Flight crew fatigue risk assessment for international flights under the COVID-19 outbreak response exemption policy.

BACKGROUND: In response to the COVID-19 outbreak, the Civil Aviation Administration of China (CAAC) has formulated Implementation Measures for Exemption of Crew Duty Periods and Flight Time Restrictions during the COVID-19 Outbreak. This exemption policy imposes temporary deviations from the approved crew duty periods and flight time restrictions for some transport airlines and regulates the use of multiple crews for continuous round-trip flights. However, no research has been conducted on flight crew fatigue under this exemption policy. That is, the exemption policy lacks theoretical analysis and scientific validation. METHODS: Firstly, flight plans for international flights under both the exemption and the CCAR-121 Policy schemes (with three flight departure scenarios: early morning, midday and evening) are designed, and flight plans are simulated based on the SAFE model. The Karolinska Sleepiness Scale (KSS) and the PVT objective test of alertness, both of which are commonly used in the aviation industry, are then selected for use in an empirical experimental study of flight crew fatigue on two flights subject to the exemption and CCAR-121 policies. RESULTS: The SAFE model simulation found that the fatigue risk results based on flight crews for flights departing in the early morning (4:00), at noon (12:00) and in the evening (20:00) indicate that the fatigue risk levels of flight crews operating under the exemption policy are overwhelmingly lower than or similar to those operating under the CCAR-121 policy. However, there were a few periods when the fatigue risk of crews flying under the exemption policy was higher than that of crews flying under the CCAR-121 policy, but at these times, the crews flying under both policies were either at a lower level of fatigue risk or were in the rest phase of their shifts. In the experimental study section, 40 pilots from each of the early morning (4:00), noon (12:00) and evening (20:00) departures operating under the exemption policy were selected to collect KSS scale data and PVT test data during their duty periods, and a total of 120 other pilots operating under the CCAR-121 policy were selected for the same experiment. First, the KSS scale data results found that flight pilots, whether flying under the exemption policy or under the CCAR-121 policy, had overall similar KSS scores, maintained KSS scores below the fatigue risk threshold (i.e., KSS score < 6) during the flights and that the empirical KSS data and the model simulation results from the KSS data were overall identical at the test nodes during the flight and had nearly identical trends. Finally, the results of the PVT objective test indicators showed that the overall change in 1/RT of the crews flying under the exemption policy was less than or similar to that of the crews flying under the CCAR-121 policy, while the maximum change in 1/RT of the crews under both policies was between 1 and 1.5. This indicates that the overall level of alertness of the crew flying under the exemption policy is higher than or similar to that of the crew flying under the CCAR-121 policy, while the change in alertness level of the crew before and after the mission is relatively small when flying under either policy. CONCLUSION: Based on the model simulation results and the results of the empirical study, it was verified that the overall fatigue risk level of flight crews operating under the exemption policy is lower than or similar to the fatigue risk level of flight crews operating under the CCAR-121 policy. Therefore, the exemption policy in response to the COVID-19 outbreak does not result in an overall increase in the level of flight crew fatigue risk compared to the original CCAR-121 policy.

[Study on homeostasis and circadian rhythm of attention performance of different chronotypes in sleep deprivation].

Difference of chronotypes makes influence to cognitive performance of individuals in routine duties. In this paper, 55 subjects with different chronotypes were subjected to continuous sleep deprivation for 30 h by using the constant routine protocol, during which core body temperature was measured continuously, and subjective sleepiness self-rating and the performance of selective attention were measured hourly. The results showed that the phase difference of core body temperature has no significant difference, yet the amplitude and term difference among the three chronotypes are significant. There was an advance in phase between subjective sleepiness self-rating and core body temperature, and the self-rating sleepiness of evening type came the latest, and the self-rating sleepiness of morning type dissipated the fastest. The response time of selective attention showed a 2 h phase delay with subjective sleepiness self-rating. And the analysis of core body temperature showed that the later the chronotype was, the greater the phase delay was. The correct rate of selective attention of different chronotypes were inconsistent with delay of subjective sleepiness self-rating and core body temperature. We provide reference for industry, aviation, military, medical and other fields to make a more scientific scheduling/ shifting based on cognitive performance characteristics of different chronotypes.

The sustained attention characteristics of flight crews on exempt and non-exempt flights.

