ABSTRACT
BACKGROUND: The ZFHX3 gene plays vital roles in embryonic development, cell proliferation, neuronal differentiation and neuronal death. This study aims to explore the relationship between ZFHX3 variants and epilepsy. METHODS: Whole-exome sequencing was performed in a cohort of 378 patients with partial (focal) epilepsy. A Drosophila Zfh2 knockdown model was used to validate the association between ZFHX3 and epilepsy. RESULTS: Compound heterozygous ZFHX3 variants were identified in eight unrelated cases. The burden of ZFHX3 variants was significantly higher in the case cohort, shown by multiple/specific statistical analyses. In Zfh2 knockdown flies, the incidence and duration of seizure-like behaviour were significantly greater than those in the controls. The Zfh2 knockdown flies exhibited more firing in excitatory neurons. All patients presented partial seizures. The five patients with variants in the C-terminus/N-terminus presented mild partial epilepsy. The other three patients included one who experienced frequent non-convulsive status epilepticus and two who had early spasms. These three patients had also neurodevelopmental abnormalities and were diagnosed as developmental epileptic encephalopathy (DEE), but achieved seizure-free after antiepileptic-drug treatment without adrenocorticotropic-hormone/steroids. The analyses of temporal expression (genetic dependent stages) indicated that ZFHX3 orthologous were highly expressed in the embryonic stage and decreased dramatically after birth. CONCLUSION: ZFHX3 is a novel causative gene of childhood partial epilepsy and DEE. The patients of infantile spasms achieved seizure-free after treatment without adrenocorticotropic-hormone/steroids implies a significance of genetic diagnosis in precise treatment. The genetic dependent stage provided an insight into the underlying mechanism of the evolutional course of illness.
Subject(s)
Epilepsies, Partial , Homeodomain Proteins , Spasms, Infantile , Animals , Child , Child, Preschool , Female , Humans , Infant , Male , Epilepsies, Partial/genetics , Epilepsies, Partial/drug therapy , Exome Sequencing , Genetic Predisposition to Disease , Homeodomain Proteins/genetics , Mutation , Spasms, Infantile/genetics , DrosophilaABSTRACT
Nanosized ultrafine particles (UFPs) from natural and anthropogenic sources are widespread and pose serious health risks when inhaled by humans. However, tracing the inhaled UFPs in vivo is extremely difficult, and the distribution, translocation, and metabolism of UFPs remain unclear. Here, we report a label-free, machine learning-aided single-particle inductively coupled plasma mass spectrometry (spICP-MS) approach for tracing the exposure pathways of airborne magnetite nanoparticles (MNPs), including external emission sources, and distribution and translocation in vivo using a mouse model. Our results provide quantitative analysis of different metabolic pathways in mice exposed to MNPs, revealing that the spleen serves as the primary site for MNP metabolism (84.4%), followed by the liver (11.4%). The translocation of inhaled UFPs across different organs alters their particle size. This work provides novel insights into the in vivo fate of UFPs as well as a versatile and powerful platform for nanotoxicology and risk assessment.
Subject(s)
Liver , Machine Learning , Magnetite Nanoparticles , Mass Spectrometry , Particle Size , Animals , Mice , Magnetite Nanoparticles/chemistry , Mass Spectrometry/methods , Liver/metabolism , Spleen/metabolism , Particulate Matter/analysis , Particulate Matter/chemistry , Tissue DistributionABSTRACT
Vitamin K2 (MK-7) has been shown to cause significant changes in different physiological processes and diseases, but its role in acute lung injury (ALI) is unclear. Therefore, in this study, we aimed to evaluate the protective effects of VK2 against LPS-induced ALI in mice. The male C57BL/6J mice were randomly divided into six groups (n = 7): the control group, LPS group, negative control group (LPS + Oil), positive control group (LPS + DEX), LPS + VK2 (L) group (VK2, 1.5 mg/kg), and LPS + VK2 (H) group (VK2, 15 mg/kg). Hematoxylin-eosin (HE) staining of lung tissue was performed. Antioxidant superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) activities, and the Ca2+ level in the lung tissue were measured. The effects of VK2 on inflammation, apoptosis, tight junction (TJ) injury, mitochondrial dysfunction, and autophagy were quantitatively assessed using Western blot analysis. Compared with the LPS group, VK2 improved histopathological changes; alleviated inflammation, apoptosis, and TJ injury; increased antioxidant enzyme activity; reduced Ca2+ overload; regulated mitochondrial function; and inhibited lung autophagy. These results indicate that VK2 could improve tight junction protein loss, inflammation, and cell apoptosis in LPS-induced ALI by inhibiting the mitochondrial dysfunction and excessive autophagy, indicating that VK2 plays a beneficial role in ALI and might be a potential therapeutic strategy.
