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The discovery of novel antitumor agents derived from natural plants is a principal objective of anticancer drug research. Frankincense, a widely recognized natural antitumor medicine, has undergone a systematic review encompassing its species, chemical constituents, and diverse pharmacological activities and mechanisms. The different species of frankincense include Boswellia serrata, Somali frankincense, Boswellia frereana, and Boswellia arabica. Various frankincense extracts and compounds exhibit antitumor, anti-inflammatory, and hepatoprotective properties and antioxidation, memory enhancement, and immunological regulation capabilities. They also have comprehensive effects on regulating flora. Frankincense and its principal chemical constituents have demonstrated promising chemoprophylactic and therapeutic abilities against tumors. This review provides a systematic summary of the mechanism of action underlying the antitumor effects of frankincense and its major constituents, thus laying the foundations for developing effective tumor-combating targets. [ABSTRACT FROM AUTHOR]

Background As a newly identified subtype of HER2-negative tumors associated with a less favorable prognosis, it remains crucial to evaluate potential prognostic and predictive factors, particularly non-invasive biomarkers, for individuals with human epidermal growth factor 2 (HER2) low early-stage breast cancer (EBC). Multiple investigations have highlighted that HER2-negative patients with EBC exhibiting high homologous recombination deficiency (HRD) scores display lower rates of pathological complete response (PCR) to neoadjuvant chemotherapy (NAC). Nevertheless, no study to date has explored the correlation between HRD and the long-term prognosis in HER2-low patients with EBC. Patients and methods This retrospective observational study focuses on primary EBC sourced from The Cancer Genome Atlas dataset (TCGA). It reveals the gene mutation landscape in EBC with low HER2 expression and elucidates the tumor immune landscape across different HRD states. Utilizing bioinformatics analysis and Cox proportional models, along with the Kaplan-Meier method, the study assesses the correlation between HRD status and disease-specific survival (DSS), disease-free interval (DFI), and progression-free interval (PFI). Subgroup analyses were conducted to identify potential variations in the association between HRD and prognosis. Results In the patients with HER2-low breast cancer, patients with homologous recombination related genes (HRRGs) defects had an HRD score about twice that of those without related genes mutations, and were at higher risk of acquiring ARID1A , ATM , and BRCA2 mutations. We also found that most immune cell abundances were significantly higher in EBC tumors with high HRD than in EBC tumors with low HRD or HRD-medium, particularly plasma B-cell abundance, CD8 T-cell abundance, and M1 macrophages. In addition, these tumors with HRD-high also appear to have significantly higher tumor immune scores and lower interstitial scores. Then, we analyzed the relationship between different HRD status and prognosis. There was statistical significance (P  = .036 and P  = .046, respectively) in DSS and PFI between the HRD-low and HRD-high groups, and patients with HRD-high EBC showed relatively poor survival outcomes. A medium HRD score (hazard ratio, HR = 2.15, 95% CI: 1.04-4.41, P  = .038) was a significant risk factor for PFI. Hormone receptor positivity is an important factor in obtaining medium-high HRD score and poor prognosis. Conclusion Higher HRD scores were associated with poorer PFI outcomes, particularly in people with HR+/HER2-low. Varied HRD states exhibited distinctions in HRRGs and the tumor immune landscape. These insights have the potential to assist clinicians in promptly identifying high-risk groups and tailoring personalized treatments for patients with HER2-low EBC, aiming to enhance long-term outcomes. [ABSTRACT FROM AUTHOR]

In this paper, we prove that the vorticity belongs to for 3D incompressible Navier–Stokes equation with space-periodic boundary conditions, then the existence of a global smooth solution is obtained. Our approach is to construct a set of auxiliary systems to approximate the original system of vorticity equation. [ABSTRACT FROM AUTHOR]

Background: The effect of two lung ventilation (TLV) with carbon dioxide artificial pneumothorax on cerebral desaturation and postoperative neurocognitive changes in elderly patients undergoing elective minimally invasive esophagectomy (MIE) is unclear. Objectives: The first aim of this study was to compare the effect of TLV and one lung ventilation (OLV) on cerebral desaturation. The second aim was to assess changes in early postoperative cognitive outcomes of two ventilation methods. Methods: This prospective, randomized, controlled trial enrolled patients 65 and older scheduled for MIE. Patients were randomly assigned (1:1) to TLV group or OLV group. The primary outcome was the incidence of cerebral desaturation events (CDE). Secondary outcomes were the cumulative area under the curve of desaturation for decreases in regional cerebral oxygen saturation (rSO2) values below 20% relative to the baseline value (AUC.20) and the incidence of delayed neurocognitive recovery. Results: Fifty-six patients were recruited between November 2019 and August 2020. TLV group had a lower incidence of CDE than OLV group [3 (10.71%) vs. 13 (48.14%), P = 0.002]. TLV group had a lower AUC.20 [0 (0–35.86) % min vs. 0 (0–0) % min, P = 0.007], and the incidence of delayed neurocognitive recovery [2 (7.4%) vs. 11 (40.7%), P = 0.009] than OLV group. Predictors of delayed neurocognitive recovery on postoperative day 7 were age (OR 1.676, 95% CI 1.122 to 2.505, P = 0.006) and AUC.20 (OR 1.059, 95% CI 1.025 to 1.094, P < 0.001). Conclusion: Compared to OLV, TLV had a lower incidence of CDE and delayed neurocognitive recovery in elderly patients undergoing MIE. The method of TLV combined with carbon dioxide artificial pneumothorax may be an option for these elderly patients. Chinese Clinical Trial Registry (identifier: ChiCTR1900027454). [ABSTRACT FROM AUTHOR]

BACKGROUND: Dural mater is punctured by using a spinal needle without drugs administrated into intrathecal space directly in dural puncture epidural (DPE) analgesia. OBJECTIVE: This study aimed to summarize the evidence of benefits and risks of DPE analgesia with 25-G spinal needles for labor pain relief. METHODS: DPE analgesia with EP analgesia for labor pain relief were systematically searched. The Embase, MEDLINE, Cochrane Central Register of Controlled Trials, Scopus and Web of Science databases were systematically searched till 6th November 2022 to find out randomized controlled trials (RCTs) comparing DPE (using 25-G spinal needles) with conventional epidural (EP) analgesia. The risk of bias was assessed with the Cochrane tool. Risk ratio, mean difference, and 95% confidence intervals were calculated. RESULTS: Seven RCTs with 761 parturients were identified. Pool data showed that DPE technique was associated with shorter time to pain score ⩽ 3/10, higher percentage with pain score ⩽ 3/10 at 10 min and 20 min, lower incidence of epidural top-up bolus and no S2 block, higher incidence of bilateral S2 blockade at 10 min and during labor, lower incidence of epidural top-up bolus and incidence of asymmetric block. No statistical difference in side effect and parturient satisfaction between DPE and EP technique. CONCLUSION: DPE technique with 25-G spinal needles was associated with faster analgesia onset and sacral coverage, greater sacral spread, lesser requirement of epidural top-up and lower incidence of asymmetric block. DPE technique with 25-G spinal needles showed a greater benefit to parturients. [ABSTRACT FROM AUTHOR]

In recent years, breast conservation surgery (BCS) and modified radical mastectomy (MRM) have been widely used in the treatment of early‐stage breast cancer. However, the effects of complications from these two surgical methods are still unclear. The purpose of this study was to evaluate the effects of BCS and MRM on postoperative wound complications in patients with early breast cancer. Eighty‐eight patients with early breast cancer were randomly divided into BCS group (n = 46) and MRM group (n = 42). The occurrence of postoperative wound complications was compared between the two groups. The results showed that BCS patients had significantly lower intraoperative surgical times, blood losses, incision lengths, drainage volumes, drainage times and lengths of hospital stays than their MRM counterparts (p < 0.05). The overall incidence of postoperative wound complications in the BCS group was significantly lower than that in the MRM group at 1 month after surgery, but the difference was not statistically significant (p < 0.001). The rate of excellent breast cosmetic outcome was significantly higher in the BCS group than in the MRM group (p < 0.001). Compared to MRM, BCS has a lower incidence of intraoperative and postoperative wound complications, better cosmetic outcomes and higher clinical value in the treatment of early‐stage breast cancer. [ABSTRACT FROM AUTHOR]

