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Abstract We perform readout of a quantum-dot hybrid qubit coupled to a superconducting resonator through a parametric, longitudinal interaction mechanism. Our experiments are performed with the qubit and resonator frequencies detuned by ~10 GHz, demonstrating that longitudinal coupling can facilitate semiconductor qubit operation in the ‘ultra-dispersive’ regime of circuit quantum electrodynamics.

Adolescent idiopathic scoliosis (AIS) is an abnormal coronal curvature of the spine that most commonly presents in adolescence. While it may be asymptomatic, AIS can cause pain, cosmetic deformity, and physical and psychological disability with curve progression. As adolescents with AIS enter adulthood, condition outcomes vary with some experiencing curve stabilization and others noting further curve progression, chronic pain, osteoporosis/fractures, declines in pulmonary and functional capacity, among others. Regular monitoring and individualized management by healthcare professionals are crucial to address the diverse challenges and provide appropriate support for a fulfilling adult life with AIS. This review examines the prevalence, risk factors, presenting symptoms, diagnosis, management, and complications of AIS in the adult population, informing targeted interventions by clinicians caring for adult patients with AIS.

Resiliency is a psychological construct that describes an individual's ability to recover from adversity and stress. Resiliency has been studied in the health care setting. In the past decade multiple studies have investigated the relationship between resiliency and patient-reported outcomes following orthopaedic surgery. The aim of this article is to review the most frequently used resiliency measures in orthopaedic surgery research and their implementation in outcome studies. The most commonly utilized resiliency measures in orthopaedic surgery are the Brief Resilience Score (BRS), Connor-Davidson Resilience Scale (CD-RISC), and the Resilience Scale (RS). These resiliency measures are each designed for use with adults and considered to be high quality, reliable, accurate, and consistent measurements of resilience.

Abstract Geothermal springs house unicellular red algae in the class Cyanidiophyceae that dominate the microbial biomass at these sites. Little is known about host-virus interactions in these environments. We analyzed the virus community associated with red algal mats in three neighboring habitats (creek, endolithic, soil) at Lemonade Creek, Yellowstone National Park (YNP), USA. We find that despite proximity, each habitat houses a unique collection of viruses, with the giant viruses, Megaviricetes, dominant in all three. The early branching phylogenetic position of genes encoded on metagenome assembled virus genomes (vMAGs) suggests that the YNP lineages are of ancient origin and not due to multiple invasions from mesophilic habitats. The existence of genomic footprints of adaptation to thermophily in the vMAGs is consistent with this idea. The Cyanidiophyceae at geothermal sites originated ca. 1.5 Bya and are therefore relevant to understanding biotic interactions on the early Earth.

Purpose: To objectively assess the accuracy of socket measurements taken during cruciate ligament reconstruction using a retrograde reaming technique. Methods: Six complete knee sawbone specimens were used to ream anterior and posterior cruciate ligament sockets in the femur and tibia in a retrograde fashion using a standard retrograde reaming device. The longest and shortest sides of the sockets were measured using a ruler. One-sided Wilcoxon signed-rank sum tests were used to evaluate whether the actual measured socket length matched the estimated length set on the drill guide. Results: One fellowship-trained surgeon reamed 24 total sockets in sawbone specimens using guides. Statistical analysis revealed a significant difference between the estimated measurement and the actual shortest tunnel length in each of the sockets. The median short side socket lengths were shorter than their respective intended depths by 4 mm for the femoral anterior cruciate ligament socket, 6 mm for the femoral posterior cruciate ligament socket, 6 mm for the tibial anterior cruciate ligament socket, and 4.5 mm for the tibial posterior cruciate ligament socket. All differences were significant at α = 0.05. Conclusions: The estimated cruciate socket lengths reamed during ligament reconstruction using a retrograde reamer and standard intra-articular measuring instrumentation were greater than the actual measured socket lengths. Clinical Relevance: Successful cruciate ligament reconstruction relies on accurate socket measurements. This study examined the accuracy of commercially available cruciate ligament socket drill guides and the implications for clinical practice, to include graft-tunnel mismatch and surface area available for healing. Surgeons may consider reaming slightly longer than estimated sockets when performing all-inside cruciate ligament reconstructions to ensure appropriate socket depth for graft fixation.

Arthroscopic shoulder procedures are one of the most common procedures used to restore function through minimally invasive techniques. With the demand for shoulder arthroscopic procedures comes the need for safe, effective, and efficient surgery that maximizes patient outcomes while minimizing complications. Many variables contribute to visualization in shoulder arthroscopy including vascular anatomy, blood pressure control, arthroscopic pump systems, turbulence control, epinephrine, and tranexamic acid. Furthermore, patient positioning can have a dramatic effect on visualization with both the beach chair position and lateral decubitus positioning having various strengths and weaknesses depending on the intended procedure being performed. The purpose of this review is to examine the benefits and complications reported in the literature for improving visualization in shoulder arthroscopy.

