Coronary sinus reducer for the treatment of refractory angina (ORBITA-COSMIC): a randomised, placebo-controlled trial.

BACKGROUND: The coronary sinus reducer (CSR) is proposed to reduce angina in patients with stable coronary artery disease by improving myocardial perfusion. We aimed to measure its efficacy, compared with placebo, on myocardial ischaemia reduction and symptom improvement. METHODS: ORBITA-COSMIC was a double-blind, randomised, placebo-controlled trial conducted at six UK hospitals. Patients aged 18 years or older with angina, stable coronary artery disease, ischaemia, and no further options for treatment were eligible. All patients completed a quantitative adenosine-stress perfusion cardiac magnetic resonance scan, symptom and quality-of-life questionnaires, and a treadmill exercise test before entering a 2-week symptom assessment phase, in which patients reported their angina symptoms using a smartphone application (ORBITA-app). Patients were randomly assigned (1:1) to receive either CSR or placebo. Both participants and investigators were masked to study assignment. After the CSR implantation or placebo procedure, patients entered a 6-month blinded follow-up phase in which they reported their daily symptoms in the ORBITA-app. At 6 months, all assessments were repeated. The primary outcome was myocardial blood flow in segments designated ischaemic at enrolment during the adenosine-stress perfusion cardiac magnetic resonance scan. The primary symptom outcome was the number of daily angina episodes. Analysis was done by intention-to-treat and followed Bayesian methodology. The study is registered with ClinicalTrials.gov, NCT04892537, and completed. FINDINGS: Between May 26, 2021, and June 28, 2023, 61 patients were enrolled, of whom 51 (44 [86%] male; seven [14%] female) were randomly assigned to either the CSR group (n=25) or the placebo group (n=26). Of these, 50 patients were included in the intention-to-treat analysis (24 in the CSR group and 26 in the placebo group). 454 (57%) of 800 imaged cardiac segments were ischaemic at enrolment, with a median stress myocardial blood flow of 1·08 mL/min per g (IQR 0·77-1·41). Myocardial blood flow in ischaemic segments did not improve with CSR compared with placebo (difference 0·06 mL/min per g [95% CrI -0·09 to 0·20]; Pr(Benefit)=78·8%). The number of daily angina episodes was reduced with CSR compared with placebo (OR 1·40 [95% CrI 1·08 to 1·83]; Pr(Benefit)=99·4%). There were two CSR embolisation events in the CSR group, and no acute coronary syndrome events or deaths in either group. INTERPRETATION: ORBITA-COSMIC found no evidence that the CSR improved transmural myocardial perfusion, but the CSR did improve angina compared with placebo. These findings provide evidence for the use of CSR as a further antianginal option for patients with stable coronary artery disease. FUNDING: Medical Research Council, Imperial College Healthcare Charity, National Institute for Health and Care Research Imperial Biomedical Research Centre, St Mary's Coronary Flow Trust, British Heart Foundation.

Placebo Control and Blinding in Randomized Trials of Procedural Interventions: A Systematic Review and Meta-Regression.