We analyzed the characteristics of sustained attention changes in flight crews during exempt and non-exempt flights. Fourteen pilots (aged 30-43 y) participated in this study, with seven involved in each flight type, all of which were intercontinental (China to North America). Pilots completed continuous performance tests (CPT) at the required flight stages without compromising safety while on duty. No significant differences in sleep and sustained attention emerged between the exempt and non-exempt flight crews. Pilots' fatigue was highest in the early morning hours. Their general stability of efficiency increased during the day and decreased at night. Non-exempt flight crews appeared to sacrifice reaction rate to improve accuracy. Exempt crews appeared to increase their test proficiency. The task stability time of the non-exempt flight crews was better than that of the exempt ones. Short-term stability was better for exempt inbound flights rather than for outbound ones. Pilots were more prone to error runs as their total time awake increased, especially on non-exempt flights. The addition of crew members to exempt flights, allowance for more in-flight rest shifts, and over-stop rest on non-exempt flights may alleviate pilot fatigue and preserve alertness.

ROS Scavenging and inflammation-directed polydopamine nanoparticles regulate gut immunity and flora therapy in inflammatory bowel disease.

Dysfunction of the intestinal mucosal immune system and dysbiosis of the intestinal microflora can induce inflammatory bowel disease. However, drug-mediated clinical treatment remains a challenge due to its poor therapeutic efficacy and severe side effects. Herein, a ROS scavenging and inflammation-directed nanomedicine is designed and fabricated by coupling polydopamine nanoparticles with mCRAMP, an antimicrobial peptide, while wrapping macrophage membrane in the outer layer. The designed nanomedicine reduced the secretion of pro-inflammatory cytokines and elevate the expression of anti-inflammatory cytokine in vivo and in vitro inflammation models, demonstrating its significant ability of improving inflammatory responses. Importantly, the macrophage membrane encapsulated nanoparticles exhibit the obviously enhanced targeting performance in local inflamed tissues. Furthermore, the 16S rRNA sequencing of fecal microorganisms showed that probiotics increased and pathogenic bacteria were inhibited after oral delivery the nanomedicine, indicating that the designed nano platform played a significant role in optimizing intestinal microbiome. Taken together, the designed nanomedicine are not only easy to prepare and exhibit high biocompatibility, but also show the inflammatory targeting property, anti-inflammatory function and positive regulation of intestinal flora, thus providing a new idea for the intervention and treatment of colitis. STATEMENT OF SIGNIFICANCE: Inflammatory bowel disease (IBD), a chronic and intractable disease, may lead to colon cancer in severe cases without effective treatment. However, clinical drugs are largely ineffective owing to insufficient therapeutic efficacies and side effects. Herein, we constructed a biomimetic polydopamine nanoparticle for oral administration to treat the IBD by modulating mucosal immune homeostasis and optimizing intestinal microorganisms. In vitro and in vivo experiments showed that the designed nanomedicine not only exhibits the anti-inflammatory function and inflammatory targeting property but also positively regulate the gut microflora. Taken together, the designed nanomedicine combined immunoregulation and intestinal microecology modulation to significantly enhance the therapeutic effect on colitis in mice, thus providing a new approach for the clinical treatment of colitis.

Effects of caffeine ingestion on physiological indexes of human neuromuscular fatigue: A systematic review and meta-analysis.

