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OBJECTIVES: This study aims to investigate the occurrence, type and correlation of early and late atrial arrhythmias following mitral valve repair in patients with no preoperative history of atrial arrhythmias. METHODS: Patients undergoing mitral valve (MV) repair for degenerative disease were included. Early and late postoperative electrocardiograms were evaluated for the incidence and type of atrial arrhythmia (atrial fibrillation [AF] or atrial tachycardia [AT]). RESULTS: The 192 patients were included. Early atrial arrhythmias occurred in 100/192 (52.1%) patients; AF in 61 (31.8%) patients, early AT in 15 (7.8%) and both in 24 (12.5%). In total 89% of patients were discharged in sinus rhythm. During a follow-up time of 7.3 years, 14 patients (7.3%) died and 49 (25.5%) patients developed late atrial arrhythmias. At 10 years, the cumulative incidence of any late atrial arrhythmia, with death as competing risk, was 64% (95% confidence interval [CI] = 55%-72%). On Fine-Gray model analysis, only early postoperative AF lasting >24 h was related to the development of late AF (hazard ratio 5.99, 95% CI = 1.78%-20.10%, p = .004). Early postoperative ATs were related to the development of late tachycardias, independent of their duration (<24 h hazard ratio 4.25, 95% CI = 1.89-9.57, p = .001 and >24 h hazard ratio 3.51, 95% CI = 1.65-7.46, p = .001). CONCLUSIONS: Early and late atrial arrhythmias were common after MV repair surgery. Only early postoperative AF lasting >24 h was a risk factor for the occurrence of late AF. Conversely, any postoperative AT was correlated to the development of late ATs.
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BACKGROUND: Various mitral valve (MV) repair techniques are nowadays in use. Non-resection techniques, that rely exclusively on Gore-Tex® neochords and annuloplasty, have been popularized; however, their efficacy in Barlow's disease, characterized by large myxomatous leaflets, is yet unclear. METHODS: Consecutive patients undergoing MV repair for Barlow's disease between 2011 and 2019 were selected on the basis of being eligible for resection and non-resection techniques. Study endpoints included overall survival, freedom from MV reintervention and recurrent regurgitation. RESULTS: Of 209 patients meeting the inclusion criteria, 135 (65%) underwent MV repair with and 74 (35%) without resection. There was one early reoperation due to residual regurgitation (resection group). Mean clinical follow-up duration was 6.1 (IQR 3.9-8.5) years. At 6 years after surgery, there was no difference in overall survival or freedom from MV reintervention. Mean echocardiographic follow-up (95% complete) duration was 3.5 (IQR 2.3-5.8) years. At 6 years, there was no difference in freedom from recurrent regurgitation rate (86.1%, 95% CI 78.5-93.7% vs. 83.0%, 95% CI 71.6-94.4%, P = 0.20) between the groups. Inverse probability-of-treatment weighting adjusted analysis demonstrated no significant difference between groups (HR 0.535, 95% CI 0.212-1.349, P = 0.20). Uni- and multivariable Cox proportional regression analysis did not demonstrate an effect of valve repair technique on the occurrence of recurrent regurgitation. CONCLUSIONS: At mid-term, the clinical and echocardiographic results of valve repair for Barlow's disease were very good and MV reintervention was rarely needed. At this time point, the results of non-resection techniques were comparable to the "gold standard" resection techniques.
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OBJECTIVES: Thoracoscopic ablation has proven to be an effective and safe rhythm control strategy, especially for persistent atrial fibrillation. However, its impact on quality of life (QoL) and potential gender differences remains unclear. METHODS: This prospective, single-centre observational study included consecutive patients with symptomatic atrial fibrillation undergoing thoracoscopic ablation. QoL was measured using the Short Form 36 (SF-36) and Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaires and longitudinal trend analysis including linear mixed models was used to assess gender-specific differences. RESULTS: A total of 191 patients were included; mean age 63.9 ± 8.6 years, 61 (31.9%) women and 148 (77.5%) with non-paroxysmal atrial fibrillation. Women were older, more symptomatic and reported lower baseline QoL. AFEQT summary scores substantially improved after three months (relative increase 51.5% from baseline; P < 0.001) and persisted up to 1-year (57.2%; P < 0.001). Women showed substantial QoL improvement, which was comparable to men at 1 year. Distinct gender-related trajectories for AFEQT were observed. Women showed more often clinically important decline over time, yet AF recurrence and age were predictive factors in both men and women. Patients with AF recurrence also experienced QoL improvements, albeit to a lesser extent than those in sinus rhythm (61.3% vs 26.9%, P < 0.001), with no differences between men and women. CONCLUSIONS: Thoracoscopic ablation for atrial fibrillation results in substantial QoL improvement and was comparable for men and women. Understanding sex-specific and age-related trajectories is important to further enhance patient-centred atrial fibrillation care.
