BACKGROUND—Sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) gene therapy improves mechanical function in heart failure and is under evaluation in a clinical trial. A critical question is whether ...SERCA2a gene therapy predisposes to increased sarcoplasmic reticulum calcium (SR Ca) leak, cellular triggered activity, and ventricular arrhythmias in the failing heart.
METHODS AND RESULTS—We studied the influence of SERCA2a gene therapy on ventricular arrhythmogenesis in a rat chronic heart failure model. ECG telemetry studies revealed a significant antiarrhythmic effect of SERCA2a gene therapy with reduction of both spontaneous and catecholamine-induced arrhythmias in vivo. SERCA2a gene therapy also reduced susceptibility to reentry arrhythmias in ex vivo programmed electrical stimulation studies. Subcellular Ca homeostasis and spontaneous SR Ca leak characteristics were measured in failing cardiomyocytes transfected in vivo with a novel AAV9.SERCA2a vector. SR Ca leak was reduced after SERCA2a gene therapy, with reversal of the greater spark mass observed in the failing myocytes, despite normalization of SR Ca load. SERCA2a reduced ryanodine receptor phosphorylation, thereby resetting SR Ca leak threshold, leading to reduced triggered activity in vitro. Both indirect effects of reverse remodeling and direct SERCA2a effects appear to underlie the antiarrhythmic action.
CONCLUSIONS—SERCA2a gene therapy stabilizes SR Ca load, reduces ryanodine receptor phosphorylation and decreases SR Ca leak, and reduces cellular triggered activity in vitro and spontaneous and catecholamine-induced ventricular arrhythmias in vivo in failing hearts. SERCA2a gene therapy did not therefore predispose to arrhythmias and may represent a novel antiarrhythmic strategy in heart failure.
Summary Objectives Human herpes virus 6 (HHV-6) can reactivate after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and may be associated with significant clinical manifestations. ...Methods Case control study of HHV-6 infections after allo-HSCT. Chromosomal integration (ciHHV-6) for viral loads ≥ 5.5-log10 copies/mL was investigated. Viral co-infections, T-cell recovery, risk factors and outcome were compared in HHV-6- and non-HHV-6-infected patients. Antiviral treatment strategies were reviewed. Results Among 366 adult allo-HSCT recipients, 75 HHV-6 infections occurred. Three (4%) recipients were ciHHV-6. HHV-6 infections were associated with CMV ( p = 0.05; sdHR 1.73, CI 0.99–3.02) and/or BKV infections ( p < 0.0001; sdHR 4.63, CI 2.04–10.53) but not EBV reactivation ( p = 0.34). A slower CD8+ T-cells recovery was observed until 6 months after allo-HSCT in the HHV-6-infected group ( p < 0.001), independently of acute and/or chronic graft- versus -host disease. The overall probability of survival after allo-HSCT was diminished for active HHV-6-infected patients ( p = 0.0326). Cord blood unit recipients had a higher risk of developing HHV-6 infection compared to bone marrow recipients ( p = 0.0007; sdHR 3.82, CI 1.76–8.27). Anti-HHV-6 treatment achieved complete response in only 2/3 of the cases. Conclusions In this series of allo-HSCT recipients, 4% were ciHHV-6, active HHV-6 infection was likely associated with CMV and BKV co-reactivations, delayed CD8+ T-cell recovery and poorer outcome.
The purpose of this meta-analysis was to summarize single-case intervention studies in which Functional Communication Training (FCT) involving augmentative and alternative communication (AAC) was ...implemented in school settings. Overall, the findings suggest that FCT involving AAC was effective in reducing challenging behaviour and promoting aided or unaided AAC use among participants with disability. FCT was more effective for the participants who engaged in less severe forms of challenging behaviour prior to intervention. Additionally, FCT was more effective when informed by a descriptive functional behaviour assessment and delivered within inclusive school settings. Implications for practice and directions for future research related to FCT for students who use AAC are addressed.
