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The emergence of a new era reaching beyond current state-of-the-art ultrashort and ultraintense laser technology has been enabled by the approval of around € 850 million worth of structural funds in 2011–2012 by the European Commission for the installation of Extreme Light Infrastructure (ELI). The ELI project consists of three pillars being built in the Czech Republic, Hungary, and Romania. This challenging proposal is based on recent technical progress allowing ultraintense laser fields in which intensities will soon be reaching as high as I0 ∼ 1023 W cm−2. This tremendous technological advance has been brought about by the invention of chirped pulse amplification by Mourou and Strickland. Romania is hosting the ELI for Nuclear Physics (ELI-NP) pillar in Măgurele near Bucharest. The new facility, currently under construction, is intended to serve the broad national, European, and international scientific community. Its mission covers scientific research at the frontier of knowledge involving two domains. The first is laser-driven experiments related to NP, strong-field quantum electrodynamics, and associated vacuum effects. The second research domain is based on the establishment of a Compton-backscattering-based, high-brilliance, and intense γ beam with Eγ ≲ 19.5 MeV, which represents a merger between laser and accelerator technology. This system will allow the investigation of the nuclear structure of selected isotopes and nuclear reactions of relevance, for example, to astrophysics with hitherto unprecedented resolution and accuracy. In addition to fundamental themes, a large number of applications with significant societal impact will be developed. The implementation of the project started in January 2013 and is spearheaded by the ELI-NP/Horia Hulubei National Institute for Physics and Nuclear Engineering (IFIN-HH). Experiments will begin in early 2020.

Deficits in the ankle plantarflexor muscles, such as weakness and contracture, occur commonly in conditions such as cerebral palsy, stroke, muscular dystrophy, Charcot-Marie-Tooth disease, and sarcopenia. While these deficits likely contribute to observed gait pathologies, determining cause-effect relationships is difficult due to the often co-occurring biomechanical and neural deficits. To elucidate the effects of weakness and contracture, we systematically introduced isolated deficits into a musculoskeletal model and generated simulations of walking to predict gait adaptations due to these deficits. We trained a planar model containing 9 degrees of freedom and 18 musculotendon actuators to walk using a custom optimization framework through which we imposed simple objectives, such as minimizing cost of transport while avoiding falling and injury, and maintaining head stability. We first generated gaits at prescribed speeds between 0.50 m/s and 2.00 m/s that reproduced experimentally observed kinematic, kinetic, and metabolic trends for walking. We then generated a gait at self-selected walking speed; quantitative comparisons between our simulation and experimental data for joint angles, joint moments, and ground reaction forces showed root-mean-squared errors of less than 1.6 standard deviations and normalized cross-correlations above 0.8 except for knee joint moment trajectories. Finally, we applied mild, moderate, and severe levels of muscle weakness or contracture to either the soleus (SOL) or gastrocnemius (GAS) or both of these major plantarflexors (PF) and retrained the model to walk at a self-selected speed. The model was robust to all deficits, finding a stable gait in all cases. Severe PF weakness caused the model to adopt a slower, "heel-walking" gait. Severe contracture of only SOL or both PF yielded similar results: the model adopted a "toe-walking" gait with excessive hip and knee flexion during stance. These results highlight how plantarflexor weakness and contracture may contribute to observed gait patterns.

A deep understanding of the internal ballistic process and the factors affecting it is of primary importance to efficiently design a gun system and ensure its safe management. One of the main goals of internal ballistics is to estimate the gas pressure into the combustion chamber and the projectile muzzle velocity in order to use the propellant to its higher efficiency while avoiding over-pressure phenomena. Dealing with the internal ballistic problem is a complex undertaking since it requires handling the interaction between different constituents during a transient time lapse with very steep rise of pressure and temperature. Several approaches have been proposed in the literature, based on different assumptions and techniques. Generally, depending on the used mathematical framework, they can be classified into two categories: computational fluid dynamics-based models and lumped-parameter ones. By focusing on gun systems, this paper offers a review of the main contributions in the field by mentioning their advantages and drawbacks. An insight into the limitations of the currently available modelling strategies is provided, as well as some considerations on the choice of one model over another. Lumped-parameter models, for example, are a good candidate for performing parametric analysis and optimisation processes of gun systems, given their minimum requirements of computer resources. Conversely, CFD-based models have a better capacity to address more sophisticated phenomena like pressure waves and turbulent flow effects. The performed review also reveals that too little attention has been given to small calibre guns since the majority of currently available models are conceived for medium and large calibre gun systems. Similarly, aspects like wear phenomena, bore deformations or projectile-barrel interactions still need to be adequately addressed and our suggestion is to dedicate more effort on it.

Movement is fundamental to human and animal life, emerging through interaction of complex neural, muscular, and skeletal systems. Study of movement draws from and contributes to diverse fields, including biology, neuroscience, mechanics, and robotics. OpenSim unites methods from these fields to create fast and accurate simulations of movement, enabling two fundamental tasks. First, the software can calculate variables that are difficult to measure experimentally, such as the forces generated by muscles and the stretch and recoil of tendons during movement. Second, OpenSim can predict novel movements from models of motor control, such as kinematic adaptations of human gait during loaded or inclined walking. Changes in musculoskeletal dynamics following surgery or due to human-device interaction can also be simulated; these simulations have played a vital role in several applications, including the design of implantable mechanical devices to improve human grasping in individuals with paralysis. OpenSim is an extensible and user-friendly software package built on decades of knowledge about computational modeling and simulation of biomechanical systems. OpenSim's design enables computational scientists to create new state-of-the-art software tools and empowers others to use these tools in research and clinical applications. OpenSim supports a large and growing community of biomechanics and rehabilitation researchers, facilitating exchange of models and simulations for reproducing and extending discoveries. Examples, tutorials, documentation, and an active user forum support this community. The OpenSim software is covered by the Apache License 2.0, which permits its use for any purpose including both nonprofit and commercial applications. The source code is freely and anonymously accessible on GitHub, where the community is welcomed to make contributions. Platform-specific installers of OpenSim include a GUI and are available on simtk.org.