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Objective: New echocardiographic definitions have been proposed for hemodynamic structural valve deterioration. We aimed to study their consistency in classifying structural valve deterioration after surgical aortic valve replacement. Methods: Data were used of patients undergoing surgical aortic valve replacement in a multicenter, prospective cohort study with a 5-year follow-up. All patients received the same stented bioprosthesis. Echocardiographic parameters were assessed by an independent core laboratory. Moderate or greater stenotic hemodynamic structural valve deterioration was defined according to Capodanno and colleagues, Dvir and colleagues, and the Valve Academic Research Consortium 3; regurgitation data were not considered in this analysis. Consistency was quantified on the basis of structural valve deterioration classification at subsequent time points. Results: A total of 1118 patients received implants. Patients' mean age was 70 years, and 75% were male. Hemodynamic structural valve deterioration at any visit was present in 51 patients (4.6%), 32 patients (2.9%), and 34 patients (3.0%) according to Capodanno, Dvir, and Valve Academic Research Consortium 3. A total of 1064 patients (95%) were never labeled with structural valve deterioration by any definition. After the first classification with structural valve deterioration, 59%, 59%, and 65% had no subsequent structural valve deterioration classification according to Capodanno, Dvir, and Valve Academic Research Consortium 3, respectively. Conclusions: The current definitions of hemodynamic structural valve deterioration are strong negative predictors but inconsistent positive discriminators for the detection of stenotic hemodynamic structural valve deterioration. Although the diagnosis of structural valve deterioration may be categorical, echocardiographic indices lack this degree of precision in the first 5 years after surgical aortic valve replacement. The inconsistency of current structural valve deterioration definitions impedes the detection of true valve degeneration, which challenges the clinical usefulness of these definitions.
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We present 2 patients with angina with no obstructive coronary artery disease and concomitant myocardial bridging. Despite maximal tolerated pharmacotherapy, symptoms remained. Invasive anatomical and hemodynamic assessment identified myocardial bridging as a contributing cause of angina. Following heart team discussion, both patients underwent successful coronary artery unroofing of the left anterior descending artery.
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The neurodevelopmental disorder Pitt Hopkins syndrome (PTHS) causes clinical symptoms similar to Rett syndrome (RTT) patients. However, RTT is caused by MECP2 mutations whereas mutations in the TCF4 gene lead to PTHS. The mechanistic commonalities underling these two disorders are unknown, but their shared symptomology suggest that convergent pathway-level disruption likely exists. We reprogrammed patient skin derived fibroblasts into induced neuronal progenitor cells. Interestingly, we discovered that MeCP2 levels were decreased in PTHS patient iNPCs relative to healthy controls and that both iNPCs and iAstrocytes displayed defects in function and differentiation in a mutation-specific manner. When Tcf4+/- mice were genetically crossed with mice overexpressing MeCP2, molecular and phenotypic defects were significantly ameliorated, underlining and important role of MeCP2 in PTHS pathology. Importantly, post-natal intracerebroventricular gene replacement therapy with adeno-associated viral vector serotype 9 (AAV9)-expressing MeCP2 (AAV9.P546.MeCP2) significantly improved iNPC and iAstrocyte function and effectively ameliorated histological and behavioral defects in Tcf4+/- mice. Combined, our data suggest a previously unknown role of MeCP2 in PTHS pathology and common pathways that might be affected in multiple neurodevelopmental disorders. Our work highlights potential novel therapeutic targets for PTHS, including upregulation of MeCP2 expression or its downstream targets or, potentially, MeCP2-based gene therapy.
