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Background: We evaluated the potential of circulating bone morphogenetic protein 10 (BMP10) as a biomarker for atrial stress and remodelling in patients with heart failure (HF), in comparison to N-terminal pro-B-type natriuretic peptide (NT-proBNP). We also assessed the predictive value of BMP10 for adverse clinical outcomes., Methods: BMP10 levels were quantified in 2085 chronic HF patients from the European BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) cohort and in 1487 patients from the Scottish validation cohort. Multivariable linear regression identified independent associates of BMP10. Proteomic analysis of 6369 proteins with subsequent gene set enrichment analysis was used to explore biological pathways associated with elevated BMP10. Cox proportional hazards models adjusting for established risk factors were used to associate BMP10 levels with clinical outcomes, including all-cause mortality and HF hospitalisation., Results: In a multivariable model including clinical and echocardiographic parameters, log-transformed and standardised BMP10 levels were significantly associated with a history of atrial fibrillation (Sβ=0.419; p<0.001), and with echocardiographic features reflecting atrial stress, such as increased left atrial diameter (Sβ=0.075; p=0.048). By contrast, these were not among the strongest associates of NT-proBNP levels. Gene set enrichment analysis showed significant overrepresentation in pathways of muscle contraction and extracellular matrix organisation. Higher log-transformed and standardised BMP10 levels predicted a combined outcome of 2-year all-cause mortality and HF rehospitalisation (HR=1.10, 95% CI=1.02-1.19), with the validation cohort yielding comparable results., Conclusion: BMP10 emerges as a novel biomarker reflecting atrial stress and remodelling in chronic HF patients. Its additional predictive value for adverse outcomes underscores its potential utility in enhancing risk stratification and guiding therapeutic interventions in HF management., Competing Interests: Competing interests: RAdB has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Novo Nordisk, and Roche; has had speaker engagements with and/or received fees from and/or served on an advisory board for Abbott, AstraZeneca, Bristol Myers Squibb, Cardior Pharmaceuticals GmbH, Novo Nordisk, and Roche; has received travel support from Abbott, Cardior Pharmaceuticals GmbH and Novo Nordisk. AAV received consultancy fees from Anacardio, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardurion, Corteria, Merck, Novartis, Novo Nordisk, Eli Lilly, Moderna, Roche Diagnostics, SalubrisBio. CCL has received consultancy fees and/or research grants from Amgen, AstraZeneca, Boehringer Ingelheim, MSD, Novartis, Novo Nordisk and Servier. SM is an employee at Roche Diagnostics International, Rotkreuz, Switzerland. The remaining authors have nothing to disclose., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

A film-forming system (FFS) represents a convenient topical dosage form for drug delivery. In this study, a non-commercial poly(lactic-co-glycolic acid) (PLGA) was chosen to formulate an FFS containing salicylic acid (SA) and methyl salicylate (MS). This unique combination is advantageous from a therapeutic point of view, as it enabled modified salicylate release. It is beneficial from a technological perspective too, because it improved thermal, rheological, and adhesive properties of the in situ film. DSC revealed complete dissolution of SA and good miscibility of MS with the polymer. MS also ensures optimal viscoelastic and adhesive properties of the film, leading to prolonged and sustained drug release. The hydrolysis of MS to active SA was very slow at skin pH 5.5, but it apparently occurred at physiological pH 7.4. The film structure is homogeneous without cracks, unlike some commercial preparations. The dissolution study of salicylates revealed different courses in their release and the influence of MS concentration in the film. The formulated PLGA-based FFS containing 5 % SA and 10 % MS is promising for sustained and prolonged local delivery of salicylates, used mainly for keratolytic and anti-inflammatory actions and pain relief., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The increasing use of cannabis during pregnancy raises concerns about its impact on fetal development. While cannabidiol (CBD) shows therapeutic promise, its effects during pregnancy remain uncertain. We investigated CBD's influence on tryptophan (TRP) metabolism in the human placenta. TRP is an essential amino acid that is metabolized via the serotonin and kynurenine (KYN) pathways, which are critical for fetal neurodevelopment. We used human term villous placental explants, an advanced ex vivo model, to study CBD's impact on key TRP metabolic enzymes. In addition, vesicles isolated from the microvillous membrane (MVM) of the human placenta were used to assess CBD's effect on placental serotonin uptake. Explants were exposed to CBD at therapeutic (0.1, 1, 2.5 μg/ml) and non-therapeutic (20 and 40 μg/ml) concentrations to determine its effects on the gene and protein expression of key enzymes in TRP metabolism and metabolite release. CBD upregulated TRP hydroxylase (TPH) and downregulated monoamine oxidase (MAO-A), resulting in reduced levels of 5-hydroxyindoleacetic acid (HIAA). It also downregulated serotonin transporter expression and inhibited serotonin transport across the MVM by up to 60% while simultaneously enhancing TRP metabolism via the kynurenine pathway by upregulating indoleamine-pyrrole 2,3-dioxygenase (IDO-1). Among kynurenine pathway enzymes, kynurenine 3 monooxygenase (KMO) was upregulated while kynurenine aminotransferase 1 (KAT-1) was downregulated; the former is associated with neurotoxic metabolite production, while the latter is linked to reduced neuroprotective metabolite levels. Overall, these results indicate that CBD modulates TRP catabolism in the human placenta, potentially disrupting the tightly regulated homeostasis of the serotonin and KYN pathways., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: CareNet is the IT-based tool for Case and Care Management (CCM) in Tyrol, which facilitates standardised documentation of CCM activities., Objectives: Analysing the pilot usage of CareNet Tyrol., Methods: Evaluation of the success and user experience of CareNet, expert interviews and a questionnaire-based assessment., Results: Feedback from users in both phases indicated that the CareNet platform provides general benefits, but falls short of fully supporting the daily work of CCM experts and avoiding the need for parallel use of different documentation tools., Conclusion: This paper provides an insight into the ongoing transition to digital documentation for CCM at LIV Tyrol. While user feedback highlights areas for improvement, digital documentation is proved to be beneficial for the CCM team.

Chronic wounds present a significant healthcare challenge in Austria as well as in other countries. The interdisciplinary approach to wound treatment involving various caregivers, doctors, and relatives, poses challenges in documentation and information exchange. To overcome these barriers and promote patient-centered care, a new telehealth-supported treatment pathway for chronic wounds has been developed. The primary focus was to regularly update the status of the chronic wound by responding to predefined questions and transmitted images of the chronic wound. This was achieved by an interdisciplinary team of experts in chronic wound care, providing a new perspective for digital implementation in the healthcare system.

Maternal immune activation during pregnancy is a risk factor for offspring neuropsychiatric disorders. Among the mechanistic pathways by which maternal inflammation can affect fetal brain development and programming, those involving tryptophan (TRP) metabolism have drawn attention because various TRP metabolites have neuroactive properties. This study evaluates the effect of bacterial (lipopolysaccharides/LPS) and viral (polyinosinic:polycytidylic acid/poly I:C) placental infection on TRP metabolism using an ex vivo model. Human placenta explants were exposed to LPS or poly I:C, and the release of TRP metabolites was analyzed together with the expression of related genes and proteins and the functional activity of key enzymes in TRP metabolism. The rate-limiting enzyme in the serotonin pathway, tryptophan hydroxylase, showed reduced expression and functional activity in explants exposed to LPS or poly I:C. Conversely, the rate-limiting enzyme in the kynurenine pathway, indoleamine dioxygenase, exhibited increased activity, gene, and protein expression, suggesting that placental infection mainly promotes TRP metabolism via the kynurenine (KYN) pathway. Furthermore, we observed that treatment with LPS or poly I:C increased activity in the kynurenine monooxygenase branch of the KYN pathway. We conclude that placental infection impairs TRP homeostasis, resulting in decreased production of serotonin and an imbalance in the ratio between quinolinic acid and kynurenic acid. This disrupted homeostasis may eventually expose the fetus to suboptimal/toxic levels of neuroactive molecules and impair fetal brain development., (© The Author(s) 2023. Published by Oxford University Press behalf of Society for the Study of Reproduction.)

Background: BMP10 (bone morphogenic protein 10) has emerged as a novel biomarker associated with the risk of ischemic stroke and other outcomes in patients with atrial fibrillation (AF). The study aimed to determine if repeated BMP10 measurements improve prognostication of cardiovascular events in patients with AF., Methods and Results: BMP10 was measured using a prototype Elecsys immunoassay in plasma samples collected at randomization and after 2 months in patients with AF randomized to apixaban or warfarin in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial (n=2878). Adjusted Cox-regression models were used to evaluate the association between 2-month BMP10 levels and outcomes. BMP10 levels increased by 7.8% ( P <0.001) over 2 months. The baseline variables most strongly associated with BMP10 levels at 2 months were baseline BMP10 levels, body mass index, sex, age, creatinine, diabetes, warfarin treatment, and AF-rhythm. During median 1.8 years follow-up, 34 ischemic strokes/systemic embolism, 155 deaths, and 99 heart failure hospitalizations occurred. Comparing the third with the first sample quartile, higher BMP10 levels at 2 months were associated with higher risk of ischemic stroke (hazard ratio [HR], 1.33 [95% CI, 0.67-2.63], P =0.037), heart failure (HR, 1.91 [95% CI, 1.17-3.12], P =0.012) and all-cause death (HR, 1.61 [95% CI, 1.17-2.21], P <0.001). Adding BMP10 levels at 2 months on top of established risk factors and baseline BMP10 levels improved the C-indices for ischemic stroke/systemic embolism (from 0.73 to 0.75), heart failure hospitalization (0.76-0.77), and all-cause mortality (0.70-0.72), all P <0.05., Conclusions: Elevated levels of BMP10 at 2 months strengthened the associations with the risk of ischemic stroke, hospitalization for heart failure, and all-cause mortality. Repeated measurements of BMP10 may further refine risk stratification in patients with AF.

