Guideline No. 446: Hysteroscopic Surgery in Fertility Therapy.

OBJECTIVE: To evaluate the indications, benefits, and risks of hysteroscopy in the management of patients with infertility and provide guidance to gynaecologists who manage common conditions in these patients. TARGET POPULATION: Patients with infertility (inability to conceive after 12 months of unprotected intercourse) undergoing investigation and treatment. BENEFITS, HARMS, AND COSTS: Hysteroscopic surgery can be used to diagnose the etiology of infertility and improve fertility treatment outcomes. All surgery has risks and associated complications. Hysteroscopic surgery may not always improve fertility outcomes. All procedures have costs, which are borne either by the patient or their health insurance provider. EVIDENCE: We searched English-language articles from January 2010 to May 2021 in PubMed/MEDLINE, Embase, Science Direct, Scopus, and Cochrane Library (see Appendix B for MeSH search terms). VALIDATION METHODS: The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See Appendix A (Tables A1 for definitions and A2 for interpretations of strong and conditional recommendations). INTENDED AUDIENCE: Gynaecologists who manage common conditions in patients with infertility. TWEETABLE ABSTRACT: When offering hysteroscopic surgery to patients with infertility, ensure it improves the live birth rate. SUMMARY STATEMENTS: RECOMMENDATIONS.

Transcriptome-wide association analyses identify an association between ARL14EP and polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder, which is accompanied by a variety of comorbidities including metabolic, reproductive, and psychiatric disorders. Genome-wide association studies have identified several genetic variants that are associated with PCOS. However, these variants often occur outside of coding regions and require further investigation to understand their contribution to PCOS. A transcriptome-wide association study (TWAS) was performed to uncover heritable gene expression profiles that are associated with PCOS in two independent cohorts. Causal gene prioritization was subsequently performed and expression of genes prioritized through these analyses was examined in 49 PCOS patients and 30 controls. TWAS analyses revealed that increased expression of ARL14EP was significantly associated with PCOS risk in the discovery (P = 1.6 × 10-6) and replication cohorts (P = 2.0 × 10-13). Gene prioritization pipelines provided further evidence that ARL14EP is the most likely causal gene at this locus. ARL14EP gene expression was shown to be significantly different between PCOS cases and controls, after adjusting for body mass index, age and testosterone levels (P = 1.2 × 10-13). This study has provided evidence for the role of ARL14EP in PCOS. Given that ARL14EP has been reported to play an important role in chromatin remodeling, variants affecting the expression of ARL14EP may also affect the expression of other genes that contribute to PCOS pathogenesis.

Guideline No. 444: Hirsutism: Evaluation and Treatment.

OBJECTIVE: This guideline reviews the etiology, diagnosis, evaluation, and treatment of hirsutism. TARGET POPULATION: Women with hirsutism. OPTIONS: Three approaches to management include: 1) mechanical hair removal; 2) suppression of androgen production; and 3) androgen receptor blockade. OUTCOMES: The main limitations of the management options include the adverse effects, costs, and duration of treatment. BENEFITS, HARMS, AND COSTS: Implementation of the recommendations in this guideline may improve the management of hirsutism in women with this condition. Adverse effects and a potential long duration of treatment are the main drawbacks to initiating treatment, as is the possibility of significant financial costs for certain treatments. EVIDENCE: A comprehensive literature review was updated to April 2022, following the same methods as for the prior Society of Obstetricians and Gynaecologists of Canada (SOGC) Hirsutism guidelines. Results were restricted to systematic reviews, randomized controlled trials, controlled clinical trials, and observational studies. There were no date limits, but results were limited to English- or French-language materials. VALIDATION METHODS: The authors rated the quality of evidence and strength of recommendations using the modified Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, along with the option of designating a recommendation as a "good practice point." See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and conditional [weak] recommendations). INTENDED AUDIENCE: Primary care providers, family medicine physicians, obstetricians and gynaecologists, reproductive endocrinologists and others who manage the care of patients with hirsutism. TWEETABLE ABSTRACT: Management of hirsutism involves a 3-pronged approach of mechanical hair removal, suppression of androgen production, and androgen receptor blockade. SUMMARY STATEMENTS: RECOMMENDATIONS.

