Empirical diagnosis of stability has received considerable attention, often focused on variance metrics for early warning signals of abrupt system change or delicate techniques measuring Lyapunov ...spectra. The theoretical foundation for the popular early warning signal approach has been limited to relatively simple system changes such as bifurcating fixed points where variability is extrinsic to the steady state. We offer a novel measurement of stability that applies in wide ranging systems that contain variability in both internal steady state dynamics and in response to external perturbations. Utilizing connections between stability, dissipation, and phase space flow, we show that stability correlates with temporal asymmetry in a measure of phase space flow contraction. Our method is general as it reveals stability variation independent of assumptions about the nature of system variability or attractor shape. After showing efficacy in a variety of model systems, we apply our technique for measuring stability to monthly returns of the S&P 500 index in the time periods surrounding the global stock market crash of October 1987. Market stability is shown to be higher in the several years preceding and subsequent to the 1987 market crash. We anticipate our technique will have wide applicability in climate, ecological, financial, and social systems where stability is a pressing concern.
Studies show that spatial interventions lead to improvements in mathematics. However, outcomes vary based on whether physical manipulatives (embodied action) are used during training. This study ...compares the effects of embodied and non‐embodied spatial interventions on spatial and mathematics outcomes. The study has a randomized, controlled, pre‐post, follow‐up, training design (N = 182; mean age 8 years; 49% female; 83.5% White). We show that both embodied and non‐embodied spatial training approaches improve spatial skills compared to control. However, we conclude that embodied spatial training using physical manipulatives leads to larger, more consistent gains in mathematics and greater depth of spatial processing than non‐embodied training. These findings highlight the potential of spatial activities, particularly those that use physical materials, for improving children's mathematics skills.
Frontotemporal dementia (FTD) is a debilitating neurodegenerative disorder with currently no disease-modifying treatment options available. Mutations in GRN are one of the most common genetic causes ...of FTD, near ubiquitously resulting in progranulin (PGRN) haploinsufficiency. Small molecules that can restore PGRN protein to healthy levels in individuals bearing a heterozygous GRN mutation may thus have therapeutic value. Here, we show that epigenetic modulation through bromodomain and extra-terminal domain (BET) inhibitors (BETi) potently enhance PGRN protein levels, both intracellularly and secreted forms, in human central nervous system (CNS)-relevant cell types, including in microglia-like cells. In terms of potential for disease modification, we show BETi treatment effectively restores PGRN levels in neural cells with a GRN mutation known to cause PGRN haploinsufficiency and FTD. We demonstrate that BETi can rapidly and durably enhance PGRN in neural progenitor cells (NPCs) in a manner dependent upon BET protein expression, suggesting a gain-of-function mechanism. We further describe a CNS-optimized BETi chemotype that potently engages endogenous BRD4 and enhances PGRN expression in neuronal cells. Our results reveal a new epigenetic target for treating PGRN-deficient forms of FTD and provide mechanistic insight to aid in translating this discovery into therapeutics.
•Largest cohort to date evaluating cuffed endotracheal tube use in patients ≤5 kg.•Cuffed endotracheal tubes decreased need for tube exchange and repeat laryngoscopy.•Cuffed endotracheal tubes did ...not increase incidence of stridor or reintubation.
Improved understanding of airway anatomy and refinement of equipment have led to the increased use of cuffed endotracheal tubes (ETTs) in infants and children. Despite expanded evidence on the potential advantages of cuffed ETTs in pediatric patients, there remains limited data on their use in infants less than 5 kilograms (kg). The current study retrospectively evaluates the perioperative use of cuffed ETTs in infants weighing 2–5 kg.
This is a retrospective study from a tertiary care children's hospital involving a 3-year period. Data regarding anesthetic care, airway management, and postoperative course were retrospectively retrieved from the electronic medical record.
The study cohort included 1162 patients, 1086 of whom had their tracheas intubated with a cuffed ETT and 76 with an uncuffed ETT. Patients were divided into two groups for analysis: 2 to <3 kg and 3 to 5 kg. In both weight groups, cuffed ETTs resulted in a decreased need for more than one laryngoscopy and a change in ETT size with no increase in postoperative airway effects including stridor.
These data provide additional information regarding the efficacy and safety of cuffed ETTs in neonates and infants.
