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This article presents a comprehensive approach to synthetic aperture radar (SAR) image retrieval for navigation in global positioning system (GPS)-denied areas. It explores the utilization of SAR images to develop navigation techniques, assuming the system can generate real-time SAR images. The navigation process involves image retrieval, where a query image is compared to stored images in a database to identify the most similar ones. The selected images serve as reference points for extracting precise location coordinates. We propose model leveraging on the notion of Siamese artificial neural networks (ANNs), inspired by the SqueezeNet architecture, that incorporates swish activation functions and a retrieval module to address challenges related to variations in unmanned aerial vehicle (UAV) height and rotations. Extensive evaluation demonstrates the effectiveness of the proposed method, with low retrieval error and feasibility for computationally constrained devices. The stability of the method is also validated using out-of-sample data. Overall, this work contributes to the advancement of SAR image retrieval and navigation in GPS-denied environments, with potential applications in navigation, target detection, terrain classification, and more.

AbstractObjectiveAutonomic disorders are common in chronic illness, and their symptoms may restrict the daily functioning of patients. However, in chronic heart failure, extensive knowledge about autonomic symptoms is still lacking. This study aims to explore self-perceived autonomic symptoms, associated factors, and their relationship with health-related quality of life in chronic heart failure.MethodsOne hundred and twenty-four patients with documented chronic heart failure (men and women; 50–86 years) and 124 sex and age-matched controls participated in this study. The participants filled validated questionnaires about autonomic symptom profile (COMPASS 31), fatigue (CIS, Checklist for individual strength), anxiety and depression (HADS, Hospital Anxiety and Depression), and health-related quality of life (SF36). Non-parametric statistics were performed to analyse the data.ResultsTotal score for autonomic symptoms was higher in chronic heart failure compared to controls [Median: 14.9; IQR: 6.2–25.1 vs.7.3; 0–18; p < 0.001], especially for orthostatic hypotension [Median: 8; IQR: 0–16 vs.0; 0–12; p < 0.001], vasomotor [Median: 0; IQR: 0–0 vs.0; 0–0; p < 0.001] and secretomotor function [Median: 0; IQR: 0–4.2 vs.0; 0–2.1; p = 0.013]. High scores for autonomic symptoms were moderate correlated with higher scores of fatigue, anxiety and depression (0.343 ≤ rs ≥ 0.420; p < 0.001) and with decreased health-related quality of life (−0.454; p < 0.01).ConclusionAutonomic symptoms, especially for orthostatic intolerance, vasomotor and secretomotor subdomains, are prevalent and are associated with fatigue complaints and poor health-related quality of life in CHF.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of hematological cancers arising from the malignant transformation of mature T cells. In a cohort of 28 PTCL cases, we identified recurrent overexpression of MYCN, a member of the MYC family of oncogenic transcription factors. Approximately half of all PTCL cases was characterized by a MYC expression signature. Inducible expression of MYCN in lymphoid cells in a mouse model caused T-cell lymphoma that recapitulated human PTCL with an MYC expression signature. Integration of mouse and human expression data identified EZH2 as a key downstream target of MYCN. Remarkably, EZH2 was found to be an essential cofactor for the transcriptional activation of the MYCN-driven gene expression program, which was independent of methyltransferase activity but dependent on phosphorylation by CDK1. MYCN-driven T-cell lymphoma was sensitive to EZH2 degradation or CDK1 inhibition, which displayed synergy with US Food and Drug Administration–approved histone deacetylase (HDAC) inhibitors.

The current study shows the research on phytochemical concerning the phenolic components of Algerian pomegranate fruit extract (Punica granatumL.) using Ultra Performance Liquid Chromatography Diode-Array Detection Electrospray Ionization Mass Spectrometry (UPLC-DAD-ESI-MS). In this study; about more than 50 phenolic compounds, including 40 phenolic acids, 5 flavonoids, 2 coumarins and ellagitannins were identified. The profile is characterized by the presence of major peak at retention time 0.59, related to Bergaptan diglucoside (40%). This latter compound and many compounds such as digalloyl lactone citric acid, dicafeoyl galloyl dihydroxymalonic acid, ferruloyl diglucosyl citrate, dicafeoyl galloyl malonyl citrate, protocatechic cafeoyl coumaroyl rhamnoside, isorhamnetin glucosyl rhamnoside, dihydrokaemferol ferruloyl cafeoyl, and bergapten triglucoside methylsulphide were first time reported and identified in the hydroalcoholic fruit extract of Algerian Punica granatum.This acquired information may be useful to validate the fruit extract of Punica granatum, as source of bioactive compounds.

The τ pathology found in Alzheimer disease (AD) is crucial in cognitive decline. Midlife development of obesity, a major risk factor of insulin resistance and type 2 diabetes, increases the risk of dementia and AD later in life. The impact of obesity on AD risk has been suggested to be related to central insulin resistance, secondary to peripheral insulin resistance. The effects of diet-induced obesity (DIO) on τ pathology remain unknown. In this study, we evaluated effects of a high-fat diet, given at an early pathological stage, in the THY-Tau22 transgenic mouse model of progressive AD-like τ pathology. We found that early and progressive obesity potentiated spatial learning deficits as well as hippocampal τ pathology at a later stage. Surprisingly, THYTau22 mice did not exhibit peripheral insulin resistance. Further, pathological worsening occurred while hippocampal insulin signaling was upregulated. Together, our data demonstrate that DIO worsens τ phosphorylation and learning abilities in τ transgenic mice independently from peripheral/central insulin resistance., Accumulation and aggregation of hyperphosphorylated τ proteins (τ pathology) into neurofibrillary tangles (NFT) is a major pathological process encountered in Alzheimer disease (AD) (1). NFT are observed early in life [...]

