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Collections of floating chironomid pupal exuviae are used to monitor water quality and assess ecological conditions. Factors controlling exuviae sinking rates are not well known, although they should have an effect on conclusions that can be drawn from collections. The current study was conducted to determine the rate of sinking under controlled laboratory conditions using water from three streams with different nutrient levels. Sinking rates ranged from less than a day to seven days, depending on microbial activity, nutrient concentrations, temperature and turbulence. Results also varied by genus, with pupal exuviae of Chironomus riparius, Diamesa nivoriunda, Orthocladius (Euorthocladius) thienemanni and Eukiefferiella sp. used in experiments. Four species of bacteria and eight genera of fungi colonized and metabolized exuviae, with bacteria dominant early and fungi dominant later in the decomposition process. Decomposition was faster in lightly chitinized abdominal conjunctive areas, which resulted in exuviae breaking apart and sinking. Examination of untreated, dewaxed and dewaxed-deproteinized exuviae indicated that untreated exuviae sank faster. Waxes appeared important for colonization and initial microbial metabolization was delayed when waxes were removed. Results confirm the importance of biological degradation of exuviae in determining floatation times. We predict that streams and other waterbodies with high dissolved nutrients will result in rapidly sinking exuviae, while exuviae in low nutrient waterbodies will float longer. Article submitted 1. October 2014, accepted 18. November 2014, published 22. December 2014.

Objective: Explore the caregiver experience of communicating about differences of sex development (DSD) with their children. Evidence-based guidance regarding how, when, and what information is shared by caregivers is lacking and is needed to inform optimal information sharing strategies for this population., Methods: Qualitative semi-structured interviews were conducted with 15 caregivers of children with DSD, recruited from 3 multidisciplinary DSD clinics. Interviews were transcribed and coded using thematic analysis., Results: Four major themes were generated: (1) communicate openly and honestly, (2) information sharing starts at a young age and occurs over time, (3) caregivers and providers should empower children with DSD by sharing positive messages to promote self-confidence and actively engaging them in their medical care, and (4) caregivers should understand and acknowledge the connection between gender identity and DSD to create a supportive environment for children experiencing gender dysphoria., Conclusion: Transparent and developmentally-appropriate information sharing by caregivers with their children is essential for educating, empowering, and supporting children with DSD. Communicating with children about DSD can be a complex process for caregivers, and healthcare providers have a key role in supporting caregiver-child communication and increasing access to education and support resources., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Genetic testing to identify germline high-risk pathogenic variants in breast cancer susceptibility genes is increasingly part of the breast cancer diagnostic pathway. Novel patient-centred pathways may offer opportunity to expand capacity and reduce turnaround time., Methods: We recruited 1140 women with unselected breast cancer to undergo germline genetic testing through the BRCA-DIRECT pathway (which includes a digital platform, postal saliva sampling and a genetic counsellor telephone helpline). Ahead of consenting to the test, participants were randomised to receive information about genetic testing digitally (569/1140, 49.9%) or via a pre-test genetic counselling consultation (571/1140, 50.1%)., Results: 1001 (87.8%) participants progressed to receive their pre-test information and consented to testing. The primary outcome, uptake of genetic testing, was higher amongst participants randomised to receive digital information compared with those randomised to a pre-test genetic counselling consultation (90.8% (95% CI: 88.5% to 93.1%) vs 84.7% (95% CI: 81.8% to 87.6%), p = 0.002, adjusted for participant age and site). Non-inferiority was observed in relation to patient knowledge, anxiety, and satisfaction., Conclusions: Findings demonstrate that standardised, digital information offers a non-inferior alternative to conventional genetic counselling, and an end-to-end patient-centred, digital pathway (supported by genetic counselling hotline) could feasibly be implemented into breast oncology settings., Clinical Trial Registration: The study is registered with, and protocol available on, ClinicalTrials.gov (NCT04842799)., (© 2024. The Author(s).)

