Spatial and temporal heterogeneity of tumor immune microenvironment between primary tumor and brain metastases in NSCLC.

BACKGROUND: Brain metastasis is a common outcome in non-small cell lung cancer, and despite aggressive treatment, its clinical outcome is still frustrating. In recent years, immunotherapy has been developing rapidly, however, its therapeutic outcomes for primary lung cancer and brain metastases are not the same, suggesting that there may be differences in the immune microenvironment of primary lung cancer and brain metastases, however, we currently know little about these differences. METHODS: Seventeen paired samples of NSCLC and their brain metastases and 45 other unpaired brain metastases samples were collected for the current study. Immunohistochemical staining was performed on all samples for the following markers: immune checkpoints CTLA-4, PD-1, PD-L1, B7-H3, B7-H4, IDO1, and EphA2; tumor-infiltrating lymphocytes (TILs) CD3, CD4, CD8, and CD20; tumor-associated microglia/macrophages (TAMs) CD68 and CD163; and tumor proliferation index Ki-67. The differences in expression of these markers were compared in 17 paired samples, and the effect of the expression level of these markers on the prognosis of patients was analyzed in lung adenocarcinoma brain metastases samples. Subsequently, multiplex immunofluorescence staining was performed in a typical lung-brain paired sample based on the aforementioned results. The multiplex immunofluorescence staining results revealed the difference in tumor immune microenvironment between primary NSCLC and brain metastases. RESULTS: In 17 paired lesions, the infiltration of CTLA-4+ (P = 0.461), PD-1+ (P = 0.106), CD3+ (P = 0.045), CD4+ (P = 0.037), CD8+ (P = 0.008), and CD20+ (P = 0.029) TILs in brain metastases were significantly decreased compared with primary tumors. No statistically significant difference was observed in the CD68 (P = 0.954) and CD163 (P = 0.654) TAM infiltration between primary NSCLC and paired brain metastases. In all the brain metastases lesions, the expression of PD-L1 is related to the time interval of brain metastases in NSCLC. In addition, the Cox proportional hazards regression models showed high expression of B7-H4 (hazard ratio [HR] = 3.276, 95% confidence interval [CI] 1.335-8.041, P = 0.010) and CD68 TAM infiltration (HR = 3.775, 95% CI 1.419-10.044, P = 0.008) were independent prognosis factors for lung adenocarcinoma brain metastases patients. CONCLUSIONS: Both temporal and spatial heterogeneity is present between the primary tumor and brain metastases of NCSLC. Brain metastases lesions exhibit a more immunosuppressive tumor immune microenvironment. B7-H4 and CD68+ TAMs may have potential therapeutic value for lung adenocarcinoma brain metastases patients.

Synthesis of narrow-spectrum anti-mycobacterial molecules without effect on the diversity of gut microbiota in mice based on the structure of rifampicin.

Rifampicin (RIF) is a broad-spectrum antimicrobial agent that is also a first-line drug for treating tuberculosis (TB). Based on the naphthyl ring structure of RIF this study synthesized 16 narrow-spectrum antimicrobial molecules that were specifically anti-Mycobacterium tuberculosis (Mtb). The most potent candidate was 2-((6-hydroxynaphthalen-2-yl) methylene) hydrazine-1-carbothioamide (compound 3c) with minimum inhibitory concentration (MIC) of 1 µg/mL against Mtb. Synergistic anti-Mtb test indicated that none of the combinations of 3c with the major anti-TB drugs are antagonistic. Consistent with RIF, compound 3c induced large amounts of reactive oxygen radicals (ROS) in the cells of Mtb. The killing kinetics of compound 3c and RIF are very similar. Furthermore, molecular docking showed that compound 3c was able to access the RIF binding pocket of the ß subunit of Mtb RNA polymerase (RNAP). Experiments in mice showed that compound 3c increased the variety of intestinal flora in mice, while RIF significantly decreased the diversity of intestinal flora in mice. In addition, compound 3c is non-toxic to animal cells with a selection index (SI) much more than 10. The evidence from this study suggests that the further development of 3c could contribute to the development of novel drug for TB treatment.

