Psychoactive substances for the treatment of neuropsychiatric disorders.

In the contemporary landscape of psychiatric medicine, critical advancements have been noted in the utilization of psychoactive substances such as hallucinogens, 3,4-methylenedioxymethamphetamine (MDMA), and ketamine for the treatment of severe mental health disorders. This review provides a detailed evaluation of these substances, focusing on their mechanisms of action and the profound clinical outcomes observed in controlled environments. Hallucinogens like lysergic acid diethylamide and psilocybin primarily target the 5-HT2A receptor agonist-2 (5-HT2AR), inducing substantial perceptual and cognitive shifts that facilitate deep psychological introspection and significant therapeutic advances, particularly in patients suffering from depression and anxiety disorders. MDMA, influencing multiple neurotransmitter systems including 5-Hydroxytryptamine (5-HT), dopamine, and norepinephrine, has been demonstrated to effectively alleviate symptoms of post-traumatic stress disorder, enhancing patients' emotional engagement and resilience during psychotherapy. Meanwhile, ketamine, a glutamate receptor antagonist, rapidly alleviates depressive symptoms, offering a lifeline for individuals with treatment-resistant depression through its fast-acting antidepressant properties. The integration of these substances into psychiatric practice has shown promising results, fundamentally changing the therapeutic landscape for patients unresponsive to traditional treatment modalities. However, the potent effects of these agents also necessitate a cautious approach in clinical application, ensuring careful dosage control, monitoring, and risk management to prevent potential abuse and mitigate adverse effects.

Physiologic Comparison of Airway Pressure Release Ventilation and Low Tidal Volume Ventilation in ARDS: A Randomized Controlled Trial.

BACKGROUND: The physiologic effects of different ventilation strategies on patients with ARDS)need to be understood better. RESEARCH QUESTION: In patients with ARDS receiving controlled mandatory ventilation, does airway pressure release ventilation (APRV) improve lung ventilation/perfusion (V˙/Q˙) matching and ventilation homogeneity compared with low tidal volume (LTV) ventilation? STUDY DESIGN AND METHODS: This study was a single-center randomized controlled trial. Patients with moderate to severe ARDS were ventilated randomly with APRV or LTV ventilation. Electrical impedance tomography (EIT) was used to assess lung ventilation and perfusion. EIT-based data and clinical variables related to respiratory and hemodynamic conditions were collected shortly before randomization (0 hours) and at 12 and 24 hours after randomization. RESULTS: A total of 40 patients were included and randomized to the APRV or LTV ventilation group (20 per group). During the 24-hour trial period, patients receiving APRV exhibited significantly increased dorsal ventilation (difference value [24 hours minus 0 hours]: median, 10.82% [interquartile range (IQR), 2.62%-13.74%] vs 0.12% [IQR, -2.81% to 4.76%]; P = .017), decreased dorsal shunt (median, -4.67% [IQR, -6.83% to 0.59%] vs 1.73% [IQR, -0.95% to 5.53%]; P = .008), and increased dorsal V˙/Q˙ matching (median, 4.13% [IQR, -0.26% to 10.47%] vs -3.29% [IQR, -5.05% to 2.81%]; P = .026) than those receiving LTV ventilation. No difference in ventral dead space was observed between study groups (P = .903). Additionally, 2 indicators of ventilation distribution heterogeneity, global inhomogeneity index and center of ventilation, significantly decreased and significantly increased, respectively, in the APRV group compared with the LTV ventilation group. Patients receiving APRV showed significantly higher Pao2 to Fio2 ratio, higher respiratory system static compliance (Crs) and lower Paco2 than those receiving LTV ventilation at 24 hours. The cardiac output was comparable in both groups. INTERPRETATION: APRV, as compared with LTV ventilation, could recruit dorsal region, reduce dorsal shunt, increase dorsal V˙/Q˙ matching, and improve ventilation homogeneity of the lungs, leading to better gas exchange and Crs in patients with moderate to severe ARDS. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT05767125; URL: www. CLINICALTRIALS: gov.

Effects of different VV ECMO blood flow rates on lung perfusion assessment by hypertonic saline bolus-based electrical impedance tomography.

