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Pulmonary macrophages exhibit a dose-dependent pattern in phagocytizing particles. Following engulfment, these macrophages are subsequently excreted with sputum, rendering macrophages and particles visible and quantifiable under light microscopy. Notably, elemental carbon within the mammalian body originates exclusively from external contaminants. Consequently, the carbon content in airway macrophages (CCAM) serves as a valid exposure biomarker, accurately estimating individual exposure to carbon-containing particulate matter (PM). This article delineates a protocol involving sputum collection, preservation, processing, slide preparation, and staining, as well as macrophage photo acquisition and analysis. After removing the macrophage nuclei, the proportion of cytoplasm area occupied by carbon particles (PCOC) was calculated to quantify carbon content in each macrophage. The results indicate an elevation in CCAM levels after exposure to carbon-containing PM. In summary, this non-invasive, precise, reliable, and standardized method enables the direct measurement of carbon particles within target cells and is utilized for large-scale quantification of individual CCAM through induced sputum.
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Carbono , Material Particulado , Escarro , Material Particulado/análise , Material Particulado/toxicidade , Humanos , Carbono/química , Carbono/toxicidade , Escarro/química , Escarro/citologia , Escarro/metabolismo , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/química , Macrófagos Alveolares/citologiaRESUMO
INTRODUCTION: Treatment selection in haemophilia is increasingly challenging given evolving therapeutic options and the need for individualization. Shared decision-making (SDM) approaches have recently gained interest, though a synthesis of available studies is lacking. AIM: A scoping review was conducted to summarize literature reporting on factors impacting treatment SDM in haemophilia and tools or models available to support such decisions. METHODS: PubMed, Embase, the Cochrane Library, Web of Science and grey literature were searched for studies published through August 2023. Original studies reporting on facilitators and barriers to haemophilia SDM and SDM tools were included and analyzed for themes, characteristics and gaps. RESULTS: A total of 625 records were identified and 14 unique studies were selected (factors influencing treatment SDM, n = 7; SDM tools, n = 7). The studies typically included input from persons with haemophilia, caregivers and healthcare practitioners (HCPs). Thematic organization of factors influencing SDM revealed three main categories: knowledge, patient characteristics and HCP-patient interactions. Availability of information was a commonly reported facilitator of SDM, while poor HCP-patient engagement was a commonly reported barrier. Tools varied in focus, with some facilitating general treatment SDM while others supported selection of certain therapy types. The studies underscored additional factors critical for SDM, such as alignment of HCP-patient perceptions, shared language and tailoring of tools to specific subpopulations. CONCLUSION: Few studies report on treatment SDM factors and tools in haemophilia; available tools vary considerably. It remains unclear whether published tools have been successfully implemented into clinical practice. Additional research is warranted.
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Tomada de Decisão Compartilhada , Hemofilia A , Humanos , Hemofilia A/terapia , Participação do PacienteRESUMO
INTRODUCTION: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by low platelet counts and increased risk of bleeding. After corticosteroids with or without intravenous immune globulin (first-line treatment), second-line treatment options include rituximab, splenectomy, thrombopoietin receptor agonists (TPO-RAs), and fostamatinib. In Canada, the choice of second-line therapy is influenced by access to medications. The goals of this narrative review are to 1) summarize the evidence for the use of TPO-RAs and other second-line therapies in ITP and 2) highlight differences in public funding criteria for TPO-RAs across provinces and territories in Canada. METHODS: We conducted a literature review of second-line therapies for ITP. We solicited information on public funding programs for TPO-RAs in Canada from health care providers, pharmacists, and provincial ministries of health. RESULTS: Head-to-head trials involving TPO-RAs, rituximab, splenectomy, and fostamatinib are lacking. There is substantial evidence of effect for TPO-RAs in improving platelet count levels, health-related quality of life, bleeding, and fatigue from placebo-controlled trials and observational studies; however, access to TPO-RAs through provincial funding programs in Canada is variable. Splenectomy failure is a prerequisite for the funding of TPO-RAs in Ontario, Manitoba, and Saskatchewan, but not in Alberta or Quebec. Other provinces either do not have access to public funding or funding is provided on a case-by-case basis. DISCUSSION: TPO-RAs are effective second-line therapies for the treatment of ITP; however, access is variable across Canada, which results in health disparities and poor uptake of international treatment guidelines.
