Anti-inflammatory response-based risk assessment in acute type A aortic dissection: A national multicenter cohort study.

Background: Early identification of patients at high risk of operative mortality is important for acute type A aortic dissection (TAAD). We aimed to investigate whether patients with distinct risk stratifications respond differently to anti-inflammatory pharmacotherapy. Methods: From 13 cardiovascular hospitals, 3110 surgically repaired TAAD patients were randomly divided into a training set (70%) and a test set (30%) to develop and validate a risk model to predict operative mortality using extreme gradient boosting. Performance was measured by the area under the receiver operating characteristic curve (AUC). Subgroup analyses were performed by risk stratifications (low versus middle-high risk) and anti-inflammatory pharmacotherapy (absence versus presence of ulinastatin use). Results: A simplified risk model was developed for predicting operative mortality, consisting of the top ten features of importance: platelet-leukocyte ratio, D-dimer, activated partial thromboplastin time, urea nitrogen, glucose, lactate, base excess, hemoglobin, albumin, and creatine kinase-MB, which displayed a superior discrimination ability (AUC: 0.943, 95 % CI 0.928-0.958 and 0.884, 95 % CI 0.836-0.932) in the derivation and validation cohorts, respectively. Ulinastatin use was not associated with decreased risk of operative mortality among each risk stratification, however, ulinastatin use was associated with a shorter mechanical ventilation duration among patients with middle-high risk (defined as risk probability >5.0 %) (ß -1.6 h, 95 % CI [-3.1, -0.1] hours; P = 0.048). Conclusion: This risk model reflecting inflammatory, coagulation, and metabolic pathways achieved acceptable predictive performances of operative mortality following TAAD surgery, which will contribute to individualized anti-inflammatory pharmacotherapy.

Contemporary use and outcome of Cabrol shunt in type A aortic dissection surgery: insight from China 5A study.

OBJECTIVE: Cabrol shunt has been introduced for surgical repair of type A aortic dissection (TAAD) without robust evidence supporting its routine preventive use. METHODS: Adult patients with TAAD from China 5A study were included if surgically repaired between 2016 and 2022. Primary outcome was operative mortality according to Society of Thoracic Surgeons criterion. Overall, we compared clinical outcomes in patients with and without Cabrol shunt, and subgroup analysis were further examined between Cabrol shunt and outcome among patients with or without root replacement. RESULTS: 3283 patients were finally identified for analysis, with median age of 51 (IQR 41-59) years, 2389 men, and 2201 treated with Cabrol shunt technique. Cabrol shunt-treated patients were more severely ill before surgery than those without Cabrol shunt. Overall, the rate of operative mortality was 6.6% (146/2201 in Cabrol shunt group and 71/1082 in non-Cabrol shunt group), with no association between Cabrol shunt and operative mortality (OR 1.012 (95% CI 0.754 to 1.357); p=0.938). Stratified by root replacement, Cabrol shunt was associated with similar risk of operative mortality either in patients without root replacement (OR 1.054 (0.747 to 1.487); p=0.764) or in patients with root replacement (OR 1.194 (0.563 to 2.536); p=0.644) (P interaction=0.765). Results were similar in multiple sensitivity analysis. CONCLUSION: Cabrol shunt was not associated with either a greatly lowered or an increased risk of operative mortality, regardless of aortic root replacement. Our study did not support the use of Cabrol shunt as a routine preventive strategy in the treatment of TAAD. TRIAL REGISTRATION NUMBER: NCT04398992.

Synthesis, characterization and properties of a novel environmentally friendly ternary hydrophilic copolymer.

A novel environmentally friendly scale inhibitor was synthesized by the free radical polymerization of itaconic acid (IA), acrylamide (AM), and sodium p-styrene sulfonate (SSS). The structures of the copolymers were characterized using FTIR, UV, and 1H-NMR, which proved successful in obtaining the expected target structures. The synthesis conditions such as monomer ratio, initiator dosage, titration time, and reaction temperature were optimized by the static scale inhibition method, and the expected polymeric scale inhibitor with a competent scale inhibition performance was obtained. The copolymer conversions at different temperatures were obtained indirectly by bromination titration, and the relationship between the molecular weight of the polymer and the scale inhibition performance at different reaction temperatures was also investigated by GPC. The results showed that the copolymer had a good ability to control calcium carbonate scaling, and the inhibition rate of CaCO3 reached 84.7% at a dose of 30 mg L-1. The microscopic morphology and structure of calcium scales were analyzed by SEM, FTIR, and XRD, and it was concluded that the copolymer could change the crystallization path of calcium carbonate from stable calcite to vaterite. That could be dispersed in water. The proposed inhibition mechanism suggests that surface complexation between polymer functional groups and Ca2+ leads to excellent solubility of the complexes. These findings suggest that the prepared green copolymers have great potential for oilfield applications.

