TIMP2 protects against sepsis-associated acute kidney injury by cAMP/NLRP3 axis-mediated pyroptosis.

The tissue inhibitor of metalloproteinases 2 (TIMP2) has emerged as a promising biomarker for predicting the risk of sepsis-associated acute kidney injury (SA-AKI). However, its exact role in SA-AKI and the underlying mechanism remains unclear. In this study, we investigated the impact of kidney tubule-specific Timp2 knockout mice on kidney injury and inflammation. Our findings demonstrated that Timp2-knockout mice exhibited more severe kidney injury than wild-type mice, along with elevated levels of pyroptosis markers NOD-like receptor protein 3 (NLRP3), Caspase1, and gasdermin D (GSDMD) in the early stage of SA-AKI. Conversely, the expression of exogenous TIMP2 in TIMP2-knockout mice still protected against kidney damage and inflammation. In in vitro experiments, using recombinant TIMP2 protein, TIMP2 knockdown demonstrated that exogenous TIMP2 inhibited pyroptosis of renal tubular cells stimulated by lipopolysaccharide (LPS). Mechanistically, TIMP2 promoted the ubiquitination and autophagy-dependent degradation of NLRP3 by increasing intracellular cyclic adenosine monophosphate (cAMP), which mediated NLRP3 degradation through recruiting the E3 ligase MARCH7, attenuating downstream pyroptosis, and thus alleviating primary tubular cell damage. These results revealed the renoprotective role of extracellular TIMP2 in SA-AKI by attenuating tubular pyroptosis, and suggested that exogenous administration of TIMP2 could be a promising therapeutic intervention for SA-AKI treatment.NEW & NOTEWORTHY Tissue inhibitor of metalloproteinase 2 (TIMP-2) has been found to be the best biomarker for predicting the risk of sepsis-associated acute kidney injury (SA-AKI). However, its role and the underlying mechanism in SA-AKI remain elusive. The authors demonstrated in this study using kidney tubule-specific knockout mice model of SA-AKI and primary renal tubule cells stimulated with lipopolysaccharide (LPS) that extracellular TIMP-2 promoted NOD-like receptor protein 3 (NLRP3) ubiquitination and autophagy-dependent degradation by increasing intracellular cyclic adenosine monophosphate (cAMP), thus attenuated pyroptosis and alleviated renal damage.

Fibroblastic reticular cell-derived exosomes are a promising therapeutic approach for septic acute kidney injury.

Sepsis-induced acute kidney injury (S-AKI) is highly lethal, and effective drugs for treatment are scarce. Previously, we reported the robust therapeutic efficacy of fibroblastic reticular cells (FRCs) in sepsis. Here, we demonstrate the ability of FRC-derived exosomes (FRC-Exos) to improve C57BL/6 mouse kidney function following cecal ligation and puncture-induced sepsis. In vivo imaging confirmed that FRC-Exos homed to injured kidneys. RNA-Seq analysis of FRC-Exo-treated primary kidney tubular cells (PKTCs) revealed that FRC-Exos influenced PKTC fate in the presence of lipopolysaccharide (LPS). FRC-Exos promoted kinase PINK1-dependent mitophagy and inhibited NLRP3 inflammasome activation in LPS-stimulated PKTCs. To dissect the mechanism underlying the protective role of Exos in S-AKI, we examined the proteins within Exos by mass spectrometry and found that CD5L was the most upregulated protein in FRC-Exos compared to macrophage-derived Exos. Recombinant CD5L treatment in vitro attenuated kidney cell swelling and surface bubble formation after LPS stimulation. FRCs were infected with a CD5L lentivirus to increase CD5L levels in FRC-Exos, which were then modified in vitro with the kidney tubular cell targeting peptide LTH, a peptide that binds to the biomarker protein kidney injury molecule-1 expressed on injured tubule cells, to enhance binding specificity. Compared with an equivalent dose of recombinant CD5L, the modified CD5L-enriched FRC-Exos selectively bound PKTCs, promoted kinase PINK-ubiquitin ligase Parkin-mediated mitophagy, inhibiting pyroptosis and improved kidney function by hindering NLRP3 inflammasome activation, thereby improving the sepsis survival rate. Thus, strategies to modify FRC-Exos could be a new avenue in developing therapeutics against kidney injury.

