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COVID-19 confronted medical care with many challenges. During the pandemic, several resources were limited resulting in renouncing or postponing medical care like carotid endarterectomy (CEA) for patients with significant carotid artery stenosis. Although according to international guidelines CEA is the first choice, carotid artery stenting (CAS) could potentially be a reasonable alternative especially during logistical restraints.

Magnetic skyrmions are topologically protected spin textures with emergent particle-like behaviors. Their dynamics under external stimuli is of great interest and importance for topological physics and spintronics applications alike. So far, skyrmions are only found to move linearly in response to a linear drive, following the conventional model treating them as isolated quasiparticles. Here, by performing time and spatially resolved resonant elastic X-ray scattering of the insulating chiral magnet Cu2OSeO3, we show that for finite-sized skyrmion crystallites, a purely linear temperature gradient not only propels the skyrmions but also induces continuous rotational motion through a chiral lattice torque. Consequently, a skyrmion crystallite undergoes a rolling motion under a small gradient, while both the rolling speed and the rotational sense can be controlled. Our findings offer a new degree of freedom for manipulating these quasiparticles toward device applications and underscore the fundamental phase difference between the condensed skyrmion lattice and isolated skyrmions.

Malaria-elimination interventions aim to extinguish hotspots and prevent transmission to nearby areas. Here, we re-analyzed a cluster-randomized trial of reactive, focal interventions (chemoprevention using artemether–lumefantrine and/or indoor residual spraying with pirimiphos-methyl) delivered within 500 m of confirmed malaria index cases in Namibia to measure direct effects (among intervention recipients within 500 m) and spillover effects (among non-intervention recipients within 3 km) on incidence, prevalence and seroprevalence. There was no or weak evidence of direct effects, but the sample size of intervention recipients was small, limiting statistical power. There was the strongest evidence of spillover effects of combined chemoprevention and indoor residual spraying. Among non-recipients within 1 km of index cases, the combined intervention reduced malaria incidence by 43% (95% confidence interval, 20–59%). In analyses among non-recipients within 3 km of interventions, the combined intervention reduced infection prevalence by 79% (6–95%) and seroprevalence, which captures recent infections and has higher statistical power, by 34% (20–45%). Accounting for spillover effects increased the cost-effectiveness of the combined intervention by 42%. Targeting hotspots with combined chemoprevention and vector-control interventions can indirectly benefit non-recipients up to 3 km away.

Background: Huntington’s disease (HD) exerts significant impacts on individuals and families worldwide. Nevertheless, data on its economic burden in Brazil are scarce, revealing a critical gap in understanding the associated healthcare costs.Objective: This study was conducted at a tertiary neurology outpatient clinic in Brazil with the aim of assessing annual healthcare service utilization and associated costs for HD patients.Methods: We conducted a cross-sectional observational study involving 34 HD patients. A structured questionnaire was applied to collect data on direct medical costs (outpatient services, medications), non-medical direct costs (complementary therapies, mobility aids, home adaptations), and indirect costs (lost productivity, caregiver costs, government benefits) over one year.Results: Significant economic impacts were observed, with average annual direct medical costs of $4686.82 per HD patient. Non-medical direct and indirect costs increased the financial burden, highlighting extensive resource utilization beyond healthcare services. Thirty-three out of 34 HD patients were unemployed or retired, and 16 relied on government benefits, reflecting broader socioeconomic implications. Despite the dataset’s limitations, it provides crucial insights into the economic impact of HD on patients and the Brazilian public health system.Conclusions: The findings underscore the urgent need for a more comprehensive evaluation of the costs to inform governmental policies related to HD. Future research is needed to expand the data pool and develop a nuanced understanding of the economic burdens of HD to help formulate effective healthcare strategies for patients.

This article examines the role of social class in the hijra(Islamic migration) of Dutch and Flemish Muslim women (born and converted) to Morocco. Through an ethnography of their home-making practices, I argue that analyzing social class is crucial to understanding their migration and religious transformation. Unlike previous intersectional studies underexploring social class, I show how my interlocutors’ shifting socioeconomic status, informed by race, gender, and religion, significantly influenced their migratory experiences. This includes motivations for migration, perceptions of Moroccan society, and the (re)acquisition of white privilege. I argue that hijra, as a transformative religious act of mobility, both emerges from and reshapes their class status through underlying mechanisms of “coloniality.” By tracing their narratives and practices of furnishing and food, I highlight the importance of including social class in analyzing hijra and, more broadly, as a key element in intersectional approaches of migration and religious change.

Currently, real-world data on doravirine are scarce. In a national prospective cohort, we assessed the effectiveness and tolerability of switching to doravirine-based antiretroviral therapy (ART) in people with HIV.

To evaluate the patient-perceived satisfaction and feasibility of a personalized eHealth application (app) for abdominal aortic aneurysm (AAA) patients undergoing surgery.

