Pivoting COVID-19 Resources for an Equitable Mpox Vaccine Response in Louisiana.

Introduction: The first case of mpox in Louisiana was identified 2 months ahead of Southern Decadence Festival in New Orleans, the largest LGBTQ+ Pride festival in the South. With mpox case numbers reflecting racial disparities, the objective was to mount an equitable vaccination response. Methods: The Louisiana Department of Health rapidly pivoted its COVID-19 resources and strategies-specifically, using vaccine strike teams and mobile events, in-state vaccine redistribution through centralized warehousing and shipping support, and community partnerships-to now control mpox transmission. Here, the authors have evaluated state-based Immunization Information System data to examine whether the vaccination response was geographically and racially equitable. Geographic equity was measured by taking into account vaccine availability as well as uptake in areas with high Social Vulnerability Index. Results: A total of 113 providers were enrolled in the vaccination program, and 96 mobile vaccination events were held in locations frequented by at-risk populations. Racial disparities among vaccine recipients decreased over time, and vaccine availability and uptake were equitable in areas with high Social Vulnerability Indices. However, Black, female, and Hispanic/Latinx patients had significantly higher risk of not completing the 2-dose series than their counterparts. Conclusions: The mpox vaccination response in Louisiana was geographically equitable, though some demographic disparities remained.

Arterial effects of anthracycline: structural and inflammatory assessments in non-human primates and lymphoma patients using 18F-FDG positron emission tomography.

Background: Anthracyclines, such as doxorubicin, are important anti-cancer therapies but are associated with arterial injury. Histopathological insights have been limited to small animal models and the role of inflammation in the arterial toxic effects of anthracycline is unclear in humans. Our aims were: 1) To evaluate aortic media fibrosis and injury in non-human primates treated with anthracyclines; 2) To assess the effect of anthracycline on aortic inflammation in patients treated for lymphoma. Methods: 1) African Green monkeys (AGM) received doxorubicin (30-60 mg/m2/biweekly IV, cumulative dose: 240 mg/m2). Blinded histopathologic analyses of collagen deposition and cell vacuolization in the ascending aorta were performed 15 weeks after the last doxorubicin dose and compared to 5 age- and gender-matched healthy, untreated AGMs. 2) Analysis of the thoracic aorta of patients with diffuse large B-cell lymphoma (DLBCL), at baseline and after doxorubicin exposure, was performed using 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in this observational study. The primary outcome was change in maximal tissue-to-background ratio (TBRmax) of the thoracic aorta from baseline to their end-of-treatment clinical PET/CT. Results: In AGMs, doxorubicin exposure was associated with greater aortic fibrosis (collagen deposition: doxorubicin cohort 6.23±0.88% vs. controls 4.67±0.54%; p=0.01) and increased intracellular vacuolization (doxorubicin 66.3 ± 10.1 vs controls 11.5 ± 4.2 vacuoles/field, p<0.0001) than untreated controls.In 101 patients with DLBCL, there was no change in aortic TBRmax after anthracycline exposure (pre-doxorubicin TBRmax 1.46±0.16 vs post-doxorubicin TBRmax 1.44±0.14, p=0.14). The absence of change in TBRmax was consistent across all univariate analyses. Conclusions: In a large animal model, anthracycline exposure was associated with aortic fibrosis. In patients with lymphoma, anthracycline exposure was not associated with aortic inflammation.Further research is required to elucidate the mechanisms of anthracycline-related vascular harm.

Exploring the relationship between sleep and aggression in adolescents: A cross sectional study using the UK Millennium cohort study.

This study aimed to establish if a significant relationship exists between sleep and aggression in a large representative adolescent cohort and explores the impact of potential confounders. This cross-sectional secondary data analysis included 10,866 males and females aged 13-15 years, from the UK-based 2015 Millenium Cohort Study (sixth sweep). Independent variables included self-report measures of sleep duration and quality. The parent reported 'Strengths and Difficulties Questionnaire' conduct score measured aggression. Binary logistic regression examined independent associations between each sleep variable and aggression. Multiple regression models then adjusted for potential confounders: age, sex, socioeconomic status, arousal, and affect. Under 8 hours of sleep on average was significantly associated with aggression when age, sex and income were controlled (p = .008). This became insignificant following adjustment for both affect and arousal. Sleep quality remained significantly associated with aggression when all confounders were controlled: 'sleep onset latency >30 minutes' and 'wakening at least a good bit of the time' increased the odds of aggression by around 27.9% (p < .001) and 43.5% respectively (p < .001). A significant association exists between poor subjective sleep quality and heightened aggression in this cohort, when all our confounders are controlled, identifying sleep quality as a potential target in treating adolescent aggression.

