Is 'Cardiopulmonary' the New 'Cardiometabolic'? Making a Case for Systems Change in COPD.

Chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) have a syndemic relationship with shared risk factors and complex interplay between genetic, environmental, socioeconomic, and pathophysiological mechanisms. CVD is among the most common comorbidities in patients with COPD and vice versa. Patients with COPD, irrespective of their disease severity, are at increased risk of CVD morbidity and mortality, driven in part by COPD exacerbations. Despite these known interrelationships, CVD is underestimated and undertreated in patients with COPD. Similarly, COPD is an independent risk-enhancing factor for adverse cardiovascular (CV) events, yet it is not incorporated into current CV risk assessment tools, leading to under-recognition and undertreatment. There is a pressing need for systems change in COPD management to move beyond symptom control towards a comprehensive cardiopulmonary disease paradigm with proactive prevention of exacerbations and adverse cardiopulmonary outcomes and mortality. However, there is a dearth of evidence defining optimal cardiopulmonary care pathways. Fortunately, there is a precedent to support systems-level change in the field of diabetes, which evolved from glycemic control to comprehensive multi-organ risk assessment and management. Key elements included integrated multidisciplinary care, intensive risk factor management, coordination between primary and specialist care, care pathways and protocols, education and self management, and disease-modifying therapies. This commentary article draws parallels between the cardiometabolic and cardiopulmonary paradigms and makes a case for systems change towards multidisciplinary, integrated cardiopulmonary care, using the evolution in diabetes care as a potential framework.

Optical coherence tomography assessment of the impact of colchicine on non-culprit coronary plaque composition after myocardial infarction.

BACKGROUND: Low-dose colchicine reduces the risk of cardiovascular events after myocardial infarction (MI). The purpose of this study was to assess the effect of colchicine post-MI on coronary plaque morphology in non-culprit segments by optical coherence tomography (OCT). METHODS AND RESULTS: COCOMO-ACS was a double-blind, placebo-controlled trial that randomized 64 patients (median age 61.5 years; 9.4% female) with acute non-ST-segment elevation MI to colchicine 0.5 mg daily or placebo for a median of 17.8 months in addition to guideline-recommended therapy. Participants underwent serial OCT imaging within a matched segment of non-culprit coronary artery which contained at least one lipid-rich plaque causing ≥20% stenosis. The primary outcome was the change in minimum fibrous cap thickness (FCT) in non-culprit segments from baseline to final visit. Of those randomized, 57 (29 placebo, 28 colchicine) had evaluable imaging at baseline and follow-up. Overall, colchicine had no effect on relative (placebo +48.0±35.1% vs. colchicine +62.4±38.1%, P=0.18) or absolute changes in minimum FCT (+29.2±20.9 µm vs. +37.2±21.3 µm, P=0.18), or change in maximum lipid arc (-38.8±32.2° vs. -54.8±46.9°, P=0.18) throughout the imaged non-culprit segment. However, in patients assigned colchicine, cap rupture was less frequent (placebo 27.6% vs. colchicine 3.6%, P=0.03). In post-hoc analysis of 43 participants who had been followed for at least 16 months, minimum FCT increased to a greater extent in the colchicine group (placebo +38.7±25.4% vs. colchicine +64.7±34.1%, P=0.005). CONCLUSION: In this study, OCT failed to detect an effect of colchicine on the minimum FCT or maximum lipid arc of plaques in non-culprit segments post-MI. The post-hoc observation that minimum FCT increased to a greater extent with colchicine after more prolonged treatment suggests longer-term studies may be required to detect the effect of anti-inflammatory therapies on plaque morphology by OCT. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry Identifier, ACTRN12618000809235, registered on the 11th of May 2018.

Targeted Treatments for Myasthenia Gravis in Children and Adolescents.

