The Feasibility of Semi-Continuous and Multi-Frequency Thoracic Bioimpedance Measurements by a Wearable Device during Fluid Changes in Hemodialysis Patients.

Repeated single-point measurements of thoracic bioimpedance at a single (low) frequency are strongly related to fluid changes during hemodialysis. Extension to semi-continuous measurements may provide longitudinal details in the time pattern of the bioimpedance signal, and multi-frequency measurements may add in-depth information on the distribution between intra- and extracellular fluid. This study aimed to investigate the feasibility of semi-continuous multi-frequency thoracic bioimpedance measurements by a wearable device in hemodialysis patients. Therefore, thoracic bioimpedance was recorded semi-continuously (i.e., every ten minutes) at nine frequencies (8-160 kHz) in 68 patients during two consecutive hemodialysis sessions, complemented by a single-point measurement at home in-between both sessions. On average, the resistance signals increased during both hemodialysis sessions and decreased during the interdialytic interval. The increase during dialysis was larger at 8 kHz (∆ 32.6 Ω during session 1 and ∆ 10 Ω during session 2), compared to 160 kHz (∆ 29.5 Ω during session 1 and ∆ 5.1 Ω during session 2). Whereas the resistance at 8 kHz showed a linear time pattern, the evolution of the resistance at 160 kHz was significantly different (p < 0.0001). Measuring bioimpedance semi-continuously and with a multi-frequency current is a major step forward in the understanding of fluid dynamics in hemodialysis patients. This study paves the road towards remote fluid monitoring.

Network analysis of the proteome and peptidome sheds light on human milk as a biological system.

Proteins and peptides found in human milk have bioactive potential to benefit the newborn and support healthy development. Research has been carried out on the health benefits of proteins and peptides, but many questions still need to be answered about the nature of these components, how they are formed, and how they end up in the milk. This study explored and elucidated the complexity of the human milk proteome and peptidome. Proteins and peptides were analyzed with non-targeted nanoLC-Orbitrap-MS/MS in a selection of 297 milk samples from the CHILD Cohort Study. Protein and peptide abundances were determined, and a network was inferred using Gaussian graphical modeling (GGM), allowing an investigation of direct associations. This study showed that signatures of (1) specific mechanisms of transport of different groups of proteins, (2) proteolytic degradation by proteases and aminopeptidases, and (3) coagulation and complement activation are present in human milk. These results show the value of an integrated approach in evaluating large-scale omics data sets and provide valuable information for studies that aim to associate protein or peptide profiles from biofluids such as milk with specific physiological characteristics.

Radiomics for the prediction of a postoperative pancreatic fistula following a pancreatoduodenectomy: A systematic review and radiomic score quality assessment.

BACKGROUND: Postoperative pancreatic fistula (POPF) is a severe complication following a pancreatoduodenectomy. An accurate prediction of POPF could assist the surgeon in offering tailor-made treatment decisions. The use of radiomic features has been introduced to predict POPF. A systematic review was conducted to evaluate the performance of models predicting POPF using radiomic features and to systematically evaluate the methodological quality. METHODS: Studies with patients undergoing a pancreatoduodenectomy and radiomics analysis on computed tomography or magnetic resonance imaging were included. Methodological quality was assessed using the Radiomics Quality Score (RQS) and Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) statement. RESULTS: Seven studies were included in this systematic review, comprising 1300 patients, of whom 364 patients (28 %) developed POPF. The area under the curve (AUC) of the included studies ranged from 0.76 to 0.95. Only one study externally validated the model, showing an AUC of 0.89 on this dataset. Overall adherence to the RQS (31 %) and TRIPOD guidelines (54 %) was poor. CONCLUSION: This systematic review showed that high predictive power was reported of studies using radiomic features to predict POPF. However, the quality of most studies was poor. Future studies need to standardize the methodology. REGISTRATION: not registered.

TFEB drives mTORC1 hyperactivation and kidney disease in Tuberous Sclerosis Complex.