Purpose: The number of seven required throws per knot was previously reported as providing sufficient security against slippage. A novel high-strength suture featuring dynamic tightening may allow for throw number reduction without compromising stability. The aims of this study were to (1) investigate the influence of the throw number and the effect of different ambient conditions on the knot security of two different high-strength sutures, and (2) compare their biomechanical competence., Methods: Two sutures (FiberWire (FW) and DynaCord (DC)) were considered for preparing alternating surgical knots. The specimens were stratified for exposure to different media during biomechanical testing-namely air (dry), saline solution (wet), and fat (fatty-wet). A monotonic tensile ramp loading to failure was applied in each test run. For each suture and ambient condition, seven specimens with three to seven throws each were tested (n = 7), evaluating their slippage and ultimate force to failure. The minimum number of throws preventing suture unraveling was determined for each suture type and condition., Results: For each suture type and condition, failure occurred via rupture in all specimens for the following minimum number of throws: FW-dry-7, wet-7, fatty-wet-7; DC-dry-6, wet-4, fatty-wet-5. When applying seven throws, FW demonstrated significantly larger slippage (6.5 ± 2.2 mm) versus DC (3.5 ± 0.4 mm) in wet (p = 0.004) but not in dry and fatty-wet conditions (p ≥ 0.313)., Conclusions: The lower number of throws providing knot security of DC versus FW in the more realistic wet and fatty-wet conditions indicates that the novel DC suture may allow to decrease the foreign body volume and save surgical time without compromising the biomechanical competence., (© 2023. The Author(s) under exclusive licence to SICOT aisbl.)

Ikaros family proteins (Ikaros, Helios, Aiolos, Eos) are zinc finger transcription factors essential for the development and function of the adaptive immune system. They also control developmental events in neurons and other cell types, suggesting that they possess crucial functions across disparate cell types. These functions are likely shared among the organisms in which these factors exist, and it is thus important to obtain a view of their distribution and conservation across organisms. How this family evolved remains poorly understood. Here we mined protein, mRNA and DNA databases to identify proteins with DNA-binding domains homologous to that of Ikaros. We show that Ikaros-related proteins exist in organisms from all four deuterostome phyla (chordates, echinoderms, hemichordates, xenacoelomorpha), but not in more distant groups. While most non-vertebrates have a single family member, this family grew to six members in the acoel worm Hofstenia miamia, three in jawless and four in jawed vertebrates. Most residues involved in DNA contact from zinc fingers 2 to 4 were identical across the Ikaros family, suggesting conserved mechanisms for target sequence recognition. Further, we identified a novel KRKxxxPxK/R motif that inhibits DNA binding in vitro which was conserved across the deuterostome phyla. We also identified a EψψxxxψM(D/E)QAIxxAIxYLGA(D/E)xL motif conserved among human Ikaros, Aiolos, Helios and subsets of chordate proteins, and motifs that are specific to subsets of vertebrate family members. Some of these motifs are targets of mutations in human patients. Finally we show that the atypical family member Pegasus emerged only in vertebrates, which is consistent with its function in bone. Our data provide a novel evolutionary perspective for Ikaros family proteins and suggest that they have conserved regulatory functions across deuterostomes., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interest., (Copyright © 2023. Published by Elsevier Inc.)

Telehealth services are becoming more and more popular, leading to an increasing amount of data to be monitored by health professionals. Machine learning can support them in managing these data. Therefore, the right machine learning algorithms need to be applied to the right data. We have implemented and validated different algorithms for selecting optimal time instances from time series data derived from a diabetes telehealth service. Intrinsic, supervised, and unsupervised instance selection algorithms were analysed. Instance selection had a huge impact on the accuracy of our random forest model for dropout prediction. The best results were achieved with a One Class Support Vector Machine, which improved the area under the receiver operating curve of the original algorithm from 69.91 to 75.88 %. We conclude that, although hardly mentioned in telehealth literature so far, instance selection has the potential to significantly improve the accuracy of machine learning algorithms.

The IKAROS family of transcription factors comprises four zinc-finger proteins (IKAROS, HELIOS, AIOLOS, and EOS), which over the last decades have been established to be critical regulators of the development and function of lymphoid cells. These factors act as homo- or heterodimers and are involved both in gene activation and repression. Their function often involves cross-talk with other regulatory circuits, such as the JAK/STAT, NF-κB, and NOTCH pathways. They control lymphocyte differentiation at multiple stages and are notably critical for lymphoid commitment in multipotent hematopoietic progenitors and for T and B cell differentiation downstream of pre-TCR and pre-BCR signaling. They also control many aspects of effector functions in mature B and T cells. They are dysregulated or mutated in multiple pathologies affecting the lymphoid system, which range from leukemia to immunodeficiencies. In this chapter, we review the molecular and physiological function of these factors in lymphocytes and their implications in human pathologies., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Objective: To evaluate blood-based biomarkers to detect endometriosis and/or adenomyosis across nine European centers (June 2014-April 2018)., Methods: This prospective, non-interventional study assessed the diagnostic accuracy of 54 blood-based biomarker immunoassays in samples from 919 women (aged 18-45 years) with suspicion of endometriosis and/or adenomyosis versus symptomatic controls. Endometriosis was stratified by revised American Society for Reproductive Medicine stage. Symptomatic controls were "pathologic symptomatic controls" or "pathology-free symptomatic controls". The main outcome measure was receiver operating characteristic-area under the curve (ROC-AUC) and Wilcoxon P values corrected for multiple testing (q values)., Results: CA-125 performed best in "all endometriosis cases" versus "all symptomatic controls" (AUC 0.645, 95% confidence interval [CI] 0.600-0.690, q < 0.001) and increased (P < 0.001) with disease stage. In "all endometriosis cases" versus "pathology-free symptomatic controls", S100-A12 performed best (AUC 0.692, 95% CI 0.614-0.769, q = 0.001) followed by CA-125 (AUC 0.649, 95% CI 0.569-0.729, q = 0.021). In "adenomyosis only cases" versus "symptomatic controls" or "pathology-free symptomatic controls", respectively, the top-performing biomarkers were sFRP-4 (AUC 0.615, 95% CI 0.551-0.678, q = 0.045) and S100-A12 (AUC 0.701, 95% CI 0.611-0.792, q = 0.004)., Conclusion: This study concluded that no biomarkers tested could diagnose or rule out endometriosis/adenomyosis with high certainty., (© 2023 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Objectives: As currently there is no existing biomechanical work on the topic of interest, the aim of the current study was to investigate the effect of cerclage banding distally to an intraoperatively occurring proximal periprosthetic femoral clamshell fracture versus a non-fractured femur after total hip arthroplasty., Methods: A diaphyseal anchoring stem was implanted in twenty paired human cadaveric femora, assigned to a treatment and a control group. In the treatment group, each specimen was fitted with a cerclage band placed 3 mm distally to a clamshell fracture, created with an extent of 40% of the anchoring length of the stem. The resulting fragment was not treated further. The contralateral specimens were left with the stems without further fracture creation or treatment. All constructs were tested under progressively increasing cyclic axial loading until failure. Relative bone-implant movements were monitored by motion tracking., Results: Number of cycles and the corresponding load at stem loosening, defined as 1 mm displacement of the stem along the shaft axis, were 31,417 ± 8870 and 3641.7 ± 887 N in the control group, and 26,944 ± 11,706 and 3194.4 ± 1170.6 N in the treatment group, respectively, with no significant differences between them, p = 0.106., Conclusion: From a biomechanical perspective, cerclage banding distally to an intraoperative clamshell fracture with an extent of 40% of the anchoring length of the stem demonstrated comparable resistance against hip stem loosening versus a non-fractured femur. It may therefore represent a valid treatment option to restore the full axial stability of a diaphyseal anchoring stem. In addition, it may be considered to keep the medial wall fragment unfixed, thus saving operative time and minimizing associated risks.

Mutations in the gene encoding the zinc-finger transcription factor Ikaros ( IKZF1 ) are found in patients with immunodeficiency, leukemia, and autoimmunity. Although Ikaros has a well-established function in modulating gene expression programs important for hematopoietic development, its role in other cell types is less well defined. Here, we uncover functions for Ikaros in thymic epithelial lineage development in mice and show that Ikzf1 expression in medullary thymic epithelial cells (mTECs) is required for both autoimmune regulator-positive (Aire + ) mTEC development and tissue-specific antigen (TSA) gene expression. Accordingly, TEC-specific deletion of Ikzf1 in mice results in a profound decrease in Aire + mTECs, a global loss of TSA gene expression, and the development of autoimmunity. Moreover, Ikaros shapes thymic mimetic cell diversity, and its deletion results in a marked expansion of thymic tuft cells and muscle-like mTECs and a loss of other Aire-dependent mimetic populations. Single-cell analysis reveals that Ikaros modulates core transcriptional programs in TECs that correlate with the observed cellular changes. Our findings highlight a previously undescribed role for Ikaros in regulating epithelial lineage development and function and suggest that failed thymic central tolerance could contribute to the autoimmunity seen in humans with IKZF1 mutations.