Background The association between different phenotypes and genotypes of circulating tumor cells (CTCs) and efficacy of neoadjuvant chemotherapy (NAC) remains uncertain. This study was conducted to evaluate the relationship of FTH1 gene-associated CTCs (F-CTC) with/without epithelial-mesenchymal transition (EMT) markers, or their dynamic changes with the efficacy of NAC in patients with non-metastatic breast cancer. Patients and Methods This study enrolled 120 patients with non-metastatic breast cancer who planned to undergo NAC. The FTH1 gene and EMT markers in CTCs were detected before NAC (T0), after 2 cycles of chemotherapy (T1), and before surgery (T2). The associations of these different types of CTCs with rates of pathological complete response (pCR) and breast-conserving surgery (BCS) were evaluated using the binary logistic regression analysis. Results F-CTC in peripheral blood ≥1 at T0 was an independent factor for pCR rate in patients with HER2-positive (odds ratio [OR]=0.08, 95% confidence interval [CI], 0.01-0.98, P =.048). The reduction in the number of F-CTC at T2 was an independent factor for BCS rate (OR = 4.54, 95% CI, 1.14-18.08, P =.03). Conclusions The number of F-CTC prior to NAC was related to poor response to NAC. Monitoring of F-CTC may help clinicians formulate personalized NAC regimens and implement BCS for patients with non-metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Purpose: To explore the predictive value of nutritional risk for all-cause death and functional outcomes among elderly acute stroke patients.Patients and Methods: A total of 479 elderly acute stroke patients were enrolled in this study. The nutritional risk of patients was screened by the GNRI and NRS-2002. The primary outcome was all-cause death, and the secondary outcome was poor prognosis defined as a modified Rankin Scale (mRS) score ≥ 3.Results: Based on the NRS-2002, patients with nutritional risk had a higher risk of all-cause death at 3 months (adjusted OR: 3.642, 95% CI 1.046~12.689) and at 3 years (adjusted OR: 2.266, 95% CI 1.259~4.076) and a higher risk of adverse functional outcomes at 3 months (adjusted OR: 2.748, 95% CI 1.518~4.972. Based on the GNRI, compared to those without nutritional risk, patients with mild malnutrition also had a higher risk of all-cause death at 3 months (adjusted OR: 7.186, 95% CI 1.550~33.315) and at 3 years (adjusted OR: 2.255, 95% CI 1.211~4.199) and a higher risk of adverse functional outcomes at 3 months (adjusted OR: 1.947, 95% CI 1.030~3.680), so patients with moderate and severe malnutrition had a higher risk of all-cause death at 3 months (adjusted OR: 6.535, 95% CI 1.380~30.945) and at 3 years (adjusted OR: 2.498, 95% CI 1.301~4.799) and a higher risk of adverse functional outcomes at 3 months (adjusted OR: 2.213, 95% CI 1.144~4.279).Conclusion: Nutritional risk increases the risk of poor short-term and long-term outcomes in elderly patients with acute stroke. For elderly stroke patients, we should pay attention to early nutritional risk screening, and effective intervention should be provided to improve the prognosis of such patients. [ABSTRACT FROM AUTHOR]

Purpose: To compare the effect of Dural puncture epidural (DPE) and conventional epidural (EP), in conjunction with programmed intermittent epidural bolus (PIEB) and low-concentration ropivacaine strategy.Methods: After written informed consent was obtained, healthy nulliparous women with singleton pregnancies, vertex presentation at 38– 42 weeks' gestation, cervical dilation of 3– 5 cm, and a desire for pain relief were randomly assigned to DPE or EP group. Dural matter was puncture with 25G Whitacre needle in DPE group. Analgesia was initiated with 15 mL of 0.1% ropivacaine over 5 minutes and was maintained by PIEB (8 mL of 0.08% ropivacaine with 2 μg/mL fentanyl every 40 min). Primary outcome was the percentage of adequate analgesia, defined as NRPS ≤ 1, at 30 minutes after the initiation of the epidural bolus.Results: Out of 130 enrolled parturients, 127 were included in final analysis (64 in DPE group, 63 in EP group). No significant difference was found in percentage of adequate analgesia at 30 minutes (risk ratio: 1.09; 95% confidence interval: 0.90– 1.31; P = 0.366). At 8, 12, 14, and 16 minutes, percentage of adequate analgesia was higher in DPE group (P = 0.023, 0.027, 0.016 and 0.033, respectively). NPRS scores in DPE group decreased more dramatically within the first 30 min. The incidence of S2 sensory blocks at 20 and 30 min in DPE group was higher (P = 0.010 and 0.006, respectively). There were no differences in patient satisfaction, delivery mode, adverse effects, fetal bradycardia, and Apgar scores at 1 and 5 minutes.Conclusion: The combination of the use of DPE technique with 25G spinal needle and PIEB technique for labor analgesia appears to enhance the quality of labor analgesia by accelerating onset and providing improved sacral blockade, without increasing adverse effects. [ABSTRACT FROM AUTHOR]

Apelin-13 may have neuroprotective effects. We aimed to determine whether serum apelin-13 could serve as a potential biomarker for severity, delayed cerebral ischemia (DCI), and prognosis after human aneurysmal subarachnoid hemorrhage (aSAH). In this prospective, observational, cohort, single-center study of 139 patients with aSAH and 139 healthy individuals, serum apelin-13 levels were determined. The indicators of stroke severity were the Hunt-Hess scale and the modified Fisher grading scale. The prognostic parameters were DCI and 6-month worse prognosis (Extended Glasgow Outcome Scale scores of 1–4). Using binary logistic regression analysis, the relationship between serum apelin-13 levels and prognosis was reported as odds ratios (ORs) with 95% confidence intervals (CIs). Under the receiver operating characteristic curve, prognostic abilities were shown as areas under the curve (AUCs) with 95% CIs. Serum apelin-13 levels were substantially lower in patients than in controls (median, 28.8 versus 48.6 ng/ml; P < 0.001), in patients with DCI than in non-DCI patients (median, 14.9 versus 31.6 ng/ml; P < 0.001), and in patients with worse prognosis than in those with good prognosis (median, 16.3 versus 33.7 ng/ml; P < 0.001). Serum apelin-13 levels were independently correlated with Hunt-Hess scores (beta, -6.836; 95% CI, -8.963–4.708; VIF, 2.219; P = 0.001) and modified Fisher scores (beta, -3.350; 95% CI, -6.151–0.549; VIF, 1.562; P = 0.019). Serum apelin-13 levels were an independent predictor of DCI (OR, 0.951; 95% CI, 0.914–0.990; P = 0.022) and worse prognosis (OR, 0.954; 95% CI, 0.916–0.993; P = 0.013). Serum apelin-13 levels significantly differentiated DCI and poor prognosis, with AUCs of 0.753 (95% CI, 0.656–0.850) and 0.791 (95% CI, 0.713–0.868) respectively. Using the Youden method, serum apelin-13 levels < 19.3 ng/ml distinguished the risk of DCI with 64.7% sensitivity and 77.1% specificity, and serum apelin-13 levels < 30.2 ng/ml discriminated the development of worse prognosis with 89.1% sensitivity and 63.4% specificity. Serum apelin-13 levels combined with Hunt-Hess scores and modified Fisher scores displayed a significantly higher AUC than any one of them for prognostic prediction (all P < 0.05). Decreased serum apelin-13 levels, which are strongly correlated with disease severity, independently predicted poor outcomes following aSAH, substantializing serum apelin-13 as a useful prognostic biomarker of aSAH. [ABSTRACT FROM AUTHOR]

A AgBr–Ag2MoO4 heterojunction with high inactivation of E. coli under visible-light illumination was constructed. The crystal structure, morphology, elemental composition, and optical properties were characterized by TEM, SEM, XRD, XPS and DRS. The photocatalytic inactivation of E. coli by AgBr, Ag2MoO4, and AgBr–Ag2MoO4 was investigated. The results indicate that AgBr–Ag2MoO4 shows the best disinfection activity compared to AgBr and Ag2MoO4, with the E. coli being almost completely inactivated after illumination for 80 min. In addition, the cell structure of the bacteria is destroyed after visible-light irradiation in the presence of the catalyst. The UV absorption detection confirms that the bacterial protein leak and the concentration of nucleic acid in the solution also increase with the increase of the reaction time, indicating that the integrity of the bacterial cell membrane is damaged. The detection of ROS scavengers indicates that the reactive species (h+, ˙OH, e− and ˙O2−) play an important role in the inactivation of bacteria. The EPR tests confirm that the amount of ˙OH is higher than that of ˙O2− during the illumination process, which is consistent with the results of the free-radical capture tests. The heterojunction of AgBr–Ag2MoO4 is beneficial for the separation of photogenerated electrons and holes during the illumination process, resulting in an improvement of the antibacterial properties. [ABSTRACT FROM AUTHOR]