Entretien avec Paula Heron, professeure de physique à l’Université de Washington, Seattle, USA. Elle nous présente les "Tutorials", méthodes pédagogiques novatrices développées au sein de l’équipe de recherche sur l’enseignement de la physique de l’Université de Washington, méthodes encore peu connues dans les universités françaises.

Nitrogen (N) excreted by poultry is converted to ammonia (NH3), presenting an environmental risk and a health risk to the farmer and animals. A study was performed to investigate the effect of reduced CP and feed form on broiler performance and welfare, meat and litter quality, N utilization, and NH3concentrations at litter level. A total of 2,232 Ross 308 male broilers was divided into 6 treatments and 6 replicates, which was fed diets in both pellet and mash forms with different CP levels of 205.0 g/kg (H, high), 187.5 g/kg (M, intermediate) and 175.0 g/kg (L, low) in the grower phase and 195.0 g/kg (H), 180.0 g/kg (M) and 165.6 g/kg (L) in the finisher phase. Individual amino acids (AA) were supplemented to maintain digestible AA-to-digestible lysine ratios. Decreasing dietary CP content to 187.5 g/kg in the grower phase and 180.0 g/kg in the finisher phase reduced NH3concentrations at litter level (P < 0.001), but a further reduction in dietary CP had no additional effect. Mash treatments had better litter qualities and lower incidences of foot and hock lesions than pellet treatments at d 38 (P < 0.001). In addition, treatments with reduced CP had lower incidence of foot lesions at d 38 (P < 0.001). Broilers fed pelleted diets had higher ADFI, ADG, and final BW, improved feed conversion ratio (FCR), and heavier carcasses (P < 0.001) than those fed mash diets over a production period of 39 d. Performance could not be maintained when birds were fed L CP pelleted diets. This study demonstrated that, with the supplementation of AA to meet requirements, the concentration of dietary CP can be reduced to 187.5 and 180.0 g/kg in the grower and finisher phases respectively, without impairing broiler performance, meat yield and quality. Mash diets were favorable when considering the overall litter quality and welfare of the birds. However, they could not maintain the same broiler performance and slaughter yield as pelleted diets. Results from the present study may assist the poultry sector towards a socially acceptable low-emission farming system.

Cancer metastasis requires the transient activation of cellular programs enabling dissemination and seeding in distant organs1. Genetic, transcriptional and translational heterogeneity contributes to this dynamic process2,3. Metabolic heterogeneity has also been observed4, yet its role in cancer progression is less explored. Here we find that the loss of phosphoglycerate dehydrogenase (PHGDH) potentiates metastatic dissemination. Specifically, we find that heterogeneous or low PHGDHexpression in primary tumours of patients with breast cancer is associated with decreased metastasis-free survival time. In mice, circulating tumour cells and early metastatic lesions are enriched with Phgdhlowcancer cells, and silencing Phgdhin primary tumours increases metastasis formation. Mechanistically, Phgdh interacts with the glycolytic enzyme phosphofructokinase, and the loss of this interaction activates the hexosamine–sialic acid pathway, which provides precursors for protein glycosylation. As a consequence, aberrant protein glycosylation occurs, including increased sialylation of integrin αvβ3, which potentiates cell migration and invasion. Inhibition of sialylation counteracts the metastatic ability of Phgdhlowcancer cells. In conclusion, although the catalytic activity of PHGDH supports cancer cell proliferation, low PHGDH protein expression non-catalytically potentiates cancer dissemination and metastasis formation. Thus, the presence of PHDGH heterogeneity in primary tumours could be considered a sign of tumour aggressiveness.

ABSTRACTCase ReportA 12-year-old boy, of Congolese roots and without medical history, first presented to our Emergency Department 3 days after blunt trauma of the left ankle. The boy represented on two more occasions in the next 3 days due to ongoing pain. On the last occasion he presented with severe hypoglycaemia. He was diagnosed with severe septic shock, secondary to subperiosteal abscess formation / osteomyelitis of the ankle.The patient was transferred to the paediatric intensive care unit where appropriate medical care was provided, including broad-spectrum antibiotic therapy, high dose vasopressor / inotropic support, surgical debridement of abscesses and below-knee amputation.Panton Valentine Leukocidin Toxin and Pyomyositis TropicalisThe causative organism was a methicillin-susceptible S. aureus, which upon further identification was a carrier of the PVL (Panton Valentine leukocidin) toxin. This pathogen is responsible for severe musculoskeletal infections. In children these infections are often associated with more severe clinical course requiring a higher need for surgical intervention and longer hospital stay.Tropical pyomyositis is a disease caused by Staphylococcus aureus, often seen in tropical countries, and classically presented with muscle abscesses. Young males between the ages of 10-40 years old are the most susceptible, and often present with a history of blunt trauma.Treatment generally requires a combination of an anti-staphylococcal agent, and an anti-toxic agent blocking bacterial protein-synthesis of PVL. Source control by surgical debridement also plays a major role in the treatment of PVL-infection. Despite agressive treatment, mortality still varies from 0.5% to 2%.

