Principles for the design of advanced flight director systems based on the theory of manual control displays

Design and development of flight director systems based on theory of manual control display

Time-Dependent Changes in Human Corticospinal Excitability Reveal Value-Based Competition for Action during Decision Processing

Our choices often require appropriate actions to obtain a preferred outcome, but the neural underpinnings that link decision making and action selection remain largely undetermined. Recent theories propose that action selection occurs simultaneously, i.e., parallel in time, with the decision process. Specifically, it is thought that action selection in motor regions originates from a competitive process that is gradually biased by evidence signals originating in other regions, such as those specialized in value computations. Biases reflecting the evaluation of choice options should thus emerge in the motor system before the decision process is complete. Using transcranial magnetic stimulation, we sought direct physiological evidence for this prediction by measuring changes in corticospinal excitability in human motor cortex during value-based decisions. We found that excitability for chosen versus unchosen actions distinguishes the forthcoming choice before completion of the decision process. Both excitability and reaction times varied as a function of the subjective value-difference between chosen and unchosen actions, consistent with this effect being value-driven. This relationship was not observed in the absence of a decision. Our data provide novel evidence in humans that internally generated value-based decisions influence the competition between action representations in motor cortex before the decision process is complete. This is incompatible with models of serial processing of stimulus, decision, and action

Neural Signatures of Value Comparison in Human Cingulate Cortex during Decisions Requiring an Effort-Reward Trade-off

UNLABELLED: Integrating costs and benefits is crucial for optimal decision-making. Although much is known about decisions that involve outcome-related costs (e.g., delay, risk), many of our choices are attached to actions and require an evaluation of the associated motor costs. Yet how the brain incorporates motor costs into choices remains largely unclear. We used human fMRI during choices involving monetary reward and physical effort to identify brain regions that serve as a choice comparator for effort-reward trade-offs. By independently varying both options' effort and reward levels, we were able to identify the neural signature of a comparator mechanism. A network involving supplementary motor area and the caudal portion of dorsal anterior cingulate cortex encoded the difference in reward (positively) and effort levels (negatively) between chosen and unchosen choice options. We next modeled effort-discounted subjective values using a novel behavioral model. This revealed that the same network of regions involving dorsal anterior cingulate cortex and supplementary motor area encoded the difference between the chosen and unchosen options' subjective values, and that activity was best described using a concave model of effort-discounting. In addition, this signal reflected how precisely value determined participants' choices. By contrast, separate signals in supplementary motor area and ventromedial prefrontal cortex correlated with participants' tendency to avoid effort and seek reward, respectively. This suggests that the critical neural signature of decision-making for choices involving motor costs is found in human cingulate cortex and not ventromedial prefrontal cortex as typically reported for outcome-based choice. Furthermore, distinct frontal circuits seem to drive behavior toward reward maximization and effort minimization. SIGNIFICANCE STATEMENT: The neural processes that govern the trade-off between expected benefits and motor costs remain largely unknown. This is striking because energetic requirements play an integral role in our day-to-day choices and instrumental behavior, and a diminished willingness to exert effort is a characteristic feature of a range of neurological disorders. We use a new behavioral characterization of how humans trade off reward maximization with effort minimization to examine the neural signatures that underpin such choices, using BOLD MRI neuroimaging data. We find the critical neural signature of decision-making, a signal that reflects the comparison of value between choice options, in human cingulate cortex, whereas two distinct brain circuits drive behavior toward reward maximization or effort minimization

Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA

Background: Early cancer detection could identify tumors at a time when outcomes are superior and treatment is less morbid. This prospective case-control sub-study (from NCT02889978 and NCT03085888) assessed the performance of targeted methylation analysis of circulating cell-free DNA (cfDNA) to detect and localize multiple cancer types across all stages at high specificity. / Participants and methods: The 6689 participants [2482 cancer (>50 cancer types), 4207 non-cancer] were divided into training and validation sets. Plasma cfDNA underwent bisulfite sequencing targeting a panel of >100 000 informative methylation regions. A classifier was developed and validated for cancer detection and tissue of origin (TOO) localization. / Results: Performance was consistent in training and validation sets. In validation, specificity was 99.3% [95% confidence interval (CI): 98.3% to 99.8%; 0.7% false-positive rate (FPR)]. Stage I–III sensitivity was 67.3% (CI: 60.7% to 73.3%) in a pre-specified set of 12 cancer types (anus, bladder, colon/rectum, esophagus, head and neck, liver/bile-duct, lung, lymphoma, ovary, pancreas, plasma cell neoplasm, stomach), which account for ∼63% of US cancer deaths annually, and was 43.9% (CI: 39.4% to 48.5%) in all cancer types. Detection increased with increasing stage: in the pre-specified cancer types sensitivity was 39% (CI: 27% to 52%) in stage I, 69% (CI: 56% to 80%) in stage II, 83% (CI: 75% to 90%) in stage III, and 92% (CI: 86% to 96%) in stage IV. In all cancer types sensitivity was 18% (CI: 13% to 25%) in stage I, 43% (CI: 35% to 51%) in stage II, 81% (CI: 73% to 87%) in stage III, and 93% (CI: 87% to 96%) in stage IV. TOO was predicted in 96% of samples with cancer-like signal; of those, the TOO localization was accurate in 93%. / Conclusions: cfDNA sequencing leveraging informative methylation patterns detected more than 50 cancer types across stages. Considering the potential value of early detection in deadly malignancies, further evaluation of this test is justified in prospective population-level studies

The scaling of X-ray variability with luminosity in Ultra-luminous X-ray sources

We investigated the relationship between the X-ray variability amplitude and X-ray luminosity for a sample of 14 bright Ultra-luminous X-ray sources (ULXs) with XMM-Newton/EPIC data, and compare it with the well established similar relationship for Active Galactic Nuclei (AGN). We computed the normalised excess variance in the 2-10 keV light curves of these objects and their 2-10 keV band intrinsic luminosity. We also determined model "variability-luminosity" relationships for AGN, under several assumptions regarding their power-spectral shape. We compared these model predictions at low luminosities with the ULX data. The variability amplitude of the ULXs is significantly smaller than that expected from a simple extrapolation of the AGN "variability-luminosity" relationship at low luminosities. We also find evidence for an anti-correlation between the variability amplitude and L(2-10 keV) for ULXs. The shape of this relationship is consistent with the AGN data but only if the ULXs data are shifted by four orders of magnitudes in luminosity. Most (but not all) of the ULXs could be "scaled-down" version of AGN if we assume that: i) their black hole mass and accretion rate are of the order of ~(2.5-30)x 10E+03 Msolar and ~ 1-80 % of the Eddington limit, and ii) their Power Spectral Density has a doubly broken power-law shape. This PDS shape and accretion rate is consistent with Galactic black hole systems operating in their so-called "low-hard" and "very-high" states.Comment: 10 pages, 5 figures, 2 tables, accepted for publication in A&

Conocimiento del personal de salud en el uso y cuidados de permanencia del catéter vesical en establecimientos de salud de Chachapoyas en el año 2022

Objetivo: Describir el nivel de conocimiento sobre el uso adecuado del catéter vesical y cuidados de permanencia del mismo en personal de establecimientos de salud de Chachapoyas en el año 2022. Metodología: Estudio tipo observacional, descriptivo y transversal. Se conto con la participación de 155 profesionales de la salud pertenecientes a los establecimientos de salud que formaban parte de la población de estudio. Los datos se obtuvieron a partir de un instrumento validad por expertos. El análisis estadístico se realizó mediante los programas estadísticos STATA versión 11 y Microsoft Excel Resultados: Se encuesto un total de 155 trabajadores de salud (médicos, internos de medicina, licenciadas en enfermería y técnicos de enfermería) evaluándose 2 dimensiones, indicaciones de uso y cuidados de permanencia, de las cuales es mayor el conocimiento en indicaciones de uso con 58.4% en los médicos y el 34.9% en licenciadas de enfermería en relación a cuidados de permanencia. Las licenciadas de enfermería tuvieron 5 veces más frecuencia de conocimiento en comparación a los internos de medicina (6.7%). A su vez se pudo determinar que el nivel de conocimiento del uso de catéter vesical es alto (56.7%), siendo los técnicos en enfermería los que presentan en su mayoría este nivel de conocimiento. Los internos de medicina tienen un nivel de conocimiento medio (3.2%). Conclusiones: Se concluye, que el personal de los diferentes establecimientos de salud de Chachapoya en el año 2022, tienen un adecuado conocimiento sobre el uso del catéter vesical, siendo su nivel alto en el caso del personal médico, de enfermería y técnicos de enfermería, así como nivel medio en el caso de los internos de medicin

