Preimplantation genetic testing for monogenic disorders: clinical experience with BRCA1 and BRCA2 from 2010-2021.

PURPOSE: Our aim was to describe the reproductive decisions and outcomes of BRCA-positive patients who used preimplantation genetic testing for monogenic disorders (PGT-M). METHODS: We performed a retrospective case series of all PGT-M cycles for BRCA variants between 2010-2021 at a large urban academic fertility center. All patients who underwent ≥ 1 cycle of IVF with PGT-M for BRCA1 or BRCA2 were included. The primary outcome was total number of BRCA-negative euploid embryos per patient. RESULTS: Sixty four patients underwent PGT-M for BRCA variants. Forty-five percent (29/64) were BRCA1-positive females, 27% (17/64) were BRCA2-positive females, 16% (10/64) were BRCA1-positive males, 11% (7/64) were BRCA2-positive males, and one was a BRCA1 and BRCA2-positive male. There were 125 retrieval cycles with PGT-M, and all cycles included PGT for aneuploidy (PGT-A). Eighty-six percent (55/64) of patients obtained at least one BRCA- negative euploid embryo, with median of 1 (range 0-10) BRCA-negative euploid embryo resulted per cycle and median 3 (range 0-10) BRCA-negative euploid embryos accumulated per patient after a median of 2 (range 1-7) oocyte retrievals. Sixty-four percent (41/64) of patients attempted at least one frozen embryo transfer (FET) with a total of 68 FET cycles. Fifty-nine percent (40/68) of embryos transferred resulted in live births. Subgroup analysis revealed different reproductive pathways for BRCA1-positive females, BRCA2-positive females, and BRCA1/2-positive males (p < 0.05). CONCLUSION: PGT-M is a viable option for BRCA-positive patients to avoid transmission while building their families. Most patients in our cohort achieved pregnancy with BRCA-negative euploid embryos.

Training clinicians in culturally relevant care: a curriculum to improve knowledge and comfort with the transgender and gender diverse population.

PURPOSE: To design a replicable simulation curriculum collaboratively with the transgender and gender diverse community to improve clinician knowledge and comfort with providing reproductive care to this population. METHODS: This is a prospective, single arm pre-post analysis of obstetrics and gynecology residents at a single academic institution after completion of a novel simulation curriculum. The primary outcome was the change in resident comfort and knowledge in providing transgender and gender diverse patient care. A thematic analysis of learner and standardized patient free text responses was analyzed for insights on perceived learner experiences. RESULTS: This curriculum was created with iterative feedback from the transgender community and involved only transgender and gender diverse-identified standardized patients. Thirty residents participated, with 22 responding to both the pre-and post-curriculum surveys, and 11 responding to a 6-month post-curriculum survey. There were significant improvements in learner comfort and knowledge after participation that were found to persist at 6 months. Qualitative analysis demonstrated that this was a positive and powerful learning experience for both residents and standardized patients. CONCLUSIONS: This simulation curriculum may be an effective and impactful tool to increase trainee comfort and knowledge of transgender and gender diverse patient care, which is important given the lack of physician training in the care for these individuals. By building the foundation with resident learners, the ultimate goal is to enhance the pool of clinicians confident and capable of caring for transgender and gender diverse patients, to increase access to care, and to improve health outcomes in this vulnerable population.

The Role of Gender in Careers in Medicine: a Systematic Review and Thematic Synthesis of Qualitative Literature.

BACKGROUND: Gender disparities exist in the careers of women in medicine. This review explores the qualitative literature to understand how gender influences professional trajectories, and identify opportunities for intervention. METHODS: A systematic review and thematic synthesis included articles obtained from PubMed, Cochrane Central Register of Controlled Trials (Ovid), EMBASE (Ovid), APA PsycInfo (Ovid), and GenderWatch (ProQuest) on June 26 2020, updated on September 10, 2020. Included studies explored specialty choice, leadership roles, practice setting, burnout, promotion, stigma, mentoring, and organizational culture. Studies taking place outside of the USA, using only quantitative data, conducted prior to 2000, or focused on other health professions were excluded. Data were extracted using a standardized extraction tool and assessed for rigor and quality using a 9-item appraisal tool. A three-step process for thematic synthesis was used to generate analytic themes and construct a conceptual model. The study is registered with PROSPERO (CRD42020199999). FINDINGS: Among 1524 studies identified, 64 were eligible for analysis. Five themes contributed to a conceptual model for the influence of gender on women's careers in medicine that resembles a developmental socio-ecological model. Gender influences career development externally through culture which valorizes masculine stereotypes and internally shapes women's integration of personal and professional values. CONCLUSION: Medical culture and structures are implicitly biased against women. Equitable environments in education, mentoring, hiring, promotion, compensation, and support for work-life integration are needed to address gender disparities in medicine. Explicit efforts to create inclusive institutional cultures and policies are essential to support a diverse workforce.

Welcome to the wild, wild north: conscientious objection policies governing Canada's medical, nursing, pharmacy, and dental professions.