Guideline No. 435: Minimally Invasive Surgery in Fertility Therapy.

OBJECTIVE: To evaluate the benefits and risks of minimally invasive procedures in the management of patients with infertility and provide guidance to gynaecologists who manage common conditions in these patients. TARGET POPULATION: Patients with infertility (inability to conceive after 12 months of unprotected intercourse) undergoing investigation and treatment. BENEFITS, HARMS, AND COSTS: Minimally invasive reproductive surgery can be used to treat infertility, improve fertility treatment outcomes, or preserve fertility. All surgery has risks and associated complications. Reproductive surgery may not improve fertility outcomes and may, in some instances, damage ovarian reserve. All procedures have costs, which are borne either by the patient or their health insurance provider. EVIDENCE: We searched English-language articles from January 2010 to May 2021 in PubMed/MEDLINE, Embase, Science Direct, Scopus, and Cochrane Library (see Appendix A for MeSH search terms). VALIDATION METHODS: The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix B (Tables B1 for definitions and B2 for interpretations of strong and conditional [weak] recommendations). INTENDED AUDIENCE: Gynaecologists who manage common conditions in patients with infertility. SUMMARY STATEMENTS: RECOMMENDATIONS.

Directive clinique no 435 : Chirurgie minimalement invasive dans les traitements de fertilité.

OBJECTIF: Évaluer les risques et bénéfices de la chirurgie minimalement invasive dans la prise en charge des patientes atteintes d'infertilité et fournir des conseils aux gynécologues qui prennent en charge les problèmes les plus fréquents chez ces patientes. POPULATION CIBLE: Patientes atteintes d'infertilité (incapacité à concevoir après 12 mois de rapports sexuels non protégés) en processus diagnostique ou sous traitement. BéNéFICES, RISQUES ET COûTS: On peut recourir à la chirurgie de la reproduction minimalement invasive pour traiter l'infertilité, améliorer les résultats des traitements de fertilité ou préserver la fertilité. Toutes les interventions chirurgicales comportent des risques et des complications associées. La chirurgie de la reproduction n'améliore pas toujours la fertilité et peut, dans certains cas, compromettre la réserve ovarienne. Toutes les interventions entraînent des coûts, lesquels sont assumés par la patiente ou son assureur. DONNéES PROBANTES: Des recherches ont été faites dans les bases de données PubMed-Medline, Embase, Science Direct, Scopus et Cochrane Library pour répertorier les articles publiés en anglais dans la période de janvier 2010 à mai 2021 (voir les termes de recherche MeSH à l'annexe A). MéTHODES DE VALIDATION: Les auteurs ont évalué la qualité des données probantes et la force des recommandations en utilisant le cadre méthodologique GRADE (Grading of Recommendations Assessment, Development and Evaluation). Voir l'annexe B en ligne (tableau B1 pour les définitions et tableau B2 pour l'interprétation des recommandations fortes et conditionnelles [faibles]). PROFESSIONNELS CONCERNéS: Gynécologues qui prennent en charge les affections courantes chez les patientes atteintes d'infertilité. DÉCLARATIONS SOMMAIRES: RECOMMANDATIONS.

Ovarian Hyperstimulation Syndrome Complicating Spontaneous Molar Pregnancy: A Case Report and Review of the Literature.

BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is traditionally associated with fertility treatments and results in elevated human chorionic gonadotropin (ßhCG) levels and fluid shifts to extravascular compartments. Rarely, spontaneous pregnancies with significant ßhCG elevations, such as molar pregnancies, can give rise to OHSS. CASE: A 24-year-old woman was diagnosed as having a molar pregnancy at approximately 12 weeks gestation following spontaneous conception. Her initial ßhCG was over 1 million IU/L. There was no evidence of metastatic disease. She underwent an uncomplicated dilation and curettage. Three days later, she presented with chest pain, shortness of breath, and abdominal discomfort. Massively enlarged ovaries were identified with bilateral pleural effusions requiring repeated thoracentesis. CONCLUSION: This case demonstrates rare sequelae of molar pregnancy. Treatment is mainly supportive, and close observation is required to manage complications. In patients with extremely elevated ßhCG levels, clinicians must remain vigilant for signs suggesting OHSS, even following evacuation of the uterus.

