Subcortical tau is linked to hypoperfusion in connected cortical regions in 4-repeat tauopathies.

Four-repeat (4R) tauopathies are neurodegenerative diseases characterized by cerebral accumulation of 4R tau pathology. The most prominent 4R tauopathies are progressive supranuclear palsy (PSP) and corticobasal degeneration characterized by subcortical tau accumulation and cortical neuronal dysfunction, as shown by PET-assessed hypoperfusion and glucose hypometabolism. Yet, there is a spatial mismatch between subcortical tau deposition patterns and cortical neuronal dysfunction, and it is unclear how these two pathological brain changes are interrelated. Here, we hypothesized that subcortical tau pathology induces remote neuronal dysfunction in functionally connected cortical regions to test a pathophysiological model that mechanistically links subcortical tau accumulation to cortical neuronal dysfunction in 4R tauopathies. We included 51 Aß-negative patients with clinically diagnosed PSP variants (n = 26) or corticobasal syndrome (n = 25) who underwent structural MRI and 18F-PI-2620 tau-PET. 18F-PI-2620 tau-PET was recorded using a dynamic one-stop-shop acquisition protocol to determine an early 0.5-2.5 min post tracer-injection perfusion window for assessing cortical neuronal dysfunction, as well as a 20-40 min post tracer-injection window to determine 4R-tau load. Perfusion-PET (i.e. early window) was assessed in 200 cortical regions, and tau-PET was assessed in 32 subcortical regions of established functional brain atlases. We determined tau epicentres as subcortical regions with the highest 18F-PI-2620 tau-PET signal and assessed the connectivity of tau epicentres to cortical regions of interest using a resting-state functional MRI-based functional connectivity template derived from 69 healthy elderly controls from the ADNI cohort. Using linear regression, we assessed whether: (i) higher subcortical tau-PET was associated with reduced cortical perfusion; and (ii) cortical perfusion reductions were observed preferentially in regions closely connected to subcortical tau epicentres. As hypothesized, higher subcortical tau-PET was associated with overall lower cortical perfusion, which remained consistent when controlling for cortical tau-PET. Using group-average and subject-level PET data, we found that the seed-based connectivity pattern of subcortical tau epicentres aligned with cortical perfusion patterns, where cortical regions that were more closely connected to the tau epicentre showed lower perfusion. Together, subcortical tau-accumulation is associated with remote perfusion reductions indicative of neuronal dysfunction in functionally connected cortical regions in 4R-tauopathies. This suggests that subcortical tau pathology may induce cortical dysfunction, which may contribute to clinical disease manifestation and clinical heterogeneity.

Multicenter Collaborative Study to Optimize Mass Spectrometry Workflows of Clinical Specimens.

The foundation for integrating mass spectrometry (MS)-based proteomics into systems medicine is the development of standardized start-to-finish and fit-for-purpose workflows for clinical specimens. An essential step in this pursuit is to highlight the common ground in a diverse landscape of different sample preparation techniques and liquid chromatography-mass spectrometry (LC-MS) setups. With the aim to benchmark and improve the current best practices among the proteomics MS laboratories of the CLINSPECT-M consortium, we performed two consecutive round-robin studies with full freedom to operate in terms of sample preparation and MS measurements. The six study partners were provided with two clinically relevant sample matrices: plasma and cerebrospinal fluid (CSF). In the first round, each laboratory applied their current best practice protocol for the respective matrix. Based on the achieved results and following a transparent exchange of all lab-specific protocols within the consortium, each laboratory could advance their methods before measuring the same samples in the second acquisition round. Both time points are compared with respect to identifications (IDs), data completeness, and precision, as well as reproducibility. As a result, the individual performances of participating study centers were improved in the second measurement, emphasizing the effect and importance of the expert-driven exchange of best practices for direct practical improvements.

Improving protocols for α-synuclein seed amplification assays: analysis of preanalytical and analytical variables and identification of candidate parameters for seed quantification.

