A scalable, spin-free approach to generate enhanced induced pluripotent stem cell-derived natural killer cells for cancer immunotherapy.

Natural killer (NK) cells play a vital role in innate immunity and show great promise in cancer immunotherapy. Traditional sources of NK cells, such as the peripheral blood, are limited by availability and donor variability. In addition, in vitro expansion can lead to functional exhaustion and gene editing challenges. This study aimed to harness induced pluripotent stem cell (iPSC) technology to provide a consistent and scalable source of NK cells, overcoming the limitations of traditional sources and enhancing the potential for cancer immunotherapy applications. We developed human placental-derived iPSC lines using reprogramming techniques. Subsequently, an optimized two-step differentiation protocol was introduced to generate high-purity NK cells. Initially, iPSCs were differentiated into hematopoietic-like stem cells using spin-free embryoid bodies (EBs). Subsequently, the EBs were transferred to ultra-low attachment plates to induce NK cell differentiation. iPSC-derived NK (iNK) cells expressed common NK cell markers (NKp46, NKp30, NKp44, CD16 and eomesodermin) at both RNA and protein levels. iNK cells demonstrated significant resilience to cryopreservation and exhibited enhanced cytotoxicity. The incorporation of a chimeric antigen receptor (CAR) construct further augmented their cytotoxic potential. This study exemplifies the feasibility of generating iNK cells with high purity and enhanced functional capabilities, their improved resilience to cryopreservation and the potential to have augmented cytotoxicity through CAR expression. Our findings offer a promising pathway for the development of potential cellular immunotherapies, highlighting the critical role of iPSC technology in overcoming challenges associated with traditional NK cell sources.

Endometrial Cell-Type Specific Regulation of the Endocannabinoids System and the Impact of Menstrual Cycle and Endometriosis.

Introduction: Anandamide (AEA) and 2-arachidonoylglycerol are endogenous agonists of the cannabinoid receptors and regulate and control many cellular functions. Their activities are governed by enzymes and proteins that regulate their synthesis, receptor binding, transport, and degradation, which are known as the endocannabinoid system (ECS). The aim of this study was to investigate the regulation of endocannabinoid activity in the endometrium by studying the RNA and protein expression of the ECS within endometrial cell types and during different menstrual cycle stages and the impact of endometriosis. Materials and Methods: The RNA expression of 70 ECS genes was assessed using RNA sequencing of isolated endometrial epithelial and stromal cells. Subsequent immunofluorescence-stained endometrial samples on ECS components of interest were objectively analyzed via an agnostic and automated image analysis pipeline to extract quantitative information. Differential gene and protein expression was investigated between the two cell types, menstrual cycle phases, and endometriosis cases and controls. Results: Sufficient RNA expression was detected for 45 genes, and 17 (38%) genes were significantly different between epithelial and stromal cells. FAAH RNA was significantly higher in epithelial cells compared with stromal cells. Protein expression analysis of the main synthesizing (NAPE-PLD) and catabolizing (FAAH and NAAA) enzymes of AEA revealed a significantly stronger epithelial expression compared to stromal cells. The RNA and protein expression of CB1 receptors was very low with no significant difference between epithelial and stromal cells. Eleven ECS genes were regulated across the menstrual cycle, and there was no gene with significant difference between endometriosis cases and controls in epithelial cells. Discussion: Differential expression of ECS genes supports a cell type-specific endocannabinoid activity in the endometrium. As endocannabinoids are short-lived signaling molecules, higher RNA and protein expression of FAAH in the epithelial cells suggests an active regulation of endocannabinoid activity in epithelial cells within the endometrium.

The impact of the COVID-19 pandemic on antenatal care provision and associated mental health, obstetric and neonatal outcomes.