ABSTRACT
Accurate identification of antibiotic resistance genes (ARGs) is crucial for improving treatment and controlling the spread of antibiotic-resistant bacteria (ARB). Herein, a novel PCR-free, centrifugation-free, and label-free magnetic fluorescent biosensor (MFB) was developed by combining polyA-medium DNA-polyT (mDNA, which contained a partial sequence of a target DNA), gold nanoparticle (AuNP)-anchored magnetic nanoparticle (Au@Fe3O4), complementary strand DNA (CS) of the target DNA, DNA concatamer with G-triplex (G3), and thioflavin T (ThT). Thereinto, Au@Fe3O4 nanoparticles were first capped by mDNA strands within 20 min using a simple hot drying method, and then CS was added and hybridized with mDNA on Au@Fe3O4. Second, a DNA concatamer was used to bind with CS on Au@Fe3O4. When an ARG was present in the sample, the CS would recognize it and release the DNA concatamer into solution by a toehold-mediated strand displacement reaction. Finally, under magnetic separation, the free DNA concatamers with G3 were taken out easily and bound with ThT, resulting in strong fluorescence signals. The fluorescence intensity of ThT was positively correlated with the concentration of the ARG. The whole analysis was accomplished within 1.5 h using 96-well plates. Remarkably, our MFB was universal; eight ARGs were detected by replacing the corresponding mDNA and CS in this study. To verify the practicability of our method, 12 clinically isolated strains were analyzed. The results of the MFB method were in good agreement with those of the quantitative real-time PCR method with an area under the curve of 0.92 (95% confidence interval: 0.8479 to 0.9932), sensitivity of 92.00%, and specificity of 91.55%. Above all, the MFB assay established here is simple, low-cost, and universal and has great potential for applications in the identification of ARGs.
Subject(s)
Biosensing Techniques , Metal Nanoparticles , Anti-Bacterial Agents/pharmacology , Gold , Heating , Angiotensin Receptor Antagonists , Angiotensin-Converting Enzyme Inhibitors , DNA/genetics , DNA/analysis , Biosensing Techniques/methodsABSTRACT
Platelet size is a determinant of platelet function. Here, a new microfluidic deterministic cytometry packed with S-shaped micropillars (S-MDC) was developed to rapidly and sensitively determine the apparent size (Dapp) of platelets, which was used to evaluate platelet function. The platelet Dapp in the diluted whole blood was rapidly and label-freely measured by S-MDC within 2 min under shear rates (0.4 mm/s) that mimicked physiological conditions. The level of CD62p on platelets scarcely changed before and after platelets went through the whole S-MDC, indicating that the platelet function was nondestructive. Notably, the human platelet Dapp determined before and after thrombin addition by S-MDC was highly coincident with the levels of CD62p on the platelet surface by flow cytometry (r = 0.819), revealing that the human platelet Dapp was available to assess the platelet activation state. In addition, the results of the rat platelet Dapp were consistent with myocardial injury of rats with myocardial ischemia before and after treatment with antiplatelet agents, suggesting that rat platelet Dapp can be used to reflect myocardial injury in vivo outcomes. These findings reveal that S-MDC is a promising technique for screening tests for a bleeding disorder, in addition to monitoring antiplatelet drugs.
Subject(s)
Blood Platelets , Microfluidics , Humans , Rats , Animals , Platelet Activation , Platelet Aggregation Inhibitors , Thrombin , Flow Cytometry/methodsABSTRACT
Lipopolysaccharide (LPS) presents a significant threat to human health. Herein, a novel method for detecting LPS was developed by coupling hybridization chain reaction (HCR), gold nanoparticles (AuNPs) agglutination (AA) triggered by a Cu(I)-catalyzed azide-alkyne cycloaddition click chemistry (CuAAC), and electrokinetic accumulation (EA) in a microfluidic chip, termed the HCR-AA-EA method. Thereinto, the LPS-binding aptamer (LBA) was coupled with the AuNP-coated Fe3O4 nanoparticle, which was connected with the polymer of H1 capped on CuO (H1-CuO) and H2-CuO. Upon LPS recognition by LBA, the polymers of H1- and H2-CuO were released into the solution, creating a "one LPS-multiple CuO" effect. Under ascorbic acid reduction, CuAAC was initiated between the alkyne and azide groups on the AuNPs' surface; then, the product was observed visually in the microchannel by EA. Finally, LPS was quantified by the integrated density of AuNP aggregates. The limit of detections were 29.9 and 127.2 fM for water samples and serum samples, respectively. The levels of LPS in the injections and serum samples by our method had a good correlation with those from the limulus amebocyte lysate test (r = 0.99), indicating high accuracy. Remarkably, to popularize our method, a low-cost, wall-power-free portable device was developed, enabling point-of-care testing.
