Establishment of a non-integrated iPSC (SDQLCHi068-A) line derived from a patient with autosomal dominant immunodeficiency-14A carrying a heterozygous mutation (c.3061G>A) in PIK3CD gene.

Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta (PIK3CD) gene (OMIM#602839) encodes the p110δ catalytic subunit, mainly expressed in immune cells, and is associated with autosomal dominant immunodeficiency-14A with lymphoproliferation (IMD14A, #615513). We generated a human iPS cell line from a 50-month-old boy with IMD14A carrying a heterozygous mutation (c.3061G>A, p.E1021K) in PIK3CD gene. This cell line retains the original mutation site and shows differentiation potential towards three germ layers in vitro, which can be used as a disease model for research.

[Endoscopic ultrasonography features of benign esophageal stenosis in children]. / å„¿ç«¥é£Ÿç®¡è‰¯æ€§ç‹­çª„çš„è¶ å£°å† é•œç‰¹å¾åˆ†æž.

OBJECTIVES: To investigate the endoscopic ultrasonography (EUS) features of benign esophageal stenosis in children. METHODS: A retrospective analysis was conducted on the medical data of the children who were diagnosed with benign esophageal stenosis from February 2019 to February 2022. The clinical manifestations, EUS findings, and treatment outcome were analyzed to summarize the EUS features of benign esophageal stenosis in children. RESULTS: A total of 42 children with benign esophageal stenosis were included. Among these children, 19 (45%) had anastomotic stenosis after surgery for esophageal atresia, with unclear echogenic boundary of the esophageal walls and uneven thicknesses of the surrounding wall on EUS, and had 0-12 sessions of endoscopic treatment (average 2.1 sessions); 5 children (12%) had corrosive esophageal stenosis and 1 child (2%) had physical esophageal stenosis, with unclear stratification of the esophageal walls on EUS, and they had 2-9 sessions of endoscopic treatment (average 5.3 sessions); 1 child (2%) had patchy irregular hypoechoic areas of the esophageal walls on EUS and was diagnosed with tracheobronchial remnants with reference to pathology; 16 children (38%) had unexplained esophageal stenosis and unclear stratification of the esophageal walls on EUS, among whom 6 received endoscopic treatment. During follow-up, 95% (40/42) of the children had significant alleviation of the symptoms such as vomiting and dysphagia. CONCLUSIONS: For benign esophageal stenosis in children, EUS can help to evaluate the degree of esophageal wall involvement in esophageal stenosis lesions, possible etiologies, and the relationship between the esophagus and the lesion and provide an important basis for selecting treatment modality and avoiding complications, thereby helping to optimize the treatment regimen.

Circ-phkb promotes cell apoptosis and inflammation in LPS-induced alveolar macrophages via the TLR4/MyD88/NF-kB/CCL2 axis.

BACKGROUND: Circular RNAs (CircRNAs) have been associated with acute lung injury (ALI), but their molecular mechanisms remain unclear. METHODS: This study developed a rat model of lipopolysaccharide (LPS)-induced ALI and evaluated the modeling effect by hematoxylin and eosin staining, Masson's trichrome staining, lung wet-to-dry weight ratio, terminal deoxynucleotidyl transferase UTP nick end labeling (TUNEL), and enzyme-linked immunosorbent assay (ELISA) detection of inflammatory factors (interleukin-1ß, tumor necrosis factor alpha, and interleukin-6). Using lung tissues from a rat model of LPS-induced ALI, we then conducted circRNA sequencing, mRNA sequencing, and bioinformatics analysis to obtain differential circRNA and mRNA expression profiles as well as potential ceRNA networks. Furthermore, we performed quantitative real-time polymerase chain reaction (qRT-PCR) assays to screen for circ-Phkb in ALI rat lung tissues, alveolar macrophages, and LPS-induced NR8383 cells. We conducted induction with or without LPS with circ-Phkb siRNA and overexpression lentivirus in NR8383. Cell Counting Kit-8, C5-Ethynyl-2'-deoxyuridine (Edu), TUNEL, and cytometry were used to identify proliferation and apoptosis, respectively. We detected inflammatory factors using ELISA. Finally, we used Western blot to detect the apoptosis-related proteins and TLR4/MyD88/NF-kB/CCL2 pathway activation. RESULTS: Our results revealed that both circRNA and mRNA profiles are different from those of the Sham group. We observed a significant circ-Phkb upregulation in NR8383 cells and LPS-exposed rats. Apoptosis and inflammation were greatly reduced when circ-Phkb expression was reduced in NR8383 cells, cell proliferation was increased, and circ-Phkb overexpression was decreased. CONCLUSIONS: In terms of mechanism, circ-Phkb suppression inhibits CCL2 expression via the TLR4/MyD88/NF-kB pathway in LPS-induced alveolar macrophages.