Purpose: To compare clinical failure, recurrent instability, patient-reported outcome measures (PROMs), and return to sport (RTS) between knotted and knotless fixation methods in arthroscopic posterior labral repair for isolated posterior shoulder instability (PSI). Methods: Multiple databases were queried according to Preferred Reported Items for Systematic Reviews and Meta-Analyses guidelines for clinical studies with Level I to IV evidence, including knotted and knotless suture anchors for arthroscopic posterior labral repair. Combined anterior and posterior instability, multidirectional instability, SLAP injuries, unspecified repair techniques, majority open procedures, and revision surgery were excluded. Results: Screening yielded 17 full-text articles reporting on 852 shoulders undergoing posterior labral repair. Recurrent instability ranged from 0% to 21%, and the rate of revision surgery ranged from 0% to 11% in knotted only, 0% in knotless only, and 2.0% to 8.1% in knotted and knotless studies. Six studies with both pre- and postoperative visual analog scale scores and 7 studies with both pre- and postoperative American Shoulder and Elbow Score scores all showed improvement in scores after intervention regardless of repair technique. Thirteen studies reported RTS or duty rates with a minimum of 79%. Conclusions: Overall recurrent instability after posterior labral repair for isolated PSI was low with improvement in PROMs and favorable RTS rates regardless of fixation method. There was no clear difference in recurrent instability or revision surgery between knotted and knotless fixation methods for isolated posterior labral repair. However, the current literature is predominantly limited by Level III and IV evidence. The quality of literature and lack of standardization on the definition of clinical failure and recurrent instability among surgeons preclude any definitive conclusion regarding one clinically superior fixation method. Level of Evidence: Level IV, systematic review of Level III and IV studies.

Introduction Simulation-based training (SBT) has gained significant traction within emergency medicine. The growing body of evidence describes the benefits that SBT can bring. However, identifying barriers and enablers when establishing successful SBT programmes in busy emergency departments (EDs), and ensuring longevity of such programmes, can be difficult.Objective We aim to identify barriers and enablers to SBT in busy EDs.Methods We explored and analysed the thoughts, experience and opinions of professionals involved in SBT and organisational support. 32 participants across 15 international sites were invited to a semistructured interview process. We included participants from a variety of backgrounds, from clinical staff to management staff. Transcribed interview data was classified and coded based on capability, opportunity and motivation behaviour (COM-B) domains and analysed based on theoretical domains framework. Frequency of the most mentioned thematic domain among participants is reported.Results The interview data revealed several common themes, including the following: knowledge and skills (90%), support and leadership (96%), mental barriers (87.5%), local culture (96.6%), dedicated space (65.2%), time constraints (46.8%), social influence (87.5%), education (90.6%), professional development (68.75%), exams (59.3%) and personal goals (93.75%). Management staff was observed to prioritise resource, staffing and flow, while the clinical cohort tended to focus on specialty and personal development when it came to simulation training in the ED.Conclusion Potential barriers and enablers to SBT and in situ simulation for EDs were identified through interviews conducted in this study. The central themes in terms of barriers and enablers were local culture, leadership, individual needs, resources and optimisation. A tailored approach is vital for establishing a successful SBT and in situ simulation programme.

High-energy particle impacts due to background or cosmic radiation have been identified as sources of correlated errors in superconducting qubit arrays. Iaia et al. achieve a suppression of correlated error rate by channeling the energy away from the qubits via a thick metal layer at the bottom of the chip.

Complete rupture of the distal biceps tendon is routinely treated with direct repair; however, chronic, mid-substance, or musculotendinous tears are challenging clinical scenarios for surgeons. Although attempts at direct repair should be considered, in cases of severe retraction or tendon deficiency, a reconstruction may be warranted. Herein the authors describe a technique for distal biceps reconstruction using allograft with a Pulvertaft weave via a standard anterior incision, similar to primary repair, with a small catchment incision more proximally for tendon retrieval. Use of this technique with dual unicortical buttons allows for early range of motion, restoration of the distal footprint, and improved biomechanical construct strength, which has proven invaluable in a population of elite and highly active military servicemembers.