SIRPα maintains macrophage homeostasis by interacting with PTK2B kinase in Mycobacterium tuberculosis infection and through autophagy and necroptosis.

BACKGROUND: To determine whether SIRPα can be a diagnostic marker of pulmonary tuberculosis (PTB) and the molecular mechanism of SIRPα regulating macrophages to kill Mycobacterium tuberculosis (MTB). METHODS: Meta-analysis combined with subsequent qRT-PCR, western-blotting and flow cytometry assay were used to detect SIRPα expression in PTB patients. Cell-based assays were used to explore the regulation of macrophage function by SIRPα. SIRPα-/- and wide type macrophages transplanted C57BL/6J mice were used to determine the function of SIRPα on MTB infection in vivo. FINDINGS: SIRPα levels are closely correlated with the treatment outcomes among PTB patients. Cell-based assay demonstrated that MTB significantly induces the expression of SIRPα on macrophages. SIRPα deficiency enhances the killing ability of macrophages against MTB through processes that involve enhanced autophagy and reduced necroptosis of macrophages. Mechanistically, SIRPα forms a direct interaction with PTK2B through its intracellular C-terminal domain, thus inhibiting PTK2B activation in macrophages. Necroptosis inhibition due to SIRPα deficiency requires PTK2B activity. The transfer of SIRPα-deficient bone marrow-derived macrophages (BMDMs) into wild type mice resulted in a drop of bacterial load in the lungs but an enhancement of inflammatory lung damage, and the combination of ulinastatin and SIRPα-/-→WT treatment could decrease the inflammation and maintain the bactericidal capacity. INTERPRETATION: Our data define SIRPα a novel biomarker for tuberculosis infection and underlying mechanisms for maintaining macrophage homeostasis. FUNDING: This work was financially supported by the Chinese National Natural Science Foundation project (No.81401635). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Association of perfusate oxygenation with cardiovascular disorder in tetralogy of fallot children: A nested case-control study.

BACKGROUND: Little is known regarding whether hyperoxic reoxygenation was associated with higher risk of cardiovascular disorder following tetralogy of Fallot repair. METHODS: We performed a nested case-control study among patients aged 1 month-18 years undergoing complete repair of tetralogy of Fallot in 2012-2018. We measured the highest perfusate oxygenation (PpO2) during aortic occlusion in 107 cardiovascular disorder cases and in 321 controls matched 1:3 to the cases on date of surgery, sex, and area of residence. We analyzed the association between PpO2 and outcome using multivariable conditional logistic regression adjusted for covariates. We further identified and integrated the risk covariates to build prediction nomograms. RESULTS: Cases had higher percentage of exposure to PpO2 > 200 mmHg (86.0% vs. 76.1%, p = .019) than controls. Patients with PpO2 > 200 mmHg had an increased risk of cardiovascular disorder compared to those with PpO2 ≤ 200 mmHg (odd ratio [OR] = 2.075, 95% confidence interval [CI] = 1.035, 4.158, p = .039) adjusted for matching, clinical and procedural covariates. Categorical PpO2, lower body mass index, lower SpO2, untreated minor aortopulmonary collateral arteries, high immediately postoperative central venous pressure, and longer cardiopulmonary bypass time were independent risk factors for cardiovascular disorder (all p < .05). Combining PpO2 nomogram slightly improved discrimination compared with covariate-based nomogram alone for training cohort (area under receiver operating characteristic curve [AUC] = 0.768 vs. 0.761) and for internal validation (AUC = 0.759 vs. 0.753). CONCLUSION: Our findings suggest association exists between high PpO2 during aortic occlusion and cardiovascular disorder risk, and nomogram integrating clinical and procedural factors may be useful in management of patients with tetralogy of Fallot.

Diagnostic performance of DNA microarray for detecting rifampicin and isoniazid resistance in Mycobacterium tuberculosis.

