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Local translation in growth cones plays a critical role in responses to extracellular stimuli, such as axon guidance cues. We previously showed that brain-derived neurotrophic factor activates translation and enhances novel protein synthesis through the activation of mammalian target of rapamycin complex 1 signaling in growth cones of dorsal root ganglion neurons. In this study, we focused on 40S ribosomal protein S6 (RPS6), 60S ribosomal protein P0/1/2 (RPP0/1/2), and actin filaments to determine how localization of ribosomal proteins changes with overall protein synthesis induced by neurotrophins. Our quantitative analysis using immunocytochemistry and super-resolution microscopy indicated that RPS6, RPP0/1/2, and actin tend to colocalize in the absence of stimulation, and that these ribosomal proteins tend to dissociate from actin and associate with each other when local protein synthesis is enhanced. We propose that this is because stimulation causes ribosomal subunits to associate with each other to form actively translating ribosomes (polysomes). This study further clarifies the role of cytoskeletal components in local translation in growth cones.

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Rationale: Airway occlusion pressure at 100 ms (P0.1) reflects central respiratory drive. Objectives: We aimed to assess factors associated with P0.1 and whether an abnormally low or high P0.1 value is associated with higher mortality and longer duration of mechanical ventilation (MV). Methods: We performed a secondary analysis of a prospective cohort study conducted in 10 ICUs in France to evaluate dyspnea in communicative MV patients. In patients intubated for more than 24 hours, P0.1 was measured with dyspnea as soon as patients could communicate and the next day. Measurements and Main Results: Among 260 patients assessed after a median time of ventilation of 4 days, P0.1 was 1.9 (1-3.5) cm H2O at enrollment, 24% had P0.1 values >3.5 cm H2O, 37% had P0.1 values between 1.5 and 3.5 cm H2O, and 39% had P0.1 values <1.5 cm H2O. In multivariable linear regression, independent factors associated with P0.1 were the presence of dyspnea (P = 0.037), respiratory rate (P < 0.001), and PaO2 (P = 0.008). Ninety-day mortality was 33% in patients with P0.1 > 3.5 cm H2O versus 19% in those with P0.1 between 1.5 and 3.5 cm H2O and 17% in those with P0.1 < 1.5 cm H2O (P = 0.046). After adjustment for the main risk factors, P0.1 was associated with 90-day mortality (hazard ratio per 1 cm H2O, 1.19 [95% confidence interval, 1.04-1.37]; P = 0.011). P0.1 was also independently associated with a longer duration of MV (hazard ratio per 1 cm H2O, 1.10 [95% confidence interval, 1.02-1.19]; P = 0.016). Conclusions: In patients receiving invasive MV, abnormally high P0.1 values may suggest dyspnea and are associated with higher mortality and prolonged duration of MV.

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BACKGROUND: Providers should adjust the depth of sedation to promote lung-protective ventilation in patients with severe ARDS. This recommendation was based on the assumption that the depth of sedation could be used to assess respiratory drive. OBJECTIVE: To assess the association between respiratory drive and sedation in patients with severe ARDS by using ventilator-measured P0.1 and RASS score. METHODS: Loss of spontaneous breathing was observed within 48 h of mechanical ventilation in patients with severe ARDS, and spontaneous breathing returned after 48 hours. P0.1 was measured by ventilator every 12 ± 2 hours, and the RASS score was measured synchronously. RESULTS: The RASS score was moderately correlated with P0.1 (R𝑆𝑝𝑒𝑎𝑟𝑚𝑎𝑛, 0.570; 95% CI, 0.475 to 0.637; p= 0.00). However, only patients with a RASS score of -5 were considered to have no excessive respiratory drive, but there was a risk for loss of spontaneous breathing. A P0.1 exceeding 3.5 cm H2O in patients with other RASS scores indicated an increase in respiratory drive. CONCLUSION: RASS score has little clinical significance in evaluating respiratory drive in severe ARDS. P0.1 should be evaluated by ventilator when adjusting the depth of sedation to promote lung-protective ventilation.