Mustard gas is a kind of erosive poison with great harm and used as a chemical weapon since World War. It has suggested that the photocatalytic technology is an effective method to eliminate it. Because the small difference in molecular structure between 2-CEES and Mustard gas, and the less toxic of 2-CEES, 2-CEES is often used as a simulator to evaluate the photocatalytic activity of catalysts. In this work, symbiotic mixture of Bi2WO6 and Bi6O6(OH)3(NO3)3·1.5H2O nanosheets doped with Mo (Mo-B-B) have been synthesized by a facile hydrothermal treatment. The samples were characterized by XRD, DRS, XPS, SEM, TEM, Raman, and PL. The photocatalytic activity of the samples was evaluated by measuring the degradation of 2-CEES under visible light irradiation. The results showed that the doped Mo reduce the Eg of bare symbiotic mixture and improve the separation efficiency of photo-generated carriers that is beneficial to photocatalytic activity. The optimum amount of doped Mo is 5% that exhibits the best activity for degradation for 2-CEES. [ABSTRACT FROM AUTHOR]

Self-trapped excitons (STEs) emission from halide perovskites with strong exciton-phonon coupling has attracted considerable attention due to the widespread application in optoelectronic devices. Nevertheless, the in-depth understanding of the relationship between exciton-phonon coupling and luminescence intensity remains incomplete. Herein, a doping-enhanced exciton-phonon coupling effect is observed in Cs3Cu2I5 nanocrystals (NCs), which leads to a remarkable increasement of their STEs emission efficiency. Mechanism study shows that the hetero-valent substitution of Cu+ with alkaline-earth metal ions (AE2+) causes a greater degree of Jahn–Teller distortion between the ground state and excited state structures of [Cu2I5]3− clusters as evidenced by our spectral analysis and first-principles calculations. As a consequence, an X-ray detector based on these Cs3Cu2I5:AE NCs delivers an X-ray imaging resolution of up to 10 lp·mm−1 and a low detection limit of 0.37 µGyair·s−1, disclosing the potential of doping-enhanced exciton-phonon coupling effect in improving STEs-emission and practical application for X-ray imaging. [ABSTRACT FROM AUTHOR]

Thermally activated delayed fluorescence (TADF) materials hold great promise as next‐generation efficient emitters due to their theoretical 100% internal quantum efficiency. However, such an intriguing photophysical mechanism is extremely rare in perovskites or their derivatives. Herein, the colloidal synthesis of two‐dimensional CsAgCl2 nanocrystals (NCs) with typical TADF feature is reported first. The TADF mechanism is investigated in detail by combining first‐principles calculations with experimental results, including temperature‐dependent spectral analysis and fs‐transient absorption spectra. A small singlet−triplet state splitting energy (0.082 eV) and a large spatial separation of charge density |Ψ|2 of valence band maximum and conduction band minimum are observed, which are prerequisites for TADF. Moreover, these CsAgCl2 NCs deliver an ultralow X‐ray detection limit of 170.5 nGyair s−1 and a high imaging resolution of 11.5 lp mm−1, much superior to the commercial scintillators. [ABSTRACT FROM AUTHOR]

This paper considers an optimal control problem of nonlinear Markov jump systems with continuous state inequality constraints. Due to the presence of continuous‐time Markov chain, no existing computation method is available to solve such an optimal control problem. In this paper, a derandomisation technique is introduced to transform the nonlinear Markov jump system into a deterministic system, which simultaneously gives rise to an equivalent deterministic dynamic optimisation problem. The control parametrisation technique is then used to partition the time horizon into a sequence of subintervals such that the control function is approximated by a piecewise constant function consistent with the partition. The heights of the piecewise constant function on the corresponding subintervals are taken as decision variables to be optimised. In this way, the approximate dynamic optimisation problem is an optimal parameter selection problem, which can be viewed as a finite dimensional optimisation problem. To solve it using a gradient‐based optimisation method, the gradient formulas of the cost function and the constraint functions are derived. Finally, a real‐world practical problem involving a bioreactor tank model is solved using the method proposed. [ABSTRACT FROM AUTHOR]

Background: Whole genome bisulfite sequencing (WGBS), possesses the aptitude to dissect methylation status at the nucleotide-level resolution of 5-methylcytosine (5-mC) on a genome-wide scale. It is a powerful technique for epigenome in various cell types, and tissues. As a recently established next-generation sequencing (NGS) platform, GenoLab M is a promising alternative platform. However, its comprehensive evaluation for WGBS has not been reported. We sequenced two bisulfite-converted mammal DNA in this research using our GenoLab M and NovaSeq 6000, respectively. Then, we systematically compared those data via four widely used WGBS tools (BSMAP, Bismark, BatMeth2, BS-Seeker2) and a new bisulfite-seq tool (BSBolt). We interrogated their computational time, genome depth and coverage, and evaluated their percentage of methylated Cs. Result: Here, benchmarking a combination of pre- and post-processing methods, we found that trimming improved the performance of mapping efficiency in eight datasets. The data from two platforms uncovered ~ 80% of CpG sites genome-wide in the human cell line. Those data sequenced by GenoLab M achieved a far lower proportion of duplicates (~ 5.5%). Among pipelines, BSMAP provided an intriguing representation of 5-mC distribution at CpG sites with 5-mC levels > ~ 78% in datasets from human cell lines, especially in the GenoLab M. BSMAP performed more advantages in running time, uniquely mapped reads percentages, genomic coverage, and quantitative accuracy. Finally, compared with the previous methylation pattern of human cell line and mouse tissue, we confirmed that the data from GenoLab M performed similar consistency and accuracy in methylation levels of CpG sites with that from NovaSeq 6000. Conclusion: Together we confirmed that GenoLab M was a qualified NGS platform for WGBS with high performance. Our results showed that BSMAP was the suitable pipeline that allowed for WGBS studies on the GenoLab M platform. [ABSTRACT FROM AUTHOR]

Most cancer‐related deaths are a result of metastasis. The development of small molecular inhibitors reversing cancer metastasis represents a promising therapeutic opportunity for cancer patients. This pan‐cancer analysis identifies oncogenic roles of membrane‐associated phosphatidylinositol transfer protein 3 (PITPNM3), which is crucial for cancer metastasis. Small molecules targeting PITPNM3 must be explored further. Here, PITPNM3‐selective small molecular inhibitors are reported. These compounds exhibit target‐specific inhibition of PITPNM3 signaling, thereby reducing metastasis of breast cancer cells. Besides, by using nanoparticle‐based delivery systems, these PITPNM3‐selective compounds loaded nanoparticles significantly repress metastasis of breast cancer in mouse xenograft models and organoid models. Notably, the results establish an important metastatic‐promoting role for PITPNM3 and offer PITPNM3 inhibition as a therapeutic strategy in metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Although mitochondrial activity is critical for angiogenesis, its mechanism is not entirely clear. Here we show that mice with endothelial deficiency of any one of the three nuclear genes encoding for mitochondrial proteins, transcriptional factor (TFAM), respiratory complex IV component (COX10), or redox protein thioredoxin 2 (TRX2), exhibit retarded retinal vessel growth and arteriovenous malformations (AVM). Single-cell RNA-seq analyses indicate that retinal ECs from the three mutant mice have increased TGFβ signaling and altered gene expressions associated with vascular maturation and extracellular matrix, correlating with vascular malformation and increased basement membrane thickening in microvesels of mutant retinas. Mechanistic studies suggest that mitochondrial dysfunction from Tfam, Cox10, or Trx2 depletion induces a mitochondrial localization and MAPKs-mediated phosphorylation of SMAD2, leading to enhanced ALK5-SMAD2 signaling. Importantly, pharmacological blockade of ALK5 signaling or genetic deficiency of SMAD2 prevented retinal vessel growth retardation and AVM in all three mutant mice. Our studies uncover a novel mechanism whereby mitochondrial dysfunction via the ALK5-SMAD2 signaling induces retinal vascular malformations, and have therapeutic values for the alleviation of angiogenesis-associated human retinal diseases. The role of mitochondrial activity in angiogenesis is not entirely understood. Here, the authors show that mitochondria as a signaling hub and their dysfunction causes augmented TGFβ signaling to induce retinal sprouting retardation and vascular malformations. [ABSTRACT FROM AUTHOR]