Abstract Global warming is a major challenge to the sustainable and humane production of food because of the increased risk of livestock to heat stress. Here, the example of the prolactin receptor (PRLR) gene is used to demonstrate how gene editing can increase the resistance of cattle to heat stress by the introduction of mutations conferring thermotolerance. Several cattle populations in South and Central America possess natural mutations in PRLR that result in affected animals having short hair and being thermotolerant. CRISPR/Cas9 technology was used to introduce variants of PRLR in two thermosensitive breeds of cattle – Angus and Jersey. Gene‐edited animals exhibited superior ability to regulate vaginal temperature (heifers) and rectal temperature (bulls) compared to animals that were not gene‐edited. Moreover, gene‐edited animals exhibited superior growth characteristics and had larger scrotal circumference. There was no evidence for deleterious effects of the mutation on carcass characteristics or male reproductive function. These results indicate the potential for reducing heat stress in relevant environments to enhance cattle productivity.

Like the marine ray Taeniura lymma, the African lungfish Protopterus dolloi possesses carbamoyl phosphate III (CPS III) in the liver and not carbamoyl phosphate I (CPS I), as in the mouse Mus musculus or as in other African lungfish reported elsewhere. However, similar to other African lungfish and tetrapods, hepatic arginase of P. dolioi is present mainly in the cytosol. Glutamine synthetase activity is present in both the mitochondrial and cytosolic fractions of the liver of P. dolloi. Therefore, we conclude that P. dolloi is a more primitive extant lungfish, which is intermediate between aquatic fish and terrestrial tetrapods, and represents a link in the fish-tetrapod continuum. During 6 days of aerial exposure, the ammonia excretion rate in P. dolloi decreased significantly to 8-16% of the submerged control. However, there were no significant increases in ammonia contents in the muscle, liver or plasma of specimens exposed to air for 6 days. These results suggest that (1) endogenous ammonia production was drastically reduced and (2) endogenous ammonia was detoxified effectively into urea. Indeed, there were significant decreases in glutamate, glutamine and lysine levels in the livers of fish exposed to air, which led to a decrease in the total free amino acid content. This indirectly confirms that the specimen had reduced its rates of proteolysis and/or amino acid catabolism to suppress endogenous ammonia production. Simultaneously, there were significant increases in urea levels in the muscle (8-fold), liver (10.5fold) and plasma (12.6-fold) of specimens exposed to air for 6 days. Furthermore, there was an increase in the hepatic ornithine-urea cycle (OUC) capacity, with significant increases in the activities of CPS III (3.8-fold), argininosuccinate synthetase + lyase (1.8-fold) and, more importantly, glutamine synthetase (2.2-fold). This is the first report on the upregulation of OUC capacity and urea synthesis rate in an African lungfish exposed to air. Upon re-immersion, the urea excretion rate increased 22-fold compared with that of the control specimen, which is the greatest increase among fish during emersion-immersion transitions and suggests that P. dolloi possesses transporters that facilitate the excretion of urea in water. [ABSTRACT FROM AUTHOR]

Recently, the all-optical Compton laser backscattering setup has become a promising approach in producing high-quality γ-rays. However, this method only produces a single γ-ray beam. In this paper, we report on the numerical study for the feasibility of producing double γ-ray beams using a 1 PW laser. Our method utilizes the all-optical setup with a structured solid target as a reflecting foil. The laser pulse is reflected by the foil after propagating a few millimeters into the underdense plasma. The reflected laser intensity is strongly boosted by the foil to invoke a radiation reaction as nonlinear Compton backscattering. Subsequently, the electron bunch traverses the foil, generating bremsstrahlung. Our simulation results show that a collimated γ-ray beam from the nonlinear Compton backscattering with the peak brilliance of 6.7 × 1020 photons/s/mm2/mrad2/0.1% BW at 15 MeV is produced. Another collimated γ-ray beam with the peak brilliance of 2.1 × 106 photons/s/mm2/mrad2/0.1% BW is produced by bremsstrahlung. The combined γ-ray beams act as a blaster and are of particular interest in nuclear interactions induced by high-energy photons. [ABSTRACT FROM AUTHOR]

Abstract Laser plasma-based accelerators provide an excellent source of collimated, bright, and adequately coherent betatron-type x-ray pulses with potential applications in science and industry. So far the laser plasma-based betatron radiation has been described within the concept of classical Liénard–Wiechert potentials incorporated in particle-in-cell simulations, a computing power-demanding approach, especially for the case of multi-petawatt lasers. In this work, we describe the laser plasma-based generation of betatron radiation at the most fundamental level of quantum mechanics. In our approach, photon emission from the relativistic electrons in the plasma bubble is described within a nonlinear quantum electrodynamics (QED) framework. The reported QED-based betatron radiation results are in excellent agreement with similar results using Liénard–Wiechert potentials, as well as in very good agreement with betatron radiation measurements, obtained with multi-10-TW lasers interacting with He and multielectron N $$_2$$ 2 gas targets. Furthermore, our QED approach results in a dramatic reduction of the computational runtime demands, making it a favorable tool for designing betatron radiation experiments, especially in multi-petawatt laser facilities.

Abstract Muscle-driven simulations have provided valuable insights in studies of walking and running, but a set of freely available simulations and corresponding experimental data for cycling do not exist. The aim of this work was to develop a set of muscle-driven simulations of cycling and to validate them by comparison with experimental data. We used direct collocation to generate simulations of 16 participants cycling over a range of powers (40–216 W) and cadences (75–99 RPM) using two optimization objectives: a baseline objective that minimized muscle effort and a second objective that additionally minimized tibiofemoral joint forces. We tested the accuracy of the simulations by comparing the timing of active muscle forces in our baseline simulation to timing in experimental electromyography data. Adding a term in the objective function to minimize tibiofemoral forces preserved cycling power and kinematics, improved similarity between active muscle force timing and experimental electromyography, and decreased tibiofemoral joint reaction forces, which better matched previously reported in vivo measurements. The musculoskeletal models, muscle-driven simulations, simulation software, and experimental data are freely shared at https://simtk.org/projects/cycling_sim for others to reproduce these results and build upon this research.

