Bridging two insect flight modes in evolution, physiology and robophysics.

Since taking flight, insects have undergone repeated evolutionary transitions between two seemingly distinct flight modes1-3. Some insects neurally activate their muscles synchronously with each wingstroke. However, many insects have achieved wingbeat frequencies beyond the speed limit of typical neuromuscular systems by evolving flight muscles that are asynchronous with neural activation and activate in response to mechanical stretch2-8. These modes reflect the two fundamental ways of generating rhythmic movement: time-periodic forcing versus emergent oscillations from self-excitation8-10. How repeated evolutionary transitions have occurred and what governs the switching between these distinct modes remain unknown. Here we find that, despite widespread asynchronous actuation in insects across the phylogeny3,6, asynchrony probably evolved only once at the order level, with many reversions to the ancestral, synchronous mode. A synchronous moth species, evolved from an asynchronous ancestor, still preserves the stretch-activated muscle physiology. Numerical and robophysical analyses of a unified biophysical framework reveal that rather than a dichotomy, these two modes are two regimes of the same dynamics. Insects can transition between flight modes across a bridge in physiological parameter space. Finally, we integrate these two actuation modes into an insect-scale robot11-13 that enables transitions between modes and unlocks a new self-excited wingstroke strategy for engineered flight. Together, this framework accounts for repeated transitions in insect flight evolution and shows how flight modes can flip with changes in physiological parameters.

Moth resonant mechanics are tuned to wingbeat frequency and energetic demands.

An insect's wingbeat frequency is a critical determinant of its flight performance and varies by multiple orders of magnitude across Insecta. Despite potential energetic benefits for an insect that matches its wingbeat frequency to its resonant frequency, recent work has shown that moths may operate off their resonant peak. We hypothesized that across species, wingbeat frequency scales with resonance frequency to maintain favourable energetics, but with an offset in species that use frequency modulation as a means of flight control. The moth superfamily Bombycoidea is ideal for testing this hypothesis because their wingbeat frequencies vary across species by an order of magnitude, despite similar morphology and actuation. We used materials testing, high-speed videography and a model of resonant aerodynamics to determine how components of an insect's flight apparatus (stiffness, wing inertia, muscle strain and aerodynamics) vary with wingbeat frequency. We find that the resonant frequency of a moth correlates with wingbeat frequency, but resonance curve shape (described by the Weis-Fogh number) and peak location vary within the clade in a way that corresponds to frequency-dependent biomechanical demands. Our results demonstrate that a suite of adaptations in muscle, exoskeleton and wing drive variation in resonant mechanics, reflecting potential constraints on matching wingbeat and resonant frequencies.

Diuretics use in the management of bronchopulmonary dysplasia in preterm infants: A systematic review.

AIM: Bronchopulmonary dysplasia (BPD), a respiratory complication associated with neonatal prematurity, presents opportunities for pharmacological intervention due to its contributing risk factors. Despite diuretics' controversial usage in BPD treatment and varying institutional practices, this review aims to consolidate evidence from clinical trials regarding diuretic use in BPD. METHODS: We conducted a systematic review following PRISMA guidelines, searching EMBASE, Medline, Web of Science and CINAHL databases (PROSPERO 2022: CRD42022328292). Covidence facilitated screening and data extraction, followed by analysis and formatting in Microsoft Excel. RESULTS: Among 430 screened records, 13 were included for analysis. Three studies assessed spironolactone and chlorothiazide combinations, two studied spironolactone and hydrochlorothiazide, while eight examined furosemide. All studies evaluated drug effects on dynamic pulmonary compliance and pulmonary resistance, serving as comparative measures in our review. CONCLUSION: Diuretics' effectiveness in treating bronchopulmonary dysplasia remains uncertain. The limited number of identified randomised controlled trials (RCTs) hampers high-level evidence-based conclusions when applying the Population, Intervention, Comparison, Outcome (PICO) approach. Conducting large prospective studies of good quality could provide more definitive insights, but the rarity of outcomes and eligible patients poses challenges. Further research, primarily focusing on RCTs assessing diuretics' safety and efficacy in this population, is warranted.

