Lessons learnt from the multi-centre LAparoscopic Versus Abdominal hysterectomy (LAVA) randomised controlled trial.

Background: The LAparoscopic Versus Abdominal hysterectomy (LAVA) randomised controlled trial comparing laparoscopic hysterectomy (LH) and abdominal hysterectomy (AH) closed prematurely on the grounds of futility. Here we identify the challenges faced and lessons learnt. Objectives: To explore the views and experiences of clinical/research staff in order to understand how these might act as barriers to trial participation and recruitment. Materials and Methods: Review of the trial progress and collation of the views and experiences of clinical/ research staff on all aspects of the trial. Data were collected from transcribed conversations, email, phone, or video conferencing interactions and analysed descriptively. Main outcome measures: Site set-up milestones, recruitment rates and reasons provided by clinical/research staff for site's declining to participate. Opinions, preferences and experiences of clinicians/researchers and challenges to participation and recruitment. Results: The mean time from initial site contact to opening was 253 days and 68 days to randomise their first participant. 265 patients were screened from 13 sites over 13 months, 154 were eligible, and 75 (59%) were randomised. Of the 53 not randomised, 23 (43%) women preferred LH whilst 6 (11%) preferred AH. The main reasons given for failure to recruit or activate set-up in the 21 sites open or in set-up, were lack of research/ clinical capacity imposed by the COVID-19 pandemic and lack of clinician equipoise. Conclusions: The main reasons for the LAVA trial failure were lack of equipoise amongst surgeons and the adverse impact of the COVID-19 pandemic on clinical/research services. What is new?: Surgeons' preference for laparoscopic hysterectomy is not shared by most patients. Many patients prefer an open hysterectomy to a laparoscopic one.

Perspectives in adhesion prevention in gynaecological surgery.

Adhesions are a frequent, clinically relevant, and often costly complication of surgery that can develop in any body location regardless of the type of surgical procedure. Adhesions result from surgical trauma inducing inflammatory and coagulation processes and to date cannot be entirely prevented. However, the extent of adhesion formation can be reduced by using good surgical technique and the use of anti-inflammatory drugs, haemostats, and barrier agents. Strategies are needed in the short-, medium- and longer-term to improve the prevention of adhesions. In the short-term, efforts are needed to increase the awareness amongst surgeons and patients about the potential risks and burden of surgically induced adhesions. To aid this in the medium- term, a risk score to identify patients at high risk of adhesion formation is being developed and validated. Furthermore, available potentially preventive measures need to be highlighted. Both clinical and health economic evaluations need to be undertaken to support the broad adoption of such measures. In the longer- term, a greater understanding of the pathogenic processes leading to the formation of adhesions is needed to help identify effective, future treatments to reliably prevent adhesions from forming and lyse existing ones.

Endometrial biopsy under direct hysteroscopic visualisation versus blind endometrial sampling for the diagnosis of endometrial hyperplasia and cancer: Systematic review and meta-analysis.

Background: Endometrial cancer is the most common gynaecological neoplasia in western countries. Diagnosis of endometrial cancer requires an endometrial biopsy. A good quality endometrial biopsy allows not only the identification of the pathology, but also preoperative histologic subtype classification. Endometrial biopsy can be performed under direct hysteroscopic visualisation, but also using blind sampling techniques. Objectives: To compare endometrial biopsy performed under direct hysteroscopic visualisation versus blind sampling for the diagnosis of endometrial hyperplasia and cancer. Materials and Methods: Systematic review and meta-analysis. Electronic databases were searched from their inception until March 2022.We included all studies comparing endometrial biopsy performed under direct hysteroscopic visualisation versus blind endometrial sampling. Main outcome measures: Sample adequacy, failure rate to detect endometrial cancer or endometrial hyperplasia, and rate of detection of endometrial cancer. The summary measures were reported as relative risk (RR) with 95% of confidence interval (CI). Results: Four studies with a total of 1,295 patients were included. Endometrial biopsy under direct hysteroscopic visualisation was associated with a significantly higher rate of sample adequacy (RR 1.13, 95% CI 1.10 to 1.17), and significantly lower risk of failure to detect endometrial cancer or endometrial hyperplasia (RR 0.16, 95% CI 0.03 to 0.92) compared to blind endometrial sampling. However, there was no significant difference between endometrial biopsies taken under direct hysteroscopic visualisation or blindly, with or without a preceding diagnostic hysteroscopy, in the rate of detection of endometrial cancer (RR 0.18, 95% CI 0.03 to 1.06). Conclusion: Hysteroscopic endometrial biopsy under direct visualisation is associated with significantly higher rate of sample adequacy and is comparable to blind endometrial sampling for the diagnosis of endometrial cancer and precancer. What is new?: Hysteroscopic endometrial biopsy under direct visualisation would be expected to reduce diagnostic failure for endometrial cancer compared to blind endometrial sampling.

