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Adverse pregnancy outcomes (APOs) affect a large proportion of pregnancies and represent an important cause of morbidity and mortality worldwide. Yet the pathophysiology of APOs is poorly understood, limiting our ability to prevent and treat these conditions. To search for genetic markers of maternal risk for four APOs, we performed multi-ancestry genome-wide association studies (GWAS) for pregnancy loss, gestational length, gestational diabetes, and preeclampsia. We clustered participants by their genetic ancestry and focused our analyses on three sub-cohorts with the largest sample sizes: European, African, and Admixed American. Association tests were carried out separately for each sub-cohort and then meta-analyzed together. Two novel loci were significantly associated with an increased risk of pregnancy loss: a cluster of SNPs located downstream of the TRMU gene (top SNP: rs142795512), and the SNP rs62021480 near RGMA. In the GWAS of gestational length we identified two new variants, rs2550487 and rs58548906 near WFDC1 and AC005052.1, respectively. Lastly, three new loci were significantly associated with gestational diabetes (top SNPs: rs72956265, rs10890563, rs79596863), located on or near ZBTB20, GUCY1A2, and RPL7P20, respectively. Fourteen loci previously correlated with preterm birth, gestational diabetes, and preeclampsia were found to be associated with these outcomes as well.

Abstract The enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB) plays an essential role in glycolysis and in the antioxidant pathway associated with glutathione. Therefore, we investigated the effects of PFKFB3 on oxidative and ischemic damage. We synthesized a fusion protein of transactivator of transcription (Tat)-PFKFB3 to facilitate its passage into the intracellular space and examine its effects against oxidative stress induced by hydrogen peroxide (H2O2) treatment and ischemic damage caused by occlusion of the common carotid arteries for 5 min in gerbils. The Tat-PFKFB3 protein was efficiently delivered into HT22 cells in a concentration- and time-dependent manner, with higher levels observed 18 h after treatment. Furthermore, treatment with 6 µM Tat-PFKFB3 demonstrated intracellular delivery into HT22 cells, as analyzed through immunocytochemical staining. Moreover, it significantly ameliorated the reduction of cell viability induced by 200 µM H2O2 treatment. Tat-PFKFB3 treatment also alleviated H2O2-induced DNA fragmentation and reactive oxygen species formation in HT22 cells. In gerbils, the intraperitoneal administration of 2 mg/kg Tat-PFKFB3 efficiently delivered the substance to all hippocampal areas, including the hippocampal CA1 region. This administration significantly mitigated ischemia-induced hyperlocomotion, long-term memory deficits, and ischemic neuronal death in the hippocampal CA1 region after ischemia. Additionally, treatment with 2 mg/kg Tat-PFKFB3 significantly ameliorated the translocation of Cdk5 from the cytosol to the nucleus in the hippocampal CA1 region 24 h after ischemia, but not in other regions. The treatment also significantly reduced reactive oxygen species formation in the CA1 region. These findings suggest that Tat-PFKFB3 reduces neuronal damage in the hippocampal CA1 region after ischemia through the reduction of Cdk5 signaling and reactive oxygen species formation. Therefore, Tat-PFKFB3 may have potential applications in reducing ischemic damage.

Abstract Explainability of convolutional neural networks (CNNs) is integral for their adoption into radiological practice. Commonly used attribution methods localize image areas important for CNN prediction but do not characterize relevant imaging features underlying these areas, acting as a barrier to the adoption of CNNs for clinical use. We therefore propose Semantic Exploration and Explainability using a Style-based Generative Adversarial Autoencoder Network (SEE-GAAN), an explainability framework that uses latent space manipulation to generate a sequence of synthetic images that semantically visualizes how clinical and CNN features manifest within medical images. Visual analysis of changes in these sequences then facilitates the interpretation of features, thereby improving explainability. SEE-GAAN was first developed on a cohort of 26,664 chest radiographs across 15,409 patients from our institution. SEE-GAAN sequences were then generated across several clinical features and CNN predictions of NT-pro B-type natriuretic peptide (BNPP) as a proxy for acute heart failure. Radiological interpretations indicated SEE-GAAN sequences captured relevant changes in anatomical and pathological morphology associated with clinical and CNN predictions and clarified ambiguous areas highlighted by commonly used attribution methods. Our study demonstrates SEE-GAAN can facilitate our understanding of clinical features for imaging biomarker exploration and improve CNN transparency over commonly used explainability methods.