Importance: Unlike medications, procedural interventions are rarely trialed against placebo prior to becoming accepted in clinical practice. When placebo-controlled trials are eventually conducted, procedural interventions may be less effective than previously believed. Objective: To investigate the importance of including a placebo arm in trials of surgical and interventional procedures by comparing effect sizes from trials of the same procedure that do and do not include a placebo arm. Data Sources: Searches of MEDLINE and Embase identified all placebo-controlled trials for procedural interventions in any specialty of medicine and surgery from inception to March 31, 2019. A secondary search identified randomized clinical trials assessing the same intervention, condition, and end point but without a placebo arm for paired comparison. Study Selection: Placebo-controlled trials of anatomically site-specific procedures requiring skin incision or endoscopic techniques were eligible for inclusion; these were then matched to trials without placebo control that fell within prespecified limits of heterogeneity. Data Extraction and Synthesis: Random-effects meta-regression, with placebo and blinding as a fixed effect and intervention and end point grouping as random effects, was used to calculate the impact of placebo control for each end point. Data were analyzed from March 2019 to March 2020. Main Outcomes and Measures: End points were examined in prespecified subgroups: patient-reported or health care professional-assessed outcomes, quality of life, pain, blood pressure, exercise-related outcomes, recurrent bleeding, and all-cause mortality. Results: Ninety-seven end points were matched from 72 blinded, placebo-controlled trials (hereafter, blinded) and 55 unblinded trials without placebo control (hereafter, unblinded), including 111 500 individual patient end points. Unblinded trials had larger standardized effect sizes than blinded trials for exercise-related outcomes (standardized mean difference [SMD], 0.59; 95% CI, 0.29 to 0.89; P < .001) and quality-of-life (SMD, 0.32; 95% CI, 0.11 to 0.53; P = .003) and health care professional-assessed end points (SMD, 0.40; 95% CI, 0.18 to 0.61; P < .001). The placebo effect accounted for 88.1%, 55.2%, and 61.3% of the observed unblinded effect size for these end points, respectively. There was no significant difference between unblinded and blinded trials for patient-reported end points (SMD, 0.31; 95% CI, -0.02 to 0.64; P = .07), blood pressure (SMD, 0.26; 95% CI, -0.10 to 0.62; P = .15), all-cause mortality (odds ratio [OR], 0.23; 95% CI, -0.26 to 0.72; P = .36), pain (SMD, 0.03; 95% CI, -0.52 to 0.57; P = .91), or recurrent bleeding events (OR, -0.12; 95% CI, -1.11 to 0.88; P = .88). Conclusions and Relevance: The magnitude of the placebo effect found in this systematic review and meta-regression was dependent on the end point. Placebo control in trials of procedural interventions had the greatest impact on exercise-related, quality-of-life, and health care professional-assessed end points. Randomized clinical trials of procedural interventions may consider placebo control accordingly.

The ability of contemporary cardiologists to judge the ischemic impact of a coronary lesion visually

BACKGROUND: Landmark trials showed that invasive pressure measurement (Fractional Flow Reserve, FFR) was a better guide to coronary stenting than visual assessment. However, present-day interventionists have benefited from extensive research and personal experience of mapping anatomy to hemodynamics. AIMS: To determine if visual assessment of the angiogram performs as well as invasive measurement of coronary physiology. METHODS: 25 interventional cardiologists independently visually assessed the single vessel coronary disease of 200 randomized participants in The Objective Randomized Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina trial (ORBITA). They gave a visual prediction of the FFR and Instantaneous Wave-free Ratio (iFR), denoted vFFR and viFR respectively. Each judged each lesion on 2 occasions, so that every lesion had 50 vFFR, and 50 viFR assessments. The group consensus visual estimates (vFFR-group and viFR-group) and individual cardiologists' visual estimates (vFFR-individual and viFR-individual) were tested alongside invasively measured FFR and iFR for their ability to predict the placebo-controlled reduction in stress echo ischemia with stenting. RESULTS: Placebo-controlled ischemia improvement with stenting was predicted by vFFR-group (p < 0.0001) and viFR-group (p < 0.0001), vFFR-individual (p < 0.0001) and viFR-individual (p < 0.0001). There were no significant differences between the predictive performance of the group visual estimates and their invasive counterparts: p = 0.53 for vFFR vs FFR and p = 0.56 for viFR vs iFR. CONCLUSION: Visual assessment of the angiogram by contemporary experts, provides significant additional information on the amount of ischaemia which can be relieved by placebo-controlled stenting in single vessel coronary artery disease.

The Radcliffe Wave is oscillating.

