Endovascular therapy of isolated posterior cerebral artery occlusion stroke with and without general anesthesia.

BACKGROUND: The optimal anesthetic strategy for endovascular therapy (EVT) in acute ischemic stroke is still under debate. The aim of this study was to compare the clinical outcomes of patients with isolated posterior cerebral artery (PCA) occlusion stroke undergoing EVT by anesthesia modality with conscious sedation (non-GA) versus general anesthesia (GA). METHODS: Patients from the Posterior CerebraL Artery Occlusion (PLATO) study were analyzed with regard to anesthetic strategy. GA was compared with non-GA using multivariable logistic regression and inverse probability of weighting treatment (IPTW) methods. The primary endpoint was the 90-day distribution of the modified Rankin Scale (mRS) score. Secondary outcomes included functional independence or return to Rankin at day 90, and successful reperfusion, defined as expanded Thrombolysis in Cerebral Infarction (eTICI) 2b to 3. Safety endpoints were symptomatic intracranial hemorrhage and mortality. RESULTS: Among 376 patients with isolated PCA occlusion stroke treated with EVT, 183 (49%) had GA. The treatment groups were comparable, although the GA group contained more patients with severe stroke and lower posterior circulation Alberta Stroke Program Early CT Score (pc-ASPECTS). On IPTW analysis, there was no difference between groups with regard to ordinal mRS shift analysis (common OR 0.89, 95% CI 0.53 to 1.51, P=0.67) or functional independence (OR 0.84, 95% CI 0.50 to 1.39, P=0.49). There were greater odds for successful reperfusion with GA (OR 1.70, 95% CI 1.17 to 2.47, P=0.01). Safety outcomes were comparable between groups. CONCLUSION: In patients with isolated PCA occlusion undergoing EVT, patients treated with GA had higher reperfusion rates compared with non-GA. Both GA and non-GA strategies were safe and functional outcomes were similar.

Enhancing thromboresistance of neurovascular nickel-titanium devices with responsive heparin hydrogel coatings.

BACKGROUND: Neurointerventional devices, particularly laser-cut thin-strut stents made of self-expanding nickel-titanium alloy, are increasingly utilized for endovascular applications in intracranial arteries and dural venous sinuses. Preventing thrombosis and stroke necessitates systemic anticoagulant and antiplatelet therapies with the risk of bleeding complications. Antithrombotic coatings present a promising solution. METHODS: In this study, we investigated the potential of hydrogels composed of four-armed poly(ethylene glycol) (starPEG) and heparin, with or without coagulation-responsive heparin release, as coatings for neurovascular devices to mitigate blood clot formation. We evaluated the feasibility and efficacy of these coatings on neurovascular devices through in vitro Chandler-Loop assays and implantation experiments in the supra-aortic arteries of rabbits. RESULTS: Stable and coagulation-responsive starPEG-heparin hydrogel coatings exhibited antithrombotic efficacy in vitro, although with a slightly reduced thromboprotection observed in vivo. Furthermore, the hydrogel coatings demonstrated robustness against shear forces encountered during deployment and elicited only marginal humoral and cellular inflammatory responses compared with the reference standards. CONCLUSION: Heparin hydrogel coatings offer promising benefits for enhancing the hemocompatibility of neurointerventional devices made of self-expanding nickel-titanium alloy. The variance in performance between in vitro and in vivo settings may be attributed to differences in low- and high-shear blood flow conditions inherent to these models. These models may represent the differences in venous and arterial systems. Further optimization is warranted to tailor the hydrogel coatings for improved efficacy in arterial applications.

Non-ischemic cerebral enhancing (NICE) lesions after flow diversion for intracranial aneurysms: a multicenter study.