OBJECTIVES: The effect of preanalytical and analytical factors on the α-synuclein (α-syn) seed amplification assay's (SAA) performance has not been fully explored. Similarly, there is limited knowledge about the most suitable assay protocol and kinetic parameters for misfolded α-syn seed quantification. METHODS: We studied the effect of centrifugation, repeated freeze-thaw cycles (up to seven), delayed freezing, detergent addition, and blood contamination on the performance of the cerebrospinal fluid (CSF) α-syn SAA real-time quaking-induced conversion (RT-QuIC). Moreover, we analysed the inter- and intra-plate variability, the recombinant protein batch effect, and the RT-QuIC parameters' variability when multiple samples were run in controlled conditions. Finally, we evaluated the assay potential of quantifying α-syn seed by assessing kinetic curves in serial CSF dilutions. RESULTS: Among tested preanalytical variables, a ≥0.01 % blood contamination and adding detergents significantly affected the RT-QuIC kinetic parameters and the number of positive replicates. Increasing the number of replicates improved result reproducibility. The number of positive replicates in serially diluted CSF samples improved discrimination between samples with high and low seeding activity, and the time to threshold (LAG) was the most reliable kinetic parameter in multiple experiment settings. CONCLUSIONS: Preanalytical variables affecting α-syn RT-QuIC performance are limited to blood contamination and detergent addition. The number of positive replicates and the LAG are the most reliable variables for quantifying α-syn seeding activity. Their consistent measurement in serial dilution experiments, especially when associated with an increased number of sample replicates, will help to develop the α-syn RT-QuIC assay further into a quantitative test.

Stroke outcomes following durable left ventricular assist device implant in patients bridged with micro-axial flow pump: Insights from a large registry.

BACKGROUND: Stroke after durable left ventricular assist device (d-LVAD) implantation portends high mortality. The incidence of ischemic and hemorrhagic stroke and the impact on stroke outcomes of temporary mechanical circulatory support (tMCS) management among patients requiring bridge to d-LVAD with micro-axial flow-pump (mAFP, Abiomed) is unsettled. METHODS: Consecutive patients, who underwent d-LVAD implantation after being bridged with mAFP at 19 institutions, were retrospectively included. The incidence of early ischemic and hemorrhagic stroke after d-LVAD implantation (<60 days) and association of pre-d-LVAD characteristics and peri-procedural management with a specific focus on tMCS strategies were studied. RESULTS: Among 341 patients, who underwent d-LVAD implantation after mAFP implantation (male gender 83.6%, age 58 [48-65] years, mAFP 5.0/5.5 72.4%), the early ischemic stroke incidence was 10.8% and early hemorrhagic stroke 2.9%. The tMCS characteristics (type of mAFP device and access, support duration, upgrade from intra-aortic balloon pump, ECMELLA, ECMELLA at d-LVAD implantation, hemolysis, and bleeding) were not associated with ischemic stroke after d-LVAD implant. Conversely, the device model (mAFP 2.5/CP vs. mAFP 5.0/5.5: HR 5.6, 95%CI 1.4-22.7, p = 0.015), hemolysis on mAFP support (HR 10.5, 95% CI 1.3-85.3, p = 0.028) and ECMELLA at d-LVAD implantation (HR 5.0, 95% CI 1.4-18.7, p = 0.016) were associated with increased risk of hemorrhagic stroke after d-LVAD implantation. Both early ischemic (HR 2.7, 95% CI 1.9-4.5, p < 0.001) and hemorrhagic (HR 3.43, 95% CI 1.49-7.88, p = 0.004) stroke were associated with increased 1-year mortality. CONCLUSIONS: Among patients undergoing d-LVAD implantation following mAFP support, tMCS characteristics do not impact ischemic stroke occurrence, while several factors are associated with hemorrhagic stroke suggesting a proactive treatment target to reduce this complication.

α-Synuclein seed amplification assay detects Lewy body co-pathology in autosomal dominant Alzheimer's disease late in the disease course and dependent on Lewy pathology burden.

