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During the past 30 years, fractional flow reserve (FFR) has moved from animal models to class IA recommendations in guidelines. However, the FLOWER-MI, RIPCORD-2, FUTURE, and FAME 3 trials in 2021 were "negative"-has FFR exceeded its expiration date? We critically examine these randomized trials in order to draw insights not just about FFR but also about study design and interpretation. Are all randomized trials created equal? No, rather we must focus on discordant decisions between angiography and FFR and highlight clinical endpoints that can be improved by percutaneous coronary intervention instead of medical therapy., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The interplay between coronary hemodynamics and plaque characteristics remains poorly understood., Objectives: The aim of this study was to compare atherosclerotic plaque phenotypes between focal and diffuse coronary artery disease (CAD) defined by coronary hemodynamics., Methods: This multicenter, prospective, single-arm study was conducted in 5 countries. Patients with functionally significant lesions based on an invasive fractional flow reserve ≤0.80 were included. Plaque analysis was performed by using coronary computed tomography angiography and optical coherence tomography. CAD patterns were assessed using motorized fractional flow reserve pullbacks and quantified by pullback pressure gradient (PPG). Focal and diffuse CAD was defined according to the median PPG value., Results: A total of 117 patients (120 vessels) were included. The median PPG was 0.66 (IQR: 0.54-0.75). According to coronary computed tomography angiography analysis, plaque burden was higher in patients with focal CAD (87% ± 8% focal vs 82% ± 10% diffuse; P = 0.003). Calcifications were significantly more prevalent in patients with diffuse CAD (Agatston score per vessel: 51 [IQR: 11-204] focal vs 158 [IQR: 52-341] diffuse; P = 0.024). According to optical coherence tomography analysis, patients with focal CAD had a significantly higher prevalence of circumferential lipid-rich plaque (37% focal vs 4% diffuse; P = 0.001) and thin-cap fibroatheroma (TCFA) (47% focal vs 10% diffuse; P = 0.002). Focal disease defined by PPG predicted the presence of TCFA with an area under the curve of 0.73 (95% CI: 0.58-0.87)., Conclusions: Atherosclerotic plaque phenotypes associate with intracoronary hemodynamics. Focal CAD had a higher plaque burden and was predominantly lipid-rich with a high prevalence of TCFA, whereas calcifications were more prevalent in diffuse CAD. (Precise Percutaneous Coronary Intervention Plan [P3]; NCT03782688)., Competing Interests: Funding and Author Disclosures The study was sponsored by the Cardiac Research Institute Aalst with unrestricted grants from HeartFlow Inc. Dr Mizukami has received consulting fees from Zeon Medical and HeartFlow Inc; and speaker fees from Abbott Vascular. Dr Leipsic is a consultant and has holding stock options in Circle CVI and HeartFlow Inc; has received a research grant from GE; and modest speaker fees from GE and Philips. Drs Sonck and Munhoz have received research grants provided by the Cardiopath Ph.D. program. Dr Nørgaard has received unrestricted institutional research grants from Siemens and HeartFlow Inc. Dr Otake has received research grants from Abbott Vascular; and speaker fees from HeartFlow Inc and Abbott Vascular. Dr Ko has received consulting fees from Canon Medical, Abbott, and Medtronic. Dr Koo has received institutional research grants from HeartFlow Inc. Dr Maeng has received advisory board and lecture fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Boston Scientific, and Novo Nordisk; and research grants from Bayer and Philips Healthcare. Dr Jensen has received unrestricted institutional research grants from Siemens and HeartFlow Inc. Dr Andreini has received research grants from GE Healthcare and Bracco. Dr Shinke has received research grants from Boston Scientific and Abbott Vascular. CT is an employee of HeartFlow Inc. Dr Barbato has received speaker fees from Boston Scientific, Abbott Vascular, and GE. Dr Johnson has received internal funding from the Weatherhead PET Center for Preventing and Reversing Atherosclerosis; significant institutional research support from St. Jude Medical (CONTRAST [Can Contrast Injection Better Approximate FFR Compared to Pure Resting Physiology?]; NCT02184117) and Philips/Volcano Corporation (DEFINE-FLOW [Combined Pressure and Flow Measurements to Guide Treatment of Coronary Stenoses]; NCT02328820) for studies using intracoronary pressure and flow sensors; has an institutional licensing agreement with Boston Scientific for the smart-minimum FFR algorithm commercialized under 510(k) K191008; and has pending patents on diagnostic methods for quantifying aortic stenosis and transcatheter aortic valve replacement physiology, as well as algorithms to correct pressure tracings from fluid-filled catheters. Dr De Bruyne has received consultancy fees from Boston Scientific and Abbott Vascular; research grants from Coroventis Research, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow Inc, and Abbott Vascular; and owns equity in Siemens, GE, Philips, HeartFlow Inc, Edwards Life Sciences, Bayer, Sanofi, and Celyad. Dr Collet has received research grants from Biosensor, Coroventis Research, Medis Medical Imaging, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow Inc, and Abbott Vascular; and consultancy fees from HeartFlow Inc, OpSens, Abbott Vascular, and Philips Volcano. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Low fractional flow reserve (FFR) after percutaneous coronary intervention (PCI) has been associated with adverse clinical outcomes. Hitherto, this assessment has been independent of the epicardial vessel interrogated., Objectives: This study sought to assess the predictive capacity of post-PCI FFR for target vessel failure (TVF) stratified by coronary artery., Methods: We performed a systematic review and individual patient-level data meta-analysis of randomized clinical trials and observational studies with protocol-recommended post-PCI FFR assessment. The difference in post-PCI FFR between left anterior descending (LAD) and non-LAD arteries was assessed using a random-effect models meta-analysis of mean differences. TVF was defined as a composite of cardiac death, target vessel myocardial infarction, and clinically driven target vessel revascularization., Results: Overall, 3,336 vessels (n = 2,760 patients) with post-PCI FFR measurements were included in 9 studies. The weighted mean post-PCI FFR was 0.89 (95% CI: 0.87-0.90) and differed significantly between coronary vessels (LAD = 0.86; 95% CI: 0.85 to 0.88 vs non-LAD = 0.93; 95% CI: 0.91-0.94; P < 0.001). Post-PCI FFR was an independent predictor of TVF, with its risk increasing by 52% for every reduction of 0.10 FFR units, and this was mainly driven by TVR. The predictive capacity for TVF was poor for LAD arteries (AUC: 0.52; 95% CI: 0.47-0.58) and moderate for non-LAD arteries (AUC: 0.66; 95% CI: 0.59-0.73; LAD vs non-LAD arteries, P = 0.005)., Conclusions: The LAD is associated with a lower post-PCI FFR than non-LAD arteries, emphasizing the importance of interpreting post-PCI FFR on a vessel-specific basis. Although a higher post-PCI FFR was associated with improved prognosis, its predictive capacity for events differs between the LAD and non-LAD arteries, being poor in the LAD and moderate in the non-LAD vessels., Competing Interests: Funding Support and Author Disclosures Dr Collet received research grants from Biosensors, HeartFlow Inc, Abbott Vascular, Insight Lifetech, GE Healthcare, Siemens and Shockwave Medical. Dr Johnson has received internal funding from the Weatherhead PET Center for Preventing and Reversing Atherosclerosis; has received significant institutional research support from St. Jude Medical (CONTRAST, NCT02184117) and Philips Volcano (DEFINE-FLOW, NCT02328820) for studies using intracoronary pressure and flow sensors; has an institutional licensing agreement with Boston Scientific for the smart-minimum FFR algorithm commercialized under 510(k) K191008; and has pending patents on diagnostic methods for quantifying aortic stenosis and TAVI physiology and also algorithms to correct pressure tracings from fluid-filled catheters. Dr Mizukami has received consultancy fees from Zeon Medical. Dr Fearon receives institutional research support from Abbott Vascular, Boston Scientific, Medtronic, and Edwards Lifesciences; he has a consulting relationship with CathWorks and Siemens; and he owns minor stock options in HeartFlow. Dr Berry receives research funding from the British Heart Foundation grant (RE/18/6134217); and is employed by the University of Glasgow, which holds consultancy and research agreements for his work with Abbott Vascular, AstraZeneca, Boehringer Ingelheim, Causeway Therapeutics, Coroventis, Genentech, GlaxoSmithKline, HeartFlow, Menarini, Neovasc, Siemens Healthcare, and Valo Health. Dr Sonck is supported by a grant provided by the CardioPath PhD program. Dr Collison has received honoraria/speaker fees from Abbott. Dr Koo has received an institutional research grant from St. Jude Medical (Abbott Vascular) and Philips Volcano. Dr Meneveau has received consultancy and speaker fees from Abbott Vascular, Edwards Lifesciences, Terumo, Boston Scientific, Bayer Healthcare, BMS-Pfizer, Boehringer, and AstraZeneca. Dr Oldroyd is an employee of Biosensors International. Dr Leipsic is a consultant for and holds stock options in Circle CVI and HeartFlow; and has a research grant from GE Healthcare. Dr Taylor is an employee of HeartFlow Inc. Dr Ko has received consultancy fees from Abbott Vascular and Medtronic; and has received research support from Canon Medical. Dr Perera has received research grant support from Abbott Vascular, HeartFlow, and Philips. Dr Leone received consultant fees and honoraria for lectures in sponsored symposia with Abbott Vascular and Bracco Imaging/ACIST Medical. Dr Matsuo has received consultancy fees from Zeon Medical; and has received speaker fees from Abbott