BACKGROUND: Non-ischemic cerebral enhancing (NICE) lesions have been reported as a rare complication of various neuroendovascular procedures, but information on their incidence after flow diversion is scant. It is unclear if specific devices or novel coating technologies may impact their occurrence. METHODS: We conducted a multicenter study on the incidence of NICE lesions after flow diverter (FD) implantation for cerebral aneurysm treatment. RESULTS: Eight centers identified 15 patients and provided detailed data. The clinical presentation ranged from asymptomatic to hemiplegia and cognitive impairment. The mean time to diagnosis after treatment was 65.1±101.5 days. Five centers disclosed information on all of their 1201 FD procedures during the inclusion period (2015-2022), during which 12 patients were diagnosed with NICE lesions in these institutions-that is, an incidence of 1%. FD coatings did not increase the incidence (6/591 patients (1%) treated with surface-modified FD vs 6/610 patients (1%) treated with bare FD; P=1.00). Significantly increased rates of 3.7% (6 cases in 161 procedures; P<0.01) and 3.3% (5 cases in 153 procedures; P<0.01) were found with stents of two specific product lines. The use of one product line was associated with a significantly lower incidence (0 cases in 499 procedures (0%); P<0.01). CONCLUSIONS: Novel stent coatings are not associated with an increased incidence of NICE lesions. The incidence rate of 1% suggests that these lesions may occur more often after flow diversion than after other endovascular treatments. We found a concerning accumulation of NICE lesion cases when FDs from two product families were used.

Incidence and outcome of perforations during medium vessel occlusion compared with large vessel occlusion thrombectomy.

BACKGROUND: Vessel perforation during thrombectomy is a severe complication and is hypothesized to be more frequent during medium vessel occlusion (MeVO) thrombectomy. The aim of this study was to compare the incidence and outcome of patients with perforation during MeVO and large vessel occlusion (LVO) thrombectomy and to report on the procedural steps that led to perforation. METHODS: In this multicenter retrospective cohort study, data of consecutive patients with vessel perforation during thrombectomy between January 1, 2015 and September 30, 2022 were collected. The primary outcomes were independent functional outcome (ie, modified Rankin Scale 0-2) and all-cause mortality at 90 days. Binomial test, chi-squared test and t-test for unpaired samples were used for statistical analysis. RESULTS: During 25 769 thrombectomies (5124 MeVO, 20 645 LVO) in 25 stroke centers, perforation occurred in 335 patients (1.3%; mean age 72 years, 62% female). Perforation occurred more often in MeVO thrombectomy (2.4%) than in LVO thrombectomy (1.0%, p<0.001). More MeVO than LVO patients with perforation achieved functional independence at 3 months (25.7% vs 10.9%, p=0.001). All-cause mortality did not differ between groups (overall 51.6%). Navigation beyond the occlusion and retraction of stent retriever/aspiration catheter were the two most common procedural steps that led to perforation. CONCLUSIONS: In our cohort, perforation was approximately twice as frequent in MeVO than in LVO thrombectomy. Efforts to optimize the procedure may focus on navigation beyond the occlusion site and retraction of stent retriever/aspiration catheter. Further research is necessary in order to identify thrombectomy candidates at high risk of intraprocedural perforation and to provide data on the effectiveness of endovascular countermeasures.

Flow diversion for compressive unruptured internal carotid artery aneurysms with neuro-ophthalmological symptoms: a systematic review and meta-analysis.

BACKGROUND: Data on the safety and efficacy of flow diverters (FD) for the treatment of unruptured internal carotid artery (ICA) aneurysms with compressive neuro-ophthalmological symptoms (NOS) are scarce and comprise mainly small case series. METHODS: We performed a search of three databases and included series with ≥10 patients, with unruptured aneurysms of the ICA and NOS, treated with FD. Random-effects analysis of treatment results and safety was performed. RESULTS: A total of 22 studies reporting on 594 patients were included. Pooled proportions of NOS recovery, improvement, transient and permanent worsening were: 47.4% (95% CI 35.0% to 60.1%); 74.5% (95% CI 67.9% to 80.2%); 7.1% (95% CI 3.3% to 14.7%); and 4.9% (95% CI 3.2% to 7.4%), respectively. Rates of complete recovery and improvement in patients with isolated visual symptoms were 30.6% (95% CI 12.5% to 57.7%) and 56.6% (95% CI 42.3% to 69.9%). Isolated oculomotor symptoms recovered completely in 47.8% (95% CI 29.9% to 66.3%) and improved in 78% (95% CI 69.2% to 84.9%). Morbidity occurred in 5% (95% CI 2.8% to 9%) and mortality in 3.9% (95% CI 2% to 7.5%) of patients. An increased likelihood of symptom improvement was observed when treatment was performed early (<1 month) after symptom onset (OR=11.22, 95% CI 3.9% to 32.5%). CONCLUSION: Flow diversion promotes recovery or improvement of compressive symptoms in a large proportion of patients but is associated with significant rates of morbidity and mortality. Transient and permanent NOS worsening is not uncommon. Early treatment is of utmost importance, as it increases the likelihood of symptom improvement more than 10-fold.