Examining Patterns and Predictors of ADHD Teens' Skill-Learning Trajectories During Enhanced FOrward Concentration and Attention Learning (FOCAL+) Training.

OBJECTIVE: Examine patterns and predictors of skill learning during multisession Enhanced FOrward Concentration and Attention Learning (FOCAL+) training. BACKGROUND: FOCAL+ teaches teens to reduce the duration of off-road glances using real-time error learning. In a randomized controlled trial, teens with ADHD received five sessions of FOCAL+ training and demonstrated significant reductions in extended glances (>2-s) away from the roadway (i.e., long-glances) and a 40% reduced risk of a crash/near-crash event. Teens' improvement in limiting long-glances as assessed after each FOCAL+ training session has not been examined. METHOD: Licensed teen (ages 16-19) drivers with ADHD (n = 152) were randomly assigned to five sessions of either FOCAL+ or modified standard driver training. Teens completed driving simulation assessments at baseline, after each training session, and 1 month and 6 months posttraining. Naturalistic driving was monitored for one year. RESULTS: FOCAL+ training produced a 53% maximal reduction in long-glances during postsession simulated driving. The number of sessions needed to achieve maximum performance varied across participants. However, after five FOCAL+ training sessions, number of long-glances was comparable irrespective of when teens achieved their maximum performance. The magnitude of reduction in long-glances predicted levels of long-glances during simulated driving at 1 month and 6 months posttraining but not naturalistic driving outcomes. FOCAL+ training provided the most benefit during training to teens who were younger and had less driving experience. CONCLUSION: FOCAL+ training significantly reduces long-glances beginning at the 1st training session. APPLICATION: Providing five FOCAL+ training sessions early on during teen driving may maximize benefit.

Examining reaction time variability on the stop-signal task in the ABCD study.

OBJECTIVE: Reaction time variability (RTV) has been estimated using Gaussian, ex-Gaussian, and diffusion model (DM) indices. Rarely have studies examined interrelationships among these performance indices in childhood, and the use of reaction time (RT) computational models has been slow to take hold in the developmental psychopathology literature. Here, we extend prior work in adults by examining the interrelationships among different model parameters in the ABCD sample and demonstrate how computational models of RT can clarify mechanisms of time-on-task effects and sex differences in RTs. METHOD: This study utilized trial-level data from the stop signal task from 8916 children (9-10 years old) to examine Gaussian, ex-Gaussian, and DM indicators of RTV. In addition to describing RTV patterns, we examined interrelations among these indicators, temporal patterns, and sex differences. RESULTS: There was no one-to-one correspondence between DM and ex-Gaussian parameters. Nonetheless, drift rate was most strongly associated with standard deviation of RT and tau, while nondecisional processes were most strongly associated with RT, mu, and sigma. Performance worsened across time with changes driven primarily by decreasing drift rate. Boys were faster and less variable than girls, likely attributable to girls' wide boundary separation. CONCLUSIONS: Intercorrelations among model parameters are similar in children as has been observed in adults. Computational approaches play a crucial role in understanding performance changes over time and can also clarify mechanisms of group differences. For example, standard RT models may incorrectly suggest slowed processing speed in girls that is actually attributable to other factors.

The Effects of Attention-Deficit/Hyperactivity Disorder Symptoms on the Association between Head Impacts and Post-Season Neurocognitive and Behavioral Outcomes.

OBJECTIVE: Having attention-deficit/hyperactivity disorder (ADHD) is a risk factor for concussion that impacts concussion diagnosis and recovery. The relationship between ADHD and repetitive subconcussive head impacts on neurocognitive and behavioral outcomes is less well known. This study evaluated the role of ADHD as a moderator of the association between repetitive head impacts on neurocognitive test performance and behavioral concussion symptoms over the course of an athletic season. METHOD: Study participants included 284 male athletes aged 13-18 years who participated in high school football. Parents completed the Strengths and Weaknesses of ADHD Symptoms and Normal Behavior (SWAN) ratings about their teen athlete before the season began. Head impacts were measured using an accelerometer worn during all practices and games. Athletes and parents completed behavioral ratings of concussion symptoms and the Attention Network Task (ANT), Digital Trail Making Task (dTMT), and Cued Task Switching Task at pre- and post-season. RESULTS: Mixed model analyses indicated that neither head impacts nor ADHD symptoms were associated with post-season athlete- or parent-reported concussion symptom ratings or neurocognitive task performance. Moreover, no relationships between head impact exposure and neurocognitive or behavioral outcomes emerged when severity of pre-season ADHD symptoms was included as a moderator. CONCLUSION: Athletes' pre-season ADHD symptoms do not appear to influence behavioral or neurocognitive outcomes following a single season of competitive football competition. Results are interpreted in light of several study limitations (e.g., single season, assessment of constructs) that may have impacted this study's pattern of largely null results.