IMPORTANCE: Surgical site infections (SSIs) are common postoperative complications and associated with significant morbidity, mortality, and costs. Prophylactic intraoperative incisional wound irrigation is used to reduce the risk of SSIs, and there is great variation in the type of irrigation solutions and their use. OBJECTIVE: To compare the outcomes of different types of incisional prophylactic intraoperative incisional wound irrigation for the prevention of SSIs in all types of surgery. DATA SOURCES: PubMed, Embase, CENTRAL, and CINAHL databases were searched up to June 12, 2023. STUDY SELECTION: Included in this study were randomized clinical trials (RCTs) comparing incisional prophylactic intraoperative incisional wound irrigation with no irrigation or comparing irrigation using different types of solutions, with SSI as a reported outcome. Studies investigating intracavity lavage were excluded. DATA EXTRACTION AND SYNTHESIS: This systematic review and network meta-analysis is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement. Two reviewers independently extracted the data and assessed the risk of bias within individual RCTs using the Cochrane Risk of Bias 2 tool and the certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation framework. A frequentist network meta-analysis was conducted, and relative risks (RRs) with corresponding 95% CIs were reported. MAIN OUTCOME AND MEASURE: The primary study outcome was SSI. RESULTS: A total of 1587 articles were identified, of which 41 RCTs were included in the systematic review, with 17 188 patients reporting 1328 SSIs, resulting in an overall incidence of 7.7%. Compared with no irrigation, antiseptic solutions (RR, 0.60; 95% CI, 0.44-0.81; high level of certainty) and antibiotic solutions (RR, 0.46; 95% CI, 0.29-0.73; low level of certainty) were associated with a beneficial reduction in SSIs. Saline irrigation showed no statistically significant difference compared with no irrigation (RR, 0.83; 95% CI, 0.63-1.09; moderate level of certainty). CONCLUSIONS AND RELEVANCE: This systematic review and network meta-analysis found high-certainty evidence that prophylactic intraoperative incisional wound irrigation with antiseptic solutions was associated with a reduction in SSIs. It is suggested that the use of antibiotic wound irrigation be avoided due to the inferior certainty of evidence for its outcome and global antimicrobial resistance concerns.

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P< 5 × 10−8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n= 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5–18.2 mmHg, P= 2.22 × 10−126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54–9.70; P= 4.13 × 10−44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781–0.801) to 0.826 (95% CI, 0.817–0.836, ∆AUROC, 0.035, P= 1.98 × 10−34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.

IMPORTANCE: Hyperbaric oxygen therapy (HBOT) is proposed as treatment for late local toxic effects after breast irradiation. Strong evidence of effectiveness is lacking. OBJECTIVE: To assess effectiveness of HBOT for late local toxic effects in women who received adjuvant radiotherapy for breast cancer. DESIGN, SETTING, AND PARTICIPANTS: This was a hospital-based, pragmatic, 2-arm, randomized clinical trial nested within the prospective UMBRELLA cohort following the trials within cohorts design in the Netherlands. Participants included 189 women with patient-reported moderate or severe breast, chest wall, and/or shoulder pain in combination with mild, moderate, or severe edema, fibrosis, or movement restriction 12 months or longer after breast irradiation. Data analysis was performed from May to September 2023. INTERVENTION: Receipt of 30 to 40 HBOT sessions over a period of 6 to 8 consecutive weeks. MAIN OUTCOMES AND MEASURES: Breast, chest wall, and/or shoulder pain 6 months postrandomization measured by the European Organization for Research and Treatment of Cancer QLQ-BR23 questionnaire. Secondary end points were patient-reported fibrosis, edema, movement restriction, and overall quality of life. Data were analyzed according to intention-to-treat (ITT) and complier average causal effect (CACE) principles. RESULTS: Between November 2019 and August 2022, 125 women (median [range] age at randomization, 56 [37-85] years) with late local toxic effects were offered to undergo HBOT (intervention arm), and 61 women (median [range] age at randomization, 60 [36-80] years) were randomized to the control arm. Of those offered HBOT, 31 (25%) accepted and completed treatment. The most common reason for not accepting HBOT was high treatment intensity. In ITT, moderate or severe pain at follow-up was reported by 58 of 115 women (50%) in the intervention arm and 32 of 52 women (62%) in the control arm (odds ratio [OR], 0.63; 95% CI, 0.32-1.23; P = .18). In CACE, the proportion of women reporting moderate or severe pain at follow-up was 32% (10 of 31) among those completing HBOT and 75% (9.7 of 12.9) among control participants expected to complete HBOT if offered (adjusted OR, 0.34; 95% CI, 0.15-0.80; P = .01). In ITT, moderate or severe fibrosis was reported by 35 of 107 (33%) in the intervention arm and 25 of 49 (51%) in the control arm (OR, 0.36; 95% CI, 0.15-0.81; P = .02). There were no significant differences in breast edema, movement restriction, and quality of life between groups in ITT and CACE. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, offering HBOT to women with late local toxic effects was not effective for reducing pain, but was effective for reducing fibrosis. In the subgroup of women who completed HBOT, a significant reduction in pain and fibrosis was observed. A smaller than anticipated proportion of women with late local toxic effects was prepared to undergo HBOT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04193722

Mesenteric artery stenting with a bare-metal stent is the current treatment for atherosclerotic chronic mesenteric ischaemia. Long-term patency of bare-metal stents is unsatisfactory due to in-stent intimal hyperplasia. Use of covered stents might improve long-term patency. We aimed to compare the patency of covered stents and bare-metal stents in patients with chronic mesenteric ischaemia.

Verheij syndrome [VRJS; OMIM 615583] is a rare autosomal dominant neurodevelopmental disorder characterized by distinct clinical features, including growth retardation, intellectual disability, cardiac, and renal anomalies. VRJS is caused by deletions of chromosome 8q24.3 or pathogenic variants in the PUF60gene. Recently, pathogenic PUF60variants have been reported in some individuals with VRJS, contributing to the variability in the clinical presentation and severity of the condition. PUF60encodes a protein involved in regulating gene expression and cellular growth. In this report, we describe a new case of VRJS with developmental delay, cardiac-, and renal abnormalities, caused by a heterozygous pathogenic PUF60variant. Surprisingly, DNA methylation analysis revealed a pattern resembling the Cornelia de Lange syndrome (CdLS) episignature, suggesting a potential connection between PUF60and CdLS-related genes. This case report further delineates the clinical and molecular spectrum of VRJS and supports further research to validate the interaction between VRJS and CdLS.

