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Background Assessing fluid responsiveness is problematic for critically ill patients with spontaneous breathing activity, such as during Pressure Support Ventilation (PSV), since spontaneous breathing activity physiologically affects heart–lung interplay. We compared the reliability of two hemodynamic tests in predicting fluid responsiveness in this clinical setting: SIGH 35 , based on a ventilator-generated sigh applied at 35 cmH 2 O for 4 s and the end-expiratory occlusion test (EEOT). Methods Prospective study conducted in a general intensive care unit (ICU) and enrolling patients in PSV showing different inspiratory effort [assessed by airway occlusion pressure (P0.1)] and requiring volume expansion (VE). Hemodynamic variables were recorded by means of the MOSTCARE ® system, patient received a VE using 4 ml/kg of crystalloids over 10 min and were considered responders if a cardiac output (CO) ≥ 10% was observed. The reliability of SIGH 35 and EEOT in discriminating fluid responsiveness was assessed using receiver operating characteristic (ROC) curve approach and the area (AUC) under ROC curves was compared. For the EEOT, we considered the percent changes of CO between baseline the end of the test, while for the SIGH 35 , the percent changes of pulse pressure (PP) between baseline and the lowest value recorded after SIGH 35 application. Results Sixty ICU patients were enrolled, and 56 patients analysed. The AUC of PP changes after SIGH 35 was 0.93 (0.84–0.99) [sensitivity of 93.1% (78.0–98.7%); specificity of 91.6 (73.0–98.9%)]; best threshold − 25% PP from baseline (grey zone − 15%/35%)]; and greater than the AUC of CO changes after EEOT [0.67 (0.52–0.81); sensitivity of 72.4% (54.3–85.3%) specificity of 70.3% (73.0–98.9%)]; best threshold 4% of CO increase from baseline (grey zone − 1%/10%)]. In the subgroup having a P0.1 < 1.5 cmH 2 O, the AUC of SIGH 35 [0.98 (0.94–0.99)] and of EEOT [0.89 (0.72–0.99] were comparable ( p  = 0.26). Conclusions In a selected ICU population undergoing PSV, SGH 35 reliably predicted fluid responsiveness and performed better than the EEOT, which is, however, still reliable in the subgroup of ICU patients having a small extent of inspiratory efforts.

We explored neural mechanisms underlying sighing in mice. Photostimulation of parafacial (pF) neuromedin B (NMB) or gastrin-releasing peptide (GRP), or preBötzinger Complex (preBötC) NMBR or GRPR neurons elicited ectopic sighs with latency inversely related to time from preceding endogenous sigh. Of particular note, ectopic sighs could be produced without involvement of these peptides or their receptors in preBötC. Moreover, chemogenetic or optogenetic activation of preBötC SST neurons induced sighing, even in the presence of NMBR and/or GRPR antagonists. We propose that an increase in the excitability of preBötC NMBR or GRPR neurons not requiring activation of their peptide receptors activates partially overlapping pathways to generate sighs, and that preBötC SST neurons are a downstream element in the sigh generation circuit that converts normal breaths into sighs.

Objective To evaluate differences regarding sigh frequency between noninvasive respiratory support types and to assess regional ventilation distribution, delta Z, and end-expiratory lung impedance differences before and after sighs. Methods Very low-birth-weight infants with gestational ages less than 32 wk were included in the study. Participants were split into two groups: those receiving continuous positive airway pressure and infants receiving high-flow nasal cannula therapy. Results The study enrolled 30 infants. The high-flow nasal cannula therapy group had more sighs per 10-min period than infants receiving continuous positive airway pressure ( p  = 0.016). Ventilation distribution was similar in the anterior and right ventilation distribution compartments pre- and post-sigh (46.30% vs. 45.68% and 54.27% vs. 55.26%, respectively). No statistically significant increase in end-expiratory lung impedance or delta Z was observed in global or separate lung regions ( p  > 0.05). Conclusion The study has demonstrated that sighs are more frequent in infants receiving high-flow nasal cannula respiratory support compared to continuous positive airway pressure. Spontaneously occurring sighs on noninvasive respiratory support due to respiratory distress syndrome (RDS) do not increase end-expiratory lung impedance or alter delta Z, and appear to have limited clinical significance. Trial Registration Prospectively registered at www.clinicaltrials.gov , reg. No. NCT04542096, reg. date 01/09/2020.

