Engineered tRNAs suppress nonsense mutations in cells and in vivo.

Nonsense mutations are the underlying cause of approximately 11% of all inherited genetic diseases1. Nonsense mutations convert a sense codon that is decoded by tRNA into a premature termination codon (PTC), resulting in an abrupt termination of translation. One strategy to suppress nonsense mutations is to use natural tRNAs with altered anticodons to base-pair to the newly emerged PTC and promote translation2-7. However, tRNA-based gene therapy has not yielded an optimal combination of clinical efficacy and safety and there is presently no treatment for individuals with nonsense mutations. Here we introduce a strategy based on altering native tRNAs into  efficient suppressor tRNAs (sup-tRNAs) by individually fine-tuning their sequence to the physico-chemical properties of the amino acid that they carry. Intravenous and intratracheal lipid nanoparticle (LNP) administration of sup-tRNA in mice restored the production of functional proteins with nonsense mutations. LNP-sup-tRNA formulations caused no discernible readthrough at endogenous native stop codons, as determined by ribosome profiling. At clinically important PTCs in the cystic fibrosis transmembrane conductance regulator gene (CFTR), the sup-tRNAs re-established expression and function in cell systems and patient-derived nasal epithelia and restored airway volume homeostasis. These results provide a framework for the development of tRNA-based therapies with a high molecular safety profile and high efficacy in targeted PTC suppression.

Middle Meningeal Artery Embolization for Management of Chronic Subdural Hematoma.

Chronic subdural hematoma (CSDH) is a prevalent medical condition with potentially severe consequences if left untreated. While surgical removal has traditionally been the standard approach for treatment, middle meningeal artery (MMA) embolization has emerged as a promising minimally invasive alternative to reduce recurrences. This comprehensive review provides the general radiology community with an overview of MMA embolization as a therapeutic option for managing CSDH. The authors base their insights on existing evidence and their institutional experience. This overview encompasses the pathophysiology of CSDH as well as the potential advantages and limitations, safety profile, and potential complications of MMA embolization as compared with surgical treatment. The imaging findings seen before and after MMA, as well as insights into the procedural techniques used at the authors' institution, are described. On the basis of reports in the current literature, MMA embolization appears to be a safe and effective therapeutic option for managing CSDH, especially in patients who are unsuitable for surgery or at risk for recurrence. Nonetheless, further research is needed to validate these findings. Results from ongoing clinical trials hold promise for future validation and the establishment of scientific evidence. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material. See the invited commentary by Chatterjee in this issue.

Four-tract probabilistic tractography technique for target selection in essential tremor treatment with magnetic resonance-guided focused ultrasound.

OBJECTIVES: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is a novel, minimally invasive ablative treatment for essential tremor (ET). The use of a four-tract probabilistic tractography technique, targeting the intersection between the dentato-rubro-thalamic tracts (both decussating and non-decussating), while evaluating the corticospinal tract and the medial lemniscus, may obtain immediate clinical results with reduced adverse events. Our aim is to present our experience with the four-tract technique for patients undergoing ET treatment with MRgFUS. METHODS: Retrospective analysis of a prospective database of consecutive patients undergoing ET treatment in a single center from February 2022 to February 2023. Procedural parameters were collected, and tremor improvement was assessed with the Clinical Rating Scale for Tremor (CRST) at baseline and at 3 and 6 months. Adverse events were also reported. RESULTS: Forty-three patients (median age, 72 years [interquartile range, 66-76]; 22 females) were evaluated. Tremor improved significatively in all CRST subsections at 3 months, including the CRST part A + B treated hand tremor (22 [19-27] vs 4 [2-7], p < 0.001) and CRST part C (16 [13-19] vs 3 [1-4], p < 0.001). Differences persisted significant at 6 months. Adverse events were few (4.1% of paresthesias and 12.5% of objective gait disturbance at follow-up) and recorded as mild. The median number of sonications was 7 [6-8] and mean operative time 68.7 ± 24.2 min. CONCLUSION: Our data show support for the feasibility and benefits of systematic targeting approach with four-tract probabilistic tractography for treating ET using MRgFUS. CLINICAL RELEVANCE STATEMENT: An approach with four-tract probabilistic tractography for treating essential tremor (ET) patients with magnetic resonance-guided focused ultrasound decreases interindividual variability with good clinical outcomes, low number of sonications, few adverse effects, and short procedure times. KEY POINTS: • The optimal target for the treatment of essential tremor with MR-guided focused ultrasound remains unknown. • Four-tract probabilistic tractography is a feasible technique that reduces interindividual variability, with good clinical results, few side effects, and short operative time. • The four-tract tractography approach can be performed using different MRI scanners and post-processing software in comparison with the initial description of the technique.

