Addition of H_2O and O_2 to Acetone and Dimethylsulfoxide Ligated Uranyl(V) Dioxocations

Gas-phase complexes of the formula [UO_2(lig)]^+ (lig = acetone (aco) or dimethylsulfoxide (dmso)) were generated by electrospray ionization (ESI) and studied by tandem ion-trap mass spectrometry to determine the general effect of ligand charge donation on the reactivity of UO_2^+ with respect to water and dioxygen. The original hypothesis that addition of O_2 is enhanced by strong σ-donor ligands bound to UO_2^+ is supported by results from competitive collision-induced dissociation (CID) experiments, which show near exclusive loss of H_2O from [UO_2(dmso)(H_2O)(O_2)]^+, whereas both H_2O and O_2 are eliminated from the corresponding [UO_2(aco)(H_2O)(O_2)]^+ species. Ligand-addition reaction rates were investigated by monitoring precursor and product ion intensities as a function of ion storage time in the ion-trap mass spectrometer: these experiments suggest that the association of dioxygen to the UO_2^+ complex is enhanced when the more basic dmso ligand was coordinated to the metal complex. Conversely, addition of H_2O is favored for the analogous complex ion that contains an aco ligand. Experimental rate measurements are supported by density function theory calculations of relative energies, which show stronger bonds between UO_2^+ and O_2 when dmso is the coordinating ligand, whereas bonds to H_2O are stronger for the aco complex

Association of ECG characteristics with clinical and echocardiographic outcome to CRT in a non-LBBB patient population

Purpose: Effectiveness of cardiac resynchronization therapy (CRT) in patients without left bundle branch block (non-LBBB) QRS morphology is limited. Additional selection criteria are needed to identify these patients. Methods: Seven hundred ninety consecutive patients with non-LBBB morphology, who received a CRT-device in 3 university centers in the Netherlands, were selected. Pre-implantation 12-lead ECGs were evaluated on morphology, duration, and area of the QRS complex, as well as on PR interval, left ventricular activation time (LVAT), and the presence of fragmented QRS (fQRS). Association of these ECG features with the primary endpoint: a combination of left ventricular assist device (LVAD) implantation, cardiac transplantation and all-cause mortality, and secondary endpoint—echocardiographic reduction of left ventricular end-systolic volume (LVESV)—were evaluated. Results: The primary endpoint occurred more often in non-LBBB patients with with PR interval ≥ 230ms, QRS area < 109μVs, and with fQRS. Multivariable regression analysis showed independent associations of QRS area (HR 2.33 [1.44, 3.77], p = 0.001) and PR interval (HR 2.03 [1.51, 2.74], p < 0.001) only. Mean LVESV reduction was significantly lower in patients with baseline RBBB, QRS duration < 150 ms, PR interval ≥ 230 ms, and in QRS area < 109 μVs. Multivariable regression analyses only showed significant associations between QRS area ≥ 109 μVs (OR 2.00 [1.09, 3.66] p = 0.025) and probability of echocardiographic response to CRT. Conclusions: In the heterogeneous non-LBBB patient population, QRS area and PR prolongation rather than traditional QRS duration and morphology are associated to both clinical and echocardiographic outcomes of CRT

Heart Size Corrected Electrical Dyssynchrony and Its Impact on Sex-specific Response to Cardiac Resynchronization Therapy