Terahertz (THz) waves have been widely hailed as a key enabling technology for future sixth generation (6G) wireless networks. Dynamic modulation of their polarization states is of great attraction for high-capacity communications and anisotropic sensing. The development of such technology is, however, still in very early stage owing to the difficulties of realizing electrical reconfigurability for THz devices. Artificially constructed metasurfaces and new nanomaterials, such as graphene, have been shown to provide revolutionary platforms for manipulating and controlling the wave properties, especially at THz frequencies. This work leverages the light–matter interaction in a graphene-integrated metasurface functioning as an electrically reconfigurable THz polarization converter. A novel graphene-gold bilayer topology is applied to construct such a metasurface which enables wide-range electrical tunability of the polarization conversion. Under a y-polarized illumination, the reflected components of x- and y-polarizations are tuned dynamically through an external bias voltage across the metasurface, thereby producing an elliptically polarized wave with tuneable ellipticity and angle. By changing the voltage from 0 V to 12 V, the reflected polarization ellipticity has been tuned from −0.94 to −0.5 at around 240 GHz, featuring linear-to-circular and linear-to-elliptical polarization conversions. Meanwhile, the polarization angle has been modulated from 12° to −23° at around 236 GHz. This work provides an experimentally validated THz graphene-integrated metasurface with wide polarization modulation depths, low biasing voltages and simple configuration. It promises great potential for applications in future THz communications and sensing.

We present a theoretical model to compute the efficiency of the generation of two or more electron–hole pairs in a semiconductor by the absorption of one photon via the process of carrier multiplication (CM). The photogeneration quantum yield of electron–hole pairs is calculated from the number of possible CM decay pathways of the electron and the hole. We apply our model to investigate the underlying cause of the high efficiency of CM in bulk 2H–MoTe2, as compared to bulk PbS and PbSe. Electronic band structures were calculated with density functional theory, from which the number of possible CM decay pathways was calculated for all initial electron and hole states that can be produced at a given photon energy. The variation of the number of CM pathways with photon energy reflects the dependence of experimental CM quantum yields on the photon energy and material composition. We quantitatively reproduce experimental CM quantum yields for MoTe2, PbS, and PbSe from the calculated number of CM pathways and one adjustable fit parameter. This parameter is related to the ratio of Coulomb coupling matrix elements and the cooling rate of the electrons and holes. Large variations of this fit parameter result in small changes in the modeled quantum yield for MoTe2, which confirms that its high CM efficiency can be mainly attributed to its extraordinary large number of CM pathways. The methodology of this work can be applied to analyze or predict the CM efficiency of other materials.

Purpose: This study aims to explore how student recruitment practitioners at regional Australian universities strategise student recruitment efforts in Thailand. There is scarce research addressing regional universities, with prior studies focusing on metropolitan universities. Similarly, most prior studies have focused on high-volume markets, with little research exploring emerging markets such as Thailand. Design/methodology/approach: Semi-structured interviews were conducted with student recruitment practitioners from regional universities that were responsible for recruiting Thai students. Thematic analysis was conducted to identify key themes. Findings: Regional universities lack strategic ambidexterity in their approach to recruiting international students. They viewed Thailand as requiring longer term investment and were unwilling to dedicate their limited resources towards developing this market at the expense of other markets that would yield enrolments to contribute towards short-term targets. Practical implications: Implications are provided with relevance to the student recruitment practitioner, with strategic ambidexterity discussed. Originality/value: The paper fills a gap in the research by exploring international student recruitment and contextualising both regional universities and Thailand as a recruitment market. This study provides useful considerations that may be relevant to other emerging markets.

van der Waals materials provide a versatile toolbox for the emergence of new quantum phenomena and fabrication of functional heterostructures. Among them, the trihalide VI3stands out for its unique magnetic and structural landscape. Here we investigate the spin and orbital magnetic degrees of freedom in the layered ferromagnet VI3by means of temperature-dependent X-ray absorption spectroscopy and X-ray magnetic circular and linear dichroism. We detect localized electronic states and reduced magnetic dimensionality, due to electronic correlations. We furthermore provide experimental evidence of (a) an unquenched orbital magnetic moment (up to 0.66(7) μB/V atom) in the ferromagnetic state and (b) an instability of the orbital moment in the proximity of the spin reorientation transition. Our results support a coherent picture where electronic correlations give rise to a strong magnetic anisotropy and a large orbital moment and establish VI3as a prime candidate for the study of orbital quantum effects.

Hepatitis E virus (HEV) infection can cause severe complications and high mortality, particularly in pregnant women, organ transplant recipients, individuals with pre-existing liver disease and immunosuppressed patients. However, there are still unmet needs for treating chronic HEV infections. Herein, we screened a best-in-class drug repurposing library consisting of 262 drugs/compounds. Upon screening, we identified vidofludimus calcium and pyrazofurin as novel anti-HEV entities. Vidofludimus calcium is the next-generation dihydroorotate dehydrogenase (DHODH) inhibitor in the phase 3 pipeline to treat autoimmune diseases or SARS-CoV-2 infection. Pyrazofurin selectively targets uridine monophosphate synthetase (UMPS). Their anti-HEV effects were further investigated in a range of cell culture models and human liver organoids models with wild type HEV strains and ribavirin treatment failure-associated HEV strains. Encouragingly, both drugs exhibited a sizeable therapeutic window against HEV. For instance, the IC50value of vidofludimus calcium is 4.6–7.6-fold lower than the current therapeutic doses in patients. Mechanistically, their anti-HEV mode of action depends on the blockage of pyrimidine synthesis. Notably, two drugs robustly inhibited ribavirin treatment failure-associated HEV mutants (Y1320H, G1634R). Their combination with IFN-α resulted in synergistic antiviral activity. In conclusion, we identified vidofludimus calcium and pyrazofurin as potent candidates for the treatment of HEV infections. Based on their antiviral potency, and also the favorable safety profile identified in clinical studies, our study supports the initiation of clinical studies to repurpose these drugs for treating chronic hepatitis E.

