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Motivation: Bulk RNA expression data are widely accessible, whereas single-cell data are relatively scarce in comparison. However, single-cell data offer profound insights into the cellular composition of tissues and cell type-specific gene regulation, both of which remain hidden in bulk expression analysis., Results: Here, we present tissueResolver, an algorithm designed to extract single-cell information from bulk data, enabling us to attribute expression changes to individual cell types. When validated on simulated data tissueResolver outperforms competing methods. Additionally, our study demonstrates that tissueResolver reveals cell type-specific regulatory distinctions between the activated B-cell-like (ABC) and germinal center B-cell-like (GCB) subtypes of diffuse large B-cell lymphomas (DLBCL)., Availability and Implementation: R package available at https://github.com/spang-lab/tissueResolver (archived as 10.5281/zenodo.14160846).Code for reproducing the results of this article is available at https://github.com/spang-lab/tissueResolver-docs archived as swh:1:dir:faea2d4f0ded30de774b28e028299ddbdd0c4f89)., (© The Author(s) 2024. Published by Oxford University Press.)

Lithium-ion batteries are pivotal in climate change mitigation. While their own carbon footprint raises concerns, existing studies are scattered, hard to compare and largely overlook the relevance of battery materials. Here, we go beyond traditional carbon footprint analysis and develop a cost-based approach, estimating emission curves for battery materials lithium, nickel and cobalt, based on mining cost data. Combining the emission curves with regionalised battery production announcements, we present carbon footprint distributions (5 th , 50 th , and 95 th percentiles) for lithium-ion batteries with nickel-manganese-cobalt (NMC811, 8-1-1 ratio; 59, 74 and 115 kg CO2 kWh -1 ) and lithium-iron-phosphate (LFP; 54, 62, 69 kg CO2 kWh -1 ) cathodes. Our findings reveal the dominating impact of material sourcing over production location, with nickel and lithium identified as major contributors to the carbon footprint and its variance. This research moves the field forward by offering a nuanced understanding of battery carbon footprints, aiding in the design of decarbonisation policies and strategies., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Prosthesis-patient mismatch after transcatheter aortic valve replacement (TAVR) can be measured echocardiographically (measured prosthesis-patient mismatch [PPMm]) or predicted (predicted prosthesis-patient mismatch [PPMp]) using published effective orifice area (EOA) reference values. However, the clinical implications of PPM post-TAVR remain unclear., Objectives: This study aimed to elucidate the prevalence of PPMm and PPMp post-TAVR and their impact on mortality in a large international cohort., Methods: The IMPPACT TAVR (Impact of Measured or Predicted Prosthesis-pAtient mismatCh after TAVR) registry included 38,808 TAVR patients from 26 international centers. Valve Academic Research Consortium 3 criteria were used to define prosthesis-patient mismatch severity. EOA was determined echocardiographically (PPMm) or predicted (PPMp) based on core lab-derived EOA reference values. The primary endpoint was 2-year all-cause mortality., Results: The prevalence of PPMp (moderate: 6.8%, severe: 0.6%) was significantly lower than that of PPMm (moderate: 20.7%, severe: 4.3%; P < 0.001) with negligible correlation between the 2 methods (Kendall's tau c correlation coefficient: 0.063; P < 0.001). In unadjusted analyses, severe PPMm adversely influenced 2-year survival (HR: 1.22; 95% CI: 1.02-1.45; P = 0.027), whereas severe PPMp was not associated with outcomes (HR: 0.81; 95% CI: 0.55-1.19; P = 0.291). After adjusting for confounders, neither PPMm nor PPMp had a significant effect on 2-year all-cause mortality., Conclusions: PPMm and PPMp were associated with different patient characteristics, with PPMm tending toward worse (especially low flow) and PPMp toward better (especially women) survival. After adjusting for confounders, neither PPMm nor PPMp significantly affected 2-year all-cause mortality. Hence, valve selection should not solely be based on hemodynamics but rather on a holistic approach, including patient and procedural specifics., Competing Interests: Funding Support and Author Disclosures This work was supported by the Deutsche Forschungsgemeinschaft (397484323) to Drs Guthoff, Matti Adam and Stephan Baldus, and Mauri; PA 2409/5-2 to Drs Thurow and Pauly; the Dean’s Office, Faculty of Medicine, University of Cologne (clinician scientist position) to Dr Guthoff; and the Center for Molecular Medicine Cologne (Baldus B-02) to Dr Stephan Baldus. Dr Abdel-Wahab’s institution has received speaker honoraria and/or consultancy fees from Abbott, Boston Scientific, and Medtronic. Dr Kim has received proctor and personal fees from Abbott, Boston Scientific, Meril Life Sciences, and Shockwave Med; is a member of the advisory boards for Abbott, Boston Scientific, and HID Imaging; and Dr Kim’s institution has received fees from Boston Scientific. Dr Nombela-Franco has served as proctor for Abbott and Edwards Lifesciences. Dr Matjaz Bunc served as proctor for TAVR procedures with Edwards Lifesciences, Medtronic, Meril, and Abbott. Matjaz Bunc is a member of the advisory boards for Medtronic and Edwards Lifesciences. Dr Veulemans has received speaker and/or study honoraria from Edwards Lifesciences, Medtronic, and Boston Scientific. Dr Tanja Rudolph has received lecture fees from Abbott, SIS Medical and Translumina. Dr Zeus has received speaker and/or study honoraria from Edwards Lifesciences, Medtronic, and Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims/hypothesis: Fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, shows some promise in alleviating beta cell stress and preserving beta cell function in preclinical studies of type 1 diabetes. The aim of this phase 2, placebo-controlled, double-blinded, randomised clinical trial was to investigate the efficacy and safety of fenofibrate in adults and adolescents with newly diagnosed type 1 diabetes., Methods: We enrolled 58 individuals (aged 16 to 40 years old) with newly diagnosed type 1 diabetes and randomised them to daily oral treatment with fenofibrate 160 mg or placebo for 52 weeks (in a block design with a block size of 4, assigned in a 1:1 ratio). Our primary outcome was change in beta cell function after 52 weeks of treatment, assessed by AUC for C-peptide levels following a 2 h mixed-meal tolerance test. Secondary outcomes included glycaemic control (assessed by HbA 1c and continuous glucose monitoring), daily insulin use, and proinsulin/C-peptide (PI/C) ratio as a marker of beta cell stress. We assessed outcome measures before and after 4, 12, 26 and 52 weeks of treatment. Blinding was maintained for participants, their healthcare providers and all staff involved in handling outcome samples and assessment., Results: The statistical analyses for the primary outcome included 56 participants (n=27 in the fenofibrate group, after two withdrawals, and n=29 in the placebo group). We found no significant differences between the groups in either 2 h C-peptide levels (mean difference of 0.08 nmol/l [95% CI -0.05, 0.23]), insulin use or glycaemic control after 52 weeks of treatment. On the contrary, the fenofibrate group showed a higher PI/C ratio at week 52 compared with placebo (mean difference of 0.024 [95% CI 0.000, 0.048], p<0.05). Blood lipidome analysis revealed that fenofibrate repressed pathways involved in sphingolipid metabolism and signalling at week 52 compared with placebo. The 52 week intervention evoked few adverse events and no serious adverse events. Follow-up in vitro experiments in human pancreatic islets demonstrated a stress-inducing effect of fenofibrate., Conclusions/interpretation: Contrary to the beneficial effects of fenofibrate found in preclinical studies, this longitudinal, randomised, placebo-controlled trial does not support the use of fenofibrate for preserving beta cell function in individuals with newly diagnosed type 1 diabetes., Trial Registration: EudraCT number: 2019-004434-41 FUNDING: This study was funded by the Sehested Hansens Foundation., (© 2024. The Author(s).)

Motion analysis is of great interest to a variety of applications, such as virtual and augmented reality and medical diagnostics. Hand movement tracking systems, in particular, are used as a human-machine interface. In most cases, these systems are based on optical or acceleration/angular speed sensors. These technologies are already well researched and used in commercial systems. In special applications, it can be advantageous to use magnetic sensors to supplement an existing system or even replace the existing sensors. The core of a motion tracking system is a localization unit. The relatively complex localization algorithms present a problem in magnetic systems, leading to a relatively large computational complexity. In this paper, a new approach for pose estimation of a kinematic chain is presented. The new algorithm is based on spatially rotating magnetic dipole sources. A spatial feature is extracted from the sensor signal, the dipole direction in which the maximum magnitude value is detected at the sensor. This is introduced as the "maximum vector". A relationship between this feature, the location vector (pointing from the magnetic source to the sensor position) and the sensor orientation is derived and subsequently exploited. By modelling the hand as a kinematic chain, the posture of the chain can be described in two ways: the knowledge about the magnetic correlations and the structure of the kinematic chain. Both are bundled in an iterative algorithm with very low complexity. The algorithm was implemented in a real-time framework and evaluated in a simulation and first laboratory tests. In tests without movement, it could be shown that there was no significant deviation between the simulated and estimated poses. In tests with periodic movements, an error in the range of 1° was found. Of particular interest here is the required computing power. This was evaluated in terms of the required computing operations and the required computing time. Initial analyses have shown that a computing time of 3 μs per joint is required on a personal computer. Lastly, the first laboratory tests basically prove the functionality of the proposed methodology.

RNA binding proteins drive proliferation and tumorigenesis by regulating the translation and stability of specific subsets of messenger RNAs (mRNAs). We have investigated the role of eukaryotic initiation factor 4B (eIF4B) in this process and identify 10-fold more RNA binding sites for eIF4B in tumour cells from patients with diffuse large B-cell lymphoma compared to control B cells and, using individual-nucleotide resolution UV cross-linking and immunoprecipitation, find that eIF4B binds the entire length of mRNA transcripts. eIF4B stimulates the helicase activity of eIF4A, thereby promoting the unwinding of RNA structure within the 5' untranslated regions of mRNAs. We have found that, in addition to its well-documented role in mRNA translation, eIF4B additionally interacts with proteins associated with RNA turnover, including UPF1 (up-frameshift protein 1), which plays a key role in histone mRNA degradation at the end of S phase. Consistent with these data, we locate an eIF4B binding site upstream of the stem-loop structure in histone mRNAs and show that decreased eIF4B expression alters histone mRNA turnover and delays cell cycle progression through S phase. Collectively, these data provide insight into how eIF4B promotes tumorigenesis., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Ubiquitination typically involves covalent linking of ubiquitin (Ub) to a lysine residue on a protein substrate. Recently, new facets of this process have emerged, including Ub modification of non-proteinaceous substrates like ADP-ribose by the DELTEX E3 ligase family. Here, we show that the DELTEX family member DTX3L expands this non-proteinaceous substrate repertoire to include single-stranded DNA and RNA. Although the N-terminal region of DTX3L contains single-stranded nucleic acid binding domains and motifs, the minimal catalytically competent fragment comprises the C-terminal RING and DTC domains (RD). DTX3L-RD catalyses ubiquitination of the 3'-end of single-stranded DNA and RNA, as well as double-stranded DNA with a 3' overhang of two or more nucleotides. This modification is reversibly cleaved by deubiquitinases. NMR and biochemical analyses reveal that the DTC domain binds single-stranded DNA and facilitates the catalysis of Ub transfer from RING-bound E2-conjugated Ub. Our study unveils the direct ubiquitination of nucleic acids by DTX3L, laying the groundwork for understanding its functional implications., Competing Interests: ED, CC, LB, SA, TS, MB, BS No competing interests declared, DH D.T.H is a consultant for Triana Biomedicines, (© 2024, Dearlove, Chatrin et al.)