Type A uncertainty evaluation can significantly benefit from incorporating prior knowledge about the precision of an employed measurement device, which allows for reliable uncertainty assessments with limited observations. The Bayesian framework, employing Bayes theorem and Markov Chain Monte Carlo (MCMC), is recommended to incorporate such prior knowledge in a statistically rigorous way. While MCMC is recommended, metrologists are usually well-familiar with plain Monte Carlo sampling and previous work demonstrated the integration of similar prior knowledge into an uncertainty evaluation framework following the plain Monte Carlo sampling of JCGM 101–the Supplement 1 to the GUM. In this work, we explore the potential and limitations of such an approach, presenting classes of data distributions for informative Type A uncertainty evaluations. Our work justifies an informative extension of the JCGM 101 Type A uncertainty evaluation from a statistical perspective, providing theoretical insight and practical guidance. Explicit distributions are proposed for input quantities in Type A scenarios, aligning with Bayesian uncertainty evaluations. In addition, inherent limitations of the JCGM 101 Monte Carlo approach are discussed concerning general Bayesian inference. Metrological examples support the theoretical findings, significantly expanding the applicability of the JCGM 101 Monte Carlo technique from a Bayesian perspective.

Providing standardized professional nursing education to multiple transplant and cellular therapy programs across the United States is critical to the health of patients and their caregivers and the support of specialized nurses. In addition, accreditation by the Commission on Cancer (CoC) requires either oncology-focused certification or a minimum of 36 cancer-related continuing nursing education (CNE) contact hours per 3-year accreditation cycle. Innovative learning methods, such as interactive online modules, are rapidly growing alternatives in delivering standardized nursing education. To improve learner engagement, critical thinking, and application of education to practice, creative techniques were employed to standardize education.

Three guidelines - interoperability, extensibility, and distribution - help design open system architectures by identifying hot spots and contracts, thereby balancing flexibility and tailorability. Since the early 1980s, OO frameworks […]

Ipomoea aquatica is a common green leafy vegetable that has numerous uses in traditional medicine. This study focused on the determination of the cytotoxic, antiradical, and antidiabetic properties of various fractions of the I. aquatica methanolic extract, as well as on the tentative identification of some bioactive compounds in the same fractions. The cytotoxicity was determined by the brine shrimp lethal test. The antioxidant activities of the I. aquatica fractions were investigated through 3 assays. The antidiabetic activity (in vitro) was measured by α -glucosidase and α -amylase inhibition assays. Phytochemical qualitative analyses demonstrated the presence of alkaloids, terpenoids, phenols, and flavonoids in the ethyl acetate-methanol and methanol fractions. The total phenolic and total flavonoid contents were found to be highest in the ethyl acetate-MeOH fractions. The evaluation of the cytotoxicity showed that the hexane-dichloromethane fraction is the most toxic, while the others are moderately toxic. The antioxidant activity assays showed that the ethyl acetate-MeOH fractions are the most potent, while the α -glucosidase and α -amylase assays revealed that the hexane-dichloromethane fraction might contain a potent antidiabetic agent. Some bioactive substances in the MeOH fractions, such as salicylic acid glucoside, 1-O-sinapoyl- β -D-glucose derivative, and dihydroferulic acid derivative, were tentatively identified. To the best of our knowledge, this is the first report to detect and identify these compounds in this species. Based on the results of this study, it may be concluded that I. aquatica is a potent antioxidant agent and could be a good candidate as a natural antioxidant in food and therapeutics. [ABSTRACT FROM AUTHOR]

Ipomoea aquatica is a common green leafy vegetable that has numerous uses in traditional medicine. This study focused on the determination of the cytotoxic, antiradical, and antidiabetic properties of various fractions of the I. aquatica methanolic extract, as well as on the tentative identification of some bioactive compounds in the same fractions. The cytotoxicity was determined by the brine shrimp lethal test. The antioxidant activities of the I. aquatica fractions were investigated through 3 assays. The antidiabetic activity (in vitro) was measured by α -glucosidase and α -amylase inhibition assays. Phytochemical qualitative analyses demonstrated the presence of alkaloids, terpenoids, phenols, and flavonoids in the ethyl acetate-methanol and methanol fractions. The total phenolic and total flavonoid contents were found to be highest in the ethyl acetate-MeOH fractions. The evaluation of the cytotoxicity showed that the hexane-dichloromethane fraction is the most toxic, while the others are moderately toxic. The antioxidant activity assays showed that the ethyl acetate-MeOH fractions are the most potent, while the α -glucosidase and α -amylase assays revealed that the hexane-dichloromethane fraction might contain a potent antidiabetic agent. Some bioactive substances in the MeOH fractions, such as salicylic acid glucoside, 1-O-sinapoyl- β -D-glucose derivative, and dihydroferulic acid derivative, were tentatively identified. To the best of our knowledge, this is the first report to detect and identify these compounds in this species. Based on the results of this study, it may be concluded that I. aquatica is a potent antioxidant agent and could be a good candidate as a natural antioxidant in food and therapeutics. [ABSTRACT FROM AUTHOR]