The local coordination environment of single atom catalysts (SACs) often determines their catalytic performance. To understand these metal–support interactions, we prepared Pt SACs on cerium dioxide (CeO2) cubes, octahedra and rods, with well-structured exposed crystal facets. The CeO2crystals were characterized by SEM, TEM, pXRD, and N2sorption, confirming the shape-selective synthesis, identical bulk structure, and variations in specific surface area, respectively. EPR, XPS, TEM and XANES measurements showed differences in the oxygen vacancy density following the trend rods > octahedra > cubes. AC-HAADF-STEM, XPS and CO-DRIFTS measurements confirmed the presence of only single Pt2+sites, with different surface platinum surface concentrations. We then compared the performance of the three catalysts in ammonia borane hydrolysis. Precise monitoring of reaction kinetics between 30–80 °C gave Arrhenius plots with hundreds of data points. All plots showed a clear inflection point, the temperature of which (rods > octahedra > cubes) correlates to the energy barrier of ammonia borane diffusion to the Pt sites. These activity differences reflect variations in the – facet dependent – degree of stabilization of intermediates by surface oxygen lone pairs and surface–metal binding strength. Our results show how choosing the right macroscopic support shape can give control over single atom catalysed reactions on the microscopic scale.

Nemaline myopathy type 6 (NEM6) or KBTBD13-related congenital myopathy is the most prevalent type of nemaline myopathy in the Netherlands and is characterised by mild childhood-onset axial, proximal and distal muscle weakness with prominent neck flexor weakness combined with slowness of movements. The most prevalent variant in the Netherlands is the c.1222C > T p.(Arg408Cys) variant in the KBTBD13gene, also called the Dutch founder variant. To provide a comprehensive clinical and functional characterisation of three patients to assess the pathogenicity of a newly identified variant in the KBTBD13gene. We present three cases (Patient 1: female, 76 years old; Patient 2: male, 63 years old; and his brother Patient 3: male, 61 years old) with a c.1222C > A p.(Arg408Ser) variant in the KBTBD13gene. Patient 1 was also included previously in a histopathological study on NEM6. Symptoms of muscle weakness started in childhood and progressed to impaired functional abilities in adulthood. All three patients reported slowness of movements. On examination, they have mild axial, proximal and distal muscle weakness. None of the patients exhibited cardiac abnormalities. Spirometry in two patients showed a restrictive lung pattern. Muscle ultrasound showed symmetrically increased echogenicity indicating fatty replacement and fibrosis in a subset of muscles and histopathological analyses revealed nemaline rods and cores. Slower muscle relaxation kinetics with in vivofunctional tests was observed. This was confirmed by in vitrofunctional tests showing impaired relaxation kinetics in isolated muscle fibres. We found a genealogic link between patient 1, and patient 2 and 3 nine generations earlier. The c.1222C > A p.(Arg408Ser) variant in the KBTBD13gene is a likely pathogenic variant causing NEM6.

In the quest for climate neutrality in the aviation industry by 2050, technology development is one of the main pathways for Airbus. Owing to their high efficiency and current density, use of superconducting DC and AC distribution lines are a potential enabler for fully electric propulsion in a longer range aircraft, in particular in the scenario where liquid hydrogen provides a cold source on board of the aircraft. The ground-based Advanced Superconducting and Cryogenic Experimental power traiN Demonstrator (ASCEND) at Airbus intends to demonstrate the potential and feasibility of a cryogenic and superconducting powertrain as a breakthrough electric propulsion solution on future electric aircraft. A direct current distribution network is used in a generic propulsion system to transfer 500 kW power from the DC supply to an electrical converter, which transforms the energy into an alternating voltage/current to drive the superconducting motor. A relatively low voltage level of 300 V, and a current of 1700 A, is chosen to optimize the safety and installation in a future aircraft by operating at relatively low voltage. The DC link consists of a 10 m long two-pole superconducting Conductor on Round Core (CORC) cable, and demountable current leads, that transfer the power from the room temperature environment to the cryogenically cooled motor control unit. Downstream of this unit a 3-phase AC link operating at 500 Hz delivers power to a superconducting motor. Both the AC and DC links are cooled with a flow of subcooled LN2. The components of the DC and AC links have been designed, manufactured and recently integrated into the ASCEND test bench in Ottobrunn, Germany. We present the powering of the DC link up to nominal current, as well as commissioning and integration experience.

Van de populatie van De Fjord, een orthopsychiatrisch centrum voor adolescenten met gedragsproblematiek, blijkt een groot aantal slachtoffer te zijn geweest van uiteenlopende vormen van geweld. In dit artikel wordt aan de hand van literatuuronderzoek geïnventariseerd welke psychologische mechanismen ten grondslag liggen aan de vicieuze cirkel die van slachtoffers daders maakt. De wijze waarop deze psychologische mechanismen tijdens de behandeling aandacht krijgen, wordt aan de hand van casuïstiek uiteengezet. Mogelijk is schematherapie een geschikte behandeling voor slachtoffers die dader worden, omdat het mechanismen die predisponeren tot daderschap doorbreekt, terwijl het mechanismen die ertegen beschermen versterkt. In a Dutch psychiatric centre for adolescents with conduct disorders, a large percentage of the population has been victimized by various forms of violence and mistreatment. By examining the literature on this subject, the psychological mechanisms that underlie the transformation of victims into perpetrators, as well as mechanisms that protect against it, are identified. Case reports illustrate the way in which these mechanisms are targeted during treatment. Schema therapy appears to be well suited for the treatment of victims turned into perpetrators, as it influences both the psychological mechanisms that enhance the vicious cycle and those that prevent it.

Abstract: The paper contains characterizations of generators and cyclic projective generators in the category of ordered right acts over an ordered monoid.