Abstract Nanowire array targets exhibit high optical absorption when interacting with short, intense laser pulses. This leads to an increased yield in the production of accelerated particles for a variety of applications. However, these interactions are sensitive to the laser prepulse and could be significantly affected. Here, we show that an array of aligned nanowires is imploded when irradiated by an Amplified Spontaneous Emission pedestal of a $$1\,\text{PW}$$ 1 PW laser with an intensity on the order of $$10^{11}\, \mathrm {W \, cm^{-2}}$$ 10 11 W cm - 2 . Using radiation hydrodynamics simulations, we demonstrate that the electron density profile is radially compressed at the tip by the rocket-like propulsion of the ablated plasma. The mass density compression increases up to $$2.9\times$$ 2.9 × when a more dense nanowire array is used. This is due to the ablation pressure from the neighboring nanowires. These findings offer valuable information for selecting an appropriate target design for experiments aimed at enhancing production of accelerated particles.

Electron transport in a nanowire exhibits a distinct behavior following the irradiation of intense laser pulse. Using particle-in-cell simulation, we observe a large-amplitude particle-driven wakefield excitation followed by electron acceleration in the solid density. Besides, we observed the quiver of the electrons across the nanowire under the action of the surrounding laser electric field facilitating deeper wakefield propagation in the nanowire with 2.5× energy gain over a flat target. These results open insights into the laser-energy coupling with nanostructure targets and radiation sources, and motivate the wakefield acceleration in solid density plasma.

In a causal inference framework, a new metric has been proposed to quantify surrogacy for a continuous putative surrogate and a binary true endpoint, based on information theory. The proposed metric, termed the individual causal association (ICA), was quantified using a joint causal inference model for the corresponding potential outcomes. Due to the non-identifiability inherent in this type of models, a sensitivity analysis was introduced to study the behavior of the ICA as a function of the non-identifiable parameters characterizing the aforementioned model. In this scenario, to reduce uncertainty, several plausible yet untestable assumptions like monotonicity, independence, conditional independence or homogeneous variance-covariance, are often incorporated into the analysis. We assess the robustness of the methodology regarding these simplifying assumptions via simulation. The practical implications of the findings are demonstrated in the analysis of a randomized clinical trial evaluating an inactivated quadrivalent influenza vaccine., (© 2024 John Wiley & Sons Ltd.)

Background: The purpose of this study was to determine the reliability of anthropometric measurements between two trained anthropometrists working in a team and one trained anthropometrist working with a child's parent/caregiver in a primary health care setting. Study Design: An observational study to determine measurement reliability was conducted in a primary care child research network in Canada. In total, 120 children 0-5 years old had their anthropometric measurement taken twice by two trained anthropometrists working in a team and twice by one trained anthropometrist working with a child's parent/caregiver. Inter- and intra-observer reliability was calculated using the technical error of measurement (TEM), relative TEM (%TEM), and the coefficient of reliability (R). Results: The %TEM values for length/height and weight were <2%, and the R coefficient values were >0.99, indicating a high degree of inter- and intra-observer reliability. The TEM values demonstrated a high degree of reliability for inter- and intra-observer measurement of length/height in comparison with other anthropometric measurement parameters. However, there was greater variation seen in the length measurement for children 0 to <2 years of age and in arm circumference measurement across both age-groups. Conclusion(s): This study suggests that anthropometric measurement taken by one trained anthropometrist with the assistance of a parent/caregiver is reliable. These findings provide evidence to support inclusion of a child's parent/caregiver with anthropometric measurement collection in clinical setting(s) to enhance feasibility and efficiency and reduce the research costs of including a second trained anthropometrist.

Purpose: AML presenting with hyperleukocytosis is associated with poor outcomes. We aim to understand the factors associated with early mortality and overall survival (OS) to help guide management and improve early mortality., Methods: We retrospectively reviewed data from 129 consecutive patients with newly diagnosed AML and a WBC count ≥100 × 10 9 /L between January 2010 and April 2020. Logistic regression models estimated odds ratios for 4-week mortality. Cox proportional hazard models estimated hazard ratios for OS., Results: The median age was 65 years (range, 23-86); the median WBC was 146 × 10 9 /L (range, 100-687). Seventy-five (58%) patients had clinical leukostasis (CL). FLT3 , NPM1 , and RAS pathway mutations were detected in 63%, 45%, and 27% of patients, respectively. Cytoreduction consisted of hydroxyurea in 124 (96%) patients, cytarabine in 69 (54%), and leukapheresis in 31 (24%). The cumulative 4-week and 8-week mortality rates were 9% and 13%, respectively, all in patients age 65 years and older. By multivariate analysis, older age, CL, and thrombocytopenia <40 × 10 9 /L were independently associated with a higher 4-week mortality rate. After a median follow-up of 49.4 months, the median OS was 14.3 months (95% CI, 7 to 21.6), with 4-year OS of 29%. Age 65 years and older, CL, tumor lysis syndrome, elevated LDH ≥2,000 U/L, elevated lactate ≥2.2 mmol/L, and poor-risk cytogenetics were independent factors associated with worse OS., Conclusion: Hyperleukocytosis is a life-threatening hematologic emergency. Early recognition and intervention including cytoreduction, blood product support, antibiotics, and renal replacement therapy may help mitigate the risk of morbidity and early mortality.

Purpose: Female Hodgkin lymphoma (HL) survivors treated with chest radiotherapy (RT) at a young age have a strongly increased risk of breast cancer (BC). Studies in childhood cancer survivors have shown that doxorubicin exposure may also increase BC risk. Although doxorubicin is the cornerstone of HL chemotherapy, the association between doxorubicin and BC risk has not been examined in HL survivors treated at adult ages., Methods: We assessed BC risk in a cohort of 1,964 female 5-year HL survivors, treated at age 15-50 years in 20 Dutch hospitals between 1975 and 2008. We calculated standardized incidence ratios, absolute excess risks, and cumulative incidences. Doxorubicin exposure was analyzed using multivariable Cox regression analyses., Results: After a median follow-up of 21.6 years (IQR, 15.8-27.1 years), 252 women had developed invasive BC or ductal carcinoma in situ. The 30-year cumulative incidence was 20.8% (95% CI, 18.2 to 23.4). Survivors treated with a cumulative doxorubicin dose of >200 mg/m 2 had a 1.5-fold increased BC risk (95% CI, 1.08 to 2.1), compared with survivors not treated with doxorubicin. BC risk increased 1.18-fold (95% CI, 1.05 to 1.32) per additional 100 mg/m 2 doxorubicin ( P trend = .004). The risk increase associated with doxorubicin (yes v no) was not modified by age at first treatment (hazard ratio [HR] age <21 years , 1.5 [95% CI, 0.9 to 2.6]; HR age ≥21 years , 1.3 [95% CI, 0.9 to 1.9) or chest RT (HR without mantle/axillary field RT , 1.9 [95% CI, 1.06 to 3.3]; HR with mantle/axillary field RT , 1.2 [95% CI, 0.8 to 1.8])., Conclusion: This study shows that treatment with doxorubicin is associated with increased BC risk in both adolescent and adult HL survivors. Our results have implications for BC surveillance guidelines for HL survivors and treatment strategies for patients with newly diagnosed HL.