INTRODUCTION: Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains. METHODS: Using an α-synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo. RESULTS: No asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed α-synuclein seeding activity in CSF in vivo. DISCUSSION: Results suggest that in ADAD LBP occurs later than AD pathology and often as amygdala- or olfactory-predominant LBP, for which CSF α-synuclein SAA has low sensitivity. HIGHLIGHTS: Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) detects misfolded α-synuclein in ≈ 10% of symptomatic autosomal dominant Alzheimer's disease (ADAD) patients. CSF RT-QuIC does not detect α-synuclein seeding activity in asymptomatic mutation carriers. Lewy body pathology (LBP) in ADAD mainly occurs as olfactory only or amygdala-predominant variants. LBP develops late in the disease course in ADAD. CSF α-synuclein RT-QuIC has low sensitivity for focal, low-burden LBP.

[18F]F-DED PET imaging of reactive astrogliosis in neurodegenerative diseases: preclinical proof of concept and first-in-human data.

OBJECTIVES: Reactive gliosis is a common pathological hallmark of CNS pathology resulting from neurodegeneration and neuroinflammation. In this study we investigate the capability of a novel monoamine oxidase B (MAO-B) PET ligand to monitor reactive astrogliosis in a transgenic mouse model of Alzheimer`s disease (AD). Furthermore, we performed a pilot study in patients with a range of neurodegenerative and neuroinflammatory conditions. METHODS: A cross-sectional cohort of 24 transgenic (PS2APP) and 25 wild-type mice (age range: 4.3-21.0 months) underwent 60 min dynamic [18F]fluorodeprenyl-D2 ([18F]F-DED), static 18 kDa translocator protein (TSPO, [18F]GE-180) and ß-amyloid ([18F]florbetaben) PET imaging. Quantification was performed via image derived input function (IDIF, cardiac input), simplified non-invasive reference tissue modelling (SRTM2, DVR) and late-phase standardized uptake value ratios (SUVr). Immunohistochemical (IHC) analyses of glial fibrillary acidic protein (GFAP) and MAO-B were performed to validate PET imaging by gold standard assessments. Patients belonging to the Alzheimer's disease continuum (AD, n = 2), Parkinson's disease (PD, n = 2), multiple system atrophy (MSA, n = 2), autoimmune encephalitis (n = 1), oligodendroglioma (n = 1) and one healthy control underwent 60 min dynamic [18F]F-DED PET and the data were analyzed using equivalent quantification strategies. RESULTS: We selected the cerebellum as a pseudo-reference region based on the immunohistochemical comparison of age-matched PS2APP and WT mice. Subsequent PET imaging revealed that PS2APP mice showed elevated hippocampal and thalamic [18F]F-DED DVR when compared to age-matched WT mice at 5 months (thalamus: + 4.3%; p = 0.048), 13 months (hippocampus: + 7.6%, p = 0.022) and 19 months (hippocampus: + 12.3%, p < 0.0001; thalamus: + 15.2%, p < 0.0001). Specific [18F]F-DED DVR increases of PS2APP mice occurred earlier when compared to signal alterations in TSPO and ß-amyloid PET and [18F]F-DED DVR correlated with quantitative immunohistochemistry (hippocampus: R = 0.720, p < 0.001; thalamus: R = 0.727, p = 0.002). Preliminary experience in patients showed [18F]F-DED VT and SUVr patterns, matching the expected topology of reactive astrogliosis in neurodegenerative (MSA) and neuroinflammatory conditions, whereas the patient with oligodendroglioma and the healthy control indicated [18F]F-DED binding following the known physiological MAO-B expression in brain. CONCLUSIONS: [18F]F-DED PET imaging is a promising approach to assess reactive astrogliosis in AD mouse models and patients with neurological diseases.

cAMP Imaging at Ryanodine Receptors Reveals ß2-Adrenoceptor Driven Arrhythmias.

[Figure: see text].