Left Atrial Appendage Ligation Using the AtriClip Device: Single-Center Study of Device Safety and Efficacy.

Objective: Left atrial appendage (LAA) occlusion at the time of cardiac surgery in patients with atrial fibrillation has been shown to reduce the incidence of postoperative embolic stroke. However, the optimal method for LAA occlusion is not universally accepted. We sought to examine the safety and effectiveness of LAA occlusion with the AtriClip epicardial occlusion device. Methods: Cardiac surgical patients with atrial fibrillation who underwent LAA AtriClip placement were evaluated prospectively. Clip placement and clinical outcomes were examined after 1 year of follow-up with transesophageal echocardiography (TEE). The presence of a 10 mm or greater residual pouch, presence of flow into the LAA, or device-related thrombus (DRT) were considered failures. Results: Ninety-seven patients were analyzed. The mean CHA2DS2-VASc score was 2.4 ± 1.4. The postoperative follow-up period ranged from 366 to 1,693 days (mean 685 days or 1.87 years). Seventy-four AtriClips were placed with video-assisted thoracic surgery, whereas 23 were placed via sternotomy or thoracotomy. Successful closure was found in 96% (93 of 97) of patients at follow-up. Failure occurred in 4 patients. No clip migration or DRT was seen on 3-dimensional imaging. Of all 97 patients, 76 (78%) were on presurgical oral anticoagulation, whereas 5 (5.1%) were on postprocedure oral anticoagulation. There were no postoperative thromboembolic events at the time of the study TEE. Conclusions: The AtriClip epicardial surgical occlusion device can provide an excellent rate of successful closure of the LAA during surgical ablation procedures without DRT.

Mechanical thrombectomy for acute ischemic stroke in COVID-19 patients: multicenter experience in 111 cases.

BACKGROUND: Data on the frequency and outcome of mechanical thrombectomy (MT) for large vessel occlusion (LVO) in patients with COVID-19 is limited. Addressing this subject, we report our multicenter experience. METHODS: A retrospective cohort study was performed of consecutive acute stroke patients with COVID-19 infection treated with MT at 26 tertiary care centers between January 2020 and November 2021. Baseline demographics, angiographic outcome and clinical outcome evaluated by the modified Rankin Scale (mRS) at discharge and 90 days were noted. RESULTS: We identified 111 out of 11 365 (1%) patients with acute or subsided COVID-19 infection who underwent MT due to LVO. Cardioembolic events were the most common etiology for LVO (38.7%). Median baseline National Institutes of Health Stroke Scale score and Alberta Stroke Program Early CT Score were 16 (IQR 11.5-20) and 9 (IQR 7-10), respectively. Successful reperfusion (mTICI ≥2b) was achieved in 97/111 (87.4%) patients and 46/111 (41.4%) patients were reperfused completely. The procedure-related complication rate was 12.6% (14/111). Functional independence was achieved in 20/108 (18.5%) patients at discharge and 14/66 (21.2%) at 90 days follow-up. The in-hospital mortality rate was 30.6% (33/108). In the subgroup analysis, patients with severe acute COVID-19 infection requiring intubation had a mortality rate twice as high as patients with mild or moderate acute COVID-19 infection. Acute respiratory failure requiring ventilation and time interval from symptom onset to groin puncture were independent predictors for an unfavorable outcome in a logistic regression analysis. CONCLUSION: Our study showed a poor clinical outcome and high mortality, especially in patients with severe acute COVID-19 infection undergoing MT due to LVO.