Background: While endoscopic step-up approach with delayed drainage (more than 28 days from diagnosis) was shown to produce the best outcomes in the treatment of pancreatic walled-off necrosis (WON), we assessed our single centre experience of early versus delayed endoscopic drainage of pancreatic necrotic collections., Methods: Patients who underwent endoscopic drainage of pancreatic necrotic collections between 2011 and 2022 under Monash Health were identified. They were excluded if below 18 years old or their follow up data were missing. The included patients' medical records, pathology results, and imaging findings were retrospectively reviewed., Results: A total of 60 patients were included. 31.58% required percutaneous drainage and 15% received either endoscopic or surgical necrosectomy. The disease related mortality was 8.47% and the average length of stay (LOS) was 70.92 days. No significant difference was shown in disease-related mortality (10.5% vs. 7.5%, P = 0.697) or LOS (75.35 vs. 68.7, P = 0.644) between early and delayed drainage cohorts, but patients who received early drainage have higher qSOFA score on the day of drainage (2 vs. 0, P = 0.004)., Discussion: Repetitive endoscopic drainage with selective percutaneous drainage is effective in the management of pancreatic necrotic collections. Early drainage should be considered in patients who developed severe sepsis., (© 2024 The Authors. ANZ Journal of Surgery published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Surgeons.)

Objective: Oral feeding difficulty is common in infants after congenital heart disease (CHD) surgical repair and is associated with prolonged hospital stay and increased risk for tube-feeding at discharge (TF). The current understanding of the enteropathogenesis of oral feeding difficulty in infants requiring CHD surgery is limited. To determine the prevalence and risk factors for TF following CHD surgery in early infancy., Study Design: This was a 6-year single-center retrospective cohort study (2016-2021) of infants under 6 months who had CHD surgery. Infants required TF were compared with infants who reached independent oral feeding (IOF)., Results: Of the final sample of 128 infants, 24 (18.8%) infants required TF at discharge. The risk factors for TF in univariate analysis include low birth weight, low 5-minute Apgar score, admitted at birth, risk adjustment in congenital heart surgery categories IV to VI, presence of genetic diagnosis, use of Prostin, higher pre- and postsurgery respiratory support, lower weight at surgery, lower presurgery oral feeding, higher presurgery milk calory, delayed postsurgery enteral and oral feeding, higher pre- and postsurgery gastroesophageal reflux disease (GERD), need for swallow study, abnormal brain magnetic resonance imaging ( p  < 0.05). In the multivariate analysis, only admitted at birth, higher presurgery milk calories, and GERD were significant risk factors for TF. TF had significantly longer hospital stay (72 vs. 17 days) and lower weight gain at discharge ( z -score: -3.59 vs. -1.94) compared with IOF ( p  < 0.05)., Conclusion: The prevalence of TF at discharge in our study is comparable to previous studies. Infants with CHD admitted at birth, received higher presurgery milk calories, and clinical GERD are significant risk factors for TF. Mitigating the effects of identified risk factors for TF will have significant impact on the quality of life for these infants and their families and may reduce health care cost., Key Points: · Oral feeding difficulty in infants after congenital heart disease surgical repair is common.. · Such infants require prolonged hospital stay and higher risk for tube-feeding at discharge.. · Identifying modifiable risk factors associated with tube-feeding can enhance clinical outcomes.., Competing Interests: None declared., (Thieme. All rights reserved.)

Within the causal association paradigm, a method is proposed to assess the validity of a continuous outcome as a surrogate for a binary true endpoint. The methodology is based on a previously introduced information-theoretic definition of surrogacy and has two main steps. In the first step, a new model is proposed to describe the joint distribution of the potential outcomes associated with the putative surrogate and the true endpoint of interest. The identifiability issues inherent to this type of models are handled via sensitivity analysis. In the second step, a metric of surrogacy new to this setting, the so-called individual causal association is presented. The methodology is studied in detail using theoretical considerations, some simulations, and data from a randomized clinical trial evaluating an inactivated quadrivalent influenza vaccine. A user-friendly R package Surrogate is provided to carry out the evaluation exercise., (© 2024 John Wiley & Sons Ltd.)