OBJECTIVE: Our study aimed to investigate the effects of different extracorporeal membrane oxygenation (ECMO) blood flow rates on lung perfusion assessment using the saline bolus-based electrical impedance tomography (EIT) technique in patients on veno-venous (VV) ECMO. METHODS: In this single-centered prospective physiological study, patients on VV ECMO who met the ECMO weaning criteria were assessed for lung perfusion using saline bolus-based EIT at various ECMO blood flow rates (gradually decreased from 4.5 L/min to 3.5 L/min, 2.5 L/min, 1.5 L/min, and finally to 0 L/min). Lung perfusion distribution, dead space, shunt, ventilation/perfusion matching, and recirculation fraction at different flow rates were compared. RESULTS: Fifteen patients were included. As the ECMO blood flow rate decreased from 4.5 L/min to 0 L/min, the recirculation fraction decreased significantly. The main EIT-based findings were as follows. (1) Median lung perfusion significantly increased in region-of-interest (ROI) 2 and the ventral region [38.21 (34.93-42.16)% to 41.29 (35.32-43.75)%, p = 0.003, and 48.86 (45.53-58.96)% to 54.12 (45.07-61.16)%, p = 0.037, respectively], whereas it significantly decreased in ROI 4 and the dorsal region [7.87 (5.42-9.78)% to 6.08 (5.27-9.34)%, p = 0.049, and 51.14 (41.04-54.47)% to 45.88 (38.84-54.93)%, p = 0.037, respectively]. (2) Dead space significantly decreased, and ventilation/perfusion matching significantly increased in both the ventral and global regions. (3) No significant variations were observed in regional and global shunt. CONCLUSIONS: During VV ECMO, the ECMO blood flow rate, closely linked to recirculation fraction, could affect the accuracy of lung perfusion assessment using hypertonic saline bolus-based EIT.

Gut-derived memory γδ T17 cells exacerbate sepsis-induced acute lung injury in mice.

Sepsis is a critical global health concern linked to high mortality rates, often due to acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). While the gut-lung axis involvement in ALI is recognized, direct migration of gut immune cells to the lung remains unclear. Our study reveals sepsis-induced migration of γδ T17 cells from the small intestine to the lung, triggering an IL-17A-dominated inflammatory response in mice. Wnt signaling activation in alveolar macrophages drives CCL1 upregulation, facilitating γδ T17 cell migration. CD44+ Ly6C- IL-7Rhigh CD8low cells are the primary migratory subtype exacerbating ALI. Esketamine attenuates ALI by inhibiting pulmonary Wnt/ß-catenin signaling-mediated migration. This work underscores the pivotal role of direct gut-to-lung memory γδ T17 cell migration in septic ALI and clarifies the importance of localized IL-17A elevation in the lung.

The potential immunological mechanisms of sepsis.

Sepsis is described as a life-threatening organ dysfunction and a heterogeneous syndrome that is a leading cause of morbidity and mortality in intensive care settings. Severe sepsis could incite an uncontrollable surge of inflammatory cytokines, and the host immune system's immunosuppression could respond to counter excessive inflammatory responses, characterized by the accumulated anti-inflammatory cytokines, impaired function of immune cells, over-proliferation of myeloid-derived suppressor cells and regulatory T cells, depletion of immune effector cells by different means of death, etc. In this review, we delve into the underlying pathological mechanisms of sepsis, emphasizing both the hyperinflammatory phase and the associated immunosuppression. We offer an in-depth exploration of the critical mechanisms underlying sepsis, spanning from individual immune cells to a holistic organ perspective, and further down to the epigenetic and metabolic reprogramming. Furthermore, we outline the strengths of artificial intelligence in analyzing extensive datasets pertaining to septic patients, showcasing how classifiers trained on various clinical data sources can identify distinct sepsis phenotypes and thus to guide personalized therapy strategies for the management of sepsis. Additionally, we provide a comprehensive summary of recent, reliable biomarkers for hyperinflammatory and immunosuppressive states, facilitating more precise and expedited diagnosis of sepsis.

Gut-brain axis in the pathogenesis of sepsis-associated encephalopathy.