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Pain and anxiety are common in patients undergoing cardiac surgery and percutaneous cardiac interventions. Virtual reality (VR) is an emerging non-pharmacological tool for pain and anxiety management. However, its application around cardiac procedures remains relatively unexplored. In this review, we perform a targeted non-systematic literature review to assess the current state-of-the-art of VR for pain and anxiety management in patients undergoing cardiac procedures. Contexts of interest were preprocedural, periprocedural, and postprocedural applications. Existing trials show inconsistent results. The majority of studies in the preprocedural (7 studies, n = 302), periprocedural (1 study, n = 99), and postprocedural stage (4 studies, n = 214) demonstrate significant reduction of pain and anxiety through VR distraction therapy or VR patient education. However, larger-scale trials (2 preprocedural studies [n = 233], 1 periprocedural study [n = 32], 2 postprocedural studies [n = 300]) report no effect. Current literature on effectiveness of VR for pain and anxiety management in cardiac surgery and interventional cardiology remains inconclusive.
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A 73-year-old male presented with angina symptoms and was diagnosed with three-vessel coronary artery disease by use of computed tomography angiography and coronary angiography. This diagnosis necessitated coronary artery bypass grafting (CABG) surgery. A custom made AI-driven algorithm was used to generate a patient-specific three-dimensional coronary artery model from computed tomography angiography imaging data. This framework enabled precise segmentation and reconstruction of the coronary vasculature, yielding an accurate anatomical and pathological representation. Subsequently, this generated model was integrated into a novel extended reality tool for preoperative planning and intraoperative guidance in CABG surgery. Both preoperatively and intraoperatively, the tool augmented spatial orientation and facilitated precise stenosis localization, thereby enhancing the surgeon's operative proficiency. This case report underscores the utility of advanced extended reality tools in cardiovascular surgery, emphasizing their pivotal role in refining surgical planning and execution.
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Background: Thoracic aortopathy includes conditions like aortic aneurysms and dissections, posing significant management challenges. In India, care delivery is complicated by geographic vastness, financial constraints, and healthcare resource disparities. Telemedicine and digital health technologies offer promising solutions. Methods: A comprehensive review of literature and clinical experiences was conducted to explore the implementation of remote care strategies for thoracic aortopathy in India. The review included studies from 2000 to 2023 and insights from cardiothoracic specialists. Results: Remote care benefits include improved access to specialized expertise, enhanced patient engagement, and optimized resource utilization. Telemedicine enables consultations without travel, and remote monitoring facilitates early intervention. However, challenges like technology integration, digital literacy, patient engagement, privacy concerns, and regulatory compliance need addressing. Discussion: Telemedicine offers significant advantages but requires overcoming challenges to ensure effective, secure care. Careful planning for technology integration, patient education, robust privacy measures, and supportive regulatory policies are essential. Addressing these issues can bridge the healthcare access gap and improve outcomes in India's diverse landscape.
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BACKGROUND: Extracorporeal blood purification has been widely used in intensive care medicine, nephrology, toxicology, and other fields. During the last decade, with the emergence of new adsorptive blood purification devices, hemoadsorption has been increasingly applied during CPB in cardiac surgery, for patients at different inflammatory risks, or for postoperative complications. Clinical evidence so far has not provided definite answers concerning this adjunctive treatment. The current systematic review aimed to critically assess the role of perioperative hemoadsorption in cardiac surgery, by summarizing the current knowledge in this clinical setting. METHODS: A literature search of PubMed, Cochrane library, and the database provided by CytoSorbents was conducted on June 1st, 2023. The search terms were chosen by applying neutral search keywords to perform a non-biased systematic search, including language variations of terms "cardiac surgery" and "hemoadsorption". The screening and selection process followed scientific principles (PRISMA statement). Abstracts were considered for inclusion if they were written in English and published within the last ten years. Publications were eligible for assessment if reporting on original data from any type of study (excluding case reports) in which a hemoadsorption device was investigated during or after cardiac surgery. Results were summarized according to sub-fields and presented in a tabular view. RESULTS: The search resulted in 29 publications with a total of 1,057 patients who were treated with hemoadsorption and 988 control patients. Articles were grouped and descriptively analyzed due to the remarkable variability in study designs, however, all reported exclusively on CytoSorb® therapy. A total of 62% (18/29) of the included articles reported on safety and no unanticipated adverse events have been observed. The most frequently reported clinical outcome associated with hemoadsorption was reduced vasopressor demand resulting in better hemodynamic stability. CONCLUSIONS: The role of hemoadsorption in cardiac surgery seems to be justified in selected high-risk cases in infective endocarditis, aortic surgery, heart transplantation, and emergency surgery in patients under antithrombotic therapy, as well as in those who develop a dysregulated inflammatory response, vasoplegia, or septic shock postoperatively. Future large randomized controlled trials are needed to better define proper patient selection, dosing, and timing of the therapy.