Comment on "Evidence of prehistoric human activity in the Falkland Islands".

Stable isotopes from archaic Falkland Islands wolves (Dusicyon australis) indicate a high trophic, marine diet. Hamley et al. argue that this is consistent with mutualism with Yaghan people. However, most D. australis had similar isotopic signatures in the European era, despite human persecution. These data therefore neither support nor refute human-mediated introduction of D. australis to the Falklands.

Impact of the COVID-19 pandemic on surgery for severe endometriosis in the UK: a national database study.

Background: The COVID-19 pandemic has had a significant effect on healthcare services, particularly affecting patients who suffer from chronic conditions. However, the pandemic's effect on endometriosis surgery is not yet known. Objectives: To determine the impact of the COVID-19 pandemic on surgery for severe endometriosis in the UK at a national, regional and centre-level. Materials and Methods: The British Society for Gynaecological Endoscopy (BSGE) collects data nationally on all operations for severe endometriosis which involve dissection of the pararectal space. Annual audits of this database were obtained from the BSGE. Publicly available data on COVID-19 cases and population were obtained from the UK Office for National Statistics. Main outcome measures: Numbers of annual BSGE-registered endometriosis operations. Results: A total of 8204 operations were performed. The number of operations decreased by 49.4% between 2019 and 2020 and then increased in 2021, but remained 10.5% below average pre-pandemic levels, indicating at least 980 missed operations between 2019-2020. Median operations per centre decreased by 51.0% in 2020 (IQR 29.4% - 75.0%) and increased in 2021 but remained 33% below pre-pandemic levels. There was no change in the type of surgery performed. All 11 administrative regions of Great Britain had reduced numbers of operations in 2020 compared with the average for 2017-2019, with a median 44.2% decrease (range 13.3% - 67.5%). Regional reduction in operations was correlated with COVID-19 infection rates (r=0.54, 95% CI of r 0.022 - 1.00, p=0.043). Conclusion: The number of operations performed annually in the UK for severe endometriosis fell dramatically during the COVID-19 pandemic and is yet to normalise. What's new?: This study shows the dramatic effect that the COVID-19 pandemic has had on UK services for endometriosis surgery, which may continue to affect patients and clinicians for a considerable time to come.

Analysis of factors that could affect symptomatic outcome in patients having laparoscopic excision of deep rectovaginal endometriosis in BSGE endometriosis centres.

OBJECTIVE: Investigate factors that influence quality of life after laparoscopic excision of deep rectovaginal endometriosis. STUDY DESIGN: A multicentre prospective cohort study involving 63 hospitals accredited as British Society for Gynaecological Endoscopy specialist endometriosis centres was conducted. The study population comprised of 8368 women who had undergone laparoscopic surgical excision of deep rectovaginal endometriosis requiring dissection of the pararectal space. The main outcome assessed was mean quality of life measured using the EuroQol 100 mm visual analogue score at 6 and 24 months after surgery according to potential prognostic factors. These factors included patient characteristics (age, smoking status, BMI), previous treatments for endometriosis, concomitant bowel surgery and surgical complications. RESULTS: Quality of life improved from a mean pre-operative score of 55/100 to 72/100 (p < 0.01), at 6 months following surgery and this elevated score was sustained at 24 months (mean VAS = 71/100; p < 0.01). Smoking and previous surgery for endometriosis were associated with significantly reduced quality of life at both 6 months (mean difference -7.7 (standard error (SE) 1.0); P < 0.01 and -2.8 (SE 0.7); P < 0.01 respectively) and 24 months after surgery (mean difference -6.8 (SE 1.8); P < 0.01 and -4.5 (SE 1.2); P < 0.01 respectively). Age over 45 years was predictive of greater clinical improvement at 6 and 24 months (mean difference 5.5 (SE 1.2); P < 0.01 and 9.7 (SE 2.2); P < 0.01) as was the use of gonadotrophin analogues (GnRHa) (mean difference 7.6 (SE 1.2); P < 0.01 and 8.9 (SE 2.0); P < 0.01). CONCLUSION(S): Laparoscopic excision of deep endometriosis in specialist centres improves quality of life. Women should be advised to stop smoking and consider pre-operative ovarian suppression. Surgery should be avoided prior to referral to a specialist centre in women diagnosed with deep rectovaginal endometriosis to achieve a better quality of life outcome.

