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The intrinsic valley degree of freedom makes bilayer graphene (BLG) a unique platform for semiconductor qubits. The single-carrier quantum dot (QD) ground state exhibits a twofold degeneracy, where the two states that constitute a Kramers pair have opposite spin and valley quantum numbers. Because of the valley-dependent Berry curvature, an out-of-plane magnetic field breaks the time-reversal symmetry of this ground state and a qubit can be encoded in the spin-valley subspace. The Kramers states are protected against known spin- and valley-mixing mechanisms because mixing requires a simultaneous change of the two quantum numbers. Here, we fabricate a tunable QD device in Bernal BLG and measure a spin-valley relaxation time for the Kramers states of 38 s at 30 mK, which is two orders of magnitude longer than the 0.4 s measured for purely spin-blocked states. We also show that the intrinsic Kane-Mele spin-orbit splitting enables a Kramers doublet single-shot readout even at zero magnetic field with a fidelity above 99%. If these long-lived Kramers states also possess long coherence times and can be effectively manipulated, electrostatically defined QDs in BLG may serve as long-lived semiconductor qubits, extending beyond the spin qubit paradigm., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Within the project "Ulcus Cruris Care", a disease management intervention to improve general practice care for patients with venous leg ulcer was developed, comprising online teaching for practice teams, standardized patient education, and case management. Implementation of the intervention was piloted and evaluated via a process evaluation. This study aims to evaluate contentedness with the intervention, implementation effort, implementation determinants, intervention fidelity, and perceived intervention effects using a mixed-methods process evaluation., Methods: The mixed-methods process evaluation explored the views of general practitioners, medical assistants and patients regarding the intervention components. Data were collected through semi-structured telephone interviews and a survey questionnaire. Qualitative data were first analyzed inductively, followed by a deductive-inductive approach based on the Theoretical Domains Framework. Survey data were analyzed descriptively., Results: Participants (n = 21) reported a strong contentedness with the intervention, high intervention fidelity, low implementation effort, and a change in perception of compression therapy as the central treatment element. Healthcare professionals emphasized increased patient education and patient and family involvement. Patients reported feeling better informed and empowered to take an active role in their treatment, primarily due to increased knowledge and skills in compression therapy. As a result, they were more content with their care and reported positive experiences with wound healing since trial participation., Conclusions: The Ulcus Cruris Care intervention can lead to a noticeable change in knowledge and potentially influence practice teams' approach to venous leg ulcer management, facilitating a significantly more frequent use of compression therapy in VLU care. A confirmatory evaluation of potential effects in a definitive RCT seems warranted.

Objective: The quality of alcohol-related prevention and treatment in US primary care is poor. The purpose of this study was to describe the extent to which Electronic Health Records (EHRs) used by 167 primary care practices across 7 states currently include the necessary prompts, clinical support, and performance reporting essential for improving alcohol-related prevention and treatment in primary care., Materials and Methods: Experts from five regional quality improvement programs identified basic EHR features needed to support evidence-based alcohol-related prevention (ie, screening and brief intervention) and treatment of alcohol use disorders (AUD). Data were collected regarding whether EHRs included these features., Results: EHRs from 21 vendors were used by the primary care practices. For prevention, 62% of the 167 practices' EHRs included a validated screening questionnaire, 46% automatically scored the screening instrument, 62% could report the percent screened, and 37% could report the percent screening positive. Only 7% could report the percent offered brief intervention. For alcohol treatment, 49% of practices could report the percent diagnosed with AUD, 58% and 91% allowed documentation of referral and treatment with AUD medication, respectively. Only 3% could report the percent of patients diagnosed with AUD who received treatment., Discussion: Most EHRs observed across 167 primary care practices across 7 US states lacked basic functionality necessary to support evidence-based alcohol-related prevention and AUD treatment. Only 3% and 7% of EHRs, respectively, included the ability to report widely recommended quality measures needed to improve the quality of recommended alcohol-related prevention and treatment in primary care., Conclusion: Improving EHR functionality is likely necessary before alcohol-related primary care can be improved., Competing Interests: The authors have no competing interests to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Current semiconductor qubits rely either on the spin or on the charge degree of freedom to encode quantum information. By contrast, in bilayer graphene the valley degree of freedom, stemming from the crystal lattice symmetry, is a robust quantum number that can therefore be harnessed for this purpose. The simplest implementation of a valley qubit would rely on two states with opposite valleys as in the case of a single-carrier bilayer graphene quantum dot immersed in a small perpendicular magnetic field (B ⊥  ≲ 100 mT). However, the single-carrier quantum dot excited states spectrum has not been resolved to date in the relevant magnetic field range. Here, we fill this gap, by measuring the parallel and perpendicular magnetic field dependence of this spectrum with an unprecedented resolution of 4 μeV. We use a time-resolved charge detection technique that gives us access to individual tunnel events. Our results come as a direct verification of the predicted spectrum and establish a new upper-bound on inter-valley mixing, equal to our energy resolution. Our charge detection technique opens the door to measuring the relaxation time of a valley qubit in a single-carrier bilayer graphene quantum dot., (© 2024. The Author(s).)

Van der Waals heterostructures provide a versatile platform for tailoring electronic properties through the integration of two-dimensional materials. Among these combinations, the interaction between bilayer graphene and transition metal dichalcogenides (TMDs) stands out due to its potential for inducing spin-orbit coupling (SOC) in graphene. Future devices concepts require the understanding of the precise nature of SOC in TMD/bilayer graphene heterostructures and its influence on electronic transport phenomena. Here, we experimentally confirm the presence of two distinct types of SOC - Ising (Δ I  = 1.55 meV) and Rashba (Δ R  = 2.5 meV) - in bilayer graphene when interfaced with molybdenum disulfide. Furthermore, we reveal a non-monotonic trend in conductivity with respect to the electric displacement field at charge neutrality. This phenomenon is ascribed to the existence of single-particle gaps induced by the Ising SOC, which can be closed by a critical displacement field. Our findings also unveil sharp peaks in the magnetoconductivity around the critical displacement field, challenging existing theoretical models., (© 2024. The Author(s).)

Domestication of dogs from their shared ancestors with wolves occurred more than 15,000 years ago and affected many characteristics of the species. We analyzed the blood RNA sequence data of 12 dogs and 11 wolves from Europe and Asia to shed more light on the domestication history of dogs. We implemented a differential gene expression analysis, a weighted gene correlation network analysis, gene ontology and genetic pathway analyses. We found that both the sample origin (Europe or Asia) and the species had a significant effect on the blood gene expression profiles of the animals. We identified 1567 differentially expressed genes between wolves and dogs and found several significantly overrepresented gene ontology terms, such as RNA polymerase II transcription regulatory region sequence-specific DNA binding or translation. We identified 11 significant gene co-expression networks, hosting a total of 4402 genes, related to DNA replication, metabolism of RNA or metabolism of proteins, for example. Our findings suggest that gene expression regulation played a cardinal role in dog domestication. We recommend further diversifying the analyzed dog and wolf populations in the future by including individuals from different dog breeds and geographical origins, in order to enhance the specificity of detecting significant, true positive genes related to domestication as well as to reduce the false positive rate.

Personalized cancer immunotherapies such as therapeutic vaccines and adoptive transfer of T cell receptor-transgenic T cells rely on the presentation of tumor-specific peptides by human leukocyte antigen class I molecules to cytotoxic T cells. Such neoepitopes can for example arise from somatic mutations and their identification is crucial for the rational design of new therapeutic interventions. Liquid chromatography mass spectrometry (LC-MS)-based immunopeptidomics is the only method to directly prove actual peptide presentation and we have developed a parameter optimization workflow to tune targeted assays for maximum detection sensitivity on a per peptide basis, termed optiPRM. Optimization of collision energy using optiPRM allows for the improved detection of low abundant peptides that are very hard to detect using standard parameters. Applying this to immunopeptidomics, we detected a neoepitope in a patient-derived xenograft from as little as 2.5 × 10 6  cells input. Application of the workflow on small patient tumor samples allowed for the detection of five mutation-derived neoepitopes in three patients. One neoepitope was confirmed to be recognized by patient T cells. In conclusion, optiPRM, a targeted MS workflow reaching ultra-high sensitivity by per peptide parameter optimization, makes the identification of actionable neoepitopes possible from sample sizes usually available in the clinic., Competing Interests: Conflicts of interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The spin degrees of freedom is crucial for the understanding of any condensed matter system. Knowledge of spin-mixing mechanisms is not only essential for successful control and manipulation of spin qubits, but also uncovers fundamental properties of investigated devices and material. For electrostatically defined bilayer graphene quantum dots, in which recent studies report spin-relaxation times T_{1} up to 50 ms with strong magnetic field dependence, we study spin-blockade phenomena at charge configuration (1,2)↔(0,3). We examine the dependence of the spin-blockade leakage current on interdot tunnel coupling and on the magnitude and orientation of externally applied magnetic field. In out-of-plane magnetic field, the observed zero-field current peak could arise from finite-temperature cotunneling with the leads; though involvement of additional spin- and valley-mixing mechanisms are necessary for explaining the persistent sharp side peaks observed. In in-plane magnetic field, we observe a zero-field current dip, attributed to the competition between the spin Zeeman effect and the Kane-Mele spin-orbit interaction. Details of the line shape of this current dip, however, suggest additional underlying mechanisms are at play.