For assessment of the use of the argon laser for tubal anastomosis, the uterine horns of 12 Sprague-Dawley rats were surgically divided and then anastomosed, 6 by argon laser photocoagulation and 6 ...by the conventional technique of microsurgery. After a 4- to 6-week postsurgical period subjects were reexamined. All microsutured anastomoses were fully patent and continuous, with no apparent fibrosis. Four of six laser subjects had complete occlusion; the other two exhibited patencies between 10% and 20% of normal luminal area. Although initially producing satisfactory union, argon laser photocoagulation proved highly tissue traumatic, resulting in poor regeneration of the anastomotic site.
Over the past decades, superconducting qubits have emerged as one of the leading hardware platforms for realizing a quantum processor. Consequently, researchers have made significant effort to ...understand the loss channels that limit the coherence times of superconducting qubits. A major source of loss has been attributed to two level systems that are present at the material interfaces. It is recently shown that replacing the metal in the capacitor of a transmon with tantalum yields record relaxation and coherence times for superconducting qubits, motivating a detailed study of the tantalum surface. In this work, the chemical profile of the surface of tantalum films grown on c‐plane sapphire using variable energy X‐ray photoelectron spectroscopy (VEXPS) is studied. The different oxidation states of tantalum that are present in the native oxide resulting from exposure to air are identified, and their distribution through the depth of the film is measured. Furthermore, it is shown how the volume and depth distribution of these tantalum oxidation states can be altered by various chemical treatments. Correlating these measurements with detailed measurements of quantum devices may elucidate the underlying microscopic sources of loss.
Tantalum superconducting qubits are a leading candidate for large‐scale quantum computing. These devices are currently limited by two‐level‐systems at material surfaces and interfaces whose microscopic origin is unknown. This study uses variable energy X‐ray photoelectron spectroscopy to determine the chemical profile of the tantalum oxide along its depth, which allows comparison with device measurements to elucidate microscopic loss mechanisms.
Pediatric rare diseases are often life-limiting conditions and/or require constant caregiving. Investigators assessed the initial efficacy of the FAmily CEntered (FACE) pediatric advance care ...planning (pACP), FACE-Rare, intervention on families' quality of life.
A pilot-phase, single-blinded, intent-to-treat, randomized controlled clinical trial enrolled families from 1 pediatric quaternary hospital between 2021 and 2023. Intervention families received 3 weekly 60-minute (FACE-Rare pACP) sessions: (1) Carer Support Needs Assessment Tool or Action Plan, (2) Carer Support Needs Assessment Tol Action Plan Review, and (3) Pediatric Next Steps: Respecting Choices pACP. Controls received treatment as usual (TAU). Outcome measures were Beck Anxiety Inventory, Family Appraisal of Caregiving, Functional Assessment of Chronic Illness Therapy (FACIT)-Spirituality, and health care utilization. Generalized mixed effect models with γ response assessed the intervention effect at 3-month follow-up.
Children (n = 21) were aged 1 to 10 years, 48% male, 24% Black; and 100% technology dependent. Primary family caregivers (n = 21) were aged 30 to 43 years, 19% male, 19% Black; and 27% household income below the Federal poverty level. Dyads underwent 1:1 randomization: 9 to FACE-Rare and 12 to TAU. TAU caregivers reported statistically lower meaning and peace than FACE-Rare caregivers (0.9, P = .03, confidence interval CI: 0.75-0.99). Black caregivers reported significantly less caregiver distress (0.7, P = .04, CI: 0.47-0.98) than non-Black caregivers. Poor families reported more anxiety (3.5, P = .002, CI: 1.62-7.94), more caregiver strain (1.2, P = .006, CI: 1.07-1.42); and less family well-being (0.8, P = .02, CI: 0.64-0.95).
FACE®-Rare was feasible, acceptable, safe, and demonstrated initial efficacy, providing greater feelings of meaning and peace to caregivers. Poverty impacted well-being. A multisite trial is needed to determine generalizability.
