High-fidelity initialization and control of electron and nuclear spins in a four-qubit register.

Single electron spins bound to multi-phosphorus nuclear spin registers in silicon have demonstrated fast (0.8 ns) two-qubit SWAP gates and long spin relaxation times (~30 s). In these spin registers, when the donors are ionized, the nuclear spins remain weakly coupled to their environment, allowing exceptionally long coherence times. When the electron is present, the hyperfine interaction allows coupling of the spin and charge degrees of freedom for fast qubit operation and control. Here we demonstrate the use of the hyperfine interaction to enact electric dipole spin resonance to realize high-fidelity ( F = 10 0 - 6 + 0 %) initialization of all the nuclear spins within a four-qubit nuclear spin register. By controllably initializing the nuclear spins to ⇓ ⇓ ⇓ , we achieve single-electron qubit gate fidelities of F = 99.78 ± 0.07% (Clifford gate fidelities of 99.58 ± 0.14%), above the fault-tolerant threshold for the surface code with a coherence time of T 2 * = 12 µ s .

Development of a digital twin of a tablet that mimics a real solid dosage form: Differences in the dissolution profile in conventional mini-USP II and a biorelevant colon model.

The performance of colon-targeted solid dosage forms is commonly assessed using standardised pharmacopeial dissolution apparatuses like the USP II or the miniaturised replica, the mini-USP II. However, these fail to replicate the hydrodynamics and shear stresses in the colonic environment, which is crucial for the tablet's drug release process. In this work, computer simulations are used to create a digital twin of a dissolution apparatus and to develop a method to create a digital twin of a tablet that behaves realistically. These models are used to investigate the drug release profiles and shear rates acting on a tablet at different paddle speeds in the mini-USP II and biorelevant colon models to understand how the mini-USP II can be operated to achieve more realistic (i.e., in vivo) hydrodynamic conditions. The behaviour of the tablet and the motility patterns used in the simulations are derived from experimental and in vivo data, respectively, to obtain profound insights into the tablet's disintegration/drug release processes. We recommend an "on-off" operating mode in the mini-USP II to generate shear rate peaks, which would better reflect the in vivo conditions of the human colon instead of constant paddle speed.

Estrogen-related receptor gamma regulates mitochondrial and synaptic genes and modulates vulnerability to synucleinopathy.

Many studies implicate mitochondrial dysfunction as a key contributor to cell loss in Parkinson disease (PD). Previous analyses of dopaminergic (DAergic) neurons from patients with Lewy-body pathology revealed a deficiency in nuclear-encoded genes for mitochondrial respiration, many of which are targets for the transcription factor estrogen-related receptor gamma (Esrrg/ERRγ). We demonstrate that deletion of ERRγ from DAergic neurons in adult mice was sufficient to cause a levodopa-responsive PD-like phenotype with reductions in mitochondrial gene expression and number, that partial deficiency of ERRγ hastens synuclein-mediated toxicity, and that ERRγ overexpression reduces inclusion load and delays synuclein-mediated cell loss. While ERRγ deletion did not fully recapitulate the transcriptional alterations observed in postmortem tissue, it caused reductions in genes involved in synaptic and mitochondrial function and autophagy. Altogether, these experiments suggest that ERRγ-deficient mice could provide a model for understanding the regulation of transcription in DAergic neurons and that amplifying ERRγ-mediated transcriptional programs should be considered as a strategy to promote DAergic maintenance in PD.

Engineering topological states in atom-based semiconductor quantum dots.

The realization of controllable fermionic quantum systems via quantum simulation is instrumental for exploring many of the most intriguing effects in condensed-matter physics1-3. Semiconductor quantum dots are particularly promising for quantum simulation as they can be engineered to achieve strong quantum correlations. However, although simulation of the Fermi-Hubbard model4 and Nagaoka ferromagnetism5 have been reported before, the simplest one-dimensional model of strongly correlated topological matter, the many-body Su-Schrieffer-Heeger (SSH) model6-11, has so far remained elusive-mostly owing to the challenge of precisely engineering long-range interactions between electrons to reproduce the chosen Hamiltonian. Here we show that for precision-placed atoms in silicon with strong Coulomb confinement, we can engineer a minimum of six all-epitaxial in-plane gates to tune the energy levels across a linear array of ten quantum dots to realize both the trivial and the topological phases of the many-body SSH model. The strong on-site energies (about 25 millielectronvolts) and the ability to engineer gates with subnanometre precision in a unique staggered design allow us to tune the ratio between intercell and intracell electron transport to observe clear signatures of a topological phase with two conductance peaks at quarter-filling, compared with the ten conductance peaks of the trivial phase. The demonstration of the SSH model in a fermionic system isomorphic to qubits showcases our highly controllable quantum system and its usefulness for future simulations of strongly interacting electrons.