Vascular Japan, Philips, and Boston Scientific. Dr Amabile reports consulting/proctoring fees from Abbott Vascular, Boston Scientific, and Shockwave Medical; and has received an institutional research grant from Abbott Vascular and Boston Scientific. Dr Piróth has received consultancy and speaker fees from Abbott Vascular, Opsens, and Boston Scientific. Dr Toth has received consultancy fees and research support from Abbott, Biotronik, Medtronic, and Terumo. Dr Ihdayhid reports receiving consulting honorarium from Abbott Medical, Edwards Lifesciences, Boston Scientific, Artrya Pty Ltd (including equity interest). Dr West is an employee of Abbott Vascular. Dr Munhoz is supported with a PhD grant from CardioPath. Dr Barbato has received speaker fees from Abbott and Boston Scientific. Dr Engstrøm has received consultancy and speaker fees from Abbott Vascular, Novo Nordisk, and Bayer AS. Dr Escaned is supported by the Intensification of Research Activity project INT22/00088 from Spanish Instituto de Salud Carlos III, and served as speaker and advisory board member for Abbott and Philips. Dr Ali has received institutional grant support Abbott, Abiomed, ACIST Medical, Amgen, Boston Scientific, Cathworks, Canon, Conavi, Heartflow, Inari, Medtronic Inc, National Institute of Health, Nipro, Opsens Medical, Medis, Philips, Shockwave, Siemens, Spectrawave, Teleflex; and consulting fees from Abiomed, AstraZeneca, Boston Scientific, Cathworks, Opsens, Philips, Shockwave and equity in Elucid, Lifelink, Spectrawave, Shockwave, VitalConnect. Dr Kern has received speaker fees from Abbott, ACIST Medical, Boston Scientific, Opsens, and Philips. Dr Pijls has received research grants from Abbott and Hexacath and consultancy fees from Abbott, GE, Philips, and HeartFlow and have equity in GE, Philips, and Heartflow. Dr De Bruyne has received institutional consulting fees from Abbott Vascular, Boston Scientific, Siemens, and GE; has received institutional grant support from Abbott Vascular, Boston Scientific, Biotronic, CathWorks, Pie Medical, and HeartFlow; and holds minor equities in Philips, Siemens, GE, Bayer, HeartFlow, Edwards Lifesciences, and Ceyliad. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Chemicals used or emitted by unconventional oil and gas development (UOGD) include reproductive/developmental toxicants. Associations between UOGD and certain birth defects were reported in a few studies, with none conducted in Ohio, which experienced a thirty-fold increase in natural gas production between 2010 and 2020., Methods: We conducted a registry-based cohort study of 965,236 live births in Ohio from 2010 to 2017. Birth defects were identified in 4653 individuals using state birth records and a state surveillance system. We assigned UOGD exposure based on maternal residential proximity at birth to active UOG wells and a metric specific to the drinking-water exposure pathway that identified UOG wells hydrologically connected to a residence ("upgradient UOG wells"). We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for all structural birth defects combined and specific birth defect types using binary exposure metrics (presence/absence of any UOG well and presence/absence of an upgradient UOG well within 10 km), adjusting for confounders. Additionally, we conducted analyses stratified by urbanicity, infant sex, and social vulnerability., Results: The odds of any structural defect were 1.13 times higher in children born to mothers living within 10 km of UOGD than those born to unexposed mothers (95%CI: 0.98-1.30). Odds were elevated for neural tube defects (OR: 1.57, 95%CI: 1.12-2.19), limb reduction defects (OR: 1.99, 95%CI: 1.18-3.35), and spina bifida (OR 1.93; 95%CI 1.25-2.98). Hypospadias (males only) was inversely related to UOGD exposure (OR: 0.62, 95%CI: 0.43-0.91). Odds of any structural defect were greater in magnitude but less precise in analyses using the hydrological-specific metric (OR: 1.30; 95%CI: 0.85-1.90), in areas with high social vulnerability (OR: 1.27, 95%CI: 0.99-1.60), and among female offspring (OR: 1.28, 95%CI: 1.06-1.53)., Conclusions: Our results suggest a positive association between UOGD and certain birth defects, and findings for neural tube defects corroborate results from prior studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: The purpose of this systematic review was to assess how messaging for human papillomavirus (HPV) vaccination to prevent different health outcomes (sexually transmitted infection, anogenital warts ([AGW], and/or cancer) influences intentions or initiation for the vaccine series., Methods: We searched PubMed, MEDLINE, and Embase databases for all previously published articles with an evaluation, discussion, or comparison of messages containing content about HPV infections, AGW, precancers, or cancer through June 3, 2021. Results about messages were summarized by study population and design., Results: We identified 25 studies evaluating or comparing messages containing content about HPV-associated outcomes. Study designs included randomized trials (n = 12), cross-sectional surveys (n = 8), and qualitative approaches (n = 5). Few studies directly compared different messages using randomized designs or included vaccination uptake as the outcome. While many studies found support for cancer prevention messages, some studies also found equal or greater support for messages focusing on prevention of sexually transmitted infection/AGW. Variability was observed within and between studied populations (parents/adults, adolescents, young adults, healthcare providers, and adult males) and gender (male and female adolescents)., Discussion: A greater understanding and deeper attention to myriad health outcomes of HPV infections could increase vaccination uptake in a variety of populations for health promotion across the lifespan., (Copyright © 2022 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

During the past 30 years, fractional flow reserve (FFR) has moved from animal models to class IA recommendations in guidelines. However, the FLOWER-MI, RIPCORD-2, FUTURE, and FAME 3 trials in 2021 were "negative"-has FFR exceeded its expiration date? We critically examine these randomized trials in order to draw insights not just about FFR but also about study design and interpretation. Are all randomized trials created equal? No, rather we must focus on discordant decisions between angiography and FFR and highlight clinical endpoints that can be improved by percutaneous coronary intervention instead of medical therapy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Subendocardial ischemia is commonly diagnosed but not quantified by imaging., Objectives: This study sought to define size and severity of subendocardial and transmural stress perfusion deficits, clinical associations, and outcomes., Methods: Regional rest-stress perfusion in mL/min/g, coronary flow reserve, coronary flow capacity (CFC), relative stress flow, subendocardial stress-to-rest ratio and stress subendocardial-to-subepicardial ratio as percentage of left ventricle were measured by positron emission tomography (PET) with rubidium Rb 82 and dipyridamole stress in serial 6,331 diagnostic PETs with prospective 10-year follow-up for major adverse cardiac events with and without revascularization., Results: Of 6,331 diagnostic PETs, 1,316 (20.7%) had severely reduced CFC with 41.4% having angina or ST-segment depression (STΔ) >1 mm during hyperemic stress, increasing with size. For 5,015 PETs with no severe CFC abnormality, 402 (8%) had angina or STΔ during stress, and 82% had abnormal subendocardial perfusion with 8.7% having angina or STΔ >1 mm during dipyridamole stress. Of 947 cases with stress-induced angina or STΔ >1 mm, 945 (99.8%) had reduced transmural or subendocardial perfusion reflecting sufficient microvascular function to increase coronary blood flow and reduce intracoronary pressure, causing reduced subendocardial perfusion; only 2 (0.2%) had normal subendocardial perfusion, suggesting microvascular disease as the cause of the angina. Over 10-year follow-up (mean 5 years), severely reduced CFC associated with major adverse cardiac events of 44.4% compared to 8.8% for no severe CFC (unadjusted P < 0.00001) and mortality of 15.2% without and 6.9% with revascularization (P < 0.00002) confirmed by multivariable Cox regression modeling. For no severe CFC, mortality was 3% with and without revascularization (P = 0.90)., Conclusions: Reduced subendocardial perfusion on dipyridamole PET without regional stress perfusion defects is common without angina, has low risk of major adverse cardiac events, reflecting asymptomatic nonobstructive diffuse coronary artery disease, or angina without stenosis. Severely reduced CFC causes angina in fewer than one-half of cases but incurs high mortality risk that is significantly reduced after revascularization., Competing Interests: Funding Support and Author Disclosures Research supported by internal funds of the Weatherhead PET Center. Dr Gould has received internal funding from the Weatherhead PET Center and is the applicant for 510(k) U.S. Food and Drug Administration–cleared HeartSee K202679 PET software. Dr Johnson has received internal funding from Weatherhead PET Center for Preventing and Reversing Atherosclerosis and research support from St. Jude Medical (for CONTRAST [Can Contrast Injection Better Approximate FFR Compared to Pure Resting Physiology] trial; NCT02184117) and Volcano/Philips Corporation (for the DEFINE-FLOW [Combined Pressure and Flow Measurements to Guide Treatment of Coronary Stenoses] trial; NCT02328820). To avoid any conflict of interest, Drs Gould, Nguyen, Johnson, and Kirkeeide waived their rights to the royalties that they were personally eligible to receive from sales of the intellectual property developed by them and licensed by the University of Texas Health Science Center (UTHealth) to third parties. UTHealth approved their request that all derived royalties be redirected to student scholarships or UTHealth’s Weatherhead PET Center research. UTHealth has a financial interest related to intellectual property via its affiliation with the UTHealth’s Weatherhead PET Imaging Center. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/purpose: Matching phasic pressure tracings between a fluid-filled catheter and high-fidelity pressure wire has received limited attention, although each part contributes half of the information to clinical decisions. We aimed to study the impact of a novel and automated method for improving the phasic calibration of a fluid-filled catheter by accounting for its oscillatory behavior., Methods/materials: Retrospective analysis of drift check tracings was performed using our algorithm that corrects for mean difference (offset), temporal delays (timing), differential sensitivity of the manifold transducer and pressure wire sensor (gain), and the oscillatory behavior of the fluid-filled catheter described by its resonant frequency and damping factor (how quickly oscillations disappear after a change in pressure)., Results: Among 2886 cases, correcting for oscillations showed a large improvement in 28 % and a medium improvement in 41 % (decrease in root mean square error >0.5 mmHg to <1 or 1-2 mmHg, respectively). 96 % of oscillators were underdamped with median damping factor 0.27 and frequency 10.6 Hz. Fractional flow reserve or baseline Pd/Pa demonstrated no clinically important bias when ignoring oscillations. However, uncorrected subcycle non-hyperemic pressure ratios (NHPR) displayed both bias and scatter., Conclusions: By automatically accounting for the oscillatory behavior of a fluid-filled catheter system, phasic matching against a high-fidelity pressure wire can be improved compared to standard equalization methods. The majority of tracings contain artifacts, mainly due to underdamped oscillations, and neglecting them leads to biased estimates of equalization parameters. No clinically important bias exists for whole-cycle metrics, in contrast to significant effects on subcycle NHPR., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Endometriosis is a common cause of pelvic pain in women, for which current treatment options are suboptimal. Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, combined with estradiol and a progestin, was evaluated for treatment of endometriosis-associated pain., Methods: In these two replicate, phase 3, multicentre, randomised, double-blind, placebo-controlled trials at 219 community and hospital research centres in Africa, Australasia, Europe, North America, and South America, we randomly assigned women aged 18-50 years with surgically or directly visualised endometriosis with or without histological confirmation, or with histological diagnosis alone. Participants were eligible if they had moderate to severe endometriosis-associated pain and, during the 35-day run-in period, a dysmenorrhoea Numerical Rating Scale (NRS) score of 4·0 or higher on two or more days and a mean non-menstrual pelvic pain NRS score of 2·5 or higher, or a mean score of 1·25 or higher that included a score of 5 or more on 4 or more days. Women received (1:1:1) once-daily oral placebo, relugolix combination therapy (relugolix 40 mg, estradiol 1 mg, norethisterone acetate 0·5 mg), or delayed relugolix combination therapy (relugolix 40 mg monotherapy followed by relugolix combination therapy, each for 12 weeks) for 24 weeks. During the double-blind randomised treatment and follow-up period, all patients, investigators, and sponsor staff or representatives involved in the conduct of the study were masked to treatment assignment. The co-primary endpoints were responder rates at week 24 for dysmenorrhoea and non-menstrual pelvic pain, both based on NRS scores and analgesic use. Efficacy and safety were analysed in the modified intent-to-treat population (randomised patients who received ≥1 study drug dose). The studies are registered at ClinicalTrials.gov (SPIRIT 1 [NCT03204318] and SPIRIT 2 [NCT03204331]) and EudraCT (SPIRIT 1 [2017-001588-19] and SPIRIT 2 [2017-001632-19]). Eligible patients who completed the SPIRIT studies could enrol in a currently ongoing 80-week open-label extension study (SPIRIT EXTENSION [NCT03654274, EudraCT 2017-004066-10]). Database lock for the on-treatment duration has occurred, and post-treatment follow-up for safety, specificially for bone mineral density and menses recovery, is ongoing at the time of publication., Findings: 638 patients were enrolled into SPIRIT 1 and randomly assigned between Dec 7, 2017, and Dec 4, 2019, to receive relugolix combination therapy (212 [33%]), placebo (213 [33%]), or relugolix delayed combination therapy (213 [33%]). 623 patients were enrolled into SPIRIT 2 and were randomly assigned between Nov 1, 2017 and Oct 4, 2019, to receive relugolix combination therapy (208 [33%]), placebo (208 [33%]), or relugolix delayed combination therapy (207 [33%]). 98 (15%) patients terminated study participation early in SPIRIT 1 and 115 (18%) in SPIRIT 2. In SPIRIT 1, 158 (75%) of 212 patients in the relugolix combination therapy group met the dysmenorrhoea responder criteria compared with 57 (27%) of 212 patients in the placebo group (treatment difference 47·6% [95% CI 39·3-56·0]; p<0·0001). In SPIRIT 2, 155 (75%) of 206 patients in the relugolix combination therapy group were dysmenorrhoea responders compared with 62 (30%) of 204 patients in the placebo group (treatment difference 44·9% [95% CI 36·2-53·5]; p<0·0001). In SPIRIT 1, 124 (58%) of 212 patients in the relugolix combination therapy group met the non-menstrual pelvic pain responder criteria versus 84 (40%) patients in the placebo group (treatment difference 18·9% [9·5-28·2]; p<0·0001). In SPIRIT 2, 136 (66%) of 206 patients were non-menstrual pelvic pain responders in the relugolix combination therapy group compared with 87 (43%) of 204 patients in the placebo group (treatment difference 23·4% [95% CI 13·9-32·8]; p<0·0001). The most common adverse events were headache, nasopharyngitis, and hot flushes. There were nine reports of suicidal ideation across both studies (two in the placebo run-in, two in the placebo group, two in the relugolix combination therapy group, and three in the delayed relugolix combination therapy group). No deaths were reported. Least squares mean percentage change in lumbar spine bone mineral density in the relugolix combination therapy versus placebo groups was -0·70% versus 0·21% in SPIRIT 1 and -0·78% versus 0·02% in SPIRIT 2, and in the delayed relugolix combination group was -2·0% in SPIRIT 1 and -1·9% in SPIRIT 2. Decreases in opioid use were seen in treated patients as compared with placebo., Interpretation: Once-daily relugolix combination therapy significantly improved endometriosis-associated pain and was well tolerated. This oral therapy has the potential to address the unmet clinical need for long-term medical treatment for endometriosis, reducing the need for opioid use or repeated surgical treatment., Funding: Myovant Sciences., Competing Interests: Declaration of interests LCG reports personal fees from Myovant Sciences. SA-S reports personal fees from Myovant Sciences, Bayer, Abbvie, and UpToDate. CMB reports fees from Myovant Sciences and ObsEva, grants from Bayer Healthcare, and role of Chair of ESHRE Endometriosis Guideline Group. BAL reports personal fees from Myovant Sciences. NPJ reports personal fees from Myovant Sciences during the conduct of the study and personal fees from Guerbet, Abbott, and Roche Diagnostrics. JCAF, YL, and RBW are employees and shareholders of Myovant Sciences. QAW is a former employee of Myovant Sciences. VM is a consultant to Myovant Sciences. All other authors declare no competing interests. The authors did not receive compensation for manuscript writing, review, and revision., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: In the field of endometriosis, several classification, staging and reporting systems have been developed, but do clinicians routinely use these classification systems, which system do they use and what are the clinicians' motivations?, Data Sources: A cross-sectional study was performed to gather data on the current use of endometriosis classification systems, problems encountered and interest in a new simple surgical descriptive system for endometriosis. Of particular focus were three systems most commonly used: the Revised American Society for Reproductive Medicine (rASRM) classification, the Endometriosis Fertility Index (EFI), and the ENZIAN classification. Data were analysed by SPSS. A survey was designed using the online SurveyMonkey tool consisting of 11 questions concerning three domains-participants background, existing classification systems and intentions with regards to a new classification system for endometriosis. Replies were collected between 15 May and 1 July 2020., Methods of Study Selection: na TABULATION, INTEGRATION AND RESULTS: The final dataset included the replies of 1178 clinicians, including surgeons, gynecologists, reproductive endocrinologists, fertility specialists and sonographers, all managing women with endometriosis in their clinical practice. Overall, 75.5% of the professionals indicate that they currently use a classification system for endometriosis. The rASRM classification system was the best known and used system, the EFI system and ENZIAN system were known by a majority of the professionals but used by only a minority. The lack of clinical relevance was most often selected as a problem with using any system. The findings of the survey suggest that clinicians worldwide are open to using a new classification system for endometriosis that can achieve standardized reporting, and is clinically relevant and simple. The findings therefore support future initiatives for the development of a new descriptive system for endometriosis and provide information on user expectations and conditions for universal uptake of such a system., Conclusion: Even with a high uptake of the existing endometriosis classification systems (rASRM, ENZIAN and EFI), most clinicians managing endometriosis would like a new simple surgical descriptive system for endometriosis., (Copyright © 2022. Published by Elsevier Inc.)

