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Background: Polycystic ovary syndrome (PCOS) is the most frequent cause of anovulatory infertility. In women with PCOS, effective ovulation induction serves as an important first-line treatment for anovulatory infertility. Individual participant data (IPD) meta-analysis is considered as the gold standard for evidence synthesis which provides accurate assessments of outcomes from primary randomised controlled trials (RCTs) and allows additional analyses for time-to-event outcomes. It also facilitates treatment-covariate interaction analyses and therefore offers an opportunity for personalised medicine., Objective and Rationale: We aimed to evaluate the effectiveness of different ovulation induction agents, in particular letrozole alone and clomiphene citrate (CC) plus metformin, as compared to CC alone, as the first-line choice for ovulation induction in women with PCOS and infertility, and to explore interactions between treatment and participant-level baseline characteristics., Search Methods: We searched electronic databases including MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials up to 20 December 2018. We included RCTs comparing the following interventions with each other or placebo/no treatment in women with PCOS and infertility: CC, metformin, CC plus metformin, letrozole, gonadotrophin and tamoxifen. We excluded studies on treatment-resistant women. The primary outcome was live birth. We contacted the investigators of eligible RCTs to share the IPD and performed IPD meta-analyses. We assessed the risk of bias by using the Cochrane risk of bias tool for RCTs., Outcomes: IPD of 20 RCTs including 3962 women with PCOS were obtained. Six RCTs compared letrozole and CC in 1284 women. Compared with CC, letrozole improved live birth rates (3 RCTs, 1043 women, risk ratio [RR] 1.43, 95% confidence interval [CI] 1.17-1.75, moderate-certainty evidence) and clinical pregnancy rates (6 RCTs, 1284 women, RR 1.45, 95% CI 1.23-1.70, moderate-certainty evidence) and reduced time-to-pregnancy (6 RCTs, 1235 women, hazard ratio [HR] 1.72, 95% CI 1.38-2.15, moderate-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline serum total testosterone levels and treatment effects on live birth (interaction RR 1.29, 95% CI 1.01-1.65). Eight RCTs compared CC plus metformin to CC alone in 1039 women. Compared with CC alone, CC plus metformin might improve clinical pregnancy rates (8 RCTs, 1039 women, RR 1.18, 95% CI 1.00-1.39, low-certainty evidence) and might reduce time-to-pregnancy (7 RCTs, 898 women, HR 1.25, 95% CI 1.00-1.57, low-certainty evidence), but there was insufficient evidence of a difference on live birth rates (5 RCTs, 907 women, RR 1.08, 95% CI 0.87-1.35, low-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline insulin levels and treatment effects on live birth in the comparison between CC plus metformin and CC (interaction RR 1.03, 95% CI 1.01-1.06)., Wider Implications: In women with PCOS, letrozole improves live birth and clinical pregnancy rates and reduces time-to-pregnancy compared to CC and therefore can be recommended as the preferred first-line treatment for women with PCOS and infertility. CC plus metformin may increase clinical pregnancy and may reduce time-to-pregnancy compared to CC alone, while there is insufficient evidence of a difference on live birth. Treatment effects of letrozole are influenced by baseline serum levels of total testosterone, while those of CC plus metformin are affected by baseline serum levels of insulin. These interactions between treatments and biomarkers on hyperandrogenaemia and insulin resistance provide further insights into a personalised approach for the management of anovulatory infertility related to PCOS., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Understanding local conformations of DNA at the level of individual nucleic acid bases and base pairs is important for elucidating molecular processes that depend on DNA sequence. Here, we apply linear absorption and circular dichroism measurements to the study of local DNA conformations, using the guanine base analog 6-methyl isoxanthopterin (6-MI) as a structural probe. We show that the spectroscopic properties of this probe can provide detailed information about the average local base and basepair conformations as a function of the surrounding DNA sequence. Based on these results we apply a simple theoretical model to calculate the circular dichroism spectra of 6-MI-substituted DNA constructs and show that our model can be used to extract information about how the local conformations of the 6-MI probe are influenced by the local base or basepair environment. We also use this probe to examine the pathway for the insertion (intercalation) of a tethered acridine ligand (9-amino-6-chloro methoxyacridine) into duplex DNA. We show that this model intercalator interacts with duplex DNA by a "displacement insertion intercalation" mechanism, whereby the acridine moiety is inserted into the DNA structure and displaces the base located opposite its attachment site. These findings suggest that site-specifically positioned base analog probes can be used to characterize the molecular and structural details of binding ligand effects on local base stacking and unstacking reactions in single- and double-stranded DNA and thus may help to define the molecular mechanisms of DNA-protein interactions that involve the site-specific intercalation of aromatic amino acid side chains into genomic DNA., (Copyright © 2019 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Objectives: To identify clinical, angiographic and hemodynamic predictors of discordance between instantaneous wave-free ratio (iFR) and fractional flow reserve (FFR)., Background: The iFR was found to be non-inferior to the gold-standard FFR for guiding coronary revascularization, although it is discordant with FFR in 20% of cases. A better understanding of the causes of discordance may enhance application of these indices., Methods: Both FFR and iFR were measured in the prospective multicenter CONTRAST study. Clinical, angiographic and hemodynamic variables were compared between patients with concordant values of FFR and iFR (cutoff ≤0.80 and ≤0.89, respectively)., Results: Out of the 587 patients included, in 466 patients (79.4%) FFR and iFR agreed: both negative, n = 244 (41.6%), or positive, n = 222 (37.8%). Compared with FFR, iFR was negative discordant (FFR+/iFR-) in 69 (11.8%) patients and positive discordant (FFR-/iFR+) in 52 (8.9%) patients. On multivariate regression, stenosis location (left main or proximal left anterior descending) (OR: 3.30[1.68;6.47]), more severe stenosis (OR: 1.77[1.35;2.30]), younger age (OR: 0.93[0.90;0.97]), and slower heart rate (OR: 0.59[0.42;0.75]) were predictors of a negative discordant iFR. Absence of a beta-blocker (OR: 0.41[0.22;0.78]), older age (OR: 1.04[1.00;1.07]), and less severe stenosis (OR: 0.69[0.53;0.89]) were predictors of a positive discordant iFR., Conclusions: During iFR acquisition, stenosis location, stenosis degree, heart rate, age and use of beta blockers influence concordance with FFR and should be taken into account when interpreting iFR., (© 2019 Wiley Periodicals, Inc.)