Experiments on ASDEX Upgrade (AUG) in 2021 and 2022 have addressed a number of critical issues for ITER and EU DEMO. A major objective of the AUG programme is to shed light on the underlying physics of confinement, stability, and plasma exhaust in order to allow reliable extrapolation of results obtained on present day machines to these reactor-grade devices. Concerning pedestal physics, the mitigation of edge localised modes (ELMs) using resonant magnetic perturbations (RMPs) was found to be consistent with a reduction of the linear peeling-ballooning stability threshold due to the helical deformation of the plasma. Conversely, ELM suppression by RMPs is ascribed to an increased pedestal transport that keeps the plasma away from this boundary. Candidates for this increased transport are locally enhanced turbulence and a locked magnetic island in the pedestal. The enhanced D-alpha (EDA) and quasi-continuous exhaust (QCE) regimes have been established as promising ELM-free scenarios. Here, the pressure gradient at the foot of the H-mode pedestal is reduced by a quasi-coherent mode, consistent with violation of the high-n ballooning mode stability limit there. This is suggestive that the EDA and QCE regimes have a common underlying physics origin. In the area of transport physics, full radius models for both L- and H-modes have been developed. These models predict energy confinement in AUG better than the commonly used global scaling laws, representing a large step towards the goal of predictive capability. A new momentum transport analysis framework has been developed that provides access to the intrinsic torque in the plasma core. In the field of exhaust, the X-Point Radiator (XPR), a cold and dense plasma region on closed flux surfaces close to the X-point, was described by an analytical model that provides an understanding of its formation as well as its stability, i.e., the conditions under which it transitions into a deleterious MARFE with the potential to result in a disruptive termination. With the XPR close to the divertor target, a new detached divertor concept, the compact radiative divertor, was developed. Here, the exhaust power is radiated before reaching the target, allowing close proximity of the X-point to the target. No limitations by the shallow field line angle due to the large flux expansion were observed, and sufficient compression of neutral density was demonstrated. With respect to the pumping of non-recycling impurities, the divertor enrichment was found to mainly depend on the ionisation energy of the impurity under consideration. In the area of MHD physics, analysis of the hot plasma core motion in sawtooth crashes showed good agreement with nonlinear 2-fluid simulations. This indicates that the fast reconnection observed in these events is adequately described including the pressure gradient and the electron inertia in the parallel Ohm’s law. Concerning disruption physics, a shattered pellet injection system was installed in collaboration with the ITER International Organisation. Thanks to the ability to vary the shard size distribution independently of the injection velocity, as well as its impurity admixture, it was possible to tailor the current quench rate, which is an important requirement for future large devices such as ITER. Progress was also made modelling the force reduction of VDEs induced by massive gas injection on AUG. The H-mode density limit was characterised in terms of safe operational space with a newly developed active feedback control method that allowed the stability boundary to be probed several times within a single discharge without inducing a disruptive termination. Regarding integrated operation scenarios, the role of density peaking in the confinement of the ITER baseline scenario (high plasma current) was clarified. The usual energy confinement scaling ITER98( p,y ) does not capture this effect, but the more recent H20 scaling does, highlighting again the importance of developing adequate physics based models. Advanced tokamak scenarios, aiming at large non-inductive current fraction due to non-standard profiles of the safety factor in combination with high normalised plasma pressure were studied with a focus on their access conditions. A method to guide the approach of the targeted safety factor profiles was developed, and the conditions for achieving good confinement were clarified. Based on this, two types of advanced scenarios (‘hybrid’ and ‘elevated’ q -profile) were established on AUG and characterised concerning their plasma performance.

Within the 9th European Framework programme, since 2021 EUROfusion is operating five tokamaks under the auspices of a single Task Force called ‘Tokamak Exploitation’. The goal is to benefit from the complementary capabilities of each machine in a coordinated way and help in developing a scientific output scalable to future largre machines. The programme of this Task Force ensures that ASDEX Upgrade, MAST-U, TCV, WEST and JET (since 2022) work together to achieve the objectives of Missions 1 and 2 of the EUROfusion Roadmap: i) demonstrate plasma scenarios that increase the success margin of ITER and satisfy the requirements of DEMO and, ii) demonstrate an integrated approach that can handle the large power leaving ITER and DEMO plasmas. The Tokamak Exploitation task force has therefore organized experiments on these two missions with the goal to strengthen the physics and operational basis for the ITER baseline scenario and for exploiting the recent plasma exhaust enhancements in all four devices (PEX: Plasma EXhaust) for exploring the solution for handling heat and particle exhaust in ITER and develop the conceptual solutions for DEMO. The ITER Baseline scenario has been developed in a similar way in ASDEX Upgrade, TCV and JET. Key risks for ITER such as disruptions and run-aways have been also investigated in TCV, ASDEX Upgrade and JET. Experiments have explored successfully different divertor configurations (standard, super-X, snowflakes) in MAST-U and TCV and studied tungsten melting in WEST and ASDEX Upgrade. The input from the smaller devices to JET has also been proven successful to set-up novel control schemes on disruption avoidance and detachment.