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Aminopiridinas , Morfolinas , Púrpura Trombocitopênica Idiopática , Pirimidinas , Receptores de Trombopoetina , Humanos , Aminopiridinas/uso terapêutico , Morfolinas/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirimidinas/uso terapêutico , Qualidade de Vida , Receptores de Trombopoetina/agonistas , Rituximab/uso terapêuticoRESUMO
INTRODUCTION: Individuals with sickle cell disease (SCD) and central venous catheters (CVC) are at high risk for venous thromboembolism (VTE). Minimal data exist regarding the use of anticoagulation as thromboprophylaxis of VTE in this demographic, and as a result, clinical equipoise exists. Prophylactic dose rivaroxaban, a direct oral anticoagulant, is efficacious and safe as thromboprophylaxis in other demographics, and may be an optimal agent in SCD with CVC. Prior to conducting a full clinical trial to assess rivaroxaban as thromboprophylaxis in SCD with CVC, a pilot study is needed to gauge its feasibility. METHODS AND ANALYSIS: THromboprophylaxis In Sickle Cell Disease pilot trial is an investigator-initiated, multicentre, double-blinded, randomised controlled trial (RCT) assessing if it is feasible and safe to conduct an adequately powered RCT comparing rivaroxaban to matching placebo as thromboprophylaxis in those with SCD and CVC. Fifty adult patients with SCD and CVC will be randomised to receive either rivaroxaban 10 mg daily or matching placebo for the duration of the CVC in situ for up to 1 year. After randomisation, follow-up visits will occur every 3 months. The primary outcomes pertain to the feasibility of a full trial and include numbers of eligible and recruited participants. Exploratory outcomes include overall incidence of VTE and bleeding complications, as well as quality of life. If the full trial is feasible, blinding will be maintained and patients in the pilot study will be included in the full trial. ETHICS AND DISSEMINATION: The trial was initially approved by the University Health Network Research Ethics Board (REB) in Toronto, Canada. All sites will obtain approval from their respective REB prior to commencement of study activities. Study results will be disseminated through presentations at medical conferences and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT05033314.
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Anemia Falciforme , Cateteres Venosos Centrais , Tromboembolia Venosa , Adulto , Humanos , Projetos Piloto , Rivaroxabana/uso terapêutico , Cateteres Venosos Centrais/efeitos adversos , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controle , Tromboembolia Venosa/tratamento farmacológico , Anemia Falciforme/complicações , Anemia Falciforme/tratamento farmacológico , Anticoagulantes/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
INTRODUCTION: Increasing rate of postpartum haemorrhage (PPH) has been observed between 2003 and 2010 in Canada. Inherited bleeding disorders contribute to the risk of PPH. AIM: To identify the trend in PPH in the last decade, assess the impact of bleeding disorders on pregnancy outcomes and evaluate their coagulation workup during pregnancy. METHODS: We conducted a population-based retrospective cohort study using the Alberta Pregnancy Birth Cohort from 2010 to 2018. We included women with von Willebrand disease (VWD) and haemophilia, identified by previously validated algorithm and matched with controls. Logistic regression was used to compute odds of PPH and other pregnancy outcomes. RESULTS: We identified 311,330 women with a total of 454,400 pregnancies with live births. The rate of PPH did not change significantly from 10.13 per 100 deliveries (95% CI 10.10-10.16) in 2010-10.72 (95% CI 10.69-10.75) in 2018 (p for trend = .35). Women with bleeding disorders were significantly more likely to experience PPH (odds ratio [OR] 2.3; 95% CI 1.5-3.6), antepartum haemorrhage (OR 2.9; 95% CI 1.5-5.9) and red cell transfusion (OR 2.8; 95% CI 1.1-7.0). We observed a nonsignificant rise in the rate of PPH in women with VWD and haemophilia. Only 49.5% pregnancies with bleeding disorders had third trimester coagulation factor levels checked. Higher odds of PPH and antepartum haemorrhage were observed even with factor levels ≥0.50 IU/mL in third trimester. CONCLUSION: Despite comprehensive care in women with bleeding disorders, they are still at higher risk of adverse pregnancy outcomes compared to population controls.