The gut-brain axis is a bidirectional communication network linking the gut and the brain, overseeing digestive functions, emotional responses, body immunity, brain development, and overall health. Substantial research highlights a connection between disruptions of the gut-brain axis and various psychiatric and neurological conditions, including depression and Alzheimer's disease. Given the impact of the gut-brain axis on behavior, cognition, and brain diseases, some studies have started to pay attention to the role of the axis in sepsis-associated encephalopathy (SAE), where cognitive impairment is the primary manifestation. SAE emerges as the primary and earliest form of organ dysfunction following sepsis, potentially leading to acute cognitive impairment and long-term cognitive decline in patients. Notably, the neuronal damage in SAE does not stem directly from the central nervous system (CNS) infection but rather from an infection occurring outside the brain. The gut-brain axis is posited as a pivotal factor in this process. This review will delve into the gut-brain axis, exploring four crucial pathways through which inflammatory signals are transmitted and elevate the incidence of SAE. These pathways encompass the vagus nerve pathway, the neuroendocrine pathway involving the hypothalamic-pituitary-adrenal (HPA) axis and serotonin (5-HT) regulation, the neuroimmune pathway, and the microbial regulation. These pathways can operate independently or collaboratively on the CNS to modulate brain activity. Understanding how the gut affects and regulates the CNS could offer the potential to identify novel targets for preventing and treating this condition, ultimately enhancing the prognosis for individuals with SAE.

The early predictive roles of NLR and NE% in in-hospital mortality of septic patients.

Background: This study aimed to retrospectively investigate the early predictive value of inflammation-related parameters in-hospital mortality of septic patients. Methods: We retrospectively recruited 606 patients from Wuhan Union Hospital from January 2009 to October 2022. The inflammation-related parameters including neutrophil-to-lymphocyte ratio (NLR), neutrophil percentage (NE%), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) in survivals and non-survivals on day 1, 2, 3 and 7 after hospitalization were collected and analyzed. Results: NLR and NE% in non-survivals (n = 185) were significantly higher than those in survivals (n = 421). The area under the receiver operating characteristic curve (AUC) of NLR or NE% was 0.880 or 0.852 on day 1, 0.770 or 0.790 on day 2, 0.784 or 0.777 on day 3, and 0.732 or 0.741 on day 7. The optimal cut-off values of NLR or NE% for predicting in-hospital mortality were 10.769 or 87.70% on day 1, 17.544 or 90.69% on day 2, 14.395 or 85.00% on day 3, and 9.105 or 83.93% on day 7. The day 1, 2 and 3 NLR and NE% were significant predictors of in-hospital mortality in the Cox proportional hazards models. Conclusions: NLR ≥10.769 and NE% ≥ 87.70% could be used early biomarkers for predicting in-hospital mortality of septic patients.

Aldehyde Dehydrogenase 2 Preserves Mitochondrial Function in the Ischemic Heart: A Redox-dependent Mechanism for AMPK Activation by Thioredoxin-1.

ABSTRACT: Aldehyde dehydrogenase 2 (ALDH2) protects the ischemic heart by activating adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling. However, the molecular mechanisms linking ALDH2 and AMPK signaling are not fully understood. This study aimed to explore the potential mechanisms linking ALDH2 and AMPK in myocardial ischemic injury. An ischemic model was established by ligating the left anterior descending coronary artery in rats. The overexpression or knockdown of ALDH2 in H9c2 cells treated with oxygen-glucose deprivation was obtained through lentivirus infection. Transferase-mediated dUTP nick-end labeling was used to evaluate apoptosis in an ischemic rat model and oxygen-glucose deprivation cells. ALDH2 activity, mitochondrial oxidative stress markers, adenosine triphosphate, respiratory control ratio, and cell viability in H9c2 cells were evaluated using a biological kit and 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide. Protein expression of ALDH2 , 4-hydroxynonenal, thioredoxin-1 (Trx-1), and AMPK-proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) signaling pathway was detected through Western blotting. ALDH2 activation reduced ischemic-induced myocardial infarct size and apoptosis. ALDH2 protected mitochondrial function by enhancing mitochondrial respiratory control ratio and adenosine triphosphate production, alleviated mitochondrial oxidative stress, and suppressed myocardial apoptosis. Moreover, ALDH2 attenuated ischemia-induced oxidative stress and maintained Trx-1 levels by reducing 4-hydroxynonenal, thereby promoting AMPK-PGC-1α signaling activation. Inhibiting Trx-1 or AMPK abolished the cardioprotective effect of ALDH2 on ischemia. ALDH2 alleviates myocardial injury through increased mitochondrial biogenesis and reduced oxidative stress, and these effects were achieved through Trx1-mediating AMPK-PGC1-α signaling activation.