The present article reports a narrative review of intervention (i.e., training) studies using Virtual Reality (VR) in sports contexts. It provides a qualitative overview and narrative summary of such studies to clarify the potential benefits of VR technology for sports performance enhancement, to extract the main characteristics of the existing studies, and to inform and guide future research. Our literature search and review eventually resulted in 12 intervention studies with a pre vs. post design focused on different sports, including target and precision sports (archery, bowling, curling, darts, golf), bat/racquet and ball sports (baseball, table tennis), goal sports (football/soccer, basketball), martial arts (karate), and sport-unspecific processes such as bodily sensations and balancing. The samples investigated in the primary studies included novice, amateur, and expert athletes (total aggregated sample size N  = 493). Many studies found statistically significant effects in relevant target skills following interventions in VR, often outperforming training effects in passive or active control conditions (e.g., using conventional training protocols). Therefore, interventions in VR (or extended reality) have the potential to elicit real effects in sports performance enhancement through training of motor and psychological skills and capabilities in athletes, including perception-action skills, strategic, tactical and decision-making, responding to unexpected events, and enhancing psychological resilience and mental performance under pressure. The neurocognitive mechanisms (e.g., visual search behavior, imagery), methodological aspects (e.g., adaptive training difficulty), and the issues of real-world transfer and generalizability via which these potential sports-performance-related improvements may occur are discussed. Finally, limitations of the present review, the included studies, the current state of the field in general as well as an outlook and future perspectives for research designs and directions are taken into consideration., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Richlan, Weiß, Kastner and Braid.)

Early detection of atrial fibrillation (AF) enables initiation of anticoagulation and early rhythm control therapy to reduce stroke, cardiovascular death, and heart failure. In a cross-sectional, observational study, we aimed to identify a combination of circulating biomolecules reflecting different biological processes to detect prevalent AF in patients with cardiovascular conditions presenting to hospital. Twelve biomarkers identified by reviewing literature and patents were quantified on a high-precision, high-throughput platform in 1485 consecutive patients with cardiovascular conditions (median age 69 years [Q1, Q3 60, 78]; 60% male). Patients had either known AF (45%) or AF ruled out by 7-day ECG-monitoring. Logistic regression with backward elimination and a neural network approach considering 7 key clinical characteristics and 12 biomarker concentrations were applied to a randomly sampled discovery cohort (n = 933) and validated in the remaining patients (n = 552). In addition to age, sex, and body mass index (BMI), BMP10, ANGPT2, and FGF23 identified patients with prevalent AF (AUC 0.743 [95% CI 0.712, 0.775]). These circulating biomolecules represent distinct pathways associated with atrial cardiomyopathy and AF. Neural networks identified the same variables as the regression-based approach. The validation using regression yielded an AUC of 0.719 (95% CI 0.677, 0.762), corroborated using deep neural networks (AUC 0.784 [95% CI 0.745, 0.822]). Age, sex, BMI and three circulating biomolecules (BMP10, ANGPT2, FGF23) are associated with prevalent AF in unselected patients presenting to hospital. Findings should be externally validated. Results suggest that age and different disease processes approximated by these three biomolecules contribute to AF in patients. Our findings have the potential to improve screening programs for AF after external validation., (© 2023. Springer Nature Limited.)

Background: Atrial fibrillation is a major risk factor for stroke and silent brain infarcts. We studied whether a multimodal approach offers additional insights to the CHA 2 DS 2 -VASc score in predicting stroke or new brain infarcts on magnetic resonance imaging (MRI) over a 2-year follow-up., Methods: Swiss-AF is a prospective, multicenter cohort study of patients with known atrial fibrillation. We included patients with available brain MRI both at enrollment and 2 years later. The dates of the baseline and follow-up visits ranged from March 2014 to November 2020. The primary outcome was assessed 2 years after baseline and was defined as a composite of clinically identified stroke or any new brain infarct on the 2-year MRI. We compared a multivariable logistic regression model including prespecified clinical, biomarker, and baseline MRI variables to the CHA 2 DS 2 -VASc score., Results: We included 1232 patients, 89.8% of them taking oral anticoagulants. The primary outcome occurred in 78 patients (6.3%). The following baseline variables were included in the final multivariate model and were significantly associated with the primary outcome: white matter lesion volume in milliliters (adjusted odds ratio [aOR], 1.91 [95% CI, 1.45-2.56]), NT-proBNP (N-terminal pro-B-type natriuretic peptide; aOR, 1.75 [95% CI, 1.20-2.63]), GDF-15 (growth differentiation factor-15; aOR, 1.68 [95% CI, 1.11-2.53]), serum creatinine (aOR, 1.50 [95% CI, 1.02-2.22]), IL (interleukin)-6 (aOR, 1.37 [95% CI, 1.00-1.86]), and hFABP (heart-type fatty acid-binding protein; aOR, 0.48 [95% CI, 0.31-0.73]). Overall performance and discrimination of the new model was superior to that of the CHA 2 DS 2 -VASc score (C statistic, 0.82 [95% CI, 0.77-0.87] versus 0.64 [95% CI, 0.58-0.70])., Conclusions: In patients with atrial fibrillation, a model incorporating white matter lesion volume on baseline MRI and selected blood markers yielded new insights on residual stroke risk despite a high proportion of patients on oral anticoagulants. This may be relevant to develop further preventive measures., Competing Interests: Disclosures Dr De Marchis reports honoraria by Bayer, Pfizer, Medtronic and a Grant from Novartis unrelated to the present work. Industry payments are made to the research fund of the University Hospital Basel. Dr Aeschbacher reports speaker fees from Roche Diagnostics. Dr Reichlin reports consultant honoraria/grants from Abbott Laboratories, Biosense Webster, Inc, Biotronik, Boston Scientific Corporation, and Medtronic. Dr Moschovitis has received consultant fees for taking part to advisory boards from Novartis, Boehringer Ingelheim, Bayer, Astra Zeneca and Daiichi Sankyo, all outside of the submitted work. Dr Wuerfel is employed at Roche. Dr Lyrer reports honoraria from Bayer, Biogen, Boehringer Ingelheim, Pfizer – all unrelated to the present work – and grants from the Swiss National Science Foundation and University Hospital Basel (intramural grant). Dr Fischer reports grant/contracts from Alexion, Biogen, Medtronic Vascular, Penumbra, Phenox, Rapid Medical, as well as support from Stryker and CSL Behring Foundation for Research and Advancement of Patient Health. Dr Conen reports consultation fees from Roche Diagnostics and Trimedics, as well as speaker fees from Servier and Pfizer. Dr Ziegler is employed at Roche Diagnostics International. Dr Kühne reports personal fees from Bayer, personal fees from Böhringer Ingelheim, personal fees from Pfizer Bristol-Myers Squibb (BMS), personal fees from Daiichi Sankyo, personal fees from Medtronic, personal fees from Biotronik, personal fees from Boston Scientific, personal fees from Johnson&Johnson, personal fees from Roche, grants from Bayer, grants from Pfizer, grants from Boston Scientific, grants from BMS, grants from Biotronik, grants from Daiichi Sankyo. Dr Bonati reports honoraria from Amgen, AstraZeneca, Bayer, BMS, Claret Medical, grants from the Swiss National Science Foundation, Swiss Heart Foundation, University of Basel, and Stiftung zur Förderung der gastroenterologischen und allgemeinen klinischen Forschung sowie der medizinischen Bildauswertung. The other authors report no conflicts.