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Hemofilia A , Hemorragia Pós-Parto , Doenças de von Willebrand , Gravidez , Feminino , Humanos , Estudos Retrospectivos , Estudos de Coortes , Hemorragia Pós-Parto/epidemiologiaRESUMO
BACKGROUND: Irrigation is used extensively to enhance grain production and ensure food security. Many studies have used crop models and global climate models to study the variation of irrigated crop yield in the context of climate change. But most considered the influence of direct climate change but neglected the influence of irrigation water availability, which is affected by land-use/cover change (LUCC) and indirect climate change, on irrigated crop yield. This study therefore developed a framework including Patch-generating Land Use Simulation model, Soil and Water Assessment Tool, Agricultural Production Systems sImulator Model, and global climate models for exploring the impacts of LUCC, direct climate change, and indirect climate change on wheat yield in a typical watershed. RESULTS: Both LUCC and climate change caused increased runoff from October to May, and thus increased the irrigation water availability, by 51.6 and 30.7 mm per growing season under 1.5 and 2.0 °C warming, respectively. The combined influence of LUCC, direct, and indirect climate change increased wheat yield by about 18.5% and 15.5% in the context of 1.5 and 2.0 °C warming, respectively. The relative contribution of LUCC, indirect climate change and direct climate change to yield was 4.7%, 41.2%, and 54.1% under 1.5 °C warming, and 13.1%, 28.7%, and 58.2% under 2.0 °C warming, respectively. CONCLUSION: We suggest that changes in irrigation water availability should be considered from a watershed perspective when simulating the influence of climate change on crop yield, especially regional crop production estimation. © 2023 Society of Chemical Industry.
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Mudança Climática , Triticum , Produtos Agrícolas , Agricultura , ÁguaRESUMO
Three copper iodide coordination polymer (CuI-p-DPA) isomers were prepared from the fluorescent organic ligand p-DPA and cuprous iodide (CuI) under different solvothermal conditions, which exhibited quenched fluorescence behaviors after forming coordination polymers (CPs). These CuI-p-DPA isomers showed discrepant fluorescence responses to thiophanate-methyl (TM). Among these CuI-p-DPA isomers, α-CuI-p-DPA exhibited the maximum fluorescence enhancement after its incubation with TM in aqueous solution. The fluorescence enhancement mechanism was that TM competed with the ligand p-DPA to coordinate with CuI clusters, and then α-CuI-p-DPA released p-DPA into the solution and induced fluorescence enhancement. The present detection method possesses the advantages of good selectivity, high sensitivity, short response time, and strong anti-interference ability with a linear range of 0.5-100 µM and a detection limit of 0.01 µM. This study not only reveals that the spatial structures of CPs play an important role in the fluorescence response ability, but also provide a new fluorescence signal-on analysis method to rapidly and sensitively determine the pesticide residue for TM.
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In this study, the establishment of a colloidal gold immunochromatographic method for the detection of cypermethrin in tobacco was achieved by using colloidal gold immunochromatography: strong specificity and high sensitivity of cypermethrin semi-antigens and encapsulants were prepared during the study. The best colloidal gold solution was prepared by spectrophotometer and transmission electron microscope screening; the preparation process of gold-labeled antibodies was optimized, and finally the product of colloidal gold rapid detection test strips for cypermethrin was developed. The results of technical parameters and detection indexes showed that the detection limit of cypermethrin in tobacco was 1 mg/kg, and there was no cross-reaction with bifenthrin, cypermethrin, cyfluthrin and phenothrin, and the detection results of 30 tobacco samples were consistent with those of gas chromatography.
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Anticorpos Monoclonais , Nicotiana , Anticorpos Monoclonais/química , Sensibilidade e Especificidade , Coloide de Ouro/química , Cromatografia de Afinidade/métodosRESUMO
In this study, monoclonal antibodies against oxamyl were prepared, and colloidal gold immunochromatography was used to design a rapid test strip product for the detection of oxamyl in tobacco with high specificity, accuracy and stability without cross-reactivity to commonly used tobacco fungicides based on the optimization of conditions such as pH value of diluent, diluent dosage, concentration of antibody marker, type of confining solution and complex solution. 5 The results of five samples of post-harvest ready-to-bake tobacco and first-harvest tobacco were consistent with the gas chromatographic method, which proved the reliability of the test strips. The limits of detection for the post-harvest and first-harvest tobacco samples were 0.1 mg/kg, and the test strips developed in this study are suitable for mass testing in tobacco laboratories with good application prospects because of their short detection time, simple pre-treatment and detection methods.
