The relationship between perioperative serum albumin and contrast-induced acute kidney injury in patients after percutaneous coronary intervention.

OBJECTIVE: Contrast-induced acute kidney injury (CI-AKI) is a common complication in patients undergoing percutaneous coronary intervention (PCI). Studies have shown that perioperative serum albumin levels may play a role in the occurrence of CI-AKI. In this study, we aimed to investigate the effect of perioperative serum albumin (delta albumin or &Alb) levels on the occurrence and long-term prognosis of CI-AKI patients after PCI. METHODS: A total of 959 patients who underwent PCI between January 2017 and January 2019 were selected for this study. A receiver operating characteristic curve was used to determine the optimal cut-off value of the &Alb level for predicting CI-AKI after PCI. Patients were divided into two groups based on the optimal cut-off value: the high &Alb group (&Alb ≥ 4.55 g/L) and the control group (&Alb < 4.55 g/L). The incidences of CI-AKI and major adverse cardiac events (MACEs, including all-cause death, nonfatal myocardial infarction, and target vessel revascularization) were compared between the groups. Cox regression analysis was used to identify predictors of long-term prognosis after PCI. RESULTS: Of the 959 patients, 147 (15.3%) developed CI-AKI after PCI. The CI-AKI group had a greater level of &Alb than did the non-CI-AKI group [(6.14 (3.90-9.10) versus 3.48 (4.31-6.57), P < 0.01)]. The incidence of CI-AKI in the high &Alb group was significantly greater than that in the low group (23.6% versus 8.3%, P < 0.01). After a 1-year follow-up, the incidence of MACEs was significantly greater in the high &Alb group than in the low group (18.6% versus 14.5%, P = 0.030). Cox regression analysis confirmed that CI-AKI was an independent predictor of MACEs at the 1-year follow-up (HR 1.43, 95% CI 1.04-1.96, P = 0.028). In addition, patients with low preoperative serum albumin levels had s significantly greater incidence of MACEs than did those with high preoperative serum albumin levels (23.2% versus 19.5%, P = 0.013). CONCLUSION: In summary, high baseline &Alb levels are an independent risk factor for CI-AKI in patients after PCI. The occurrence of CI-AKI in the perioperative period is also an independent predictor of long-term prognosis after PCI. These findings highlight the importance of monitoring &Alb levels and taking steps to prevent CI-AKI in patients undergoing PCI.

Modified Theoretical Model Predicts Radial Support Capacity of Polymer Braided Stents.

BACKGROUND AND OBJECTIVE: Self-expanding polymer braided stents are expected to replace metallic stents in the treatment of Peripheral Arterial Disease, which seriously endangers human health. To restore the patency of blocked peripheral arteries with different properties and functions, the radial supporting capacity of the stent should be considered corresponding to the vessel. A theoretical model can be established as an effective method to study the radial supporting capacity of the stent which can shorten the stent design cycle and realize the customization of the stent according to lesion site. However, the classical model developed by Jedwab and Clerc of radial force is only limited to metallic braided stents, and the predictions for polymer braided stents are deviated. METHODS: In this paper, based on the limitation of the J&C model for polymer braided stents, a modified radial force model for polymer braided stents was proposed, which considered the friction between monofilaments and the torsion of the monofilaments. And the modified model was verified by radial force tests of polymer braided stents with different structures and monofilaments. RESULTS: Compared with the J&C model, the proposed modified model has better predictability for the radial force of polymer braided stents that prepared with different braided structure and polymer monofilaments. The root mean squared error of modified model is 0.041±0.026, while that of the J&C model is 0.246±0.111. CONCLUSIONS: For polymer braided stents, the friction between the polymer monofilaments and the torsion of the monofilaments during the radial compression cannot be ignored. The radial force prediction accuracy of the modified model considering these factors was significantly improved. This work provides a research basis on the theoretical model of polymer braided stents, and improves the feasibility of rapid personalized customization of polymer braided stents.

Strengthen oriented poly (L-lactic acid) monofilaments via mechanical training.