Accuracy of 18F-FDG PET/CT in patients with the suspicion of cardiac implantable electronic device infections.

BACKGROUND: Utility of 18F-FDG PET/CT in diagnosing infective endocarditis (IE) associated with cardiac implantable electronic devices (CIEDs) is not well established. Current ESC guidelines recommend the use of FDG-PET imaging in patients with CIEDs and positive blood cultures, but the number of studies evaluating the diagnostic performance of FDG-PET imaging in these patients remain limited. Our objective was to assess the diagnostic yield of 18F-FDG PET/CT in patients with suspected CIED infections, differentiating between pocket infection (PI) and lead infection (CIED-IE). METHODS AND RESULTS: From 2013 to 2018, all patients (n = 63) admitted to a hospital with suspected CIED infection were prospectively recruited, undergoing a diagnostic work-up including a PET/CT. Explanted devices and material from the pocket were cultured. 14 cases corresponded to isolated PI and 13 were categorized as CIED-IE. Considering radionuclide uptake in the intracardiac portion of the lead, sensitivity and specificity of PET/CT for CIED-IE were 38.5% and 98.0%, respectively. Positive (19.2) and negative (0.6) likelihood ratio values, suggest that a positive PET/CT is much more probable to correspond to a patient with CIED-IE, whereas it is not possible to exclude this diagnosis when negative. For PI, sensitivity and specificity were 72.2% and 95.6%, respectively. CONCLUSIONS: The yield of 18F-FDG PET/CT for suspected CIED infections differs depending on the site of infection. Due to very high specificity but poor sensitivity, negative studies must be interpreted with caution if the suspicion of CIED-IE is high.

Humoral response to heterologous prime-booster vaccination in heart transplant recipients aged 18-70 years primed with a viral vector SARS-CoV-2 vaccine.

Solid organ transplant recipients have demonstrated a blunted immune response to standard 2-dose vaccination against SARS-CoV-2. This study sought to determine the humoral response to heterologous booster vaccination (viral vector vaccine dose 1 and 2 + mRNA booster). Heart transplant recipients, aged 18 to 70 years of age who initially received two doses of the viral vector ChAdOx1 nCoV-19 vaccine followed by a BNT162b2 mRNA booster were recruited. A detectable antibody response in the absence of prior SARS-CoV-2 was the primary outcome measured. This was defined as an anti-spike titre of ≥0.8 U/mL on the Elecsys anti-SARS-CoV-2 S immunoassay. A total of 80 heart transplant patients (mean age 49 ± 13 years, 28% female) were included. Blood samples were drawn at a median of 30 (IQR 28-33) days after the BNT162b2 mRNA booster. The frequency of a detectable antibody response increased from 37.5% (n = 30) after dose 2 to 56% (n = 45) post dose 3 (p < 0.001). A non-detectable antibody response was significantly more common in recipients with a shorter time interval from transplantation (p < 0.001), lower likelihood of cardiac allograft vasculopathy (p = 0.003) and in those prescribed a triple versus dual immunosuppressant regime (p = 0.009) and a tacrolimus versus cyclosporine basedregimen (p = 0.007). Despite heterologous prime-booster vaccination 44% of this vulnerable population ultimately continue to have no detectable antibodies.

Transcranial Doppler 6 h after Successful Reperfusion as a Predictor of Infarct Volume.