Clinical Characteristics of Anaphylaxis in Children Aged 0-16 Years in Xi'an, China.

INTRODUCTION: Anaphylaxis is a serious systemic hypersensitivity reaction that usually has a rapid onset and may cause death. The aim of this study was to clarify the clinical characteristics of anaphylaxis in children of all ages in Xi'an, China. METHODS: A retrospective study was conducted on anaphylaxis cases in the emergency department of the Affiliated Children's Hospital of Xi'an Jiaotong University between January 1, 2016, and July 1, 2021. The statistical methods used were the χ2 test, Fisher's exact test, and Z-test. RESULTS: A total of 110 cases of anaphylaxis were collected: 70% were male, 13 were <1 year old, 17 were 1-2 years old, 42 were 3-6 years old, 38 were 7-16 years old, 10 (9.1%) had ≥2 anaphylaxis, and 75 (68.1%) had a previous history of allergy. The triggers of anaphylaxis were analyzed: 50 cases (45.5%) were induced by food, 37 cases (33.6%) by drugs, 6 cases (5.5%) by insect bites, 4 cases (3.6%) by exercise, and 12 cases (11.8%) by unknown causes. Common food allergens were milk (20%, 10/50), buckwheat (16%, 8/50), eggs (14%, 7/50), and fruits (14%, 7/50). The most common drug triggers were antibiotics (59.4%, 22/37), non-steroidal anti-inflammatory drugs (NSAIDs) (10.8%, 4/37), vaccines (10.8%, 4/37), and herbal medicines (10.8%, 4/37). Common food allergens vary by age: milk and eggs for infants, fruit for children aged 1-2 years, and buckwheat for children older than 3 years. Ninety-eight cases (89.1%) had skin mucosal involvement, 78 (70.9%) had respiratory compromise, 45 (40.9%) had cardiovascular compromise, and 31 (28.2%) had gastrointestinal symptoms. Cardiovascular compromise and reduced level of consciousness were statistically different between the age groups (p < 0.05). Twenty cases (18.2%) had resolved spontaneously when they reached the hospital, 53 cases (48.1%) received epinephrine, 18 (16.4%) were hospitalized, and 2 (1.8%) experienced a biphasic reaction. CONCLUSIONS: Males are overrepresented in children with anaphylaxis, and food and drugs are common triggers in children. However, the types of common food triggers differ across age groups, and infants are more likely to have cardiovascular compromise and a reduced level of consciousness. However, the use of epinephrine remains inadequate. The training of clinical staff in recognizing anaphylaxis needs to be strengthened.

Synthesis, antimycobacterial evaluation, and molecular docking study of 1,2,4-triazole derivatives.

Fifteen 1,2,4-triazole derivatives were synthesised in this study and their MIC values against Mycobacterium tuberculosis (Mtb) ranged from 2 to 32 µg/mL. Furthermore, their antimycobacterial activity was positively correlated with the KatG enzyme docking score. Among the 15 compounds, compound 4 showed the strongest bactericidal activity with an MIC of 2 µg/mL. The selectivity index of compound 4 is more than 10, indicating that the compound has low toxicity to animal cells and has the potential to become a drug. Molecular docking indicates that compound 4 can bind firmly to the Mtb KatG active site. The experimental results showed that compound 4 inhibited Mtb KatG and caused the accumulation of ROS in Mtb cells. We speculate that compound 4 causes the accumulation of ROS by inhibiting KatG, and ROS produces oxidative destruction, leading to the death of Mtb. This study provides a new idea for the development of novel anti-Mtb drugs.

MiR-506 targets polypyrimidine tract-binding protein 1 to inhibit airway inflammatory response and remodeling via mediating Wnt/ß-catenin signaling pathway.

