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.

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.

NLRC3 expression in macrophage impairs glycolysis and host immune defense by modulating the NF-κB-NFAT5 complex during septic immunosuppression.

Impairment of innate immune cell function and metabolism underlies immunosuppression in sepsis; however, a promising therapy to orchestrate this impairment is currently lacking. In this study, high levels of NOD-like receptor family CARD domain containing-3 (NLRC3) correlated with the glycolytic defects of monocytes/macrophages from septic patients and mice that developed immunosuppression. Myeloid-specific NLRC3 deletion improved macrophage glycolysis and sepsis-induced immunosuppression. Mechanistically, NLRC3 inhibits nuclear factor (NF)-κB p65 binding to nuclear factor of activated T cells 5 (NFAT5), which further controls the expression of glycolytic genes and proinflammatory cytokines of immunosuppressive macrophages. This is achieved by decreasing NF-κB activation-co-induced by TNF-receptor-associated factor 6 (TRAF6) or mammalian target of rapamycin (mTOR)-and decreasing transcriptional co-activator p300 activity by inducing NLRC3 sequestration of mTOR and p300. Genetic inhibition of NLRC3 disrupted the NLRC3-mTOR-p300 complex and enhanced NF-κB binding to the NFAT5 promoter in concert with p300. Furthermore, intrapulmonary delivery of recombinant adeno-associated virus harboring a macrophage-specific NLRC3 deletion vector significantly improved the defense of septic mice that developed immunosuppression upon secondary intratracheal bacterial challenge. Collectively, these findings indicate that NLRC3 mediates critical aspects of innate immunity that contribute to an immunocompromised state during sepsis and identify potential therapeutic targets.

Associations between HIV infection and frailty status and its individual components: Are frailty components disproportionally affected?

OBJECTIVE: We aimed to examine whether HIV infection was independently associated with frailty status and its individual components. METHODS: This cross-sectional investigation included people living with HIV (PLWH) and HIV-negative individuals from the baseline survey of the Comparative HIV and Aging Research in Taizhou (CHART) cohort, China. Frailty phenotype was based on five components: weight loss, low physical activity, exhaustion, weak grip strength and slow gait speed. Frailty was defined as the presence of at least three components, and prefrailty was defined as one or two components. Logistic regression models were used to analyse the factors associated with frailty and its components. RESULTS: In all, 2475 people living with HIV (age 45.5 ± 14.9 years; 76.2% male) and 4948 HIV-negative individuals (age 45.5 ± 14.8 years; 76.3% male) were included. Among PLWH, median CD4 count was 395 cells/µL and 78% were currently on antiretroviral therapy (ART). Frailty and prefrailty were significantly more prevalent in PLWH (3.2% vs 1.9% and 32.9% vs 27.9%) overall and at ages 18-39 (1.4% vs 0.2% and 22.7% vs 19.0%), 40-59 (2.5% vs 0.9% and 30.9% vs 27.9%) and 60-90 years (8.4% vs 7.4% and 57.1% vs 45.8%). HIV infection was associated with frailty and prefrailty [adjusted odds ratio (aOR) = 1.48, 95% confidence interval (CI): 1.06-2.08; and aOR = 1.18, 95% CI: 1.05-1.33, respectively] after adjusting for confounding variables, but were strengthened with further adjustment for multimorbidity (aOR = 1.62, 95% CI: 1.14-2.28; and aOR = 1.22, 95% CI: 1.09-1.37), and were no longer significant with further adjustment for depressive symptoms and sleep disorders (aOR = 1.02, 95% CI: 0.71-1.46; and aOR = 1.06, 95% CI: 0.94-1.20). Among individual components, HIV infection was positively associated with weak grip strength and slow gait speed, but negatively associated with low physical activity and exhaustion in all the adjusted models described. CONCLUSIONS: Frailty and prefrailty occur more often and earlier in PLWH. However, grip strength and gait speed are affected to a greater extent, highlighting their potential as screening and intervention targets to prevent or slow frailty among PLWH.

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.

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.

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.