OBJECTIVES: The COVID-19 pandemic imposed many challenges on pregnant women, including rapid changes to antenatal care aimed at reducing the societal spread of the virus. This study aimed to assess how the pandemic affected perinatal mental health and other pregnancy and neonatal outcomes in a tertiary unit in Queensland, Australia. METHODS: This was a retrospective cohort study of pregnant women booked for care between March 2019 - June 2019 and March 2020 - June 2020. A total of 1984 women were included with no confirmed cases of COVID-19. The primary outcome of this study was adverse maternal mental health defined as an Edinburgh Postnatal Depression Scale score of ≥13 or an affirmative response to 'EPDS Question 10'. Secondary outcomes were preterm birth <37 weeks and <32 weeks, mode of birth, low birth weight, malpresentation in labour, hypertensive disease, anaemia, iron/vitamin B12 deficiency, stillbirth and a composite of neonatal morbidity and mortality. RESULTS: There were no differences in the primary perinatal mental health outcomes. The rates of composite adverse neonatal outcomes (27 vs. 34 %, p<0.001) during the pandemic were higher; however, there was no difference in perinatal mortality (p=1.0), preterm birth (p=0.44) or mode of delivery (p=0.38). CONCLUSIONS: Although there were no adverse consequences on maternal mental health during the pandemic, there was a concerning increase in neonatal morbidity potentially due to the altered model of maternity care implemented in the early COVID-19 pandemic.

Obesity and male infertility.

The worldwide prevalence of obesity is increasing among both sexes, with associated impacts on chronic health and medical comorbidities. Similarly, the effects of obesity on reproductive health are increasingly being recognized. Adiposity is associated with reduced fertility in men, with a complex and multifactorial etiology. The reported effects of obesity on semen parameters and impaired fertility are contrasting, with some studies showing a clear reduction in reproductive outcomes associated with increased body mass index, while others do not show such impacts. These controversies may be due to the complex pathophysiology and interplay between gonadotropins and end organs, as well as genetic and epigenetic changes and oxidative stress on male fertility and function. These different aspects have led to heterogeneous participants in studies and varying implications for assisted reproductive outcomes as well as offspring health. Treatment modalities to manage obesity include lifestyle, medical, and surgical options, with emerging and effective medical treatments showing promise in reproductive outcomes.

State of the art: Intrapartum antibiotics in cesarean section, the infant microbiota and allergic diseases.

With increasing rates of cesarean section worldwide and international guidelines advising pre-incision antibiotics, neonatal exposure to pre-birth antibiotics is higher than ever before. Emerging evidence has raised concern regarding the impact of such antibiotics on the neonatal intestinal microbiota, immune system development and health conditions later in life. This narrative review investigates current protocols for intrapartum prophylactic antibiotics in cesarean section, how this and other factors may affect the neonatal intestinal microbiota and whether intrapartum antibiotics used for cesarean section are linked to the development of allergic disease.

Safety of performing classical versus low transverse caesarean sections in extremely preterm and very preterm births: Maternal and neonatal complications.

AIMS: Improved survivability of extremely preterm infants has led to increased rates of caesarean sections. Short-term maternal and neonatal risks of classical caesarean sections (CCS) in the context of extreme prematurity remain unclear. The aim was to examine maternal and neonatal complications associated with CCSs versus low transverse caesarean sections (LTCS) at extremely preterm (23 0/7-27 6/7 weeks) and very preterm gestational ages (28 0/7-31 6/7 weeks). METHODS: A retrospective cohort study was conducted at Royal Brisbane and Womens Hospital, Queensland, Australia between 2016 and 2020. Maternal and neonatal outcomes were examined using univariate and multivariate statistical analysis. RESULTS: CCSs (extremely preterm: n = 93; very preterm: n = 83) were associated with higher estimated blood loss than LTCS (extremely preterm: n = 70; very preterm: n = 287) in very preterm births (CCS: 638 ± 410 mL; LTCS: 556 ± 397 mL; P = 0.01). There was no significant difference in composite maternal outcomes between CCS and LTCS for extremely preterm (adjusted odds ratio (aOR): 1.11; 95% confidence interval (CI): 0.58-2.12; P = 0.75) or very preterm births (aOR: 1.08; 95% CI: 0.63-1.94; P = 0.79) after accounting for multiple pregnancy, placenta accreta and non-cephalic fetal presentations. Although CCSs were associated with lower Apgar scores at 1 min post-birth than LTCSs at very preterm gestational ages (CCS: 5.58 ± 2.10; LTCS: 6.25 ± 2.14; P = 0.02), there was no statistical difference in the rates of intraoperative neonatal injuries or composite outcomes when corrected for low birth weight. CONCLUSION: Short-term maternal and neonatal outcomes do not significantly differ between CCS and LTCS for extremely preterm or very preterm births.

Protocol for the Endometriosis Research Queensland Study (ERQS): an integrated cohort study approach to improve diagnosis and stratify treatment.