Septum resection versus expectant management in women with a septate uterus: an international multicentre open-label randomized controlled trial.

STUDY QUESTION: Does septum resection improve reproductive outcomes in women with a septate uterus? SUMMARY ANSWER: Hysteroscopic septum resection does not improve reproductive outcomes in women with a septate uterus. WHAT IS KNOWN ALREADY: A septate uterus is a congenital uterine anomaly. Women with a septate uterus are at increased risk of subfertility, pregnancy loss and preterm birth. Hysteroscopic resection of a septum may improve the chance of a live birth in affected women, but this has never been evaluated in randomized clinical trials. We assessed whether septum resection improves reproductive outcomes in women with a septate uterus, wanting to become pregnant. STUDY DESIGN, SIZE, DURATION: We performed an international, multicentre, open-label, randomized controlled trial in 10 centres in The Netherlands, UK, USA and Iran between October 2010 and September 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with a septate uterus and a history of subfertility, pregnancy loss or preterm birth were randomly allocated to septum resection or expectant management. The primary outcome was conception leading to live birth within 12 months after randomization, defined as the birth of a living foetus beyond 24 weeks of gestational age. We analysed the data on an intention-to-treat basis and calculated relative risks with 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE: We randomly assigned 80 women with a septate uterus to septum resection (n = 40) or expectant management (n = 40). We excluded one woman who underwent septum resection from the intention-to-treat analysis, because she withdrew informed consent for the study shortly after randomization. Live birth occurred in 12 of 39 women allocated to septum resection (31%) and in 14 of 40 women allocated to expectant management (35%) (relative risk (RR) 0.88 (95% CI 0.47 to 1.65)). There was one uterine perforation which occurred during surgery (1/39 = 2.6%). LIMITATIONS, REASONS FOR CAUTION: Although this was a major international trial, the sample size was still limited and recruitment took a long period. Since surgical techniques did not fundamentally change over time, we consider the latter of limited clinical significance. WIDER IMPLICATIONS OF THE FINDINGS: The trial generated high-level evidence in addition to evidence from a recently published large cohort study. Both studies unequivocally do not reveal any improvements in reproductive outcomes, thereby questioning any rationale behind surgery. STUDY FUNDING/COMPETING INTEREST(S): There was no study funding. M.H.E. reports a patent on a surgical endoscopic cutting device and process for the removal of tissue from a body cavity licensed to Medtronic, outside the scope of the submitted work. H.A.v.V. reports personal fees from Medtronic, outside the submitted work. B.W.J.M. reports grants from NHMRC, personal fees from ObsEva, personal fees from Merck Merck KGaA, personal fees from Guerbet, personal fees from iGenomix, outside the submitted work. M.G. reports several research and educational grants from Guerbet, Merck and Ferring (location VUMC) outside the scope of the submitted work. The remaining authors have nothing to declare. TRIAL REGISTRATION NUMBER: Dutch trial registry: NTR 1676. TRIAL REGISTRATION DATE: 18 February 2009. DATE OF FIRST PATIENT'S ENROLMENT: 20 October 2010.

Cervical dilatation and preparation prior to outpatient hysteroscopy: a systematic review and meta-analysis.