The topology of the electronic band structure of solids can be described by its Berry curvature distribution across the Brillouin zone. We theoretically introduce and experimentally demonstrate a general methodology based on the measurement of energy- and momentum-resolved optical transition rates, allowing to reveal signatures of Berry curvature texture in reciprocal space. By performing time- and angle-resolved photoemission spectroscopy of atomically thin WSe 2 using polarization-modulated excitations, we demonstrate that excitons become an asset in extracting the quantum geometrical properties of solids. We also investigate the resilience of our measurement protocol against ultrafast scattering processes following direct chiroptical transitions.

Despite the importance of citrullination in physiology and disease, global identification of citrullinated proteins, and the precise targeted sites, has remained challenging. Here we employed quantitative-mass-spectrometry-based proteomics to generate a comprehensive atlas of citrullination sites within the HL60 leukemia cell line following differentiation into neutrophil-like cells. We identified 14,056 citrullination sites within 4,008 proteins and quantified their regulation upon inhibition of the citrullinating enzyme PADI4. With this resource, we provide quantitative and site-specific information on thousands of PADI4 substrates, including signature histone marks and transcriptional regulators. Additionally, using peptide microarrays, we demonstrate the potential clinical relevance of certain identified sites, through distinct reactivities of antibodies contained in synovial fluid from anti-CCP-positive and anti-CCP-negative people with rheumatoid arthritis. Collectively, we describe the human citrullinome at a systems-wide level, provide a resource for understanding citrullination at the mechanistic level and link the identified targeted sites to rheumatoid arthritis., (© 2024. The Author(s).)

Objective:  The effect of the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor alirocumab on platelet aggregation among patients with acute myocardial infarction (AMI) remains unknown. We aimed to explore the effect of alirocumab added to high-intensity statin therapy on P2Y12 reaction unit (PRU) among AMI patients receiving dual antiplatelet therapy (DAPT) with a potent P2Y12 inhibitor (ticagrelor or prasugrel). In addition, we assessed circulating platelet-derived noncoding RNAs (microRNAs and YRNAs)., Methods:  This was a prespecified, powered, pharmacodynamic substudy of the PACMAN trial, a randomized, double-blind trial comparing biweekly alirocumab (150 mg) versus placebo in AMI patients undergoing percutaneous coronary intervention. Patients recruited at Bern University Hospital, receiving DAPT with a potent P2Y12 inhibitor, and adherent to the study drug (alirocumab or placebo) were analyzed for the current study. The primary endpoint was PRU at 4 weeks after study drug initiation as assessed by VerifyNow P2Y12 point-of-care assays., Results:  Among 139 randomized patients, the majority of patients received ticagrelor DAPT at 4 weeks (57 [86.4%] in the alirocumab group vs. 69 [94.5%] in the placebo group, p  = 0.14). There were no significant differences in the primary endpoint PRU at 4 weeks between groups (12.5 [interquartile range, IQR: 27.0] vs. 19.0 [IQR: 30.0], p  = 0.26). Consistent results were observed in 126 patients treated with ticagrelor (13.0 [IQR: 20.0] vs. 18.0 [IQR: 27.0], p  = 0.28). Similarly, platelet-derived noncoding RNAs did not significantly differ between groups., Conclusion:  Among AMI patients receiving DAPT with a potent P2Y12 inhibitor, alirocumab had no significant effect on platelet reactivity as assessed by PRU and platelet-derived noncoding RNAs., Competing Interests: Y.U. reports personal fees from Infraredx outside the submitted work. S.L. is employed by CTU Bern, University of Bern, which has a staff policy of not accepting honoraria or consultancy fees. However, CTU Bern is involved in design, conduct, or analysis of clinical studies funded by not-for-profit and for-profit organizations. In particular, pharmaceutical and medical device companies provide direct funding to some of these studies. D.S. reports receiving personal fees from Sanofi-Aventis (Suisse) outside the submitted work. S.S. reports research grants to the institution from Edwards Lifesciences, Medtronic, Boston Scientific, and Abbott, and personal fees from Boston Scientific, Teleflex, and BTG. M.V. reports research grants to the institution from Terumo and Concept Medical and consulting fees from AstraZeneca, Terumo, Alvimedica/CID, Abiomed, Amgen, Abbott Vascular, Daiichi Sankyo, Bayer, CoreFLOW, DORSIA PHARMACEUTICALS LTD, Universität Basel Dept. Klinische Forschung, Vifor, Bristol Myers Squib SA, Biotronik, Boston Scientific, Medtronic, Vesalio, Novartis, Chiesi, PhaseBio, and ECRI, outside the submitted work. S.W. reports research and educational grants to the institution from Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardinal Health, CardioValve, Corflow Therapeutics, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Guerbet, InfraRedx, Janssen-Cilag, Johnson & Johnson, Medicure, Medtronic, Merck Sharp & Dohm, Miracor Medical, Novartis, Novo Nordisk, Organon, OrPha Suisse, Pfizer, Polares, Regeneron, Sanofi-Aventis, Servier, Sinomed, Terumo, Vifor, and V-Wave. S.W. serves as unpaid advisory board member and/or unpaid member of the steering/executive group of trials funded by Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Boston Scientific, Biotronik, Bristol Myers Squibb, Edwards Lifesciences, Janssen, MedAlliance, Medtronic, Novartis, Polares, Recardio, Sinomed, Terumo, V-Wave, and Xeltis, but has not received personal payments by pharmaceutical companies or device manufacturers. He is also member of the steering/executive committee group of several investigator-initiated trials that receive funding by industry without impact on his personal remuneration. M.M. is a British Heart Foundation (BHF) Chair Holder (CH/16/3/32406) with BHF program grant support (RG/F/21/110053). He is also supported by the Leducq Foundation (18CVD02) and VASCage-C (Research Centre on Vascular Aging and Stroke), an R&D K-Centre of the Austrian Research Promotion Agency (COMET program—Competence Centres for Excellent Technologies) funded by the Austrian Ministry for Transport, Innovation and Technology, the Austrian Ministry for Digital and Economic Affairs, and the federal states Tyrol, Salzburg, and Vienna with the grant number FSG 868624. He has filed and licensed patents on microRNAs as biomarkers. L.R. received a grant to the institution for the conduction of the PACMAN AMI study by Sanofi, Regeneron, and Infraredx. L.R. received research grants to the institution by Abbott, Boston Scientific, Biotronik, and Heartflow, and speaker or consultation fees by Abbott, Amgen, AstraZeneca, Canon, Novo Nordisk, Medtronic, Occlutech, and Sanofi., (Thieme. All rights reserved.)

Biostimulants (Bio-effectors, BEs) comprise plant growth-promoting microorganisms and active natural substances that promote plant nutrient-acquisition, stress resilience, growth, crop quality and yield. Unfortunately, the effectiveness of BEs, particularly under field conditions, appears highly variable and poorly quantified. Using random model meta-analyses tools, we summarize the effects of 107 BE treatments on the performance of major crops, mainly conducted within the EU-funded project BIOFECTOR with a focus on phosphorus (P) nutrition, over five years. Our analyses comprised 94 controlled pot and 47 field experiments under different geoclimatic conditions, with variable stress levels across European countries and Israel. The results show an average growth/yield increase by 9.3% (n=945), with substantial differences between crops (tomato > maize > wheat) and growth conditions (controlled nursery + field (Seed germination and nursery under controlled conditions and young plants transplanted to the field) > controlled > field). Average crop growth responses were independent of BE type, P fertilizer type, soil pH and plant-available soil P (water-P, Olsen-P or Calcium acetate lactate-P). BE effectiveness profited from manure and other organic fertilizers, increasing soil pH and presence of abiotic stresses (cold, drought/heat or salinity). Systematic meta-studies based on published literature commonly face the inherent problem of publication bias where the most suspected form is the selective publication of statistically significant results. In this meta-analysis, however, the results obtained from all experiments within the project are included. Therefore, it is free of publication bias. In contrast to reviews of published literature, our unique study design is based on a common standardized protocol which applies to all experiments conducted within the project to reduce sources of variability. Based on data of crop growth, yield and P acquisition, we conclude that application of BEs can save fertilizer resources in the future, but the efficiency of BE application depends on cropping systems and environments., Competing Interests: PN is employed since 01.10.2022 at Yara GmbH Co & KG., Germany. NM is employed since 01.06.2021 at Yara GmbH Co & KG., Germany. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Nkebiwe, Stevens Lekfeldt, Symanczik, Thonar, Mäder, Bar-Tal, Halpern, Biró, Bradáčová, Caniullan, Choudhary, Cozzolino, Di Stasio, Dobczinski, Geistlinger, Lüthi, Gómez-Muñoz, Kandeler, Kolberg, Kotroczó, Kulhanek, Mercl, Tamir, Moradtalab, Piccolo, Maggio, Nassal, Szalai, Juhos, Fora, Florea, Poşta, Lauer, Toth, Tlustoš, Mpanga, Weber, Weinmann, Yermiyahu, Magid, Müller, Neumann, Ludewig and de Neergaard.)

