Metabolic memory of Δ9-tetrahydrocannabinol exposure in pluripotent stem cells and primordial germ cells-like cells.

Cannabis, the most consumed illicit psychoactive drug in the world, is increasingly used by pregnant women. However, while cannabinoid receptors are expressed in the early embryo, the impact of phytocannabinoids exposure on early embryonic processes is lacking. Here, we leverage a stepwise in vitro differentiation system that captures the early embryonic developmental cascade to investigate the impact of exposure to the most abundant phytocannabinoid, Δ9-tetrahydrocannabinol (Δ9-THC). We demonstrate that Δ9-THC increases the proliferation of naive mouse embryonic stem cells (ESCs) but not of their primed counterpart. Surprisingly, this increased proliferation, dependent on the CB1 receptor binding, is only associated with moderate transcriptomic changes. Instead, Δ9-THC capitalizes on ESCs' metabolic bivalence by increasing their glycolytic rates and anabolic capabilities. A memory of this metabolic rewiring is retained throughout differentiation to Primordial Germ Cell-Like Cells in the absence of direct exposure and is associated with an alteration of their transcriptional profile. These results represent the first in-depth molecular characterization of the impact of Δ9-THC exposure on early stages of germline development.

Cannabis is the most widely used illicit drug in the world, with 4.3% of the global adult population estimated to have used it in the previous year. In particular, the consumption of cannabis by pregnant women has almost doubled in recent years and is particularly increased in those aged under 18. The main psychoactive component in cannabis, known as Δ9-THC, activates cannabinoid receptors in the brain, including the receptor CB1. Recent research has shown that CB1 is also active in the mouse embryo, but it remained unclear if Δ9-THC could also affect the development of an embryo. To better understand the potential effects of this exposure, scientists can study stem cells that develop into germ cells (which go on to form egg and sperm), which have been grown in the laboratory. Emerging research has shown that germ cells are particularly sensitive to changes in their environment and due to their role in reproduction, changes can have knock-on effects for embryos. Verdikt et al. studied the effects of Δ9-THC on mouse embryonic stem cells, finding that it caused them to multiply more quickly. This was dependent on both Δ9-THC binding to the CB1 receptor that causes the psychoactive effects of cannabis in the brain and an increased energy metabolism. Blocking an important metabolic pathway called glycolysis caused the Δ9-THC-treated cells to return to a normal multiplication rate. The exposed stem cells also gave rise to germ cells with abnormal metabolism and altered gene expression, suggesting that this metabolic 'memory' can be passed on to cells in the next developmental stage. Overall, the findings indicate that exposure to Δ9-THC alters the metabolism in early embryonic cells of mice and that these effects can be lasting. This emphasises the need for further research on the impact of cannabis use during pregnancy, particularly as the drug's availability is expected to increase significantly with changes in regulation. The work also contributes to research highlighting the inheritance of metabolism.

Metabolic memory of Δ9-tetrahydrocannabinol exposure in pluripotent stem cells and primordial germ cells-like cells.

Cannabis, the most consumed illicit psychoactive drug in the world, is increasingly used by pregnant women. However, while cannabinoid receptors are expressed in the early embryo, the impact of phytocannabinoids exposure on early embryonic processes is lacking. Here, we leverage a stepwise in vitro differentiation system that captures early embryonic developmental cascade to investigate the impact of exposure to the most abundant phytocannabinoid, Δ9-tetrahydrocannabinol (Δ9-THC). We demonstrate that Δ9-THC increases the proliferation of naïve mouse embryonic stem cells (ESCs) but not of their primed counterpart. Surprisingly, this increased proliferation, dependent on the CB1 receptor binding, is only associated with moderate transcriptomic changes. Instead, Δ9-THC capitalizes on ESCs' metabolic bivalence by increasing their glycolytic rates and anabolic capabilities. A memory of this metabolic rewiring is retained throughout differentiation to Primordial Germ Cell-Like Cells in the absence of direct exposure and is associated with an alteration of their transcriptional profile. These results represent the first in-depth molecular characterization of the impact of Δ9-THC exposure on early stages of germline development.

Transgenerational inheritance and its modulation by environmental cues.

The epigenome plays an important role in shaping phenotypes. However, whether the environment can alter an organism's phenotype across several generations through epigenetic remodeling in the germline is still a highly debated topic. In this chapter, we briefly review the mechanisms of epigenetic inheritance and their connection with germline development before highlighting specific developmental windows of susceptibility to environmental cues. We further discuss the evidence of transgenerational inheritance to a range of different environmental cues, both epidemiological in humans and experimental in rodent models. Doing so, we pinpoint the current challenges in demonstrating transgenerational inheritance to environmental cues and offer insight in how recent technological advances may help deciphering the epigenetic mechanisms at play. Together, we draw a detailed picture of how our environment can influence our epigenomes, ultimately reshaping our phenotypes, in an extended theory of inheritance.

Availability of Fertility Preservation Information on the Websites of U.S. News and World Report Top-Ranked Pediatric Cancer Programs.