The first genetic counseling (GC) graduate training program was established in the United States (U.S.) in 1969 and GC is an emerging field of healthcare in many countries. Each year, at least 7% of applicants to U.S.-based GC graduate programs come from countries outside the U.S. ("international GC applicants''). To address the unique needs of international GC applicants, volunteers from the International Special Interest Group (ISIG) of the National Society of Genetic Counselors (NSGC) launched a semi-structured mentorship program (the "International Genetic Counseling Mentorship Program'' (IGCMP)) in 2021, which provides individualized mentorship and optional group activities for networking and learning. Fifty-two people from 19 countries signed up for the IGCMP across three application cycles. Of these, 47 were eligible to participate as mentees, and most were interested in one-on-one virtual meetings with international GCs in the U.S. (n = 41/47, 87.2%). An assessment form was sent to 17 mentees who applied to GC graduate school after participating in the first or second cycle of the IGCMP. Of the 12 responses received, 10 (83.3%) reported being extremely satisfied with their individual mentor(s), and the one-on-one meeting with a mentor was considered helpful to both the application and interview process by nine (75.0%) respondents. Importantly, feedback about program improvement revealed an interest in connecting with additional international applicants and mentors and all respondents expressed interest in receiving mentorship throughout graduate school. Future directions include collaborating with other mentorship and graduate programs to further enhance support for international applicants., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Menopausal hormone therapy (MHT) can alleviate menopausal symptoms but has been associated with an increased risk of breast cancer. MHT prescription should be preceded by individualised risk/benefit evaluation; however, data outlining the impact of family history alongside different MHT therapeutic approaches are lacking., Aim: To quantify the risks associated with MHT use in women with varying breast cancer family histories of developing and dying from breast cancer., Design and Setting: An epidemiological modelling study for women in England using the BOADICEA breast cancer prediction model and data relating to MHT use and breast cancer risk taken from research by the Collaborative Group on Hormonal Factors in Breast Cancer., Method: The risk of developing and dying from breast cancer between the ages of 50 and 80 years was modelled in women with four different breast cancer family history profiles: 'average', 'modest', 'intermediate', and 'strong' by using 1) background risks of breast cancer by age and family history, 2) relative risks for breast cancer associated with MHT use, and 3) 10-year breast cancer-specific net mortality rates. This study modelled use of combined oestrogen-progestogen MHT (cyclical or continuous) and oestrogen-only MHT., Results: For a woman of 'average' family history taking no MHT, the cumulative breast cancer risk (age 50-80 years) is 9.8%, and the risk of dying from the breast cancer is 1.7%. In this model, 5 years' exposure to combined-cyclical MHT (age 50-55 years) was calculated to increase these risks to 11.0% and 1.8%, respectively. For a woman with a 'strong' family history taking no MHT, the cumulative breast cancer risk is 19.6% (age 50-80 years), and the risk of dying from the breast cancer is 3.2%. With 5 years' exposure to MHT (age 50-55 years), this model showed that these risks increase to 22.4% and 3.5%, respectively., Conclusion: In this model, both family history and MHT are associated with increased risk of breast cancer. Estimates of the risks of breast cancer associated with MHT for women with different family histories can be used to support decision making around MHT prescription for women experiencing menopausal symptoms., (© The Authors.)

Competing Interests: Aisha Furqan holds stocks in Natera, Inc, and is a cofounder of the nonprofit Pakistani Society of Medical Genetics. Smita K. Rao is the cofounder of Genexsure LLC, which is a genetic counseling telemedicine company. Rawan Awwad is one of the cofounders of Arab Society of Genetic Counselors. All other authors have no conflicts of interest.

Introduction: Patient decision aids (PtDA) complement shared decision-making with healthcare professionals and improve decision quality. However, PtDA often lack theoretical underpinning. We are codesigning a PtDA to help people with increased genetic cancer risks manage choices. The aim of an innovative workshop described here was to engage with the people who will use the PtDA regarding the theoretical underpinning and logic model outlining our hypothesis of how the PtDA would lead to more informed decision-making., Methods: Short presentations about psychological and behavioural theories by an expert were interspersed with facilitated, small-group discussions led by patients. Patients were asked what is important to them when they make health decisions, what theoretical constructs are most meaningful and how this should be applied to codesign of a PtDA. An artist created a visual summary. Notes from patient discussions and the artwork were analysed using reflexive thematic analysis., Results: The overarching theme was: It's personal. Contextual factors important for decision-making were varied and changed over time. There was no one 'best fit' theory to target support needs in a PtDA, suggesting an inductive, flexible framework approach to programme theory would be most effective. The PtDA logic model was revised based on patient feedback., Conclusion: Meaningful codesign of PtDA including discussions about the theoretical mechanisms through which they support decision-making has the potential to lead to improved patient care through understanding the intricately personal nature of health decisions, and tailoring content and format for holistic care., Patient Contribution: Patients with lived experience were involved in codesign and coproduction of this workshop and analysis as partners and coauthors. Patient discussions were the primary data source. Facilitators provided a semi-structured guide, but they did not influence the patient discussions or provide clinical advice. The premise of this workshop was to prioritise the importance of patient lived experience: to listen, learn, then reflect together to understand and propose ideas to improve patient care through codesign of a PtDA., (© 2023 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Purpose: To assess the contribution of germline pathogenic variants (PVs) in population-based series of breast cancers and the best strategy to improve detection rates., Methods: Three cohort studies were utilized, including a hospital-based series identified from new UK mainstream testing criteria (group-1), offering testing to all women (group-2-BReast CAncer [BRCA]-DIRECT), and a Greater Manchester cohort study recruited from the mammography screening population (group-3-Predicting Risk of Cancer at Screening). DNA samples from women with breast cancer were sequenced for PVs in BRCA1 , BRCA2 , and Partner and Localiser of BRCA2 ( PALB2 ). The Manchester score (MS) was used at different points thresholds. Current mainstream criteria include women diagnosed <40 years and all triple negative <60 years or an MS ≥15., Results: Thirty-six PVs ( BRCA1  = 9 , BRCA2  = 18 , PALB2  = 9) were identified among 1061 women with breast cancer (3.4%). Mainstreaming criteria identified 21 of 36 (58%) of PVs by testing 190 women; detection rate (8.4%), specificity = 83.5%. A better detection rate was found using an MS threshold of 12-points with 66.7% (24/36) sensitivity and 85.7% specificity in 171 women. No PVs were identified in 158 women with grade-1 invasive cancers. The best strategy to detect all PVs was an MS ≥3 with specificity of 32.6%., Conclusion: In order to detect higher PV rates on a population basis the best strategy is to reduce the MS threshold for genetic testing., Competing Interests: D. Gareth Evans, non-executive director, Everything Genetic Ltd. D. Gareth Evans has interests not related to this work. Consulting or Advisory Role: AstraZeneca, Springworks, Travel, Accommodations; Other Expenses: AstraZeneca. All other authors declare no conflicts of interest., (© 2023 The Authors.)