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Cardiac Surgical Procedures , Humans , Cardiac Surgical Procedures/adverse effects , Treatment Outcome , Risk Factors , Postoperative Complications/therapy , Postoperative Complications/etiology , Cardiopulmonary Bypass/adverse effects , Male , Female , Risk Assessment , Aged , Middle AgedABSTRACT
Background: Fear overgeneralization is a promising pathogenic mechanism of clinical anxiety. A dominant model posits that hippocampal pattern separation failures drive overgeneralization. Hippocampal network-targeted transcranial magnetic stimulation (HNT-TMS) has been shown to strengthen hippocampal-dependent learning/memory processes. However, no study has examined whether HNT-TMS can alter fear learning/memory. Methods: Continuous theta burst stimulation was delivered to individualized left posterior parietal stimulation sites derived via seed-based connectivity, precision functional mapping, and electric field modeling methods. A vertex control site was also stimulated in a within-participant, randomized controlled design. Continuous theta burst stimulation was delivered prior to 2 visual discrimination tasks (1 fear based, 1 neutral). Multilevel models were used to model and test data. Participants were undergraduates with posttraumatic stress symptoms (final n = 25). Results: Main analyses did not indicate that HNT-TMS strengthened discrimination. However, multilevel interaction analyses revealed that HNT-TMS strengthened fear discrimination in participants with lower fear sensitization (indexed by responses to a control stimulus with no similarity to the conditioned fear cue) across multiple indices (anxiety ratings: ß = 0.10, 95% CI, 0.04 to 0.17, p = .001; risk ratings: ß = 0.07, 95% CI, 0.00 to 0.13, p = .037). Conclusions: Overgeneralization is an associative process that reflects deficient discrimination of the fear cue from similar cues. In contrast, sensitization reflects nonassociative responding unrelated to fear cue similarity. Our results suggest that HNT-TMS may selectively sharpen fear discrimination when associative response patterns, which putatively implicate the hippocampus, are more strongly engaged.
Fear overgeneralization is a promising pathogenic mechanism of clinical anxiety that is thought to be driven by deficient hippocampal discrimination. Using hippocampal networktargeted transcranial magnetic stimulation (HNT-TMS) in healthy participants with symptoms of posttraumatic stress, Webler et al. report that HNT-TMS did not strengthen discrimination overall, but it did strengthen fear discrimination in participants with lower fear sensitization. Sensitization reflects nonassociative fear responding unrelated to fear cue similarity and therefore is not expected to engage the hippocampal discrimination function. These results suggest that HNT-TMS may selectively sharpen fear discrimination when the hippocampal discrimination function is more strongly engaged.
