History repeats itself : the relevance of historical pandemics to the medical school curriculum

Introduction: The dramatic global impact of the coronavirus pandemic has increased consideration on epidemiological progressions of pandemics. Measures implemented to reduce viral transmission have been largely historical, comparable in nature with the 1918 and 2009 influenza pandemics, demonstrating the importance of clinicians’ awareness on historical pandemics. Despite this, literature suggests medical students’ knowledge on previous pandemics is poor. Objectives: This study aims to gather stakeholder information from UK medical students on the importance of including the history of pandemics in the medical school curriculum. Methods: A cross-sectional cohort study conducted via a mixed question type online survey was distributed to all UK medical schools to explore stakeholder views. Grounded theory emergent coding was used to generate themes to free-text answers and SPSS and Excel were used to analyse quantitative data using pivot tables and Fishers exact tests. Results: Two hundred and forty-one students consented to take part from eight medical schools in the UK with 98% of these students completing the questionnaire. 34% of students reported having teaching on pandemics with 78% of students stating it would be beneficial. Knowledge was poor with 5.7% of students achieving 100% on knowledge-based questions. 72% of students believed that learning about the history of medicine would be beneficial with 87% of these students referring to ‘benefiting (the) future’ in their answers. Additionally, 79% of students thought it would be beneficial to learn about historical pandemics with reference to the current COVID-19 pandemic. Conclusion: To date, this is the only UK based study assessing stakeholders’ views on including the history of pandemics in the medical school curriculum. Our findings demonstrate that medical students wish to have more historical content included in their degree to better prepare tomorrow's doctors for situations that may occur when history repeats itself

Lessons learned from bovine subclinical endometritis:A systematic review exploring its potential relevance to chronic endometritis in women

Chronic endometritis (CE) in humans is asymptomatic inflammation of the endometrium, associated with poor reproductive outcomes. Similarly, asymptomatic endometrial inflammation in cows, termed subclinical endometritis (SCE), is associated with adverse reproductive outcomes. While the pathophysiology and treatment options for CE in humans remain poorly defined, the well-known financial implications of SCE in dairy cows have attracted intensive research. We performed a systematic review to determine potential areas of interest in human CE research, by analysing emergent themes that arose in studies of SCE in cows. A literature search for studies of subclinical endometritis in cows published between 1990 and November 2021 was performed across Embase, Medline, Scopus and CINAHL. Studies of symptomatic or clinical endometritis were excluded. A thematic analysis across two broad themes was explored: i) diagnostic methods of SCE and ii) pathophysiology of SCE. In total, 51 bovine studies were included. Twelve studies reported on diagnostic methodology. The primary emergent theme was the use of cytology for the diagnosis of SCE. Cytological analysis has a lower sensitivity than histopathology but is less invasive and more specific than alternative techniques such as ultrasound, vaginoscopy or metabolic markers. The subthemes related to pathophysiology were identified as the type of endometritis, metabolic stress, artificial insemination, infective causes and altered cellular pathways. Despite the lack of symptoms, cellular pathways of inflammation including NF-κB, MAPK and inflammasomes were found to be activated. The key themes related to the diagnosis and pathophysiology of SCE in cows identified in this systematic review highlight potential areas for future research into human CE.</p

Routine use of cell salvage during cesarean section : a practice evaluation

Introduction: Intraoperative cell salvage is a well‐documented alternative to donor blood transfusion given the scarcity of donor blood pools and the incumbent risk of allogenic blood transfusion. Its use in obstetrics has been limited by concern over fetal alloimmunization due to the risk of fetomaternal hemorrhage. However, there are a paucity of studies reporting on outcome. The aim of this study was to report on a four‐year experience of routine use of intraoperative cell salvage and the impact on subsequent pregnancy outcomes. Material and methods: This was a tertiary center retrospective service evaluation cohort study and included all women undergoing cesarean section between December 2014 and November 2018 in a tertiary obstetric unit, identifying women who had reinfusion of intraoperative cell salvage. Data regarding index pregnancy as well as subsequent pregnancies at the hospital were extracted from hospital electronic records. Subsequent pregnancy outcome and maternal antibody status in that pregnancy were collected up until November 2022. Results: During the study period, 6656 cesarean sections were performed, with 436 (6.6%) receiving reinfusion of salvaged blood. The mean volume of reinfused blood was 396 mL. A total of 49 (0.7%) women received donor blood transfusion. Of those who received reinfusion of salvaged blood, 79 (18.1%) women had subsequent pregnancies over the eight‐year follow‐up period. There was one case (0.23%) of fetal cell alloimmunization demonstrated by the presence of anti‐D antibodies on the subsequent pregnancy booking bloods. Conclusions: Routine intraoperative cell salvage may be used to reduce the need for blood transfusion during cesarean section. The risk of fetal cell alloimmunization in a future pregnancy following reinfusion of intraoperative cell salvage is one in 436. Given an apparent small risk of fetal cell alloimmunization, further work is required to establish the safety profile of intraoperative cell salvage in pregnancy