Germline pathogenic variants (GPVs) in the cancer predisposition genes BRCA1 , BRCA2 , MLH1 , MSH2 , MSH6 , BRIP1 , PALB2 , RAD51D and RAD51C are identified in approximately 15% of patients with ovarian cancer (OC). While there are clear guidelines around clinical management of cancer risk in patients with GPV in BRCA1 , BRCA2 , MLH1 , MSH2 and MSH6 , there are few guidelines on how to manage the more moderate OC risk in patients with GPV in BRIP1 , PALB2 , RAD51D and RAD51C , with clinical questions about appropriateness and timing of risk-reducing gynaecological surgery. Furthermore, while recognition of RAD51C and R AD51D as OC predisposition genes has been established for several years, an association with breast cancer (BC) has only more recently been described and clinical management of this risk has been unclear. With expansion of genetic testing of these genes to all patients with non-mucinous OC, new data on BC risk and improved estimates of OC risk, the UK Cancer Genetics Group and CanGene-CanVar project convened a 2-day meeting to reach a national consensus on clinical management of BRIP1 , PALB2 , RAD51D and RAD51C carriers in clinical practice. In this paper, we present a summary of the processes used to reach and agree on a consensus, as well as the key recommendations from the meeting., Competing Interests: Competing interests: HH received honoraria from AstraZeneca for advisory roles. CT received honoraria from AstraZeneca and Roche for advisory roles, which were donated in full to charity (https://tukongote.com/, registration number 11511580, charity number 1186151). RM declares research funding from Barts & the London Charity, Rosetrees Trust, GSK, Eve Appeal, CRUK and Yorkshire Cancer Research outside this work; and honorarium for advisory board membership from AstraZeneca/MSD/GSK/EGL. DME was in receipt of research funding from AstraZeneca. ANR had prior consultancy arrangements with Abcodia and Everything Genetic. ACA was listed as a creator of BOADICEA, which was licensed by Cambridge Enterprise for commercial purposes., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: Germline genetic testing affords multiple opportunities for women with breast cancer, however, current UK NHS models for delivery of germline genetic testing are clinician-intensive and only a minority of breast cancer cases access testing., Methods: We designed a rapid, digital pathway, supported by a genetics specialist hotline, for delivery of germline testing of BRCA1/BRCA2/PALB2 (BRCA-testing), integrated into routine UK NHS breast cancer care. We piloted the pathway, as part of the larger BRCA-DIRECT study, in 130 unselected patients with breast cancer and gathered preliminary data from a randomised comparison of delivery of pretest information digitally (fully digital pathway) or via telephone consultation with a genetics professional (partially digital pathway)., Results: Uptake of genetic testing was 98.4%, with good satisfaction reported for both the fully and partially digital pathways. Similar outcomes were observed in both arms regarding patient knowledge score and anxiety, with <5% of patients contacting the genetics specialist hotline. All progression criteria established for continuation of the study were met., Conclusion: Pilot data indicate preliminary demonstration of feasibility and acceptability of a fully digital pathway for BRCA-testing and support proceeding to a full powered study for evaluation of non-inferiority of the fully digital pathway, detailed quantitative assessment of outcomes and operational economic analyses., Trial Registration Number: ISRCTN87845055., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Purpose: Non-invasive imaging is central to hepatocellular carcinoma (HCC) diagnosis; however, conventional modalities are limited by smaller tumors and other chronic diseases that are often present in patients with HCC, such as cirrhosis. This pilot study evaluated the feasibility of (4S)-4-(3-[ 18 F]fluoropropyl)-L-glutamic acid ([ 18 F]FSPG) positron emission tomography (PET)/X-ray computed tomography (CT) to image HCC. [ 18 F]FSPG PET/CT was compared to standard-of-care (SOC) magnetic resonance imaging (MRI) and CT, and [ 11 C]acetate PET/CT, commonly used in this setting. We report the largest cohort of HCC patients imaged to date with [ 18 F]FSPG PET/CT and present the first comparison to [ 11 C]acetate PET/CT and SOC imaging. This study represents the first in a US HCC population, which is distinguished by different underlying comorbidities than non-US populations., Procedures: x C- transporter RNA and protein levels were evaluated in HCC and matched liver samples from The Cancer Genome Atlas (n = 16) and a tissue microarray (n = 83). Eleven HCC patients who underwent prior MRI or CT scans were imaged by [ 18 F]FSPG PET/CT, with seven patients also imaged with [ 11 C]acetate PET/CT., Results: x C- transporter RNA and protein levels were elevated in HCC samples compared to background liver. Over 50 % of low-grade HCCs and ~70 % of high-grade tumors exceeded background liver protein expression. [ 18 F]FSPG PET/CT demonstrated a detection rate of 75 %. [ 18 F]FSPG PET/CT also identified an HCC devoid of typical MRI enhancement pattern. Patients scanned with [ 18 F]FSPG and [ 11 C]acetate PET/CT exhibited a 90 and 70 % detection rate, respectively. In dually positive tumors, [ 18 F]FSPG accumulation consistently resulted in significantly greater tumor-to-liver background ratios compared with [ 11 C]acetate PET/CT., Conclusions: [ 18 F]FSPG PET/CT is a promising modality for HCC imaging, and larger studies are warranted to examine [ 18 F]FSPG PET/CT impact on diagnosis and management of HCC. [ 18 F]FSPG PET/CT may also be useful for phenotyping HCC tumor metabolism as part of precision cancer medicine.