Unrepaired Maternal Vein of Galen Malformation in Pregnancy: A Case Report.

We present a case of a pregnant patient with an unrepaired vein of Galen malformation (VGAM) and left ventricular (LV) dilation. Patients with VGAM lesions typically present during childhood with cardiac failure or developmental delay prompting embolization. Therefore, it is highly unusual for an adult to present with an unrepaired lesion.1 It poses challenges for obstetric and anesthetic management during pregnancy and delivery to reduce the risk of heart failure, arrhythmia, and intracranial hemorrhage. Our patient safely delivered a term neonate by cesarean delivery with neuraxial analgesia at a Level IV Maternal Care Center.

Estrogen-related Receptor Alpha (ERRα) is Required for PGC-1α-dependent Gene Expression in the Mouse Brain.

Deficiency in peroxisome proliferator-activated receptor gamma coactivator 1-alpha. (PGC-1α) expression or function is implicated in numerous neurological and psychiatric disorders. PGC-1α is required for the expression of genes involved in synchronous neurotransmitter release, axonal integrity, and metabolism, especially in parvalbumin-positive interneurons. As a transcriptional coactivator, PGC-1α requires transcription factors to specify cell-type-specific gene programs; while much is known about these factors in peripheral tissues, it is unclear if PGC-1α utilizes these same factors in neurons. Here, we identified putative transcription factors controlling PGC-1α-dependent gene expression in the brain using bioinformatics and then validated the role of the top candidate in a knockout mouse model. We transcriptionally profiled cells overexpressing PGC-1α and searched for over-represented binding motifs in the promoters of upregulated genes. Binding sites of the estrogen-related receptor (ERR) family of transcription factors were enriched, and blockade of ERRα attenuated PGC-1α-mediated induction of mitochondrial and synaptic genes in cell culture. Localization in the mouse brain revealed enrichment of ERRα expression in parvalbumin-expressing neurons with tight correlation of expression with PGC-1α across brain regions. In ERRα null mice, PGC-1α-dependent genes were reduced in multiple regions, including neocortex, hippocampus, and cerebellum, though not to the extent observed in PGC-1α null mice. Behavioral assessment revealed ambulatory hyperactivity in response to amphetamine and impairments in sensorimotor gating without the overt motor impairment characteristic of PGC-1α null mice. These data suggest that ERRα is required for normal levels of expression of PGC-1α-dependent genes in neurons but that additional factors may be involved in their regulation.

Ectopic Cushing's Syndrome Secondary to Metastatic Paraganglioma.

Paraneoplastic or ectopic Cushing's syndrome (CS) is a rare cause of endogenous hypercortisolism. It is due to ectopic adrenocorticotropic hormone (ACTH) secretion and has been reported in association with a variety of neuroendocrine tumors such as small-cell lung carcinoma, carcinoid tumors, and medullary carcinoma of the thyroid. Paragangliomas (PGLs) are rare neuroendocrine tumors that can secrete catecholamines. Case reports and reports of ectopic ACTH secretion from metastatic PGLs causing CS are exceedingly rare. We present a case of a 38-year-old female, who presented with typical signs, symptoms, and complications of CS, secondary to a PGL with widespread metastases, which eventually led to her demise.

The virtual physiological human gets nerves! How to account for the action of the nervous system in multiphysics simulations of human organs.

This article shows how to couple multiphysics and artificial neural networks to design computer models of human organs that autonomously adapt their behaviour to environmental stimuli. The model simulates motility in the intestine and adjusts its contraction patterns to the physical properties of the luminal content. Multiphysics reproduces the solid mechanics of the intestinal membrane and the fluid mechanics of the luminal content; the artificial neural network replicates the activity of the enteric nervous system. Previous studies recommended training the network with reinforcement learning. Here, we show that reinforcement learning alone is not enough; the input-output structure of the network should also mimic the basic circuit of the enteric nervous system. Simulations are validated against in vivo measurements of high-amplitude propagating contractions in the human intestine. When the network has the same input-output structure of the nervous system, the model performs well even when faced with conditions outside its training range. The model is trained to optimize transport, but it also keeps stress in the membrane low, which is exactly what occurs in the real intestine. Moreover, the model responds to atypical variations of its functioning with 'symptoms' that reflect those arising in diseases. If the healthy intestine model is made artificially ill by adding digital inflammation, motility patterns are disrupted in a way consistent with inflammatory pathologies such as inflammatory bowel disease.