Advancing Health Equity: The Role of a Community-Academic-Public Health-Practice (CAPP) Partnership in Addressing COVID-19 Disparities in Louisiana.

We assessed the impact of an innovative Louisiana community-academic-public health-practice (CAPP) partnership in addressing COVID-19-associated Black-White vaccination disparities over 19 months. Initially (April 2021), the cumulative vaccinations for Black versus White Louisianans were 54 542 per 100 000 versus 62 435 per 100 000, respectively. By October 2022, cumulative vaccinations for Black versus White Louisianans were 142 437 per 100 000 versus 132 488 per 100 000, respectively. The vaccination equity score increased from 908 out of 1000 in April 2021 to 942 out of 1000 in October 2022. CAPP partnership efforts contributed to addressing initial Black-White COVID-19 vaccination disparities. (Am J Public Health. 2024;114(S1):S55-S58. https://doi.org/10.2105/AJPH.2023.307509).

Preventing Recurrent Cardioembolic Stroke: Right Approach, Right Patient (PRECISE) Study Protocol.

Cardiac rhythm monitoring is performed to search for atrial fibrillation (AF) after ischaemic stroke or transient ischaemic attack (TIA). Prolonged cardiac rhythm monitoring increases AF detection but is challenging to implement in many healthcare settings and is not needed for all people after ischaemic stroke/TIA. We aimed to develop and validate a model that includes clinical, electrocardiogram (ECG), blood-based, and genetic biomarkers to identify people with a low probability of AF detection after ischaemic stroke or TIA. We will recruit 675 consenting participants who are aged over 18 years, who were admitted with ischaemic stroke or TIA in the 5 days prior, who are not known to have AF, and who would be suitable for anticoagulation if AF is found. We will collect baseline demographic and clinical data, a 12-lead ECG, and a venous blood sample for blood biomarkers (including midregional pro-atrial natriuretic peptide, MRproANP) and genetic data. We will perform up to 28 days of cardiac rhythm monitoring using an R-test or patch device to search for AF in all participants. The sample size of 675 participants is based on true sensitivity of 92.5%, null hypothesis sensitivity of 80%, 80% power, and 5% significance. The primary outcome is AF detection ≥30 s duration during 28 days of cardiac rhythm monitoring. Secondary outcomes are AF detection at 1-year, recurrent cardiovascular events, and mortality and will be identified by electronic linkage and telephone follow-up. The results will guide the development of a more personalized care pathway to search for AF after ischaemic stroke or TIA. This could help to reduce cardiac rhythm monitoring for people with a low probability of AF detection and allow more intensive cardiac monitoring to be focused on people who are more likely to have AF and benefit. Participants will be consented for their data to be used in future research studies, providing a rich resource for stroke and cardiovascular research communities.

Attributions for extreme weather events: science and the people.

Both climate scientists and non-scientists (laypeople) attribute extreme weather events to various influences. Laypeople's attributions for these events are important as these attributions likely influence their views and actions about climate change and extreme events. Research has examined laypeople's attribution scepticism about climate change in general; however, few climate scientists are familiar with the processes underpinning laypeople's attributions for individual extreme events. Understanding these lay attributions is important for scientists to communicate their findings to the public. Following a brief summary of the way climate scientists calculate attributions for extreme weather events, we focus on cognitive and motivational processes that underlie laypeople's attributions for specific events. These include a tendency to prefer single-cause rather than multiple-cause explanations, a discounting of whether possible causes covary with extreme events, a preference for sufficient causes over probabilities, applying prevailing causal narratives, and the influence of motivational factors. For climate scientists and communicators who wish to inform the public about the role of climate change in extreme weather events, these patterns suggest several strategies to explain scientists' attributions for these events and enhance public engagement with climate change. These strategies include showing more explicitly that extreme weather events reflect multiple causal influences, that climate change is a mechanism that covaries with these events and increases the probability and intensity of many of these events, that human emissions contributing to climate change are controllable, and that misleading communications about weather attributions reflect motivated interests rather than good evidence.