BACKGROUND: Airway remodeling, which contributes to the clinical course of childhood asthma, occurs due to airway inflammation and is featured by anomalous biological behaviors of airway smooth muscle cells (ASMCs). microRNA (miRNA) plays an essential role in the etiopathogenesis of asthma. OBJECTIVE: This research was aimed to characterize miR-506 in asthma and uncover potential regulatory machinery. MATERIAL AND METHODS: The asthmatic cell model was established by treating ASMCs with transforming growth factor-beta1 (TGF-ß1) and assessed by the levels of interleukin (IL)-1ß and interferon gamma (IFN-γ). Using real-time quantitative polymerase chain reaction, mRNA expression of miR-506 and polypyrimidine tract-binding protein 1 (PTBP1) was measured. Cell counting kit-8 and Transwell migration tests were used for estimating the capacity of ASMCs to proliferate and migrate. Luciferase reporter assay was used to corroborate whether miR-506 was directly bound to PTBP1. Expression of PTBP1, collagen I and III, and essential proteins of the wingless-related integration (Wnt)/ß-catenin pathway (ß-catenin, c-MYC and cyclin D1) was accomplished by Western blot analysis. The involvement of Wnt/ß-catenin signaling in asthma was confirmed by Wnt signaling pathway inhibitor (IWR-1). RESULTS: miR-506 was poorly expressed in asthmatic tissues and cell model. Functionally, overexpression of miR-506 reduced aberrant proliferation, migration, inflammation and collagen deposition of ASMCs triggered by TGF-ß1. Mechanically, miR-506 directly targeted the 3' untranslated region (3-UTR) of PTBP1 and had a negative regulation on PTBP1 expression. Moreover, overexpression of miR-506 suppressed the induction of Wnt/ß-catenin pathway. The administration of IWR-1 further validated negative correlation between miR-506 and the Wnt/ß-catenin pathway in asthma. CONCLUSION: Our data indicated that targeting miR-506/PTBP1/Wnt/ß-catenin axis might point in a helpful direction for treating asthma in children.

Double/triple hit lymphoma in the gastrointestinal tract: clinicopathological features, PD-L1 expression and screening strategy.

We aimed to detect the clinicopathological features and immune microenvironment of double-hit/triple-hit lymphoma in the gastrointestinal tract (GI-DHL/THL) and identify the best diagnostic strategies. A total of 114 cases, including 15 GI-DHL/THL, 42 non-GI-DHL/THL and 57 control diffuse large B-cell lymphoma (DLBCL) cases, were comparatively analyzed for their clinicopathological characteristics, the expression of the immune-regulatory checkpoint PD-L1 and immune microenvironment. We applied univariate and multivariate analyses to determine predictors of DHL/THL. GI-DHL/THL patients showed a higher prevalence of previous infection with hepatitis B virus (HBV) than those with GI-DLBCL. Morphologically, 87% of cases exhibited features of DLBCL. Regarding immunohistochemistry results, the MYC protein expression and the Ki-67 proliferation index were significantly higher in the GI-DHL/THL group than in the GI-DLBCL group. The main source of PD-L1 expression in DHL was tumor-associated macrophages, whereas some tumor cells were positive for PD-L1 in GI-DLBCL cases, as determined through multiplex immunofluorescence staining. The multivariable logistic analysis suggested that 5 variables, namely, age, Mum1, CD10, MYC, and HBV infection status, reflect the risk of DHL/THL. The GI-DHL/THL group show different clinicopathological features and immune microenvironments from DLBCL, which might suggest that different signaling pathways are involved. More work is needed to elucidate the pathogenic mechanism of GI-DHL/THL.

Monitoring Bevacizumab-Induced Tumor Vascular Normalization by Intravoxel Incoherent Motion Diffusion-Weighted MRI.