Myasthenia gravis (MG) is an antibody-mediated disorder of the neuromuscular junction affecting children and adults. MG is a treatable condition with most patients requiring immunosuppression for disease control and/or remission. Juvenile myasthenia gravis (JMG) is rare in comparison with adult-onset MG but given the same underlying pathophysiology, treatment strategies are similar to those in adults. Until recently, there were only a few randomised controlled trials (RCTs) for MG treatments in adults and none in children, and management strategies were primarily based on expert consensus. In addition, treatment options for refractory MG cases have been severely limited, resulting in poor long-term quality of life in such patients due to the significant disease burden. Recently, there have been several RCTs focussing on novel therapeutic strategies with potentially promising outcomes, suggesting a change in MG management over the coming years and access to more effective and faster-acting drugs for MG patients. This paper will review current and new MG treatments including efgartigimod, eculizumab, rozanolixizumab, ravulizumab, and zilucoplan, with a focus on juvenile myasthenia gravis.

Apixaban vs rivaroxaban in patients with atrial fibrillation at high or low bleeding risk: A population-based cohort study.

BACKGROUND: Despite many atrial fibrillation (AF) patients being at risk of bleeding, very limited data are available on bleeding rates of different direct oral anticoagulants based on the spectrum of bleeding risk. OBJECTIVE: We aimed to compare the risk of major bleeding and thromboembolic events with apixaban vs rivaroxaban for AF patients stratified by bleeding risk. METHODS: We conducted a population-based, retrospective cohort study of all adult patients (66 years or older) with AF in Ontario, Canada, who were treated with apixaban or rivaroxaban between April 1, 2011, and March 31, 2020. Bleeding risk was estimated by the HAS-BLED score, with high bleeding risk defined as a score of ≥3. The primary safety outcome was major bleeding, and the primary efficacy outcome was thromboembolic events. Comparisons were adjusted for baseline comorbidities by inverse probability of treatment weighting. RESULTS: This study included 18,156 AF patients with high bleeding risk and 55,186 AF patients with low bleeding risk. Apixaban use was more common in patients with high bleeding risk; 63% of high-risk patients used apixaban compared with 56% of low-risk patients. Apixaban users had lower rates of major bleeding in high-risk patients (2.9% vs 4.2% per year; hazard ratio [HR], 0.69; 95% CI, 0.58-0.81) and in low-risk patients (1.8% vs 2.9% per year; HR, 0.63; 95% CI, 0.56-0.70) compared with rivaroxaban. There were no differences in rates of thromboembolic events, 3.1% vs 3.0% per year (HR, 1.02; 95% CI, 0.86-1.22) in high-risk patients and 1.9% vs 1.9% per year (HR, 1.00; 95% CI, 0.89-1.14) in low-risk patients. CONCLUSION: In older AF patients with high or low bleeding risk, treatment with apixaban was associated with lower rates of major bleeding with no difference in risk for thromboembolic events compared with rivaroxaban.

Case report: Treatment response of NF-1-associated bladder ganglioneuroma to trametinib.

We present the clinical course of a 4-year-old girl with neurofibromatosis type 1-associated, unresectable, symptomatic urinary bladder ganglioneuroma. She was initially trialed on sirolimus without response and subsequently responded to MEK inhibitor trametinib, with improvement clinically and radiographically over 10 months. This report broadens the repertoire of therapeutic strategies for MEK inhibition in diseases related to the MAPK pathway.

A Novel Spiked Washer and Screw Technique Provides a Biomechanically Superior Posterolateral Corner and Arcuate Fracture Repair.

Posterolateral corner and arcuate fractures can cause significant disruption to the stability and kinematics of the knee. This study aimed to determine the biomechanical performance of a novel spiked washer (SW) and intramedullary screw technique compared with a tension slide technique (TST) for the repair of arcuate fractures. Sixteen matched fresh-frozen cadaver knees underwent repair. Each specimen underwent transection of the posterolateral corner and lateral capsule along with a proximal fibula osteotomy to simulate an arcuate fracture. Eight specimens underwent repair with a SW technique and 8 underwent repair with a TST. Each specimen underwent cyclic loading followed by load to failure. Gap formation, ultimate load to failure, energy to failure, and stiffness were assessed. The SW technique had significantly less gap formation and higher load to failure. Furthermore, the SW technique had significantly higher stiffness and energy to failure. A SW and screw technique provided a significantly stronger construct with less gap formation when compared with a TST. [Orthopedics. 202x;4x(x):xx-xx.].