Ipomoea aquatica is a common green leafy vegetable that has numerous uses in traditional medicine. This study focused on the determination of the cytotoxic, antiradical, and antidiabetic properties of various fractions of the I. aquatica methanolic extract, as well as on the tentative identification of some bioactive compounds in the same fractions. The cytotoxicity was determined by the brine shrimp lethal test. The antioxidant activities of the I. aquatica fractions were investigated through 3 assays. The antidiabetic activity (in vitro) was measured by α -glucosidase and α -amylase inhibition assays. Phytochemical qualitative analyses demonstrated the presence of alkaloids, terpenoids, phenols, and flavonoids in the ethyl acetate-methanol and methanol fractions. The total phenolic and total flavonoid contents were found to be highest in the ethyl acetate-MeOH fractions. The evaluation of the cytotoxicity showed that the hexane-dichloromethane fraction is the most toxic, while the others are moderately toxic. The antioxidant activity assays showed that the ethyl acetate-MeOH fractions are the most potent, while the α -glucosidase and α -amylase assays revealed that the hexane-dichloromethane fraction might contain a potent antidiabetic agent. Some bioactive substances in the MeOH fractions, such as salicylic acid glucoside, 1-O-sinapoyl- β -D-glucose derivative, and dihydroferulic acid derivative, were tentatively identified. To the best of our knowledge, this is the first report to detect and identify these compounds in this species. Based on the results of this study, it may be concluded that I. aquatica is a potent antioxidant agent and could be a good candidate as a natural antioxidant in food and therapeutics. [ABSTRACT FROM AUTHOR]

Ipomoea aquatica is a common green leafy vegetable that has numerous uses in traditional medicine. This study focused on the determination of the cytotoxic, antiradical, and antidiabetic properties of various fractions of the I. aquatica methanolic extract, as well as on the tentative identification of some bioactive compounds in the same fractions. The cytotoxicity was determined by the brine shrimp lethal test. The antioxidant activities of the I. aquatica fractions were investigated through 3 assays. The antidiabetic activity (in vitro) was measured by α -glucosidase and α -amylase inhibition assays. Phytochemical qualitative analyses demonstrated the presence of alkaloids, terpenoids, phenols, and flavonoids in the ethyl acetate-methanol and methanol fractions. The total phenolic and total flavonoid contents were found to be highest in the ethyl acetate-MeOH fractions. The evaluation of the cytotoxicity showed that the hexane-dichloromethane fraction is the most toxic, while the others are moderately toxic. The antioxidant activity assays showed that the ethyl acetate-MeOH fractions are the most potent, while the α -glucosidase and α -amylase assays revealed that the hexane-dichloromethane fraction might contain a potent antidiabetic agent. Some bioactive substances in the MeOH fractions, such as salicylic acid glucoside, 1-O-sinapoyl- β -D-glucose derivative, and dihydroferulic acid derivative, were tentatively identified. To the best of our knowledge, this is the first report to detect and identify these compounds in this species. Based on the results of this study, it may be concluded that I. aquatica is a potent antioxidant agent and could be a good candidate as a natural antioxidant in food and therapeutics. [ABSTRACT FROM AUTHOR]

Tight regulation of IL-7Rα expression is essential for normal T-cell development. IL-7Rα gain-of-function mutations are known drivers of T-cell acute lymphoblastic leukemia (T-ALL). Although a subset of patients with T-ALL display high IL7R messenger RNA levels and cases with IL7R gains have been reported, the impact of IL-7Rα overexpression, rather than mutational activation, during leukemogenesis remains unclear. In this study, overexpressed IL-7Rα in tetracycline-inducible Il7r transgenic and Rosa26 IL7R knockin mice drove potential thymocyte self-renewal, and thymus hyperplasia related to increased proliferation of T-cell precursors, which subsequently infiltrated lymph nodes, spleen, and bone marrow, ultimately leading to fatal leukemia. The tumors mimicked key features of human T-ALL, including heterogeneity in immunophenotype and genetic subtype between cases, frequent hyperactivation of the PI3K/Akt pathway paralleled by downregulation of p27Kip1 and upregulation of Bcl-2, and gene expression signatures evidencing activation of JAK/STAT, PI3K/Akt/mTOR and Notch signaling. Notably, we also found that established tumors may no longer require high levels of IL-7R expression upon secondary transplantation and progressed in the absence of IL-7, but remain sensitive to inhibitors of IL-7R–mediated signaling ruxolitinib (Jak1), AZD1208 (Pim), dactolisib (PI3K/mTOR), palbociclib (Cdk4/6), and venetoclax (Bcl-2). The relevance of these findings for human disease are highlighted by the fact that samples from patients with T-ALL with high wild-type IL7R expression display a transcriptional signature resembling that of IL-7–stimulated pro-T cells and, critically, of IL7R-mutant cases of T-ALL. Overall, our study demonstrates that high expression of IL-7Rα can promote T-cell tumorigenesis, even in the absence of IL-7Rα mutational activation.