BACKGROUND: Accurate monitoring of tumor blood vessel normalization progression is beneficial to accurate treatment of patients. At present, there is a lack of safe and noninvasive monitoring methods. PURPOSE: To serial monitor the vascular normalization time window of tumor antiangiogenesis treatment through intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) and histopathological methods. STUDY TYPE: Exploratory animal study. POPULATION: Sixty rat C6 glioma models were randomly and equally divided into the control groups (N = 30) and bevacizumab treatment groups (N = 30). Twenty-five for magnetic resonance imaging (MRI) and five for electron microscope testing in each group. FIELD STRENGTH/SEQUENCE: T1-weighted imaging (T1WI), T2WI with a fast spin echo sequence and IVIM-DWI with a spin-echo echo-planar imaging sequence at 3 T. ASSESSMENT: IVIM-DWI quantitative parameters (f, D, D*, and fD*) were obtained on days 0, 2, 4, 6, and 8 after bevacizumab treatment. After MRI, the microvessel density (MVD), pericyte coverage, and hypoxia-inducible factor-1α (HIF-1α) were assessed. Electron microscope observation was performed at each time point. STATISTICAL TESTS: One-way analysis of variance and Student's t-tests were used to compare differences within and between groups. Spearman's correlation coefficient (r) assess the correlation between IVIM and pathological parameters. The intragroup correlation coefficient was determined to assess the repeatability of each IVIM parameter. RESULTS: The IVIM-DWI perfusion parameters (f and fD*) of the treated group were higher than the control group on days 2 and 4. Compared to the control group, MVD decreased on days 2 and pericyte coverage increased on days 4 in the treatment group. Electron microscopy showed that the tight junctions of the treatment group were prolonged on days 2-4. In the control group, f had the highest correlation with MVD (r = 0.689). In the treated group, f had a good correlation with pericyte coverage (r = 0.557), HIF-1α had a moderately positive correlation with f (r = 0.480) and fD*(r = 0.447). DATA CONCLUSION: The vascular normalization time window of bevacizumab treatment of glioma was days 2-4 after antiangiogenesis treatment, which could be monitored noninvasively by IVIM-DWI. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.

AAV13 Enables Precise Targeting of Local Neural Populations.

As powerful tools for local gene delivery, adeno-associated viruses (AAVs) are widely used for neural circuit studies and therapeutical purposes. However, most of them have the characteristics of large diffusion range and retrograde labeling, which may result in off-target transduction during in vivo application. Here, in order to achieve precise gene delivery, we screened AAV serotypes that have not been commonly used as gene vectors and found that AAV13 can precisely transduce local neurons in the brain, with a smaller diffusion range than AAV2 and rigorous anterograde labeling. Then, AAV13-based single-viral and dual-viral strategies for sparse labeling of local neurons in the brains of C57BL/6 or Cre transgenic mice were developed. Additionally, through the neurobehavioral test in the ventral tegmental area, we demonstrated that AAV13 was validated for functional monitoring by means of carrying Cre recombinase to drive the expression of Cre-dependent calcium-sensitive indicator. In summary, our study provides AAV13-based toolkits for precise local gene delivery, which can be used for in situ small nuclei targeting, sparse labeling and functional monitoring.

Glioma grading, molecular feature classification, and microstructural characterization using MR diffusional variance decomposition (DIVIDE) imaging.

OBJECTIVE: To evaluate the potential of diffusional variance decomposition (DIVIDE) for grading, molecular feature classification, and microstructural characterization of gliomas. MATERIALS AND METHODS: Participants with suspected gliomas underwent DIVIDE imaging, yielding parameter maps of fractional anisotropy (FA), mean diffusivity (MD), anisotropic mean kurtosis (MKA), isotropic mean kurtosis (MKI), total mean kurtosis (MKT), MKA/MKT, and microscopic fractional anisotropy (µFA). Tumor type and grade, isocitrate dehydrogenase (IDH) 1/2 mutant status, and the Ki-67 labeling index (Ki-67 LI) were determined after surgery. Statistical analysis included 33 high-grade gliomas (HGG) and 17 low-grade gliomas (LGG). Tumor diffusion metrics were compared between HGG and LGG, among grades, and between wild and mutated IDH types using appropriate tests according to normality assessment results. Receiver operating characteristic and Spearman correlation analysis were also used for statistical evaluations. RESULTS: FA, MD, MKA, MKI, MKT, µFA, and MKA/MKT differed between HGG and LGG (FA: p = 0.047; MD: p = 0.037, others p < 0.001), and among glioma grade II, III, and IV (FA: p = 0.048; MD: p = 0.038, others p < 0.001). All diffusion metrics differed between wild-type and mutated IDH tumors (MKI: p = 0.003; others: p < 0.001). The metrics that best discriminated between HGG and LGGs and between wild-type and mutated IDH tumors were MKT and FA respectively (area under the curve 0.866 and 0.881). All diffusion metrics except FA showed significant correlation with Ki-67 LI, and MKI had the highest correlation coefficient (rs = 0.618). CONCLUSION: DIVIDE is a promising technique for glioma characterization and diagnosis. KEY POINTS: • DIVIDE metrics MKI is related to cell density heterogeneity while MKA and µFA are related to cell eccentricity. • DIVIDE metrics can effectively differentiate LGG from HGG and IDH mutation from wild-type tumor, and showed significant correlation with the Ki-67 labeling index. • MKI was larger than MKA which indicates predominant cell density heterogeneity in gliomas. • MKA and MKI increased with grade or degree of malignancy, however with a relatively larger increase in the cell eccentricity metric MKA in relation to the cell density heterogeneity metric MKI.