INTRODUCTION: Endometriosis is a common gynaecological disease associated with pelvic pain and subfertility. There are no non-invasive diagnostic tests, medical management requires suppression of oestrogens and surgical removal is associated with risk. Endometriosis is a complex genetic disease with variants in at least 27 genetic regions associated with susceptibility. Previous research has implicated a variety of biological mechanisms in multiple cell types. Endometrial and endometriotic epithelial cells acquire somatic mutations at frequency higher than expected in normal tissue. Stromal cells have altered adhesive capacity and immune cells show altered cytotoxicity. Understanding the functional consequences of these genetic variants on each cell type requires the collection of patient symptoms, clinical and genetic data and disease-relevant tissue in an integrated program. METHODS AND ANALYSIS: The aims of this study are to collect tissue associated with endometriosis, chart the genetic architecture related to endometriosis in this tissue, isolate and propagate patient-specific cellular models, understand the functional consequence of these genetic variants and how they interact with environmental factors in pathogenesis and treatment response.We will collect patient information from online questionnaires prior to surgery and at 6 and 12 months postsurgery. Treating physicians will document detailed surgical data. During surgery, we will collect blood, peritoneal fluid, endometrium and endometriotic tissue. Tissue will be used to isolate and propagate in vitro models of individual cells. Genome wide genotyping and gene expression data will be generated. Somatic mutations will be identified via whole genome sequencing. ETHICS AND DISSEMINATION: The study has been approved and will be monitored by the Metro North Human Research Ethics committee (HREC) and research activities at the University of Queensland (UQ) will be overseen by the UQ HREC with annual reports submitted. Research results will be published in peer-reviewed journals and presented at conferences were appropriate. This study involves human participants and was approved by RBWH Human Research Ethics Committee; HREC/2019/QRBW/56763.The University of Queensland; 2017002744. Participants gave informed consent to participate in the study before taking part.

Gene expression of the endocannabinoid system in endometrium through menstrual cycle.

Endocannabinoids mediate cellular functions and their activity is controlled by a complex system of enzymes, membrane receptors and transport molecules. Endocannabinoids are present in endometrium, a cyclical regenerative tissue requiring tightly regulated cellular mechanisms for maturation. The objective of this study was to investigate the gene expression of key elements involved in the endocannabinoid system across the menstrual cycle. RNA was isolated from endometrial tissue and genome-wide gene expression datasets were generated using RNA-sequencing. An a priori set of 70 genes associated with endocannabinoid system were selected from published literature. Gene expression across the menstrual cycle was analyzed using a moderated t test, corrected for multiple testing with Bonferroni's method. A total of 40 of the 70 genes were present in > 90% of the samples, and significant differential gene expression identified for 29 genes. We identified 4 distinct regulation patterns for synthesizing enzymes, as well as a distinct regulation pattern for degradations and transporting enzymes. This study charts the expression of endometrial endocannabinoid system genes across the menstrual cycle. Altered expression of genes that control endocannabinoid may allow fine control over endocannabinoid concentrations and their influence on cellular function, maturation and differentiation as the endometrium matures through the menstrual cycle.

Altered differentiation of endometrial mesenchymal stromal fibroblasts is associated with endometriosis susceptibility.

Cellular development is tightly regulated as mature cells with aberrant functions may initiate pathogenic processes. The endometrium is a highly regenerative tissue, shedding and regenerating each month. Endometrial stromal fibroblasts are regenerated each cycle from mesenchymal stem cells and play a pivotal role in endometriosis, a disease characterised by endometrial cells that grow outside the uterus. Why the cells of some women are more capable of developing into endometriosis lesions is not clear. Using isolated, purified and cultured endometrial cells of mesenchymal origin from 19 women with (n = 10) and without (n = 9) endometriosis we analysed the transcriptome of 33,758 individual cells and compared these to clinical characteristics and in vitro growth profiles. We show purified mesenchymal cell cultures include a mix of mesenchymal stem cells and two endometrial stromal fibroblast subtypes with distinct transcriptomic signatures indicative of varied progression through the differentiation processes. The fibroblast subgroup characterised by incomplete differentiation was predominantly (81%) derived from women with endometriosis and exhibited an altered in vitro growth profile. These results uncover an inherent difference in endometrial cells of women with endometriosis and highlight the relevance of cellular differentiation and its potential to contribute to disease susceptibility.

The association between induction of labour in nulliparous women at term and subsequent spontaneous preterm birth: a retrospective cohort study.

