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    91184 research outputs found

    Large-scale effective connectivity analysis reveals the existence of two mutual inhibitory systems in patients with major depression

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    It is posited that cognitive and affective dysfunction in patients with major depression disorder (MDD) may be caused by dysfunctional signal propagation in the brain. By leveraging dynamic causal modeling, we investigated large-scale directed signal propagation (effective connectivity) among distributed large-scale brain networks with 43 MDD patients and 56 healthy controls. The results revealed the existence of two mutual inhibitory systems: the anterior default mode network, auditory network, sensorimotor network, salience network and visual networks formed an “emotional” brain, while the posterior default mode network, central executive networks, cerebellum and dorsal attention network formed a “rational brain”. These two networks exhibited excitatory intra-system connectivity and inhibitory inter-system connectivity. Patients were characterized by potentiated intra-system connections within the “emotional/sensory brain”, as well as over-inhibition of the “rational brain” by the “emotional/sensory brain”. The hierarchical architecture of the large-scale effective connectivity networks was then analyzed using a PageRank algorithm which revealed a shift of the controlling role of the “rational brain” to the “emotional/sensory brain” in the patients. These findings inform basic organization of distributed large-scale brain networks and furnish a better characterization of the neural mechanisms of depression, which may facilitate effective treatment

    Investigation of the impact of probes and internals on power and flow in stirred tank reactors

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    This study characterises the power requirements and flow patterns in several commercial stirred tank bioreactors with working volumes ranging from 60 mL to 1 L, and investigates the isolated impact of internals, i.e. baffles and probes, on the power number, P0. Results show that the presence of probes leads to a rise of the turbulent power number, P0, equivalent to the presence of baffles, and as the number of internals increases the variation of P0 gets smaller until it plateaus for large probe quantity and high-volume blockage. Internals have a greater impact on flow with radial flow impellers, causing a significant increase in P0 in comparison to axial flow impellers. An experimental and computational flow dynamics study is also conducted to investigate the interaction between the probe wake and the impeller trailing vortices, and an estimate is provided of the form drag from the pressure distribution acting on the probe, with a good agreement to the corresponding power number increase. A comparison between P0 data obtained from conventional-cylindrical and novel-streamlined probe configurations shows that optimising probe geometry and location with respect to the incoming flow can be an effective approach for reducing power requirements, local values energy dissipation rate and stress levelsinside the tank. This study provides valuable insights into the impact of internal components and flow type on power input per unit volume, P/V, in small-scale bioreactors and supports the development of more robust scaling procedures for the biopharma industry

    A caustic terminating at an inflection point

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    We present an asymptotic and numerical study of the evolution of an incoming wavefield which has a caustic close to a curve with an inflection point. Our results reveal the emergence of a wavefield which resembles that of a shadow boundary but has a maximum amplitude along the tangent at the inflection point

    Detection of the significant impact of source clustering on higher-order statistics with DES Year 3 weak gravitational lensing data

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    We measure the impact of source galaxy clustering on higher-order summary statistics of weak gravitational lensing data. By comparing simulated data with galaxies that either trace or do not trace the underlying density field, we show this effect can exceed measurement uncertainties for common higher-order statistics for certain analysis choices. We evaluate the impact on different weak lensing observables, finding that third moments and wavelet phase harmonics are more affected than peak count statistics. Using Dark Energy Survey Year 3 data we construct null tests for the source-clustering-free case, finding a p-value of p = 4 × 10−3 (2.6σ) using third-order map moments and p = 3 × 10−11 (6.5σ) using wavelet phase harmonics. The impact of source clustering on cosmological inference can be either be included in the model or minimized through ad-hoc procedures (e.g. scale cuts). We verify that the procedures adopted in existing DES Y3 cosmological analyses were sufficient to render this effect negligible. Failing to account for source clustering can significantly impact cosmological inference from higher-order gravitational lensing statistics, e.g. higher-order N-point functions, wavelet-moment observables, and deep learning or field level summary statistics of weak lensing maps

    Ibrutinib-based therapy reinvigorates CD8 T cells compared to chemoimmunotherapy: immune-monitoring from the E1912 trial