Introduction to the Special Issue on COVID-19.

The COVID-19 pandemic has been a global event affecting all aspects of human life and society, including acoustic aspects. In this Special Issue on COVID-19 and acoustics, we present 48 papers discussing the acoustical impacts of the pandemic and how we deal with it. The papers are divided into seven categories which include: physical masking and speech production, speech perception, noise, the underwater soundscape, the urban soundscape, pathogen transmissibility, and medical diagnosis.

The relationship between resilience and neurophysiological stress in Special Operations Forces combat service members.

Military resilience research is increasing due to the growing literature associating resilience with stress adaptation. This study aimed to investigate which physiological stress adaptation components were associated with resilience in Special Operations Forces combat service members. Special Operations Forces combat service members (n = 117) self-reported resilience (ER89) and lifetime clinician-confirmed mild traumatic brain injury history. Participants also underwent transcranial Doppler ultrasonography to measure middle cerebral artery velocity during rest and a breath-holding task. Neither resilience nor mild traumatic brain injury history was significantly associated with middle cerebral artery velocity percent increase following breath-holding; younger Special Operations Forces combat service members had a higher percent increase in middle cerebral artery velocity following a breath-holding task. Resilience was negatively associated with time to return to baseline middle cerebral artery velocity following peak velocity; whereas, mild traumatic brain injury history did not have a significant association. The Special Operations Forces combat service members that scored higher in resilience tended to return to baseline middle cerebral artery velocity following peak velocity faster than their less resilient counterparts. More resilient Special Operations Forces combat service members recovered faster from physiological stress (breath-holding) than less resilient counterparts. This is the first study to investigate resilience and cerebrovascular stress response and recovery in this population. Our initial findings indicated that the Ego Resiliency Scale may be an optimal resilience psychometric and should be used to evaluate effective military resilience trainings, which aim to improve performance and mental health.

The hawkmoth wingbeat is not at resonance.

Flying insects have elastic materials within their exoskeletons that could reduce the energetic cost of flight if their wingbeat frequency is matched to a mechanical resonance frequency. Flapping at resonance may be essential across flying insects because of the power demands of small-scale flapping flight. However, building up large-amplitude resonant wingbeats over many wingstrokes may be detrimental for control if the total mechanical energy in the spring-wing system exceeds the per-cycle work capacity of the flight musculature. While the mechanics of the insect flight apparatus can behave as a resonant system, the question of whether insects flap their wings at their resonant frequency remains unanswered. Using previous measurements of body stiffness in the hawkmoth, Manduca sexta, we develop a mechanical model of spring-wing resonance with aerodynamic damping and characterize the hawkmoth's resonant frequency. We find that the hawkmoth's wingbeat frequency is approximately 80% above resonance and remains so when accounting for uncertainty in model parameters. In this regime, hawkmoths may still benefit from elastic energy exchange while enabling control of aerodynamic forces via frequency modulation. We conclude that, while insects use resonant mechanics, tuning wingbeats to a simple resonance peak is not a necessary feature for all centimetre-scale flapping flyers.

Rapid frequency modulation in a resonant system: aerial perturbation recovery in hawkmoths.