In order to clarify the fates of fertilizer N in coastal saline soil-wheat systems with different salinization degrees, this study was conducted to determine the 15N uptake rates in various parts of wheat plant at maturity stage and the residual 15N in three different saline soils and the 15N loss of soil-wheat systems by using the 15N-labeled urea N tracing method in the Yellow River Delta. The results showed that: (1) The increase of soil salinity from 0.2% to 1% promoted the wheat plant to absorb N from soil and not from fertilizer and significantly inhibited the dry matter mass accumulation and 15N uptakes of each wheat parts and whole plant, but especially increased the total N concentration of wheat roots, stems, leaves, and grains. The aggravation of soil salinity significantly enhanced the distribution ratios of 15N uptakes and Ndffs in the wheat roots, stems, and leaves to depress the salt stress. (2) The 15N residues were mainly concentrated in the 0~20 cm saline soil layer and decreased as the soil profile deepened from 0 to 100 cm; the 15N residues decreased in the 0~40 cm soil profile layer and accumulated in the 40~100 cm with the increase of soil salinization degrees significantly. (3) The fates of 15N applied to the coastal saline soil-wheat system were wheat uptakes 1.53~13.96%, soil residues 10.05~48.69%, losses 37.35~88.42%, with the lowest 15N uptake and utilization in the three saline soils, the highest residual rate in lightly saline soils, and the highest loss in moderately and heavily saline soils. The increase of soil salinity inhibits wheat uptakes and soil residues and intensifies the losses from fertilizer 15N. Therefore, the fate of fertilizer N losses significantly increased as the degree of soil salinity increased. The conventional N management that was extremely inefficient for more N loss should be optimized to enhance the N efficiency and wheat yield of the coastal saline soil-wheat system in the Yellow River Delta. [ABSTRACT FROM AUTHOR]

A novel luminescent isoreticular metal–organic framework Zn4O(ECMTDC)3·10DMF (Cz-MOF-1), where ECMTDC denotes 3-(9-ethyl-9H-carbazol-3-yl)-4-methylthieno[2,3-b]thiophene-2,5-dicarboxylate and DMF denotes N,N-dimethylformamide, was successfully synthesized via solvothermal methods from Zn(NO3)2·6H2O and H2ECMTDC in DMF. Powder X-ray diffraction experiments along with scanning electron microscopy images indicate that Cz-MOF-1 has excellent water stability compared with other Zn4O-based MOFs, which can be attributed to the hydrophobic surroundings around the Zn4O clusters formed from N-ethylcarbazolyl and methyl groups. Cz-MOF-1 displays a strong deep blue light emission (452 nm) and a quantum efficiency of 3.74%, and has high selectivity and sensitivity for the detection of Fe3+, Cr2O72− and DCN. Furthermore, the possible luminescence sensing mechanisms have been discussed in detail, which are supported by PXRD analysis, UV-vis spectroscopy and density functional theory (DFT). [ABSTRACT FROM AUTHOR]

The role of CD39 pathway in Th1 cell function in tuberculosis (TB) is rarely elucidated. The present study aims to investigate the modulating mechanism of CD39 pathway during Mycobacterium tuberculosis (MTB) infection. CD39 expression was examined on host immune cells among patients with TB. The relationship between CD39 expression and Th1 cell function was analysed. Patients with TB displayed dramatically higher CD39 expression on Th1 cells than healthy controls, and a significantly increased expression of surface markers, including activation, exhaustion and apoptosis markers, were noted in CD39+ Th1 cells in comparison with CD39− Th1 cells. Conversely, CD39 expression on Th1 cells was associated with diminished number of polyfunctional cells producing Th1‐type cytokines, and CD39+ Th1 cells showed obviously lower proliferation potential. Notably, tetramer analysis demonstrated a predominant CD39 expression on TB‐specific CD4+ cells, which was associated with higher apoptosis and lower cytokine‐producing ability. Transcriptome sequencing identified 27 genes that were differentially expressed between CD39+ and CD39− Th1 cells, such as IL32, DUSP4 and RGS1. Inhibition of CD39 pathway could enhance the activation, proliferation and cytokine‐producing ability of Th1 cells. Furthermore, there was a significantly negative correlation between CD39 expression on Th1 cells and nutritional status indicators such as lymphocyte count and albumin levels, and we observed a significant decline in CD39 expression on Th1 cells after anti‐TB treatment. CD39 is predominantly expressed on TB‐specific Th1 cells and correlated with their exhausted function, which suggests that CD39 could serve as a prominent target for TB therapy. [ABSTRACT FROM AUTHOR]

Autophagy, a lysosome-mediated cellular degradation pathway, recycles intracellular components to maintain metabolic balance and survival. Autophagy plays an important role in tumor immunotherapy as a "double-edged sword" that can both promote and inhibit tumor progression. Autophagy acts on innate and adaptive immunity and interacts with immune cells to modulate tumor immunotherapy. The discovery of autophagy inducers and autophagy inhibitors also provides new insights for clinical anti-tumor therapy. However, there are also difficulties in the application of autophagy-related regulators, such as low bioavailability and the lack of efficient selectivity. This review focuses on autophagy-related immunogenic regulation and its application in cancer therapy. [ABSTRACT FROM AUTHOR]

Nutritional Risk Screening index is a standard tool to assess nutritional risk, but epidemiological data are scarce on controlling nutritional status (CONUT) as a prognostic marker in acute haemorrhagic stroke (AHS). We aimed to explore whether the CONUT may predict a 3-month functional outcome in AHS. In total, 349 Chinese patients with incident AHS were consecutively recruited, and their malnutrition risks were determined using a high CONUT score of ≥ 2. The cohort patients were divided into high-CONUT (≥ 2) and low-CONUT (< 2) groups, and primary outcomes were a poor functional prognosis defined as the modified Rankin Scale (mRS) score of ≥ 3 at post-discharge for 3 months. Odds ratios (OR) with 95 % confidence intervals (CI) for the poor functional prognosis at post-discharge were estimated by using a logistic analysis with additional adjustments for unbalanced variables between the high-CONUT and low-CONUT groups. A total of 328 patients (60·38 ± 12·83 years; 66·77 % male) completed the mRS assessment at post-discharge for 3 months, with 172 patients at malnutrition risk at admission and 104 patients with a poor prognosis. The levels of total cholesterol and total lymphocyte counts were significantly lower in high-CONUT patients than low-CONUT patients (P = 0·012 and < 0·001, respectively). At 3-month post discharge, there was a greater risk for the poor outcome in the high-CONUT compared with the low-CONUT patients at admission (OR: 2·32, 95 % CI: 1·28, 4·17). High-CONUT scores independently predict a 3-month poor prognosis in AHS, which helps to identify those who need additional nutritional managements. [ABSTRACT FROM AUTHOR]

Background: Stroke is a leading cause of death and functional impairment in older people. To assess the prospective association between fasting blood glucose-to-glycated hemoglobin ratio and all-cause mortality and poor prognosis in stroke patients.Methods: A total of 971 Chinese inpatients with acute stroke (mean age of 65.7) were consecutively enrolled in the prospective clinical study and followed up for 12 months after discharge. Stress hyperglycemia was measured using the ratio of fasting blood glucose (FBG, mmol/L)/glycated hemoglobin (HbA1c, %). The primary outcome was all-cause mortality, and secondary outcomes were poor prognosis defined as infectious complications, a National Institutes of Health Stroke Scale (NIHSS) score ≥ 6, a Barthel Index score ≤ 60, or a modified Rankin Scale (mRS) score of 3-6, presented as multivariate-adjusted odds ratios (ORs) with 95% confidence intervals (CIs) across the quartiles of the FBG/HbA1c ratio.Results: There were 35 (4.1%) all-cause deaths at 3 months and 85 (11.4%) at 12 months. The inpatients with the highest quartile of the FBG/HbA1c ratio had a higher risk of all-cause death at 3 months (adjusted OR: 5.16, 95% CI: 1.03-25.74) and at 12 months (adjusted OR: 2.59, 95% CI: 1.14-5.89)) and a higher risk of infectious complications (adjusted OR 2.37, 95% CI 1.27-4.43) and dysfunction (adjusted OR 1.79, 95% CI 1.06-3.01) during hospitalization than inpatients with the lowest quartile.Conclusions: Stress hyperglycemia, measured by the FBG/HbA1c ratio, was associated with an increased risk of adverse outcomes, including all-cause death, infectious complications, and dysfunction after stroke. [ABSTRACT FROM AUTHOR]