Background - Women are less likely to receive cardiac resynchronization therapy (CRT), yet, they are more responsive to the therapy and respond at shorter QRS duration. The present study hypothesized that a relatively larger left ventricular (LV) electrical dyssynchrony in smaller hearts contributes to the better CRT response in women. For this the vectorcardiography-derived QRS area is used, since it allows for a more detailed quantification of electrical dyssynchrony compared to conventional electrocardiographic markers. Methods - Data from a multicenter registry of 725 CRT patients (median follow-up: 4.2 years [IQR: 2.7-6.1]) were analyzed. Baseline electrical dyssynchrony was evaluated using the QRS area, and the corrected QRS area for heart size using the LV end-diastolic volume (QRSarea/LVEDV). Impact of the QRSarea/LVEDV-ratio on the association between sex and LV reverse remodeling (end-systolic volume change: ΔLVESV) and sex and the composite outcome of all-cause mortality, LV assist device implantation or heart transplantation was assessed. Results - At baseline, women (n=228) displayed larger electrical dyssynchrony than men (QRS area: 132±55μVs vs 123±58μVs, p=0.043) which was, even more pronounced for the QRSarea/LVEDV-ratio (0.76±0.46μVs/ml vs 0.57±0.34μVs/ml, p<0.001). After multivariable analyses female sex was associated with ΔLVESV (β 0.12, p=0.003) and a lower occurrence the composite outcome (HR 0.59 (0.42-0.85), p=0.004). A part of the female advantage regarding reverse remodeling was attributed to the larger QRSarea/LVEDV-ratio in women (25-fold change in Beta from 0.12 to 0.09). The larger QRSarea/LVEDV-ratio did not contribute to the better survival observed in women. In both volumetric responders and non-responders, female sex remained strongly associated with a lower risk of the composite outcome (adjusted HR 0.59 (0.36-0.97), p=0.036 and 0.55 (0.33-0.90), p=0.018, respectively). Conclusions - Greater electrical dyssynchrony in smaller hearts contributes in part to more reverse remodeling observed in women after CRT, but this does not explain their better long-term outcomes

Reduction in the QRS area after cardiac resynchronization therapy is associated with survival and echocardiographic response

Introduction Recent studies have shown that the baseline QRS area is associated with the clinical response after cardiac resynchronization therapy (CRT). In this study, we investigated the association of QRS area reduction ( increment QRS area) after CRT with the outcome. We hypothesize that a larger increment QRS area is associated with a better survival and echocardiographic response. Methods and Results Electrocardiograms (ECG) obtained before and 2-12 months after CRT from 1299 patients in a multi-center CRT-registry were analyzed. The QRS area was calculated from vectorcardiograms that were synthesized from 12-lead ECGs. The primary endpoint was a combination of all-cause mortality, heart transplantation, and left ventricular (LV) assist device implantation. The secondary endpoint was the echocardiographic response, defined as LV end-systolic volume reduction >= of 15%. Patients with increment QRS area above the optimal cut-off value (62 mu Vs) had a lower risk of reaching the primary endpoint (hazard ratio: 0.43; confidence interval [CI] 0.33-0.56, p = 109 mu Vs, survival, and echocardiographic response were better when the increment QRS area was >= 62 mu Vs (p = 109 mu Vs, increment QRS area was the only significant predictor of survival (OR: 0.981; CI: 0.967-0.994, p = .006). Conclusion increment QRS area is an independent determinant of CRT response, especially in patients with a large baseline QRS area. Failure to achieve a large QRS area reduction with CRT is associated with a poor clinical outcome

One naive T cell, multiple fates in CD8+ T cell differentiation

The mechanism by which the immune system produces effector and memory T cells is largely unclear. To allow a large-scale assessment of the development of single naive T cells into different subsets, we have developed a technology that introduces unique genetic tags (barcodes) into naive T cells. By comparing the barcodes present in antigen-specific effector and memory T cell populations in systemic and local infection models, at different anatomical sites, and for TCR–pMHC interactions of different avidities, we demonstrate that under all conditions tested, individual naive T cells yield both effector and memory CD8+ T cell progeny. This indicates that effector and memory fate decisions are not determined by the nature of the priming antigen-presenting cell or the time of T cell priming. Instead, for both low and high avidity T cells, individual naive T cells have multiple fates and can differentiate into effector and memory T cell subsets

Modelling cross-reactivity and memory in the cellular adaptive immune response to influenza infection in the host