Atrial fibrillation (AF) is the most common rhythm disorder with a high risk for cardioembolic strokes. Interventional occlusion of the left atrial appendage (LAA) is an alternative to the widely established stroke prevention with oral anticoagulation. Complications through LAA closure (LAAC) are rare and usually occur periinterventional. We present a case of an 87-year-old patient who presents for elective LAAC. After placement of the LAA occluder (Amplatzer Amulet device 25 mm) in the LAA and partial resheathing, the patient developed a pericardial effusion (PE), became hemodynamically unstable and went into cardiac arrest with the need for cardiopulmonary resuscitation (CPR). After drainage of the PE, we closed the causative LAA-perforation using a persistent foramen ovale (PFO)-occluder device (Amplatzer Talisman, 25 mm). Thereby we were able to successfully seal the perforation and stabilize the patient. The patient was monitored at our intensive care unit for 2 days and left the hospital in good condition a few days after. Procedural complications during interventional LAAC are rare but can be serious. The most common complication, PE, requires percutaneous drainage and often cardiac surgery. We present a case in which a perforation and following PE with hemodynamic relevance and need for CPR was resolved with an interventional strategy through implantation of a PFO-occluder into the perforation. With this approach we were able to show that in the right setting even serious complications can be treated by interventional measures, thereby not only saving the patient's life, but also avoiding cardiac surgery., (© 2024 The Author(s). Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)

Background: Patients with mitral regurgitation (MR) and morphologic presence of relevant mitral annular calcification (MAC) represent a challenging phenotypic subset with limited treatment options., Objectives: The aim of this study was to assess the feasibility of transcatheter mitral valve replacement (TMVR) using dedicated devices for the treatment of MAC patients., Methods: Consecutive patients with symptomatic MR receiving TMVR and with available computed tomography data from the CHOICE-MI (Choice of Optimal Transcatheter Treatment for Mitral Insufficiency) multicenter registry were stratified by the presence of none or mild mitral annular calcification (MAC none/mild ) vs moderate or severe mitral annular calcification (MAC mod/sev )., Results: Among 279 eligible patients (median age = 76.0 years [Q1-Q3: 71.0-81.0 years], EuroSCORE II = 6.2% [Q1-Q3: 3.9%-12.1%]), 222 (79.6%) presented with MAC none/mild and 57 (20.4%) with MAC mod/sev . Patients with MAC mod/sev  had a higher prevalence of extracardiac arteriopathy (P = 0.011) and primary MR (P < 0.001). Although the technical success rate and the extent of MR elimination did not differ, TMVR treatment in MAC mod/sev patients was associated with higher rates of postprocedural bleeding complications (P = 0.02) and renal failure (P < 0.001). Functional improvement at the 1- and 2-year follow-up did not differ between groups. At the 2-year follow-up, there were no differences between patients with MAC mod/sev and MAC none/mild regarding all-cause mortality (38.5% vs 37.7%; P = 0.76), cardiovascular mortality (21.3% vs 24.9%; P = 0.97), and all-cause mortality or heart failure hospitalization (52.4% vs 46.7%; P = 0.28) CONCLUSIONS: TMVR in patients with MAC mod/sev is associated with higher rates of postprocedural complications but similar rates of survival, MR resolution, and functional improvement compared to MAC none/mild . Further studies are necessary to define the role of dedicated TMVR devices in this population. (Choice of Optimal Transcatheter Treatment for Mitral Insufficiency Registry [CHOICE-MI]; NCT04688190)., Competing Interests: Funding Support and Author Disclosures This study was supported by a grant from the German Heart Foundation. Dr Coisne is a proctor for Abbott Vascular; and has received speaker fees for Abbot Vascular, Edwards Lifesciences, GE Healthcare, Merck Sharp & Dohme, and Pfizer. Dr Ludwig has received travel compensation from Edwards Lifesciences; has received honoraria from Bayer and Abbott; is a consultant for NVT; and was supported by a research grant from the German Heart Foundation. Dr Ali has received research grants from Medtronic and Edwards Lifesciences. Dr Duncan is a consultant for and has received honoraria from Abbott Laboratories, Edward Lifesciences, and Medtronic. Dr Kalbacher has received personal fees from Abbott, Edwards Lifesciences, Pi-Cardia Ltd, and Medtronic. Dr Rudolph has received speaker honoraria from Abbott Vascular. Dr Hausleiter has received consulting fees, speaker honoraria, and support of research projects paid to the institution from Abbott Vascular and Edwards Lifesciences. Dr Ruge serves as a physician proctor for Abbott and Edwards Lifesciences; is a consultant for Medtronic, Abbott, and Edwards Lifesciences; and is a member of the Abbott Advisory Board. Dr Schmidt has received consultant fees and travel support from Cardiovalve. Dr Taramasso is consultant or has received consultancy fees from Abbott, Edwards Lifesciences, Medtronic, Boston Scientific, Shenqi Medical, MEDIRA, PiCardia, CoreMedic, Cardiovalve, Simulands, CoreQuest, HiD Imaging, and OneCrea Medical. Dr Denti has received speaker honoraria from Abbott and Edwards Lifesciences; and has received consultant fees from Approxima, HVR, InnovHeart, and Pi-Cardia Ltd. Dr Andreas is a proctor, consultant, and speaker for Edwards Lifesciences, Abbott, Medtronic, Boston, and Zoll; and has received institutional research grants from Edwards Lifesciences, Abbott, Medtronic, and LSI. 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.)

Introduction: IgG4-related disease is an immune-mediated condition characterized by tissue infiltration of IgG4-positive plasma cells. Involvement of the spinal meninges results in hypertrophic spinal pachymeningitis (HSP), causing spinal cord and nerve root compression., Research Question and Case Description: In this review, we present a case of IgG4-related hypertrophic spinal pachymeningitis. Furthermore, we provide an updated literature review on IgG4-related HSP., Materials and Methods: We describe the case of a 45-year-old male presenting with cervical myelopathy. MR-imaging showed a ventrodorsal thickening of the meninges resulting in spinal cord compression. The patient underwent surgical decompression through laminectomy and excision of the dural thickening. The pathological findings demonstrated hypertrophic pachymeningitis with further examination showing large-scale dural infiltration of IgG4-positive lymphocytes. Adjuvant therapy with methylprednisolone and rituximab resulted in full neurological recovery with no signs of recurrence on MRI or clinically 12 months postoperatively.An updated review of the literature regarding IgG4-related HSP was performed according to PRISMA-guidelines. Relevant articles were searched from the PubMed, Web of Science and Embase databases. Patient characteristics, MRI- and histopathological findings, treatment modality and outcome were reviewed., Results: The literature review provided a summary of 52 available cases, which included the one cases from our centre. Progressive worsening of neurological impairment was observed in 28 patients (58%). The lesions involved the thoracic spine (n = 33, 62.2%), cervical spine (n = 35, 70%), lumbar spine (n = 10, 20%), and sacral spine (n = 1, 2.2%). The dural thickening typically appeared as striated, fusiform, or oval changes, with homogeneous and patterns being the most common. Surgical decompression followed by immunosuppressive treatment was the main choice of therapy. The disease proved fatal in one case., Discussion and Conclusion: IgG4-related HSP usually affects the cervical and thoracic dura and therefore often presents with myelopathy. Surgical decompression in cases of neurological deficits may prevent permanent neurological impairment. Immunosuppressive therapy constitutes the cornerstone in the treatment IgG4-related HSP., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors.)

Astronomical precision spectroscopy underpins searches for life beyond Earth, direct observation of the expanding Universe and constraining the potential variability of physical constants on cosmological scales. Laser frequency combs can provide the required accurate and precise calibration to the astronomical spectrographs. For cosmological studies, extending the calibration with such astrocombs to the ultraviolet spectral range is desirable, however, strong material dispersion and large spectral separation from the established infrared laser oscillators have made this challenging. Here, we demonstrate astronomical spectrograph calibration with an astrocomb in the ultraviolet spectral range below 400 nm. This is accomplished via chip-integrated highly nonlinear photonics in periodically-poled, nano-fabricated lithium niobate waveguides in conjunction with a robust infrared electro-optic comb generator, as well as a chip-integrated microresonator comb. These results demonstrate a viable route towards astronomical precision spectroscopy in the ultraviolet and could contribute to unlock the full potential of next-generation ground-based and future space-based instruments., (© 2024. The Author(s).)

Recent studies have shown that the extramuscular connective tissue (ECT) is thickened and stiffened in delayed onset muscle soreness (DOMS). However, contrarily to the normal population, severe DOMS is rare in athletes or highly trained individuals. The present randomized, controlled trial therefore aimed to investigate pain as well as microcirculation and stiffness of the ECT and the erector spinae muscle following submaximal eccentric trunk extension exercise not causing DOMS. The effect of manual treatment by a therapist (myofascial release; MFR) on these parameters was to be studied. Trained healthy participants (n = 21; 31.3 ± 9.6 years; > 4 h exercise per week) performed submaximal eccentric exercise of the trunk extensors. One group was manually treated (n = 11), while the other group (n = 10) received placebo treatment with sham laser therapy. Stiffness of the ECT and the erector spinae muscle (shear wave elastography), microcirculation (white light and laser Doppler spectroscopy), palpation pain (100 mm visual analogue scale, VAS) and pressure pain threshold (indentometry, PPT) were assessed before (t 0 ), 24 h (t 24 ) and 48 h (t 48 ) after conditions. Erector spinae muscle stiffness increased after eccentric exercise from t 0 to t 24 (0.875 m/s) and from t 0 to t 48 (0.869 m/s). After MFR, erector spinae muscle stiffness decreased in contrast to placebo treatment at t 24 (-0.66 m/s), while ECT stiffness remained unchanged. Oxygen saturation increased (17-20.93%) and relative haemoglobin decreased (-9.1 - -12.76 AU) after eccentric exercise and MFR differed from placebo treatment at t 48 (-3.71 AU). PPT differed after MFR from placebo treatment at t 48 (20.69 N/mm), while VAS remained unchanged. Multiple linear regression showed that ECT stiffness and group membership predicted erector spinae muscle stiffness. MFR could have a positive effect on pain, microcirculation and muscle stiffness after submaximal eccentric exercise, suggesting better recovery, which needs to be confirmed by future work., (© Journal of Sports Science and Medicine.)