The transcriptional regulators that drive regulatory T (Treg) cell development and function remain partially understood. Helios (Ikzf2) and Eos (Ikzf4) are closely-related members of the Ikaros family of transcription factors. They are highly expressed in CD4 + Treg cells and functionally important for Treg cell biology, as mice deficient for either Helios or Eos are susceptible to autoimmune diseases. However, it remains unknown if these factors exhibit specific or partially redundant functions in Treg cells. Here we show that mice with germline deletions of both Ikzf2 and Ikzf4 are not very different from animals with single Ikzf2 or Ikzf4 deletions. Double knockout Treg cells differentiate normally, and efficiently suppress effector T cell proliferation in vitro. Both Helios and Eos are required for optimal Foxp3 protein expression. Surprisingly, Helios and Eos regulate different, largely non-overlapping, sets of genes. Only Helios is required for proper Treg cell aging, as Helios deficiency results in reduced Treg cell frequencies in the spleen of older animals. These results indicate that Helios and Eos are required for distinct aspects of Treg cell function., Competing Interests: Declaration of competing interest All authors declare that they have no competing interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Serotonin (5-HT) is a biogenic monoamine with diverse functions in multiple human organs and tissues. During pregnancy, tightly regulated levels of 5-HT in the fetoplacental unit are critical for proper placental functions, fetal development, and programming. Despite being a non-neuronal organ, the placenta expresses a suite of homeostatic proteins, membrane transporters and metabolizing enzymes, to regulate monoamine levels. We hypothesized that placental 5-HT clearance is important for maintaining 5-HT levels in the fetoplacental unit. We therefore investigated placental 5-HT uptake from the umbilical circulation at physiological and supraphysiological levels as well as placental metabolism of 5-HT to 5-hydroxyindoleacetic acid (5-HIAA) and 5-HIAA efflux from trophoblast cells., Methods: We employed a systematic approach using advanced organ-, tissue-, and cellular-level models of the human placenta to investigate the transport and metabolism of 5-HT in the fetoplacental unit. Human placentas from uncomplicated term pregnancies were used for perfusion studies, culturing explants, and isolating primary trophoblast cells., Results: Using the dually perfused placenta, we observed a high and concentration-dependent placental extraction of 5-HT from the fetal circulation. Subsequently, within the placenta, 5-HT was metabolized to 5-hydroxyindoleacetic acid (5-HIAA), which was then unidirectionally excreted to the maternal circulation. In the explant cultures and primary trophoblast cells, we show concentration- and inhibitor-dependent 5-HT uptake and metabolism and subsequent 5-HIAA release into the media. Droplet digital PCR revealed that the dominant gene in all models was MAO-A, supporting the crucial role of 5-HT metabolism in placental 5-HT clearance., Conclusions: Taken together, we present transcriptional and functional evidence that the human placenta has an efficient 5-HT clearance system involving (1) removal of 5-HT from the fetal circulation by OCT3, (2) metabolism to 5-HIAA by MAO-A, and (3) selective 5-HIAA excretion to the maternal circulation via the MRP2 transporter. This synchronized mechanism is critical for regulating 5-HT in the fetoplacental unit; however, it can be compromised by external insults such as antidepressant drugs., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Aims: Several biomarkers are associated with clinical outcomes in patients with atrial fibrillation (AF), but a causal relationship has not been established. This study aimed to evaluate angiopoietin-2, a novel candidate biomarker of endothelial inflammation and vascular remodelling, in patients with AF., Methods and Results: Angiopoietin-2 was measured in plasma obtained from patients with AF treated with aspirin monotherapy (exploration cohort, n = 2987) or with oral anticoagulation (validation cohort, n = 13 079). Regression models were built to assess the associations between angiopoietin-2, clinical characteristics, and outcomes. In both cohorts, plasma angiopoietin-2 was independently associated with AF on the baseline electrocardiogram and persistent/permanent AF, age, history of heart failure, female sex, tobacco use/smoking, body mass index, renal dysfunction, diabetes, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Angiopoietin-2 was independently associated with subsequent hospitalization for heart failure after adjusting for age, creatinine, and clinical characteristics in the exploration cohort [c-index 0.79, 95% confidence interval (CI) 0.75-0.82; third vs. first quartile, hazard ratio (HR) 1.74, 95% CI 1.26-2.41] and in the validation cohort (c-index 0.76, 95% CI 0.74-0.78; HR 1.58, 95% CI 1.37-1.82). In both cohorts, the association persisted when also adjusting for NT-proBNP (P ≤ 0.001). In full multivariable models also adjusted for NT-proBNP, angiopoietin-2 did not show statistically significant associations with ischaemic stroke, cardiovascular and all-cause death, or major bleeding that were consistent across the two cohorts., Conclusions: In patients with AF, plasma levels of angiopoietin-2 were independently associated with subsequent hospitalization for heart failure and provided incremental prognostic value to clinical risk factors and NT-proBNP., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: An increased risk of intracranial hemorrhage (ICH) associated with statins has been reported, but data on the relationship between statin use and cerebral microbleeds (CMBs) in patients with atrial fibrillation (AF), a population at high bleeding and cardiovascular risk, are lacking., Aims: To explore the association between statin use and blood lipid levels with the prevalence and progression of CMBs in patients with AF with a particular focus on anticoagulated patients., Methods: Data of Swiss-AF, a prospective cohort of patients with established AF, were analyzed. Statin use was assessed during baseline and throughout follow-up. Lipid values were measured at baseline. CMBs were assessed using magnetic resonance imagining (MRI) at baseline and at 2 years follow-up. Imaging data were centrally assessed by blinded investigators. Associations of statin use and low-density lipoprotein (LDL) levels with CMB prevalence at baseline or CMB progression (at least one additional or new CMB on follow-up MRI at 2 years compared with baseline) were assessed using logistic regression models; the association with ICH was assessed using flexible parametric survival models. Models were adjusted for hypertension, smoking, body mass index, diabetes, stroke/transient ischemic attack, coronary heart disease, antiplatelet use, anticoagulant use, and education., Results: Of the 1693 patients with CMB data at baseline MRI (mean ± SD age 72.5 ± 8.4 years, 27.6% women, 90.1% on oral anticoagulants), 802 patients (47.4%) were statin users. The multivariable adjusted odds ratio (adjOR) for CMBs prevalence at baseline for statin users was 1.10 (95% CI = 0.83-1.45). AdjOR for 1 unit increase in LDL levels was 0.95 (95% CI = 0.82-1.10). At 2 years, 1188 patients had follow-up MRI. CMBs progression was observed in 44 (8.0%) statin users and 47 (7.4%) non-statin users. Of these patients, 64 (70.3%) developed a single new CMB, 14 (15.4%) developed 2 CMBs, and 13 developed more than 3 CMBs. The multivariable adjOR for statin users was 1.09 (95% CI = 0.66-1.80). There was no association between LDL levels and CMB progression (adjOR 1.02, 95% CI = 0.79-1.32). At follow-up 14 (1.2%) statin users had ICH versus 16 (1.3%) non-users. The age and sex adjusted hazard ratio (adjHR) was 0.75 (95% CI = 0.36-1.55). The results remained robust in sensitivity analyses excluding participants without anticoagulants., Conclusions: In this prospective cohort of patients with AF, a population at increased hemorrhagic risk due to anticoagulation, the use of statins was not associated with an increased risk of CMBs.

Aims: Atrial remodelling, defined as a change in atrial structure, promotes atrial fibrillation (AF). Bone morphogenetic protein 10 (BMP10) is an atrial-specific biomarker released to blood during atrial development and structural changes. We aimed to validate whether BMP10 is associated with AF recurrence after catheter ablation (CA) in a large cohort of patients., Methods and Results: We measured baseline BMP10 plasma concentrations in AF patients who underwent a first elective CA in the prospective Swiss-AF-PVI cohort study. The primary outcome was AF recurrence lasting longer than 30 s during a follow-up of 12 months. We constructed multivariable Cox proportional hazard models to determine the association of BMP10 and AF recurrence. A total of 1112 patients with AF (age 61 ± 10 years, 74% male, 60% paroxysmal AF) was included in our analysis. During 12 months of follow-up, 374 patients (34%) experienced AF recurrence. The probability for AF recurrence increased with increasing BMP10 concentration. In an unadjusted Cox proportional hazard model, a per-unit increase in log-transformed BMP10 was associated with a hazard ratio (HR) of 2.28 (95% CI 1.43; 3.62, P < 0.001) for AF recurrence. After multivariable adjustment, the HR of BMP10 for AF recurrence was 1.98 (95% CI 1.14; 3.42, P = 0.01), and there was a linear trend across BMP10 quartiles (P = 0.02 for linear trend)., Conclusion: The novel atrial-specific biomarker BMP10 was strongly associated with AF recurrence in patients undergoing CA for AF., Clinicaltrials.gov Identifier: NCT03718364; https://clinicaltrials.gov/ct2/show/NCT03718364., Competing Interests: Conflict of interest: P.B. received research funding from the University of Basel, the ‘Stiftung für Herzschrittmacher und Elektrophysiologie’, the ‘Freiwillige Akademische Gesellschaft Basel’, and the Swiss Heart Foundation and Johnson&Johnson, all outside the submitted work, and reports personal fees from Abbott, Boston Scientific, and Pfizer BMS. D.C. received consultancy fees from Roche Diagnostics and Trimedics and speaker fees from Servier and BMS/Pfizer. S.K. received funding from the ‘Stiftung für Herzschrittmacher und Elektrophysiologie’. M.K. received personal fees from Daiichi Sankyo and grants from the Swiss National Science Foundation, Swiss Heart Foundation, Foundation for CardioVascular Research Basel, Bayer, Pfizer, Boston Scientific, BMS, Biotronik, and Daiichi Sankyo. S.O. received research grants from the Swiss National Science Foundation and Swiss Heart Foundation, Foundation for CardioVascular Research Basel, and F. Hoffmann-La Roche Ltd and educational and speaker grants from F. Hoffmann-La Roche Ltd, Bayer, Novartis, Sanofi, AstraZeneca, Daiichi Sankyo, and Pfizer. C.S. is a member of the Advisory Board of Medtronic Europe and Advisory Board of Boston Scientific Europe and has received educational grants from Biosense Webster and Biotronik, research grants from the European Union’s FP7 program and Biosense Webster, and lecture and consulting fees from Abbott, Medtronic, Biosense Webster, Boston Scientific, Micro-Port, and Biotronik. All remaining authors have declared no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: To compare construct stability of cement augmented sacroiliac screws using two different cementation sites in a biomechanical fragility fracture model of the pelvis., Methods: A fracture model with an incomplete fracture of the sacral ala and complete fracture of the anterior pelvic ring mimicking a FFP IIB fragility fracture of the pelvis was established in five fresh frozen human cadaveric pelvises. Sacral fracture stabilization was achieved with bilateral 7.3 mm fully threaded sacroiliac screws. Cement augmentation was performed at the tip of the screw (body of S1; Group A) on one side, and at the midshaft of the screw (sacral ala; Group B) on the contralateral side. Biomechanical testing was conducted separately on both sides comprising cyclic loading of axial forces transferred through the tested hemipelvis from L5 to the ipsilateral acetabulum. Combined angular displacement in flexion and internal rotation ("gap angle"), angular displacement of the ilium in relation to the screw ("screw tilt ilium"), and screw tip cutout were evaluated., Results: Relative interfragmentary movements were associated with significantly higher values in group A versus group B for "gap angle" (2.4° vs. 1.4°; p < 0.001), and for "screw tilt ilium" (3.3° vs. 1.4°; p < 0.001), respectively. No significant difference was indicated for screw tip cutout between the two groups (0.6 mm [Group A] vs. 0.8 mm [Group B]; p = 0.376)., Conclusion: The present study demonstrated less fragment and screw displacements in a FFP IIB fracture model under physiologic cyclic loading by cement augmentation of sacroiliac screws at the level of the lateral mass compared to the center of vertebral body of S1., (© 2022. The Author(s).)

Background: The Integrated Treatment Pathway Stroke Tyrol was introduced for the care of people after an acute stroke event and includes four phases: acute prehospital care, inpatient treatment, inpatient rehabilitation and ambulatory, outpatient rehabilitation. For the 4th phase, the ambulatory rehabilitation of patients after discharge, the ICT platform "StrokeNet Tyrol" was established., Methods: Requirements and processes along the pathway and between the interdisciplinary team were taken into account for implementation based on a modular software architecture. Flexible rights and role concept was developed to support efficient collaboration of the heterogenic professions., Results: The routine usage of 342 users with 8 different roles, 2,219 registered patient cases within the last 4 years and first results of the integrated benchmarking solution give a positive impression regarding feasibility and effectiveness., Conclusion: To this point, a comprehensive infrastructure for the Ambulatory Tyrolean Stroke Pathway has been established. Results from outcome analyses and comparative studies could help to further improve usability and to expand the area of application for other indications.