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OBJECTIVES: The objective of this analysis was to assess the normal haemodynamic performance of contemporary surgical aortic valves at 1 year postimplant in patients undergoing surgical aortic valve replacement for significant valvular dysfunction. By pooling data from 4 multicentre studies, this study will contribute to a better understanding of the effectiveness of surgical aortic valve replacement procedures, aiding clinicians and researchers in making informed decisions regarding valve selection and patient management. METHODS: Echocardiograms were assessed by a single core laboratory. Effective orifice area, dimensionless velocity index, mean aortic gradient, peak aortic velocity and stroke volume were evaluated. RESULTS: The cohort included 2958 patients. Baseline age in the studies ranged from 70.1 ± 9.0 to 83.3 ± 6.4 years, and Society of Thoracic Surgeons risk of mortality was 1.9 ± 0.7 to 7.5 ± 3.4%. Twenty patients who had received a valve model implanted in fewer than 10 cases were excluded. Ten valve models (all tissue valves; n = 2938 patients) were analysed. At 1 year, population mean effective orifice area ranged from 1.46 ± 0.34 to 2.12 ± 0.59 cm2, and dimensionless velocity index, from 0.39 ± 0.07 to 0.56 ± 0.15. The mean gradient ranged from 8.6 ± 3.4 to 16.1 ± 6.2 mmHg with peak aortic velocity of 1.96 ± 0.39 to 2.65 ± 0.47 m/s. Stroke volume was 75.3 ± 19.6 to 89.8 ± 24.3 ml. CONCLUSIONS: This pooled cohort is the largest to date of contemporary surgical aortic valves with echocardiograms analysed by a single core lab. Overall haemodynamic performance at 1 year ranged from good to excellent. These data can serve as a benchmark for other studies and may be useful to evaluate the performance of bioprosthetic surgical valves over time. CLINICAL TRIAL REGISTRATION NUMBER: NCT02088554, NCT02701283, NCT01586910 and NCT01531374.
Subject(s)
Aortic Valve , Bioprosthesis , Heart Valve Prosthesis Implantation , Heart Valve Prosthesis , Hemodynamics , Humans , Hemodynamics/physiology , Aortic Valve/surgery , Aortic Valve/diagnostic imaging , Aged , Female , Male , Aged, 80 and over , Heart Valve Prosthesis Implantation/methods , Echocardiography , Middle Aged , Prosthesis DesignABSTRACT
OBJECTIVES: Surgical aortic valve replacement through conventional sternotomy yields excellent results. Minimally invasive techniques are deemed equally safe and serve as a viable and less traumatic alternative. However, it is unclear how both surgical techniques affect patient-reported outcomes. The objective of this trial is to compare postoperative cardiac-related quality of life and postoperative pain after upper hemisternotomy and conventional surgical aortic valve replacement. METHODS: In this single-centre, open-label, investigator-initiated randomized clinical trial, patients were randomized to upper hemisternotomy or conventional full median sternotomy. Patients unable to undergo randomization were monitored prospectively (registry group). Primary outcome was cardiac-specific quality of life, measured with the Kansas City Cardiomyopathy Questionnaire up to 1 year postoperatively. RESULTS: Patients undergoing upper hemisternotomy had a significantly higher physical limitation domain score across all postoperative time points than patients undergoing conventional surgical aortic valve replacement (estimated mean difference 2.12 points; P = 0.014). Patients undergoing upper hemisternotomy were more likely to have a pain score <30 the first 2 days postoperatively than patients undergoing conventional surgical aortic valve replacement (odds ratio 2.63; P = 0.007). This was associated with reduced opioid analgesic intake. Postoperative surgical outcome did not differ between both groups. CONCLUSIONS: Surgical aortic valve replacement through both conventional sternotomy and upper hemisternotomy resulted in clinically similar and important improvements in quality of life, with a small advantage for upper hemisternotomy, while there was no compromise in safety.
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Background: Post-cardiotomy cardiogenic shock (PCCS), which is defined as severe low cardiac output syndrome after cardiac surgery, has a mortality rate of up to 90%. No study has yet been performed to compare patients with PCCS treated by conservative means to patients receiving additional mechanical circulatory support with veno-arterial extracorporeal membrane oxygenation (ECMO). Methods: A single-center retrospective analysis from January 2018 to June 2022 was performed. Results: Out of 7028 patients who underwent cardiac surgery during this time period, 220 patients (3%) developed PCCS. The patients were stratified according to their severity of shock based on the Stage Classification Expert Consensus (SCAI) group. Known risk factors for shock-related mortality, including the vasoactive-inotropic score (VIS) and plasma lactate levels, were assessed at structured intervals. In patients treated additionally with ECMO (n = 73), the in-hospital mortality rate was 60%, compared to an in-hospital mortality rate of 85% in patients treated by conservative means (non-ECMO; n = 52). In 18/73 (25%) ECMO patients, the plasma lactate level normalized within 48 h, compared to 2/52 (4%) in non-ECMO patients. The morbidity of non-ECMO patients compared to ECMO patients included a need for dialysis (42% vs. 60%), myocardial infarction (19% vs. 27%), and cerebrovascular accident (17% vs. 12%). Conclusions: In conclusion, the additional use of ECMO in PCCS holds promise for enhancing outcomes in these critically ill patients, more rapid improvement of end-organ perfusion, and the normalization of plasma lactate levels.