Our Sun lies within 300 parsecs of the 2.7-kiloparsecs-long sinusoidal chain of dense gas clouds known as the Radcliffe Wave1. The structure's wave-like shape was discovered using three-dimensional dust mapping, but initial kinematic searches for oscillatory motion were inconclusive2-7. Here we present evidence that the Radcliffe Wave is oscillating through the Galactic plane while also drifting radially away from the Galactic Centre. We use measurements of line-of-sight velocity8 for 12CO and three-dimensional velocities of young stellar clusters to show that the most massive star-forming regions spatially associated with the Radcliffe Wave (including Orion, Cepheus, North America and Cygnus X) move as though they are part of an oscillating wave driven by the gravitational acceleration of the Galactic potential. By treating the Radcliffe Wave as a coherently oscillating structure, we can derive its motion independently of the local Galactic mass distribution, and directly measure local properties of the Galactic potential as well as the Sun's vertical oscillation period. In addition, the measured drift of the Radcliffe Wave radially outwards from the Galactic Centre suggests that the cluster whose supernovae ultimately created today's expanding Local Bubble9 may have been born in the Radcliffe Wave.

A double-blind, randomised, placebo-controlled trial of the coronary sinus Reducer in refractory angina: design and rationale of the ORBITA-COSMIC trial.

The coronary sinus Reducer (CSR) is an hourglass-shaped device which creates an artificial stenosis in the coronary sinus. Whilst placebo-controlled data show an improvement in angina, these results are unreplicated and are the subject of further confirmatory research. The mechanism of action of this unintuitive therapy is unknown. The Coronary Sinus Reducer Objective Impact on Symptoms, MRI Ischaemia, and Microvascular Resistance (ORBITA-COSMIC) trial is a randomised, placebo-controlled, double-blind trial investigating the efficacy of the CSR. Patients with (i) established epicardial coronary artery disease, (ii) angina on maximally tolerated antianginal medication, (iii) evidence of myocardial ischaemia and (iv) no further options for percutaneous coronary intervention or coronary artery bypass grafting will be enrolled. Upon enrolment, angina and quality-of-life questionnaires, treadmill exercise testing and quantitative stress perfusion cardiac magnetic resonance (CMR) imaging will be performed. Participants will record their symptoms daily on a smartphone application throughout the trial. After a 2-week symptom assessment phase, participants will be randomised in the cardiac catheterisation laboratory to CSR or a placebo procedure. After 6 months of blinded follow-up, all prerandomisation tests will be repeated. A prespecified subgroup will undergo invasive coronary physiology assessment at prerandomisation and follow-up. The primary outcome is stress myocardial blood flow on CMR. Secondary outcomes include angina frequency, quality of life and treadmill exercise time. (ClinicalTrials.gov: NCT04892537).

The ability of contemporary cardiologists to judge the ischemic impact of a coronary lesion visually.

BACKGROUND: Landmark trials showed that invasive pressure measurement (Fractional Flow Reserve, FFR) was a better guide to coronary stenting than visual assessment. However, present-day interventionists have benefited from extensive research and personal experience of mapping anatomy to hemodynamics. AIMS: To determine if visual assessment of the angiogram performs as well as invasive measurement of coronary physiology. METHODS: 25 interventional cardiologists independently visually assessed the single vessel coronary disease of 200 randomized participants in The Objective Randomized Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina trial (ORBITA). They gave a visual prediction of the FFR and Instantaneous Wave-free Ratio (iFR), denoted vFFR and viFR respectively. Each judged each lesion on 2 occasions, so that every lesion had 50 vFFR, and 50 viFR assessments. The group consensus visual estimates (vFFR-group and viFR-group) and individual cardiologists' visual estimates (vFFR-individual and viFR-individual) were tested alongside invasively measured FFR and iFR for their ability to predict the placebo-controlled reduction in stress echo ischemia with stenting. RESULTS: Placebo-controlled ischemia improvement with stenting was predicted by vFFR-group (p < 0.0001) and viFR-group (p < 0.0001), vFFR-individual (p < 0.0001) and viFR-individual (p < 0.0001). There were no significant differences between the predictive performance of the group visual estimates and their invasive counterparts: p = 0.53 for vFFR vs FFR and p = 0.56 for viFR vs iFR. CONCLUSION: Visual assessment of the angiogram by contemporary experts, provides significant additional information on the amount of ischaemia which can be relieved by placebo-controlled stenting in single vessel coronary artery disease.

Physiology and Intravascular Imaging Coregistration-Best of all Worlds?