Background Patients with atrial fibrillation (AF) face an increased risk of death and major adverse cardiovascular events (MACE). We aimed to assess the predictive value of the novel atrial-specific biomarker BMP10 (bone morphogenetic protein 10) for death and MACE in patients with AF in comparison with NT-proBNP (N-terminal prohormone of B-type natriuretic peptide). Methods and Results BMP10 and NT-proBNP were measured in patients with AF enrolled in Swiss-AF (Swiss Atrial Fibrillation Study), a prospective multicenter cohort study. A total of 2219 patients were included (median follow-up 4.3 years [interquartile range 3.9, 5.1], mean age 73±9 years, 73% male). In multivariable Cox proportional hazard models, the adjusted hazard ratio (aHR) associated with 1 ng/mL increase of BMP10 was 1.60 (95% CI, 1.37-1.87) for all-cause death, and 1.54 (95% CI, 1.35-1.76) for MACE. For all-cause death, the concordance index was 0.783 (95% CI, 0.763-0.809) for BMP10, 0.784 (95% CI, 0.765-0.810) for NT-proBNP, and 0.789 (95% CI, 0.771-0.815) for both biomarkers combined. For MACE, the concordance index was 0.732 (95% CI, 0.715-0.754) for BMP10, 0.747 (95% CI, 0.731-0.768) for NT-proBNP, and 0.750 (95% CI, 0.734-0.771) for both biomarkers combined. When grouping patients according to NT-proBNP categories (<300, 300-900, >900 ng/L), higher aHRs were observed in patients with high BMP10 in the categories of low NT-proBNP (all-cause death aHR, 2.28 [95% CI, 1.15-4.52], MACE aHR, 1.88 [95% CI, 1.07-3.28]) and high NT-proBNP (all-cause death aHR, 1.61 [95% CI, 1.14-2.26], MACE aHR, 1.38 [95% CI, 1.07-1.80]). Conclusions BMP10 strongly predicted all-cause death and MACE in patients with AF. BMP10 provided additional prognostic information in low- and high-risk patients according to NT-proBNP stratification. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02105844.

To biomechanically evaluate the stability of a diaphyseal anchored, cementless stem in presence of a proximal periprosthetic femoral medial wall defect compared to the stability of the same stem in an intact femur. Twenty-two paired human cadaveric femora were pairwise assigned either to a fracture group, featuring a proximal medial wall defect involving 40% of the stems medial anchorage distance, or a control group with native specimens. The specimens were tested under a monotonically increasing cyclic axial loading protocol. Load, cycles, and multiples of the respective body weight at implant loosening was measured. Mean initial stiffness was 2243.9 ± 467.9 N/mm for the intact group and 2190.1 ± 474.8 N/mm for the fracture group. Mean load to loosening in the intact group was 3210.5 ± 1073.2 N and 2543.6 ± 576.4 N in the fracture group, with statistical significance. Mean cycles to loosening in the intact group were 27104.9 ± 10731.7 and 20431.5 ± 5763.7 in the fracture group, with statistical significance. Mean multiples of the resulting body weight at loosening in the intact group was 548.3 ± 158.5% and 441.4 ± 104% in the fracture group, with statistical significance. A medial wall defect involving 40% of the medial anchorage distance significantly decreases the axial stability of a diaphyseal anchored stem. However, mechanical failure occurred beyond physiological stress. At loosening rates of about 4 multiples of the body weight in the fracture group, a "safe zone" remains of a 0.5-fold body weight for maximum loads and twofold body weights for average loads., (© 2022 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Objectives: Helical plates are preferably used for proximal humeral shaft fracture fixation and potentially avoid radial nerve irritation., Aims: Safety of applying four different long plate designs (straight, 45°-, 90°-helical and ALPS) with MIPO technique as well as assessment and comparison of their distances to adjacent anatomical structures., Methods: MIPO was performed in 16 human cadaveric humeri using either a straight (group 1), a 45°-helical (group 2), a 90°-helical (group 3) plate, or an ALPS (group 4). Applying CT angiography, distances between brachial arteries and plates were evaluated. All specimens were dissected and distances to the axillary, radial and musculocutaneous nerve were evaluated., Results: No specimens demonstrated injuries of the anatomical structures at risk after MIPO with all investigated plate designs. Closest overall distance (mean (range); mm) between each plate and the radial nerve was 1 (1-3) in group 1, 7 (2-11) in group 2, 14 (7-25) in group 3 and 6 (3-8) in group 4. It was significantly bigger in group 3 and significantly smaller in group 1 compared to all other groups, p < 0.001. Closest overall distance between each plate and the musculocutaneous nerve was 16 (8-28) in group 1, 11 (7-18) in group 2, 3 (2-4) in group 3 and 6 (3-8) in group 4. It was significantly bigger in group 1 and significantly smaller in group 3 compared to all other groups, p < 0.001., Conclusions: MIPO with 45°- and 90°-helical plates as well as with ALPS is safely feasible and demonstrates significantly bigger distances to the radial nerve compared to straight plates. However, the distances remain small and attention must be paid to the musculocutaneous nerve and the brachial artery when MIPO is applied using ALPS, 45°- and 90°-helical implants., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Aims: Biomarkers specifically related to atrial tissue may increase the understanding of the pathophysiology of atrial fibrillation (AF) and further improve risk prediction in this setting. Bone morphogenetic protein 10 (BMP10) is a protein expressed in the atrial myocardium. We evaluated the association between BMP10 and the risk of ischaemic stroke and other cardiovascular events in large cohorts of patients with AF, treated with and without oral anticoagulation (OAC)., Methods and Results: BMP10 was measured in plasma samples collected at randomisation in patients with AF without OAC in the ACTIVE A and AVERROES trials (n = 2974), and with OAC in the ARISTOTLE trial (n = 13 079). BMP10 was analysed with a prototype Elecsys immunoassay. Associations with outcomes were evaluated by Cox-regression models adjusted for clinical characteristics, kidney function, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Median concentrations of BMP10 were 2.47 and 2.44 ng/mL, in the non-OAC and OAC cohort, respectively. Increasing BMP10 was associated with lower body mass index, older age, female sex, kidney dysfunction, and AF rhythm. BMP10 was consistently associated with ischaemic stroke. In the non-OAC cohort, BMP10 increased the concordance index of the multivariable model from 0.713 to 0.733 (P = 0.004) and in the OAC cohort from 0.673 to 0.694 (P < 0.001). Additionally, BMP10 maintained a significant prognostic value after additionally adjusting for NT-proBNP. BMP10 was not independently associated with bleeding or with death., Conclusion: The novel atrial biomarker BMP10 was independently associated with ischaemic stroke in patients with AF irrespective of OAC treatment. BMP10 seems to be more specifically related to the risk of ischaemic stroke in AF., One-Sentence Summary: In this study, BMP10 may be a novel specific biomarker of ischaemic stroke in patients with atrial fibrillation, irrespective of oral anticoagulation., Competing Interests: Conflict of interest: Dr Hijazi reports lecture and consulting fees from Boehringer Ingelheim, Bristol Myers Squibb, Pfizer and Roche Diagnostics International. Dr Benz has nothing to disclose. Mr Lindbäck reports institutional research grant from Roche Diagnostics International. Dr Alexander reports institutional research grants from Artivion/CryoLife, Bayer, Bristol Myers Squibb, CSL Behring, Ferring, Humacyte, and XaTek and consulting or honoraria payments from AbbVie, Akros, Artivion/CryoLife, AtriCure, Bristol Myers Squibb, Ferring, GlaxoSmithKline, Janssen, Pfizer, Portola, and Quantum Genomics. Dr Connolly reports institutional research grants and honoraria from Boehringer Ingelheim, Portola/Alexion Pharmaceuticals, Bristol Myers Squibb/Pfizer, Bayer, and Daiichi Sankyo. Dr Eikelboom reports institutional research grants and honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, and Sanofi. Dr Granger reports grants and consulting fees from Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Janssen Pharmaceutica Products, L.P., Medtronic Foundation, Novartis; grants from Daiichi Sankyo, AKROS, Apple, GlaxoSmithKline, AstraZeneca, the U.S. Food and Drug Administration; consulting fees from Abbvie, Abiomed, Athos Therapeutic, LLC, Bayer Corporation US, Boston Scientific Corporation, Espero BioPharma, National Institutes of Health, Philips, Rhoshan Pharmaceuticals, Roche Diagnostics, CeleCor Therapeutics, Correvio, Merck, NovoNordisk. Drs. Kastner and Ziegler are employees of Roche Diagnostics GmbH. Dr Lopes reports institutional research grants and consulting fees from Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi; consulting fees from Amgen, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Merck, and Portola. Dr Oldgren reports institutional research grants and fees paid to his institution for advisory boards and lectures from Roche Diagnostics International; fees paid to his institution for advisory boards, study steering committees, and lectures from AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Pfizer, and Sanofi; fees paid to his institution for advisory boards, safety committees, and lectures from Daichii Sankyo. Dr Siegbahn reports institutional research grants from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, GlaxoSmithKline, and Roche Diagnostics International. Dr Wallentin reports institutional research grants from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, GlaxoSmithKline, Roche Diagnostics International, Merck & Co; consulting fees from Abbott; holds two patents involving GDF-15 licensed to Roche Diagnostics (EP2047275B1 and US8951742B2)., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The present multi-study article investigates the subjective experience of professional football (a.k.a. soccer) referees and players during the COVID-19 pandemic and the so-called ghost games (i.e., games without supporters). Referees from the Austrian Football Association completed questionnaires inquiring about self-efficacy, motivation, and general personal observations and perceptions (e.g., arousal or confidence). In addition, two players and one referee in the Austrian Football Bundesliga were interviewed retrospectively regarding their subjective experience during ghost games and the effects of emotions on behavior and performance using semi-structured, video-taped interviews. Results of the referee survey indicate that the most profound differences between regular games and ghost games lie in the domain of intrinsic motivation and multiple aspects of subjective experience. Specifically, the experience in ghost games compared with regular games was reported by referees as being significantly less motivating, less excited/tense, less emotional, less focused, and overall, more negative, despite being easier to referee and the players behaving more positively. Qualitative analyses of the video-taped interview footage indicated (i) substantial inter-individual variability regarding the extent of the effect of the empty stadiums on the subjective experience of emotions, (ii) consequently, different strategies to regulate emotions and arousal from suboptimal to optimal levels, both before and during competition, and (iii) interactions between reported emotions, arousal, motivation, self-confidence, behavior and performance on the pitch. In addition, non-verbal expressions of emotion were captured using fully automated AI-software that coded facial movements during interviews. The results of this exploratory facial expression analysis revealed varying degrees of arousal and valence in relation to the content of the statements during the interviews, demonstrating the convergent validity of our findings. Our findings contribute to the growing literature on the effects of football games without fans during the COVID-19 pandemic and provide insights into the subjective experience of professional football referees. Concerning referees and players alike, emotions are investigated as potential processes related to home-field advantage and performance in professional football by means of a multi-methods approach. Further, the combination of qualitative and quantitative measures-as well as verbal and non-verbal communication channels-can deepen our understanding of the emotional influence of (missing) spectators on the subjective experience and the behavior of sports professionals is discussed., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2023.)