Adoptive transfer of ex vivo expanded regulatory T cells improves immune cell engraftment and therapy-refractory chronic GvHD.

Graft-versus-host disease (GvHD) is still the major non-relapse, life-limiting complication after hematopoietic stem cell transplantation. Modern pharmacologic immunosuppression is often insufficient and associated with significant side effects. Novel treatment strategies now include adoptive transfer of ex vivo expanded regulatory T cells (Tregs), but their efficacy in chronic GvHD is unknown. We treated three children suffering from severe, therapy-refractory GvHD with polyclonally expanded Tregs generated from the original stem cell donor. Third-line maintenance immunosuppression was tapered to cyclosporin A and low-dose steroids shortly before cell transfer. Regular follow-up included an assessment of the subjective and objective clinical development, safety parameters, and in-depth immune monitoring. All patients showed marked clinical improvement with substantially decreased GvHD activity. Laboratory follow-up showed a significant enhancement of the immunologic engraftment, including lymphocytes and dendritic cells. Monitoring the fate of Tregs by next-generation sequencing demonstrated clonal expansion. In summary, adoptive transfer of Tregs was well tolerated and able to modulate an established undesired T cell mediated allo-response. Although no signs of overimmunosuppression were detectable, the treatment of patients with invasive opportunistic infections should be undertaken with caution. Further controlled studies are necessary to confirm these encouraging effects and eventually pave the way for adoptive Treg therapy in chronic GvHD.

Clinical adoptive regulatory T Cell therapy: State of the art, challenges, and prospective.

Rejection of solid organ transplant and graft versus host disease (GvHD) continue to be challenging in post transplantation management. The introduction of calcineurin inhibitors dramatically improved recipients' short-term prognosis. However, long-term clinical outlook remains poor, moreover, the lifelong dependency on these toxic drugs leads to chronic deterioration of graft function, in particular the renal function, infections and de-novo malignancies. These observations led investigators to identify alternative therapeutic options to promote long-term graft survival, which could be used concomitantly, but preferably, replace pharmacologic immunosuppression as standard of care. Adoptive T cell (ATC) therapy has evolved as one of the most promising approaches in regenerative medicine in the recent years. A range of cell types with disparate immunoregulatory and regenerative properties are actively being investigated as potential therapeutic agents for specific transplant rejection, autoimmunity or injury-related indications. A significant body of data from preclinical models pointed to efficacy of cellular therapies. Significantly, early clinical trial observations have confirmed safety and tolerability, and yielded promising data in support of efficacy of the cellular therapeutics. The first class of these therapeutic agents commonly referred to as advanced therapy medicinal products have been approved and are now available for clinical use. Specifically, clinical trials have supported the utility of CD4+CD25+FOXP3+ regulatory T cells (Tregs) to minimize unwanted or overshooting immune responses and reduce the level of pharmacological immunosuppression in transplant recipients. Tregs are recognized as the principal orchestrators of maintaining peripheral tolerance, thereby blocking excessive immune responses and prevent autoimmunity. Here, we summarize rationale for the adoptive Treg therapy, challenges in manufacturing and clinical experiences with this novel living drug and outline future perspectives of its use in transplantation.

Flow diversion for internal carotid artery aneurysms with compressive neuro-ophthalmologic symptoms: clinical and anatomical results in an international multicenter study.