Abstract Healthcare organisations worldwide are affected by the shortage of health professionals due to work-related stress and health professional leaders play an important role by implementing effective strategies. Therefore, this study aims to investigate whether the STRAIN intervention program (using evidence-based training for health professional leaders) can reduce work-related stress among health professionals. This study is based on a cluster randomised controlled trial, consists of three measurements and includes 165 participating hospitals, nursing homes and home care organisations. A total of 206 health professional leaders took part in the intervention programme and 19,340 health professionals participated in the study. Results showed no significant differences (p > 0.05) between the intervention and control group regarding the effort-reward imbalance ratio, quantitative demands, opportunities for development, bond with the organisation, quality of leadership, social community, role clarity, rewards, difficulties with demarcation and work–private life conflict. Pre-/post-test analysis revealed a tendency for significant positive results (p

Abstract To gain a deeper understanding of skeletal muscle function in younger age and aging in elderly, identification of molecular signatures regulating these functions under physiological conditions is needed. Although molecular studies of healthy muscle have been conducted on adults and older subjects, there is a lack of research on infant muscle in terms of combined morphological, transcriptomic and proteomic profiles. To address this gap of knowledge, we performed RNA sequencing (RNA-seq), tandem mass spectrometry (LC–MS/MS), morphometric analysis and assays for mitochondrial maintenance in skeletal muscle biopsies from both, infants aged 4–28 months and adults aged 19–65 years. We identified differently expressed genes (DEGs) and differentially expressed proteins (DEPs) in adults compared to infants. The down-regulated genes in adults were associated with functional terms primarily related to sarcomeres, cellular maintenance, and metabolic, immunological and developmental processes. Thus, our study indicates age-related differences in the molecular signatures and associated functions of healthy skeletal muscle. Moreover, the findings assert that processes previously associated solely with aging are indeed part of development and healthy aging. Hence, combined findings of this study also indicate that age-dependent controls are crucial in muscle disease studies, as otherwise the comparative results may not be reliable.

Abstract REBa $$_2$$ 2 Cu $$_3$$ 3 O $$_{7-\text {x}}$$ 7 - x (REBCO, RE = rare earth)-coated conductor is a competitive option in terms of current-carrying capacity and high-stress durability in developing high-field magnets for nuclear magnetic resonance (NMR) research. Meanwhile, a technical challenge in utilizing a stand-alone REBCO NMR magnet is an unexpected difference in the field uniformity between the designed and measured values after being constructed and charged, i.e., harmonic errors. Bortot et al., and Li et al., reported analytic evidence of the related issue. However, sufficient research has not yet been conducted, so evidence should be supplemented further. Here we report harmonic errors due to screening current and inconsistent conductor thickness, confirmed by a 400 MHz 1H NMR magnet development project. The magnet was first charged up to its operating current, and then multiple overcharge-discharge cycles were applied, which was an empirically optimized operation protocol. A field mapping device obtained magnetic fields at designated locations in the room-temperature bore. The result showed over 100 ppm field uniformity difference between designed and measured values. A simulation model was developed considering screening current and inconsistent conductor thickness for reproducing the field distribution. Comparison of voltages and fields between simulation and measurement validated the model. Further analysis of the overcharge-discharge effect on harmonic errors demonstrated that even and odd-order harmonics are mainly attributed to screening current and geometric inconsistency while confirming the limitation of the screening current mitigation effect. Hence, we concluded that the desirable requirement of the sub-ppm level field uniformity generation might be barely possible with the current REBCO NMR magnet design approach.

