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Purpose Neurally adjusted ventilatory assist (NAVA) is a ventilatory mode that tailors the level of assistance delivered by the ventilator to the electromyographic activity of the diaphragm. The objective of this study was to compare NAVA and pressure support ventilation (PSV) in the early phase of weaning from mechanical ventilation. Methods A multicentre randomized controlled trial of 128 intubated adults recovering from acute respiratory failure was conducted in 11 intensive care units. Patients were randomly assigned to NAVA or PSV. The primary outcome was the probability of remaining in a partial ventilatory mode (either NAVA or PSV) throughout the first 48 h without any return to assist-control ventilation. Secondary outcomes included asynchrony index, ventilator-free days and mortality. Results In the NAVA and PSV groups respectively, the proportion of patients remaining in partial ventilatory mode throughout the first 48 h was 67.2 vs. 63.3 % ( P  = 0.66), the asynchrony index was 14.7 vs. 26.7 % ( P  < 0.001), the ventilator-free days at day 7 were 1.0 day [1.0–4.0] vs. 0.0 days [0.0–1.0] ( P  < 0.01), the ventilator-free days at day 28 were 21 days [4–25] vs. 17 days [0–23] ( P  = 0.12), the day-28 mortality rate was 15.0 vs. 22.7 % ( P  = 0.21) and the rate of use of post-extubation noninvasive mechanical ventilation was 43.5 vs. 66.6 % ( P  < 0.01). Conclusions NAVA is safe and feasible over a prolonged period of time but does not increase the probability of remaining in a partial ventilatory mode. However, NAVA decreases patient–ventilator asynchrony and is associated with less frequent application of post-extubation noninvasive mechanical ventilation. Trial Registration. clinicaltrials.gov Identifier: NCT02018666.

Young healthy adults can hear tones up to at least 20 kHz. However, clinical audiometry, by which hearing loss is diagnosed, is limited at high frequencies to 8 kHz. Evidence suggests there is salient information at extended high frequencies (EHFs; 8 to 20 kHz) that may influence speech intelligibility, but whether that information is used in challenging listening conditions remains unknown. Difficulty understanding speech in noisy environments is the most common concern people have about their hearing and usually the first sign of age-related hearing loss. Digits-in-noise (DIN), a widely used test of speech-in-noise perception, can be sensitized for detection of high-frequency hearing loss by low-pass filtering the broadband masking noise. Here, we used standard and EHF audiometry, self-report, and successively higher cutoff frequency filters (2 to 8 kHz) in a DIN test to investigate contributions of higher-frequency hearing to speech-in-noise perception. Three surprising results were found. First, 74 of 116 “normally hearing,” mostly younger adults had some hearing loss at frequencies above 8 kHz. Early EHF hearing loss may thus be an easily measured, preventive warning to protect hearing. Second, EHF hearing loss correlated with self-reported difficulty hearing in noise. Finally, even with the broadest filtered noise (≤8 kHz), DIN hearing thresholds were significantly better (P < 0.0001) than those using broadband noise. Sound energy above 8 kHz thus contributes to speech perception in noise. People with “normal hearing” frequently report difficulty hearing in challenging environments. Our results suggest that one contribution to this difficulty is EHF hearing loss.