SARS-CoV-2 Vaccination-Induced Immunogenicity in Heart Transplant Recipients.

Among heart transplant (HT) recipients, a reduced immunological response to SARS-CoV-2 vaccination has been reported. We aimed to assess the humoral and T-cell response to SARS-CoV-2 vaccination in HT recipients to understand determinants of immunogenicity. HT recipients were prospectively enrolled from January 2021 until March 2022. Anti-SARS-CoV-2-Spike IgG levels were quantified after two and three doses of a SARS-CoV-2 vaccine (BNT162b2, mRNA1273, or AZD1222). Spike-specific T-cell responses were assessed using flow cytometry. Ninety-one patients were included in the study (69% male, median age 55 years, median time from HT to first vaccination 6.1 years). Seroconversion rates were 34% after two and 63% after three doses. Older patient age (p = 0.003) and shorter time since HT (p = 0.001) were associated with lower antibody concentrations after three vaccinations. There were no associations between vaccine types or immunosuppressive regimens and humoral response, except for prednisolone, which was predictive of a reduced response after two (p = 0.001), but not after three doses (p = 0.434). A T-cell response was observed in 50% after two and in 74% after three doses. Despite three vaccine doses, a large proportion of HT recipients exhibits a reduced immune response. Additional strategies are desirable to improve vaccine immunogenicity in this vulnerable group of patients.

Mechanical circulatory support for adults in Japan: A 10-year perspective.

Globalization in Asia and consequent strengthening of healthcare economic factors in tandem with an increasing heart failure (HF) population have enhanced potential for development and progress in the fields of HF medicine and mechanical circulatory support (MCS). In Japan, there are unique opportunities to investigate the outcome of acute and chronic MCS and a national registry for percutaneous and implantable left ventricular assist device (LVAD) including Impella pumps has been established. A Peripheral extracorporeal membrane oxygenation (ECMO) for acute MCS has been used in more than 7000 patients annually and Impella usage in more than 4000 patients over the past 4 years was noted. Recently, a novel centrifugal pump with hydrodynamically levitated impeller was developed and approved for mid-term extracorporeal circulatory support. In terms of chronic MCS more than 1200 continuous flow LVADs have been implanted during the past decade, and 2-year survival rate after primary LVAD implantation is 91%. Because of donor organ shortage, more than 70% of heart transplant recipients required LVAD support for more than 3 years and prevention and treatment of complications during long-term LVAD support have become important. Five important topics including hemocompatibility-related complications, LVAD infections, aortic valve insufficiency, right ventricular failure and cardiac recovery during LVAD support are discussed in this review for improving clinical outcomes. Findings from Japan will continue to provide useful information regarding MCS for the Asia-Pacific region and beyond.

From escalation to weaning strategies: how to integrate the ECMELLA concept.

The additional implantation of a micro-axial flow pump (mAFP) in patients receiving extracorporeal life support by a veno-arterial extracorporeal membrane oxygenation (V-A ECMO) for cardiogenic shock (CS) has gained interest in recent years. Thus far, retrospective propensity score-matched studies, case series, and meta-analyses have consistently shown an improved survival in patients treated with the so-called ECMELLA concept. The pathophysiological context is based on the modification of V-A ECMO-related side effects and the additive benefit of myocardial unloading. From this point of view, knowledge and detection of these pathophysiological mechanisms are of utmost importance to successfully manage mechanical circulatory support in CS. In this article, we describe best practices for the indication of the two devices as well as escalation and de-escalation approaches including implantation and explantation strategies that are key for success.

Differential utilization of Impella devices, extracorporeal membrane oxygenation, and combined therapies as escalation and de-escalation strategies.

Cardiogenic shock (CS) is a life-threatening condition characterized by a state of inadequate systemic tissue perfusion caused by cardiac dysfunction. When to implement, change, or remove the use of a temporary mechanical circulatory support (tMCS) in patients with CS is dependent on the aetiology and severity. Here, patient scenarios underlying the need to escalate, de-escalate, wean, or bridge from tMCS devices are taken into consideration by interdisciplinary heart failure and CS teams. This includes a comprehensive review of and focus on the rationale for specific device escalation and de-escalation strategies, device selection, and general management.