Percutaneous coronary intervention is increasingly guided by coronary physiology and optimized using intravascular imaging. Pressure-based measurements determine the significance of a stenosis using hyperemic or nonhyperemic pressure ratios (eg, the instantaneous wave-free ratio). Intravascular ultrasound and optical coherence tomography provide cross-sectional and longitudinal detail regarding plaque composition and vessel characteristics. These facilitate lesion preparation and optimization of stent sizing and positioning. This review explores the evidence-base and practical aspects of coregistering pressure gradient assessment and intravascular imaging with angiography. We then discuss gaps in the evidence and what is needed to help integrate these techniques into clinical practice.

A Placebo-Controlled Trial of Percutaneous Coronary Intervention for Stable Angina.

BACKGROUND: Percutaneous coronary intervention (PCI) is frequently performed to reduce the symptoms of stable angina. Whether PCI relieves angina more than a placebo procedure in patients who are not receiving antianginal medication remains unknown. METHODS: We conducted a double-blind, randomized, placebo-controlled trial of PCI in patients with stable angina. Patients stopped all antianginal medications and underwent a 2-week symptom assessment phase before randomization. Patients were then randomly assigned in a 1:1 ratio to undergo PCI or a placebo procedure and were followed for 12 weeks. The primary end point was the angina symptom score, which was calculated daily on the basis of the number of angina episodes that occurred on a given day, the number of antianginal medications prescribed on that day, and clinical events, including the occurrence of unblinding owing to unacceptable angina or acute coronary syndrome or death. Scores range from 0 to 79, with higher scores indicating worse health status with respect to angina. RESULTS: A total of 301 patients underwent randomization: 151 to the PCI group and 150 to the placebo group. The mean (±SD) age was 64±9 years, and 79% were men. Ischemia was present in one cardiac territory in 242 patients (80%), in two territories in 52 patients (17%), and in three territories in 7 patients (2%). In the target vessels, the median fractional flow reserve was 0.63 (interquartile range, 0.49 to 0.75), and the median instantaneous wave-free ratio was 0.78 (interquartile range, 0.55 to 0.87). At the 12-week follow-up, the mean angina symptom score was 2.9 in the PCI group and 5.6 in the placebo group (odds ratio, 2.21; 95% confidence interval, 1.41 to 3.47; P<0.001). One patient in the placebo group had unacceptable angina leading to unblinding. Acute coronary syndromes occurred in 4 patients in the PCI group and in 6 patients in the placebo group. CONCLUSIONS: Among patients with stable angina who were receiving little or no antianginal medication and had objective evidence of ischemia, PCI resulted in a lower angina symptom score than a placebo procedure, indicating a better health status with respect to angina. (Funded by the National Institute for Health and Care Research Imperial Biomedical Research Centre and others; ORBITA-2 ClinicalTrials.gov number, NCT03742050.).

Dementia research in Ireland: What should we prioritise?

Background: Dementia research prioritisation allows for the systematic allocation of investment in dementia research by governments, funding agencies and the private sector. There is currently a lack of information available in Ireland regarding priority areas for dementia research. To address this gap, a dementia research prioritisation exercise was undertaken, consisting of an online survey of professionals in the dementia field and workshops for people living with dementia and family carers. Methods: (1) An anonymous online survey of professionals, based on an existing WHO global survey: the global survey was adapted to an Irish context and participants were asked to score 65 thematic research avenues under five criteria; (2) A mixed-methods exercise for people living with dementia and family carers: this involved two facilitated workshops where participants voted on the research themes they felt were important to them and should be addressed through research. Results: Eight of the top ten research priorities in the survey of professionals ( n=108) were focused on the delivery and quality of care and services for people with dementia and carers. Other research avenues ranked in the top ten focused on themes of timely and accurate diagnosis of dementia in primary health-care practices and diversifying therapeutic approaches in clinical trials. Participants in the workshops ( n=13) ranked 'better drugs and treatment for people with dementia', 'dementia prevention/ risk reduction' and 'care for people with dementia and carers' as their top priority areas. Conclusions: Findings from this prioritisation exercise will inform and motivate policymakers, funders and researchers to support and conduct dementia-focused research and ensure that the limited resources made available are spent on research that has the most impact for those who will benefit from and use the results of research.