Recurrent pregnancy loss is associated with a pro-senescent decidual response during the peri-implantation window

During the implantation window, the endometrium becomes poised to transition to a pregnant state, a process driven by differentiation of stromal cells into decidual cells (DC). Perturbations in this process, termed decidualization, leads to breakdown of the feto-maternal interface and miscarriage, but the underlying mechanisms are poorly understood. Here, we reconstructed the decidual pathway at single-cell level in vitro and demonstrate that stromal cells first mount an acute stress response before emerging as DC or senescent DC (snDC). In the absence of immune cell-mediated clearance of snDC, secondary senescence transforms DC into progesterone-resistant cells that abundantly express extracellular matrix remodelling factors. Additional single-cell analysis of midluteal endometrium identified DIO2 and SCARA5 as marker genes of a diverging decidual response in vivo. Finally, we report a conspicuous link between a pro-senescent decidual response in peri-implantation endometrium and recurrent pregnancy loss, suggesting that pre-pregnancy screening and intervention may reduce the burden of miscarriage

Preconceptual administration of doxycycline in women with recurrent miscarriage and chronic endometritis : protocol for the Chronic Endometritis and Recurrent Miscarriage (CERM) trial, a multicentre, double-blind, placebo-controlled, adaptive randomised trial with an embedded translational substudy

Introduction: Recurrent miscarriage is a common condition with a substantial associated morbidity. A hypothesised cause of recurrent miscarriage is chronic endometritis (CE). The aetiology of CE remains uncertain. An association between CE and recurrent miscarriage has been shown. This study will aim to determine if preconceptual administration of doxycycline, in women with recurrent miscarriages, and CE, reduces first trimester miscarriages, increasing live births. Methods and analysis: Chronic Endometritis and Recurrent Miscarriage is a multicentre, double-blind adaptive trial with an embedded translational substudy. Women with a history of two or more consecutive first trimester losses with evidence of CE on endometrial biopsy (defined as ≥5 CD138 positive cells per 10 mm2) will be randomised to oral doxycycline or placebo for 14 days. A subset will be recruited to a mechanistic substudy in which microbial swabs and preintervention/postintervention endometrial samples will be collected. Up to 3062 women recruited from 29 National Health Service (NHS) hospital sites across the UK are expected to be screened with up to 1500 women randomised in a 1:1 ratio. Women with a negative endometrial biopsy (defined as <5 CD138 positive cells per 10 mm2) will also be followed up to test validity of the tool. The primary outcome is live births plus pregnancies ≥24 + 0 weeks gestation at the end of the trial, in the first or subsequent pregnancy. Secondary clinical outcomes will also be assessed. Exploratory outcomes will assess the effect of doxycycline treatment on the endometrial microbiota, the differentiation capacity of the endometrium and the senescent profile of the endometrium with CE. Ethics and dissemination: Ethical approval has been obtained from the NHS Research Ethics Committee Northwest-Haydock (19/NW/0462). Written informed consent will be gained from all participants. The results will be published in an open-access peer-reviewed journal and reported in the National Institute for Health and Care Research journals library. Trial registration number: ISRCTN23947730

The endometrial microbiota and early pregnancy loss

The human endometrium is a dynamic entity that plays a pivotal role in mediating the complex interplay between the mother and developing embryo. Endometrial disruption can lead to pregnancy loss, impacting both maternal physical and psychological health. Recent research suggests that the endometrial microbiota may play a role in this, although the exact mechanisms are still being explored, aided by recent technological advancements and our growing understanding of host immune responses. Suboptimal or dysbiotic vaginal microbiota, characterized by increased microbial diversity and reduced Lactobacillus dominance, has been associated with various adverse reproductive events, including miscarriage. However, the mechanisms linking the lower reproductive tract microbiota with pregnancy loss remain unclear. Recent observational studies implicate a potential microbial continuum between the vaginal and endometrial niche in patients with pregnancy loss; however, transcervical sampling of the low biomass endometrium is highly prone to cross-contamination, which is often not controlled for. In this review, we explore emerging evidence supporting the theory that a dysbiotic endometrial microbiota may modulate key inflammatory pathways required for successful embryo implantation and pregnancy development. We also highlight that a greater understanding of the endometrial microbiota, its relationship with the local endometrial microenvironment, and potential interventions remain a focus for future research

Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids.