Purpose: To evaluate the availability of fertility preservation (FP) services and educational resources on the websites of top-ranked U.S. pediatric cancer programs. Methods: Cross-sectional survey of information and resources related to FP on websites from top-ranked pediatric cancer programs according to the 2018-2019 U.S.-News & World Report (USNWR) ranking. Factors that predicted the website availability of FP information or a fertility team were analyzed, as was availability in Spanish and for specific groups by sex and puberty status. As a surrogate marker of comprehensive oncological services, the availability of resources for psychological support was compared to FP. Results: A fertility team was referenced on the website of 36% of programs, but only 32% provided FP educational resources for patients. Among them, 100%, 93.8%, 93.8%, and 68.8% provided specific information for postpubertal females, prepubertal females, postpubertal males, and prepubertal males, respectively. The majority (93.8%) did not provide information in Spanish. The ranking on USNWR (p < 0.05) and patient volume (p < 0.05) positively correlated with the availability of FP information and fertility team on the program's website. Information regarding psychological support was provided more often than information regarding FP (96% vs. 32%, p < 0.05). Conclusion: The majority of the top-ranked pediatric cancer programs in the United States do not list FP resources or a fertility team on their website. The lack of resources is particularly concerning for the Spanish-speaking population, as well as for prepubertal males. This may be potentially hindering access to FP and contributing to health care disparities.

Measures of Patient Dissatisfaction With Health Care in Polycystic Ovary Syndrome: Retrospective Analysis.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common reproductive and metabolic disorder in women; however, many clinicians may not be well versed in scientific advances that aid understanding of the associated reproductive, metabolic, and psychological abnormalities. Women with PCOS are dissatisfied with health care providers, the diagnostic process, and the initial treatment of PCOS and seek information through alternative sources. This has affected the patient-physician relationship by allowing medical information acquired through the internet, whether correct or not, to become accessible to patients and reshape their health care perspective. Patient dissatisfaction with health care providers regarding PCOS raises questions about the responsibilities of academic institutions to adequately train and maintain the competence of clinicians and government agencies to sufficiently support scientific investigation in this field. OBJECTIVE: The primary aim was to examine internet searching behaviors of the public regarding PCOS vs another highly prevalent gynecologic disorder. The secondary aim was to explore satisfaction with health care among patients with PCOS and their internet use. The tertiary aim was to examine medical education in reproductive endocrinology and infertility (REI) during obstetrics and gynecology (Ob/Gyn) residency as a proxy for physician knowledge in this field. METHODS: Google search trends and StoryBase quantified monthly Google absolute search volumes for search terms related to PCOS and fibroids (January 2004 to December 2017; United States). The reproductive disorder, fibroids, was selected as a comparison group because of its high prevalence among women. Between female groups, monthly absolute search volumes and their trends were compared. A Web-based questionnaire (June 2015 to March 2018) explored health care experiences and the internet use of women with PCOS. REI rotation information during Ob/Gyn residency in the United States was obtained from the Association of Professors of Gynecology and Obstetrics website. RESULTS: For PCOS (R=0.89; P<.01), but not fibroids (R=0.09; P=.25), monthly absolute search volumes increased significantly. PCOS-related monthly absolute search volumes (mean 384,423 searches, SD 88,756) were significantly greater than fibroid-related monthly absolute search volumes (mean 348,502 searches, SD 37,317; P<.05). PCOS was diagnosed by an Ob/Gyn in 60.9% (462/759) of patients, and 57.3% (435/759) of patients were dissatisfied with overall care. Among patients with PCOS, 98.2% (716/729) searched for PCOS on the Web but only 18.8% (143/729) of patients joined an online PCOS support group or forum. On average, Ob/Gyn residencies dedicated only 4% (2/43) of total block time to REI, whereas 5.5% (11/200) of such residencies did not offer any REI rotations. CONCLUSIONS: Over time, PCOS has been increasingly searched on the Web compared with another highly prevalent gynecologic disorder. Patients with PCOS are dissatisfied with their health care providers, who would benefit from an improved understanding of PCOS during Ob/Gyn residency training.

Now Anyone Can Kegel: One-Time Office Teaching of Pelvic Floor Muscle Exercises.

OBJECTIVE: In women with pelvic floor disorders, we sought to determine time-to-teach (TTT) correct pelvic floor muscle (PFM) contraction, prevalence of inappropriate muscle contractions, and the association between TTT with PFM strength (PFMS). METHODS: From August 2017 to April 2018, patients from 2 pelvic floor disorder clinics participated in a prospective study examining PFMS. Assessment of PFMS was performed to obtain TTT, inappropriate accessory muscle, and Modified Oxford Grading Scale scores for pelvic floor muscle contractions 1 to pelvic floor muscle contractions 2. RESULTS: Of 100 women, 77 were from low-resource setting and 23 from high-resource setting. Mean TTT overall was 64.1 seconds (±26.0; range, 9-160 seconds), and mean TTT between settings was not significant. Mean overall TTT was significantly less than 90 seconds. Seventy-one women (71%) demonstrated at least 1 inappropriate accessory muscle, and of those, up to 50% of patients contracting 2 accessory muscle groups with abdominal muscles most frequently contracted at baseline. Thirty-nine percent of patients had a PFM contraction of at least 3 at baseline compared with 82% of patients upon completion of teaching, with 60% of women with scores of 4 or 5. The mean difference overall between baseline and pelvic floor muscle contractions 3 was 1.27 (confidence interval, 1.08-1.46; P < 0.001), and this increase was significant. CONCLUSIONS: One-time PFMS teaching can be done in a time-proficient fashion and is translatable across high-resource and low-resource settings. Most patients show improvement in PFMS immediately and can quickly acquire this learned skill for proper home practice.