Aims: The instantaneous wave-free ratio (iFR) and whole-cycle Pd/Pa investigate coronary physiology during non-hyperaemic conditions. To test for unique physiologic properties of the wave-free period when making resting coronary pressure measurements, we compared post hoc a diastolic pressure ratio (dPR) and Pd/Pa against iFR for numerical similarity and test/retest repeatability., Methods and Results: Eight hundred and ninety-three lesions from 833 subjects were included from the VERIFY 2 and CONTRAST studies. Diastolic pressure ratio and a linear transform of Pd/Pa were compared against iFR for diagnostic performance. Mean difference between dPR and iFR [Δ = -0.006 ± 0.011, r2 = 0.993, area under receiver operating characteristic (ROC) curve (AUC) = 0.997] mirrored the difference of two iFR measurements repeated immediately (Δ = <0.001 ± 0.004, r2 = 0.998, AUC = 1.00). Minor variations in the definition of dPR changed its value by <1-2% over a broad range of the cardiac cycle. A linear transform of Pd/Pa showed very good diagnostic performance (Δ = -0.012 ± 0.031, r2 = 0.927, AUC = 0.979). Post hoc iFR values were validated against real-time iFR values and matched almost exactly (average Δ = <0.001 ± 0.004, 99.6% within ±0.01)., Conclusions: Our dPR offers numerical equivalency to iFR. Despite different technical approaches for identifying the relevant period of diastole, the agreement between dPR and iFR and the insensitivity of dPR to minor variations in its definition further confirm numerical equivalency among resting metrics., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Objectives: To compare, in women with infertility, the effectiveness and safety of tubal flushing using oil-based contrast medium, water-based contrast medium or their combination, and no tubal flushing, and to evaluate the effectiveness of tubal flushing on fertility outcome over time., Methods: We performed a systematic review and network meta-analysis, searching the electronic databases MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials, and trial registries, up to 25 September 2018. We included randomized controlled trials (RCTs) comparing the following interventions with each other or with no intervention in women with infertility: tubal flushing using water-based contrast medium, tubal flushing using oil-based contrast medium or additional tubal flushing with oil-based medium following diagnostic tubal flushing with water-based medium. The outcomes included clinical pregnancy, live birth, ongoing pregnancy, miscarriage, ectopic pregnancy and adverse events., Results: Of the 283 studies identified through the search, 14 RCTs reporting on 3852 women with infertility were included. Network meta-analysis showed that tubal flushing using oil-based contrast medium was associated with higher odds of clinical pregnancy within 6 months after randomization and more subsequent live births compared with tubal flushing using water-based medium (odds ratio (OR), 1.67 (95% CI, 1.38-2.03), moderate certainty of evidence; and OR, 2.18 (95% CI, 1.30-3.65), low certainty of evidence, respectively) and compared with no intervention (OR, 2.28 (95% CI, 1.50-3.47), moderate certainty of evidence; and OR, 2.85 (95% CI, 1.41-5.74), low certainty of evidence, respectively). These results agreed with those of the pairwise meta-analysis. For clinical pregnancy within 6 months, there was insufficient evidence of a difference between tubal flushing with water-based contrast medium and no intervention (OR, 1.36 (95% CI, 0.91-2.04), low certainty of evidence). For fertility outcomes after 6 months, there was insufficient evidence of a difference in any comparison (low to very low certainty of evidence). Compared with tubal flushing using water-based contrast medium, the use of oil-based contrast medium was associated with higher odds of asymptomatic intravasation (OR, 5.06 (95% CI, 2.29-11.18), moderate certainty of evidence)., Conclusions: In women with infertility undergoing fertility workup, tubal flushing using oil-based contrast medium probably increases clinical pregnancy rates within 6 months after randomization and may increase subsequent live-birth rates, compared with tubal flushing using water-based contrast medium and compared with no intervention. Evidence on fertility outcomes beyond 6 months is inadequate to draw firm conclusions. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.)

Aims: To evaluate effects of caffeine on quantitative myocardial perfusion by positron emission tomography (PET) and associated major adverse cardiovascular events (MACE)., Methods and Results: Serum caffeine was measured for all 6087 PETs with 328 positive results (5.4%). Paired caffeine positive/negative PETs (84 patients for dipyridamole with median caffeine 1.6 mg/L, and additional 25 volunteers for regadenoson with median caffeine 7.4 mg/L) were compared for quantitative perfusion. Multivariate regression analysis for associations among caffeine, clinical/imaging variables, predicted caffeine probability was performed. MACEs were followed up to 9 years after PETs. For caffeine vs. no caffeine, respectively, stress flow was 1.74 ± 0.55 vs. 2.14 ± 0.53 for dipyridamole and 1.82 ± 0.61 vs. 2.33 ± 0.49 mL/min/g for regadenoson, and coronary flow reserve (CFR) was 2.26 ± 0.67 vs. 2.67 ± 0.72 for dipyridamole and 1.84 ± 0.33 vs. 2.31 ± 0.41 for regadenoson (all P < 0.001). Subjects were reclassified from high-risk CFR ≤2.0 with caffeine to low-risk CFR >2.0 without caffeine in 66.7% and 80% of dipyridamole and regadenoson caffeine-no-caffeine pairs, respectively. While relative images showed no differences, caffeine significantly altered coronary flow capacity (CFC) to false negative and false positive severity in 2.1% and 5.5% of the 328 caffeine positives, respectively (0.1% and 0.3% of 6087 PETs) but without change in severity guided management in most patients (92.4% of 328 caffeine or 99.6% of total 6087 PETs)., Conclusion: Even low serum caffeine levels reduce quantitative perfusion during vasodilatory stress with false positive or false negative results minimized by empathic instruction, CFC analysis or repeat PET after strict caffeine abstention for definitive individualized risk stratification and management., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Pharmacologic reversal of serious or intolerable side effects (SISEs) from vasodilator stress is an important safety and comfort measure for patients experiencing such effects. While typically performed using intravenous aminophylline, recurrent shortages of this agent have led to a greater need to limit its use and consider alternative agents. This information statement provides background and recommendations addressing indications for vasodilator reversal, timing of a reversal agent, incidence of observed SISE with vasodilator stress, clinical and logistical considerations for aminophylline-based reversal, and alternative non-aminophylline based reversal protocols.

Introduction: Studies have shown in vitro fertilization (IVF) treatment to have a significant impact on women's quality of life. In addition, anxiety is experienced during IVF treatment and prior to knowing the outcome from a treatment cycle. Although support services are available at many IVF clinics, the uptake of these opportunities may not be high. Acupuncture is used by women undertaking IVF treatment in the belief that it improves their reproductive outcomes, and some studies suggest that it may reduce anxiety. The objective of this study was to examine the effects of acupuncture compared with sham acupuncture on quality of life and anxiety for women undergoing an IVF cycle., Material and Methods: A multicenter randomized controlled trial was conducted in Australia and New Zealand. Women were eligible if they were aged 18-42 years, undergoing a fresh IVF cycle and not using acupuncture. Recruitment occurred between June 2011 and October 2015. Women were randomized to acupuncture or a sham acupuncture control group and three treatments were administered, the first treatment between day 6 and 8 of ovarian stimulation, and two treatments were given on the day of embryo transfer. The primary outcome was livebirth. Secondary outcomes included quality of life and anxiety, and were assessed at baseline, on the day of embryo transfer and 14 weeks from trial entry., Results: In all, 848 women were randomized to the trial, 608 women underwent an embryo transfer, of which 526 (86%) received all three treatments. Adjusted analysis found that women receiving acupuncture reported reduced anxiety following embryo transfer (mean difference [MD] -1.1, 95% CI -2.2 to -0.1, P = 0.03). Unadjusted analysis of quality of life did not differ between groups following embryo transfer. Adjusted analyses by per protocol found a significant positive change for the acupuncture group for the general health MOS Short Form 36 (SF36) domain (MD 2.6, 95% CI 0.5-4.7, P = 0.01) following embryo transfer. The benefit was not sustained at 14 weeks (MD 0.1, 95% CI -2.7 to 2.9)., Conclusions: Acupuncture may reduce anxiety at embryo transfer. Quality of life did not differ between the groups. Women experience reduced emotional well-being 3 months following the IVF cycle, highlighting ongoing unmet psycho-social needs., (© 2018 Nordic Federation of Societies of Obstetrics and Gynecology.)