OBJECTIVES: The aim of the study is to analyze the hemodynamic changes in the middle cerebral artery (MCA) after endovascular revascularization in acute ischemic stroke (AIS) due to large vessel occlusion and its association with the infarct volume size in the control head CT. MATERIALS AND METHODS: Prospective study of patients with AIS due to internal carotid artery terminus or M1 segment of the MCA occlusion, who underwent endovascular treatment with a final TICI 2b-3 score, without concomitant stenosis ≥50% in both cervical carotid arteries. Transcranial Doppler ultrasound (TCD) of both MCAs was carried out at 6 h after the endovascular procedure. Mean flow velocities (MFV) after arterial reperfusion and its association with the infarct volume size in 24-36 h control head CT were determined. RESULTS: 91 patients (51 women) were included with a median age of 78 years and National institute of Health Stroke Scale of 18. The MCA was occluded in 76.92%, and intravenous thrombolysis was administered in 40.7%. The incidence of symptomatic intracranial hemorrhage was 5.5%. At three months, mortality was 19.8% and a 52.7% of patients achieved functional independence (modified Rankin Scale 0-2). After a multivariable logistic regression analysis, an increase in the MFV greater than 50% at 6 h in the treated MCA compared to contralateral MCA, was an independent predictor of large infarct volume in the control head CT with an OR 9.615 (95%CI: 1.908-47.620), p=0.006 CONCLUSIONS: Increased MFV assessed by TCD examination following endovascular recanalization is independently associated with larger infarct volume.

Mechanical Thrombectomy in Medium Vessel Occlusions: Blind Exchange With Mini-Pinning Technique Versus Mini Stent Retriever Alone.

BACKGROUND AND PURPOSE: Mechanical thrombectomy techniques for intracranial medium vessel occlusions (MeVOs) have evolved in recent years, although the optimal approach is still unclear. The aim of this study was to investigate the effectiveness and safety of mechanical thrombectomy in MeVOs using mini (0.017 inches microcatheter compatible) stent retrievers combined with low-profile (0.035 inches distal inner diameter) distal aspiration catheters through the blind exchange/mini-pinning (BEMP) technique compared with mini stent retrievers alone. METHODS: Retrospective review of a prospectively maintained database of patients treated with the BEMP technique or mini stent retriever alone for intracranial MeVOs from 2017 to 2020 in a comprehensive stroke center. Both groups were compared about baseline characteristics, occlusion site, clinical presentation, clot cause, procedural outcomes (MeVO first-pass and final expanded Thrombolysis in Cerebral Ischemia score, the mini stent retriever used, number of passes with the front-line approach, and need of rescue therapy), safety outcomes (emboli to unwanted territories and hemorrhagic complications), and clinical outcomes at 90 days. Multivariable logistic regression analysis was performed with potential predictors of vessel recanalization to find independent variables associated with MeVO first-pass expanded Thrombolysis in Cerebral Ischemia 2c/3 recanalization. RESULTS: We reviewed 102 patients/106 MeVOs treated with the BEMP technique (n=56) or mini stent retriever (n=50). There was a higher rate of MeVO first-pass expanded Thrombolysis in Cerebral Ischemia 2c/3 recanalization (57% versus 34%, P=0.017), lower need of rescue therapy (7.1% versus 22%, P=0.028), and lower rate of emboli to new territory (1.8% versus 12%, P=0.035) and symptomatic intracranial hemorrhage (1.9% versus 12.8%, P=0.038) with the BEMP technique. After multivariable analysis, the sole independent factor associated to MeVO first-pass expanded Thrombolysis in Cerebral Ischemia 2c/3 recanalization was the BEMP technique (odds ratio, 2.72 [95% CI, 1.19-6.22]; P=0.018). CONCLUSIONS: In the setting of MeVOs, the BEMP technique may lead to higher rates of the first-pass recanalization and a lower incidence of symptomatic intracranial hemorrhage than mini stent retrievers alone.

Morphological characterization of vegetation by real-time three-dimensional transesophageal echocardiography in infective endocarditis: Prognostic impact.