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BACKGROUND: A variety of parameters and diaphragmatic ultrasound in ventilator weaning has been studied extensively, and the findings yield inconsistent conclusions. The parasternal intercostal muscle holds important substantial respiratory reserve capacity when the central drive is enhanced, the predictive value of combining parasternal intercostal muscle ultrasound parameters with P0.1(airway occlusion pressure at 100 msec) in assessing ventilator weaning outcomes is still unknown. OBJECTIVES: Our study aimed to evaluate the predictive efficacy of parasternal intercostal muscle ultrasound in conjunction with P0.1 in determining weaning failure. METHODS: We recruited patients who had been admitted to ICU and had been receiving mechanical ventilation for over two days. All patients underwent a half-hour spontaneous breathing trial (SBT) with low-level pressure support ventilation (PSV). They were positioned semi-upright for parasternal intercostal muscle ultrasound evaluations, including parasternal intercostal muscle thickness (PIMT), and parasternal intercostal muscle thickening fraction (PIMTF); P0.1 was obtained from the ventilator. Weaning failure was defined as the need for non-invasive positive pressure ventilation or re-intubation within 48 h post-weaning. RESULTS: Of the 56 enrolled patients with a mean age of 63.04 ± 15.80 years, 13 (23.2%) experienced weaning failure. There were differences in P0.1 (P = .001) and PIMTF (P = .017) between the two groups, but also in patients with a diaphragm thickness ≥ 2 mm. The predictive threshold values were PIMTF ≥ 13.15% and P0.1 ≥ 3.9 cmH2O for weaning failure. The AUROC for predicting weaning failure was 0.721 for PIMTF, 0.792 for P0.1, and 0.869 for the combination of PIMTF and P0.1. CONCLUSIONS: The parasternal intercostal muscle thickening fraction and P0.1 are independently linked to weaning failure, especially in patients with normal diaphragm thickness. The combination of parasternal intercostal muscle thickening fraction and P0.1 can serve as a valuable tool for the precise clinical prediction of weaning outcomes. TRIAL REGISTRATION: Chinese Clinical Trial Registry website (ChiCTR2200065422).

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BACKGROUND: Most ventilators measure airway occlusion pressure (occlusion P0.1) by occluding the breathing circuit; however, some ventilators can predict P0.1 for each breath without occlusion. Nevertheless, few studies have verified the accuracy of continuous P0.1 measurement. The aim of this study was to evaluate the accuracy of continuous P0.1 measurement compared with that of occlusion methods for various ventilators using a lung simulator. METHODS: A total of 42 breathing patterns were validated using a lung simulator in combination with 7 different inspiratory muscular pressures and 3 different rise rates to simulate normal and obstructed lungs. PB980 and Dräger V500 ventilators were used to obtain occlusion P0.1 measurements. The occlusion maneuver was performed on the ventilator, and a corresponding reference P0.1 was recorded from the ASL5000 breathing simulator simultaneously. Hamilton-C6, Hamilton-G5, and Servo-U ventilators were used to obtain sustained P0.1 measurements (continuous P0.1). The reference P0.1 measured with the simulator was analyzed by using a Bland-Altman plot. RESULTS: The 2 lung mechanical models capable of measuring occlusion P0.1 yielded values equivalent to reference P0.1 (bias and precision values were 0.51 and 1.06, respectively, for the Dräger V500, and were 0.54 and 0.91, respectively, for the PB980). Continuous P0.1 for the Hamilton-C6 was underestimated in both the normal and obstructive models (bias and precision values were -2.13 and 1.91, respectively), whereas continuous P0.1 for the Servo-U was underestimated only in the obstructive model (bias and precision values were -0.86 and 1.76, respectively). Continuous P0.1 for the Hamilton-G5 was mostly similar to but less accurate than occlusion P0.1 (bias and precision values were 1.62 and 2.06, respectively). CONCLUSIONS: The accuracy of continuous P0.1 measurements varies based on the characteristics of the ventilator and should be interpreted by considering the characteristics of each system. Moreover, measurements obtained with an occluded circuit could be desirable for determining the true P0.1.

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We aimed to identify the threshold for P0.1 in a breath-by-breath manner measured by the Hamilton C6 on quasi-occlusion for high respiratory drive and inspiratory effort. In this prospective observational study, we analyzed the relationships between airway P0.1 on quasi-occlusion and esophageal pressure (esophageal P0.1 and esophageal pressure swing). We also conducted a linear regression analysis and derived the threshold of airway P0.1 on quasi-occlusion for high respiratory drive and inspiratory effort. We found that airway P0.1 measured on quasi-occlusion had a strong positive correlation with esophageal P0.1 measured on quasi-occlusion and esophageal pressure swing, respectively. Additionally, the P0.1 threshold for high respiratory drive and inspiratory effort were calculated at approximately 1.0 cmH2O from the regression equations. Our calculations suggest a lower threshold of airway P0.1 measured by the Hamilton C6 on quasi-occlusion than that which has been previously reported.