The aim of this study was to reveal the microbial and kinetic impacts of acute and chronic exposure to one of the frequently administered antibiotics, i.e., sulfamethoxazole, on an activated sludge biomass. Respirometric analysis and model evaluation of the oxygen utilization rate profiles were the backbone of this study. The results showed that continuous exposure to sulfamethoxazole resulted in the inhibition of substrate storage and an increase in the endogenous decay rates by twofold, which was supported by analysis of the resistance genes. A mild inhibition on the growth and hydrolysis kinetics was also observed. Moreover, sulfamethoxazole had a binding impact with available organic carbon, resulting in a slightly less oxygen consumption. DNA sequencing and antibiotic resistance gene analyses showed that continuous exposure to sulfamethoxazole caused a change in the community structure at the species level. Resistant bacteria including Arthrobacter sp. and members of the Chitinophagaceae and Intrasporangiaceae families were found to have dominated the bacterial community. The impact of intermittent exposure was also investigated, and the results indicated a drop in the severity of the impact after 20 days of intermittence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Pala-Ozkok, Katipoglu-Yazan, Olmez-Hanci, Jonas, Ubay-Cokgor and Orhon.)

Background: Endoscopic papillectomy (EP) offers a safe and effective method for resection of ampullary adenomas. Data regarding the long-term resolution of adenoma following EP are limited. The aim of this study therefore was to examine the timing of recurrence after EP of ampullary adenomas., Methods: This was a single-center retrospective study including patients who received EP for ampullary adenomas from 8/2000 to 1/2018. Patients with confirmed complete eradication of adenoma were included in the recurrence analysis with recurrence defined as finding adenomatous histology after 1 negative surveillance endoscopy. Kaplan-Meier estimates were calculated to determine recurrence rates., Results: Of the 165 patients who underwent EP, 136 patients (mean age 61.9, 51.5% female) had adenomatous histology with a mean lesion size of 21.2 mm. A total of 124 (91.2%) achieved complete eradication with a follow-up of 345.8 person-years. Recurrence occurred in 20 (16.1%) patients at a mean of 3.2 (± 3) years (range 0.5-9.75 years) for a recurrence rate of 5.8 (95% CI 3.6-8.8) per 100 person-years. Nine (45%) recurrences occurred after the 1st 2 years of surveillance. Recurrence rate did not differ by baseline pathology [low-grade dysplasia: 5.2 (95% CI 3.0-9.0), high-grade dysplasia: 6.9 (95% CI 2.3-15.5), adenocarcinoma: 7.7 (95% CI 0.9-25.1)]., Conclusion: Recurrence remains a significant concern after EP. Given the timing of recurrence, long surveillance periods may be necessary. Larger multicenter studies are needed, however, to determine appropriate surveillance intervals., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Focused assessment with sonography for trauma (FAST) is a valuable ultrasound procedure in emergency settings, and there is a need for evidence-based education in FAST to ensure competencies. Immersive virtual reality (IVR) is a progressive training modality gaining traction in the field of ultrasound training. IVR holds several economic and practical advantages to the common instructor-led FAST courses using screen-based simulation (SBS)., Methods: This prospective, interventional cohort study investigated whether training FAST using IVR unsupervised and out-of-hospital was non-inferior to a historical control group training at a 90 min SBS course in terms of developing FAST competencies in novices. Competencies were assessed in both groups using the same post-training simulation-based FAST test with validity evidence, and a non-inferiority margin of 2 points was chosen., Results: A total of 27 medical students attended the IVR course, and 27 junior doctors attended the SBS course. The IVR group trained for a median time of 117 min and scored a mean 14.2 ± 2.0 points, compared with a mean 13.7 ± 2.5 points in the SBS group. As the lower bound of the 95% confidence interval at 13.6 was within the range of the non-inferiority margin (11.7-13.7 points), training FAST in IVR for a median of 117 min was found non-inferior to training at a 90 min SBS course. No significant correlation was found between time spent in IVR and test scores., Conclusion: Within the limitations of the use of a historical control group, the results suggest that IVR could be an alternative to SBS FAST training and suitable for unsupervised, out-of-hospital courses in basic FAST competencies., Competing Interests: Conflict of interest K.J., J.D.L., R.O.J., and O.G. were all involved in development of the IVR module. R.O.J. is the chief executive officer and co-founder of VitaSim, which provided the virtual reality software used in this study. J.D.L. was previously employed by VitaSim as a part-time learning consultant. C.F. has voiced a previous VitaSim IVR module. Neither participated in the assessment of the participants’ US skills or data analysis. The remaining authors do not have any conflicts of interest to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Interlayer excitons in van der Waals heterostructures are fascinating for applications like exciton condensation, excitonic devices and moiré-induced quantum emitters. The study of these charge-transfer states has almost exclusively focused on band edges, limiting the spectral region to the near-infrared regime. Here we explore the above-gap analogues of interlayer excitons in bilayer WSe 2 and identify both neutral and charged species emitting in the ultraviolet. Even though the transitions occur far above the band edge, the states remain metastable, exhibiting linewidths as narrow as 1.8 meV. These interlayer high-lying excitations have switchable dipole orientations and hence show prominent Stark splitting. The positive and negative interlayer high-lying trions exhibit significant binding energies of 20-30 meV, allowing for a broad tunability of transitions via electric fields and electrostatic doping. The Stark splitting of these trions serves as a highly accurate, built-in sensor for measuring interlayer electric field strengths, which are exceedingly difficult to quantify otherwise. Such excitonic complexes are further sensitive to the interlayer twist angle and offer opportunities to explore emergent moiré physics under electrical control. Our findings more than double the accessible energy range for applications based on interlayer excitons., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background and Aims: The European Union Medical Device Regulation 2017/745 challenges key stakeholders to follow transparent and rigorous approaches to the clinical evaluation of medical devices. The purpose of this study is a systematic evaluation of published clinical evidence underlying selected high-risk cardiovascular medical devices before and after market access in the European Union (CE-marking) between 2000 and 2021., Methods: Pre-specified strategies were applied to identify published studies of prospective design evaluating 71 high-risk cardiovascular devices in seven different classes (bioresorbable coronary scaffolds, left atrial appendage occlusion devices, transcatheter aortic valve implantation systems, transcatheter mitral valve repair/replacement systems, surgical aortic and mitral heart valves, leadless pacemakers, subcutaneous implantable cardioverter-defibrillator). The search time span covered 20 years (2000-21). Details of study design, patient population, intervention(s), and primary outcome(s) were summarized and assessed with respect to timing of the corresponding CE-mark approval., Results: At least one prospective clinical trial was identified for 70% (50/71) of the pre-specified devices. Overall, 473 reports of 308 prospectively designed studies (enrolling 97 886 individuals) were deemed eligible, including 81% (251/308) prospective non-randomized clinical trials (66 186 individuals) and 19% (57/308) randomized clinical trials (31 700 individuals). Pre-registration of the study protocol was available in 49% (150/308) studies, and 16% (48/308) had a peer-reviewed publicly available protocol. Device-related adverse events were evaluated in 82% (253/308) of studies. An outcome adjudication process was reported in 39% (120/308) of the studies. Sample size was larger for randomized in comparison to non-randomized trials (median of 304 vs. 100 individuals, P < .001). No randomized clinical trial published before CE-mark approval for any of the devices was identified. Non-randomized clinical trials were predominantly published after the corresponding CE-mark approval of the device under evaluation (89%, 224/251). Sample sizes were smaller for studies published before (median of 31 individuals) than after (median of 135 individuals) CE-mark approval (P < .001). Clinical trials with larger sample sizes (>50 individuals) and those with longer recruitment periods were more likely to be published after CE-mark approval, and were more frequent during the period 2016-21., Conclusions: The quantity and quality of publicly available data from prospective clinical investigations across selected categories of cardiovascular devices, before and after CE approval during the period 2000-21, were deemed insufficient. The majority of studies was non-randomized, with increased risk of bias, and performed in small populations without provision of power calculations, and none of the reviewed devices had randomized trial results published prior to CE-mark certification., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Evidence to support immediate P2Y 12 inhibitor loading in ST-segment elevation myocardial infarction (STEMI) is limited., Objectives: This study sought to compare outcomes of STEMI patients receiving immediate or delayed P2Y 12 inhibitor treatment., Methods: Using data from the prospective Bern-PCI registry between 2016 and 2020, we stratified STEMI patients undergoing percutaneous coronary intervention according to time periods with different institutional recommendations regarding P2Y 12 inhibitor pretreatment. In cohort 1 (October 2016-September 2018), immediate P2Y 12 inhibitor treatment was recommended. In cohort 2 (October 2018-September 2020), P2Y 12 inhibitor treatment was recommended after coronary anatomy was confirmed. The primary endpoint was a composite of major adverse cardiac or cerebrovascular events (MACCEs) defined as all-cause death, recurrent myocardial infarction, stroke, or definite stent thrombosis at 30 days. Sensitivity analysis included only patients in whom these recommendations were followed., Results: Cohort 1 included 1,116 patients; pretreatment was actually given in 708 (63.4%). Cohort 2 included 847 patients; pretreatment was withheld in 798 (94.2%). The mean age was 65 ± 13 years, and 24% were female. Baseline characteristics were well-balanced between groups. The median difference for P2Y 12 loading to angiography was 52 minutes between cohort 1 and 2 and 100 minutes between patients receiving vs not receiving pretreatment. Rates of MACCEs were similar between cohort 1 and cohort 2 (10.1% vs 8.1%; adjusted HR: 0.91; 95% CI: 0.65-1.28; P = 0.59) and between patients receiving vs not receiving pretreatment (7.1% vs 8.4%; adjusted HR: 1.17; 95% CI: 0.78-1.74; P = 0.45)., Conclusions: In this cohort study of patients with STEMI undergoing primary percutaneous coronary intervention, P2Y 12 inhibitor pretreatment was not associated with improved MACCEs., Competing Interests: Funding Support and Author Disclosures Dr Rohla has received advisory fees from Daiichi Sankyo, Sanofi Aventis, COR2ED, Novartis and Medtronic; and has received lecturing fees from Daiichi Sankyo, Biotronik, and Takeda Pharma, all outside of the submitted work. Dr Stortecky has received research grants to the institution from Edwards Lifesciences, Medtronic, Abbott Vascular, and Boston Scientific; and has received speaker fees from Boston Scientific. Dr Praz has received travel expenses from Abbott Vascular, Polares Medical, and Edwards Lifesciences. Dr Pilgrim has received research grants to the institution from Medtronic, Abbott, Biotronik, Boston Scientific, and Edwards Lifesciences; and has received speaker fees/consultancy from Medtronic, Biotronik, Boston Scientific, Abbott, and HighLife SAS. Dr Windecker reports research, travel, or educational grants to the institution without personal remuneration from Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Braun, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardinal Health, CardioValve, Cordis Medical, Corflow Therapeutics, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Farapulse Inc Fumedica, Guerbet, Idorsia, Inari Medical, InfraRedx, Janssen-Cilag, Johnson & Johnson, Medalliance, Medicure, Medtronic, Merck Sharp and Dohm, Miracor Medical, Novartis, Novo Nordisk, Organon, OrPha Suisse, Pharming Tech. Pfizer, Polares, Regeneron, Sanofi-Aventis, Servier, Sinomed, Terumo, Vifor, and V-Wave; has served as an advisory board member and/or member of the steering/executive group of trials funded by Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Boston Scientific, Biotronik, Bristol Myers Squibb, Edwards Lifesciences, MedAlliance, Medtronic, Novartis, Polares, Recardio, Sinomed, Terumo, and V-Wave with payments to the institution but no personal payments; is member of the steering/executive committee group of several investigator-initiated trials that receive funding by industry without impact on his personal remuneration; is vice president of the European Society of Cardiology; and is associate editor of the JACC: Cardiovascular Interventions. Dr Räber has received research grants to the institution by Abbott, Biotronik, Heartflow, Sanofi, and Regeneron; and has received speaker/consultation fees from Abbott, Amgen, AstraZeneca, Canon, Novo Nordisk, Medtronic, Sanofi, Occlutech, and Vifor. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Modified vaccinia Ankara (MVA) virus does not replicate in human cells and is the vaccine deployed to curb the current outbreak of mpox. Here, we conduct a multiplexed proteomic analysis to quantify >9000 cellular and ~80% of viral proteins throughout MVA infection of human fibroblasts and macrophages. >690 human proteins are down-regulated >2-fold by MVA, revealing a substantial remodelling of the host proteome. >25% of these MVA targets are not shared with replication-competent vaccinia. Viral intermediate/late gene expression is necessary for MVA antagonism of innate immunity, and suppression of interferon effectors such as ISG20 potentiates virus gene expression. Proteomic changes specific to infection of macrophages indicate modulation of the inflammatory response, including inflammasome activation. Our approach thus provides a global view of the impact of MVA on the human proteome and identifies mechanisms that may underpin its abortive infection. These discoveries will prove vital to design future generations of vaccines., (© 2023. The Author(s).)