Tuberous Sclerosis Complex (TSC) is caused by TSC1 or TSC2 mutations, leading to hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and lesions  in multiple organs including lung (lymphangioleiomyomatosis) and kidney (angiomyolipoma and renal cell carcinoma). Previously, we found that TFEB is constitutively active in TSC. Here, we generated two mouse models of TSC in which kidney pathology is the primary phenotype. Knockout of TFEB rescues kidney pathology and overall survival, indicating that TFEB is the primary driver of renal disease in TSC. Importantly, increased mTORC1 activity in the TSC2 knockout kidneys is normalized by TFEB knockout. In TSC2-deficient cells, Rheb knockdown or Rapamycin treatment paradoxically increases TFEB phosphorylation at the mTORC1-sites and relocalizes TFEB from nucleus to cytoplasm. In mice, Rapamycin treatment normalizes lysosomal gene expression, similar to TFEB knockout, suggesting that Rapamycin's benefit in TSC is TFEB-dependent. These results change the view of the mechanisms of mTORC1 hyperactivation in TSC and may lead to therapeutic avenues.

Exercise pulmonary hypertension by the mPAP/CO slope in primary mitral regurgitation.

AIMS: Exercise-induced pulmonary hypertension (PH), defined by a mean pulmonary arterial pressure over cardiac output (mPAP/CO) slope >3 mmHg/L/min, has important diagnostic and prognostic implications. The aim of this study is to investigate the value of the mPAP/CO slope in patients with more than moderate primary mitral regurgitation (MR) with preserved ejection fraction and no or discordant symptoms. METHODS AND RESULTS: A total of 128 consecutive patients were evaluated with exercise echocardiography and cardiopulmonary testing. Clinical outcome was defined as the composite of mitral valve intervention, new-onset atrial fibrillation, cardiovascular hospitalization, and all-cause mortality. The mean age was 63 years, 61% were male, and the mean LVEF was 66 ± 6%. The mPAP/CO slope correlated with peak VO2 (r = -0.52, P < 0.001), while the peak systolic pulmonary artery pressure (sPAP) did not (r = -0.06, P = 0.584). Forty-six per cent (n = 59) had peak exercise sPAP ≥60 mmHg, and 37% (n = 47) had mPAP/CO slope >3 mmHg/L/min. Event-free survival was 55% at 1 year and 46% at 2 years, with reduced survival in patients with mPAP/CO slope >3 mmHg/L/min (hazard ratio, 4.9; 95% confidence interval, 2.9-8.2; P < 0.001). In 53 cases (41%), mPAP/CO slope and peak sPAP were discordant: patients with slope >3 mmHg/L/mmHg and sPAP <60 mmHg (n = 21) had worse outcome vs. peak sPAP ≥60 mmHg and normal slope (n = 32, log-rank P = 0.003). The mPAP/CO slope improved predictive models for outcome, incremental to resting and exercise sPAP, and peak VO2. CONCLUSION: Exercise PH defined by the mPAP/CO slope >3 mmHg/L/min is associated with decreased exercise capacity and a higher risk of adverse events in significant primary MR and no or discordant symptoms. The slope provides a greater prognostic value than single sPAP measures and peak VO2.

Corrigendum: The human milk proteome and allergy of mother and child: exploring associations with protein abundances and protein network connectivity.

[This corrects the article DOI: 10.3389/fimmu.2022.977470.].

Zero-Frequency Chiral Magnonic Edge States Protected by Nonequilibrium Topology.

Topological bosonic excitations must, in contrast to their fermionic counterparts, appear at finite energies. This is a key challenge for magnons, as it prevents straightforward excitation and detection of topologically protected magnonic edge states and their use in magnonic devices. In this Letter, we show that in a nonequilibrium state, in which the magnetization is pointing against the external magnetic field, the topologically protected chiral edge states in a magnon Chern insulator can be lowered to zero frequency, making them directly accessible by existing experimental techniques. We discuss the spin-orbit torque required to stabilize this nonequilibrium state, and show explicitly using numerical Landau-Lifshitz-Gilbert simulations that the edge states can be excited with a microwave field. Finally, we consider a propagating spin wave spectroscopy experiment, and demonstrate that the edge states can be directly detected.

