Saliva-based microRNA diagnostic signature for the superficial peritoneal endometriosis phenotype.

OBJECTIVE: Patients with superficial peritoneal endometriosis (SPE) present with symptoms suggestive of endometriosis but clinical and imaging exams are inconclusive. Consequently, laparoscopy is usually necessary to confirm diagnosis. The present study aimed to evaluate the accuracy of microRNAs (miRNAs) to diagnose patients with SPE from the ENDOmiARN cohort STUDY DESIGN: This prospective study (NCT04728152) included 200 saliva samples obtained between January and June 2021 from women with pelvic pain suggestive of endometriosis. All patients underwent either laparoscopy and/or MRI to confirm the presence of endometriosis. Among the patients with endometriosis, two groups were defined: an SPE phenotype group of patients with peritoneal lesions only, and a non-SPE control group of patients with other endometriosis phenotypes (endometrioma and/or deep endometriosis). Data analysis consisted of two parts: (i) identification of a set of miRNA biomarkers using next-generation sequencing (NGS), and (ii) development of a saliva-based miRNA signature for the SPE phenotype in patients with endometriosis based on a Random Forest (RF) model. RESULTS: Among the 153 patients with confirmed endometriosis, 10.5 % (n = 16) had an SPE phenotype. Of the 2633 known miRNAs, the feature selection method generated a signature of 89 miRNAs of the SPE phenotype. After validation, the best model, representing the most accurate signature had a 100 % sensitivity, specificity, and AUC. CONCLUSION: This signature could constitute a new diagnostic strategy to detect the SPE phenotype based on a simple biological test and render diagnostic laparoscopy obsolete. PRéCIS: We generated a saliva-based signature to identify patients with superficial peritoneal endometriosis which is the most challenging form of endometriosis to diagnose and which is often either misdiagnosed or requires invasive laparoscopy.

A 26-28 GHz, Two-Stage, Low-Noise Amplifier for Fifth-Generation Radio Frequency and Millimeter-Wave Applications.

This paper presents a high-gain low-noise amplifier (LNA) operating at the 5G mm-wave band. The full design combines two conventional cascode stages: common base (CB) and common emitter (CS). The design technique reduces the miller effect and uses low-voltage supply and low-current-density transistors to simultaneously achieve high gain and low noise figures (NFs). The two-stage LNA topology is analyzed and designed using 0.25 µm SiGe BiCMOS process technology from NXP semiconductors. The measured circuit shows a small signal gain at 26 GHz of 26 dB with a gain error below 1 dB on the entire frequency band (26-28 GHz). The measured average NF is 3.84 dB, demonstrated over the full frequency band under 15 mA current consumption per stage, supplied with a voltage of 3.3 V.

Comparison of two cancellation strategies to lower the risk of multiple pregnancies in gonadotropin stimulated intrauterine insemination cycles.

OBJECTIVE: To compare two cancellation policies in controlled ovarian stimulation-intrauterine insemination (COS-IUI) cycles to lower the risk of multiple pregnancies (MP). DESIGN: We performed a bicentric retrospective cohort study in two academic medical centers: Angers (group A) and Besançon (group B) University Hospitals. We included 7056 COS-IUI cycles between 2011 and 2019. In group A, cancellation strategy was based on an algorithm taking into account the woman's age, the serum estradiol level, and the number of follicles of 14 mm or greater on ovulation trigger day. In group B, cancellation strategy was case-by-case and physician-dependent, based on the woman's age, number of follicles of 15 mm or greater, and the previous number of failed COS-IUI cycles, without any predefined cut-off. Our main outcome measures were the MP rate (MPR) and the live-birth rate (LBR). RESULTS: We included 884 clinical pregnancies (790 singletons, 86 twins, and 8 triplets) obtained from 6582 COS-IUI cycles. MPR was significantly lower in group A compared with group B (8.1% vs 13.3%, P = 0.01), but LBR were comparable (10.8% vs 11.8%, P = 0.19). Multivariate logistic regression found the following to be risk factors for MP: the "cancellation strategy" effect (adjusted odds ratio [aOR] 1.63, 95% confidence interval [CI] 1.02-2.60) and the number of follicles of 14 mm or greater (aOR 1.39, 95% CI 1.16-1.66). Cycle cancellation rate for excessive response was significantly lower in group A compared with group B (1.3% vs 2.4%, P < 0.001). CONCLUSIONS: The use of an algorithm based on the woman's age, serum estradiol level and number of follicles of at least 14 mm on trigger day allows the MPR to be reduced without impacting the LBR.