Protein Kinase N1 Level Predicts Acute Kidney Injury in Patients Undergoing Cardiac Surgery: A Prospective Cohort Study.

INTRODUCTION: The objective of this study was to examine the utility of protein kinase N1 (PKN1) as a biomarker of cardiac surgery-associated AKI (CSA-AKI). METHODS: A prospective cohort study of 110 adults undergoing on-pump cardiac surgery was conducted. The associations between post-operative PKN1 and CSA-AKI, AKI severity, need for renal replacement therapy (RRT), duration of AKI, length of ICU stay, and post-operative hospital stay were evaluated. RESULTS: Patients were categorized into three groups according to PKN1 tertiles. The incidence of CSA-AKI in the third tertile was 3.4-fold higher than that in the first. PKN1 was an independent risk factor for CSA-AKI. The discrimination of PKN1 to CSA-AKI assessed by ROC curve indicated that the AUC was 0.70, and the best cutoff was 5.025 ng/mL. This group (>5.025 ng/mL) was more likely to develop CSA-AKI (p < 0.001). The combined AUC of EuroSCORE, aortic cross-clamp time, and PKN1 was 0.82 (p < 0.001). A higher level of PKN1 was related to increased need for RRT, longer duration of AKI, and length of ICU and post-operative hospital stays. CONCLUSIONS: PKN1 could be a potential biomarker for the prediction of CSA-AKI. The combination of PKN1, EuroSCORE, and aortic cross-clamp time was likely to predict the occurrence of CSA-AKI.

Explainable artificial intelligence model for mortality risk prediction in the intensive care unit: a derivation and validation study.

BACKGROUND: The lack of transparency is a prevalent issue among the current machine-learning (ML) algorithms utilized for predicting mortality risk. Herein, we aimed to improve transparency by utilizing the latest ML explicable technology, SHapley Additive exPlanation (SHAP), to develop a predictive model for critically ill patients. METHODS: We extracted data from the Medical Information Mart for Intensive Care IV database, encompassing all intensive care unit admissions. We employed nine different methods to develop the models. The most accurate model, with the highest area under the receiver operating characteristic curve, was selected as the optimal model. Additionally, we used SHAP to explain the workings of the ML model. RESULTS: The study included 21 395 critically ill patients, with a median age of 68 years (interquartile range, 56-79 years), and most patients were male (56.9%). The cohort was randomly split into a training set (N = 16 046) and a validation set (N = 5349). Among the nine models developed, the Random Forest model had the highest accuracy (87.62%) and the best area under the receiver operating characteristic curve value (0.89). The SHAP summary analysis showed that Glasgow Coma Scale, urine output, and blood urea nitrogen were the top three risk factors for outcome prediction. Furthermore, SHAP dependency analysis and SHAP force analysis were used to interpret the Random Forest model at the factor level and individual level, respectively. CONCLUSION: A transparent ML model for predicting outcomes in critically ill patients using SHAP methodology is feasible and effective. SHAP values significantly improve the explainability of ML models.

Efficacy and Safety of Ciprofol Sedation in ICU Patients Undergoing Mechanical Ventilation: A Multicenter, Single-Blind, Randomized, Noninferiority Trial.

OBJECTIVES: To determine the effectiveness and safety of ciprofol for sedating patients in ICUs who required mechanical ventilation (MV). DESIGN: A multicenter, single-blind, randomized, noninferiority trial. SETTING: Twenty-one centers across China from December 2020 to June 2021. PATIENTS: A total of 135 ICU patients 18 to 80 years old with endotracheal intubation and undergoing MV, who were expected to require sedation for 6-24 hours. INTERVENTIONS: One hundred thirty-five ICU patients were randomly allocated into ciprofol ( n = 90) and propofol ( n = 45) groups in a 2:1 ratio. Ciprofol or propofol were IV infused at loading doses of 0.1 mg/kg or 0.5 mg/kg, respectively, over 4 minutes ± 30 seconds depending on the physical condition of each patient. Ciprofol or propofol were then immediately administered at an initial maintenance dose of 0.3 mg/kg/hr or 1.5 mg/kg/hr, to achieve the target sedation range of Richmond Agitation-Sedation Scale (+1 to -2). Besides, continuous IV remifentanil analgesia was administered (loading dose: 0.5-1 µg/kg, maintenance dose: 0.02-0.15 µg/kg/min). MEASUREMENTS AND MAIN RESULTS: Of the 135 patients enrolled, 129 completed the study. The primary endpoint-sedation success rates of ciprofol and propofol groups were 97.7% versus 97.8% in the full analysis set (FAS) and were both 100% in per-protocol set (PPS). The noninferiority margin was set as 8% and confirmed with a lower limit of two-sided 95% CI for the inter-group difference of -5.98% and -4.32% in the FAS and PPS groups. Patients who received ciprofol had a longer recovery time ( p = 0.003), but there were no differences in the remaining secondary endpoints (all p > 0.05). The occurrence rates of treatment-emergent adverse events (TEAEs) or drug-related TEAEs were not significantly different between the groups (all p > 0.05). CONCLUSIONS: Ciprofol was well tolerated, with a noninferior sedation profile to propofol in Chinese ICU patients undergoing MV for a period of 6-24 hours.