Test amplification exploits the knowledge embedded in an existing test suite to strengthen it. A typical test amplification technique transforms the initial tests into additional test methods that increase the mutation coverage. Although past research demonstrated the benefits, additional steps need to be taken to incorporate test amplifiers in the everyday workflow of developers. This paper describes a proof-of-concept bot integrating Small-Ampwith GitHub-Actions. The bot decides for itself which tests to amplify and does so within a limited time budget. To integrate the bot into the GitHub-Actionsworkflow, we incorporate three special-purpose features: (i) prioritization (to fit the process within a given time budget), (ii) sharding (to split lengthy tests into smaller chunks), and (iii) sandboxing (to make the amplifier crash-resilient). We evaluate our approach by installing the proof-of-concept extension of Small-Ampon five open-source projects deployed on GitHub. Our results show that a test amplification bot is feasible at a project level by integrating it into the build system. Moreover, we quantify the impact of prioritization, sharding, and sandboxing so that other test amplifiers may benefit from these special-purpose features. Our proof-of-concept demonstrates that the entry barrier for adopting test amplification can be significantly lowered.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive leukemia that is most frequent in children and is characterized by the presence of few chromosomal rearrangements and 10 to 20 somatic mutations in protein-coding regions at diagnosis. The majority of T-ALL cases harbor activating mutations in NOTCH1 together with mutations in genes implicated in kinase signaling, transcriptional regulation, or protein translation. To obtain more insight in the level of clonal heterogeneity at diagnosis and during treatment, we used single-cell targeted DNA sequencing with the Tapestri platform. We designed a custom ALL panel and obtained accurate single-nucleotide variant and small insertion-deletion mutation calling for 305 amplicons covering 110 genes in about 4400 cells per sample and time point. A total of 108 188 cells were analyzed for 25 samples of 8 T-ALL patients. We typically observed a major clone at diagnosis (>35% of the cells) accompanied by several minor clones of which some were less than 1% of the total number of cells. Four patients had >2 NOTCH1 mutations, some of which present in minor clones, indicating a strong pressure to acquire NOTCH1 mutations in developing T-ALL cells. By analyzing longitudinal samples, we detected the presence and clonal nature of residual leukemic cells and clones with a minor presence at diagnosis that evolved to clinically relevant major clones at later disease stages. Therefore, single-cell DNA amplicon sequencing is a sensitive assay to detect clonal architecture and evolution in T-ALL.

BackgroundThe Daily-PROactive and Clinical visit-PROactive Physical Activity (D-PPAC and C-PPAC) instruments in chronic obstructive pulmonary disease (COPD) combines questionnaire with activity monitor data to measure patients’ experience of physical activity. Their amount, difficulty and total scores range from 0 (worst) to 100 (best) but require further psychometric evaluation.ObjectiveTo test reliability, validity and responsiveness, and to define minimal important difference (MID), of the D-PPAC and C-PPAC instruments, in a large population of patients with stable COPD from diverse severities, settings and countries.MethodsWe used data from seven randomised controlled trials to evaluate D-PPAC and C-PPAC internal consistency and construct validity by sex, age groups, COPD severity, country and language as well as responsiveness to interventions, ability to detect change and MID.ResultsWe included 1324 patients (mean (SD) age 66 (8) years, forced expiratory volume in 1 s 55 (17)% predicted). Scores covered almost the full range from 0 to 100, showed strong internal consistency after stratification and correlated as a priori hypothesised with dyspnoea, health-related quality of life and exercise capacity. Difficulty scores improved after pharmacological treatment and pulmonary rehabilitation, while amount scores improved after behavioural physical activity interventions. All scores were responsive to changes in self-reported physical activity experience (both worsening and improvement) and to the occurrence of COPD exacerbations during follow-up. The MID was estimated to 6 for amount and difficulty scores and 4 for total score.ConclusionsThe D-PPAC and C-PPAC instruments are reliable and valid across diverse COPD populations and responsive to pharmacological and non-pharmacological interventions and changes in clinically relevant variables.

To determine whether a positive fluid balance is associated with AKI and mortality in sepsis and septic shock patients.

Introduction:Emergency and disaster situations have a major impact on hospitals, some of which are already overloaded daily. The recent COVID-19 outbreak, attacks in Brussels, floods in Wallonia and influx of Ukrainian refugees show that the risk of facing a disaster and involvement of local hospitals (and stakeholders) is real. However, how hospitals implement their own hospital disaster plan (HDP), the position of the hospital disaster coordinator (HDC) and the real efficacy of these measures remain unclear. Therefore, an evaluation tool with an expert-consensus set of Key Performance Indicators (KPIs) and an evaluation of the HDC position is neededMethod:A semi-quantitative survey, as part of evaluation research, was designed by a research group. This questionnaire was based on the document analysis of the main topics of the national template and accompanying legislation. To establish consensus on the importance of the KPIs concerning the HDP, a three-round email-based modified Delphi study (Policy Delphi) was undertaken.Results:For a task group, 15 qualified multidisciplinary professionals (in-hospital) agreed to participate, 11 completed all rounds. As a pilot group, a total of 25 ‘experts on the field’, were purposively selected from Belgian hospitals, nine of them completed the questionnaire. The modified Delphi reached the agreed consensus threshold (i.e.75%), resulting in five main themes: demographic characteristics/profile HDC, hospital incident management system (HIMS), pre-incident phase, incident phase, post-incident phase. Collectively including a core set of 289 KPIs (29 indicators to assess progress concerning the HDC position).Conclusion:This study employed a modified Delphi approach to establish consensus, resulting in the development of an evaluation tool to measure hospital disaster preparedness and to evaluate progress of the HDC position within Belgian hospitals. All indicators were considered relevant and immediately implementable. When the implementation of KPIs is completed, the statement is that a HIMS exists within the hospitals.