Subject(s)
Click Chemistry , Gold , Lipopolysaccharides , Metal Nanoparticles , Gold/chemistry , Metal Nanoparticles/chemistry , Lipopolysaccharides/analysis , Humans , Azides/chemistry , Limit of Detection , Copper/chemistry , Alkynes/chemistry , Aptamers, Nucleotide/chemistryABSTRACT
Background Microwave ablation (MWA) is currently under preliminary investigation for the treatment of multifocal papillary thyroid carcinoma (PTC) and has shown promising treatment efficacy. Compared with surgical resection (SR), MWA is minimally invasive and could preserve thyroid function. However, a comparative analysis between MWA and SR is warranted to draw definitive conclusions. Purpose To compare MWA and SR for preoperative US-detected T1N0M0 multifocal PTC in terms of overall and 1-, 3-, and 5-year progression-free survival rates and complication rates. Materials and Methods In this retrospective study, 775 patients with preoperative US-detected T1N0M0 multifocal PTC treated with MWA or SR across 10 centers between May 2015 and December 2021 were included. Propensity score matching (PSM) was performed for patients in the MWA and SR groups, followed by comparisons between the two groups. The primary outcomes were overall and 1-, 3-, and 5-year progression-free survival (PFS) rates and complication rates. Results After PSM, 229 patients (median age, 44 years [IQR 36.5-50.5 years]; 179 female) in the MWA group and 453 patients (median age, 45 years [IQR 37-53 years]; 367 female) in the SR group were observed for a median of 20 months (range, 12-74 months) and 26 months (range, 12-64 months), respectively. MWA resulted in less blood loss, shorter incision length, and shorter procedure and hospitalization durations (all P < .001). There was no evidence of differences in overall and 1-, 3-, or 5-year PFS rates (all P > .05) between MWA and SR (5-year rate, 77.2% vs 83.1%; P = .36) groups. Permanent hoarseness (2.2%, P = .05) and hypoparathyroidism (4.0%, P = .005) were encountered only in the SR group. Conclusion There was no evidence of a significant difference in PFS rates between MWA and SR for US-detected multifocal T1N0M0 PTC, and MWA resulted in fewer complications. Therefore, MWA is a feasible option for selected patients with multifocal T1N0M0 PTC. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Georgiades in this issue.
Subject(s)
Microwaves , Thyroid Neoplasms , Humans , Female , Adult , Middle Aged , Microwaves/therapeutic use , Retrospective Studies , Thyroid Cancer, Papillary/diagnostic imaging , Thyroid Cancer, Papillary/surgery , Hospitalization , Thyroid Neoplasms/diagnostic imaging , Thyroid Neoplasms/surgeryABSTRACT
Cap RNA methylations play important roles in the replication, evasion of host RNA sensor recognition, and pathogenesis. Coronaviruses possess both guanine N7- and 2'-O-ribose methyltransferases (N7-MTase and 2'-O-MTase) encoded by nonstructural protein (nsp) 14 and nsp16/10 complex, respectively. In this study, we reconstituted the two-step RNA methylations of N7-MTase and 2'-O-MTase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro and demonstrated its common and different features in comparison with that of SARS-CoV. We revealed that the nsp16/10 2'-O-MTase of SARS-CoV-2 has a broader substrate selectivity than the counterpart of SARS-CoV and can accommodate both unmethylated and uncapped RNA substrates in a sequence-independent manner. Most intriguingly, the substrate selectivity of nsp16/10 complex is not determined by the apoenzyme of nsp16 MTase but by its cofactor nsp10. These results provide insight into the unique features of SARS-CoV-2 MTases and may help develop strategies to precisely intervene in the methylation pathway and pathogenesis of SARS-CoV-2.