Introduction: The use of combination therapy of oral acetaminophen and topical diclofenac, having complementary mechanisms of action, is an attractive strategy to enhance the analgesic response in osteoarthritis (OA) pain. While topical diclofenac is considered as well tolerated due to its low systemic exposure, concerns of liver toxicity with acetaminophen at standard analgesic doses remain. Thus, this study aimed to assess the liver safety profile of acetaminophen, particularly in OA management, using a model-based meta-analysis (MBMA). Methods: A literature review was conducted using the MEDLINE database to identify randomized clinical trials (RCTs) reporting liver toxicity on acetaminophen use. An MBMA was implemented to assess the deviation from the upper limit of normal (ULN) of alanine aminotransferase or aspartate aminotransferase, namely > 0–1 × ULN, > 1.5–2 × ULN, and > 3 × ULN representing mild, moderate, and severe risk of liver abnormality, respectively. Results: A total of 15 RCTs were included in the MBMA, encompassing over 4800 subjects and exposure to acetaminophen ranging from 2 to 26 weeks. Of the 15 included studies, eight involved patients with OA pain, four involved healthy subjects and three were in patients with conditions such as asthma, glaucoma, chronic pain, and cardiovascular disease. Acetaminophen 1500–4000 mg/day was found to exhibit 23% (95% confidence interval (CI): 17.74–29.20), 1.35% (95% CI: 0.17–2.51) and 0.01% (95% CI: 0.00–0.32) increased risk for mild, moderate, and severe liver injury, respectively, versus placebo. Moreover, at therapeutic doses, no correlation was identified between acetaminophen intake and liver abnormality risk. Conclusions: Overall, our analysis shows that short-term (~ 8–16 weeks) acetaminophen use at therapeutically recommended doses is associated with a low risk of clinically relevant changes in liver enzymes. Given the good tolerability of topical diclofenac, the findings support the safety of the combination of acetaminophen and topical diclofenac, at least over the short term, as treatment for mild-to-moderate OA pain.

The semiconductors industry benefits greatly from the integration of machine learning (ML)-based techniques in technology computer-aided design (TCAD) methods. The performance of ML models, however, relies heavily on the quality and quantity of training datasets. They can be particularly difficult to obtain in the semiconductor industry due to the complexity and expense of the device fabrication. In this article, we propose a self-augmentation strategy for improving ML-based device modeling using variational autoencoder (VAE)-based techniques. These techniques require a small number of experimental data points and do not rely on TCAD tools. To demonstrate the effectiveness of our approach, we apply it to a deep neural network (DNN)-based prediction task for the ohmic resistance value in gallium nitride (GaN) devices. A 70% reduction in mean absolute error (MAE) when predicting experimental results is achieved. The inherent flexibility of our approach allows easy adaptation to various tasks, thus making it highly relevant to many applications of the semiconductor industry.

The 16p11.2 deletion syndrome is a clinically heterogeneous disorder, characterized by developmental delay, intellectual disability, hyperphagia, obesity, macrocephaly and psychiatric problems. Cases with 16p11.2 duplication syndrome have similar neurodevelopmental problems, but typically show a partial ‘mirror phenotype’ with underweight and microcephaly. Various copy number variants (CNVs) of the chromosomal 16p11.2 region have been described. Most is known about the ‘typical’ 16p11.2 BP4-BP5 (29.6–30.2 Mb; ~600 kb) deletions and duplications, but there are also several published cohorts with more distal 16p11.2 BP2-BP3 CNVs (28.8–29.0 Mb; ~220 kb), who exhibit clinical overlap. We assessed 100 cases with various pathogenic 16p11.2 CNVs and compared their clinical characteristics to provide more clear genotype-phenotype correlations and raise awareness of the different 16p11.2 CNVs. Neurodevelopmental and weight issues were reported in the majority of cases. Cases with distal 16p11.2 BP2-BP3 deletion showed the most severe obesity phenotype (73.7% obesity, mean BMI SDS 3.2). In addition to the more well defined typical 16p11.2 BP4-BP5 and distal 16p11.2 BP2-BP3 CNVs, we describe the clinical features of five cases with other, overlapping, 16p11.2 CNVs in more detail. Interestingly, four cases had a second genetic diagnosis and 18 cases an additional gene variant of uncertain significance, that could potentially help explain the cases’ phenotypes. In conclusion, we provide an overview of our Dutch cohort of cases with various pathogenic 16p11.2 CNVs and relevant second genetic findings, that can aid in adequately recognizing, diagnosing and counseling of individuals with 16p11.2 CNVs, and describe the personalized medicine for cases with these conditions.

Atypical chemokine receptor 3 (ACKR3), formerly referred to as CXCR7, is considered to be an interesting drug target. In this study, we report on the synthesis, pharmacological characterization and radiolabeling of VUF15485, a new ACKR3 small-molecule agonist, that will serve as an important new tool to study this β-arrestin-biased chemokine receptor. VUF15485 binds with nanomolar affinity (pIC50= 8.3) to human ACKR3, as measured in [125I]CXCL12 competition binding experiments. Moreover, in a bioluminescence resonance energy transfer-based β-arrestin2 recruitment assay VUF15485 acts as a potent ACKR3 agonist (pEC50= 7.6) and shows a similar extent of receptor activation compared with CXCL12 when using a newly developed, fluorescence resonance energy transfer-based ACKR3 conformational sensor. Moreover, the ACKR3 agonist VUF15485, tested against a (atypical) chemokine receptor panel (agonist and antagonist mode), proves to be selective for ACKR3. VUF15485 labeled with tritium at one of its methoxy groups ([3H]VUF15485), binds ACKR3 saturably and with high affinity (Kd= 8.2 nM). Additionally, [3H]VUF15485 shows rapid binding kinetics and consequently a short residence time (<2 minutes) for binding to ACKR3. The selectivity of [3H]VUF15485 for ACKR3, was confirmed by binding studies, whereupon CXCR3, CXCR4, and ACKR3 small-molecule ligands were competed for binding against the radiolabeled agonist. Interestingly, the chemokine ligands CXCL11 and CXCL12 are not able to displace the binding of [3H]VUF15485 to ACKR3. The radiolabeled VUF15485 was subsequently used to evaluate its binding pocket. Site-directed mutagenesis and docking studies using a recently solved cryo-EM structure propose that VUF15485 binds in the major and the minor binding pocket of ACKR3.SIGNIFICANCE STATEMENTThe atypical chemokine receptor atypical chemokine receptor 3 (ACKR3) is considered an interesting drug target in relation to cancer and multiple sclerosis. The study reports on new chemical biology tools for ACKR3, i.e., a new agonist that can also be radiolabeled and a new ACKR3 conformational sensor, that both can be used to directly study the interaction of ACKR3 ligands with the G protein-coupled receptor.