Protocol and rationale of the Australian multicentre registry for serial cardiac computed tomography angiography (ARISTOCRAT): a prospective observational study of the natural history of pericoronary adipose tissue attenuation and radiomics.

Background: Vascular inflammation plays a crucial role in the development of atherosclerosis and atherosclerotic plaque rupture resulting in acute coronary syndrome (ACS). Pericoronary adipose tissue (PCAT) attenuation quantified from routine coronary computed tomography angiography (CCTA) has emerged as a promising non-invasive imaging biomarker of coronary inflammation. However, a detailed understanding of the natural history of PCAT attenuation is required before it can be used as a surrogate endpoint in trials of novel therapies targeting coronary inflammation. This article aims to explore the natural history of PCAT attenuation and its association with changes in plaque characteristics. Methods: The Australian natuRal hISTOry of periCoronary adipose tissue attenuation, RAdiomics and plaque by computed Tomographic angiography (ARISTOCRAT) registry is a multi-centre observational registry enrolling patients undergoing clinically indicated serial CCTA in 9 centres across Australia. CCTA scan parameters will be matched across serial scans. Quantitative analysis of plaque and PCAT will be performed using semiautomated software. Discussion: The primary endpoint is to explore temporal changes in patient-level and lesion-level PCAT attenuation by CCTA and their associations with changes in plaque characteristics. Secondary endpoints include evaluating: (I) impact of statin therapy on PCAT attenuation and plaque characteristics; and (II) changes in PCAT attenuation and plaque characteristics in specific subgroups according to sex and risk factors. ARISTOCRAT will further our understanding of the natural history of PCAT attenuation and its association with changes in plaque characteristics. Trial Registration: This study has been prospectively registered with the Australia and New Zealand Clinical Trials Registry (ACTRN12621001018808).

Evaluating the safety of high-intensity focused ultrasound treatment for rectal endometriosis: results from a French prospective multicentre study including 60 patients.

STUDY QUESTION: Is increasing the intensity of high-intensity focused ultrasound (HIFU) by 30% in the treatment of rectal endometriosis a safe procedure? SUMMARY ANSWER: This study demonstrates the safety of a 30% increase in the intensity of HIFU in the treatment of rectal endometriosis, with no Clavien-Dindo Grade III complications overall, and namely no rectovaginal fistulae. WHAT IS KNOWN ALREADY: A feasibility study including 20 patients with rectal endometriosis demonstrated, with no severe complications, a significant improvement in digestive disorders, dysmenorrhoea, dyspareunia, and health status, although the volume of the endometriosis nodule did not appear to be reduced. STUDY DESIGN, SIZE, DURATION: A prospective multicentre cohort study was conducted between 2020 and 2022 with 60 patients with symptomatic rectal endometriosis. Following the failure of medical treatment, HIFU treatment was offered as an alternative to surgery. PARTICIPANTS/MATERIALS, SETTING, METHODS: As the main objective of this study was to examine safety, all adverse events observed during the 6 months of follow-up were analysed and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) and Clavien-Dindo classifications. Secondary objectives included evaluating the evolution of symptoms using validated questionnaires: gynaecological and digestive pain symptoms with a visual analogue scale, health status with the Medical Outcomes Study 36-item Short Form (SF-36) questionnaire, average post-operative daily pain level, and analgesic medication required in the 10 days following treatment. MRI was also performed at Day 1 to detect early complications. Finally, we performed a blinded MRI review of the evolution of the nodule at 6 months post-treatment. MAIN RESULTS AND THE ROLE OF CHANCE: The procedure was performed under spinal anaesthesia for 30% of the patients. The median duration of treatment was 32 min. Fifty-five patients left the hospital on Day 1. MRI scans performed on Day 1 did not highlight any early-onset post-operative complication. Using the Clavien-Dindo classification, we listed 56.7% Grade I events, 3.4% Grade II events, and no events Grade III or higher. At 1, 3, and 6 months, all gynaecologic, digestive and general symptoms, as well as health status, had significantly improved. The evolution of the nodule was also significant (P < 0.001) with a 28% decrease in volume. LIMITATIONS, REASONS FOR CAUTION: The main objective was safety and not effectiveness. The study was not randomized and there was no control group. WIDER IMPLICATIONS OF THE FINDINGS: HIFU treatment for rectal endometriosis results in an improvement of symptoms with low morbidity; as such, for selected patients, it could be a valuable alternative to surgical approaches following the failure of medical treatment. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the company EDAP TMS. Professors Dubernard and Rousset are consultants for EDAP TMS. Dubernard received travel support from EDAP-TMS. Dr F. Chavrier received industrial grants from EDAP-TMS. He has developed a device for generating focused ultrasonic waves with reduced treatment time. This device has been patented by EDAP-TMS. Dr Lafon received industrial grants from EDAP-TMS; he declares that EDAP-TMS provided funding directly to INSERM to support a young researcher chair in therapeutic ultrasound, which is unrelated to the current study. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT04494568.