PURPOSE: Vegetation size is a prognostic predictor in infective endocarditis (IE) and guides surgical management. The aim of this study was to evaluate the accuracy of real-time 3-dimensional transesophageal echocardiography (RT3DTEE) compared to 2DTEE in the diagnosis and characterization of vegetation, as well as its potential clinical impact. METHODS: Two hundred and three consecutive patients with IE were recruited (2009-2016) and retrospectively analyzed. Vegetation diameters and area from 68 patients were measured by 2DTEE and RT3DTEE at admission. The association between size and systemic embolisms was evaluated with logistic regression models. Differences in the discriminative power for the best dimensions' cutoff points were assessed by comparing the area under the ROC curves (AUC). RESULTS: Vegetation size and area were larger by RT3DTEE (P < 0.001) than by 2DTEE, and RT3DTEE was especially relevant in the characterization of nonfiliform vegetation, Morphology was strongly associated with friability, being sessile vegetation less likely to embolize, compared to filiform and raceme-shaped ones (15.4% vs 46% vs 50%). Major diameter by RT3DTEE had better embolic predictive performance than 2DTEE (AUC 0.76 [0.57-0.89] vs 0.71 [0.53-0.86]; P = 0.611). The best cutoff points associated with embolic events during the infection were 17 mm for RT3DTEE and 15 mm for 2DTEE. Based exclusively on vegetation size, the proportion of patients meeting a surgical indication according to current guidelines is higher using RT3DTEE. CONCLUSIONS: RT3DTEE allows a better characterization of IE vegetation than 2DTEE, what may have a clinical impact on surgical management and also prognostic due to a more accurate prediction of embolic risk.

Celecoxib Treatment Improves Neurologic Deficit and Reduces Selective Neuronal Loss and Glial Response in Rats after Transient Middle Cerebral Artery Occlusion.

Areas of selective neuronal loss (SNL) represent the first morphologic signs of damage in the penumbra region and are considered putative targets for ischemic stroke therapy. We performed a novel assessment of measuring the effects of the anti-inflammatory agent celecoxib by analyzing simultaneously the different neural populations (neurons, astrocytes, and microglia cells) in SNL and non-SNL areas. Rats were subjected to 1 hour of middle cerebral artery occlusion (MCAO) and treated with celecoxib 1 and 24 hours after ischemia. Infarct volume measurements and triple immunostaining of neurons (neuronal nuclear antigen), microglia (ionized calcium-binding adaptor molecule 1), and astroglia were performed after 12 and 48 hours of reperfusion. Motor response was tested by standard behavioral assays at 3, 12, 24, and 48 hours. Confocal analysis revealed that the percentage of SNL areas, microglia densities, and glial activation increased at 48 hours of reperfusion. Celecoxib treatment improved the neurologic deficit, reduced the infarct volume by 50% after 48 hours of reperfusion, and resulted in a reduced percentage of SNL areas and microglia and astroglia reactivity after 48 hours of reperfusion. This study proves, for the first time, that celecoxib presents postischemic neuroprotective effects in a transient MCAO model, prevents or delays the presence of SNL areas, and reduces glial activation.

Postmitotic regulation of sensory area patterning in the mammalian neocortex by Lhx2.

Current knowledge suggests that cortical sensory area identity is controlled by transcription factors (TFs) that specify area features in progenitor cells and subsequently their progeny in a one-step process. However, how neurons acquire and maintain these features is unclear. We have used conditional inactivation restricted to postmitotic cortical neurons in mice to investigate the role of the TF LIM homeobox 2 (Lhx2) in this process and report that in conditional mutant cortices area patterning is normal in progenitors but strongly affected in cortical plate (CP) neurons. We show that Lhx2 controls neocortical area patterning by regulating downstream genetic and epigenetic regulators that drive the acquisition of molecular properties in CP neurons. Our results question a strict hierarchy in which progenitors dominate area identity, suggesting a novel and more comprehensive two-step model of area patterning: In progenitors, patterning TFs prespecify sensory area blueprints. Sequentially, sustained function of alignment TFs, including Lhx2, is essential to maintain and to translate the blueprints into functional sensory area properties in cortical neurons postmitotically. Our results reemphasize critical roles for Lhx2 that acts as one of the terminal selector genes in controlling principal properties of neurons.

Left common carotid artery agenesis with bovine origin of the left internal carotid artery.

The absence of the left common carotid artery, with separate origins of the external carotid and internal carotid arteries from the aortic arc is a well-described but extremely rare congenital anomaly. We present a unique case of agenesis of left common carotid artery depicted at MR angiography where the left internal carotid artery had a bovine origin (from the brachiocephalic trunk) and the left external carotid artery arose from the aortic arc. In addition, it is important to diagnose this anatomical variant especially prior to interventional procedures, as it could hinder the catheterization of these arteries.

Role of BRCA1 in brain development.