Centimetre-scale fliers must contend with the high power requirements of flapping flight. Insects have elastic elements in their thoraxes which may reduce the inertial costs of their flapping wings. Matching wingbeat frequency to a mechanical resonance can be energetically favourable, but also poses control challenges. Many insects use frequency modulation on long timescales, but wingstroke-to-wingstroke modulation of wingbeat frequencies in a resonant spring-wing system is potentially costly because muscles must work against the elastic flight system. Nonetheless, rapid frequency and amplitude modulation may be a useful control modality. The hawkmoth Manduca sexta has an elastic thorax capable of storing and returning significant energy. However, its nervous system also has the potential to modulate the driving frequency of flapping because its flight muscles are synchronous. We tested whether hovering hawkmoths rapidly alter frequency during perturbations with vortex rings. We observed both frequency modulation (32% around mean) and amplitude modulation (37%) occurring over several wingstrokes. Instantaneous phase analysis of wing kinematics revealed that more than 85% of perturbation responses required active changes in neurogenic driving frequency. Unlike their robotic counterparts that abdicate frequency modulation for energy efficiency, synchronous insects use wingstroke-to-wingstroke frequency modulation despite the power demands required for deviating from resonance.

Drug mechanism-of-action discovery through the integration of pharmacological and CRISPR screens.

Low success rates during drug development are due, in part, to the difficulty of defining drug mechanism-of-action and molecular markers of therapeutic activity. Here, we integrated 199,219 drug sensitivity measurements for 397 unique anti-cancer drugs with genome-wide CRISPR loss-of-function screens in 484 cell lines to systematically investigate cellular drug mechanism-of-action. We observed an enrichment for positive associations between the profile of drug sensitivity and knockout of a drug's nominal target, and by leveraging protein-protein networks, we identified pathways underpinning drug sensitivity. This revealed an unappreciated positive association between mitochondrial E3 ubiquitin-protein ligase MARCH5 dependency and sensitivity to MCL1 inhibitors in breast cancer cell lines. We also estimated drug on-target and off-target activity, informing on specificity, potency and toxicity. Linking drug and gene dependency together with genomic data sets uncovered contexts in which molecular networks when perturbed mediate cancer cell loss-of-fitness and thereby provide independent and orthogonal evidence of biomarkers for drug development. This study illustrates how integrating cell line drug sensitivity with CRISPR loss-of-function screens can elucidate mechanism-of-action to advance drug development.

Posttraumatic Stress Disorder in Elite Athletes.

ABSTRACT: Posttraumatic stress disorder (PTSD), which may develop following exposure to severe trauma, can occur in all people at any age. PTSD affects approximately 10 million Americans, with an incidence of approximately 3.5% diagnosed every year. Elite athletes are not immune to posttraumatic stress. While difficult to precisely quantify, an estimated 1 in 8 elite athletes suffers from PTSD. Because of its complex presentation, PTSD can be challenging to diagnose and effectively treat in athletes. Several barriers unique to elite athletes exist which may inadvertently delay or prevent access to the appropriate clinical experts. Several best practice models for mental health screening in elite athletes have been developed in the past decade. Treatment of PTSD in the athlete population is similar to trauma-informed treatment in the general population, but should involve the athlete's multidisciplinary team of clinical experts to account for unique demands and preferences in the context of sport.

Antibiotic Delays and Feasibility of a 1-Hour-From-Triage Antibiotic Requirement: Analysis of an Emergency Department Sepsis Quality Improvement Database.

STUDY OBJECTIVE: We identify factors associated with delayed emergency department (ED) antibiotics and determine feasibility of a 1-hour-from-triage antibiotic requirement in sepsis. METHODS: We studied all ED adult septic patients in accordance with Centers for Medicare & Medicaid Services Severe Sepsis and Septic Shock National Quality Measures in 2 consecutive 12-month intervals. During the second interval, a quality improvement intervention was conducted: a sepsis screening protocol plus case-specific feedback to clinicians. Data were abstracted retrospectively through electronic query and chart review. Primary outcomes were antibiotic delay greater than 3 hours from documented onset of hypoperfusion (per Centers for Medicare & Medicaid Services Severe Sepsis and Septic Shock National Quality Measures) and antibiotic delay greater than 1 hour from triage (per 2018 Surviving Sepsis Campaign recommendations). RESULTS: We identified 297 and 357 septic patients before and during the quality improvement intervention, respectively. Before and during quality improvement intervention, antibiotic delay in accordance with Centers for Medicare & Medicaid Services measures occurred in 30% and 21% of cases (-9% [95% confidence interval -16% to -2%]); and in accordance with 2018 Surviving Sepsis Campaign recommendations, 85% and 71% (-14% [95% confidence interval -20% to -8%]). Four factors were independently associated with both definitions of antibiotic delay: vague (ie, nonexplicitly infectious) presenting symptoms, triage location to nonacute areas, care before the quality improvement intervention, and lower Sequential [Sepsis-related] Organ Failure Assessment scores. Most patients did not receive antibiotics within 1 hour of triage, with the exception of a small subset post-quality improvement intervention who presented with explicit infectious symptoms and triage hypotension. CONCLUSION: The quality improvement intervention significantly reduced antibiotic delays, yet most septic patients did not receive antibiotics within 1 hour of triage. Compliance with the 2018 Surviving Sepsis Campaign would require a wholesale alteration in the management of ED patients with either vague symptoms or absence of triage hypotension.