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    Bruton's tyrosine kinase Inhibitors (BTKis) that target B cell receptor signaling have led to a paradigm shift in CLL treatment. BTKis have been shown to reduce abnormally high CLL-associated T cell counts and the expression of immune checkpoint receptors concomitantly with tumor reduction. However, the impact of BTKi therapy on T cell function has not been fully characterized. Here, we performed longitudinal immunophenotypic and functional analysis of pre- and on-treatment (6- and 12-months) peripheral blood samples from patients in the phase 3 E1912 trial comparing ibrutinib-rituximab to fludarabine, cyclophosphamide and rituximab (FCR). Intriguingly, we report that despite reduced overall T cell counts, higher numbers of T cells including effector CD8+ subsets at baseline and at the 6-month time-point associated with no infections and favorable progression-free survival (PFS) in the ibrutinib-rituximab arm. Assays demonstrated enhanced anti-CLL T cell killing function during ibrutinib-rituximab, including a switch from predominantly CD4+ T-cell:CLL immune synapses at baseline to increased CD8+ lytic synapses on-therapy. Conversely, in the FCR arm, higher T cell numbers correlated with adverse clinical responses and showed no functional improvement. We further demonstrate the potential of exploiting rejuvenated T cell cytotoxicity during ibrutinib-rituximab using the bispecific antibody glofitamab - supporting combination immunotherapy approaches

    The end of an entire biome? World's largest wetland, the Pantanal, is menaced by the Hidrovia project which is uncertain to sustainably support large-scale navigation

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    The resurgent navigation project known as the Hidrovia Paraguay-Paraná threatens the integrity of the Pantanal, the world's largest wetland, which is considered a biome of its own. Intensive barge navigation is intended to transport crops (soybean, sugar, corn) and cement, iron and manganese from areas of production in Brazil, Paraguay and Bolivia to the oceanic ports of the Plata River. This short communication assembles the information available on the potential impacts of the planned deepening of the natural channel of the Paraguay River in its ~700 km-long upper section. These river channel alterations would disconnect the river from its floodplain, shorten the inundation period, and shrink the wetland area, resulting in severe degradation of the globally outstanding biological and cultural diversity of the Pantanal. The river sediments are mostly sandy and would require perpetual dredging. The reaches needing the most intensive dredging are those of the highest ecological value, protected as a National Park, UNESCO World Heritage and Biosphere Reserves, and various Indigenous reserves and Ramsar sites. Climate change is projected to increase the occurrence of low water periods. Between 2019 and 2021, navigation was impossible even in the already-deepened reaches of the Paraguay River between Corumbá and Asuncion during long periods of the year. Thus, despite considerable financial and technical efforts, the success of the navigation project is doubtful, whereas enormous environmental, cultural, and social impacts can be anticipated. For these reasons, the Brazilian government had already turned down the project in 2000. We suggest alternative, less impactful modes of transport of commodities, e.g., via railway

    Fabrication and characterization of coated ceramic membranes from natural sources for water treatment applications

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    This study aimed to fabricate ceramic membranes for water treatment applications using natural and costeffective materials. This is the first-time white clay, Arabic gum, and marble powder were used in ceramic membranes. Two ceramic membranes were fabricated using an extrusion process: substrate A and substrate B. The JMP software (Version 15) was used to obtain the optimal recipes for the two substrates, which were white clay (62.7 %), silica flour (32.3 %), and Arabic gum (5 %) for substrate A and white clay (63 %), silica flour (26.8 %), and marble powder (10.2 %) for substrate B. Additionally, the effect of waste glass in the coating layer on the separation rate was examined. The ceramic membranes were analysed using various techniques, including X-ray fluorescence (XRF), X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FT-IR), laser diffraction particle size analysis, thermogravimetric analysis (TGA), and a universal testing machine. The morphologies of the membranes were observed using scan electron microscopy (SEM), and their chemical resistances were evaluated. The flux across the substrates was measured using a crossflow filtration system, and it was found that substrate B had a higher flux (116 L/m2 h) than substrate A (77 L/m2 h). This was probably due to its higher porosity (34 %) compared to substrate A (29 %). Substrate A, with a coating layer (CO-2), exhibited the highest removal efficiency of approximately 99.2 % for synthetic feed water composed of tap water and bentonite clay, with an average particle size of 1.1 μm and turbidity of 13 ± 0.2 NTU. The costs of ceramic membranes A and B were estimated to be approximately 51 and 47 USD/m2 , respectively. Their cost-effectiveness results from the use of low-cost materials that do not require high sintering temperatures. This study demonstrates that these ceramic membranes are not only affordable but also possess desirable properties for water treatment applications

    Drivers of divergent assessments of bisphenol-A hazards to semen quality by various European agencies, regulators and scientists