Polymer materials have found extensive applications in the clinical and medical domains due to their exceptional biocompatibility and biodegradability. Compared to metallic counterparts, polymers, particularly Poly (L-lactic acid) (PLLA), are more suitable for fabricating biodegradable stents. As a viscoelastic material, PLLA monofilaments exhibit a creep phenomenon under sustained tensile stress. This study explores the use of creep to enhance the mechanical attributes of PLLA monofilaments. By subjecting the highly oriented monofilaments to controlled, constant force stretching, we achieved notable improvements in their mechanical characteristics. The results, as confirmed by tensile testing and dynamic mechanical analysis, revealed a remarkable 67 % increase in total elongation and over a 20 % rise in storage modulus post-mechanical training. Further microscopic analyses, including Atomic Force Microscopy (AFM) and Scanning Electron Microscopy (SEM), revealed enhanced spacing and cavity formation. These mechanical advancements are attributed to the unraveling and a more orderly arrangement of molecular chains in the amorphous regions. This investigation offers a promising approach for augmenting the mechanical properties of PLLA monofilaments, potentially benefiting their application in biomedical engineering.

Combined NMR and molecular dynamics conformational filter identifies unambiguously dynamic ensembles of Dengue protease NS2B/NS3pro.

The dengue protease NS2B/NS3pro has been reported to adopt either an 'open' or a 'closed' conformation. We have developed a conformational filter that combines NMR with MD simulations to identify conformational ensembles that dominate in solution. Experimental values derived from relaxation parameters for the backbone and methyl side chains were compared with the corresponding back-calculated relaxation parameters of different conformational ensembles obtained from free MD simulations. Our results demonstrate a high prevalence for the 'closed' conformational ensemble while the 'open' conformation is absent, indicating that the latter conformation is most probably due to crystal contacts. Conversely, conformational ensembles in which the positioning of the co-factor NS2B results in a 'partially' open conformation, previously described in both MD simulations and X-ray studies, were identified by our conformational filter. Altogether, we believe that our approach allows for unambiguous identification of true conformational ensembles, an essential step for reliable drug discovery.

Alcohol dehydrogenase 1 is a tubular mitophagy-dependent apoptosis inhibitor against septic acute kidney injury.

Alcohol dehydrogenase 1 (ADH1) is an alcohol-oxidizing enzyme with poorlydefined biology. Here we report that ADH1 is highly expressed in kidneys of mice with lethal endotoxemia and is transcriptionally upregulated in tubular cells by lipopolysaccharide (LPS) stimuli through TLR4/NF-κB cascade. The Adh1 knockout (Adh1KO) mice with lethal endotoxemia displayed increased susceptibility to acute kidney injury (AKI) but not systemic inflammatory response. Adh1KO mice develop more severe tubular cell apoptosis in comparison to Adh1 wild-type (Adh1WT) mice during course of lethal endotoxemia. ADH1 deficiency facilitates the LPS-induced tubular cell apoptosis in a caspase-dependent manner. Mechanistically, ADH1 deficiency dampens tubular mitophagy that relies on PINK1-Parkin pathway characterized by the reduced membrane potential, reactive oxygen species (ROS) and release of fragmented mtDNA to cytosol. Kidney-specific overexpression of PINK1 and Parkin by adeno-associated viral vector 9 (AAV9) delivery ameliorates AKI exacerbation in Adh1KO mice with lethal endotoxemia. Our study supports the notion that ADH1 is critical for blockade of tubular apoptosis mediated by mitophagy, allowing the rapid identification and targeting of alcohol-metabolic route applicable to septic AKI.

Macrophage-driven cardiac inflammation and healing: insights from homeostasis and myocardial infarction.