Esketamine mitigates cognitive impairment following exposure to LPS by modulating the intestinal flora/subdiaphragmatic vagus nerve/spleen axis.

INTRODUCTION: Susceptibility to secondary infection often increases after primary infection. Secondary infections can lead to more severe inflammatory injuries; however, the underlying mechanisms are not yet fully elucidated. OBJECTIVE: To investigate whether esketamine treatment immediately after primary lipopolysaccharide (LPS) exposure could alleviate cognitive impairment caused by secondary infection. METHODS: Mice were injected intraperitoneally (IP) with LPS (5 mg/kg) 10 days apart. Esketamine (10, 15, or 30 mg/kg) was administered IP immediately after the primary LPS injection. Splenectomy or subdiaphragmatic vagotomy (SDV) was performed 7 days before secondary LPS exposure or broad-spectrum antibiotic administration. RESULTS: Splenomegaly was observed after the primary LPS injection on Days 3 and 10. Splenomegaly was attenuated by treatment with 30 mg/kg esketamine. Esketamine treatment prevented increased plasma proinflammatory cytokines levels and cognitive dysfunction induced by secondary LPS exposure. Mice that underwent splenectomy or SDV had lower proinflammatory cytokines levels, higher hippocampal brain-derived neurotrophic factor (BDNF) levels, and improved cognitive function 1 day after secondary infection, which was not further improved by esketamine. Fecal microbiota transplantation (FMT) from endotoxic mice treated with esketamine attenuated hippocampal BDNF downregulation and cognitive dysfunction only in pseudo germ-free (PGF) mice without splenectomy. FMT with fecal suspensions from esketamine-treated endotoxic mice abrogated splenomegaly only in PGF mice without SDV. Blocking BDNF signaling blocked esketamine's ameliorating effects on secondary LPS exposure-induced cognitive dysfunction. CONCLUSION: The intestinal flora/subdiaphragmatic vagus nerve/spleen axis-mediated hippocampal BDNF downregulation significantly affected secondary LPS-induced systemic inflammation and cognitive dysfunction. Esketamine preserves cognitive function via this mechanism.

Remimazolam besylate versus propofol for deep sedation in critically ill patients: a randomized pilot study.

OBJECTIVE: To compare the efficacy and safety of remimazolam besylate and propofol for deep sedation in critically ill patients. METHODS: In this single-center, prospective, randomized, controlled pilot study, patients in the intensive care unit (ICU) requiring deep sedation were randomized to receive remimazolam besylate or propofol intravenously. Deep sedation was defined as a Richmond Agitation and Sedation Scale (RASS) score of - 4 or - 5. Sedation depth was monitored using RASS and Narcotrend Index (NI). The primary outcome was the percentage of time within the target sedation range without rescue sedation. The secondary outcomes included ventilator-free hours within 7 days, successful extubation, length of ICU stay, and 28-day mortality. Adverse events during the interventional period were also recorded. RESULTS: Thirty patients were assigned to each group. The median (IQR) RASS score was - 5.0 (- 5.0, - 4.0), and the median (IQR) NI value was 29.0 (21.0, 37.0) during the intervention period. Target RASS was reached a median of 100% of the sedation time in the two groups. No significant differences were observed in ventilator-free hours within 7 days, successful extubation, length of ICU stay, or 28-day mortality among groups. Hypotension occurred in 16 (53.3%) patients of remimazolam group and 18 (60.0%) patients of propofol group (p > 0.05). No patient experienced bradycardia. CONCLUSIONS: Remimazolam besylate appears to be an effective and safe agent for short-term deep sedation in critically ill patients. Our findings warrant large sample-sized randomized clinical trials.

Relationship of close contact settings with transmission and infection during the SARS-CoV-2 Omicron BA.2 epidemic in Shanghai.