Machine learning-based identification of CYBB and FCAR as potential neutrophil extracellular trap-related treatment targets in sepsis.

Objective: Sepsis related injury has gradually become the main cause of death in non-cardiac patients in intensive care units, but the underlying pathological and physiological mechanisms remain unclear. The Third International Consensus Definitions for Sepsis and Septic Shock (SEPSIS-3) definition emphasized organ dysfunction caused by infection. Neutrophil extracellular traps (NETs) can cause inflammation and have key roles in sepsis organ failure; however, the role of NETs-related genes in sepsis is unknown. Here, we sought to identify key NETs-related genes associate with sepsis. Methods: Datasets GSE65682 and GSE145227, including data from 770 patients with sepsis and 54 healthy controls, were downloaded from the GEO database and split into training and validation sets. Differentially expressed genes (DEGs) were identified and weighted gene co-expression network analysis (WGCNA) performed. A machine learning approach was applied to identify key genes, which were used to construct functional networks. Key genes associated with diagnosis and survival of sepsis were screened out. Finally, mouse and human blood samples were collected for RT-qPCR verification and flow cytometry analysis. Multiple organs injury, apoptosis and NETs expression were measured to evaluated effects of sulforaphane (SFN). Results: Analysis of the obtained DEGs and WGCNA screened a total of 3396 genes in 3 modules, and intersection of the results of both analyses with 69 NETs-related genes, screened out seven genes (S100A12, SLC22A4, FCAR, CYBB, PADI4, DNASE1, MMP9) using machine learning algorithms. Of these, CYBB and FCAR were independent predictors of poor survival in patients with sepsis. Administration of SFN significantly alleviated murine lung NETs expression and injury, accompanied by whole blood CYBB mRNA level. Conclusion: CYBB and FCAR may be reliable biomarkers of survival in patients with sepsis, as well as potential targets for sepsis treatment. SFN significantly alleviated NETs-related organs injury, suggesting the therapeutic potential by targeting CYBB in the future.

Characterization of GSDME in amphioxus provides insights into the functional evolution of GSDM-mediated pyroptosis.

Members of the gasdermin (GSDM) family are pore-forming effectors that cause membrane permeabilization and pyroptosis, a lytic proinflammatory type of cell death. To reveal the functional evolution of GSDM-mediated pyroptosis at the transition from invertebrates to vertebrates, we conducted functional characterization of amphioxus GSDME (BbGSDME) and found that it can be cleaved by distinct caspase homologs, yielding the N253 and N304 termini with distinct functions. The N253 fragment binds to cell membrane, triggers pyroptosis, and inhibits bacterial growth, while the N304 performs negative regulation of N253-mediated cell death. Moreover, BbGSDME is associated with bacteria-induced tissue necrosis and transcriptionally regulated by BbIRF1/8 in amphioxus. Interestingly, several amino acids that are evolutionarily conserved were found to be important for the function of both BbGSDME and HsGSDME, shedding new lights on the functional regulation of GSDM-mediated inflammation.

[Analysis of a child with Johanson-Blizzard syndrome due to novel compound heterozygous variants of UBR1 gene].