Preliminary Experience of Extracorporeal Cytokine Hemoadsorption during Left Ventricular Assist Device Implantation in Cardiogenic Shock Patients.

BACKGROUND: Systemic inflammation due to cardiogenic shock is associated with vasoplegia leading to organ hypoperfusion, right heart failure, and poor clinical outcome. Extracorporeal cytokine hemoadsorption emerged to attenuate excessive levels of inflammatory cytokines, potentially improving patient outcomes. Nevertheless, its prognostic impact during high-risk left ventricular assist device (LVAD) implantation remains unknown. METHODS: In total, 40 consecutive patients with advanced heart failure underwent continuous-flow LVAD implantation at our institution between 2018 and 2020. Out of 25 high-risk patients in cardiogenic shock (Interagency Registry for Mechanically Assisted Circulatory Support profile 1 and 2), 9 patients (CytoSorb group) underwent LVAD implantation with and 16 patients (control group) without simultaneous cytokine hemoadsorption during cardiopulmonary bypass. Besides preoperative patient characteristics, postoperative lactate clearance, vasopressor administration and mean arterial pressure, perioperative complication, and 30-day mortality rates were retrospectively analyzed. RESULTS: Apart from an increased rate of reoperations within the CytoSorb group, baseline characteristics including the severity of ventricular dysfunction and consecutive signs of end-organ failure were similar in both groups. Preoperative short-term mechanical circulatory support bridging was comparable (66.7 vs. 75%; p = 0.66) prior to LVAD implantation. Procedural characteristics including intraoperative volume management and postoperative vasopressor administration were similar in both groups. There was no difference regarding postoperative lactate clearance, although postoperative mean arterial pressure was significantly higher in the control group (71.3 vs. 57.4 mm Hg; p < 0.01). Furthermore, the 30-day mortality rate was significantly higher in the CytoSorb group (33.3 vs. 0.0%; p = 0.01). CONCLUSION: Extracorporeal cytokine hemoadsorption during high-risk LVAD implantation was not associated with a decrease of postoperative vasopressor support, improved hemodynamics, or an accelerated lactate clearance.

Rationale and Initiative of the Impella in Cardiac Surgery (ImCarS) Register Platform.

OBJECTIVES: Cardiac support systems are being used increasingly more due to the growing prevalence of heart failure and cardiogenic shock. Reducing cardiac afterload, intracardiac pressure, and flow support are important factors. Extracorporeal membrane oxygenation (ECMO) and intracardiac microaxial pump systems (Impella) as non-permanent MCS (mechanical circulatory support) are being used increasingly. METHODS: We reviewed the recent literature and developed an international European registry for non-permanent MCS. RESULTS: Life-threatening conditions that are observed preoperatively often include reduced left ventricular function, systemic hypoperfusion, myocardial infarction, acute and chronic heart failure, myocarditis, and valve vitia. Postoperative complications that are commonly observed include severe systemic inflammatory response, ischemia-reperfusion injury, trauma-related disorders, which ultimately may lead to low cardiac output (CO) syndrome and organ dysfunctions, which necessitates a prolonged ICU stay. Choosing the appropriate device for support is critical. The management strategies and complications differ by system. The "heart-team" approach is inevitably needed.However despite previous efforts to elucidate these topics, it remains largely unclear which patients benefit from certain systems, when is the right time to initiate (MCS), which support system is appropriate, what is the optimal level and type of support, which therapeutic additive and supportive strategies should be considered and ultimately, what are the future prospects and therapeutic developments. CONCLUSION: The European cardiac surgical register ImCarS has been established as an IIT with the overall aim to evaluate data received from the daily clinical practice in cardiac surgery. Interested colleagues are cordially invited to join the register. CLINICAL REGISTRATION NUMBER: DRKS00024560. POSITIVE ETHICS VOTE: AZ 246/20 Faculty of Medicine, Justus-Liebig-University-Gießen.