Interaction of declined handgrip strength and HIV infection on neurocognitive impairment.

Neurocognitive impairment (NCI) persists among people living with HIV (PLWH) despite the success of combination antiretroviral therapy (cART). Although muscular waning or decreased handgrip strength has been widely reported to be associated with cognitive erosion in general elders, such association has not been examined in PLWH who commonly experience decreased handgrip strength and NCI. Furthermore, whether HIV infection modifies such association remains to be addressed. A cross-sectional analysis was conducted with 2808 HIV-positive and 5402 HIV-negative adults participating in the baseline survey of the CHART (Comparative HIV and Aging Research in Taizhou) cohort, China, 2017 - 2019. HIV-positive individuals showed weaker handgrip strength than HIV-negative controls (34.0 kg vs 37.7 kg). Multivariate logistic regression analysis indicated that both HIV infection (aOR = 4.35, p < 0.001) and every 5-kg decrease in "Handgrip strength" (aOR = 1.27, p < 0.001) were significantly associated with NCI, and there was a significant interaction between reduced handgrip strength and HIV infection on NCI (aOR = 1.14, p = 0.015). In stratified analyses adjusting for potential confounders, the association between reduced handgrip strength and NCI was significant among PLWH at all age groups but only significant among HIV-negative controls at 30 - 44 and 60 - 89 ages. Handgrip strength decline is significantly associated with the risk of NCI among PLWH. HIV infection may exacerbate the adverse effect of poor handgrip strength on NCI, especially at younger ages. Early detection of handgrip strength decline could facilitate delivery of compensatory strategies or assistive services to PLWH with or at high risk of NCI.

The gut-liver axis in sepsis: interaction mechanisms and therapeutic potential.

Sepsis is a potentially fatal condition caused by dysregulation of the body's immune response to an infection. Sepsis-induced liver injury is considered a strong independent prognosticator of death in the critical care unit, and there is anatomic and accumulating epidemiologic evidence that demonstrates intimate cross talk between the gut and the liver. Intestinal barrier disruption and gut microbiota dysbiosis during sepsis result in translocation of intestinal pathogen-associated molecular patterns and damage-associated molecular patterns into the liver and systemic circulation. The liver is essential for regulating immune defense during systemic infections via mechanisms such as bacterial clearance, lipopolysaccharide detoxification, cytokine and acute-phase protein release, and inflammation metabolic regulation. When an inappropriate immune response or overwhelming inflammation occurs in the liver, the impaired capacity for pathogen clearance and hepatic metabolic disturbance can result in further impairment of the intestinal barrier and increased disruption of the composition and diversity of the gut microbiota. Therefore, interaction between the gut and liver is a potential therapeutic target. This review outlines the intimate gut-liver cross talk (gut-liver axis) in sepsis.

Remimazolam besylate versus propofol for long-term sedation during invasive mechanical ventilation: a pilot study.

OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of remimazolam besylate compared with propofol in maintaining mild-to-moderate sedation in patients receiving long-term mechanical ventilation. METHODS: In this single-centered randomized pilot study, adult patients mechanically ventilated longer than 24 h were randomized to receive remimazolam besylate or propofol. The target sedation range was - 3 to 0 on the Richmond Agitation and Sedation Scale (RASS). The primary outcome was the percentage of time in the target sedation range without rescue sedation. The secondary outcomes were ventilator-free days at day 7, the length of ICU stay and 28-day mortality. RESULTS: Thirty patients were assigned to each group. No difference was identified between the remimazolam group and propofol group in median age [60.0 (IQR, 51.5-66.3) years vs. 64.0 (IQR, 55.0-69.3) years, respectively, p = 0.437] or the median duration of study drug infusion [55.0 (IQR, 28.3-102.0) hours vs. 41.0 (IQR, 24.8-74.3) hours, respectively, p = 0.255]. The median percentage of time in the target RASS range without rescue sedation was similar in remimazolam and propofol groups [73.2% (IQR, 41.5-97.3%) vs. 82.8% (IQR, 65.6-100%), p = 0.269]. No differences were identified between the two groups in terms of ventilator-free days at day 7, length of ICU stay, 28-day mortality or adverse events. CONCLUSIONS: This pilot study suggested that remimazolam besylate was effective and safe for long-term sedation in mechanically ventilated patients compared with propofol.