OBJECTIVE: To analyze the clinical and genetic characteristics of a boy featuring unexplained developmental delay, malnutrition and distinct facial appearance. METHODS: Physical examination was carried out for the child. Peripheral blood samples were collected from the child and his parents for the extraction of genomic DNA and trio-whole exome sequencing. Candidate variants were verified by Sanger sequencing. RESULTS: The patient had facial dysmorphism including nasal alae aplasia, scalp defect and teeth deformities, in addition with recurrent diarrhea due to pancreatic exocrine insufficiency. DNA sequencing revealed that he has harbored compound heterozygous variants of the UBR1 gene, namely c.3167C>G (p.S1056X) and c.1911+14C>G, which were inherited from his father and mother, respectively. Database search has suggested the c.3167C>G to be a novel nonsense variant and c.1911+14C>G a known splicing variant. Based on the guidelines of the American College of Medical Genetics and Genomics, the two variants were predicted to be pathogenic and likely pathogenic, respectively. CONCLUSION: The child was diagnosed with Johanson-Blizzard syndrome due to the compound heterozygous variants of the UBR1 gene. Above finding has enriched the mutational spectrum of the UBR1 gene and provided a basis for genetic counseling for this family.

Mesenchymal stromal cells alleviate acute respiratory distress syndrome through the cholinergic anti-inflammatory pathway.

Mesenchymal stromal cells (MSCs) have been considered a promising alternative for treatment of acute respiratory distress syndrome (ARDS). However, there is significant heterogeneity in their therapeutic efficacy, largely owing to the incomplete understanding of the mechanisms underlying the therapeutic activities of MSCs. Here, we hypothesize that the cholinergic anti-inflammatory pathway (CAP), which is recognized as a neuroimmunological pathway, may be involved in the therapeutic mechanisms by which MSCs mitigate ARDS. Using lipopolysaccharide (LPS) and bacterial lung inflammation models, we found that inflammatory cell infiltration and Evans blue leakage were reduced and that the expression levels of choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) in lung tissue were significantly increased 6 hours after MSC infusion. When the vagus nerve was blocked or α7 nicotinic acetylcholine (ACh) receptor (α7nAChR)-knockout mice were used, the therapeutic effects of MSCs were significantly reduced, suggesting that the CAP may play an important role in the effects of MSCs in ARDS treatment. Our results further showed that MSC-derived prostaglandin E2 (PGE2) likely promoted ACh synthesis and release. Additionally, based on the efficacy of nAChR and α7nAChR agonists, we found that lobeline, the nicotinic cholinergic receptor excitation stimulant, may attenuate pulmonary inflammation and alleviate respiratory symptoms of ARDS patients in a clinical study (ChiCTR2100047403). In summary, we reveal a previously unrecognized MSC-mediated mechanism of CAP activation as the means by which MSCs alleviate ARDS-like syndrome, providing insight into the clinical translation of MSCs or CAP-related strategies for the treatment of patients with ARDS.

Genotypic and phenotypic characteristics of 12 chinese children with glycogen storage diseases.

Background: Glycogen storage diseases (GSDs) are known as a group of disorders characterized by genetic errors leading to accumulation of glycogen in various tissues. Since different types of GSD can sometimes be clinically indistinguishable, next generation sequencing is becoming a powerful tool for clinical diagnosis. Methods: 12 patients with suspected GSDs and their parents were enrolled in this study. The clinical and laboratory data of the patients were reviewed. Causative gene variants were identified in the patients using whole exome sequencing (WES) and verified by Sanger sequencing. Results: Genetic testing and analysis showed that 7 patients were diagnosed with GSD II (Pompe disease), 2 patients with GSD III, 1 patient with GSD VI, and 2 patients with GSD IXα. A total number of 18 variants were identified in 12 patients including 11 variants in GAA gene, 3 variants in AGL gene, 2 variants in PYGL gene and 2 variants in PHKA2 gene, of which 9 variants were reported and 9 variants were novel. SIFT, Polyphen-2, Mutation Taster, and REVEL predicted the novel variants (except GAA c.1052_1075 + 47del) to be disease-causing. The 3D structures of wild/mutant type GAA protein were predicted indicating that variants p. Trp621Gly, p. Pro541Leu, p. Ser800Ile and p. Gly293Trp might affect the proteins function via destroying hydrogen bonds or conformational constraints. Neither liver size nor laboratory findings allow for a differentiation among GSD III, GSD VI and GSD IXα. Conclusion: Our study expanded the variation spectrum of genes associated with GSDs. WES, in combination with clinical, biochemical, and pathological hallmarks, could provide accurate results for diagnosing and sub-typing GSD and related diseases in clinical setting.