Cardiovascular magnetic resonance in pregnancy: insights from the cardiac hemodynamic imaging and remodeling in pregnancy (CHIRP) study.

BACKGROUND: Cardiovascular disease in pregnancy is the leading cause of maternal mortality in North America. Although transthoracic echocardiography (TTE) is the most widely used imaging modality for the assessment of cardiovascular function during pregnancy, little is known on the role of cardiovascular magnetic resonance (CMR). The objective of the Cardiac Hemodynamic Imaging and Remodeling in Pregnancy (CHIRP) study was to compare TTE and CMR in the non-invasive assessment of maternal cardiac remodeling during the peripartum period. METHODS: Between 2010-2012, healthy pregnant women aged 18 to 35 years were prospectively enrolled. All women underwent TTE and CMR during the third trimester and at least 3 months postpartum (surrogate for non-pregnant state). RESULTS: The study population included a total of 34 women (mean age 29 ± 3 years). During the third trimester, TTE and CMR demonstrated an increase in left ventricular end-diastolic volume from 95 ± 11 mL to 115 ± 14 mL and 98 ± 6 mL to 125 ± 5 mL, respectively (p<0.05). By TTE and CMR, there was also an increase in left ventricular (LV) mass during pregnancy from 111 ± 10 g to 163 ± 11 g and 121 ± 5 g to 179 ± 5 g, respectively (p<0.05). Although there was good correlation between both imaging modalities for LV mass, stroke volume, and cardiac output, the values were consistently underestimated by TTE. CONCLUSION: This CMR study provides reference values for cardiac indices during normal pregnancy and the postpartum state.

Remote discovery of an asymptomatic bowel perforation by a mid-urethral sling.

Bowel perforation is a rare complication of mid-urethral sling procedures and is usually reported shortly after the surgery. We report a remotely discovered asymptomatic bowel injury found at the time of subsequent surgery. The patient with a history of several prior pelvic surgeries underwent an uneventful retropubic mid-urethral sling placement. Five years later, during an abdominal sacrocolpopexy procedure, mesh from the mid-urethral sling was found perforating the wall of the cecum and fixating it to the right pelvic sidewall. Cecal wedge resection was performed to excise the sling mesh. Asymptomatic bowel perforation by mid-urethral sling mesh has not been previously reported. Pelvic and abdominal surgeons should be aware of the possibility of finding this injury in patients with prior sling surgeries.

Fertility-sparing surgery for diffuse adenomyosis: a narrated, stepwise approach to the Osada procedure.