In Canada, as in many developed countries, healthcare conscientious objection is growing in visibility, if not in incidence. Yet the country's health professional policies on conscientious objection are in disarray. The article reports the results of a comprehensive review of policies relevant to conscientious objection for four Canadian health professions: medicine, nursing, pharmacy and dentistry. Where relevant policies exist in many Canadian provinces, there is much controversy and potential for confusion, due to policy inconsistencies and terminological vagueness. Meanwhile, in Canada's three most northerly territories with significant Aboriginal populations, whose already precarious health is influenced by funding and practitioner shortages, there are major policy gaps applicable to conscientious objection. In many parts of the country, as a result of health professionals' conscientious refusals, access to some legal health services - including but not limited to reproductive health services such as abortion - has been seriously impeded. Although policy reform on conscientious conflicts may be difficult, and may generate strenuous opposition from some professional groups, for the sake of both patients and providers, such policy change must become an urgent priority.

Fertility Preservation for Adolescent and Young Adult Transmen: A Case Series and Insights on Oocyte Cryopreservation.

Background: The opportunity for fertility preservation in adolescent and young adult (AYA) transmen is growing. Many AYA transmen desire future biologic children and are interested in ways to preserve fertility through oocyte cryopreservation prior to full gender affirmation, yet utilization of oocyte cryopreservation remains low. Additionally, standard practice guidelines currently do not exist for the provision of oocyte cryopreservation to AYA transmen. Our objective was to review our experience with oocyte cryopreservation in adolescent and young adult transmen in order to synthesize lessons regarding referral patterns, utilization, and oocyte cryopreservation outcomes as well as best practices to establish treatment guidance. Methods: This is a case series of all AYA transmen (aged 10 to 25 years) who contacted, consulted or underwent oocyte cryopreservation at a single high volume New York City based academic fertility center between 2009 and 2021. Results: Forty-four adolescent and young adult transmen made contact to the fertility center over the study period. Eighty percent (35/44) had a consultation with a Reproductive and Endocrinology specialist, with a median age of 16 years (range 10 to 24 years) at consultation. The majority were testosterone-naive (71%, 25/35), and had not pursued gender affirming surgery (86%, 30/35). Expedited initiation of testosterone remained the most commonly cited goal (86%, 30/35). Fifty-seven percent (20/35) pursued oocyte cryopreservation. Ninety-five percent (19/20) underwent successful transvaginal oocyte aspiration, with a median of 22 oocytes retrieved and 15 mature oocytes cryopreserved. There were no significant adverse events. At time of review, no patient has returned to utilize their cryopreserved oocytes. Conclusions: Oocyte cryopreservation is a safe fertility preservation option in AYA transmen and is an important aspect of providing comprehensive transgender care. Insights from referral patterns, utilization, and oocyte cryopreservation outcomes from a single center's experience with adolescent and young adult transmen can be integrated to identify lessons learned with the goal of providing transparency surrounding the oocyte cryopreservation process, improving the education and comfort of patients and providers with fertility preservation, and easing the decision to pursue an oocyte cryopreservation cycle in parallel to gender-affirmatory care.

Universal SARS-CoV-2 polymerase chain reaction screening and assisted reproductive technology in a coronavirus disease 2019 pandemic epicenter: screening and cycle outcomes from a New York City fertility center.

OBJECTIVE: To evaluate the prevalence of coronavirus disease 2019 (COVID-19) and efficacy of a universal screening program in patients undergoing controlled ovarian stimulation (COS). DESIGN: Single-center retrospective cohort study. SETTING: Academic fertility center in an epicenter of the COVID-19 pandemic. PATIENT(S): All patients undergoing COS from June 17, 2019, to February 28, 2021. INTERVENTION(S): Universal COVID-19 screening starting June 17, 2020, with SARS-CoV-2 polymerase chain reaction testing within 5 days of oocyte retrieval, patient-reported symptom screening, and temperature monitoring. MAIN OUTCOMES MEASURE(S): The primary outcome was the number of positive COVID-19 cases in patients undergoing COS cycles. The secondary outcomes were cycle outcomes compared with before COVID-19 COS cycles, adverse outcomes in COVID-canceled cycles, and center-specific COVID-19 detection rates compared with New York City cases. RESULT(S): From June 17, 2020, to February 28, 2021, 1,696 COS cycles were initiated with only seven positive COVID-19 cases for an overall positivity rate of 0.4%. When compared with before COVID cycles from June 17, 2019, to February 28, 2020, the volume of COS cycles were higher, while the overall cycle cancelation rate was lower during COVID-19. Cycle outcomes including oocyte yield and blast utilization rates were unchanged from pre-COVID cycles. Cases of COVID-19, while very low, occurred more frequently during surges in New York City rates. CONCLUSION(S): Assisted reproductive technology can be performed during the COVID-19 pandemic utilizing frequent universal screening and safe practices with low SARS-CoV-2 positivity, low cycle cancelation rates, and positive patient outcomes.