Finite versus Indefinite Nucleos(t)ide Analogue Therapy of Patients with Chronic Hepatitis B Exhibiting Negative HBsAg Levels after Treatment.

Aim: To determine whether a decrease in HBsAg to <0.05 IU/mL could be a criterion for cessation of finite nucleos(t)ide analogue (NUC) therapy in patients with chronic hepatitis B (CHB). Methods: This was a retrospective analysis of 6715 patients with CHB between January 1998 and May 2016. Patients were followed up every 12-24 weeks. Among 104 patients achieving HBsAg levels < 0.05 IU/mL, 71 were eligible for inclusion in the analysis: 31 received finite NUC therapy, and 40 received indefinite NUC therapy. In the finite therapy group, 9 patients received no NUC consolidation therapy, 6 received short-term (<1 year) consolidation, and 16 received long-term (>1 year) consolidation. The outcome measures were alanine aminotransferase (ALT), total bilirubin, albumin, hepatitis B virus DNA, and HBsAg levels. Results: Baseline parameters and characteristics at the time when HBsAg levels had fallen to <0.05 IU/mL were similar between the finite and indefinite therapy groups. No patients experienced viral breakthrough/relapse during a median follow-up of 120 weeks. There were little or no differences in long-term outcomes between the finite and indefinite therapy groups and between the short-term and long-term consolidation groups. Conclusions: Discontinuation of NUCs may be acceptable in patients whose HBsAg levels fall to <0.05 IU/mL. Consolidation therapy lasting <1 year appears adequate to prevent poor long-term prognosis.

Efficacy of comprehensive unit-based safety program to prevent ventilator associated-pneumonia for mechanically ventilated patients in China: A propensity-matched analysis.

Background: Ventilator-associated pneumonia (VAP) is the most common healthcare-associated infection (HAI) in patients with mechanical ventilation. VAP is largely preventable, and a comprehensive unit-based safety program (CUSP) has effectively reduced HAI. In this study, we aim to comprehensively investigate the effect of implementing the CUSP in patients requiring mechanical ventilation. Methods: In this uncontrolled before-and-after trial conducted in two intensive care unit (ICU) settings in China, patients requiring invasive mechanical ventilation were enrolled. Patients were divided into two groups based on the implementation of CUSP. The primary outcome was the incidence of VAP. The secondary outcomes were the time from intubation to VAP, days of antibiotic use for VAP treatments, rate of other infection, length of stay (LOS) in ICU, hospital LOS, and safety culture score. Joinpoint regression analysis was used to test the changes in trends of VAP rate for statistical significance. Propensity score matching (1:1 matching) was used to reduce the potential bias between CUSP and no CUSP groups. Univariate and multivariate logistic/linear regression analyses were performed to evaluate the association between the use of CUSP and clinical outcomes. This study was registered at the Chinese Clinical Trial Registry (chictr.org.cn), registration number: ChiCTR1900025391. Results: A total of 1,004 patients from the transplant ICU (TICU) and 1,001 patients from the surgical ICU (SICU) were enrolled in the study from January 2016 to March 2022. Before propensity score matching, the incidences of VAP decreased from 35.1/1,000 ventilator days in the no CUSP group to 12.3/1,000 ventilator days in the CUSP group in the TICU setting (adjusted odds ratio [OR], 0.30; 95% confidence interval [CI], 0.15-0.59). The results of the joinpoint regression analysis confirmed that the implementation of CUSP significantly decreased the incidences of VAP. After propensity score matching in TICU setting, the CUSP group reported a lower incidence of VAP (30.4 vs. 9.7‰, P = 0.003; adjusted OR = 0.26, 95% CI: 0.10-0.76), lower wound infection (3.4 vs. 0.9%, P = 0.048; adjusted OR = 0.73, 95% CI: 0.50-0.95), shorter ICU LOS [3.5(2.3-5.3) vs. 2.5(2.0-4.5) days; P = 0.003, adjusted estimate = -0.34, 95% CI: -0.92 to -0.14], and higher safety culture score (149.40 ± 11.74 vs. 153.37 ± 9.74; P = 0.002). Similar results were also observed in the SICU setting between the no CUSP and CUSP group. Conclusions: The implementation of CSUP for patients receiving mechanical ventilation could significantly reduce the incidences of VAP, and other infections, prolong the time until the VAP occurrence, reduces the days of antibiotic use for VAP, shorten the ICU and hospital LOS, and enhance the awareness of safety culture.