This paper investigates transport AC loss in CORC cables for the ground-based demonstrator ASCEND at Airbus, which studies the feasibility of a superconducting powertrain for electric aircraft. The demonstrator includes a three-phase AC link consisting of three parallel cables operating at 500 Hz and 2350 A peak current. The transport AC loss of the three-phase cable is estimated using a 2D model assuming equal current in all tapes. The model predicts an AC loss of 40 W at 77.5 K and 0.4 W at 65 K. A second model is proposed, which computes the current distribution between the tapes in a single cable using mutual inductance matrices for helical tape conductors. This model predicts that, at 500 Hz, the outer two layers of a CORC cable carry a disproportionate fraction of the current. This will lead to additional AC loss if the critical current in the outer layers is exceeded. AC transport loss was measured on single CORC cables. Both models significantly underestimate the measured loss. Also, a frequency-dependent quench current below the DC critical current was observed at 48 Hz and 96 Hz.

Mowat-Wilson syndrome (MOWS) is a rare congenital disease caused by haploinsufficiency of ZEB2, encoding a transcription factor required for neurodevelopment. MOWS is characterized by intellectual disability, epilepsy, typical facial phenotype and other anomalies, such as short stature, Hirschsprung disease, brain and heart defects. Despite some recognizable features, MOWS rarity and phenotypic variability may complicate its diagnosis, particularly in the neonatal period. In order to define a novel diagnostic biomarker for MOWS, we determined the genome-wide DNA methylation profile of DNA samples from 29 individuals with confirmed clinical and molecular diagnosis. Through multidimensional scaling and hierarchical clustering analysis, we identified and validated a DNA methylation signature involving 296 differentially methylated probes as part of the broader MOWS DNA methylation profile. The prevalence of hypomethylated CpG sites agrees with the main role of ZEB2 as a transcriptional repressor, while differential methylation within the ZEB2locus supports the previously proposed autoregulation ability. Correlation studies compared the MOWS cohort with 56 previously described DNA methylation profiles of other neurodevelopmental disorders, further validating the specificity of this biomarker. In conclusion, MOWS DNA methylation signature is highly sensitive and reproducible, providing a useful tool to facilitate diagnosis.

To determine the feasibility of a pivotal randomised clinical trial of intravenous (IV) iron and erythropoietin in adult survivors of critical illness with anaemia requiring treatment in the intensive care unit.

Abdominal aortic aneurysm (AAA) is a common disease with substantial heritability. In this study, we performed a genome-wide association meta-analysis from 14 discovery cohorts and uncovered 141 independent associations, including 97 previously unreported loci. A polygenic risk score derived from meta-analysis explained AAA risk beyond clinical risk factors. Genes at AAA risk loci indicate involvement of lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation and inflammation as key mechanisms in AAA pathogenesis. These genes also indicate overlap between the development of AAA and other monogenic aortopathies, particularly via transforming growth factor β signaling. Motivated by the strong evidence for the role of lipid metabolism in AAA, we used Mendelian randomization to establish the central role of nonhigh-density lipoprotein cholesterol in AAA and identified the opportunity for repurposing of proprotein convertase, subtilisin/kexin-type 9 (PCSK9) inhibitors. This was supported by a study demonstrating that PCSK9loss of function prevented the development of AAA in a preclinical mouse model.

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

The presequence translocase of the mitochondrial inner membrane (TIM23) represents the major route for the import of nuclear-encoded proteins into mitochondria1,2. About 60% of more than 1,000 different mitochondrial proteins are synthesized with amino-terminal targeting signals, termed presequences, which form positively charged amphiphilic α-helices3,4. TIM23 sorts the presequence proteins into the inner membrane or matrix. Various views, including regulatory and coupling functions, have been reported on the essential TIM23 subunit Tim17 (refs. 5–7). Here we mapped the interaction of Tim17 with matrix-targeted and inner membrane-sorted preproteins during translocation in the native membrane environment. We show that Tim17 contains conserved negative charges close to the intermembrane space side of the bilayer, which are essential to initiate presequence protein translocation along a distinct transmembrane cavity of Tim17 for both classes of preproteins. The amphiphilic character of mitochondrial presequences directly matches this Tim17-dependent translocation mechanism. This mechanism permits direct lateral release of transmembrane segments of inner membrane-sorted precursors into the inner membrane.

