The use of expanded carrier screening of gamete donors

STUDY QUESTION What are the sperm and egg donor rejection rates after expanded carrier screening (ECS)? SUMMARY ANSWER Using an ECS panel looking at 46/47 genes, 17.6% of donors were rejected. WHAT IS KNOWN ALREADY The use of ECS is becoming commonplace in assisted reproductive technology, including testing of egg and sperm donors. Most national guidelines recommend rejection of donors if they are carriers of a genetic disease. If the use of ECS increases, there will be a decline in the number of donors available. STUDY DESIGN, SIZE, DURATION A review of the current preconception ECS panels available to donors was carried out through an online search. The genetic testing results of donors from Cryos International were analysed to determine how many were rejected on the basis of the ECS. PARTICIPANTS/MATERIALS, SETTING, METHODS Data on gamete donors and their carrier status was provided by Cryos International, who screen donors using their own bespoke ECS panel. The ECS panels identified through the review were compared to the Cryos International panel and data. MAIN RESULTS AND THE ROLE OF CHANCE A total of 16 companies and 42 associated ECS panels were reviewed. There were a total of 2673 unique disorders covered by the panels examined, with a mean of 329 disorders screened. None of these disorders were common to all panels. Cryos International screen 46 disorders in males and 47 in females. From 883 candidate donors, 17.6% (155/883) were rejected based on their ECS result. Carriers of alpha-thalassaemia represented the largest proportion of those rejected (19.4%, 30/155), then spinal muscular atrophy (15.5%, 24/155) and cystic fibrosis (14.8%, 23/155). LIMITATIONS, REASONS FOR CAUTION Panel information was found on company websites and may not have been accurate. WIDER IMPLICATIONS OF THE FINDINGS This study highlights the need for consistent EU regulations and guidelines that allow genetic matching of gamete donors to their recipients, preventing the need to reject donors who are known carriers. A larger ECS panel would be most beneficial; however, this would not be viable without matching of donors and recipients. STUDY FUNDING/COMPETING INTEREST(S) No specific funding was obtained. J.C.H. is the founder of Global Women Connected, a platform to discuss women’s health issues and the Embryology and PGD Academy, who deliver education in clinical embryology. She has been paid to give a lecture by Cryos in 2019. A-B.S. is an employee of Cryos International. TRIAL REGISTRATION NUMBER N/

Effects of regulating the European Internal Market on the integration of variable renewable energy

ABSTRACT: The new proposal for regulating the European Internal Market for Electricity (EIME) can motivate the harmonization of the various National markets. The process of harmonizing the day-ahead markets (DAMs) is at an advanced stage, with an efficiency in the use of interconnectors of 86%. However, the harmonization of both intraday (IDMs) and balancing markets (BMs) is still in its infancy, with an efficiency in the use of interconnectors of 50 and 19%, respectively. The new proposal brings new targets to DAMs, and European countries should make efforts to comply with them. The same is true for IDMs and BMs, but involving more ambitious targets, requiring higher efforts to be accomplished. Both the analysis of the various National markets (according to their compliance with the new proposal for regulating the EIME) and the advantages of the new proposal for key market participants (particularly, consumers, variable renewable generation, and conventional generation) are presented. The analysis indicates that the proposal contributes to a potential increase of the general welfare of market participants. However, some aspects of the proposal can negatively affect the revenue obtained from the National markets, notably for variable renewable generation and conventional generation. This article is categorized under: Wind Power > Systems and Infrastructure Energy Policy and Planning > Economics and Policy Energy Systems Analysis > Economics and Policy Energy and Development > Economics and Policyinfo:eu-repo/semantics/publishedVersio

Effects of virtual reality erotica on ejaculate quality of sperm donors: a balanced and randomized controlled cross-over within-subjects trial

Background Previous research has shown that the type and duration of erotic material that men have access to during masturbation can influence semen parameters. To our knowledge, the use of virtual reality (VR) headsets to present erotica has not previously been studied. We reasoned that, because VR can provide a more immersive experience to the user, semen parameters of masturbatory ejaculates may be altered. Methods This study had a balanced and randomized controlled cross-over within-subjects design. 504 ejaculates were collected from 63 sperm donors at 4 locations in Denmark. During masturbation each donor was instructed to observe erotic material either on a touch screen monitor or using a VR headset. The order of each pair of within-subject treatments was randomized by the throw of a dice. Anonymized data were analysed with linear mixed and piecewise structural equation models. Results Both abstinence period and VR-use influenced the total number of motile spermatozoa ejaculated. For short abstinence periods, VR-use increased the number of motile sperm in the ejaculate. However, the difference between VR and non-VR ejaculates decreased as abstinence period increased such that there was no difference at the mean abstinence period of 58 h. For longer abstinence periods, total motile sperm counts were lower, on average, when men used VR compared to those that did not. Conclusion The use of VR headsets to view erotica had a strong positive effect on the number of motile sperm in an ejaculate when the donor’s abstinence time was short (< 24 h). VR-use could improve the ejaculate quality of men who are asked to provide samples after a short period of abstinence, such as men in infertile partnerships producing samples for ART or cancer patients depositing sperm before treatment