Background and Aims: Glycoprotein (GP) IIb/IIIa inhibitors are recommended in acute myocardial infarction (AMI) for bailout treatment in case of angiographic microvascular obstruction (MVO), also termed no-reflow phenomenon, after percutaneous coronary intervention (PCI) with, however, lacking evidence (class IIa, level C)., Methods: The investigator-initiated, international, multicenter REVERSE-FLOW trial randomized 120 patients with AMI and Thrombolysis In Myocardial Infarction flow grade ≤2 after primary PCI to optimal medical therapy with or without GP IIb/IIIa inhibitor. The primary endpoint was infarct size (%LV) assessed by cardiac magnetic resonance (CMR). Secondary endpoints included CMR-derived MVO and 30-day adverse clinical events. The trial is registered with ClinicalTrials.gov: NCT02739711., Results: The population was predominantly male (76.7%) with a median age of 66 years and ST-elevation myocardial infarction in 73.3% of patients. Clinical and angiographic characteristics were well balanced between the cohorts. Patients in the treatment group (n=62) received eptifibatide (n=41) or tirofiban (n=21). Infarct size assessed by CMR imaging was similar in both study groups (25.4% of left ventricular mass [LV] vs. 25.2%LV; p=0.386). However, the number of patients with evidence of CMR-derived MVO (74.5% vs. 92.2%; p=0.017) and the extent of MVO (2.1%LV vs. 3.4%LV; p=0.025) were significantly reduced in the GP IIb/IIIa inhibitor group compared to controls. Thirty-day outcome showed an increased bleeding risk after GP IIb/IIIa inhibitor administration restricted to non-life-threatening bleedings (22.6% vs. 6.9%; p=0.016) without differences in all-cause mortality (4.8% vs. 3.4%; p=0.703)., Conclusions: Bailout GP IIb/IIIa inhibition in AMI patients with angiographic MVO failed to reduce the primary endpoint infarct size but decreased CMR-derived MVO and led to an increase in non-fatal bleeding events., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Substantial evidence supports that Fc-mediated effector functions of anti-spike Abs contribute to anti-SARS-Cov-2 protection. We have previously shown that two non-neutralizing but opsonic mAbs targeting the receptor-binding domain and N-terminal domain (NTD), Ab81 and Ab94, respectively, are protective against lethal Wuhan SARS-CoV-2 infection in K18-hACE2 mice. In this article, we investigated whether these protective non-neutralizing Abs maintain Fc-mediated function and Ag binding against mutated SARS-CoV-2 variants. Ab81 and Ab94 retained their nanomolar affinity and Fc-mediated function toward Omicron and its subvariants, such as BA.2, BA.4, BA.5, XBB, XBB1.5, and BQ1.1. However, when encountering the more heavily mutated BA.2.86, Ab81 lost its function, whereas the 10 new mutations in the NTD did not affect Ab94. In vivo experiments with Ab94 in K18-hACE2 mice inoculated with a stringent dose of 100,000 PFU of the JN.1 variant revealed unexpected results. Surprisingly, this variant exhibited low disease manifestation in this animal model with no weight loss or death in the control group. Still, assessment of mice using a clinical scoring system showed better protection for Ab94-treated mice, indicating that Fc-mediated functions are still beneficial. Our work shows that a protective anti-receptor-binding domain non-neutralizing mAb lost reactivity when BA.2.86 emerged, whereas the anti-NTD mAb was still functional. Finally, this work adds new insight into the evolution of the SARS-CoV-2 virus by reporting that JN.1 is substantially less virulent in vivo than previous strains., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Reduced shear strain and deformability of the thoracolumbar fascia has been linked to low back pain. A number of ultrasound examination methods have been developed for laboratory rather than clinical practice. The aim of this study was to examine the reliability and discriminative validity (patients vs. healthy individuals) of an ultrasound (US) measurement method for the quantification of thoracolumbar fascia deformation (TLFD). A cross-sectional study with US assessment and rater blinding was conducted in a manual therapy clinic and a university laboratory. 16 acute low back pain (aLBP) patients and 15 healthy individuals performed a standardized trunk extension task. US measurements of TLFD were carried out independently by two raters by imaging the TLF in the starting and ending positions of the movement. Intra-rater and inter-rater reliability were calculated using intraclass correlation coefficients (ICCs) and minimal detectable changes (MDC) were calculated. Receiver operating characteristic (ROC) curve analysis was used to determine the cut-off for TLFD to discriminate the study groups. Kappa statistics were performed to assess rater agreement in discrimination. Intra-rater reliability was excellent (ICC: .92, MDC: 5.54 mm, p < .001) and inter-rater reliability was good (ICC: .78, MDC: 8.70 mm, p < .001). The cut-off for TLFD was 6 mm with a sensitivity of 100% and a specificity of 93.75% and the raters agreed moderately (κ = 0.74, p < .001) when distinguishing patients and controls. The reliability of the US method for assessing TLFD is moderate to excellent, and the ability to discriminate aLBP patients from healthy individuals is moderate. The method could be used to capture an additional parameter in morphological aLBP screenings., (© 2024. The Author(s).)

Background and Objectives: Delayed cerebral ischemia (DCI) is one of the main contributing factors to poor clinical outcome after aneurysmal subarachnoid hemorrhage (SAH). Unsuccessful treatment can cause irreversible brain injury in the form of DCI-related infarction. We aimed to assess the association between the location, distribution, and size of DCI-related infarction in relation to clinical outcome., Methods: Consecutive patients with SAH treated at 2 university hospitals between 2014 and 2019 (Helsinki, Finland) and between 2006 and 2020 (Aachen, Germany) were included. Size of DCI-related infarction was quantitatively measured as absolute volume (in milliliters). In a semiquantitative fashion, infarction in 14 regions of interest (ROIs) according to a modified Alberta Stroke Program Early CT Score (ASPECTS) was noted. The association of infarction in these ROIs along predefined regions of eloquent brain, with clinical outcome, was assessed. For this purpose, 1-year outcome was measured by the Glasgow Outcome Scale (GOS) and dichotomized into favorable (GOS 4-5) and unfavorable (GOS 1-3)., Results: Of 1,190 consecutive patients with SAH, 155 (13%) developed DCI-related infarction. One-year outcome data were available for 148 (96%) patients. A median overall infarct volume of 103 mL (interquartile range 31-237) was measured. DCI-related infarction was significantly associated with 1-year unfavorable outcome (odds ratio [OR] 4.89, 95% CI 3.36-7.34, p < 0.001). In patients with 1-year unfavorable outcome, vascular territories more frequently affected were left middle cerebral artery (affected in 49% of patients with unfavorable outcome vs in 30% of patients with favorable outcome; p = 0.029), as well as left (44% vs 18%; p = 0.003) and right (52% vs 14%; p < 0.001) anterior cerebral artery supply areas. According to the ASPECTS model, the right M3 (OR 8.52, 95% CI 1.41-51.34, p = 0.013) and right A2 (OR 7.84, 95% CI 1.97-31.15, p = 0.003) regions were independently associated with unfavorable outcome., Discussion: DCI-related infarction was associated with a 5-fold increase in the odds of unfavorable outcome, after 1 year. Ischemic lesions in specific anatomical regions are more likely to contribute to unfavorable outcome., Trial Registration Information: Data collection in Aachen was registered in the German Clinical Trial Register (DRKS00030505); on January 3, 2023.

Objectives: Right heart catheterization (RHC) is a common diagnostic tool and of special importance in the diagnosis of pulmonary hypertension (PH). Until today, there have been no clear instructions or guidelines on which venous access to prefer. This meta-analysis assessed whether the choice of the venous access site for elective RHC has an impact on procedural or clinical outcomes., Methods: A structured literature search was performed. Single-arm reports and controlled trials reporting event data were eligible. The primary endpoint was a composite of access-related and overall complications., Results: Nineteen studies, including 6509 RHC procedures, were eligible. The results were analyzed in two groups. The first group compared central venous access (CVA; n = 2072) with peripheral venous access (PVA; n = 2680) and included only multi-arm studies (n = 12, C/P comparison). In the second group, all studies (n = 19, threeway comparison) were assessed to compare the three individual access ways. The overall complication rate was low at 1.0% (n = 68). The primary endpoint in the C/P comparison occurred significantly less for PVA than for CVA (0.1% vs. 1.2%; p = 0.004). In the threeway comparison, PVA had a significantly lower complication rate than femoral access (0.3% vs. 1.1%; p = 0.04). Jugular access had the numerically highest complication rate (2.0%), but the difference was not significant compared to peripheral (0.3%; p = 0.29) or femoral access (1.1%; p = 0.32)., Conclusion: This meta-analysis showed that PVA for RHC has a significantly lower complication rate than CVA. There was a low level of certainty and high heterogeneity. This pooled data analysis indicated PVA as the primary venous access for RHC., Competing Interests: Disclosures Florian Genske: no disclosures. Elias Rawish: no disclosures. Sascha Macherey-Meyer: BayerVitalAG: travel expenses, research grants from Elisabeth&Rudolf Hirsch foundation. Carina Büchel: no disclosures. Momir Dejanovikj: no disclosures. Dominik Jurczyk: Janssen: travel expenses and lecture honoraria. Julia Schulten-Baumer: no disclosures. Christoph Marquetand: no disclosures. Thomas Stiermaier: no disclosures. Ingo Eitel: no disclosures. Stephan Rosenkranz: Speaker or consultant fees from Abbott, Acceleron, Actelion, Aerovate, Altavant, AOP, AstraZeneca, Bayer, Boehringer-Ingelheim, Edwards, Ferrer, Gossamer, Inari, Janssen, Lilly, MSD, and United Therapeutics; and research grants to his institution from AstraZeneca, Bayer, Janssen, and MSD; and reports research funding from non-commercial sources from Deutsche Forschungsgemeinschaft (DFG), Deutsche Stiftung für Herzforschung (DSHF), Bundesministerium für Bildung und Forschung (BMBF), Zentrum für Molekulare Medizin Köln (ZMMK), Boll-Stiftung, Fischer-Stiftung, Fresenius-Stiftung, and Grimmke-Stiftung. Christian Frerker: no disclosures. Tobias Schmidt: Janssen: lecture honoraria and consult fees, (Copyright © 2024 Hellenic Society of Cardiology. Published by Elsevier Inc. All rights reserved.)