Comparative effectiveness and safety of apixaban and rivaroxaban in older patients with atrial fibrillation: A population-based cohort study.

BACKGROUND: There are no clinical trials with a head-to-head comparison between the 2 most commonly used oral anticoagulants (apixaban and rivaroxaban) in patients with atrial fibrillation (AF). The comparative efficacy and safety between these drugs remain unclear, especially in older patients who are at the highest risk for stroke and bleeding. OBJECTIVE: The purpose of this study was to compare the risk of major bleeding and thromboembolic events between apixaban and rivaroxaban in older patients with AF. METHODS: We conducted a population-based retrospective cohort study of all adult patients (66 years or older) with AF in Ontario, Canada, who were treated with apixaban or rivaroxaban between April 1, 2011, and March 31, 2020. The primary safety outcome was major bleeding, and the primary efficacy outcome was thromboembolic events. Secondary outcomes included any bleeding. Rates and hazard ratios (HRs) were adjusted for baseline comorbidities with inverse probability of treatment weighting. RESULTS: This study included 42,617 patients with AF treated with apixaban and 30,725 patients treated with rivaroxaban. After inverse probability of treatment weighting using the propensity score, patients in the apixaban and rivaroxaban groups were well balanced for baseline values of demographic characteristics, comorbidities, and medications; both groups had a similar mean age of 77.4 years, and 49.9% were female. At 1 year, the apixaban group had a lower risk for both major bleeding with an absolute risk reduction at 1 year of 1.1% (2.1% vs 3.2%; HR 0.65; 95% confidence interval [CI] 0.59-0.71]) and any bleeding (8.1% vs 10.9%; HR 0.73; 95% CI 0.69-0.77), with no difference in the risk for thromboembolic events (2.2% vs 2.2%; HR 1.02; 95% CI 0.92-1.13). CONCLUSION: In patients with AF, 66 years or older, treatment with apixaban was associated with lower risk for major bleeding, with no difference in the risk for thromboembolic events compared with rivaroxaban.

Implications of Five Different Risk Models In Primary Prevention Guidelines.