Type VI secretion systems (T6SSs) deliver cytotoxic effector proteins into target bacteria and eukaryotic host cells. Antibacterial effectors are invariably encoded with cognate immunity proteins ...that protect the producing cell from self-intoxication. Here, we identify transposon insertions that disrupt the
immunity gene of Enterobacter cloacae and induce autopermeabilization through unopposed activity of the Tle phospholipase effector. This hyperpermeability phenotype is T6SS dependent, indicating that the mutants are intoxicated by Tle delivered from neighboring sibling cells rather than by internally produced phospholipase. Unexpectedly, an in-frame deletion of
does not induce hyperpermeability because Δ
null mutants fail to deploy active Tle. Instead, the most striking phenotypes are associated with disruption of the
lipoprotein signal sequence, which prevents immunity protein localization to the periplasm. Immunoblotting reveals that most hyperpermeable mutants still produce Tli, presumably from alternative translation initiation codons downstream of the signal sequence. These observations suggest that cytosolic Tli is required for the activation and/or export of Tle. We show that Tle growth inhibition activity remains Tli dependent when phospholipase delivery into target bacteria is ensured through fusion to the VgrG β-spike protein. Together, these findings indicate that Tli has distinct functions, depending on its subcellular localization. Periplasmic Tli acts as a canonical immunity factor to neutralize incoming effector proteins, while a cytosolic pool of Tli is required to activate the phospholipase domain of Tle prior to T6SS-dependent export.
Gram-negative bacteria use type VI secretion systems deliver toxic effector proteins directly into neighboring competitors. Secreting cells also produce specific immunity proteins that neutralize effector activities to prevent autointoxication. Here, we show the Tli immunity protein of Enterobacter cloacae has two distinct functions, depending on its subcellular localization. Periplasmic Tli acts as a canonical immunity factor to block Tle lipase effector activity, while cytoplasmic Tli is required to activate the lipase prior to export. These results indicate Tle interacts transiently with its cognate immunity protein to promote effector protein folding and/or packaging into the secretion apparatus.
Bionic prostheses have restorative potential. However, the complex interplay between intuitive motor control, proprioception, and touch that represents the hallmark of human upper limb function has ...not been revealed. Here, we show that the neurorobotic fusion of touch, grip kinesthesia, and intuitive motor control promotes levels of behavioral performance that are stratified toward able-bodied function and away from standard-of-care prosthetic users. This was achieved through targeted motor and sensory reinnervation, a closed-loop neural-machine interface, coupled to a noninvasive robotic architecture. Adding touch to motor control improves the ability to reach intended target grasp forces, find target durometers among distractors, and promote prosthetic ownership. Touch, kinesthesia, and motor control restore balanced decision strategies when identifying target durometers and intrinsic visuomotor behaviors that reduce the need to watch the prosthetic hand during object interactions, which frees the eyes to look ahead to the next planned action. The combination of these three modalities also enhances error correction performance. We applied our unified theoretical, functional, and clinical analyses, enabling us to define the relative contributions of the sensory and motor modalities operating simultaneously in this neural-machine interface. This multiperspective framework provides the necessary evidence to show that bionic prostheses attain more human-like function with effective sensory-motor restoration.
Background Disparate lower-extremity ultrasonography (LUS) screening practices among trauma institutions reflecta lack of consensus regarding screening indications and whether screening improves ...outcomes. We hypothesized that LUS screening for deep-vein thrombosis (DVT) is not associated with a reduced incidence of pulmonary embolism (PE). Methods The 2012 ACS National Trauma Data Bank Research Data Set was queried to identify 442,108 patients treated at institutions reporting at least one LUS and at least one DVT. Institutions performing LUS on more than 2% of admitted patients were designated high-screening facilities and remaining institutions were designated low-screening facilities. Patient characteristics and risk factors were used to develop a logistic regression model to assess the independent associations between LUS and DVT and between LUS and PE. Results Overall, DVT and PE were reported in 0.94% and 0.37% of the study population, respectively. DVT and PE were reported more commonly in designated high-screening than low-screening facilities (DVT: 1.12% vs 0.72%, P < .0001; PE: 0.40% vs 0.33%, P = .0004). Multivariable logistic regression demonstrated that LUS was associated independently with DVT (odds ratio 1.43, confidence interval 1.34–1.53) but not PE (odds ratio 1.01, confidence interval 0.92–1.12) (c-statistic 0.86 and 0.85, respectively). Sensitivity analyses performed at various rates for designating HS facilities did not alter the significance of these relationships. Conclusion LUS in trauma patients is not associated with a change in the incidence of PE. Aggressive LUS DVT screening protocols appear to detect many clinically insignificant DVTs for which subsequent therapeutic intervention may be unnecessary, and the use of these protocols should be questioned.