Correction: MicroRNA-377-3p released by mesenchymal stem cell exosomes ameliorates lipopolysaccharide-induced acute lung injury by targeting RPTOR to induce autophagy.

This work was supported by National 13th Five-Year Science and Technology Plan Major Projects of China (2017ZX10203205-006-001); National Key R&D Plan (2017YFA0104304); National Natural Science Foundation of China (81770648 81972286); Guangdong Natural Science Foundation (2015A030312013, 2018A0303130305); Science and Technology Program of Guangdong Province (2017B020209004, 20169013, 2017B030314027). This has now been corrected in both the PDF and HTML versions of the Article.

MicroRNA-377-3p released by mesenchymal stem cell exosomes ameliorates lipopolysaccharide-induced acute lung injury by targeting RPTOR to induce autophagy.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the severe lung damage and respiratory failure without effective therapy. However, there was a lack of understanding of the mechanism by which exosomes regulate autophagy during ALI/ARDS. Here, we found lipopolysaccharide (LPS) significantly increased inflammatory factors, administration of exosomes released by human umbilical cord mesenchymal stem cells (hucMSCs) successfully improved lung morphometry. Further studies showed that miR-377-3p in the exosomes played a pivotal role in regulating autophagy, leading to protect LPS induced ALI. Compared to exosomes released by human fetal lung fibroblast cells (HFL-1), hucMSCs-exosomes overexpressing miR-377-3p more effectively suppressed the bronchoalveolar lavage (BALF) and inflammatory factors and induced autophagy, causing recoveration of ALI. Administration of miR-377-3p expressing hucMSCs-exosomes or its target regulatory-associated protein of mTOR (RPTOR) knockdown significantly reduced ALI. In summary, miR-377-3p released by hucMSCs-exosomes ameliorated Lipopolysaccharide-induced acute lung injury by targeting RPTOR to induce autophagy in vivo and in vitro.

Mesenchymal stromal cells ameliorate acute lung injury induced by LPS mainly through stanniocalcin-2 mediating macrophage polarization.

BACKGROUND: Acute lung injury (ALI) is a devastating syndrome with no effective pharmacological therapies in the clinic. Mesenchymal stromal cells (MSCs) have been demonstrated to promote inflammation resolution and tissue repair in ALI. However, the specific mechanisms of this have not been clearly elucidated. Stanniocalcin-2 (STC2) is a stress-responsive protein that has anti-oxidative properties. Our previous study found that STC2 is a highly expressed stanniocalcin in MSCs, which may be involved in immunomodulatory activities. However, the role of STC2 in MSCs to resolve ALI has never been elucidated. METHODS: Specific shRNA was used to downregulate STC2 in MSCs. We detected ROS, cell apoptosis, and paracrine factors changes in MSCs. STC2-associated antioxidant genes were also investigated by Co-immunoprecipitation (Co-IP) and immunofluorescence. Macrophage (THP1 cells) phenotype transitions were measured by flow cytometry after coculturing with MSCs in vitro. Then, we used MSCs to treat LPS-induced ALI in mice, and assessed injury scores inflammation, and antioxidant activities in the lungs of the mice. Alveolar macrophage (AM) phenotypes and CFSE-labeled MSC apoptosis in collected bronchoalveolar fluids (BALF) were also analyzed by flow cytometry. RESULTS: After the STC2 knockdown, MSCs increased ROS generation and cell apoptosis after PX12 pretreatment. The antioxidant protein Nrf2 was colocalized with STC2 in the nucleus. A lack of STC2 expression in MSCs produced less interleukin 10 (IL10) and blunted macrophage polarization in THP1 cells. Furthermore, in the murine LPS-induced ALI model, the STC2 knockdown counteracted the inflammatory resolution and antioxidative effect of MSCs in the lungs. MSCshSTC2-treated mice had a higher lung injury score than the controls, which may be attributed to diminished AM polarization and increased apoptosis of MSCs in vivo. CONCLUSIONS: Collectively, these results suggested that STC2 is essential to the anti-oxidative and anti-inflammation properties of MSCs and could prove to be crucial for stem cell therapies for ALI.