BACKGROUND: Scientific data on the safety and efficacy of flow diverter stents (FDS) for the treatment of unruptured internal carotid artery (ICA) aneurysms with compressive neuro-ophthalmological symptoms are scarce. We studied this subject in a retrospective international multicenter series, pooling data of 9 tertiary care neurointerventional departments. OBJECTIVE: To investigate, in a retrospective, multicentric cohort of patients presenting with visual or oculomotor symptoms attributed to a compressive carotid artery in an unruptured intracranial aneurysm, the safety and efficacy profiles of FDS, by analyzing neuro-opthalmologic symptom evolution following FDS placement, complications, and aneurysm obliteration rates. METHODS: All patients treated since 2015 with a FDS for an unruptured aneurysm of the ICA with signs of compressive cranial nerve symptoms (CN II, III, IV, VI) were included. RESULTS: We treated 55 patients with 55 aneurysms; 21 (38.2%) patients had oculomotor and 15 (27.3%) visual symptoms only; 19 (34.5%) presented with a combination of both. Treatment-related morbidity/mortality occurred in 7.2% and 3.6%, respectively. At last imaging follow-up (13.1±10.5 months) rates of complete aneurysm occlusion, neck remnant, and aneurysm remnant were 72%, 14%, and 14%, respectively. At last clinical follow-up after 13±10.5 months, 19/51 (37.3%) patients had recovered completely and 18/51 (35.3%) had recovered at least partially from their neuro-ophthalmological symptoms. In multivariable models, a longer delay between symptom onset and treatment was associated with higher odds for incomplete recovery and lower odds for any improvement (aOR 1.03 (95% CI 1.01 to 1.07), p=0.047 and 0.04 (0-0.81), p=0.020). Incomplete recovery was independently associated with older age and fusiform aneurysms. CONCLUSION: FDS are effective to treat patients with compressive aneurysms of the ICA causing neuro-ophthalmological symptoms, especially when treatment is initiated early after symptom onset, and aneurysm occlusion is adequate. However, serious complications are not rare.

Parts and Wholes in Scene Processing.

During natural vision, our brains are constantly exposed to complex, but regularly structured, environments. Real-world scenes are defined by typical part-whole relationships, where the meaning of the whole scene emerges from configurations of localized information present in individual parts of the scene. Such typical part-whole relationships suggest that information from individual scene parts is not processed independently, but that there are mutual influences between the parts and the whole during scene analysis. Here, we review recent research that used a straightforward, but effective approach to study such mutual influences: By dissecting scenes into multiple arbitrary pieces, these studies provide new insights into how the processing of whole scenes is shaped by their constituent parts and, conversely, how the processing of individual parts is determined by their role within the whole scene. We highlight three facets of this research: First, we discuss studies demonstrating that the spatial configuration of multiple scene parts has a profound impact on the neural processing of the whole scene. Second, we review work showing that cortical responses to individual scene parts are shaped by the context in which these parts typically appear within the environment. Third, we discuss studies demonstrating that missing scene parts are interpolated from the surrounding scene context. Bridging these findings, we argue that efficient scene processing relies on an active use of the scene's part-whole structure, where the visual brain matches scene inputs with internal models of what the world should look like.

A heart-team hybrid approach for atrial fibrillation: a single-centre long-term clinical outcome cohort study.

OBJECTIVES: The Cox-maze IV is the gold standard for surgical ablation of atrial fibrillation (AF). A heart-team hybrid approach using selected epicardial thoracoscopic surgical ablations and completion endocardial ablations to replicate the Cox-maze IV lesion set has gained popularity and early results have been promising. We herein report our single-centre long-term clinical outcomes using the heart-team hybrid approach with 455 patients. METHODS: From 1 March 2013 to 1 July 2019, we prospectively collected data on all patients referred to our heart team for rhythm-control strategy for AF. Baseline characteristics, procedural complications and long-term freedom from AF (FFAF) both on and off anti-arrhythmic drug therapy were analysed. Ambulatory monitoring (>7 days) was obtained at 3 months and annually thereafter. RESULTS: Four hundred and fifty-five patients completed the hybrid approach. Four hundred and forty-five (97.8%) patients had non-paroxysmal AF (long-standing persistent AF n = 249, 54.7%; persistent AF n = 196, 43.1%; paroxysmal AF n = 10, 2.2%). Average duration of AF was 5.9 ± 6.1 years. Average left atrial diameter was 4.8 ± 0.8 cm. FFAF at 3, 12, 24 and 36 months was 92%, 87%, 81% and 72%, respectively. FFAF without the use of anti-arrhythmic medications was 75%, 81%, 76% and 66%. Any surgical complications occurred in 28 (6.1%) patients. CONCLUSIONS: A heart-team hybrid strategy for the treatment of AF is safe and effective. In a predominantly non-paroxysmal population with AF, at the 3-year follow-up, FFAF in patients on and off anti-arrhythmic drugs approaches that of patients who had the Cox-maze IV.