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Patients living with Amyotrophic Lateral Sclerosis (ALS) experience respiratory weakness and, eventually, failure due to inspiratory motor neuron degeneration. Routine pulmonary function tests (e.g., maximum inspiratory pressure (MIP)) are used to assess disease progression and ventilatory compromise. However, these tests are poor discriminators between respiratory drive and voluntary respiratory function at rest. To better understand ALS disease progression, we can look into compensatory strategies and how patients consciously react to the occlusion and the effort produced to meet the ventilatory challenge of the occlusion. This ventilatory challenge, especially beyond the P0.1 (200 ms and 300 ms), provides information regarding the patient's ability to recruit additional respiratory muscles as a compensatory strategy. Utilizing a standard P0.1 protocol to assess respiratory drive, we extend the occlusion time analysis to 200 ms and 300 ms (Detected Occlusion Response (DOR)) in order to capture compensatory respiratory mechanics. Furthermore, we followed an Acute Intermittent Hypoxia (AIH) protocol known to increase phrenic nerve discharge to evaluate the compensatory strategies. Inspiratory pressure, the rate of change in pressure, and pressure generation normalized to MIP were measured at 100 ms, 200 ms, and 300 ms after an occlusion. Airway occlusions were performed three times during the experiment (i.e., baseline, 30 and 60 minutes post-AIH). Results indicated that while AIH did not elicit change in the P0.1 or MIP, the DOR increased for ALS patients. These results support the expected therapeutic role of AIH and indicate the potential of the DOR as a metric to detect compensatory changes.

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PURPOSE: Symptoms often persistent for more than 4 weeks after COVID-19-now commonly referred to as 'Long COVID'. Independent of initial disease severity or pathological pulmonary functions tests, fatigue, exertional intolerance and dyspnea are among the most common COVID-19 sequelae. We hypothesized that respiratory muscle dysfunction might be prevalent in persistently symptomatic patients after COVID-19 with self-reported exercise intolerance. METHODS: In a small cross-sectional pilot study (n = 67) of mild-to-moderate (nonhospitalized) and moderate-to-critical convalescent (formerly hospitalized) patients presenting to our outpatient clinic approx. 5 months after acute infection, we measured neuroventilatory activity P0.1, inspiratory muscle strength (PImax) and total respiratory muscle strain (P0.1/PImax) in addition to standard pulmonary functions tests, capillary blood gas analysis, 6 min walking tests and functional questionnaires. RESULTS: Pathological P0.1/PImax was found in 88% of symptomatic patients. Mean PImax was reduced in hospitalized patients, but reduced PImax was also found in 65% of nonhospitalized patients. Mean P0.1 was pathologically increased in both groups. Increased P0.1 was associated with exercise-induced deoxygenation, impaired exercise tolerance, decreased activity and productivity and worse Post-COVID-19 functional status scale. Pathological changes in P0.1, PImax or P0.1/PImax were not associated with pre-existing conditions. CONCLUSIONS: Our findings point towards respiratory muscle dysfunction as a novel aspect of COVID-19 sequelae. Thus, we strongly advocate for systematic respiratory muscle testing during the diagnostic workup of persistently symptomatic, convalescent COVID-19 patients.

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BACKGROUND: The ventilatory mechanics of patients with COPD and obesity-hypoventilation syndrome (OHS) are changed when there is air trapping and auto-PEEP, which increase respiratory effort. P0.1 measures the ventilatory drive and, indirectly, respiratory effort. The aim of the study was to measure P0.1 in subjects with COPD or OHS on treatment with positive pressure and to analyze their changes in P0.1 after treatment. METHODS: With a prospective design, subjects with COPD and OHS were studied in whom positive airway pressure was applied in their treatment. P0.1 was determined at study inclusion and after 6 months of treatment. RESULTS: A total of 88 subjects were analyzed: 56% were males, and the mean age of 65 ± 9 y old. Fifty-four (61%) had OHS, and 34 (39%) had COPD. Fifty (56%) had air trapping, with an initial P0.1 value of 3.0 ± 1.3 cm H2O compared with 2.1 ± 0.7 cm H2O for subjects who did not have air trapping (P = .001). After 6 months of treatment, subjects who had air trapping had similar P0.1 as those who did not: 2.3 ± 1.1 and 2.1 ± 1 cm H2O, respectively (P = .53). In subjects with COPD, initial P0.1 was 2.9 ± 1.4 cm H2O and at 6 months 2.2 ± 1.1 cm H2O (P = .02). In subjects with OHS, initial P0.1 was 2.4 ± 1.1 cm H2O and at 6 months 2.2 ± 1.0 cm H2O (P = .28). CONCLUSIONS: COPD and air trapping were associated with greater P0.1 as a marker of respiratory effort. A decrease in P0.1 indicates less respiratory effort after treatment.