Competing Interests: Funding Support and Author Disclosures Dr Munhoz has received research grants provided by the CardioPath PhD program. Dr Collet has received research grants from Biosensors, HeartFlow, and Abbott Vascular; and has received consultancy fees from HeartFlow, Abbott Vascular, Boston Scientific, Opsens, and Philips/Volcano. Dr Johnson has received internal funding from the Weatherhead PET Center for Preventing and Reversing Atherosclerosis; has received significant institutional research support from St. Jude Medical and Philips/Volcano Corporation; has an institutional licensing agreement with Boston Scientific for the smart-minimum FFR algorithm; and has pending patents on diagnostic methods and algorithms. Dr Matsuo serves as an advisory board member for Zeon Medical; and receives lecture fees from Abbott Vascular Japan, Boston Scientific Japan, and Phillips Japan. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Objective: In the field of endometriosis, several classification, staging and reporting systems have been developed. Which endometriosis classification, staging and reporting systems have been published and validated for use in clinical practice?, Data Sources: A systematic PUBMED literature search was performed. Data were extracted and summarized., Methods of Study Selection: na TABULATION, INTEGRATION AND RESULTS: Twenty-two endometriosis classification, staging and reporting systems have been published between 1973 and 2021, each developed for specific, and different, purposes. There still is no international agreement on how to describe the disease. Studies evaluating the different systems are summarized showing a discrepancy between the intended and the evaluated purpose, and a general lack of validation data confirming a correlation with pain symptoms or quality of life for any of the current systems. A few studies confirm the value of the ENZIAN system for surgical description of deep endometriosis. With regards to infertility, the endometriosis fertility index has been confirmed valid for its intended purpose., Conclusion: Of the 22 endometriosis classification, staging and reporting systems identified in this historical overview, only a few have been evaluated for the purpose for which they were developed. The literature search was limited to PUBMED. Unpublished classification, staging or reporting systems, or those published in books were not considered. It can be concluded that there is no international agreement on how to describe endometriosis or how to classify it, and that most classification/staging systems show no or very little correlation with patient outcomes. This overview of existing systems is a first step in working towards a universally accepted endometriosis classification., Competing Interests: Conflict of Interest Dr. Horne reports grant funding from the MRC, NIHR, CSO, Wellbeing of Women, Roche Diagnostics, Astra Zeneca, Ferring, Charles Wolfson Charitable Trust, Standard Life, Consultancy fees from Roche Diagnostics, AbbVie, Nordic Pharma and Ferring, outside the submitted work; In addition, Dr. Horne has a patent Serum biomarker for endometriosis pending. Dr. Johnson reports personal fees from Abbott, Guerbet, Myovant Sciences, Vifor Pharma, Roche Diagnostics, personal fees from Abbott, Guerbet, personal fees from Guerbet, Myovant Sciences, Vifor Pharma, Roche Diagnostics, outside the submitted work; he is also President of the World Endometriosis Society and chair of the trust board. Dr. Missmer reports grants and personal fees from AbbVie, and personal fees from Roche outside the submitted work. Dr. Tomassetti reports grants, non-financial support and other from Merck SA, non-financial support and other from Gedeon Richter, non-financial support from Ferring Pharmaceuticals, outside the submitted work and without private revenue. Dr. Zondervan reports grants from Bayer Healthcare, MDNA Life Sciences, Roche Diagnostics Inc, Volition Rx, outside the submitted work; she is also a Board member (Secretary) of the World Endometriosis Society and World Endometriosis Research Foundation, Research Advisory Board member of Wellbeing of Women, UK (research charity), and Chair, Research Directions Working Group, World Endometriosis Society. The other authors had nothing to disclose., (Copyright © 2021. Published by Elsevier Inc.)

Objective: Different classification systems have been developed for endometriosis, using different definitions for the disease, the different subtypes, symptoms and treatments. In addition, an International Glossary on Infertility and Fertility Care has been published in 2017 by the International Committee for Monitoring Assisted Reproductive Technologies (ICMART) in collaboration with other organisations. An international working group convened over the development of a classification or descriptive system for endometriosis. As a basis for such system, a terminology for endometriosis was considered a condition sine qua non. The aim of the current study was to develop a set of terms and definitions be prepared on endometriosis that would be the basis for standardization in disease description, classification and research., Data Sources: The working group listed a number of terms relevant to be included in the terminology, documented currently used and published definitions, and discussed and adapted them until consensus was reached within the working group. Following stakeholder review, further terms were added, and definitions further clarified. Although definitions were collected through published literature, the final set of terms and definitions is to be considered consensus-based. After finalization of the first draft, the members of the international societies and other stakeholders were consulted for feedback and comments, which lead to further adaptations., Methods of Study Selection: na TABULATION, INTEGRATION, AND RESULTS: A list of 49 terms and definitions in the field of endometriosis is presented, including a definition for endometriosis and its subtypes, different locations, interventions, symptoms and outcomes. Endometriosis is defined as a disease characterized by the presence of endometrium-like epithelium and/or stroma outside the endometrium and myometrium, usually with an associated inflammatory process., Conclusion: The current paper outlines a list of 49 terms and definitions in the field of endometriosis. The application of the defined terms aims to facilitate harmonization in endometriosis research and clinical practice. Future research may require further refinement of the presented definitions., Competing Interests: Conflict of interest A.W.H. reports grant funding from the MRC, NIHR, CSO, Wellbeing of Women, Roche Diagnostics, Astra Zeneca, Ferring, Charles Wolfson Charitable Trust, Standard Life, Consultancy fees from Roche Diagnostics, AbbVie, Nordic Pharma and Ferring, outside the submitted work. In addition, A.W.H. has a patent Serum biomarker for endometriosis pending. N.P.J. reports personal fees from Abbott, Guerbet, Myovant Sciences, Vifor Pharma, Roche Diagnostics outside the submitted work; he is also President of the World Endometriosis Society and chair of the trust board. S.M. reports grants and personal fees from AbbVie, and personal fees from Roche outside the submitted work. C.T. reports grants, nonfinancial support and other from Merck SA, non-financial support and other from Gedeon Richter, non-financial support from Ferring Pharmaceuticals, outside the submitted work and without private revenue. K.T.Z. reports grants from Bayer Healthcare, MDNA Life Sciences, Roche Diagnostics Inc, Volition Rx, outside the submitted work; she is also a Board member (Secretary) of the World Endometriosis Society and World Endometriosis Research Foundation, Research Advisory Board member of Wellbeing of Women, UK (research charity), and Chair, Research Directions Working Group, World Endometriosis Society. J.P reports personal fees from Hologic, Inc., outside the submitted work; he is also a member of the executive boards of ASRM and SRS. The other authors had nothing to disclose., (Copyright © 2021 AAGL. All rights reserved.)