Breast cancer susceptibility gene 1 (BRCA1) is a breast and ovarian cancer tumor suppressor whose loss leads to DNA damage and defective centrosome functions. Despite its tumor suppression functions, BRCA1 is most highly expressed in the embryonic neuroepithelium when the neural progenitors are highly proliferative. To determine its functional significance, we deleted BRCA1 in the developing brain using a neural progenitor-specific driver. The phenotype is characterized by severe agenesis of multiple laminated cerebral structures affecting most notably the neocortex, hippocampus, cerebellum, and olfactory bulbs. Major phenotypes are caused by excess apoptosis, as these could be significantly suppressed by the concomitant deletion of p53. Certain phenotypes attributable to centrosomal and cell polarity functions could not be rescued by p53 deletion. A double KO with the DNA damage sensor kinase ATM was able to rescue BRCA1 loss to a greater extent than p53. Our results suggest distinct apoptotic and centrosomal functions of BRCA1 in neural progenitors, with important implications to understand the sensitivity of the embryonic brain to DNA damage, as well as the developmental regulation of brain size.

Hippocampus and cerebral cortex present a different autophagic response after oxygen and glucose deprivation in an ex vivo rat brain slice model.

AIMS: To evaluate the neuroprotective role of autophagy in the cerebral cortex and hippocampus using an ex vivo animal model of stroke in brain slices. METHODS: Brain slices were maintained for 30 min in oxygen and glucose deprivation (OGD) followed by 3 h in normoxic conditions to simulate the reperfusion that follows ischaemia in vivo (RL, reperfusion-like). Phagophore formation (Beclin 1 and LC3B) as well as autophagy flux (p62/SQSTM1, Atg5, Atg7 and polyubiquitin) markers were quantified by Western blot and/or qPCR. The release of lactate dehydrogenase (LDH) and glutamate in the medium was used as a measure of the mortality in the absence and in the presence of the autophagy inhibitor 3-methyladenine. RESULTS: Striking differences in the autophagy markers were observed between the hippocampus and cerebral cortex in normoxic conditions. OGD/RL induced increases both in the phagophore formation and in the autophagy flux in the first three hours in the cerebral cortex that were not observed in the hippocampus. The blocking of autophagy increased the OGD/RL-induced mortality, increased the glutamate release in both the cerebral cortex and hippocampus and abolished the OGD-induced decrease in the polyubiquitinated proteins in the cerebral cortex. CONCLUSIONS: We conclude that OGD induces a rapid autophagic response in the cerebral cortex that plays a neuroprotective role. Polyubiquitination levels and control of the glutamate release appear to be involved in the neuroprotective role of autophagy.

Antiapoptotic protein Lifeguard is required for survival and maintenance of Purkinje and granular cells.

Lifeguard (LFG) is an inhibitor of Fas-mediated cell death and is highly expressed in the cerebellum. We investigated the biological role of LFG in the cerebellum in vivo, using mice with reduced LFG expression generated by shRNA lentiviral transgenesis (shLFG mice) as well as LFG null mice. We found that LFG plays a role in cerebellar development by affecting cerebellar size, internal granular layer (IGL) thickness, and Purkinje cell (PC) development. All these features are more severe in early developmental stages and show substantial recovery overtime, providing a remarkable example of cerebellar plasticity. In adult mice, LFG plays a role in PC maintenance shown by reduced cellular density and abnormal morphology with increased active caspase 8 and caspase 3 immunostaining in shLFG and knockout (KO) PCs. We studied the mechanism of action of LFG as an inhibitor of the Fas pathway and provided evidence of the neuroprotective role of LFG in cerebellar granule neurons (CGNs) and PCs in an organotypic cerebellar culture system. Biochemical analysis of the Fas pathway revealed that LFG inhibits Fas-mediated cell death by interfering with caspase 8 activation. This result is supported by the increased number of active caspase 8-positive PCs in adult mice lacking LFG. These data demonstrate that LFG is required for proper development and survival of granular and Purkinje cells and suggest LFG may play a role in cerebellar disorders.

Right ventricular dysfunction: pathophysiology, experimental models, evaluation, and treatment.