Impact of thrombus surface on first pass reperfusion in contact aspiration and stent retriever thrombectomy.

BACKGROUND: To assess whether thrombus surface morphology has an impact on first pass reperfusion in contact aspiration (CA) and stent retriever (SR) thrombectomy. METHODS: From January 2016 to December 2018, consecutive stroke patients with an occlusion of the middle cerebral artery and thrombectomy (CA or SR) were examined in this retrospective study. We assessed patients' characteristics, procedural data and clinical outcome. Thrombus surface on pretreatment digital subtraction angiography (DSA) was categorized into regular versus irregular phenotype by blinded three-reader-consensus. Primary outcome was successful reperfusion (modified treatment in cerebral ischemia (mTICI) 2b-3) after first pass. Data analysis was stratified according to thrombectomy technique and thrombus phenotype. RESULTS: Among 203 patients (76 years (IQR 65.5-81.9), 47.3% male, National Institutes of Health Stroke Scale Score 16 (IQR 12-20)), 155 patients were treated primarily with CA and 48 with SR. 40% (n=62/155) CA and 41.7% (n=20/48) SR-treated patients had a regular thrombus phenotype. In the CA group, successful reperfusion after first pass was more frequently obtained in patients with regular compared with irregular phenotype (69.4% (n=43/62) vs 34.4% (n=32/93); P<0.0001). In contrast, in the SR group, reperfusion after first pass was achieved in 35% (n=7/20; P=0.01) of patients with regular phenotypes. In the CA group, median number of passes (1 (1-2) vs 2 (1-4); P<0.00001) and time from reaching the thrombus to reperfusion (19±27 vs 38±36 min; P=0.0001) were lower among patients with a regular phenotype. CONCLUSION: Direct CA is associated with higher rates of successful first pass reperfusion in patients with a regular thrombus phenotype in pretreatment DSA.

Regulatory T cells for minimising immune suppression in kidney transplantation: phase I/IIa clinical trial.

OBJECTIVE: To assess whether reshaping of the immune balance by infusion of autologous natural regulatory T cells (nTregs) in patients after kidney transplantation is safe, feasible, and enables the tapering of lifelong high dose immunosuppression, with its limited efficacy, adverse effects, and high direct and indirect costs, along with addressing several key challenges of nTreg treatment, such as easy and robust manufacturing, danger of over immunosuppression, interaction with standard care drugs, and functional stability in an inflammatory environment in a useful proof-of-concept disease model. DESIGN: Investigator initiated, monocentre, nTreg dose escalation, phase I/IIa clinical trial (ONEnTreg13). SETTING: Charité-University Hospital, Berlin, Germany, within the ONE study consortium (funded by the European Union). PARTICIPANTS: Recipients of living donor kidney transplant (ONEnTreg13, n=11) and corresponding reference group trial (ONErgt11-CHA, n=9). INTERVENTIONS: CD4+ CD25+ FoxP3+ nTreg products were given seven days after kidney transplantation as one intravenous dose of 0.5, 1.0, or 2.5-3.0×106 cells/kg body weight, with subsequent stepwise tapering of triple immunosuppression to low dose tacrolimus monotherapy until week 48. MAIN OUTCOME MEASURES: The primary clinical and safety endpoints were assessed by a composite endpoint at week 60 with further three year follow-up. The assessment included incidence of biopsy confirmed acute rejection, assessment of nTreg infusion related adverse effects, and signs of over immunosuppression. Secondary endpoints addressed allograft functions. Accompanying research included a comprehensive exploratory biomarker portfolio. RESULTS: For all patients, nTreg products with sufficient yield, purity, and functionality could be generated from 40-50 mL of peripheral blood taken two weeks before kidney transplantation. None of the three nTreg dose escalation groups had dose limiting toxicity. The nTreg and reference groups had 100% three year allograft survival and similar clinical and safety profiles. Stable monotherapy immunosuppression was achieved in eight of 11 (73%) patients receiving nTregs, while the reference group remained on standard dual or triple drug immunosuppression (P=0.002). Mechanistically, the activation of conventional T cells was reduced and nTregs shifted in vivo from a polyclonal to an oligoclonal T cell receptor repertoire. CONCLUSIONS: The application of autologous nTregs was safe and feasible even in patients who had a kidney transplant and were immunosuppressed. These results warrant further evaluation of Treg efficacy and serve as the basis for the development of next generation nTreg approaches in transplantation and any immunopathologies. TRIAL REGISTRATION: NCT02371434 (ONEnTreg13) and EudraCT:2011-004301-24 (ONErgt11).

