A study protocol for live and deceased donor uterus transplantation as a treatment for women with uterine factor infertility.

AIM: Uterus transplantation (UTx) is an emerging treatment option for women with uterine factor infertility (UFI) or the absence of a functional uterus. This is the study protocol for the first human UTx clinical trial in Australia. MATERIALS AND METHODS: This protocol outlines the approved training program used to plan, diagnose, screen, and treat patients who may be eligible for UTx using living and deceased donors. This multi-site clinical research study includes three tertiary hospital sites within New South Wales (NSW), Australia - Prince of Wales, Royal Hospital for Women and Westmead Hospitals. Our UTx protocol is based on that used by our collaborative partner, the inaugural UTx team in Gothenburg, Sweden. The Swedish UTx team provides ongoing preceptorship for the Australian UTx team. Ethics approval for six UTx procedures using living or deceased donors (Western Sydney Local Health District Human Research Ethics Committee: 2019/ETH138038) was granted in 2020. RESULTS: Results from surgeries and live births will be published. Data will be prospectively entered into the registry of the International Society of Uterus Transplantation (ISUTx), a sub-section of The Transplantation Society (TTS). TRIAL ID: ACTRN12622000917730. DISCUSSION: A multidisciplinary research team has been formed between three tertiary hospitals in Sydney - The Royal Hospital for Women, Prince of Wales and Westmead Hospitals; and with the Swedish UTx, University of Gothenburg. The Swedish team pioneered animal and human UTx studies since 1998, including publishing the first live birth after UTx. (1) This Australian trial commenced in January 2023. CONCLUSION: Uterus transplantation gives women with UFI the opportunity to be gestational and genetic mothers. It is a complex procedure for both the donor and recipient, with medical and surgical risks. An extensive multidisciplinary approach is required to optimise patient safety and graft outcomes. This protocol outlines our Australian UTx team strategy for screening, recruitment, surgical approach, and clinical management of UTx recipients and donors.

Perfusion magnetic resonance imaging in Asherman syndrome.

BACKGROUND: Microvascular scarring compromises the functionality of the endometrium, and vascular flow at the junctional zone (JZ) may be the key to understanding poor reproductive outcomes in women with Asherman syndrome (AS). AIMS: To investigate whether vascular perfusion of the uterus, measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is impaired in women with intrauterine adhesions (IUA) and AS. MATERIALS AND METHODS: A prospective observational cohort pilot study of 23 women with IUA treated with hysteroscopic synecholysis and a control group of two patients with cervix cancer were subject to DCE-MRI with gadolinium to assess uterine vascularity. Twelve regions of interest (ROIs) were allocated on the DCE-MRI image incorporating the JZ, with control ROI placed at the psoas muscle. Individual ROIs were compared to the mean total perfusion (TP) in the same uterus. Pre- and post-operative perfusion analyses were performed on five women. Receiver operator curves (ROC) were used to analyse MRI as a predictor of IUA. RESULTS: There was no significant difference in perfusion; a trend toward reduced perfusion was observed in women with IUA compared to the controls. The ROC was predictive of higher-grade and inoperable IUA. CONCLUSIONS: Reduced perfusion on DCE-MRI as assessed by ROC predicted higher-stage AS. The results of this study support further investigation of DCE-MRI as a prognostic tool for AS prior to surgical intervention to assist in providing prognostic guidance for women suffering from AS.

A survey of cost, access and outcomes for cannabinoid-based medicinal product use by Australians with endometriosis.

People with endometriosis use cannabis to manage their symptoms. This study aimed to identify costs, modes of administration, product composition, and self-reported effectiveness for those accessing medicinal cannabis in Australia. There were 192 survey responses analysed. Most (63.5%) used a 'cannabis clinic' doctor, incurring an initial consultation cost of $100-$200+ (10.2% Medicare bulk-billed) and median cannabinoid medicine costs of $300AUD per month. Cost was a major barrier to access, necessitating reducing dosage (76.1%) and/or consuming illicit cannabis (42.9%), despite a prescription. Most (77%) medical consumers used two or more cannabis products, with delta-9-tetrahydrocannabinol predominant oil and flower products most frequently prescribed.

Social Media, Endometriosis, and Evidence-Based Information: An Analysis of Instagram Content.