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Nicotiana , Fitas Reagentes , Fitas Reagentes/análise , Reprodutibilidade dos Testes , Coloide de Ouro/química , Sensibilidade e EspecificidadeRESUMO
The rapid and accurate determination of triadimenol residues is of great significance. In this study, based on the advantages of high efficiency, rapidity, reliability, simplicity and low cost of immunology, a test strip product for the rapid detection of triadimenol residues in tobacco was designed based on the optimization of conditions such as pH and dosage of diluent, concentration of antibody stock solution, type of confining solution and complex solution, with high specificity, accuracy and The results of 20 samples of fresh and first roasted tobacco were all consistent with the method of gas chromatography, which proved the reliability of the test strips. The detection limit for fresh and roasted tobacco was 5 mg/kg, and the test strips developed in this study are suitable for mass testing of tobacco samples in tobacco-related laboratories because of their short detection time, simple pre-treatment and detection methods, and good application prospects.
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Nicotiana , Fitas Reagentes , Fitas Reagentes/análise , Reprodutibilidade dos Testes , Coloide de Ouro/química , Sensibilidade e EspecificidadeRESUMO
Immature oocyte (germinal vesicle stage, GV) vitrification can avoid a cycle of ovarian stimulation, which is friendly to patients with hormone-sensitive tumors. However, the in vitro maturation of vitrification-thawed GV oocyte usually results in aneuploidy, and the underlying mechanism remains unclear. Stable spindle poles are important for accurate chromosome segregation. Acentriolar microtubule-organizing centers (aMTOCs) undergo fragmentation and reaggregation to form spindle poles. Microtubule nucleation is facilitated via the perichromosome Ran after GVBD, which plays an important role in aMTOCs fragmentation. This study showed that vitrification may reduce microtubule density by decreasing perichromosomal Ran levels, which reduced the localization of pKIF11, thereby decreased the fragmentation of aMTOCs and formed a more focused spindle pole, ultimately resulted in aneuploidy. This study revealed the mechanism of abnormal spindle pole formation in vitrified oocytes and offered a theoretical support to further improve the quality of vitrified oocytes.
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Vitrificação , Animais , Camundongos , Oócitos , Aneuploidia , Ciclo Celular , Polos do FusoRESUMO
Enhanced rock weathering (ERW) in farmland is an emerging carbon dioxide removal technology with crushed silicate rocks for soil improvement. However, due to climatic variability and field data limitations, uncertainties remain regarding the influence of ERW on food security and soil carbon pools in temperate regions. This study focused to evaluate the crop productivity and carbon sequestration potential of farmland ERW in China by conducting field monitoring in different humid regions and ERW performance model. Additionally, the contribution of climate, soil, and management factors to ERW-mediated yield and carbon sequestration changes was explored using random forest and correlation networks. Field monitoring indicated that farmland ERW significantly improved crop yield in humid region (13.5 ± 5.2 %), along with notable improvements in soil pH and available nutrients. Precipitation (10.4-16.7 %) and soil pH (9.7-16.8 %) had the highest contribution on ERW mediated yield and carbon sequestration changes, but the contribution of management factors (24-26.2 %), especially N input (2.7-7.0 %), should not be disregarded. The model evaluation demonstrated that the carbon sequestration rate of farmland ERW in China can reach 0.28-0.40 Gt yr-1, thereby presenting an opportunity to expand and accelerate the nationally determined contributions of China. The mean sequestration cost of farmland ERW was 633 ± 161 CNY ¥ t-CO2-1, which was an attractive sequestration price considering the positive benefits of rock powder on soil pH and nutrients. Deploying ERW in acidified and mineral nutrient deficient regions was able to serve as an alternative to lime and part chemical fertilizers to improve yield and maximize agricultural sustainability and resource co-benefits. Farmland ERW also has the potential to resource silicate waste to assist traditional, difficult-to-decarbonize industries to reduce carbon emissions. As a result, a comprehensive assessment of existing artificial silicate waste materials could further expand the application of farmland ERW.
