Although relationship restoration is an important outcome of forgiveness, little is known about how forgiveness facilitates such an outcome. In addition, in forgiveness research, little attention is ...paid to the perspective of the offender. We address these two shortcomings simultaneously, testing the idea that forgiveness promotes offender gratitude, which in turn encourages offender pro‐relational intentions. Across three experimental studies, participants were induced to believe they had transgressed; recalled a time when they had transgressed; and imagined transgressing. In studies 1 and 2, forgiveness was manipulated; in Study 3, victim motivation for forgiving was manipulated. State gratitude – in comparison with guilt, indebtedness, and positive affect – was consistently found to play the primary mediating role between forgiveness and pro‐relational intentions.
Abstract
Extracellular vesicles (EVs) are nanoparticles found in all biological fluids, capable of transporting biological material around the body. Extensive research into the physiological role of ...EVs has led to the development of the Minimal Information for Studies of Extracellular Vesicles (MISEV) framework in 2018. This framework guides the standardisation of protocols in the EV field. To date, the focus has been on EVs of human origin. As comparative medicine progresses, there has been a drive to study similarities between diseases in humans and animals. To successfully research EVs in felines, we must validate the application of the MISEV guidelines in this group. EVs were isolated from the plasma of healthy humans and felines. EV characterisation was carried out according to the MISEV guidelines. Human and feline plasma showed a similar concentration of EVs, comparable expression of known EV markers and analogous particle to protein ratios. Mass spectrometry analyses showed that the proteomic signature of EVs from humans and felines were similar. Asymmetrical flow field flow fractionation, showed two distinct subpopulations of EVs isolated from human plasma, whereas only one subpopulation was isolated from feline plasma. Metabolomic profiling showed similar profiles for humans and felines. In conclusion, isolation, and characterisation of EVs from humans and felines show that MISEV2018 guidelines may also be applied to felines. Potential comparative medicine studies of EVs may provide a model for studying naturally occurring diseases in both humans and felines.
Abstract Purpose The International Conference on Harmonisation E14 guideline mandates an intensive cardiac safety evaluation in a clinical thorough QT study, typically in healthy subjects, for all ...new non-antiarrhythmic drugs with systemic bioavailability. This thorough QT study investigated the effects of therapeutic (2 mg) and supratherapeutic (10 mg) doses of siponimod (BAF312) on cardiac repolarization in healthy subjects. Methods The study was a randomized, double-blind, parallel-group, placebo- and moxifloxacin-controlled, multiple oral dose study. Eligible subjects were randomly assigned to 3 groups to receive siponimod (up-titration to 2 and 10 mg over 18 days), placebo (Days −1 to 18), or moxifloxacin 400 mg Days 10 and 18). Triplicate ECGs were extracted at prespecified time points from Holter ECGs recorded from 1 hour predose until 24 hours postdose at baseline and on-treatment assessment Days 10 and 18. The primary pharmacodynamic variable was the time-matched, placebo-corrected, baseline-adjusted mean QTcF (ΔΔQTcF) at steady-state conditions. In addition, the pharmacokinetic parameters of siponimod and its main circulating metabolite M3 and its metabolite M5 were evaluated. Findings Of the 304 enrolled subjects, 281 (92.4%) were included in the pharmacodynamic analysis and 270 (88.8%) completed the study. The upper bounds of the 2-sided 90% confidence intervals (CIs) for ΔΔQTcF at both siponimod doses were within the regulatory threshold of 10 milliseconds (ms) at all predefined on-treatment time points, with the absence of any dose-related effects. The highest observed upper limits of the 2-sided 90% CIs of 9.8 and 9.6 ms for therapeutic and supratherapeutic doses, respectively, were both observed at 3 hours postdose. No treatment-emergent QTc values >480 ms and no QTc increases of >60 ms from baseline were observed. Similar results were obtained with individualized heart rate correction of cardiac repolarization (QTcI). Assay validity was demonstrated by maximum ΔΔQTcF of >5 ms after 400 mg moxifloxacin on both on-treatment assessment days. The selected supratherapeutic dose produced approximately 5-fold higher exposures (Cmax and AUC) than the therapeutic dose, and was considered appropriate to investigate the effects of siponimod on QT/QTc at substantial multiples of the anticipated maximum therapeutic exposure. Implications The findings provide evidence that siponimod is not associated with a significant arrhythmogenic potential related to QT prolongation.