BACKGROUND: A lack of consensus exists across guidelines as to which risk model should be used for the primary prevention of cardiovascular disease (CVD). Our objective was to determine potential improvements in the number needed to treat (NNT) and number of events prevented (NEP) using different risk models in patients eligible for risk stratification. METHODS: A retrospective observational cohort was assembled from primary care patients in Ontario, Canada between January 1st, 2010, to December 31st, 2014 and followed for up to 5 years. Risk estimation was undertaken in patients 40-75 years of age, without CVD, diabetes, or chronic kidney disease using the Framingham Risk Score (FRS), Pooled Cohort Equations (PCEs), a recalibrated FRS (R-FRS), Systematic Coronary Risk Evaluation 2 (SCORE2), and the low-risk region recalibrated SCORE2 (LR-SCORE2). RESULTS: The cohort consisted of 47,399 patients (59% women, mean age 54). The NNT with statins was lowest for SCORE2 at 40, followed by LR-SCORE2 at 41, R-FRS at 43, PCEs at 55, and FRS at 65. Models that selected for individuals with a lower NNT recommended statins to fewer, but higher risk patients. For instance, SCORE2 recommended statins to 7.9% of patients (5-year CVD incidence 5.92%). The FRS, however, recommended statins to 34.6% of patients (5-year CVD incidence 4.01%). Accordingly, the NEP was highest for the FRS at 406 and lowest for SCORE2 at 156. CONCLUSIONS: Newer models such as SCORE2 may improve statin allocation to higher risk groups with a lower NNT but prevent fewer events at the population level.

Tandem lesions associate with angiographic progression of coronary artery stenoses.

Background: Although the clinical factors associated with progression of coronary artery disease have been well studied, the angiographic predictors are less defined. Objectives: Our objective was to study the clinical and angiographic factors that associate with progression of coronary artery stenoses. Methods: We conducted a retrospective analysis of consecutive patients undergoing multiple, clinically indicated invasive coronary angiograms with an interval greater than 6 months, between January 2013 and December 2016. Lesion segments were analysed using Quantitative Coronary Angiography (QCA) if a stenosis ≥ 20 % was identified on either angiogram. Stenosis progression was defined as an increase ≥ 10 % in stenosis severity, with progressor groups analysed on both patient and lesion levels. Mixed-effects regression analyses were performed to evaluate factors associated with progression of individual stenoses. Results: 199 patients were included with 881 lesions analysed. 108 (54.3 %) patients and 186 (21.1 %) stenoses were classified as progressors. The median age was 65 years (IQR 56-73) and the median interval between angiograms was 2.1 years (IQR 1.2-3.0). On a patient level, age, number of lesions and presence of multivessel disease at baseline were each associated with progressor status. On a lesion level, presence of a stenosis downstream (OR 3.07, 95 % CI 2.04-4.63, p < 0.001) and circumflex artery stenosis location (OR 1.81, 95 % CI 1.21-2.7, p = 0.004) were associated with progressor status. Other lesion characteristics did not significantly impact progressor status or change in stenosis severity. Conclusion: Coronary lesions which have a downstream stenosis may be at increased risk of stenosis progression. Further research into the mechanistic basis of this finding is required, along with its implications for plaque vulnerability and clinical outcomes.

ZIF-8 Vibrational Spectra: Peak Assignments and Defect Signals.

Zeolitic imidazolate framework (ZIF-8) is a promising material for gas separation applications. It also serves as a prototype for numerous ZIFs, including amorphous ones, with a broader range of possible applications, including sensors, catalysis, and lithography. It consists of zinc coordinated with 2-methylimidazolate (2mIm) and has been synthesized with methods ranging from liquid-phase to solvent-free synthesis, which aim to control its crystal size and shape, film thickness and microstructure, and incorporation into nanocomposites. Depending on the synthesis method and postsynthesis treatments, ZIF-8 materials may deviate from the nominal defect-free ZIF-8 crystal structure due to defects like missing 2mIm, missing zinc, and physically adsorbed 2mIm trapped in the ZIF-8 pores, which may alter its performance and stability. Infrared (IR) spectroscopy has been used to assess the presence of defects in ZIF-8 and related materials. However, conflicting interpretations by various authors persist in the literature. Here, we systematically investigate ZIF-8 vibrational spectra by combining experimental IR spectroscopy and first-principles molecular dynamics simulations, focusing on assigning peaks and elucidating the spectroscopic signals of putative defects present in the ZIF-8 material. We attempt to resolve conflicting assignments from the literature and to provide a comprehensive understanding of the vibrational spectra of ZIF-8 and its defect-induced variations, aiming toward more precise quality control and design of ZIF-8-based materials for emerging applications.

