Miracle-dz/UniFAR-FTUs huggingface dataset:
Health technology assessment for digital technologies that manage chronic disease: a systematic review

Abstract Objective A growing number of evaluation frameworks have emerged over recent years addressing the unique benefits and risk profiles of new classes of digital health technologies (DHTs). This systematic review aims to identify relevant frameworks and synthesize their recommendations into DHT-specific content to be considered when performing Health Technology Assessments (HTAs) for DHTs that manage chronic noncommunicable disease at home. Methods Searches were undertaken of Medline, Embase, Econlit, CINAHL, and The Cochrane Library (January 2015 to March 2020), and relevant gray literature (January 2015 to August 2020) using keywords related to HTA, evaluation frameworks, and DHTs. Included framework reference lists were searched from 2010 until 2015. The EUNetHTA HTA Core Model version 3.0 was selected as a scaffold for content evaluation. Results Forty-four frameworks were identified, mainly covering clinical effectiveness (n = 30) and safety (n = 23) issues. DHT-specific content recommended by framework authors fell within 28 of the 145 HTA Core Model issues. A further twenty-two DHT-specific issues not currently in the HTA Core Model were recommended. Conclusions Current HTA frameworks are unlikely to be sufficient for assessing DHTs. The development of DHT-specific content for HTA frameworks is hampered by DHTs having varied benefit and risk profiles. By focusing on DHTs that actively monitor/treat chronic noncommunicable diseases at home, we have extended DHT-specific content to all nine HTA Core Model domains. We plan to develop a supplementary evaluation framework for designing research studies, undertaking HTAs, and appraising the completeness of HTAs for DHTs.
When is Ambivalence Good for Family Firms? Understanding the Impact of Family Managers’ Emotional Ambivalence on Decision Making

Abstract It has been suggested in the family business literature that the pursuit of socioemotional wealth (SEW) has both a bright and dark side and these conflicting priorities can have a negative impact on the quality of decisions made by family managers. This paper presents a model which recognizes that ambivalence emanating from socioemotional wealth may also lead to high calibre decision-making under certain contexts. In particular, we explain how emotional ambivalence can affect the decision-making abilities of family managers. Although emotional complexity and the resulting ambivalence is seen as an undesirable situation, we argue that this could also result in positive outcomes under certain circumstances. More specifically, emotional ambivalence prompts leaders to adopt a broader perspective and consider several alternatives before reaching a decision, hence enhancing decision-making quality. However, we acknowledge that emotional ambivalence may also lead to an overly restrictive focus on the family’s interests occasionally leading to inferior family-centric decisions.
Kap-β2/Transportin mediates β-catenin nuclear transport in Wnt signaling

Wnt signaling is essential for many aspects of embryonic development including the formation of the primary embryonic axis. In addition, excessive Wnt signaling drives multiple diseases including cancer highlighting its importance for disease pathogenesis. β-catenin is a key effector in this pathway that translocates into the nucleus and activates Wnt responsive genes. However, due to our lack of understanding of β-catenin nuclear transport, therapeutic modulation of Wnt signaling has been challenging. Here, we took an unconventional approach to address this long-standing question by exploiting a heterologous model system, the budding yeast Saccharomyces cerevisiae, which contains a conserved nuclear transport machinery. In contrast to prior work, we demonstrate that β-catenin accumulates in the nucleus in a Ran dependent manner, suggesting the use of a nuclear transport receptor (NTR). Indeed, a systematic and conditional inhibition of NTRs revealed that only Kap104, the orthologue of Kap-β2/Transportin-1 (TNPO1), was required for β-catenin nuclear import. We further demonstrate direct binding between TNPO1 and β-catenin that is mediated by a conserved amino acid sequence that resembles a PY NLS. Finally, using Xenopus secondary axis and TCF/LEF reporter assays, we demonstrate that our results in yeast can be directly translated to vertebrates. By elucidating the NLS in β-catenin and its cognate NTR, our study provides new therapeutic targets for a host of human diseases caused by excessive Wnt signaling. Indeed, we demonstrate that a small chimeric peptide designed to target TNPO1 can reduce Wnt signaling as a first step towards therapeutics.
Identification of a new Infectious Pancreatic Necrosis Virus (IPNV) isolate in Atlantic salmon (Salmo salar L.) that causes mortality in resistant fish

