The sex of organ geometry.

Organs have a distinctive yet often overlooked spatial arrangement in the body1-5. We propose that there is a logic to the shape of an organ and its proximity to its neighbours. Here, by using volumetric scans of many Drosophila melanogaster flies, we develop methods to quantify three-dimensional features of organ shape, position and interindividual variability. We find that both the shapes of organs and their relative arrangement are consistent yet differ between the sexes, and identify unexpected interorgan adjacencies and left-right organ asymmetries. Focusing on the intestine, which traverses the entire body, we investigate how sex differences in three-dimensional organ geometry arise. The configuration of the adult intestine is only partially determined by physical constraints imposed by adjacent organs; its sex-specific shape is actively maintained by mechanochemical crosstalk between gut muscles and vascular-like trachea. Indeed, sex-biased expression of a muscle-derived fibroblast growth factor-like ligand renders trachea sexually dimorphic. In turn, tracheal branches hold gut loops together into a male or female shape, with physiological consequences. Interorgan geometry represents a previously unrecognized level of biological complexity which might enable or confine communication across organs and could help explain sex or species differences in organ function.

Luteal phase support in assisted reproductive technology.

Infertility affects one in six couples, with in vitro fertilization (IVF) offering many the chance of conception. Compared to the solitary oocyte produced during the natural menstrual cycle, the supraphysiological ovarian stimulation needed to produce multiple oocytes during IVF results in a dysfunctional luteal phase that can be insufficient to support implantation and maintain pregnancy. Consequently, hormonal supplementation with luteal phase support, principally exogenous progesterone, is used to optimize pregnancy rates; however, luteal phase support remains largely 'black-box' with insufficient clarity regarding the optimal timing, dosing, route and duration of treatment. Herein, we review the evidence on luteal phase support and highlight remaining uncertainties and future research directions. Specifically, we outline the physiological luteal phase, which is regulated by progesterone from the corpus luteum, and evaluate how it is altered by the supraphysiological ovarian stimulation used during IVF. Additionally, we describe the effects of the hormonal triggers used to mature oocytes on the degree of luteal phase support required. We explain the histological transformation of the endometrium during the luteal phase and evaluate markers of endometrial receptivity that attempt to identify the 'window of implantation'. We also cover progesterone receptor signalling, circulating progesterone levels associated with implantation, and the pharmacokinetics of available progesterone formulations to inform the design of luteal phase support regimens.

Systematic review of randomised controlled trials on interventions aimed at promoting colorectal cancer screening amongst ethnic minorities.

OBJECTIVES: Significant disparities exist between different ethnic groups when it comes to participation in colorectal cancer (CRC) screening programmes. A variety of interventions have been proposed to improve participation rates of ethnic minorities for CRC screening. This systematic review aims to appraise the evidence available from published randomised controlled trials (RCTs) and to identify effective interventions aimed at promoting CRC screening amongst underserved ethnic minorities. DESIGN: We searched EmBASE, Medline, PsychInfo, Scopus and CINAHL for RCTs that analysed interventions to promote CRC screening in all ethnic minorities. CRC screening was measured as documented or self-reported screening rates. The protocol of this study was registered prospectively on PROSPERO with the registration number CRD42020216384. RESULTS: We identified 42 relevant RCT articles, out of 1805 articles highlighted by the initial search. All except one were conducted in the US. The most frequently studied ethnic groups were African-Americans (33%), East Asians (30%), and Hispanics/Latinos (23%). In total, 7/42 (16%) RCTs had multiple arms. Interventions mainly intended to educate (52%), provide patient navigation services (21%), or provide a combination of these interventions (19%). We demonstrate that combination methods are most effective. CONCLUSION: Many RCTs, mostly in the US, have trialed interventions aimed to increase CRC screening uptake amongst ethnic minorities to varying success. We conclude that using a combination of methods with patient navigation, education, and cultural tailoring is most effective at increasing CRC screening uptake amongst ethnic minorities. This highlights that multiple factors may hinder CRC screening and finding a one-size-fits-all solution that can be reliably implemented among different cultures and countries may be complex.

Remote multimodality monitoring of maternal physiology from the first trimester to postpartum period: study results.