Evaluating Readability, Understandability, and Actionability of Online Printable Patient Education Materials for Cholesterol Management: A Systematic Review.

BACKGROUND: Dyslipidemia management is a cornerstone in cardiovascular disease prevention and relies heavily on patient adherence to lifestyle modifications and medications. Numerous cholesterol patient education materials are available online, but it remains unclear whether these resources are suitable for the majority of North American adults given the prevalence of low health literacy. This review aimed to (1) identify printable cholesterol patient education materials through an online search, and (2) evaluate the readability, understandability, and actionability of each resource to determine its utility in practice. METHODS AND RESULTS: We searched the MEDLINE database for peer-reviewed educational materials and the websites of Canadian and American national health organizations for gray literature. Readability was measured using the Flesch-Kincaid Grade Level, and scores between fifth- and sixth-grade reading levels were considered adequate. Understandability and actionability were scored using the Patient Education Materials Assessment Tool and categorized as superior (>80%), adequate (50%-70%), or inadequate (<50%). Our search yielded 91 results that were screened for eligibility. Among the 22 educational materials included in the study, 15 were identified through MEDLINE, and 7 were from websites. The readability across all materials averaged an 11th-grade reading level (Flesch-Kincaid Grade Level=11.9±2.59). The mean±SD understandability and actionability scores were 82.8±6.58% and 40.9±28.60%, respectively. CONCLUSIONS: The readability of online cholesterol patient education materials consistently exceeds the health literacy level of the average North American adult. Many resources also inadequately describe action items for individuals to self-manage their cholesterol, representing an implementation gap in cardiovascular disease prevention.

Metabolic effects of testosterone added to intensive lifestyle intervention in older men with obesity and hypogonadism.

BACKGROUND: Whether testosterone replacement therapy (TRT) conveys additional cardiometabolic benefit to an intensive lifestyle therapy (LT) in older men with obesity and hypogonadism remains unclear. OBJECTIVE: To determine whether TRT augments the effect of LT on metabolic outcomes in older men with obesity and hypogonadism. DESIGN: Secondary analysis of a randomized, double-blind, placebo-controlled trial. SETTING: Veterans Affairs Medical Center. PARTICIPANTS: 83 older (age ≥ 65 years) men with obesity (BMI ≥ 30 kg/m2) and persistently low AM testosterone (< 10.4 nmol/L) associated with frailty. INTERVENTIONS: LT (weight management and exercise training) plus either testosterone (LT+TRT) or placebo (LT+Pbo) for six months. OUTCOME MEASURES: Primary outcome was change in glycated hemoglobin (HbA1c). Secondary outcomes included changes in other glucometabolic and lipid profile components, liver enzymes, inflammatory markers, adipokines; subcutaneous, visceral, intramuscular, and hepatic fat; blood pressure, and metabolic syndrome score. RESULTS: HbA1c decreased similarly in LT+TRT and LT+Pbo groups (-0.5% vs. -0.6%, respectively; p= 0.35). While TRT showed no synergistic effect with LT on ameliorating secondary outcomes, it eliminated the augmentative effect of LT on high-density lipoprotein cholesterol concentration (5.4 ± 1.0 mg/dL in LT+Pbo group vs. 0.2 ± 1.1 mg/dL in LT+TRT group, p= 0.01) and adiponectin levels (-408 ± 489 ng/mL in TRT+LT group vs 1832 ± 468 ng/mL in LT+Pbo group, p= 0.02). CONCLUSION: In older men with obesity and hypogonadism, adding TRT for six months to LT does not result in further improved cardiometabolic profiles, and could potentially blunt some of the metabolic benefits induced by LT.