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Although the general location of functional neural networks is similar across individuals, there is vast person-to-person topographic variability. To capture this, we implemented precision brain mapping functional magnetic resonance imaging methods to establish an open-source, method-flexible set of precision functional network atlases-the Masonic Institute for the Developing Brain (MIDB) Precision Brain Atlas. This atlas is an evolving resource comprising 53,273 individual-specific network maps, from more than 9,900 individuals, across ages and cohorts, including the Adolescent Brain Cognitive Development study, the Developmental Human Connectome Project and others. We also generated probabilistic network maps across multiple ages and integration zones (using a new overlapping mapping technique, Overlapping MultiNetwork Imaging). Using regions of high network invariance improved the reproducibility of executive function statistical maps in brain-wide associations compared to group average-based parcellations. Finally, we provide a potential use case for probabilistic maps for targeted neuromodulation. The atlas is expandable to alternative datasets with an online interface encouraging the scientific community to explore and contribute to understanding the human brain function more precisely.
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Brain , Connectome , Magnetic Resonance Imaging , Humans , Magnetic Resonance Imaging/methods , Brain/physiology , Brain/diagnostic imaging , Adolescent , Male , Female , Adult , Young Adult , Nerve Net/physiology , Nerve Net/diagnostic imaging , Brain Mapping/methods , Atlases as Topic , Child , Probability , Neural Pathways/physiologyABSTRACT
Heart surgery may be complicated by acute lung injury and adult respiratory distress syndrome. Expression and release of mucins MUC5AC and MUC5B in the lungs has been reported to be increased in acute lung injury. The aim of our study was to [1] investigate the perioperative changes of MUC5AC, MUC5B and other biomarkers in mini-bronchoalveolar lavage (minBAL), and [2] relate these to clinical outcomes after cardiac surgery. In this prospective cohort study in 49 adult cardiac surgery patients pre- and post-surgery non-fiberscopic miniBAL fluids were analysed for MUC5AC, MUC5B, IL-8, human neutrophil elastase, and neutrophils. All measured biomarkers increased after surgery. Perioperative MUC5AC-change showed a significant negative association with postoperative P/F ratio (p = 0.018), and a positive association with ICU stay (p = 0.027). In conclusion, development of lung injury after cardiac surgery and prolonged ICU stay are associated with an early increase of MUC5AC as detected in mini-BAL.
Subject(s)
Acute Lung Injury , Cardiac Surgical Procedures , Adult , Humans , Bronchoalveolar Lavage Fluid , Prospective Studies , Acute Lung Injury/diagnosis , Acute Lung Injury/etiology , Cardiac Surgical Procedures/adverse effects , Biomarkers/analysis , Mucin 5AC/metabolismABSTRACT
Background: Although various hemodynamic parameters to assess prosthetic performance are available, prosthesis-patient mismatch (PPM) is defined exclusively by effective orifice area (EOA) index thresholds. Adjusting for the Society of Thoracic Surgeons predicted risk of mortality (STS PROM), we aimed to explore the added value of postoperative hemodynamic parameters for the prediction of all-cause mortality at 5 years after aortic valve replacement. Methods: Data were obtained from the Pericardial Surgical Aortic Valve Replacement (PERIGON) Pivotal Trial, a multicenter prospective cohort study examining the performance of the Avalus bioprosthesis. Candidate predictors were assessed at the first follow-up visit; patients who had no echocardiography data, withdrew consent, or died before this visit were excluded. Candidate predictors included peak jet velocity, mean pressure gradient, EOA, predicted and measured EOA index, Doppler velocity index, indexed internal prosthesis orifice area, and categories for PPM. The performance of Cox models was investigated using the c-statistic and net reclassification improvement (NRI), among other tools. Results: A total of 1118 patients received the study valve, of whom 1022 were eligible for the present analysis. In univariable analysis, STS PROM was the sole significant predictor of all-cause mortality (hazard ratio, 1.40; 95% confidence interval, 1.26-1.55). When extending the STS PROM with single hemodynamic parameters, neither the c-statistics nor the NRIs demonstrated added prognostic value compared to a model with STS PROM alone. Similar findings were observed when multiple hemodynamic parameters were added. Conclusions: The STS PROM was found to be the main predictor of patient prognosis. The additional prognostic value of postoperative hemodynamic parameters for the prediction of all-cause mortality was limited.