To evaluate the efficacy and safety of ianalumab (VAY736), a B cell-depleting, B cell activating factor receptor-blocking, monoclonal antibody, in patients with active primary Sjögren's syndrome ...(pSS) in a double-blind, placebo-controlled, phase II, single-centre study.
Patients with pSS, EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) ≥6, were randomised to ianalumab single infusion at either 3 mg/kg (n=6), 10 mg/kg (n=12) or placebo (n=9). Outcomes were measured blinded at baseline and weeks 6, 12, 24, and unblinded at end of study (EoS) when B cell numbers had recovered. Clinical outcomes included ESSDAI, EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI), salivary flow rate, ocular staining score, physician global assessment and patient assessments of fatigue and general quality of life. Laboratory-based measures included circulating leucocyte subsets and markers of B cell activity.
A similar trend showing positive therapeutic effect by ianalumab was observed across the primary clinical outcome (ESSDAI) and all secondary clinical outcomes (ESSPRI, Multidimensional Fatigue Inventory, Short Form-36, global assessments by physician and patient) versus the placebo-treated group. Rapid and profound B cell depletion of long-lasting duration occurred after a single infusion of ianalumab at either dose. Serum Ig light chains decreased, with return to baseline levels at EoS. Changes in some clinical outcomes persisted through to EoS in the higher dose group. Adverse effects were largely limited to mild to moderate infusion reactions within 24 hours of ianalumab administration.
Overall results in this single-dose study suggest potent and sustained B cell depletion by ianalumab could provide therapeutic benefits in patients with pSS without major side effects.
In humans, increased red blood cell distribution width (RDW) values are associated with higher morbidity and mortality in a variety of pathological processes. The main objective of this study was to ...evaluate RDW in dogs with a diverse range of pathologies. Clinical data from 276 dogs were retrospectively evaluated. Significantly higher RDW values were found in dogs with primary immune-mediated hemolytic anemia (
< 0.0001), immune-mediated thrombocytopenia (
< 0.0004), hyperadrenocorticism (
< 0.0001), hypothyroidism (
= 0.0220), hepatic vascular anomaly (
< 0.0001), pneumonia (
< 0.0001), chronic kidney disease (
= 0.0005), multi-centric lymphoma (
= 0.0002), and myxomatous mitral valve degeneration (
= 0.0032). However, there was extensive overlap with the values from healthy dogs, limiting the diagnostic value of RDW in this setting. Although RDW may have a role as a potential prognostic indicator, further studies would be necessary to address this.
Accuracy and precision of a prototype point-of-care (POC) hemoglobin (Hb) and oxygen saturation (SO2) analyzer were compared to a benchtop analyzer, as well as the use of the prototype in a field ...setting. Arterial and venous Hb concentrations (Hb) and SO2 were determined from 180 whole-blood samples from dogs, cats, and horses. Hemoglobin concentrations and SO2 values were consistently lower (P < .0001) for the prototype compared to the benchtop analyzer. Deming's regression and Bland–Altman bias representation with concordance analysis revealed good accuracy and precision but poor concordance. When separated out by species, concordance was moderate to excellent for canine but poor for equine samples; accuracy and precision were unchanged. When separated by sample type, there was loss of accuracy and precision for equine arterial SO2 and canine venous SO2. Whole-blood jugular venous Hb and SO2 values determined for 26 horses before and after exercise using the prototype analyzer in a wide range of temperatures revealed good consistency and precision. In conclusion, the prototype POC had good concordance with the benchtop analyzer for canine but not equine samples, with good accuracy and precision for equine and canine Hb and SO2. Concordance results indicate the prototype's calibration settings may need to be adjusted for different species and sample type if using the comparative benchtop analyzer's reference values. Overall, the prototype POC analyzer had good accuracy and precision for the two analytes for both species and sample types, was simple and practical to use in the field, and may be a suitable substitute for a benchtop analyzer.
•Prototype analyzer had good accuracy and precision for hemoglobin and oxygen saturation (SO2) measurement.•Hemoglobin and SO2 calculations consistently lower with prototype analyzer.•Good agreement between prototype and benchtop analyzer for canine samples.•Poor agreement between prototype and benchtop analyzer for equine samples.•Some loss in accuracy for equine arterial SO2 and canine venous SO2.
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