Early and prompt reperfusion therapy has markedly improved the survival rates among patients enduring myocardial infarction (MI). Nonetheless, the resulting adverse remodeling and the subsequent onset of heart failure remain formidable clinical management challenges and represent a primary cause of disability in MI patients worldwide. Macrophages play a crucial role in immune system regulation and wield a profound influence over the inflammatory repair process following MI, thereby dictating the degree of myocardial injury and the subsequent pathological remodeling. Despite numerous previous biological studies that established the classical polarization model for macrophages, classifying them as either M1 pro-inflammatory or M2 pro-reparative macrophages, this simplistic categorization falls short of meeting the precision medicine standards, hindering the translational advancement of clinical research. Recently, advances in single-cell sequencing technology have facilitated a more profound exploration of macrophage heterogeneity and plasticity, opening avenues for the development of targeted interventions to address macrophage-related factors in the aftermath of MI. In this review, we provide a summary of macrophage origins, tissue distribution, classification, and surface markers. Furthermore, we delve into the multifaceted roles of macrophages in maintaining cardiac homeostasis and regulating inflammation during the post-MI period.

Impact of calcification on Murray law-based quantitative flow ratio for physiological assessment of intermediate coronary stenoses.

BACKGROUND: To investigate the influence of coronary calcification on the diagnostic performance of Murray law-based quantitative flow ratio (µQFR) in identifying hemodynamically significant coronary lesions referenced to fractional flow reserve (FFR). METHODS: A total of 571 intermediate lesions from 534 consecutive patients (66.1 ± 10.0 years, 67.2% males) who underwent coronary angiography and simultaneous FFR measurement were included. Calcific deposits were graded by angiography as none or mild (spots), moderate (involving ≤ 50% of the reference vessel diameter), and severe (> 50%). Performance of µQFR to detect functional ischemia (FFR ≤ 0.80) was evaluated, including diagnostic parameters and areas under the receiver-operating curves (AUCs). RESULTS: The discrimination of ischemia by µQFR was comparable between none/mild and moderate/severe calcification (AUC: 0.91 [95% confidence interval: 0.88-0.93] vs. 0.87 [95% confidence interval: 0.78-0.94]; p = 0.442). No statistically significant difference was observed for µQFR between the two categories in sensitivity (0.70 vs. 0.69, p = 0.861) and specificity (0.94 vs. 0.90, p = 0.192). Moreover, µQFR showed significantly higher AUCs than quantitative coronary angiographic diameter stenosis in both vessels with none/mild (0.91 vs. 0.78, p < 0.001) and moderate/severe calcification (0.87 vs. 0.69, p < 0.001). By multivariable analysis, there was no association between calcification and µQFR-FFR discordance (adjusted odds ratio: 1.529, 95% confidence interval: 0.788-2.968, p = 0.210) after adjustment for other confounding factors. CONCLUSIONS: µQFR demonstrated robust and superior diagnostic performance for lesion-specific ischemia compared with angiography alone regardless of coronary calcification.

Sex Differences in Murray Law-Based Quantitative Flow Ratio Among Patients With Intermediate Coronary Lesions.

Background The Murray law-based quantitative flow ratio (µQFR) is a novel technique that simulates fractional flow reserve (FFR) from a single angiographic view. However, the impact of sex differences on the diagnostic performance of µQFR has not been investigated. Methods and Results In this study, FFR and µQFR were assessed in 497 intermediate stenoses (30%-70% by visual estimation) from 460 patients (34.3% female). Physiological significance was defined as FFR ≤0.80 or µQFR ≤0.80. After adjusting for potential confounders, female sex was independently associated with higher FFR (P=0.048 and 0.026, respectively) and µQFR (P=0.001 for both) in both fully adjusted and stepwise backward models. µQFR provided superior diagnostic accuracy compared with angiography alone for detecting FFR ≤0.80 in both women (area under the curve, 0.93 [95% CI, 0.88-0.97] versus 0.80 [95% CI, 0.73-0.86]; P=0.001) and men (area under the curve, 0.88 [95% CI, 0.84-0.92] versus 0.73 [95% CI, 0.68-0.78]; P<0.001), with comparable performance between the sexes (P=0.175). In the multivariable analysis, sex was not a significant factor contributing to the overall disagreement between FFR and µQFR. Conclusions Regardless of angiographic stenosis severity, women tend to have higher FFR and µQFR values than men. Furthermore, µQFR performs similarly well in both sexes and offers improved diagnostic accuracy over angiography alone, indicating its potential as a reliable, wire-free tool to identify functional ischemia.