Abstract The aim of this study was to evaluate the long-term efficacy of a single ultrasound-guided high-intensity focused ultrasound (US-HIFU) treatment in patients with breast fibroadenoma (FA) in terms of volume and pain reduction as well as palpation findings. From december 2013 until november 2014 27 women with a symptomatic FA were treated in one HIFU-session. Follow-up visits were performed after 7 days, 6 months and 1, 2, 3 and 5 years with clinical examination and ultrasound. One year after the procedure, a core needle biopsy of the residual lesion was offered. There was a significant volume reduction 6 months after HIFU from 1083.10 to 347.13 mm3 (p

Abstract We investigated the long-term patterns and effects of transfusion on the clinical outcome of patients undergoing percutaneous coronary intervention (PCI) using a nationwide registry. Five-year clinical outcome of all Koreans undergoing PCI using stent in year 2011 (n = 48,786) was investigated. Primary outcome was the incidence density of transfusion. The association of transfusion with major adverse clinical event (MACE) consisting all-cause death, revascularization, critically ill cardiovascular status, or stroke was assessed after adjusting the propensity of each patient for transfusion. The 5-year incidence density of transfusion was 4.74 (95% confidence interval [CI] 4.70–4.79) per 100 person-year. Patients who received transfusion were older and had higher frequency of clinical risk factors (p

Abstract Preliminary work has shown that portal hypertension plays a key role for the prognosis in patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE). Specifically, the presence of ascites appears to be a strong negative predictor for these patients. However, it remains unclear whether different ascites volumes influence prognosis. Therefore, the aim of this work was to investigate the influence of different ascites volumes on survival for patients with HCC undergoing TACE. A total of 327 treatment-naïve patients with HCC undergoing initial TACE at our tertiary care center between 2010 and 2020 were included. In patients with ascites, the fluid was segmented, and the volume quantified by slice-wise addition using contrast-enhanced CT imaging. Median overall survival (OS) was calculated and univariate and multivariate Cox regression analysis has been performed. Ascites was present in 102 (31.9%) patients. Ascites volume as continuous variable was significantly associated with an increased hazard ratio in univariate analysis (p

Abstract Telomerase reverse transcriptase (TERT) promoter mutations are associated with tumor aggressiveness. This study aimed to demonstrate the ultrasonographic (US) features of TERT promoter-mutated follicular thyroid cancer (FTC) and evaluate their predictive performance. A total of 63 patients with surgically confirmed FTC between August 1995 and April 2021 were included. All data were available for analysis of preoperative US findings and TERT promoter mutation results. Genomic DNA was extracted from the archived surgical specimens to identify TERT promoter mutations. Logistic regression analysis was performed to compare US findings between TERT promoter-mutated and wild-type FTCs. Of the 63 patients with FTC, 10 (15.9%) had TERT promoter mutations. TERT promoter-mutated FTCs demonstrated significantly different US suspicion categories compared to wild-type FTCs (Ps = 0.0054 for K-TIRADS and 0.0208 for ACR-TIRADS), with a trend toward an increasing prevalence of the high suspicion category (40.0% for both K-TIRADS and ACR-TIRADS; Ps for trend = 0.0030 for K-TIRADS and 0.0032 for ACR-TIRADS). Microlobulated margins and punctate echogenic foci were independent risk factors associated with TERT promoter mutation in FTC (odds ratio = 9.693, 95% confidence interval = 1.666–56.401, p = 0.0115 for margins; odds ratio = 8.033, 95% confidence interval = 1.424–45.309, p = 0.0182 for punctate echogenic foci). There were no significant differences in the composition and echogenicity of the TERT promoter-mutated and wild-type FTCs. TERT promoter-mutated FTCs were categorized more frequently as high suspicion by the K-TIRADS and ACR-TIRADS. Based on US findings, the independent risk factors for TERT promoter mutations in FTC are microlobulated margins and punctate echogenic foci.