Subject(s)
COVID-19 , Methyltransferases , Humans , Methyltransferases/genetics , SARS-CoV-2/genetics , RNA Methylation , RNA CapsABSTRACT
Sovleplenib (HMPL-523) is a selective spleen tyrosine kinase (Syk) inhibitor with anti-tumor activity in preclinical models of B-cell malignancy. We conducted a dose-escalation and dose-expansion phase I study of sovleplenib in patients with relapsed/ refractory mature B-cell tumors. Dose escalation followed a 3+3 design; patients received oral sovleplenib (200-800 mg once daily [q.d.] or 200 mg twice daily [b.i.d.], 28-day cycles). During dose expansion, patients were enrolled into four cohorts per lymphoma classification and treated at the recommended phase II dose (RP2D) (clinicaltrials gov. Identifier: NCT02857998). Overall, 134 Chinese patients were enrolled (dose escalation, N=27; dose expansion, N=107). Five patients experienced dose-limiting toxicities: one each of amylase increased (200 mg q.d.), febrile neutropenia (800 mg q.d.), renal failure (800 mg q.d.), hyperuricemia and blood creatine phosphokinase increased (200 mg b.i.d.) and blood bilirubin increased and pneumonia (200 mg b.i.d.). RP2D was determined as 600 mg (>65 kg) or 400 mg (≤65 kg) q.d.. The primary efficacy end point of independent review committee-assessed objective response rate in indolent B-cell lymphoma was 50.8% (95% confidence interval: 37.5- 64.1) in 59 evaluable patients at RP2D (follicular lymphoma: 60.5%, marginal zone lymphoma: 28.6%, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, 0%). The most common (≥10% patients) grade ≥3 treatment-related adverse events in the dose-expansion phase were decreased neutrophil count (29.9%), pneumonia (12.1%) and decreased white blood cell count (11.2%). Pharmacokinetic exposures increased dose-proportionally with ascending dose levels from 200-800 mg, without observed saturation. Sovleplenib showed anti-tumor activity in relapsed/refractory B-cell lymphoma with acceptable safety. Further studies are warranted.
Subject(s)
Lymphoma, B-Cell , Protein Kinase Inhibitors , Syk Kinase , Humans , Middle Aged , Male , Female , Syk Kinase/antagonists & inhibitors , Aged , Adult , Lymphoma, B-Cell/drug therapy , Lymphoma, B-Cell/pathology , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/adverse effects , Young Adult , Aged, 80 and over , Treatment Outcome , Drug Resistance, Neoplasm/drug effects , Maximum Tolerated Dose , Pyrazines/administration & dosage , Pyrazines/therapeutic use , Pyrazines/pharmacokinetics , Pyrazines/adverse effects , Recurrence , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Indazoles , MorpholinesABSTRACT
OBJECTIVE: To evaluate the feasibility, safety and efficacy of concurrent simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) combined with nimotuzumab in the treatment of locally advanced esophageal squamous cell cancer (ESCC). METHODS: Eligible patients were histologically proven to have locally advanced ESCC, and were unable to tolerate or refuse concurrent chemoradiotherapy (CCRT). Enrolled patients underwent concurrent SIB-IMRT in combination with nimotuzumab. SIB-IMRT: For the planning target volume of clinical target volume (PTV-C), the prescription dose was 50.4 Gy/28fractions, 1.8 Gy/fraction, 5fractions/week, concurrently, the planning target volume of gross tumor (PTV-G) undergone an integrated boost therapy, with a prescription dose of 63 Gy/28fractions, 2.25 Gy/fraction, 5 fractions/week. Nimotuzumab was administered concurrently with radiotherapy, 200 mg/time, on D1, 8, 15, 22, 29, and 36, with a total accumulation of 1200 mg through intravenous infusion. The primary endpoint of the study was the safety and efficacy of the combined treatment regimen, and the secondary endpoints were 1-year, 2-year, and 3-year local control and survival outcomes. RESULTS: (1) From December 2018 to August 2021, 35 patients with stage II-IVA ESCC were enrolled and 34 patients completed the full course of radiotherapy and the intravenous infusion of full-dose nimotuzumab. The overall completion rate of the protocol was 97.1%. (2) No grade 4-5 adverse events occurred in the entire group. The most common treatment-related toxicity was acute radiation esophagitis, with a total incidence of 68.6% (24/35). The incidence of grade 2 and 3 acute esophagitis was 25.7% (9/35) and 17.1% (6/35), respectively. The incidence of acute radiation pneumonitis was 8.6% (3/35), including one case each of Grades 1, 2, and 3 pneumonitis. Adverse events in other systems included decreased blood cells, hypoalbuminemia, electrolyte disturbances, and skin rash. Among these patients, five experienced grade 3 electrolyte disturbances during the treatment period (three with grade 3 hyponatremia and two with grade 3 hypokalemia). (3) Efficacy: The overall CR rate was 22.8%, PR rate was 71.4%, ORR rate was 94.2%, and DCR rate was 97.1%.(4) Local control and survival: The 1-, 2-, and 3-year local control (LC) rate, progression-free survival(PFS) rate, and overall survival(OS) rate for the entire group were 85.5%, 75.4%, and 64.9%; 65.7%, 54.1%, and 49.6%; and 77.1%, 62.9%, and 54.5%, respectively. CONCLUSIONS: The combination of SIB-IMRT and nimotuzumab for locally advanced esophageal cancer demonstrated good feasibility, safety and efficacy. It offered potential benefits in local control and survival. Acute radiation esophagitis was the primary treatment-related toxicity, which is clinically manageable. This comprehensive treatment approach is worthy of further clinical exploration (ChiCTR1900027936).