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.)

Because randomized coronary revascularization trials in stable coronary artery disease (CAD) have shown no reduced myocardial infarction (MI) or mortality, the threshold of quantitative myocardial perfusion severity was analyzed for association with reduced death, MI, or stroke after revascularization within 90 d after PET. Methods: In a prospective long-term cohort of stable CAD, regional, artery-specific, quantitative myocardial perfusion by PET, coronary revascularization within 90 d after PET, and all-cause death, MI, and stroke (DMS) at 9-y follow-up (mean ± SD, 3.0 ± 2.3 y) were analyzed by multivariate Cox regression models and propensity analysis. Results: For 3,774 sequential rest-stress PET scans, regional, artery-specific, severely reduced coronary flow capacity (CFC) (coronary flow reserve ≤ 1.27 and stress perfusion ≤ 0.83 cc/min/g) associated with 60% increased hazard ratio for major adverse cardiovascular events and 30% increased hazard of DMS that was significantly reduced by 54% associated with revascularization within 90 d after PET ( P = 0.0369), compared with moderate or mild CFC, coronary flow reserve, other PET metrics or medical treatment alone. Depending on severity threshold for statistical certainty, up to 19% of this clinical cohort had CFC severity associated with reduced DMS after revascularization. Conclusion: CFC by PET provides objective, regional, artery-specific, size-severity physiologic quantification of CAD severity associated with high risk of DMS that is significantly reduced after revascularization within 90 d after PET, an association not seen for moderate to mild perfusion abnormalities or medical treatment alone., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

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.)

Aims: The aim of this study was to evaluate the predictability of resting distal coronary pressure wave forms for fractional flow reserve (FFR)., Methods and Results: Resting coronary wave forms were qualitatively evaluated for the presence of (i) dicrotic notch, (ii) diastolic dipping, and (iii) ventricularisation. In a development cohort (n=88), a scoring system was developed that was then applied to a validation cohort (n=428) using a multivariable linear regression model to predict FFR and receiver operating characteristics (ROC) to predict FFR ≤0.8. In the development cohort, all three qualitative parameters were independent predictors of FFR. However, in a multivariable linear regression model in the validation cohort, qualitative wave form analysis did not further improve the ability of resting distal coronary to aortic pressure ratio (Pd/Pa) (p=0.80) or instantaneous wave-free ratio (iFR) (p=0.26) to predict FFR. Using ROC, the area under the curve of resting Pd/Pa (0.86 versus 0.86, p=0.08) and iFR (0.86 versus 0.86, p=0.26) did not improve by adding qualitative analysis., Conclusions: Qualitative coronary wave form analysis showed moderate classification agreement in predicting FFR but did not add substantially to the resting pressure gradients Pd/Pa and iFR; however, when discrepancies between quantitative and qualitative analyses are observed, artefact or pressure drift should be considered.

Aims: To assess the effect of fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) with contemporary drug-eluting stents on the composite of cardiac death or myocardial infarction (MI) vs. medical therapy in patients with stable coronary lesions., Methods and Results: We performed a systematic review and meta-analysis of individual patient data (IPD) of the three available randomized trials of contemporary FFR-guided PCI vs. medical therapy for patients with stable coronary lesions: FAME 2 (NCT01132495), DANAMI-3-PRIMULTI (NCT01960933), and Compare-Acute (NCT01399736). FAME 2 enrolled patients with stable coronary artery disease (CAD), while the other two focused on non-culprit lesions in stabilized patients after acute coronary syndrome. A total of 2400 subjects were recruited from 54 sites world-wide with 1056 randomly assigned to FFR-guided PCI and 1344 to medical therapy. The pre-specified primary outcome was a composite of cardiac death or MI. We included data from extended follow-ups for FAME 2 (up to 5.5 years follow-up) and DANAMI-3-PRIMULTI (up to 4.7 years follow-up). After a median follow-up of 35 months (interquartile range 12-60 months), a reduction in the composite of cardiac death or MI was observed with FFR-guided PCI as compared with medical therapy (hazard ratio 0.72, 95% confidence interval 0.54-0.96; P = 0.02). The difference between groups was driven by MI., Conclusion: In this IPD meta-analysis of the three available randomized controlled trials to date, FFR-guided PCI resulted in a reduction of the composite of cardiac death or MI compared with medical therapy, which was driven by a decreased risk of MI.

Background: Currently, invasive physiologic assessment such as fractional flow reserve is widely used worldwide with different adoption rates around the globe. Patient characteristics and physician preferences often differ in the Asia-Pacific (APAC) region with respect to treatment strategy, techniques, lesion complexity, access to coronary physiology and imaging devices, as well as patient management. Thus, there is a need to construct a consensus document on recommendations for use of physiology-guided percutaneous coronary intervention (PCI) in APAC populations. This document serves as an overview of recommendations describing the best practices for APAC populations to achieve more consistent and optimal clinical outcomes., Methods and Results: A comprehensive multiple-choice questionnaire was provided to 20 interven- tional cardiologists from 10 countries in the APAC region. Clinical evidence, tips and techniques, and clinical situations for the use of physiology-guided PCI in APAC were reviewed and used to propose key recommendations. There are suggestions to continue to develop evidence for lesion and patient types that will benefit from physiology, develop directions for future research in health economics and local data, develop appropriate use criteria in different countries, and emphasize the importance of education of all stakeholders. A consensus recommendation to enhance the penetration of invasive physiology-based therapy was to adopt the 5E approach: Evidence, Education, Expand hardware, Economics and Expert consensus., Conclusions: This consensus document and recommendations support interventional fellows and cardiologists, hospital administrators, patients, and medical device companies to build confidence and encourage wider implementation of invasive coronary physiology-guided therapy in the APAC region.

Pharmacologic reversal of serious or intolerable side effects (SISE) from vasodilator stress is an important safety and comfort measure for patients experiencing such effects. While typically performed using intravenous aminophylline, recurrent shortages of this agent have led to a greater need to limit its use and consider alternative agents. This information statement provides background and recommendations addressing indications for vasodilator reversal, timing of a reversal agent, incidence of observed SISE with vasodilator stress, clinical and logistical considerations for aminophylline-based reversal, and alternative non-aminophylline based reversal protocols.