Comparison of whole body versus thoracic bioimpedance in relation to ultrafiltration volume and systolic blood pressure during hemodialysis.

In contrast to whole body bioimpedance, which estimates fluid status at a single point in time, thoracic bioimpedance applied by a wearable device could enable continuous measurements. However, clinical experience with thoracic bioimpedance in patients on dialysis is limited. To test the reproducibility of whole body and thoracic bioimpedance measurements and to compare their relationship with hemodynamic changes during hemodialysis, these parameters were measured pre- and end-dialysis in 54 patients during two sessions. The resistance from both bioimpedance techniques was moderately reproducible between two dialysis sessions (intraclass correlations of pre- to end-dialysis whole body and thoracic resistance between session 1 and 2 were 0.711 [0.58-0.8] and 0.723 [0.6-0.81], respectively). There was a very high to high correlation between changes in ultrafiltration volume and changes in whole body thoracic resistance. Changes in systolic blood pressure negatively correlated to both bioimpedance techniques. Although the relationship between changes in ultrafiltration volume and changes in resistance was stronger for whole body bioimpedance, the relationship with changes in blood pressure was at least comparable for thoracic measurements. These results suggest that thoracic bioimpedance, measured by a wearable device, may serve as an interesting alternative to whole body measurements for continuous hemodynamic monitoring during hemodialysis.NEW & NOTEWORTHY We examined the role of whole body and thoracic bioimpedance in hemodynamic changes during hemodialysis. Whole body and thoracic bioimpedance signals were strongly related to ultrafiltration volume and moderately, negatively, to changes in blood pressure. This work supports the further development of a wearable device measuring thoracic bioimpedance longitudinally in patients on hemodialysis. As such, it may serve as an innovative tool for continuous hemodynamic monitoring during hemodialysis in hospital or in a home-based setting.

Oxford brain health clinic: protocol and research database.

INTRODUCTION: Despite major advances in the field of neuroscience over the last three decades, the quality of assessments available to patients with memory problems in later life has barely changed. At the same time, a large proportion of dementia biomarker research is conducted in selected research samples that often poorly reflect the demographics of the population of patients who present to memory clinics. The Oxford Brain Health Clinic (BHC) is a newly developed clinical assessment service with embedded research in which all patients are offered high-quality clinical and research assessments, including MRI, as standard. METHODS AND ANALYSIS: Here we describe the BHC protocol, including aligning our MRI scans with those collected in the UK Biobank. We evaluate rates of research consent for the first 108 patients (data collection ongoing) and the ability of typical psychiatry-led NHS memory-clinic patients to tolerate both clinical and research assessments. ETHICS AND DISSEMINATION: Our ethics and consenting process enables patients to choose the level of research participation that suits them. This generates high rates of consent, enabling us to populate a research database with high-quality data that will be disseminated through a national platform (the Dementias Platform UK data portal).

Context-dependent T-cell Receptor Gene Repertoire Profiles in Proliferations of T Large Granular Lymphocytes.