circBGN accelerates gastric cancer cell proliferation and invasion via activating IL6/STAT3 signaling pathway.

Circular RNAs participate in the pathogenesis of various tumors, including gastric cancer (GC). In this study, we investigated the role of circBGN in regulating proliferation and invasion of GC cells and elucidated the mechanism. The expression of circBGN was assessed by quantitative reverse-transcription PCR and in situ hybridization. In addition, loss- and gain-of-function investigations in vitro and in vivo were performed to determine the biological functions of circBGN. Luciferase reporter assays and rescue experiments were applied to investigate the interaction between circBGN and miR-149-5p as well as the relationship between miR-149-5p and IL6. Our results showed that circBGN expression was significantly elevated in GC tissues and cells. Knockdown of circBGN dramatically suppressed GC cell proliferation and invasion in vitro. Xenograft experiments revealed that knockdown of circBGN delayed tumor growth in vivo. Furthermore, circBGN can directly bind to miR-149-5p, thereby preventing miR-149-5p from binding to its target mRNA [IL6 mRNA], thus activating IL6/STAT3 signaling pathway. Rescue assays indicated that circBGN regulates GC cell proliferation and invasion by upregulating miR-149-5p/IL6 axis output. Taken together, our investigation indicates that circBGN supports GC progression by activating IL6/STAT3 signaling pathway, thus pointing to a new possible therapeutic target in GC.

TIMP2 mediates endoplasmic reticulum stress contributing to sepsis-induced acute kidney injury.

Tissue inhibitor of metalloproteinase 2 (TIMP2) has been recognized as an important biomarker for predicting acute kidney injury (AKI) because of its involvement in the process of inflammation and apoptosis in septic AKI. Endoplasmic reticulum (ER) stress, a condition of disrupted ER homeostasis, is implicated in multiple pathophysiological processes, including kidney disease. Herein, we investigated the correlation between ER stress and septic AKI and further explored how TIMP2 regulated ER stress-mediated apoptosis. To assess the role of TIMP2 in sepsis-induced AKI, we used a cecal ligation and puncture (CLP) model in mice with tubule-specific deficiency of TIMP2 (Ksp-Cre/TIMP2flox/flox ) and their wild-type counterparts. Compared to the wild-type mice, TIMP2-deficient mice demonstrated lower serum creatinine levels and decreased ER stress-mediated apoptosis when subjected to CLP. Interestingly, in human kidney (HK-2) cells, overexpression of TIMP2 caused ER stress, whereas TIMP2 knockdown attenuated lipopolysaccharide-induced ER stress and apoptosis. TIMP2 interacted with the binding immunoglobulin protein, an ER chaperone, and facilitates its extracellular secretion, thereby triggering ER stress. This study identified that the deletion of TIMP2 in mouse tubules mitigated sepsis-induced AKI by inhibiting ER stress-mediated apoptosis, which might be a potential therapeutic strategy to alleviate renal injury.

Construction of an Artificial Light-Harvesting System with Efficient Photocatalytic Activity in an Aqueous Solution Based on a FRET-Featuring Metallacage.