Infectious pancreatic necrosis (IPN) is an important viral disease of salmonids that can affect fish during various life cycles. In Atlantic salmon, selecting for genetically resistant animals against IPN has been one of the most highly praised success stories in the history of fish breeding. The findings that resistance against this disease has a significant genetic component, which is mainly controlled by variations in a single gene, has helped to reduce the IPN outbreaks over the past decade to a great extent. In this paper, we present the identification of a new isolate of the IPN virus, from a field outbreak, that had caused mortality, even in the genetically resistant animals. We recovered and assembled the full-length genome of this virus, following deep-sequencing of an infected tissue. The comparative sequence analysis revealed that for the critical amino acid motifs, previously found to be associated with the degree of virulence, the newly identified isolate is similar to the virus’s avirulent form. However, we detected a set of deduced amino acid residues, particularly in the hypervariable region of the polyprotein, that collectively are unique to this strain compared to all other reference sequences assessed in this study. We suggest that these mutations have likely equipped the virus with the capacity to escape the host defence mechanism more efficiently, even in the genetically deemed IPN resistant animals.
Label-free three-dimensional analyses of live cells with deep-learning-based segmentation exploiting refractive index distributions

Visualisations and analyses of cellular and subcellular organelles in biological cells is crucial for the study of cell biology. However, existing imaging methods require the use of exogenous labelling agents, which prevents the long-time assessments of live cells in their native states. Here we propose and experimentally demonstrate three-dimensional segmentation of subcellular organelles in unlabelled live cells, exploiting a 3D U-Net-based architecture. We present the high-precision three-dimensional segmentation of cell membrane, nucleus membrane, nucleoli, and lipid droplets of various cell types. Time-lapse analyses of dynamics of activated immune cells are also analysed using label-free segmentation.
Karyon: a computational framework for the diagnosis of hybrids, aneuploids, and other nonstandard architectures in genome assemblies

Recent technological developments have made genome sequencing and assembly accessible to many groups. However, the presence in sequenced organisms of certain genomic features such as high heterozygosity, polyploidy, aneuploidy, or heterokaryosis can challenge current standard assembly procedures and result in highly fragmented assemblies. Hence, we hypothesized that genome databases must contain a non-negligible fraction of low-quality assemblies that result from such type of intrinsic genomic factors. Here we present Karyon, a Python-based toolkit that uses raw sequencing data and de novo genome assembly to assess several parameters and generate informative plots to assist in the identification of non-chanonical genomic traits. Karyon includes automated de novo genome assembly and variant calling pipelines. We tested Karyon by diagnosing 35 highly fragmented publicly available assemblies from 19 different Mucorales (Fungi) species. Our results show that 6 (17%) of the assemblies presented signs of unusual genomic configurations, suggesting that these are common, at least within the Fungi.
Computing Minimal Boolean Models of Gene Regulatory Networks

Models of Gene Regulatory Networks (GRNs) capture the dynamics of the regulatory processes that occur within the cell as a means to understand the variability observed in gene expression between different conditions. Arguably the simplest mathematical construct used for modeling is the Boolean network, which dictates a set of logical rules for transition between states described as Boolean vectors. Due to the complexity of gene regulation and the limitations of experimental technologies, in most cases knowledge about regulatory interactions and Boolean states is partial. In addition, the logical rules themselves are not known a-priori. Our goal in this work is to create an algorithm that finds the network that fits the data optimally, and identify the network states that correspond to the noise-free data. We present a novel methodology for integrating experimental data and performing a search for the optimal consistent structure via optimization of a linear objective function under a set of linear constraints. In addition, we extend our methodology into a heuristic that alleviates the computational complexity of the problem for datasets that are generated by single-cell RNA-Sequencing(scRNA-Seq). We demonstrate the effectiveness of these tools using a public scRNA-Seq dataset and the GRN that is associated with it. Our methodology will enable researchers to obtain a better understanding of the dynamics of gene regulatory networks and their biological role.
Excavations at Kiriath-jearim, 2019: Preliminary Report

In this article we report the results of the second season of excavations at Kiriath-jearim (Deir el-ʿAzar). The following topics are emphasized: layout and date of the supposed monumental Iron IIB summit compound; nature of the Iron IIC settlement; date of the Hellenistic fortification; characteristics of the Early Roman period activity. An archaeo-historical analysis follows the presentation of the new data, including updates on past interpretations.
Immunological Identification and Characterization of the Capsid Scaffold Protein Encoded by UL26.5 of Herpes Simplex Virus Type 2

Herpes simplex virus type 2 (HSV2), a pathogen that causes genital herpes lesions, interferes with the host immune system via various known and unknown mechanisms. This virus has been used to study viral antigenic composition. Convalescent serum from HSV2-infected patients was used to identify viral antigens via 2-D protein electrophoresis and immunoblotting. The serum predominantly recognized several capsid scaffold proteins encoded by gene UL26.5, mainly ICP35. This protein has been primarily reported to function temporarily in viral assembly but is not expressed in mature virus particles. Further immunological studies suggested that this protein elicits specific antibody and cytotoxic T lymphocyte (CTL) responses in mice, but these responses do not result in a clinical protective effect in response to HSV2 challenge. The data suggested that immunodominance of ICP35 might be used to design an integrated antigen with other viral glycoproteins.
How to Determine Accurate Conformational Ensembles by Metadynamics Metainference: A Chignolin Study Case