Background: The occurrence of somatic mutations in patients with no evidence of hematological disorders is called clonal hematopoiesis (CH). CH, whose subtypes include CH of indeterminate potential and clonal cytopenia of undetermined significance, has been associated with both hematologic cancers and systemic comorbidities. However, CH's effect on patients, especially those with concomitant malignancies, is not fully understood., Methods: We performed a retrospective evaluation of all patients with CH at a tertiary cancer center. Patient characteristics, mutational data, and outcomes were collected and analyzed., Results: Of 78 individuals included, 59 (76%) had a history of cancer and 60 (77%) had moderate to severe comorbidity burdens. DNMT3A, TET2, TP53, and ASXL1 were the most common mutations. For the entire cohort, the 2-year overall survival rate was 79% (95% CI: 70, 90), while the median survival was not reached. Of 20 observed deaths, most were related to primary malignancies (n = 7, 35%), comorbidities (n = 4, 20%), or myeloid neoplasms (n = 4, 20%). Twelve patients (15%) experienced transformation to a myeloid neoplasm. According to the clonal hematopoiesis risk score, the 3-year transformation rate was 0% in low-risk, 15% in intermediate-risk (p = 0.098), and 28% in high-risk (p = 0.05) patients. By multivariate analysis, transformation was associated with variant allele frequency ≥0.2 and hemoglobin <10 g/dL., Conclusions: In a population including mostly cancer patients, CH was associated with comorbidities and myeloid transformation in patients with higher mutational burdens and anemia. Nevertheless, such patients were less likely to die of their myeloid neoplasm than of primary malignancy or comorbidities., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Parallel imaging and compressed sensing reconstructions of large MRI datasets often have a prohibitive computational cost that bottlenecks clinical deployment, especially for three-dimensional (3D) non-Cartesian acquisitions. One common approach is to reduce the number of coil channels actively used during reconstruction as in coil compression. While effective for Cartesian imaging, coil compression inherently loses signal energy, producing shading artifacts that compromise image quality for 3D non-Cartesian imaging. We propose coil sketching, a general and versatile method for computationally-efficient iterative MR image reconstruction., Theory and Methods: We based our method on randomized sketching algorithms, a type of large-scale optimization algorithms well established in the fields of machine learning and big data analysis. We adapt the sketching theory to the MRI reconstruction problem via a structured sketching matrix that, similar to coil compression, considers high-energy virtual coils obtained from principal component analysis. But, unlike coil compression, it also considers random linear combinations of the remaining low-energy coils, effectively leveraging information from all coils., Results: First, we performed ablation experiments to validate the sketching matrix design on both Cartesian and non-Cartesian datasets. The resulting design yielded both improved computatioanal efficiency and preserved signal-to-noise ratio (SNR) as measured by the inverse g-factor. Then, we verified the efficacy of our approach on high-dimensional non-Cartesian 3D cones datasets, where coil sketching yielded up to three-fold faster reconstructions with equivalent image quality., Conclusion: Coil sketching is a general and versatile reconstruction framework for computationally fast and memory-efficient reconstruction., (© 2023 International Society for Magnetic Resonance in Medicine.)

Background: The introduction of rituximab significantly improved the prognosis of diffuse large B-cell lymphoma (DLBCL), emphasizing the importance of evaluating the long-term consequences of exposure to radiotherapy, alkylating agents and anthracycline-containing (immuno)chemotherapy among DLBCL survivors., Methods: Long-term risk of subsequent malignant neoplasms (SMNs) was examined in a multicenter cohort comprising 2373 5-year DLBCL survivors treated at ages 15-61 years in 1989-2012. Observed SMN numbers were compared with expected cancer incidence to estimate standardized incidence ratios (SIRs) and absolute excess risks (AERs/10 000 person-years). Treatment-specific risks were assessed using multivariable Cox regression., Results: After a median follow-up of 13.8 years, 321 survivors developed one or more SMNs (SIR 1.5, 95% CI 1.3-1.8, AER 51.8). SIRs remained increased for at least 20 years after first-line treatment (SIR ≥20-year follow-up 1.5, 95% CI 1.0-2.2, AER 81.8) and were highest among patients ≤40 years at first DLBCL treatment (SIR 2.7, 95% CI 2.0-3.5). Lung (SIR 2.0, 95% CI 1.5-2.7, AER 13.4) and gastrointestinal cancers (SIR 1.5, 95% CI 1.2-2.0, AER 11.8) accounted for the largest excess risks. Treatment with >4500 mg/m 2 cyclophosphamide/>300 mg/m 2 doxorubicin versus ≤2250 mg/m 2 /≤150 mg/m 2 , respectively, was associated with increased solid SMN risk (hazard ratio 1.5, 95% CI 1.0-2.2). Survivors who received rituximab had a lower risk of subdiaphragmatic solid SMNs (hazard ratio 0.5, 95% CI 0.3-1.0) compared with survivors who did not receive rituximab., Conclusion: Five-year DLBCL survivors have an increased risk of SMNs. Risks were higher for survivors ≤40 years at first treatment and survivors treated with >4500 mg/m 2 cyclophosphamide/>300 mg/m 2 doxorubicin, and may be lower for survivors treated in the rituximab era, emphasizing the need for studies with longer follow-up for rituximab-treated patients., Competing Interests: Disclosure MJK has received research support from Kite/Gilead and financial compensation for attending advisory boards and/or presentations from Roche, Kite/Gilead, Novartis, BMS/Celgene, Miltenyi Biotec, Takeda and Adicet Bio. All other authors have declared no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Bleeding from a visceral artery pseudoaneurysm (VAPA) is a rare but significant complication of bariatric surgery. Patients may present with gastrointestinal (GI) haemorrhage in the forms of haematemesis, melaena, haematochezia or haemodynamic compromise. Although CT angiogram, endoscopy and laparoscopy form essential parts of diagnostic assessment, small pseudoaneurysms with intermittent bleeding may be overlooked. We report the case of a man in his 40s who presented to the emergency department with massive GI bleeding and subsequent haemodynamic instability, secondary to a pseudoaneurysm from a vascular injury during a recent bariatric procedure. This case highlights the diagnostic challenges of obscure, intermittent bleeding involving the bypassed stomach with unremarkable investigation findings, and aims to raise awareness among clinicians in considering the less common postgastric-bypass complications., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Three-dimensional UTE MRI has shown the ability to provide simultaneous structural and functional lung imaging, but it is limited by respiratory motion and relatively low lung parenchyma SNR. The purpose of this paper is to improve this imaging by using a respiratory phase-resolved reconstruction approach, named motion-compensated low-rank reconstruction (MoCoLoR), which directly incorporates motion compensation into a low-rank constrained reconstruction model for highly efficient use of the acquired data., Theory and Methods: The MoCoLoR reconstruction is formulated as an optimization problem that includes a low-rank constraint using estimated motion fields to reduce the rank, optimizing over both the motion fields and reconstructed images. The proposed reconstruction along with XD and motion state-weighted motion-compensation (MostMoCo) methods were applied to 18 lung MRI scans of pediatric and young adult patients. The data sets were acquired under free-breathing and without sedation with 3D radial UTE sequences in approximately 5 min. After reconstruction, they went through ventilation analyses. Performance across reconstruction regularization and motion-state parameters were also investigated., Results: The in vivo experiments results showed that MoCoLoR made efficient use of the data, provided higher apparent SNR compared with state-of-the-art XD reconstruction and MostMoCo reconstructions, and yielded high-quality respiratory phase-resolved images for ventilation mapping. The method was effective across the range of patients scanned., Conclusion: The motion-compensated low-rank regularized reconstruction approach makes efficient use of acquired data and can improve simultaneous structural and functional lung imaging with 3D-UTE MRI. It enables the scanning of pediatric patients under free-breathing and without sedation., (© 2023 International Society for Magnetic Resonance in Medicine.)

