47,369 research outputs found

    Factors influencing development and outcome of equine gastrointestinal disease

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    Gastrointestinal diseases are a common cause of morbidity and mortality in horses. Colic refers to clinical signs attributed to abdominal pain in horses. The pathology underlying colic is diverse, which makes accurate prediction of survival challenging. Equine Gastric Ulcer Syndrome (EGUS) is common in horses and can be both a cause and associated comorbidity of colic and colic treatment. EGUS and other gastrointestinal diseases have significant implications on horse welfare and performance, as well as a negative economic impact on the equine industry. The two investigations comprising this thesis address separately the prognosis of surgical colic and efficacy of prophylactic medications for prevention of EGUS. Objective 1: Horses requiring an exploratory laparotomy for treatment of colic may have different risk factors for non-survival than a broader equine colic population, including horses with colic responsive to medical management. Development of accurate pre-operative predictive models in a surgical colic population may assist clinicians in prognosticating outcomes for these patients. The objective of this study was to compare the predictive performance of cohort-specific versus previously published univariate and multivariate models for survival in horses undergoing exploratory laparotomy for treatment of colic. Medical records from a single referral hospital were reviewed retrospectively for all horses undergoing exploratory laparotomy over a 12-year period. Preoperative, perioperative, and postoperative data of 302 horses were obtained. Cohort-specific models to predict outcome were developed by backwards stepwise generalized multiple linear regression. Cohort-specific and previously published models were applied to cohort data to predict outcome. Sensitivity, specificity, positive and negative predictive values (PPV, NPV), and accuracy for prediction of short-term survival were calculated. Short-term survival rate was 51.7%. Perioperative factors associated with short-term survival in the population studied included age, sex, admission heart rate, mucous membrane appearance, ionized calcium, blood pH, and total solids. Predictive models derived from cohort-specific data outperformed models developed from broader colic populations in previous studies, suggesting that population-specific factors contribute to patient survival. Findings support continued use of commonly considered variables in clinical assessment of surgical colic patients. However, no single parameter or published predictive model performs adequately to replace the value of clinician judgement. Objective 2: Hospitalized horses may be exposed to known risk factors for EGUS, including fasting and non-steroidal anti-inflammatory drug (NSAID) administration, putting them at high risk for formation of both squamous (ESGD) and glandular (EGGD) gastric ulcers. Prophylactic anti-ulcer medication selection is complicated by differences in etiology and response to treatment of these two types of ulcers. This study tested the hypothesis that prophylactic administration of omeprazole or sucralfate would be equally effective for prevention of EGUS in horses exposed to a combined fasting/NSAID ulcer induction model. Fourteen adult horses with baseline ESGD and EGGD scores ≀ 2 were included in a randomized crossover experimental design. Horses received either omeprazole or sucralfate while undergoing the fasting/NSAID protocol, allowed an 8-week washout period, and then administered the alternate treatment. Serial gastroscopy, ultrasound, and hematology documented treatment effects. ESGD and EGGD worsened over time under both treatments. However, post-treatment EGGD scores were significantly higher (worse) for horses receiving sucralfate compared to omeprazole. Healthy horses developed severe ESGD and EGGD within 5 days of exposure to fasting/NSAID protocol; the use of omeprazole was superior to sucralfate for mitigating the formation of gastric ulcers in this study.LimitedAuthor requested closed access (OA after 2yrs) in Vireo ETD syste

    Case report: Immune modulation after PD-1 inhibitor therapy in a patient with extranodal NK/T-cell lymphoma secondary to chronic active Epstein-Barr virus disease unveiled by single-cell transcriptomics

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    Chronic active Epstein-Barr virus disease (CAEBV) is a systemic lymphoproliferative disorder that is closely linked to Epstein-Barr virus (EBV) infection. The clinical course and severity of CAEBV can vary, and in some cases, it can progress to overt lymphoma, which is characterized by extranodal natural killer/T-cell lymphoma (ENKTL) and has a poor clinical outcome. Although anti-programmed cell death protein-1 (PD-1) therapy has shown effectiveness in some patients with EBV-associated disease, it has been less successful in others, and the exact mechanism of action of PD-1 inhibitor therapy in these diseases remains unclear. In this report, we describe a patient who was diagnosed with ENKTL secondary to CAEBV and experienced rapid disease progression accompanied by hyperinflammation after receiving PD-1 inhibitor therapy. Single-cell RNA sequencing revealed a significant increase in the patient’s lymphocyte count, especially in natural killer cells, with increased activity following PD-1 inhibitor therapy. This case raises questions about the efficacy and safety of PD-1 inhibitor therapy in patients with EBV-associated diseases

    International Consensus Conference for Advanced Breast Cancer, Lisbon 2019: ABC5 Consensus – Assessment by a German Group of Experts