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Urban carbon emissions are one of the most important areas contributing to the growth of carbon emissions, and resource-dependent cities with natural resource extraction and processing as their leading industries tend to have higher carbon emissions. Ordos is the city with the highest coal production in China, and its economic development is dominated by coal, oil and gas, and other resource extraction and processing industries, with industrial activities making a large contribution to carbon emissions. At the same time, Ordos has undergone rapid industrialization in recent years, but still faces the problem of environmental pollution, epitomizing a typical resource-dependent city in China. Therefore, this paper takes Ordos as an example and uses the Generalized Divisa Index Method (GDIM) to study the drivers of industrial carbon emissions in Ordos from 2005-2020, a typical resource-dependent city in China, and further analyzes are conducted in relation to the three phases of development. Based on the key drivers, the Monte Carlo method is used to forecast industrial carbon emissions from 2021 to 2030. The results show that the most important factors driving the growth of industrial carbon emissions are the scale of industrial output and industrial energy consumption, while the intensity of industrial energy investment is the most important factor mitigating industrial carbon emissions, and that energy efficiency and carbon intensity of energy consumption can also mitigate carbon emissions after economic transformation. At the same time, investment is the factor with the greatest potential for optimization on the path to emissions reduction.
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Carbono , Indústrias , Cidades , Carbono/análise , China , Desenvolvimento Econômico , Carvão Mineral/análise , Dióxido de Carbono/análiseRESUMO
To address challenges associated with climate change, population growth and decline in international trade linked to the COVID-19 pandemic, determining whether national crop production can meet populations' requirements and contribute to socio-economic resilience is crucial. Three crop models and three global climate models were used in conjunction with predicted population changes. Compared with wheat production in 2000-2010, total production and per capita wheat production were significantly (P < 0.05) increase in 2020-2030, 2030-2040 and 2040-2050, respectively, under RCP4.5 and RCP8.5 due to climate change in China. However, when considering population and climate changes, the predicted per capita production values were 125.3 ± 0.3, 127.1 ± 2.3 and 128.8 ± 2.7 kg during the 2020-2030, 2030-2040, 2040-2050 periods under RCP4.5, or 126.2 ± 0.7, 128.7 ± 2.5, and 131.0 ± 4.1 kg, respectively, under RCP8.5. These values do not significantly differ (P > 0.05) from the baseline level (127.9 ± 1.3 kg). The average per capita production in Loess Plateau and Gansu-Xinjiang subregions declined. In contrast, per capita production in the Huanghuai, Southwestern China, and Middle-Lower Yangtze Valleys subregions increased. The results suggest that climate change will increase total wheat production in China, but population change will partly offset the benefits to the grain market. In addition, domestic grain trade will be influenced by both climate and population changes. Wheat supply capacity will decline in the main supply areas. Further research is required to address effects of the changes on more crops and in more countries to obtain deeper understanding of the implications of climate change and population growth for global food production and assist formulation of robust policies to enhance food security. Supplementary Information: The online version contains supplementary material available at 10.1007/s12571-023-01351-x.
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For simulation to be an effective tool for the development and testing of autonomous vehicles, the simulator must be able to produce realistic safety-critical scenarios with distribution-level accuracy. However, due to the high dimensionality of real-world driving environments and the rarity of long-tail safety-critical events, how to achieve statistical realism in simulation is a long-standing problem. In this paper, we develop NeuralNDE, a deep learning-based framework to learn multi-agent interaction behavior from vehicle trajectory data, and propose a conflict critic model and a safety mapping network to refine the generation process of safety-critical events, following real-world occurring frequencies and patterns. The results show that NeuralNDE can achieve both accurate safety-critical driving statistics (e.g., crash rate/type/severity and near-miss statistics, etc.) and normal driving statistics (e.g., vehicle speed/distance/yielding behavior distributions, etc.), as demonstrated in the simulation of urban driving environments. To the best of our knowledge, this is the first time that a simulation model can reproduce the real-world driving environment with statistical realism, particularly for safety-critical situations.
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Oocyte vitrification has been widely application in female fertility preservation. Recent studies found that vitrification of immature (germinal vesicle stage, GV) oocytes increased the risk of aneuploidy during meiotic maturation; however, the underlying mechanisms and the strategies to prevent this defect remain unexplored. In this study, we found that vitrification of GV oocytes decreased the first polarbody extrusion rate (90.51 ± 1.04% vs. 63.89 ± 1.39%, p < 0.05) and increased the aneuploid rate (2.50% vs. 20.00%, p < 0.05), accompanied with a series of defects during meiotic maturation, including aberrant spindle morphology, chromosome misalignment, incorrect Kinetochore-Microtubule attachments (KT-MTs) and weakened spindle assembly checkpoint protein complex (SAC) function. We also found that vitrification disrupted mitochondrial function by increasing mitochondrial Ca2+ levels. Importantly, inhibition of mitochondrial Ca2+ entry by 1 µM Ru360 significantly restored mitochondrial function and rescued the meiotic defects, indicating that the increase of mitochondrial Ca2+, at least, was a cause of meiotic defects in vitrified oocytes. These results shed light on the molecular mechanisms of oocyte vitrification-induced adverse effects of meiotic maturation and provided a potential strategy to improve oocyte cryopreservation protocols further.