BACKGROUND: Caffeine is often used as a stimulant during fatigue, but the standard of characteristic physiological indicators of the effect of caffeine on neuromuscular fatigue has not been unified. The purpose of this systematic review and meta-analysis is to summarize current experimental findings on the effects of caffeine on physiological indexes before and after neuromuscular fatigue, identify some characteristic neuromuscular physiological indexes to assess the potential effects of caffeine. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-analyses are followed. We systematically searched PubMed, Google academic, and Web of Science for randomized controlled trials. We searched for studies on caffeine's (i) effects on neuromuscular fatigue and (ii) the influence of physiological indexes changes. Meta-analysis was performed for standardized mean differences (SMD) between caffeine and placebo trials in individual studies. RESULTS: The meta-analysis indicated that caffeine significantly improves voluntary activation (VA) (SMD = 1.46;95%CI:0.13, 2.79; p < .00001), PTw (SMD = 1.11, 95%CI: -1.61, 3.84; p < .00001), and M-wave (SMD = 1.10, 95%CI: -0.21, 2.41; p < .00001), and a significant difference (p = .003) on measures of Peak Power (PP), and insignificant difference on measures of heart rate (HR) (I2  = 0.0, p = .84) and Maximal oxygen uptake (VO2 ) (I2  = 0.0, p = .76). CONCLUSION: The analysis showed that caffeine intake had a relatively large effect on VA, potentiated twitch (PTw), M-wave, which can be used as characteristic indexes of caffeine's impact on neuromuscular fatigue. This conclusion tends to indicate the effects of caffeine on neuromuscular fatigue during endurance running or jumping or muscle bending and stretching. The caffeine intake had a big effect on the electromyogram (EMG) and peak power (PP), and its effect role needs to be further verified, this conclusion tends to indicate the effect of caffeine on neuromuscular fatigue during jumping or elbow bending moment movements. HR, VO2 , maximal voluntary contraction (MVC) cannot be used as the characteristic indexes of caffeine on neuromuscular fatigue. This conclusion tends to indicate the effect of caffeine on neuromuscular fatigue during endurance exercise. However, the results of meta-analysis are based on limited evidence and research scale, as well as individual differences of participants and different physical tasks, so it is necessary to interpret the results of meta-analysis cautiously. Therefore, future research needs to explore other physiological indicators and their indicative effects in order to determine effective and accurate characteristic indicators of caffeine on neuromuscular fatigue.

Fatigue during Long-Haul Flights of Different Crew Compositions under Exemption from Layover and Flight Time during COVID-19.

Pilot fatigue and alertness are critical for civil aviation safety. Intercontinental pilots are more prone to fatigue and sleepiness due to jet lag, prolonged workdays, and disrupted rhythms. The Civil Aviation Administration of China excused enlarged flight crews from mandatory layovers and reimposed flight duration restrictions during COVID-19. This study investigates the sleep quality and attentional performance of pilots on intercontinental flights. The fifteen pilots who performed intercontinental flights in different crew compositions wore a body movement recorder, which has been proven to accurately estimate sleep duration and sleep efficiency. The crew's attentional performance and self-report were monitored at specified flight phases. In conclusion, the larger crews slept longer and more efficiently on board, particularly pilots in charge of takeoff and landing responsibilities. Crews on four-pilot layover flights were more alert before the takeoff of the inbound flights than exempt flights, but there was no significant difference towards the end of the mission. The new long-haul flight organization did not result in fatigue or decreased attention in the pilots. This study expands on the research by validating a novel intercontinental flight operation model under the COVID-19 scenario and highlighting critical spots for future fatigue management in various crew compositions.

Effects of total sleep deprivation on execution lapses during vigilance tasks.

Total sleep deprivation (TSD) results in reduced efficiency of cognitive resources. Moreover, when the available cognitive resources are less than required, individuals exhibit lapses in responsiveness. Accordingly, this study explored the effects of TSD on executive function and the characteristics of execution lapses. Functional near-infrared spectroscopy was used to monitor the prefrontal cortex's functional connections in resting and tasking states for various sleep deprivation durations. Data from participants' attentional performance test and self-reported fatigue were collected over 30 hours of wakefulness. Task performance was compared based on time of day, time on task, and reaction time. The results show that participants' arousal level significantly decreased post 14 hours (P < .05), while sleepiness increased. The prefrontal cortex connection and attentional performance dropped at the Window of Circadian Low (3:00 ~ 6:00). The number of execution lapses was higher during the initiation, inhibition, and fatigue phases and rose markedly post 14 hours of wakefulness. We conclude that maintaining better inhibition control requires a reasonable extension of the reaction time. Moreover, subjective perception is significantly correlated with task performance and right prefrontal connection strength. This study presents the scientific evidence for measures to address consistently long working hours and disrupted circadian rhythms.

Dependence of Membrane Tether Strength on Substrate Rigidity Probed by Single-Cell Force Spectroscopy.

Substrate rigidity modulates cell mechanics, which affect cell migration and proliferation. Quantifying the effects of substrate rigidity on cancer cell mechanics requires a quantifiable parameter that can be measured for individual cells, as well as a substrate platform with rigidity being the only variable. Here we used single-cell force spectroscopy to pull cancer cells on substrates varying only in rigidity, and extracted a parameter from the force-distance curves to be used to quantify the properties of membrane tethers. Our results showed that tether force increases with substrate rigidity until it reaches its asymptotic limit. The variations are similar for all three cancer cell lines studied, and the largest change occurs in the rigidity regions of softer tissues, indicating a universal response of cancer cell elasticity to substrate rigidity.

