Omecamtiv mecarbil is a cardiac-selective myosin activator and potential heart failure treatment, but its electrophysiological profile remains incompletely characterized. We investigated omecamtiv mecarbil in a Langendorff-perfused rabbit heart model. Forty-eight rabbit hearts were retrogradely perfused; twenty-four in a ventricular and twenty-four in an atrial setup. In the ventricular setup, action potential duration at 90% repolarization (APD90), QT interval, and dispersion of repolarization were assessed during pacing at seven cycle lengths. After baseline recordings, Group 1 (n = 12) received 1, 5 and 10 µM omecamtiv mecarbil sequentially, while Group 2 (n = 12) received 100 µM sotalol followed by 5 µM omecamtiv mecarbil. In the atrial setup, Group 3 (n = 12) received 5 and 10 µM omecamtiv mecarbil, and Group 4 (n = 12) received isoproterenol/acetylcholine (IsoACh) to increase atrial fibrillation (AF) susceptibility, followed by 5 µM omecamtiv mecarbil. Omecamtiv mecarbil alone shortened ventricular APD90 and QT interval, increased dispersion of repolarization, and raised ventricular arrhythmia incidence. Sotalol prolonged APD90, QT interval, and dispersion, with a marked rise in VT episodes; additional omecamtiv mecarbil did not further prolong repolarization but increased arrhythmia susceptibility further. In the atrial setup, omecamtiv mecarbil alone prolonged conduction time and increased AF inducibility. Under IsoACh, which shortened atrial APD and refractoriness and increased AF episodes, additional omecamtiv mecarbil slowed atrial conduction and markedly suppressed AF. In summary, omecamtiv mecarbil was proarrhythmic at the ventricular level, particularly under reduced repolarization reserve, but showed antiarrhythmic effects in an IsoACh-induced AF model and proarrhythmic properties in the healthy atrium, indicating a substrate-dependent electrophysiological profile.

Genetic evaluations usually include many correlated traits. Their evaluation and use in the selection index rely on genetic parameters that change over time, with these changes potentially accelerating under genomic selection. However, estimating the changes with current methods and large genomic information is computationally prohibitive, and interpreting changes in relationships among many traits is difficult. The purpose of this study is to present a methodology to visualize changes in complex relationships among traits over time. Data included genetic correlations among 18 linear conformation traits of US Holsteins, computed by GPP (Genetic Parameters via Predictivity), for yearly time slices from 2010 to 2020, using all available pedigree, phenotypic, and genomic information. GPP relies on predictivity of adjusted phenotypes from validation population on EBV from reference population and allows estimation by time slices using complete commercial data. In 2010, the reference population included cows born in 2000-2008, and the validation population included cows born in 2009-2011. In subsequent years, the population advanced by one year. Using genetic correlations for the year 2020, each trait was regressed on 2, 3, and 4 remaining conformation (also known as type) traits chosen by the best fit (R[2]). Regression coefficients were then recomputed for the years 2010-2019. Graphs of the coefficients over time for each trait and 2-4 traits in the regression indicated changing relationships among the traits over time. For example, with 2 traits in the regression, fore udder attachment was estimated as a function of udder depth and rear udder width (R[2] = 0.84); the addition of stature increased R[2] by 0.03 and adding body depth increased R[2] by an additional 0.04. Biplots of 2 principal components in the 4-trait model indicated that the impact of rear udder width was similar to that of body depth and stature in 2010 but more differentiated in 2020. In general, predictions with 4 traits were less stable. Changes in the dynamics of correlated traits can be visualized by regression coefficients from equations involving 2 to 4 correlated traits and corresponding biplots of the 2 principal components.