RhANP attenuates endotoxin-derived cognitive dysfunction through subdiaphragmatic vagus nerve-mediated gut microbiota-brain axis.

BACKGROUND: Atrial natriuretic peptide (ANP) secreted from atrial myocytes is shown to possess anti-inflammatory, anti-oxidant and immunomodulatory effects. The aim of this study is to assess the effect of ANP on bacterial lipopolysaccharide (LPS)-induced endotoxemia-derived neuroinflammation and cognitive impairment. METHODS: LPS (5 mg/kg) was given intraperitoneally to mice. Recombinant human ANP (rhANP) (1.0 mg/kg) was injected intravenously 24 h before and/or 10 min after LPS injection. Subdiaphragmatic vagotomy (SDV) was performed 14 days before LPS injection or 28 days before fecal microbiota transplantation (FMT). ANA-12 (0.5 mg/kg) was administrated intraperitoneally 30 min prior to rhANP treatment. RESULTS: LPS (5.0 mg/kg) induced remarkable splenomegaly and an increase in the plasma cytokines at 24 h after LPS injection. There were positive correlations between spleen weight and plasma cytokines levels. LPS also led to increased protein levels of ionized calcium-binding adaptor molecule (iba)-1, cytokines and inducible nitric oxide synthase (iNOS) in the hippocampus. LPS impaired the natural and learned behavior, as demonstrated by an increase in the latency to eat the food in the buried food test and a decrease in the number of entries and duration in the novel arm in the Y maze test. Combined prophylactic and therapeutic treatment with rhANP reversed LPS-induced splenomegaly, hippocampal and peripheral inflammation as well as cognitive impairment. However, rhANP could not further enhance the protective effects of SDV on hippocampal and peripheral inflammation. We further found that PGF mice transplanted with fecal bacteria from rhANP-treated endotoxemia mice alleviated the decreased protein levels of hippocampal polyclonal phosphorylated tyrosine kinase receptor B (p-TrkB), brain-derived neurotrophic factor (BDNF) and cognitive impairment, which was abolished by SDV. Moreover, TrkB/BDNF signaling inhibitor ANA-12 abolished the improving effects of rhANP on LPS-induced cognitive impairment. CONCLUSIONS: Our results suggest that rhANP could mitigate LPS-induced hippocampal inflammation and cognitive dysfunction through subdiaphragmatic vagus nerve-mediated gut microbiota-brain axis.

Baseline kidney function is associated with vancomycin-induced acute kidney injury in children: a prospective nested case-control study.

BACKGROUND: Children with kidney insufficiency are susceptible to vancomycin-induced acute kidney injury (VIAKI), but there is a lack of compelling clinical data. We conducted a nested case-control study to evaluate the relationship between kidney insufficiency and incidence of VIAKI in children. METHODS: Patients were considered to have VIAKI if they met the criteria for eGFR change according to pRIFLE-I or p-RIFLE-F. Case group comprised patients who developed VIAKI. Case-control ratio was 1:3; patients were matched for age, severity, and nature of illness and initial vancomycin dose. Primary endpoint was incidence of VIAKI at three levels of kidney function, calculated using Kaplan-Meier curve and log-rank test. Secondary endpoint was treatment-related in-hospital mortality amongst case and control groups. RESULTS: Amongst 386 children who fit study criteria, 31 developed VIAKI (8.03%). Thirty-one cases and 93 controls were selected from the observed cohort. Three risk factors were identified for VIAKI: moderate kidney insufficiency (OR 8.8, 2.4-32.8), vancomycin trough concentration ≥ 15 µg/mL (OR 7.7, 1.7-34.4), and furosemide use (OR 24.8, 6.4-98.2). A significant difference in time to VIAKI was noted between patients with moderate kidney insufficiency and patients with mild kidney insufficiency or normal kidney function (p < 0.001). In-hospital mortality rate in case group was 45.2%, compared to 18.3% in control group (p < 0.01). CONCLUSIONS: Children with moderate kidney insufficiency are more likely to develop VIAKI than those with normal and mild kidney insufficiency. Patients who develop VIAKI have higher in-hospital mortality than those who do not develop VIAKI.