Background: Besides transcatheter edge-to-edge repair (TEER), there are new interventional treatment options for mitral and tricuspid regurgitation in evaluation, such as a complete replacement of the valve through a prosthesis., Case Summary: A 78-year-old previous coronary artery bypass graft-operated patient with symptomatic severe mitral regurgitation and tricuspid regurgitation was sequentially treated by a transfemoral transcatheter mitral and tricuspid valve prosthesis (Cardiovalve; Cardiovalve Ltd, Israel) due to unfavourable mitral valve anatomy. The transcatheter mitral valve implantation (TMVI) was performed first and after progression of the tricuspid regurgitation, a second transcatheter valve prosthesis was implanted in tricuspid position (TTVI) 1.5 years later. Imaging showed a twin look-alike picture of a mitral and tricuspid prosthesis and showing the possibility of a complete transcatheter based replacement of the mitral and tricuspid valve., Discussion: This case shows the possibility of a Cardiovalve prosthesis being used for TMVI and TTVI in a single patient. Especially in TEER ineligible patients, it might be a good treatment option after device approval., Competing Interests: Conflict of interest: T.S., C.F., and K.-H.K. received speaker honoraria and travel expenses from Cardiovalve., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: Little is known of the processes that trigger neutrophil activation in the joint of patients with oligoarticular juvenile idiopathic arthritis (oJIA), and if synovial fibroblasts (S-Fib) play an important role in the activation. Therefore, we aimed to investigate whether S-Fib derived from oJIA patients drive neutrophil activation., Methods: Synovial fluid (SF) was collected from patients with oJIA. S-Fib were isolated from the SF of n  = 7 patients through passaging. Subsequently, the S-Fib were primed or not with 20% of pooled SF. Supernatants were used to study migration of neutrophils in a transwell system. Additionally, the influence of S-Fib on neutrophils were studied in co-cultures. Phenotype and viability were assessed by flow cytometry. Neutrophil function was tested through the production of reactive oxygen species (ROS), and supernatants were tested for myeloperoxidase (MPO) release and elastase activity., Results: Supernatants of S-Fib induced neutrophil migration ( n  = 5, p  = 0.0491), which was further pronounced using supernatants from SF-primed S-Fib ( p  = 0.0063). Additionally, co-culture between SF-primed S-Fib and neutrophils resulted in prolonged viability ( n  = 5, p  = 0.0094), with little effect on activation markers, e.g., CD11b. Conversely, co-culture did not induce functional alterations ( n  = 4), such as production of ROS ( p  > 0.1570), release of MPO ( p  > 0.4934) or elastase activity ( p  > 0.0904). Finally, supernatant stimulation did not replicate the results of prolonged viability ( p  = 0.9102), suggesting a role of cell-contact., Conclusion: S-Fib from patients with oJIA induce migration of neutrophils via soluble mediators and, in addition, S-Fib prolong neutrophil viability in a cell-contact dependent manner. These mechanisms could be important for accumulation of neutrophils during arthritis., 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., (© 2024 Schmidt, Mossberg, Berthold, Król, Linge, Bengtsson, Kahn, Månsson and Kahn.)

Telomeres are the protective nucleoprotein structures at the end of linear eukaryotic chromosomes. Telomeres' repetitive nature and length have traditionally challenged the precise assessment of the composition and length of individual human telomeres. Here, we present Telo-seq to resolve bulk, chromosome arm-specific and allele-specific human telomere lengths using Oxford Nanopore Technologies' native long-read sequencing. Telo-seq resolves telomere shortening in five population doubling increments and reveals intrasample, chromosome arm-specific, allele-specific telomere length heterogeneity. Telo-seq can reliably discriminate between telomerase- and ALT-positive cancer cell lines. Thus, Telo-seq is a tool to study telomere biology during development, aging, and cancer at unprecedented resolution., (© 2024. The Author(s).)

Recent developments in machine-learning (ML) and deep-learning (DL) have immense potential for applications in proteomics, such as generating spectral libraries, improving peptide identification, and optimizing targeted acquisition modes. Although new ML/DL models for various applications and peptide properties are frequently published, the rate at which these models are adopted by the community is slow, which is mostly due to technical challenges. We believe that, for the community to make better use of state-of-the-art models, more attention should be spent on making models easy to use and accessible by the community. To facilitate this, we developed Koina, an open-source containerized, decentralized and online-accessible high-performance prediction service that enables ML/DL model usage in any pipeline. Using the widely used FragPipe computational platform as example, we show how Koina can be easily integrated with existing proteomics software tools and how these integrations improve data analysis.

Aim: This population-based study investigated the occurrence of capillary leak syndrome (CLS) in children with multisystem inflammatory syndrome in children (MIS-C), associated with COVID-19. We also examined associations between CLS and MIS-C disease severity., Methods: All eligible individuals aged 0-18 years, who were diagnosed with MIS-C in Skåne, southern Sweden, from 1 April 2020 to 31 July 2021, were studied. They were all included in the Pediatric Rheumatology Quality Register and clinical and laboratory data were compared between patients with and without CLS., Results: We included 31 patients (61% male) with MIS-C in the study. The median age at diagnosis was 10.6 years (range 1.99-17.15) and 45% developed CLS. All six patients who required intensive care had CLS. Patients with CLS also had a higher incidence of reduced cardiac function, measured as low ejection fraction. The CLS group exhibited significantly higher C-reactive protein values (p < 0.001) and N-terminal pro-B-type natriuretic peptide levels (p < 0.001), as well as lower platelet counts (p = 0.03), during the first week of treatment. Individuals with CLS also received more intense immunosuppression., Conclusion: CLS was a common complication of MIS-C in our study and these patients had a more severe disease course that required more intensive treatment., (© 2024 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Objectives: Current research suggests static stretch-induced maximal strength increases and muscle hypertrophy with potential to substitute resistance-training routines. However, most studies investigated the plantar flexors. This study explored the effects of a static stretching program on maximal strength, hypertrophy and flexibility of the pectoralis major and compared the effects with those of traditional resistance training., Methods: Eighty-one (81) active participants were allocated to either a static stretching, strength-training or control group. Pectoralis stretching was applied 15 min/day, 4 days per week for 8 weeks, while resistance training trained 3 days per week, 5 × 12 repetitions., Results: There was an increase in all parameters (strength: p < 0.001, ƞ 2  = 0.313, muscle thickness: p < 0.001, ƞ 2  = 0.157-0.264, flexibility: p < 0.001, ƞ 2  = 0.316) and a time*group interaction (strength: p = 0.001, ƞ 2  = 0.154, muscle thickness: p = 0.008-0.001, ƞ 2  = 0.117-0.173, flexibility: p < 0.001, ƞ 2  = 0.267). Post-hoc testing showed no difference between both intervention groups regarding maximal strength and muscle thickness (p = 0.905-0.983, d = 0.036-0.087), while flexibility increased in the stretching group (p = 0.001, d = 0.789)., Conclusion: Stretching showed increases in maximal strength and hypertrophy, which were comparable with commonly used resistance training. Based on current literature, the influence of mechanical tension as the underlying mechanism is discussed. Furthermore, as equipment and comparatively long stretching durations are requested to induce meaningful strength increases in recreationally active participants, practical application seems limited to special circumstances., (© 2024. The Author(s).)

Purpose: Stretch-induced force deficit suggests an acute stretch-specific strength capacity loss, which is commonly attributed to EMG reductions. Since those deficits could also be attributed to general fatigue induced by overloading the muscle, this study aimed to compare stretching with an exhausting calf raise programme to compare strength and stretching responses., Method: This study included 16 participants with different, high-duration calf muscle stretching effects (10, 20, 30 min of stretching) with resistance training (RT) (3 × 12 repetitions) performed until muscle failure, by using a cross-over study design with pre-post comparisons. Strength was tested via isometric plantar flexor diagnostics, while flexibility was assessed using the knee-to-wall test (KtW) and an isolated goniometer test., Results: Using a three-way ANOVA, RT strength decreases were greater compared to 10 and 20 min of stretching ( p = 0.01-0.02), but similar to those of 30 min of stretching. ROM in the KtW showed no specific stretch-induced increases, while only the stretching conditions enhanced isolated tested ROM ( p < 0.001-0.008). No RT-related isolated ROM increases were observed., Conclusions: The results showed both interventions had similar effects on strength and ROM in the calf muscles. More holistic explanatory approaches such as fatigue and warm-up are discussed in the manuscript and call for further research.

Objectives: The association of pulmonary hypertension (PH) with the outcome after mitral transcatheter edge-to-edge repair (M-TEER) focusing on the new ESC/ERS guidelines definition for PH., Background: PH is frequently found in patients with mitral regurgitation and is associated with lower survival rates. Recent studies were based on echocardiographic parameters, but results based on invasive haemodynamics differentiating distinct types of PH using the new definition for PH are missing., Methods: 449 consecutive M-TEER-treated patients from December 2009 to February 2015 were included in this retrospective analysis. All patients were stratified by the distinct types of PH (no PH, precapillary PH, isolated postcapillary PH, combined post-PH and precapillary PH) according to the definitions of the ESC/ERS guidelines for the diagnosis of PH from 2015 (meanPA cut-off <25 mm Hg, pulmonary capillary wedge pressure (PCWP) cut-off ≤15 mm Hg, diastolic pulmonary gradient cut-off ≥7 mm Hg or pulmonary vascular resistance (PVR) >3 WU) and 2022 (meanPA cut-off ≤20 mm Hg, PCWP cut-off ≤15 mm Hg, PVR cut-off ≥3 WU)., Results: Patients with any type of PH (2015: meanPA cut-off 25 mm Hg; 2022: meanPA cut-off >20 mm Hg) showed a higher risk of death after M-TEER compared with patients with no PH (2015: HR 1.61 (95% CI 1.25 to 2.07); p<0.001 and 2022: HR 2.09 (95% CI 1.54 to 2.83); p<0.001). Based on the new PH definition, each PH subgroup showed a lower survival after M-TEER compared with patients with no PH. Echocardiographic estimated systolic PAP showed a correlation with invasively measured mean pulmonary artery pressure (mPAP) (r=0.29, p<0.001) and systolic pulmonary arterial pressure (r=0.34,p<0.001). Cox-regression analysis showed higher invasive diastolic, systolic and mean pulmonary pressures were associated with higher all-cause mortality (p<0.001). In addition, invasive measured higher right atrial pressure, lower pulmonary arterial compliance, higher PVR and higher wedge pressure were identified as predictors of all-cause mortality after M-TEER., Conclusions: The new PH definition discriminates PH groups and mortality better than the old definition. The lower threshold of mPAP of 20mmHg improved prognostication in this cohort of patients., Competing Interests: Competing interests: TU, BF, K-HK and SR declare the full disclosure of any relationship with industry. IE received lecture honoraria and research grants by Abbott and lecture honoraria by Edwards. HA received travel support by Abbott. T. Schmidt, S. Willems, CF received lecture honoraria and travel support from Abbott Vascular and Edwards Lifesciences. RP received lecture honoraria from Abbott Vascular and Edwards and is a consultant for Edwards. SB received lecture honoraria and research grants from Edwards and Abbott., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Streptococcus pyogenes can cause invasive disease with high mortality despite adequate antibiotic treatments. To address this unmet need, we have previously generated an opsonic IgG1 monoclonal antibody, Ab25, targeting the bacterial M protein. Here, we engineer the IgG2-4 subclasses of Ab25. Despite having reduced binding, the IgG3 version promotes stronger phagocytosis of bacteria. Using atomic simulations, we show that IgG3's Fc tail has extensive movement in 3D space due to its extended hinge region, possibly facilitating interactions with immune cells. We replaced the hinge of IgG1 with four different IgG3-hinge segment subclasses, IgGh xx . Hinge-engineering does not diminish binding as with IgG3 but enhances opsonic function, where a 47 amino acid hinge is comparable to IgG3 in function. IgGh 47 shows improved protection against S. pyogenes in a systemic infection mouse model, suggesting that IgGh 47 has promise as a preclinical therapeutic candidate. Importantly, the enhanced opsonic function of IgGh 47 is generalizable to diverse S. pyogenes strains from clinical isolates. We generated IgGh 47 versions of anti-SARS-CoV-2 mAbs to broaden the biological applicability, and these also exhibit strongly enhanced opsonic function compared to the IgG1 subclass. The improved function of the IgGh 47 subclass in two distant biological systems provides new insights into antibody function., (© 2024. The Author(s).)