The time course of spatial attention during naturalistic visual search.

In daily life, attention is often directed to high-level object attributes, such as when we look out for cars before crossing a road. Previous work used MEG decoding to investigate the influence of such category-based attention on the time course of object category representations. Attended object categories were more strongly represented than unattended categories from 180 msec after scene onset. In the present study, we used a similar approach to determine when attention is spatially focused on the target. Participants completed two tasks. In the first, they detected cars and people at varying locations in photographs of real-world scenes. In the second, they detected a cross that appeared at salient locations in an array of lines. Multivariate classifiers were trained on data of the artificial salience experiment and tested on data of the naturalistic visual search experiment. Results showed that the location of both target and distracter objects could be accurately decoded shortly after scene onset (50 msec). However, the emergence of spatial attentional selection - reflected in better decoding of target location than distracter location - emerged only later in time (240 msec). Target presence itself (irrespective of location and category) could be decoded from 180 msec after stimulus onset. Combined with earlier work, these results suggest that naturalistic category search operates through an initial spatially-global modulation of category processing that then guides attention to the location of the target.

Prostate-Specific Membrane Antigen Expression in Distal Radius Fracture.

A 79-year old man with prostate cancer under active surveillance for 5 years was referred for a PSMA-PET/MRI for re-evaluation because of a rising prostate-specific antigen value. PET/MRI revealed a ribbonlike tracer accumulation in a healing fracture of the distal radius. This case illustrates that PSMA expression may occur in healing bone fractures in the distal radius. It can be assumed that benign causes of tracer accumulations in the upper extremities are missed in PET/CT due to elevated position of the arms during image acquisition.

The T-cell fingerprint of MALT1 paracaspase revealed by selective inhibition.

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is essential for immune responses triggered by antigen receptors but the contribution of its paracaspase activity is not fully understood. Here, we studied how MALT1 proteolytic function regulates T-cell activation and fate after engagement of the T-cell receptor pathway. We show that MLT-827, a potent and selective MALT1 paracaspase inhibitor, does not prevent the initial phase of T-cell activation, in contrast to the pan-protein kinase C inhibitor AEB071. However, MLT-827 strongly impacted cell expansion after activation. We demonstrate this is the consequence of profound inhibition of IL-2 production as well as reduced expression of the IL-2 receptor alpha subunit (CD25), resulting from defective canonical NF-κB activation and accelerated mRNA turnover mechanisms. Accordingly, MLT-827 revealed a unique transcriptional fingerprint of MALT1 protease activity, providing evidence for broad control of T-cell signaling pathways. Altogether, this first report with a potent and selective inhibitor elucidates how MALT1 paracaspase activity integrates several T-cell activation pathways and indirectly controls gamma-chain receptor dependent survival, to impact on T-cell expansion.

Gender Differences in Clinical Outcomes after Catheter Ablation of Atrial Fibrillation.