In 2021 JET exploited its unique capabilities to operate with T and D–T fuel with an ITER-like Be/W wall (JET-ILW). This second major JET D–T campaign (DTE2), after DTE1 in 1997, represented the culmination of a series of JET enhancements—new fusion diagnostics, new T injection capabilities, refurbishment of the T plant, increased auxiliary heating, in-vessel calibration of 14 MeV neutron yield monitors—as well as significant advances in plasma theory and modelling in the fusion community. DTE2 was complemented by a sequence of isotope physics campaigns encompassing operation in pure tritium at high T-NBI power. Carefully conducted for safe operation with tritium, the new T and D–T experiments used 1 kg of T (vs 100 g in DTE1), yielding the most fusion reactor relevant D–T plasmas to date and expanding our understanding of isotopes and D–T mixture physics. Furthermore, since the JET T and DTE2 campaigns occurred almost 25 years after the last major D–T tokamak experiment, it was also a strategic goal of the European fusion programme to refresh operational experience of a nuclear tokamak to prepare staff for ITER operation. The key physics results of the JET T and DTE2 experiments, carried out within the EUROfusion JET1 work package, are reported in this paper. Progress in the technological exploitation of JET D–T operations, development and validation of nuclear codes, neutronic tools and techniques for ITER operations carried out by EUROfusion (started within the Horizon 2020 Framework Programme and continuing under the Horizon Europe FP) are reported in (Litaudon et al Nucl. Fusion accepted), while JET experience on T and D–T operations is presented in (King et al Nucl. Fusion submitted).

Building on prior analysis of ASDEX Upgrade (AUG) experiments (Henderson et al 2023 Nucl. Fusion 63 086024), this study compares simple analytical formula predictions for divertor detachment onset and reattachment timescales in JET experiments. Detachment onset primarily scales with divertor neutral pressure, impurity concentration, power directed to the targets, machine size, and integral perpendicular power decay length. JET experiments, focusing on seeding mixtures of Ne and Ar, align with the detachment onset predictions. Radiation efficiencies among the impurities show good agreement with the model predictions, contrasting with AUG observations which suggested higher efficiency for Ar and lower efficiency for Ne. The time taken to re-ionise the neutral volume in front of the outer target in fully detached divertor conditions was measured following both abrupt increases in injected neutral beam power and, separately, cutting of the impurity gas flow. Re-ionisation of the neutrals occurs within approximately 1 s on JET, which aligns with the simple model prediction derived from AUG data. While the AUG results are not new, their comparison with the JET results enhances understanding, reinforcing confidence in using simple models to predict future reactor scenarios.

Abstract Background Population parameters such as reproductive success are critical for sustainably managing ungulate populations, however obtaining these data is often difficult, expensive, and invasive. Movement-based methods that leverage Global Positioning System (GPS) relocation data to identify parturition offer an alternative to more invasive techniques such as vaginal implant transmitters, but thus far have only been applied to relocation data with a relatively fine (one fix every

Plain language summary Surgery to correct defects in the heart that are present at birth sometimes requires the use of artificial blood vessels called vascular grafts. Tissue-engineered vascular grafts (TEVGs) are scaffolds seeded with cells that can develop into functional blood vessels over time. We conducted a series of laboratory and computer-based experiments to investigate how TEVGs develop into functional blood vessels, and demonstrated two phases of changes to the TEVG after implantation: an early phase driven by inflammation, and a later phase driven by the mechanical properties of the tissue. At later time points, the resulting blood vessels demonstrated the ability to grow and respond to blood flow in similar ways to the body’s own blood vessels. These results provide insight into the processes by which TEVGs become functional blood vessels, with implications for future clinical use of this technology.

Abstract One major challenge to scaling quantum dot qubits is the dense wiring requirements, making it difficult to envision fabricating large 2D arrays of nearest-neighbor-coupled qubits necessary for error correction. We describe a method to ameliorate this issue by spacing out the qubits using superconducting resonators facilitated by 3D integration. To prove the viability of this approach, we use integration to couple an off-chip high-impedance TiN resonator to a double quantum dot in a Si/SiGe heterostructure. Using the resonator as a dispersive gate sensor, we tune the device down to the single electron regime with an SNR = 5.36. Characterizing the individual systems shows 3D integration can be done while maintaining low-charge noise for the quantum dots and high-quality factors for the superconducting resonator (single photon Q L = 2.14 × 104 with Q i ≈ 3 × 105), necessary for readout and high-fidelity two-qubit gates.

Organization of extracellular matrix (ECM) components, including collagens, proteoglycans, and elastin, is essential for maintaining the structure and function of heart valves throughout life. Mutations in ECM genes cause connective tissue disorders, including Osteogenesis Imperfecta (OI), and progressive debilitating heart valve dysfunction is common in these patients. Despite this, effective treatment options are limited to end-stage interventions. Mice with a homozygous frameshift mutation in col1a2 serve as a murine model of OI (oim/oim), and therefore, they were used in this study to examine the pathobiology of aortic valve (AoV) disease in this patient population at structural, functional, and molecular levels. Temporal echocardiography of oim/oim mice revealed AoV dysfunction by the late stages of disease in 12-month-old mice. However, structural and proteomic changes were apparent much earlier, at 3 months of age, and were associated with disturbances in ECM homeostasis primarily related to collagen and proteoglycan abnormalities and disorganization. Together, findings from this study provide insights into the underpinnings of late onset AoV dysfunction in connective tissue disease patients that can be used for the development of mechanistic-based therapies administered early to halt progression, thereby avoiding late-stage surgical intervention.