Keeping it in the family: Use of the grandmother, mother, and child technique to navigate complex anatomy during Coronary sinus Reducer Implantation.

The Coronary Sinus Reducer® (CSR) is an emerging therapy for refractory angina recommended once no further pharmacologic or coronary revascularization options are available. We present the case of a 72-year-old man who underwent CSR implantation. Complex coronary sinus anatomy necessitated an innovative "grandmother, mother, and child" catheter approach.

Development of artificial intelligence tools for invasive Doppler-based coronary microvascular assessment.

Aims: Coronary flow reserve (CFR) assessment has proven clinical utility, but Doppler-based methods are sensitive to noise and operator bias, limiting their clinical applicability. The objective of the study is to expand the adoption of invasive Doppler CFR, through the development of artificial intelligence (AI) algorithms to automatically quantify coronary Doppler quality and track flow velocity. Methods and results: A neural network was trained on images extracted from coronary Doppler flow recordings to score signal quality and derive values for coronary flow velocity and CFR. The outputs were independently validated against expert consensus. Artificial intelligence successfully quantified Doppler signal quality, with high agreement with expert consensus (Spearman's rho: 0.94), and within individual experts. Artificial intelligence automatically tracked flow velocity with superior numerical agreement against experts, when compared with the current console algorithm [AI flow vs. expert flow bias -1.68 cm/s, 95% confidence interval (CI) -2.13 to -1.23 cm/s, P < 0.001 with limits of agreement (LOA) -4.03 to 0.68 cm/s; console flow vs. expert flow bias -2.63 cm/s, 95% CI -3.74 to -1.52, P < 0.001, 95% LOA -8.45 to -3.19 cm/s]. Artificial intelligence yielded more precise CFR values [median absolute difference (MAD) against expert CFR: 4.0% for AI and 7.4% for console]. Artificial intelligence tracked lower-quality Doppler signals with lower variability (MAD against expert CFR 8.3% for AI and 16.7% for console). Conclusion: An AI-based system, trained by experts and independently validated, could assign a quality score to Doppler traces and derive coronary flow velocity and CFR. By making Doppler CFR more automated, precise, and operator-independent, AI could expand the clinical applicability of coronary microvascular assessment.

ADR3, a next generation i-body to human RANKL, inhibits osteoclast formation and bone resorption.

Osteoporosis is a chronic skeletal condition characterized by low bone mass and deteriorated microarchitecture of bone tissue and puts tens of millions of people at high risk of fractures. New therapeutic agents like i-bodies, a class of next-generation single-domain antibodies, are needed to overcome some limitations of conventional treatments. An i-body is a human immunoglobulin scaffold with two long binding loops that mimic the shape and position of those found in shark antibodies, the variable new antigen receptors of sharks. Its small size (∼12 kDa) and long binding loops provide access to drug targets, which are considered undruggable by traditional monoclonal antibodies. Here, we have successfully identified a human receptor activator of nuclear factor-κB ligand (RANKL) i-body, ADR3, which demonstrates a high binding affinity to human RANKL (hRANKL) with no adverse effect on the survival or proliferation of bone marrow-derived macrophages. Differential scanning fluorimetry suggested that ADR3 is stable and able to tolerate a wide range of physical environments (including both temperature and pH). In addition, in vitro studies showed a dose-dependent inhibitory effect of ADR3 on osteoclast differentiation, podosome belt formation, and bone resorption activity. Further investigation on the mechanism of action of ADR3 revealed that it can inhibit hRANKL-mediated signaling pathways, supporting the in vitro functional observations. These clues collectively indicate that hRANKL antagonist ADR3 attenuates osteoclast differentiation and bone resorption, with the potential to serve as a novel therapeutic to protect against bone loss.

Structure-Activity Relationship Studies of Antimalarial Plasmodium Proteasome Inhibitors─Part II.