Subject(s)
Antibodies, Monoclonal, Humanized , Chemoradiotherapy , Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Radiotherapy, Intensity-Modulated , Humans , Male , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Female , Middle Aged , Esophageal Squamous Cell Carcinoma/therapy , Esophageal Squamous Cell Carcinoma/radiotherapy , Esophageal Squamous Cell Carcinoma/pathology , Esophageal Squamous Cell Carcinoma/mortality , Radiotherapy, Intensity-Modulated/methods , Radiotherapy, Intensity-Modulated/adverse effects , Esophageal Neoplasms/radiotherapy , Esophageal Neoplasms/pathology , Esophageal Neoplasms/therapy , Esophageal Neoplasms/mortality , Esophageal Neoplasms/drug therapy , Aged , Chemoradiotherapy/methods , Adult , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Agents, Immunological/administration & dosage , Treatment OutcomeABSTRACT
This multicenter, open-label, single-arm trial (ClinicalTrials.gov, NCT05236621) was conducted to confirm the efficacy and safety of generic pomalidomide plus dexamethasone in Chinese patients with relapsed or refractory multiple myeloma (RRMM). Total 79 eligible RRMM patients were planned to be included. Patients were treated with generic pomalidomide (4 mg daily on days 1-21, orally) and low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22, orally; 20 mg for patients aged > 75 years) in 28-day cycles until disease progression with a maximum treatment duration of 2 years. The primary endpoint is the overall response rate (ORR) assessed by the independent review committee per the 2016 International Myeloma Working Group guidelines. A total of 85 eligible patients were included in this study from 32 centers in China, with a median age of 62.0 (range, 39-76) years, a median prior line of therapy of 4 (range, 1-16), and 41.2% patients with high-risk cytogenetics. The ORR was 38.8% (95% confidence interval (CI), 28.44-50.01). The disease control rate was 67.1% (95% CI, 56.02-76.87), meanwhile, the median progression-free survival was 5.55 months (95% CI, 3.68-7.52). Among the treatment-related adverse events (TRAEs), infective pneumonia (17.6%) was the most frequent non-hematologic adverse event, while a decrease in neutrophil count (52.9%) was the most common grade ≥ 3 TRAE. The study results indicated that the generic pomalidomide demonstrated consistent efficacy and a safety profile similar to the branded pomalidomide when combined with low-dose dexamethasone in Chinese RRMM patients.Registration number ClinicalTrials.gov NCT05236621, retrospectively registered on February 11, 2022.