Social media platforms are used for support and as resources by people from the endometriosis community who are seeking advice about diagnosis, education, and disease management. However, little is known about the scientific accuracy of information circulated on Instagram about the disease. To fill this gap, this study analysed the evidence-based nature of content on Instagram about endometriosis. A total of 515 Instagram posts published between February 2022 and April 2022 were gathered and analysed using a content analysis method, resulting in sixteen main content categories, including "educational", which comprised eleven subcategories. Claims within educational posts were further analysed for their evidence-based accuracy, guided by a process which included fact-checking all claims against the current scientific evidence and research. Of the eleven educational subcategories, only four categories (cure, scientific article, symptoms, and fertility) comprised claims that were at least 50% or greater evidence-based. More commonly, claims comprised varying degrees of evidence-based, mixed, and non-evidence-based information, and some categories, such as surgery, were dominated by non-evidence-based information about the disease. This is concerning as social media can impact real-life decision-making and management for individuals with endometriosis. Therefore, this study suggests that health communicators, clinicians, scientists, educators, and community groups trying to engage with the endometriosis online community need to be aware of social media discourses about endometriosis, while also ensuring that accurate and translatable information is provided.

Surgeon reported measures of stress and anxiety prior to and after elective gynecological surgery.

INTRODUCTION: Performing surgical procedures is a recognized source of stress for surgeons. Vocational stress is an important contributor to performance, patient care, and burnout with dispositional and environmental factors contributing. Accurately assessing surgeon stress is critical to measuring effectiveness of stress reduction programs. The primary aim was to identify differences between surgeons' self-reported anticipated stress and anxiety prior to gynecological surgery, compared with their recollection of experienced stress and anxiety during surgery. Secondary aims assessed any differences by level of training, surgical type, and surgeon role. MATERIAL AND METHODS: Attending and resident gynecologists performing routine elective surgeries completed a visual analog scale (VAS) assessing perceived stress and the State-Trait Anxiety Inventory (STAI) prior to and immediately after completing 161 elective surgeries including total laparoscopic hysterectomy, laparoscopic excision of moderate-severe endometriosis, or hysteroscopic myomectomy. RESULTS: Eight attending gynecologists and nine residents participated. Residents commenced as primary surgeon in 62/90 (69%) procedures. Stress experienced during surgery was greater than anticipated in 92/161 (57%) surgery episodes (mean VAS increase: 3.9; 95% CI: 1.1-6.8, p = 0.009). State anxiety was greater than anticipated in 99/161 (62%) episodes (mean state anxiety increase: 4.4; 95% CI: 3.0-5.8, p < 0.001). Greater preprocedural anticipatory stress and anxiety was observed in residents vs. attending gynecologists (VAS 51.9 vs. 22.8, p < 0.001; state anxiety 38.3 vs. 28.1, p < 0.001) and in primary vs. assistant surgeons (VAS 47.2 vs. 29.9, p < 0.001; state anxiety 36.9 vs. 28.3, p < 0.001). Intraoperative stress and anxiety were greater in primary surgeons (VAS 50.4 vs. 30.5, p < 0.001; anxiety 41.3 vs. 32.5, p < 0.001) and residents (VAS 43.4 vs. 31.7, p < 0.001; anxiety 53.5 vs. 33.7, p < 0.001) compared with assistants and attending gynecologists. Perceived stress and anxiety were positively correlated at both timepoints (r = 0.68, p < 0.001; r = 0.82, p < 0.001). CONCLUSIONS: When asked to reflect on stress experienced during surgery, our data show that stress during surgery is greater than anticipated for many surgical episodes. Self-reported stress symptoms commence prior to surgery and are more commonly reported by surgeons operating as primary surgeon and by those in training. Future research should focus on determinants of presurgical stress and examine when stressors become inhibitory to performance.

Patient-Reported Outcome Measures Used in Randomized Controlled Trials Following Surgical Intervention for Endometriosis: A Structured Review from the AAGL Practice Guidelines Group.