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    The downward revision of the bisphenol A (BPA) Health-based Guidance Value (HBGV) by the European Food Safety Authority (EFSA) has led to disagreements with other regulatory agencies, among them the German Federal Institute for Risk Assessment (BfR). The BfR has recently published an alternative Tolerable Daily Intake (TDI), 1000-times higher than the EFSA HBGV of 0.2 ng/kg/d. While the EFSA value is defined in relation to immunotoxicity, the BfR alternative TDI is based on declines in sperm counts resulting from exposures in adulthood. Earlier, we had used semen quality deteriorations to estimate a BPA Reference Dose (RfD) of 3 ng/kg/d for use in mixture risk assessments of male reproductive health. We derived this estimate from animal studies of gestational BPA exposures which both EFSA and BfR viewed as irrelevant for human hazard characterisations. Here, we identify factors that drive these diverging views. We find that the fragmented, endpoint-oriented study evaluation system used by EFSA and BfR, with its emphasis on data that can support dose-response analyses, has obscured the overall BPA effect pattern relevant to male reproductive effects. This has led to a disregard for the effects of gestational BPA exposures. We also identify problems with the study evaluation schemes used by EFSA and BfR which leads to the omission of entire streams of evidence from consideration. The main driver of the diverging views of EFSA and BfR is the refusal by BfR to accept immunotoxic effects as the basis for establishing an HBGV. We find that switching from immunotoxicity to declines in semen quality as the basis for deriving a BPA TDI by deterministic or probabilistic approaches produces values in the range of 2.4-6.6 ng/kg/d, closer to the present EFSA HBGV of 0.2 ng/kg/d than the BfR TDI of 200 ng/kg/d. The proposed alternative BfR value is the result of value judgements which erred on the side of disregarding evidence that could have supported a lower TDI. The choices made in terms of selecting key studies and methods for dose-response analyses produced a TDI that comes close to doses shown to produce effects on semen quality in animal studies and in human studies of adult BPA exposures

    The Hipster Economy: Taste and authenticity in late modern capitalism

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    Today, being authentic has become an aspiration and an imperative. The notion of authenticity shapes the consumption habits of individuals in the most diverse contexts such as food and drinks, clothing, music, tourism and the digital sphere, even leading to the resurgence of apparently obsolescent modes of production such as craft. It also significantly transforms urban areas, their local economies and development. The Hipster Economy analyses this complex set of related phenomena to argue that the quest for authenticity has been a driver of Western societies from the emersion of capitalism and industrial society to today. From this premise, the book advances multiple original contributions. First, it explains why and how authenticity has become a fundamental value orienting consumers' taste in late modern capitalism; second, it proposes a novel conceptualisation of the aesthetic regime of consumption; third, the book constitutes the first detailed analysis of the resurgence of the neo-craft industries, their entrepreneurs, and the economic imaginary of consumption underpinning them, and fourth, it analyses how the hipster economy is impacting the urban space, favouring new logic of urban development with contrasting outcomes

    Association of nurse understaffing and limited nursing work experience with in-hospital mortality among patients: A longitudinal register-based study

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    BACKGROUND: Although nurse understaffing and limited nursing work experience may affect hospital patients' risk of mortality, relatively little longitudinal patient-level evidence on these associations is available. Hospital administrative data could provide important information about the level of staffing, nurses' work experience and patient mortality over time. OBJECTIVE: To examine whether daily exposure to nurse understaffing and limited nursing work experience is associated with patient mortality, using patient-level data with different exposure time windows and accounting for several patient-related characteristics. METHODS: This longitudinal register-based study combined administrative data on patients (clinical database Auria) and employees (Titania® shift-scheduling) from one hospital district in Finland in 2013-2019, covering a total of 254,446 hospital stays in 40 units. We quantified nurse understaffing as the number of days with low nursing hours in relation to target hours (3 years of in-hospital experience, and those aged over 25 (<90 % of the annual unit median). We used two survival model designs to analyze the associations between nurse understaffing and limited nursing work experience and the in-hospital mortality of the patients: we considered these exposures during the first days in hospital and as a cumulative proportion of days with suboptimal staffing during the first 30 days. RESULTS: In total, 1.5 % (N = 3937) of the hospital stays ended in death. A 20 % increase in the proportion of days with nurse understaffing was associated with an increased, 1.05-fold mortality risk at the patient level (95 % confidence interval, 1.01-1.10). The cumulative proportion of days with limited nursing work experience, or the combination of nurse understaffing and limited work experience were not associated with increased risk of death among all patients. However, both indicators of limited nursing work experience were associated with an increased mortality risk among patients with comorbidities (HR 1.05, 95 % CI 1.02-1.08 and HR 1.05, 95 % CI 1.00-1.10, respectively). CONCLUSIONS: Nurse understaffing was associated with a slight, but a potentially critical increase in patient in-hospital mortality. Limited nursing work experience was associated with increased in-hospital mortality in a subgroup of patients with comorbidities. Increased use of administrative data on planned and realized working hours could be a routine tool for reducing avoidable in-hospital mortality


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