Systematic assessment of intrinsic factors influencing visual attention performances in air traffic control via clustering algorithm and statistical inference.

The intrinsic factors (IF) influencing visual attention performance (VAP) might cause potential human errors, such as "error/mistake", "forgetting" and "omission". It is a key issue to develop a systematic assessment of IF in order to distinguish the levels of VAP. Motivated by the Stimulus-Response (S-R) model, we take an interactive cancellation test-Neuron Type Test (NTT)-to explore the IF and present the corresponding systematic assessment. The main contributions of this work include three elements: a) modeling the IF on account of attention span, attention stability, distribution-shift of attention with measurable parameters by combining the psychological and statistical concepts; b) proposing quantitative analysis methods for assessing the IF via its computational representation-intrinsic qualities (IQ)-in the sense of computational model; and c) clustering the IQ of air traffic control (ATC) students in the feature space of interest. The response sequences of participants collected with the NTT system are characterized by three parameters: Hurst exponent, normalized number of decisions (NNoD) and error rate of decisions (ERD). The K-means clustering is applied to partition the feature space constructed from practical data of VAP. For the distinguishable clusters, the statistical inference is utilized to refine the assessment of IF. Our comprehensive analysis shows that the IQ can be classified into four levels, i.e., excellent, good, moderate and unqualified, which has a potential application in selecting air traffic controllers subject to reducing the risk of the inadequacy of attention performances in aviation safety management.

Correlating Conformational Dynamics with the Von Willebrand Factor Reductase Activity of Factor H Using Single Molecule Force Measurements.

Activation of proteins often involves conformational transitions, and these switches are often difficult to characterize in multidomain proteins. Full-length factor H (FH), consisting of 20 small consensus repeat domains (150 kD), is a complement control protein that regulates the activity of the alternative complement pathway. Different preparations of FH can also reduce the disulfide bonds linking large Von Willebrand factor (VWF) multimers into smaller, less adhesive forms. In contrast, commercially available purified FH (pFH) has little or no VWF reductase activity unless the pFH is chemically modified by either ethylenediaminetetraacetic acid (EDTA) or urea. We used atomic force microscopy single molecule force measurements to investigate different forms of FH, including recombinant FH and pFH, in the presence or absence of EDTA and urea, and to correlate the conformational changes to its activities. We found that the FH conformation depends on the method used for sample preparation, which affects the VWF reductase activity of FH.

Single molecule force measurements of perlecan/HSPG2: A key component of the osteocyte pericellular matrix.

Perlecan/HSPG2, a large, monomeric heparan sulfate proteoglycan (HSPG), is a key component of the lacunar canalicular system (LCS) of cortical bone, where it is part of the mechanosensing pericellular matrix (PCM) surrounding the osteocytic processes and serves as a tethering element that connects the osteocyte cell body to the bone matrix. Within the pericellular space surrounding the osteocyte cell body, perlecan can experience physiological fluid flow drag force and in that capacity function as a sensor to relay external stimuli to the osteocyte cell membrane. We previously showed that a reduction in perlecan secretion alters the PCM fiber composition and interferes with bone's response to a mechanical loading in vivo. To test our hypothesis that perlecan core protein can sustain tensile forces without unfolding under physiological loading conditions, atomic force microscopy (AFM) was used to capture images of perlecan monomers at nanoscale resolution and to perform single molecule force measurement (SMFMs). We found that the core protein of purified full-length human perlecan is of suitable size to span the pericellular space of the LCS, with a measured end-to-end length of 170±20 nm and a diameter of 2-4 nm. Force pulling revealed a strong protein core that can withstand over 100 pN of tension well over the drag forces that are estimated to be exerted on the individual osteocyte tethers. Data fitting with an extensible worm-like chain model showed that the perlecan protein core has a mean elastic constant of 890 pN and a corresponding Young's modulus of 71 MPa. We conclude that perlecan has physical properties that would allow it to act as a strong but elastic tether in the LCS.

Single-molecule force measurements of the polymerizing dimeric subunit of von Willebrand factor.