Abstract Smooth pursuit eye movements are considered a well-established and quantifiable biomarker of sensorimotor function in psychosis research. Identifying psychotic syndromes on an individual level based on neurobiological markers is limited by heterogeneity and requires comprehensive external validation to avoid overestimation of prediction models. Here, we studied quantifiable sensorimotor measures derived from smooth pursuit eye movements in a large sample of psychosis probands (N = 674) and healthy controls (N = 305) using multivariate pattern analysis. Balanced accuracies of 64% for the prediction of psychosis status are in line with recent results from other large heterogenous psychiatric samples. They are confirmed by external validation in independent large samples including probands with (1) psychosis (N = 727) versus healthy controls (N = 292), (2) psychotic (N = 49) and non-psychotic bipolar disorder (N = 36), and (3) non-psychotic affective disorders (N = 119) and psychosis (N = 51) yielding accuracies of 65%, 66% and 58%, respectively, albeit slightly different psychosis syndromes. Our findings make a significant contribution to the identification of biologically defined profiles of heterogeneous psychosis syndromes on an individual level underlining the impact of sensorimotor dysfunction in psychosis.

Abstract Adverse pregnancy outcomes (APOs) affect a large proportion of pregnancies and represent an important cause of morbidity and mortality worldwide. Yet the pathophysiology of APOs is poorly understood, limiting our ability to prevent and treat these conditions. To search for genetic markers of maternal risk for four APOs, we performed multi-ancestry genome-wide association studies (GWAS) for pregnancy loss, gestational length, gestational diabetes, and preeclampsia. We clustered participants by their genetic ancestry and focused our analyses on three sub-cohorts with the largest sample sizes: European, African, and Admixed American. Association tests were carried out separately for each sub-cohort and then meta-analyzed together. Two novel loci were significantly associated with an increased risk of pregnancy loss: a cluster of SNPs located downstream of the TRMU gene (top SNP: rs142795512), and the SNP rs62021480 near RGMA. In the GWAS of gestational length we identified two new variants, rs2550487 and rs58548906 near WFDC1 and AC005052.1, respectively. Lastly, three new loci were significantly associated with gestational diabetes (top SNPs: rs72956265, rs10890563, rs79596863), located on or near ZBTB20, GUCY1A2, and RPL7P20, respectively. Fourteen loci previously correlated with preterm birth, gestational diabetes, and preeclampsia were found to be associated with these outcomes as well.

Abstract In contrast to inherited transthyretin amyloidosis (A-ATTRv), neuropathy is not a classic leading symptom of wild type transthyretin amyloidosis (A-ATTRwt). However, neurological symptoms are increasingly relevant in A-ATTRwt as well. To better understand the role of neurological symptoms in A-ATTRwt, A-ATTRwt patients were prospectively characterized at Amyloidosis Center Charité Berlin (ACCB) between 2018 and 2023 using detailed neurological examination, quality of life questionnaires, and analysis of age- and BMI-adapted serum neurofilament light chain (NFL) levels. 16 out of 73 (21.9%) patients presented with a severe neuropathy which we defined by a Neuropathy Impairment Score (NIS) of 20 or more. In this group, quality of life was reduced, peripheral neuropathy was more severe, and spinal stenosis and joint replacements were frequent. Age- and BMI matched serum NFL levels were markedly elevated in patients with a NIS ≥ 20. We therefore conclude that highly abnormal values in neuropathy scores such as the NIS occur in A-ATTRwt, and have an important impact on quality of life. Both peripheral neuropathy and spinal canal stenosis are likely contributors. Serum NFL may serve as a biomarker for neurological affection in patients with A-ATTRwt. It will be important to consider neurological aspects of A-ATTRwt for diagnosis, clinical follow-up, and future treatment development.