Background Assessment of fluid responsiveness is problematic in intensive care unit (ICU) patients, in particular for those undergoing modes of partial support, such as pressure support ventilation (PSV). We propose a new test, based on application of a ventilator-generated sigh, to predict fluid responsiveness in ICU patients undergoing PSV. Methods This was a prospective bi-centric interventional study conducted in two general ICUs. In 40 critically ill patients with a stable ventilatory PSV pattern and requiring volume expansion (VE), we assessed the variations in arterial systolic pressure (SAP), pulse pressure (PP) and stroke volume index (SVI) consequent to random application of 4-s sighs at three different inspiratory pressures. A radial arterial signal was directed to the MOSTCARE™ pulse contour hemodynamic monitoring system for hemodynamic measurements. Data obtained during sigh tests were recorded beat by beat, while all the hemodynamic parameters were averaged over 30 s for the remaining period of the study protocol. VE consisted of 500 mL of crystalloids over 10 min. A patient was considered a responder if a VE-induced increase in cardiac index (CI) ≥ 15% was observed. Results The slopes for SAP, SVI and PP of were all significantly different between responders and non-responders ( p  < 0.0001, p  = 0.0004 and p  < 0.0001, respectively). The AUC of the slope of SAP (0.99; sensitivity 100.0% (79.4–100.0%) and specificity 95.8% (78.8–99.9%) was significantly greater than the AUC for PP (0.91) and SVI (0.83) ( p  = 0.04 and 0.009, respectively). The SAP slope best threshold value of the ROC curve was − 4.4° from baseline. The only parameter found to be independently associated with fluid responsiveness among those included in the logistic regression was the slope for SAP ( p  = 0.009; odds ratio 0.27 (95% confidence interval (CI 95 ) 0.10–0.70)). The effects produced by the sigh at 35 cmH 2 0 (Sigh 35 ) are significantly different between responders and non-responders. For a 35% reduction in PP from baseline, the AUC was 0.91 (CI 95 0.82–0.99), with sensitivity 75.0% and specificity 91.6%. Conclusions In a selected ICU population undergoing PSV, analysis of the slope for SAP after the application of three successive sighs and the nadir of PP after Sigh 35 reliably predict fluid responsiveness. Trial registration Australian New Zealand Clinical Trials Registry, ACTRN12615001232527 . Registered on 10 November 2015.

Background High-frequency oscillatory ventilation (HFOV) is widely used in neonates with respiratory distress syndrome (RDS) to optimize lung recruitment while minimizing ventilator-induced lung injury. Sigh breaths have been incorporated into HFOV to improve alveolar recruitment in cases of atelectasis. However, the safety of this approach, particularly in extremely preterm neonates, remains unclear. This study aimed to evaluate whether the use of sigh breaths during HFOV increased the risk of developing tension pneumothorax within the first 96 h after birth in neonates born at 22–25 weeks of gestation with RDS. Methods This retrospective cohort study included neonates born at 22–25 weeks of gestation between 2014 and 2023 who required rescue HFOV within 4 h of birth due to respiratory acidosis. Among 66 eligible neonates, 2 were excluded due to congenital anomalies, leaving 64 included for analysis. The study population was categorized into three groups: (1) neonates with atelectasis who received sigh breaths ( n  = 16), (2) neonates with atelectasis who did not receive sigh breaths ( n  = 3), and (3) neonates without atelectasis who did not receive sigh breaths ( n  = 45). The primary outcome was the incidence of tension pneumothorax within 12–96 h post-birth. Results Tension pneumothorax occurred in 10 neonates (15.6%). Bivariable analysis revealed a significant association between the use of sigh breaths and tension pneumothorax ( p  = 0.007). Firth’s penalized logistic regression demonstrated that neonates with atelectasis who received sigh breaths had a significantly higher risk of developing tension pneumothorax (odds ratio = 5.5, 95% confidence interval: 1.2–23.9, p  = 0.02) compared to those without atelectasis who did not receive sigh breaths. In contrast, no significant difference was observed between neonates with and without atelectasis who did not receive sigh breaths. Conclusions While sigh breaths during HFOV may facilitate alveolar recruitment in preterm neonates with atelectasis, their use appears to significantly increase the risk of tension pneumothorax. Given the vulnerability of extremely preterm lungs, caution is required when implementing sigh breaths in this population. Further prospective studies are needed to refine ventilation strategies and minimize complications in extremely preterm neonates.