Nicotinamide adenine dinucleotide phosphate oxidase 2-derived reactive oxygen species contribute to long-term potentiation of C-fiber-evoked field potentials in spinal dorsal horn and persistent mirror-image pain following high-frequency stimulus of the sciatic nerve.

High-frequency stimulation (HFS) of the sciatic nerve has been reported to produce long-term potentiation (LTP) and long-lasting pain hypersensitivity in rats. However, the central underlying mechanism remains unclear. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) belongs to a group of electron-transporting transmembrane enzymes that produce reactive oxygen species (ROS). Here, we found that NOX2 was upregulated in the lumbar spinal dorsal horn after HFS of the left sciatic nerve, which induced bilateral pain and spinal LTP in both male and female rats. Blocking NOX2 with blocking peptide or shRNA prevented the development of bilateral mechanical allodynia, the induction of spinal LTP, and the phosphorylation of N-methyl-d-aspartate (NMDA) receptor 2B (GluN2B) and nuclear factor kappa-B (NF-κB) p65 after HFS. Moreover, NOX2 shRNA reduced the frequency and amplitude of both spontaneous excitatory postsynaptic currents and miniature excitatory postsynaptic currents in laminar II neurons. Furthermore, 8-hydroxyguanine (8-OHG), an oxidative stress marker, was increased in the spinal dorsal horn. Spinal application of ROS scavenger, Phenyl-N-tert-butylnitrone (PBN), depressed the already established spinal LTP. Spinal application of H2O2, one ROS, induced LTP and bilateral mechanical allodynia, increased the frequency and amplitude of spontaneous excitatory postsynaptic currents in laminar II neurons, and phosphorylated GluN2B and p65 in the dorsal horn. This study provided electrophysiological and behavioral evidence that NOX2-derived ROS in the spinal cord contributed to persistent mirror-image pain by enhancing the synaptic transmission, which was mediated by increasing presynaptic glutamate release and activation of NMDA receptor and NF-κB in the spinal dorsal horn.

High-dose ulinastatin to prevent late-onset acute renal failure after orthotopic liver transplantation.

Purpose: To compare the efficacy and safety of two distinct doses of ulinastatin on late-onset acute renal failure (LARF) following orthotopic liver transplantation (OLT).Methods: The high-risk recipients that underwent OLT were divided into two groups according to ulinastatin dose: low-dose (LD) ulinastatin group, 0.8 million U/d; high-dose (HD) ulinastatin group, 1.6 million U/d. The primary outcome was the incidence of LARF, which was defined the newly onset acute kidney injury (AKI) stage III (KDIGO, 2012) within 7-28 post-transplant days. The second outcomes were early multiple organ retrieval assessments, length of hospital stay and safety events.Results: A total of 174 recipients were included (LD ulinastatin group, n = 55; HD ulinastatin group, n = 119). There was no significant difference in the incidence of LARF between LD (8/55, 14.50%) and HD (9/119, 7.56%) ulinastatin groups (HD vs. LD, HR, 0.49; 95%CI, 0.17-1.37; p = .1295). Multivariate Cox proportion risk regression model revealed HD ulinastatin (HR, 0.57; 95%CI, 0.38-0.98; p = .0464) was an independent protective factor for LARF. Early lactate level, oxygenation, AKI stage, graft function, and sequential organ failure assessment [SOFA] score were significantly improved in HD ulinastatin group versus LD ulinastatin group. No significant adverse events were observed in either group.Conclusions: Higher dose of ulinastatin (1.6 million U/d) might be preferable to prevent LARF after OLT, and it may contribute to the enhancement of early multiple organ recovery and thus attenuate the incidence of LARF.