Background. Chlorogenic acid (CGA) is a polyphenolic compound with antioxidant and anti-inflammatory properties. CGA has been shown to improve neuroinflammation. This study is aimed at elucidating the exact mechanism by which CGA reduces neuroinflammation. Methods. Oxygen and glucose deprivation (OGD) was utilized to treat BV2 microglia and HT-22 hippocampal neurons to engineer an in vitro model of hypoxic ischemia reperfusion. The levels of inflammatory factors (IL-1β, IL-6, TNF-α, IL-4, and IL-10) and oxidative stress factors (MDA, SOD, and GSH-PX) in microglia were determined by ELISA kits. The neuron proliferation was assessed by CCK-8 assay, and LDH kit was used to determine LDH release in neurons. The fluorescent dye DCF-DA was employed to measure ROS levels in neurons. Correlation of MIR497HG, miR-29b-3p, and SIRT1/NF-κB in neurons and microglia was determined by qRT-PCR. Expressions of inflammatory proteins (COX2, iNOS), oxidative stress pathways (Nrf2, HO-1), and apoptosis-related proteins (Bcl-2, Bax, caspase3, caspase8, and caspase9) in microglia or neurons were determined by western blot. The interactions between MIR497HG and miR-29b-3p, as well as between miR-29b-3p and SIRT1, were determined by dual luciferase assay and RIP assay. Results. CGA attenuated OGD-mediated inflammation and oxidative stress in microglia and inhibited microglia-mediated neuronal apoptosis. CGA increased the levels of MIR497HG and SIRT1 and suppressed the levels of miR-29b-3p in BV2 and HT-22 cells. MIR497HG knockdown, miR-29b-3p upregulation, and SIRT1 inhibition inhibited CGA-mediated anti-inflammatory and neuronal protective functions. There is a targeting correlation between MIR497HG, miR-29b-3p, and Sirt1. MIR497HG sponges miR-29b-3p to regulate SIRT1 expression in an indirect manner. Conclusion. CGA upregulates MIR497HG to curb miR-29b-3p expression, hence initiating the SIRT1/NF-κB signaling pathway and repressing OGD-elicited inflammation, oxidative stress, and neuron apoptosis. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the risk factors of increased hidden blood loss (HBL) after total hip arthroplasty (THA) for femoral neck fracture in elderly women and establish the nomogram prediction model for the guidance to reduce HBL in clinic. Patients and Methods: A total of 206 elderly female patients with femoral neck fracture who underwent THA in Northern Jiangsu People's Hospital from January 2019 to November 2021 were included. The demographic and relevant clinical information of the patients were collected. Pearson, independent sample t-test, multiple linear regression and other statistical methods were used for correlation analysis by SPSS 22.0 statistical software. Moreover, the risk factors of postoperative HBL increase in THA patients were obtained and the nomogram prediction model for the guidance to reduce HBL in clinic was established. Results: HBL was 626 ± 400 mL, accounting for 72.8% ± 18.4% of the perioperative total blood loss (TBL) (799 ± 411 mL), while blood loss of HGB was 15.1± 10.4 g/L. Multiple linear regression analysis showed that HBL was associated with lower age (regression coefficient = − 9.271, P = 0.010), operative time (regression coefficient = 2.653, P = 0.004), preoperative blood calcium (< 2.25 mmol/L) (regression coefficient = 232.492, P < 0.001), hypertension (regression coefficient = 150.352, P = 0.002) and osteoporosis (regression coefficient = 276.072, P < 0.001). R software was used to construct the nomogram prediction model and draw the ROC curve and calibration curve. The area under the curve (AUC) is 0.92 and the slope of calibration curve is close to 1. Conclusion: Based on the five independent risk factors including age, operative time, preoperative blood calcium, hypertension and osteoporosis, the nomogram can predict the risk of HBL after THA for femoral neck fracture in elderly women with favorable differentiation and accuracy. [ABSTRACT FROM AUTHOR]

Background: Approximate 25% HER2-positive (HER2+) breast cancer (BC) patients treated with trastuzumab recurred rapidly. However, the mechanisms underlying trastuzumab resistance remained largely unclear. Methods: Trastuzumab-resistant associated circRNAs were identified by circRNAs high-throughput screen and qRT-PCR in HER2+ breast cancer tissues with different trastuzumab response. The biological roles of trastuzumab-resistant associated circRNAs were detected by cell vitality assay, colony formation assay, Edu assay, patient-derived xenograft (PDX) models and orthotopic animal models. For mechanisms research, the co-immunoprecipitation, Western blot, immunofluorescence, and pull down assays confirmed the relevant mechanisms of circRNA and binding proteins. Results: We identified a circRNA circCDYL2, which was overexpressed in trastuzumab-resistant patients, which conferred trastuzumab resistance in breast cancer cells in vitro and in vivo. Mechanically, circCDYL2 stabilized GRB7 by preventing its ubiquitination degradation and enhanced its interaction with FAK, which thus sustained the activities of downstream AKT and ERK1/2. Trastuzumab-resistance of HER2+ BC cells with high circCDYL2 could be reversed by FAK or GRB7 inhibitor. Clinically, HER2+ BC patients with high levels of circCDYL2 developed rapid recurrence and had shorter disease-free survival (DFS) and overall survival (OS) following anti-HER2 therapy compared to those with low circCDYL2. Conclusions: circCDYL2-GRB7-FAK complex plays a critical role in maintaining HER2 signaling, which contributes to trastuzumab resistance and circCDYL2 is a potential biomarker for trastuzumab-resistance in HER2+ BC patients. [ABSTRACT FROM AUTHOR]

Background: The differential diagnosis between tuberculous meningitis (TBM) and bacterial meningitis (BM) remains challenging in clinical practice. This study aimed to establish a diagnostic model that could accurately distinguish TBM from BM. Methods: Patients with TBM or BM were recruited between January 2017 and January 2021 at Tongji Hospital (Qiaokou cohort) and Sino-French New City Hospital (Caidian cohort). The detection for indicators involved in cerebrospinal fluid (CSF) and T-SPOT assay were performed simultaneously. Multivariate logistic regression was used to create a diagnostic model. Results: A total of 174 patients (76 TBM and 98 BM) and another 105 cases (39 TBM and 66 BM) were enrolled from Qiaokou cohort and Caidian cohort, respectively. Significantly higher level of CSF lymphocyte proportion while significantly lower levels of CSF chlorine, nucleated cell count, and neutrophil proportion were observed in TBM group when comparing with those in BM group. However, receiver operating characteristic (ROC) curve analysis showed that the areas under the ROC curve (AUCs) produced by these indicators were all under 0.8. Meanwhile, tuberculosis-specific antigen/phytohemagglutinin (TBAg/PHA) ratio yielded an AUC of 0.889 (95% CI, 0.840–0.938) in distinguishing TBM from BM, with a sensitivity of 68.42% (95% CI, 57.30%–77.77%) and a specificity of 92.86% (95% CI, 85.98%–96.50%) when a cutoff value of 0.163 was used. Consequently, we successfully established a diagnostic model based on the combination of TBAg/PHA ratio, CSF chlorine, CSF nucleated cell count, and CSF lymphocyte proportion for discrimination between TBM and BM. The established model showed good performance in differentiating TBM from BM (AUC: 0.949; 95% CI, 0.921–0.978), with 81.58% (95% CI, 71.42%–88.70%) sensitivity and 91.84% (95% CI, 84.71%–95.81%) specificity. The performance of the diagnostic model obtained in Qiaokou cohort was further validated in Caidian cohort. The diagnostic model in Caidian cohort produced an AUC of 0.923 (95% CI, 0.867–0.980) with 79.49% (95% CI, 64.47%–89.22%) sensitivity and 90.91% (95% CI, 81.55%–95.77%) specificity. Conclusions: The diagnostic model established based on the combination of four indicators had excellent utility in the discrimination between TBM and BM. [ABSTRACT FROM AUTHOR]

Background: Novel approaches for tuberculosis (TB) diagnosis, especially for distinguishing active TB (ATB) from latent TB infection (LTBI), are urgently warranted. The present study aims to determine whether the combination of HLA-DR on Mycobacterium tuberculosis (MTB)-specific cells and TB antigen/phytohemagglutinin (TBAg/PHA) ratio could facilitate MTB infection status discrimination. Methods: Between June 2020 and June 2021, participants with ATB and LTBI were recruited from Tongji Hospital (Qiaokou cohort) and Sino-French New City Hospital (Caidian cohort), respectively. The detection of HLA-DR on MTB-specific cells upon TB antigen stimulation and T-SPOT assay were simultaneously performed on all subjects. Results: A total of 116 (54 ATB and 62 LTBI) and another 84 (43 ATB and 41 LTBI) cases were respectively enrolled from Qiaokou cohort and Caidian cohort. Both HLA-DR on IFN-γ+TNF-α+ cells and TBAg/PHA ratio showed discriminatory value in distinguishing between ATB and LTBI. Receiver operator characteristic (ROC) curve analysis showed that HLA-DR on IFN-γ+TNF-α+ cells produced an area under the ROC curve (AUC) of 0.886. Besides, TBAg/PHA ratio yield an AUC of 0.736. Furthermore, the combination of these two indicators resulted in the accurate discrimination with an AUC of 0.937. When the threshold was set as 0.36, the diagnostic model could differentiate ATB from LTBI with a sensitivity of 92.00% and a specificity of 81.82%. The performance obtained in Qiaokou cohort was further validated in Caidian cohort. Conclusions: The combination of HLA-DR on MTB-specific cells and TBAg/PHA ratio could serve as a robust tool to determine TB disease states. [ABSTRACT FROM AUTHOR]