T cell large granular lymphocyte (T-LGL) lymphoproliferations constitute a disease spectrum ranging from poly/oligo to monoclonal. Boundaries within this spectrum of proliferations are not well established. T-LGL lymphoproliferations co-occur with a wide variety of other diseases ranging from autoimmune disorders, solid tumors, hematological malignancies, post solid organ, and hematopoietic stem cell transplantation, and can therefore arise as a consequence of a wide variety of antigenic triggers. Persistence of a dominant malignant T-LGL clone is established through continuous STAT3 activation. Using next-generation sequencing, we profiled a cohort of 27 well-established patients with T-LGL lymphoproliferations, aiming to identify the subclonal architecture of the T-cell receptor beta (TRB) chain gene repertoire. Moreover, we searched for associations between TRB gene repertoire patterns and clinical manifestations, with the ultimate objective of discriminating between T-LGL lymphoproliferations developing in different clinical contexts and/or displaying distinct clinical presentation. Altogether, our data demonstrates that the TRB gene repertoire of patients with T-LGL lymphoproliferations is context-dependent, displaying distinct clonal architectures in different settings. Our results also highlight that there are monoclonal T-LGL cells with or without STAT3 mutations that cause symptoms such as neutropenia on one end of a spectrum and reactive oligoclonal T-LGL lymphoproliferations on the other. Longitudinal analysis revealed temporal clonal dynamics and showed that T-LGL cells might arise as an epiphenomenon when co-occurring with other malignancies, possibly reactive toward tumor antigens.

Arrythmia-Mediated Valvular Heart Disease.

The aging population is rising at record pace worldwide. Along with it, a steep increase in the prevalence of atrial fibrillation and heart failure with preserved ejection fraction is to be expected. Similarly, both atrial functional mitral and tricuspid regurgitation (AFMR and AFTR) are increasingly observed in daily clinical practice. This article summarizes all current evidence regarding the epidemiology, prognosis, pathophysiology, and therapeutic options. Specific attention is addressed to discern AFMR and AFTR from their ventricular counterparts, given their different pathophysiology and therapeutic needs.

Liminal design: A conceptual framework and three-step approach for developing technology that delivers transcendence and deeper experiences.

As ubiquitous technology is increasingly mediating our relationships with the world and others, we argue that the sublime is struggling to find room in product design primarily aimed at commercial and transactional goals such as speed and efficiency. We suggest a new category of products to promote deeper and more meaningful experiences, specifically those offering liminality, transcendence, and personal transformation. This paper introduces a conceptual framework and three-step design approach looking at narrative participation in design through abstractions to promote, hold and deepen more complex emotions. We explore implications from a theoretical point of view and suggest product examples for how the model might be applied in practice.

Games in Times of a Pandemic: Structured Overview of COVID-19 Serious Games.

BACKGROUND: The COVID-19 pandemic introduced an urgent need for effective strategies to disseminate crucial knowledge and improve people's subjective well-being. Complementing more conventional approaches to knowledge dissemination, game-based interventions were developed to create awareness and educate people about the pandemic, hoping to change their attitudes and behavior. OBJECTIVE: This study provided an overview and analysis of digital and analog game-based interventions in the context of the COVID-19 pandemic. As major pandemics and other large-scale disruptive events are expected to increase in frequency in the coming decades, this analysis aimed to inform the design, uptake, and effects of similar future interventions. METHODS: From November 2021 to April 2022, Scopus, Google, and YouTube were searched for articles and videos describing COVID-19-themed game-based interventions. Information regarding authorship, year of development or launch, country of origin, license, deployment, genre or type, target audience, player interaction, in-game goal, and intended transfer effects was extracted. Information regarding intervention effectiveness was retrieved where possible. RESULTS: A diverse assortment of 23 analog and 43 digital serious games was identified, approximately one-third of them (25/66, 38%) through scientific articles. Most of these games were developed by research institutions in 2020 (13/66, 20%) and originated in Europe and North America (38/66, 58%). A limited number (20/66, 30%) were tested on relatively small samples, using a diversity of research methods to assess the potential changes in participants' knowledge, attitudes, and behaviors as well as their gameplay experience. Although most of the evaluated games (11/20, 55%) effectively engaged and motivated the players, increased awareness, and improved their understanding of COVID-19-related issues, the games' success in influencing people's behavior was often unclear or limited. CONCLUSIONS: To increase the impact of similar future interventions aimed at disseminating knowledge and influencing people's attitudes and behaviors during a large-scale crisis, some considerations are suggested. On the basis of the study results and informed by existing game theories, recommendations are made in relation to game development, deployment, and distribution; game users, design, and use; game design terminology; and effectiveness testing for serious games.