BACKGROUND: While rifampicin (RFP) and isoniazid (INH) are the most commonly used first-line antituberculosis drugs, multidrug resistance in Mycobacterium tuberculosis poses a threat to the success of tuberculosis (TB) control programs. Clinical practice guidelines and expert consensuses recommend drug susceptibility testing (DST) before the initiation of antituberculosis treatment. However, traditional DST is time-consuming and has high requirements for laboratory conditions. The recently developed molecular diagnostic techniques, such as DNA microarray, offer new options. We thus investigated the diagnostic value of DNA microarray in detecting RFP + INH-resistant TB, with an attempt to identify simple, efficient, and accurate drug-resistant TB testing methods. METHODS: The clinical features and DST results of patients diagnosed with pulmonary tuberculosis by Bactec MGIT 960 liquid culture system (Becton, Dickinson and Company, Franklin Lakes, NJ, USA) who received DNA microarray analysis in our center from July 2019 to July 2020 were retrospectively analyzed. Level of agreement between liquid culture and DNA microarray technology was assessed by using the Cohen kappa coefficient. With the results of liquid culture as the gold standard, the sensitivity and specificity of the DNA microarray were calculated, and the receiver operating characteristic (ROC) curves were used to assess the diagnostic values of the DNA microarray in detecting RFP + INH-resistant TB. RESULTS: A total of 825 patients were enrolled. The sensitivity and specificity of DNA microarray were 0.84 and 0.94, respectively, in the detection of RFP resistance, with an area under the curve (AUC) of 0.89 [95% confidence interval (CI): 0.87-0.91)] and a Cohen kappa coefficient of 0.78 (95% CI: 0.72-0.83). For INH resistance, the sensitivity and specificity of the DNA microarray were 0.73 and 0.97, respectively, with an AUC of 0.85 (95% CI: 0.82-0.87) and a Cohen kappa coefficient of 0.75 (95% CI: 0.70-0.80). CONCLUSIONS: The DNA microarray had high specificity and sensitivity in detecting RFP + INH-resistant TB. As a rapid, accurate, and practical technique, it can be routinely performed in clinical laboratories.

Performance of Xpert® MTB/RIF in diagnosing tuberculous pleuritis using thoracoscopic pleural biopsy.

BACKGROUND: Etiological diagnosis of tuberculous pleuritis is challenging, owing to a paucity of Mycobacterium tuberculosis (MTB) in the affected region. Moreover, currently available methods, such as the detection of acid-fast bacilli and microbiological culture, are not always conducive to timely diagnosis and treatment. In this study, we evaluated the performance of Xpert® MTB/RIF assay (hereinafter referred to as "Xpert") in detecting MTB in difficult-to-diagnose patients using suspensions of pleural biopsy tissue specimens obtained under direct thoracoscopic guidance. METHODS: One hundred and sixty patients with an unexplained pleural effusion were included from the Shenyang Tenth People's Hospital and Shenyang Chest Hospital, China, between 2017 and 2018. The included patients underwent thoracoscopy under local anesthesia, with an intercostal incision of approximately 1.0 cm for biopsy. The biopsy specimens were used for pathological and etiological examinations. The Xpert test was evaluated for its sensitivity and specificity, as well as positive and negative predictive values (PPV and NPV, respectively), against data obtained using standards: the BACTEC™ MGIT™ 960 liquid culture system and a composite reference standard (CRS). RESULTS: The sensitivity and specificity of Xpert were 68.8 and 64.6%, respectively, against the MGIT 960 culture data. The PPV and NPV of Xpert were 56.4 and 75.6%, respectively. The sensitivity of Xpert was 69.0% against the CRS data, which was significantly higher than that of MGIT 960 culture (56.6%). The PPV and NPV of Xpert against the CRS data were 100.0 and 57.3%, respectively. CONCLUSIONS: Xpert is a good rule-in test but has limited value as a rule-out test for the diagnosis of tuberculosis pleuritis.

Pullulan reduces the non-specific amplification of loop-mediated isothermal amplification (LAMP).

Loop-mediated isothermal amplification (LAMP) has been developed as a versatile method for nucleic acid analysis in many applications. However, non-specific LAMP leading to false-positive outcomes has been observed frequently. To solve this problem, we selected six molecules as the additives for evaluating their effects on the improvement of the LAMP specificity. Experimental results show that bovine serum albumin (BSA) and DL-dithiothreitol (DTT) have negative effects on the LAMP specificity; dimethyl sulfoxide (DMSO), tetramethylene sulfoxide (TMSO), and glycerol could inhibit the non-specific LAMP moderately. Surprisingly, pullulan shows an ability to inhibit the non-specific amplification of LAMP significantly without affecting the sample amplification of LAMP, and this inhibitory effect is concentration dependent. Thus, pullulan could be considered as the most promising additive to improve the amplification specificity in the LAMP-based detection and analysis of nucleic acids.

McSpoligotyping, a One-Step Melting Curve Analysis-Based Protocol for Spoligotyping of Mycobacterium tuberculosis.