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Preservação da Fertilidade , Vitrificação , Feminino , Animais , Oócitos/fisiologia , Criopreservação/métodos , Criopreservação/veterinária , Preservação da Fertilidade/veterinária , Mitocôndrias , AneuploidiaRESUMO
INTRODUCTION: Despite expert-based recommendations, real-world adherence to immune thrombocytopenia (ITP) guidelines is unclear. The impact of geographic and socioeconomic disparities on the quality of care and outcomes is unknown. We sought to determine the association between geographic remoteness and material deprivation on ITP care and outcomes. METHODS: We conducted a multi-centre retrospective cohort study of adults with chronic ITP requiring a second-line therapy between 2012 and 2019 in the province of Alberta, Canada. Socioeconomic status was measured using the Pampalon material deprivation index quintiles. Geographic disparities were assessed by the driving distance to a major centre, with geographic remoteness defined as >200 km from major centre. We examined the impact of geographic and material deprivation on quality of care, resource utilization (hospitalizations, transfusions), and outcomes (major bleeding, all-cause mortality and ITP-related mortality). Cox proportional hazards models were used to examine the impact of geographic remoteness, rural residence and material deprivation on overall survival and ITP-related survival. RESULTS: We included 326 ITP patients, median age of ITP diagnosis was 57 years, 182 (56 %) were female. Most patients (58 %) lived within 20 km of a major centre, whereas 49 (15 %) lived in a geographically remote area (>200 km). Geographic remoteness was significantly associated with material deprivation and lower likelihood of management by hematologists (84 % vs 99 %, P = 0.0001). It was also associated with lower rates of hepatitis C (71 % vs 89 %, P = 0.005) and hepatitis B testing (69 % vs 86 %, P = 0.03), and a non-significant trend towards lower rates of HIV testing (73 % vs 83 %, P = 0.051) compared with those <20 km from a major centre. Incomplete hyposplenic vaccinations among splenectomized patients (52 %), early splenectomy within 12 months of ITP diagnosis (35 %), inappropriate platelet transfusions (41 %), and inappropriate hospitalizations for asymptomatic thrombocytopenia (16 %) were common regardless of geographic distribution. There were 28 (9 %) ITP-related deaths (major bleeding or infections), most occurred within the first year of ITP diagnosis. Material deprivation, but not geographic remoteness, was an independent predictor of all-cause mortality (aHR 1.9, 95 % CI 1.1-3.3 in the most deprived quintile vs least deprived quintile). Rural residence trended towards increased hazard of ITP-related deaths (aHR 1.7, 95 % CI 0.9-3.2). CONCLUSION: We demonstrated substantial deviations of ITP care from consensus guidelines, and geographic disparities in access to care and diagnostic workup. Future quality improvement initiatives are critical to improve the quality of care and reduce inequities.
