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The limited efficacy of monotherapy and the insufficient clinical experience with triple therapy (levosimendan, dapagliflozin, and sacubitril/valsartan) warrant further investigation. The aim of this study was to evaluate the effects of triple therapy on left ventricular function in children with advanced heart failure whose left ventricular function had not improved despite classical heart failure treatment and who remained dependent on inotropes.
Methods:
The study included children who were admitted to the hospital with advanced heart failure and who were still inotrope-dependent at a mean of 42 days after the start of classical heart failure treatment and then started triple therapy at our hospital.
Results:
The study included 18 patients, 8 (44%) males, with a median age of 4 years (2–7 years). Before and after classical treatment and after triple treatment, statistically significant improvement in two-dimensional left ventricular ejection fraction (%) (median values 30; 38; 55, respectively), left ventricular end-diastolic diameter (median values 44; 45; 40 mm), left ventricular end-systolic diameter (median values 38; 36; 29 mm), left ventricular end-diastolic diameter (z score) (median values 4.2; 3.2; 2.7), left ventricular end-systolic diameter (z score) (median values 5.8; 4.8; 3.2), Simpson left ventricular ejection fraction (%) (median values 29; 36.5; 55), Simpson left ventricular end-diastolic volume (median values 60; 55; 43 ml), left ventricular end-systolic volume (median values 43; 40; 18. 5 ml), left ventricular global longitudinal strain four-chamber (median values -8.1;-10;-19), left ventricular global longitudinal strain three-chamber (median values -5.9;-8.9;-14), and left ventricular global longitudinal strain mean (median values -6.9;-9.7;-19) values was observed (all values p < 0.05).
Conclusions:
In children admitted to the hospital with advanced heart failure whose left ventricular function has not improved with classical therapy, it seems likely that both left ventricular systolic and diastolic function will improve, inotrope dependency will resolve, and patients can be discharged with the new triple drug therapy.
Direct numerical simulations (DNS) are performed to investigate the dependence of the Prandtl number ($\textit{Pr}$) and radius ratio ($\eta =r_{i}/r_{o}$) on the asymmetry of the mean temperature radial profiles in turbulent Rayleigh–Bénard convection (RBC) within spherical shells. Unlike planar RBC, the temperature drop, and the thermal and viscous boundary layer thicknesses, at the inner and outer boundaries are not identical in spherical shells. These differences in the boundary layer properties in spherical RBC contribute to the observed asymmetry in the radial profiles of temperature and velocity. The asymmetry originates from the differences in curvature and gravity at the two boundaries, and in addition, is influenced by $\textit{Pr}$. To investigate the $\eta$ and $\textit{Pr}$ dependence of these asymmetries, we perform simulations of Oberbeck–Boussinesq convection for $\eta = 0.2,0.6$ and $0.1 \leqslant Pr \leqslant 50$, and for a range of Rayleigh numbers ($Ra$) varying between $5 \times 10^{6}$ and $5 \times 10^{7}$. The Prandtl numbers that we choose cover a broad range of geophysical relevance, from low-$\textit{Pr}$ regimes ($\textit{Pr}=0.1$) representative of gas giants such as Jupiter and Saturn, to high-$\textit{Pr}$ regimes characteristic of organic flows used in the convection experiments ($\textit{Pr}=50$). A centrally condensed mass, with the gravity profile $g \sim 1/r^{2}$, is employed in this study. Our results show that the asymmetry at smaller $\eta$ exhibits a stronger $\textit{Pr}$ dependence than at larger $\eta$. Various assumptions for quantifying this asymmetry are evaluated, revealing that different assumptions are valid in different $\textit{Pr}$ regimes. It is shown that the assumption of the equal characteristic plume separation at the inner and outer boundaries, as well as the assumption of the identical thermal fluctuation scales between the two boundary layers, is valid only for $0.2 \lesssim Pr \lesssim 1$. In contrast, assumptions based on the equivalency of the local thermal boundary layer Rayleigh numbers and laminar natural-convective boundary layers are validated at $\textit{Pr}=50$ for the explored parameter space. Furthermore, new assumptions based on the statistical analysis of the inter-plume islands are proposed for $\textit{Pr}=0.1$ and $50$, and these are validated against the DNS data. These findings provide insights into the $(Pr,\eta)$ dependence of asymmetry in spherical RBC, and offer a framework for studying similar systems in geophysical and astrophysical contexts.
Plumes generated from a point buoyant source are relevant to hydrothermal vents in lakes and oceans on and beyond Earth. They play a crucial role in determining heat and material transport and thereby local biospheres. In this study, we investigate the development of rotating point plumes in an unstratified environment using both theory and numerical simulations. We find that in a sufficiently large domain, point plumes cease to rise beyond a penetration height $h_{{f}}$, at which buoyancy flux from the heat source is leaked laterally to the ambient fluid. The height $h_{{f}}$ is found to scale with the rotational length scale $h_{ \!{ f}}\sim L_{ \!\textit{ rot}}^p\equiv ({F_0}/{f^3})^{{1}/{4}},$ where $F_0$ is the source buoyancy flux, and $f=2\varOmega$ is the Coriolis parameter ($\varOmega$ is the rotation rate). In a limited domain, the plume may reach the top boundary or merge with neighbouring plumes. Whether rotational effects dominate depends on how $L_{\textit{rot}}^{p}$ compares to the height of the domain $H$ and the distance between the plumes $L$. Four parameter regimes can therefore be identified, and are explored here through numerical simulation. Our study advances the understanding of hydrothermal plumes and heat/material transport, with applications ranging from subsurface lakes to oceans in icy worlds such as Snowball Earth, Europa and Enceladus.