Subject(s)
Multiple Myeloma , Thalidomide/analogs & derivatives , Humans , Adult , Middle Aged , Aged , Multiple Myeloma/drug therapy , Dexamethasone , Neoplasm Recurrence, Local/drug therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
In this prospective, multicenter, Phase 2 clinical trial (NCT02987244), patients with peripheral T-cell lymphomas (PTCLs) who had responded to first-line chemotherapy with cyclophosphamide, doxorubicin or epirubicin, vincristine or vindesine, etoposide, and prednisone (Chi-CHOEP) were treated by autologous stem cell transplantation (ASCT) or with chidamide maintenance or observation. A total of 85 patients received one of the following interventions: ASCT (n = 15), chidamide maintenance (n = 44), and observation (n = 26). estimated 3 PFS and OS rates were 85.6%, 80.8%, and 49.4% (P = 0.001). The two-year OS rates were 85.6%, 80.8%, and 69.0% (P = 0.075).The ASCT and chidamide maintenance groups had significantly better progression-free survival (PFS) than the observation group (P = 0.001, and P = 0.01, respectively). The overall survival (OS) differed significantly between the chidamide maintenance group and the observation group ( P = 0.041). The multivariate and propensity score matching analyses for PFS revealed better outcomes in the subjects in the chidamide maintenance than observation groups (P = 0.02). The ASCT and chidamide maintenance groups had significant survival advantages over the observation group. In the post-remission stage of the untreated PTCL patients, single-agent chidamide maintenance demonstrated superior PFS and better OS than observation. Our findings highlight the potential benefit of chidamide in this patient subset, warranting further investigation through larger prospective trials. Clinical trial registration: clinicaltrial.gov, NCT02987244. Registered 8 December 2016, http://www.clinicaltrials.gov/ct2/show/NCT02987244 .
Subject(s)
Aminopyridines , Antineoplastic Combined Chemotherapy Protocols , Benzamides , Hematopoietic Stem Cell Transplantation , Lymphoma, T-Cell, Peripheral , Humans , Lymphoma, T-Cell, Peripheral/therapy , Lymphoma, T-Cell, Peripheral/mortality , Lymphoma, T-Cell, Peripheral/drug therapy , Male , Female , Adult , Middle Aged , Aminopyridines/therapeutic use , Benzamides/therapeutic use , Prospective Studies , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , China/epidemiology , Transplantation, Autologous , Aged , Survival Rate , Young Adult , Maintenance Chemotherapy , Autografts , Remission Induction , AdolescentABSTRACT
BACKGROUND: Existing panels for lower respiratory tract infections (LRTIs) are slow and lack quantification of important pathogens and antimicrobial resistance, which are not solely responsible for their complex etiology and antibiotic resistance. BioFire FilmArray Pneumonia (PN) panels may provide rapid information on their etiology. METHODS: The bronchoalveolar lavage fluid of 187 patients with LRTIs was simultaneously analyzed using a PN panel and cultivation, and the impact of the PN panel on clinical practice was assessed. The primary endpoint was to compare the consistency between the PN panel and conventional microbiology in terms of etiology and drug resistance, as well as to explore the clinical significance of the PN panel. The secondary endpoint was pathogen detection using the PN panel in patients with community-acquired pneumonia (CAP) or hospital-acquired pneumonia (HAP). RESULTS: Fifty-seven patients with HAP and 130 with CAP were included. The most common pathogens of HAP were Acinetobacter baumannii and Klebsiella pneumoniae, with the most prevalent antimicrobial resistance (AMR) genes being CTX-M and KPC. For CAP, the most common pathogens were Haemophilus influenzae and Staphylococcus aureus, with the most frequent AMR genes being CTX-M and VIM. Compared with routine bacterial culture, the PN panel demonstrated an 85% combined positive percent agreement (PPA) and 92% negative percent agreement (NPA) for the qualitative identification of 13 bacterial targets. PN detection of bacteria with higher levels of semi-quantitative bacteria was associated with more positive bacterial cultures. Positive concordance between phenotypic resistance and the presence of corresponding AMR determinants was 85%, with 90% positive agreement between CTX-M-type extended-spectrum beta-lactamase gene type and phenotype and 100% agreement for mecA/C and MREJ. The clinical benefit of the PN panel increased by 25.97% compared with traditional cultural tests. CONCLUSION: The bacterial pathogens and AMR identified by the PN panel were in good agreement with conventional cultivation, and the clinical benefit of the PN panel increased by 25.97% compared with traditional detection. Therefore, the PN panel is recommended for patients with CAP or HAP who require prompt pathogen diagnosis and resistance identification.