Introduction: There is increasing evidence in the literature to support venous sinus stenting in patients with idiopathic intracranial hypertension who fail first-line therapy. Venous sinus stenting is a safe and successful technique compared with cerebrospinal fluid diversion procedures. This study examines the clinical outcomes of patients post intracranial venous stenting for intracranial hypertension across three tertiary hospitals in Western Australia., Methods: A retrospective analysis was performed on 83 consecutive patients treated with intracranial venous stenting for IIH at three tertiary hospitals from October 2013 to March 2020. Data were collected from outpatient clinic letters, electronic discharge letters, electronic radiological imaging and procedural reports., Results: 89.2% patients were able to cease Acetazolomide post stenting. 78.3% patients reported resolution of headaches. 84.3% patients demonstrated resolution of their papilloedema. 91.6% patients demonstrated improvement of their visual acuity. Compared with a recent meta-analysis by Satti and Chaudry in 2015, our results demonstrated a higher technical success rate and lower complication rates., Conclusion: Our study findings support the paradigm shift from CSF diversion procedures to venous sinus stenting in patients with IIH who fail first-line therapy. Venous sinus stenting has a high technical success rate and significantly lower complication rates than other invasive treatments., (© 2023 Royal Australian and New Zealand College of Radiologists.)

Although venetoclax-based lower-intensity regimens have greatly improved outcomes for older adults with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy, the optimal induction for older patients with newly diagnosed AML who are suitable candidates for hematopoietic stem cell transplant (HSCT) is controversial. We retrospectively analyzed the post HSCT outcomes of 127 patients ≥60 years of age who received induction therapy at our institution with intensive chemotherapy (IC; n = 44), lower-intensity therapy (LIT) without venetoclax (n = 29), or LIT with venetoclax (n = 54) and who underwent allogeneic HSCT in the first remission. The 2-year relapse-free survival (RFS) was 60% with LIT with venetoclax vs 54% with IC, and 41% with LIT without venetoclax; the 2-year overall survival (OS) was 72% LIT with venetoclax vs 58% with IC, and 41% with LIT without venetoclax. The benefit of LIT with venetoclax induction was greatest in patients with adverse-risk AML (2-year OS: 74%, 46%, and 29%, respectively). Induction with LIT, with or without venetoclax, was associated with the lowest rate of nonrelapse mortality (NRM) (2-year NRM: 17% vs 27% with IC; P = .04). Using multivariate analysis, the type of induction therapy did not significantly affect any of the post HSCT outcomes evaluated; hematopoietic cell transplantation-specific comorbidity index was the only factor that independently predicted RFS and OS. LIT plus venetoclax followed by HSCT is a feasible treatment strategy in older, fit, HSCT-eligible patients with newly diagnosed AML and may be particularly beneficial for those with adverse-risk disease., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Pevonedistat is a first-in-class, small molecular inhibitor of NEDD8-activating enzyme that has clinical activity in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Preclinical data suggest synergy of pevonedistat with azacitidine and venetoclax., Methods: This single-center, phase 1/2 study evaluated the combination of azacitidine, venetoclax and pevonedistat in older adults with newly diagnosed secondary AML or with MDS or chronic myelomonocytic leukemia (CMML) after failure of hypomethylating agents. Patients received azacitidine 75 mg/m 2 IV on days 1-7, venetoclax at maximum dose of 200-400 mg orally on days 1-21 (AML cohort) or days 1-14 (MDS/CMML cohort) and pevonedistat 20 mg/m 2 IV on days 1, 3 and 5 for up to 24 cycles. The primary endpoints for the phase 2 portion of the study were the CR/CRi rate in the AML cohort and the overall response rate (CR + mCR + PR + HI) in the MDS/CMML cohort., Findings: Forty patients were enrolled (32 with AML and 8 with MDS/CMML). In the AML cohort, the median age was 74 years (range 61-86 years), and 27 patients (84%) had at least one adverse risk cyto-molecular feature, including 15 (47%) with a TP53 mutation or MECOM rearrangement; seventeen patients (53%) had received prior therapy for a preceding myeloid disorder. The CR/CRi rate was 66% (CR 50%; CRi 16%), and the median overall survival (OS) was 8.1 months. In the MDS/CMML cohort, 7 patients (87%) were high or very high risk by the IPSS-R. The overall response rate was 75% (CR 13%; mCR with or without HI 50%; HI 13%). The most common grade 3-4 adverse events were infection in 16 patients (35%), febrile neutropenia in 10 patients (25%) and hypophosphatemia in 9 patients (23%). In an exploratory analysis, early upregulation of NOXA expression was observed, with subsequent decrease in MCL-1 and FLIP, findings consistent with preclinical mechanistic studies of pevonedistat. Upregulation of CD36 was observed, which may have contributed to therapeutic resistance., Conclusions: The triplet combination of azacitidine, venetoclax and pevonedistat shows encouraging activity in this very poor-risk population of patients with AML, MDS or CMML. Trial registration ClinicalTrials.gov (NCT03862157)., (© 2023. The Author(s).)