Background and Objectives : Intramedullary nailing of trochanteric fractures can be challenging and sometimes the clinical situation does not allow perfect implant positioning. The aim of this study was (1) to compare in human cadaveric femoral heads the biomechanical competence of two recently launched cephalic implants inserted in either an ideal (centre-centre) or less-ideal anterior off-centre position, and (2) to investigate the effect of bone cement augmentation on their fixation strength in the less-ideal position. Materials and Methods : Fourty-two paired human cadaveric femoral heads were assigned for pairwise implantation using either a TFNA helical blade or a TFNA screw as head element, implanted in either centre-centre or 7 mm anterior off-centre position. Next, seven paired specimens implanted in the off-centre position were augmented with bone cement. As a result, six study groups were created as follows: group 1 with a centre-centre positioned helical blade, paired with group 2 featuring a centre-centre screw, group 3 with an off-centre positioned helical blade, paired with group 4 featuring an off-centre screw, and group 5 with an off-centre positioned augmented helical blade, paired with group 6 featuring an off-centre augmented screw. All specimens were tested until failure under progressively increasing cyclic loading. Results : Stiffness was not significantly different among the study groups ( p = 0.388). Varus deformation was significantly higher in group 4 versus group 6 ( p = 0.026). Femoral head rotation was significantly higher in group 4 versus group 3 ( p = 0.034), significantly lower in group 2 versus group 4 ( p = 0.005), and significantly higher in group 4 versus group 6 ( p = 0.007). Cycles to clinically relevant failure were 14,919 ± 4763 in group 1, 10,824 ± 5396 in group 2, 10,900 ± 3285 in group 3, 1382 ± 2701 in group 4, 25,811 ± 19,107 in group 5 and 17,817 ± 11,924 in group 6. Significantly higher number of cycles to failure were indicated for group 1 versus group 2 ( p = 0.021), group 3 versus group 4 ( p = 0.007), and in group 6 versus group 4 ( p = 0.010). Conclusions : From a biomechanical perspective, proper centre-centre implant positioning in the femoral head is of utmost importance. In cases when this is not achievable in a clinical setting, a helical blade is more forgiving in the less ideal (anterior) malposition when compared to a screw, the latter revealing unacceptable low resistance to femoral head rotation and early failure. Cement augmentation of both off-centre implanted helical blade and screw head elements increases their resistance against failure; however, this effect might be redundant for helical blades and is highly unpredictable for screws.

Purpose: Helical plates potentially avoid the medial neurovascular structures of the thigh. Two implant designs for additional medial 90° helical plate in double plate constructs for geriatric patients and 180° helical plate for single plating in young patients are potential alternatives to widely used standard straight plates., Aims: (1) assess the distances to adjacent anatomical structures being at risk when applying medial 90° and 180° helical plates with MIPO technique to the femur, (2) compare these distances with medial straight plates, and (3) correlate measurements performed during surgical dissection with CT angiography., Methods: MIPO was performed in ten human cadaveric femoral pairs using either a 90° helical 14-hole LCP (Group 1) or a 180° helical 15-hole LCP-DF (Group 2). Using CT angiography, distances between femoral arteries and plates as well as distances between plates and perforating vessels were evaluated. Following, specimens were dissected and distances determined again. All plates were removed and measurements were repeated with straight medial plates (Group 3)., Results: Overall closest distances between plates and femoral arteries were 14.5 mm (11-19 mm) in Group 1, 21.6 mm (15-24 mm) in Group 2 and 6.5 mm (5-8 mm) in Group 3, with significant differences between Group 3 and both other groups (p < 0.001). Distances to the nearest perforating vessels were 22.4 mm (15-30 mm) in Group 1 and 1.2 mm (1-2 mm) in Group 2. Measurement techniques (visual after surgical disection and CT angiography) demonstrated a strong correlation (p < 0.010)., Conclusions: Inserting 90° and 180° helical plates with MIPO technique is safe, however, attention must be paid to the medial neurovascular structures with 90° helical plates and to the proximal perforating vessels with 180° helical plates. Helical plates can avoid irritation of medial neurovascular structures - compared with straight plates - although care must be taken during their distal insertion. Measurements during surgical dissection correlate with CT angiography., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background and Objectives: Freehand distal interlocking of intramedullary nails is technically demanding and prone to handling issues. It requires precise placement of a screw through the nail under fluoroscopy guidance and can result in a time consuming and radiation expensive procedure. Dedicated training could help overcome these problems. The aim of this study was to assess construct and face validity of new Digitally Enhanced Hands-On Surgical Training (DEHST) concept and device for training of distal interlocking of intramedullary nails. Materials and Methods: Twenty-nine novices and twenty-four expert surgeons performed interlocking on a DEHST device. Construct validity was evaluated by comparing captured performance metrics-number of X-rays, nail hole roundness, drill tip position and drill hole accuracy-between experts and novices. Face validity was evaluated with a questionnaire concerning training potential and quality of simulated reality using a 7-point Likert scale. Results: Face validity: mean realism of the training device was rated 6.3 (range 4-7). Training potential and need for distal interlocking training were both rated with a mean of 6.5 (range 5-7), with no significant differences between experts and novices, p ≥ 0.234. All participants (100%) stated that the device is useful for procedural training of distal nail interlocking, 96% wanted to have it at their institution and 98% would recommend it to colleagues. Construct validity: total number of X-rays was significantly higher for novices (20.9 ± 6.4 versus 15.5 ± 5.3, p = 0.003). Success rate (ratio of hit and miss attempts) was significantly higher for experts (novices hit: n = 15; 55.6%; experts hit: n = 19; 83%, p = 0.040). Conclusion: The evaluated training device for distal interlocking of intramedullary nails yielded high scores in terms of training capability and realism. Furthermore, construct validity was proven by reliably discriminating between experts and novices. Participants indicate high further training potential as the device may be easily adapted to other surgical tasks.

Background: Telehealth services for chronic diseases are becoming more and more popular since they are expected to improve health outcomes and reduce costs. Especially for diabetes patients, life-long disease management is required. However, there are situations in a patient's life, when motivation to continue the participation in disease management programs is low and the dropout-risk is high., Objectives: We analysed if an adherence management module provided to healthcare professionals within a pre-existing diabetes telehealth service can improve the long-term adherence., Methods: The adherence to the agreed data submission protocol was determined prior and post implementation of the adherence management module., Results: Adherence to the agreed data submission protocol was higher after implementation of the adherence management module as compared to previous years., Conclusion: Adherence to the agreed data submission protocol can be improved by helping healthcare professionals to identify patients at risk of dropout. Further analyses are indicated to proof these results in a prospective study.

Heart failure is a serious disease which increases mortality as well as hospital admission rates for affected patients. Disease management programs supported by telehealth solutions are cost-effective approaches for reducing all-cause mortality and heart failure hospitalizations. A 6-minute walk test (6MWT) app could help heart failure patients to self-monitor their functional capacity. We have developed such an application capable of tracking the geolocation, guiding users through a 6MWT and providing the walked distance after six minutes. Besides common global navigation satellite system (GNSS) filtering methods like a Kalman filter, we have investigated the impact of positioning the device (tablet) and GNSS reception on the accuracy of the test. In a field experiment, we gathered 166 6MWT recordings with the developed mobile application. Applying the Kalman filter reduced the overall relative error from 35.5 % to 3.7 %. Wearing the tablet on the body led to significantly better results than holding it in the hand (p < .001). The average accuracy of 2.2 % of body-worn measurements was below previously defined thresholds for reliable results. It thus allows to define a procedure on how to perform and integrate an accurate 6MWT in telehealth settings for clinical decision support in heart failure patients.