Angina with no angiographic stenosis, commonly called "microvascular angina," encompasses a wide continuum of coronary pathophysiology in conflicting published reports. Comprehensive quantitative myocardial perfusion offers new insights beyond overly simplistic coronary flow reserve. Integrating regional absolute stress flow, relative stress flow, coronary flow reserve, and qualitative subendocardial perfusion gradient on tomograms of relative images, provides correct diagnosis, quantitative physiological classification, and potential treatment. Angina without angiographic stenosis is associated with abnormal quantitative perfusion with rare, but instructive, exceptions. However, microvascular dysfunction without angina is common, particularly associated with risk factors. Reduced subendocardial/epicardial relative activity is common with diffuse coronary artery disease without focal stenosis with or without angina depending on the severity of reduced subendocardial perfusion. Precision quantitative myocardial perfusion in 5,900 cases objectively classifies angina with no angiographic stenosis into 4 categories: subendocardial ischemia due to diffuse coronary artery disease (most common), overlooked stenosis, diffuse microvascular dysfunction due to risk factors or specific microvasculopathies, and nonischemic cardiac pain mechanisms (rare), or some mix of these prototypes, of which 95% associate with risk factors, or subclinical or clinically manifest coronary atherosclerosis needing vigorous risk factor treatment., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Randomised controlled trials have reported instantaneous wave-free ratio (iFR) to be non-inferior to fractional flow reserve (FFR) for major adverse cardiovascular events at one year; however, iFR is limited by sensitive landmarking of the pressure waveform, and the assumption that maximal flow and minimal resistance occur during a fixed period of diastole. We sought to validate the resting full-cycle ratio (RFR), a novel non-hyperaemic index of coronary stenosis severity based on unbiased identification of the lowest distal coronary pressure to aortic pressure ratio (Pd/Pa), independent of the ECG, landmark identification, and timing within the cardiac cycle., Methods and Results: VALIDATE-RFR was a retrospective study designed to derive and validate the RFR. The primary endpoint was the agreement between RFR and iFR. RFR was retrospectively determined in 651 waveforms in which iFR was measured using a proprietary Philips/Volcano wire. RFR was highly correlated to iFR (R2=0.99, p<0.001), with a mean bias of -0.002 (95% limits of agreement -0.023 to 0.020). The diagnostic performance of RFR versus iFR was diagnostic accuracy 97.4%, sensitivity 98.2%, specificity 96.9%, positive predictive value 94.5%, negative predictive value 99.0%, area under the receiver operating characteristic curve of 0.996, and diagnostically equivalent within 1% (mean difference -0.002; 95% CI: -0.009 to 0.006, p=0.03). The RFR was detected outside diastole in 12.2% (341/2,790) of all cardiac cycles and 32.4% (167/516) of cardiac cycles in the right coronary artery where the sensitivity of iFR compared to FFR was lowest (40.6%)., Conclusions: RFR is diagnostically equivalent to iFR but unbiased in its ability to detect the lowest Pd/Pa during the full cardiac cycle, potentially unmasking physiologically significant coronary stenoses that would be missed by assessment dedicated to specific segments of the cardiac cycle.

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.)

Aims: Echocardiography and tomographic imaging have documented dynamic changes in aortic stenosis (AS) geometry and severity during both the cardiac cycle and stress-induced increases in cardiac output. However, corresponding pressure gradient vs. flow relationships have not been described., Methods and Results: We recruited 16 routine transcatheter aortic valve implantations (TAVI's) for graded dobutamine infusions both before and after implantation; 0.014″ pressure wires in the aorta and left ventricle (LV) continuously measured the transvalvular pressure gradient (ΔP) while a pulmonary artery catheter regularly assessed cardiac output by thermodilution. Before TAVI, ΔP did not display a consistent relationship with transvalvular flow (Q). Neither linear resistor (median R2 0.16) nor quadratic orifice (median R2 < 0.01) models at rest predicted stress observations; the severely stenotic valve behaved like a combination. The unitless ratio of aortic to left ventricular pressures during systolic ejection under stress conditions correlated best with post-TAVI flow improvement. After TAVI, a highly linear relationship (median R2 0.96) indicated a valid valve resistance., Conclusion: Pressure loss vs. flow curves offer a fundamental fluid dynamic synthesis for describing aortic valve pathophysiology. Severe AS does not consistently behave like an orifice (as suggested by Gorlin) or a resistor, whereas TAVI devices behave like a pure resistor. During peak dobutamine, the ratio of aortic to left ventricular pressures during systolic ejection provides a 'fractional flow reserve' of the aortic valve that closely approximates the complex, changing fluid dynamics. Because resting assessment cannot reliably predict stress haemodynamics, 'valvular fractional flow' warrants study to explain exertional symptoms in patients with only moderate AS at rest.

Objective: To evaluate the efficacy and safety of elagolix, an oral, nonpeptide gonadotropin-releasing hormone antagonist, over 12 months in women with endometriosis-associated pain., Methods: Elaris Endometriosis (EM)-III and -IV were extension studies that evaluated an additional 6 months of treatment after two 6-month, double-blind, placebo-controlled phase 3 trials (12 continuous treatment months) with two elagolix doses (150 mg once daily and 200 mg twice daily). Coprimary efficacy endpoints were the proportion of responders (clinically meaningful pain reduction and stable or decreased rescue analgesic use) based on average monthly dysmenorrhea and nonmenstrual pelvic pain scores. Safety assessments included adverse events, clinical laboratory tests, and endometrial and bone mineral density assessments. The power of Elaris EM-III and -IV was based on the comparison to placebo in Elaris EM-I and -II with an expected 25% dropout rate., Results: Between December 28, 2012, and October 31, 2014 (Elaris EM-III), and between May 27, 2014, and January 6, 2016 (Elaris EM-IV), 569 participants were enrolled. After 12 months of treatment, Elaris EM-III responder rates for dysmenorrhea were 52.1% at 150 mg once daily (Elaris EM-IV 550.8%) and 78.2% at 200 mg twice daily (Elaris EMIV 575.9%). Elaris EM-III nonmenstrual pelvic pain responder rates were 67.5% at 150 mg once daily (Elaris EM-IV 566.4%) and 69.1% at 200 mg twice daily (Elaris EM-IV 567.2%).”After 12 months of treatment, Elaris EM-III dyspareunia responder rates were 45.2% at 150 mg once daily (Elaris EM-IV=45.9%) and 60.0% at 200 mg twice daily (Elaris EM-IV=58.1%). Hot flush was the most common adverse event. Decreases from baseline in bone mineral density and increases from baseline in lipids were observed after 12 months of treatment. There were no adverse endometrial findings., Conclusion: Long-term elagolix treatment provided sustained reductions in dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia. The safety was consistent with reduced estrogen levels and no new safety concerns were associated with long-term elagolix use., Clinical Trial Registration: ClinicalTrials.gov, NCT01760954 and NCT02143713.