Background: Posttraumatic stress disorder (PTSD) and substance use disorders (SUD) commonly co-occur. Several treatments for co-occurring PTSD and SUD (PTSD + SUD) exist, yet evidence for comparative treatment effectiveness is restricted by a historical emphasis on symptom severity and substance consumption endpoints instead of recovery-oriented outcomes. Moreover, extant syntheses relied on conventional analytic approaches prioritizing standardized mean group differences, instead of clinically significant change (CSC), and included few pharmacological randomized clinical trials (RCTs).Objective: In an extension of Project Harmony (R01AA025853), this study (R01DA061338) will apply novel quantitative approaches addressing limitations of prior work to elucidate which PTSD + SUD treatments work best overall and at the individual level.Method: This study will harmonize data from over 60 RCTs (N > 8,000) and use meta-analysis of individual patient data, integrative data analysis, and propensity score weighting to assess the comparative effectiveness of pharmacological, behavioral, and combination treatments for PTSD + SUD. Clinical severity outcomes will be measured as latent PTSD symptom severity, alcohol consumption, and other drug consumption. Recovery outcomes will be estimated from indicators of psychosocial functioning and substance use consequences. State-of-the-art CSC methodologies will be used in analyses of the original Project Harmony dataset (36 RCTs; N = 4,046), which will evaluate the proportion of patients in each treatment class that showed (non)significant improvement or worsening along clinical and recovery outcomes. Analyses of the expanded Project Harmony dataset will assess comparative effectiveness of active PTSD + SUD treatment classes, compared to treatment as usual, on clinical severity and recovery outcomes.Conclusions: By applying modernized quantitative methodologies to patient-level data from at least 60 RCTs, this study will advance the field's understanding of which PTSD + SUD treatment approaches are most effective across multiple indicators (i.e. clinical severity and recovery outcomes). This study is registered in the International Prospective Register of Systematic Reviews (PROSPERO identifier CRD420251250349).

Comprehensive knowledge of feline vascular anatomy is essential for accurate diagnostic imaging interpretation and safe thoracic cardiovascular surgery. This study aimed to characterize the branching patterns, quantitative morphometry, and precise topographical positions of the aortic arch branches and subclavian arteries in domestic cats (Felis catus). Twenty adult cat cadavers from Northwestern Iran were examined. Coloured latex was injected into the aortic arch, followed by fixation in 10% neutral buffered formalin and subsequent meticulous gross dissection. Topographical positions relative to thoracic skeletal landmarks and morphometric distances were recorded. Non-parametric Mann-Whitney U tests were used for statistical comparisons between identified patterns. Two branching configurations of the brachiocephalic trunk were identified: a bifurcated pattern (85%, n = 17) and a trifurcated pattern (15%, n = 3). The aortic arch was predominantly located at the fourth intercostal space (90%). For the left subclavian artery, three branching patterns were identified, with sequential origin (VT-IT-CCT-SC) being predominant (55%). The right subclavian artery exhibited three distinct arrangements, dominated by sequential (45%) and opposite [IT≡VT] origins (45%). Significant side-dependent variations were observed in the branching order and topography. Morphometric distances (BC + RS, BC-LS, and LCC-RCC) showed no statistically significant differences between bifurcated and trifurcated patterns (p > 0.05). Feline aortic arch branches exhibit substantial topographical variation despite overall metric consistency across branching types. The observed bilateral asymmetry and internal thoracic artery positional mobility likely reflect distinct embryological origin pathways. These findings provide critical baseline anatomical data for improving the accuracy and safety of feline surgical interventions and diagnostic imaging interpretation.

IntroductionMultiple myeloma (MM), an incurable plasma cell malignancy, is one of the most challenging cancers to diagnose. Diagnostic delays are associated with increased complications and worse outcomes. Existing knowledge of MM diagnostic pathways largely relies on secondary data that fails to capture important details of MM patients' diagnostic journeys. The aim of this study was to explore patients' journeys from initial symptom onset to MM diagnosis and to identify barriers and facilitators to timely diagnostic resolution.MethodsWe conducted a qualitative descriptive study using semi-structured interviews with adults diagnosed with MM within the past 10 years from the United States. Interviews, conducted in English or Spanish, were analyzed using reflexive thematic analysis guided by the Model of Pathways to Treatment.ResultsWe interviewed 34 participants living with MM (38.2% Black, 35.3% White, 20.6% Hispanic, 5.9% Asian). Facilitators of timely diagnosis included recognition of health changes by patients or others, persistent advocacy, and routine primary care engagement. Barriers included misattribution of symptoms by patients and providers, prolonged conservative management, and limited awareness of MM among patients.ConclusionsMM diagnosis is frequently delayed due to non-specific symptoms, misattribution, and limited disease awareness. Regular primary care engagement and advocacy facilitate earlier diagnosis. Interventions targeting public awareness, increased primary care knowledge of MM signs and appropriate testing, and improved access to care may help reduce diagnostic delays.