Extensive efforts are underway to develop bacteriophages as therapies against antibiotic-resistant bacteria. However, these efforts are confounded by the instability of phage preparations and a lack of suitable tools to assess active phage concentrations over time. In this study, we use dynamic light scattering (DLS) to measure changes in phage physical state in response to environmental factors and time, finding that phages tend to decay and form aggregates and that the degree of aggregation can be used to predict phage bioactivity. We then use DLS to optimize phage storage conditions for phages from human clinical trials, predict bioactivity in 50-y-old archival stocks, and evaluate phage samples for use in a phage therapy/wound infection model. We also provide a web application (Phage-Estimator of Lytic Function) to facilitate DLS studies of phages. We conclude that DLS provides a rapid, convenient, and nondestructive tool for quality control of phage preparations in academic and commercial settings., (© The Author(s) 2023. Published by Oxford University Press on behalf of National Academy of Sciences.)

We purified two novel bacteriophages from soil collected in Sioux County, Iowa: BAjuniper and Tedro. These bacteriophages were isolated from the host, Microbacterium foliorum . BAjuniper was assigned to cluster EB, and Tedro was assigned to cluster EF. Both phages display genomes typical of other phages in their clusters., Competing Interests: The authors declare no conflict of interest.

Pancreatic ductal adenocarcinoma (PDAC) is generally refractory to immune checkpoint blockade, although patients with genetically unstable tumors can show modest therapeutic benefit. We previously demonstrated the presence of tumor-reactive CD8 + T cells in PDAC samples. Here, we charted the tumor-infiltrating T cell repertoire in PDAC by combining single-cell transcriptomics with functional testing of T cell receptors (TCRs) for reactivity against autologous tumor cells. On the basis of a comprehensive dataset including 93 tumor-reactive and 65 bystander TCR clonotypes, we delineated a gene signature that effectively distinguishes between these T cell subsets in PDAC, as well as in other tumor indications. This revealed a high frequency of tumor-reactive TCR clonotypes in three genetically unstable samples. In contrast, the T cell repertoire in six genetically stable PDAC tumors was largely dominated by bystander T cells. Nevertheless, multiple tumor-reactive TCRs were successfully identified in each of these samples, thereby providing a perspective for personalized immunotherapy in this treatment-resistant indication.

Despite proven effectiveness, compression therapy is applied in only 20-40% of patients with venous leg ulceration, leading to avoidable chronification and morbidity. The Ulcus Cruris Care project was established to develop a new disease-management concept comparable to existing programs for chronic diseases to support evidence-based treatment of venous leg ulceration. This prospective controlled study assessed its first implementation. Interventional elements comprised online training for general practitioner practices, software support for case management, and educational materials for patients. A total of 20 practices and 40 patients were enrolled in a 1:1 ratio to the intervention and control group. Guideline-conform compression therapy was applied more frequently in the intervention group (19/20 [95%] vs. 11/19 [58%]; p = 0.006). For patients with ulcers existing ≤ 6 months, the healing rate at 12 weeks was 8/11 [73%] (intervention) compared to 4/11 [36%] (control; p = 0.087). Patients after intervention had higher scores for self-help and education in the PACIC-5A questionnaire (42.9 ± 41.6 vs. 11.4 ± 28.8; p = 0.044). Treatment costs were EUR 1.380 ± 1.347 (intervention) and EUR 2.049 ± 2.748 (control; p = 0.342). The results of this study indicate that the Ulcus Cruris Care intervention may lead to a significant improvement in care. Consequently, a broader rollout in German healthcare seems warranted.