NASA's InSight has detected a large magnitude seismic event, labeled S1222a. The event has a moment magnitude of MWMa${\\mathrm{M}}_{\\mathrm{W}}^{\\text{Ma}}$ 4.7, with five times more seismic moment compared to the second largest event. The event is so large that features are clearly observed that were not seen in any previously detected events. In addition to body phases and Rayleigh waves, we also see Love waves, minor arc surface wave overtones, and multi‐orbit surface waves. At long periods, the coda event exceeds 10 hr. The event locates close to the North‐South dichotomy and outside the tectonically active Cerberus Fossae region. S1222a does not show any evident geological or tectonic features. The event is extremely rich in frequency content, extending from below 1/30 Hz up to 35 Hz. The event was classified as a broadband type event; we also observe coda decay and polarization similar to that of very high frequency type events. Plain Language Summary After 3 years of seismic monitoring of Mars by InSight Seismic Experiment for Interior Structure instrument, we detected a marsquake largest ever observed during the mission. The event is larger by factor of 5 in seismic moment compared to previously detected events. With such an energetic event, we discovered various seismic features that was never observed before. For the first time, we were able to detect body waves and surface waves with their overtones. The large variety of detected seismic phases will enable us to probe the internal structure of Mars. Second, the event was located outside a well‐known seismically active region of Cerberus Fossae. This might indicate that event do not come from the same fault system with other major marsquakes. Finally, this event shows simultaneously features of marsquakes that were previously classified into different types. S1222a is classified as a broadband event with a wide frequency range of seismic energy. At the same time, the coda shape and decay at high frequency resembles that of very high frequency type events. It was an open question how different types of marsquakes are excited of what makes such differences and such event will be a key to uncover such mystery of marsquakes. Key Points InSight detected on 4 May 2022 a MWMa${\\mathrm{M}}_{\\mathrm{W}}^{\\text{Ma}}$ 4.7 marsquake, S1222a, which is the largest seismic event detected so far The exceptional signal‐to‐noise allows multiple phases to be identified, with a rich collection of surface waves S1222a was located 37° southeast of the InSight landing site and close to the Martian dichotomy boundary

Surface ozone concentrations typically peak during the daytime, driven by active photochemical production, and decrease gradually after sunset, due to chemical destruction and dry deposition. Here, we report that nocturnal ozone enhancement (NOE, defined as an ozone increase of more than 5 ppbv h−1 in 1 of any 2 adjacent hours between 20:00 and 06:00 LT, local time) events are observed at multiple monitoring sites in China at a high frequency, which has not been recognized in previous studies. We present an overview of the general characteristics of NOE events in China and explore the possible mechanisms based on 6 years of observations from the national monitoring network. We find that the mean annual frequency of NOE events is 41±10 % (i.e., about 140 d would experience an NOE event per year) averaged over all 814 Chinese sites between 2014 and 2019, which is 46 % larger than that over Europe or the United States. The NOE event frequency is higher in industrialized city clusters (>50 %) than in regions with lighter ozone pollution, and it is higher in the warm season (46 %) than in the cold season (36 %), consistent with the spatiotemporal evolution of ozone levels. The mean ozone peak during NOE events reaches 37±6 ppbv in the warm season. The ozone enhancements are within 5–15 ppbv h−1 during 85 % of the NOE events; however, in about 10 % of cases, the ozone increases can exceed 20 ppbv h−1. We propose that high photochemistry-induced ozone during the daytime provides a rich ozone source in the nighttime residual layer, determining the overall high frequency of NOE events in China, and that enhanced atmospheric mixing then triggers NOE events by allowing the ozone-rich air in the residual layer to mix into the nighttime boundary layer. This is supported by our analyses which show that 70 % (65 %) of the NOE events are associated with increases in friction velocity (planetary boundary layer height), indicative of enhanced atmospheric mixing, and also supported by the observed sharp decreases in surface NO2 and CO concentrations with ozone increases in NOE events, a typical signal of mixing with air in the residual layer. Three case studies in Beijing and Guangzhou show that synoptic processes such as convective storms and low-level jets can lead to NOE events by aggravating vertical mixing. Horizontal transport of ozone-rich plumes may also be a supplementary driver of NOE events. Our results summarize, for the first time, the characteristics and mechanism of NOE events in China based on nationwide and long-term observations, and our findings emphasize the need for more direct measurements and modeling studies on the nighttime ozone evolution from the surface to the residual layer.