Development and Characterization of Celecoxib Solid Self-nanoemulsifying Drug Delivery Systems (S-SNEDDS) Prepared Using Novel Cellulose-Based Microparticles as Adsorptive Carriers.

Self-nanoemulsifying drug delivery systems (SNEDDS) represent an interesting platform for improving the oral bioavailability of poorly soluble lipophilic drugs. While Liquid-SNEDDS (L-SNEDDS) effectively solubilize the drug in vivo, they have several drawbacks, including poor storage stability. Solid-SNEDDS (S-SNEDDS) combine the advantages of L-SNEDDS with those of solid dosage forms, particularly stability. The aim of the present study was to convert celecoxib L-SNEDDS into S-SNEDDS without altering their release behavior. Various commercially available adsorptive carrier materials were investigated, as well as novel cellulose-based microparticles prepared by spray drying from an aqueous dispersion containing Diacel® 10 and methyl cellulose or gum arabic as a binder prior to their use. Particle size and morphology of the carrier materials were screened by scanning electron microscopy and their effects on the loading capacity for L-SNEDDS were investigated, and comparative in vitro dissolution studies of celecoxib L-SNEDDS and the different S-SNEDDS were performed immediately after preparation and after 3 months of storage. Among the adsorptive carrier materials, the novel cellulose-based microparticles were found to be the most suitable for the preparation of celecoxib S-SNEDDS from L-SNEDDS, enabling the preparation of a solid, stable formulation while preserving the in vitro release performance of the L-SNEDDS formulation.

Left Ventricular Unloading Is Associated With Lower Mortality in Patients With Cardiogenic Shock Treated With Venoarterial Extracorporeal Membrane Oxygenation: Results From an International, Multicenter Cohort Study.

BACKGROUND: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly used to treat cardiogenic shock. However, VA-ECMO might hamper myocardial recovery. The Impella unloads the left ventricle. This study aimed to evaluate whether left ventricular unloading in patients with cardiogenic shock treated with VA-ECMO was associated with lower mortality. METHODS: Data from 686 consecutive patients with cardiogenic shock treated with VA-ECMO with or without left ventricular unloading using an Impella at 16 tertiary care centers in 4 countries were collected. The association between left ventricular unloading and 30-day mortality was assessed by Cox regression models in a 1:1 propensity score-matched cohort. RESULTS: Left ventricular unloading was used in 337 of the 686 patients (49%). After matching, 255 patients with left ventricular unloading were compared with 255 patients without left ventricular unloading. In the matched cohort, left ventricular unloading was associated with lower 30-day mortality (hazard ratio, 0.79 [95% CI, 0.63-0.98]; P=0.03) without differences in various subgroups. Complications occurred more frequently in patients with left ventricular unloading: severe bleeding in 98 (38.4%) versus 45 (17.9%), access site-related ischemia in 55 (21.6%) versus 31 (12.3%), abdominal compartment in 23 (9.4%) versus 9 (3.7%), and renal replacement therapy in 148 (58.5%) versus 99 (39.1%). CONCLUSIONS: In this international, multicenter cohort study, left ventricular unloading was associated with lower mortality in patients with cardiogenic shock treated with VA-ECMO, despite higher complication rates. These findings support use of left ventricular unloading in patients with cardiogenic shock treated with VA-ECMO and call for further validation, ideally in a randomized, controlled trial.

Effects of glutamine for prevention of radiation-induced esophagitis: a double-blind placebo-controlled trial.