HMGB1 aggravates lipopolysaccharide-induced acute lung injury through suppressing the activity and function of Tregs.

BACKGROUND: CD4+CD25+FoxP3+ T helper cells (Tregs), a subgroup of CD4+ T helper cells, are critical effectors that protect against acute lung injury (ALI) by contact-dependent suppression or releasing anti-inflammatory cytokines including interleukin-10 (IL-10), and transforming growth factor (TGF-ß). HMGB1 (High mobility group box 1 protein) was identified as a nuclear non-histone DNA-binding chromosomal protein, which participates in the regulation of lung inflammatory response and pathological processes in ALI. Previous studies have suggested that Tregs overexpresses the HMGB1-recognizing receptor. However, the interaction of HMGB1 with Tregs in ALI is still unclear. OBJECTIVE: To investigate whether HMGB1 aggravates ALI by suppressing immunosuppressive function of Tregs. METHODS: Anti-HMGB1 antibody and recombinant mouse HMGB1 (rHMGB1) were administered in lipopolysaccharide (LPS)-induced ALI mice and polarized LPS-primed Tregs in vitro. The Tregs pre-stimulated with or without rHMGB1 were adoptively transferred to ALI mice and depleted by Diphtheria toxin (DT). For coculture experiment, isolated Tregs were first pre-stimulated with or without rHMGB1 or anti-HMGB1 antibody, then they were cocultured with bone marrow-derived macrophages (BMMs) under LPS stimulation. RESULTS: Tregs protected against acute lung pathological injury. HMGB1 modulated the suppressive function of Tregs as follows: reduction in the number of the cells and the activity of Tregs, the secretion of anti-inflammatory cytokines (IL-10, TGF-ß) from Tregs, the production of IL-2 from CD4+ T cells and CD11c+ DCs, and the M2 polarization of macrophages, as well as inducing proinflammatory response of macrophages. CONCLUSIONS: HMGB1 could aggravate LPS induced-ALI through suppressing the activity and function of Tregs.

Poor-sleep is associated with slow recovery from lymphopenia and an increased need for ICU care in hospitalized patients with COVID-19: A retrospective cohort study.

Sleep is known to play an important role in immune function. However, the effects of sleep quality during hospitalization for COVID-19 remain unclear. This retrospective, single-center cohort study was conducted to investigate the effects of sleep quality on recovery from lymphopenia and clinical outcomes in hospitalized patients with laboratory-confirmed COVID-19 admitted to the West District of Wuhan Union Hospital between January 25 and March 15, 2020. The Richards-Campbell sleep questionnaire (RCSQ) and Pittsburgh Sleep Quality Index (PSQI) were used to assess sleep quality. The epidemiological, demographic, clinical, laboratory, treatment, and outcome data were collected from electronic medical records and compared between the good-sleep group and poor-sleep group. In all, 135 patients (60 in good-sleep group and 75 in poor-sleep group) were included in this study. There were no significant between-group differences regarding demographic and baseline characteristics, as well as laboratory parameters upon admission and in-hospital treatment. Compared with patients in the good-sleep group, patients in the poor-sleep group had lower absolute lymphocyte count (ALC) (day 14: median, 1.10 vs 1.32, P = 0.0055; day 21: median, 1.18 vs 1.48, P = 0.0034) and its reduced recovery rate (day 14: median, 56.91 vs 69.40, P = 0.0255; day 21: median, 61.40 vs 111.47, P = 0.0003), as well as increased neutrophil-to-lymphocyte ratio (NLR; day 14: median, 3.17 vs 2.44, P = 0.0284; day 21: median, 2.73 vs 2.23, P = 0.0092) and its associated deterioration rate (day 14: median, -39.65 vs -61.09, P = 0.0155; day 21: median, -51.40% vs -75.43, P = 0.0003). Nine [12.0%] patients in the poor-sleep group required ICU care (P = 0.0151); meanwhile, none of the patients in good-sleep group required ICU care. Patients in the poor-sleep group had increased duration of hospital stay (33.0 [23.0-47.0] days vs 25.0 [20.5-36.5] days, P = 0.0116) compared to those in the good-sleep group. An increased incidence of hospital-acquired infection (seven [9.3%] vs one [1.7%]) was observed in the poor-sleep group compared to the good-sleep group; however, this difference was not significant (P = 0.1316). In conclusion, poor sleep quality during hospitalization in COVID-19 patients with lymphopenia is associated with a slow recovery from lymphopenia and an increased need for ICU care.