Over the past few decades, the design and construction of high-efficiency artificial light-harvesting systems (LHSs) involving multistep fluorescence-resonance energy transfer (FRET) processes have gradually received considerable attention within wide fields ranging from supramolecular chemistry to chemical biology and even materials science. Herein, through coordination-driven self-assembly, a novel tetragonal prismatic metallacage featuring a FRET process using tetraphenylethene (TPE) units as donors and BODIPY units as acceptors has been conveniently synthesized. Subsequently, taking advantage of supramolecular hydrophobic interactions, a promising artificial LHS involving two-step FRET processes from TPE to BODIPY and then to Nile Red (NiR) has been successfully fabricated in an aqueous solution using the FRET-featuring metallacage, NiR, and an amphiphilic polymer (mPEG-DSPE). Notably, this obtained aqueous LHS exhibits highly efficient photocatalytic activity in the dehalogenation of a bromoacetophenone derivate. This study provides a unique strategy for fabricating artificial LHSs in aqueous solutions with multistep FRET processes and further promotes the future development of mimicking the photosynthesis process.

The Effect of Iron Overload on the Mobilization of Peripheral Blood Hematopoietic Stem Cells in Pediatric Patients with Thalassemia Major.

INTRODUCTION: The purpose of this study was to examine the effect of iron overload on the mobilization of peripheral blood stem cells (PBSCs) in pediatric patients with ß-thalassemia major (TM). METHODS: We retrospectively reviewed the records of 226 patients with TM from whom PBSCs were collected. Iron overload was based on serum ferritin level, and liver and cardiac iron overload was measured by magnetic resonance imaging (MRI) T2*. RESULTS: The mean age of the TM patients was 7.35 ± 3.41 years. Of the patients, only 171 received MRI. Of the 171 patients, 35 had normal liver iron levels, 39 mild liver iron overload, 90 intermediate liver iron overload, and 7 severe liver iron overload. The intermediate + severe group was associated with significantly higher age and BMI and lower leukapheresis product white blood cell count and CD34+ cell levels (all, p < 0.05). CONCLUSION: Leukapheresis indices were similar between patients with different degrees of iron overload according to the ferritin level and cardiac iron overload, in which the later might be due to the small number of patients with cardiac overload. In patients with TM, the intermediate and severe liver iron overload was associated with poorer mobilization of PBSCs.

Synergistic effect of elevated glucose levels with SARS-CoV-2 spike protein induced NOX-dependent ROS production in endothelial cells.

BACKGROUND: Diabetic patients infected with coronavirus disease 2019 (COVID-19) often have a higher probability of organ failure and mortality. The potential cellular mechanisms through which blood glucose exacerbates tissue damage due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is still unclear. METHODS AND RESULTS: We cultured endothelial cells within differing glucose mediums with an increasing concentration gradient of SARS-CoV-2 Spike protein (S protein). S protein can cause the reduction of ACE2 and TMPRSS2, and activation of NOX2 and NOX4. A high glucose medium was shown to aggravate the decrease of ACE2 and activation of NOX2 and NOX4 in cultured cells, but had no effect on TMPRSS2. S protein mediated activation of the ACE2-NOX axis induced oxidative stress and apoptosis within endothelial cells, leading to cellular dysfunction via the reduction of NO and tight junction proteins which may collectively be exacerbated by elevated glucose. In addition, the glucose variability model demonstrated activation of the ACE2-NOX axis in a similar manner observed in the high glucose model in vitro. CONCLUSIONS: Our present study provides evidence for a mechanism through which hyperglycemia aggravates endothelial cell injury resulting from S protein mediated activation of the ACE2-NOX axis. Our research thus highlights the importance of strict monitoring and control of blood glucose levels within the context of COVID-19 treatment to potentially improve clinical outcomes.

The safety and efficacy of mesenchymal stromal cells in ARDS: a meta-analysis of randomized controlled trials.