Single flux quantum (SFQ) digital logic has been proposed for the scalable control of next-generation superconducting-qubit arrays. In the initial implementation, SFQ-based gate fidelity was limited by quasiparticle (QP) poisoning induced by the dissipative on-chip SFQ driver circuit. In this work, we introduce a multichip-module architecture to suppress phonon-mediated QP poisoning. Here, the SFQ elements and qubits are fabricated on separate chips that are joined with In-bump bonds. We use interleaved randomized benchmarking to characterize the fidelity of SFQ-based gates and we demonstrate an error per Clifford gate of 1.2(1)%, an order-of-magnitude reduction over the gate error achieved in the initial realization of SFQ-based qubit control. We use purity benchmarking to quantify the contribution of incoherent error at 0.96(2)%; we attribute this error to photon-mediated QP poisoning mediated by the resonant millimeter-wave antenna modes of the qubit and SFQ-qubit coupler. We anticipate that a straightforward redesign of the SFQ driver circuit to limit the bandwidth of the SFQ pulses will eliminate this source of infidelity, allowing SFQ-based gates with error approaching approximate known theoretical limits, of order 0.1% for resonant sequences and 0.01% for more complex pulse sequences involving variable pulse-to-pulse separation.

Abstract Background Many women with hyperglycaemia in pregnancy do not receive care during and after pregnancy according to standards recommended in international guidelines. The burden of hyperglycaemia in pregnancy falls disproportionately upon Indigenous peoples worldwide, including Aboriginal and Torres Strait Islander women in Australia. The remote and regional Australian context poses additional barriers to delivering healthcare, including high staff turnover and a socially disadvantaged population with a high prevalence of diabetes. Methods A complex health systems intervention to improve care for women during and after a pregnancy complicated by hyperglycaemia will be implemented in remote and regional Australia (the Northern Territory and Far North Queensland). The Theoretical Domains Framework was used during formative work with stakeholders to identify intervention components: (1) increasing workforce capacity, skills and knowledge and improving health literacy of health professionals and women; (2) improving access to healthcare through culturally and clinically appropriate pathways; (3) improving information management and communication; (4) enhancing policies and guidelines; (5) embedding use of a clinical register as a quality improvement tool. The intervention will be evaluated utilising the RE-AIM framework at two timepoints: firstly, a qualitative interim evaluation involving interviews with stakeholders (health professionals, champions and project implementers); and subsequently a mixed-methods final evaluation of outcomes and processes: interviews with stakeholders; survey of health professionals; an audit of electronic health records and clinical register; and a review of operational documents. Outcome measures include changes between pre- and post-intervention in: proportion of high risk women receiving recommended glucose screening in early pregnancy; diabetes-related birth outcomes; proportion of women receiving recommended postpartum care including glucose testing; health practitioner confidence in providing care, knowledge and use of relevant guidelines and referral pathways, and perception of care coordination and communication systems; changes to health systems including referral pathways and clinical guidelines. Discussion This study will provide insights into the impact of health systems changes in improving care for women with hyperglycaemia during and after pregnancy in a challenging setting. It will also provide detailed information on process measures in the implementation of such health system changes.

ABSTRACT Butorphanol–Azaperone–Medetomidine (BAM) is a relatively new drug mixture compounded for the past decade to immobilize mammals, particularly ungulates. Despite its increased use in recent years, scant research has quantified the physiologic responses of immobilized animals or assessed its relative efficacy using different trapping methods. We tested the safety and efficacy of BAM for use in the immobilization of 198 free‐ranging white‐tailed deer (Odocoileus virginianus) captured using drop‐nets, Clover traps, and gun‐propelled darts from 1 January 2014 to 28 July 2016 in Kentucky and Indiana, USA. Use of BAM produced a safe and satisfactory plane of immobilization that rarely required treatment of side effects. First signs of induction were observed on average at 4.4 ± 0.2 (standard error) minutes post–intramuscular administration, and deer reached lateral recumbency at 8.6 ± 0.4 minutes. Times to first signs of induction and the induction period were longer for adults than for juveniles, while times to the first sign of reversal, lifting head, and standing were longer for juveniles than adults. Although physiologic responses of deer during induction were within published norms, respiration rates, body temperature, heart rates, and oxygen saturation typically declined throughout the immobilization period. Our BAM dose did not affect time to recovery or heart rate. Regardless of trapping method, on average, heart rate was 61.2 ± 0.7 beats/minute, respiratory rate was 29.1 ± 0.5 breaths/minute, temperature was 38.93° ± 0.04° C, and oxygen saturation was 85.0% ± 0.3%. Deer showed first signs of reversal at 4.3 ± 0.3 minutes after administration of the reversal agent intramuscularly or half‐intramuscularly and half‐intravenously and were fully recovered after 6.3 ± 0.4 minutes. In summary, we found that BAM was an efficacious and safe drug to use on white‐tailed deer captured by a variety of trapping methods. © 2020 The Wildlife Society.