Cold chain requirements limit vaccine accessibility and deployment. SPVX02, is a lyophilised, fridge-free version of Tetadif tetanus-diphtheria vaccine, stable for at least 24 months at temperatures up to 30 °C.

Venous thromboembolism (VTE), including deep-vein thrombosis and pulmonary embolism, is the third most common cause of vascular death worldwide and a major contributor to costly and debilitating non-fatal complications. Despite the changing landscape of risk factors, preventive and diagnostic strategies, risk stratification and therapies, no contemporary global summary of the burden of VTE is available. In a collaborative, multinational effort, we provide a global overview of the incidence and outcomes of VTE. Reliable data were available for only a limited number of countries (predominantly in Northern America, Western Europe and Oceania), with notable regional differences. During 2012-2016, the global annual incidence of deep-vein thrombosis ranged from 25.1 to 131.5 per 100,000 of the population. The incidence of pulmonary embolism rose from 2012-2016 to 2017-2022 in Northern America and Asia but remained stable in Oceania. Among patients with pulmonary embolism, 30-day all-cause mortality ranged globally from 1.0% to 9.0%, and the 1-year cumulative incidence of recurrent VTE ranged from 2.9% to 8.1%. These findings reveal the substantial global burden of VTE, sources of heterogeneity and stark regional gaps in the data, demanding coordinated surveillance, standardized reporting and research into local and global drivers to curb worldwide morbidity and mortality.

Syllable perception requires the continuous integration of segmental (consonants and vowels) and suprasegmental (lexical tones) information. While native listeners of tonal languages exhibit pre-attentive integration of these dimensions, it remains unclear whether non-tonal second language (L2) learners can develop such integration through L2 experience. The present study employed electroencephalogram (EEG) to record mismatch negativity (MMN) responses in a passive oddball paradigm, investigating the perceptual integration of consonants, vowels, and tones. Twenty-four native Mandarin listeners (L1 group) and fifteen non-tonal L2 learners of Mandarin (L2 group) were recruited. Stimuli included a standard syllable (/da1/), three single-deviants (/ga1/, /du1/, /da4/), and three double-deviants (/gu1/, /ga4/, /du4/). MMN additivity analyses compared original double-deviant MMN amplitudes against the sum of corresponding single-deviant MMN amplitudes. The L1 group exhibited robust sub-additive MMN patterns across all double-deviant combinations (consonant-vowel [CV], consonant-tone [CT], and vowel-tone [VT]), demonstrating integrated processing across all phonological dimensions. The L2 group showed delayed MMN peak latencies and reduced pre-attentive sensitivity to single consonant and single tone deviations. Crucially, they exhibited additivity for CV and CT combinations (independent processing), but a selective sub-additive trend for the VT combination, which we interpret as preliminary evidence for vowel-tone integration. These findings provide tentative support the TTRACE model and refine the dimensional transfer hypothesis, suggesting that non-tonal L1 biases may be partially overcome through L2 experience when phonological dimensions share tight acoustic proximity within the syllable nucleus (i.e., vowel-tone integration). Non-tonal L2 learners display a developmental pattern rooted in acoustic salience and bottom-up physical binding.

Communities of Practice (CoPs) are widely used to foster collaboration and knowledge exchange across disciplines. However, systematic evaluations of them remain limited due to the dynamic nature of CoPs and the lack of tested methodologies. In this manuscript, we present the evaluation of a CoP conducted by pairing the Value Creation Framework with guidance developed by the Centers for Disease Control (CDC). Through qualitative analysis using a structured coding framework, we examine participants' experiences in the CoP and assess how the CoP generated value for its members, the barriers that may have hindered value creation, and the perceived benefits of participation in the CoP at both personal and organizational levels. We explored two dynamic pairs of value cycles (i.e., immediate and potential; applied and realized), identified barriers (i.e., capacity) and facilitators (e.g., discussion-oriented atmosphere, relationship building, and trust) to value, and visualized how value flows across cycles to ensure CoPs meet members' needs. Our findings demonstrate the utility of this systematic approach, highlighting the individual and organizational benefits of participation in a conservation-focused CoP while providing a concrete example of how the VCF can be operationalized in practice.