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.

Effect of an Herbal-Based Injection on 28-Day Mortality in Patients With Sepsis: The EXIT-SEP Randomized Clinical Trial.

Importance: Previous research has suggested that Xuebijing injection (XBJ), an herbal-based intravenous preparation, may reduce mortality among patients with sepsis. Objective: To determine the effect of XBJ vs placebo on 28-day mortality among patients with sepsis. Design, Setting, and Participants: The Efficacy of Xuebijing Injection in Patients With Sepsis (EXIT-SEP) trial was a multicenter, randomized double-blind, placebo-controlled trial conducted in intensive care units at 45 sites and included 1817 randomized patients with sepsis (sepsis 3.0) present for less than 48 hours. Patients aged 18 to 75 years with a Sequential Organ Failure Assessment score of 2 to 13 were enrolled. The study was conducted from October 2017 to June 2019. The final date of follow-up was July 26, 2019. Data analysis was performed from January 2020 to August 2022. Interventions: The patients were randomized to receive either intravenous infusion of XBJ (100 mL, n = 911) or volume-matched saline placebo (n = 906) every 12 hours for 5 days. Main Outcomes and Measures: The primary outcome was 28-day mortality. Results: Among the 1817 patients who were randomized (mean [SD] age, 56.5 [13.5] years; 1199 [66.0%] men), 1760 (96.9%) completed the trial. In these patients, the 28-day mortality rate was significantly different between the placebo group and the XBJ group (230 of 882 patients [26.1%] vs 165 of 878 patients [18.8%], respectively; P < .001). The absolute risk difference was 7.3 (95% CI, 3.4-11.2) percentage points. The incidence of adverse events was 222 of 878 patients (25.3%) in the placebo group and 200 of 872 patients (22.9%) in the XBJ group. Conclusions and Relevance: In this randomized clinical trial among patients with sepsis, the administration of XBJ reduced 28-day mortality compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT03238742.

Auto- and paracrine rewiring of NIX-mediated mitophagy by insulin-like growth factor-binding protein 7 in septic AKI escalates inflammation-coupling tubular damage.

AIMS: Inflammation-coupling tubular damage (ICTD) contributes to pathogenesis of septic acute kidney injury (AKI), in which insulin-like growth factor-binding protein 7 (IGFBP-7) serves as a biomarker for risk stratification. The current study aims to discern how IGFBP-7 signalling influences ICTD, the mechanisms that underlie this process and whether blockade of the IGFBP-7-dependent ICTD might have therapeutic value for septic AKI. MATERIALS AND METHODS: In vivo characterization was carried out in B6/JGpt-Igfbp7em1Cd1165/Gpt mice subjected to cecal ligation and puncture (CLP). Transmission electron microscopy, immunofluorescence, flow cytometry, immunoblotting, ELISA, RT-qPCR and dual-luciferase reporter assays were used to determine mitochondrial functions, cell apoptosis, cytokine secretion and gene transcription. KEY FINDINGS: ICTD augments the transcriptional activity and protein secretion of tubular IGFBP-7, which enables an auto- and paracrine signalling via deactivation of IGF-1 receptor (IGF-1R). Genetic knockout (KO) of IGFBP-7 provides renal protection, improves survival and resolves inflammation in murine models of cecal ligation and puncture (CLP), while administering recombinant IGFBP-7 aggravates ICTD and inflammatory invasion. IGFBP-7 perpetuates ICTD in a NIX/BNIP3-indispensable fashion through dampening mitophagy that restricts redox robustness and preserves mitochondrial clearance programs. Adeno-associated viral vector 9 (AAV9)-NIX short hairpin RNA (shRNA) delivery ameliorates the anti-septic AKI phenotypes of IGFBP-7 KO. Activation of BNIP3-mediated mitophagy by mitochonic acid-5 (MA-5) effectively attenuates the IGFBP-7-dependent ICTD and septic AKI in CLP mice. SIGNIFICANCE: Our findings identify IGFBP-7 is an auto- and paracrine manipulator of NIX-mediated mitophagy for ICTD escalation and propose that targeting the IGFBP-7-dependent ICTD represents a novel therapeutic strategy against septic AKI.