Background: There is a lack of comparative data on transcatheter aortic valve implantation (TAVI) in degenerated surgical prostheses (valve-in-valve [ViV])., Aims: We sought to compare outcomes of using two self-expanding transcatheter heart valve (THV) systems for ViV., Methods: In this retrospective multicentre registry, we included consecutive patients undergoing transfemoral ViV using either the ACURATE neo/neo2 (ACURATE group) or the Evolut R/PRO/PRO+ (EVOLUT group). The primary outcome measure was technical success according to Valve Academic Research Consortium (VARC)-3. Secondary outcomes were 30-day all-cause mortality, device success (VARC-3), coronary obstruction (CO) requiring intervention, rates of severe prosthesis-patient mismatch (PPM), and aortic regurgitation (AR) ≥moderate. Comparisons were made after 1:1 propensity score matching., Results: The study cohort comprised 835 patients from 20 centres (ACURATE n=251; EVOLUT n=584). In the matched cohort (n=468), technical success (ACURATE 92.7% vs EVOLUT 88.9%; p=0.20) and device success (69.7% vs 73.9%; p=0.36) as well as 30-day mortality (2.8% vs 1.6%; p=0.392) were similar between the two groups. The mean gradients and rates of severe PPM, AR ≥moderate, or CO did not differ between the groups. Technical and device success were higher for the ACURATE platform among patients with a true inner diameter (ID) >19 mm, whereas a true ID ≤19 mm was associated with higher device success - but not technical success - among Evolut recipients., Conclusions: ViV TAVI using either ACURATE or Evolut THVs showed similar procedural outcomes. However, a true ID >19 mm was associated with higher device success among ACURATE recipients, whereas in patients with a true ID ≤19 mm, device success was higher when using Evolut.

Delayed onset muscle soreness (DOMS) of the lower back is considered a surrogate for acute low back pain (aLBP) in experimental studies. Of note, it is often unquestioningly assumed to be muscle pain. To date, there has not been a study analyzing lumbar DOMS in terms of its pain origin, which was the aim of this study. Sixteen healthy individuals (L-DOMS) were enrolled for the present study and matched to participants from a previous study (n = 16, L-PAIN) who had undergone selective electrical stimulation of the thoracolumbar fascia and the multifidus muscle. DOMS was induced in the lower back of the L-DOMS group using eccentric trunk extensions performed until exhaustion. On subsequent days, pain on palpation (100-mm analogue scale), pressure pain threshold (PPT), and the Pain Sensation Scale (SES) were used to examine the sensory characteristics of DOMS. Pain on palpation showed a significant increase 24 and 48 h after eccentric training, whereas PPT was not affected (p > 0.05). Factor analysis of L-DOMS and L-PAIN sensory descriptors (SES) yielded a stable three-factor solution distinguishing superficial thermal ("heat pain ") from superficial mechanical pain ("sharp pain") and "deep pain." "Heat pain " and "deep pain" in L-DOMS were almost identical to sensory descriptors from electrical stimulation of fascial tissue (L-PAIN, all p > 0.679) but significantly different from muscle pain (all p < 0.029). The differences in sensory description patterns as well as in PPT and self-reported DOMS for palpation pain scores suggest that DOMS has a fascial rather than a muscular origin., (© 2023. The Author(s).)

Background: Delayed cerebral ischemia (DCI) is one of the main contributors to poor clinical outcome after aneurysmal subarachnoid hemorrhage (SAH). Endovascular spasmolysis with intra-arterial nimodipine (IAN) may resolve angiographic vasospasm, but its effect on infarct prevention and clinical outcome is still unclear. We report the effect of IAN on infarction rates and functional outcome in a consecutive series of SAH patients., Methods: To assess the effectiveness of IAN, we collected functional outcome data of all SAH patients referred to a single tertiary center since its availability (2011-2020). IAN was primarily reserved as a last tier option for DCI refractory to induced hypertension (iHTN). Functional outcome was assessed after 12 months according to the Glasgow Outcome Scale (GOS, favorable outcome = GOS4-5)., Results: Out of 376 consecutive SAH patients, 186 (49.5%) developed DCI. Thereof, a total of 96 (25.5%) patients remained unresponsive to iHTN and received IAN. DCI-related infarction was observed in 44 (45.8%) of IAN-treated patients with a median infarct volume of 111.6 mL (Q 1 : 51.6 to Q 3 : 245.7). Clinical outcome was available for 84 IAN-treated patients. Of those, a total of 40 (47.6%) patients reached a favorable outcome after 1 year. Interventional complications were observed in 9 (9.4%) of the IAN-treated patients., Conclusion: Intra-arterial spasmolysis using nimodipine infusion was associated with low treatment specific complications. Despite presenting a subgroup of severely affected SAH patients, almost half of IAN-treated patients were able to lead an independent life after 1 year of follow-up., Trial Registration Number: German Clinical Trial Register DRKS00030505., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

G protein-coupled receptor 30 (GPR30), also named G protein-coupled estrogen receptor (GPER), and the β 1 -adrenergic receptor (β1AR) are G protein-coupled receptors (GPCR) that are implicated in breast cancer progression. Both receptors contain PSD-95/Discs-large/ZO-1 homology (PDZ) motifs in their C-terminal tails through which they interact in the plasma membrane with membrane-associated guanylate kinase (MAGUK) scaffold proteins, and in turn protein kinase A anchoring protein (AKAP) 5. GPR30 constitutively and PDZ-dependently inhibits β1AR-mediated cAMP production. We hypothesized that this inhibition is a consequence of a plasma membrane complex of these receptors. Using co-immunoprecipitation, confocal immunofluorescence microscopy, and bioluminescence resonance energy transfer (BRET), we show that GPR30 and β1AR reside in close proximity in a plasma membrane complex when transiently expressed in HEK293. Deleting the GPR30 C-terminal PDZ motif (-SSAV) does not interfere with the receptor complex, indicating that the complex is not PDZ-dependent. MCF7 breast cancer cells express GPR30, β1AR, MAGUKs, and AKAP5 in the plasma membrane, and co-immunoprecipitation revealed that these proteins exist in close proximity also under native conditions. Furthermore, expression of GPR30 in MCF7 cells constitutively and PDZ-dependently inhibits β1AR-mediated cAMP production. AKAP5 also inhibits β1AR-mediated cAMP production, which is not additive with GPR30-promoted inhibition. These results argue that GPR30 and β1AR form a PDZ-independent complex in MCF7 cells through which GPR30 constitutively and PDZ-dependently inhibits β1AR signaling via receptor interaction with MAGUKs and AKAP5., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Heart rate variability (HRV) describes fluctuations in time intervals between heartbeats and reflects autonomic activity. HRV is reduced in stressed patients with musculoskeletal pain and improved after osteopathic manipulative treatment and mind-body interventions. Heart-focused palpation (HFP) combines manual and mind-body approaches to facilitate relaxation. This randomised controlled pilot study investigated the feasibility and sample size for a future randomised controlled trial and the effect of a single treatment with HFP or sham HFP (SHAM) on short-term HRV. A total of Thirty-three adults (47.7 ± 13.5 years old) with stress and musculoskeletal pain completed the trial with acceptable rates of recruitment (8.25 subjects per site/month), retention (100%), adherence (100%), and adverse events (0%). HFP ( n = 18), but not SHAM ( n = 15), significantly increased the root mean square of successive RR interval differences ( p = 0.036), standard deviation of the NN intervals ( p = 0.009), and ratio of the low-frequency to high-frequency power band ( p = 0.026). HFP and SHAM significantly decreased the heart rate ( p < 0.001, p = 0.009) but not the stress index and ratio of the Poincaré plot standard deviation along and perpendicular to the line of identity ( p > 0.05). A power analysis calculated 72 participants. Taken together, the study was feasible and HFP improved HRV in stressed subjects with musculoskeletal pain, suggesting a parasympathetic effect.

Background: Transcatheter repair emerges as a treatment option in patients with tricuspid regurgitation (TR) and high surgical risk., Aims: This study aimed to compare leaflet-based and annuloplasty-based transcatheter repair in patients with TR., Methods: In a retrospective analysis consecutive patients undergoing either transcatheter edge-to-edge repair (TEER) or direct annuloplasty (AP) for relevant TR at 2 centers were compared with respect to baseline characteristics, procedural efficacy and safety (death, myocardial infarction, procedure or device-related cardiothoracic surgery, or stroke at 30 days)., Results: 161 patients (57% female, median age 79 [75-82] years) with comparable clinical baseline characteristics in the TEER (n = 87) and AP (n = 74) group were examined. Baseline TR grade was significantly less severe in the TEER compared to the AP group (torrential 9.2 vs. 31.1%, p = 0.001). Technical success and improvement of TR grades were not significantly different across groups. In analysis matched for baseline TR severity, reduction of TR grade to less than moderate was significantly more common in the AP group (47.8 vs. 26.1%, p = 0.031). Major or more severe bleeding occurred in 9.2% of TEER and 20.3% of AP patients (p = 0.049) without any fatal bleedings. Major adverse events (MAE) were similar across groups with four patients (4.7%) in the TEER group and five patients (6.9%) in the AP group (p = 0.733) and 6-month survival did not differ significantly., Conclusions: Differences observed between patients treated with TEER and AP provide first evidence for tailoring distinct transcatheter treatment techniques to individual patient characteristics., (© 2023. The Author(s).)