Machine learning for classification of hypertension subtypes using multi-omics: A multi-centre, retrospective, data-driven study.

BACKGROUND: Arterial hypertension is a major cardiovascular risk factor. Identification of secondary hypertension in its various forms is key to preventing and targeting treatment of cardiovascular complications. Simplified diagnostic tests are urgently required to distinguish primary and secondary hypertension to address the current underdiagnosis of the latter. METHODS: This study uses Machine Learning (ML) to classify subtypes of endocrine hypertension (EHT) in a large cohort of hypertensive patients using multidimensional omics analysis of plasma and urine samples. We measured 409 multi-omics (MOmics) features including plasma miRNAs (PmiRNA: 173), plasma catechol O-methylated metabolites (PMetas: 4), plasma steroids (PSteroids: 16), urinary steroid metabolites (USteroids: 27), and plasma small metabolites (PSmallMB: 189) in primary hypertension (PHT) patients, EHT patients with either primary aldosteronism (PA), pheochromocytoma/functional paraganglioma (PPGL) or Cushing syndrome (CS) and normotensive volunteers (NV). Biomarker discovery involved selection of disease combination, outlier handling, feature reduction, 8 ML classifiers, class balancing and consideration of different age- and sex-based scenarios. Classifications were evaluated using balanced accuracy, sensitivity, specificity, AUC, F1, and Kappa score. FINDINGS: Complete clinical and biological datasets were generated from 307 subjects (PA=113, PPGL=88, CS=41 and PHT=112). The random forest classifier provided ∼92% balanced accuracy (∼11% improvement on the best mono-omics classifier), with 96% specificity and 0.95 AUC to distinguish one of the four conditions in multi-class ALL-ALL comparisons (PPGL vs PA vs CS vs PHT) on an unseen test set, using 57 MOmics features. For discrimination of EHT (PA + PPGL + CS) vs PHT, the simple logistic classifier achieved 0.96 AUC with 90% sensitivity, and ∼86% specificity, using 37 MOmics features. One PmiRNA (hsa-miR-15a-5p) and two PSmallMB (C9 and PC ae C38:1) features were found to be most discriminating for all disease combinations. Overall, the MOmics-based classifiers were able to provide better classification performance in comparison to mono-omics classifiers. INTERPRETATION: We have developed a ML pipeline to distinguish different EHT subtypes from PHT using multi-omics data. This innovative approach to stratification is an advancement towards the development of a diagnostic tool for EHT patients, significantly increasing testing throughput and accelerating administration of appropriate treatment. FUNDING: European Union's Horizon 2020 Research and Innovation Programme under Grant Agreement No. 633983, Clinical Research Priority Program of the University of Zurich for the CRPP HYRENE (to Z.E. and F.B.), and Deutsche Forschungsgemeinschaft (CRC/Transregio 205/1).

Unravelling the Distinct Effects of Systolic and Diastolic Blood Pressure Using Mendelian Randomisation.

A true discrepancy between the effect of systolic blood pressure (SBP) and diastolic blood pressure (DBP) on cardiovascular (CV) outcomes remains unclear. This study performed two-sample Mendelian randomization (MR) using genetic instruments that exclusively predict SBP, DBP or both to dissect the independent effect of SBP and DBP on a range of CV outcomes. Genetic predisposition to higher SBP and DBP was associated with increased risk of coronary artery disease (CAD), myocardial infarction (MI), stroke, heart failure (HF), atrial fibrillation (AF), chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). Genetically proxied SBP exclusively was associated with CAD (OR 1.18, 95% CI: 1.03-1.36, per 10 mmHg), stroke (1.44[1.28-1.62]), ischemic stroke (1.49[1.30-1.69]), HF (1.41[1.20-1.65]), AF (1.28[1.15-1.43]), and T2DM (1.2[1.13-1.46]). Genetically proxied DBP exclusively was associated with stroke (1.21[1.06-1.37], per 5 mmHg), ischemic stroke (1.24[1.09-1.41]), stroke small-vessel (1.35[1.10-1.65]) and CAD (1.19[1.00-1.41]). Multivariable MR using exclusive SBP and DBP instruments showed the predominant effect of SBP on CAD (1.23[1.05-1.44], per 10 mmHg), stroke (1.39[1.20-1.60]), ischemic stroke (1.44[1.25-1.67]), HF (1.42[1.18-1.71]), AF (1.26[1.10-1.43]) and T2DM (1.31[1.14-1.52]). The discrepancy between effects of SBP and DBP on outcomes warrants further studies on underpinning mechanisms which may be amenable to therapeutic targeting.