Efficacy and safety of haloperidol for delirium prevention in adult patients: An updated meta-analysis with trial sequential analysis of randomized controlled trials.

STUDY OBJECTIVE: To identify the efficacy and safety of haloperidol prophylaxis in adult patients with a high risk for delirium. DESIGN: A meta-analysis with trial sequential analysis of randomized controlled trials. INTERVENTION: A comprehensive search was performed in PubMed, the ISI Web of Knowledge, the Cochrane Library, and Embase databases from inception through to March 2019.Citation screening, data abstraction and quality assessment were performed in duplicate. Meta-analysis with trial sequential analysis (TSA) were used to assess the primary and secondary outcomes. In addition, we used the Grading of Recommendations Assessment Development and Evaluation (GRADE) to evaluate the certainty of the body of evidence. MAIN RESULTS: We appraised 8 RCTs involving 3034 patients that that were in compliance with inclusion and exclusion criterion. Pooled analyses indicated patients receiving haloperidol prophylaxis and placebo or normal saline did not significantly differ in incidence of delirium (relative risk [RR] = 0.90, 95% confidence interval [CI] = 0.70 to 1.15), with TSA inconclusive. Notably, compared with the control group, use of haloperidol significantly decreased the duration of delirium (Mean difference [MD] -0.94; 95% CI -1.82 to -0.06 days), with a marked heterogeneity. Additionally, haloperidol prophylaxis does not significantly affect duration of mechanical ventilation, length of intensive care unit (ICU) stay, length of hospital stay and mortality. In terms of safety profiles, haloperidol was not associated with increased risk for QTc prolongation, extrapyramidal symptoms, or adverse events. GRADE indicated the level of evidence was very low for a benefit from haloperidol prophylaxis. CONCLUSIONS: The results of our meta-analysis suggested the use of prophylactic haloperidol compared with placebo had no beneficial impacts on incidence of delirium, duration of mechanical ventilation, length of intensive care unit (ICU) stay, length of hospital stay and mortality in adult patients. It appeared to have a positive effect on duration of delirium, while with a significant heterogeneity. These findings do not support the routine usage of haloperidol for delirium prevention. TRIAL REGISTRATION: PROSPERO registration number: CRD42018100511. Registered on 17 July 2018.

The Accuracy of Urinary TIMP-2 and IGFBP7 for the Diagnosis of Cardiac Surgery-Associated Acute Kidney Injury: A Systematic Review and Meta-Analysis.

BACKGROUND: Tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) are recent promising markers for identification of cardiac surgery-associated acute kidney injury (CSA-AKI). The aim of this study was systematically and quantitatively to evaluate the accuracy of urinary TIMP-2 and IGFBP7 for the diagnosis of CSA-AKI. METHODS: Three databases including PubMed, ISI web of knowledge, and Embase were systematically searched from inception to March 2018. Two investigators conducted the processes of literature search study selection, data extraction, and quality evaluation independently. Meta-DiSc and STATA were used for all statistical analyses. RESULTS: A total of 8 studies comprising 552 patients were included in this meta-analysis. Pooled sensitivity and specificity with corresponding 95% confidence intervals (CIs) were 0.79 (95% CI, 0.71-0.86, I 2 = 74.2%) and 0.76 (95% CI, 0.72-0.80, I 2 = 80.8%), respectively. Pooled positive likelihood ratio (LR), negative LR, and diagnostic odds ratio were 3.49 (95% CI, 2.44-5.00, I 2 = 61.5%), 0.31(95% CI, 0.19-0.51, I 2 = 51.8%), and 14.89 (95% CI, 7.31-30.32, I 2 = 27.9%), respectively. The area under curve estimated by summary receiver operating characteristic was 0.868 (standard error [SE] 0.032) with a Q* value of 0.799 (SE 0.032). Sensitivity analysis demonstrated that one study notably affected the stability of pooled results. One of the subgroups investigated-AKI threshold-could account for partial heterogeneity. CONCLUSION: Urinary TIMP-2 and IGFBP7 is a helpful biomarker for early diagnosis of CSA-AKI. And, the potential of this biomarker with a broader spectrum of clinical settings may be the focus of future studies.