Distributional characterizations and testing for differences of relatedness and inbreeding of a subpopulation of American Hereford bulls.

Beta distributions are characterized by two determining parameters and a parameter space from 0 to 1, and may be useful for examining population genetic parameters such as the relationship or inbreeding coefficients. Often subpopulations exist within breeds that are congregated around particular lineages of cattle or ancestors that breeders value. These subpopulations are more related to each other than to the majority of other animals; they may have higher inbreeding as well. Value may be added to these subpopulations because of their relatedness with important or renowned ancestors. The objectives of this work were to compare the relatedness and inbreeding of a group of 26 modern bulls from a subpopulation of the American Hereford breed relative to 1) 30 males with the most descendants present in the pedigree, 2) 15 renowned American Hereford bulls considered important individuals in the breed's history, and 3) 19 prominent subpopulation male ancestors. Conformance of the mean relationship coefficients of the bulls with the three groups and the mean inbreeding coefficient with all pedigree animals to beta distributions was assessed by 1) visually determining the parameters of the beta distributions based on the entire pedigree, 2) testing the mean relationship coefficient or inbreeding coefficient of the group of subpopulation bulls for its positional inclusion in those distributions, and 3) bootstrap sampling methodology. The mean relationship coefficients of the 26 Trask bulls with the 30 bulls with the most descendants, the 15 renowned ancestors, and the 19 Trask male ancestors were 0.15, 0.132, and 0.208, respectively. Testing of these means in beta distributions indicated that the group of 26 Trask bulls were no more related to the three groups of bulls than all of the animals in the pedigree (0.06 < P < 0.25). Bootstrap sampling indicated that the 26 bulls were more related to the three groups of male ancestors than the remainder of the animals in the pedigree (P < 0.0001). The mean inbreeding coefficient of the 26 bulls (0.13) did not differ from the overall inbreeding coefficient (0.056) when tested using a beta distribution; however, bootstrap sampling indicated otherwise (P < 0.0001). Results may indicate the inadequacy of visually parameterizing a beta distribution. Quantification of pedigree relatedness of a group of animals to key ancestors, especially with no DNA available, may add value to that group and individuals.

Tobacco smoking in young people seeking treatment for mental ill-health: what are their attitudes, knowledge and behaviours towards quitting?

INTRODUCTION: Tobacco smoking is a leading cause of preventable death and disease worldwide. Adults with mental ill-health smoke tobacco at substantially higher rates than other adults, with public health approaches effective in the population overall having less impact on those with mental ill-health. However, less is known about the tobacco smoking behaviours, attitudes and knowledge of young people with mental ill-health, despite this being the peak period of onset for both mental illness and cigarette smoking. METHODS: Young people attending a youth mental health centre (providing both primary and specialist care) in Melbourne, Australia were approached by youth peer researchers and asked to complete a survey about smoking behaviours, attitudes and knowledge. We examined smoking and associated attitudes in the sample overall, and as a function of the services accessed. RESULTS: In total, 114 young people completed the survey, with 56.3% reporting lifetime cigarette smoking, 42.0% smoking in the last 12 months and 28.6% in the past week. Of current regular smokers, 75.0% acknowledged they should quit in the future; however, only 23.5% planned to do so in the next month, with 44.4% confident that they could quit. Participants lacked knowledge about interactions between tobacco smoking, mental and physical health. CONCLUSIONS: Youth presenting for mental ill-health had high rates of cigarette smoking relative to population rates. Presentation at youth mental health services may represent a critical window for early intervention to reduce the lifetime impacts of cigarette smoking in mental ill-health. Interventions to support smoking cessation in this group are urgently needed.

A window into portal hemodynamics in adult fontan patients?