Niemann-Pick disease, type C1 (NPC1) is a lysosomal storage disorder characterised by progressive neurodegeneration. In preclinical testing, 2-hydroxypropyl-β-cyclodextrins (HPβCD) significantly delayed cerebellar Purkinje cell loss, slowed progression of neurological manifestations, and increased lifespan in mouse and cat models of NPC1. The aim of this study was to assess the safety and efficacy of lumbar intrathecal HPβCD. In this open-label, dose-escalation phase 1–2a study, we gave monthly intrathecal HPβCD to participants with NPC1 with neurological manifestation at the National Institutes of Health (NIH), Bethesda, MD, USA. To explore the potential effect of 2-week dosing, three additional participants were enrolled in a parallel study at Rush University Medical Center (RUMC), Chicago, IL, USA. Participants from the NIH were non-randomly, sequentially assigned in cohorts of three to receive monthly initial intrathecal HPβCD at doses of 50, 200, 300, or 400 mg per month. A fifth cohort of two participants received initial doses of 900 mg. Participants from RUMC initially received 200 or 400 mg every 2 weeks. The dose was escalated based on tolerance or safety data from higher dose cohorts. Serum and CSF 24(S)-hydroxycholesterol (24[S]-HC), which serves as a biomarker of target engagement, and CSF protein biomarkers were evaluated. NPC Neurological Severity Scores (NNSS) were used to compare disease progression in HPβCD-treated participants relative to a historical comparison cohort of 21 NPC1 participants of similar age range. Between Sept 21, 2013, and Jan 19, 2015, 32 participants with NPC1 were assessed for eligibility at the National Institutes of Health. 18 patients were excluded due to inclusion criteria not met (six patients), declined to participate (three patients), pursued independent expanded access and obtained the drug outside of the study (three patients), enrolled in the RUMC cohort (one patient), or too late for the trial enrolment (five patients). 14 patients were enrolled and sequentially assigned to receive intrathecal HPβCD at a starting dose of 50 mg per month (three patients), 200 mg per month (three patients), 300 mg per month (three patients), 400 mg per month (three patients), or 900 mg per month (two patients). During the first year, two patients had treatment interrupted for one dose, based on grade 1 ototoxicity. All 14 patients were assessed at 12 months. Between 12 and 18 months, one participant had treatment interrupted at 17 months due to hepatocellular carcinoma, one patient had dose interruption for 2 doses based on caregiver hardship and one patient had treatment interrupted for 1 dose for mastoiditis. 11 patients were assessed at 18 months. Between Dec 11, 2013, and June 25, 2014, three participants were assessed for eligibility and enrolled at RUMC, and were assigned to receive intrathecal HPβCD at a starting dose of 200 mg every 2 weeks (two patients), or 400 mg every two weeks (one patient). There were no dropouts in this group and all 3 patients were assessed at 18 months. Biomarker studies were consistent with improved neuronal cholesterol homoeostasis and decreased neuronal pathology. Post-drug plasma 24(S)-HC area under the curve (AUC8-72) values, an indicator of neuronal cholesterol homoeostasis, were significantly higher than post-saline plasma 24(S)-HC AUC8-72 after doses of 900 mg (p=0·0063) and 1200 mg (p=0·0037). CSF 24(S)-HC concentrations in three participants given either 600 or 900 mg of HPβCD were increased about two fold (p=0·0032) after drug administration. No drug-related serious adverse events were observed. Mid-frequency to high-frequency hearing loss, an expected adverse event, was documented in all participants. When managed with hearing aids, this did not have an appreciable effect on daily communication. The NNSS for the 14 participants treated monthly increased at a rate of 1·22, SEM 0·34 points per year compared with 2·92, SEM 0·27 points per year (p=0·0002) for the 21 patient comparison group. Decreased progression was observed for NNSS domains of ambulation (p=0·0622), cognition (p=0·0040) and speech (p=0·0423). Patients with NPC1 treated with intrathecal HPβCD had slowed disease progression with an acceptable safety profile. These data support the initiation of a multinational, randomised, controlled trial of intrathecal HPβCD. National Institutes of Health, Dana's Angels Research Trust, Ara Parseghian Medical Research Foundation, Hope for Haley, Samantha's Search for the Cure Foundation, National Niemann-Pick Disease Foundation, Support of Accelerated Research for NPC Disease, Vtesse, Janssen Research and Development, a Johnson & Johnson company, and Johnson & Johnson.

High-frequency oscillatory ventilation has been advocated for hypoxemia accompanying the acute respiratory distress syndrome. In this trial comparing HFOV with conventional ventilation, HFOV had no significant effect on 30-day mortality. The acute respiratory distress syndrome (ARDS) is a severe, diffuse inflammatory lung condition caused by a range of acute illnesses. Mortality in affected patients is high, 1 and survivors may have functional limitations for years. 2 , 3 Although mechanical ventilation can initially be lifesaving in patients with ARDS, it can also further injure the patients' lungs and contribute to death. 4 High-frequency oscillatory ventilation (HFOV) was first used experimentally in the 1970s to minimize the hemodynamic effects of mechanical ventilation. 5 Patients' lungs are held inflated to maintain oxygenation, and carbon dioxide is cleared by small volumes of gas moved in and out of . . .