OBJECTIVES/GOALS: Our long-term goal is to understand how both genetic and environmental (GxE) factors contribute to neurodevelopmental disorders (NDDs) so that we may potentially intervene in disease pathogenesis and design therapies to address functional deficiencies. METHODS/STUDY POPULATION: Our studies use a novel GxE model to determine how cephalosporin antibiotic exposure alters the gut microbiome, hippocampal neurogenesis, and behavior in the genetically vulnerable 16p11.2 microdeletion (16pDel) mouse. This mouse models one of the most frequently observed genetic risk variants implicated in NDDs, including ~1% of autism diagnoses. Wildtype and 16pDel littermates were exposed to saline or the cephalosporin, cefdinir, from postnatal days 5-9. We quantified changes in gut microbiota composition using 16S rRNA gene sequencing and utilized immunoblotting, immunohistochemistry, and bulk RNA gene sequencing to assess changes in hippocampal neurogenesis. An additional cohort of saline or cefdinir-exposed mice were subjected to a behavioral battery to assess changes in sociability and anxiety. RESULTS/ANTICIPATED RESULTS: We leveraged the next-generation microbiome bioinformatics platform, Quantitative Insights Into Microbial Ecology 2 (QIIME2) to analyze 16S rRNA gene sequencing datasets of P13 cecal samples from saline- and cefdinir-exposed mice. We found successful perturbations to the gut microbiome following early life cefdinir exposure. Further, we found a robust 50% reduction in hippocampal cyclin E protein in cefdinir-exposed 16pDel male mice, which was replicated in a second independent experiment. This reduction extended to the S-phase cell entry and general stem cell population, quantified by EdU+ and Ki67+ cell numbers, respectively. Lastly, in our first cohort of mice for behavioral studies, we found reduced sociability and increased anxiety-like behaviors in cefdinir-exposed mice. DISCUSSION/SIGNIFICANCE: The findings from this GxE model will provide mechanistic insights into the causes of NDDs; they may inform practice guidelines so as to reduce this environmental exposure; and may suggest interventions like probiotics for those at risk in order to overcome altered gut microbiome composition and restore hippocampal neurogenesis defects.

Using newly developed spectroscopic models to measure the divertor concentration of Ne and Ar, it is shown that the experimental detachment threshold on ASDEX Upgrade with Ar-only and mixtures of Ar+N or Ne+N scales as expected in comparison with an analytical equation derived by Kallenbach et al (2016 Plasma Phys. Control. Fusion 58 045013). However, it is found that Ar radiates more efficiently and Ne less efficiently in the scrape-off layer than the model predicts. By separately increasing the neutral beam injection power and cutting the impurity gas flow, it is shown that the partially detached and strongly detached X-point radiator scenarios reattach in ≈100 ms and ≈250 ms, respectively. The former timescale is set by the core energy confinement time, whereas the latter has an additional delay caused by the time required for the ionisation front to move from the X-point to the target. A simple equation with scalable geometric terms to predict the ionisation front movement time in future machines is proposed.

Background: The optimal timing of anterior cruciate ligament (ACL) reconstruction (ACLR) remains a controversial topic. Previous reviews have demonstrated that there are no differences between early and delayed ACLR; however, these studies have been limited by heterogeneous definitions of acute ACL injury. Purpose: To evaluate postoperative patient functional outcomes and risk for arthrofibrosis after acute arthroscopic ACLR performed ≤10 days after injury. Study Design: Systematic review; Level of evidence, 4. Methods: A systematic review was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines using multiple medical databases. Inclusion criteria were studies that evaluated postoperative range of motion outcomes for patients undergoing ACLR ≤10 days after initial ACL injury. For included comparative studies comparing patient groups undergoing ACLR ≤10 days and patients undergoing "delayed" ACLR after ≥3 weeks of initial injury, quantitative analysis was performed to assess for differences in postoperative arthrofibrosis, reoperation rates, and patient-reported outcomes between groups. DerSimonian-Laird binary random-effects models were constructed to quantitatively describe the association between the ACLR time period and patient outcomes by generating effect estimates in the form of odds ratios with 95% CIs. Qualitative analysis was performed to describe variably reported patient outcomes and the risk of arthrofibrosis after ACLR for noncomparative studies. Results: Screening yielded 6 full-text articles with 448 patients who underwent ACLR (296 ACLR <10 days, 152 ACLR >3 weeks), with a pooled mean age of 28.1 years. For studies amenable to quantitative analysis, there were no significant differences between ACLR performed ≤10 days and ACLR performed at the 3-week point or after in terms of postoperative stiffness (3 studies; odds ratio, 1.27; P =.508), Tegner scores (2 studies; mean difference, –0.056; P =.155), or reoperation for stiffness (3 studies; odds ratio, 0.869; P =.462). The overall incidence of postoperative arthrofibrosis after 12 months of follow-up was 11 of 296 (3.7%) for ACLRs performed ≤10 days versus 6 of 152 (3.9%) for those performed at the 3-week point or after. Conclusion: ACLR performed ≤10 days after the inciting injury does not increase the risk of postoperative arthrofibrosis and demonstrates similar patient-reported outcomes compared with ACLR performed at the 3-week point or after. [ABSTRACT FROM AUTHOR]