Purpose Acute radiation-induced esophagitis (ARIE) leads to treatment delays, decreased quality of life (QOL), and secondary adverse events such as weight loss. Grade 3 ARIE occurs in 15%-30% of patients undergoing radiotherapy to the esophagus, leading to disruption or discontinuation of treatment. The purpose of this study was to assess the effects of glutamine, a common nutritional supplement, on ARIE in patients with thoracic malignancies. Patients and methods This double-blind, placebo-controlled trial enrolled patients with advanced thoracic malignancies receiving concurrent chemotherapy/radiotherapy or radiotherapy alone, with radiation doses to the esophagus ≥45 Gy. Patients were randomized (1:1) to receive 4 g of glutamine or glycine placebo twice daily. The primary objective was to determine whether glutamine decreases the severity of ARIE in these patients. Secondary objectives included assessment of the effects of glutamine on other measures of ARIE, weight, symptom burden measure assessed by the MD Anderson Symptom Inventory (MDASI-HN) questionnaire and the toxicity profile of glutamine. Results At the time of interim analysis, 53 patients were enrolled: 27 in the glutamine arm and 26 in the placebo arm. There was no difference in the incidence of esophagitis in the first 6 weeks of radiotherapy between the glutamine and placebo arms (74% versus 68%; P = 1.00). There were no significant differences between the two arms for time to onset of esophagitis. The duration of ARIE was shorter (6.3 versus 7.1 weeks; P = 0.54) and median weight loss was lower (0.9 kg versus 2.8 kg; p = 0.83) in the glutamine arm versus the placebo arm. The groups differ significantly in core symptom severity (2.1 vs 1.5, p < .03) but not in head and neck specific symptom severity (1.2 vs 1.1, p < .60) nor in symptom interference (2.1 vs 1.7, p < .22). There was no grade 3 or higher adverse event at least possibly related to glutamine. The study was terminated for futility following interim analysis. Conclusion Oral glutamine was not associated with significant improvement in severity of ARIE, weight loss, head and neck specific symptoms or symptom interference compared with placebo in patients with advanced thoracic malignancies receiving radiotherapy to the esophagus.Clinical trial information. NCT01952847, and date of registration is September 30, 2013.

A Customized Screening Tool Approach for the Development of a Self-Nanoemulsifying Drug Delivery System (SNEDDS).

The present study focused on establishing a novel, (pre-)screening approach that enables the development of promising performing self-nanoemulsifying drug delivery systems (SNEDDSs) with a limited number of experiments. The strategic approach was based on first identifying appropriate excipients (oils/lipids, surfactants, and co-solvents) providing a high saturation solubility for lipophilic model compounds with poor aqueous solubility. Excipients meeting these requirements were selected for SNEDDS development, and a special triangular mixture design was applied for determining excipient ratios for the SNEDDS formulations. Celecoxib and fenofibrate were used as model drugs. Formulations were studied applying a specific combination of in vitro characterization methods. Specifications for a promising SNEDDS formulation were self-imposed: a very small droplet size (< 50 nm), a narrow size distribution of these droplets (PDI < 0.15) and a high transmittance following SNEDDS dispersion in water (> 99% in comparison with purified water). Excipients that provided a nanoemulsion after dispersion were combined, and ratios were optimized using a customized mapping method in a triangular mixture design. The best performing formulations were finally studied for their in vitro release performance. Results of the study demonstrate the efficiency of the customized screening tool approach. Since it enables successful SNEDDS development in a short time with manageable resources, this novel screening tool approach could play an important role in future SNEDDS development. Graphical abstract.

Transvenous lead extraction after heart transplantation: How to avoid abandoned lead fragments.