INTRODUCTION: We analysed case-contact clusters during the Omicron BA.2 epidemic in Shanghai to assess the risk of infection of contacts in different settings and to evaluate the effect of demographic factors on the association of infectivity and susceptibility to the Omicron variant. METHODS: Data on the settings and frequency of contact, demographic characteristics and comorbidities of index cases, contacts and secondary cases were analysed. Independent effect of multiple variables on the risk for transmission and infection was evaluated using generalised estimating equations. RESULTS: From 1 March to 1 June 2022, we identified 450 770 close contacts of 90 885 index cases. The risk for infection was greater for contacts in farmers' markets (fixed locations where farmers gather to sell products, adjusted OR (aOR): 3.62; 95% CI 2.87 to 4.55) and households (aOR: 2.68; 95% CI 2.15 to 3.35). Children (0-4 years) and elderly adults (60 years and above) had higher risk for infection and transmission. During the course of the epidemic, the risk for infection and transmission in different age groups initially increased, and then decreased on about 21 April (17th day of citywide home quarantine). Compared with medical workers (reference, aOR: 1.00), unemployed contacts (aOR: 1.77; 95% CI 1.53 to 2.04) and preschoolers (aOR: 1.61; 95% CI 1.26 to 2.05) had the highest risk for infection; delivery workers (aOR: 1.90, 95% CI 1.51 to 2.40) and public service workers (aOR: 1.85; 95% CI 1.64 to 2.10) had the highest risk for transmission. Contacts who had comorbidities (aOR: 1.10; 95% CI 1.09 to 1.12) had a higher risk for infection, particularly those with lung diseases or immune deficiency. CONCLUSION: Farmers' markets and households were the main setting for transmission of Omicron. Children, the elderly, delivery workers and public service workers had the highest risk for transmission and infection. These findings should be considered when implementing targeted interventions.

Diterpenoids from Euphorbia fischeriana with Kv1.3 Inhibitory Activity.

Euphorbia diterpenoids possess inhibitory effects of Kv1.3 ion channel, but most of this research has focused on diterpenoids with jatrophane-related or ingenane-related skeletons. In the present study, nine undescribed (1-9) and 16 known (10-25) diterpenoids, based on jatrophane, lathyrane, ingenane, abietane, and atisane skeletons, were identified from the methanol extract of the aerial parts of Euphorbia fischeriana. The structures were established by analysis of the spectroscopic data as well as by single-crystal X-ray diffraction analysis. Among the isolated diterpenoids, macrocyclic jatrophanes and lathyranes exerted Kv1.3 blocking activity. Compound 8 exhibited good selectivity on the inhibition of the Kv 1.3 channel rather than hERG channel, with a selectivity index over 7.0. The selective activity of lathyrane diterpenoids indicates that macrocyclic diterpenoids have the potential to be further investigated as therapeutic agents for the treatment of autoimmune diseases.

Anisodamine hydrobromide in the treatment of critically ill patients with septic shock: a multicenter randomized controlled trial.

BACKGROUND: Septic shock is the development of sepsis to refractory circulatory collapse and metabolic derangements, characterized by persistent hypotension and increased lactate levels. Anisodamine hydrobromide (Ani HBr) is a Chinese medicine used to improve blood flow in circulatory disorders. The purpose of this study was to determine the therapeutic efficacy of Ani HBr in the treatment of patients with septic shock. METHODS: This was a prospective, multicenter, randomized controlled trial focusing on patients with septic shock in 16 hospitals in China. Patients were randomly assigned in a 1:1 ratio to either the treatment group or the control group. The primary endpoint was 28-day mortality. The secondary outcomes included 7-day mortality, hospital mortality, hospital length of stay, vasopressor-free days within 7 days, etc. These indicators were measured and collected at 0, 6h, 24h, 48h, 72h and 7d after the diagnosis. RESULTS: Between September 2017 and March 2021, 404 subjects were enrolled. 203 subjects received Ani HBr and 201 subjects were assigned to the control group. The treated group showed lower 28-day mortality than the control group. Stratified analysis further showed significant differences in 28-day mortality between the two groups for patients with a high level of illness severity. We also observed significant differences in 7-day mortality, hospital mortality and some other clinical indicators between the two groups. CONCLUSION: Ani HBr might be an important adjuvant to conventional treatment to reduce 28-day mortality in patients with septic shock. A large-scale prospective randomized multicenter trial is warranted to confirm our results.