This study presents an automated methodology to generate training data for surface water mapping from a single Sentinel-2 granule at 10 m (4 band, VIS/NIR) or 20 m (9 band, VIS/NIR/SWIR) resolution ...without the need for ancillary training data layers. The 20 m method incorporates an ensemble of three spectral indexes with optimal band thresholds, whereas the 10 m method achieves similar results using fewer bands and a single spectral index. A spectrally balanced and randomly generated set of training data based on the index values and optimal thresholds is used to fit machine learning classifiers. Statistical validation compares the 20 m ensemble-only method to the 20 m ensemble method with a random forest classifier. Results show the 20 m ensemble-only method had an overall accuracy of 89.5% (±1.7%), whereas the ensemble method combined with the random forest classifier performed better, with a ~4.8% higher overall accuracy: 20 m method (94.3% (±1.3%)) with optimal spectral index and SWIR thresholds of −0.03 and 800, respectively, and 10 m method (93.4% (±1.5%)) with optimal spectral index and NIR thresholds of −0.01 and 800, respectively. Comparison of other supervised classifiers trained automatically with the framework typically resulted in less than 1% accuracy improvement compared with the random forest, suggesting that training data quality is more important than classifier type. This straightforward framework enables accurate surface water classification across diverse geographies, making it ideal for development into a decision support tool for water resource managers.
The midcrustal seismicity along the Main Himalayan Thrust in Nepal presents lateral variations along the rupture of the 2015 Gorkha earthquake. In order to resolve these variations, we relocate the ...seismicity north of Kathmandu, during a period well covered by the Nepal National Seismological Network, using a double-difference algorithm. The 550 relocated events highlight a complex pattern of clustered seismicity within the unstable-stable transition zone. Part of the seismicity is densely clustered on a southward dipping plane which ruptured on January 31st 1997 (ML=5.8), activating a backthrust with a geometry consistent with the centroid moment tensor of this event calculated in this study. At its eastern end, the midcrustal cluster is offset by 20km to the south suggesting the presence of a tear fault. The analysis of the time sequence allows constraining a scenario involving stress transfer between these local midcrustal structures, beginning more than one month before the 1997 main shock. The temporal evolution of the seismicity is strikingly similar for two other transient seismic swarm episodes which developed hundreds of kilometers apart along the Main Himalayan Thrust at the same time. The local stress field appears responsible for the higher sensitivity of these regions to subtle strain transients developing along the Main Himalayan Thrust.
•Lateral variations of seismicity North of Kathmandu in the trace of Gorkha earthquake•Stress transfer between local midcrustal structures•Simultaneous transient seismic swarms along the unstable-stable transition zone
212PbVMT01 is a melanocortin 1 receptor (MC1R) targeted theranostic ligand in clinical development for alpha particle therapy for melanoma. 212Pb has an elementally matched gamma-emitting isotope ...203Pb; thus, 203PbVMT01 can be used as an imaging surrogate for 212PbVMT01. 212PbVMT01 human serum stability studies have demonstrated retention of the 212Bi daughter within the chelator following beta emission of parent 212Pb. However, the subsequent alpha emission from the decay of 212Bi into 208Tl results in the generation of free 208Tl. Due to the 10.64-hour half-life of 212Pb, accumulation of free 208Tl in the injectate will occur. The goal of this work is to estimate the human dosimetry for 212PbVMT01 and the impact of free 208Tl in the injectate on human tissue absorbed doses. Human 212PbVMT01 tissue absorbed doses were estimated from murine 203PbVMT01 biodistribution data, and human biodistribution values for 201Tl chloride (a cardiac imaging agent) from published data were used to estimate the dosimetry of free 208Tl. Results indicate that the dose-limiting tissues for 212PbVMT01 are the red marrow and the kidneys, with estimated absorbed doses of 1.06 and 8.27 mGyRBE = 5/MBq. The estimated percent increase in absorbed doses from free 208Tl in the injectate is 0.03% and 0.09% to the red marrow and the kidneys, respectively. Absorbed doses from free 208Tl result in a percent increase of no more than 1.2% over 212PbVMT01 in any organ or tissue. This latter finding indicates that free 208Tl in the 212PbVMT01 injectate will not substantially impact estimated tissue absorbed doses in humans.
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![Dosimetry of [212Pb]VMT01, ...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1420-3049_1433-1373/small "Dosimetry of [212Pb]VMT01, a MC1R-Targeted Alpha Therapeutic Compound, and Effect of Free 208Tl on Tissue Absorbed Doses")