Intrinsically disordered proteins (IDPs) are often multifunctional and frequently posttranslationally modified. Deleted in split hand/split foot 1 (Dss1-Sem1 in budding yeast) is a highly multifunctional IDP associated with a range of protein complexes. However, it remains unknown if the different functions relate to different modified states. In this work, we show that Schizosaccharomyces pombe Dss1 is a substrate for casein kinase 2 in vitro, and we identify three phosphorylated threonines in its linker region separating two known disordered ubiquitin-binding motifs. Phosphorylations of the threonines had no effect on ubiquitin-binding but caused a slight destabilization of the C-terminal α-helix and mediated a direct interaction with the forkhead-associated (FHA) domain of the RING-FHA E3-ubiquitin ligase defective in mitosis 1 (Dma1). The phosphorylation sites are not conserved and are absent in human Dss1. Sequence analyses revealed that the Txx(E/D) motif, which is important for phosphorylation and Dma1 binding, is not linked to certain branches of the evolutionary tree. Instead, we find that the motif appears randomly, supporting the mechanism of ex nihilo evolution of novel motifs. In support of this, other threonine-based motifs, although frequent, are nonconserved in the linker, pointing to additional functions connected to this region. We suggest that Dss1 acts as an adaptor protein that docks to Dma1 via the phosphorylated FHA-binding motifs, while the C-terminal α-helix is free to bind mitotic septins, thereby stabilizing the complex. The presence of Txx(D/E) motifs in the disordered regions of certain septin subunits may be of further relevance to the formation and stabilization of these complexes., (© 2023 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)

Background: Whether ultrathin-strut stents are particularly beneficial for lesions requiring implantation of more than 1 stent is unknown., Methods: In a post-hoc lesion-level analysis of 2 randomized trials comparing ultrathin-strut biodegradable polymer Sirolimus-eluting stents (BP-SES) vs thin-strut durable polymer Everolimus-eluting stents (DP-EES), lesions were stratified into multistent lesions (MSL) vs single-stent lesions (SSL). The primary endpoint was target lesion failure (TLF), a composite of lesion-related unclear/cardiac death, myocardial infarction (MI), or revascularization, at 24 months., Results: Among 5328 lesions in 3397 patients, 1492 (28%) were MSL (722 with BP-SES, 770 with DP-EES). At 2 years, TLF occurred in 63 lesions (8.9%) treated with BP-SES and 60 lesions (7.9%) treated with DP-EES in the MSL-group (subdistibution hazard ratio [SHR], 1.13; 95% CI, 0.77-1.64; P = .53), and in 121 (6.4%) and 136 (7.4%) lesions treated with BP-SES and DP-EES respectively (SHR, 0.86; 95% CI, 0.62-1.18; P = .35) in the SSL-group (P for interaction = .241). While the rates of lesion-related MI or revascularization were significantly lower in SSL treated with BP-SES as compared to DP-EES (3.5% vs 5.2%; SHR, 0.67; 95% CI 0.46-0.97; P = .036), no significant difference was observed in MSL (7.1% vs 5.4%; SHR, 1.31; 95% CI 0.85-2.03; P = .216) with significant interaction between groups (P for interaction = .014)., Conclusions: Rates of TLF are similar between ultrathin-strut BP-SES and thin-strut DP-EES in MSL and SSL. The use of ultrathin-strut BP-SES vs thin-strut DP-EES did not prove to be particularly beneficial for the treatment of multistent lesions., Trial Registration: Post-hoc analysis from the BIOSCIENCE (NCT01443104) and BIOSTEMI (NCT02579031) trials., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Strict monitoring of blood glucose during pregnancy is essential for ensuring optimal maternal and neonatal outcomes. Telemedicine could be a promising solution for supporting diabetes management; however, an updated meta-analysis is warranted. This study assesses the effects of telemedicine solutions for managing gestational and pregestational diabetes., Methods: PubMed, EMBASE, Cochrane Library Central Register of Controlled Trials, and CINAHL were searched up to October 14, 2020. All randomized trials assessing the effects of telemedicine in managing diabetes in pregnancy relative to any comparator without the use of telemedicine were included. The primary outcome was infant birth weight. A meta-analysis comparing the mean difference (MD) in birth weight across studies was applied, and subgroup and sensitivity analyses were performed. The revised Cochrane tool was applied to assess the risk of bias, and the certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach., Results: From a total of 18 studies, ten (totaling 899 participants) were used to calculate the effect on infant birth weight. The results nonsignificantly favored the control (MD of 19.34 g; [95% confidence interval, CI -47.8; 86.47]), with moderate effect certainty. Heterogeneity was moderate ( I 2 = 37.39%). Statistically significant secondary outcomes included differences in two-hour glucose tolerance postpartum (gestational diabetes; two studies: standardized mean difference 9.62 mg/dL [95% CI: 1.95; 17.28]) that favored the control (GRADE level, very low) and risk of shoulder dystocia (four studies: log odds -1.34 [95% CI: -2.61; -0.08]) that favored telemedicine (GRADE, low)., Conclusions: No evidence was found to support telemedicine as an alternative to usual care when considering maternal and fetal outcomes. However, further research is needed, including economic evaluations., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Atomically thin layered van der Waals heterostructures feature exotic and emergent optoelectronic properties. With growing interest in these novel quantum materials, the microscopic understanding of fundamental interfacial coupling mechanisms is of capital importance. Here, using multidimensional photoemission spectroscopy, we provide a layer- and momentum-resolved view on ultrafast interlayer electron and energy transfer in a monolayer-WSe 2 /graphene heterostructure. Depending on the nature of the optically prepared state, we find the different dominating transfer mechanisms: while electron injection from graphene to WSe 2 is observed after photoexcitation of quasi-free hot carriers in the graphene layer, we establish an interfacial Meitner-Auger energy transfer process following the excitation of excitons in WSe 2 . By analysing the time-energy-momentum distributions of excited-state carriers with a rate-equation model, we distinguish these two types of interfacial dynamics and identify the ultrafast conversion of excitons in WSe 2 to valence band transitions in graphene. Microscopic calculations find interfacial dipole-monopole coupling underlying the Meitner-Auger energy transfer to dominate over conventional Förster- and Dexter-type interactions, in agreement with the experimental observations. The energy transfer mechanism revealed here might enable new hot-carrier-based device concepts with van der Waals heterostructures., (© 2023. Springer Nature Limited.)

Human tripartite motif protein 5α (TRIM5α) is a well-characterized restriction factor for some RNA viruses, including HIV 1-5 ; however, reports are limited for DNA viruses 6,7 . Here we demonstrate that TRIM5α also restricts orthopoxviruses and, via its SPRY domain, binds to the orthopoxvirus capsid protein L3 to diminish virus replication and activate innate immunity. In response, several orthopoxviruses, including vaccinia, rabbitpox, cowpox, monkeypox, camelpox and variola viruses, deploy countermeasures. First, the protein C6 binds to TRIM5 via the RING domain to induce its proteasome-dependent degradation. Second, cyclophilin A (CypA) is recruited via interaction with the capsid protein L3 to virus factories and virions to antagonize TRIM5α; this interaction is prevented by cyclosporine A (CsA) and the non-immunosuppressive derivatives alisporivir and NIM811. Both the proviral effect of CypA and the antiviral effect of CsA are dependent on TRIM5α. CsA, alisporivir and NIM811 have antiviral activity against orthopoxviruses, and because these drugs target a cellular protein, CypA, the emergence of viral drug resistance is difficult. These results warrant testing of CsA derivatives against orthopoxviruses, including monkeypox and variola., (© 2023. The Author(s).)

Background: Treatment with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors on top of statins leads to plaque regression and stabilisation. The effects of PCSK9 inhibitors on coronary physiology and angiographic diameter stenosis (DS%) are unknown., Aims: This study aimed to investigate the effects of the PCSK9 inhibitor alirocumab on coronary haemodynamics as assessed by quantitative flow ratio (QFR) and DS% by three-dimensional quantitative coronary angiography (3D-QCA) in non-infarct-related arteries (non-IRA) among acute myocardial infarction (AMI) patients., Methods: This was a prespecified substudy of the randomised controlled PACMAN-AMI trial, comparing alirocumab versus placebo on top of rosuvastatin. QFR and 3D-QCA were assessed at baseline and 1 year in any non-IRA ≥2.0 mm and 3D-QCA DS% >25%. The prespecified primary endpoint was the number of patients with a mean QFR increase at 1 year, and the secondary endpoint was the change in 3D-QCA DS%., Results: Of 300 enrolled patients, 265 had serial follow-up, of which 193 underwent serial QFR/3D-QCA analysis in 282 non-IRA. At 1 year, QFR increased in 50/94 (53.2%) patients with alirocumab versus 40/99 (40.4%) with placebo (Δ12.8%; odds ratio 1.7, 95% confidence interval [CI]: 0.9 to 3.0; p=0.076). DS% decreased by 1.03±7.28% with alirocumab and increased by 1.70±8.27% with placebo (Δ-2.50%, 95% CI: -4.43 to -0.57; p=0.011)., Conclusions: Treatment of AMI patients with alirocumab versus placebo for 1 year resulted in a significant regression in angiographic DS%, whereas no overall improvement of coronary haemodynamics was observed., Clinicaltrials: gov: NCT03067844.