OBJECTIVE: To equip reproductive surgeons with an approach to the Osada procedure and critical prophylactic hemostatic measures that optimize perioperative outcomes. DESIGN: Stepwise demonstration of the Osada procedure with narrated video footage. SETTING: Definitive management of symptomatic adenomyosis requires hysterectomy. However, adenomyomectomy can improve symptoms and restore anatomy while maintaining fertility potential. Limited but comparable perioperative outcomes exist for minimally invasive methods of adenomyomectomy, and most involve resection of focal, not diffuse, adenomyosis. Among the literature involving resection of diffuse adenomyosis using minimally invasive methods, relatively small volumes of resected tissue are reported and none include obstetric outcomes. Most published reports for excision of diffuse adenomyosis involve laparotomic resection, likely because of specific intraoperative challenges curtailed by this approach. In response, a laparoscopic-assisted laparotomic approach was developed in 2011 by Dr. Hisao Osada, a reproductive surgeon in Japan. This procedure involves aggressive excision of adenomyotic tissue with prophylactic hemostatic techniques and subsequent uterine wall reconstruction using a triple-flap method. Compared with other excisional methods for diffuse adenomyomectomy, the Osada procedure has the best reported obstetric outcomes. PATIENT(S): A 37-year-old nulliparous female presented with pelvic pain, bulk symptoms, abnormal uterine bleeding, and infertility. Physical examination demonstrated a 20-week, bulky uterus with limited bimanual mobility. Her endometrial cavity was inaccessible because of marked anatomic distortion. Magnetic resonance imaging revealed marked abnormality of her endometrial contour because of a 15 cm adenomyoma with diffuse adenomyomatous tissue in the posterior uterine compartment. Prior interventions included a trial of combined hormonal contraceptive, leuprolide acetate, and tranexamic acid. She was interested in fertility-sparing adenomyomectomy to address symptoms and fertility potential and chose to proceed with the Osada procedure. She was optimized medically with oral and parenteral iron therapy to bring her hemoglobin from 55-111 g/L preoperatively. Institutional review board approval and informed consent from the patient were obtained. INTERVENTION(S): The Osada procedure was performed using the following 8 surgical steps: Systemic administration of tranexamic acid was also administered intraoperatively. MAIN OUTCOME MEASURE(S): Perioperative blood loss, anatomic normalization, symptom remediation, and maintenance of fertility potential. RESULTS: Perioperative blood loss was minimal, 469 g of adenomyotic tissue was extracted, and discharge was on postoperative day 2 without any complications. Three months later, cyclic pain and bleeding had improved markedly, ultrasound confirmed Doppler flow throughout the uterus, hysterosalpingogram demonstrated a nonobliterated endometrial cavity and tubal patency, and magnetic resonance imaging confirmed normalized uterine dimensions measuring 11 × 7 cm from 19 × 10 cm. Most literature supports waiting at least 6-12 months and until demonstration of normalized uterine blood flow in the operated area before attempting conception. CONCLUSION: Fertility-sparing excision of diffuse adenomyosis can be achieved safely using the Osada procedure, following the 8 discrete steps demonstrated in this video. Reproductive surgeons can reference this video to teach and maintain this important procedure.

The ability to achieve complete revascularization is associated with improved in-hospital survival in cardiogenic shock due to myocardial infarction: Manitoba cardiogenic SHOCK Registry investigators.

OBJECTIVES: To identify predictors of survival in a retrospective multicentre cohort of patients with cardiogenic shock undergoing coronary angiography and to address whether complete revascularization is associated with improved survival in this cohort. BACKGROUND: Early revascularization is the standard of care for cardiogenic shock. Coronary bypass grafting and percutaneous intervention have complimentary roles in achieving this revascularization. METHODS: A total of 210 consecutive patients (mean age 66 ± 12 years) at two tertiary centres from 2002 to 2006 inclusive with a diagnosis of cardiogenic shock were evaluated. Univariate and multivariate predictors of in-hospital survival were identified utilizing logistic regression. RESULTS: ST elevation infarction occurred in 67% of patients. Thrombolysis was administered in 34%, PCI was attempted in 62% (88% stented, 76% TIMI 3 flow), CABG was performed in 22% (2.7 grafts, 14 valve procedures), and medical therapy alone was administered to the remainder. The overall survival to discharge was 59% (CABG 68%, PCI 57%, medical 48%). Independent predictors of mortality included complete revascularization (P = 0.013, OR = 0.26 (95% CI: 0.09-0.76), hyperlactatemia (P = 0.046, OR = 1.14 (95% CI: 1.002-1.3) per mmol increase), baseline renal insufficiency (P = 0.043, OR = 3.45, (95% CI: 1.04-11.4), and the presence of anoxic brain injury (P = 0.008, OR = 8.22 (95% CI: 1.73-39.1). Within the STEMI with concomitant multivessel coronary disease subgroup of this population (N = 101), independent predictors of survival to discharge included complete revascularization (P = 0.03, OR = 2.5 (95% CI: 1.1-6.2)) and peak lactate (P = 0.02). CONCLUSIONS: The ability to achieve complete revascularization may be strongly associated with improved in-hospital survival in patients with cardiogenic shock.

Impact of the COVID-19 pandemic on radiography practice: findings from a UK radiography workforce survey.