Purpose: To develop a respiratory-resolved motion-compensation method for free-breathing, high-resolution coronary magnetic resonance angiography (CMRA) using a 3D cones trajectory., Methods: To achieve respiratory-resolved 0.98 mm resolution images in a clinically relevant scan time, we undersample the imaging data with a variable-density 3D cones trajectory. For retrospective motion compensation, translational estimates from 3D image-based navigators (3D iNAVs) are used to bin the imaging data into four phases from end-expiration to end-inspiration. To ensure pseudo-random undersampling within each respiratory phase, we devise a phyllotaxis readout ordering scheme mindful of eddy current artifacts in steady state free precession imaging. Following binning, residual 3D translational motion within each phase is computed using the 3D iNAVs and corrected for in the imaging data. The noise-like aliasing characteristic of the combined phyllotaxis and cones sampling pattern is leveraged in a compressed sensing reconstruction with spatial and temporal regularization to reduce aliasing in each of the respiratory phases., Results: In initial studies of six subjects, respiratory motion compensation using the proposed method yields improved image quality compared to non-respiratory-resolved approaches with no motion correction and with 3D translational correction. Qualitative assessment by two cardiologists and quantitative evaluation with the image edge profile acutance metric indicate the superior sharpness of coronary segments reconstructed with the proposed method (P < 0.01)., Conclusion: We have demonstrated a new method for free-breathing, high-resolution CMRA based on a variable-density 3D cones trajectory with modified phyllotaxis ordering and respiratory-resolved motion compensation with 3D iNAVs., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The Shinnar-Le-Roux (SLR) algorithm is widely used to design frequency selective pulses with large flip angles. We improve its design process to generate pulses with lower energy (by as much as 26%) and more accurate phase profiles. Concretely, the SLR algorithm consists of two steps: (1) an invertible transform between frequency selective pulses and polynomial pairs that represent Cayley-Klein (CK) parameters and (2) the design of the CK polynomial pair to match the desired magnetization profiles. Because the CK polynomial pair is bi-linearly coupled, the original algorithm sequentially solves for each polynomial instead of jointly. This results in sub-optimal pulses. Instead, we leverage a convex relaxation technique, commonly used for low rank matrix recovery, to address the bi-linearity. Our numerical experiments show that the resulting pulses are almost always globally optimal in practice. For slice excitation, the proposed algorithm results in more accurate linear phase profiles. And in general the improved pulses have lower energy than the original SLR pulses.

Background: Young children are often accompanied by their parent/caregiver when attending primary healthcare visits, where clinical procedures such as anthropometric measurements are conducted. Parents are not typically involved in their child's anthropometric measurement collection, and there are no recommendations for parental involvement during visits. The objective of this study was to describe parents' experiences with being involved in their child's anthropometric measurements., Methods: A 10-question survey comprised of scaled and open-ended questions was self-administered to participants after child anthropometric measurement collection including length/height, weight, head, arm, and waist circumference. Survey data were analyzed using a general inductive approach and thematic analysis. Surveys were collected in participating TARGet Kids! primary care practice sites in Toronto, Canada. Survey respondents included 30 parents of children < 2 years of age, and 30 parents of children 2-5 years of age., Results: 76% of parents with children aged < 2 years and 93% of those with children aged 2-5 years rated their overall experience in being involved in their child's anthropometric measurement as enjoyable or thoroughly enjoyable. Analysis of open-ended survey questions revealed five themes: [1] parent interest in child growth; [2] ease of anthropometric measurement; [3] extended clinic visit; [4] child discomfort; and [5] interest in participating in research., Conclusion: Parents reported a high degree of enjoyment in being involved in their child's anthropometric measurements. Parent participation in anthropometric measurement may improve parental satisfaction with children's primary healthcare. Future research may include assessing the reliability of measurements taken with the support of a parent/caregiver., (© 2023. The Author(s).)

This study investigates the roles of the socio-economic, land use, built environment, and weather factors in shaping up the demand for bicycle-sharing trips during the COVID-19 pandemic in Toronto. It uses "Bike Share Toronto" ridership data of 2019 and 2020 and a two-stage methodology. First, multilevel modelling is used to analyze how the factors affect monthly station-level trip generation during the pandemic compared to pre-pandemic period. Then, a geographically weighted regression analysis is performed to better understand how the relationships vary by communities and regions. The study results indicate that the demand of the service for commuting decreased, and the demand for recreational and maintenance trips increased significantly during the pandemic. In addition, higher-income neighborhoods are found to generate fewer weekday trips, whereas neighbourhoods with more immigrants experienced an increase in bike-share ridership during the pandemic. Moreover, the pandemic trip generation rates are more sensitive to the availability of bicycle facilities within station buffers than pre-pandemic rates. The results also suggest significant spatial heterogeneity in terms of the level of influence of the explanatory factors on the demand for bicycle-sharing during the pandemic. Based on the findings, some neighbourhood-specific policy recommendations are made, which inform decisions regarding the locations and capacity of new stations and the management of existing stations so that equity concerns about the usage of the system are adequately accounted for., Competing Interests: Conflict of interestOn behalf of all authors, the corresponding author states that there is no conflict of interest., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

The DEAD-box RNA helicase 41 gene, DDX41 , is frequently mutated in hereditary myeloid neoplasms, identified in 2% of entire patients with AML/MDS. The pathogenesis of DDX41 mutation is related to the defect in the gene's normal functions of RNA and innate immunity. About 80% of patients with germline DDX41 mutations have somatic mutations in another allele, resulting in the biallelic DDX41 mutation. Patients with the disease with DDX41 mutations reportedly often present with the higher-grade disease, but there are conflicting reports about its impact on survival outcomes. Recent studies using larger cohorts reported a favorable outcome with a better response to standard therapies in patients with DDX41 mutations to patients without DDX41 mutations. For stem-cell transplantation, it is important for patients with DDX41 germline mutations to identify family donors early to improve outcomes. Still, there is a gap in knowledge on whether germline DDX41 mutations and its pathology features can be targetable for treatment, and what constitutes an appropriate screening/surveillance strategy for identified carriers. This article reviews our current understanding of DDX41 mutations in myeloid neoplasms in pathologic and clinical features and their clinical implications.