Rationale and Design for the LOnger-term effects of SARS-CoV-2 INfection on blood Vessels And blood pRessure (LOCHINVAR): an observational phenotyping study.

INTRODUCTION: COVID-19 may lead to long-term endothelial consequences including hypertension, stroke and myocardial infarction. A pilot study 'COVID-19 blood pressure endothelium interaction study', which found that patients with normal blood pressure (BP) at the time of hospital admission with COVID-19 showed an 8.6 mm Hg higher BP ≥12 weeks after recovery, compared with a group without COVID-19. The 'LOnger-term effects of SARS-CoV-2 INfection on blood Vessels And blood pRessure'(LOCHINVAR) study is designed to provide definitive evidence of the long-term impact of COVID-19 on BP. METHODS AND ANALYSIS: The LOCHINVAR study is an observational clinical phenotyping study comparing longitudinal BP change between individuals with and without COVID-19 infection. 150 participants (30-60 years) with no history of hypertension and not on BP lowering medications will be recruited to the study to attend three visits (baseline, 12 months, 18 months). Cases will be patients who were admitted to the Queen Elizabeth University Hospital (QEUH), Glasgow, UK, with suspected/confirmed COVID-19 until 31 December 2021 and who were alive at discharge. Controls will be those who have never had confirmed COVID-19 infection. All participants will undergo clinical and vascular phenotyping studies which will include 24-hour ambulatory BP monitoring systolic BP (ABPM SBP), brachial flow-mediated dilatation urine and blood samples to assess the renin-angiotensin system, vascular inflammation and immune status. The primary outcome is the change in systolic 24-hour ABPM (ABPM SBP) between the cases and controls. Sample size was calculated to detect a mean difference of 5 mm Hg ABPM SBP at 80% power. ETHICS AND DISSEMINATION: The protocol of this study has been approved by the West of Scotland Research Ethics Committee 5 (21/WS/0075), Scotland, UK. Written informed consent will be provided by all study participants. Study findings will be submitted to international peer-reviewed hypertension journals and will be presented at international scientific meetings. TRIAL REGISTRATION NUMBER: NCT05087290.

Estimating How Sounds Modulate Orientation Representation in the Primary Visual Cortex Using Shallow Neural Networks.

Audiovisual perception results from the interaction between visual and auditory processing. Hence, presenting auditory and visual inputs simultaneously usually improves the accuracy of the unimodal percepts, but can also lead to audiovisual illusions. Cross-talks between visual and auditory inputs during sensory processing were recently shown to occur as early as in the primary visual cortex (V1). In a previous study, we demonstrated that sounds improve the representation of the orientation of visual stimuli in the naïve mouse V1 by promoting the recruitment of neurons better tuned to the orientation and direction of the visual stimulus. However, we did not test if this type of modulation was still present when the auditory and visual stimuli were both behaviorally relevant. To determine the effect of sounds on active visual processing, we performed calcium imaging in V1 while mice were performing an audiovisual task. We then compared the representations of the task stimuli orientations in the unimodal visual and audiovisual context using shallow neural networks (SNNs). SNNs were chosen because of the biological plausibility of their computational structure and the possibility of identifying post hoc the biological neurons having the strongest influence on the classification decision. We first showed that SNNs can categorize the activity of V1 neurons evoked by drifting gratings of 12 different orientations. Then, we demonstrated using the connection weight approach that SNN training assigns the largest computational weight to the V1 neurons having the best orientation and direction selectivity. Finally, we showed that it is possible to use SNNs to determine how V1 neurons represent the orientations of stimuli that do not belong to the set of orientations used for SNN training. Once the SNN approach was established, we replicated the previous finding that sounds improve orientation representation in the V1 of naïve mice. Then, we showed that, in mice performing an audiovisual detection task, task tones improve the representation of the visual cues associated with the reward while deteriorating the representation of non-rewarded cues. Altogether, our results suggest that the direction of sound modulation in V1 depends on the behavioral relevance of the visual cue.

Dynamic Distortion of Orientation Representation after Learning in the Mouse Primary Visual Cortex.