Objectives: The longitudinal and systematic evaluation of immunity in coronavirus disease 2019 (COVID-19) patients is rarely reported. Methods: Parameters involved in innate, adaptive, and humoral immunity were continuously monitored in COVID-19 patients from onset of illness until 45 days after symptom onset. Results: This study enrolled 27 mild, 47 severe, and 46 deceased COVID-19 patients. Generally, deceased patients demonstrated a gradual increase of neutrophils and IL-6 but a decrease of lymphocytes and platelets after the onset of illness. Specifically, sustained low numbers of CD8+ T cells, NK cells, and dendritic cells were noted in deceased patients, while these cells gradually restored in mild and severe patients. Furthermore, deceased patients displayed a rapid increase of HLA-DR expression on CD4+ T cells in the early phase, but with a low level of overall CD45RO and HLA-DR expressions on CD4+ and CD8+ T cells, respectively. Notably, in the early phase, deceased patients showed a lower level of plasma cells and antigen-specific IgG, but higher expansion of CD16+CD14+ proinflammatory monocytes and HLA-DR−CD14+ monocytic-myeloid-derived suppressor cells (M-MDSCs) than mild or severe patients. Among these immunological parameters, M-MDSCs showed the best performance in predicting COVID-19 mortality, when using a cutoff value of ≥10%. Cluster analysis found a typical immunological pattern in deceased patients on day 9 after onset, which was characterized as the increase of inflammatory markers (M-MDSCs, neutrophils, CD16+CD14+ monocytes, and IL-6) but a decrease of host immunity markers. Conclusions: This study systemically characterizes the kinetics of immunity of COVID-19, highlighting the importance of immunity in patient prognosis. [ABSTRACT FROM AUTHOR]

Background: Rapid and effective discrimination between active tuberculosis (ATB) and latent tuberculosis infection (LTBI) remains a challenge. There is an urgent need for developing practical and affordable approaches targeting this issue. Methods: Participants with ATB and LTBI were recruited at Tongji Hospital (Qiaokou cohort) and Sino-French New City Hospital (Caidian cohort) based on positive T-SPOT results from June 2020 to January 2021. The expression of activation markers including HLA-DR, CD38, CD69, and CD25 was examined on Mycobacterium tuberculosis (MTB)-specific CD4+ T cells defined by IFN-γ, TNF-α, and IL-2 expression upon MTB antigen stimulation. Results: A total of 90 (40 ATB and 50 LTBI) and another 64 (29 ATB and 35 LTBI) subjects were recruited from the Qiaokou cohort and Caidian cohort, respectively. The expression patterns of Th1 cytokines including IFN-γ, TNF-α, and IL-2 upon MTB antigen stimulation could not differentiate ATB patients from LTBI individuals well. However, both HLA-DR and CD38 on MTB-specific cells showed discriminatory value in distinguishing between ATB patients and LTBI individuals. As for developing a single candidate biomarker, HLA-DR had the advantage over CD38. Moreover, HLA-DR on TNF-α+ or IL-2+ cells had superiority over that on IFN-γ+ cells in differentiating ATB patients from LTBI individuals. Besides, HLA-DR on MTB-specific cells defined by multiple cytokine co-expression had a higher ability to discriminate patients with ATB from LTBI individuals than that of MTB-specific cells defined by one kind of cytokine expression. Specially, HLA-DR on TNF-α+IL-2+ cells produced an AUC of 0.901 (95% CI, 0.833–0.969), with a sensitivity of 93.75% (95% CI, 79.85–98.27%) and specificity of 72.97% (95% CI, 57.02–84.60%) as a threshold of 44% was used. Furthermore, the performance of HLA-DR on TNF-α+IL-2+ cells for differential diagnosis was obtained with validation cohort data: 90.91% (95% CI, 72.19–97.47%) sensitivity and 68.97% (95% CI, 50.77–82.73%) specificity. Conclusions: We demonstrated that HLA-DR on MTB-specific cells was a potentially useful biomarker for accurate discrimination between ATB and LTBI. [ABSTRACT FROM AUTHOR]

Background: Searching the risk factors for carbapenem-resistant Enterobacteriaceae (CRE) infection is important in clinical practice. In the present study, we aim to investigate bacterial characteristics of colonizing strains and their correlation with subsequent CRE infection.Methods: Between May 2018 and January 2019, patients hospitalized in the department of haematology and intensive care unit (ICU) were screened for CRE by rectal swabs and monitored for the outcome of infection. We identified the species and carbapenemase-encoding genes of colonizing strains and performed antimicrobial susceptibility tests and multilocus sequence typing (MLST). Risk factors for subsequent CRE infections were ascertained by univariate and multivariable analysis.Results: We collected a total of 219 colonizing strains from 153 patients. Klebsiella pneumoniae was the most abundant species, and MLST analysis showed rich diversity. K. pneumoniae carbapenemase (KPC) was predominant in the infection group (72.4%). In the non-infection group, 35.4% of strains were non-carbapenemase-producing CRE (NCP-CRE), and New Delhi metallo-β-lactamase (NDM) was predominant (42.2%). The rate of high-level carbapenem resistance (minimum inhibitory concentration [MIC] ≥ 64 mg/L for meropenem and ertapenem, ≥ 32 mg/L for imipenem) was remarkably higher in the infection group than in the non-infection group (P <  0.001). Univariate analysis showed that K. pneumoniae, high-level carbapenem resistance, CP-CRE and KPC-CRE were infection risk factors after CRE colonization. On multivariable analysis with different carbapenemase dichotomizations, KPC-CRE (adjusted odds ratio [aOR], 4.507; 95% confidence interval [CI], 1.339-15.171; P = 0.015) or imipenem MIC ≥ 32 mg/L (aOR, 9.515; 95% CI, 1.617-55.977; P = 0.013) were respectively identified as independent risk factors for subsequent infection.Conclusions: Patients colonized with KPC-CRE or strains with an imipenem MIC ≥ 32 mg/L were at particularly high risk of subsequent CRE infections during their hospital stay. [ABSTRACT FROM AUTHOR]

Background: Easily accessible tools that reliably stratify Mycobacterium tuberculosis (MTB) infection are needed to facilitate the improvement of clinical management. The current study attempts to reveal lymphocyte-related immune characteristics of active tuberculosis (ATB) patients and establish immunodiagnostic model for discriminating ATB from latent tuberculosis infection (LTBI) and healthy controls (HC). Methods: A total of 171 subjects consisted of 54 ATB, 57 LTBI, and 60 HC were consecutively recruited at Tongji hospital from January 2019 to January 2021. All participants were tested for lymphocyte subsets, phenotype, and function. Other examination including T-SPOT and microbiological detection for MTB were performed simultaneously. Results: Compared with LTBI and HC, ATB patients exhibited significantly lower number and function of lymphocytes including CD4+ T cells, CD8+ T cells and NK cells, and significantly higher T cell activation represented by HLA-DR and proportion of immunosuppressive cells represented by Treg. An immunodiagnostic model based on the combination of NK cell number, HLA-DR+CD3+ T cells, Treg, CD4+ T cell function, and NK cell function was built using logistic regression. Based on receiver operating characteristic curve analysis, the area under the curve (AUC) of the diagnostic model was 0.920 (95% CI, 0.867-0.973) in distinguishing ATB from LTBI, while the cut-off value of 0.676 produced a sensitivity of 81.48% (95% CI, 69.16%-89.62%) and specificity of 91.23% (95% CI, 81.06%-96.20%). Meanwhile, AUC analysis between ATB and HC according to the diagnostic model was 0.911 (95% CI, 0.855-0.967), with a sensitivity of 81.48% (95% CI, 69.16%-89.62%) and a specificity of 90.00% (95% CI, 79.85%-95.34%). Conclusions: Our study demonstrated that the immunodiagnostic model established by the combination of lymphocyte-related indicators could facilitate the status differentiation of MTB infection. [ABSTRACT FROM AUTHOR]