BACKGROUND: There are uncertainties about the benefit of routine cervical preparation and/or cervical dilatation before outpatient hysteroscopy. OBJECTIVE: To determine if cervical preparation and/or routine mechanical dilatation reduces pain during outpatient hysteroscopy. SEARCH STRATEGY: MEDLINE, EMBASE, CINAHL and CENTRAL were searched on 19 October 2020, using keywords 'hysteroscopy', 'cervical preparation', 'cervical ripening', 'cervical dilatation', 'outpatient', 'office' and/or 'ambulatory' and associated medical subject headings. SELECTION CRITERIA: Randomised controlled trials investigating the benefit of cervical preparation and/or cervical dilatation on pain in women undergoing outpatient hysteroscopy were included. DATA COLLECTION AND ANALYSIS: Two independent reviewers selected eligible trials and extracted data on pain, feasibility, adverse events and satisfaction/acceptability for meta-analysis. MAIN RESULTS: The literature search yielded 807 records, of which 24 were included for review and 19 provided data for meta-analysis. No trials investigated the role of routine mechanical cervical dilatation. Cervical preparation significantly reduced pain during outpatient hysteroscopy; standard mean difference (SMD) -0.67, 95% confidence interval (CI) -1.05 to -0.29. Feasibility also improved as priming provided significantly easier hysteroscopic entry (SMD 0.89, 95% CI 0.32-1.46), greater cervical dilatation (SMD 0.81, 95% CI 0.08-1.53) and shorter procedural times (SMD -0.51, 95% CI -0.88 to -0.13). Cervical preparation, however, incurred significantly more adverse effects, mainly comprising genital tract bleeding, abdominal pain and gastrointestinal symptoms (odds ratio 2.94, 95% CI 1.58-5.47). There were limited data regarding satisfaction, acceptability and complications. CONCLUSIONS: Cervical preparation reduces pain and improves feasibility associated with outpatient hysteroscopy but increases the risk of adverse effects. TWEETABLE ABSTRACT: Cervical preparation before outpatient hysteroscopy reduces pain, enhances feasibility but increases adverse effects.

Short stay laparoscopic hysterectomy: An evaluation of feasibility and patient satisfaction.

BACKGROUND: Short-stay total laparoscopic hysterectomy (TLH) could lead to reduced hospital costs and decrease complications associated with hospitalisation such as hospital acquired-infection and venous thromboembolism. OBJECTIVE: To evaluate the feasibility, safety and patient satisfaction of a novel short 'less than 23-hour' stay TLH protocol. MATERIAL AND METHODS: Prospective cohort study, at Birmingham Women's Hospital, United Kingdom including eligible women undergoing TLH for benign indications or early stage cervical/endometrial cancer. MAIN OUTCOME MEASURES: Feasibility of discharge within 23-hours following TLH. Surgical complications and readmission rates were collected within 30-days of hysterectomy and patient's satisfaction was assessed at 6-weeks. RESULTS: Of the 128 eligible women, 104/128 women (81%) were discharged within 23-hours of admission, of which 62/104 or 60% (48.4% of the whole cohort) were discharged on the same day. Adenomyosis/fibroids, and previous caesarean sections were associated with a greater likelihood of stay beyond 23-hours (P<0.05). The overall complications rate was 13/128 (10%) with two grade-3 Clavien-Dindo intraoperative complications; one serosal bowel injury oversewn and one ureteric injury requiring reimplantation. The readmissions rate was 5/128 (4%). 94% of patients were 'happy' or 'very happy' with the pathway, although satisfaction was higher in short-stay patients (RR 1.2; 95% CI 0.95-1.94). CONCLUSION: Hospital discharge within 23-hours of TLH appears to be safe, feasible and acceptable to patients where a standardised, multidisciplinary care protocol is used. WHAT IS NEW?: Our study is the first prospective case series in the UK reporting the safety and acceptability for performing laparoscopic hysterectomy as a 23-hour day case procedure.

Getting back to business: considerations for restarting non-cancer gynaecological surgery following the COVID-19 peak.

As we begin to pass the first peak of the coronavirus pandemic, the backlog of routine gynaecological surgical work is becoming more apparent and continues to build day by day. The potential for further pandemic surges remain; however it is imperative that elective gynaecological surgery is restored safely, ethically and in a timely manner. The risks of COVID-19 transmission and potential increased surgical morbidity must be weighed up against the patient's ongoing symptoms and quality of life. Universal screening and testing of patients attending for routine surgery, as well as staff testing and retesting, will be fundamental to reducing the risks to both patients and staff, and avoiding the higher morbidity encountered when operating on asymptomatic infected patients. The aim of this paper is to explore pathways to safely reintroduce elective benign gynaecological surgery and the challenges that will be encountered including patient counselling and informed consent, surgical prioritisation and the screening and testing of patients and staff, as well as the logistical and ethical challenges of reintroducing benign surgery during COVID-19 times.