The aim of this paper was to evaluate the effect of telemedical care of gestational diabetes mellitus (GDM) patients with the digital treatment pathway model DiabCare Tirol., Methods: 27 courses of patients with GDM, who were telemonitored through the integrated care program DiabCare Tirol in a diabetes outpatient clinic in Tyrol, Austria during the COVID-19 pandemic in 2020, were analyzed. In addition, randomized controlled trials (RCTs) on telemedicine interventions for GDM were researched, and their results were used for comparison with this disease management method. The patient outcome analysis was used to examine the effects of the integrated care program involving telemonitoring support and compared them to the results of RCTs in which participants were randomly assigned to one of two groups, either mobile monitored or standard treatment group., Results: The feasibility of the digital treatment pathway model was confirmed in practice, as the trend analysis of the 27 GDM patients involved showed significantly improved glycaemic control. Results of RCT studies tend to support the findings of DiabCare Tirol., Conclusion: Benefits of telemonitoring with integrated care to support conventional therapy cannot be dismissed, especially in times of the pandemic. Continuous outcome research with larger patient numbers will be necessary to confirm the effectiveness of telemonitoring in a regular care setting.

Our understanding of cell fate decisions in hematopoietic stem cells is incomplete. Here, we show that the transcription factor Helios is highly expressed in murine hematopoietic stem and progenitor cells (HSPCs), where it is required to suppress the separation of the platelet/megakaryocyte lineage from the HSPC pool. Helios acts mainly in quiescent cells, where it directly represses the megakaryocyte gene expression program in cells as early as the stem cell stage. Helios binding promotes chromatin compaction, notably at the regulatory regions of platelet-specific genes recognized by the Gata2 and Runx1 transcriptional activators, implicated in megakaryocyte priming. Helios null HSPCs are biased toward the megakaryocyte lineage at the expense of the lymphoid and partially resemble cells of aging animals. We propose that Helios acts as a guardian of HSPC pluripotency by continuously repressing the megakaryocyte fate, which in turn allows downstream lymphoid priming to take place. These results highlight the importance of negative and positive priming events in lineage commitment., Competing Interests: Disclosures: The authors declare no competing interests exist., (© 2021 Cova et al.)

Frailty and falls are a major public health problem in older adults. Muscle weakness of the lower and upper extremities are risk factors for any, as well as recurrent falls including injuries and fractures. While the Timed Up-and-Go (TUG) test is often used to identify frail members and fallers, tensiomyography (TMG) can be used as a non-invasive tool to assess the function of skeletal muscles. In a clinical study, we evaluated the correlation between the TMG parameters of the skeletal muscle contraction of 23 elderly participants (22 f, age 86.74 ± 7.88) and distance-based TUG test subtask times. TUG tests were recorded with an ultrasonic-based device. The sit-up and walking phases were significantly correlated to the contraction and delay time of the muscle vastus medialis ( ρ = 0.55-0.80, p < 0.01). In addition, the delay time of the muscles vastus medialis ( ρ = 0.45, p = 0.03) and gastrocnemius medialis ( ρ = -0.44, p = 0.04) correlated to the sit-down phase. The maximal radial displacements of the biceps femoris showed significant correlations with the walk-forward times ( ρ = -0.47, p = 0.021) and back ( ρ = -0.43, p = 0.04). The association of TUG subtasks to muscle contractile parameters, therefore, could be utilized as a measure to improve the monitoring of elderly people's physical ability in general and during rehabilitation after a fall in particular. TUG test subtask measurements may be used as a proxy to monitor muscle properties in rehabilitation after long hospital stays and injuries or for fall prevention.

Background: Little is known about the clinical value of Insulin-like growth factor-binding protein-7 (IGFBP7), a cellular senescence marker, in an elderly general population with multiple co-morbidities and high prevalence of asymptomatic cardiovascular ventricular dysfunction. Inflammation and fibrosis are hallmarks of cardiac aging and remodelling. Therefore, we assessed the clinical performance of IGFBP7 and two other biomarkers reflecting these pathogenic pathways, the growth differentiation factor-15 (GFD-15) and amino-terminal propeptide of type I procollagen (P1NP), for their association with cardiac phenotypes and outcomes in the PREDICTOR study., Methods: 2001 community-dwelling subjects aged 65-84 years who had undergone centrally-read echocardiography, were selected through administrative registries. Atrial fibrillation (AF) and 4 echocardiographic patterns were assessed: E/e' (> 8), enlarged left atrial area, left ventricular hypertrophy (LVH) and reduced midwall circumference shortening (MFS). All-cause and cardiovascular mortality and hospitalization were recorded over a median follow-up of 10.6 years., Results: IGFBP7 and GDF-15, but not P1NP, were independently associated with prevalent AF and echocardiographic variables after adjusting for age and sex. After adjustment for clinical risk factors and cardiac patterns or NT-proBNP and hsTnT, both IGFBP7 and GDF-15 independently predicted all-cause mortality, hazard ratios 2.13[1.08-4.22] and 2.03[1.62-2.56] per unit increase of Ln-transformed markers, respectively., Conclusions: In a community-based elderly cohort, IGFBP7 and GDF-15 appear associated to cardiac alterations as well as to 10-year risk of all-cause mortality.

Objectives: Tensiomyography (TMG) derived contraction time (Tc) and amplitude (Dm) are related to muscle fibre composition and to muscle atrophy/tone, respectively. However, the link between mobility and TMG-derived skeletal muscle contractile properties in older persons is unknown. The aim of the study was to correlate lower limb skeletal muscle contractile properties with balance and mobility measures in senior female residents of retirement homes in Austria., Methods: Twenty-eight female participants (aged from 67-99 years) were included in measurements of contractile properties (TMG) of four skeletal muscles: vastus lateralis, vastus medialis, biceps femoris and gastrocnemius medialis. Their balance and mobility performance was measured using a timed up and go test (TUG)., Results: Time needed to complete TUG is negatively correlated to biceps femoris (r= -0.490; p= 0.008), vastus lateralis (r= -0.414; p=0.028) and vastus medialis (r= -0.353; p=0.066) Dm and positively correlated to vastus lateralis Tc (r=0.456; p=0.015). Overall, vastus lateralis Tc and vastus medialis Dm explained 37% of TUG time variance., Conclusions: Our study demonstrates that TMG-derived quadriceps muscle contractile parameters are correlated with the balance and mobility function in female nursing home residents., Competing Interests: The authors have no conflict of interest.

Telehealth services for long-term monitoring of chronically ill patients are becoming more and more common, leading to huge amounts of data collected by patients and healthcare professionals each day. While most of these data are structured, some information, especially concerning the communication between the stakeholders, is typically stored as unstructured free-texts. This paper outlines the differences in analyzing free-texts from the heart failure telehealth network HerzMobil as compared to the diabetes telehealth network DiabMemory. A total of 3,739 free-text notes from HerzMobil and 228,109 notes from DiabMemory, both written in German, were analyzed. A pre-existing, regular expression based algorithm developed for heart failure free-texts was adapted to cover also the diabetes scenario. The resulting algorithm was validated with a subset of 200 notes that were annotated by three scientists, achieving an accuracy of 92.62%. When applying the algorithm to heart failure and diabetes texts, we found various similarities but also several differences concerning the content. As a consequence, specific requirements for the algorithm were identified.

The production of proinflammatory cytokines, particularly granulocyte-macrophage colony-stimulating factor (GM-CSF), by pathogenic CD4 + T cells is central for mediating tissue injury in inflammatory and autoimmune diseases. However, the factors regulating the T cell pathogenic gene expression program remain unclear. Here, we investigated how the Ikaros transcription factor regulates the global gene expression and chromatin accessibility changes in murine T cells during Th17 polarization and after activation via the T cell receptor (TCR) and CD28. We found that, in both conditions, Ikaros represses the expression of genes from the pathogenic signature, particularly Csf2 , which encodes GM-CSF. We show that, in TCR/CD28-activated T cells, Ikaros binds a critical enhancer downstream of Csf2 and is required to regulate chromatin accessibility at multiple regions across this locus. Genome-wide Ikaros binding is associated with more compact chromatin, notably at multiple sites containing NFκB or STAT5 target motifs, and STAT5 or NFκB inhibition prevents GM-CSF production in Ikaros-deficient cells. Importantly, Ikaros also limits GM-CSF production in TCR/CD28-activated human T cells. Our data therefore highlight a critical conserved transcriptional mechanism that antagonizes GM-CSF expression in T cells., Competing Interests: The authors declare no competing interest.