BACKGROUND: Fontan circulation alters portal venous hemodynamics, causing chronic passive hepatic congestion and fibrosis. This congestion increases liver stiffness (LS) leading to overestimates of liver fibrosis as measured by ultrasound shear wave elastography (SWE) of the liver. We evaluated whether Fontan circulation has a similar effect on spleen stiffness (SS) and SS/LS ratio as measured by SWE. METHODS: We retrospectively compared the SS of adult Fontan patients to age and gender matched, control patients without congenital heart disease. We correlated SS measurements to LS measurements and also performed a limited subgroup analysis of SS in Fontan patients with various manifestations of Fontan Associated Liver Disease. RESULTS: SS in Fontan patients was similar to healthy controls (1.43 vs. 1.36 m/s, p = 0.26). LS was elevated in 78% of the Fontan patients (mean 1.68 m/s, SD 0.31, 95% CI 1.53-1.85). The correlation between LS and SS was modest (Pearson's correlation coefficient, r = 0.5) but did not reach statistical significance (p = 0.06). The mean SS/LS ratio was 0.85 (95% CI 0.77-0.94). CONCLUSION: Based on our study cohort, SS in Fontan patients is similar to age and gender matched control patients without congenital heart disease. The SS/LS ratio, however, is frequently less than 1, which is lower than that reported in both healthy patients and those with other forms of non-cardiac liver disease. SS and SS/LS ratio may be a useful indicator of portal hemodynamics in Fontan patients.

Neonatal Cardiac Emergencies: A Multidisciplinary Simulation Curriculum for Neonatology and Pediatric Cardiology Fellows.

Introduction: Although care for neonates with cardiac disease is frequently provided by neonatologists and pediatric cardiologists, training in the multidisciplinary management of neonatal cardiac emergencies is not often included in fellowship training. We created a multidisciplinary simulation curriculum to address the skills needed for neonatal cardiac care. Methods: Neonatology and pediatric cardiology fellows participated in 1-hour simulations on 3 different days. They managed a neonate with: (1) cyanosis, (2) cardiogenic shock, and (3) an unstable arrhythmia. Using both remote consultation and bedside evaluation, the participants diagnosed and jointly established a management plan for the infant. During the debrief, facilitators reviewed the clinical decisions and multidisciplinary management skills of the participants. Participants completed pre- and postparticipation surveys to evaluate the curriculum's effect on their confidence in the management of neonatal cardiac disease. Results: Thirty-three paired survey responses from 20 participants (11 neonatology and 9 pediatric cardiology) reported a mean overall satisfaction score of 4.6 (SD = 0.7) based on a 5-point Likert scale. Postparticipation confidence scores improved significantly in: (1) the recognition of the signs of congenital heart disease (pre = 4.1, post = 4.5, p = .01), (2) differentiation of cardiac cyanosis from noncardiac cyanosis (pre = 3.9, post = 4.2, p = .05), and (3) confidence in discussing cardiac concerns with consultants (pre = 3.3, post = 4.1, p = .02). Discussion: This multidisciplinary simulation improved fellows' confidence in the management of neonates with cardiac disease and provided an opportunity to practice team work, remote consultation, and cross-disciplinary communication.

Valley interference and spin exchange at the atomic scale in silicon.

Tunneling is a fundamental quantum process with no classical equivalent, which can compete with Coulomb interactions to give rise to complex phenomena. Phosphorus dopants in silicon can be placed with atomic precision to address the different regimes arising from this competition. However, they exploit wavefunctions relying on crystal band symmetries, which tunneling interactions are inherently sensitive to. Here we directly image lattice-aperiodic valley interference between coupled atoms in silicon using scanning tunneling microscopy. Our atomistic analysis unveils the role of envelope anisotropy, valley interference and dopant placement on the Heisenberg spin exchange interaction. We find that the exchange can become immune to valley interference by engineering in-plane dopant placement along specific crystallographic directions. A vacuum-like behaviour is recovered, where the exchange is maximised to the overlap between the donor orbitals, and pair-to-pair variations limited to a factor of less than 10 considering the accuracy in dopant positioning. This robustness remains over a large range of distances, from the strongly Coulomb interacting regime relevant for high-fidelity quantum computation to strongly coupled donor arrays of interest for quantum simulation in silicon.

The duality between particle methods and artificial neural networks.