New class of RNA biomarker for endometriosis diagnosis: The potential of salivary piRNA expression.

OBJECTIVES: In contrast to miRNA expression, little attention has been given to piwiRNA (piRNA) expression among endometriosis patients. The aim of the present study was to explore the human piRNAome and to investigate a potential piRNA saliva-based diagnostic signature for endometriosis. METHODS: Data from the prospective "ENDOmiRNA" study (ClinicalTrials.gov Identifier: NCT04728152) were used. Saliva samples from 200 patients were analyzed in order to evaluate human piRNA expression using the piRNA bank. Next Generation Sequencing (NGS), barcoding of unique molecular identifiers and both Artificial Intelligence (AI) and machine learning (ML) were used. For each piRNA, sensitivity, specificity, and ROC AUC values were calculated for the diagnosis of endometriosis. RESULTS: 201 piRNAs were identified, none had an AUC ≥ 0.70, and only three piRNAs (piR-004153, piR001918, piR-020401) had an AUC between ≥ 0.6 and < 0.70. Seven were differentially expressed: piR-004153, piR-001918, piR-020401, piR-012864, piR-017716, piR-020326 and piR-016904. The respective correlation and accuracy to diagnose endometriosis according to the F1-score, sensitivity, specificity, and AUC ranged from 0 to 0.862 %, 0-0.961 %, 0.085-1, and 0.425-0.618. A correlation was observed between the patients' age (≥35 years) and piR-004153 (p = 0.002) and piR-017716 (p = 0.030). Among the 201 piRNAs, four were differentially expressed in patients with and without hormonal treatment: piR-004153 (p = 0.015), piR-020401 (p = 0.001), piR-012864 (p = 0.036) and piR-017716 (p = 0.009). CONCLUSION: Our results support the link between piRNAs and endometriosis physiopathology and establish its utility as a potential diagnostic biomarker using saliva samples. Per se, piRNA expression should be analyzed along with the clinical status of a patient.

Update on the management of endometriosis-associated pain in France.

The French National College of Obstetricians and Gynecologists (CNGOF) published guidelines for managing endometriosis-associated pain in 2018. Given the development of new pharmacological therapies and a review that was published in 2021, most national and international guidelines now suggest a new therapeutic approach. In addition, a novel validated screening method based on patient questionnaires and analysis of 109-miRNA saliva signatures, which combines biomarkers and artificial intelligence, opens up new avenues for overcoming diagnostic challenges in patients with pelvic pain and for avoiding laparoscopic surgery when sonography and MRI are not conclusive. Dienogest (DNG) 2 mg has been a reimbursable healthcare expense in France since 2020, and, according to recent studies, it is at least as effective as combined hormonal contraception (CHC) and can be used as an alternative to CHC for first-line treatment of endometriosis-associated pain. Since 2018, the literature concerning the use of DNG has grown considerably, and the French guidelines should be modified accordingly. The levonorgestrel intrauterine system (LNG IUS) and other available progestins per os, including DNG, or the subcutaneous implant, can be offered as first-line therapy, gonadotropin-releasing hormone (GnRH) agonists with add-back therapy (ABT) as second-line therapy. Oral GnRH antagonists are promising new medical treatments for women with endometriosis-associated pain. They competitively bind to GnRH receptors in the anterior pituitary, preventing native GnRH from binding to GnRH receptors and from stimulating the secretion of luteinizing hormone and follicle-stimulating hormone. Consequently, estradiol and progesterone production is reduced. Oral GnRH antagonists will soon be on the market in France. Given their mode of action, their efficacy is comparable to that of GnRH agonists, with the advantage of oral administration and rapid action with no flare-up effect. Combination therapy with ABT is likely to allow long-term treatment with minimal impact on bone mass. GnRH antagonists with ABT may thus be offered as second-line treatment as an alternative to GnRH agonists with ABT. This article presents an update on the management of endometriosis-associated pain in women who do not have an immediate desire for pregnancy.