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Púrpura Trombocitopênica Idiopática , Trombocitopenia , Humanos , Adulto , Feminino , Pessoa de Meia-Idade , Masculino , Púrpura Trombocitopênica Idiopática/epidemiologia , Púrpura Trombocitopênica Idiopática/terapia , Púrpura Trombocitopênica Idiopática/diagnóstico , Estudos Retrospectivos , Trombocitopenia/complicações , Hospitalização , Hemorragia/etiologiaRESUMO
The major oxidized product of cholesterol, 7-Ketocholesterol (7KCh), causes cellular oxidative damage. In the present study, we investigated the physiological responses of cardiomyocytes to 7KCh. A 7KCh treatment inhibited the growth of cardiac cells and their mitochondrial oxygen consumption. It was accompanied by a compensatory increase in mitochondrial mass and adaptive metabolic remodeling. The application of [U-13C] glucose labeling revealed an increased production of malonyl-CoA but a decreased formation of hydroxymethylglutaryl-coenzyme A (HMG-CoA) in the 7KCh-treated cells. The flux of the tricarboxylic acid (TCA) cycle decreased, while that of anaplerotic reaction increased, suggesting a net conversion of pyruvate to malonyl-CoA. The accumulation of malonyl-CoA inhibited the carnitine palmitoyltransferase-1 (CPT-1) activity, probably accounting for the 7-KCh-induced suppression of ß-oxidation. We further examined the physiological roles of malonyl-CoA accumulation. Treatment with the inhibitor of malonyl-CoA decarboxylase, which increased the intracellular malonyl-CoA level, mitigated the growth inhibitory effect of 7KCh, whereas the treatment with the inhibitor of acetyl-CoA carboxylase, which reduced malonyl-CoA content, aggravated such a growth inhibitory effect. Knockout of malonyl-CoA decarboxylase gene (Mlycd-/-) alleviated the growth inhibitory effect of 7KCh. It was accompanied by improvement of the mitochondrial functions. These findings suggest that the formation of malonyl-CoA may represent a compensatory cytoprotective mechanism to sustain the growth of 7KCh-treated cells.
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Carnitina O-Palmitoiltransferase , Malonil Coenzima A , Humanos , Malonil Coenzima A/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Coração , Transtornos do CrescimentoRESUMO
One critical bottleneck that impedes the development and deployment of autonomous vehicles is the prohibitively high economic and time costs required to validate their safety in a naturalistic driving environment, owing to the rarity of safety-critical events1. Here we report the development of an intelligent testing environment, where artificial-intelligence-based background agents are trained to validate the safety performances of autonomous vehicles in an accelerated mode, without loss of unbiasedness. From naturalistic driving data, the background agents learn what adversarial manoeuvre to execute through a dense deep-reinforcement-learning (D2RL) approach, in which Markov decision processes are edited by removing non-safety-critical states and reconnecting critical ones so that the information in the training data is densified. D2RL enables neural networks to learn from densified information with safety-critical events and achieves tasks that are intractable for traditional deep-reinforcement-learning approaches. We demonstrate the effectiveness of our approach by testing a highly automated vehicle in both highway and urban test tracks with an augmented-reality environment, combining simulated background vehicles with physical road infrastructure and a real autonomous test vehicle. Our results show that the D2RL-trained agents can accelerate the evaluation process by multiple orders of magnitude (103 to 105 times faster). In addition, D2RL will enable accelerated testing and training with other safety-critical autonomous systems.
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Automação , Veículos Autônomos , Aprendizado Profundo , Segurança , Automação/métodos , Automação/normas , Condução de Veículo , Veículos Autônomos/normas , Reprodutibilidade dos Testes , HumanosRESUMO
INTRODUCTION: Improvements in treatment strategies have led to increased life expectancy of persons with haemophilia (PWH). Consequently, age-related comorbidities become increasingly relevant. AIM: To evaluate the prevalence of age-related comorbidities, mortality, health service utilisation and predictors of hospitalisation in PWH compared to the general population. METHODS: We conducted a population-based retrospective cohort study using linked administrative data. Men with haemophilia were identified in Alberta, Canada (2012-2019) with a validated case definition and were age-matched with male population controls. We calculated the prevalence of major comorbidities, all-cause mortality, and examined health service utilisation including Emergency Department visits and hospitalisations. Logistic regression was applied to identify predictors of hospitalisation. RESULTS: We identified 198 and 329 persons with moderately severe haemophilia and mild/moderate, respectively. Moderately severe haemophilia had a higher risk of death (standardised mortality ratio 3.2, 95% confidence interval [CI] 1.4-6.3) compared to the general population. PWH had a significantly higher prevalence of hypertension, liver diseases and malignancies than controls. Moderately severe haemophilia was associated with significantly higher rates of hospitalisations (52.5% vs. 14.5%), Emergency Department visits (89.1% vs. 62.7%) and intensive care admissions (8.9% vs. 2.3%). Age > 65 years (adjusted odds ratio [aOR] 6.8) and presence of multiple comorbidities (aOR 3.9) were significant predictors of hospitalisations among PWH. CONCLUSION: Despite advanced care, haemophilia is associated with higher acute care utilisation than the general population, highlighting the substantial burden of illness on patients and the health care system.