The algorithm behind particle methods is extremely versatile and used in a variety of applications that range from molecular dynamics to astrophysics. For continuum mechanics applications, the concept of 'particle' can be generalized to include discrete portions of solid and liquid matter. This study shows that it is possible to further extend the concept of 'particle' to include artificial neurons used in Artificial Intelligence. This produces a new class of computational methods based on 'particle-neuron duals' that combines the ability of computational particles to model physical systems and the ability of artificial neurons to learn from data. The method is validated with a multiphysics model of the intestine that autonomously learns how to coordinate its contractions to propel the luminal content forward (peristalsis). Training is achieved with Deep Reinforcement Learning. The particle-neuron duality has the advantage of extending particle methods to systems where the underlying physics is only partially known, but we have observations that allow us to empirically describe the missing features in terms of reward function. During the simulation, the model evolves autonomously adapting its response to the available observations, while remaining consistent with the known physics of the system.

Modelling and simulation of the hydrodynamics and mixing profiles in the human proximal colon using Discrete Multiphysics.

The proximal part of the colon offers opportunities to prolong the absorption window following oral administration of a drug. In this work, we used computer simulations to understand how the hydrodynamics in the proximal colon might affect the release from dosage forms designed to target the colon. For this purpose, we developed and compared three different models: a completely-filled colon, a partially-filled colon and a partially-filled colon with a gaseous phase present (gas-liquid model). The highest velocities of the liquid were found in the completely-filled model, which also shows the best mixing profile, defined by the distribution of tracking particles over time. No significant differences with regard to the mixing and velocity profiles were found between the partially-filled model and the gas-liquid model. The fastest transit time of an undissolved tablet was found in the completely-filled model. The velocities of the liquid in the gas-liquid model are slightly higher along the colon than in the partially-filled model. The filling level has an impact on the exsisting shear forces and shear rates, which are decisive factors in the development of new drugs and formulations.

A two-qubit gate between phosphorus donor electrons in silicon.

Electron spin qubits formed by atoms in silicon have large (tens of millielectronvolts) orbital energies and weak spin-orbit coupling, giving rise to isolated electron spin ground states with coherence times of seconds1,2. High-fidelity (more than 99.9 per cent) coherent control of such qubits has been demonstrated3, promising an attractive platform for quantum computing. However, inter-qubit coupling-which is essential for realizing large-scale circuits in atom-based qubits-has not yet been achieved. Exchange interactions between electron spins4,5 promise fast (gigahertz) gate operations with two-qubit gates, as recently demonstrated in gate-defined silicon quantum dots6-10. However, creating a tunable exchange interaction between two electrons bound to phosphorus atom qubits has not been possible until now. This is because it is difficult to determine the atomic distance required to turn the exchange interaction on and off while aligning the atomic circuitry for high-fidelity, independent spin readout. Here we report a fast (about 800 picoseconds) [Formula: see text] two-qubit exchange gate between phosphorus donor electron spin qubits in silicon using independent single-shot spin readout with a readout fidelity of about 94 per cent on a complete set of basis states. By engineering qubit placement on the atomic scale, we provide a route to the realization and efficient characterization of multi-qubit quantum circuits based on donor qubits in silicon.

Subjective morbidity following radial free flap reconstruction in head and neck tumour patients.

OBJECTIVE: Evaluation of post-operative donor site disability remains unaddressed in radial forearm free flap cases. This study aimed to assess donor site dysfunction following radial forearm free flap harvest using validated general, disease-specific and site-specific disability questionnaires. METHODS: In this retrospective case series of 24 patients at a tertiary academic medical centre, patients were assessed using the Short Form 36 Health Survey, Short Musculoskeletal Function Assessment questionnaire, and Disabilities of the Arm, Shoulder and Hand questionnaire. One-sample z-tests were performed, comparing means of the cohort to controls. RESULTS: Compared to population controls, the cohort had higher mean scores for the Disabilities of the Arm, Shoulder and Hand questionnaire (18.22 vs 10.1, p < 0.01), and Short Musculoskeletal Function Assessment questionnaire bothersome index (21.44 vs 13.77, p = 0.04), and a lower mean score for the Short Form 36 Health Survey physical component (38.88 vs 50, p < 0.01), indicating a greater disability for the cohort compared to controls. CONCLUSION: Radial forearm free flap harvest causes significant long-term donor site disability in head and neck tumour patients. The Disabilities of the Arm, Shoulder and Hand questionnaire is a concise tool for measuring this dysfunction.