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    The 5th International Consensus Conference for Advanced Breast Cancer (ABC5) took place on November 14–16, 2019, in Lisbon, Portugal. Its aim is to standardize the treatment of advanced breast cancer based on the available evidence and to ensure that all breast cancer patients worldwide receive adequate treatment and access to new therapies. This year, the conference focused on developments and study results in the treatment of patients with hormone receptor-positive/HER2-negative breast cancer as well as precision medicine. As in previous years, patient advocates from around the world were integrated into the ABC conference and had seats on the ABC consensus panel. In the present paper, a working group of German breast cancer experts comments on the results of the on-site ABC5 consensus votes by ABC panelists regarding their applicability for routine treatment in Germany. These comments take the recommendations of the Breast Committee of the Gynecological Oncology Working Group (Arbeitsgemeinschaft GynĂ€kologische Onkologie; AGO) into account. The report and assessment presented here pertain to the preliminary results of the ABC5 consensus. The final version of the statements will be published in Annals of Oncology and The Breast

    Factors associated with the clinical outcome of patients with relapsed/refractory CD19+acute lymphoblastic leukemia treated with ARI-0001 CART19-cell therapy

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    The prognosis of patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) remains poor, particularly for those relapsing after allogeneic hema-topoietic cell transplantation (alloHCT). Novel agents such as inotuzumab ozogamicin or blinatumomab achieve increased response rates, but these are generally transient unless followed by alloHCT. Chimeric antigen receptors (CAR) targeting CD19 have shown promising results in R/R ALL, and one of these products (tisagenlecleucel) has been approved for the treatment of patients with R/R ALL up to 25 years of age

    MarrowQuant 2.0: A Digital Pathology Workflow Assisting Bone Marrow Evaluation in Experimental and Clinical Hematology.

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    Bone marrow (BM) cellularity assessment is a crucial step in the evaluation of BM trephine biopsies for hematologic and nonhematologic disorders. Clinical assessment is based on a semiquantitative visual estimation of the hematopoietic and adipocytic components by hematopathologists, which does not provide quantitative information on other stromal compartments. In this study, we developed and validated MarrowQuant 2.0, an efficient, user-friendly digital hematopathology workflow integrated within QuPath software, which serves as BM quantifier for 5 mutually exclusive compartments (bone, hematopoietic, adipocytic, and interstitial/microvasculature areas and other) and derives the cellularity of human BM trephine biopsies. Instance segmentation of individual adipocytes is realized through the adaptation of the machine-learning-based algorithm StarDist. We calculated BM compartments and adipocyte size distributions of hematoxylin and eosin images obtained from 250 bone specimens, from control subjects and patients with acute myeloid leukemia or myelodysplastic syndrome, at diagnosis and follow-up, and measured the agreement of cellularity estimates by MarrowQuant 2.0 against visual scores from 4 hematopathologists. The algorithm was capable of robust BM compartment segmentation with an average mask accuracy of 86%, maximal for bone (99%), hematopoietic (92%), and adipocyte (98%) areas. MarrowQuant 2.0 cellularity score and hematopathologist estimations were highly correlated (R <sup>2</sup> = 0.92-0.98, intraclass correlation coefficient [ICC] = 0.98; interobserver ICC = 0.96). BM compartment segmentation quantitatively confirmed the reciprocity of the hematopoietic and adipocytic compartments. MarrowQuant 2.0 performance was additionally tested for cellularity assessment of specimens prospectively collected from clinical routine diagnosis. After special consideration for the choice of the cellularity equation in specimens with expanded stroma, performance was similar in this setting (R <sup>2</sup> = 0.86, n = 42). Thus, we conclude that these validation experiments establish MarrowQuant 2.0 as a reliable tool for BM cellularity assessment. We expect this workflow will serve as a clinical research tool to explore novel biomarkers related to BM stromal components and may contribute to further validation of future digitalized diagnostic hematopathology workstreams