With increasing reports of resistance to artemisinins and artemisinin-combination therapies, targeting the Plasmodium proteasome is a promising strategy for antimalarial development. We recently reported a highly selective Plasmodium falciparum proteasome inhibitor with anti-malarial activity in the humanized mouse model. To balance the permeability of the series of macrocycles with other drug-like properties, we conducted further structure-activity relationship studies on a biphenyl ether-tethered macrocyclic scaffold. Extensive SAR studies around the P1, P3, and P5 groups and peptide backbone identified compound TDI-8414. TDI-8414 showed nanomolar antiparasitic activity, no toxicity to HepG2 cells, high selectivity against the Plasmodium proteasome over the human constitutive proteasome and immunoproteasome, improved solubility and PAMPA permeability, and enhanced metabolic stability in microsomes and plasma of both humans and mice.

Physiology and Intravascular Imaging Coregistration-Best of all Worlds?

Percutaneous coronary intervention is increasingly guided by coronary physiology and optimized using intravascular imaging. Pressure-based measurements determine the significance of a stenosis using hyperemic or nonhyperemic pressure ratios (eg, the instantaneous wave-free ratio). Intravascular ultrasound and optical coherence tomography provide cross-sectional and longitudinal detail regarding plaque composition and vessel characteristics. These facilitate lesion preparation and optimization of stent sizing and positioning. This review explores the evidence-base and practical aspects of coregistering pressure gradient assessment and intravascular imaging with angiography. We then discuss gaps in the evidence and what is needed to help integrate these techniques into clinical practice.

Health professionals delivering oral health interventions in early childhood: A scoping review of Australian and New Zealand literature.

ISSUE ADDRESSED: Dental caries is highly prevalent in very young Australian and New Zealand children. Health professionals other than registered dental professionals can help prevent early childhood caries, promoting oral health to assist families establish preventative oral health habits at a child's early age. This review identifies oral health promotion (OHP) delivered by nondental health professionals in Australia and New Zealand involving very young children. METHODS: Databases (MEDLINE, CINAHL, Embase, Emcare, Web of Science, Scopus, ProQuest, Google Scholar, TROVE) and digital libraries were searched between 2001 and 2021 for eligible studies and grey literature. Studies with a focus on preventative oral health strategies in a primary health care context were included. RESULTS: The review identified 76 studies. Seven met the inclusion criteria, and were conducted in Australia across metropolitan, rural, and remote settings. Studies that successfully engaged nondental health professionals to promote oral health to families reported a positive change in oral health practices among very young children. Delivering OHP during a child's early life stage positively influenced their oral health outcomes. CONCLUSIONS: Integration of dental and primary health care increased access to oral health care and advanced positive oral health outcomes for children. With adequate training, resources, and support mechanisms, nondental health professionals can deliver oral health strategies that facilitate behaviour change in parents to improve children's oral health. So What? Health promotion generates enabling conditions that support and empower families to improve and maintain their oral health. Nondental health professionals can play a crucial role promoting oral health for very young children and improving equitable access to preventative oral health care.

Remote digital smart device follow-up in prospective clinical trials: early insights from ORBITA-2, ORBITA-COSMIC, and ORBITA-STAR.

Smart devices are a fundamental media for acquisition, processing, storage, and transfer of digital health data. The global penetration and high frequency usage of smart devices such as smartphones and fitness monitors provide us an opportunity for incorporation into clinical trials to generate more clinically meaningful data. Reporting of angina can significantly vary between patients and also within patients at different timepoints. Furthermore, the nature of angina can lead to variation in ways patients adapt their activities of daily living and hence reporting of symptoms and quality of life. Current clinical trials investigating the effects of intervention on angina do not accurately incorporate these patient centred outcomes and considerations. Hence, methods to contemporaneously assess daily angina burden in a convenient, patient focused, and cost-effective manner are priorities for contemporary clinical trials to address. In this article, we provide our insights into the use of remote digital smart devices in clinical trials of stable coronary artery disease conducted by our research group. We discuss how our experiences from previous trials necessitated its incorporation and will provide us with important data that will inform clinical practice. We discuss the benefits and current challenges and limitations of smart device incorporation while providing our procedural workflow for how we incorporated smart devices into our clinical trials for others to consider. We hope that this approach will allow us to understand the perceptions and implications of angina on patient lives with greater granularity than previously explored.