Insight on Non-Coding RNAs from Biofluids in Ovarian Tumors.

Ovarian tumors are the most frequent adnexal mass, raising diagnostic and therapeutic issues linked to a large spectrum of tumors, with a continuum from benign to malignant. Thus far, none of the available diagnostic tools have proven efficient in deciding strategy, and no consensus exists on the best strategy between "single test", "dual testing", "sequential testing", "multiple testing options" and "no testing". In addition, there is a need for prognostic tools such as biological markers of recurrence and theragnostic tools to detect women not responding to chemotherapy in order to adapt therapies. Non-coding RNAs are classified as small or long based on their nucleotide count. Non-coding RNAs have multiple biological functions such as a role in tumorigenesis, gene regulation and genome protection. These ncRNAs emerge as new potential tools to differentiate benign from malignant tumors and to evaluate prognostic and theragnostic factors. In the specific setting of ovarian tumors, the goal of the present work is to offer an insight into the contribution of biofluid non-coding RNAs (ncRNA) expression.

Assessment of the self-confidence of obstetrics & gynecology fellows to perform a postpartum hemostasis hysterectomy.

INTRODUCTION: Hemostasis Hysterectomy (HH) is a last resort surgical procedure performed in situations of uncontrolled post-partum hemorrhage in maternity wards. The chances of being confronted with this situation are scarce during residency, and the situation is not well suited for teaching. Nevertheless, every obstetrician-gynecologist can be confronted with this stressful situation, and should therefore possess the surgical competence required, regardless of his routine practice. The aim of the present study is to evaluate clinical exposure and self-awareness concerning HH amongst obstetrics and gynecology residents and fellows. MATERIEL AND METHODS: We performed a survey amongst French obstetrics and gynecology fellows. An anonymous survey was sent by email between December 1, 2020 to July 1, 2021. RESULTS: Half of the interrogated fellows had practiced (as operator) an HH during residency with a senior and only 22,6% in post-residency. During the last year of residency 70% of them had performed less than 10 scheduled hysterectomies as primary operator. The laparoscopic approach was the most frequently practiced. Very few hysterectomies were performed as primary operator. Fellows with a surgical or mixed activity (both gynecological surgery and obstetrical activity in current practice) felt significantly more capable of performing HH compared to those with exclusive obstetrical or reproductive medicine activity; respectively 60% vs 36%, p = 0.008; Odds Ratio: 2.629 (95% CI 1.2214; 5.8094). CONCLUSION: The number of scheduled hysterectomies or HH performed as primary operator is very low during residency or fellowship. It remains largely inferior to the number deemed necessary in previous publications about the learning curve for scheduled hysterectomy, which varies from 18 to 80 interventions. Nowadays, the increasing number of residents, added to the decrease of hemostasis hysterectomies through better management of post-partum hemorrhage, pushes towards the development of specific training, such as "damage control simulation".

Endometriosis-associated infertility diagnosis based on saliva microRNA signatures.

RESEARCH QUESTION: Can a saliva-based miRNA signature for endometriosis-associated infertility be designed and validated by analysing the human miRNome? DESIGN: The prospective ENDOmiARN study (NCT04728152) included 200 saliva samples obtained between January 2021 and June 2021 from women with pelvic pain suggestive of endometriosis. All patients underwent either laparoscopy, magnetic resonance imaging, or both. Patients diagnosed with endometriosis were allocated to one of two groups according to their fertility status. Data analysis consisted of identifying a set of miRNA biomarkers using next-generation sequencing, and development of a saliva-based miRNA signature of infertility among patients with endometriosis based on a random forest model. RESULTS: Among the 153 patients diagnosed with endometriosis, 24% (n = 36) were infertile and 76% (n = 117) were fertile. Small RNA-sequencing of the 153 saliva samples yielded approximately 3712 M raw sequencing reads (from ∼13.7 M to ∼39.3 M reads/sample). Of the 2561 known miRNAs, the feature selection method generated a signature of 34 miRNAs linked to endometriosis-associated infertility. After validation, the most accurate signature model had a sensitivity, specificity and area under the curve of 100%. CONCLUSION: A saliva-based miRNA signature for endometriosis-associated infertility is reported. Although the results still require external validation before using the signature in routine practice, this non-invasive tool is likely to have a major effect on care provided to women with endometriosis.