OBJECTIVE: No consensus currently exists regarding patient-reported outcome measure (PROM) instruments. This structured review was conducted to identify the PROMs used by randomized controlled trials (RCTs) that evaluated surgical treatment in patients with endometriosis. DATA SOURCES: Two parallel searches were conducted by a medical librarian using Ovid MEDLINE, Ovid Embase, and Cochrane Library for RCTs published from 2000 to July 2022. One search focused on studies reporting quality of life (QoL), and the second search focused on studies reporting pain and sexual, bowel, and bladder function. METHOD OF STUDY SELECTION: During the title and abstract screening and reference check, 600 results were identified on PROMs relating to QoL and 465 studies on PROMs relating to pain and sexual, bowel, and/or bladder function and an evaluation of 17 and 12 studies conducted, respectively. The inclusion criteria involved selecting RCTs that focused on surgical intervention and assessing QoL, pain, and sexual, bowel, and/or bladder function using PROMs. TABULATION, INTEGRATION, AND RESULTS: Covidence software was used to organize and identify duplicate articles through screening. We developed a data extraction form to collect key information about each included study, as well as the pertinent PROMs used in the study. Assessment of the risk of bias of each study was also performed. A total of 19 studies were identified involving 2089 participants and a total of 16 PROMs used across the studies; 9 of 19 studies (47%) were rated as having a low risk of bias. There were no high-risk studies identified in this review. CONCLUSION: This study identified a large number of RCTs in surgical treatment of endometriosis that used various PROMs to assess QoL, pain, and bladder, bowel, and sexual function. The PROMs used by high-quality RCTs for QoL include Endometriosis Health Profile-30, Endometriosis Health Profile-5, Short-Form 36, Short-Form 12, and EQ-5D; for bowel-related symptoms Knowles-Eccersley-Scott-Symptom Questionnaire, Gastrointestinal Quality of Life Index, and Cleveland Clinic Fecal Incontinence Severity Scoring System/Wexner; for bladder-related function Bristol Female Lower Urinary Tract Symptoms, International Prostate Symptom Score, Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire, and Urinary Symptom Profile; and finally for sexual function Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire and Sexual Activity Questionnaire. Unlike other domains, only one tool (visual analog scale) was the dominant PROM used for the assessment of pain. In addition, the use of more than one PROM in each study to assess different aspects of patient's health and pain symptoms did not become prevalent until after 2015.

Non-invasive tests for endometriosis are here; how reliable are they, and what should we do with the results?

A reliable non-invasive biomarker for endometriosis is highly likely in the coming years. In the lead-up to this, clinicians need to be aware of commercially available tests as they become accessible, be aware of the level of evidence to support them and be prepared to counsel and manage patients who present with the results of such tests. One such test gaining popularity in Europe was developed using a machine-based learning algorithm to analyse thousands of microRNAs based on a 200-patient cohort with suspected endometriosis in France. We explore the background science for this commercially available test; outline the questions that remain to be answered; and caution against its use outside of a research setting.

Treatment of rectosigmoid endometriosis by laparoscopic reverse submucosal dissection (LRSD): The Sydney partial thickness discoid excision technique.

BACKGROUND: Laparoscopic reverse submucosal dissection (LRSD) is a standardised surgical technique for removal of rectosigmoid endometriosis which optimises the anatomical dissection plane for excision of endometriotic nodules. AIM: This cohort study assesses the outcomes of the first cohort of women treated by LRSD, for deeply infiltrating rectosigmoid endometriosis. MATERIALS AND METHODS: Primary outcomes assessed were complication rate as defined by the Clavien-Dindo system, and completion of the planned LRSD. Secondary outcomes include mucosal breach, specimen margin involvement, length of hospital admission, and a comparison of pre-operative and post-operative pain, bowel function and quality of life surveys. These included the Endometriosis Health Profile Questionnaire (EHP-30), the Knowles-Eccersley-Scott Symptom Questionnaire (KESS) and the Wexner scale. RESULTS: Of 19 patients treated, one required a segmental resection. The median length of hospital admission was two days (range 1-5) and no post-operative complications occurred. Median pain visual analogue scales (scale 0-10) were higher prior to surgery (dysmenorrhoea 9.0, dyspareunia 7.5, dyschezia 9.0, pelvic pain 6.0) compared to post-surgical median scores (dysmenorrhoea 5.0, dyspareunia 4.0, dyschezia 2.0, pelvic pain 4.0) at a median of six months (range 4-32). Quality of life studies suggested improvement following surgery with pre-operative median EHP-30 and KESS scores (EHP-30: 85 (5-106), KESS score 9 (0-20)) higher than post-operative scores (EHP-30: 48.5 (0-80), KESS score: 3 (0-19)). CONCLUSION: This series highlights the feasibility of LRSD with low associated morbidity as a progression of partial thickness discoid excision (rectal shaving) for the treatment of rectosigmoid deep infiltrating endometriosis.

A Prospective Study of Bladder Function Following Endometriosis Surgery With Up to Eight years Follow-up.