OBJECTIVES: To evaluate the rate of subsequent spontaneous preterm birth in patients with previous induction of labour at term compared to women with previous spontaneous labour at term. METHODS: This was a retrospective cohort study of all women with consecutive births at the Royal Brisbane and Women's Hospital between 2014 and 2018. All nulliparous women with a singleton pregnancy and induction of labour at term or in spontaneous labour at term in the index pregnancy were included. Data was extracted from electronic medical records. The outcome of spontaneous preterm birth in the subsequent pregnancy was compared between patients with previous term induction of labour and in previous term spontaneous labour. RESULTS: A total of 907 patients with consecutive births met the inclusion criteria; of which 269 (29.7%) had a term induction of labour and 638 (70.3%) had a term spontaneous labour in the index pregnancy. The overall subsequent spontaneous preterm birth rate was 2.3%. Nulliparous women who underwent term induction of labour were less likely to have a subsequent preterm birth compared to nulliparous women in term spontaneous labour (0.74 vs. 2.98%; odds ratio [OR], 0.25; 95% confidence interval, 0.06-1.07; p=0.0496) in the index pregnancy. This however was not significant once adjusted for confounders (adjusted OR, 0.29; p=0.10). Spontaneous preterm birth was associated with a previous spontaneous labour compared to induction of labour between 37 to 37+6 and 38 to 38+6 weeks (adjusted OR 0.18 and 0.21; p=0.02 and 0.004 respectively). CONCLUSIONS: Term induction of labour does not increase the risk of subsequent spontaneous preterm birth compared to spontaneous labour at term in nulliparous women. Further research is needed to validate these findings in a larger cohort of women and to evaluate the effect of elective IOL among low-risk nulliparous women.

Caesarean section rates: applying the modified ten-group Robson classification in an Australian tertiary hospital.

The aim of this study was to determine the main contributors to caesarean section (CS) rates at an Australian tertiary hospital. We conducted a retrospective review of women who delivered in an Australian tertiary hospital between 2014 and 2017. Women were allocated according to a modified Robson Ten-Group Classification System and CS indications were collected in nulliparous women and women with previous CS. The largest contributor to the 35.7% overall CS rate was women with a term cephalic infant and a previous CS (31.5% relative CS rate) and the most common indication was repeat CS. The group CS rate in nulliparous women with a cephalic term infant was higher when labour was induced compared to occurring spontaneously (36.6% and 18.1% respectively). The primary CS indication for these women was labour dystocia and maternal request was the most common CS indication for nulliparous women with a pre-labour CS.IMPACT STATEMENTWhat is already known on this subject? Significantly increasing caesarean section (CS) rates continue to prompt concern due to the associated neonatal and maternal risks. The World Health Organisation have endorsed the Robson Ten-Group Classification System to identify and analyse CS rate contributors.What do the results of this study add? We have used the modified Robson Ten-Group Classification System to identify that women with cephalic term infants who are nulliparous or who have had a previous CS are the largest contributors to overall CS rates. CS rates were higher in these nulliparous women if labour was induced compared to occurring spontaneously and the primary CS indication was labour dystocia. In nulliparous women with a CS prior to labour the most common CS indication was maternal request. Majority of women with a previous CS elected for a repeat CS.What are the implications of these findings for clinical practice? Future efforts should focus on minimising repeat CS in multiparous women and primary CS in nulliparous women. This may be achieved by redefining the definition of labour dystocia, exploring maternal request CS reasoning and critically evaluating induction timing and indication. Appropriately promoting a trial of labour in women with a previous CS in suitable candidates may reduce repeat CS incidence.

When is it too late? Ovarian preservation and duration of symptoms in ovarian torsion.