The paperfolding sequences form an uncountable class of infinite sequences over the alphabet $\{ -1, 1 \}$ that describe the sequence of folds arising from iterated folding of a piece of paper, followed by unfolding. In this note, we observe that the sequence of run lengths in such a sequence, as well as the starting and ending positions of the nth run, is $2$-synchronised and hence computable by a finite automaton. As a specific consequence, we obtain the recent results of Bunder, Bates and Arnold [‘The summed paperfolding sequence’, Bull. Aust. Math. Soc.110 (2024), 189–198] in much more generality, via a different approach. We also prove results about the critical exponent and subword complexity of these run-length sequences.
This study aimed to investigate the potential association between the breeding values for somatic cell scores in milk (SCS) and polymorphisms in genes that encode for cytokines (CXCL8, TGF-β1 and IFN-γ) and CD4. These genes were selected because of their critical roles in immune regulation and their known involvement in mastitis-related inflammatory processes. To gain a comprehensive breeding perspective, the association study was conducted simultaneously with breeding values for productive traits in 558 Italian Simmental cows, a widespread dual-purpose dairy and beef bovine breed that is adaptable to harsh farming and breeding conditions.
The association analysis showed that only three of the nine chosen markers, one in IFN-γ and two in CD4, significantly associated with somatic cell breeding values, without effects on the other dairy traits. Only one of the two CD4 SNPs has been considered, being in linkage disequilibrium. The two remaining SNPs were grouped into three haplotypes (A–G, 88%; A–A, 5%; and T–G, 7%, respectively), and Haplotype-3 significantly affected the breeding values for SCS. The combination of Haplotype-1 with Haplotype-2 resulted in a significant decrease, while with Haplotype-3 led to a considerable improvement in SCS breeding values. It was noted that the functional haplotypic combinations examined did not significantly affect the production breeding values. This research could provide interesting polymorphisms for genomic evaluation of Italian Simmental dairy cows, increasing the accuracy of breeding values, assisting breeders in selecting animals with enhanced immune responses, minimising the economic impact of mastitis, and improving overall herd health and productivity.
The Terra Ferrifera project investigates the landscape and environmental conditions of mass iron production in one of the oldest iron production centres in central Europe: Mazovia, Poland (fourth century BC–fourth century AD). Spatial analyses, settlement pattern studies, prospection, excavation and archaeobotanical analyses provide insights into one of its microregions.
The anarchic embrace of difference in the encounters of and variations on Western and non-Western spiritual practices in Martinique reveals ways of disrupting the univocal, linear, and centralizing violence of plantation society. Examining the various techniques of collective ecstasy through song, dance, and other sacramental signs of spirit possession calls attention to anticolonial models of social organization, and presencing.
We study aeolian saltation over an erodible bed at full transport capacity in a wind tunnel with a relatively thick boundary layer. Lagrangian tracking of size-selected spherical particles resolves their concentration, velocity and acceleration. The mean particle concentration follows an exponential profile, while the mean particle velocity exhibits a convex shape. In contrast to current assumptions, both quantities appear sensitive to the friction velocity. The distributions of horizontal accelerations are positively skewed, though they contain negative tails associated with particles travelling faster than the fluid. The mean wind velocity profiles, reconstructed down to millimetric distances from the bed using the particle equation of motion, have an approximately constant logarithmic slope and do not show a focal point. The aerodynamic drag force increases with distance from the wall and, for the upward moving particles, exceeds the gravity force already at a few particle diameters from the bed. The vertical drag component resists the motion of both upward and downward moving particles with a magnitude comparable to the lift force, which is much smaller than gravity but non-negligible. Coupling the assumption of ballistic vertical motion and the measured streamwise velocities, the mean trajectories are reconstructed and found to be strongly influenced by aerodynamic drag. This is also confirmed by the direct identification of trajectory apexes, and demonstrated over a wide range of friction velocities. Taken together, these results indicate that aerodynamic drag and lift may play a more significant role in the saltation process than presently recognized, being complementary rather than alternative to splash processes.
Danon disease is an X-linked disorder caused by variants in the lysosome-associated membrane protein-2 (LAMP2) gene located on Xq24. Due to its inheritance in an X-chromosome dominant manner, males typically experience more severe manifestations than females.