Septum resection in women with a septate uterus: a cohort study.

STUDY QUESTION: Does septum resection improve reproductive outcomes in women with a septate uterus? SUMMARY ANSWER: In women with a septate uterus, septum resection does not increase live birth rate nor does it decrease the rates of pregnancy loss or preterm birth, compared with expectant management. WHAT IS KNOWN ALREADY: The septate uterus is the most common uterine anomaly with an estimated prevalence of 0.2-2.3% in women of reproductive age, depending on the classification system. The definition of the septate uterus has been a long-lasting and ongoing subject of debate, and currently two classification systems are used worldwide. Women with a septate uterus may be at increased risk of subfertility, pregnancy loss, preterm birth and foetal malpresentation. Based on low quality evidence, current guidelines recommend removal of the intrauterine septum or, more cautiously, state that the procedure should be evaluated in future studies. STUDY DESIGN, SIZE, DURATION: We performed an international multicentre cohort study in which we identified women mainly retrospectively by searching in electronic patient files, medical records and databases within the time frame of January 2000 until August 2018. Searching of the databases, files and records took place between January 2016 and July 2018. By doing so, we collected data on 257 women with a septate uterus in 21 centres in the Netherlands, USA and UK. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included women with a septate uterus, defined by the treating physician, according to the classification system at that time. The women were ascertained among those with a history of subfertility, pregnancy loss, preterm birth or foetal malpresentation or during a routine diagnostic procedure. Allocation to septum resection or expectant management was dependent on the reproductive history and severity of the disease. We excluded women who did not have a wish to conceive at time of diagnosis. The primary outcome was live birth. Secondary outcomes included pregnancy loss, preterm birth and foetal malpresentation. All conceptions during follow-up were registered but for the comparative analyses, only the first live birth or ongoing pregnancy was included. To evaluate differences in live birth and ongoing pregnancy, we used Cox proportional regression to calculate hazard rates (HRs) and 95% CI. To evaluate differences in pregnancy loss, preterm birth and foetal malpresentation, we used logistic regression to calculate odds ratios (OR) with corresponding 95% CI. We adjusted all reproductive outcomes for possible confounders. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 257 women were included in the cohort. Of these, 151 women underwent a septum resection and 106 women had expectant management. The median follow-up time was 46 months. During this time, live birth occurred in 80 women following a septum resection (53.0%) compared to 76 women following expectant management (71.7%) (HR 0.71 95% CI 0.49-1.02) and ongoing pregnancy occurred in 89 women who underwent septum resection (58.9%), compared to 80 women who had expectant management (75.5%) (HR 0.74 (95% CI 0.52-1.06)). Pregnancy loss occurred in 51 women who underwent septum resection (46.8%) versus 31 women who had expectant management (34.4%) (OR 1.58 (0.81-3.09)), while preterm birth occurred in 26 women who underwent septum resection (29.2%) versus 13 women who had expectant management (16.7%) (OR 1.26 (95% CI 0.52-3.04)) and foetal malpresentation occurred in 17 women who underwent septum resection (19.1%) versus 27 women who had expectant management (34.6%) (OR 0.56 (95% CI 0.24-1.33)). LIMITATIONS, REASONS FOR CAUTION: Our retrospective study has a less robust design compared with a randomized controlled trial. Over the years, the ideas about the definition of the septate uterus has changed, but since the 257 women with a septate uterus included in this study had been diagnosed by their treating physician according to the leading classification system at that time, the data of this study reflect the daily practice of recent decades. Despite correcting for the most relevant patient characteristics, our estimates might not be free of residual confounding. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that septum resection, a procedure that is widely offered and associated with financial costs for society, healthcare systems or individuals, does not lead to improved reproductive outcomes compared to expectant management for women with a septate uterus. The results of this study need to be confirmed in randomized clinical trials. STUDY FUNDING/COMPETING INTEREST(S): A travel for JFWR to Chicago was supported by the Jo Kolk Studyfund. Otherwise, no specific funding was received for this study. The Department of Obstetrics and Gynaecology, University Medical Centre, Groningen, received an unrestricted educational grant from Ferring Pharmaceutical Company unrelated to the present study. BWM reports grants from NHMRC, personal fees from ObsEva, personal fees from Merck, personal fees from Guerbet, other payment from Guerbet and grants from Merck, outside the submitted work. The other authors declare no conficts of interest. TRIAL REGISTRATION NUMBER: N/A.