OBJECTIVES: Current antenatal care largely relies on widely spaced appointments, hence only a fraction of the pregnancy period is subject to monitoring. Continuous monitoring of physiological parameters could represent a paradigm shift in obstetric care. Here, we analyse the data from daily home monitoring in pregnancy and consider the implications of this approach for tracking pregnancy health. METHODS: Prospective feasibility study of continuous home monitoring of blood pressure, weight, heart rate, sleep and activity patterns from the first trimester to 6 weeks postpartum. RESULTS: Fourteen out of 24 women completed the study (58%). Compared to early pregnancy [week 13, median heart rate (HR) 72/min, interquartile range (IQR) 12.8], heart rate increased by week 35 (HR 78/min, IQR 16.6; P  = 0.041) and fell postpartum (HR 66/min, IQR 11.5, P  = 0.021). Both systolic and diastolic blood pressure were lower at mid-gestation (week 20: SBP 103 mmHg, IQR 6.6; DPB 63 mmHg, IQR 5.3 P  = 0.005 and P  = 0.045, respectively) compared to early pregnancy (week 13, SBP 107 mmHg, IQR 12.4; DPB 67 mmHg, IQR 7.1). Weight increased during pregnancy between each time period analyzed, starting from week 15. Smartwatch recordings indicated that activity increased in the prepartum period, while deep sleep declined as pregnancy progressed. CONCLUSION: Home monitoring tracks individual physiological responses to pregnancy in high resolution that routine clinic visits cannot. Changes in the study protocol suggested by the study participants may improve compliance for future studies, which was particularly low in the postpartum period. Future work will investigate whether distinct adaptative patterns predate obstetric complications, or can predict long-term maternal cardiovascular health.

The feasibility of multimodality remote monitoring of maternal physiology during pregnancy.

CONDENSED ABSTRACT: To ascertain whether remote multimodality cardiovascular monitoring of health in pregnancy is feasible, 24 participants were asked to daily monitor body weight, heart rate, blood pressure, activity levels, and sleep patterns. Study participants took on average 4.3 (standard deviation = 2.20) home recordings of each modality per week across the 3 trimesters and 2.0 postpartum (standard deviation = 2.41), out of a recommended maximum of 7. Thus, remote monitoring indicative of cardiovascular health throughout and after pregnancy might be feasible for routine clinical care or within the context of a research study.

Changing Student Perception of an Online Integrated Structured Clinical Examination During the COVID-19 Pandemic.

BACKGROUND: The COVID-19 pandemic has created a hiatus in in-person clinical assessments due to safety and logistical concerns. We aimed to evaluate student perception and utility of an online Integrated Structured Clinical Examinations (ISCEs) during the pandemic. METHODS: Final-year medical students from a single institution were offered an online mock ISCE through a student-to-student ("near-peer") teaching-programme. A questionnaire-based cross-sectional study was conducted pre- and post-online mock ISCE. RESULTS: Sixty-four students completed the study. Pre- and post-data showed an increase in confidence (p<0.0001), less worry regarding the online format (p<0.0001) and less anxiety about excelling in ISCEs (p<0.001). Students felt that having done the mock, an online format would more positively affect their overall performance (p=0.007). CONCLUSION: This study demonstrates a positive change in student perception and confidence in online ISCEs. Online ISCEs are thus feasible, though sole reliance on this format may provide an incomplete assessment of student's overall clinical competency.

Virtual Interview, Real Anxiety: Prospective Evaluation of a Focused Teaching Programme on Confidence Levels Among Medical Students Applying for Academic Clinical Posts.

BACKGROUND: In 2020, final year medical students applying for the United Kingdom's competitive academic training posts face an additional challenge because interviews are conducted online rather than in-person. We assessed how this new format influences anxiety and the impact of a targeted course on candidates' confidence levels. METHODS: A mixed-methods national teaching programme including online bespoke mock interviews was delivered to prospective Academic Foundation Programme applicants. Pre- and post-interview questionnaires assessed anxiety levels subjectively and using a Measure of Anxiety in Selection Interviews (MASI) scores. RESULTS: Individuals self-reported greater confidence, experience and preference for interviews delivered in-person as compared to online interviews. Post-course, there was an increase in self-reported confidence specific to online interviews (p = 0.009) and lower MASI scores in three of five domains, indicating reduced anxiety (social anxiety: p = 0.004, performance anxiety: p <0.001, behavioral anxiety: p = 0.003). CONCLUSION: A structured course can increase confidence and reduce anxiety for online academic medicine interviews.

The BCL-2 pathway preserves mammalian genome integrity by eliminating recombination-defective oocytes.