Method:
The whole exome sequencing was conducted on a cohort of 218 children diagnosed with hypertrophic cardiomyopathy; four children with hypertrophic cardiomyopathy carrying the LAMP2 variants were diagnosed at our centre. Variants in the LAMP2 gene were summarised, and their pathogenicity and conservation were analysed using bioinformatics methods. A retrospective analysis of genotype-phenotype associations was also conducted in conjunction with previously reported cases.
Results:
Four patients with Danon disease were diagnosed in our single centre by gene sequencing; they all presented with myocardial hypertrophy as the initial manifestation. Both male patients manifested symptoms from infancy, while disease onset in the two female cases occurred below the average age reported for females. Through gene sequencing, a total of four variants were identified in these four patients, including one splicing variant: c.865-1G>C, one loss of heterozygosity variant: loss1 exon:4-9), one frameshift variant: c.973delG(p.(L325Wfs×21)), and one stop codon variant: c.467T>G(p.(L156*)).
Conclusion:
This study identified four patients with LAMP2 gene variants, thereby enriching the documented genetic landscape of LAMP2-associated disorders. Bioinformatics analyses corroborated the pathogenicity of these variants. Additionally, we emphasised that women with suspected Danon disease should be thoroughly evaluated, and the possibility of implantable cardioverter defibrillator implantation and heart transplantation should be considered and discussed as early as possible.
Many language assessments – particularly those considered high-stakes – have the potential to significantly impact a person’s educational, employment and social opportunities, and should therefore be subject to ethical and regulatory considerations regarding their use of artificial intelligence (AI) in test design, development, delivery, and scoring. It is timely and crucial that the community of language assessment practitioners develop a comprehensive set of principles that can ensure ethical practices in their domain of practice as part of a commitment to relational accountability. In this chapter, we contextualize the debate on ethical AI in L2 assessment within global policy documents, and identify a comprehensive set of principles and considerations which pave the way for a shared discourse to underpin an ethical approach to the use of AI in language assessment. Critically, we advocate for an “ethical-by-design” approach in language assessment that promotes core ethical values, balances inherent tensions, mitigates associated risks, and promotes ethical practices.
Airbreathing waveriders often use the fuselage forebody as the pre-compression surface of the inlet, which tends to encounter complex internal-external flow coupling issues. First, the osculating cone method is employed, and a wide-speed-range airbreathing waverider is designed by partitioning it into the waverider forebody, elongated body and waverider aft body, achieving full waverider characteristics. Next, the configuration is optimised to address the internal-external flow coupling issue. The calculations show that the optimised configuration improves the lift-to-drag ratio by more than 20% and the total pressure recovery coefficient by more than 30% in both operating conditions compared to the baseline configuration. Finally, data mining techniques are applied to analyse the data from the optimisation process. It reveals the interdependent relationship between the vehicle’s internal and external flow performance, with the cone shock wave angle and wing extension line length having the most significant impact on aerodynamic performance, thereby generating design knowledge. The content of this paper covers configuration design, optimisation and data mining. The entire process is highly generalisable and can serve as a reference for other aircraft configuration design optimisation tasks. The resulting design knowledge can also provide valuable insights for researchers in future airbreathing waverider designs.
This article explores the dispute between the philosopher Immanuel Kant and the physician Johann Daniel Metzger over the moral autonomy of individuals with mental illness. Situating the debate within the broader context of the evolving philosophical and medical professions in eighteenth-century Germany, the article examines how a professional conflict emerged over who – the physician or the philosopher – should serve as the legal authority in cases where moral responsibility was in question. The analysis shows that this was not merely a theoretical issue for Kant, but a practical one, brought to the fore by the infanticide trial of Margarethe Kaveczynska, in which Kant’s friend, Theodor Gottlieb Hippel, presided as judge. The article argues that while Kant’s vision for the practical application of his anthropology influenced his conception of moral autonomy, he ultimately lost ground to the rising authority of the medical profession.
This study examines the dynamics of vortical interactions and their implications for mitigating thermoacoustic instability in a turbulent combustor. The regions of intense vortical interactions are identified as vortical communities in the network space of weighted directed vortical networks constructed from two-dimensional experimental velocity data. One can expect vortical interactions in the combustor to be strongest near the moment of vortex shedding, as the shed vortices gradually weaken due to dissipation while convecting downstream. However, we show that, during the state of thermoacoustic instability, there is a non-trivial consistent phase lag of approximately $52^\circ$ between the shedding of the coherent structures from the backward-facing step and the time instant when the vortical interactions attain their local maximum value. We explain this phase lag by investigating the correlation between acoustic pressure fluctuations, spatio-temporal dynamics of coherent structures and vortical interactions in the reaction field of the combustor. We also show the aperiodic variation of vortical interactions during the states of combustion noise and aperiodic epochs of intermittency. Furthermore, the spatio-temporal evolution of pairs of vortical communities with the maximum inter-community interactions provides insight into explaining the critical regions detected in the reaction field during the states of intermittency and thermoacoustic instability, also identified in previous studies. We further show that the most efficient suppression of thermoacoustic instability via air microjet injection is achieved when steady air jets are introduced to disrupt the maximum inter-community interactions present during the state of thermoacoustic instability.