Background: Distinguishing between active tuberculosis (ATB) and latent tuberculosis infection (LTBI) remains challenging. Methods: Between 2013 and 2019, 2,059 (1,097 ATB and 962 LTBI) and another 883 (372 ATB and 511 LTBI) participants were recruited based on positive T-SPOT.TB (T-SPOT) results from Qiaokou (training) and Caidian (validation) cohorts, respectively. Blood routine examination (BRE) was performed simultaneously. Diagnostic model was established according to multivariate logistic regression. Results: Significant differences were observed in all indicators of BRE and T-SPOT assay between ATB and LTBI. Diagnostic model built on BRE showed area under the curve (AUC) of 0.846 and 0.850 for discriminating ATB from LTBI in the training and validation cohorts, respectively. Meanwhile, TB-specific antigens spot-forming cells (SFC) (the larger of early secreted antigenic target 6 and culture filtrate protein 10 SFC in T-SPOT assay) produced lower AUC of 0.775 and 0.800 in the training and validation cohorts, respectively. The diagnostic model based on combination of BRE and T-SPOT showed an AUC of 0.909 for differentiating ATB from LTBI, with 78.03% sensitivity and 90.23% specificity when a cutoff value of 0.587 was used in the training cohort. Application of the model to the validation cohort showed similar performance. The AUC, sensitivity, and specificity were 0.910, 78.23%, and 90.02%, respectively. Furthermore, we also assessed the performance of our model in differentiating ATB from LTBI with lung lesions. Receiver operating characteristic analysis showed that the AUC of established model was 0.885, while a threshold of 0.587 yield a sensitivity of 78.03% and a specificity of 85.69%, respectively. Conclusions: The diagnostic model based on combination of BRE and T-SPOT could provide a reliable differentiation between ATB and LTBI. [ABSTRACT FROM AUTHOR]

This paper considers an optimal train control problem with two challenging, non-standard constraints: a speed constraint that is piecewise-constant with respect to the train's position, and control constraints that are non-smooth functions of the train's speed. We formulate this problem as an optimal switching control problem in which the mode switching times are decision variables to be optimized, and the track gradient and speed limit in each mode are constant. Then, using control parameterization and time-scaling techniques, we approximate the switching control problem by a finite-dimensional optimization problem, which is still subject to the challenging speed limit constraint (imposed continuously during each mode) and the non-smooth control constraints. We show that the speed constraint can be transformed into a finite number of point constraints. We also show that the non-smooth control constraints can be approximated by a sequence of conventional (smooth) inequality constraints. The resulting approximate problem can be viewed as a nonlinear programming problem and solved using gradient-based optimization algorithms, where the gradients of the cost and constraint functions are computed via the sensitivity method. A case study using data for a real subway line shows that the proposed method yields a realistic optimal control profile without the undesirable control fluctuations that can occur with the pseudospectral method. [ABSTRACT FROM AUTHOR]

Background: Inadequate tuberculosis (TB) diagnostics, especially for discrimination between active TB (ATB) and latent TB infection (LTBI), are major hurdle in the reduction of the disease burden. The present study aims to investigate the role of lymphocyte non-specific function detection for TB diagnosis in clinical practice. Methods: A total of 208 participants including 49 ATB patients, 64 LTBI individuals, and 95 healthy controls were recruited at Tongji hospital from January 2019 to October 2020. All subjects were tested with lymphocyte non-specific function detection and T-SPOT assay. Results: Significantly positive correlation existed between lymphocyte non-specific function and phytohemagglutinin (PHA) spot number. CD4+ T cell non-specific function showed the potential for differentiating patients with negative T-SPOT results from those with positive T-SPOT results with an area under the curve (AUC) of 0.732 (95% CI, 0.572-0.893). The non-specific function of CD4+ T cells, CD8+ T cells, and NK cells was found significantly lower in ATB patients than in LTBI individuals. The AUCs presented by CD4+ T cell non-specific function, CD8+ T cell non-specific function, and NK cell non-specific function for discriminating ATB patients from LTBI individuals were 0.845 (95% CI, 0.767-0.925), 0.770 (95% CI, 0.683-0.857), and 0.691 (95% CI, 0.593-0.789), respectively. Application of multivariable logistic regression resulted in the combination of CD4+ T cell non-specific function, NK cell non-specific function, and culture filtrate protein-10 (CFP-10) spot number as the optimally diagnostic model for differentiating ATB from LTBI. The AUC of the model in distinguishing between ATB and LTBI was 0.939 (95% CI, 0.898-0.981). The sensitivity and specificity were 83.67% (95% CI, 70.96%-91.49%) and 90.63% (95% CI, 81.02%-95.63%) with the threshold as 0.57. Our established model showed superior performance to TB-specific antigen (TBAg)/PHA ratio in stratifying TB infection status. Conclusions: Lymphocyte non-specific function detection offers an attractive alternative to facilitate TB diagnosis. The three-index diagnostic model was proved to be a potent tool for the identification of different events involved in TB infection, which is helpful for the treatment and management of patients. [ABSTRACT FROM AUTHOR]

Background: Given that there is no rapid and effective method for distinguishing active tuberculosis (ATB) from latent tuberculosis infection (LTBI), the discrimination between these two statuses remains challenging. This study sought to investigate the value of nutritional indexes and tuberculosis‐specific antigen/phytohemagglutinin ratio (TBAg/PHA ratio) for distinguishing ATB from LTBI. Methods: Participants were consecutively recruited based on positive T‐SPOT.TB results between January 2018 and January 2020. ATB was diagnosed by positive mycobacterial culture and/or positive GeneXpert MTB/RIF, with clinical symptoms and radiological characteristics suggestive of ATB. Individuals with positive T‐SPOT.TB but without the evidence of ATB were defined as LTBI. Patients younger than 17 years and undergoing anti‐TB treatment were excluded. Results: A total of 709 (312 ATB and 397 LTBI) and another 309 (120 ATB and 189 LTBI) subjects were respectively recruited from Tongji Hospital (Qiaokou cohort) and Sino‐French New City Hospital (Caidian cohort). The level of prealbumin was significantly lower in ATB than in LTBI. With a cut‐off value of 139 mg/L, the sensitivity and specificity of prealbumin in distinguishing ATB from LTBI were 50.96% (45.41%‐56.51%) and 91.69% (88.97%‐94.40%). Meanwhile, TBAg/PHA ratio was found statistically higher in ATB compared with LTBI. If using the threshold of 0.29, the sensitivity and specificity of TBAg/PHA ratio were 65.71% (60.44%‐70.97%) and 90.93% (88.11%‐93.76%), respectively. Moreover, the combination of prealbumin and TBAg/PHA ratio (obtaining by diagnostic model) yielded better specificity (90.18%, [87.25%‐93.10%]) and sensitivity (87.18%, [83.47%‐90.89%]), while the clinical utility index (CUI) positive and CUI negative were respectively 0.76 and 0.81. After anti‐TB treatment, TBAg/PHA ratio was declined while the level of prealbumin was restored (Wilcoxon test, P < 0.001). Furthermore, the performance of diagnostic model obtained in Qiaokou cohort was confirmed in Caidian cohort. Conclusions: The diagnostic model based on combination of prealbumin and TBAg/PHA ratio is a rapid and accurate tool for discriminating ATB from LTBI. [ABSTRACT FROM AUTHOR]

Background: Pneumocystis jiroveci pneumonia (PJP) is the most common opportunistic infection in immunocompromised patients. The accurate prediction of PJP development in patients undergoing immunosuppressive therapy remains challenge. Methods: Patients undergoing immunosuppressive treatment and with confirmed pneumocystis jiroveci infection were enrolled. Another group of matched patients with immunosuppressant treatment but without signs of infectious diseases were enrolled to control group. Results: A total of 80 (40 PJP, 40 non-PJP) participants were enrolled from Tongji Hospital. None of the patients were HIV positive. The routine laboratory indicators, such as LYM, MON, RBC, TP, and ALB, were significantly lower in PJP patients than in non-PJP patients. Conversely, LDH in PJP patients was significantly higher than in non-PJP controls. For immunological indicators, the numbers of T, B, and NK cells were all remarkably lower in PJP patients than in non-PJP controls, whereas the functional markers such as HLA-DR, CD45RO and CD28 expressed on CD4+ or CD8+ T cells had no statistical difference between these two groups. Cluster analysis showing that decrease of host immunity markers including CD3+, CD4+ and CD8+ T cells, and increase of tissue damage marker LDH were the most typical characteristics of PJP patients. A further established model based on combination of CD8+ T cells and LDH showed prominent value in distinguishing PJP from non-PJP, with AUC of 0.941 (95% CI, 0.892-0.990). Conclusions: A model based on combination of routine laboratory and immunological indicators shows prominent value for predicting the development of PJP in HIV-negative patients undergoing immunosuppressive therapy. [ABSTRACT FROM AUTHOR]