Covid 19 pandemic and gynaecological laparoscopic surgery: knowns and unknowns.

The worldwide impact of COVID 19 continues to be felt as hospitals in all countries reduce elective and non-urgent cases to allow staffing and resources to be deployed elsewhere. Urgent gynaecological and cancer procedures are continuing, and it is imperative all theatre staff are protected and risks of SARS-CoV-2 viral transmission reduced when operating on asymptomatic, suspected or confirmed COVID 19 patients. In particular, there are concerns relating to the transmission of COVID 19 during gynaecological laparoscopic surgery, arising from the potential generation of SARS-CoV-2 contaminated aerosols from CO2 leakage and the creation of smoke from the use of energy devices. The aim of this paper is to review all the up to date evidence, including experiences from China and Italy, to guide the safe management of such patients when undergoing gynaecological procedures.

Wavelength transduction from a 3D microwave cavity to telecom using piezoelectric optomechanical crystals.

Microwave-to-optical transduction has received a great deal of interest from the cavity optomechanics community as a landmark application for electro-optomechanical systems. In this Letter, we demonstrate a novel transducer that combines high-frequency mechanical motion and a microwave cavity for the first time. The system consists of a 3D microwave cavity and a gallium arsenide optomechanical crystal, which has been placed in the microwave electric field maximum. This allows the microwave cavity to actuate the gigahertz-frequency mechanical breathing mode in the optomechanical crystal through the piezoelectric effect, which is then read out using a telecom optical mode. The gallium arsenide optomechanical crystal is a good candidate for low-noise microwave-to-telecom transduction, as it has been previously cooled to the mechanical ground state in a dilution refrigerator. Moreover, the 3D microwave cavity architecture can naturally be extended to couple to superconducting qubits and to create hybrid quantum systems.

Nonlinear population dynamics are ubiquitous in animals.

Nonlinear dynamics, where a change in the input is not proportional to a change in the output, are often found throughout nature, for example in biochemical kinetics. Because of the complex suite of interacting abiotic and biotic variables present in ecosystems, animal population dynamics are often thought to be driven in a nonlinear, state-dependent fashion. However, so far these have only been identified in model organisms and some natural systems. Here we show that nonlinear population dynamics are ubiquitous in nature. We use nonlinear forecasting to analyse 747 datasets of 228 species to find that insect population trends were highly nonlinear (74%), followed by mammals (58%), bony fish (49%) and birds (35%). This indicates that linear, equilibrium-based model assumptions may fail at predicting population dynamics across a wide range of animal taxa. We show that faster-reproducing animals are more likely to have nonlinear and high-dimensional dynamics, supporting past ecological theory. Lastly, only a third of time series were predictable beyond two years; therefore, the ability to predict animal population trends using these methods may be limited. Our results suggest that the complex dynamics necessary to cause regime shifts and other transitions may be inherent in a wide variety of animals.

Elimination of Thermomechanical Noise in Piezoelectric Optomechanical Crystals.

Mechanical modes are a potentially useful resource for quantum information applications, such as quantum-level wavelength transducers, due to their ability to interact with electromagnetic radiation across the spectrum. A significant challenge for wavelength transducers is thermomechanical noise in the mechanical mode, which pollutes the transduced signal with thermal states. In this Letter, we eliminate thermomechanical noise in the GHz-frequency mechanical breathing mode of a piezoelectric optomechanical crystal using cryogenic cooling in a dilution refrigerator. We optically measure an average thermal occupancy of the mechanical mode of only 0.7±0.4 phonons, providing a path towards low-noise microwave-to-optical conversion in the quantum regime.