Background: The exact incidence and predictors of new-onset atrial fibrillation (AF) after percutaneous closure of patent foramen ovale (PFO) are unknown., Objective: We sought to find post-procedural AF incidence rates and differences due to different screening strategies and devices., Methods: A systematic search was conducted in Cochrane, MEDLINE and EMBASE. Controlled trials fulfilling the inclusion criteria were included into this meta-analysis. The incidence of new-onset AF was the primary outcome. Further parameters were surveillance strategy, device type, AF treatment and neurological events. New AF was determined as early onset within one month after implantation and late thereafter., Results: 8 controlled trials and 16 cohort studies were eligible for quantitative analysis. 7643 patients received percutaneous PFO closure after cryptogenic stroke or transient ischaemic attack, 117 with other indications, whereas 1792 patients formed the control group. Meta-analysis of controlled trials showed an AF incidence of 5.1% in the interventional and 1.6% in the conservative arm, respectively (OR 3.17, 95% CI 1.46-6.86, P = 0.03, I 2  = 55%). 4.7% received high-quality surveillance strategy with Holter-ECG or Loop recorder whereby AF incidence was overall higher compared to the low-quality group with 12-lead ECG only (3.3-15% vs. 0.2-4.3%). Heterogeneous results on time of AF onset were found, limited by different follow-up strategies. CardioSEAL and Starflex seemed to have higher AF incidences in early and late onset with 4.5% and 4.2%, respectively., Conclusion: Percutaneous PFO closure led to higher AF post-procedural incidence compared to the conservative strategy. Heterogeneity in surveillance and follow-up strategy limited the generalizability., Trial Registration: Registered on PROSPERO (CRD42022359945)., (© 2023. The Author(s).)

To address global sustainability challenges, (public) policy interventions are needed to induce or accelerate technological change. While most policy interventions occur on the local level, their innovation effects can spill over to other jurisdictions, potentially having global impact. These spillovers can increase or reduce the incentive for interventions. Lacking to date are computational models that capture these spillover dynamics. Here, we devise a conceptual and methodological approach to quantify ex ante the effects of local demand-side interventions on global competition between incumbent and novel technologies. We introduce two factors that moderate global spillovers-relative size of selection environments and relative innovation potential of competing technologies. Our approach incorporates both factors in a techno-economic discrete choice model that evaluates technology competition over time through endogenized technological learning. We apply this modeling framework to the case of road freight. Different demand-pull interventions and shocks are modeled to assess spillover effects. In the case of road freight, electric vehicles experience growth in most application segments but can still be accelerated substantially through public policy intervention-spillovers occur if strong public interventions are introduced in large regions or in multiple combined regions under club policy interventions. These findings are discussed in the context of club policy interventions and a modeled geopolitical shock in China. A full sensitivity analysis of model input parameters and intervention or shock dynamics reveals high model robustness. Finally, we discuss the implications of the road-freight case study as it might inform the progress of other niche technologies in transitioning sectors.

Objective: This study evaluates the precision of a commercially available spine planning software in automatic spine labelling and screw-trajectory proposal., Methods: The software uses automatic segmentation and registration of the vertebra to generate screw proposals. 877 trajectories were compared. Four neurosurgeons assessed suggested trajectories, performed corrections, and manually planned pedicle screws. Additionally, automatic identification/labelling was evaluated., Results: Automatic labelling was correct in 89% of the cases. 92.9% of automatically planned trajectories were in accordance with G&R grade A + B. Automatic mode reduced the time spent planning screw trajectories by 7 s per screw to 20 s per vertebra. Manual mode yielded differences in screw-length between surgeons (largest distribution peak: 5 mm), automatic in contrast at 0 mm. The size of suggested pedicle screws was significantly smaller (largest peaks in difference between 0.5 and 3 mm) than the surgeon's choice., Conclusion: Automatic identification of vertebrae works in most cases and suggested pedicle screw trajectories are acceptable. So far, it does not substitute for an experienced surgeon's assessment., (© 2023 The Authors. The International Journal of Medical Robotics and Computer Assisted Surgery published by John Wiley & Sons Ltd.)

Recently, it has been shown that the extramuscular connective tissue (ECT) is likely involved in delayed onset muscle soreness (DOMS). Therefore, the aim of the present study was to investigate the effects of maximal trunk extension eccentric exercise (EE) on ECT thickness, self-reported DOMS, ECT stiffness, skin temperature, and possible correlations between these outcomes. Healthy adults (n = 16, 29.34 ± 9.87 years) performed fatiguing EE of the trunk. A group of highly active individuals (TR, n = 8, > 14 h of sport per week) was compared with a group of less active individuals (UTR, n = 8, < 2 h of sport per week). Ultrasound measurements of ECT thickness, stiffness with MyotonPro and IndentoPro, skin temperature with infrared thermography, and pain on palpation (100 mm visual analog scale, VAS) as a surrogate for DOMS were recorded before (t 0 ), immediately (t 1 ), 24 h (t 24 ), and 48 h (t 48 ) after EE. ECT thickness increased after EE from t 0 to t 24 (5.96 mm to 7.10 mm, p = 0.007) and from t 0 to t 48 (5.96 mm to 7.21 mm, p < 0.001). VAS also increased from t 0 to t 24 (15.6 mm to 23.8 mm, p < 0.001) and from t 0 to t 48 (15.6 mm to 22.8 mm, p < 0.001). Skin temperature increased from t 1 to t 24 (31.6° Celsius to 32.7° Celsius, p = 0.032) and t 1 to t 48 (31.6° Celsius to 32.9° Celsius, p = 0.003), while stiffness remained unchanged (p > 0.05). Correlation analysis revealed no linear relationship between the outcomes within the 48-hour measurement period. The results may confirm previous findings of possible ECT involvement in the genesis of DOMS in the extremities also for the paraspinal ECT of trunk extensors. Subsequent work should focus on possible interventions targeting the ECT to prevent or reduce DOMS after strenuous muscle EE., (© Journal of Sports Science and Medicine.)

Background: Transcatheter mitral valve replacement (TMVR) using dedicated devices is an alternative therapy for high-risk patients with symptomatic mitral regurgitation (MR)., Aims: This study aimed to assess the 2-year outcomes and predictors of mortality in patients undergoing TMVR from the multicentre CHOICE-MI Registry., Methods: The CHOICE-MI Registry included consecutive patients with symptomatic MR treated with 11 different dedicated TMVR devices at 31 international centres. The investigated endpoints included mortality and heart failure hospitalisation rates, procedural complications, residual MR, and functional status. Multivariable Cox regression analysis was applied to identify independent predictors of 2-year mortality., Results: A total of 400 patients, median age 76 years (interquartile range [IQR] 71, 81), 59.5% male, EuroSCORE II 6.2% (IQR 3.8, 12.0), underwent TMVR. Technical success was achieved in 95.2% of patients. MR reduction to ≤1+ was observed in 95.2% at discharge with durable results at 1 and 2 years. New York Heart Association Functional Class had improved significantly at 1 and 2 years. All-cause mortality was 9.2% at 30 days, 27.9% at 1 year and 38.1% at 2 years after TMVR. Chronic obstructive pulmonary disease, reduced glomerular filtration rate, and low serum albumin were independent predictors of 2-year mortality. Among the 30-day complications, left ventricular outflow tract obstruction, access site and bleeding complications showed the strongest impact on 2-year mortality., Conclusions: In this real-world registry of patients with symptomatic MR undergoing TMVR, treatment with TMVR was associated with a durable resolution of MR and significant functional improvement at 2 years. Two-year mortality was 38.1%. Optimised patient selection and improved access site management are mandatory to improve outcomes.

Electrifying sub-Saharan Africa (SSA) requires major investments and policy intervention. Existing analyses focus on the levelized cost of electricity at aggregate levels, leaving the feasibility and affordability of reaching Sustainable Development Goal #7 - access to affordable, reliable, sustainable and modern energy for all - by country unclear. Here, we use the electrification model OnSSET to estimate granular and spatially explicit levelized costs of electricity and costs per person per day (pp/d) for 40 countries in SSA. We find that solar-powered mini-grids and standalone systems drastically lower the cost of electrifying remote and high-cost areas, particularly for lower tiers of electrification. On average, least-cost electrification in SSA at Tier 3 (ca. 365 kWh/household/year), can be provided at 14c USD/kWh or 7c USD pp/d. These results are sensitive to demand assumptions, for example, misguided electrification planning or oversizing due to overestimated demand can lead to substantial cost increases. Our results highlight large variances within countries, which we propose to visualise using electrification cost curves by country. Policymakers should consider such cost curves and use a tailored approach by country and region to reach SDG7 in SSA., (© 2023. Springer Nature Limited.)

Climate change is gaining importance on the agenda of senior decision makers in the private sector. Hence, corporate renewable electricity (RE) procurement may become more relevant to the energy transition. RE100 is the largest corporate initiative to foster RE procurement with 315 corporate members as of 2021. Yet, the contribution of such initiatives to the energy transition remains unclear, because public reporting is aggregated on the global level. Here, we develop an approach to map the electricity procured by RE100 companies to jurisdictions worldwide, which allows estimating whether and where RE100 can have a transformative impact. We find that these companies source electricity in 129 jurisdictions, accounting for <1% of total electricity generation (RE and non-RE), thus dampening the hopes about the impact of RE100 on the global energy transition. RE100 companies procure 1.4% of available RE, exceeding 20% in nine jurisdictions. To increase its impact, RE100 should focus on interim targets and expansion. By 2030, stringent and frequent interim targets could lead to a cumulated additional 361 TWh of RE procured by RE100 companies, and a realistic membership expansion could lead to procurement of 7.7% of globally available RE by RE100 companies., (© 2023. Springer Nature Limited.)

Motivation: Mixed molecular data combines continuous and categorical features of the same samples, such as OMICS profiles with genotypes, diagnoses, or patient sex. Like all high-dimensional molecular data, it is prone to incorrect values that can stem from various sources for example the technical limitations of the measurement devices, errors in the sample preparation, or contamination. Most anomaly detection algorithms identify complete samples as outliers or anomalies. However, in most cases, not all measurements of those samples are erroneous but only a few one-dimensional features within the samples are incorrect. These one-dimensional data errors are continuous measurements that are either located outside or inside the normal ranges of their features but in both cases show atypical values given all other continuous and categorical features in the sample. Additionally, categorical anomalies can occur for example when the genotype or diagnosis was submitted wrongly., Results: We introduce ADMIRE (Anomaly Detection using MIxed gRaphical modEls), a novel approach for the detection and correction of anomalies in mixed high-dimensional data. Hereby, we focus on the detection of single (one-dimensional) data errors in the categorical and continuous features of a sample. For that the joint distribution of continuous and categorical features is learned by mixed graphical models, anomalies are detected by the difference between measured and model-based estimations and are corrected using imputation. We evaluated ADMIRE in simulation and by screening for anomalies in one of our own metabolic datasets. In simulation experiments, ADMIRE outperformed the state-of-the-art methods of Local Outlier Factor, stray, and Isolation Forest., Availability and Implementation: All data and code is available at https://github.com/spang-lab/adadmire. ADMIRE is implemented in a Python package called adadmire which can be found at https://pypi.org/project/adadmire., (© The Author(s) 2023. Published by Oxford University Press.)