Interest in the right ventricle has substantially increased due to advances in knowledge of its pathophysiology and prognostic implications across a wide spectrum of diseases. However, we are still far from understanding the multiple mechanisms that influence right ventricular dysfunction, its evaluation continues to be challenging, and there is a shortage of specific treatments in most scenarios. This review article aims to update knowledge about the physiology of the right ventricle, its transition to dysfunction, diagnostic tools, and available treatments from a translational perspective.

Valvulitis: a new echocardiographic criterion for the diagnosis of bioprosthetic aortic valve infective endocarditis.

INTRODUCTION AND OBJECTIVES: Diffuse homogeneous hypoechoic leaflet thickening, with a wavy leaflet motion documented by transesophageal echocardiography (TEE), has been described in some cases of prosthetic valve endocarditis (PVE) involving aortic bioprosthesis (AoBio-PVE). This echocardiographic finding has been termed valvulitis. We aimed to estimate the prevalence of valvulitis, precisely describe its echocardiographic characteristics, and determine their clinical significance in patients with AoBio-PVE. METHODS: From 2011 to 2022, 388 consecutive patients with infective endocarditis (IE) admitted to a tertiary care hospital were prospectively included in a multipurpose database. For this study, all patients with AoBio-PVE (n=86) were selected, and their TEE images were thoroughly evaluated by 3 independent cardiologists to identify all cases of valvulitis. RESULTS: The prevalence of isolated valvulitis was 12.8%, and 20.9% of patients had valvulitis accompanied by other classic echocardiographic findings of IE. A total of 9 out of 11 patients with isolated valvulitis had significant valve stenosis, whereas significant aortic valve regurgitation was documented in only 1 patient. Compared with the other patients with AoBio-PVE, cardiac surgery was less frequently performed in patients with isolated valvulitis (27.3% vs 62.7%, P=.017). In 4 out of 5 patients with valve stenosis who did not undergo surgery but underwent follow-up TEE, valve gradients significantly improved with appropriate antibiotic therapy. CONCLUSIONS: Valvulitis can be the only echocardiographic finding in infected AoBio and needs to be identified by imaging specialists for early diagnosis. However, this entity is a diagnostic challenge and additional imaging techniques might be required to confirm the diagnosis. Larger series are needed.

Unfolded protein response to global ischemia following 48 h of reperfusion in the rat brain: the effect of age and meloxicam.

The unfolded protein response (UPR) in the hippocampal regions Cornu Ammonis 1 hippocampal region, Cornu Ammonis 3 hippocampal region, and dentate gyrus, as well as in the cerebral cortex of 3-month-old and 18-month-old rats were studied in a model of 15 min of global cerebral ischemia followed by 48 h of reperfusion. UPR was measured by quantifying the protein disulfide isomerase (PDI), C/EBP-homologous protein (CHOP), GRP78 and GRP94 transcripts using qPCR and the amounts of PDI and GRP78 by western blot. The study shows how the mRNA levels of these genes were similar in 3-month-old and 18-month-old sham-operated animals, but the ischemic insult elicited a noticeable increase in the expression of these genes in young animals that was scarcely appreciable in older animals. The striking increase in the mRNA levels of these genes in 3-month-old animals was abolished or even reverted by treatment with meloxicam, an anti-inflammatory agent. Western blot assays showed that the UPR was still detectable 48 h after ischemia in some of the studied areas, and provided evidence that the UPR is different between young and older animals. Western blot assays carried out in young animals also showed that meloxicam elicited different effects on the levels of PDI and GRP78 in the cerebral cortex and the hippocampus. We conclude that the UPR response to ischemic/reperfusion insult is age- and probably inflammation-dependent and could play an important role in ischemic vulnerability. The UPR appears to be strongly decreased in aged animals, suggesting a reduced ability for cell survival. In this study, we conclude that the unfolded protein response (UPR) to ischemic/reperfusion insult is age- and probably inflammation-dependent and could play an important role in ischemic vulnerability. The UPR strongly decreased in aged rats, suggesting a reduced ability for cell survival. The increase in the mRNA levels of UPR gene transcripts in 3-month-old animals was abolished or even reverted by treatment with meloxicam, an anti-inflammatory agent.

Mechanical thrombectomy is cost-effective versus medical management alone around Europe in patients with low ASPECTS.