OBJECTIVES: Radiographers are key patient-facing healthcare professionals involved in many aspects of patient care. The working patterns and professional practice of the radiography workforce (RW) has been altered during the COVID-19 pandemic. This survey aimed to assess the impact of the pandemic on radiography practice in the United Kingdom (UK). METHODS: An online cross-sectional survey of the UK RW was performed (March 25th to April 26th, 2020). The survey sought information regarding 1. Demographics 2. Impact of the pandemic on professional practice 3. Infection prevention/control and 4. COVID-19 related stress. Data collected was analysed using the Statistical Package for Social Sciences (v.26). RESULTS: A total of 522 responses were received, comprising n = 412 (78.9%) diagnostic and n = 110 (21.1%) therapeutic RW categories from across the UK. 12.5% (65/522) of the respondents were redeployed. Redeployment did not appear to contribute (p = 0.31) to work-related stress. However, fear of contracting the infection and perceived inadequate personal protective equipment (PPE) were identified as key contributors to stress during the study period. Compared to the therapeutic RW, a significantly higher proportion of the diagnostic RW identified fear of being infected as a major stressor (166/412 (40.3%) vs 30/110 (27.3%), p = 0.01). CONCLUSION: This survey has demonstrated changes to clinical practice, in particular to working patterns, service delivery and infection prevention and control were key contributors to workplace-related stress during the pandemic. ADVANCES IN KNOWLEDGE: Timely and adequate staff training and availability of PPE as well as psychosocial support during future pandemics would enhance quality patient and staff safety.

The Discovery of N-(1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-((6- ((methylamino)methyl)pyrimidin-4-yl)oxy)-1H-indole-1-carboxamide (Acrizanib), a VEGFR-2 Inhibitor Specifically Designed for Topical Ocular Delivery, as a Therapy for Neovascular Age-Related Macular Degeneration.

A noninvasive topical ocular therapy for the treatment of neovascular or "wet" age-related macular degeneration would provide a patient administered alternative to the current standard of care, which requires physician administered intravitreal injections. This manuscript describes a novel strategy for the use of in vivo models of choroidal neovascularization (CNV) as the primary means of developing SAR related to efficacy from topical administration. Ultimately, this effort led to the discovery of acrizanib (LHA510), a small-molecule VEGFR-2 inhibitor with potency and efficacy in rodent CNV models, limited systemic exposure after topical ocular administration, multiple formulation options, and an acceptable rabbit ocular PK profile.

Core Replacements in a Potent Series of VEGFR-2 Inhibitors and Their Impact on Potency, Solubility, and hERG.

Anti-VEGF therapy has been a clinically validated treatment of age-related macular degeneration (AMD). We have recently reported the discovery of indole based oral VEGFR-2 inhibitors that provide sustained ocular retention and efficacy in models of wet-AMD. We disclose herein the synthesis and the biological evaluation of a series of novel core replacements as an expansion of the reported indole based VEGFR-2 inhibitor series. Addition of heteroatoms to the existing core and/or rearranging the heteroatoms around the 6-5 bicyclic ring structure produced a series of compounds that generally retained good on-target potency and an improved solubility profile. The hERG affinity was proven not be dependent on the change in lipophilicity through alteration of the core structure. A serendipitous discovery led to the identification of a new indole-pyrimidine connectivity: from 5-hydroxy to 6-hydroxyindole with potentially vast implication on the in vitro/in vivo properties of this class of compounds.

Synthesis of vinylogous carbamates by rhodium(II)-catalyzed olefination of tertiary formamides with a silylated diazoester.

Treatment of tertiary formamides with a silylated diazoester in the presence of a rhodium(II) catalyst leads to the formation of 3-amino-2-silyloxyacrylates in good yield. No olefination is observed if a nonsilylated diazo compound is employed. [reaction: see text]

Discovery of Oral VEGFR-2 Inhibitors with Prolonged Ocular Retention That Are Efficacious in Models of Wet Age-Related Macular Degeneration.

The benefit of intravitreal anti-VEGF therapy in treating wet age-related macular degeneration (AMD) is well established. Identification of VEGFR-2 inhibitors with optimal ADME properties for an ocular indication provides opportunities for dosing routes beyond intravitreal injection. We employed a high-throughput in vivo screening strategy with rodent models of choroidal neovascularization and iterative compound design to identify VEGFR-2 inhibitors with potential to benefit wet AMD patients. These compounds demonstrate preferential ocular tissue distribution and efficacy after oral administration while minimizing systemic exposure.