The vast and heterogeneous data being constantly generated in clinics can provide great wealth for patients and research alike. The quickly evolving field of medical informatics research has contributed numerous concepts, algorithms, and standards to facilitate this development. However, these difficult relationships, complex terminologies, and multiple implementations can present obstacles for people who want to get active in the field. With a particular focus on medical informatics research conducted in Germany, we present in our Viewpoint a set of 10 important topics to improve the overall interdisciplinary communication between different stakeholders (eg, physicians, computational experts, experimentalists, students, patient representatives). This may lower the barriers to entry and offer a starting point for collaborations at different levels. The suggested topics are briefly introduced, then general best practice guidance is given, and further resources for in-depth reading or hands-on tutorials are recommended. In addition, the topics are set to cover current aspects and open research gaps of the medical informatics domain, including data regulations and concepts; data harmonization and processing; and data evaluation, visualization, and dissemination. In addition, we give an example on how these topics can be integrated in a medical informatics curriculum for higher education. By recognizing these topics, readers will be able to (1) set clinical and research data into the context of medical informatics, understanding what is possible to achieve with data or how data should be handled in terms of data privacy and storage; (2) distinguish current interoperability standards and obtain first insights into the processes leading to effective data transfer and analysis; and (3) value the use of newly developed technical approaches to utilize the full potential of clinical data., (©Markus Wolfien, Najia Ahmadi, Kai Fitzer, Sophia Grummt, Kilian-Ludwig Heine, Ian-C Jung, Dagmar Krefting, Andreas Kühn, Yuan Peng, Ines Reinecke, Julia Scheel, Tobias Schmidt, Paul Schmücker, Christina Schüttler, Dagmar Waltemath, Michele Zoch, Martin Sedlmayr. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 24.07.2023.)

Introduction: Elevated intracranial pressure (ICP) and blood components are the main trigger factors starting the complex pathophysiological cascade following subarachnoid hemorrhage (SAH). It is not clear whether they independently contribute to tissue damage or whether their impact cannot be differentiated from each other. We here aimed to establish a rat intracranial hypertension model that allows distinguishing the effects of these two factors and investigating the relationship between elevated ICP and hypoperfusion very early after SAH., Methods: Blood or four different types of fluids [gelofusine, silicone oil, artificial cerebrospinal fluid (aCSF), aCSF plus xanthan (CX)] were injected into the cisterna magna in anesthetized rats, respectively. Arterial blood pressure, ICP and cerebral blood flow (CBF) were continuously measured up to 6 h after injection. Enzyme-linked immunosorbent assays were performed to measure the pro-inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) in brain cortex and peripheral blood., Results: Silicone oil injection caused deaths of almost all animals. Compared to blood, gelofusine resulted in lower peak ICP and lower plateau phase. Artificial CSF reached a comparable ICP peak value but failed to reach the ICP plateau of blood injection. Injection of CX with comparable viscosity as blood reproduced the ICP course of the blood injection group. Compared with the CBF course after blood injection, CX induced a comparable early global ischemia within the first minutes which was followed by a prompt return to baseline level with no further hypoperfusion despite an equal ICP course. The inflammatory response within the tissue did not differ between blood or blood-substitute injection. The systemic inflammation was significantly more pronounced in the CX injection group compared with the other fluids including blood., Discussion: By cisterna magna injection of blood substitution fluids, we established a subarachnoid space occupying rat model that exactly mimicked the course of ICP in the first 6 h following blood injection. Fluids lacking blood components did not induce the typical prolonged hypoperfusion occurring after blood-injection in this very early phase. Our study strongly suggests that blood components rather than elevated ICP play an important role for early hypoperfusion events in SAH., 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 © 2023 Hao, Conzen-Dilger, Schmidt, Harder, Schöps, Clauser, Schubert and Lindauer.)

Background: Alterations in posture, lumbopelvic kinematics, and movement patterns are commonly seen in patients with low back pain. Therefore, strengthening the posterior muscle chain has been shown to result in significant improvement in pain and disability status. Recent studies suggest that thoracolumbar fascia (TLF) has a major impact on the maintenance of spinal stability and paraspinal muscle activity, and thus is likely to have an equal impact on deadlift performance., Objective: Aim of the study was to evaluate the role of thoracolumbar fascia deformation (TFLD) during spinal movement in track and field athletes (TF) as well as individuals with and without acute low back pain (aLBP)., Methods: A case-control study was performed with n  = 16 aLBP patients (cases) and two control groups: untrained healthy individuals (UH, n  = 16) and TF ( n  = 16). Participants performed a trunk extension task (TET) and a deadlift, being assessed for erector spinae muscle thickness (EST) and TLFD using high-resolution ultrasound imaging. Mean deadlift velocity (VEL) and deviation of barbell path (DEV) were measured by means of a three-axis gyroscope. Group differences for TLFD during the TET were examined using ANOVA. Partial Spearman rank correlations were calculated between TLFD and VEL adjusting for baseline covariates, EST, and DEV. TLFD during deadlifting was compared between groups using ANCOVA adjusting for EST, DEV, and VEL., Results: TLFD during the TET differed significantly between groups. TF had the largest TLFD (-37.6%), followed by UH (-26.4%), while aLBP patients had almost no TLFD (-2.7%). There was a strong negative correlation between TLFD and deadlift VEL in all groups (r = -0.65 to -0.89) which was highest for TF ( r  = -0.89). TLFD during deadlift, corrected for VEL, also differed significantly between groups. TF exhibited the smallest TLFD (-11.9%), followed by aLBP patients (-21.4%), and UH (-31.9%)., Conclusion: TFLD maybe a suitable parameter to distinguish LBP patients and healthy individuals during lifting tasks. The cause-effect triangle between spinal movement, TFLD and movement velocity needs to be further clarified., Clinical Trial Registration: https://drks.de/register/de/trial/DRKS00027074/, German Clinical Trials Register DRKS00027074., 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 © 2023 Brandl, Wilke, Egner, Reer, Schmidt and Schleip.)

Background: Transcatheter mitral valve replacement (TMVR) is an emerging therapeutic alternative for patients with secondary mitral regurgitation (MR). Outcomes of TMVR versus guideline-directed medical therapy (GDMT) have not been investigated for this population. This study aimed to compare clinical outcomes of patients with secondary MR undergoing TMVR versus GDMT alone., Methods: The CHOICE-MI registry (Choice of Optimal Transcatheter Treatment for Mitral Insufficiency) included patients with MR undergoing TMVR using dedicated devices. Patients with MR pathogeneses other than secondary MR were excluded. Patients treated with GDMT alone were derived from the control arm of the COAPT trial (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation). We compared outcomes between the TMVR and GDMT groups, using propensity score matching to adjust for baseline differences., Results: After propensity score matching, 97 patient pairs undergoing TMVR (72.9±8.7 years; 60.8% men; transapical access, 91.8%) versus GDMT (73.1±11.0 years; 59.8% men) were compared. At 1 and 2 years, residual MR was ≤1+ in all patients of the TMVR group compared with 6.9% and 7.7%, respectively, in those receiving GDMT alone (both P <0.001). The 2-year rate of heart failure hospitalization was significantly lower in the TMVR group (32.8% versus 54.4%; hazard ratio, 0.59 [95% CI, 0.35-0.99]; P =0.04). Among survivors, a higher proportion of patients were in the New York Heart Association functional class I or II in the TMVR group at 1 year (78.2% versus 59.7%; P =0.03) and at 2 years (77.8% versus 53.2%; P =0.09). Two-year mortality was similar in the 2 groups (TMVR versus GDMT, 36.8% versus 40.8%; hazard ratio, 1.01 [95% CI, 0.62-1.64]; P =0.98)., Conclusions: In this observational comparison, over 2-year follow-up, TMVR using mostly transapical devices in patients with secondary MR was associated with significant reduction of MR, symptomatic improvement, less frequent hospitalizations for heart failure, and similar mortality compared with GDMT., Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT04688190 (CHOICE-MI) and NCT01626079 (COAPT)., Competing Interests: Disclosures Dr Ludwig reports travel compensation from Edwards; speaker honoraria from Abbott; and advisory fees from Bayer. Dr Conradi reports being on the advisory board at Abbott, Medtronic, and Boston Scientific and personal fees from Edwards. Dr Cohen reports research grant and consulting fees from Abbott, Edwards Lifesciences, Boston Scientific, and Medtronic AC; is a proctor at Abbott; and is a speaker at Abbott and General Electric Healthcare. Dr Scotti is a consultant for NeoChord. Dr Abraham reports research grant from the National Institutes of Health–National Heart, Lung, and Blood Institute (National Institutes of Health 1 UG3/UH3 HL140144-01, 08/01/18-07/31/22, LOFT-HF [Impact of Low Flow Nocturnal Oxygen Therapy on Hospital Readmission/Mortality in Patients With Heart Failure and Central Sleep Apnea]); consulting at Abbott, Boehringer Ingelheim, and Zoll; honoraria from Impulse Dynamics; and salary from V-Wave Medical. Dr Ben Ali reports grants from Medtronic and Edwards. Dr Kar reports grants and consulting from Abbott, Boston Scientific, Edwards, and 4TECH and stock at 4TECH. Dr Scott Lim reports grants from Abbott, Boston Scientific, Corvia, Edwards, Medtronic, Trisol, and V-Wave and is a consultant at Ancora, Philips, Valgen, and Venus. Dr Duncan is a consultant at Abbott, Edwards, and Medtronic. Dr Adamo reports personal fees from Edwards and Boston Scientific and grants and honoraria from Medtronic. Dr Muller is on the advisory board at Abbott, Medtronic, and Edwards. Dr Petronio is a consultant at Medtronic, Boston Scientific, and Abbott. Dr Ruge is on the advisory board at Abbott and is a proctor at Abbott and Edwards. Dr Sondergaard reports grants and consulting at Edwards and Medtronic. Dr Adam reports grants and honoraria from Medtronic and personal fees from Boston Scientific and Edwards. Dr Dahle is a proctor/speaker at Abbott and Edwards. Dr Kempfert reports honoraria from Edwards, Medtronic, Abbott, and CryoLife. Dr Garatti is a proctor at Abbott. Dr Schmidt reports honoraria and travel support from Abbott and Cardiovalve. Dr Tang is a proctor/consultant at Medtronic; consultant/advisory board at Abbott; consultant at NeoChord; advisory board at JenaValve; and honoraria from Siemens and EastEnd Medical. Dr Redwood is a proctor at and reports personal fees from Edwards and is on the advisory board at Medtronic. Dr Taramasso is a consultant at Abbott, Edwards, Boston Scientific, Shenqi Medical, Simulands, Occlufit, MTEx, Medira, 4tech, and CoreMedic and reports personal fees from Cardiovalve. Dr Praz is a consultant at Edwards. Dr Fam is a consultant at Edwards, Abbott, and Cardiovalve. Dr Dumonteil is a consultant/proctor at Abbott, Boston Scientific, Edwards, and Medtronic. Dr von Bardeleben reports consulting/honoraria from Abbott, Edwards, and Medtronic and research grants to the university from Abbott and Edwards. Dr Rudolph reports honoraria from Abbott. Dr Reardon is a consultant at Medtronic, Boston, Abbott, and Gore (all funds to the department). Dr Metra reports personal fees from Actelion, Amgen, Livanova, Servier, Vifor Pharma as member of the Executive or Data Monitoring Committees of sponsored clinical trials, AstraZeneca, Abbott, Bayer, Boheringer Ingelhelm, and Edwards Therapeutics for participation to advisory boards and speeches at sponsored meetings. Dr Denti reports personal fees from Abbott and Edwards. Dr Mack reports being a co-Principal Investigator for the PARTNER trial (Placement of Aortic Transcatheter Valve Trial; Edwards) and COAPT trial (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation; Abbott) and is a study chair for the APOLLO trial (Transcatheter Mitral Valve Replacement With the Medtronic Intrepid TMVR System in Patients With Severe Symptomatic Mitral Regurgitation; Medtronic). Dr Hausleiter reports consulting fees, speaker honoraria, and research support to the institution from Abbott and Edwards. Dr Asch reports institutional contracts from Abbott, Neovasc, Ancora, Mitralign, Medtronic, Boston Scientific, Edwards Lifesciences, Biotronik, and Livanova. Dr Latib is on the advisory board at Medtronic, Boston Scientific, Philips, Edwards, and Abbott. Dr Lindenfeld reports grant support from AstraZeneca and consulting at Abbott, Alleviant, AstraZeneca, Cordio, CVRx, Edwards, Boehringer Ingelheim, Merck, Medtronic, Vascular Dynamics, and V-Wave. Dr Modine is a consultant at Abbott, Edwards, and Medtronic. Dr Stone reports honoraria from Medtronic, Pulnovo, and Infraredx; is a consultant at Valfix, TherOx, Robocath, HeartFlow, Ablative Solutions, Vectorious, Miracor, Neovasc, Abiomed, Ancora, Elucid Bio, Occlutech, CorFlow, Apollo Therapeutics, Impulse Dynamics, Cardiomech, Gore, Amgen, Adona Medical, and Millennia Biopharma; and reports equity/options at Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, and Xenter. Dr Stone’s daughter is an employee at Medtronic. Dr Stone’s employer, Mount Sinai Hospital, receives research support from Abbott, Abiomed, Bioventrix, Cardiovascular Systems, Inc, Phillips, Biosense Webster, Shockwave, Vascular Dynamics, Pulnovo, and V-wave. Dr Granada is the President and Chief Executive Officer of Cardiovascular Research Foundation. The other authors report no conflicts.