Background: The prevalence of overweight (15%) and obesity (6%) in children under 5 years of age in Canada are high, and young children with overweight and obesity are at increased risk of the development of chronic disease(s) in adulthood. Prior research has demonstrated very few published trials on effective obesity prevention interventions in young children at risk of obesity, within primary healthcare settings. The aim of this study is to determine if 18-48-month-old children at risk for obesity, who are randomized to receive the Parents Together program (i.e., intervention group), have reduced body mass index z-score (zBMI), compared to those not receiving the intervention, at a 12-month follow-up. Secondary clinical outcomes between the intervention and control groups will be compared at 12 months., Methods: A pragmatic, parallel group, 1:1, superiority, randomized control trial (RCT) through the TARGetKids! Practice Based Research Network will be conducted. Young children (ages 18-48 months) who are at increased risk for childhood obesity will be invited to participate. Parents who are enrolled in the intervention group will participate in eight weekly group sessions and 4-5 coaching visits, facilitated by a trained public health nurse. Children and parents who are enrolled in the control group will receive the usual health care. The primary outcome will be compared between intervention arms using an analysis of covariance (ANCOVA). Feasibility and acceptability will be assessed by parent focus groups and interviews, and fidelity to the intervention will be measured using nurse-completed checklists. A cost-effectiveness analysis (CEA) will be conducted., Discussion: This study will aim to reflect the social, cultural, and geographic diversity of children in primary care in Toronto, Ontario, represented by an innovative collaboration among applied child health researchers, community health researchers, and primary care providers (i.e., pediatricians and family physicians in three different models of primary care). Clinical and implementation outcomes will be used to inform future research to test this intervention in a larger number, and diverse practices across diverse geographic settings in Ontario., Trial Registration: ClinicalTrials.gov NCT03219697. Registered on June 27, 2017., (© 2023. The Author(s).)

The meta-analytic approach has become the gold-standard methodology for the evaluation of surrogate endpoints and several implementations are currently available in SAS and R. The methodology is based on hierarchical models that are numerically demanding and, when the amount of data is limited, maximum likelihood algorithms may not converge or may converge to an ill-conditioned maximum such as a boundary solution. This may produce misleading conclusions and have negative implications for the evaluation of new drugs. In the present work, we explore the use of two distinct functions in R ( lme and lmer ) and the MIXED procedure in SAS to assess the validity of putative surrogate endpoints in the meta-analytic framework, via simulations and the analysis of a real case study. We describe some problems found with the lmer function in R that led to a poorer performance as compared with the lme function and MIXED procedure.

Background and Purpose: Studies have shown the potential of cone-beam computed tomography (CBCT)-guided online adaptive radiotherapy (oART) for prostate cancer patients in a simulation environment. The aim of this study was to evaluate the feasibility of the clinical implementation of CBCT-guided oART for prostate cancer patients., Materials and Methods: Between February and July 2020, eleven prostate cancer patients were treated with CBCT-guided oART using a fractionation scheme of 20 × 3 Gy to the prostate and 20 × 2.7/3.0 Gy to the seminal vesicles for more advanced stages. The on-couch adaptive workflow consisted of influencer (prostate, seminal vesicles, rectum, bladder) review, target review, scheduled (re-calculated) and adapted (re-optimized) plan generation, an independent QA procedure and treatment delivery. Treatment time, proportion of adapted fractions and reasons for plan adaptation were evaluated., Results: Mean total treatment time (±SD) from CBCT acquisition to end of treatment delivery was 17.5 ± 3.2 min (range: 10.8-28.8 min). In all 220 fractions, the PTV coverage was increased for the adapted plan compared to the scheduled plan. The V60Gy of bladder and rectum were below the constraints (<5% and <3%) for both scheduled and adapted plans in 171 out of 220 fractions and for the adapted plan only in 30 out of 220 fractions. In 19 out of 220 fractions, the V60Gy of the bladder and/or rectum was above the constraint for the adapted plan., Conclusions: The clinical implementation of CBCT-guided oART is feasible for prostate cancer patients. The adaptive workflow is possible within twenty minutes on average with a dedicated team., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Acute myeloid leukemia (AML) is historically associated with poor prognosis, especially in older AML patients unfit for intensive chemotherapy. The development of Venetoclax, a potent oral BH3 (BCL-2 homology domain 3) mimetic, has transformed the AML treatment. However, the short duration of response and development of resistance remain major concerns. Understanding mechanisms of resistance is pivotal to devising new strategies and designing rational drug combination regimens. In this review, we will provide a comprehensive summary of the known mechanisms of resistance to Venetoclax and discuss Venetoclax-based combination therapies. Key contributing factors to Venetoclax resistance include dependencies on alternative anti-apoptotic BCL-2 family proteins and selection of the activating kinase mutations. Mutational landscape governing response to Venetoclax and strategic approaches developed considering current knowledge of mechanisms of resistance will be addressed., Competing Interests: Marina Konopleva: Consultant for AbbVie, Genentech, F. Hoffman La-Roche, Stemline Therapeutics, Amgen, Forty-Seven, KisoJi, Janssen; serves as advisory board member for Stemline Therapeutics, F. Hoffman La-Roche, Janssen; holds shares from Reata Pharmaceuticals; honoraria from Forty-Seven and F. Hoffman La-Roche; research funding from AbbVie, Genentech, F. Hoffman La-Roche, Eli Lilly, Cellectis, Calithera, Stemline Therapeutics, Ablynx, Agios, Ascentage, Astra Zeneca, Rafael Pharmaceutical, Sanofi, and Forty-Seven., (© The Author(s) 2022.)

Cross-presenting dendritic cells (DC) offer an attractive target for vaccination due to their unique ability to process exogenous antigens for presentation on MHC class I molecules. Recent reports have established that these DC express unique surface receptors and play a critical role in the initiation of anti-tumor immunity, opening the way for the development of vaccination strategies specifically targeting these cells. This study investigated whether targeting cross-presenting DC by two complementary mechanisms could improve vaccine effectiveness, in both a viral setting and in a murine melanoma model. Our novel vaccine construct contained the XCL1 ligand, to target uptake to XCR1 + cross-presenting DC, and a cell penetrating peptide (CPP) with endosomal escape properties, to enhance antigen delivery into the cross-presentation pathway. Using a prime-boost regimen, we demonstrated robust expansion of antigen-specific T cells following vaccination with our CPP-linked peptide vaccine and protective immunity against HSV-1 skin infection, where vaccine epitopes were natively expressed by the virus. Additionally, our novel vaccination strategy slowed tumor outgrowth in a B16 murine melanoma model, compared to adjuvant only controls, suggesting antigen-specific anti-tumor immunity was generated following vaccination. These findings suggest that novel strategies to target the antigen cross-presentation pathway in DC may be beneficial for the generation of anti-tumor immunity.