Von Willebrand factor (VWF) multimers are large adhesive proteins that are essential to the initiation of hemostatic plugs at sites of vascular injury. The binding of VWF multimers to platelets, as well as VWF proteolysis, is regulated by shear stresses that alter VWF multimeric conformation. We used single molecule manipulation with atomic force microscopy (AFM) to investigate the effect of high fluid shear stress on soluble dimeric and multimeric forms of VWF. VWF dimers are the smallest unit that polymerizes to construct large VWF multimers. The resistance to mechanical unfolding with or without exposure to shear stress was used to evaluate VWF conformational forms. Our data indicate that, unlike recombinant VWF multimers (RVWF), recombinant dimeric VWF (RDVWF) unfolding force is not altered by high shear stress (100dynes/cm^{2} for 3 min at 37^{∘}C). We conclude that under the shear conditions used (100dynes/cm^{2} for 3 min at 37^{∘}C), VWF dimers do not self-associate into a conformation analogous to that attained by sheared large VWF multimers.

Detecting the Biopolymer Behavior of Graphene Nanoribbons in Aqueous Solution.

Graphene nanoribbons (GNR), can be prepared in bulk quantities for large-area applications by reducing the product from the lengthwise oxidative unzipping of multiwalled carbon nanotubes (MWNT). Recently, the biomaterials application of GNR has been explored, for example, in the pore to be used for DNA sequencing. Therefore, understanding the polymer behavior of GNR in solution is essential in predicting GNR interaction with biomaterials. Here, we report experimental studies of the solution-based mechanical properties of GNR and their parent products, graphene oxide nanoribbons (GONR). We used atomic force microscopy (AFM) to study their mechanical properties in solution and showed that GNR and GONR have similar force-extension behavior as in biopolymers such as proteins and DNA. The rigidity increases with reducing chemical functionalities. The similarities in rigidity and tunability between nanoribbons and biomolecules might enable the design and fabrication of GNR-biomimetic interfaces.

DNA under Force: Mechanics, Electrostatics, and Hydration.

Quantifying the basic intra- and inter-molecular forces of DNA has helped us to better understand and further predict the behavior of DNA. Single molecule technique elucidates the mechanics of DNA under applied external forces, sometimes under extreme forces. On the other hand, ensemble studies of DNA molecular force allow us to extend our understanding of DNA molecules under other forces such as electrostatic and hydration forces. Using a variety of techniques, we can have a comprehensive understanding of DNA molecular forces, which is crucial in unraveling the complex DNA functions in living cells as well as in designing a system that utilizes the unique properties of DNA in nanotechnology.

Reconstructing multiple free energy pathways of DNA stretching from single molecule experiments.

Free energy landscapes provide information on the dynamics of proteins and nucleic acid folding. It has been demonstrated that such landscapes can be reconstructed from single molecule force measurement data using Jarzynski's equality, which requires only stretching data. However, when the process is reversible, the Crooks fluctuation theorem combines both stretch and relaxation force data for the analysis and can offer more rapid convergence of free energy estimates of different states. Here we demonstrate that, similar to Jarzynski's equality, the Crooks fluctuation theorem can be used to reconstruct the full free energy landscapes. In addition, when the free energy landscapes exhibit multiple folding pathways, one can use Jarzynski's equality to reconstruct individual free energy pathways if the experimental data show distinct work distributions. We applied the method to reconstruct the overstretching transition of poly(dA) to demonstrate that the nonequilibrium work theorem combined with single molecule force measurements provides a clear picture of the free energy landscapes.

Effect of urea concentration on aggregation of amyloidogenic hexapeptides (NFGAIL).

We have performed large-scale all-atom molecular dynamics (MD) simulations to study the aggregation behavior of four NFGAIL hexapeptides in the aqueous urea solution, with a urea concentration ranging from 0 to 5 M. We find that urea in general suppresses the peptide aggregation, but suppression slows down in the intermediation concentration regime around 3 M. Two competing mechanisms of urea are determined: urea molecules accumulated near the first solvation shell (FSS) tend to unfold the hexapeptide, which favors aggregation; on the other hand, the tight hydrogen bonds formed between urea and peptide mainchains hinder the association of peptides which disfavors the formation of the ß-sheet. Furthermore, the different nonlinear urea concentration dependences of the urea-peptide and peptide-peptide hydrogen bonds lead to a nonmonotonic behavior, with a weak enhancement in the peptide aggregation around 3 M.