STUDY OBJECTIVE: To assess long-term urinary function for women having laparoscopic surgery for endometriosis. DESIGN: Institutional Review Board-approved nested cohort study within a larger randomized controlled trial assessing urinary function following any benign laparoscopy for gynecological presentations. SETTING: Two tertiary-level university-affiliated hospitals. PATIENTS: Women with histologically confirmed endometriosis within the randomized controlled trial between April 2012 and November 2019, where baseline urinary function was determined. INTERVENTIONS: Women with histologically confirmed endometriosis were contacted between February and October 2020, and urinary function was re-assessed. MEASUREMENTS AND MAIN RESULTS: Urinary function was assessed using validated questionnaires across the domains of filling, voiding, incontinence, and quality of life determined distant from surgery. Higher scores correlated with a greater severity of symptoms. From 518/711 (72.9%) women with histologically confirmed endometriosis, 289/518 (55.8%) consented to the nested study. At a mean of 50 months (range 12-103 months) post-operatively, 35 participants (12.1%) had sought treatment for bladder symptoms, and 81 participants (28.0%) reported at least one urinary tract infection since their index surgery. There was a significant worsening of symptoms for filling, voiding, incontinence, and quality of life pre-operative to post-operatively (2.27 vs 3.32, 0.93 vs 2.02, 1.06 vs 2.32, 0.83 vs 2.13 respectively, p <.001). There was no statistically significant difference in urinary questionnaire scores in participants with and without uterovesical endometriosis. There was no statistically significant difference in any parameter when comparing any revised American Society of Reproductive Medicine (rASM) stage of endometriosis. Participants who had post-operative urinary retention reported a higher mean voiding score than those who did not (3.24 vs 1.94, p = .017), while participants with post-operative urinary tract infection reported a higher mean frequency score than those who did not (5.17 vs 3.24, p = .016). CONCLUSION: This study suggests a decline in urinary function over time following laparoscopic surgery for endometriosis that is not dependent on the severity or location of the disease.

Botulinum Toxin for the Management of Pelvic Floor Tension Myalgia and Persistent Pelvic Pain: A Systematic Review and Meta-analysis.

OBJECTIVE: To systematically review the literature on use of botulinum toxin to treat pelvic floor tension myalgia and persistent pelvic pain. DATA SOURCES: The ClinicalTrials.gov , PubMed, EMBASE, and Scopus databases were searched from inception to November 2022 by two independent assessors (B.L.K. and F.G.L.). Identified studies were screened by title and abstract and included after full-text review. Data extraction was subsequently performed and recorded in Microsoft Excel. METHODS: This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines after registration in PROSPERO (CRD42022289132). All randomized studies, prospective studies with more than five participants, and retrospective studies with more than 10 participants published in English or French and assessing the use of botulinum toxin for the treatment of pelvic floor tension myalgia and persistent pelvic pain in women were included. Meta-analyses were performed on randomized data. TABULATION, INTEGRATION, AND RESULTS: Of 4,722 articles identified, 24 satisfied inclusion criteria. A meta-analysis of five randomized controlled trials totaling 329 participants demonstrated no differences in patient- and clinician-reported outcome measures, including pain, dyspareunia, sexual function, and vaginal manometry. Mean duration of follow-up was 6 months. A qualitative analysis of 14 prospective and four retrospective studies including 804 participants is supportive of botulinum toxin; however, the quality of data is low, and there is marked heterogeneity between studies. CONCLUSION: Meta-analyses of randomized data do not support the use of botulinum toxin to treat pelvic floor tension myalgia and persistent pelvic pain. Failure of these data to confirm the findings of nonrandomized prospective studies that suggest a treatment benefit may be attributable to the absence of placebo control and confounding outcomes obtained from an active comparator group. Further randomized controlled trials with true placebo are strongly recommended. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42022289132.

The Place of Cannabinoids in the Treatment of Gynecological Pain.

Cannabis sativa (L), a plant with an extensive history of medicinal usage across numerous cultures, has received increased attention over recent years for its therapeutic potential for gynecological disorders such as endometriosis, chronic pelvic pain, and primary dysmenorrhea, due at least in part to shortcomings with current management options. Despite this growing interest, cannabis inhabits an unusual position in the modern medical pharmacopoeia, being a legal medicine, legal recreational drug, and an illicit drug, depending on jurisdiction. To date, the majority of studies investigating cannabis use have found that most people are using illicit cannabis, with numerous obstacles to medical cannabis adoption having been identified, including outdated drug-driving laws, workplace drug testing policies, the cost of quality-assured medical cannabis products, a lack of cannabis education for healthcare professionals, and significant and persistent stigma. Although currently lacking robust clinical trial data, a growing evidence base of retrospective data, cohort studies, and surveys does support potential use in gynecological pain conditions, with most evidence focusing on endometriosis. Cannabis consumers report substantial reductions in pelvic pain, as well as common comorbid symptoms such as gastrointestinal disturbances, mood disorders such as anxiety and depression, and poor sleep. Substitution effects were reported, with >50% reduction or cessation in opioid and/or non-opioid analgesics being the most common. However, a substantial minority report not disclosing cannabis consumption to their health professional. Therefore, while such deprescribing trends are potentially beneficial, the importance of medical supervision during this process is paramount given the possibility for withdrawal symptoms.