Disentangling the impact of straw incorporation on soil microbial communities: Enhanced network complexity and ecological stochasticity.

Straw incorporation is typically employed to enhance the nutrient content of soil and promote crop growth in intensive agricultural systems. Despite studies regarding the effects of straw incorporation on soil microbial communities, the underlying mechanisms of its effect on community co-occurrence interactions and assembly processes remain poorly understood. Herein, soil samples with or without straw incorporation were collected across a latitudinal gradient from north to central China. We found that straw incorporation considerably altered the structure of soil microbial community. The relative abundance of bacterial Latescibacterota and fungal Mortierellomycota were higher in straw-amended soils owing to their ability to decompose straw residues. The co-occurrence network in straw-amended soil exhibited greater complexity, including more network connectivity and keystone species, and higher average degrees and clustering coefficients compared with the control sample network. The network robustness and vulnerability indices suggested that straw incorporation increased the microbial network stability. Normalized stochastic ratios demonstrated that the stochastic process was the dominant mechanisms shaping the assembly of microbial communities in straw-amended soils. Concurrently, null model analysis revealed that straw increased the contribution of dispersal limitation to the assembly of bacterial and fungal communities. The migration rate of the microbial community, obtained from Sloan neutral community model, was relatively low in straw-amended soil at all the sample sites, potentially indicating the great importance of dispersal limitation. These findings would enhance our understanding of the ecological patterns and interactions of soil microbial communities in response to straw incorporation.

[Role of cholinergic anti-inflammatory pathway in Ghrelin regulation of peptide transporter 1 expression in small intestinal epithelium of septic rats].