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Fragile X syndrome is a neurodevelopmental disorder caused by silencing of the fragile X messenger ribonucleotide gene. Patients display a wide spectrum of symptoms ranging from intellectual and learning disabilities to behavioural challenges including autism spectrum disorder. In addition to this, patients also display a diversity of symptoms due to mosaicism. These factors make fragile X syndrome a difficult syndrome to manage and suggest that a single targeted therapeutic approach cannot address all the symptoms. To this end, we utilized Healx's data-driven drug discovery platform to identify a treatment strategy to address the wide range of diverse symptoms among patients. Computational methods identified the combination of ibudilast and gaboxadol as a treatment for several pathophysiological targets that could potentially reverse multiple symptoms associated with fragile X syndrome. Ibudilast is an approved broad-spectrum phosphodiesterase inhibitor, selective against both phosphodiesterase 4 and phosphodiesterase 10, and has demonstrated to have several beneficial effects in the brain. Gaboxadol is a GABAA receptor agonist, selective against the delta subunit, which has previously displayed encouraging results in a fragile X syndrome clinical trial. Alterations in GABA and cyclic adenosine monophosphate metabolism have long since been associated with the pathophysiology of fragile X syndrome; however, targeting both pathways simultaneously has never been investigated. Both drugs have a good safety and tolerability profile in the clinic making them attractive candidates for repurposing. We set out to explore whether the combination of ibudilast and gaboxadol could demonstrate therapeutic efficacy in a fragile X syndrome mouse model. We found that daily treatment with ibudilast significantly enhanced the ability of fragile X syndrome mice to perform a number of different cognitive assays while gaboxadol treatment improved behaviours such as hyperactivity, aggression, stereotypy and anxiety. Importantly, when ibudilast and gaboxadol were co-administered, the cognitive deficits as well as the aforementioned behaviours were rescued. Moreover, this combination treatment showed no evidence of tolerance, and no adverse effects were reported following chronic dosing. This work demonstrates for the first time that by targeting multiple pathways, with a combination treatment, we were able to rescue more phenotypes in a fragile X syndrome mouse model than either ibudilast or gaboxadol could achieve as monotherapies. This combination treatment approach holds promise for addressing the wide spectrum of diverse symptoms in this heterogeneous patient population and may have therapeutic potential for idiopathic autism.
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Identification of replicable neuroimaging correlates of attention-deficit hyperactivity disorder (ADHD) has been hindered by small sample sizes, small effects, and heterogeneity of methods. Given evidence that ADHD is associated with alterations in widely distributed brain networks and the small effects of individual brain features, a whole-brain perspective focusing on cumulative effects is warranted. The use of large, multisite samples is crucial for improving reproducibility and clinical utility of brain-wide MRI association studies. To address this, a polyneuro risk score (PNRS) representing cumulative, brain-wide, ADHD-associated resting-state functional connectivity was constructed and validated using data from the Adolescent Brain Cognitive Development (ABCD, N = 5,543, 51.5% female) study, and was further tested in the independent Oregon-ADHD-1000 case-control cohort (N = 553, 37.4% female). The ADHD PNRS was significantly associated with ADHD symptoms in both cohorts after accounting for relevant covariates (p < 0.001). The most predictive PNRS involved all brain networks, though the strongest effects were concentrated among the default mode and cingulo-opercular networks. In the longitudinal Oregon-ADHD-1000, non-ADHD youth had significantly lower PNRS (Cohen's d = -0.318, robust p = 5.5 × 10-4) than those with persistent ADHD (age 7-19). The PNRS, however, did not mediate polygenic risk for ADHD. Brain-wide connectivity was robustly associated with ADHD symptoms in two independent cohorts, providing further evidence of widespread dysconnectivity in ADHD. Evaluation in enriched samples demonstrates the promise of the PNRS approach for improving reproducibility in neuroimaging studies and unraveling the complex relationships between brain connectivity and behavioral disorders.