A critical role for ATF2 transcription factor in the regulation of E-selectin expression in response to non-endotoxin components of Neisseria meningitidis

Vascular injury is a serious complication of sepsis due to the gram-negative bacterium Neisseria meningitidis. One of the critical early steps in initiating this injury is via the interaction of leucocytes, particularly neutrophils, with adhesion molecules expressed on inflamed endothelium. We have previously demonstrated that both lipopolysaccharide (LPS) and non-LPS components of meningococci can induce very high levels of expression of the vascular endothelial cell adhesion molecule E-selectin, which is critical for early tethering and capture of neutrophils onto endothelium under flow. Using an LPS-deficient strain of meningococcus, we showed that very high levels of expression can be induced in primary endothelial cells, even in the context of weak activation of the major host signal transduction factor [nuclear factor-κB (NF-κB)]. In this study, we show that the particular propensity for N. meningitidis to induce high levels of expression is regulated at a transcriptional level, and demonstrate a significant role for phosphorylation of the ATF2 transcription factor, likely via mitogen-activated protein (MAP) kinases, on the activity of the E-selectin promoter. Furthermore, inhibition of E-selectin expression in response to the lpxA- strain by a p38 inhibitor indicates a significant role of a p38-dependent MAPK signalling pathway in ATF2 activation. Collectively, these data highlight the role that LPS and other bacterial components have in modulating endothelial function and their involvement in the pathogenesis of meningococcal sepsis. Better understanding of these multiple mechanisms induced by complex stimuli such as bacteria, and the specific inflammatory pathways they activate, may lead to improved, focused interventions in both meningococcal and potentially bacterial sepsis more generally

Nebulised amphotericin B to eradicate Candida colonisation from the respiratory tract in critically ill patients receiving selective digestive decontamination: a cohort study

INTRODUCTION: Colonisation of the lower respiratory tract with Candida species occurs in 25% of mechanically ventilated critically ill patients, and is associated with increased morbidity. Nebulised amphotericin B has been used to eradicate Candida as part of selective decontamination of the digestive tract (SDD) protocols, but its effectiveness is unknown. We aimed to determine the effectiveness of nebulised amphotericin B in eradicating Candida respiratory tract colonisation in patients receiving SDD. METHODS: We included consecutive mechanically ventilated patients during a four-year period. Microbiological screening was performed upon admission and twice weekly thereafter according to a standardised protocol. A colonisation episode was defined as the presence of Candida species in two consecutive sputum samples taken at least one day apart. To correct for time-varying bias and possible confounding, we used a multistate approach and performed time-varying Cox regression with adjustment for age, disease severity, Candida load at baseline and concurrent corticosteroid use. RESULTS: Among 1,819 patients, colonisation with Candida occurred 401 times in 363 patients; 333 of these events were included for analysis. Decolonisation occurred in 51 of 59 episodes (86%) and in 170 of 274 episodes (62%) in patients receiving and not receiving nebulised amphotericin B, respectively. Nebulised amphotericin B was associated with an increased rate of Candida eradication (crude HR 2.0; 95% CI 1.4 to 2.7, adjusted HR 2.2; 95% CI 1.6 to 3.0). Median times to decolonisation were six and nine days, respectively. The incidence rate of ventilator-associated pneumonia, length of stay and mortality did not differ between both groups. CONCLUSIONS: Nebulised amphotericin B reduces the duration of Candida colonisation in the lower respiratory tracts of mechanically ventilated critically ill patients receiving SDD, but data remain lacking that this is associated with a meaningful improvement in clinical outcomes. Until more evidence becomes available, nebulised amphotericin B should not be used routinely as part of the SDD protocol