Learning is an essential cognitive mechanism allowing behavioral adaptation through adjustments in neuronal processing. It is associated with changes in the activity of sensory cortical neurons evoked by task-relevant stimuli. However, the exact nature of those modifications and the computational advantages they may confer are still debated. Here, we investigated how learning an orientation discrimination task alters the neuronal representations of the cues orientations in the primary visual cortex (V1) of male and female mice. When comparing the activity evoked by the task stimuli in naive mice and the mice performing the task, we found that the representations of the orientation of the rewarded and nonrewarded cues were more accurate and stable in trained mice. This better cue representation in trained mice was associated with a distortion of the orientation representation space such that stimuli flanking the task-relevant orientations were represented as the task stimuli themselves, suggesting that those stimuli were generalized as the task cues. This distortion was context dependent as it was absent in trained mice passively viewing the task cues and enhanced in the behavioral sessions where mice performed best. Those modifications of the V1 population orientation representation in performing mice were supported by a suppression of the activity of neurons tuned for orientations neighboring the orientations of the task cues. Thus, visual processing in V1 is dynamically adapted to enhance the reliability of the representation of the learned cues and favor generalization in the task-relevant computational space.SIGNIFICANCE STATEMENT Performance improvement in a task often requires facilitating the extraction of the information necessary to its execution. Here, we demonstrate the existence of a suppression mechanism that improves the representation of the orientations of the task stimuli in the V1 of mice performing an orientation discrimination task. We also show that this mechanism distorts the V1 orientation representation space, leading stimuli flanking the task stimuli orientations to be generalized as the task stimuli themselves.

Inhibition of myocardial cathepsin-L release during reperfusion following myocardial infarction improves cardiac function and reduces infarct size.

AIMS: Identifying novel mediators of lethal myocardial reperfusion injury that can be targeted during primary percutaneous coronary intervention (PPCI) is key to limiting the progression of patients with ST-elevation myocardial infarction (STEMI) to heart failure. Here, we show through parallel clinical and integrative preclinical studies the significance of the protease cathepsin-L on cardiac function during reperfusion injury. METHODS AND RESULTS: We found that direct cardiac release of cathepsin-L in STEMI patients (n = 76) immediately post-PPCI leads to elevated serum cathepsin-L levels and that serum levels of cathepsin-L in the first 24 h post-reperfusion are associated with reduced cardiac contractile function and increased infarct size. Preclinical studies demonstrate that inhibition of cathepsin-L release following reperfusion injury with CAA0225 reduces infarct size and improves cardiac contractile function by limiting abnormal cardiomyocyte calcium handling and apoptosis. CONCLUSION: Our findings suggest that cathepsin-L is a novel therapeutic target that could be exploited clinically to counteract the deleterious effects of acute reperfusion injury after an acute STEMI.

Post-stenting fractional flow reserve vs coronary angiography for optimization of percutaneous coronary intervention (TARGET-FFR).

AIMS: A fractional flow reserve (FFR) value ≥0.90 after percutaneous coronary intervention (PCI) is associated with a reduced risk of adverse cardiovascular events. TARGET-FFR is an investigator-initiated, single-centre, randomized controlled trial to determine the feasibility and efficacy of a post-PCI FFR-guided optimization strategy vs. standard coronary angiography in achieving final post-PCI FFR values ≥0.90. METHODS AND RESULTS: After angiographically guided PCI, patients were randomized 1:1 to receive a physiology-guided incremental optimization strategy (PIOS) or a blinded coronary physiology assessment (control group). The primary outcome was the proportion of patients with a final post-PCI FFR ≥0.90. Final FFR ≤0.80 was a prioritized secondary outcome. A total of 260 patients were randomized (131 to PIOS, 129 to control) and 68.1% of patients had an initial post-PCI FFR <0.90. In the PIOS group, 30.5% underwent further intervention (stent post-dilation and/or additional stenting). There was no significant difference in the primary endpoint of the proportion of patients with final post-PCI FFR ≥0.90 between groups (PIOS minus control 10%, 95% confidence interval -1.84 to 21.91, P = 0.099). The proportion of patients with a final FFR ≤0.80 was significantly reduced when compared with the angiography-guided control group (-11.2%, 95% confidence interval -21.87 to -0.35], P = 0.045). CONCLUSION: Over two-thirds of patients had a physiologically suboptimal result after angiography-guided PCI. An FFR-guided optimization strategy did not significantly increase the proportion of patients with a final FFR ≥0.90, but did reduce the proportion of patients with a final FFR ≤0.80.