OBJECTIVE: To investigate the role of cholinergic anti-inflammatory pathway in the regulation of peptide transporter 1 (PepT1) expression in small intestinal epithelium of septic rats by Ghrelin. METHODS: One hundred adult male Sprague-Dawley (SD) rats were randomly divided into sham operation group, sepsis group, sepsis+vagotomy group, sepsis+Ghrelin group, and sepsis+vagotomy+Ghrelin group, with 20 rats in each group. In the sham operation group, the cecum was separated after laparotomy, without ligation and perforation. In the sepsis group, the rats received cecal ligation puncture (CLP). In the sepsis+vagotomy group, the rats received CLP and vagotomy after laparotomy. In the sepsis+Ghrelin group, 100 µmol/L Ghrelin was intravenously injected after CLP immediately. The rats in the sepsis+vagotomy+Ghrelin group received CLP and vagotomy at the same time, then the Ghrelin was intravenously injected immediately with the same dose as the sepsis+Ghrelin group. Ten rats in each group were taken to observe their survival within 7 days. The remaining 10 rats were sacrificed 20 hours after the operation to obtain venous blood and small intestinal tissue. The condition of the abdominal intestine was observed. The injury of intestinal epithelial cells was observed with transmission electron microscopy. The contents of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) in serum and small intestinal tissue were detected by enzyme-linked immunosorbent assay (ELISA). The brush border membrane vesicle (BBMV) was prepared, the levels of mRNA and protein expression of PepT1 in the small intestinal epithelium were detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and Western blotting. RESULTS: All rats in the sham operation group survived at 7 days after operation. The 7-day cumulative survival rate of rats in the sepsis group was significantly lower than that in the sham operation group (20% vs. 100%, P < 0.05). The cumulative survival rate of rats after Ghrelin intervention was improved (compared with sepsis group: 40% vs. 20%, P < 0.05), but the protective effect of Ghrelin was weakened after vagotomy (compared with sepsis+Ghrelin group: 10% vs. 40%, P < 0.05). Compared with the sham operation group, in the sepsis group, the small intestine and cecum were dull red, the intestinal tubules were swollen and filled with gas, the intestinal epithelial cells were seriously injured under transmission electron microscopy, the levels of TNF-α and IL-1ß in serum and small intestinal were significantly increased, and the expression levels of PepT1 mRNA and protein in the small intestinal epithelium were significantly decreased. It indicated that the sepsis rat model was successfully prepared. After vagotomy, the intestinal swelling and gas accumulation became worse in septic rats, leading to the death of all rats. Compared with the sepsis group, the abdominal situation in the sepsis+Ghrelin group was improved, the injury of intestinal epithelial cells was alleviated, the serum and small intestinal TNF-α and IL-1ß were significantly decreased [serum TNF-α (ng/L): 253.27±23.32 vs. 287.90±19.48, small intestinal TNF-α (ng/L): 95.27±11.47 vs. 153.89±18.15, serum IL-1ß (ng/L): 39.16±4.47 vs. 54.26±7.27, small intestinal IL-1ß (ng/L): 28.47±4.13 vs. 42.26±2.59, all P < 0.05], and the expressions of PepT1 mRNA and protein in the small intestinal epithelium were significantly increased [PepT1 mRNA (2-ΔΔCt): 0.66±0.05 vs. 0.53±0.06, PepT1 protein (PepT1/GAPDH): 0.80±0.04 vs. 0.60±0.05, both P < 0.05]. Compared with the sepsis+Ghrelin group, after vagotomy in the sepsis+vagotomy+Ghrelin group, the effect of Ghrelin on reducing the release of inflammatory factors in sepsis rats was significantly reduced [serum TNF-α (ng/L): 276.58±19.88 vs. 253.27±23.32, small intestinal TNF-α (ng/L): 144.28±12.99 vs. 95.27±11.47, serum IL-1ß (ng/L): 48.15±3.21 vs. 39.16±4.47, small intestinal IL-1ß (ng/L): 38.75±4.49 vs. 28.47±4.13, all P < 0.05], the up-regulated effect on the expression of PepT1 in small intestinal epithelium was lost [PepT1 mRNA (2-ΔΔCt): 0.58±0.03 vs. 0.66±0.05, PepT1 protein (PepT1/GAPDH): 0.70±0.02 vs. 0.80±0.04, both P < 0.05], and the injury of small intestinal epithelial cells was worse. CONCLUSIONS: Ghrelin plays a protective role in sepsis by promoting cholinergic neurons to inhibit the release of inflammatory factors, thereby promoting the transcription and translation of PepT1.

Performance of the J-CTO score versus other risk scores for predicting procedural difficulty in coronary chronic total occlusion interventions.

BACKGROUND: Although the Japanese chronic total occlusion (J-CTO) score is widely used to assess the complexity of revascularization for CTO lesions, ambiguous and conflicting results are reported in validation studies. Therefore, we aimed to quantitatively evaluate the effectiveness of the J-CTO score and explore the heterogeneity of its comparison with other CTO scores. METHODS: PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov databases were systematically searched from January 1st, 2011 to December 23rd, 2021. Studies that examined the accuracy of the J-CTO score were eligible. Where feasible, estimates of discrimination and calibration were pooled with a random-effects model. The Prediction model Risk Of Bias ASsessment Tool (PROBAST) was used for risk-of-bias assessment. This study was reported according to PRISMA guidelines and prospectively registered with PROSPERO (CRD42019126161). RESULTS: Of 28 included studies (N = 34,944 lesions), 24 were eligible for meta-analysis. The J-CTO score demonstrated significant discrimination for 30-min wire crossing (summary C-statistic 0.76; 95% CI 0.68-0.84) and technical success (0.68; 95% CI 0.61-0.74) despite significant heterogeneity. Only 19 (33%) of the 58 pairwise comparisons with 14 competing scores that were based on discrimination reported a statistical result. The J-CTO score performed worse (relative difference of C-statistics >5%) in eight out of 33 independent comparisons but better in another 13. Methodological shortcomings resulted from only one study evaluating model calibration appropriately. CONCLUSION: The discrimination power of the J-CTO score was useful for time-efficient wire crossing and moderate for angiographic success. Head-to-head comparisons of CTO scores would benefit from standardized reporting and appropriate statistical methods.Key messagesThe J-CTO score has useful discrimination in predicting 30-min wire crossing while performing moderately for technical success.After excluding optimism bias, there is insufficient independent evidence supporting the superiority of newly introduced models over the J-CTO score.Standardized methodology and assessment are needed to achieve a better understanding of CTO scores, especially for their calibration.