Background: Fractional flow reserve (FFR)-guided coronary artery bypass graft (CABG) surgery has been associated with lower number of graft anastomoses, lower rate of on-pump surgery, and higher graft patency rate as compared with angiography-guided CABG surgery. However, no clinical benefit has been reported to date., Methods and Results: Consecutive patients (n=627) treated by CABG between 2006 and 2010 were retrospectively included. In 198 patients, at least 1 stenosis was grafted according to FFR (FFR-guided group), whereas in 429 patients all stenoses were grafted based on angiography (angiography-guided group). The 2 coprimary end points were overall death or myocardial infarction and major adverse cardiovascular events (composite of overall death, myocardial infarction, and target vessel revascularization) up to 6-year follow-up. In the FFR-guided group, patients were significantly younger (66 [57-73] versus 70 [63-76]; P <0.001), more often male (82% versus 72%; P =0.008), and less often diabetic (21% versus 30%; P =0.023). Clinical follow-up (median, 85 [66-104] months) was analyzed in 396 patients after 1:1 propensity-score matching for these 3 variables. The rate of overall death or myocardial infarction was significantly lower in the FFR-guided (n=31 [16%] versus n=49 [25%]; hazard ratio, 0.59 [95% confidence interval, 0.38-0.93]; P =0.020) as compared with the angiography-guided group. Major adverse cardiovascular events rate was also numerically lower in the FFR-guided than in the angiography-guided group (n=42 [21%] versus n=52 [26%]; hazard ratio, 0.77 [95% confidence interval, 0.51-1.16]; P =0.21)., Conclusions: FFR-guided CABG is associated with a significant reduction in the rate of overall death or myocardial infarction at 6-year follow-up as compared with angiography-guided CABG., (© 2018 American Heart Association, Inc.)

Importance: Acupuncture is widely used by women undergoing in vitro fertilization (IVF), although the evidence for efficacy is conflicting., Objective: To determine the efficacy of acupuncture compared with a sham acupuncture control performed during IVF on live births., Design, Setting, and Participants: A single-blind, parallel-group randomized clinical trial including 848 women undergoing a fresh IVF cycle was conducted at 16 IVF centers in Australia and New Zealand between June 29, 2011, and October 23, 2015, with 10 months of pregnancy follow-up until August 2016., Interventions: Women received either acupuncture (n = 424) or a sham acupuncture control (n = 424). The first treatment was administered between days 6 to 8 of follicle stimulation, and 2 treatments were administered prior to and following embryo transfer. The sham control used a noninvasive needle placed away from the true acupuncture points., Main Outcomes and Measures: The primary outcome was live birth, defined as the delivery of 1 or more living infants at greater than 20 weeks' gestation or birth weight of at least 400 g., Results: Among 848 randomized women, 24 withdrew consent, 824 were included in the study (mean [SD] age, 35.4 [4.3] years); 371 [45.0%] had undergone more than 2 previous IVF cycles), 607 proceeded to an embryo transfer, and 809 (98.2%) had data available on live birth outcomes. Live births occurred among 74 of 405 women (18.3%) receiving acupuncture compared with 72 of 404 women (17.8%) receiving sham control (risk difference, 0.5% [95% CI, -4.9% to 5.8%]; relative risk, 1.02 [95% CI, 0.76 to 1.38])., Conclusions and Relevance: Among women undergoing IVF, administration of acupuncture vs sham acupuncture at the time of ovarian stimulation and embryo transfer resulted in no significant difference in live birth rates. These findings do not support the use of acupuncture to improve the rate of live births among women undergoing IVF., Trial Registration: anzctr.org.au Identifier: ACTRN12611000226909.

Aims: Hypothermia reduces reperfusion injury and infarct size in animal models of acute myocardial infarction if started before reperfusion. Human studies have not confirmed benefit, probably due to insufficient myocardial cooling and adverse systemic effects. This study sought to assess the safety and feasibility of a novel method for selective, sensor-monitored intracoronary hypothermia., Methods and Results: Ten patients undergoing primary percutaneous coronary intervention (PPCI) were included. Saline at room temperature was administered distal to the culprit lesion through an inflated overthe- wire balloon (OTWB) in order to cool the endangered myocardium for 10 minutes (occlusion phase). Next, the OTWB was deflated and cooling continued with saline at 4°C for another 10 minutes (reperfusion phase). A sensor-tipped temperature wire in the distal coronary artery allowed titration of the infusion rate to achieve the desired coronary temperature (6°C below body temperature). Target coronary temperature was achieved within 27 seconds (median; IQR 21-46). Except for two patients with inferior wall infarction experiencing transient conduction disturbances, no side effects occurred. Systemic temperature remained unchanged. Finally, PPCI was performed as per routine., Conclusions: Selective hypothermia of the infarct area by intracoronary infusion of saline provides a novel method to reduce coronary temperature quickly and guarantee local myocardial hypothermia. In anterior wall myocardial infarctions, the protocol appeared safe, without serious haemodynamic or systemic side effects. In inferior wall myocardial infarctions, transient conduction abnormalities of short duration occurred. Potentially, selective intracoronary delivery of hypothermia could attenuate reperfusion injury caused by traditional PPCI.

Because current reperfusion strategies in acute myocardial infarction (AMI) seem to be exhausted in terms of additional mortality benefit, there remains a need for new methods to attenuate reperfusion injury and, thereby, further reduce myocardial infarct size and improve long-term survival. Therapeutic hypothermia (32-35°C) diminishes reperfusion injury and reduces infarct size in a variety of animal models of AMI if provided before reperfusion. In human studies this reduction has not been confirmed so far, most likely because systemic cooling acts slowly, and therefore, the target temperature is not reached in time or at all in a substantial number of patients. Furthermore, systemic cooling can cause adverse effects such as severe shivering, volume overload, and an enhanced adrenergic state. In most randomized clinical trials, however, subgroups of patients with anterior myocardial infarction that reached the target temperature before reperfusion did show a reduction in infarct size. To transform therapeutic hypothermia into a clinically feasible treatment for AMI, its method must be modified. An ideal technique should be quick enough to achieve sufficient myocardial hypothermia before reperfusion, without significant delay and without the adverse effects of systemic cooling. In this review, we propose a novel, potentially feasible method of selective intracoronary hypothermia to overcome the problems encountered with prior techniques.