Improving tracheostomy care in the United Kingdom: results of a guided quality improvement programme in 20 diverse hospitals.

BACKGROUND: Inconsistent and poorly coordinated systems of tracheostomy care commonly result in frustrations, delays, and harm. Quality improvement strategies described by exemplar hospitals of the Global Tracheostomy Collaborative have potential to mitigate such problems. This 3 yr guided implementation programme investigated interventions designed to improve the quality and safety of tracheostomy care. METHODS: The programme management team guided the implementation of 18 interventions over three phases (baseline/implementation/evaluation). Mixed-methods interviews, focus groups, and Hospital Anxiety and Depression Scale questionnaires defined outcome measures, with patient-level databases tracking and benchmarking process metrics. Appreciative inquiry, interviews, and Normalisation Measure Development questionnaires explored change barriers and enablers. RESULTS: All sites implemented at least 16/18 interventions, with the magnitude of some improvements linked to staff engagement (1536 questionnaires from 1019 staff), and 2405 admissions (1868 ICU/high-dependency unit; 7.3% children) were prospectively captured. Median stay was 50 hospital days, 23 ICU days, and 28 tracheostomy days. Incident severity score reduced significantly (n=606; P<0.01). There were significant reductions in ICU (-;0.25 days month-1), ventilator (-;0.11 days month-1), tracheostomy (-;0.35 days month-1), and hospital (-;0.78 days month-1) days (all P<0.01). Time to first vocalisation and first oral intake both decreased by 7 days (n=733; P<0.01). Anxiety decreased by 44% (from 35.9% to 20.0%), and depression decreased by 55% (from 38.7% to 18.3%) (n=385; both P<0.01). Independent economic analysis demonstrated £33 251 savings per patient, with projected annual UK National Health Service savings of £275 million. CONCLUSIONS: This guided improvement programme for tracheostomy patients significantly improved the quality and safety of care, contributing rich qualitative improvement data. Patient-centred outcomes were improved along with significant efficiency and cost savings across diverse UK hospitals. CLINICAL TRIAL REGISTRATION: IRAS-ID-206955; REC-Ref-16/LO/1196; NIHR Portfolio CPMS ID 31544.

Neuroinflammatory Biomarkers Associated With Mild Traumatic Brain Injury History in Special Operations Forces Combat Soldiers.

BACKGROUND: Special Operations Forces (SOF) combat soldiers are frequently exposed to blast and blunt neurotrauma, most often classified as mild traumatic brain injury (mTBI). Repetitive mTBI may increase the risk of developing long-term neurological sequelae. Identifying changes in neuroinflammatory biomarkers before chronic conditions emerge could serve as preliminary evidence of developing neuropathology. OBJECTIVE: To determine the effects of mTBI history, lifetime mTBI incidence, and recency on blood biomarker concentrations of axonal protein neurofilament light (NfL), glycolytic enzyme neuron-specific enolase (NSE), astrocyte-expressed S100 calcium-binding protein B (S100B), and neurotrophic cytokine interleukin-6 (IL-6) in healthy, active duty SOF combat soldiers. METHODS: Self-reported mTBI history/recency and fasted blood samples were collected in this cross-sectional study of 104 asymptomatic SOF combat soldiers. Biomarker concentrations were quantified using commercial enzyme-linked immunosorbent assays. Mann-Whitney U and Kruskal-Wallis tests were used to compare groups. Post hoc tests with appropriate corrections were conducted as warranted. RESULTS: Soldiers with mTBI history had higher NSE concentrations than those without (z = -2.60, P = .01). We also observed significant main effects of lifetime mTBI incidence on NSE (χ(3) = 9.52, P = .02) and S100B (χ(3) = 8.21, P = .04) concentrations and a significant main effect of mTBI recency on NfL concentration (χ(2) = 6.02, P = .049). CONCLUSION: The SOF combat soldiers with mTBI history had increased NSE. Longitudinal studies in this population are needed due to between-subject heterogeneity in biomarker concentrations. The NfL concentrations in our SOF combat soldiers-regardless of mTBI history or recency-were similar to values previously reported in civilian acute TBI patients.