The microbial ars operon encodes the primary bacterial defense response to the environmental toxicant, arsenic. An important component of this operon is the arsR gene, which encodes ArsR, a member of the family of proteins categorized as DNA-binding transcriptional repressors. As currently documented, ArsR regulates its own expression as well as other genes in the same ars operon. This study examined the roles of four ArsR proteins in the well-developed model Gram-negative bacterium Agrobacterium tumefaciens 5A. RNASeq was used to compare and characterize gene expression profiles in ± arsenite-treated cells of the wild-type strain and in four different arsR mutants. We report that ArsR-controlled transcription regulation is truly global, extending well beyond the current ars operon model, and includes both repression as well as apparent activation effects. Many cellular functions are significantly influenced, including arsenic resistance, phosphate acquisition/metabolism, sugar transport, chemotaxis, copper tolerance, iron homeostasis, and many others. While there is evidence of some regulatory overlap, each ArsR exhibits its own regulatory profile. Furthermore, evidence of a regulatory hierarchy was observed; i.e. ArsR1 represses arsR4, ArsR4 activates arsR2, and ArsR2 represses arsR3. Additionally and unexpectedly, aioB (arsenite oxidase small subunit) expression was shown to be under partial positive control by ArsR2 and ArsR4. Summarizing, this study demonstrates the regulatory portfolio of arsenite-activated ArsR proteins and includes essentially all major cellular functions. The broad bandwidth of arsenic effects on microbial metabolism assists in explaining and understanding the full impact of arsenic in natural ecosystems, including the mammalian gut.

Transmon qubits fabricated with tantalum metal have been shown to possess energy relaxation times greater than 400μs and, as such, present an attractive platform for high precision, correlated noise studies across multiple higher-energy transitions. Tracking the multilevel fluctuating qudit frequencies with a precision enabled by the high coherence of the device allows us to extract the charge offset and quasiparticle dynamics. We observe qualitatively different charge-offset behavior in the tantalum device than those measured in previous low-frequency charge-noise studies. In particular, we find the charge-offset dynamics are dominated by rare, discrete jumps between a finite number of quasistationary charge configurations, a previously unobserved charge-noise process in superconducting qubits.

It is unclear whether the gut microbiome can mitigate or exacerbate arsenic toxicity. Here, Coryell et al. show that the human gut microbiome protects mice from arsenic-induced mortality, with protection levels correlating with the relative abundance of the human commensal Faecalibacterium.

Future fusion reactors require a safe, steady state divertor operation. A possible solution for the power exhaust challenge is the detached divertor operation in scenarios with high radiated power fractions. The radiation can be increased by seeding impurities, such as N for dominant scrape-off-layer radiation, Ne or Ar for SOL and pedestal radiation and Kr for dominant core radiation.Recent experiments on two of the all-metal tokamaks, ASDEX Upgrade (AUG) and JET, demonstrate operation with high radiated power fractions and a fully-detached divertor by N, Ne or Kr seeding with a conventional divertor in a vertical target geometry. For both devices similar observations can be made. In the scenarios with the highest radiated power fraction, the dominant radiation originates from the confined region, in the case of N and Ne seeding concentrated in a region close to the X-point.Applying these seed impurities for highly radiative scenarios impacts local plasma parameters and alters the impurity transport in the pedestal region. Thus, plasma confinement and stability can be affected. A proper understanding of the effects by these impurities is required in order to predict the applicability of such scenarios for future devices.

Probenecid has been used for decades in the treatment of gout but recently has also been found to improve outcomes in patients with heart failure via stimulation of the transient receptor potential vanilloid 2 (TRPV2) channel in cardiomyocytes. This study tested the use of probenecid on a novel mouse model of peripartum cardiomyopathy (PPCM) as a potential treatment option. A human mutation of the human heat shock protein 20 (Hsp20-S10F) in mice has been recently shown to result in cardiomyopathy, when exposed to pregnancies. Treatment with either probenecid or control sucrose water was initiated after the first pregnancy in both wild type and Hsp20-S10F mice. Serial echocardiography was performed during subsequent pregnancies and hearts were collected after the third pregnancies for staining and molecular analysis. Hsp20-S10F mice treated with probenecid had decreased mortality, hypertrophy, TRPV2 expression and molecular parameters of heart failure. Probenecid treatment also decreased apoptosis as evidenced by an increase in the level of Bcl-2/Bax. Probenecid improved survival in a novel mouse model of PPCM and may be an appropriate therapy for humans with PPCM as it has a proven safety and tolerability in patients with heart failure.