Helicobacter pylori Infection Aggravates Dysbiosis of Gut Microbiome in Children With Gastritis.

Introduction:Helicobacter pylori infection consistently leads to chronic and low degree of inflammatory response in gastric mucosa and is closely related with gastrointestinal and extra-gastric diseases. Effects of local microbiome in the stomach have been studied in adults and children with H. pylori infection. It is, however, not known whether the intestinal microbial community differs in children with varying H. pylori infection. The aim of this study is to characterize the altered composition of microbiome induced by H. pylori infection and in gastritis. Materials and Methods: This study involved 154 individuals, including 50 children affected by H. pylori-induced gastritis, 42 children with H. pylori-negative gastritis, and 62 healthy controls. Gut microbiome composition was analyzed using 16S rRNA gene-based pyrosequencing. Fecal bacterial diversity and composition were then compared. Results: On the basis of an analysis of similarities and differences, we found that children with H. pylori-induced gastritis exhibited gut bacteria dysbiosis. The ratio of Firmicutes/Bacteroidetes (F:B) at the phylum level had dramatically decreased in H. pylori-positive gastritis group (HPG) and H. pylori-negative gastritis group (HNG), compared with the healthy control group (HCG). At the family and genus levels, relative abundance of Bacteroidaceae and Enterobacteriaceae was prevalent in HPG and HNG, whereas relative abundance of Lachnospiraceae, Bifidobacteriaceae, and Lactobacillaceae was seen in HCG. Prevalence of different taxa of gut microbiome at the class, order, family, and genus levels was also observed among the three groups. Conclusions: Gastritis can cause changes in composition of fecal microbiome, which is exacerbated by H. pylori infection. These changes in gut microbiome may be related to drug resistance and development of chronic gastrointestinal diseases.

Higher vs. Lower DP for Ventilated Patients with Acute Respiratory Distress Syndrome: A Systematic Review and Meta-Analysis.

OBJECTIVES: Driving pressure (DP) has recently become a promising mediator for the identification of the effects of mechanical ventilation on outcomes in acute respiratory distress syndrome (ARDS). The aim of this study was to systematically and quantitatively update and assess the association between DP and mortality among ventilated patients with ARDS. METHODS: PubMed, the Cochrane Library, ISI Web of Knowledge, and Embase were systematically searched from inception to June 2018. Two investigators conducted the literature search study selection, data extraction, and quality evaluation independently. RevMan 5.3 software was used for all statistical analyses. RESULTS: A total of seven studies comprising 8010 patients were included in this meta-analysis. Higher DP showed a significant association with higher mortality (pooled risk ratio, 1.10; 95% [CI], 1.05-1.16; I 2 =58%). Sensitivity analysis indicated that one study significantly affected the stability of pooled results. One of the subgroups investigated, ARDS severity, could account for the heterogeneity. An exploratory post hoc subgroup analysis and higher DP significantly increased mortality in the mild to severe ARDS subgroup (RR 1.28; 95% [CI], 1.14-1.43; I 2 =0), but not in the moderate to severe ARDS subgroup (RR 1.18; 95% [CI], 0.95-1.46; I 2 =52%). CONCLUSION: Higher DP was significantly associated with an increased risk of death among ventilated patients with ARDS. But it did not seem to predict prognosis to moderate to severe ARDS. Future prospective randomized clinical trials are needed to verify the results of this meta-analysis and address the unresolved questions about optimum cutoff values for DP. TRIAL REGISTRATION: This trial is registered with PROSPERO (CRD42018102146), on 11 August 2018.