The direct repeat (DR) region in the Mycobacterium tuberculosis (MTB) genome is composed of highly polymorphic direct variant repeats, which are the basis of spacer oligonucleotide typing (spoligotyping) to study the population structure and epidemiology of M. tuberculosis However, the membrane hybridization-based detection format requires various post-PCR manipulations and is prone to carryover contamination, restricting its wide use in high-TB-burden and resource-limited countries. We developed a one-step spoligotyping protocol, termed McSpoligotyping, based on real-time PCR. The typing results can be generated within 3 h by a single step of DNA addition. When evaluated with a collection of 1,968 isolates of MTB, McSpoligotyping agreed 97.71% (1,923/1,968) by sample and 99.93% (84,568/84,624) by spacer with traditional spoligotyping. Sequencing results showed that McSpoligotyping was even more accurate than spoligotyping (99.34% versus 98.37%). Further exploration of the false results of McSpoligotyping revealed the presence of single-nucleotide polymorphisms in the DR region. We concluded that McSpoligotyping could be used in epidemiology studies of tuberculosis by taking advantage of the shortened procedure, ease of use, and compatibility of results with standard spoligotyping.

Prospective Comparison of QFT-GIT and T-SPOT.TB Assays for Diagnosis of Active Tuberculosis.

T-SPOT.TB and QuantiFERON-TB Gold In-Tube (QFT-GIT) tests, as two commercial blood assays for diagnosing active tuberculosis (ATB), are not yet fully validated. Especially, there are no reports on comparing the efficacy between the two tests in the same population in China. A multicenter, prospective comparison study was undertaken at four hospitals specializing in pulmonary diseases. A total of 746 suspected pulmonary TB were enrolled and categorized, including 185 confirmed TB, 298 probable TB and 263 non-TB. Of 32 patients with indeterminate test results (ITRs), age and underlying disease were associated with the rate of ITRs. Furthermore, the rate of ITRs determined by T-SPOT.TB was lower than QFT-GIT (0.4% vs. 4.3%, P < 0.01). When excluding ITRs, the sensitivities of T-SPOT.TB and QFT-GIT were 85.2% and 84.8%, and specificities of 63.4% and 60.5%, respectively in the diagnosis of ATB. The two assays have an overall agreement of 92.3%, but exhibited a poor linear correlation (r2 = 0.086) between the levels of interferon-γ release detected by the different assays. Although having some heterogeneity in detecting interferon-γ release, both the QFT-GIT and T-SPOT.TB demonstrated high concordance in diagnosing ATB. However, neither of them showed suitability in the definitive diagnosis of the disease.

GeneXpert MTB/RIF for rapid diagnosis and rifampin resistance detection of endobronchial tuberculosis.

BACKGROUND AND OBJECTIVE: Delayed diagnosis and treatment of tuberculosis (TB) contribute to poor outcomes, especially for endobronchial TB (EBTB), which typically leads to tracheobronchial stenosis. Finding rapid and accurate diagnostic tools for EBTB is crucial. GeneXpert Mycobacterium tuberculosis (MTB)/rifampin (RIF) was recommended by the World Health Organization (WHO) as a standard molecular biological diagnostic technique for MTB. The aim of this study was to evaluate the efficacy of GeneXpert MTB/RIF for diagnosing EBTB and for evaluating RIF resistance. METHODS: Biopsy tissue and bronchial brushings from EBTB patients were prospectively assessed with GeneXpert MTB/RIF. The diagnostic yields of auramine O-stained sputum smears and bronchial brush smears were obtained, and the results were compared with the cultures of sputum and biopsy tissues for MTB. RESULTS: In 61 confirmed cases of EBTB, the sensitivities of sputum smear, bronchial brush smear, sputum culture and tissue culture to diagnose EBTB were 13.1%, 32.8%, 36.1% and 68.9%, respectively. For bronchial brushings and biopsies, our data showed sensitivities of 57.4% and 63.9%, respectively, and a specificity of 100% for GeneXpert MTB/RIF, and these results were superior to those of sputum smears, bronchial brush smears and sputum culture. GeneXpert MTB/RIF for bronchial brushings and biopsies showed complementarity in its diagnostic performance. Resistance to RIF was identified in 17.4% (8/46) of GeneXpert MTB-positive cases. CONCLUSION: GeneXpert MTB/RIF may enable more rapid EBTB diagnosis and determination of RIF resistance, which are crucial for timely treatment.

Structural and genetic analysis of START superfamily protein MSMEG_0129 from Mycobacterium smegmatis.