BACKGROUND: Many patients awaiting heart transplantation (HTX) have a cardiac implantable electronic device (CIED). Lead removal is often still a part of the HTX procedure. Abandoned lead fragments carry a risk for infections and prohibit magnetic resonance imaging (MRI) imaging. This study evaluated the concept of an elective lead management algorithm after HTX. METHODS AND RESULTS: Between 2009 and 2018, 102 consecutive patients with previously implanted CIED underwent HTX. Lead removal by manual traction during HTX was performed in 74 patients until December 2014. Afterward, treatment strategy was changed and 28 patients received elective lead extraction procedures in a hybrid operating room (OR) using specialized extraction tools. Total of 74 patients with 157 leads underwent lead extraction by manual traction during HTX. The mean lead age was 32.3 ± 38.7 months. Postoperative X-ray revealed abandoned intravascular lead fragments in 31(41.9%) patients, resulting in a complete lead extraction rate of only 58.1%. The high rate of unsuccessful lead extractions led to the change in the extraction strategy in 2015. Since then, HTX was performed in 28 CIED patients. In those patients, 64 leads with a mean lead age of 53.8 ± 42.8 months were treated in an elective lead extraction procedure. No major or minor complications occurred during lead extraction. All leads could be removed completely, resulting in a procedural success rate of 100%. CONCLUSION: Our results demonstrate that chronically implanted leads should be removed in an elective procedure, using appropriate extraction tools. This enables complete lead extraction, which reduces the infection risk in this patient population with the necessity for permanent immunosuppressive therapy and allows further MRI surveillance.

Procedural volume and outcomes in patients undergoing VA-ECMO support.

BACKGROUND: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly used in patients with critical cardiopulmonary failure. To investigate the association between hospital VA-ECMO procedure volume and outcomes in a large, nationwide registry. METHODS: By using administrative data from the German Federal Health Monitoring System, we analyzed all VA-ECMO procedures performed in Germany from 2013 to 2016 regarding the association of procedural volumes with outcomes and complications. RESULTS: During the study period, 10,207 VA-ECMO procedures were performed; mean age was 61 years, 43.4% had prior CPR, and 71.2% were male patients. Acute coronary syndrome was the primary diagnosis for VA-ECMO implantation (n = 6202, 60.8%). The majority of implantations (n = 5421) were performed at hospitals in the lowest volume category (≤ 50 implantations per year). There was a significant association between annualized volume of VA-ECMO procedures and 30-day in-hospital mortality for centers with lower vs. higher volume per year. Multivariable logistic regression showed an increased 30-day in-hospital mortality at hospitals with the lowest volume category (adjusted odds ratio 1.13, 95% confidence interval [CI] 1.01-1.27, p = 0.034). Similarly, higher likelihood for complications was observed at hospitals with lower vs. higher annual VA-ECMO volume (adjusted odds ratio 1.46, 95% CI 1.29-1.66, p = 0.001). CONCLUSIONS: In this analysis of more than 10,000 VA-ECMO procedures for cardiogenic shock, the majority of implantations were performed at hospitals with the lowest annual volume. Thirty-day in-hospital mortality and likelihood for complications were higher at hospitals with the lowest annual VA-ECMO volume.

Sex differences in preformed panel-reactive antibody levels and outcomes in patients undergoing heart transplantation.

BACKGROUND: Sex differences in panel-reactive antibody (PRA) levels in heart transplant recipients and their association with transplant-related outcomes are mostly unknown. METHODS: In 20 181 (24.7% women) first-time heart transplant recipients included from July 2004 to March 2015 in the prospective Organ Procurement and Transplantation Network (OPTN), we studied sex differences in most recent (mr) and peak (p)PRA and outcomes (graft failure, rejection, cardiac allograft vasculopathy [CAV], retransplantation, and mortality). Median follow-up (all-cause mortality) was 6 years. Analyses are based on OPTN data (March 6, 2017). RESULTS: MrPRA levels were associated with all-cause mortality (hazard ratio, 95% confidence interval: class I 1.03, 1.01-1.04, P < 0.001) and acute rejection (class II 1.08, 1.03-1.14, P = 0.0044). PPRA levels were associated with all-cause mortality (class I 1.02, 1.00-1.04, P = 0.015) and CAV (class II 1.03, 1.01-1.06, P = 0.020). Sex interactions were seen for the association of pPRA and graft failure with a higher risk in women, and for pPRA and CAV with a higher risk in men. CONCLUSIONS: PRA were associated with different transplant-related outcomes in both sexes. However, women with elevated pPRA were shown to be at higher risk for graft failure, whereas higher levels of pPRA were more hazardous for men in developing CAV.