Factors associated with prognosis of dysembryoplastic neuroepithelial tumors patients after surgical resection: a retrospective observational study.

OBJECTIVE: To explore factors that might be associated with prognosis of dysembryoplastic neuroepithelial tumors (DNTs). METHODS: DNTs patients who were admitted to the Department of Neurosurgery of Xiangya Hospital between 1 January 2010 and 31 December 2018 and underwent surgical resection were retrospectively analyzed. Clinical, neuroimaging, and pathological features of DNTs were compared among patients with different outcomes and analyzed using the Kaplan-Meier curves and univariable Cox regression analysis. RESULTS: Thirty-three DNTs patients were included finally, of which the average age at seizure onset was 11.59 ± 7.46 years old and the average duration of seizures prior to surgical resection was 3.00 ± 4.68 years. After surgical resection, the patients were followed up for 2.39 ± 1.97 years, and 28 patients (84.85%) were seizure-free (class I of the Engel Outcome Scale) while five patients (15.15%) were seizure-continuous (class II or III of the Engel Outcome Scale). When compared with seizure-free patients, seizure-continuous patients had greater age at seizure onset and longer duration of seizures before surgical resection (p < .05). No variables were found to be statistically significantly associated with prognosis in univariable Cox regression analysis, but patients with extra-temporal DNTs were found to have better prognosis than those with temporal DNTs (log-rank test p = .048). CONCLUSIONS: Elder seizure onset age, longer duration of seizures prior to surgical resection, and a temporal location may be risk factors of poor prognosis for DNTs patients after surgical resection.

Efficacy and safety of vagus nerve stimulation in the treatment of refractory epilepsy. / è¿·èµ°ç¥žç»åˆºæ¿€æœ¯æ²»ç–—éš¾æ²»æ€§ç™«ç—«çš„ç–—æ•ˆå’Œå®‰å ¨æ€§.

OBJECTIVES: Vagus nerve stimulation (VNS) is a neuromodulative therapeutic technique for patients with drug-resistant epilepsy who are not suitable for resection or who have experienced a failed resection. This study aims to explore the efficacy and safety of VNS in patients with refractory epilepsy, and to analyze the influential factors for the efficacy. METHODS: A retrospective review of clinical data were conducted for 35 patients, who were treated for refractory epilepsy through VNS surgery in the Department of Neurosurgery, Xiangya Hospital, Central South University from April 2016 to August 2019. All patients were analyzed in terms of the clinical and follow-up data. RESULTS: After a mean follow-up of 26 months (6-47 months), outcome was as follows: 7 patients were MuHugh class I, 13 patients were MuHugh class II, 8 patients were MuHugh class III, and 7 patients were MuHugh class IV-V. The total efficacy rate in the short duration group was significantly higher than that in the long duration group (77.8% vs 50.0%, P=0.013), whereas different ages (P=0.382), gender (P=0.824), types of seizure (P=0.829), and MRI features (P=0.791) showed no correlation with efficacy. None patients developed permanent complication postoperatively. CONCLUSIONS: VNS is a safe and effective option in treating patients with refractory epilepsy, especially for those with short duration.

[Biological and epidemiological characteristics of the pathogen of hypertrophy sorosis scleroteniosis, Ciboria shiraiana].