Validation of a Salivary miRNA Signature of Endometriosis - Interim Data.

BACKGROUND: The discovery of a saliva-based micro­ribonucleic acid (miRNA) signature for endometriosis in 2022 opened up new perspectives for early and noninvasive diagnosis of the disease. The 109-miRNA saliva signature is the product of miRNA biomarkers and artificial intelligence (AI) modeling. We designed a multicenter study to provide external validation of its diagnostic accuracy. We present here an interim analysis. METHODS: The first 200 patients included in the multicenter prospective ENDOmiRNA Saliva Test study (NCT05244668) were included for interim analysis. The study population comprised women from 18 to 43 years of age with a formal diagnosis of endometriosis or with suspected endometriosis. Epidemiologic, clinical, and saliva sequencing data were collected between November 2021 and March 2022. Genomewide miRNA expression profiling by small RNA sequencing using next-generation sequencing (NGS) was performed, and a random forest algorithm was used to assess the diagnostic accuracy. RESULTS: In this interim analysis of the external validation cohort, with a population prevalence of 79.5%, the 109-miRNA saliva diagnostic signature for endometriosis had a sensitivity of 96.2% (95% confidence interval [CI], 93.7 to 97.3%), specificity of 95.1% (95% CI, 85.2 to 99.1%), positive predictive value of 95.1% (95% CI, 85.2 to 99.1%), negative predictive value of 86.7% (95% CI, 77.6 to 90.3%), positive likelihood ratio of 19.7 (95% CI, 6.3 to 108.8), negative likelihood ratio of 0.04 (95% CI, 0.03 to 0.07), and area under the receiver operating characteristic curve of 0.96 (95% CI, 0.92 to 0.98). CONCLUSIONS: The use of NGS and AI in the sequencing and analysis of miRNA provided a saliva-based miRNA signature for endometriosis. Our interim analysis of a prospective multicenter external validation study provides support for its ongoing investigation as a diagnostic tool. (Funded by Ziwig and the Conseil Régional d'Ile de France [Grant EX024087]; ClinicalTrials.gov number, NCT05244668.)

The role of peak serum estradiol level in the prevention of multiple pregnancies in gonadotropin stimulated intrauterine insemination cycles.

The objective was to assess whether the measurement of serum estradiol (E2) level on trigger day in controlled ovarian stimulation with intrauterine insemination (COS-IUI) cycles helps lower the multiple pregnancy (MP) rate. We performed a unicentric observational study. We included all patients who underwent COS-IUI and had a subsequent clinical pregnancy (CP) between 2011 and 2019. Our main outcome measure was the area under Receiver-Operating Characteristic (ROC) curve. We included 455 clinical pregnancies (CP) obtained from 3387 COS-IUI cycles: 418 singletons, 35 twins, and 2 triplets. The CP, MP, and live birth rates were respectively 13.4%, 8.1% and 10.8%. The area under ROC curve for peak serum E2 was 0.60 (0.52-0.69). The mean E2 level was comparable between singletons and MP (260.1 ± 156.1 pg/mL vs. 293.0 ± 133.4 pg/mL, p = 0.21, respectively). Univariate and multivariate logistic regression analysis showed that E2 level was not predictive of MP rate (aOR: 1.13 (0.93-1.37) and 1.06 (0.85-1.32), respectively). Our study shows that, when strict cancelation criteria based on the woman's age and follicular response on ultrasound are applied, the measurement of peak serum E2 levels does not help reduce the risk of MP in COS-IUI cycles.

Late fetal demise, a risk factor for post-traumatic stress disorder.