Mesenchymal stromal cells (MSC) have shown potential efficacy in both animal and human trials of acute respiratory distress syndrome (ARDS). Especially during the COVID-19 pandemic, MSC was intensely studied for treating COVID-19-induced ARDS. The purpose of this study is to evaluate the safety and efficacy of MSC in ARDS via a meta-analysis of randomized controlled trials (RCTs). Therefore, a meta-analysis of RCTs of MSC as a therapy for ARDS was conducted. The protocol of this review was registered on Open Science Framework. With no language restriction and according to the "PICOs" principle, searches were conducted on Pubmed and Embase to retrieve any clinical literature on MSC for ARDS. Any RCT, which compared MSC to controls for ARDS, where MSC and controls were intravenously infused, of any dosage, was eligible for inclusion. A total of 13 RCTs, which evaluated MSC versus control for treating ARDS, enrolling a total of 655 cases, met the inclusion criteria and appeared in this meta-analysis. A heterogeneity assessment was carried out using the χ2 test, where a P value less than 0.05 was considered significant. The choice of a fixed-effect or a random-effect model was decided by the I2 value in each of the analyses. This meta-analysis indicated that there was no significant difference in terms of adverse events between MSC and control for ARDS (OR = 0.64, 95% CI [0.34, 1.20], P = 0.17, and I2 = 0%). In comparison with control, MSC could reduce the mortality of ARDS (OR = 0.66, 95% CI [0.46, 0.96], P = 0.03, and I2 = 10%). Based on the results of our meta-analysis, the safety of MSC was demonstrated to be non-inferior to that of standard treatment, and MSC may reduce the mortality rate of ARDS. Though the heterogeneity in the main results was low (I2 < 25%), more high-quality and large-scale clinical trials are needed to further confirm our findings.

ROS-induced lipid peroxidation modulates cell death outcome: mechanisms behind apoptosis, autophagy, and ferroptosis.

Reactive oxygen species (ROS) mediate lipid peroxidation and produce 4-hydroxynonenal and other related products, which play an important role in the process of cell death, including apoptosis, autophagy, and ferroptosis. Lipid peroxidation of phospholipid bilayers can promote mitochondrial apoptosis, endoplasmic reticulum stress, and other complex molecular signaling pathways to regulate apoptosis. Lipid peroxidation and its products also act at different stages of autophagy, affecting the formation of autophagosomes and the recruitment of downstream proteins. In addition, we discuss the important role of ROS and lipid peroxides in ferroptosis and the regulatory role of nuclear factor erythroid 2-related factor 2 in ferroptosis under a background of oxidation. Finally, from the perspectives of promotion, inhibition, transformation, and common upstream molecules, we summarized the crosstalk among apoptosis, autophagy, and ferroptosis in the context of ROS. Our review discusses the role of ROS and lipid peroxidation in apoptosis, autophagy, and ferroptosis and their possible crosstalk mechanisms, so as to provide new insights and directions for the study of diseases related to pathological cell death. This review also has referential significance for studying the exact mechanism of ferroptosis mediated by lipid peroxidation.

Efficacy and Safety of a Low-Flow Extracorporeal Carbon Dioxide Removal System in Acute Respiratory Failure, a Pilot Study in China.

BACKGROUND: Low-flow extracorporeal carbon dioxide removal (LF-ECCO2R) has the potential to play an important role in the management of adults with acute respiratory failure. However, it has never been tested in China. The study aimed at exploring the safety and efficacy on LF-ECCO2R for acute respiratory failure in a Chinese tertiary intensive care unit (ICU). MATERIALS AND METHODS: We performed a retrospective case note review of patients admitted to our tertiary regional ICU and commenced on LF-ECCO2R from June 2020 to September 2021. The LF-ECCO2R device we used was ProLUNG® system (Estor S.p.A., Milan, Italy). The device employed a nonporous poly-4-methyl-1-pentene membrane lung with a surface area of 1.81 m2 and run at an extracorporeal blood flow between 100 and 450 mL/min. Demographic and physiologic data (including ventilation parameters and arterial blood gases) as well as the outcome of LF-ECCO2R treatment were recorded. RESULTS: A total of 12 cases were included. A statistically significant reduction in respiratory rate, driving pressure, PaCO2, and blood lactate was observed. In addition, there was a statistically significant improvement in pH and PaO2/FiO2. Six out of 12 patients (50%) were discharged alive from ICU. Three complications related to LF-ECCO2R were reported, none resulting in serious adverse outcomes. CONCLUSION: Our clinical series indicated that LF-ECCO2R seemed to be safely applied in patients with acute respiratory failure. The efficacy of CO2 removal as well as the improved respiratory parameters was also observed. However, large-scale randomized clinical trials are needed to confirm the effects.

Clinical application of a fixed reference line in the ultrasound quantitative diagnosis of female pelvic organ prolapse.