Objective: We studied the biological and the epidemiological characteristics of the pathogen of hypertrophy sorosis scleroteniosis, which is a devastating fungal disease of mulberry. Methods: We studied the asexual and sexual reproductive phase stages of C. shiraiana, including the infection ability of hyphal, dormancy of sclerotia, the structures, release, number and germination of ascospores from apothecia, as well as the phenology of sclerotial germination. Results: In C. shiraiana, hyphae had no infection ability toward the female flowers of mulberry. Sclerotia of C. shiraiana must undergo cold treatment above 6 weeks, then the dormancy-breaking sclerotia could germinate to apothecia. One to fifteen apothecia were germinated from one sclerotium, and the number of ascospores in a 1.5 cm diameter apothecia could contain up to (5.6-6.3)×107. Ascospore C. shiraiana had significantly higher germination rates in acid than in neutral and alkaline environments. From late January to middle April, sclerotia germinated to apothecia, and got the highest value in the middle of March. Conclusion: C. shiraiana is a formidable pathogen to cause epidemic disease and damage in mulberry.

The dual effects of autophagy in myocardial hypertrophy.

Autophagy played a crucial role for survival when cells were suffering from nutrient deprivation, as autophagy could engulf and degenerate macromolecules to provide new nutrients and energy. Autophagy also plays an essential role in maintaining cellular homeostasis, which was activated in response to the cellular stresses in hypertensive heart disease. Interestingly, many studies had proven that the baseline and up-regulation of autophagy played a beneficial role in myocardial hypertrophy while other studies found that up-regulated autophagy was associated with myopathies. In this review, we showed the signalling pathways which were involved in myocardial hypertrophy. Besides, we talked about the protective as well as harmful effects of autophagy in myocardial hypertrophy. Finally, we proposed the possible reasons of dual effects of autophagy in hypertrophy, including the degree of the activation, the stage of the disease and the signalling pathways responsible for the activation of autophagy, etc.

Disseminated Acanthamoeba castellanii infection in a patient with AIDS: a case report and literature review.

Background: Acanthamoeba castellanii infection is a rare condition primarily occurring in immunocompromised patients with extremely high mortality. Currently, there is no standard treatment for this condition, and successful treatment reports are scarce. Case presentation: We present a case of Acanthamoeba castellanii infection in a 63-year-old female patient with AIDS, who was admitted to our hospital with symptoms of fever, skin ulcers, subcutaneous nodules, and food regurgitation from the nose while eating. After initial empirical treatment failed, a biopsy of the subcutaneous nodule was performed, and metagenomic next-generation sequencing (mNGS) technology was used to detect pathogenic microorganisms in both the biopsy specimen and blood samples. The results revealed Acanthamoeba castellanii infection. Additionally, histopathological examination of the biopsy specimen and cytological examination of the secretions from the ulcer surface also confirmed this pathogenic infection. The patient's symptoms significantly improved upon discharge after adjusting the treatment regimen to a combination of anti-amebic therapy. Conclusion: Immunocompromised patients presenting with unexplained fever and skin or sinus lesions should be evaluated for Acanthamoeba castellanii infection. Multi-drug combination therapy is required for this organism infection, and a standard treatment protocol still needs further research. Metagenomic next-generation sequencing is a valuable tool for early diagnosis of unknown pathogen infections.

19 Schiff bases as antimycobacterial agents: synthesis, molecular docking and a plausible mechanism of action.

Aim: To discover novel anti-Mycobacterium tuberculosis (Mtb) drugs, 19 compounds were synthesized; their anti-Mtb effects were evaluated and mechanisms of action were preliminarily explored. Materials & methods: The compounds were synthesized and their anti-Mtb activity was elucidated using resazurin microtiter assays. The plausible target of the potential compound was investigated by microimaging techniques, gas chromatography-mass spectrometry analysis and molecular docking. Results: 19 compounds inhibited Mtb growth with minimum inhibitory concentrations ranging from 1 to 32 µg/ml. Compounds 1-17 showed inhibition of Mtb KatG enzyme. Compound 19, the most potent, might be an inhibitor of Pks13 polyketide synthase. Conclusion: This study suggests that 2-((6-fluoropyridin-3-yl)methylene) hydrazine-1-carbothioamide (19) is a potential anti-Mtb lead compound with a novel mechanism of action.