The ATR checkpoint kinase coordinates cellular responses to DNA replication stress. Budding yeast contain three activators of Mec1 (the ATR orthologue); however, only TOPBP1 is known to activate ATR in vertebrates. We identified ETAA1 as a replication stress response protein in two proteomic screens. ETAA1-deficient cells accumulate double-strand breaks, sister chromatid exchanges, and other hallmarks of genome instability. They are also hypersensitive to replication stress and have increased frequencies of replication fork collapse. ETAA1 contains two RPA-interaction motifs that localize ETAA1 to stalled replication forks. It also interacts with several DNA damage response proteins including the BLM/TOP3α/RMI1/RMI2 and ATR/ATRIP complexes. It binds ATR/ATRIP directly using a motif with sequence similarity to the TOPBP1 ATR-activation domain; and like TOPBP1, ETAA1 acts as a direct ATR activator. ETAA1 functions in parallel to the TOPBP1/RAD9/HUS1/RAD1 pathway to regulate ATR and maintain genome stability. Thus, vertebrate cells contain at least two ATR-activating proteins., Competing Interests: The authors have no competing financial interests.

Proper DNA replication is critical to maintain genome stability. When the DNA replication machinery encounters obstacles to replication, replication forks stall and the replication stress response is activated. This response includes activation of cell cycle checkpoints, stabilization of the replication fork, and DNA damage repair and tolerance mechanisms. Defects in the replication stress response can result in alterations to the DNA sequence causing changes in protein function and expression, ultimately leading to disease states such as cancer. To identify additional genes that control the replication stress response, we performed a three-parameter, high content, whole genome siRNA screen measuring DNA replication before and after a challenge with replication stress as well as a marker of checkpoint kinase signalling. We identified over 200 replication stress response genes and subsequently analyzed how they influence cellular viability in response to replication stress. These data will serve as a useful resource for understanding the replication stress response., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Accurate replication of DNA is imperative for the maintenance of genomic integrity. We identified Enhancer of Rudimentary Homolog (ERH) using a whole-genome RNA interference (RNAi) screen to discover novel proteins that function in the replication stress response. Here we report that ERH is important for DNA replication and recovery from replication stress. ATR pathway activity is diminished in ERH-deficient cells. The reduction in ATR signaling corresponds to a decrease in the expression of multiple ATR pathway genes, including ATR itself. ERH interacts with multiple RNA processing complexes, including splicing regulators. Furthermore, splicing of ATR transcripts is deficient in ERH-depleted cells. Transcriptome-wide analysis indicates that ERH depletion affects the levels of ∼1,500 transcripts, with DNA replication and repair genes being highly enriched among those with reduced expression. Splicing defects were evident in ∼750 protein-coding genes, which again were enriched for DNA metabolism genes. Thus, ERH regulation of RNA processing is needed to ensure faithful DNA replication and repair., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)