Death-associated Protein Kinase 1 Mediates Ventilator-induced Lung Injury in Mice by Promoting Alveolar Epithelial Cell Apoptosis.

BACKGROUND: Alveolar epithelial cell apoptosis is implicated in the onset of ventilator-induced lung injury. Death-associated protein kinase 1 (DAPK1) is associated with cell apoptosis. The hypothesis was that DAPK1 participates in ventilator-induced lung injury through promoting alveolar epithelial cell apoptosis. METHODS: Apoptosis of mouse alveolar epithelial cell was induced by cyclic stretch. DAPK1 expression was altered (knockdown or overexpressed) in vitro by using a small interfering RNA or a plasmid, respectively. C57/BL6 male mice (n = 6) received high tidal volume ventilation to establish a lung injury model. Adeno-associated virus transfection of short hairpin RNA and DAPK1 inhibitor repressed DAPK1 expression and activation in lungs, respectively. The primary outcomes were alveolar epithelial cell apoptosis and lung injury. RESULTS: Compared with the control group, the 24-h cyclic stretch group showed significantly higher alveolar epithelial cell apoptotic percentage (45 ± 4% fold vs. 6 ± 1% fold; P < 0.0001) and relative DAPK1 expression, and this group also demonstrated a reduced apoptotic percentage after DAPK1 knockdown (27 ± 5% fold vs. 53 ± 8% fold; P < 0.0001). A promoted apoptotic percentage in DAPK1 overexpression was observed without stretching (49 ± 6% fold vs. 14 ± 3% fold; P < 0.0001). Alterations in B-cell lymphoma 2 and B-cell lymphoma 2-associated X are associated with DAPK1 expression. The mice subjected to high tidal volume had higher DAPK1 expression and alveolar epithelial cell apoptotic percentage in lungs compared with the low tidal volume group (43 ± 6% fold vs. 4 ± 2% fold; P < 0.0001). Inhibition of DAPK1 through adeno-associated virus infection or DAPK1 inhibitor treatment appeared to be protective against lung injury with reduced lung injury score, resolved pulmonary inflammation, and repressed alveolar epithelial cell apoptotic percentage (47 ± 4% fold and 48 ± 6% fold; 35 ± 5% fold and 34 ± 4% fold; P < 0.0001, respectively). CONCLUSIONS: DAPK1 promotes the onset of ventilator-induced lung injury by triggering alveolar epithelial cell apoptosis through intrinsic apoptosis pathway in mice.

Clinical course and predictors of 60-day mortality in 239 critically ill patients with COVID-19: a multicenter retrospective study from Wuhan, China.