Background: Takotsubo syndrome (TTS) is a reversible form of heart failure with incompletely understood pathophysiology., Objectives: This study analyzed altered cardiac hemodynamics during TTS to elucidate underlying disease mechanisms., Methods: Left ventricular (LV) pressure-volume loops were recorded in 24 consecutive patients with TTS and a control population of 20 participants without cardiovascular diseases., Results: TTS was associated with impaired LV contractility (end-systolic elastance 1.74 mm Hg/mL vs 2.35 mm Hg/mL [P = 0.024]; maximal rate of change in systolic pressure over time 1,533 mm Hg/s vs 1,763 mm Hg/s [P = 0.031]; end-systolic volume at a pressure of 150 mm Hg, 77.3 mL vs 46.4 mL [P = 0.002]); and a shortened systolic period (286 ms vs 343 ms [P < 0.001]). In response, the pressure-volume diagram was shifted rightward with significantly increased LV end-diastolic (P = 0.031) and end-systolic (P < 0.001) volumes, which preserved LV stroke volume (P = 0.370) despite a lower LV ejection fraction (P < 0.001). Diastolic function was characterized by prolonged active relaxation (relaxation constant 69.5 ms vs 45.9 ms [P < 0.001]; minimal rate of change in diastolic pressure -1,457 mm Hg/s vs -2,192 mm Hg/s [P < 0.001]), whereas diastolic stiffness (1/compliance) was not affected during TTS (end-diastolic volume at a pressure of 15 mm Hg, 96.7 mL vs 109.0 mL [P = 0.942]). Mechanical efficiency was significantly reduced in TTS (P < 0.001) considering reduced stroke work (P = 0.001), increased potential energy (P = 0.036), and a similar total pressure-volume area compared with that of control subjects (P = 0.357)., Conclusions: TTS is characterized by reduced cardiac contractility, a shortened systolic period, inefficient energetics, and prolonged active relaxation but unaltered diastolic passive stiffness. These findings may suggest decreased phosphorylation of myofilament proteins, which represents a potential therapeutic target in TTS. (Optimized Characterization of Takotsubo Syndrome by Obtaining Pressure Volume Loops [OCTOPUS]; NCT03726528)., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: Monocytes are key effector cells in inflammatory processes. We and others have previously shown that synovial monocytes in childhood-onset arthritis are activated. However, very little is known about how they contribute to disease and attain their pathological features. Therefore, we set out to investigate the functional alterations of synovial monocytes in childhood-onset arthritis, how they acquire this phenotype, and whether these mechanisms could be used to tailorize treatment., Methods: The function of synovial monocytes was analysed by assays believed to reflect key pathological events, such as T-cell activation-, efferocytosis- and cytokine production assays using flow cytometry in untreated oligoarticular juvenile idiopathic arthritis (oJIA) patients (n=33). The effect of synovial fluid on healthy monocytes was investigated through mass spectrometry and functional assays. To characterize pathways induced by synovial fluid, we utilized broad-spectrum phosphorylation assays and flow cytometry, as well as inhibitors to block specific pathways. Additional effects on monocytes were studied through co-cultures with fibroblast-like synoviocytes or migration in transwell systems., Results: Synovial monocytes display functional alterations with inflammatory and regulatory features, e.g., increased ability to induce T-cell activation, resistance to cytokine production following activation with LPS and increased efferocytosis. In vitro , synovial fluid from patients induced the regulatory features in healthy monocytes, such as resistance to cytokine production and increased efferocytosis. IL-6/JAK/STAT signalling was identified as the main pathway induced by synovial fluid, which also was responsible for a majority of the induced features. The magnitude of synovial IL-6 driven activation in monocytes was reflected in circulating cytokine levels, reflecting two groups of low vs. high local and systemic inflammation. Remaining features, such as an increased ability to induce T-cell activation and markers of antigen presentation, could be induced by cell-cell interactions, specifically via co-culture with fibroblast-like synoviocytes., Conclusions: Synovial monocytes in childhood-onset arthritis are functionally affected and contribute to chronic inflammation, e.g., via promoting adaptive immune responses. These data support a role of monocytes in the pathogenesis of oJIA and highlight a group of patients more likely to benefit from targeting the IL-6/JAK/STAT axis to restore synovial homeostasis., 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 © 2023 Schmidt, Dahlberg, Berthold, Król, Arve-Butler, Rydén, Najibi, Mossberg, Bengtsson, Kahn, Månsson and Kahn.)

The pathophysiology of degenerative cervical myelopathy (DCM) is characterized by chronic compression-induced damage to the spinal cord leading to secondary harm such as disruption of the blood spinal cord barrier (BSCB). It is therefore the purpose of this study to analyze BSCB disruption in pre- and postoperative DCM patients and to correlate those with the clinical status and postoperative outcome. This prospectively controlled cohort included 50 DCM patients (21 female; 29 male; mean age: 62.9 ± 11.2 years). As neurological healthy controls, 52 (17 female; 35 male; mean age 61.8 ± 17.3 years) patients with thoracic abdominal aortic aneurysm (TAAA) and indication for open surgery were included. All patients underwent a neurological examination and DCM-associated scores (Neck Disability Index, modified Japanese Orthopaedic Association Score) were assessed. To evaluate the BSCB status, blood and cerebrospinal fluid (CSF) samples (lumbar puncture or CSF drainage) were taken preoperatively and in 15 DCM patients postoperatively (4 female; 11 male; mean age: 64.7 ± 11.1 years). Regarding BSCB disruption, CSF and blood serum were examined for albumin, immunoglobulin (Ig) G, IgA and IgM. Quotients for CSF/serum were standardized and calculated according to Reiber diagnostic criteria. Significantly increased preoperative CSF/serum quotients were found in DCM patients as compared to control patients: Albumin Q (p < .001), IgA Q (p < .001) and IgG Q (p < .001). IgM Q showed no significant difference (T = - 1.15, p = .255). After surgical decompression, neurological symptoms improved in DCM patients, as shown by a significantly higher postoperative mJOA compared to the preoperative score (p = .001). This neurological improvement was accompanied by a significant change in postoperative CSF/serum quotients for Albumin (p = .005) and IgG (p = .004) with a trend of a weak correlation between CSF markers and neurological recovery. This study further substantiates the previous findings, that a BSCB disruption in DCM patients is evident. Interestingly, surgical decompression appears to be accompanied by neurological improvement and a reduction of CSF/serum quotients, implying a BSCB recovery. We found a weak association between BSCB recovery and neurological improvement. A BSCB disruption might be a key pathomechanism in DCM patients, which could be relevant to treatment and clinical recovery., (© 2023. The Author(s).)

Background: The need for permanent pacemaker (PPM) implantation is a common complication after transcatheter aortic valve replacement (TAVR). Deep implantation position is a risk factor for PPM implantation. Thus, in the field of self-expandable (SE) transcatheter heart valves (THV) cusp overlap projection (COP) technique was implemented to reduce parallax, allowing a more precise guidance of implantation depth., Aims: This meta-analysis aims to report the outcome of patients undergoing TAVR with SE THV using COP versus conventional implantation technique (CIT)., Methods: Systematical search in MEDLINE and EMBASE yielded five observational controlled studies comparing both implantation techniques for the SE Evolut prosthesis (Medtronic Intern. Ltd., CA, USA) and fulfilling the inclusion criteria for meta-analysis., Results: Totally, 1227 patients were included, comprising 641 who underwent COP and 586 CIT TAVR. Incidence of post-procedural need for PPM implantation was significantly lower in COP group (9.8% vs 20.6%; OR = 0.43; p < 0.00001). This was accompanied by significantly higher implantation position in COP group (mean difference distance from distal end of the intraventricular portion of the THV to the non-coronary cusp (NCC): - 1.03 mm; p = 0.00001). Incidence of new-onset left bundle branch block did not differ. Regarding procedural and 30-day mortality, technical success, post-procedural aortic regurgitation, and rates of multiple device implantation, no difference between COP and CIT was found., Conclusion: COP is an effective and safe implantation technique to reduce the need for a permanent pacemaker implantation during TAVR with SE Evolut prosthesis., (© 2023. The Author(s).)