Objectives: The aim of this study was to assess clinical outcomes after combined pressure and flow assessment of coronary lesions., Background: Although fractional flow reserve (FFR) remains the invasive reference standard for revascularization, approximately 40% of stenoses have discordant coronary flow reserve (CFR). Optimal treatment for these disagreements remains unclear., Methods: A total of 455 subjects with 668 lesions were enrolled from 12 sites in 6 countries. Only lesions with reduced FFR and CFR underwent revascularization; all other combinations received initial medical therapy., Results: Fourteen percent of lesions had FFR ≤0.8 but CFR ≥2.0 while 23% of lesions had FFR >0.8 but CFR <2.0. During 2-year follow-up, the primary endpoint of composite all-cause death, myocardial infarction, and revascularization in lesions with FFR ≤0.8 but CFR ≥2.0 (10.8% event rate) compared with lesions with FFR >0.8 and CFR ≥2.0 (6.2% event rate) exceeded the prespecified +10% noninferiority margin (P = 0.090). Target vessel failure models using both continuous FFR and continuous CFR found that only higher FFR was associated with reduced target vessel failure (Cox P = 0.007) after initial medical treatment. Central core laboratory review accepted 69.8% of all tracings with mean differences of <0.01 for FFR and <0.02 for CFR, indicating no material impact on clinical measurements or outcomes., Conclusions: All-cause death, myocardial infarction, and revascularization after 2 years was not noninferior between lesions with FFR ≤0.8 but CFR ≥2.0 and lesions with FFR >0.8 and CFR ≥2.0. These results do not support using invasive CFR ≥2.0 to defer revascularization for lesions with reduced FFR if the patient would otherwise be a candidate on the basis of the entire clinical scenario and treatment preference., Competing Interests: Funding Support and Author Disclosures Dr Johnson has received significant institutional research support from Philips Volcano for this study; has received significant institutional research support from St. Jude Medical (CONTRAST [Can Contrast Injection Better Approximate FFR Compared to Pure Resting Physiology?]; NCT02184117) for a different study using intracoronary pressure sensors; and has an institutional licensing agreement with Boston Scientific for the smart minimum FFR algorithm, commercially available as 510(k) K191008. Dr Matsuo serves as advisory board member for Zeon Medical; and receives lecture fees from Abbott Vascular Japan, Boston Scientific Japan, and Phillips Japan. Drs Johnson, Kirkeeide, and Gould have received internal funding from the Weatherhead PET Center for Preventing and Reversing Atherosclerosis; and have patents pending on diagnostic methods for quantifying aortic stenosis and transcatheter aortic valve replacement physiology, as well as algorithms to correct pressure tracings from fluid-filled catheters. Dr Gould is the 510(k) applicant for CFR Quant (K113754) and HeartSee (K143664, K171303, K202679), software packages for cardiac positron emission tomographic image processing, analysis, and absolute flow quantification. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: In chronic coronary syndromes, guidelines mandate invasive functional guidance of revascularization whenever non-invasive proof of ischemia is missing. ISIS-2 survey aimed to evaluate how the adoption of guideline recommendation on ischemia-guided revascularization has evolved over the last 5-7 years., Methods: In ISIS-2 participants assessed five complete angiograms, presenting only intermediate stenoses without information on non-invasive pre-testing. Fractional flow reserve was known for each stenosis, but remained undisclosed. Participants could determine stenosis significance either by angiography or by requesting an adjunctive invasive diagnostic method (intravascular imaging or functional tests). Primary endpoint was the rate of requesting adjunctive functional assessment. Secondary endpoints were the rate of concordance between angiography-based decisions and know functional severity. ISIS-2 utilized the same web-based platform as ISIS-1 in 2013. (NCT04001452)., Results: 334 participants performed 2059 lesion evaluations: 1202 (59%) decisions were based solely on angiography without expressed need for further evaluation. These decisions were discordant with known functional significance in 39%, mainly with potential of overtreatment. Participants requested invasive functional assessment in 643 (31%) and intravascular imaging in 214 (10%) cases. Compared to ISIS-1 the rate of purely angiography-based decisions has decreased (59% vs 66%; p < 0.001), while invasive functional tests were more frequently requested (31% vs 25%; p < 0.001)., Conclusions: ISIS-2 suggests an evolving pattern in the intention to integrate invasive coronary physiology into the revascularization decisions. However, the disconnect between recommendations and current thinking is still dominant., (Copyright © 2021. Published by Elsevier B.V.)

Objectives: This study sought to determine the relationship between the severity of reduced quantitative perfusion parameters and mortality with and without revascularization., Background: The physiological mechanisms for differential mortality risk of coronary flow reserve (CFR) and coronary flow capacity (CFC) before and after revascularization are unknown., Methods: Global and regional rest-stress (ml/min/g), CFR, their regional per-pixel combination as CFC, and relative stress in ml/min/g were measured as percent of LV in all serial routine 5,274 diagnostic PET scans with systematic follow-up over 10 years (mean 4.2 ± 2.5 years) for all-cause mortality with and without revascularization., Results: Severely reduced CFR of 1.0 to 1.5 and stress perfusion ≤1.0 cc/min/g incurred increasing size-dependent risks that were additive because regional severely reduced CFC (CFCsevere) was associated with the highest major adverse cardiac event rate of 80% (p < 0.0001 vs. either alone) and a mortality risk of 14% (vs. 2.3% for no CFCsevere; p = 0.001). Small regions of CFCsevere ≤0.5% predicted high risk (p < 0.0001 vs. no CFCsevere) related to a wave front of border zones at risk around the small most severe center. By receiver-operating characteristic analysis, relative stress topogram maps of stress (ml/min/g) as a fraction of LV defined these border zones at risk or for mildly reduced CFC (area under the curve [AUC]: 0.69) with a reduced relative tomographic subendocardial-to-subepicardial ratio. CFCsevere incurred the highest mortality risk that was reduced by revascularization (p = 0.005 vs. no revascularization) for artery-specific stenosis not defined by global CFR or stress perfusion alone., Conclusions: CFC is associated with the size-dependent highest mortality risk resulting from the additive risk of CFR and stress (ml/min/g) that is significantly reduced after revascularization, a finding not seen for global CFR. Small regions of CFCsevere ≤0.5% of LV also carry a high risk because of the surrounding border zones at risk defined by relative stress perfusion and a reduced relative subendocardial-to-subepicardial ratio., Competing Interests: Funding Support and Author Disclosures This work was supported by internal funds of the Weatherhead PET Center. Dr. Gould has received internal funding from the Weatherhead PET Center; and is the 510(k) applicant for Food and Drug Administration–cleared HeartSee K171303 PET software (to avoid any conflict of interest. Dr. Gould assigned any royalties arising from PET software to the University of Texas for research or student scholarships). Dr. Johnson has received internal funding from the Weatherhead PET Center for Preventing and Reversing Atherosclerosis; and has received research support from St. Jude Medical (for NCT02184117) and Volcano/Philips Corporation (for NCT02328820). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Can imaging provide sufficient risk stratification to warrant revascularization of a stable plaque with negative fractional flow reserve (FFR)? Prophylactic stenting could at best be applied selectively since the composite group of FFR-negative lesions has a death or myocardial infarction rate of approximately 1%/year or less but modern stents have a rate of 2% to 3.5%/year. Because vulnerable features exist in a minority of lesions, at least 9,000 patients must be screened in order to enroll a cohort with sufficient risk. While several ongoing randomized trials are testing the concept of plaque sealing in FFR-negative lesions, preventive stenting depends on such a small effect that sample sizes to validate or refute its benefit become prohibitive. Since FFR provides a quantitative, straightforward, and reproducible metric of plaque vulnerability and burden without the need for or expense of additional catheter devices, intracoronary imaging cannot meaningfully guide prophylactic stenting when faced with a negative FFR., Competing Interests: Funding Support and Author Disclosures Dr. Pijls has received institutional grant support from Hexacath and Abbott; serves as a consultant for Abbott, Opsens, and GE Health; and possesses equity in Philips, GE, ASML, and Heartflow. Drs. Gould and Johnson have received internal funding from the Weatherhead PET Center for Preventing and Reversing Atherosclerosis. Drs. Pijls, Gould, and Johnson have a patent pending on diagnostic methods for quantifying aortic stenosis and TAVI physiology. Dr. Gould is the 510(k) applicant for CFR Quant (K113754) and HeartSee (K143664 and K171303), software packages for cardiac positron emission tomography image processing, analysis, and absolute flow quantification. Dr. Johnson has an institutional licensing and consulting agreement with Boston Scientific for the smart minimum fractional flow reserve algorithm; and has received significant institutional research support from St. Jude Medical (CONTRAST, NCT02184117) and Volcano/Philips (DEFINE-FLOW, NCT02328820) for studies using intracoronary pressure and flow sensors. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Pressure loss versus transvalvular flow analysis challenges physiologic models of current aortic valve stenosis. New conceptual frameworks are needed to explain these real-world observations., Methods and Results: A patient-specific, 3D-printed, silicon model of a stenotic valve was placed inside an in-vitro haemodynamic model of the circulatory system. Instantaneous pressure and flow in the aorta and left ventricle were simulated according to measured patient specific parameters. Thereafter, a realistic transcatheter aortic valve was implanted (TAVI) in the model. Simulated post-TAVI mean pressure gradients resembled patient observations (3.7 ± 0.7 mmHg vs 6.7 ± 2.3 mmHg), but pre-TAVI measurements underestimated the pressure gradient (35.1 ± 0.6 mmHg vs 45.3 ± 1.5 mmHg)., Conclusion: Patient-specific 3D-printed stenotic aortic valve models could simulate baseline haemodynamics. A TAVI procedure was successfully performed on the 3D silicone rubber valve in a physiologic in-vitro model. Pre-TAVI haemodynamics in the model underestimated in-patient mean pressure gradient, whereas post TAVI pressure gradient was predicted correctly with the TAVI valve inside the 3D printed model. This study shows that these types of models could be used to study AS hemodynamics with the TAVI valve inside the 3D printed model. Improvements in the 3D-printed model, like addition of calcification and fine-tuning of the haemodynamic model, could further enhance accuracy of the simulation., Competing Interests: Declaration of competing interest JmZ, RM, JJDR, KLPMJ, MV, NHJP, FNV, PALT and MCR do not report any conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

We are proposing a shift in mindset in the field of endometriosis, whereby care for patients with endometriosis mirrors that of patients with gynaecological cancer. To achieve this, we advocate for the recognition of complex benign gynaecology as a subspecialty. Since the establishment of gynaecological oncology as a subspecialty, outcomes for patients with ovarian cancer have improved, with their care managed by multidisciplinary teams in specialized units. Despite the marked difference in the primary treatment goal between these two conditions, they share common diagnostic and therapeutic challenges. We believe that care management by a multidisciplinary team of dedicated and specialized health care professionals will lead to improved outcomes, including improved quality of life, for people living with endometriosis., (Copyright © 2020 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Objective: We performed a systematic review and meta-analysis with the aim to answer whether operative laparoscopy is an effective treatment in a woman with demonstrated endometriosis compared with alternative treatments. Moreover, we aimed to assess the risks of operative laparoscopy compared with those of alternatives. In addition, we aimed to systematically review the literature on the impact of patient preference on decision making around surgery., Data Sources: We searched MEDLINE, Embase, PsycINFO, ClinicalTrials.gov, CINAHL, Scopus, OpenGrey, and Web of Science from inception through May 2019. In addition, a manual search of reference lists of relevant studies was conducted., Methods of Study Selection: Published and unpublished randomized controlled trials (RCTs) in any language describing a comparison between surgery and any other intervention were included, with particular reference to timing and its impact on pain and fertility. Studies reporting on keywords including, but not limited to, endometriosis, laparoscopy, pelvic pain, and infertility were included. In the anticipated absence of RCTs on patient preference, all original research on this topic was considered eligible., Tabulation, Integration, and Results: In total, 1990 studies were reviewed. Twelve studies were identified as being eligible for inclusion to assess outcomes of pain (n = 6), fertility (n = 7), quality of life (n = 1), and disease progression (n = 3). Seven studies of interest were identified to evaluate patient preferences. There is evidence that operative laparoscopy may improve overall pain levels at 6 months compared with diagnostic laparoscopy (risk ratio [RR], 2.65; 95% confidence interval [CI], 1.61-4.34; p <.001; 2 RCTs, 102 participants; low-quality evidence). Because the quality of the evidence was very low, it is uncertain if operative laparoscopy improves live birth rates. Operative laparoscopy probably yields little or no difference regarding clinical pregnancy rates compared with diagnostic laparoscopy (RR, 1.29; 95% CI, 0.99-1.92; p = .06; 4 RCTs, 624 participants; moderate-quality evidence). It is uncertain if operative laparoscopy yields a difference in adverse outcomes when compared with diagnostic laparoscopy (RR, 1.98; 95% CI, 0.84-4.65; p = .12; 5 RCTs, 554 participants; very-low-quality evidence). No studies reported on the progression of endometriosis to a symptomatic state or progression of extent of disease in terms of volume of lesions and locations in asymptomatic women with endometriosis. We found no studies that reported on the timing of surgery. No quantitative or qualitative studies specifically aimed at elucidating the factors informing a woman's choice for surgery were identified., Conclusion: Operative laparoscopy may improve overall pain levels but may have little or no difference with respect to fertility-related or adverse outcomes when compared with diagnostic laparoscopy. Additional high-quality RCTs, including comparing surgery to medical management, are needed, and these should report adverse events as an outcome. Studies on patient preference in surgical decision making are needed (International Prospective Register of Systematic Review registration number: CRD42019135167)., (Copyright © 2019 AAGL. Published by Elsevier Inc. All rights reserved.)

This was a systematic review and meta-analysis to examine the efficacy, effectiveness and safety of acupuncture as an adjunct to embryo transfer compared with controls to improve reproductive outcomes. The primary outcome was clinical pregnancy. Twenty trials and 5130 women were included in the review. The meta-analysis found increased pregnancies (risk ratio [RR] 1.32, 95% confidence interval [CI] 1.07-1.62, 12 trials, 2230 women), live births (RR 1.30, 95% CI 1.00-1.68, 9 trials, 1980 women) and reduced miscarriage (RR 1.43, 95% CI 1.03-1.98, 10 trials, 2042 women) when acupuncture was compared with no adjunctive control. There was significant heterogeneity, but no significant differences between acupuncture and sham controls. Acupuncture may have a significant effect on clinical pregnancy rates, independent of comparator group, when used in women who have had multiple previous IVF cycles, or where there was a low baseline pregnancy rate. The findings suggest acupuncture may be effective when compared with no adjunctive treatment with increased clinical pregnancies, but is not an efficacious treatment when compared with sham controls, although non-specific effects may be active in both acupuncture and sham controls. Future research examining the effects of acupuncture for women with poorer IVF outcomes is warranted., (Copyright © 2018. Published by Elsevier Ltd.)

Research Question: Does pre-IVF Lipiodol ® increase the success of IVF treatment in women with endometriosis or repeat implantation failure (RIF) compared with IVF alone?, Design: Lipiodol is known to enhance natural fertility, especially amongst women with endometriosis. The effect of Lipiodol may accrue through an impact on the endometrium that enhances receptivity to implantation. A randomized controlled trial (RCT) was carried out on 70 women due to undergo IVF. Women with endometriosis or RIF in previous IVF treatments, recruited from IVF clinics in New Zealand and in Pune, India, received either Lipiodol by hysterosalpingogram or no intervention prior to IVF treatment., Results: Between May 2009 and January 2014, 33 women were randomized to Lipiodol plus IVF and 37 to IVF alone. When pregnancies resulting from fresh embryo transfer from the IVF cycle under study were considered, live birth rates were 8/33 (24%) in the pre-IVF Lipiodol group and 11/37 (30%) in the IVF only group (relative risk [RR] 0.81; 95% confidence interval [CI] 0.37 to 1.8). Live birth rates from pregnancies within 6 months were 11/33 (33%) and 12/37 (32%) in these respective groups (RR 1.03; 95% CI, 0.53 to 2.0). The trial was underpowered to detect smaller differences between treatment and control groups., Conclusions: No evidence was found of benefit of Lipiodol prior to fresh embryo transfer in women with endometriosis or RIF. It is suggested that this treatment should not be undertaken purely as an adjuvant in IVF other than in the context of a further well-designed RCT., (Copyright © 2018 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Objectives: The goal of this study was to investigate sex differences in adenosine-free coronary pressure indexes., Background: Several adenosine-free coronary pressure wire indexes have been proposed to assess the functional significance of coronary artery lesions; however, there is a theoretical concern that sex differences may affect diagnostic performance because of differences in resting flow and distal myocardial mass., Methods: In this CONTRAST (Can Contrast Injection Better Approximate FFR Compared to Pure Resting Physiology?) substudy, contrast fractional flow reserve (cFFR), obtained during contrast-induced submaximal hyperemia, the instantaneous wave-free ratio (iFR), and distal/proximal coronary pressure ratio (Pd/Pa) were compared with fractional flow reserve (FFR) in 547 men and 216 women. Using FFR ≤0.8 as a reference, the diagnostic performance of each index was compared., Results: Men and women had similar diameter stenosis (p = 0.78), but women were less likely to have FFR ≤0.80 than men (42.5% vs. 51.5%, p = 0.04). Sensitivity was similar among cFFR, iFR, and Pd/Pa when comparing women and men, respectively (cFFR, 77.5% vs. 75.3%; p = 0.69; iFR, 84.9% vs. 79.4%; p = 0.30; Pd/Pa, 78.8% vs. 77.3%; p = 0.78). cFFR was more specific than iFR or Pd/Pa regardless of sex (cFFR, 94.3% vs. 95.8%; p = 0.56; iFR, 75.6% vs. 80.1%; p = 0.38; Pd/Pa, 80.6% vs. 78.7%; p = 0.69). By receiver-operating characteristic curve analysis, cFFR provided better diagnostic accuracy than resting indexes irrespective of sex (p ≤ 0.0001)., Conclusions: Despite the theoretical concern, the diagnostic sensitivity and specificity of cFFR, iFR, and Pd/Pa did not differ between the sexes. Irrespective of sex, cFFR provides the best diagnostic performance., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to compare site-reported measurements of fractional flow reserve (FFR) with FFR analysis by an independent core laboratory (CL)., Background: FFR is an index of coronary stenosis severity that has been validated in multiple trials and is widely used in clinical practice. However, the incidence of suboptimal FFR measurements is unknown., Methods: Patients undergoing FFR assessment within the CONTRAST (Can Contrast Injection Better Approximate FFR Compared to Pure Resting Physiology) study had paired, repeated measurements of multiple physiological metrics per local practice. An independent central physiology CL analyzed blinded pressure tracings off-line in a standardized fashion for comparison., Results: A total of 763 patients were included in the study; 4,946 distal coronary artery pressure/aortic pressure (nonhyperemic) and FFR tracings were analyzed by the CL (mean 6.5 tracings per patient). Pull-back data were available for 616 patients (80.7%), of whom 108 (17.5%) had signal drift, defined as distal coronary artery pressure/aortic pressure (nonhyperemic) <0.97 or >1.03. Among the remaining 4,217 tracings without evidence of signal drift, 222 (5.3%) were noted to have ventricularization of the aortic waveform, and 168 (4.0%) had aortic waveform distortion. Excluding cases with signal drift and waveform distortion, there was excellent agreement between CL-calculated and site-reported FFR, with a mean difference of 0.003 ± 0.02. Predictors of distorted waveforms were smaller guiding catheter size (odds ratio: 6.30; 95% confidence interval: 3.22 to 12.32; p < 0.001) and intracoronary adenosine use (odds ratio: 0.13; 95% confidence interval: 0.05 to 0.33; p < 0.001)., Conclusions: This FFR CL analysis showed that almost 10% of tracings demonstrated waveform artifacts, and an additional 17.5% had signal drift. Among adequate tracings, there was a close correlation between site-reported and CL-analyzed FFR values. Attention to detail is critical for FFR studies to ensure adequate technique and optimal results., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: Positron emission tomography (PET) quantifies stress myocardial perfusion (in cc/min/g) and coronary flow reserve to guide noninvasively the management of coronary artery disease. This study determined their test-retest precision within minutes and daily biological variability essential for bounding clinical decision-making or risk stratification based on low flow ischemic thresholds or follow-up changes., Background: Randomized trials of fractional flow reserve-guided percutaneous coronary interventions established an objective, quantitative, outcomes-driven standard of physiological stenosis severity. However, pressure-derived fractional flow reserve requires invasive coronary angiogram and was originally validated by comparison to noninvasive PET., Methods: The time course and test-retest precision of serial quantitative rest-rest and stress-stress global myocardial perfusion by PET within minutes and days apart in the same patient were compared in 120 volunteers undergoing serial 708 quantitative PET perfusion scans using rubidium 82 (Rb-82) and dipyridamole stress with a 2-dimensional PET-computed tomography scanner (GE DST 16) and University of Texas HeartSee software with our validated perfusion model., Results: Test-retest methodological precision (coefficient of variance) for serial quantitative global myocardial perfusion minutes apart is ±10% (mean ΔSD at rest ±0.09, at stress ±0.23 cc/min/g) and for days apart is ±21% (mean ΔSD at rest ±0.2, at stress ±0.46 cc/min/g) reflecting added biological variability. Global myocardial perfusion at 8 min after 4-min dipyridamole infusion is 10% higher than at standard 4 min after dipyridamole., Conclusions: Test-retest methodological precision of global PET myocardial perfusion by serial rest or stress PET minutes apart is ±10%. Day-to-different-day biological plus methodological variability is ±21%, thereby establishing boundaries of variability on physiological severity to guide or follow coronary artery disease management. Maximum stress increases perfusion and coronary flow reserve, thereby reducing potentially falsely low values mimicking ischemia., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This work compares the diagnostic performance of adenosine-free coronary pressure wire indices based on lesion location., Background: Several adenosine-free coronary pressure wire indices have been proposed to assess the functional significance of coronary artery lesions; however, there is a theoretical concern that lesion location and the mass of perfused myocardium may affect diagnostic performance., Methods: A total of 763 patients were prospectively enrolled from 12 institutions. Fractional flow reserve (FFR) and contrast-based FFR (cFFR) were obtained during adenosine-induced maximal hyperemia and contrast-induced submaximal hyperemia respectively, whereas the instantaneous wave-free ratio (iFR) and distal pressure/aortic pressure (Pd/Pa) were obtained at rest. Using an FFR of ≤0.80 as a reference standard, the diagnostic accuracy of each index was compared based on lesion location (left main or proximal left anterior descending artery [LM/pLAD] compared with other lesion locations)., Results: The median FFR, cFFR, iFR, and Pd/Pa were 0.81 (interquartile range [IQR]: 0.74 to 0.87), 0.86 (IQR: 0.79 to 0.91), 0.90 (IQR: 0.85 to 0.94), and 0.92 (IQR: 0.88 to 0.95), respectively. The cFFR, iFR, and Pd/Pa were less accurate in LM/pLAD compared with other lesion locations (cFFR: 80.3% vs. 87.8%; iFR: 73.3% vs. 81.8%; Pd/Pa: 71.4% vs. 81.1%, respectively). By receiver-operating characteristics curve analysis, cFFR provided better diagnostic accuracy than resting indices regardless of lesion location (p ≤0.0001 vs. iFR and Pd/Pa for both groups)., Conclusions: The cFFR, iFR, and Pd/Pa are less accurate in LM/pLAD compared with other lesion locations, likely related to the larger amount of myocardium supplied by LM/pLAD. Nevertheless, cFFR provides the best diagnostic accuracy among the adenosine-free indices, regardless of lesion location., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study compared the diagnostic performance with adenosine-derived fractional flow reserve (FFR) ≤0.8 of contrast-based FFR (cFFR), resting distal pressure (Pd)/aortic pressure (Pa), and the instantaneous wave-free ratio (iFR)., Background: FFR objectively identifies lesions that benefit from medical therapy versus revascularization. However, FFR requires maximal vasodilation, usually achieved with adenosine. Radiographic contrast injection causes submaximal coronary hyperemia. Therefore, intracoronary contrast could provide an easy and inexpensive tool for predicting FFR., Methods: We recruited patients undergoing routine FFR assessment and made paired, repeated measurements of all physiology metrics (Pd/Pa, iFR, cFFR, and FFR). Contrast medium and dose were per local practice, as was the dose of intracoronary adenosine. Operators were encouraged to perform both intracoronary and intravenous adenosine assessments and a final drift check to assess wire calibration. A central core lab analyzed blinded pressure tracings in a standardized fashion., Results: A total of 763 subjects were enrolled from 12 international centers. Contrast volume was 8 ± 2 ml per measurement, and 8 different contrast media were used. Repeated measurements of each metric showed a bias <0.005, but a lower SD (less variability) for cFFR than resting indexes. Although Pd/Pa and iFR demonstrated equivalent performance against FFR ≤0.8 (78.5% vs. 79.9% accuracy; p = 0.78; area under the receiver-operating characteristic curve: 0.875 vs. 0.881; p = 0.35), cFFR improved both metrics (85.8% accuracy and 0.930 area; p < 0.001 for each) with an optimal binary threshold of 0.83. A hybrid decision-making strategy using cFFR required adenosine less often than when based on either Pd/Pa or iFR., Conclusions: cFFR provides diagnostic performance superior to that of Pd/Pa or iFR for predicting FFR. For clinical scenarios or health care systems in which adenosine is contraindicated or prohibitively expensive, cFFR offers a universal technique to simplify invasive coronary physiological assessments. Yet FFR remains the reference standard for diagnostic certainty as even cFFR reached only ∼85% agreement., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