Long-term sedation with remimazolam besylate versus propofol in critically ill patients during invasive mechanical ventilation: a study protocol for a multicenter randomized non-inferior trial.

Background: Remimazolam besylate is a novel ultra-short-acting benzodiazepine that can potentially be a safe and effective sedative in intensive care units. This study aims to assess whether remimazolam besylate is not inferior to propofol in maintaining mild-to-moderate sedation in critically ill patients receiving long-term mechanical ventilation. Methods and analysis: This is a multicenter, randomized, single-blind, propofol-controlled, non-inferiority study. Eligible patients are randomly assigned to receive remimazolam besylate or propofol in a 1:1 ratio to maintain a Richmond Agitation-Sedation Scale score between -3 and 0. When patients are under-sedated, rescue sedation of dexmedetomidine is added. The primary outcome is the percentage of time in the target sedation range. The secondary outcomes are hours free from the invasive ventilator in 7 days, successful extubation in 7 days, and weaning time, the length of intensive care unit stay, the length of hospital stay, and mortality in 28 days. Modified intention-to-treat and safety analysis is performed. Clinical trial registration number: https://clinicaltrials.gov/ct2/show/NCT05555667.

[Expert consensus on implementation strategy of awake prone positioning for non-intubated patients in China (2023)].

The awake prone position plays an important role in the treatment of hypoxemia and the improvement of respiratory distress symptoms in non-intubated patients. It is widely used in clinical practice because of its simple operation, safety, and economy. To enable clinical medical staff to scientifically and normatively implement prone position for awake patients without intubation, the committees of consensus formulation, guided by evidence-based methodology and Delphi method, conducted literature search, literature quality evaluation and evidence synthesis around seven topics, including indications and contraindications, evaluation, implementation, monitoring and safety management, termination time, complication prevention and health education of awake prone position. After two rounds of expert letter consultation, Expert consensus on implementation strategy of awake prone positioning for non-intubated patients in China (2023) was formulated, and provide guidance for clinical medical staff.

Abnormal glucose metabolism in virus associated sepsis.

Sepsis is identified as a potentially lethal organ impairment triggered by an inadequate host reaction to infection (Sepsis-3). Viral sepsis is a potentially deadly organ impairment state caused by the host's inappropriate reaction to a viral infection. However, when a viral infection occurs, the metabolism of the infected cell undergoes a variety of changes that cause the host to respond to the infection. But, until now, little has been known about the challenges faced by cellular metabolic alterations that occur during viral infection and how these changes modulate infection. This study concentrates on the alterations in glucose metabolism during viral sepsis and their impact on viral infection, with a view to exploring new potential therapeutic targets for viral sepsis.

Effects of airway pressure release ventilation on lung physiology assessed by electrical impedance tomography in patients with early moderate-to-severe ARDS.

OBJECTIVE: The aim of this study was to investigate the physiological impact of airway pressure release ventilation (APRV) on patients with early moderate-to-severe acute respiratory distress syndrome (ARDS) by electrical impedance tomography (EIT). METHODS: In this single-center prospective physiological study, adult patients with early moderate-to-severe ARDS mechanically ventilated with APRV were assessed by EIT shortly after APRV (T0), and 6 h (T1), 12 h (T2), and 24 h (T3) after APRV initiation. Regional ventilation and perfusion distribution, dead space (%), shunt (%), and ventilation/perfusion matching (%) based on EIT measurement at different time points were compared. Additionally, clinical variables related to respiratory and hemodynamic condition were analyzed. RESULTS: Twelve patients were included in the study. After APRV, lung ventilation and perfusion were significantly redistributed to dorsal region. One indicator of ventilation distribution heterogeneity is the global inhomogeneity index, which decreased gradually [0.61 (0.55-0.62) to 0.50 (0.42-0.53), p < 0.001]. The other is the center of ventilation, which gradually shifted towards the dorsal region (43.31 ± 5.07 to 46.84 ± 4.96%, p = 0.048). The dorsal ventilation/perfusion matching increased significantly from T0 to T3 (25.72 ± 9.01 to 29.80 ± 7.19%, p = 0.007). Better dorsal ventilation (%) was significantly correlated with higher PaO2/FiO2 (r = 0.624, p = 0.001) and lower PaCO2 (r = -0.408, p = 0.048). CONCLUSIONS: APRV optimizes the distribution of ventilation and perfusion, reducing lung heterogeneity, which potentially reduces the risk of ventilator-induced lung injury.