    Complement mediated synapse elimination in schizophrenia

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    Schizophrenia (SCZ) is a devastating psychiatric disorder with a typically age of onset in late adolescence. The heritability is estimated to be in between 60-80% and large-scale genome-wide studies have revealed a prominent polygenic component to SCZ risk and identified more than three-hundred common risk variants. Despite a better understanding of which genetic risk variants that increases SCZ risk, it has been challenging to map out the pathophysiology of the disorder. This has stalled the development of target drugs and current treatment options display moderate efficacy and are prone to produce side-effects. SCZ is generally considered a neurodevelopmental disorder and it was proposed more than forty years ago that physiological removal of less active synapses in adolescence, i.e., synaptic pruning, is increased in SCZ and hereby causes the core symptoms of the disorder. This theory has then been supported by post-mortem brain tissue and imaging studies displaying decreased synapse density in SCZ. More recently, it was then shown that the most strongly associated risk loci can largely be explained by copy numbers of a gene coding for the complement factor 4A (C4A). As microglia prune synapses with the help of complement signalling, we therefore decided to use a recently developed human 2D in vitro assay to assess microglial uptake of synaptic structures in models based on cells from individuals with SCZ and healthy controls (study I). We observed excessive uptake of synaptic structures in SCZ models and by mixing synapses from healthy controls with microglia from SCZ patients, and vice versa, we showed the contribution of microglial and neuronal factors contributing to this excessive uptake of synaptic structures. We then developed an in vitro assay to study neuronal complement deposition dependent on copy numbers of C4A in the neuronal lines. Complement 3 (C3) deposition increased by C4A copy numbers but was independent of C4B copy numbers (also unrelated to SCZ risk). Similar C4A copy numbers correlated with the extent of microglial uptake of synapses. Microglial uptake of synaptic structures could also be inhibited by the tetracycline minocycline that also decreased risk of developing SCZ in an electronic health record cohort. In study II, we cerebrospinal fluid (CSF) from first-episode psychosis patients to measure protein levels of C4A. In two independent cohorts, we observed elevated C4A levels (although not C4B levels) in first-episode patients that later were to develop SCZ and could show correlations with markers of synapse density. However, elevated C4A levels could not fully be explained by more copy numbers of C4A in individuals with SCZ and in vitro experiments revealed that SCZ-associated cytokines can induce C4A mRNA expression while also correlating with C4A in patient-derived CSF. In study III, we set-up a 3D brain organoid models to more fully comprehensively capture processes in the developing human brain and then also included innately developing microglia. We display synaptic pruning within these models and use single cell RNA sequencing to validate them. In conclusion, this thesis uses patient-derived cellular modelling to uncover a disease mechanism in SCZ that link genetic risk variants with bona fide protein changes in living patients

    Characterization of Dutch-Cocoa produced using potash extract from cocoa pod husk as an alkalizing bioresource

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    Abstract Alkalizing agents in the processing of Dutch-Cocoa are often imported from developing countries. This occurs amidst humongous quantities of Cocoa Pod Husk (CPH) that are largely rotting away. This study therefore appraises the inherent alkalizing potentials of CPH, including its physicochemical and safety characteristics in the production of Dutch-Cocoa. CPH was calcined, potash extracted, characterized, and applied in formulation (1% to 5% conc.) in Dutch-production of Cocoa. Quality parameters of the resultant product were analyzed following AOAC procedures (p ≀ 0.05). In addition, rats(n=30) were fed it over a 21-day duration while nutritional and safety indicators were monitored. Sensory properties were also evaluated. The results showed some predominant properties of CPH potash extract [Potassium 35.7%, pH 12.3, alkalinity 15.6 g/100 g CO3] and Dutch-cocoa [protein (15.8% to 16.5%), colour (Hunter L,a,b) 36.9, 8.8, 11.7 light - dark red), dispersibility (1.5 to 2.3), wettability (143.7 s), sedimentation (20.7% to 49.3%)] which favourably compared with commercial variants. Apparent digestibility (AD%) was significant (Protein 86%, Fat 88%, Fiber 66% etc) (p ≀ .0.05). Safety indices exhibited no deleterious effect and the product was adjudged acceptable. Dutch-cocoa produced using CPH-derived-potash as an alternate alkalizing bioresource is feasible, while simultaneously providing an environmentally friendly outlet for CP

    Prediction of Nonrelapse Mortality in Patients with Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia Receiving Allogeneic Stem Cell Transplantation with Posttransplantation Cyclophosphamide-based Graft Versus Host Disease Prophylaxis

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    Graft versus host disease (GVHD) prophylaxis with posttransplantation cyclophosphamide (PTCY) has been established to reduce severe GVHD, and thereby potentially reducing nonrelapse mortality (NRM) after allogeneic stem cell transplantation (alloSCT). We evaluated the predictive capacity of established NRM-risk scores in patients receiving PTCY-based GVHD prophylaxis, and subsequently developed and validated a novel PTCY-specific NRM-risk model. Adult patients (n = 1861) with AML or ALL in first complete remission who received alloSCT with PTCY-based GVHD prophylaxis were included. The PTCY-risk score was developed using multivariable Fine and Gray regression, selecting parameters from the hematopoietic cell transplantation-comorbidity index (HCT-CI) and European Group for Blood and Marrow Transplantation (EBMT) score with a subdistribution hazard ratio (SHR) of ≄1.2 for 2-year NRM in the training set (70% split), which was validated in the test set (30%). The performance of the EBMT score, HCT-CI, and integrated EBMT score was relatively poor for discriminating 2-year NRM (c-statistic 51.7%, 56.6%, and 59.2%, respectively). The PTCY-risk score included 10 variables which were collapsed in 3 risk groups estimating 2-year NRM of 11% ± 2%, 19% ± 2%, and 36% ± 3% (training set, c-statistic 64%), and 11% ± 2%, 18% ± 3%, and 31% ± 5% (test set, c-statistic 63%), which also translated into different overall survival. Collectively, we developed an NRM-risk score for acute leukemia patients receiving PTCY that better predicted 2-year NRM compared with existing models, which might be applicable to the specific toxicities of high-dose cyclophosphamide