This 10-year retrospective study between 2008 and 2018, aims to investigate the duration of symptoms of ovarian torsion and the subsequent rate of ovarian preservation. Eighty-six women with surgically confirmed ovarian torsion were included. The median duration from the onset of pain symptoms to presentation (26.0 vs 6.0 h, p < .001) and from presentation to surgery (11.0 vs 5.5 h, p = .010) were significantly longer in women who required an oophorectomy compared to women who had conservative surgery. There was no significant difference in symptoms, signs or investigations except ultrasound finding of an enlarged ovary (94.9% vs 76.9%, p = .026). Awareness of the condition among the community and healthcare is crucial and routine investigations should not delay management as positive Doppler flow on ultrasound does not exclude an ovarian torsion.Impact StatementWhat is already known on this subject? Ovarian torsion is a gynaecological emergency and may lead to ovarian necrosis, infection and peritonitis. Early recognition is essential in preserving the ovary, particularly in patients with future fertility aspirations. Currently there is no consensus regarding the time period of ovarian viability after the onset of symptoms.What do the results of this study add? We have demonstrated a significant difference in the duration from the onset of symptoms to surgery. Furthermore, the duration from the onset of symptoms to presentation (26.0 vs 6.0 h, p<.001) and from presentation to surgery (11.0 vs 5.5 h, p=.010) were significantly longer in women who required an oophorectomy compared to women who had conservative surgery. There was no significant difference in symptoms, signs or investigations except ultrasound finding of an enlarged ovary.What are the implications of these findings for clinical practice and/or further research? Women with known ovarian cysts in particular should be educated of the risk of ovarian torsion. Routine investigations should not delay management as it does not exclude an ovarian torsion. Although our study suggests that early presentation and management would reduce the risk of oophorectomy, prospective studies are required to confirm the findings.

The risk of preterm delivery and pregnancy outcomes in women with asymptomatic short cervix: a retrospective cohort study.

OBJECTIVE: Routine cervical length measurement in asymptomatic pregnant women to prevent preterm birth has not been universally adopted due to poor predictive accuracy. The purpose of our study was to evaluate the risk of preterm delivery and pregnancy outcomes in women with asymptomatic short cervix and examine the implications of gestational age at presentation on these outcomes. STUDY DESIGN: This was a retrospective cohort study of women with singleton pregnancies who presented prior to or at 32 + 0 weeks with an asymptomatic short cervix (≤25 mm) between April 2014 to March 2018 at a single tertiary maternity center. Women with cervical length ≤25 mm were grouped into four cohorts according to gestational age at presentation: Obstetric outcomes were compared between the cohorts and the general cohort of women delivering during the same period. Outcomes were compared using Mann-Whitney U, chi-square tests, and logistic regression. Survival analysis was carried out to compare the probability of delivery for each subgroup. RESULTS: The rate of spontaneous preterm birth <37 weeks was highest in the cohort presenting at 25 + 0-27 + 6 weeks, and lowest in the first cohort presenting at <22 + 0 (60.0 versus 22.2%, p < .05). When compared with the general cohort, the rate of spontaneous preterm birth at <37-week gestation was significantly higher in the asymptomatic short cervix cohort (40.4 versus 8.7%, p < .001), with a 7.1-fold increase in the relative risk of spontaneous PTB. CONCLUSIONS: In asymptomatic women, cervical shortening showed significant increase in the risk of preterm birth. Our study findings suggest that routine cervical screening may be helpful in predicting risk of preterm birth even in women who are considered low-risk for preterm birth.

Prediction of time of delivery using cervical length measurement in women with threatened preterm labor.

OBJECTIVE: To evaluate the use of transvaginal (TV) sonographic cervical length (CL) measurement alone in predicting time of delivery in women who present in threatened preterm labor. METHODS: A retrospective cohort study at Royal Brisbane and Women's Hospital of all women who presented between 22 weeks and 0 days and 35 weeks and six-day gestation in threatened preterm labor and were admitted for ongoing management including a TV sonographic CL measure. The accuracy of CL for predicting time of delivery was compared between women with a short cervix (CL < 25 mm) and those with a normal cervix (CL ≥25 mm). The predictive accuracy of CL for spontaneous preterm delivery was analyzed with different outcome-specific thresholds. RESULTS: One hundred and forty-six women with threatened preterm labor met the inclusion criteria; of which 74 (50.7%) had a short cervix and 72 (49.3%) had a normal cervix. The group with short cervix were more likely to deliver prematurely before 37-week gestation, as well as a shorter time interval between initial presentation and delivery and delivery within 14 days from presentation (p = .0002, p = .0001, and p = .0001, respectively). Similarly, with respect to the area under the receiver operator characteristic curves, CL measurement was found to be significant for time of delivery before or after 37 weeks (p < .0001), preterm delivery before 34 (p = .0003) and 31 (p < .0001) weeks; and preterm delivery within 14 days from presentation (p < .0001). Cervical length measurement has a high negative predictive value ranging from 94.9 to 97.1% depending on the different CL threshold used. CONCLUSIONS: Cervical length measurement at the time of presentation was significantly associated with the risk of preterm delivery in women presenting with threatened preterm labor and a short cervix. Cervical length measurement was also helpful in predicting time of delivery within 14 days from presentation. The negative predictive value and predictive accuracy of CL as a single measure were of significance.