Subject(s)
Anti-Infective Agents , Community-Acquired Infections , Pneumonia , Respiratory Tract Infections , Humans , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Drug Resistance, Bacterial/genetics , Pneumonia/microbiology , Bacteria/genetics , Respiratory Tract Infections/diagnosis , Community-Acquired Infections/diagnosis , Community-Acquired Infections/microbiologyABSTRACT
The arylazopyrazole 3pzH as a novel photoswitch exhibits quantitative switching and high thermal stability. In this work, combined electronic structure calculations and ab initio multiple spawning (AIMS) dynamic simulations were performed to systemically investigate the cis â trans photoisomerization mechanism and the chiral preference after photoexcitation of 3pzH to the first excited singlet state (S1). Unlike most of the azoheteroarene photoswitches reported previously, many twisted and T-shaped cis isomers were found to be stable for 3pzH in the S0 state, owing to the moderate interaction between the hydrogen atom and π electrons of the aromatic ring. Two twisted cis isomers with different chirality ((M)-Z1 and (P)-Z1), the most stable T-shaped cis isomer ((T)-Z2), and the most stable planar trans isomer (E2) were selected as the initial structures to carry out the AIMS nonadiabatic dynamic simulations. Following excitation to the S1 state, all of the cis isomers decayed to conical intersection (CI) regions via the same bicycle pedal mechanism, while the evolution of the trans isomers to their CI regions was achieved via rotation around the NâN bond. More importantly, chiral preferences were found for the twisted cis isomers in the S1 state through the AIMS dynamic simulations due to the steric effect and static electronic repulsion. Notably, chirality was also observed in S1 isomerization starting from the planar E2 isomer because of the dynamic effect. After the nonadiabatic transition to the S0 state, the bicycle pedal mechanism was found to play a crucial role in cis â trans photoisomerization. The simulated photoisomerization productivities were generally consistent with past experimental observations. Our calculations not only uncover the underlying reason for the excellent photoswitching properties of 3pzH but also enrich the knowledge of photoisomerization for azoheteroarene photoswitches, which will surely benefit their rational design.
ABSTRACT
Machine learning is capable of effectively predicting the potential energies of molecules in the presence of high-quality data sets. Its application in the construction of ground- and excited-state potential energy surfaces is attractive to accelerate nonadiabatic molecular dynamics simulations of photochemical reactions. Because of the huge computational cost of excited-state electronic structure calculations, the construction of a high-quality data set becomes a bottleneck. In the present work, we first built two data sets. One was obtained from surface hopping dynamics simulations at the semiempirical OM2/MRCI level. Another was extracted from the dynamics trajectories at the CASSCF level, which was reported previously. The ground- and excited-state potential energy surfaces of ethylene-bridged azobenzene at the CASSCF computational level were constructed based on the former low-level data set. Although non-neural network machine learning methods can achieve good or modest performance during the training process, only neural network models provide reliable predictions on the latter external test data set. The BPNN and SchNet combined with the Δ-ML scheme and the force term in the loss functions are recommended for dynamics simulations. Then, we performed excited-state dynamics simulations of the photoisomerization of ethylene-bridged azobenzene on machine learning potential energy surfaces. Compared with the lifetimes of the first excited state (S1) estimated at different computational levels, our results on the E isomer are in good agreement with the high-level estimation. However, the overestimation of the Z isomer is unimproved. It suggests that smaller errors during the training process do not necessarily translate to more accurate predictions on high-level potential energies or better performance on nonadiabatic dynamics simulations, at least in the present case.
ABSTRACT
Background and Objective: Lung adenocarcinoma is the most common type of lung cancer with highly incidence and mortality. Due to the overlap of morphological features, it is difficult to distinguish clinically between preinvasive lesions (in situ adenocarcinoma, AIS) and invasive lesions (minimally invasive adenocarcinoma, MIA), which appear as ground glass cloudy nodules. This study was performed to probe the application value of artificial intelligence (AI)-based dual source CT scanning in the differentiation of AIS as well as MIA. Methods: The clinical data of 136 patients in Shanghai Baoshan Hospital of Integrated Traditional Chinese and Western Medicine from January 2019 to January 2022 were retrospectively analyzed. The accuracy of AI in distinguishing lung AIS (n=76) and MIA (n=60) were analyzed. The effectiveness of AI in detecting nodules and its diagnostic efficacy for AIS and MIA were explored. Results: The proportion of patients with clear and regular lesion boundaries in AIS was higher than that in MIA. The mean lesion diameter of AIS patients was shorter than MIA patients. There was no difference in the CT value between AIS and MIA in the ground glass nodule density area of pure ground glass nodule and mixed ground glass nodule, but the CT value of the solid nodule density area in AIS was lower. The occurrence of pulmonary vascular abnormality, air bronchogram sign, and pleural depression in AIS patients were lower than MIA patients. The detection rate of AI for lung adenocarcinoma with nodule diameter ≤ 5 mm, complete solid nodules and ground glass nodules was significantly higher than radiologists. The sensitivity, specificity, positive prediction rate, negative prediction rate and accuracy of AI detection were significantly higher than radiologists. Conclusion: AI-based dual source CT scanning can clearly show the morphological characteristics of lung adenocarcinoma, which is helpful for the differential diagnosis of lung AIS as well as MIA.