When an organism is challenged with a pathogen a cascade of events unfolds. The innate immune system rapidly mounts a preliminary nonspecific defense, while the acquired immune system slowly develops microbe-killing specialists. These responses cause inflammation, and along with the pathogen cause direct and indirect tissue damage, which anti-inflammatory mediators seek to temper. This interplay of systems is credited for maintaining homeostasis but may produce unexpected results such as disease tolerance. Tolerance is characterized by the persistence of pathogen and damage mitigation, where the relevant mechanisms are poorly understood. In this work we develop an ordinary differential equations model of the immune response to infection in order to identify key components in tolerance. Bifurcation analysis uncovers health, immune- and pathogen-mediated death clinical outcomes dependent on pathogen growth rate. We demonstrate that decreasing the inflammatory response to damage and increasing the strength of the immune system gives rise to a region in which limit cycles, or periodic solutions, are the only biological trajectories. We then describe areas of parameter space corresponding to disease tolerance by varying immune cell decay, pathogen removal, and lymphocyte proliferation rates., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Extensive efforts are underway to develop bacteriophages as therapies against antibiotic-resistant bacteria. However, these efforts are confounded by the instability of phage preparations and a lack of suitable tools to assess active phage concentrations over time. Here, we use Dynamic Light Scattering (DLS) to measure changes in phage physical state in response to environmental factors and time, finding that phages tend to decay and form aggregates and that the degree of aggregation can be used to predict phage bioactivity. We then use DLS to optimize phage storage conditions for phages from human clinical trials, predict bioactivity in 50-year-old archival stocks, and evaluate phage samples for use in a phage therapy/wound infection model. We also provide a web-application (Phage-ELF) to facilitate DLS studies of phages. We conclude that DLS provides a rapid, convenient, and non-destructive tool for quality control of phage preparations in academic and commercial settings., Competing Interests: Competing Interest Statement: AO-B, JDB, RM are members of Felix Biotechnology, Inc., a phage therapy company. All other authors declare they have no competing interests.

Propagation of light-emitting quasiparticles is of central importance across the fields of condensed matter physics and nanomaterials science. We experimentally demonstrate diffusion of excitons in the presence of a continuously tunable Fermi sea of free charge carriers in a monolayer semiconductor. Light emission from tightly bound exciton states in electrically gated WSe 2 monolayer is detected using spatially and temporally resolved microscopy. The measurements reveal a nonmonotonic dependence of the exciton diffusion coefficient on the charge carrier density in both electron and hole doped regimes. Supported by analytical theory describing exciton-carrier interactions in a dissipative system, we identify distinct regimes of elastic scattering and quasiparticle formation determining exciton diffusion. The crossover region exhibits a highly unusual behavior of an increasing diffusion coefficient with increasing carrier densities. Temperature-dependent diffusion measurements further reveal characteristic signatures of freely propagating excitonic complexes dressed by free charges with effective mobilities up to 3 × 10 3 cm 2 /(V s).

Aims: Routine revascularization in patients with ST-segment elevation myocardial infarction (STEMI) presenting >48 h after symptom onset is not recommended., Methods and Results: We compared outcomes of STEMI patients undergoing percutaneous coronary intervention (PCI) according to total ischaemic time. Patients included in the Bern-PCI registry and the Multicenter Special Program University Medicine ACS (SPUM-ACS) between 2009 and 2019 were analysed. Based on symptom-to-balloon-time, patients were categorized as early (<12 h), late (12-48 h), or very late presenters (>48 h). Co-primary endpoints were all-cause mortality and target lesion failure (TLF), a composite of cardiac death, target vessel myocardial infarction, and target lesion revascularization at 1 year. Of 6589 STEMI patients undergoing PCI, 73.9% were early, 17.2% late, and 8.9% very late presenters. The mean age was 63.4 years, and 22% were female. At 1 year, all-cause mortality occurred more frequently in late vs. early [5.8 vs. 4.4%, hazard ratio (HR) 1.34, 95% confidence interval (CI) 1.01-1.78, P = 0.04] and very late (6.8%) vs. early presenters (HR 1.59, 95% CI 1.12-2.25, P < 0.01). There was no excess in mortality comparing very late and late presenters (HR 1.18, 95% CI 0.79-1.77, P = 0.42). Target lesion failure was more frequent in late vs. early (8.3 vs. 6.5%, HR 1.29, 95% CI 1.02-1.63, P = 0.04) and very late (9.4%) vs. early presenters (HR 1.47, 95% CI 1.09-1.97, P = 0.01), and similar between very late and late presenters (HR 1.14, 95% CI 0.81-1.60, P = 0.46). Following adjustment, heart failure, impaired renal function, and previous gastrointestinal bleeding, but not treatment delay, were the main drivers of outcomes., Conclusion: PCI >12 h after symptom onset was associated with less favourable outcomes, but very late vs. late presenters did not have an excess in events. While benefits seem uncertain, (very) late PCI appeared safe., Competing Interests: Conflict of interest: M.R. has received advisory fees from Daiichi Sankyo, Sanofi Aventis, COR2ED, and Novartis, and lecturing fees from Daiichi Sankyo, Biotronik, and Takeda Pharma, all outside of the submitted work. F.T. reports no potential conflicts of interest with respect to the submitted work. G.C.M.S. reports no potential conflicts of interest with respect to the submitted work. R.K. reports no potential conflicts of interest with respect to the submitted work. B.G. reports no potential conflicts of interest with respect to the submitted work. N.R. reports no potential conflicts of interest with respect to the submitted work. S.B. reports no potential conflicts of interest with respect to the submitted work. D.N. reports no potential conflicts of interest with respect to the submitted work. F.M. has received honoraria for advisory boards and conferences on dyslipidaemia from Amgen, Astra Zeneca, BMS, Eli Lilly, MSD, Sanofi, and Pfizer. J.D.H. reports no potential conflicts of interest with respect to the submitted work. T.P. has received research grants to the institution from Medtronic, Abbott, Biotronik, Boston Scientific, and Edwards Lifesciences; speaker fees/consultancy from Medtronic, Biotronik, Boston Scientific, Abbott, and HighLife SAS. O.M. reports no potential conflicts of interest with respect to the submitted work. C.M.M. reports funding for the consortium of SPUM-ACS, research grants from Sanofi (outside of the submitted work), and consulting fees from Novartis. T.L. declares institutional educational and research grants outside this work from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Daichi-Sankyo, Novartis, and Vifor, consulting fees from Daichi-Sankyo, Philipps, Pfizer, and Ineeo Inc. T.L. holds leadership positions at the European Society of Cardiology, Swiss Heart Foundation, and the Foundation for Cardiovascular Research—Zurich Heart House. M.R. has received institutional research grants from Terumo, Boston Scientific, Medtronic, Abbott Vascular, and Biotronik outside the submitted work. D.H. reports no potential conflicts of interest with respect to the submitted work. S.W. has received research grants to the institution from Abbott, Boston Scientific, Biosensors, Biotronik, the Medicines Company, Medtronic, and St. Jude Medical and honoraria from Abbott, Astra Zeneca, Eli Lilly, Boston Scientific, Biosensors, Biotronik, Medtronic, and Edwards. L.R. has received research grants to the institution by Abbott, Biotronik, Heartflow, Sanofi, Regeneron, and speaker/consultation fees by Abbott, Amgen, AstraZeneca, Canon, Novo Nordisk, Medtronic, Sanofi, Occlutech, Vifor., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Fragment-based drug discovery has played an important role in medicinal chemistry and pharmaceutical research. Despite numerous demonstrated successes, the limited diversity and overrepresentation of planar, sp 2 -rich structures in commercial libraries often hamper the full potential of this approach. Hence, the thorough design of screening libraries inevitably determines the probability for meaningful hits and subsequent structural elaboration. Against this background, we present the generation of an exclusive fragment library based on iterative entry nomination by a specifically designed computational workflow: "Fragtory". Following a pharmacophore diversity-driven approach, we used Fragtory in an interdisciplinary academic setting to guide both tailored synthesis efforts and the implementation of in-house compounds to build a curated 288-member library of sp 3 -enriched fragments. Subsequent NMR screens against a model protein and hit validation by protein crystallography led to the identification of structurally novel ligands that were further characterized by isothermal titration calorimetry, demonstrating the applicability of our experimental approach.