Impact of early surgical management on tubo-ovarian abscesses.

This 5-year retrospective study aimed to investigate whether early surgical management improves outcomes in patients presenting with a tubo-ovarian abscess (TOA). Patient characteristics, investigation results and treatment outcomes were compared. 50 women were diagnosed with a TOA during the study period. Nineteen (38.0%) were treated with antibiotics (medical group) and thirty one (62.0%) were treated surgically on admission (early surgical group). The early surgical group was associated with a high success rate of 96.8% and the lowest risk of readmission within 12 months (16.1%). There was no significant difference in the length of stay between the early surgical and the successful medical group.Impact StatementWhat is already known on this subject? Tubo-ovarian abscess (TOA) is an inflammatory mass that forms most commonly as a complication of untreated pelvic inflammatory disease (PID). Traditionally, TOAs are treated first with broad-spectrum intra-venous antibiotics, with surgical intervention considered after 72 h. It is not known whether early surgical intervention would be beneficial to patient outcomes compared to traditional management.What do the results of this study add? In this study, we have demonstrated a high success rate with early surgical management. Readmission rate was lowest in the early surgical group compared to the medical and late surgical group. This suggests that early surgical intervention may be beneficial, compared to the standard management of trialling antibiotics and then proceeding to surgery 72 h later.What are the implications of these findings for clinical practice and/or further research? Our study suggests that early surgery may be beneficial in the management of TOAs. Although we were unable to demonstrate statistical significance, our data suggest that it would be worthwhile to investigate white blood cell (WBC) and C-reactive protein (CRP) further as a potential predictor for failure of medical management. In the future, more studies comparing early surgical management with medical and late surgical management could inform clinicians of the best mode of treatment for these patients.

Does the length of second stage of labour or second stage caesarean section in nulliparous women increase the risk of preterm birth in subsequent pregnancies?

OBJECTIVES: This study aimed to investigate the role of prolonged second stage of labour and second stage caesarean section on the risk of spontaneous preterm birth (sPTB) in a subsequent pregnancy. METHODS: This was a retrospective cohort study of nulliparous women with two consecutive singleton deliveries between 2014 and 2017 at a tertiary centre. In the vaginal delivery cohort, subsequent pregnancy outcomes for women with a prolonged second stage (>2 h) were compared with those with a normal second stage (≤2 h). In the caesarean delivery cohort, women with a first stage or a second stage were compared with the vaginal delivery cohort. The primary outcome was subsequent sPTB. RESULTS: A total of 821 women met inclusion criteria, of which 74.8% (614/821) delivered vaginally and 25.2% (207/821) delivered by caesarean section. There was no association between a prolonged second stage in the index pregnancy and subsequent sPTB (aOR 0.70, 95% CI 0.13-3.83, p=0.7). The risk of subsequent sPTB was threefold for those with a second stage caesarean section; however this did not reach statistical significance. CONCLUSIONS: A prolonged second stage of labour in the index pregnancy is not associated with an increased risk of subsequent sPTB. A second stage caesarean section in the index pregnancy may be associated with an increased risk of subsequent sPTB, however there was no statistically significant difference. These findings are important for counseling and suggest that the effects of these factors are not clinically significant to justify additional interventions in the subsequent pregnancy.

The role of the endocannabinoid system in aetiopathogenesis of endometriosis: A potential therapeutic target.

Endometriosis affects a large proportion of women during their reproductive years and is associated with pain and infertility, also affecting psychological wellbeing and quality of life. The pathogenesis of the disease remains unclear, although it is believed to be multifactorial. The endocannabinoid system (ECS) consists of a number of ligands, receptors and enzymes, and has gained interests in endometriosis research. This review aims to summarise all available evidence reporting the roles of the ECS in endometriosis. A literature search of the PubMed, EMBASE, and Web of Science electronic medical databases was performed. Original and review articles published in peer-reviewed journals were included. No publication date or publication status restrictions were imposed. Significant differences in the concentrations and expressions of the components of the ECS were reported in the eutopic and ectopic endometrium, and the systemic circulation of women with endometriosis compared to controls. Endometriosis appears to be associated with downregulation of CB1 receptors and upregulation of TRPV1 receptors. The role of CB1 and progesterone in anti-inflammatory action and the role of TRPV1 in inflammation and pain are of particular interests. Furthermore, the ECS has been reported to be involved in processes relevant to endometriosis, including cell migration, cell proliferation, apoptosis, inflammation, and interacts with sex steroid hormones. The ECS may play a role in disease establishment, progression, and pain in endometriosis. However, reports are based on studies of limited size and there are inconsistencies among the definition of their control groups. There are also conflicting reports regarding precise involvement of the ECS in endometriosis. Future research with larger numbers, strict inclusion and exclusion criteria and detailed clinical information is imperative.