The cellular adaptive immune response plays a key role in resolving influenza infection. Experiments where individuals are successively infected with different strains within a short timeframe provide insight into the underlying viral dynamics and the role of a cross-reactive immune response in resolving an acute infection. We construct a mathematical model of within-host influenza viral dynamics including three possible factors which determine the strength of the cross-reactive cellular adaptive immune response: the initial naive T cell number, the avidity of the interaction between T cells and the epitopes presented by infected cells, and the epitope abundance per infected cell. Our model explains the experimentally observed shortening of a second infection when cross-reactivity is present, and shows that memory in the cellular adaptive immune response is necessary to protect against a second infection.Comment: 35 pages, 12 figure

Old Voters on New Dimensions:Why Do Voters Vote for Pensioners' Parties? The Case of the Netherlands

This article analyzes the electoral support of the Dutch pensioners’ party 50Plus. Due to its open electoral system and aging population, the Netherlands is a key case to study pensioners’ parties. Our study shows that this pensioners’ party appeals to voters who are characterized by their age and their dependence on the welfare state as well as their policy positions on new lines of political conflict. In particular, their position on the new economic dimension (which concerns welfare state reform) and the new cultural dimension (which concerns immigration and EU integration) is distinct. Moreover, even when the majority of voters for this new party once supported the larger mainstream parties, they are now dissatisfied with the established politics. With rapidly aging populations across established democracies, this study is not just relevant for those studying pensioners’ parties, but rather gives an important insight into the electoral dynamics and popular support for mainstream politics, the welfare state, and social security

Incidence of premature battery depletion in subcutaneous cardioverter-defibrillator patients: insights from a multicenter registry.

BACKGROUND The subcutaneous ICD established its role in the prevention of sudden cardiac death in recent years. The occurrence of premature battery depletion in a large subset of potentially affected devices has been a cause of concern. The incidence of premature battery depletion has not been studied systematically beyond manufacturer-reported data. METHODS Retrospective data and the most recent follow-up data on S-ICD devices from fourteen centers in Europe, the US, and Canada was studied. The incidence of generator removal or failure was reported to investigate the incidence of premature S-ICD battery depletion, defined as battery failure within 60 months or less. RESULTS Data from 1054 devices was analyzed. Premature battery depletion occurred in 3.5% of potentially affected devices over an observation period of 49 months. CONCLUSIONS The incidence of premature battery depletion of S-ICD potentially affected by a battery advisory was around 3.5% after 4 years in this study. Premature depletion occurred exclusively in devices under advisory. This is in line with the most recently published reports from the manufacturer. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04767516

Maturation-Dependent Licensing of Naive T Cells for Rapid TNF Production

The peripheral naïve T cell pool is comprised of a heterogeneous population of cells at various stages of development, which is a process that begins in the thymus and is completed after a post-thymic maturation phase in the periphery. One hallmark of naïve T cells in secondary lymphoid organs is their unique ability to produce TNF rapidly after activation and prior to acquiring other effector functions. To determine how maturation influences the licensing of naïve T cells to produce TNF, we compared cytokine profiles of CD4+ and CD8+ single positive (SP) thymocytes, recent thymic emigrants (RTEs) and mature-naïve (MN) T cells during TCR activation. SP thymocytes exhibited a poor ability to produce TNF when compared to splenic T cells despite expressing similar TCR levels and possessing comparable activation kinetics (upregulation of CD25 and CD69). Provision of optimal antigen presenting cells from the spleen did not fully enable SP thymocytes to produce TNF, suggesting an intrinsic defect in their ability to produce TNF efficiently. Using a thymocyte adoptive transfer model, we demonstrate that the ability of T cells to produce TNF increases progressively with time in the periphery as a function of their maturation state. RTEs that were identified in NG-BAC transgenic mice by the expression of GFP showed a significantly enhanced ability to express TNF relative to SP thymocytes but not to the extent of fully MN T cells. Together, these findings suggest that TNF expression by naïve T cells is regulated via a gradual licensing process that requires functional maturation in peripheral lymphoid organs