OBJECTIVE: This study explored using an improved ultrasound (US) for quantitative evaluation of the degree of pelvic organ prolapse(POP). DESIGN: A transluminal probe was used to standardize ultrasound imaging of pelvic floor organ displacements. A US reference line was fixed between the lower edge of the pubic symphysis and the central axis of the pubic symphysis at a 30°counterclockwise angle. METHOD: Points Aa, Ba, C and Bp on pelvic organ prolapse quantification (POP-Q) were then compared with the points on pelvic floor ultrasound (PFUS). RESULTS: One hundred thirteen patients were included in the analysis of the standard US plane. Correlations were good in the anterior and middle compartments (PBN:Aa, ICC = 0.922; PBB:Ba, ICC = 0.923; and PC:C, ICC = 0.925), and Bland-Altman statistical maps corresponding to the average difference around the 30°horizontal line were close to 0. Correlations were poor in the posterior compartment (PRA:Bp, ICC = 0.444). However, eight (7.1%) cases of intestinal hernia and 21 (18.6%) cases of rectocele were diagnosed. CONCLUSIONS: Introital PFUS using an intracavitary probe, which is gently placed at the introitus of the urethra and the vagina, may be accurately used to evaluate organ displacement. The application of a 30°horizontal line may improve the repeatability of the US diagnosis of POP.

Exosomes Highlight Future Directions in the Treatment of Acute Kidney Injury.

Acute kidney injury (AKI) is a severe health problem associated with high morbidity and mortality rates. It currently lacks specific therapeutic strategies. This review focuses on the mechanisms underlying the actions of exosomes derived from different cell sources, including red blood cells, macrophages, monocytes, mesenchymal stem cells, and renal tubular cells, in AKI. We also investigate the effects of various exosome contents (such as miRNA, lncRNA, circRNA, mRNA, and proteins) in promoting renal tubular cell regeneration and angiogenesis, regulating autophagy, suppressing inflammatory responses and oxidative stress, and preventing fibrosis to facilitate AKI repair. Moreover, we highlight the interactions between macrophages and renal tubular cells through exosomes, which contribute to the progression of AKI. Additionally, exosomes and their contents show promise as potential biomarkers for diagnosing AKI. The engineering of exosomes has improved their clinical potential by enhancing isolation and enrichment, target delivery to injured renal tissues, and incorporating small molecular modifications for clinical use. However, further research is needed to better understand the specific mechanisms underlying exosome actions, their delivery pathways to renal tubular cells, and the application of multi-omics research in studying AKI.

Investigation on the effectiveness of ventilation dilution on mitigating COVID-19 patients' secondary airway damage due to exposure to disinfectants.

Chlorine-containing disinfectants are widely used in hospitals to prevent hospital-acquired severe acute respiratory syndrome coronavirus 2 infection. Meanwhile, ventilation is a simple but effective means to maintain clean air. It is essential to explore the exposure level and health effects of coronavirus disease 2019 patients' inhalation exposure to by-products of chloride-containing disinfectants under frequent surface disinfection and understand the role of ventilation in mitigating subsequent airway damage. We determined ventilation dilution performance and indoor air quality of two intensive care unit wards of the largest temporary hospital constructed in China, Leishenshan Hospital. The chloride inhalation exposure levels, and health risks indicated by interleukin-6 and D-dimer test results of 32 patients were analysed. The mean ± standard deviation values of the outdoor air change rate in the two intensive care unit wards were 8.8 ± 1.5 h-1 (Intensive care unit 1) and 4.1 ± 1.4 h-1 (Intensive care unit 2). The median carbon dioxide and fine particulate matter concentrations were 480 ppm and 19 µg/m3 for intensive care unit 1, and 567 ppm and 21 µg/m3 for intensive care unit 2, all of which were around the average levels of those in permanent hospitals (579 ppm and 21 µg/m3). Of these patients, the median (lower quartile, upper quartile) chloride exposure time and calculated dose were 26.66 (2.89, 57.21) h and 0.357 (0.008, 1.317) mg, respectively. A statistically significant positive correlation was observed between interleukin-6 and D-dimer concentrations. To conclude, ventilation helped maintain ward air cleanliness and health risks were not observed.

Renin-Angiotensin System Pathway Therapeutics Associated With Improved Outcomes in Males Hospitalized With COVID-19.