Undergraduate students in an environmental chemistry laboratory course were taught QuEChERS (quick, easy, cheap, effective, rugged, and safe), a sample preparation procedure that is commonly used in ...pesticide laboratories involving an acetonitrile salt-out extraction of fresh produce samples followed by solid-phase dispersive cleanup using a combination of sorbents. The cleaned extract was solvent exchanged into toluene and analyzed for pesticides by capillary gas chromatography–mass spectrometry in selective ion monitoring mode (GC–MS/SIM). Students utilized QuEChERS to analyze spiked and incurred pesticide residues in several types of plant foods and applied GC–MS/SIM for the simultaneous quantitation and identification of pesticides. Several chemistry, laboratory, and instrumental concepts were demonstrated such as sample preparation, aspects of method validation, and interpretation of chromatographic and mass spectrometric results. This experiment received favorable responses from the students because of the “real-world” applicability of the QuEChERS procedure, the use of GC–MS analysis, and concepts transferred from lecture to the laboratory.
We performed power‐spectral analyses on 133 globally distributed lake‐level time series after removing annual variability. Lake‐level power spectra are found to be power‐law functions of frequency ...over the range of 20
d−1 to 27
yr−1, suggesting that lake levels are globally a
f−β‐type noise. The spectral exponent (
β), i.e., the best‐fit slope of the logarithm of the power spectrum to the logarithm of frequency, is a nonlinear function of lake surface area, indicating that lake size is an important control on the magnitude of water‐level variability over the range of time scales we considered. A simple cellular model for lake‐level fluctuations that reproduces the observed spectral‐scaling properties is presented. The model (an adaptation of a surface‐growth model with random deposition and relaxation) is based on the equations governing flow in an unconfined aquifer with stochastic inputs and outputs of water (e.g., random storms). The agreement between observation and simulation suggests that lake surface area, spatiotemporal stochastic forcing, and diffusion of the groundwater table are the primary factors controlling lake water‐level variability in natural (unmanaged) lakes. Water‐level variability is generally considered to be a manifestation of climate trends or climate change, yet our work shows that an input with short or no memory (i.e., weather) gives rise to a long‐memory nonstationary output (lake water‐level). This work forms the basis for a null hypothesis of lake water‐level variability that should be disproven before water‐level trends are to be attributed to climate.
Key Points:
Lake‐level spectra are globally power‐law over periods of 20 days to 27 years
Spectral slope of lake‐levels are a nonlinear function of logarithm of surface area
Numerical modeling shows lake‐level variability can be internally generated
Many centers advocate aggressive lower extremity deep venous thrombosis (DVT) screening using ultrasound (LUS) for patients meeting high-risk criteria. We hypothesized that a high-risk screening ...protocol is impractical and costly to implement.
The University of Virginia's trauma database was queried to identify 6,656 patients admitted between 2009 and 2013. Patient characteristics and outcomes were recorded. Multivariate analyses were performed on patients who underwent LUS to assess the association between patient characteristics and the development of DVT. A predictive model for DVT was applied to the entire population to determine performance and resources required for implementation.
Overall, 2,350 (35.3%) of admitted patients underwent LUS. A total of 146 patients (6.2%) developed DVT. Patients who underwent LUS were significantly older (54.5 years vs. 50.4 years, p < 0.0001), had higher Injury Severity Scores (ISSs) (13.5 vs. 8.6, p < 0.0001), and had longer admissions to the intensive care unit (5.6 days vs. 0.9 days, p < 0.0001). Backward selection multivariable logistic regression identified intensive care unit length of stay, transfusion of blood products, spinal cord injury, and pelvic fracture to be associated with DVT (c statistic, 0.76). The model was applied to the entire population to evaluate probability of DVT (c statistic, 0.87). Predictive performance and costs were determined using a cost per LUS of $228. The most sensitive threshold for screening would detect 53% of DVTs, require screening of 26% of all trauma patients, and cost nearly $600,000 to implement during the study period.
Although a predictive model identified high-risk criteria for the development of DVT at our institution, the model demonstrated poor sensitivity and positive predictive value. These results suggest that implementing a high-risk screening protocol in trauma patients would require a costly and burdensome commitment of resources and that high-risk DVT screening protocols may not be practical or cost-effective for trauma patients.
Therapeutic/care management study, level IV.
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