Abstract While onion cultivars, irrigation and soil and crop management have been given much attention in Brazil to boost onion yields, nutrient management at field scale is still challenging due to large dosage uncertainty. Our objective was to develop an accurate feature-based fertilization model for onion crops. We assembled climatic, edaphic, and managerial features as well as tissue tests into a database of 1182 observations from multi-environment fertilizer trials conducted during 13 years in southern Brazil. The complexity of onion cropping systems was captured by machine learning (ML) methods. The RReliefF ranking algorithm showed that the split-N dosage and soil tests for micronutrients and S were the most relevant features to predict bulb yield. The decision-tree random forest and extreme gradient boosting models were accurate to predict bulb yield from the relevant predictors (R2 > 90%). As shown by the gain ratio, foliar nutrient standards for nutritionally balanced and high-yielding specimens producing > 50 Mg bulb ha−1 set apart by the ML classification models differed among cultivars. Cultivar × environment interactions support documenting local nutrient diagnosis. The split-N dosage was the most relevant controllable feature to run future universality tests set to assess models’ ability to generalize to growers’ fields.

Abstract The clinical impact of different polymer technologies in newer-generation drug-eluting stents (DESs) for patients with acute myocardial infarction (AMI) complicated by cardiogenic shock (CS) remains poorly understood. We investigated the efficacy and safety of durable polymer DESs (DP-DESs) compared with biodegradable polymer DESs (BP-DESs). A total of 620 patients who underwent percutaneous coronary intervention with newer-generation DESs for AMI complicated by CS was divided into two groups based on polymer technology: the DP-DES group (n = 374) and the BP-DES group (n = 246). The primary outcome was target vessel failure (TVF) during a 12-month follow-up, defined as a composite of cardiac death, myocardial infarction, or target vessel revascularization. Both the DP-DES and BP-DES groups exhibited low stent thrombosis rates (1.3% vs. 1.6%, p = 0.660). The risk of TVF did not significantly differ between the two groups (34.2% vs. 28.5%, hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.69–1.29, p = 0.721). This finding remained consistent after adjustment with inverse probability of treatment weighting (28.1% vs. 25.1%, HR 0.98, 95% CI 0.77–1.27, p = 0.899). In AMI patients complicated by CS, the risk of a composite of cardiac death, myocardial infarction, or target vessel revascularization was not significantly different between those treated with DP-DESs and those treated with BP-DESs. Trial registration: RESCUE registry, https://clinicaltrials.gov/ct2/show/NCT02985008 , NCT02985008.

Abstract Morning chronotypes are associated with healthier metabolic profiles and lifestyles compared to evening chronotypes. However, limited research examined the relationship between chronotype, dietary intake, and metabolic health using accurate measures such as food records. This cross-sectional study aimed to investigate the association between chronotype, dietary intake, and metabolic health markers in a cohort of Ukrainian individuals. Chronotypes were determined using the Morningness-Eveningness Questionnaire (MEQ) in 110 healthy to obese individuals (30–75 years) without type 2 diabetes. Dietary intake was derived from weighed seven days food diaries, anthropometrics and blood markers of glucose and lipid metabolism were measured. Morning chronotypes were significantly older and exhibited distinct dietary patterns, including lower intake of fat and animal protein and higher intake of carbohydrates when compared to evening chronotypes (p

Abstract This study aimed to develop and evaluate a sarcopenia prediction model by fusing numerical features from shear-wave elastography (SWE) and gray-scale ultrasonography (GSU) examinations, using the rectus femoris muscle (RF) and categorical/numerical features related to clinical information. Both cohorts (development, 70 healthy subjects; evaluation, 81 patients) underwent ultrasonography (SWE and GSU) and computed tomography. Sarcopenia was determined using skeletal muscle index calculated from the computed tomography. Clinical and ultrasonography measurements were used to predict sarcopenia based on a linear regression model with the least absolute shrinkage and selection operator (LASSO) regularization. Furthermore, clinical and ultrasonography features were combined at the feature and score levels to improve sarcopenia prediction performance. The accuracies of LASSO were 70.57 ± 5.00–81.54 ± 4.83 (clinical) and 69.00 ± 4.52–69.73 ± 5.47 (ultrasonography). Feature-level fusion of clinical and ultrasonography (accuracy, 70.29 ± 6.63 and 83.55 ± 4.32) showed similar performance with clinical features. Score-level fusion by AdaBoost showed the best performance (accuracy, 73.43 ± 6.57–83.17 ± 5.51) in the development and evaluation cohorts, respectively. This study might suggest the potential of machine learning fusion techniques to enhance the accuracy of sarcopenia prediction models and improve clinical decision-making in patients with sarcopenia.