MIR503HG Loss Promotes Endothelial-to-Mesenchymal Transition in Vascular Disease.

[Figure: see text].

Is independence enough? Rehabilitation should include autonomy and social engagement to achieve quality of life.

PURPOSE: This discussion paper argues that holding independence as the central goal for rehabilitation has limitations that hinder successful outcomes. It shows why autonomy and social engagement should also serve as goals of rehabilitation, in order to achieve quality of life and effective functioning. METHODS: The paper reviews problems arising from the over-emphasis on independence in rehabilitation. Although independence is a valuable goal on some tasks, it is sometimes not possible or desirable and is best complimented by autonomy and social engagement. Autonomy recognises that enacting some goals requires the support of other people. Autonomy is thus linked to social engagement (connectivity) in the workplace and personal relationships. The paper applies this framework to motor and cognitive disabilities. RESULTS: The inclusion of autonomy and social engagement as goals for rehabilitation addresses the limitations of independence and can serve the unifying aim of enhancing the person's quality of life. These goals apply equally to motor disabilities and the cognitive and behavioural effects of injuries which affect personal and work relationships. CONCLUSIONS: Rehabilitation is likely to be more effective if it aims at a combination of independence, autonomy and social engagement, in service of the goal of a good quality of life.

Pooled Analysis of Bleeding, Major Adverse Cardiovascular Events, and All-Cause Mortality in Clinical Trials of Time-Constrained Dual-Antiplatelet Therapy After Percutaneous Coronary Intervention.

Background The net clinical benefit of dual antiplatelet therapy (DAPT) reflects the paradoxical effects of an increased risk of bleeding and a reduced risk of major adverse cardiovascular events. A time-constrained approach to DAPT has been recently investigated in 5 multicenter trials including GLOBAL LEADERS, STOPDAPT2 (Short and Optimal Duration of Dual Antiplatelet Therapy After Everolimus-Eluting Cobalt-Chromium Stent-2), SMART-CHOICE, TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention), and TICO (Ticagrelor Monotherapy After 3 Months in the Patients Treated With New Generation Sirolimus Stent for Acute Coronary Syndrome). Methods and Results We undertook a pooled analysis of these trials to assess the overall associations between time-constrained P2Y12 inhibitor monotherapy (aspirin-free regimen) for bleeding events, major adverse cardiovascular events, and all-cause mortality as compared to standard care with DAPT for at least 12 months post-percutaneous coronary intervention. We implemented a DerSimonian and Laird random effects meta-analysis using the metafor package in R. 32 361 randomized trial participants, including 16 898 (52.2%) who had a history of acute coronary syndrome, underwent percutaneous coronary intervention, and had outcome data available. P2Y12 inhibitor monotherapy from 1 to 3 months was associated with a reduced risk for bleeding (hazard ratio [HR] 0.60; 95% CI, 0.45-0.81), including in the acute coronary syndrome group in which the magnitude of risk reduction was greatest (HR 0.50; 95% CI, 0.41-0.61). The estimates of the effect of P2Y12 inhibitor monotherapy on the HR were also favorable for major adverse cardiovascular events (0.88; 95% CI, 0.77-1.02) and all-cause mortality (0.85; 95% CI, 0.71-1.03). Conclusions Compared with DAPT for 12 months post-percutaneous coronary intervention, P2Y12 inhibitor monotherapy from 1 to 3 months substantially reduces the risk of major and fatal bleeding and, in addition, confers potentially protective effects, for major adverse cardiovascular events and all-cause mortality. Considering patient safety, the results support a strategy of DAPT for 1 to 3 months followed by aspirin-free P2Y12 inhibitor monotherapy.

Towards development of a statistical framework to evaluate myotonic dystrophy type 1 mRNA biomarkers in the context of a clinical trial.