Objective: We propose a novel technique called pressure-bounded coronary flow reserve (pb-CFR) and demonstrate its application to the randomized DEFER trial., Background: Intracoronary flow reserve assessment remains underutilized relative to pressure measurements partly due to less robust tools., Methods: While rest and hyperemic intracoronary pressure measurements cannot quantify CFR exactly, they do provide upper and lower bounds. We validated pb-CFR invasively against traditional CFR, then applied it to high fractional flow reserve (FFR ≥ 0.75) lesions in DEFER randomized to revascularization or medical therapy., Results: pb-CFR showed an 84.4% accuracy to predict invasive CFR < 2 or CFR ≥ 2 in 107 lesions. In its proof of concept application to DEFER lesions with FFR ≥ 0.75, the 28 with pb-CFR < 2 compared to 28 with pb-CFR ≥ 2 had a non-significant reduction in freedom from angina (61% vs. 71% at 5 years, P = 0.57) and a non-significantly higher rate of major adverse cardiac events (MACE, 25% vs. 15%, P = 0.34). Lesions with FFR ≥ 0.75 but pb-CFR < 2 showed no difference in freedom from angina (61% vs. 50%, P = 0.54) or MACE (25% vs. 38%, P = 0.27) between the 28 randomized to medical therapy and the 16 randomized to revascularization., Conclusions: pb-CFR offers a new method for studying FFR/CFR discordances using regular pressure wire measurements. As an example application, DEFER suggested that low pb-CFR with high FFR may be a risk marker for more angina and worse outcomes, but that this risk cannot be modified by revascularization. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Background: Recently, 2 randomized controlled trials showed that the instantaneous wave-free ratio (iFR), a resting coronary physiological index, is noninferior to fractional flow reserve for guiding revascularization. The resting distal to aortic coronary pressure (P d /P a ) measured at rest is another adenosine-free index widely available in the cardiac catheterization laboratory; however, little is known about the agreement of P d /P a using iFR as a reference standard., Objectives: The goal of this study was to investigate the agreement of P d /P a with iFR., Methods: A total of 763 patients were prospectively enrolled from 12 institutions. iFR and P d /P a were measured under resting conditions. Using iFR ≤0.89 as a reference standard, the agreement of P d /P a and its best cutoff value were assessed., Results: According to the independent core laboratory analysis, iFR and P d /P a were analyzable in 627 and 733 patients (82.2% vs. 96.1%; p < 0.001), respectively. The median iFR and P d /P a were 0.90 (interquartile range: 0.85 to 0.94) and 0.92 (interquartile range: 0.88 to 0.95), and the 2 indices were highly correlated (R 2  = 0.93; p < 0.001; iFR = 1.31 * P d /P a -0.31). According to the receiver-operating characteristic curve analysis, P d /P a showed excellent agreement (area under the curve: 0.98; 95% confidence interval: 0.97 to 0.99; p < 0.001) with a best cutoff value of P d /P a  ≤0.91. The diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 93.0%, 91.4%, 94.4%, 93.3%, and 92.7%, respectively. These results were similar in patients with acute coronary syndrome and stable angina., Conclusions: P d /P a was analyzable in a significantly higher number of patients than iFR. P d /P a showed excellent agreement with iFR, suggesting that it could be applied clinically in a similar fashion. (Can Contrast Injection Better Approximate FFR Compared to Pure Resting Physiology? [CONTRAST]; NCT02184117)., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: This study independently evaluated the diagnostic performance of electrocardiographic (ECG) criteria to predict the infarct-related artery (IRA) in patients with an acute ST-segment elevation myocardial infarction (STEMI). While a number of ECG criteria have been proposed to predict the IRA in STEMI, many of these "rules" came from modestly sized populations and did not undergo external validation. Therefore, we aimed to evaluate popular criteria from the literature in an independent cohort., Methods and Results: All acute STEMI cases over a 10-year period from a single hospital were retrospectively identified. We excluded patients with a missing pre-intervention ECG, irretrievable angiographic films, prior coronary artery bypass grafting, left bundle branch block, ventricular pacing, or not meeting strict STEMI criteria. After review of the angiograms for the IRA, cases with either no or multiple culprits were excluded. We included 480 subjects meeting STEMI criteria in inferior leads (192, 40%), anterior leads (184, 38%), both anterior and inferior leads (88, 18%), isolated lateral leads (nine, 2%), or a posterior pattern (seven, 1%). Notably, every pattern except isolated lateral STEMI included an IRA in both the right and left coronary arteries., Conclusions: Existing ECG criteria to predict the IRA in STEMI have modest diagnostic performance when externally validated, and lower than in the original reports. Distinguishing the level of obstruction in the left anterior descending artery remains especially challenging. Hence, their use should be pragmatic when selecting an initial catheter for treating STEMI, since discordances will occur when compared to the actual angiogram.

Background: Contrast fractional flow reserve (cFFR) is a method for assessing functional significance of coronary stenoses, which is more accurate than resting indices and does not require adenosine. However, contrast media volume and osmolality may affect the degree of hyperemia and therefore diagnostic performance., Methods and Results: cFFR, instantaneous wave-free ratio, distal pressure/aortic pressure at rest, and FFR were measured in 763 patients from 12 centers. We compared the diagnostic performance of cFFR between patients receiving low or iso-osmolality contrast (n=574 versus 189) and low or high contrast volume (n=341 versus 422) using FFR≤0.80 as a reference standard. The sensitivity, specificity, and overall accuracy of cFFR for the low versus iso-osmolality groups were 73%, 93%, and 85% versus 87%, 90%, and 89%, and for the low versus high contrast volume groups were 69%, 99%, and 83% versus 82%, 93%, and 88%. By receiver operating characteristics (ROC) analysis, cFFR provided better diagnostic performance than resting indices regardless of contrast osmolality and volume ( P <0.001 for all groups). There was no significant difference between the area under the curve of cFFR in the low- and iso-osmolality groups (0.938 versus 0.957; P =0.40) and in the low- and high-volume groups (0.939 versus 0.949; P =0.61). Multivariable logistic regression analysis showed that neither contrast osmolality nor volume affected the overall accuracy of cFFR; however, both affected the sensitivity and specificity., Conclusions: The overall accuracy of cFFR is greater than instantaneous wave-free ratio and distal pressure/aortic pressure and not significantly affected by contrast volume and osmolality. However, contrast volume and osmolality do affect the sensitivity and specificity of cFFR., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02184117., (© 2017 American Heart Association, Inc.)

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.)

Background: Endometriosis is a chronic, estrogen-dependent condition that causes dysmenorrhea and pelvic pain. Elagolix, an oral, nonpeptide, gonadotropin-releasing hormone (GnRH) antagonist, produced partial to nearly full estrogen suppression in previous studies., Methods: We performed two similar, double-blind, randomized, 6-month phase 3 trials (Elaris Endometriosis I and II [EM-I and EM-II]) to evaluate the effects of two doses of elagolix - 150 mg once daily (lower-dose group) and 200 mg twice daily (higher-dose group) - as compared with placebo in women with surgically diagnosed endometriosis and moderate or severe endometriosis-associated pain. The two primary efficacy end points were the proportion of women who had a clinical response with respect to dysmenorrhea and the proportion who had a clinical response with respect to nonmenstrual pelvic pain at 3 months. Each of these end points was measured as a clinically meaningful reduction in the pain score and a decreased or stable use of rescue analgesic agents, as recorded in a daily electronic diary., Results: A total of 872 women underwent randomization in Elaris EM-I and 817 in Elaris EM-II; of these women, 653 (74.9%) and 632 (77.4%), respectively, completed the intervention. At 3 months, a significantly greater proportion of women who received each elagolix dose met the clinical response criteria for the two primary end points than did those who received placebo. In Elaris EM-I, the percentage of women who had a clinical response with respect to dysmenorrhea was 46.4% in the lower-dose elagolix group and 75.8% in the higher-dose elagolix group, as compared with 19.6% in the placebo group; in Elaris EM-II, the corresponding percentages were 43.4% and 72.4%, as compared with 22.7% (P<0.001 for all comparisons). In Elaris EM-I, the percentage of women who had a clinical response with respect to nonmenstrual pelvic pain was 50.4% in the lower-dose elagolix group and 54.5% in the higher-dose elagolix group, as compared with 36.5% in the placebo group (P<0.001 for all comparisons); in Elaris EM-II, the corresponding percentages were 49.8% and 57.8%, as compared with 36.5% (P=0.003 and P<0.001, respectively). The responses with respect to dysmenorrhea and nonmenstrual pelvic pain were sustained at 6 months. Women who received elagolix had higher rates of hot flushes (mostly mild or moderate), higher levels of serum lipids, and greater decreases from baseline in bone mineral density than did those who received placebo; there were no adverse endometrial findings., Conclusions: Both higher and lower doses of elagolix were effective in improving dysmenorrhea and nonmenstrual pelvic pain during a 6-month period in women with endometriosis-associated pain. The two doses of elagolix were associated with hypoestrogenic adverse effects. (Funded by AbbVie; Elaris EM-I and EM-II ClinicalTrials.gov numbers, NCT01620528 and NCT01931670 .).