Abstract Echocardiographic differentiation of cardiac amyloidosis (CA) and Fabry disease (FD) is often challenging using standard echocardiographic parameters. We retrospectively analyzed the diagnostic accuracy of right heart and left atrial strain parameters to discriminate CA from FD using receiver operating characteristic curve analyses and logistic regression models. A total of 47 FD and 88 CA patients with left ventricular wall thickening were analyzed. The comparison of both cardiomyopathies revealed significantly reduced global and free wall longitudinal right ventricular strain (RVS; global RVS: CA − 13 ± 4%, n = 67, vs. FD − 18 ± 4%, n = 39, p

Abstract With the slowdown of improvement in conventional von Neumann systems, increasing attention is paid to novel paradigms such as Ising machines. They have very different approach to solving combinatorial optimization problems. Ising machines have shown great potential in solving binary optimization problems like MaxCut. In this paper, we present an analysis of these systems in boolean satisfiability (SAT) problems. We demonstrate that, in the case of 3-SAT, a basic architecture fails to produce meaningful acceleration, largely due to the relentless progress made in conventional SAT solvers. Nevertheless, careful analysis attributes part of the failure to the lack of two important components: cubic interactions and efficient randomization heuristics. To overcome these limitations, we add proper architectural support for cubic interaction on a state-of-the-art Ising machine. More importantly, we propose a novel semantic-aware annealing schedule that makes the search-space navigation much more efficient than existing annealing heuristics. Using numerical simulations, we show that such an “Augmented” Ising Machine for SAT is projected to outperform state-of-the-art software-based, GPU-based and conventional hardware SAT solvers by orders of magnitude.

Abstract Zika virus infection causes multiple clinical issues, including Guillain–Barré syndrome and neonatal malformation. Vaccination is considered as the only strategy for the prevention of ZIKV-induced clinical issues. This study developed a plant-based recombinant vaccine that transiently expressed the ZIKV envelope protein (ZikaEnv:aghFc) in Nicotiana benthamiana and evaluated the protective immunity afforded by it in immunocompetent mice. ZikaEnv:aghFc induced both humoral and cellular immunity at a low dose (1–5 μg). This immune-inducing potential was enhanced further when adjuvanted CIA09A. In addition, antigen-specific antibodies and neutralizing antibodies were vertically transferred from immunized females to their progeny and afforded both protective immunity to ZIKV and cross-protection to Dengue virus infection. These results suggest that our plant-based ZIKV vaccine provides a safe and efficient protective strategy with a competitive edge.

Abstract Isozymes are enzymes that catalyze identical biological reactions, yet exhibit slight variations in structures and catalytic efficiency, which enables the precise adjustment of metabolism to fulfill the specific requirements of a particular tissue or stage of development. Methionine aminopeptidase (MetAP) isozymes function a critical role in cleaving N-terminal methionine from nascent proteins to generate functional proteins. In humans, two distinct MetAP types I and II have been identified, with type I further categorized into cytosolic (MetAP1) and mitochondrial (MetAP1D) variants. However, despite extensive structural studies on both bacterial and human cytosolic MetAPs, the structural information remains unavailable for human mitochondrial MetAP. This study was aimed to elucidate the high-resolution structures of human mitochondrial MetAP1D in its apo-, cobalt-, and methionine-bound states. Through a comprehensive analysis of the determined structures and a docking simulation model with mitochondrial substrate peptides, we present mechanistic insights into the cleavage process of the initiator methionine from mitochondrial proteins. Notably, despite the shared features at the active site between the cytosolic and mitochondrial MetAP type I isozymes, we identified distinct structural disparities within the active-site pocket primarily contributed by two specific loops that could play a role in accommodating specific substrates. These structural insights offer a basis for the further exploration of MetAP isozymes as critical players in cellular processes and potential therapeutic applications.