Myotonic dystrophy type 1 (DM1) is a rare genetic disorder, characterised by muscular dystrophy, myotonia, and other symptoms. DM1 is caused by the expansion of a CTG repeat in the 3'-untranslated region of DMPK. Longer CTG expansions are associated with greater symptom severity and earlier age at onset. The primary mechanism of pathogenesis is thought to be mediated by a gain of function of the CUG-containing RNA, that leads to trans-dysregulation of RNA metabolism of many other genes. Specifically, the alternative splicing (AS) and alternative polyadenylation (APA) of many genes is known to be disrupted. In the context of clinical trials of emerging DM1 treatments, it is important to be able to objectively quantify treatment efficacy at the level of molecular biomarkers. We show how previously described candidate mRNA biomarkers can be used to model an effective reduction in CTG length, using modern high-dimensional statistics (machine learning), and a blood and muscle mRNA microarray dataset. We show how this model could be used to detect treatment effects in the context of a clinical trial.

Percutaneous coronary intervention versus medical therapy in patients with angina and grey-zone fractional flow reserve values: a randomised clinical trial.

INTRODUCTION: There is conflicting evidence regarding the benefits of percutaneous coronary intervention (PCI) in patients with grey zone fractional flow reserve (GZFFR artery) values (0.75-0.80). The prevalence of ischaemia is unknown. We wished to define the prevalence of ischaemia in GZFFR artery and assess whether PCI is superior to optimal medical therapy (OMT) for angina control. METHODS: We enrolled 104 patients with angina with 1:1 randomisation to PCI or OMT. The artery was interrogated with a Doppler flow/pressure wire. Patients underwent Magnetic Resonance Imaging (MRI) with follow-up at 3 and 12 months. The primary outcome was angina status at 3 months using the Seattle Angina Questionnaire (SAQ). RESULTS: 104 patients (age 60±9 years), 79 (76%) males and 79 (76%) Left Anterior Descending (LAD) stenoses were randomised. Coronary physiology and SAQ were similar. Of 98 patients with stress perfusion MRI data, 17 (17%) had abnormal perfusion (≥2 segments with ≥25% ischaemia or ≥1 segment with ≥50% ischaemia) in the target GZFFR artery. Of 89 patients with invasive physiology data, 26 (28%) had coronary flow velocity reserve <2.0 in the target GZFFR artery. After 3 months of follow-up, compared with patients treated with OMT only, patients treated by PCI and OMT had greater improvements in SAQ angina frequency (21 (28) vs 10 (23); p=0.026) and quality of life (24 (26) vs 11 (24); p=0.008) though these differences were no longer significant at 12 months. CONCLUSIONS: Non-invasive evidence of major ischaemia is uncommon in patients with GZFFR artery. Compared with OMT alone, patients randomised to undergo PCI reported improved symptoms after 3 months but these differences were no longer significant after 12 months. TRIAL REGISTRATION NUMBER: NCT02425969.

A randomized controlled trial of a physiology-guided percutaneous coronary intervention optimization strategy: Rationale and design of the TARGET FFR study.

Post-percutaneous coronary intervention (PCI) fractional flow reserve (FFR) ≥0.90 confers an improved cardiac prognosis. There are currently limited data available to determine how often it is possible to improve an angiographically acceptable but physiologically suboptimal result. A physiology-guided optimization strategy can achieve a clinically meaningful increase in the proportion of patients achieving a final post-PCI FFR ≥0.90 compared to standard care. Following angiographically successful PCI procedures, 260 patients will be randomized (1:1) to receive either a physiology-guided incremental optimization strategy (intervention group) or blinded post-PCI coronary physiology measurements (control group). Patients undergoing successful, standard-of-care PCI for either stable angina or non-ST-segment-elevation myocardial infarction who meet the study's inclusion and exclusion criteria will be eligible for randomization. The primary endpoint is defined as the proportion of patients with a final post-PCI FFR result ≥0.90. Secondary endpoints include change from baseline in Seattle Angina Questionnaire and EQ-5D-5L scores at 3 months and the rate of target vessel failure and its components (cardiac death, myocardial infarction, stent thrombosis, unplanned rehospitalization with target vessel revascularization) at 3 months and 1 year. 260 individual patients were successfully randomized between March 2018 and November 2019. Key baseline demographics of the study population are reported within. TARGET FFR is an investigator-initiated, prospective, single-center, randomized controlled trial of an FFR-guided PCI optimization strategy. The study has completed recruitment and is now in clinical follow-up. It is anticipated that primary results will be presented in Autumn 2020. ClinicalTrials.gov Identifier: NCT03259815. [Correction added on Apr 3 2020, after first online publication: Clinical Trials identifier added.].