Aims: Fractional flow reserve (FFR) has proven to its prognostic and therapeutic value. However, the additive prognostic value of coronary flow reserve (CFR) remains unclear. This study sought to investigate the clinical utility of combined FFR and CFR measurements to predict outcomes., Methods and Results: Using the prospective, multicentre Interventional Cardiology Research Incooperation Society-FFR registry, a total of 2088 lesions from 1837 patients were included in this substudy. Based on baseline and hyperaemic pressure gradients, we computed physiologic limits of CFR [the so called pressure-bounded (pb) CFR] and classified lesions as low (<2) or high (≥2). The primary endpoint was major adverse cardiac events (MACE, a composite of cardiac death, myocardial infarction, and revascularization) analysed on a per-patient basis. During a median follow-up of 1.9 years (inter-quartile range: 1.0-3.0 years), MACE occurred in 5.7% of patients with FFR ≤0.80 vs. 2.8% of patients with FFR >0.80 [adjusted hazard ratio (aHR): 2.15, 95% confidence interval (CI): 1.19-3.89; P = 0.011. In contrast, the incidence of MACE did not differ between patients with pb-CFR < 2 vs. pb-CFR ≥ 2 (4.2% vs. 4.2%; aHR: 0.98, CI: 0.60 to 1.58; P = 0.92). Incorporation of FFR significantly improved model prediction of MACE (global χ2 38.8-48.1, P = 0.002). However, pb-CFR demonstrated no incremental utility to classify outcomes (global χ2 48.1-48.2, P > 0.99)., Conclusions: In this large, prospective registry of over 2000 coronary lesions, FFR was strongly associated with clinical outcomes. In contrast, a significant association between pb-CFR and clinical events could not be determined and adding knowledge of pb-CFR did not improve prognostication over FFR alone., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

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.)

Background: Different adenosine stress imaging protocols have not been systemically validated for absolute myocardial perfusion and coronary flow reserve (CFR) by positron emission tomography, where submaximal stress precludes assessing physiological severity of coronary artery disease., Methods and Results: In 127 volunteers, serial rest-stress positron emission tomography scans using rubidium-82 with various adenosine infusion protocols identified (1) the protocol with maximum stress perfusion and CFR, (2) test-retest precision in same subject, (3) stress perfusion and CFR after adenosine compared with dipyridamole, (4) heterogeneity of coronary flow capacity combining stress perfusion and CFR, and (5) potential relevance for patients with risk factors or coronary artery disease. The adenosine 6-minute infusion with rubidium-82 injection at 3 minutes caused CFR that was significantly 15.7% higher than the 4-minute adenosine infusion with rubidium-82 injection at 2 minutes and significantly more homogeneous by Kolmogorov-Smirnov analysis for histograms of 1344 pixel range of perfusion in paired positron emission tomographies. In a coronary artery disease cohort separate from volunteers of this study, compared with the 3/6-minute protocol, the 2/4-minute adenosine protocol would potentially have changed 332 of 1732 (19%) positron emission tomographies at low-risk physiological severity CFR ≥2.3 to CFR <2.0, thereby implying high-risk quantitative severity potentially appropriate for interventions but because of suboptimal stress of the 2/4 protocol in some patients., Conclusions: The 6-minute adenosine infusion with rubidium-82 activation at 3 minutes produced CFR that averaged 15.7% higher than that in the 2/4-minute protocol, thereby potentially providing essential information for personalized management in some patients., (© 2017 American Heart Association, Inc.)