Cannabis, whether purchased illicitly, or obtained through legal means, is commonly used by those with chronic pelvic pain, especially people with endometriosis. People report several benefits from using cannabis, including being able to reduce their normal medications including opioid based painkillers, but often don't tell their health professional about this. This could lead to issues with withdrawal symptoms, so clinicians should be aware of the high prevalence of use of cannabis in this population.

"A glimmer of hope" - Perceptions, barriers, and drivers for medicinal cannabis use amongst Australian and New Zealand people with endometriosis.

Previous quantitative research has shown that cannabis use, mostly illicit, is used for symptom management amongst those with endometriosis living in Australia or New Zealand, but the drivers and barriers for use of legal, medicinal cannabis in this population are currently unclear. This study sought to investigate, via online focus-groups, the perceptions, barriers, drivers, and experiences associated with cannabis use, whether legal or illicit, amongst 37 Australians and New Zealanders, aged 18-55, with a medical diagnosis of endometriosis. Previous cannabis usage was not required to participate. Discussion topics included strategies employed to manage symptoms, exploration of current medications, previous use of cannabis for pain management, and interest in using medicinal cannabis as a management strategy. Participants with moderate to severe symptoms of medically diagnosed endometriosis reported inadequacies with their current medical and self-management strategies and were inclined to try medicinal cannabis, both as part of their medical management and as part of a clinical trial. Barriers to medicinal cannabis adoption identified in this cohort included high costs of legal cannabis products, lack of clarity and fairness in current roadside drug testing laws and workplace drug testing policies, concern over the impact of stigma affecting familial, social and workplace life domains, and subsequent judgement and the lack of education/engagement from their medical providers regarding cannabis use. Given the interest in medicinal cannabis and the reported lack of effective symptom management, clinical trials are urgently required to determine the potential role that medicinal cannabis may play in reducing the symptoms of endometriosis.

Identifying molecular phenotypes in sepsis: an analysis of two prospective observational cohorts and secondary analysis of two randomised controlled trials.

BACKGROUND: In sepsis and acute respiratory distress syndrome (ARDS), heterogeneity has contributed to difficulty identifying effective pharmacotherapies. In ARDS, two molecular phenotypes (hypoinflammatory and hyperinflammatory) have consistently been identified, with divergent outcomes and treatment responses. In this study, we sought to derive molecular phenotypes in critically ill adults with sepsis, determine their overlap with previous ARDS phenotypes, and evaluate whether they respond differently to treatment in completed sepsis trials. METHODS: We used clinical data and plasma biomarkers from two prospective sepsis cohorts, the Validating Acute Lung Injury biomarkers for Diagnosis (VALID) study (N=1140) and the Early Assessment of Renal and Lung Injury (EARLI) study (N=818), in latent class analysis (LCA) to identify the optimal number of classes in each cohort independently. We used validated models trained to classify ARDS phenotypes to evaluate concordance of sepsis and ARDS phenotypes. We applied these models retrospectively to the previously published Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis and Septic Shock (PROWESS-SHOCK) trial and Vasopressin and Septic Shock Trial (VASST) to assign phenotypes and evaluate heterogeneity of treatment effect. FINDINGS: A two-class model best fit both VALID and EARLI (p<0·0001). In VALID, 804 (70·5%) of the 1140 patients were classified as hypoinflammatory and 336 (29·5%) as hyperinflammatory; in EARLI, 530 (64·8%) of 818 were hypoinflammatory and 288 (35·2%) hyperinflammatory. We observed higher plasma pro-inflammatory cytokines, more vasopressor use, more bacteraemia, lower protein C, and higher mortality in the hyperinflammatory than in the hypoinflammatory phenotype (p<0·0001 for all). Classifier models indicated strong concordance between sepsis phenotypes and previously identified ARDS phenotypes (area under the curve 0·87-0·96, depending on the model). Findings were similar excluding participants with both sepsis and ARDS. In PROWESS-SHOCK, 1142 (68·0%) of 1680 patients had the hypoinflammatory phenotype and 538 (32·0%) had the hyperinflammatory phenotype, and response to activated protein C differed by phenotype (p=0·0043). In VASST, phenotype proportions were similar to other cohorts; however, no treatment interaction with the type of vasopressor was observed (p=0·72). INTERPRETATION: Molecular phenotypes previously identified in ARDS are also identifiable in multiple sepsis cohorts and respond differently to activated protein C. Molecular phenotypes could represent a treatable trait in critical illness beyond the patient's syndromic diagnosis. FUNDING: US National Institutes of Health.