OBJECTIVES: To determine whether angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors are associated with improved outcomes in hospitalized patients with COVID-19 according to sex and to report sex-related differences in renin-angiotensin system (RAS) components. DESIGN: Prospective observational cohort study comparing the effects of ARB or ACE inhibitors versus no ARBs or ACE inhibitors in males versus females. Severe acute respiratory syndrome coronavirus 2 downregulates ACE-2, potentially increasing angiotensin II (a pro-inflammatory vasoconstrictor). Sex-based differences in RAS dysregulation may explain sex-based differences in responses to ARBs because the ACE2 gene is on the X chromosome. We recorded baseline characteristics, comorbidities, prehospital ARBs or ACE inhibitor treatment, use of organ support and mortality, and measured RAS components at admission and days 2, 4, 7, and 14 in a subgroup ( n = 46), recorded d -dimer ( n = 967), comparing males with females. SETTING: ARBs CORONA I is a multicenter Canadian observational cohort of patients hospitalized with acute COVID-19. This analysis includes patients admitted to 10 large urban hospitals across the four most populated provinces. PATIENTS: One-thousand six-hundred eighty-six patients with polymerase chain reaction-confirmed COVID-19 (February 2020 to March 2021) for acute COVID-19 illness were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Males on ARBs before admission had decreased use of ventilation (adjusted odds ratio [aOR] = 0.52; p = 0.007) and vasopressors (aOR = 0.55; p = 0.011) compared with males not on ARBs or ACE inhibitors. No significant effects were observed in females for these outcomes. The test for interaction was significant for use of ventilation ( p = 0.006) and vasopressors ( p = 0.044) indicating significantly different responses to ARBs according to sex. Males had significantly higher plasma ACE-1 at baseline and angiotensin II at day 7 and 14 than females. CONCLUSIONS: ARBs use was associated with less ventilation and vasopressors in males but not females. Sex-based differences in RAS dysregulation may contribute to sex-based differences in outcomes and responses to ARBs in COVID-19.

Evaluating the prognostic value of CD56 in pediatric acute myeloid leukemia.

BACKGROUND: Many cytogenetic changes and gene mutations are associated with acute myeloid leukemia (AML) survival outcomes. CD56 is related to poor prognosis when expressed in adult AML patients. However, the prognostic value of CD56 in children with AML has rarely been reported. In this research, we aimed to evaluate the prognostic value of CD56 in childhood AML. METHODS: The present retrospective study included 145 newly diagnosed pediatric patients with de novo AML (excluding AML-M3) in two hospitals between January 2015 and April 2021. RESULTS: The total median (range) age was 75 (8-176) months, and the median follow-up time was 35 months. No significant difference in the 3-year overall survival rate was noted between the CD56-positive and CD56-negative groups (67.0% vs. 79.3%, P = 0.157) who received chemotherapy. However, among high-risk patients, the CD56-positive group had a worse overall survival rate and event-free survival rate (P < 0.05). Furthermore, among high-risk patients, the CD56-positive group had higher relapse and mortality rates than the CD56-negative group (P < 0.05). CONCLUSIONS: CD56 represents a potential factor of poor prognosis in specific groups of children with AML and should be considered in the risk stratification of the disease. Given the independent prognostic value of CD56 expression, we should consider integrating this marker with some immunophenotypic or cytogenetic abnormalities for comprehensive analysis.

Effect of therapeutic versus prophylactic anticoagulation therapy on clinical outcomes in COVID-19 patients: a systematic review with an updated meta-analysis.