Attitudes of sperm donors towards offspring, identity release and extended genetic screening

Research question What is sperm donors’ attitude towards offspring, anonymity and extended genetic screening? Design An online questionnaire for sperm donors was administered at Cryos International in the USA and Denmark between 9 and 30 September 2020. A total of 233 donors (37 in the USA and 196 in Denmark) completed the questionnaire. This study is unique because it was performed in a setting that allows donors to choose to be either ID-release or non-ID-release donors. Results Most donors had two motives to donate: helping childless people and/or financial compensation. ID-release donors differed significantly from non-ID-release donors in numerous aspects of the donation, including relationships with the offspring, information sharing with others and wanting information about offspring. In general, donors had a very positive attitude towards genetic testing and extended genetic screening. Conclusions Offering the possibility for donors to be either ID-release or non-ID-release allows more donors to be recruited than if only one option were available. The multiple differences between the two donor types suggests that these are groups with profoundly different attitudes towards donation. The general attitude of donors towards genetic testing and expanded genetic screening is very positive but further studies on the attitude of candidate donors are needed

BRCAness Profile of Sporadic Ovarian Cancer Predicts Disease Recurrence

BACKGROUND:The consequences of defective homologous recombination (HR) are not understood in sporadic ovarian cancer, nor have the potential role of HR proteins other than BRCA1 and BRCA2 been clearly defined. However, it is clear that defects in HR and other DNA repair pathways are important to the effectiveness of current therapies. We hypothesize that a subset of sporadic ovarian carcinomas may harbor anomalies in HR pathways, and that a BRCAness profile (defects in HR or other DNA repair pathways) could influence response rate and survival after treatment with platinum drugs. Clinical availability of a BRCAness profile in patients and/or tumors should improve treatment outcomes. OBJECTIVE:To define the BRCAness profile of sporadic ovarian carcinoma and determine whether BRCA1, PARP, FANCD2, PTEN, H2AX, ATM, and P53 protein expression correlates with response to treatment, disease recurrence, and recurrence-free survival. MATERIALS AND METHODS:Protein microarray analysis of ovarian cancer tissue was used to determine protein expression levels for defined DNA repair proteins. Correlation with clinical and pathologic parameters in 186 patients with advanced stage III-IV and grade 3 ovarian cancer was analyzed using Chi square, Kaplan-Meier method, Cox proportional hazard model, and cumulative incidence function. RESULTS:High PARP, FANCD2 and BRCA1 expressions were significantly correlated with each other; however, elevated p53 expression was associated only with high PARP and FANCD2. Of all patients, 9% recurred within the first year. Among early recurring patients, 41% had high levels of PARP, FANCD2 and P53, compared to 19.5% of patients without early recurrence (p = 0.04). Women with high levels of PARP, FANCD2 and/or P53 had first year cumulative cancer incidence of 17% compared with 7% for the other groups (P = 0.03). CONCLUSIONS:Patients with concomitantly high levels of PARP, FANCD2 and P53 protein expression are at increased risk of early ovarian cancer recurrence and platinum resistance

Association of Type and Location of BRCA1 and BRCA2 Mutations With Risk of Breast and Ovarian Cancer (vol 313, pg 1347, 2015)

Heli Nevanlinna ja Kristiina Aittomäki ovat CIMBA Consortium -työryhmän jäseniä.IMPORTANCE Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE To identify mutation-specific cancer risks for carriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19 581 carriers of BRCA1 mutations and 11 900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. EXPOSURES Mutations of BRCA1 or BRCA2. MAIN OUTCOMES AND MEASURES Breast and ovarian cancer risks. RESULTS Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317(12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682(6%) with ovarian cancer, 272(2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% Cl, 1.22-1.74; P = 2 x 10(-6)), c.4328 to c.4945 (BCCR2; RH R = 1.34; 95% Cl, 1.01-1.78; P =.04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% Cl, 1.22-1.55; P = 6 x 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% Cl, 0.56-0.70; P = 9 x 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% Cl, 1.06-2.78; P =.03), c.772 to c.1806 (BCCRI; RHR = 1.63; 95% Cl, 1.10-2.40; P =.01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% Cl, 1.69-3.16; P =.00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% Cl, 0.44-0.60; P = 6 x 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% Cl, 0.41-0.80; P =.001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. CONCLUSIONS AND RELEVANCE Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.Peer reviewe

Cancer risks associated with germline PALB2 pathogenic variants: An international study of 524 families

PURPOSE To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10-76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10-3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10-3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 3 1022). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 × 10-3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers

Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores

PurposeBRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigatedfor the first time to our knowledgeassociations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/2 mutations and implications for cancer risk prediction.Materials and MethodsWe genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights.ResultsIn male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 x 10(-6)). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 x 10(-9)). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively.ConclusionPRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.Peer reviewe