Adapting UK Biobank imaging for use in a routine memory clinic setting: The Oxford Brain Health Clinic.

The Oxford Brain Health Clinic (BHC) is a joint clinical-research service that provides memory clinic patients and clinicians access to high-quality assessments not routinely available, including brain MRI aligned with the UK Biobank imaging study (UKB). In this work we present how we 1) adapted the UKB MRI acquisition protocol to be suitable for memory clinic patients, 2) modified the imaging analysis pipeline to extract measures that are in line with radiology reports and 3) explored the alignment of measures from BHC patients to the largest brain MRI study in the world (ultimately 100,000 participants). Adaptations of the UKB acquisition protocol for BHC patients include dividing the scan into core and optional sequences (i.e., additional imaging modalities) to improve patients' tolerance for the MRI assessment. We adapted the UKB structural MRI analysis pipeline to take into account the characteristics of a memory clinic population (e.g., high amount of white matter hyperintensities and hippocampal atrophy). We then compared the imaging derived phenotypes (IDPs) extracted from the structural scans to visual ratings from radiology reports, non-imaging factors (age, cognition) and to reference distributions derived from UKB data. Of the first 108 BHC attendees (August 2020-November 2021), 92.5 % completed the clinical scans, 88.0 % consented to use of data for research, and 43.5 % completed the additional research sequences, demonstrating that the protocol is well tolerated. The high rates of consent to research makes this a valuable real-world quality research dataset routinely captured in a clinical service. Modified tissue-type segmentation with lesion masking greatly improved grey matter volume estimation. CSF-masking marginally improved hippocampal segmentation. The IDPs were in line with radiology reports and showed significant associations with age and cognitive performance, in line with the literature. Due to the age difference between memory clinic patients of the BHC (age range 65-101 years, average 78.3 years) and UKB participants (44-82 years, average 64 years), additional scans on elderly healthy controls are needed to improve reference distributions. Current and future work aims to integrate automated quantitative measures in the radiology reports and evaluate their clinical utility.

The human milk proteome and allergy of mother and child: Exploring associations with protein abundances and protein network connectivity.

Background: The human milk proteome comprises a vast number of proteins with immunomodulatory functions, but it is not clear how this relates to allergy of the mother or allergy development in the breastfed infant. This study aimed to explore the relation between the human milk proteome and allergy of both mother and child. Methods: Proteins were analyzed in milk samples from a subset of 300 mother-child dyads from the Canadian CHILD Cohort Study, selected based on maternal and child allergy phenotypes. For this selection, the definition of "allergy" included food allergy, eczema, allergic rhinitis, and asthma. Proteins were analyzed with non-targeted shotgun proteomics using filter-aided sample preparation (FASP) and nanoLC-Orbitrap-MS/MS. Protein abundances, based on label-free quantification, were compared using multiple statistical approaches, including univariate, multivariate, and network analyses. Results: Using univariate analysis, we observed a trend that milk for infants who develop an allergy by 3 years of age contains higher abundances of immunoglobulin chains, irrespective of the allergy status of the mother. This observation suggests a difference in the milk's immunological potential, which might be related to the development of the infant's immune system. Furthermore, network analysis showed overall increased connectivity of proteins in the milk of allergic mothers and milk for infants who ultimately develop an allergy. This difference in connectivity was especially noted for proteins involved in the protein translation machinery and may be due to the physiological status of the mother, which is reflected in the interconnectedness of proteins in her milk. In addition, it was shown that network analysis complements the other methods for data analysis by revealing complex associations between the milk proteome and mother-child allergy status. Conclusion: Together, these findings give new insights into how the human milk proteome, through differences in the abundance of individual proteins and protein-protein associations, relates to the allergy status of mother and child. In addition, these results inspire new research directions into the complex interplay of the mother-milk-infant triad and allergy.