Study Question: What is the global consensus on the classification of endometriosis that considers the views of women with endometriosis?, Summary Answer: We have produced an international consensus statement on the classification of endometriosis through systematic appraisal of evidence and a consensus process that included representatives of national and international, medical and non-medical societies, patient organizations, and companies with an interest in endometriosis., What Is Known Already: Classification systems of endometriosis, developed by several professional organizations, traditionally have been based on lesion appearance, pelvic adhesions, and anatomic location of disease. One system predicts fertility outcome and none predicts pelvic pain, response to medications, disease recurrence, risks for associated disorders, quality of life measures, and other endpoints important to women and health care providers for guiding appropriate therapeutic options and prognosis., Study Design, Size, Duration: A consensus meeting, in conjunction with pre- and post-meeting processes, was undertaken., Participants/materials, Setting, Methods: A consensus meeting was held on 30 April 2014 in conjunction with the World Endometriosis Society's 12th World Congress on Endometriosis. Rigorous pre- and post-meeting processes, involving 55 representatives of 29 national and international, medical and non-medical organizations from a range of disciplines, led to this consensus statement., Main Results and the Role of Chance: A total of 28 consensus statements were made. Of all, 10 statements had unanimous consensus, however none of the statements was made without expression of a caveat about the strength of the statement or the statement itself. Two statements did not achieve majority consensus. The statements covered women's priorities, aspects of classification, impact of low resources, as well as all the major classification systems for endometriosis. Until better classification systems are developed, we propose a classification toolbox (that includes the revised American Society for Reproductive Medicine and, where appropriate, the Enzian and Endometriosis Fertility Index staging systems), that may be used by all surgeons in each case of surgery undertaken for women with endometriosis. We also propose wider use of the World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project surgical and clinical data collection tools for research to improve classification of endometriosis in the future, of particular relevance when surgery is not undertaken., Limitations, Reasons for Caution: This consensus process differed from that of formal guideline development, although based on the same available evidence. A different group of international experts from those participating in this process may have yielded subtly different consensus statements., Wider Implications of the Findings: This is the first time that a large, global, consortium-representing 29 major stake-holding organizations, from 19 countries - has convened to systematically evaluate the best available evidence on the classification of endometriosis and reach consensus. In addition to 21 international medical organizations and companies, representatives from eight national endometriosis organizations were involved, including lay support groups, thus generating and including input from women who suffer from endometriosis in an endeavour to keep uppermost the goal of optimizing quality of life for women with endometriosis., Study Funding/competing Interests: The World Endometriosis Society convened and hosted the consensus meeting. Financial support for participants to attend the meeting was provided by the organizations that they represented. There was no other specific funding for this consensus process. Mauricio Abrao is an advisor to Bayer Pharma, and a consultant to AbbVie and AstraZeneca; G David Adamson is the Owner of Advanced Reproductive Care Inc and Ziva and a consultant to Bayer Pharma, Ferring, and AbbVie; Deborah Bush has received travel grants from Fisher & Paykel Healthcare and Bayer Pharmaceuticals; Linda Giudice is a consultant to AbbVie, Juniper Pharmaceutical, and NextGen Jane, holds research grant from the NIH, is site PI on a clinical trial sponsored by Bayer, and is a shareholder in Merck and Pfizer; Lone Hummelshoj is an unpaid consultant to AbbVie; Neil Johnson has received conference expenses from Bayer Pharma, Merck-Serono, and MSD, research funding from AbbVie, and is a consultant to Vifor Pharma and Guerbet; Jörg Keckstein has received a travel grant from AbbVie; Ludwig Kiesel is a consultant to Bayer Pharma, AbbVie, AstraZeneca, Gedeon Richter, and Shionogi, and holds a research grant from Bayer Pharma; Luk Rombauts is an advisor to MSD, Merck Serono, and Ferring, and a shareholder in Monash IVF. The following have declared that they have nothing to disclose: Kathy Sharpe Timms; Rulla Tamimi; Hugh Taylor., Trial Registration Number: N/A., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To compare the effectiveness of alternative first line treatment options for women with WHO group II anovulation wishing to conceive., Design: Systematic review and network meta-analysis., Data Sources: Cochrane Central Register of Controlled Trials, Medline, and Embase, up to 11 April 2016., Study Selection: Randomised controlled trials comparing eight ovulation induction treatments in women with WHO group II anovulation: clomiphene, letrozole, metformin, clomiphene and metformin combined, tamoxifen, gonadotropins, laparoscopic ovarian drilling, and placebo or no treatment. Study quality was measured on the basis of the methodology and categories described in the Cochrane Collaboration Handbook. Pregnancy, defined preferably as clinical pregnancy, was the primary outcome; live birth, ovulation, miscarriage, and multiple pregnancy were secondary outcomes., Results: Of 2631 titles and abstracts initially identified, 54 trials reporting on 7173 women were included. All pharmacological treatments were superior to placebo or no intervention in terms of pregnancy and ovulation. Compared with clomiphene alone, both letrozole and the combination of clomiphene and metformin showed higher pregnancy rates (odds ratio 1.69, 95% confidence interval 1.33 to 2.14; 1.71, 1.28 to 2.27; respectively). Letrozole led to higher live birth rates when compared with clomiphene alone (1.67, 1.11 to 2.49). Metformin led to lower multiple pregnancy rates compared with clomiphene alone (0.22, 0.05 to 0.93)., Conclusions: In women with WHO group II anovulation, letrozole and the combination of clomiphene and metformin are superior to clomiphene alone in terms of pregnancy. Compared with clomiphene alone, letrozole is the only treatment showing a significantly higher rate of live birth., Systematic Review Registration: PROSPERO CRD42015027579., Readers' Note: This is the second version of this paper. The original version was corrected following the retraction of two studies and removal of another which were ineligible (references 40, 41, and 75 of the original paper). These studies are not shown in this version. A tracked changes version of the original version is attached as a supplementary file to the correction notice, which explains the issue further., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Adenosine-free coronary pressure wire metrics have been proposed to test the functional significance of coronary artery lesions, but it is unexplored whether their diagnostic performance might be altered in patients with diabetes., Methods: We performed a post-hoc analysis of the CONTRAST study, which prospectively enrolled an international cohort of patients undergoing routine fractional flow reserve (FFR) assessment for standard indications. Paired, repeated measurements of all physiology metrics (Pd/Pa, iFR, contrast-based FFR, and FFR) were made. A central core laboratory analyzed blinded pressure tracings in a standardized fashion., Results: Of 763 subjects enrolled at 12 international centers, 219 (29%) had diabetes. The two groups were well-balanced for age, clinical presentation (stable or unstable), coronary vessel studied, volume and type of intracoronary contrast, and volume of intracoronary adenosine. A binary threshold of cFFR ≤ 0.83 produced an accuracy superior to both Pd/Pa and iFR when compared with FFR ≤ 0.80 in the absence of significant interaction with diabetes status; indeed, accuracy in subgroups of patients with or without diabetes was similar for cFFR (86.7 vs 85.4% respectively; p = 0.76), iFR (84.2 vs 80.0%, p = 0.29) and Pd/Pa (81.3 vs 78.9%, p = 0.55). There was no significant heterogeneity between patients with or without diabetes in terms of sensitivity and specificity of all metrics. The area under the receiver operating characteristic (ROC) curve was largest for cFFR compared with Pd/Pa and iFR which were equivalent (cFFR 0.961 and 0.928; Pd/Pa 0.916 and 0.870; iFR 0.911 and 0.861 in diabetic and non-diabetic patients respectively)., Conclusions: cFFR provides superior diagnostic performance compared with Pd/Pa or iFR for predicting FFR irrespective of diabetes (clinicaltrials.gov identifier NCT02184117).

This article acts as a summary of the recently published papers by the World Endometriosis Research Foundation aiming to set up the Endometriosis Phenome and Biobanking Harmonisation Project.  The objective of this project is to standardise recording of patient history and characteristics, recording of surgical procedure and extent of disease as well as collection, processing and storage of specimens and consequently create a reliable resource for research into endometriosis., Competing Interests: Competing interests: Neil Johnson has received conference expenses from Bayer Pharma, Merck-Serono, and MSD, research funding from AbbVie, and is a consultant to Vifor Pharma and Guerbet.

Introduction: Endometriosis is a common gynaecological disease characterised by pain and subfertility. Randomised controlled trials evaluating treatments for endometriosis have reported many different outcomes and outcome measures. This variation restricts effective data synthesis limiting the usefulness of research to inform clinical practice. To address these methodological concerns, we aim to develop, disseminate and implement a core outcome set for endometriosis engaging with key stakeholders, including healthcare professionals, researchers and women with endometriosis., Methods and Analysis: An international steering group has been established, including healthcare professionals, researchers and patient representatives. Potential outcomes identified from a systematic review of the literature will be entered into a modified Delphi method. Key stakeholders will be invited to participate including healthcare professionals, researchers and women with endometriosis. Participants will be invited to score individual outcomes on a nine-point Likert scale anchored between 1 (not important) and 9 (critical). Repeated reflection and rescoring should promote whole and individual stakeholder group converge towards consensus, 'core', outcomes. High-quality outcome measures will be associated with core outcomes., Ethics and Dissemination: The implementation of a core outcome set for endometriosis within future clinical trials, systematic reviews and clinical guidelines will enhance the availability of comparable data to facilitate evidence-based patient care. This study was prospectively registered with Core Outcome Measures in Effectiveness Trials Initiative; number: 691., Competing Interests: NPJ has received conference expenses from Bayer Pharma, Merck-Serono and MSD; research funding from AbbVie and has been a consultant to Vifor Pharma. The remaining authors report no competing interests., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

In this paper we report on a very sensitive biosensor based on gold asymmetric nanoantennas that are capable of enhancing the molecular resonances of C-H bonds. The nanoantennas are arranged as arrays of asymmetric-split H-shape (ASH) structures, tuned to produce plasmonic resonances with reflectance double peaks within the mid-infrared vibrational resonances of C-H bonds for the assay of deposited films of the molecule 17β-estradiol (E2), used as an analyte. Measurements and numerical simulations of the reflectance spectra have enabled an estimated enhancement factor on the order of 10 5 to be obtained for a thin film of E2 on the ASH array. A high sensitivity value of 2335 nm/RIU was achieved, together with a figure of merit of approximately 8. Our experimental results were corroborated using numerical simulations for the C-H stretch vibrational resonances from the analyte, superimposed on the plasmonic resonances of the ASH nanoantennas.