The evolution of charge structure involved in lightning discharge of a thunderstorm over the central Tibetan Plateau is investigated for the first time, based on the data from very high frequency interferometer, radar and sounding. During the developing‐mature stage, the TP thunderstorm exhibited a tripolar charge structure evolved from an initial inverted dipole. At the mature stage, a bottom‐heavy tripole charge structure is clearly presented, with a strong lower positive charge center (LPCC) at temperatures above −10°C, a middle negative charge region between −30°C and −15°C, and an upper positive charge region at T < −30°C. As the LPCC was depleted, the charge structure evolved into a normal tripole with a pocket LPCC. The merging between different convective cells resulted in the formation of two adjacent negative charge regions located directly and obliquely above the LPCC, and horizontally arranged different charge regions were simultaneously involved in the same lightning discharge. Plain Language Summary Tibetan Plateau thunderstorms usually exhibit special convective structures. Using the data from the accurate lightning VHF interferometer, electric field mill, fast/slow antenna and C‐band radar, the evolution of the charge structure of thunderstorms and their influence on lightning discharges are investigated. Our observation for the first time revealed the charge structure evolution of the central‐TP thunderstorm which involved in the lightning discharge, exhibiting a bottom heavy tripole charge structure with a large LPCC in the mature stage evolved from an initial inverted dipole and the usual tripole in the dissipating stage of the thunderstorm. Under different magnitudes of the LPCC, different types of lightning discharges including ‐IC, +IC and ‐CG flashes were generated, indicating the crucial effects of LPCC on the lightning discharge types. Key Points The charge structure of the TP thunderstorm evolves from an initial inverted dipole to a mature stage tripole with a strong LPCC Horizontally distributed negative charge zones from cell merger are simultaneously involved in the discharge of a single lightning flash Differences in the relative magnitude of LPCC leads to various types of lightning discharges

We present numerical and analytical predictions of mucociliary clearance based on the continuum description of a viscoelastic mucus film, where momentum transfer from the beating cilia is represented via a Navier-slip boundary condition introduced by Bottier et al. (PLoS Comput. Biol., vol. 13, issue 7, 2017a, e1005552). Mucus viscoelasticity is represented via the Oldroyd-B model, where the relaxation time and the viscosity ratio have been fitted to experimental data for the storage and loss moduli of different types of real mucus, ranging from healthy to diseased conditions. We solve numerically the fully nonlinear governing equations for inertialess flow, and develop analytical solutions via asymptotic expansion in two limits: (i) weak viscoelasticity, i.e. low Deborah number; (ii) low cilia beat amplitude (CBA). All our approaches predict a drop in the mucus flow rate in relation to the Newtonian reference value, as the cilia beat frequency is increased. This relative drop increases with decreasing CBA and slip length. In diseased conditions, e.g. mucus properties characteristic of cystic fibrosis, the drop reaches 30 % in the physiological frequency range. In the case of healthy mucus, no significant drop is observed, even at very high frequency. This contrasts with the deterioration of microorganism propulsion predicted by the low-amplitude theory of Lauga (Phys. Fluids, vol. 19, issue 8, 2007, 083104), and is due to the larger beat amplitude and slip length associated with mucociliary clearance. In the physiological range of the cilia beat frequency, the low-amplitude prediction is accurate for both healthy and diseased conditions. Finally, we find that shear-thinning, modelled via a multi-mode Giesekus model, does not significantly alter our weakly viscoelastic and low-amplitude predictions based on the Oldroyd-B model.