OBJECTIVE: To demonstrate, by a cost-effectiveness analysis, the efficiency of mechanical thrombectomy (MT) versus medical management (MM) in patients with a low Alberta Stroke Program Early CT Score (ASPECTS) from the RESCUE Study. METHODS: A cost-effectiveness model was designed to project both direct medical costs and quality-adjusted life-years (QALYs) of MT versus MM in eight European countries (Spain, UK, France, Italy, Belgium, Germany, Sweden, and the Netherlands). Our model was created based on previously published health-economic data in those countries. Procedure costs, acute, mid-term, and long-term care costs were projected based on expected modified Rankin Scale (mRS) scores as reported in the RESCUE-Japan LIMIT trial. RESULTS: MT was found to be a cost-effective option in eight different countries across Europe (Spain, Italy, UK, France, Belgium, Germany, the Netherlands, and Sweden). with a lifetime incremental cost-effectiveness ratio varying from US$2 875 to US$11 202/QALY depending on the country. A cost-effectiveness acceptability curve showed 100% acceptability of MT at the willingness to pay (WTP) of US$40 000 for the eight countries. CONCLUSIONS: MT is efficient versus MM alone for patients with low ASPECTS in eight countries across Europe. Patients with a large ischemic core could be treated with MT because it is both clinically beneficial and economically sustainable.

Impact of Balloon Guide Catheters in Elderly Patients Treated with Mechanical Thrombectomy: Insights from the ROSSETTI Registry.

BACKGROUND AND PURPOSE: Several nonrandomized studies have demonstrated the effectiveness of balloon guide catheters in treating patients with anterior circulation large-vessel occlusion. However, their impact on the elderly populations has been underreported. We aimed to analyze the effect of balloon guide catheters in a cohort of elderly patients (80 years of age or older) with anterior circulation large-vessel occlusion. MATERIALS AND METHODS: Consecutive patients from June 2019 to June 2022 were collected from the ROSSETTI Registry. Demographic and clinical data, angiographic endovascular technique, and clinical outcome were compared between balloon guide catheter and non-balloon guide catheter groups. We studied the association between balloon guide catheters and the rate of complete recanalization after a single first-pass effect modified TICI 2c-3, as well as their association with functional independence at 3 months. RESULTS: A total of 808 patients were included during this period, 465 (57.5%) of whom were treated with balloon guide catheters. Patients treated with balloon guide catheters were older, had more neurologic severity at admission and lower baseline ASPECTS, and were less likely to receive IV fibrinolytics. No differences were observed in terms of the modified first-pass effect between groups (45.8 versus 39.9%, P = .096). In the multivariable regression analysis, balloon guide catheter use was not independently associated with a modified first-pass effect or the final modified TICI 2c-3, or with functional independence at 3 months. CONCLUSIONS: In our study, balloon guide catheter use during endovascular treatment of anterior circulation large-vessel occlusion in elderly patients did not predict the first-pass effect, near-complete final recanalization, or functional independence at 3 months. Further studies, including randomized clinical trials, are needed to confirm these results.

Non-invasive electromechanical assessment during atrial fibrillation identifies underlying atrial myopathy alterations with early prognostic value.

Electromechanical characterization during atrial fibrillation (AF) remains a significant gap in the understanding of AF-related atrial myopathy. This study reports mechanistic insights into the electromechanical remodeling process associated with AF progression and further demonstrates its prognostic value in the clinic. In pigs, sequential electromechanical assessment during AF progression shows a progressive decrease in mechanical activity and early dissociation from its electrical counterpart. Atrial tissue samples from animals with AF reveal an abnormal increase in cardiomyocytes death and alterations in calcium handling proteins. High-throughput quantitative proteomics and immunoblotting analyses at different stages of AF progression identify downregulation of contractile proteins and progressive increase in atrial fibrosis. Moreover, advanced optical mapping techniques, applied to whole heart preparations during AF, demonstrate that AF-related remodeling decreases the frequency threshold for dissociation between transmembrane voltage signals and intracellular calcium transients compared to healthy controls. Single cell simulations of human atrial cardiomyocytes also confirm the experimental results. In patients, non-invasive assessment of the atrial electromechanical relationship further demonstrate that atrial electromechanical dissociation is an early prognostic indicator for acute and long-term rhythm control.