Liver disease is a common cause of morbidity and mortality, and many patients would benefit from liver transplantation. However, because of a shortage of suitable donor livers, even of those patients who are placed on the donor liver waiting list, many do not survive the waiting time for transplantation. Therefore, alternative treatments for end-stage liver disease need to be explored. Recent advances in organoid technology might serve as a solution to overcome the donor liver shortage in the future. In this overview, we highlight the potential of organoid technology for cell therapy and tissue engineering approaches. Both organoid-based approaches could be used as treatment for end-stage liver disease patients. Additionally, organoid-based cell therapy can also be used to repair liver grafts ex vivo to increase the supply of transplantable liver tissue. The potential of both approaches to become clinically available is carefully assessed, including their clinical, ethical, and economic implications. We provide insight into what aspects should be considered further to allow alternatives to donor liver transplantation to be successfully clinically implemented.

High-temperature superconducting REBa$_{2}$ Cu$_{3}$O$_{7-x}$ (rebco) conductors have the potential to generate a high magnetic field over a broad temperature range. The corresponding accelerator magnet technology, still in its infancy, can be attractive for future energy-frontier particle colliders such as a multi-TeV muon collider. To help develop the technology, we explore the requirements and potential characteristics of a rebco magnet, operating at 4.2 or 20 K, with a dipole field of 8–10 T in a clear aperture of 150 mm. We use the canted $\cos \theta$ magnet configuration to reduce the electromagnetic stresses on the conductors. We present the resulting dipole fields, field gradients for combined-function cases, conductor stresses, magnet dimensions and conductor lengths. We also discuss the conductor performance that is required to achieve the target dipole field at 4.2 and 20 K. The information can provide useful input to the development of rebco magnet and conductor technology for collider-ring magnets in a muon collider.

The ground-based Advanced Superconducting and Cryogenic Experimental power train Demonstrator (ASCEND) at Airbus intends to demonstrate the potential and feasibility of a cryogenic and superconducting powertrain as a breakthrough electric propulsion solution on future electric aircraft. A direct current distribution network is used in a propulsion chain to transfer 500 kW of power from the source to an electrical converter, which transforms the power into an alternating voltage/current to drive a superconducting motor. The working point of 1,700 A and 300 V is chosen for safety and installation reasons by operating at relatively low voltage. The direct current (DC) bus of ASCEND will be formed by a pair of high-temperature superconducting CORC cables inserted into a 10-meter-long narrow cryostat, resulting in a compact and lightweight solution. The 2-meter-long alternating current (AC) bus between the inverter and the electric motor is formed by a three-phase CORC cable. The challenge associated with 500 Hz operation in which a balance between AC loss in the cable and the size and mass of the system needs to be found, will be outlined. The AC and DC buses include several devices that connect the liquid nitrogen cooled power cables with the other system components that, in the case of the room temperature generator, operate at significantly higher temperatures. These devices thus include conduction-cooled current leads that are dimensioned to minimize the heat inleak from the warm to the cold environment. An overview of the design of the AC and DC buses and connecting devices will be provided and some of the design and operational challenges will be outlined.

Topological defects are fundamental concepts in physics, but little is known about the transition between distinct types across different dimensionalities. In topological magnetism, as in field theory, the transition between 1D strings and 0D monopoles is a key process whose observation has remained elusive. Here, we introduce a novel mechanism that allows for the controlled stabilization of emergent monopoles and show that magnetic skyrmion strings can be folded into monopoles. Conversely, they act as seeds out of which the entire string structure can unfold, containing its complete information. In chiral magnets, this process can be observed by resonant elastic X-ray scattering when the objects are in proximity to a polarized ferromagnet, whereby a pure monopole lattice is emerging on the surface. Our experimental proof of the reversible evolution from monopole to string sheds new light on topological defects and establishes the emergent monopole lattice as a new 3D topological phase.

Purpose: Octogenarians are known to have less-favorable outcomes following ruptured abdominal aortic aneurysm (rAAA) repair compared with their younger counterparts. Accurate information regarding perioperative outcomes following rAAA-repair is important to evaluate current treatment practice. The aim of this study was to evaluate perioperative outcomes of octogenarians and to identify factors associated with mortality and major complications after open surgical repair (OSR) or endovascular aneurysm repair (EVAR) of a rAAA using nationwide, real-world, contemporary data.Methods: All patients that underwent EVAR or OSR of an infrarenal or juxtarenal rAAA between January 1, 2013, and December 31, 2018, were prospectively registered in the Dutch Surgical Aneurysm Audit (DSAA) and included in this study. The primary outcome was the comparison of perioperative outcomes of octogenarians versus non-octogenarians, including adjustment for confounders. Secondary outcomes were the identification of factors associated with mortality and major complications in octogenarians.Results: The study included 2879 patients, of which 1146 were treated by EVAR (382 octogenarians, 33%) and 1733 were treated by OSR (410 octogenarians, 24%). Perioperative mortality of octogenarians following EVAR was 37.2% versus 14.8% in non-octogenarians (adjusted OR=2.9, 95% CI=2.8–3.0) and 50.0% versus 29.4% following OSR (adjusted OR=2.2, 95% CI=2.2–2.3). Major complication rates of octogenarians were 55.4% versus 31.8% in non-octogenarians following EVAR (OR=2.7, 95% CI=2.1–3.4), and 68% versus 49% following OSR (OR=2.2, 95% CI=1.8–2.8). Following EVAR, 30.6% of the octogenarians had an uncomplicated perioperative course (UPC) versus 49.5% in non-octogenarians (OR=0.5, 95% CI=0.4–0.6), while following OSR, UPC rates were 20.7% in octogenarians versus 32.6% in non-octogenarians (OR=0.5, 95% CI=0.4–0.7). Cardiac or pulmonary comorbidity and loss of consciousness were associated with mortality and major complications in octogenarians. Interestingly, female octogenarians had lower mortality rates following EVAR than male octogenarians (adjusted OR=0.7, 95% CI=0.6–0.8).Conclusion: Based on this nationwide study with real-world registry data, mortality rates of octogenarians following ruptured AAA-repair were high, especially after OSR. However, a substantial proportion of these octogenarians following OSR and EVAR had an uneventful recovery. Known preoperative factors do influence perioperative outcomes and reflect current treatment practice.