DNA double-strand breaks (DSBs) are toxic to mammalian cells. However, during meiosis, more than 200 DSBs are generated deliberately, to ensure reciprocal recombination and orderly segregation of homologous chromosomes. If left unrepaired, meiotic DSBs can cause aneuploidy in gametes and compromise viability in offspring. Oocytes in which DSBs persist are therefore eliminated by the DNA-damage checkpoint. Here we show that the DNA-damage checkpoint eliminates oocytes via the pro-apoptotic BCL-2 pathway members Puma, Noxa and Bax. Deletion of these factors prevents oocyte elimination in recombination-repair mutants, even when the abundance of unresolved DSBs is high. Remarkably, surviving oocytes can extrude a polar body and be fertilised, despite chaotic chromosome segregation at the first meiotic division. Our findings raise the possibility that allelic variants of the BCL-2 pathway could influence the risk of embryonic aneuploidy.

Meiotic Kinetochores Fragment into Multiple Lobes upon Cohesin Loss in Aging Eggs.

Chromosome segregation errors during female meiosis are a leading cause of pregnancy loss and human infertility. The segregation of chromosomes is driven by interactions between spindle microtubules and kinetochores. Kinetochores in mammalian oocytes are subjected to special challenges: they need to withstand microtubule pulling forces over multiple hours and are built on centromeric chromatin that in humans is decades old. In meiosis I, sister kinetochores are paired and oriented toward the same spindle pole. It is well established that they progressively separate from each other with advancing female age. However, whether aging also affects the internal architecture of centromeres and kinetochores is currently unclear. Here, we used super-resolution microscopy to study meiotic centromere and kinetochore organization in metaphase-II-arrested eggs from three mammalian species, including humans. We found that centromeric chromatin decompacts with advancing maternal age. Kinetochores built on decompacted centromeres frequently lost their integrity and fragmented into multiple lobes. Fragmentation extended across inner and outer kinetochore regions and affected over 30% of metaphase-II-arrested (MII) kinetochores in aged women and mice, making the lobular architecture a prominent feature of the female meiotic kinetochore. We demonstrate that a partial cohesin loss, as is known to occur in oocytes with advancing maternal age, is sufficient to trigger centromere decompaction and kinetochore fragmentation. Microtubule pulling forces further enhanced the fragmentation and shaped the arrangement of kinetochore lobes. Fragmented kinetochores were frequently abnormally attached to spindle microtubules, suggesting that kinetochore fragmentation could contribute to the maternal age effect in mammalian eggs.

Chromosome errors in human eggs shape natural fertility over reproductive life span.

Chromosome errors, or aneuploidy, affect an exceptionally high number of human conceptions, causing pregnancy loss and congenital disorders. Here, we have followed chromosome segregation in human oocytes from females aged 9 to 43 years and report that aneuploidy follows a U-curve. Specific segregation error types show different age dependencies, providing a quantitative explanation for the U-curve. Whole-chromosome nondisjunction events are preferentially associated with increased aneuploidy in young girls, whereas centromeric and more extensive cohesion loss limit fertility as women age. Our findings suggest that chromosomal errors originating in oocytes determine the curve of natural fertility in humans.

A microscopy-based approach for studying meiosis in live and fixed human oocytes.

Human eggs frequently carry an incorrect number of chromosomes, which is a leading cause of pregnancy loss and congenital disorders. The origins of high aneuploidy rates in human eggs have remained largely unclear. This is due to two main reasons: first, the availability of human eggs is limited so that studies of fixed human eggs typically involve very small numbers and limited quantifications. Second, methods for studying meiosis in live human eggs have been missing. The ever rising prevalence of Assisted Reproductive Technologies has facilitated a recent breakthrough in the field. The mechanistic basis of meiosis in humans can now be examined directly in live eggs. Here, we present a robust method for culturing human eggs in vitro and describe how meiotic processes in human eggs can be studied in real time using fluorescent reporters. We further describe methods for the in-depth analysis of immunolabeled eggs by super-resolution light microscopy.

Sister kinetochore splitting and precocious disintegration of bivalents could explain the maternal age effect.

Aneuploidy in human eggs is the leading cause of pregnancy loss and Down's syndrome. Aneuploid eggs result from chromosome segregation errors when an egg develops from a progenitor cell, called an oocyte. The mechanisms that lead to an increase in aneuploidy with advanced maternal age are largely unclear. Here, we show that many sister kinetochores in human oocytes are separated and do not behave as a single functional unit during the first meiotic division. Having separated sister kinetochores allowed bivalents to rotate by 90 degrees on the spindle and increased the risk of merotelic kinetochore-microtubule attachments. Advanced maternal age led to an increase in sister kinetochore separation, rotated bivalents and merotelic attachments. Chromosome arm cohesion was weakened, and the fraction of bivalents that precociously dissociated into univalents was increased. Together, our data reveal multiple age-related changes in chromosome architecture that could explain why oocyte aneuploidy increases with advanced maternal age.