Background High-flow nasal cannula (HFNC) oxygen therapy is being increasingly used to prevent post-extubation hypoxemic respiratory failure and reintubation. However, evidence to support the use of HFNC in chronic obstructive pulmonary disease (COPD) patients with hypercapnic respiratory failure after extubation is limited. This study was conducted to test if HFNC is non-inferior to non-invasive ventilation (NIV) in preventing post-extubation treatment failure in COPD patients previously intubated for hypercapnic respiratory failure. Methods COPD patients with hypercapnic respiratory failure who were already receiving invasive ventilation were randomized to HFNC or NIV at extubation at two large tertiary academic teaching hospitals. The primary endpoint was treatment failure, defined as either resumption of invasive ventilation or switching to the other study treatment modality (NIV for patients in the NFNC group or vice versa). Results Ninety-six patients were randomly assigned to the HFNC group or NIV group. After secondary exclusion, 44 patients in the HFNC group and 42 patients in the NIV group were included in the analysis. The treatment failure rate in the HFNC group was 22.7% and 28.6% in the NIV group—risk difference of − 5.8% (95% CI, − 23.8–12.4%, p  = 0.535), which was significantly lower than the non-inferior margin of 9%. Analysis of the causes of treatment failure showed that treatment intolerance in the HFNC group was significantly lower than that in the NIV group, with a risk difference of − 50.0% (95% CI, − 74.6 to − 12.9%, p  = 0.015). One hour after extubation, the mean respiratory rates of both groups were faster than their baseline levels before extubation ( p  < 0.050). Twenty-four hours after extubation, the respiratory rate of the HFNC group had returned to baseline, but the NIV group was still higher than the baseline. Forty-eight hours after extubation, the respiratory rates of both groups were not significantly different from the baseline. The average number of daily airway care interventions in the NIV group was 7 (5–9.3), which was significantly higher than 6 (4–7) times in the HFNC group ( p  = 0.006). The comfort score and incidence of nasal and facial skin breakdown of the HFNC group was also significantly better than that of the NIV group [7 (6–8) vs 5 (4–7), P  < 0.001] and [0 vs 9.6%, p  = 0.027], respectively. Conclusion Among COPD patients with severe hypercapnic respiratory failure who received invasive ventilation, the use of HFNC after extubation did not result in increased rates of treatment failure compared with NIV. HFNC also had better tolerance and comfort than NIV. Trial registration chictr.org ( ChiCTR1800018530 ). Registered on 22 September 2018, http://www.chictr.org.cn/usercenter.aspx

Test the hypothesis that the center of ventilation, a measure of ventro-dorsal atelectasis, is posterior during supraglottic ventilation indicating better dependent-lung ventilation. Secondarily, we tested the hypothesis that supraglottic ventilation improves oxygenation and carbon dioxide elimination. Supraglottic and subglottic jet ventilation are both used during laryngotracheal surgery. Supraglottic jet ventilation may better prevent atelectasis and provide superior ventilation. Randomized, cross-over trial. Operating rooms. Patients having elective micro-laryngotracheal surgery. Patients were sequentially ventilated for 5 min with one randomly selected type of jet ventilation before being switched to the alternative method. Regional ventilation distribution was estimated using electrical impedance tomography, with arterial oxygenation and carbon dioxide partial pressures being simultaneously evaluated. Thirty patients completed the study. There were no statistically significant or clinically meaningful differences in the center of ventilation with supraglottic and subglottic ventilation. However, ventilation with the supraglottic approach was about 4 % higher in the ventromedial lung region and about 4 % lower in the dorsal lung. Surprisingly, arterial blood oxygenation was considerably worse with supraglottic (173 [156, 199] mmHg) than subglottic ventilation (293 [244, 340] mmHg). Arterial carbon dioxide partial pressure was near 40 mmHg with each approach, although slightly lower with supraglottic jet ventilation. The center of ventilation distribution, a measure of atelectasis, was similar with supraglottic and subglottic jet ventilation. Subglottic jet ventilation improved the dorsal-dependent lung region and provided superior arterial oxygenation. Both techniques effectively eliminated carbon dioxide, with the supraglottic approach demonstrating slightly superior efficacy. •In a cross-over trial, we compared supraglottic and subglottic jet ventilation during open-airway laryngeal surgery.•Jet ventilation did not significantly shift the overall center of ventilation as determined by EIT.•Supraglottic jet ventilation worsened ventilation in dorsal lung regions compared to subglottic jet ventilation by 4 %.•Oxygenation was substantially better with subglottic than supraglottic jet ventilation.•Either type of jet ventilation appears suitable for open-airway laryngeal surgery.