Reversal of the detrimental effects of social isolation on ischemic cerebral injury and stroke-associated pneumonia by inhibiting small intestinal γδ T-cell migration into the brain and lung.

Social isolation (ISO) is associated with an increased risk and poor outcomes of ischemic stroke. However, the roles and mechanisms of ISO in stroke-associated pneumonia (SAP) remain unclear. Adult male mice were single- or pair-housed with an ovariectomized female mouse and then subjected to transient middle cerebral artery occlusion. Isolated mice were treated with the natriuretic peptide receptor A antagonist A71915 or anti-gamma-delta (γδ) TCR monoclonal antibody, whereas pair-housed mice were treated with recombinant human atrial natriuretic peptide (rhANP). Subdiaphragmatic vagotomy (SDV) was performed 14 days before single- or pair-housed conditions. We found that ISO significantly worsened brain and lung injuries relative to pair housing, which was partially mediated by elevated interleukin (IL)-17A levels and the migration of small intestine-derived inflammatory γδ T-cells into the brain and lung. However, rhANP treatment or SDV could ameliorate ISO-exacerbated post-stroke brain and lung damage by reducing IL-17A levels and inhibiting the migration of inflammatory γδ T-cells into the brain and lung. Our results suggest that rhANP mitigated ISO-induced exacerbation of SAP and ischemic cerebral injury by inhibiting small intestine-derived γδ T-cell migration into the lung and brain, which could be mediated by the subdiaphragmatic vagus nerve.

Mechanosensitive ion channel Piezo1 mediates mechanical ventilation-exacerbated ARDS-associated pulmonary fibrosis.

INTRODUCTION: Pulmonary fibrosis is a major cause of the poor prognosis of acute respiratory distress syndrome (ARDS). While mechanical ventilation (MV) is an indispensable life-saving intervention for ARDS, it may cause the remodeling process in lung epithelial cells to become disorganized and exacerbate ARDS-associated pulmonary fibrosis. Piezo1 is a mechanosensitive ion channel that is known to play a role in regulating diverse physiological processes, but whether Piezo1 is necessary for MV-exacerbated ARDS-associated pulmonary fibrosis remains unknown. OBJECTIVES: This study aimed to explore the role of Piezo1 in MV-exacerbated ARDS-associated pulmonary fibrosis. METHODS: Human lung epithelial cells were stimulated with hydrochloric acid (HCl) followed by mechanical stretch for 48 h. A two-hitmodel of MV afteracidaspiration-inducedlunginjuryin mice was used. Mice were sacrificed after 14 days of MV. Pharmacological inhibition and knockout of Piezo1 were used to delineate the role of Piezo1 in MV-exacerbated ARDS-associated pulmonary fibrosis. In some experiments, ATP or the ATP-hydrolyzing enzyme apyrase was administered. RESULTS: The stimulation of human lung epithelial cells to HCl resulted in phenotypes of epithelial-mesenchymal transition (EMT), which were enhanced by mechanical stretching. MV exacerbated pulmonary fibrosis in mice exposed to HCl. Pharmacologicalinhibitionorknockout of Piezo1 attenuated the MV-exacerbated EMT process and lung fibrosis in vivo and in vitro. Mechanistically, the observed effects were mediated by Piezo1-dependent Ca2+ influx and ATP release in lung epithelial cells. CONCLUSIONS: Our findings identify a key role for Piezo1 in MV-exacerbated ARDS-associated pulmonary fibrosis that is mediated by increased ATP release in lung epithelial cells. Inhibiting Piezo1 may constitute a novelstrategyfor the treatment of MV-exacerbated ARDS-associated pulmonary fibrosis.