Mycobacterium tuberculosis is a notorious pathogen that continues to threaten human health. Rv0164, an antigen of both T- and B cells conserved across mycobacteria, and MSMEG_0129, its close homolog in Mycobacterium smegmatis, are predicted members of the START domain superfamily, but their molecular function is unknown. Here, gene knockout studies demonstrate MSMEG_0129 is essential for bacterial growth, suggesting Rv0164 may be a potential drug target. The MSMEG_0129 crystal structure determined at 1.95 Å reveals a fold similar to that in polyketide aromatase/cyclases ZhuI and TcmN from Streptomyces sp. Structural comparisons and docking simulations, however, infer that MSMEG_0129 and Rv0164 are unlikely to catalyze polyketide aromatization/cyclization, but probably play an irreplaceable role during mycobacterial growth, for example, in lipid transfer during cell envelope synthesis.

Evaluation of the relationship between MARCO and CD36 single-nucleotide polymorphisms and susceptibility to pulmonary tuberculosis in a Chinese Han population.

BACKGROUND: Gene polymorphisms impact greatly on a person's susceptibility to pulmonary tuberculosis (PTB). Macrophage receptor with collagenous structure (MARCO) and CD36 are two scavenger receptors (SRs) that can recognize Mycobacterium tuberculosis (Mtb) and play a key role in tuberculosis infection. Gene polymorphisms of MARCO and CD36 may contribute to tuberculosis risk. METHODS: To investigate whether genetic polymorphisms of MARCO and CD36 are associated with susceptibility to PTB, genomic DNA samples from patients (n = 202) and healthy controls (n = 216) were collected and analyzed by polymerase chain reaction with high-resolution melting analysis. RESULTS: We studied two single nucleotide polymorphisms (SNPs) in MARCO (rs12998782 and rs17009726) and three SNPs in CD36 (rs1194182, rs3211956 and rs10499859). Rs12998782 (P = 0.018) might be associated with susceptibility to PTB. Rs1194182 (P < 0.01) and rs10499859 (P < 0.001) might be associated with resistance to PTB. Rs17009726 and rs3211956 were not associated with susceptibility/resistance to PTB. CONCLUSIONS: These data showed that MARCO rs12998782 may increase PTB risk while two SNPs of CD36, rs1194182 and rs10499859 may reduce the risk, indicating MARCO and CD36 as important receptors in response to PTB.

Impact of Metal Contacts on the Performance of Multilayer HfS2 Field-Effect Transistors.

HfS2 is one of the emerging transition metal dichalcogenides and is very promising for low-power nanoelectronics and high-sensitivity optoelectronic device applications. We studied the band structures of 1T-HfS2 with different thicknesses by first principles simulation, and the impact of different metal contacts to the HfS2 device performance has been experimentally studied. Back-gate and top-gate HfS2 field-effect transistors (FETs) were fabricated, and better electrical characteristics have been achieved with the FETs with the Ti/Au contact as compared with the Pt-contacted FETs. Thin layers of Pt and Ti/Au films were deposited on HfS2 flakes to investigate the metal/HfS2 interface by using scanning electron microscopy, atomic force microscopy, and Raman spectroscopy. A smoother Ti/Au film was formed on HfS2, resulting in higher carrier injection and transport efficiency. The phonon behavior being dominated by the interface chemical bonding at the Ti/Au contact region has been confirmed with the more sensitive A1g phonon mode from the bilayer HfS2.

Regulation of cAMP on the first mitotic cell cycle of mouse embryos.

Mitosis promoting factor (MPF) plays a central role during the first mitosis of mouse embryo. We demonstrated that MPF activity increased when one-cell stage mouse embryo initiated G2/M transition following the decrease of cyclic adenosine 3', 5'-monophosphate (cAMP) and cAMP-dependent protein kinase (PKA) activity. When cAMP and PKA activity increases again, MPF activity decreases and mouse embryo starts metaphase-anaphase transition. In the downstream of cAMP/PKA, there are some effectors such as polo-like kinase 1 (Plk1), Cdc25, Mos (mitogen-activated protein kinase kinase kinase), MEK (mitogen-activated protein kinase kinase), mitogen-activated protein kinase (MAPK), Wee1, anaphase-promoting complex (APC), and phosphoprotein phosphatase that are involved in the regulation of MPF activity. Here, we demonstrated that following activation of MPF, MAPK activity was steady, whereas Plk1 activity fluctuated during the first cell cycle. Plk1 activity was the highest at metaphase and decreased at metaphase-anaphase transition. Further, we established a mathematical model using Gepasi algorithm and the simulation was in agreement with the experimental data. Above all the evidences, we suggested that cAMP and PKA might be the upstream factors which were included in the regulation of the first cell cycle development of mouse embryo.