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E−08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E−07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E−08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E−08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. Conclusions We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.

Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10−8 and 4.42 × 10−8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.

Agriculture is by far the biggest water consumer on our planet, accounting for 70 per cent of all freshwater withdrawals. Climate change and a growing world population increase pressure on agriculture to use water more efficiently (‘more crop per drop’). Water‐use efficiency (WUE) and drought tolerance of crops are complex traits that are determined by many physiological processes whose interplay is not well understood. Here, we describe a combinatorial engineering approach to optimize signalling networks involved in the control of stress tolerance. Screening a large population of combinatorially transformed plant lines, we identified a combination of calcium‐dependent protein kinase genes that confers enhanced drought stress tolerance and improved growth under water‐limiting conditions. Targeted introduction of this gene combination into plants increased plant survival under drought and enhanced growth under water‐limited conditions. Our work provides an efficient strategy for engineering complex signalling networks to improve plant performance under adverse environmental conditions, which does not depend on prior understanding of network function.

BACKGROUND: Individuals with intellectual and developmental disabilities demonstrate disparities in sexual and reproductive health (SRH) compared to individuals without disabilities (e.g., lack of sexual education and knowledge, increased rates of abuse, unplanned pregnancies and sexually transmitted infections). Therefore, the purpose of this study was to identify topics healthcare providers address and perceived barriers and supports to SRH education. METHODS: We conducted semi-structured interviews with healthcare providers (N = 12). RESULTS: Providers address relationships, safety, protection and appropriate sexual behaviours with clients with intellectual and developmental disabilities. Parent education and client-centred care were identified as supports, while the patient's level of understanding, the provider's lack of knowledge or access to resources and to appropriate referrals were identified as barriers to SRH education. CONCLUSION: Future studies are needed to link providers to resources they can use to provide comprehensive, accessible SRH education for clients with intellectual and developmental disabilities.