BACKGROUND: The global numbers of confirmed cases and deceased critically ill patients with COVID-19 are increasing. However, the clinical course, and the 60-day mortality and its predictors in critically ill patients have not been fully elucidated. The aim of this study is to identify the clinical course, and 60-day mortality and its predictors in critically ill patients with COVID-19. METHODS: Critically ill adult patients admitted to intensive care units (ICUs) from 3 hospitals in Wuhan, China, were included. Data on demographic information, preexisting comorbidities, laboratory findings at ICU admission, treatments, clinical outcomes, and results of SARS-CoV-2 RNA tests and of serum SARS-CoV-2 IgM were collected including the duration between symptom onset and negative conversion of SARS-CoV-2 RNA. RESULTS: Of 1748 patients with COVID-19, 239 (13.7%) critically ill patients were included. Complications included acute respiratory distress syndrome (ARDS) in 164 (68.6%) patients, coagulopathy in 150 (62.7%) patients, acute cardiac injury in 103 (43.1%) patients, and acute kidney injury (AKI) in 119 (49.8%) patients, which occurred 15.5 days, 17 days, 18.5 days, and 19 days after the symptom onset, respectively. The median duration of the negative conversion of SARS-CoV-2 RNA was 30 (range 6-81) days in 49 critically ill survivors that were identified. A total of 147 (61.5%) patients deceased by 60 days after ICU admission. The median duration between ICU admission and decease was 12 (range 3-36). Cox proportional-hazards regression analysis revealed that age older than 65 years, thrombocytopenia at ICU admission, ARDS, and AKI independently predicted the 60-day mortality. CONCLUSIONS: Severe complications are common and the 60-day mortality of critically ill patients with COVID-19 is considerably high. The duration of the negative conversion of SARS-CoV-2 RNA and its association with the severity of critically ill patients with COVID-19 should be seriously considered and further studied.

Patients with COVID-19 in 19 ICUs in Wuhan, China: a cross-sectional study.

BACKGROUND: A COVID-19 outbreak started in Wuhan, China, last December and now has become a global pandemic. The clinical information in caring of critically ill patients with COVID-19 needs to be shared timely, especially under the situations that there is still a largely ongoing spread of COVID-19 in many countries. METHODS: A multicenter prospective observational study investigated all the COVID-19 patients received in 19 ICUs of 16 hospitals in Wuhan, China, over 24 h between 8 AM February 2h and 8 AM February 27, 2020. The demographic information, clinical characteristics, vital signs, complications, laboratory values, and clinical managements of the patients were studied. RESULTS: A total of 226 patients were included. Their median (interquartile range, IQR) age was 64 (57-70) years, and 139 (61.5%) patients were male. The duration from the date of ICU admission to the study date was 11 (5-17) days, and the duration from onset of symptoms to the study date was 31 (24-36) days. Among all the patients, 155 (68.6%) had at least one coexisting disease, and their sequential organ failure assessment score was 4 (2-8). Organ function damages were found in most of the patients: ARDS in 161 (71.2%) patients, septic shock in 34 (15.0%) patients, acute kidney injury occurred in 57 (25.2%) patients, cardiac injury in 61 (27.0%) patients, and lymphocytopenia in 160 (70.8%) patients. Of all the studied patients, 85 (37.6%) received invasive mechanical ventilation, including 14 (6.2%) treated with extracorporeal membrane oxygenation (ECMO) at the same time, 20 (8.8%) received noninvasive mechanical ventilation, and 24 (10.6%) received continuous renal replacement therapy. By April 9, 2020, 87 (38.5%) patients were deceased and 15 (6.7%) were still in the hospital. CONCLUSIONS: Critically ill patients with COVID-19 are associated with a higher risk of severe complications and need to receive an intensive level of treatments. COVID-19 poses a great strain on critical care resources in hospitals. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000030164. Registered on February 24, 2020, http://www.chictr.org.cn/edit.aspx?pid=49983&htm=4.