All Levels of Providers Can Effectively and Efficiently Teach Pelvic Floor Strength Assessment at Time of Pelvic Examination.

OBJECTIVE: In women who undergo provider-guided vaginal biofeedback of pelvic floor muscle strength, we sought to determine whether the level of the provider correlates with the patient's ability to achieve adequate pelvic floor muscle contractions (PFMCs). METHODS: From August 2017 to April 2018, patients from 2 urogynecology clinics were recruited to participate in an institutional review board-approved, prospective study examining PFMCs. Pelvic examination and teaching session were done by providers who had specific training on how to assess pelvic floor muscle strength using the validated, modified Oxford scale. Patients were asked to perform a baseline PFMC during a 2-digit pelvic examination. Thereafter, patients were counseled to relax their muscles, identify the levator ani muscles during provider teaching, and perform 3 consecutive provider-guided PFMCs. The strength of each PFMC was measured, and the time-to-teach (TTT) was recorded. The level of provider and TTT were correlated with PFMC1 to PFMC3 using Spearman correlation coefficient. RESULTS: One hundred women participated. Obstetrics/gynecology (OB/GYN) residents (post-graduate years 1-4) evaluated 20 patients; female pelvic medicine and reconstructive surgery fellowship trainees (post-graduate years 5-7), 38 patients; OB/GYN nurse practitioners, 18 patients; generalist OB/GYN faculty, 9 patients; and female pelvic medicine and reconstructive surgery faculty, 15 patients. There was no correlation between level of provider and TTT or between level of provider and strength of PFMC1, PFMC2, or PFMC3. CONCLUSIONS: At the time of pelvic floor muscle assessment, the level of provider does not impact teaching time or PFMC1 to PFMC3. Teaching pelvic floor muscle exercise is a cost-effective, low-resource tool to improve patient care, and providers of any level should be encouraged to teach pelvic floor muscle exercise to patients at the time of office examination.

Multiple Myeloma 1 Transcription Factor Is Superior to CD138 as a Marker of Plasma Cells in Endometrium.

Chronic endometritis is characterized by plasma cell (PC) infiltration of endometrial stroma. Identification of PCs can be challenging by routine hematoxylin and eosin (H&E) stain due to the low numbers of PCs or to their being obscured by other cells in the stroma. CD138 is widely used as an ancillary immunohistochemistry stain to identify PCs; however, it has a high background reaction. In this study, multiple myeloma 1 (MUM1) transcription factor is introduced as an alternative PC marker in endometrial tissues. In this study, 311 endometrial biopsies, submitted to rule out chronic endometritis, were selected. They were divided into Group I (n = 87) and Group II (n = 224). Both had MUM1 and H&E while Group I also had accompanying CD138 stains. In both groups combined, MUM1 detected plasma cells in 48% of the cases, while CD138 and H&E identified the cells in 23% and 15% of the biopsies, respectively. In addition to having a clean background, MUM1 is a more sensitive stain than CD138 for detection of PCs in endometrium.

Analysis of Reported Adverse Events with Uterine Artery Embolization for Leiomyomas.

STUDY OBJECTIVE: To analyze and investigate reports associated with uterine artery embolization used for treatment of myomas using this database. DESIGN: A retrospective review of the Manufacturer and User Facility Device Experience (MAUDE) database for events related to uterine artery embolization (Canadian Task Force Classification III). SETTING: The MAUDE database was accessed online. PATIENTS: Patients with myomas undergoing uterine artery embolization. INTERVENTIONS: The MAUDE database was accessed online and searched for events related to uterine artery embolization reported between 1998 and 2018. These reports were reviewed and analyzed, reported events were categorized, and other relevant information was collected and tabulated. MEASUREMENTS AND MAIN RESULTS: A total of 193 reports published during the study period were identified. Pain was the most frequently reported event (68 events; 35.2%), followed by vaginal discharge (45 events; 23.3%), operational misfire (37 events; 19.2%), and fever or infectious complications (36 events; 18.7%). A surgical procedure was required in 27 events (14.0%), with hysterectomy reported in 7.8% of the events. Death following this procedure was mentioned in 5 events (2.6%). CONCLUSION: The MAUDE database may be useful for clinicians using a Food and Drug Administration-approved medical device to identify the occurrence of adverse events and complications. A variety of adverse events associated with the use of uterine artery embolization were reported to the MAUDE database related to its use in the treatment of uterine myomas. We encourage physicians to review the MAUDE database when using medical devices, because this is an important tool to assess uncommon but major problems that could be associated with a medical device.