Background: Previous systematic reviews have aimed to clarify the effect of telemedicine on diabetes. However, such reviews often have a narrow focus, which calls for a more comprehensive systematic review within the field. Hence, the objective of the present systematic review, meta-analysis, and meta-regression is to evaluate the effectiveness of telemedicine solutions versus any comparator without the use of telemedicine on diabetes-related outcomes among adult patients with type 2 diabetes (T2D)., Methods: This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We considered telemedicine randomized controlled trials (RCT) including adults (≥18 years) diagnosed with T2D. Change in glycated hemoglobin (HbA1c, %) was the primary outcome. PubMed, EMBASE, and the Cochrane Library Central Register of Controlled Trials (CENTRAL) were searched on October 14, 2020. An overall treatment effect was estimated using a meta-analysis performed on the pool of included studies based on the mean difference (MD). The revised Cochrane risk-of-bias tool was applied and the certainty of evidence was graded using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach., Results: The final sample of papers included a total of 246, of which 168 had sufficient information to calculate the effect of HbA1c%. The results favored telemedicine, with an MD of -0.415% (95% confidence interval [CI] = -0.482% to -0.348%). The heterogeneity was great (I 2 = 93.05%). A monitoring component gave rise to the higher effects of telemedicine., Conclusions: In conclusion, telemedicine may serve as a valuable supplement to usual care for patients with T2D. The inclusion of a telemonitoring component seems to increase the effect of telemedicine.

2D hybrid perovskites are currently in the spotlight of material research for light-harvesting and -emitting applications. It remains extremely challenging, however, to externally control their optical response due to the difficulties of introducing electrical doping. Here, an approach of interfacing ultrathin sheets of perovskites with few-layer graphene and hexagonal boron nitride into gate-tunable, hybrid heterostructures, is demonstrated. It allows for bipolar, continuous tuning of light emission and absorption in 2D perovskites by electrically injecting carriers to densities as high as 10 12  cm -2 . This reveals the emergence of both negatively and positively charged excitons, or trions, with binding energies up to 46 meV, among the highest measured for 2D systems. Trions are shown to dominate light emission and propagate with mobilities reaching 200 cm 2 V -1 s -1 at elevated temperatures. The findings introduce the physics of interacting mixtures of optical and electrical excitations to the broad family of 2D inorganic-organic nanostructures. The presented strategy to electrically control the optical response of 2D perovskites highlights it as a promising material platform toward electrically modulated light-emitters, externally guided charged exciton currents, and exciton transistors based on layered, hybrid semiconductors., (© 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

A multitude of histone chaperones are required to support histones from their biosynthesis until DNA deposition. They cooperate through the formation of histone co-chaperone complexes, but the crosstalk between nucleosome assembly pathways remains enigmatic. Using exploratory interactomics, we define the interplay between human histone H3-H4 chaperones in the histone chaperone network. We identify previously uncharacterized histone-dependent complexes and predict the structure of the ASF1 and SPT2 co-chaperone complex, expanding the role of ASF1 in histone dynamics. We show that DAXX provides a unique functionality to the histone chaperone network, recruiting histone methyltransferases to promote H3K9me3 catalysis on new histone H3.3-H4 prior to deposition onto DNA. Hereby, DAXX provides a molecular mechanism for de novo H3K9me3 deposition and heterochromatin assembly. Collectively, our findings provide a framework for understanding how cells orchestrate histone supply and employ targeted deposition of modified histones to underpin specialized chromatin states., Competing Interests: Declaration of interests C.M.H. and A.G. are inventors on a patent covering the therapeutic targeting of TONSL for cancer therapy. A.G. is co-founder and chief scientific officer of Ankrin Therapeutics. A.G. is a member of Molecular Cell’s Scientific Advisory Board. A.I. and M.V.-A. are cofounders of EpiQMAx. G.M. is co-founder and member of the board of directors of Twelve Bio and is a member of the Scientific Advisory Board at Ensoma., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The coupling energies between the buckled dimers of the Si(001) surface were determined through analysis of the anisotropic critical behavior of its order-disorder phase transition. Spot profiles in high-resolution low-energy electron diffraction as a function of temperature were analyzed within the framework of the anisotropic two-dimensional Ising model. The validity of this approach is justified by the large ratio of correlation lengths, ξ&#95;{∥}^{+}/ξ&#95;{⊥}^{+}=5.2 of the fluctuating c(4×2) domains above the critical temperature T&#95;{c}=(190.6±10)  K. We obtain effective couplings J&#95;{∥}=(-24.9±1.3)  meV along the dimer rows and J&#95;{⊥}=(-0.8±0.1)  meV across the dimer rows, i.e., antiferromagneticlike coupling of the dimers with c(4×2) symmetry.

Focused lung ultrasound (FLUS) has high diagnostic accuracy in many common conditions seen in a variety of emergency settings. Competencies are essential for diagnostic success and patient safety but can be challenging to acquire in clinical environments. Immersive virtual reality (IVR) offers an interactive risk-free learning environment and is progressing as an educational tool. First, this study explored the educational impact of novice FLUS users participating in a gamified or non-gamified IVR training module in FLUS by comparing test scores using a test with proven validity evidence. Second, the learning effect was assessed by comparing scores of each group with known test scores of novices, intermediates and experienced users in FLUS. A total of 48 participants were included: 24 received gamified and 24 received non-gamified IVR training. No significant difference was found between gamified (mean = 15.5 points) and non-gamified (mean = 15.2 points), indicating that chosen gamification elements for our setup did not affect learning outcome (p = 0.66). The mean scores of both groups did not significantly differ from those of known intermediate users in FLUS (gamified p = 0.63, non-gamified p = 0.24), indicating that both IVR modules could be used as unsupervised out-of-hospital training for novice trainees in FLUS., Competing Interests: Conflict of interest disclosure R.O.J. is a co-founder and co-owner of VitaSim. R.O.J. advised the main author J.D.L. on technical solutions to developing the ultrasound training module in virtual reality. R.O.J. had no influence on data collection, data analysis, interpretation or publishing decisions. The remaining authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Despite recent educational advances, the need for a national standardized primary palliative care curriculum for health professions students remains evident. Methods: An interprofessional leadership team developed a set of core learning objectives built on previously published competencies. A survey was then sent to palliative care experts for feedback and consensus. Results: Twenty-eight of 31 objectives met a 75% consensus threshold, 2 were combined with others, and 12 were refined based on survey feedback. Discussion: With interprofessional input at all stages, we finalized a comprehensive list of 26 learning objectives for a primary palliative care curriculum targeting health professions students. These objectives will be widely available through an online course but can also be adopted for use by individual educators across health professions institutions. These objectives and related curriculum are critical to producing practice-ready clinicians who are prepared to care for the burgeoning population of seriously ill patients.

The capacity of host cells to detect and restrict an infecting virus rests on an array of cell-autonomous antiviral effectors and innate immune receptors that can trigger inflammatory processes at tissue and organismal levels. Dynamic changes in protein abundance, subcellular localisation, post-translational modifications and interactions with other biomolecules govern these processes. Proteomics is therefore an ideal experimental tool to discover novel mechanisms of host antiviral immunity. Additional information can be gleaned both about host and virus by systematic analysis of viral immune evasion strategies. In this review, we summarise recent advances in proteomic technologies and their application to antiviral innate immunity., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Opioid induced chest wall rigidity was first described in the early 1950s during surgical anesthesia and has often been referred to as fentanyl induced rigid chest syndrome (FIRCS). It has most commonly been described in the setting of procedural sedation and bronchoscopy, characterized by pronounced abdominal and thoracic rigidity, asynchronous ventilation, and respiratory failure. FIRCS has been infrequently described in the setting of continuous analgesia in critically ill adult patients. We postulate that FIRCS can occur in this setting and is likely under recognized, leading to increased morbidity and mortality., Methods: Patients admitted to the intensive care unit with suspected FIRCS were included in this retrospective analysis. The objective of this analysis is to describe the clinical presentation and treatment strategies for FIRCS., Results: Forty-two patients exhibiting symptoms of FIRCS were included in this analysis. Twenty-two of the forty-two patients with descriptive documentation had evidence of thoracic or abdominal rigidity on examination (52.4%). Twelve of sixteen (75%) patients treated solely with naloxone had documented ventilator compliance following intervention, compared to six of eleven (55%) managed with cisatracurium alone. Nine of twelve patients who ultimately received naloxone after initial treatment with cisatracurium had documented ventilator compliance following naloxone administration (75%). Standard interventions, including sedation optimization and ventilator adjustments were attempted to rule out and treat other potential causes of dyssynchrony. In most cases, the administration of naloxone resulted in appropriate compliance with both ventilator and patient-initiated breaths, suggesting the ventilator dyssynchrony was due to fentanyl., Conclusions: This is the largest case series to date describing FIRCS in the intensive care setting. Recognition and prompt management is necessary for improved patient outcomes. Research is needed to increase awareness and recognition, identify patient risk factors, and analyze the efficacy and safety of interventions.