ABSTRACT
Near-infrared light-driven photocatalytic CO2 reduction (NIR-CO2PR) holds tremendous promise for the production of valuable commodity chemicals and fuels. However, designing photocatalysts capable of reducing CO2 with low energy NIR photons remains challenging. Herein, a novel NIR-driven photocatalyst comprising an anionic Ru complex intercalated between NiAl-layered double hydroxide nanosheets (NiAl-Ru-LDH) is shown to deliver efficient CO2 photoreduction (0.887â µmol h-1) with CO selectivity of 84.81 % under 1200â nm illumination and excellent stability over 50 testing cycles. This remarkable performance results from the intercalated Ru complex lowering the LDH band gap (0.98â eV) via a compression-related charge redistribution phenomenon. Furthermore, transient absorption spectroscopy data verified light-induced electron transfer from the Ru complex towards the LDH sheets, increasing the availability of electrons to drive CO2PR. The presence of hydroxyl defects in the LDH sheets promotes the adsorption of CO2 molecules and lowers the energy barriers for NIR-CO2PR to CO. To our knowledge, this is one of the first reports of NIR-CO2PR at wavelengths up to 1200â nm in LDH-based photocatalyst systems.
ABSTRACT
BACKGROUND: Academic procrastination is especially prevalent among nursing students in higher vocational colleges and it is considered an important factor of poor academic performance. However, existing research mainly focused on the overall level of academic procrastination, and little is known about the individual heterogeneity of academic procrastination among nursing students in higher vocational colleges. Thus, the aim of this study was to clarify the subgroups and factors of academic procrastination among nursing students in higher vocational college and explore academic procrastination networks of the latent subgroups. METHODS: A cross-sectional study with online survey. 1369 nursing students in one higher vocational college were recruited using convenience sampling. Participants completed electronic questionnaires that collected demographic and academic characteristics, perceived stress, and academic procrastination. Latent profile analysis, multinomial logistic regression analysis, and network analysis were performed to analyze the data. RESULTS: Three latent profiles of academic procrastination were identified: low (32.4 %), medium (53.3 %), and high (14.3 %). Higher vocational college nursing students who have reset an exam, low professional identity, and perceived more stress are more likely to have higher academic procrastination than other profiles. Network analysis showed that academic procrastination networks structure of the three latent profiles had distinct central components. For the low academic procrastination group, AP11 ("I make study plans, but I often fail to stick to them") and AP12 ("If there is no external pressure, I tend to postpone assignments or reports with deadlines") were the core components. For the medium academic procrastination group, AP17 ("I always wait until I can't postpone my academic tasks any longer before starting them") and AP16 ("I always tend to postpone on assignments or other academic tasks") were the central components. For the high academic procrastination group, AP16 and AP7 ("When studying in my dorm room, I often stop to do other things") were the essential components. CONCLUSIONS: There is heterogeneity in higher vocational college nursing students' academic procrastination that can be classified into three latent profiles. The examined factors of academic procrastination and identified the central components of academic procrastination networks of the three latent profiles help nurse educators tailor targeted interventions.
Subject(s)
Procrastination , Students, Nursing , Humans , Female , Male , Students, Nursing/psychology , Cross-Sectional Studies , Young Adult , Adult , Universities , Surveys and Questionnaires , Stress, Psychological/psychologyABSTRACT
Staphylococcus aureus can cause localized infections such as abscesses and pneumonia, as well as systemic infections such as bacteremia and sepsis. Especially, methicillin-resistant S. aureus often presents multidrug resistance, which becomes a major clinical challenge. One of the most common reasons for methicillin-resistant S. aureus antibiotic resistance is the presence of biofilms. Natural antimicrobial peptides derived from different species have shown effectiveness in combating S. aureus biofilms. In this review, we summarize the inhibitory activity of antimicrobial peptides against S. aureus planktonic cells and biofilms. We also summarize the possible inhibitory mechanisms, involving cell adhesion inhibition, membrane fracture, biofilm disruption and DNA disruption. We believe this can provide the basis for further research against S. aureus biofilm-associated infections.
When a bacterial infection is treated, sometimes not all bacteria are killed. This is because they have ways to evade the treatment's action. Therefore, it is important to develop new drugs, although this is difficult, expensive and time-consuming. This paper summarizes new types of natural antimicrobials that could be used against bacteria, how they work and how well.