The polycomb repressive complex 2, with core components EZH2, SUZ12, and EED, is responsible for writing histone 3 lysine 27 trimethylation histone marks associated with gene repression. Analysis of sequence data from 419 T-cell acute lymphoblastic leukemia (T-ALL) cases demonstrated a significant association between SUZ12 and JAK3 mutations. Here we show that CRISPR/Cas9-mediated inactivation of Suz12 cooperates with mutant JAK3 to drive T-cell transformation and T-ALL development. Gene expression profiling integrated with ChIP-seq and ATAC-seq data established that inactivation of Suz12 led to increased PI3K/mammalian target of rapamycin (mTOR), vascular endothelial growth factor (VEGF), and WNT signaling. Moreover, a drug screen revealed that JAK3/Suz12 mutant leukemia cells were more sensitive to histone deacetylase (HDAC)6 inhibition than JAK3 mutant leukemia cells. Among the broad genome and gene expression changes observed on Suz12 inactivation, our integrated analysis identified the PI3K/mTOR, VEGF/VEGF receptor, and HDAC6/HSP90 pathways as specific vulnerabilities in T-ALL cells with combined JAK3 and SUZ12 mutations.

Physical activity is important to maintain health. Patients who reduce their physical activity are at increased risk of developing comorbidities and faster decline in health. Interventions to enhance physical activity require a behavior change from patients and these interventions have become increasingly popular in chronic obstructive pulmonary disease. However, few interventions have shown long-term effects and all focused on enhancing physical activity rather than the maintenance thereof. In patients with very low exercise tolerance or with significant symptom burden, enhancing physical activity be difficult and interventions should first focus on enhancing exercise tolerance.

Introduction: Acute lymphoblastic leukemia (ALL), the most common pediatric malignancy, is caused by the accumulation of multiple genomic aberrations in developing lymphocytes. In children, high hyperdiploidy (HeH) is the most prevalent subtype of B-cell ALL (B-ALL), which is associated with a superior outcome. However, because of the high incidence of HeH B-ALL in children, this subtype is responsible for about 25% of all relapses. The prediction of relapse remains difficult, especially in these good risk subtypes. Recent studies indicate that ALL is a heterogeneous disease, with multiple leukemia clones at diagnosis, each having a distinct set of mutations. We hypothesize that these different subclones have a different sensitivity to treatment and that samples with more heterogeneity are more prone to relapse. We used single-cell sequencing to determine the clonal heterogeneity of HeH B-ALL at diagnosis and followed the clonal evolution during chemotherapy treatment.

Anatomie van de hardcorepunk, een anti-autoritair genre dat niet te veel wil groeien. [ABSTRACT FROM AUTHOR]

IL-33 is shown to play a cell-intrinsic role in maintenance of the functional identity of regulatory T cells in the tumor microenvironment. Genetic inhibition of IL-33 potentiates the therapeutic effect of checkpoint inhibitor immunotherapy in a melanoma mouse tumor model.

Next-generation sequencing has provided a detailed overview of the various genomic lesions implicated in the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL). Typically, 10–20 protein-altering lesions are found in T-ALL cells at diagnosis. However, it is currently unclear in which order these mutations are acquired and in which progenitor cells this is initiated. To address these questions, we used targeted single-cell sequencing of total bone marrow cells and CD34+CD38−multipotent progenitor cells for four T-ALL cases. Hierarchical clustering detected a dominant leukemia cluster at diagnosis, accompanied by a few smaller clusters harboring only a fraction of the mutations. We developed a graph-based algorithm to determine the order of mutation acquisition. Two of the four patients had an early event in a known oncogene (MED12, STAT5B) among various pre-leukemic events. Intermediate events included loss of 9p21 (CDKN2A/B) and acquisition of fusion genes, while NOTCH1mutations were typically late events. Analysis of CD34+CD38−cells and myeloid progenitors revealed that in half of the cases somatic mutations were detectable in multipotent progenitor cells. We demonstrate that targeted single-cell sequencing can elucidate the order of mutation acquisition in T-ALL and that T-ALL development can start in a multipotent progenitor cell.

The lack of (inter-)laboratory standardization has hampered the application of universal cutoff values for Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers and their transfer to general clinical practice. The automation of the AD biomarker immunoassays is suggested to generate more robust results than using manual testing. Open-access platforms will facilitate the integration of automation for novel biomarkers, allowing the introduction of the protein profiling concept. A feasibility study was performed on an automated open-access platform of the commercial immunoassays for the 42-amino-acid isoform of amyloid-β (Aβ1–42), Aβ1–40, and total tau in CSF. Automated Aβ1–42, Aβ1–40, and tau immunoassays were performed within predefined acceptance criteria for bias and imprecision. Similar accuracy was obtained for ready-to-use calibrators as for reconstituted lyophilized kit calibrators. When compared with the addition of a standard curve in each test run, the use of a master calibrator curve, determined before and applied to each batch analysis as the standard curve, yielded an acceptable overall bias of −2.6% and −0.9% for Aβ1−42and Aβ1–40, respectively, with an imprecision profile of 6.2% and 8.4%, respectively. Our findings show that transfer of commercial manual immunoassays to fully automated open-access platforms is feasible, as it performs according to universal acceptance criteria.