Mycobacteroides abscessus is an opportunistic pathogen ubiquitous in the environment owing to its ability to remain viable on nutrient-poor surfaces. It is a frequent cause of infections in the cosmetic industry, with patients being infected through cutaneous invasive procedures such as tattooing, piercings and cosmetic surgeries. In immunocompromised hosts, infections can be severe and difficult to treat as M. abscessus has many intrinsic and acquired resistances to different classes of antibiotics. Tigecycline, a tetracycline derivative introduced two decades ago, is a broad-spectrum antibiotic with activity on bacteria that are resistant to many existing antibiotics. Unfortunately, tigecycline-resistant strains of M. abscessus have been reported in recent years. This study aimed to investigate the resistance mechanism of CL7, a tigecycline-resistant, spontaneous mutant derived from M. abscessus ATCC 19977. CL7 notably had a 7 amino-acid truncation in the SigH protein, a sigma factor (transcriptional activator) responsible for mycobacterial responses to environmental stress. RNA sequencing showed that sigH and other genes were up-regulated in CL7 (as compared to ATCC 19977). The gene set enrichment analysis demonstrated that the SigH regulon was significantly over-represented among these genes up-regulated in CL7. A bacterial-2-hybrid assay was performed to investigate the effect of the mutation on the SigH interaction with RshA, the anti-sigma factor that inhibits SigH intracellularly. The results, supported by RNA sequencing, showed that the interaction between RshA and the mutant SigH was impeded. This reduced interaction could lead to a decreased inhibition of SigH by RshA, causing the up-regulation of the sigH gene. Coupled with the RNA polymerase, SigH would then up-regulate genes under its regulation, leading to tigecycline resistance. In general, this study enhances our understanding of tigecycline resistance mechanisms in M. abscessus , and contributes to the development of novel antibacterial therapies and diagnostic tools for managing M. abscessus infections.

Background Sigh breaths may impact outcomes in acute hypoxemic respiratory failure (AHRF) during assisted mechanical ventilation. We investigated whether sigh breaths may impact mortality in predefined subgroups of patients enrolled in the PROTECTION multicenter clinical trial according to: 1.the physiological response in oxygenation to Sigh (responders versus non-responders) and 2.the set levels of positive end-expiratory pressure (PEEP) (High vs. Low-PEEP). If mortality differed between Sigh and No Sigh, we explored physiological daily differences at 7-days. Results Patients were randomized to pressure support ventilation (PSV) with Sigh (Sigh group) versus PSV with no sigh (No Sigh group). (1) Sighs were not associated with differences in 28-day mortality in responders to baseline sigh-test. Contrarily-in non-responders-56 patients were randomized to Sigh (55%) and 28-day mortality was lower with sighs (17%vs.36%, log-rank p = 0.031). (2) In patients with PEEP > 8cmH 2 O no difference in mortality was observed with sighs. With Low-PEEP, 54 patients were randomized to Sigh (48%). Mortality at 28-day was reduced in patients randomised to sighs (13%vs.31%, log-rank p = 0.021). These findings were robust to multivariable adjustments. Tidal volume, respiratory rate and ventilatory ratio decreased with Sigh as compared with No Sigh at 7-days. Ventilatory ratio was associated with mortality and successful extubation in both non-responders and Low-PEEP. Conclusions Addition of Sigh to PSV could reduce mortality in AHRF non-responder to Sigh and exposed to Low-PEEP. Results in non-responders were not expected. Findings in the low PEEP group may indicate that insufficient PEEP was used or that Low PEEP may be used with Sigh. Sigh may reduce mortality by decreasing physiologic dead space and ventilation intensity and/or optimizing ventilation/perfusion mismatch. Clinical Trial Registration : ClinicalTrials.gov; Identifier: NCT03201263.