Background: To establish a risk prediction model for carbapenem-resistant Enterobacteriaceae (CRE) bloodstream infection (BSI) in intestinal carriers. Methods: CRE screenings were performed every two weeks in hematology department and intensive care unit (ICU). Patients with positive CRE rectal swab screening were identified using electronic medical records from 15 May 2018 to 31 December 2019. Intestinal carriers who developed CRE BSI were compared with those who did not develop CRE infection. A 1:1 matched case-control study was conducted. The control group was selected by stratified random sampling based on the department to ensure that all the departments were represented. Univariate logistic analysis, multivariate logistic analysis and stepwise regression analysis were carried on a variety of patient factors and microbial factors. Results: A total of 42 cases were included. Multivariate analysis showed that gastrointestinal injury (OR 86.819, 95% CI 2.584– 2916.592, P=0.013), tigecycline exposure (OR 14.991, 95% CI 1.816– 123.737, P=0.012) and carbapenem resistance score (OR 11.236, 95% CI 1.811– 69.700, P=0.009) were independent risk factors for CRE BSI in intestinal carriers (P< 0.050). They were included in the Logistic regression model to predict BSI. According to receiver operating characteristic (ROC) curve analysis, the cut-off value of the model was 0.722, and the sensitivity, specificity and area under the curve (AUC) were 90.5%, 85.7% and 0.921, respectively. Conclusion: The risk prediction model based on gastrointestinal injury, tigecycline exposure and carbapenem resistance score of colonizing strain can effectively predict CRE BSI in patients with CRE colonization. Early CRE screening and detection for inpatients in key departments may promote early warning and reduce the risk of nosocomial infection of CRE. [ABSTRACT FROM AUTHOR]

Cerebral cavernous malformations (CCMs) are vascular abnormalities that primarily occur in adulthood and cause cerebral hemorrhage, stroke, and seizures. CCMs are thought to be initiated by endothelial cell (EC) loss of any one of the three Ccm genes: CCM1 (KRIT1), CCM2 (OSM), or CCM3 (PDCD10). Here we report that mice with a brain EC-specific deletion of Pdcd10 (Pdcd10BECKO) survive up to 6-12 months and develop bona fide CCM lesions in all regions of brain, allowing us to visualize the vascular dynamics of CCM lesions using transcranial two-photon microscopy. This approach reveals that CCMs initiate from protrusion at the level of capillary and post-capillary venules with gradual dissociation of pericytes. Microvascular beds in lesions are hyper-permeable, and these disorganized structures present endomucin-positive ECs and α-smooth muscle actin-positive pericytes. Caveolae in the endothelium of Pdcd10BECKO lesions are drastically increased, enhancing Tie2 signaling in Ccm3-deficient ECs. Moreover, genetic deletion of caveolin-1 or pharmacological blockade of Tie2 signaling effectively normalizes microvascular structure and barrier function with attenuated EC-pericyte disassociation and CCM lesion formation in Pdcd10BECKO mice. Our study establishes a chronic CCM model and uncovers a mechanism by which CCM3 mutation-induced caveolae-Tie2 signaling contributes to CCM pathogenesis. Animal models that fully recapitulate human CCM pathogenesis are not currently available. Here, the authors establish a novel CCM model and reveal that caveolae-Tie2 signaling is involved in CCMs formation at the level of venules, which is accompanied by gradual dissociation of pericytes. [ABSTRACT FROM AUTHOR]

Background: Vacuum drains have been extensively applied to prevent seroma formation after breast surgery. However, the usage of negative suction drainage is mainly determined by surgeon's experience and preferences. The aim of this study is to prospectively compare the drain effect after breast surgery between the low and high vacuum drains. Methods: This prospectively randomized trial (from January 2018 to June 2019) involved 188 patients who were subjected to modified radical mastectomy (group A, n=128) or immediate breast reconstruction with implants (group B, n=60). In each group, patients were randomized to receive high vacuum drain (pressure=– 98 kPa) or low vacuum drain (pressure=– 12 kPa) after surgery. Days of drain permanence, which means the duration of drainage, was the primary endpoint. Results: According to the comparison of days of drain permanence, the effect of a low vacuum drain is not inferior to a high vacuum drain in group A (pectoral drain, P< 0.001; axillary drain, P< 0.001) or group B (submuscular drain, P=0.002). The complications frequently occurred on patients with high vacuum drain (11.7%), such as seroma formation. The expense of low vacuum drain was significantly lower than high vacuum drain in both groups (P< 0.01). Conclusion: The drain effect of the low vacuum drain is not inferior to a high vacuum drain in both group A and group B. The low vacuum drain was effective, relatively cheap, and did not increase the incidence of complications; it is therefore more recommended after breast surgery. [ABSTRACT FROM AUTHOR]

Background: We aim to evaluate the prognostic and predictive value of TOP2A and HER2 expression in T1N0 breast cancer patients. Methods: 299 cases with T1N0 breast cancer were obtained from the Oncomine database (Cohort 1) and 963 of T1N0 breast cancer patients from Sun Yat-sen Memorial Hospital (Cohort 2) were retrospectively enrolled. Kaplan–Meier product was applied to estimate survival curve. Cox proportional hazard models was used to identify prognostic factors. We used PSM (propensity score matching) to balance clinicopathologic characteristics among four groups of different HER2/TOP2A status. Survival between groups and chemotherapy regimens were analyzed, before and after PSM. Results: In Cohort 1, we found that the group with HER2+ and higher expression of TOP2A mRNA was associated with poor breast cancer-specific survival (BCSS) compared to the group of HER2− with lower expression of TOP2A mRNA. In Cohort 2, HER2+ patients with higher TOP2A protein expression had greater risk of recurrence and distant recurrence compared to HER2− patients with lower expression of TOP2A protein. Among the patients who developed both HER2+ and higher expression of TOP2A protein and received chemotherapy, patients who received an anthracycline-based regimen had a significantly better recurrence-free survival (RFS) than those with a non-anthracycline-based regime. Conclusion: Patients with both HER2+ and high expression level of TOP2A protein predicts poor prognosis in T1N0 breast cancer patients. Patients with double positive for TOP2A protein and HER2 may benefit from anthracycline-based regimens. [ABSTRACT FROM AUTHOR]

Background: There are currently rare satisfactory markers for predicting the death of patients with coronavirus disease 2019 (COVID-19). The aim of this study is to establish a model based on the combination of serum cytokines and lymphocyte subsets for predicting the prognosis of the disease. Methods: A total of 739 participants with COVID-19 were enrolled at Tongji Hospital from February to April 2020 and classified into fatal (n = 51) and survived (n = 688) groups according to the patient's outcome. Cytokine profile and lymphocyte subset analysis was performed simultaneously. Results: The fatal patients exhibited a significant lower number of lymphocytes including B cells, CD4+ T cells, CD8+ T cells, and NK cells and remarkably higher concentrations of cytokines including interleukin-2 receptor, interleukin-6, interleukin-8, and tumor necrosis factor-α on admission compared with the survived subjects. A model based on the combination of interleukin-8 and the numbers of CD4+ T cells and NK cells showed a good performance in predicting the death of patients with COVID-19. When the threshold of 0.075 was used, the sensitivity and specificity of the prediction model were 90.20% and 90.26%, respectively. Meanwhile, interleukin-8 was found to have a potential value in predicting the length of hospital stay until death. Conclusions: Significant increase of cytokines and decrease of lymphocyte subsets are found positively correlated with in-hospital death. A model based on the combination of three markers provides an attractive approach to predict the prognosis of COVID-19. [ABSTRACT FROM AUTHOR]

Carbapenem-resistant organisms (CROs) are associated with considerable mortality clinically. There is a lack of effective tool to predict individual prognosis. We aim to determine if host immunity can be utilized to predict the prognosis of patients infected with CRO. From December 2018 to August 2019, we recruited CRO-infected patients to evaluate risk factors for 30-day mortality. Clinical, routine laboratory, immune and microbiological features were investigated and subjected to univariate and multivariate analyses. The final predictive models were established based on the regression coefficients of multivariate logistic regression. A total of 127 CRO-infected patients were enrolled in our study, including 85 survivors and 42 non-survivors. The number and IFN-γ producing ability of lymphocytes were remarkably decreased in non-survivors. The number of IFN-γ+CD4+ T cells could effectively predict 30-day mortality of CRO infection. Its area under the receiver operating characteristic (ROC) curve, sensitivity, specificity and accuracy, were 0.889 (95% confidence interval [CI], 0.834–0.945), 81.0, 80.0, and 80.3%, respectively. In multivariate analysis of laboratory parameters, IFN-γ+CD4+ T cell number and creatinine concentration were selected for the 2-marker model to predict prognosis fleetly. Its area under the ROC curve, sensitivity, specificity and accuracy were 0.894 (95% CI, 0.841–0.947), 83.3, 82.4, and 82.7%, respectively. Impaired lymphocyte function was an important factor to affect the outcome of CRO-infected patients. A 2-marker model based on the combination of IFN-γ+CD4+ T cell number and creatinine showed good performance in predicting the prognosis of CRO infection. [ABSTRACT FROM AUTHOR]