T-cell acute lymphoblastic leukemia (T-ALL) is caused by the accumulation of multiple mutations combined with the ectopic expression of transcription factors in developing T cells. However, the molecular basis underlying cooperation between transcription factor expression and additional oncogenic mutations in driving T-ALL has been difficult to assess due to limited robust T-cell model systems. Here we utilize a new ex vivo pro-T-cell model to study oncogenic cooperation. Using a systems biological approach we first dissect the pro-T-cell signaling network driven by interleukin-7, stem cell factor and Notch1 and identify key downstream Akt, Stat, E2f and Myc genetic signaling networks. Next, this pro-T-cell system was used to demonstrate that ectopic expression of the TAL1 transcription factor and Pten deletion are bona-fide cooperating events resulting in an increased stem cell signature, upregulation of a specific E2f signaling network and metabolic reprogramming with higher influx of glucose carbons into the tricarboxylic acid cycle. This ex vivo pro-T-cell system thereby provides a powerful new model system to investigate how normal T-cell signaling networks are perturbed and/or hijacked by different oncogenic events found in T-ALL.

Mutations in the interleukin-7 receptor (IL7R) or the Janus kinase 3 (JAK3) kinase occur frequently in T-cell acute lymphoblastic leukemia (T-ALL) and both are able to drive cellular transformation and the development of T-ALL in mouse models. However, the signal transduction pathways downstream of JAK3 mutations remain poorly characterized. Here we describe the phosphoproteome downstream of the JAK3(L857Q)/(M511I) activating mutations in transformed Ba/F3 lymphocyte cells. Signaling pathways regulated by JAK3 mutants were assessed following acute inhibition of JAK1/JAK3 using the JAK kinase inhibitors ruxolitinib or tofacitinib. Comprehensive network interrogation using the phosphoproteomic signatures identified significant changes in pathways regulating cell cycle, translation initiation, mitogen-activated protein kinase and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT signaling, RNA metabolism, as well as epigenetic and apoptotic processes. Key regulatory proteins within pathways that showed altered phosphorylation following JAK inhibition were targeted using selumetinib and trametinib (MEK), buparlisib (PI3K) and ABT-199 (BCL2), and found to be synergistic in combination with JAK kinase inhibitors in primary T-ALL samples harboring JAK3 mutations. These data provide the first detailed molecular characterization of the downstream signaling pathways regulated by JAK3 mutations and provide further understanding into the oncogenic processes regulated by constitutive kinase activation aiding in the development of improved combinatorial treatment regimens.

Ruim 33.000 oudere mantelzorgers in Vlaanderen zorgen thuis voor een ernstig hulpbehoevende partner. In een meerderheid van de gevallen is er niemand anders uit de directe omgeving betrokken bij de zorg. Wanneer de gepaste ondersteuning ontbreekt, liggen overbelasting en gezondheidsproblemen op de loer. Niet zelden worden deze mantelzorgers gekarakteriseerd als de ‘hidden patient’. Wie zijn ze, hoe beleven ze de zorg voor hun hulpbehoevende partner en krijgen ze de nodige ondersteuning? In welke mate verschillen ze van andere mantelzorgers?

The Janus kinase 3 (JAK3) tyrosine kinase is mutated in 10% to 16% of T-cell acute lymphoblastic leukemia (T-ALL) cases. JAK3 mutants induce constitutive JAK/STAT signaling and cause leukemia when expressed in the bone marrow cells of mice. Surprisingly, we observed that one third of JAK3-mutant T-ALL cases harbor 2 JAK3 mutations, some of which are monoallelic and others that are biallelic. Our data suggest that wild-type JAK3 competes with mutant JAK3 (M511I) for binding to the common γ chain and thereby suppresses its oncogenic potential. We demonstrate that JAK3 (M511I) can increase its limited oncogenic potential through the acquisition of an additional mutation in the mutant JAK3 allele. These double JAK3 mutants show increased STAT5 activation and increased potential to transform primary mouse pro–T cells to interleukin-7–independent growth and were not affected by wild-type JAK3 expression. These data extend our insight into the oncogenic properties of JAK3 mutations and provide an explanation of why progression of JAK3-mutant T-ALL cases can be associated with the accumulation of additional JAK3 mutations.