Excessive sighs have been described as one type of dysfunctional breathing (DB). Cardiopulmonary exercise testing (CPET) is one of the diagnostic options for DB and allows for a subjective evaluation of sighs. However, no validated method exists to automatically quantify sighs during CPET. We aimed to develop such a method. We used two Swiss cohorts of patients with persistent dyspnea after SARS-CoV-2 infection using CPET. In the derivation cohort (n = 48), we tested different filters to find the one that was the least influenced by outliers of tidal volume (VT) using a subjective approach. The selected filter (rolling median of 15 values) was applied in the validation cohort (n = 77) to detect spikes of VT above 2 times the value of the associated centered filtered value. Every automatically detected spike of VT from the cohort was analyzed by two experienced raters using continuous volume and flow-over-time graphs reconstructed from high resolution data acquisition. In the validation cohort, 203 automatically detected spikes of VT were visually analyzed by two raters. Of the 203 detected spikes, 199 corresponded to a sigh. The Cohen’s Kappa (95% CI) between the raters was 0.89 (0.67–1). In conclusion, we developed a simple automated method for the objective quantification of sighs during CPET. It could be used to establish normative values of sighs during CPET and explore the associations between sighs and symptoms of patients with DB.

The respiratory system maintains homeostatic levels of oxygen (O 2 ) and carbon dioxide (CO 2 ) in the body through rapid and efficient regulation of breathing frequency and depth (tidal volume). The commonly used methods of analyzing breathing data in behaving experimental animals are usually subjective, laborious, and time-consuming. To overcome these hurdles, we optimized an analysis toolkit for the unsupervised study of respiratory activities in animal subjects. Using this tool, we analyzed breathing behaviors of the common marmoset ( Callithrix jacchus ), a New World non-human primate model. Using whole-body plethysmography in room air as well as acute hypoxic (10% O 2 ) and hypercapnic (6% CO 2 ) conditions, we describe breathing behaviors in awake, freely behaving marmosets. Our data indicate that marmosets’ exposure to acute hypoxia decreased metabolic rate and increased sigh rate. However, the hypoxic condition did not augment ventilation. Hypercapnia, on the other hand, increased both the frequency and depth (i.e., tidal volume) of breathing.

Background Corynebacterium glutamicum is used in the industrial production of amino acids and nucleotides. During the course of fermentation, C. glutamicum cells face various stresses and employ multiple regulatory genes to cope with the oxidative stress. The osnR gene plays a negative regulatory role in redox-dependent oxidative-stress responses, but the underlying mechanism is not known yet. Results Overexpression of the osnR gene in C. glutamicum affected the expression of genes involved in the mycothiol metabolism. ChIP-seq analysis revealed that OsnR binds to the promoter region of multiple genes, including osnR and cg0026, which seems to function in the membrane-associated redox metabolism. Studies on the role of the osnR gene involving in vitro assays employing purified OsnR proteins and in vivo physiological analyses have identified that OsnR inhibits the transcription of its own gene. Further, oxidant diamide stimulates OsnR-binding to the promoter region of the osnR gene. The genes affected by the overexpression of osnR have been found to be under the control of σ H . In the osnR -overexpressing strain, the transcription of sigH is significantly decreased and the stimulation of sigH transcription by external stress is lost, suggesting that osnR and sigH form an intimate regulatory network. Conclusions Our study suggests that OsnR not only functions as a transcriptional repressor of its own gene and of those involved in redox-dependent stress responses but also participates in the global transcriptional regulation by controlling the transcription of other master regulators, such as sigH .