We discuss the historical development of clinical coronary physiology, emphasizing coronary flow reserve (CFR) and fractional flow reserve (FFR). Our analysis focuses on the clinical motivations and technologic advances that prompted and enabled the application of physiology for patient diagnosis. CFR grew from the general concepts of physiologic and coronary reserve, linking the anatomic severity of a lesion to its impact on hyperemic flow. FFR developed from existing models relating pressure measurements to the potential for flow to increase after removing a stenosis. Because pressure measurements have proved easier and more robust than flow measurements, FFR has become the dominant metric., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: The present study sought to establish the dosage of intracoronary (IC) adenosine associated with minimal side effects and above which no further increase in flow can be expected., Background: Despite the widespread adoption of IC adenosine in clinical practice, no wide-ranging, dose-response study has been conducted. A recurring debate still exists regarding its optimal dose., Methods: In 30 patients, Doppler-derived flow velocity measurements were obtained in 10 right coronary arteries (RCAs) and 20 left coronary arteries (LCAs) free of stenoses >20% in diameter. Flow velocity was measured at baseline and after 8 ml bolus administrations of arterial blood, saline, contrast medium, and 9 escalating doses of adenosine (4 to 500 μg). The hyperemic value was expressed in percent of the maximum flow velocity reached in a given artery (Q/Qmax, %)., Results: Q/Qmax did not increase significantly beyond dosages of 60 μg for the RCA and 160 μg for LCA. Heart rate did not change, whereas mean arterial blood pressure decreased by a maximum of 7% (p < 0.05) after bolus injections of IC adenosine. The incidence of transient A-V blocks was 40% after injection of 100 μg in the RCA and was 15% after injection of 200 μg in the LCA. The duration of the plateau reached 12 ± 13 s after injection of 100 μg in the RCA and 21 ± 6 s after the injection of 200 μg in the LCA. A progressive prolongation of the time needed to return to baseline was observed. Hyperemic response after injection of 8 ml of contrast medium reached 65 ± 36% of that achieved after injection of 200 μg of adenosine., Conclusions: This wide-ranging, dose-response study indicates that an IC adenosine bolus injection of 100 μg in the RCA and 200 μg in the LCA induces maximum hyperemia while being associated with minimal side effects., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study classified and quantified the variation in fractional flow reserve (FFR) due to fluctuations in systemic and coronary hemodynamics during intravenous adenosine infusion., Background: Although FFR has become a key invasive tool to guide treatment, questions remain regarding its repeatability and stability during intravenous adenosine infusion because of systemic effects that can alter driving pressure and heart rate., Methods: We reanalyzed data from the VERIFY (VERification of Instantaneous Wave-Free Ratio and Fractional Flow Reserve for the Assessment of Coronary Artery Stenosis Severity in EverydaY Practice) study, which enrolled consecutive patients who were infused with intravenous adenosine at 140 μg/kg/min and measured FFR twice. Raw phasic pressure tracings from the aorta (Pa) and distal coronary artery (Pd) were transformed into moving averages of Pd/Pa. Visual analysis grouped Pd/Pa curves into patterns of similar response. Quantitative analysis of the Pd/Pa curves identified the "smart minimum" FFR using a novel algorithm, which was compared with human core laboratory analysis., Results: A total of 190 complete pairs came from 206 patients after exclusions. Visual analysis revealed 3 Pd/Pa patterns: "classic" (sigmoid) in 57%, "humped" (sigmoid with superimposed bumps of varying height) in 39%, and "unusual" (no pattern) in 4%. The Pd/Pa pattern repeated itself in 67% of patient pairs. Despite variability of Pd/Pa during the hyperemic period, the "smart minimum" FFR demonstrated excellent repeatability (bias -0.001, SD 0.018, paired p = 0.93, r(2) = 98.2%, coefficient of variation = 2.5%). Our algorithm produced FFR values not significantly different from human core laboratory analysis (paired p = 0.43 vs. VERIFY; p = 0.34 vs. RESOLVE)., Conclusions: Intravenous adenosine produced 3 general patterns of Pd/Pa response, with associated variability in aortic and coronary pressure and heart rate during the hyperemic period. Nevertheless, FFR - when chosen appropriately - proved to be a highly reproducible value. Therefore, operators can confidently select the "smart minimum" FFR for patient care. Our results suggest that this selection process can be automated, yet comparable to human core laboratory analysis., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The goal of this study was to compare regadenoson and dipyridamole hyperemia for quantitative myocardial perfusion imaging., Background: Regadenoson is commonly used for stress perfusion imaging. However, no study in nuclear cardiology has employed a paired design to compare quantitative hyperemic flow from regadenoson to more traditional agents such as dipyridamole. Additionally, the timing of regadenoson bolus relative to tracer administration can be expected to affect quantitative flow., Methods: Subjects underwent 2 rest/stress cardiac positron emission tomography scans using an Rb-82 generator. Each scan employed dipyridamole and a second drug in random sequence, either regadenoson according to 5 timing sequences or repeated dipyridamole. A validated retention model quantified absolute flow and coronary flow reserve., Results: A total of 176 pairs compared regadenoson (126 pairs, split unevenly among 5 timing sequences) or repeated dipyridamole (50 pairs). The cohort largely had few symptoms, only risk factors, and nearly normal relative uptake images, with 8% typical angina or dyspnea, 20% manifest coronary artery disease, and a minimum quadrant average of 80% (interquartile range: 76% to 83%) on dipyridamole scans. Hyperemic flow varied among regadenoson timing sequences but showed consistently lower stress flow and coronary flow reserve compared with dipyridamole. A timing sequence most similar to the regadenoson package insert achieved about 80% of dipyridamole hyperemia, whereas further delaying radiotracer injection reached approximately 90% of dipyridamole hyperemia. Because of the small numbers of pairs for each regadenoson timing protocol and a paucity of moderate or large perfusion defects, we did not observe a difference in relative uptake., Conclusions: With the standard timing protocol from the package insert, regadenoson achieved only 80% of dipyridamole hyperemia quantitatively imaged by cardiac positron emission tomography using Rb-82. A nonstandard protocol using a more delayed radionuclide injection after the regadenoson bolus improved its effect to 90% of dipyridamole hyperemia., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Heart rate (HR) and RR interval are inversely related., Objective: The purpose of this study was to determine which parameter better describes the autonomic changes that occur after exercise and which provides stronger prognostic significance., Methods: Healthy volunteers (n = 33) underwent sequential bicycle exercise tests with selective autonomic blockade during exercise to define HR and RR interval changes in recovery due to parasympathetic effect, sympathetic effect, and sympathetic-parasympathetic interaction. The prognostic significance of resting HR and RR interval was assessed in a cohort study (n = 33,781). The prognostic significance of exercise HR and RR interval and 1-minute HR and RR interval recovery was assessed in patients referred for exercise testing (n = 2387)., Results: Parasympathetic effect on HR and RR interval both increased in recovery (P < .001), while the sympathetic effect on HR declined (P < .001) and the sympathetic effect on the RR interval paradoxically increased. Significant sympathetic-parasympathetic interaction was noted with the HR analysis but not with the RR interval. Resting HR and RR interval had similar prognostic implications by age and gender. While resting and exercise HR and RR interval had similar prognostic implications, 1-minute HR recovery was a multivariate predictor of mortality (HR 0.81; 95%CI 0.69-0.95), while 1-minute RR interval recovery was not., Conclusion: Based on these findings, HR (and its changes) is not necessarily interchangeable with the RR interval (and its changes) in either physiologic or prognostic studies. It is important to consider underlying physiologic constraints and identify wisely which parameter (or even other transformation of these parameters) is most suitable for a given analysis., (Copyright © 2014 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

The importance of providing evidence-based health care in reproduction medicine has resulted in a wealth of research which has largely focused on patient outcomes. Comparatively little is known about the knowledge and attitudes of health professionals who are often required to contribute to research. This study sought to examine the knowledge and attitudes to research of reproductive medicine health professionals and to explore the motivators and barriers to participating in research. A cross-sectional online survey was developed from previous research. The survey was distributed to members of the Fertility Society of Australia between November 2012 and February 2013. Ninety-six health professionals consented to participate and completed the questionnaire. The majority acknowledged the importance of research in informing practice and improving patient outcomes. While many clinicians expressed an interest in participating in research, time and resources were acknowledged as barriers that hindered their involvement. Collaborations with academics may offer a pathway to building the evidence to improve patient care. There is increasing focus on improving patient outcomes from reproductive treatment by using research to inform clinical practice. However little is known about the views of reproductive nurses, counsellors and doctors about the role of research in their day to day clinical work. This study examined the knowledge and attitudes to research of reproductive medicine health professionals, and explored factors that may motivate or create barriers to their involvement in research. We conducted a survey in Australia between November 2012 and February 2013. Ninety-six health professionals consented to participate and completed the questionnaire. The majority indicated the importance of research influencing their clinical practice, and the role research has with improving patient outcomes. Many clinicians indicated they would like to participate in research, however time and resources were acknowledged as barriers which stopped their involvement., (Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)