More than 25% of all children grow up with a chronic disease. They are at higher risk for developmental and psychosocial problems. However, children who function resiliently manage to adapt positively to these challenges. We aim to systematically review how resilience is defined and measured in children with a chronic disease. A search of PubMed, Cochrane, Embase, and PsycINFO was performed on December 9, 2022, using resilience, disease, and child/adolescent as search terms. Two reviewers independently screened articles for inclusion according to predefined criteria. Extraction domains included study characteristics, definition, and instruments assessing resilience outcomes, and resilience factors. Fifty-five out of 8766 articles were identified as relevant. In general, resilience was characterized as positive adaptation to adversity. The included studies assessed resilience by the outcomes of positive adaptation, or by resilience factors, or both. We categorized the assessed resilience outcomes into three groups: personal traits, psychosocial functioning, and disease-related outcomes. Moreover, myriad of resilience factors were measured, which were grouped into internal resilience factors (cognitive, social, and emotional competence factors), disease-related factors, and external factors (caregiver factors, social factors, and contextual factors). Our scoping review provides insight into the definitions and instruments used to measure resilience in children with a chronic disease. More knowledge is needed on which resilience factors are related to positive adaptation in specific illness-related challenges, which underlying mechanisms are responsible for this positive adaptation, and how these underlying mechanisms interact with one another.

ABSTRACTFor this special issue we invited authors to consider the practice of accounting and the mobilisation of accountability in the contested spaces where worlds and values coexist in pluralist societies. We consider how accounting, as a technical practice, privileges market or economic interests and reflect on the implications for accountability to non-economic actors. Despite the limitations of accounting as merely technical, there is potential for accounting in a broader sphere to be enabling. This overview considers studies that have harnessed interdisciplinary approaches to identify the challenges for social and environmental accounting practice. In doing so, we acknowledge that achieving a normative ideal of accountability in pluralist societies requires a consensus understanding of the ‘common good’, the role of social movements in promoting an emancipatory civil society while recognising the problematic nature of politically mediated discourse.

AbstractOne of the advances in the test blanket module program within the ITER project in the last few years concerned the evolution of the pipe forest (PF) and bioshield plug (BP) designs. In support of the design phase, nuclear analyses to assess several responses in the fusion neutronics environment inside the port interspace (PI) with the existence of the evolved PF and BP are deemed essential. Nuclear analyses were commenced using the new PF and BP with developing the neutronics models and performing preliminary assessment of the radiation fields and shutdown dose rate (SDDR) in the PI. In this paper, the results of a full suite of nuclear analyses are discussed, which covers more configurations and radiation sources, in two plasma operational modes: on and off. For the plasma-on mode, different shielding options were examined. The results show a clear benefit of combining the installation of shielding panels on the PF enclosure with those in the BP “dogleg,” through which the pipes penetrate to the port cell area. For the plasma-off mode, the SDDR was assessed from different sources: activated components and residual LiPb layers in pipes after drainage. As maintenance operations are foreseen during the lifetime of the facility, the SDDR was also assessed for access conditions, open BP doors, and transport conditions, with PF extracted in the gallery.

Purpose: The purpose of the study was to specify the perceived outdated nature and lack of definitional clarity associated with the concept of work and further to outline that the nature of work has dramatically changed in the 21st century, while definitions of work referenced in research remain those that were dominant in the previous century. Lastly, the study aimed to propose an updated conceptualisation and definition of work to aid future research. Design/methodology/approach: A scoping literature review was adopted as the methodology guiding the study. A scoping review is particularly suited to identifying the conceptual boundaries on a given multi-disciplinary topic and is used to map the key concepts underpinning a research area as well as to clarify working definitions. Findings: Nine main themes underpinning the concept of work were extracted from the extant literature. These were assimilated with contemporary literature across multiple disciplines. Contexts of work as they relate to dimensions of work and workspace are developed and visualised. A proposed contemporary definition of work is presented. Research limitations/implications: The aim of the study was to address the problem with current and future research continuing to refer to traditional conceptualisations of work, while the nature of work has dramatically changed. The findings are preliminary and intended to stimulate further discourse towards a greater consensus of a definition. The implications of proposing an updated definition of work is that it is intended to better inform future research reflective of its multi-disciplinary and significantly changed nature. Practical implications: The implications to practice are the main impetus of this study. The authors found that research associated with work was being confounded by traditional and outdated interpretations, excluding alternative forms of work or not recognising its multi-dimensionality. It is proposed by the paper that an updated conceptualisation of the nature of work in this era, as it is reflected across disciplines and practice, would positively contribute to the understanding, management and conceptualisation of work in practice. Originality/value: A systematic literature review across disciplines of the definition of work will reveal the outdated nature and disparate interpretation of the concept of work. An inclusive, multi-disciplinary and contemporary definition of work has not been suggested. This scoping review was conducted to address this problem and gap in the literature. Further, this paper presents a multi-dimensional and spatial conceptualisation of work that is proposed to better inform future research and practice associated with work.

ABSTRACTSchool counselling is not an isolated school-based intervention but rather as part of a more holistic social wellbeing system where there are many stakeholders. Studies have examined students’, school counsellors’, teachers’, and administrators’ perceptions of school counselling. Research that focuses on the perceptions of community counsellors of school counselling is rare. This paper reports on a quantitative survey study of community counsellors’ perceptions in Singapore. Findings indicate some expectations such as school counsellors could offer some family counselling and perceptions such as confidentiality could be strengthened in schools, were widely held among community counsellors. Findings also suggest deeper understanding of both school and community counsellors’ perceptions is needed to strengthen collaboration for better mental health support for children and youths.