BackgroundThis study aimed to investigate whether adjunctive inspiratory muscle training (IMT) can enhance the well-established benefits of pulmonary rehabilitation (PR) in patients with COPD.Methods219 patients with COPD (FEV1: 42%±16% predicted) with inspiratory muscle weakness (PImax: 51±15 cm H2O) were randomised into an intervention group (IMT+PR; n=110) or a control group (Sham-IMT+PR; n=109) in this double-blind, multicentre randomised controlled trial between February 2012 and October 2016 (ClinicalTrials.gov NCT01397396). Improvement in 6 min walking distance (6MWD) was a priori defined as the primary outcome. Prespecified secondary outcomes included respiratory muscle function and endurance cycling time.FindingsNo significant differences between the intervention group (n=89) and the control group (n=85) in improvements in 6MWD were observed (0.3 m, 95% CI −13 to 14, p=0.967). Patients who completed assessments in the intervention group achieved larger gains in inspiratory muscle strength (effect size: 1.07, p<0.001) and endurance (effect size: 0.79, p<0.001) than patients in the control group. 75 s additional improvement in endurance cycling time (95% CI 1 to 149, p=0.048) and significant reductions in Borg dyspnoea score at isotime during the cycling test (95% CI −1.5 to −0.01, p=0.049) were observed in the intervention group.InterpretationImprovements in respiratory muscle function after adjunctive IMT did not translate into additional improvements in 6MWD (primary outcome). Additional gains in endurance time and reductions in symptoms of dyspnoea were observed during an endurance cycling test (secondary outcome)Trial registration numberNCT01397396; Results.

The molecular pathways underlying tau pathology–induced synaptic/cognitive deficits and neurodegeneration are poorly understood. One prevalent hypothesis is that hyperphosphorylation, misfolding, and fibrillization of tau impair synaptic plasticity and cause degeneration. However, tau pathology may also result in the loss of specific physiological tau functions, which are largely unknown but could contribute to neuronal dysfunction. In the present study, we uncovered a novel function of tau in its ability to regulate brain insulin signaling. We found that tau deletion leads to an impaired hippocampal response to insulin, caused by altered IRS-1 and PTEN (phosphatase and tensin homologue on chromosome 10) activities. Our data also demonstrate that tau knockout mice exhibit an impaired hypothalamic anorexigenic effect of insulin that is associated with energy metabolism alterations. Consistently, we found that tau haplotypes are associated with glycemic traits in humans. The present data have far-reaching clinical implications and raise the hypothesis that pathophysiological tau loss-of-function favors brain insulin resistance, which is instrumental for cognitive and metabolic impairments in Alzheimer’s disease patients.

RationaleReduced physical activity (PA) in patients with COPD is associated with a poor prognosis. Increasing PA is a key therapeutic target, but thus far few strategies have been found effective in this patient group.ObjectivesTo investigate the effectiveness of a 12-week semiautomated telecoaching intervention on PA in patients with COPD in a multicentre European randomised controlled trial.Methods343 patients from six centres, encompassing a wide spectrum of disease severity, were randomly allocated to either a usual care group (UCG) or a telecoaching intervention group (IG) between June and December 2014. This 12-week intervention included an exercise booklet and a step counter providing feedback both directly and via a dedicated smartphone application. The latter provided an individualised daily activity goal (steps) revised weekly and text messages as well as allowing occasional telephone contacts with investigators. PA was measured using accelerometry during 1 week preceding randomisation and during week 12. Secondary outcomes included exercise capacity and health status. Analyses were based on modified intention to treat.Main resultsBoth groups were comparable at baseline in terms of factors influencing PA. At 12 weeks, the intervention yielded a between-group difference of mean, 95% CI (lower limit – upper limit; ll-ul) +1469, 95% CI (971 to 1965) steps/day and +10.4, 95% CI (6.1 to 14.7) min/day moderate PA; favouring the IG (all p≤0.001). The change in 6-min walk distance was significantly different (13.4, 95% CI (3.40 to 23.5) m, p<0.01), favouring the IG. In IG patients, an improvement could be observed in the functional state domain of the clinical COPD questionnaire (p=0.03) compared with UCG. Other health status outcomes did not differ.ConclusionsThe amount and intensity of PA can be significantly increased in patients with COPD using a 12-week semiautomated telecoaching intervention including a step counter and an application installed on a smartphone.Trial registration number:NCT02158065.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive childhood leukemia that is caused by the accumulation of multiple genomic lesions resulting in transcriptional deregulation and increased cell proliferation and survival. Through analysis of gene expression data, we provide evidence that the hedgehog pathway is activated in 20% of T-ALL samples. Hedgehog pathway activation is associated with ectopic expression of the hedgehog ligands Sonic hedgehog (SHH) or Indian hedgehog (IHH), and with upregulation of the transcription factor GLI1. Ectopic expression of SHH or IHH in mouse T cells in vivo caused hedgehog pathway activation in both lymphoid and epithelial cells in the thymus and resulted in increased expression of important T-cell stimulatory ligands (Dll4, Il7, and Vegf) by thymic epithelial cells. In T-ALL cell lines, pharmacological inhibition or short interfering RNA–mediated knockdown of SMO or GLI1 led to decreased cell proliferation. Moreover, primary T-ALL cases with high GLI1 messenger RNA levels, but not those with low or undetectable GLI1 expression, were sensitive to hedgehog pathway inhibition by GANT61 or GDC-0449 (vismodegib) using ex vivo cultures and in vivo xenograft models. We identify the hedgehog pathway as a novel therapeutic target in T-ALL and demonstrate that hedgehog inhibitors approved by the US Food and Drug Administration could be used for the treatment of this rare leukemia.