Decidual remodelling of midluteal endometrium leads to a short implantation window after which the uterine mucosa either breaks down or is transformed into a robust matrix that accommodates the placenta throughout pregnancy. To gain insights into the underlying mechanisms, we established and characterized endometrial assembloids, consisting of gland-like organoids and primary stromal cells. Single-cell transcriptomics revealed that decidualized assembloids closely resemble midluteal endometrium, harbouring differentiated and senescent subpopulations in both glands and stroma. We show that acute senescence in glandular epithelium drives secretion of multiple canonical implantation factors, whereas in the stroma it calibrates the emergence of anti-inflammatory decidual cells and pro-inflammatory senescent decidual cells. Pharmacological inhibition of stress responses in pre-decidual cells accelerated decidualization by eliminating the emergence of senescent decidual cells. In co-culture experiments, accelerated decidualization resulted in entrapment of collapsed human blastocysts in a robust, static decidual matrix. By contrast, the presence of senescent decidual cells created a dynamic implantation environment, enabling embryo expansion and attachment, although their persistence led to gradual disintegration of assembloids. Our findings suggest that decidual senescence controls endometrial fate decisions at implantation and highlight how endometrial assembloids may accelerate the discovery of new treatments to prevent reproductive failure

Characterization of highly proliferative decidual precursor cells during the window of implantation in human endometrium

Pregnancy depends on the wholesale transformation of the endometrium, a process driven by differentiation of endometrial stromal cells (EnSC) into specialist decidual cells. Upon embryo implantation, decidual cells impart the tissue plasticity needed to accommodate a rapidly growing conceptus and invading placenta, although the underlying mechanisms are unclear. Here we characterize a discrete population of highly proliferative mesenchymal cells (hPMC) in midluteal human endometrium, coinciding with the window of embryo implantation. Single-cell transcriptomics demonstrated that hPMC express genes involved in chemotaxis and vascular transmigration. Although distinct from resident EnSC, hPMC also express genes encoding pivotal decidual transcription factors and markers, most prominently prolactin. We further show that hPMC are enriched around spiral arterioles, scattered throughout the stroma, and occasionally present in glandular and luminal epithelium. The abundance of hPMC correlated with the in vitro colony-forming unit activity of midluteal endometrium and, conversely, clonogenic cells in culture express a gene signature partially conserved in hPMC. Cross-referencing of single-cell RNA-sequencing data sets indicated that hPMC differentiate into a recently discovered decidual subpopulation in early pregnancy. Finally, we demonstrate that recurrent pregnancy loss is associated with hPMC depletion. Collectively, our findings characterize midluteal hPMC as novel decidual precursors that are likely derived from circulating bone marrow-derived mesenchymal stem/stromal cells and integral to decidual plasticity in pregnancy

The diagnosis and related endometrial dysfunction of chronic endometritis in recurrent pregnancy loss

Recurrent pregnancy loss is a common condition carrying stark physical and psychological morbidity. Chronic endometritis (CE) is a purported cause with an emerging body of literature demonstrating an association. Despite this the pathophysiology of this association is poorly understood. This thesis aims to understand further the pathophysiology of CE through understanding the biological significance of the diagnostic methodology of CE and profiling the effect of CE on the characteristics of the endometrium. A three-fold approach to this is taken. Firstly, through systematic review and meta-analysis, current CE diagnostic methodology was reviewed. This demonstrated a wide heterogeneity in methodology with under-reporting of key steps. A wide range in reported CE prevalence was seen. Diagnostic methodology was shown to affect the ability to predict clinical outcome. Secondly, given the variance in prevalence, the primary diagnostic methodology utilising the plasma cell marker CD138 was explored. Evaluation of the constitutive endometrial expression of CD138 was undertaken. Immunohistochemical and transcriptional profiling demonstrated proliferative phase constitutive stromal expression of CD138 which dissipated on transition into the secretory phase. This finding suggested that CD138+ CE may be related to disordered progression of the endometrium across the menstrual cycle. Two-distinct sub types of CE based on immunohistochemical staining pattern were identified. Thirdly, using both histological and molecular timing, this timing relationship was examined in a prospective clinical study. CD138+ endometrium was shown to be associated with impaired endometrial timing. This was also associated with alterations in the balance between decidualised and senescent endometrial cells. Nevertheless, a causal relationship with the endometrial microbiota was not seen. These findings are the first to demonstrate a relationship between impaired endometrial timing and CE further elucidating the likely pathophysiological mechanisms by which CE predisposes to miscarriage. Furthermore, two distinct sub-types of CE may provide a clinical triage platform for differing treatment approaches