Unilateral Ureteric Endometriosis at the Pelvic Brim Resulting in Complete Loss of Renal Function.

Deep infiltrating endometriosis of the urinary tract is rare but can result in ureteric obstruction, hydroureteronephrosis and renal failure. Ureteric endometriosis usually affects the distal third of the left ureter among women of reproductive age. Greater awareness of ureteric endometriosis and a multidisciplinary approach in the management is essential to achieve optimal outcomes. We present an atypical case of right ureteric obstruction due to endometriosis at the pelvic brim resulting in complete loss of renal function and necessitating nephroureterectomy.

Management of caesarean scar pregnancy with high dose intravenous methotrexate infusion therapy: 10-year experience at a single tertiary centre.

OBJECTIVE: Incidence of caesarean scar pregnancy (CSP) is increasing due to rising caesarean section rate and advanced imaging modalities. At present, there is no consensus to recommend any specific intervention. In our centre, we have adopted the high dose intravenous methotrexate therapy followed by folinic acid for the management of CSP. In this retrospective study, we report the success rate and safety of this regimen. STUDY DESIGN: This was a 10-year retrospective study of women with CSP who received high dose methotrexate therapy with folinic acid at a tertiary centre from 1 st January 2008 to 31 st December 2017. Treatment regimen consisted of a bolus dose of intravenous methotrexate followed by methotrexate infusion over 12 h. Oral folinic acid rescues were given post treatment. Successful treatment was confirmed with either resolution of serum beta-human chorionic gonadotropin or subsequent intrauterine pregnancy. RESULTS: Of 28 women with CSP who were treated with the regimen, 24 women (85.7%) were treated successfully with methotrexate alone. 3 women (10.7%) required suction evacuation following initial treatment with methotrexate and folinic acid. There was no serious side effect from methotrexate. Advanced gestational age, higher serum ß-hCG, larger gestational sac diameter and crown-rump length, and the presence of embryonic cardiac activity were associated with methotrexate failure or need for additional therapy. CONCLUSIONS: Our high dose intravenous methotrexate infusion therapy with folinic acid is effective and well tolerated. Caution is needed with factors associated with failure. Ensuring follow up ultrasound for live CSP and follow up ß-hCG for all women with CSP is essential.

The efficacy of quantitative fetal fibronectin in predicting spontaneous preterm birth in symptomatic women: A retrospective cohort study.

BACKGROUND: Recent data suggest that quantitative measurements of fetal fibronectin can be used accurately to predict increased risk of preterm birth. AIM: The purpose of this study was to demonstrate that the quantification of fetal fibronectin improves diagnostic accuracy in women who present with symptoms suggestive of threatened preterm labour (TPL) using a quantitative fetal fibronectin (qfFN) bedside analyser. STUDY DESIGN: This was a retrospective cohort study of pregnant women who presented between 22+6 and 32+6  weeks gestation with symptoms of TPL who had qfFN measured using the Rapid fFN Q10 system. The ability to predict spontaneous preterm birth (sPTB) within 48 h, 14 days and <34 weeks gestation at qfFN thresholds of 10, 50 and 200 ng/mL was assessed. RESULTS: The overall rate of sPTB <34 weeks was 4.1% (n = 373). For deliveries within 48 h, within 14 days and <34 weeks, a qfFN threshold of 200 ng/mL had positive predictive values of 26.7%, 42.9% and 46.7%, respectively, when compared to patients with qfFN values of 0-9 ng/mL. The corresponding relative risks were 68.5, 53.8 and 38.0, respectively CONCLUSION: Quantitative fetal fibronectin testing with thresholds of 10, 50 and 200 ng/mL allows for more accurate prediction of preterm birth in symptomatic women. This higher degree of discrimination allows for more directed interventions for high-risk patients and reduces the cost and burden of unnecessary treatment for low-risk patients.