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PURPOSE: Increased respiratory drive and respiratory effort are major features of acute hypoxemic respiratory failure (AHRF) and might help to predict the need for intubation. We aimed to explore the feasibility of a non-invasive respiratory drive evaluation and describe how these parameters may help to predict the need for intubation. MATERIALS AND METHODS: We conducted a prospective observational study. All consecutive patients with COVID-19-related AHRF requiring high-flow nasal cannula (HFNC) were screened for inclusion. Physiologic data (including: occlusion pressure (P0.1), tidal volume (Vt), inspiratory time (Ti), peak and mean inspiratory flow (Vt/Ti)) were collected during a short continuous positive airway pressure (CPAP) session. Measurements were repeated once, 12-24 h later. RESULTS: Measurements were completed in 31 patients after the screening of 45 patients (70%). P0.1 was high (4.4 [2.7-5.1]), but it was not significantly higher in patients who were intubated. The Vt (p = .006), Vt/Ti (p = .019), minute ventilation (p = .006), and Ti/Ttot (p = .003) were higher among intubated patients compared to non-intubated patients. Intubated patients had a significant increase in their diaphragm thickening fraction, Vt, and Vt/Ti over time. CONCLUSIONS: Non-invasive assessment of respiratory drive was feasible in patients with AHRF and showed an increased P0.1, although it was not predictive of intubation.

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PURPOSE: The predictive value of airway occlusion pressure at 100 milliseconds (P0.1) on weaning outcome has been controversial. We performed a meta-analysis to investigate the predictive value of P0.1 on successful weaning from mechanical ventilation. MATERIALS AND METHODS: We searched MEDLINE, Cochrane Central Register of Controlled Trials, and EMBASE, and two authors independently screened articles. The pooled sensitivity, specificity and the summary receiver operating characteristic (sROC) curve were estimated. Diagnostic odds ratio (DOR) was calculated using meta-regression analysis. RESULTS: We included 12 prospective observational studies (n = 1089 patients). Analyses of sROC curves showed the area under the curve of 0.81 (95% confidence interval (CI): 0.77 to 0.84) for P0.1. The pooled sensitivity and specificity were 86% (95% CI, 72 to 94%) and 58% (95% CI, 37% to 76%) with substantial heterogeneity respectively. DOR was 20.09 (p = 0.019, 95%CI: 1.63-247.15). After filling the missing data using the trim-and-fill method to adjust publication bias, DOR was 36.23 (p = 0.002, 95%CI: 3.56-372.41). CONCLUSION: This meta-analysis suggests that P0.1 is a useful tool to predict successful weaning. To determine clinical utility, a large prospective study investigating the sensitivity and specificity of P0.1 on weaning outcomes from mechanical ventilation is warranted.

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Rationale: Monitoring and controlling respiratory drive and effort may help to minimize lung and diaphragm injury. Airway occlusion pressure (P0.1) is a noninvasive measure of respiratory drive.Objectives: To determine 1) the validity of "ventilator" P0.1 (P0.1vent) displayed on the screen as a measure of drive, 2) the ability of P0.1 to detect potentially injurious levels of effort, and 3) how P0.1vent displayed by different ventilators compares to a "reference" P0.1 (P0.1ref) measured from airway pressure recording during an occlusion.Methods: Analysis of three studies in patients, one in healthy subjects, under assisted ventilation, and a bench study with six ventilators. P0.1vent was validated against measures of drive (electrical activity of the diaphragm and muscular pressure over time) and P0.1ref. Performance of P0.1ref and P0.1vent to detect predefined potentially injurious effort was tested using derivation and validation datasets using esophageal pressure-time product as the reference standard.Measurements and Main Results: P0.1vent correlated well with measures of drive and with the esophageal pressure-time product (within-subjects R2 = 0.8). P0.1ref >3.5 cm H2O was 80% sensitive and 77% specific for detecting high effort (≥200 cm H2O ⋅ s ⋅ min-1); P0.1ref ≤1.0 cm H2O was 100% sensitive and 92% specific for low effort (≤50 cm H2O ⋅ s ⋅ min-1). The area under the receiver operating characteristics curve for P0.1vent to detect potentially high and low effort were 0.81 and 0.92, respectively. Bench experiments showed a low mean bias for P0.1vent compared with P0.1ref for most ventilators but precision varied; in patients, precision was lower. Ventilators estimating P0.1vent without occlusions could underestimate P0.1ref.Conclusions: P0.1 is a reliable bedside tool to assess respiratory drive and detect potentially injurious inspiratory effort.