BACKGROUND: Previous studies demonstrate a reduced risk of thrombosis and mortality with anticoagulant treatment in patients with COVID-19 than in those without anticoagulation treatment. However, an open question regarding the efficacy and safety of therapeutic anticoagulation (T-AC) versus a lower dose, prophylaxis anticoagulation (P-AC) in COVID-19 patients is still controversial. METHODS: We systematically reviewed currently available randomized clinical trials (RCTs) and observational studies (OBs) from January 8, 2019, to January 8, 2022, and compared prophylactic and therapeutic anticoagulant treatment in COVID-19 patients. The primary outcomes were risk of mortality, major bleeding, and the secondary outcomes included venous and arterial thromboembolism. Subgroup analysis was also performed between critically ill and non-critically ill patients with COVID-19 and between patients with higher and lower levels of D-dimer. Sensitivity analysis was performed to decrease the bias and the impact of population heterogeneity. RESULTS: We identified 11 RCTs and 17 OBs fulfilling our inclusion criteria. In the RCTs analyses, there was no statistically significant difference in the relative risk of mortality between COVID-19 patients with T-AC treatment and those treated with P-AC (RR 0.95, 95% CI, 0.78-1.15, P = 0.60). Similar results were also found in the OBs analyses (RR 1.21, 95% CI, 0.98-1.49, P = 0.08). The pooling meta-analysis using a random-effects model combined with effect sizes showed that in the RCTs and OBs analyses, patients with COVID-19 who received T-AC treatment had a significantly higher relative risk of the major bleeding event than those with P-AC treatment in COVID-19 patients (RCTs: RR 1.76, 95% CI, 1.19-2.62, P = 0.005; OBs: RR 2.39, 95% CI, 1.56-3.68, P < 0.0001). Compared with P-AC treatment in COVID-19 patients, patients with T-AC treatment significantly reduced the incidence of venous thromboembolism (RR 0.51, 95% CI, 0.39-0.67, P<0.00001), but it is not associated with arterial thrombosis events (RR 0.97, 95% CI, 0.66-1.42, P = 0.87). The subgroup analysis of OBs shows that the mortality risk significantly reduces in critically ill COVID-19 patients treated with T-AC compared with those with P-AC treatment (RR 0.58, 95% CI, 0.39-0.86, P = 0.007), while the mortality risk significantly increases in non-critically ill COVID-19 patients treated with T-AC (RR 1.56, 95% CI, 1.34-1.80, P < 0.00001). In addition, T-AC treatment does not reduce the risk of mortality in COVID-19 patients with high d-dimer levels in RCTs. Finally, the overall sensitivity analysis after excluding two RCTs studies remains consistent with the previous results. CONCLUSIONS: In our integrated analysis of included RCTs and OBs, there is no significant difference between the mortality of T-AC and P-AC treatment in unselected patients with COVID-19. T-AC treatment in COVID-19 patients significantly reduced the incidence of venous thromboembolism but showed a higher risk of bleeding than those with P-AC treatment. In addition, P-AC treatment was superior to T-AC treatment in non-critically ill COVID-19 patients, the evidence supporting the necessity for T-AC treatment in critically ill COVID-19 patients came only from OBs. TRIAL REGISTRATION: Protocol registration: The protocol was registered at PROSPERO (CRD42021293294).

Prognosis and antibody profiles in survivors of critical illness from COVID-19: a prospective multicentre cohort study.

BACKGROUND: There is a need to assess the long-term outcomes of survivors of critical illness from COVID-19. METHODS: Ninety-two survivors of critical illness from COVID-19 from four hospitals in Hubei Province, China participated in this prospective cohort study. Multiple characteristics, including lung function (lung volumes, diffusing capacity for carbon monoxide, chest computed tomography scores, and walking capacity); immune status (SARS-CoV-2-neutralising antibody and all subtypes of immunoglobulin (Ig) G against SARS-CoV-2, immune cells in response to ex vivo antigen peptide stimuli, and lymphocyte count and its subtypes); liver, coagulation, and kidney functions; quality of life; cognitive function; and mental status, were assessed after 3, 6, and 12 months of follow-up. RESULTS: Amongst the 92 enrolled survivors, 72 (78%) patients required mechanical ventilation. At 12 months, the predicted percentage diffusing capacity of lung for carbon monoxide was 82% (inter-quartile range [IQR]: 76-97%) with a residual volume of 77 (64-88)%. Other lung function parameters and the 6-min walk test improved gradually over time and were almost back to normal by 12 months. The titres of IgG and neutralising antibody to COVID-19 remained high at 12 months compared with those of controls who were not infected with COVID-19, although IgG titres decreased significantly from 34.0 (IQR: 23.8-74.3) to 15.0 (5.8-24.3) AU ml-1 (P<0.001), whereas neutralising antibodies decreased from 29.99 (IQR: 19.43-53.93) AU ml-1 at 6 months to 19.75 (13.1-29.8) AU ml-1 (P<0.001) at 12 months. In general, liver, kidney, physical, and mental functions also improved over time. CONCLUSIONS: Survivors of critical illness from COVID-19 show some persistent long-term impairments in lung function. However, a majority of these tests were normal by 12 months. These patients still had detectable levels of neutralising antibodies against SARS-CoV-2 and all types of IgG at 12 months, but the levels had declined over this time period. CLINICAL TRIAL REGISTRATION: None.