Activation of death-associated protein kinase 1 promotes neutrophil apoptosis to accelerate inflammatory resolution in acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a uniform progression of overwhelming inflammation in lung tissue with extensive infiltration of inflammatory cells. Neutrophil apoptosis is thought to be a significant process in the control of the resolution phase of inflammation. It has been proved that 5-Aza-2'-deoxycytidine (Aza) can inhibit cancer by activating death-associated protein kinase 1 (DAPK1) to promote apoptosis. However, the effect of DAPK1 on neutrophil apoptosis is unclear, and research on the role of Aza in inflammation is lacking. Here, we investigated whether Aza can regulate DAPK1 expression to influence the fate of neutrophils in ARDS. In vitro, we stimulated neutrophil-like HL-60 (dHL-60) cells with different concentrations of Aza for different durations and used RNA interference to up- or downregulate DAPK1 expression. We observed that culturing dHL-60 cells with Aza increased apoptosis by inhibiting NF-κB activation to modulate the expression of Bcl-2 family proteins, which was closely related to the levels of DAPK1. In vivo, ARDS was evoked by intratracheal instillation of lipopolysaccharide (LPS; 3 mg/kg). One hour after LPS administration, mice were treated with Aza (1 mg/kg, i.p.). To inhibit DAPK1 expression, mice were intraperitoneally injected with a DAPK1 inhibitor. Aza treatment accelerated inflammatory resolution in LPS-induced ARDS by suppressing pulmonary edema, alleviating lung injury and decreasing the infiltration of inflammatory cells in bronchoalveolar lavage fluid (BALF). Moreover, Aza reduced the production of proinflammatory cytokines. However, administration of the DAPK1 inhibitor attenuated the protective effects of Aza. Similarly, the proapoptotic function of Aza was prevented when DAPK1 was inhibited either in vivo or in vitro. In summary, Aza promotes neutrophil apoptosis by activating DAPK1 to accelerate inflammatory resolution in LPS-induced ARDS. This study provides the first evidence that Aza prevents LPS-induced neutrophil survival by modulating DAPK1 expression.

HIV and Aging in Mainland China: Implications for Control and Prevention Research.

PURPOSE OF REVIEW: The last 15 years have witnessed a dramatic change in HIV-related epidemiology amidst improvements in treatment and care in China. With proper treatment, HIV is now considered a chronic disease. As a consequence, many people living with HIV (PLWH) now present age-related comorbidities. We reviewed 13 topical issues concerning the epidemiology of aging with HIV in mainland China. RESULTS: Many of aging-related issues associated with the biological and physical aspects of living with HIV addressed in mainland China are consistent with the global literature. Greater prevalence of age-related comorbidities among PLWH was observed. Beyond biological mechanisms associated with HIV infection and traditional risk factors, other factors play a vital role in the aging process among PLWH. A stronger focus on screening, prevention, and management of non-HIV co-morbidities among PLWH is now warranted. Macro-social factors need to be integrated into next generation of clinical and/or behavioral HIV research to inform disease progression and management as well as prevention.

MicroRNA-7 Exerts Antiangiogenic Effect on Colorectal Cancer via ERK Signaling.

BACKGROUND: Recent studies have suggested that microRNA-7 (miR-7) family members may play important roles in human cancer by regulating cell proliferation, apoptosis, migration, and invasion. Therefore, the present study aimed to investigate the clinical significance and biological function of miR-7 in colorectal cancer (CRC). METHODS: Initially, cancer and adjacent tissues were collected from 76 patients with CRC. Then, microvascular density was detected using the Weidner counting method. The functional role of miR-7 in CRC was determined using ectopic expression, knockdown, and reporter assay experiments. The vasculogenic mimicry density was determined. Expression of miR-7, epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK1/2), vascular endothelial growth factor, and thrombospondin-1 was determined. 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assays, scratch tests, and Transwell assays were conducted to examine cell proliferation, migration, and invasion, respectively. Finally, flow cytometry was applied to evaluate cell apoptosis. RESULTS: CRC tissues showed increased microvascular density and EGFR expression, activated ERK signaling, and miR-7 downregulation. EGFR was a target gene of miR-7. miR-7 overexpression and EGFR silencing decreased vasculogenic mimicry density, cell migration, and cell invasion, but increased cell apoptosis. In addition, miR-7 overexpression and EGFR silencing upregulated thrombospondin-1 and downregulated EGFR, ERK1/2, and vascular endothelial growth factor. Furthermore, we observed that the effect of miR-7 inhibition was abolished after EGFR silencing. CONCLUSIONS: Overexpressed miR-7 suppresses angiogenesis of CRC cells through ERK signaling by downregulating EGFR. It may identify new targets for CRC treatment.