The reliability and usefulness of molecular dynamics simulations of equilibrium processes rests on their statistical precision and their capability to generate conformational ensembles in agreement with available experimental knowledge. Metadynamics Metainference (M&M), coupling molecular dynamics with the enhanced sampling ability of Metadynamics and with the ability to integrate experimental information of Metainference, can in principle achieve both goals. Here we show that three different Metadynamics setups provide converged estimate of the populations of the three-states populated by a model peptide. Errors are estimated correctly by block averaging, but higher precision is obtained by performing independent replicates. One effect of Metadynamics is that of dramatically decreasing the number of effective frames resulting from the simulations and this is relevant for M&M where the number of replicas should be large enough to capture the conformational heterogeneity behind the experimental data. Our simulations allow also us to propose that monitoring the relative error associated with conformational averaging can help to determine the minimum number of replicas to be simulated in the context of M&M simulations. Altogether our data provides useful indication on how to generate sound conformational ensemble in agreement with experimental data.
Screening of Chorioamnionitis Using Volatile Organic Compound Detection in Exhaled Breath: A Pre-clinical Proof of Concept Study

Chorioamnionitis is a major risk factor for preterm birth and an independent risk factor for postnatal morbidity for which currently successful therapies are lacking. Emerging evidence indicates that the timing and duration of intra-amniotic infections are crucial determinants for the stage of developmental injury at birth. Insight into the dynamical changes of organ injury after the onset of chorioamnionitis revealed novel therapeutic windows of opportunity. Importantly, successful development and implementation of therapies in clinical care is currently impeded by a lack of diagnostic tools for early (prenatal) detection and surveillance of intra-amniotic infections. In the current study we questioned whether an intra-amniotic infection could be accurately diagnosed by a specific volatile organic compound (VOC) profile in exhaled breath of pregnant sheep. For this purpose pregnant Texel ewes were inoculated intra-amniotically with Ureaplasma parvum and serial collections of exhaled breath were performed for 6 days. Ureaplasma parvum infection induced a distinct VOC-signature in expired breath of pregnant sheep that was significantly different between day 0 and 1 vs. day 5 and 6. Based on a profile of only 15 discriminatory volatiles, animals could correctly be classified as either infected (day 5 and 6) or not (day 0 and 1) with a sensitivity of 83% and a specificity of 71% and an area under the curve of 0.93. Chemical identification of these distinct VOCs revealed the presence of a lipid peroxidation marker nonanal and various hydrocarbons including n-undecane and n-dodecane. These data indicate that intra-amniotic infections can be detected by VOC analyses of exhaled breath and might provide insight into temporal dynamics of intra-amniotic infection and its underlying pathways. In particular, several of these volatiles are associated with enhanced oxidative stress and undecane and dodecane have been reported as predictive biomarker of spontaneous preterm birth in humans. Applying VOC analysis for the early detection of intra-amniotic infections will lead to appropriate surveillance of these high-risk pregnancies, thereby facilitating appropriate clinical course of action including early treatment of preventative measures for pre-maturity-associated morbidities.
The Effects of Transcranial Direct Current Stimulation on Balance and Gait in Stroke Patients: A Systematic Review and Meta-Analysis

Objective: Balance dysfunction after stroke often results in individuals unable to maintain normal posture, limits the recovery of gait and functional independence. We explore the short-term effects of transcranial direct current stimulation (tDCS) on improving balance function and gait in stroke patients. Methods: We systematically searched on PubMed, Web of Science, EMBASE, Cochrane Central Register of Controlled Trials, and Google Scholar for studies that explored the effects of tDCS on balance after stroke until August 2020. All involved studies used at least one measurement of balance, gait, or postural control as the outcome. Results: A total of 145 studies were found, of which 10 (n = 246) met the inclusion criteria and included in our studies. The present meta-analysis showed that active tDCS have beneficial effects on timed up and go test (TUGT) [mean difference (MD): 0.35; 95% confidence interval (CI): 0.11 to 0.58] and Functional Ambulation Category (FAC) (MD: −2.54; 95% CI: −3.93 to −1.15) in stroke patients. However, the results were not significant on the berg balance scale (BBS) (MD: −0.20; 95% CI: −1.44 to 1.04), lower extremity subscale of Fugl-Meyer Assessment (FMA-LE) (MD: −0.43; 95% CI: −1.70 to 0.84), 10-m walk test (10 MWT) (MD: −0.93; 95% CI: −2.68 to 0.82) and 6-min walking test (6 MWT) (MD: −2.55; 95% CI: −18.34 to 13.23). Conclusions: In conclusion, we revealed that tDCS might be an effective option for restoring walking independence and functional ambulation for stroke patients in our systematic review and meta-analysis. Systematic Review Registration: CRD42020207565.
Adaptive and Energy-Efficient Optimal Control in CPGs Through Tegotae-Based Feedback