Understanding Misdemeanor Enforcement: The Roles of Calls for Service and Community Characteristics.

This study examines the roles of calls for service (i.e., police-related 911 calls) and community characteristics in explaining variation in enforcement rates for low-level, misdemeanor offenses, which make up the large majority of police enforcement activity. The study site is Prince George's County, Maryland, and the unit of analysis is the police department's 65 patrol beats, studied over a 10-year period, during 2006-2015. Overall, misdemeanor enforcement rates vary at the beat level, and that variation can be largely explained using a combination of indicators about community characteristics and calls for service. The findings indicate, though, that the calls for service rate is the most important variable in explaining misdemeanor enforcement variation. These findings inform both future research on police activity, and current policy debates about what drives enforcement rates and the role of discretion in enforcement outcomes.

Sensitivity to PI3K and AKT inhibitors is mediated by divergent molecular mechanisms in subtypes of DLBCL.

Activated B-cell-like (ABC) and germinal center B-cell-like diffuse large B-cell lymphoma (DLBCL) represent the 2 major molecular DLBCL subtypes. They are characterized by differences in clinical course and by divergent addiction to oncogenic pathways. To determine activity of novel compounds in these 2 subtypes, we conducted an unbiased pharmacologic in vitro screen. The phosphatidylinositol-3-kinase (PI3K) α/δ (PI3Kα/δ) inhibitor AZD8835 showed marked potency in ABC DLBCL models, whereas the protein kinase B (AKT) inhibitor AZD5363 induced apoptosis in PTEN-deficient DLBCLs irrespective of their molecular subtype. These in vitro results were confirmed in various cell line xenograft and patient-derived xenograft mouse models in vivo. Treatment with AZD8835 induced inhibition of nuclear factor κB signaling, prompting us to combine AZD8835 with the Bruton's tyrosine kinase inhibitor ibrutinib. This combination was synergistic and effective both in vitro and in vivo. In contrast, the AKT inhibitor AZD5363 was effective in PTEN-deficient DLBCLs through downregulation of the oncogenic transcription factor MYC. Collectively, our data suggest that patients should be stratified according to their oncogenic dependencies when treated with PI3K and AKT inhibitors.

Multiscale multiphysics data-informed modeling for three-dimensional ocean acoustic simulation and prediction.

Three-dimensional (3D) underwater sound field computations have been used for a few decades to understand sound propagation effects above sloped seabeds and in areas with strong 3D temperature and salinity variations. For an approximate simulation of effects in nature, the necessary 3D sound-speed field can be made from snapshots of temperature and salinity from an operational data-driven regional ocean model. However, these models invariably have resolution constraints and physics approximations that exclude features that can have strong effects on acoustics, example features being strong submesoscale fronts and nonhydrostatic nonlinear internal waves (NNIWs). Here, work to predict NNIW fields to improve 3D acoustic forecasts using an NNIW model nested in a tide-inclusive data-assimilating regional model is reported. The work was initiated under the Integrated Ocean Dynamics and Acoustics project. The project investigated ocean dynamical processes that affect important details of sound-propagation, with a focus on those with strong intermittency (high kurtosis) that are challenging to predict deterministically. Strong internal tides and NNIW are two such phenomena, with the former being precursors to NNIW, often feeding energy to them. Successful aspects of the modeling are reported along with weaknesses and unresolved issues identified in the course of the work.