B cells are salient features of pancreatic ductal adenocarcinoma (PDAC) tumors, yet their role in this disease remains controversial. Murine studies have indicated a protumoral role for B cells, whereas clinical data show tumor-infiltrating B cells are a positive prognostic factor, both in PDAC and other cancers. This disparity needs to be clarified in order to develop effective immunotherapies. In this study, we provide new evidence that reconcile human and mouse data and highlight the importance of using relevant preclinical tumor models when assessing B cell function. We compared B cell infiltration and activation in both a genetic model of murine PDAC (KPC mouse) and an injectable orthotopic model. A pronounced B cell infiltrate was only observed in KPC tumors and correlated with T cell infiltration, mirroring human disease. In contrast, orthotopic tumors exhibited a relative paucity of B cells. Accordingly, KPC-derived B cells displayed markers of B cell activation (germinal center entry, B cell memory, and plasma cell differentiation) accompanied by significant intratumoral immunoglobulin deposition, a feature markedly weaker in orthotopic tumors. Tumor immunoglobulins, however, did not appear to form immune complexes. Furthermore, in contrast to the current paradigm that tumor B cells are immunosuppressive, when assessed as a bulk population, intratumoral B cells upregulated several proinflammatory and immunostimulatory genes, a distinctly different phenotype to that of splenic-derived B cells; further highlighting the importance of studying tumor-infiltrating B cells over B cells from secondary lymphoid organs. In agreement with the current literature, genetic deletion of B cells (μMT mice) resulted in reduced orthotopic tumor growth, however, this was not recapitulated by treatment with B-cell-depleting anti-CD20 antibody and, more importantly, was not observed in anti-CD20-treated KPC mice. This suggests the result from B cell deficient mice might be caused by their altered immune system, rather than lack of B cells. Therefore, our data indicate B cells do not favor tumor progression. In conclusion, our analysis of relevant preclinical models shows B cells to be active members of the tumor microenvironment, producing immunostimulatory factors that might support the adaptive antitumor immune response, as suggested by human PDAC studies.

We describe an approach to the high-fidelity measurement of a superconducting qubit using an on-chip microwave photon counter. The protocol relies on the transient response of a dispersively coupled measurement resonator to map the state of the qubit to “bright” and “dark” cavity pointer states that are characterized by a large differential photon occupation. Following this mapping, we photodetect the resonator using the Josephson photomultiplier, which transitions between classically distinguishable flux states when cavity photon occupation exceeds a certain threshold. Our technique provides access to the binary outcome of projective quantum measurement at the millikelvin stage without the need for quantum-limited preamplification and thresholding at room temperature. We achieve raw single-shot measurement fidelity in excess of 98% across multiple samples using this approach in total measurement times under 500 ns. In addition, we show that the backaction and crosstalk associated with our measurement protocol can be mitigated by exploiting the intrinsic damping of the Josephson photomultiplier itself.

Arsenite (AsIII) oxidation is a microbially-catalyzed transformation that directly impacts arsenic toxicity, bioaccumulation, and bioavailability in environmental systems. The genes for AsIII oxidation (aio) encode a periplasmic AsIII sensor AioX, transmembrane histidine kinase AioS, and cognate regulatory partner AioR, which control expression of the AsIII oxidase AioBA. The aio genes are under ultimate control of the phosphate stress response via histidine kinase PhoR. To better understand the cell-wide impacts exerted by these key histidine kinases, we employed 1H nuclear magnetic resonance (1H NMR) and liquid chromatography-coupled mass spectrometry (LC-MS) metabolomics to characterize the metabolic profiles of ΔphoR and ΔaioS mutants of Agrobacterium tumefaciens 5A during AsIII oxidation. The data reveals a smaller group of metabolites impacted by the ΔaioS mutation, including hypoxanthine and various maltose derivatives, while a larger impact is observed for the ΔphoR mutation, influencing betaine, glutamate, and different sugars. The metabolomics data were integrated with previously published transcriptomics analyses to detail pathways perturbed during AsIII oxidation and those modulated by PhoR and/or AioS. The results highlight considerable disruptions in central carbon metabolism in the ΔphoR mutant. These data provide a detailed map of the metabolic impacts of AsIII, PhoR, and/or AioS, and inform current paradigms concerning arsenic–microbe interactions and nutrient cycling in contaminated environments.