Background: The occurrence of congestive heart failure (CHF) hospitalization among patients with atrial fibrillation (AF) is a poor prognostic marker., Objective: The purpose of this study was to assess whether insulin-like growth factor-binding protein 7 (IGFBP-7), a marker of myocardial damage, identifies AF patients at high risk for this complication., Methods: We analyzed 2 prospective multicenter observational cohort studies that included 3691 AF patients. Levels of IGFBP-7 and N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured from frozen plasma samples at baseline. The primary endpoint was hospitalization for CHF. Multivariable adjusted Cox regression analyses were constructed., Results: Mean patient age was 69 ± 12 years, 1028 (28%) were female, and 879 (24%) had a history of CHF. The incidence per 1000 patient-years across increasing IGFBP-7 quartiles was 7, 10, 32, and 85. The corresponding multivariable adjusted hazard ratios (aHRs) (95% confidence interval [CI]) were 1.0, 1.05 (0.63-1.77), 2.38 (1.50-3.79), and 4.37 (2.72-7.04) (P for trend <.001). In a subgroup of 2812 patients without pre-existing CHF at baseline, the corresponding aHRs were 1.0, 0.90 (0.47-1.72), 1.69 (0.94-3.04), and 3.48 (1.94-6.24) (P for trend <.001). Patients with IGFBP-7 and NT-proBNP levels above the biomarker-specific median had a higher risk of incident CHF hospitalization (aHR 5.20; 3.35-8.09) compared to those with only 1 elevated marker (elevated IGFBP-7 aHR 2.17; 1.30-3.60); elevated NT-proBNP aHR 1.97; 1.17-3.33); or no elevated marker (reference)., Conclusion: Higher plasma levels of IGFBP-7 were strongly and independently associated with CHF hospitalization in AF patients. The prognostic information provided by IGFBP-7 was additive to that of NT-proBNP., (Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Large-scale screening for atrial fibrillation (AF) requires reliable methods to identify at-risk populations. Using an experimental semi-quantitative biomarker assay, B-type natriuretic peptide (BNP) and fibroblast growth factor 23 (FGF23) were recently identified as the most suitable biomarkers for detecting AF in combination with simple morphometric parameters (age, sex, and body mass index [BMI]). In this study, we validated the AF model using standardised, high-throughput, high-sensitivity biomarker assays., Methods and Findings: For this study, 1,625 consecutive patients with either (1) diagnosed AF or (2) sinus rhythm with CHA2DS2-VASc score of 2 or more were recruited from a large teaching hospital in Birmingham, West Midlands, UK, between September 2014 and February 2018. Seven-day ambulatory ECG monitoring excluded silent AF. Patients with tachyarrhythmias apart from AF and incomplete cases were excluded. AF was diagnosed according to current clinical guidelines and confirmed by ECG. We developed a high-throughput, high-sensitivity assay for FGF23, quantified plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) and FGF23, and compared results to the previously used multibiomarker research assay. Data were fitted to the previously derived model, adjusting for differences in measurement platforms and known confounders (heart failure and chronic kidney disease). In 1,084 patients (46% with AF; median [Q1, Q3] age 70 [60, 78] years, median [Q1, Q3] BMI 28.8 [25.1, 32.8] kg/m2, 59% males), patients with AF had higher concentrations of NT-proBNP (median [Q1, Q3] per 100 pg/ml: with AF 12.00 [4.19, 30.15], without AF 4.25 [1.17, 15.70]; p < 0.001) and FGF23 (median [Q1, Q3] per 100 pg/ml: with AF 1.93 [1.30, 4.16], without AF 1.55 [1.04, 2.62]; p < 0.001). Univariate associations remained after adjusting for heart failure and estimated glomerular filtration rate, known confounders of NT-proBNP and FGF23. The fitted model yielded a C-statistic of 0.688 (95% CI 0.656, 0.719), almost identical to that of the derived model (C-statistic 0.691; 95% CI 0.638, 0.744). The key limitation is that this validation was performed in a cohort that is very similar demographically to the one used in model development, calling for further external validation., Conclusions: Age, sex, and BMI combined with elevated NT-proBNP and elevated FGF23, quantified on a high-throughput platform, reliably identify patients with AF., Trial Registration: Registry IRAS ID 97753 Health Research Authority (HRA), United Kingdom., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: LF has received institutional research grants and non-financial support from European Union, British Heart Foundation, Medical Research Council (UK), and DFG and Gilead. PK and LF are listed as inventors on two patents held by University of Birmingham (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). PKi has received additional support for research from the European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Centre for Heart Research, from several drug and device companies active in atrial fibrillation, honoraria from several such companies. PKa is an employee of Roche Diagnostics GmbH. AZ is an employee of Roche Diagnostics Intl. All other authors have reported no relationships relevant to the contents of this paper to disclose.

Objective: A third of people over 65 years experiences at least one fall a year. The Timed Up-and-Go (TUG) test is commonly used to assess gait and balance and to evaluate an individual's risk of falling., Approach: We conducted a clinical study with 46 older participants for evaluating the fall risk assessment capabilities of an ultra-sound based TUG test device. The fall protocols over a period of one year were used to classify participants as fallers and non-fallers. For frailty evaluation, state-of-the-art questionnaires were used. Fall recordings were compared to six TUG test measurements that were recorded in fallers and non-fallers., Main Results: TUG test data were available for 39 participants (36 f, age 84.2 ± 8.2, BMI 26.0 ± 5.1). Twenty-three participants did fall at least once within the fall screening period. We fitted two different regression and probability models into a region of interest of the distance over time curve as derived from the TUG device. We found that the coefficient of determination for Gaussian bell-shaped curves (p < 0.05, AUC = 0.71) and linear regression lines (p < 0.02, AUC = 0.74) significantly separated fallers from non-fallers. Subtasks of the TUG test like the sit-up time showed near significance (p < 0.07, AUC = 0.67)., Significance: We found that specific features calculated from the TUG distance over time curve were significantly different between fallers and non-fallers in our study population. Automatic recording and analysis of TUG measurements could, therefore, reduce time of measurements and improve precision as compared to other methods currently being used in the assessments of fall risk.

Digitalized healthcare services offer remote and cost-effective treatment of diabetes patients. Thus, the present online study analyzed the readiness to use telemonitoring among Austrian diabetes patients. We developed and validated a German version of the patient telehealth readiness assessment tool and performed quantitative context analysis of free-text comments on perceived barriers and benefits of telemonitoring. Participants (n = 41, 42.6% females) achieved a medium average readiness level for telemonitoring. The three top benefits were intensified care, shorter travel and waiting times, and better therapy adjustment. The top three barriers were data privacy issues, loss of personal communication and focus on blood sugar, and teledoctor competence. Diabetes patients represent a suitable target group for remote treatment opportunities. However, a shift from traditional face-to-face medical care to exclusive telemonitoring treatment from diagnosis to consultation and treatment requires fundamental new legal framework conditions.

The IKZF1 gene, which encodes the Ikaros transcription factor, is frequently deleted or mutated in patients with B-cell precursor acute lymphoblastic leukemias that express oncogenes, like BCR-ABL, which activate the JAK-STAT5 pathway. Ikaros functionally antagonizes the transcriptional programs downstream of IL-7/STAT5 during B cell development, as well as STAT5 activity in leukemic cells. However, the mechanisms by which Ikaros interferes with STAT5 function is unknown. We studied the genomic distribution of Ikaros and STAT5 on chromatin in a murine pre-B cell line, and found that both proteins colocalize on >60% of STAT5 target regions. Strikingly, Ikaros activity leads to widespread loss of STAT5 binding at most of its genomic targets within two hours of Ikaros induction, suggesting a direct mechanism. Ikaros did not alter the level of total or phosphorylated STAT5 proteins, nor did it associate with STAT5. Using sequences from the Cish, Socs2 and Bcl6 genes that Ikaros and STAT5 target, we show that both proteins bind overlapping sequences at GGAA motifs. Our results demonstrate that Ikaros antagonizes STAT5 DNA binding, in part by competing for common target sequences. Our study has implications for understanding the functions of Ikaros and STAT5 in B cell development and transformation., Competing Interests: The authors have declared that no competing interests exist.

Placental homeostasis of tryptophan is essential for fetal development and programming. The two main metabolic pathways (serotonin and kynurenine) produce bioactive metabolites with immunosuppressive, neurotoxic, or neuroprotective properties and their concentrations in the fetoplacental unit must be tightly regulated throughout gestation. Here, we investigated the expression/function of key enzymes/transporters involved in tryptophan pathways during mid-to-late gestation in rat placenta and fetal organs. Quantitative PCR and heatmap analysis revealed the differential expression of several genes involved in serotonin and kynurenine pathways. To identify the flux of substrates through these pathways, Droplet Digital PCR, western blot, and functional analyses were carried out for the rate-limiting enzymes and transporters. Our findings show that placental tryptophan metabolism to serotonin is crucial in mid-gestation, with a subsequent switch to fetal serotonin synthesis. Concurrently, at term, the close interplay between transporters and metabolizing enzymes of both placenta and fetal organs orchestrates serotonin homeostasis and prevents hyper/hypo-serotonemia. On the other hand, the placental production of kynurenine increases during pregnancy, with a low contribution of fetal organs throughout gestation. Any external insult to this tightly regulated harmony of transporters and enzymes within the fetoplacental unit may affect optimal in utero conditions and have a negative impact on fetal programming.

L-Tryptophan is an essential amino acid and a precursor of several physiologically active metabolites. In the placenta, the serotonin and kynurenine metabolic pathways of tryptophan metabolism have been identified, giving rise to various molecules of neuroactive or immunoprotective properties, such as serotonin, melatonin, kynurenine, kynurenic acid, or quinolinic acid. Current literature suggests that optimal levels of these molecules in the fetoplacental unit are crucial for proper placenta functions, fetal development and programming. Placenta is a unique endocrine organ that, being equipped with a battery of biotransformation enzymes and transporters, precisely orchestrates homeostasis of tryptophan metabolic pathways. However, because pregnancy is a dynamic process and placental/fetal needs are continuously changing throughout gestation, placenta must adapt to these changes and ensure proper communication in the feto-placental unit. Therefore, in this study we investigated alterations of placental tryptophan metabolic pathways throughout gestation. Quantitative polymerase chain reaction (PCR) analysis of 21 selected genes was carried out in first trimester ( n = 13) and term ( n = 32) placentas. Heatmap analysis with hierarchical clustering revealed differential gene expression of serotonin and kynurenine pathways across gestation. Subsequently, digital droplet PCR, Western blot, and functional analyses of the rate-limiting enzymes suggest preferential serotonin synthesis early in pregnancy with a switch to kynurenine production toward term. Correspondingly, increased function and/or protein expression of serotonin degrading enzyme and transporters at term indicates efficient placental uptake and metabolic degradation of serotonin. Lastly, gene expression analysis in choriocarcinoma-derived cell lines (BeWo, BeWo b30, JEG-3) revealed dissimilar expression patterns and divergent effect of syncytialization compared to primary trophoblast cells isolated from human term placentas; these findings show that the commonly used in vitro placental models are not suitable to study placental handling of tryptophan. Altogether, our data provide the first comprehensive evidence of changes in placental homeostasis of tryptophan and its metabolites as a function of gestational age, which is critical for proper placental function and fetal development., (Copyright © 2020 Karahoda, Abad, Horackova, Kastner, Zaugg, Cerveny, Kucera, Albrecht and Staud.)