Late-term fetal demise including fetal death in utero, late miscarriage and late termination of pregnancy are relatively frequent occurrences. Post-traumatic stress disorder (PTSD) is a pathology that finds its roots in exposure to a life-threatening event or an event related to death. Exposure to fetal death during a late-term fetal demise is, therefore, a situation at risk of trauma. The objective of this study was to assess the prevalence of PTSD symptoms in the short term among patients faced with late fetal demise, and to identify potential risk factors. All women were assessed at 15 days, one month, and three months after late fetal demise using the Impact of Event Scale-Revised (IES-R) and the Peritraumatic Dissociative Experiences Questionnaire (PDEQ). At 15 days, 44.2% of patients presented a pathological score on the IES-R (≥ 33). At one month and three months, this figure was 34.1% and 9.1% respectively. Factor associated with PTSD symptoms were: peritraumatic dissociation (p = 0.014), seeing the fetus during hospitalization (p = 0.035), holding the fetus in one's arms (p = 0.046), and the organization of a funeral service (p = 0.025). Patients experiencing late fetal demise are at significant risk of trauma. Care providers should remain vigilant to identify high-risk situations to offer appropriate care.Clinical trials registration number: NCT03433989.

Endometriosis Associated-miRNome Analysis of Blood Samples: A Prospective Study.

The aim of our study was to describe the bioinformatics approach to analyze miRNome with Next Generation Sequencing (NGS) of 200 plasma samples from patients with and without endometriosis. Patients were prospectively included in the ENDO-miRNA study that selected patients with pelvic pain suggestive of endometriosis. miRNA sequencing was performed using an Novaseq6000 sequencer (Illumina, San Diego, CA, USA). Small RNA-seq of 200 plasma samples yielded ~4228 M raw sequencing reads. A total of 2633 miRNAs were found differentially expressed. Among them, 8.6% (n = 229) were up- or downregulated. For these 229 miRNAs, the F1-score, sensitivity, specificity, and AUC ranged from 0-88.2%, 0-99.4%, 4.3-100%, and 41.5-68%, respectively. Utilizing the combined bioinformatic and NGS approach, a specific and broad panel of miRNAs was detected as being potentially suitable for building a blood signature of endometriosis.

Risk factors for operative vaginal delivery after a previous instrumental delivery.

OBJECTIVES: The aim of the present study was to assess factors associated with a repeat operative vaginal delivery (OVD) in women with a previous history of OVD. METHODS: A single-centre retrospective observational study was performed in the maternity ward of the Angers University Hospital between 20/09/2010 and 01/04/2021. All the patients who underwent an OVD between 01/09/2010 and 31/10/2013 (delivery n°1, n = 1215) and who subsequently delivered up to the 01/04/2021 (delivery n°2, n = 652) were included. Multivariate logistic regression was used to assess the risk of subsequent recurrent OVD, adjusted for clinical potential confounder based on univariate analysis. RESULTS: Among the 520/652 (79.7%) patients who delivered vaginally during delivery n°2, 51/520 (9.8%) had undergone a repeated OVD. Gestational age, parity, history of uterine scars, percentage of labour's induction and the duration of labor were similar between patients who delivered spontaneously and those who required an OVD during delivery n°2. There were 7/51 (13.7%) patients who underwent an OVD during delivery n°2 with a newborn in cephalic posterior presentation compared to 20/469(4.3%) in cases of spontaneous vaginal delivery n°2 (p < 0.01). A posterior cephalic presentation increased the risk of subsequent OVD by 3.7 [Confidence Interval 95% (1.4-9.6), p < 0.01] CONCLUSION: In the case of a history of OVD, a low proportion of women required a repeated OVD (9.8%). The only factor associated with the need for repeated OVD was a persistent fetal cephalic posterior presentation at the time of delivery.

Salivary MicroRNA Signature for Diagnosis of Endometriosis.

BACKGROUND: Endometriosis diagnosis constitutes a considerable economic burden for the healthcare system with diagnostic tools often inconclusive with insufficient accuracy. We sought to analyze the human miRNAome to define a saliva-based diagnostic miRNA signature for endometriosis. METHODS: We performed a prospective ENDO-miRNA study involving 200 saliva samples obtained from 200 women with chronic pelvic pain suggestive of endometriosis collected between January and June 2021. The study consisted of two parts: (i) identification of a biomarker based on genome-wide miRNA expression profiling by small RNA sequencing using next-generation sequencing (NGS) and (ii) development of a saliva-based miRNA diagnostic signature according to expression and accuracy profiling using a Random Forest algorithm. RESULTS: Among the 200 patients, 76.5% (n = 153) were diagnosed with endometriosis and 23.5% (n = 47) without (controls). Small RNA-seq of 200 saliva samples yielded ~4642 M raw sequencing reads (from ~13.7 M to ~39.3 M reads/sample). Quantification of the filtered reads and identification of known miRNAs yielded ~190 M sequences that were mapped to 2561 known miRNAs. Of the 2561 known miRNAs, the feature selection with Random Forest algorithm generated after internally cross validation a saliva signature of endometriosis composed of 109 miRNAs. The respective sensitivity, specificity, and AUC for the diagnostic miRNA signature were 96.7%, 100%, and 98.3%. CONCLUSIONS: The ENDO-miRNA study is the first prospective study to report a saliva-based diagnostic miRNA signature for endometriosis. This could contribute to improving early diagnosis by means of a non-invasive tool easily available in any healthcare system.