Head and neck squamous cell carcinomas (HNSCC) caused by infections with high-risk human papillomaviruses (HPV) are responsible for an increasing number of head and neck cancers, particularly in the oropharynx. Despite the significant biological differences between HPV-driven and HPV-negative HNSCC, treatment strategies are similar and not HPV targeted. HPV-driven HNSCC are known to be more sensitive to treatment, particularly to radiotherapy, which is at least partially due to HPV-induced immunogenicity. The development of novel therapeutic strategies that are specific for HPV-driven cancers requires tumor models that reflect as closely as possible the characteristics and complexity of human tumors and their response to treatment. Current HPV-positive cancer models lack one or more hallmarks of their human counterpart. This study presents the development of a new HPV16 oncoprotein-dependent tumor model in MHC-humanized mice, modeling the major biologic features of HPV-driven tumors and presenting HLA-A2-restricted HPV16 epitopes. Furthermore, this model was developed to be orthotopic (base of tongue). Thus, it also reflects the correct tumor microenvironment of HPV-driven HNSCC. The cancer cells are implanted in a manner that allows the exact control of the anatomical location of the developing tumor, thereby homogenizing tumor growth. In conclusion, the new model is suited to study HPV16-specific therapeutic vaccinations and other immunotherapies, as well as tumor-targeted interventions, such as surgery or radiotherapy, or a combination of all these modalities.

ADP-ribosylation is a posttranslational modification (PTM) that has crucial functions in a wide range of cellular processes. Although mass spectrometry (MS) in recent years has emerged as a valuable tool for profiling ADP-ribosylation on a system level, the use of conventional MS methods to profile ADP-ribosylation sites in an unbiased way remains a challenge. Here, we describe a protocol for identification of ADP-ribosylated proteins in vivo on a proteome-wide level, and localization of the amino acid side chains modified with this PTM. The method relies on the enrichment of ADP-ribosylated peptides using the Af1521 macrodomain (Karras GI, Kustatscher G, Buhecha HR, Allen MD, Pugieux C, Sait F, Bycroft M, Ladurner AG, EMBO J 24:1911-1920, 2005), followed by liquid chromatography-high-resolution tandem MS (LC-MS/MS) with electron transfer dissociation-based peptide fragmentation methods, resulting in accurate localization of ADP-ribosylation sites. This protocol explains the step-by-step enrichment and identification of ADP-ribosylated peptides from cell culture to data processing using the MaxQuant software suite., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Optoelectronic functionalities of monolayer transition-metal dichalcogenide (TMDC) semiconductors are characterized by the emergence of externally tunable, correlated many-body complexes arising from strong Coulomb interactions. However, the vast majority of such states susceptible to manipulation has been limited to the region in energy around the fundamental bandgap. We report the observation of tightly bound, valley-polarized, UV-emissive trions in monolayer TMDC transistors: quasiparticles composed of an electron from a high-lying conduction band with negative effective mass, a hole from the first valence band, and an additional charge from a band-edge state. These high-lying trions have markedly different optical selection rules compared to band-edge trions and show helicity opposite to that of the excitation. An electrical gate controls both the oscillator strength and the detuning of the excitonic transitions, and therefore the Rabi frequency of the strongly driven three-level system, enabling excitonic quantum interference to be switched on and off in a deterministic fashion., (© 2022. The Author(s).)

Purpose: Our study analyzes the influence of minimally invasive vs. open surgery on the postoperative need for nursing care in patients with colorectal carcinoma. Colorectal cancer is an age-related disease, and oncologic surgery is increasingly performed in elderly patients. Long-term effects of the procedural choice on patients' self-sufficiency and autonomy have not been scientifically addressed so far., Methods: Multivariable logistic regression models based on claims data from a statutory health insurer (AOK, Baden-Württemberg, Germany) were applied to assess potential risk factors for assignment patients to a nursing care level, a German scale to categorize individual need for nursing care, at 12 and 36 months after colorectal cancer surgery., Results: A total of 3996 patients were eligible to be included in the analysis. At 36 months postoperatively, 44 of 427 (10.3%) patients after minimally invasive colon cancer surgery and 231 of 1287 (17.9%) patients after open procedure were newly graded into a nursing care level (OR = 0.62, 95%CI = 0.44-0.90, p = 0.010). Thirty-four of 251 (13.5%) patients receiving minimally invasive rectal cancer surgery compared to 142 of 602 (23.6%) patients after open approach were newly assigned to a nursing care level (OR = 0.53, 95%CI = 0.34-0.81, p = 0.003)., Conclusions: Laparoscopically assisted resection of colorectal cancer seems to be superior in preserving physical autonomy of elderly patients with colorectal cancer., (© 2022. The Author(s).)

Attempts to develop a therapeutic vaccine against human papillomavirus (HPV)-induced malignancies have mostly not been clinically successful to date. One reason may be the hypoxic microenvironment present in most tumors, including cervical cancer. Hypoxia dysregulates the levels of human leukocyte antigen (HLA) class I molecules in different tumor entities, impacts the function of cytotoxic T cells, and leads to decreased protein levels of the oncoproteins E6 and E7 in HPV-transformed cells. Therefore, we investigated the effect of hypoxia on the presentation of HPV16 E6- and E7-derived epitopes in cervical cancer cells and its effect on epitope-specific T cell cytotoxicity. Hypoxia induced downregulation of E7 protein levels in all analyzed cell lines, as assessed by Western blotting. However, contrary to previous reports, no perturbation of antigen processing and presentation machinery (APM) components and HLA-A2 surface expression upon hypoxia treatment was detected by mass spectrometry and flow cytometry, respectively. Cytotoxicity assays performed in hypoxic conditions showed differential effects on the specific killing of HPV16-positive cervical cancer cells by epitope-specific CD8 + T cell lines in a donor- and peptide-specific manner. Effects of hypoxia on the expression of PD-L1 were ruled out by flow cytometry analysis. Altogether, our results under hypoxia show a decreased expression of E6 and E7, but an intact APM, and epitope- and donor-dependent effects on T cell cytotoxicity towards HPV16-positive target cells. This suggests that successful immunotherapies can be developed for hypoxic HPV-induced cervical cancer, with careful choice of target epitopes, and ideally in combination with hypoxia-alleviating measures., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mohan, Wellach, Özerdem, Veits, Förster, Foehr, Bonsack and Riemer.)

Human milk (HM) is the recommended nutrition for premature infants, but it may require processing to ensure microbial safety. The current standard is Holder pasteurisation (HoP), i.e. heating milk at 62.5 ± 0.5°C for 30 min, which eliminates bacteria but destroys heat labile bioactive HM components. We aimed to test an alternative thermal method, high-temperature short-time (HTST) pasteurisation using a modified Holder pasteurisation platform as this method has shown to preserve proteins in experimental HM flow pasteurisers. We analysed the ability of this batch process to eliminate bacterial species and to retain alkaline phosphatase, secretory immunoglobulin A and lactoferrin in HM. HTST at 81°C/5 s was as effective as HoP in bacterial count reduction while the retention of bioactive components was only improved at 62°C/5 s as compared to 72°C/5 s and HoP. HTST is a promising alternative to HoP but an optimal temperature-time combination needs to be determined for each technical platform separately., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Manzardo, Toll, Müller, Nickel, Jonas, Baumgartner, Wenzel and Klotz.)

Purpose: To develop a methodology that can be used to measure the temporal latency of a respiratory gating system., Methods: The gating system was composed of an automatic gating interface (Response) and an in-house respiratory motion monitoring system featuring an optically tracked surface marker. Two approaches were used to measure gating latencies. A modular approach involved measuring separately the latency of the gating system's complementary metal-oxide-semiconductor tracking camera, tracking software, and a gating latency of the LINAC. Additionally, an end-to-end approach was used to measure the total latency of the gating system. End-to-end latencies were measured using the displacement of a radiographic target moving at known velocities during the gating process., Results: Summing together the latencies of each of the modular components investigated yielded a total beam-on latency of 1.55 s and a total beam-off latency of 0.49 s. End-to-end beam-on and beam-off latency was found to be 1.49 and 0.34 s, respectively. In each case, no statistically significant differences were found between the end-to-end latency of the gating system and the summation of the individually measured components., Conclusion: Two distinct approaches to quantify gating latencies were presented. Measuring the end-to-end latency of the gating system provided an independent means of validating the modular approach. It is expected that the beam-on latencies reported in this work could be reduced by altering the control system configuration of the LINAC. The modular approach can be used to decouple the individual latencies of the gating system, but future improvements in the temporal resolution of the service graphing feature are needed to reduce the uncertainty of LINAC-related gating latencies measured using this approach. Both approaches are generalizable and can be used together when designing a quality assurance program for a respiratory gating system., (© 2022 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)