Pathogen load and species monitored by droplet digital PCR in patients with bloodstream infections: A prospective case series study.

BACKGROUND AND OBJECTIVES: Bloodstream infection (BSI) is a life-threatening condition in critically ill patients, but pathogen quantification techniques during treatment are laborious. This study aimed to explore the impact of monitoring pathogen DNA load changes and polymicrobial infection in blood by droplet digital polymerase chain reaction (ddPCR) on the prognosis of patients with BSIs. METHODS: This prospective case series study was conducted in the general intensive care unit of the Zhejiang Provincial People's Hospital and included patients with BSIs from May 2020 to January 2021. Pathogens DNA load and presence of polymicrobial BSIs were dynamically monitored by ddPCR. RESULTS: Sixteen patients with BSIs proven by blood culture were recruited (87.5% men; mean age, 69.3 ± 13.7 years). All pathogens identified by blood culture were Gram-negative bacteria, among which seven were multidrug-resistant strains. The 28-day mortality rate was 62.5%. Compared to the 28-day survivors, the non-survivors were older (P = 0.04), had higher pathogen DNA load on the second (day 3-4) and third (day 6-7) ddPCR assay (P < 0.01 in both cases). In addition, the changes of pathogen DNA load in the 28-day survivors had a downward trend in the first three ddPCR assay, whereas stable load or an upward trend was observed in the 28-day non-survivors. Moreover, the number of pathogen species in patients with BSIs in the 28-day survivors decreased during the period of effective antibiotic treatment. CONCLUSION: The changes of pathogen DNA load and species monitored in blood by ddPCR may be used to determine antibiotic efficacy and make a more accurate prognostic assessment in patients with BSIs.

Assignment of IVL-Methyl side chain of the ligand-free monomeric human MALT1 paracaspase-IgL3 domain in solution.

Mucosa-associated lymphoid tissue protein 1 (MALT1) plays a key role in adaptive immune responses by modulating specific intracellular signalling pathways that control the development and proliferation of both T and B cells. Dysfunction of these pathways is coupled to the progress of highly aggressive lymphoma as well as to potential development of an array of different immune disorders. In contrast to other signalling mediators, MALT1 is not only activated through the formation of the CBM complex together with the proteins CARMA1 and Bcl10, but also by acting as a protease that cleaves multiple substrates to promote lymphocyte proliferation and survival via the NF-κB signalling pathway. Herein, we present the partial 1H, 13C Ile/Val/Leu-Methyl resonance assignment of the monomeric apo form of the paracaspase-IgL3 domain of human MALT1. Our results provide a solid ground for future elucidation of both the three-dimensional structure and the dynamics of MALT1, key for adequate development of inhibitors, and a thorough molecular understanding of its function(s).

Plasmid-Borne AFM Alleles in Pseudomonas aeruginosa Clinical Isolates from China.

Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a pathogen of global concern due to the fact that therapeutic drugs are limited. Metallo-ß-lactamase (MBL)-producing P. aeruginosa has become a critical part of CRPA. Alcaligenes faecalis metallo-ß-lactamase (AFM) is a newly identified subclass B1b MBL. In this study, 487 P. aeruginosa strains isolated from patients and the environment in an intensive care unit were screened for AFM alleles. Five AFM-producing strains were identified, including four AFM-2-producing strains (ST262) and one AFM-4-producing strain (ST671). AFM-2-producing strains were isolated from rectal and throat swabs, and AFM-4-producing strains were isolated from the water sink. The blaAFM-2 carrying plasmids belonged to the IncP-2 type, while the blaAFM-4 carrying plasmid pAR19438 was a pSTY-like megaplasmid. Plasmid pAR19438 was acquired blaAFM-4 by the integration of the Tn1403-like transposon. All blaAFM genes were embedded in an ISCR29-blaAFM unit core module flanked by class 1 integrons. The core module of blaAFM-2 was ISCR29-ΔgroL-blaAFM-2-bleMBL-ΔtrpF-ΔISCR, while the core module of blaAFM-4 was ISCR29-ΔgroL-blaAFM-2-bleMBL-ΔtrpF-ISCR-msrB-msrA-yfcG-corA-ΔISCR. The flanking sequences of ISCR29-blaAFM units also differed. The expression of AFM-2 and AFM-4 in DH5α and PAO1 illustrated the same effect for the evaluation of the MICs of ß-lactams, except for aztreonam. Identification of AFM-4 underscores that the quick spread and emerging development of mutants of MBLs require continuous surveillance in P. aeruginosa. IMPORTANCE Acquiring metallo-ß-lactamase genes is one of the important carbapenem resistance mechanisms of P. aeruginosa. Alcaligenes faecalis metallo-ß-lactamase is a newly identified metallo-ß-lactamase, the prevalence and genetic context of which need to be explored. In this study, we identified AFM-producing P. aeruginosa strains among clinical isolates and found a new mutant of AFM, AFM-4. The blaAFM-4 carrying plasmid pAR19438 was a pSTY-like megaplasmid, unlike the plasmids encoding other blaAFM alleles. The genetic context of blaAFM-4 was also different. However, AFM-2 and AFM-4 had the same impacts on antibiotic susceptibility. The presence and transmission of AFM alleles in P. aeruginosa pose a challenge to clinical practice.

Retraction Notice to: Kcnq1ot1/miR-381-3p/ETS2 Axis Regulates Inflammation in Mouse Models of Acute Respiratory Distress Syndrome.

[This retracts the article DOI: 10.1016/j.omtn.2019.10.036.].

l- to d-Amino Acid Substitution in the Immunodominant LCMV-Derived Epitope gp33 Highlights the Sensitivity of the TCR Recognition Mechanism for the MHC/Peptide Structure and Dynamics.

Presentation of pathogen-derived epitopes by major histocompatibility complex I (MHC-I) can lead to the activation and expansion of specific CD8+ T cell clones, eventually resulting in the destruction of infected target cells. Altered peptide ligands (APLs), designed to elicit immunogenicity toward a wild-type peptide, may affect the overall stability of MHC-I/peptide (pMHC) complexes and modulate the recognition by T cell receptors (TCR). Previous works have demonstrated that proline substitution at position 3 (p3P) of different MHC-restricted epitopes, including the immunodominant LCMV-derived epitope gp33 and escape variants, may be an effective design strategy to increase epitope immunogenicity. These studies hypothesized that the p3P substitution increases peptide rigidity, facilitating TCR binding. Here, molecular dynamics simulations indicate that the p3P modification rigidifies the APLs in solution predisposing them for the MHC-I loading as well as once bound to H-2Db, predisposing them for TCR binding. Our results also indicate that peptide position 6, key for interaction of H-2Db/gp33 with the TCR P14, takes a suboptimal conformation before as well as after binding to the TCR. Analyses of H-2Db in complex with APLs, in which position 6 was subjected to an l- to d-amino acid modification, revealed small conformational changes and comparable pMHC thermal stability. However, the l- to d-modification reduced significantly the binding to P14 even in the presence of the p3P modification. Our combined data highlight the sensitivity of the TCR for the conformational dynamics of pMHC and provide further tools to dissect and modulate TCR binding and immunogenicity via APLs.