Machine learning algorithms as new screening approach for patients with endometriosis.

Endometriosis-a systemic and chronic condition occurring in women of childbearing age-is a highly enigmatic disease with unresolved questions. While multiple biomarkers, genomic analysis, questionnaires, and imaging techniques have been advocated as screening and triage tests for endometriosis to replace diagnostic laparoscopy, none have been implemented routinely in clinical practice. We investigated the use of machine learning algorithms (MLA) in the diagnosis and screening of endometriosis based on 16 key clinical and patient-based symptom features. The sensitivity, specificity, F1-score and AUCs of the MLA to diagnose endometriosis in the training and validation sets varied from 0.82 to 1, 0-0.8, 0-0.88, 0.5-0.89, and from 0.91 to 0.95, 0.66-0.92, 0.77-0.92, respectively. Our data suggest that MLA could be a promising screening test for general practitioners, gynecologists, and other front-line health care providers. Introducing MLA in this setting represents a paradigm change in clinical practice as it could replace diagnostic laparoscopy. Furthermore, this patient-based screening tool empowers patients with endometriosis to self-identify potential symptoms and initiate dialogue with physicians about diagnosis and treatment, and hence contribute to shared decision making.

Post procedural pregnancy occurrence risk after endometrial ablation.

OBJECTIVE: The objective of the study was to analyse the pregnancy rate after curettage, 1G (Endometrial resection) and 2G (Endometrial ablation) procedures in women with abnormal uterine bleeding (AUB-O,E,N) to evaluate the rate of pregnancy following these procedures and to improve pre and post-therapeutic women information. METHODS: This retrospective study analyzed data extracted from the French Hospital medical information database. All hospital stays with a diagnostic code for AUB and an appropriate surgical procedure coded between 2009 and 2015 were identified. A total of 109,884 women were included. Of these, 88,165 were followed up for 18 months, 80,054 for 24 months and 33,251 for 60 months. Outcomes were compared between second generation (2G) procedures, first-generation (1G) procedures (endometrial resection) and curettage. The rate of pregnancy was the primary end point. RESULTS: 7863 women underwent a 2G surgical procedure (7.2%), 39,935 a 1G procedure (36.3%) and 38,923 a curettage (35.4%). The mean age of the women was 46 years (IC.95: 36.7-52.5), with no difference in age between groups. The rate of pregnancy after 2G, 1G and curettage was respectively 13 (1.5%), 617 (10.1%) and 1025 (11.1%). The primary endpoint was significantly different between 2G and 1G and curettage (p<0.0001) CONCLUSION: 2G procedures result in lower risk of pregnancy without requiring specific training for surgeons. However, endometrial ablation cannot be considered as a sterilization method nor an effective contraceptive procedure. In the absence of sterilization of either partner, women should continue to use contraception whatever their age and menstrual status.

Ex utero intrapartum technique (EXIT): Indications, procedure methods and materno-fetal complications - A literature review.

A congenital malformation of the head, neck or thorax can lead to upper airway compression with a risk of asphyxia or neonatal death. To secure and protect the upper airway, the Ex Utero Intrapartum Therapy (EXIT) procedure has been developed. The procedure allows delivery of the fetus via a hysterotomy while relying on the placenta as the organ of respiration for the fetus prior to clamping of the umbilical cord. A high level of expertise is necessary for successful completion of the EXIT procedure, which is not void of maternal and fetal risks. In this literature review, we present the indications, procedure methods and materno-fetal complications associated with the EXIT procedure.