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Objective: The goal of this study is to evaluate pulmonary function and respiratory center drive in patients with early-stage idiopathic Parkinson's disease (IPD) to facilitate early diagnosis of Parkinson's Disease (PD). Methods: 43 IPD patients (Hoehn and Yahr scale of 1) and 41 matched healthy individuals (e.g., age, sex, height, weight, BMI) were enrolled in this study. Motor status was evaluated using the Movement Disorders Society-Unified PD Rating Scale (MDS-UPDRS). Pulmonary function and respiratory center drive were measured using pulmonary function tests (PFT). All IPD patients were also subjected to a series of neuropsychological tests, including Non-Motor Symptoms Questionnaire (NMSQ), REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ), Beck Depression Inventory (BDI) and Mini Mental State Examination (MMSE). Results: IPD patients and healthy individuals have similar forced vital capacity (FVC), forced expiratory volume in 1s (FEV1), forced expiratory volume in 1s/forced vital capacity (FEV1/FVC), peak expiratory flow (PEF), and carbon monoxide diffusion capacity (DLCOcSB). Reduced respiratory muscle strength, maximal inspiratory pressure (PImax) and maximal expiratory pressure (PEmax) was seen in IPD patients (p = 0.000 and p = 0.002, respectively). Importantly, the airway occlusion pressure after 0.1 s (P0.1) and respiratory center output were notably higher in IPD patients (p = 0.000) with a remarkable separation of measured values compared to healthy controls. Conclusion: Our findings suggest that abnormal pulmonary function is present in early stage IPD patients as evidenced by significant changes in PImax, PEmax, and P0.1. Most importantly, P0.1 may have the potential to assist with the identification of IPD in the early stage.

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BACKGROUND: Hyperoxia-induced hypercapnia in subjects with COPD is mainly explained by alterations in the ventilation/perfusion ratio. However, it is unclear why respiratory drive does not prevent CO2 retention. Some authors have highlighted the importance of respiratory drive in CO2 increases during hyperoxia. The aim of the study was to examine the effects of hyperoxia on respiratory drive in subjects with COPD. METHODS: Fourteen intubated, ready-to-wean subjects with COPD were studied during normoxia and hyperoxia. A CO2 response test was then performed with the rebreathing method to measure the hypercapnic drive response, defined as the ratio of change in airway-occlusion pressure 0.1 s after the start of inspiratory flow (ΔP(0.1)) to change in P(aCO2) (ΔP(aCO2)), and the hypercapnic ventilatory response, defined as the ratio of change in minute volume (ΔV̇(E)) to ΔP(aCO2). RESULTS: Hyperoxia produced a significant increase in P(aCO2) (55 ± 9 vs 58 ± 10 mm Hg, P = .02) and a decrease in pH (7.41 ± 0.05 vs 7.38 ± 0.05, P = .01) compared with normoxia, with a non-significant decrease in V̇(E) (9.9 ± 2.9 vs 9.1 ± 2.3 L/min, P = .16) and no changes in P(0.1) (2.85 ± 1.40 vs 2.82 ± 1.16 cm H2O, P = .97) The correlation between hyperoxia-induced changes in V̇(E) and P(aCO2) was r(2) = 0.38 (P = .02). Median ΔP(0.1)/ΔP(aCO2) and ΔV̇(E)/ΔP(aCO2) did not show significant differences between normoxia and hyperoxia: 0.22 (0.12-0.49) cm H2O/mm Hg versus 0.25 (0.14-0.34) cm H2O/mm Hg (P = .30) and 0.37 (0.12-0.54) L/min/mm Hg versus 0.35 (0.12-0.96) L/min/mm Hg (P = .20), respectively. CONCLUSIONS: In ready-to-wean subjects with COPD exacerbations, hyperoxia is followed by an increase in P(aCO2), but it does not significantly modify the respiratory drive or the ventilatory response to hypercapnia.

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