To obtain biologically inspired robotic control, the architecture of central pattern generators (CPGs) has been extensively adopted to generate periodic patterns for locomotor control. This is attributed to the interesting properties of nonlinear oscillators. Although sensory feedback in CPGs is not necessary for the generation of patterns, it plays a central role in guaranteeing adaptivity to environmental conditions. Nonetheless, its inclusion significantly modifies the dynamics of the CPG architecture, which often leads to bifurcations. For instance, the force feedback can be exploited to derive information regarding the state of the system. In particular, the Tegotae approach can be adopted by coupling proprioceptive information with the state of the oscillation itself in the CPG model. This paper discusses this policy with respect to other types of feedback; it provides higher adaptivity and an optimal energy efficiency for reflex-like actuation. We believe this is the first attempt to analyse the optimal energy efficiency along with the adaptivity of the Tegotae approach.
Isotopic Tracers Suggest Limited Trans-Oceanic Movements and Regional Residency in North Pacific Blue Sharks (Prionace glauca)

Blue sharks (Prionace glauca) are globally distributed, large-bodied pelagic sharks that make extensive migrations throughout their range. In the North Pacific, mark-recapture studies have shown trans-Pacific migrations, but knowledge gaps in migration frequency hinder understanding of regional connectivity and assessments of regional demography for stock assessments. Here, we use oceanographic gradients of stable isotope ratios (i.e., regional isoscapes) to determine exchange rates of blue sharks between the East and West North Pacific Ocean (EPO and WPO). We generated regional δ13C and δ15N distributions for blue sharks from published values in the North Pacific (n = 180; both sexes, juveniles and adults combined). Discriminant analysis suggested low trans-Pacific exchange, categorizing all western (100%) and most eastern (95.3%) blue sharks as resident to their sampling region, with isotopic niche overlap of WPO and EPO highly distinct (0.01–5.6% overlap). Limited trans-Pacific movements suggest that other mechanisms maintain genetic mixing of the North Pacific blue shark population. Potential finer scale movement structure was indicated by isotopic differences in sub-regions of the eastern and western Pacific, though application of mixing models are currently limited by aberrantly low blue shark δ13C values across studies. Our results suggest that blue shark population dynamics may be effectively assessed on a regional basis (i.e., WPO and EPO). We recommend further studies to provide size- and sex-specific movement patterns based on empirical isotopic values with large sample sizes from targeted regions. Strategically applied stable isotope approaches can continue to elucidate migration dynamics of mobile marine predators, complementing traditional approaches to fisheries biology and ecology.
Accuracy of the Radiographic Assessment of Lung Edema Score for the Diagnosis of ARDS

Background: Bilateral opacities on chest radiographs are part of the Berlin Definition for Acute Respiratory Distress Syndrome (ARDS) but have poor interobserver reliability. The “Radiographic Assessment of Lung Edema” (RALE) score was recently proposed for evaluation of the extent and density of alveolar opacities on chest radiographs of ARDS patients. The current study determined the accuracy of the RALE score for the diagnosis and the prognosis of ARDS. Methods: Post-hoc analysis of a cohort of invasively ventilated intensive care unit (ICU) patients expected to need invasive ventilation for >24 h. The Berlin Definition was used as the gold standard. The RALE score was calculated for the first available chest radiograph after start of ventilation in the ICU. The primary endpoint was the diagnostic accuracy for ARDS of the RALE score. Secondary endpoints included the prognostic value of the RALE score for ICU and hospital mortality, and the association with ARDS severity, and the PaO2/FiO2. Receiver operating characteristic (ROC) curves were constructed, and the optimal cutoff was used to determine sensitivity, specificity and the negative and positive predictive value of the RALE score for ARDS. Results: The study included 131 patients, of whom 30 had ARDS (11 mild, 15 moderate, and 4 severe ARDS). The first available chest radiograph was obtained median 0 [0 to 1] days after start of invasive ventilation in ICU. Compared to patients without ARDS, a higher RALE score was found in patients with ARDS (24 [interquartile range (IQR) 16–30] vs. 6 [IQR 3–11]; P < 0.001), with RALE scores of 20 [IQR 14–24], 26 [IQR 16–32], and 32 [IQR 19–36] for mild, moderate and severe ARDS, respectively, (P = 0.166). The area under the ROC for ARDS was excellent (0.91 [0.86–0.96]). The best cutoff for ARDS diagnosis was 10 with 100% sensitivity, 71% specificity, 51% positive predictive value and 100% negative predictive value. The RALE score was not associated with ICU or hospital mortality, and weakly correlated with the PaO2/FiO2. Conclusion: In this cohort of invasively ventilated ICU patients, the RALE score had excellent diagnostic accuracy for ARDS.