Objective: To explore gender differences in real-world outcomes after catheter ablation of atrial fibrillation (AF). Background: Compared to men, women with AF have greater thromboembolic risk and tend to be more symptomatic. Catheter ablation is generally more effective than antiarrhythmic drug therapy alone. However, there is limited data on the influence of gender on AF ablation outcomes. Methods: We analyzed medical claims of 45 million United States patients enrolled in a variety of employee-sponsored and fee-for-service plans. We identified patients who underwent an AF ablation from 2007 to 2011 and evaluated 30-day safety and one-year effectiveness outcomes. Results: Of the 21,091 patients who underwent an AF ablation, 7,460 (29%) were female. Women, compared to men, were older (62±11 vs. 58±11 years), had higher CHADS2 (1.2±1.1 vs. 1.0±1.0), higher CHA2DS2-VASc (2.9±1.5 vs. 1.6±1.4), and higher Charlson comorbidity index scores (1.2±1.3 vs. 1.0±1.2)(p<0.001 for all). Following ablation, women had higher risk of 30-day complications of hemorrhage (2.7 vs. 2.0%,p<0.001) and tamponade (3.8 vs. 2.9%,p<0.001). In multivariable analyses, women were more likely to have a re-hospitalization for AF (adjusted HR 1.12,p=0.009), but less likely to have repeat AF ablation (adjusted HR 0.92,p=0.04) or cardioversion (adjusted HR 0.75,p<0.001). Conclusion: Women have increased hospitalization rates after AF ablation and are more likely to have a procedural complication. Despite the higher rate of hospital admissions for AF after ablation, women were less likely to undergo repeat ablation or cardioversion. These data call for greater examination of barriers and facilitators to sustain rhythm control strategies in women.

Caloric restriction and intermittent fasting alter hepatic lipid droplet proteome and diacylglycerol species and prevent diabetes in NZO mice.

Caloric restriction and intermittent fasting are known to improve glucose homeostasis and insulin resistance in several species including humans. The aim of this study was to unravel potential mechanisms by which these interventions improve insulin sensitivity and protect from type 2 diabetes. Diabetes-susceptible New Zealand Obese mice were either 10% calorie restricted (CR) or fasted every other day (IF), and compared to ad libitum (AL) fed control mice. AL mice showed a diabetes prevalence of 43%, whereas mice under CR and IF were completely protected against hyperglycemia. Proteomic analysis of hepatic lipid droplets revealed significantly higher levels of PSMD9 (co-activator Bridge-1), MIF (macrophage migration inhibitor factor), TCEB2 (transcription elongation factor B (SIII), polypeptide 2), ACY1 (aminoacylase 1) and FABP5 (fatty acid binding protein 5), and a marked reduction of GSTA3 (glutathione S-transferase alpha 3) in samples of CR and IF mice. In addition, accumulation of diacylglycerols (DAGs) was significantly reduced in livers of IF mice (P=0.045) while CR mice showed a similar tendency (P=0.062). In particular, 9 DAG species were significantly reduced in response to IF, of which DAG-40:4 and DAG-40:7 also showed significant effects after CR. This was associated with a decreased PKCε activation and might explain the improved insulin sensitivity. In conclusion, our data indicate that protection against diabetes upon caloric restriction and intermittent fasting associates with a modulation of lipid droplet protein composition and reduction of intracellular DAG species.

Glucagon regulates its own synthesis by autocrine signaling.

Peptide hormones are powerful regulators of various biological processes. To guarantee continuous availability and function, peptide hormone secretion must be tightly coupled to its biosynthesis. A simple but efficient way to provide such regulation is through an autocrine feedback mechanism in which the secreted hormone is "sensed" by its respective receptor and initiates synthesis at the level of transcription and/or translation. Such a secretion-biosynthesis coupling has been demonstrated for insulin; however, because of insulin's unique role as the sole blood glucose-decreasing peptide hormone, this coupling is considered an exception rather than a more generally used mechanism. Here we provide evidence of a secretion-biosynthesis coupling for glucagon, one of several peptide hormones that increase blood glucose levels. We show that glucagon, secreted by the pancreatic α cell, up-regulates the expression of its own gene by signaling through the glucagon receptor, PKC, and PKA, supporting the more general applicability of an autocrine feedback mechanism in regulation of peptide hormone synthesis.