Metformin and erlotinib synergize to inhibit basal breast cancer.

Basal-like breast cancers (BBCs) are enriched for increased EGFR expression and decreased expression of PTEN. We found that treatment with metformin and erlotinib synergistically induced apoptosis in a subset of BBC cell lines. The drug combination led to enhanced reduction of EGFR, AKT, S6 and 4EBP1 phosphorylation, as well as prevented colony formation and inhibited mammosphere outgrowth. Our data with other compounds suggested that biguanides combined with EGFR inhibitors have the potential to outperform other targeted drug combinations and could be employed in other breast cancer subtypes, as well as other tumor types, with activated EGFR and PI3K signaling. Analysis of BBC cell line alterations led to the hypothesis that loss of PTEN sensitized cells to the drug combination which was confirmed using isogenic cell line models with and without PTEN expression. Combined metformin and erlotinib led to partial regression of PTEN-null and EGFR-amplified xenografted MDA-MB-468 BBC tumors with evidence of significant apoptosis, reduction of EGFR and AKT signaling, and lack of altered plasma insulin levels. Combined treatment also inhibited xenografted PTEN null HCC-70 BBC cells. Measurement of trough plasma drug levels in xenografted mice and a separately performed pharmacokinetics modeling study support possible clinical translation.

A secreted PTEN phosphatase that enters cells to alter signaling and survival.

Phosphatase and tensin homolog on chromosome ten (PTEN) is a tumor suppressor and an antagonist of the phosphoinositide-3 kinase (PI3K) pathway. We identified a 576-amino acid translational variant of PTEN, termed PTEN-Long, that arises from an alternative translation start site 519 base pairs upstream of the ATG initiation sequence, adding 173 N-terminal amino acids to the normal PTEN open reading frame. PTEN-Long is a membrane-permeable lipid phosphatase that is secreted from cells and can enter other cells. As an exogenous agent, PTEN-Long antagonized PI3K signaling and induced tumor cell death in vitro and in vivo. By providing a means to restore a functional tumor-suppressor protein to tumor cells, PTEN-Long may have therapeutic uses.

Lack of effect of coenzyme q10 on doxorubicin cytotoxicity in breast cancer cell cultures.

UNLABELLED: BACKGROUND/HYPOTHESES: Doxorubicin is a standard adjuvant therapy for early-stage breast cancer, and it significantly improves disease-free and overall survival. However, 3% to 20% of breast cancer patients develop chronic cardiomyopathic changes and congestive heart failure because of doxorubicin therapy. Doxorubicin-induced cardiotoxicity is thought to be due to the increased generation of reactive oxygen species within cardiac myocyte mitochondria. Coenzyme Q10 (CoQ10) is a lipid-soluble antioxidant that may protect against mitochondrial reactive oxygen species and thus prevent doxorubicin-induced cardiotoxicity. Despite the potential benefits of CoQ10 in preventing cardiotoxicity, it is not known if CoQ10 diminishes the antineoplastic effects of doxorubicin therapy. STUDY DESIGN: In vitro cell culture experiments. METHODS: Breast cancer cell lines (MDA-MB-468 and BT549) were tested for their ability to uptake exogenous CoQ10 using high-performance liquid chromatography. Breast cancer cell lines were then treated with doxorubicin and a range of CoQ10 concentrations to determine the effect of CoQ10 on doxorubicin's cytotoxicity. RESULTS: This study demonstrated that intracellular and mitochondrial CoQ10 concentrations increased substantially as higher exogenous concentrations were administered to breast cancer cells. CoQ10 had no effect on the ability of doxorubicin to induce apoptosis or inhibit growth or colony formation in both the cell lines tested when applied over a wide dose range, which encompassed typical basal plasma levels and plasma levels above those typically achieved by supplemented patients. CONCLUSION: The clinical testing of CoQ10 as a supplement to prevent doxorubicin-induced cardiotoxicity requires confidence that it does not decrease the efficacy of chemotherapy. These results support the hypothesis that CoQ10 does not alter the antineoplastic properties of doxorubicin. Further in vivo studies, as well as combination chemotherapy studies, would be reassuring before a large-scale clinical testing of CoQ10 as a cardioprotective drug.

Trisomy 18: a case study.

Trisomy 18 is a devastating genetic disorder that can be characterized by multiple congenital anomalies. Some of these anomalies have no medical significance, but merely provide clues to suggest the diagnosis. The most common form of trisomy 18 is the nondisjunction type, which affects every cell of the body with an extra chromosome 18. Mfected infants are typically born with a prominent occiput, short eye fissures with droopy eyelids, micrognathia, external ear variations, clenched fist with index finger overlapping the third finger and fifth finger overlapping the fourth, small fingernails and toenails, underdeveloped or altered thumbs, "rocker-bottom" feet, and redundant skin at the back of the neck. Congenital heart defects are common. The mortality rate among infants with trisomy 18 is high as a result of cardiac and renal malformations, feeding difficulties, sepsis, and central apnea caused by central nervous system defects. A case study is provided.