The presence of ST-elevation in lead aVR predicts significant left main coronary artery stenosis in cardiogenic shock resulting from myocardial infarction: the Manitoba cardiogenic shock registry.

INTRODUCTION: Electrocardiographic (ECG) predictors of significant angiographic left main coronary artery stenosis (LMCS>50%) have been described in acute myocardial infarction using ST-segment elevation in lead aVR (aVR-STE). However, there is a paucity of data on its association with LMCS>50% in the setting of cardiogemic shock (CGS). METHODS: We investigated 210 consecutive, unselected, patients from Sept. 2002-2006 with CGS due to acute myocardial infarction undergoing cardiac catheterization. Of those, 191 patients with interpretable ECG tracings for aVR-STE analysis formed our study sample. aVR-STE was defined as ST-segment elevation≥1mm in aVR while LMCS>50% on coronary angiogram was defined as any left main lesion that demonstrated >50% lumen narrowing or equivalent by direct visualization or quantitative coronary angiography analysis. RESULTS: There was 59% survival to discharge of this predominantly male cohort (median age 68±12years; 31% females). Fifty three (28%) cases had aVR-STE while 27 (14%) had LMCS>50%. Of those, 16 patients who had aVR-STE also had LMCS>50% (sensitivity 59%, specificity 77%, positive predictive value 30%, negative predictive value 92% for predicting LMCS>50%). Multivariate analysis revealed that aVR-STE was the only significant predictor of LMCS>50% was (p=0.014; Odds Ratio=3.06; 95% Confidence Interval 1.26-7.47). CONCLUSION: In CGS due to acute myocardial infarction, aVR-STE>1mm proves to be an important predictor of LMCS>50%. Such data could be helpful in further risk stratification for optimal management during CGS.

An effective prodrug strategy to selectively enhance ocular exposure of a cannabinoid receptor (CB1/2) agonist.

Glaucoma is a leading cause of vision loss and blindness, with increased intraocular pressure (IOP) a prominent risk factor. IOP can be efficaciously reduced by administration of topical agents. However, the repertoire of approved IOP-lowering drug classes is limited, and effective new alternatives are needed. Agonism of the cannabinoid receptors CB1/2 significantly reduces IOP clinically and experimentally. However, development of CB1/2 agonists has been complicated by the need to avoid cardiovascular and psychotropic side effects. 1 is a potent CB1/2 agonist that is highly excluded from the brain. In a phase I study, compound 1 eyedrops were well tolerated and generated an IOP-lowering trend but were limited in dose and exposure due to poor solubility and ocular absorption. Here we present an innovative strategy to rapidly identify compound 1 prodrugs that are efficiently metabolized to the parent compound for improved solubility and ocular permeability while maintaining low systemic exposures.

Presurgical management of dysmenorrhea and endometriosis in a patient with Mayer-Rokitansky-Kuster-Hauser syndrome.

OBJECTIVE: To report a patient with Mayer-Rokitansky-Kuster-Hauser syndrome with functional endometrium treated with preoperative continuous combined low-dose monophasic oral contraceptives. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 12-year-old nulligravid adolescent girl. INTERVENTION(S): Preoperative continuous combined low-dose monophasic oral contraceptives for 7 months, and laparoscopic resection of the rudimentary uterus and uterine horns with unilateral salpingo-oophorectomy. MAIN OUTCOME MEASURE(S): Relief of pain after hormonal treatment and the operative procedure. RESULT(S): Successful preoperative treatment of endometriosis and pain before definitive diagnosis and removal of müllerian remnants in a patient with Mayer-Rokitansky-Kuster-Hauser syndrome. CONCLUSION(S): Patients with obstructive müllerian malformations with functional endometrium can be preoperatively managed with continuous combined low-dose monophasic oral contraceptives to control pain and treat endometriosis. This may permit a delay in surgical intervention to facilitate other investigations and to allow thorough counselling of the patient and her family about the implications of the diagnosis.