Globally, more than 1.6 million people die of tuberculosis (TB) and about 11 million new cases occur each year. The emergence of drug-resistant Mycobacterium tuberculosis (Mtb) has made it difficult to effectively treat TB. Therefore, 19 drugs were synthesized and assayed in the laboratory to verify whether they could inhibit the growth of Mtb. All compounds exhibit anti-Mtb effects at relatively low concentrations. Among them, compound 19 had a strong anti-Mtb effect, and its bactericidal effect on Mtb even exceeded that of isoniazid. In addition, it was preliminarily determined that compound 19 is a novel inhibitor of a key enzyme in the biosynthesis of Mtb cell walls. These findings demonstrate a potential new treatment option for TB but more research is needed to confirm the safety of these drugs.

General anesthesia versus local anesthesia for deep brain stimulation targeting of STN in Parkinson's disease: A systematic review and meta-analysis.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) is a viable therapeutic for advanced Parkinson's disease. However, the efficacy and safety of STN-DBS under local anesthesia (LA) versus general anesthesia (GA) remain controversial. This meta-analysis aims to compare them using an expanded sample size. METHODS: The databases of Embase, Cochrane Library and Medline were systematically searched for eligible cohort studies published between 1967 and 2023. Clinical efficacy was assessed using either Unified Parkinson's Disease Rating Scale (UPDRS) section III scores or levodopa equivalent dosage requirements. Subgroup analyses were performed to assess complications (adverse effects related to stimulation, general neurological and surgical complications, and hardware-related complications). RESULTS: Fifteen studies, comprising of 13 retrospective cohort studies and 2 prospective cohort studies, involving a total of 943 patients were included in this meta-analysis. The results indicate that there were no significant differences between the 2 groups with regards to improvement in UPDRS III score or postoperative levodopa equivalent dosage requirement. However, subgroup analysis revealed that patients who underwent GA with intraoperative imaging had higher UPDRS III score improvement compared to those who received LA with microelectrode recording (MER) (P = .03). No significant difference was found in the improvement of UPDRS III scores between the GA group and LA group with MER. Additionally, there were no notable differences in the incidence rates of complications between these 2 groups. CONCLUSIONS: Our meta-analysis indicates that STN-DBS performed under GA or LA have similar clinical outcomes and complications. Therefore, GA may be a suitable option for patients with severe symptoms who cannot tolerate the procedure under LA. Additionally, the GA group with intraoperative imaging showed better clinical outcomes than the LA group with MER. A more compelling conclusion would require larger prospective cohort studies with a substantial patient population and extended long follow-up to validate.

Improving Molecule-Metal Surface Reaction Networks Using the Meta-Generalized Gradient Approximation: CO2 Hydrogenation.

Density functional theory is widely used to gain insights into molecule-metal surface reaction networks, which is important for a better understanding of catalysis. However, it is well-known that generalized gradient approximation (GGA) density functionals (DFs), most often used for the study of reaction networks, struggle to correctly describe both gas-phase molecules and metal surfaces. Also, GGA DFs typically underestimate reaction barriers due to an underestimation of the self-interaction energy. Screened hybrid GGA DFs have been shown to reduce this problem but are currently intractable for wide usage. In this work, we use a more affordable meta-GGA (mGGA) DF in combination with a nonlocal correlation DF for the first time to study and gain new insights into a catalytically important surface reaction network, namely, CO2 hydrogenation on Cu. We show that the mGGA DF used, namely, rMS-RPBEl-rVV10, outperforms typical GGA DFs by providing similar or better predictions for metals and molecules, as well as molecule-metal surface adsorption and activation energies. Hence, it is a better choice for constructing molecule-metal surface reaction networks.

Metagenomic next-generation sequencing-assisted diagnosis of a rare case of primary cutaneous acanthamoebiasis in an HIV patient: a case report.

Pathogenic and free-living Acanthamoeba are widely distributed in the environment and have been reported to cause keratitis and universally fatal encephalitis. Primary cutaneous acanthamoebiasis caused by Acanthamoeba is exceedingly rare and presents as isolated necrotic cutaneous lesions without involvement of the cornea or central nervous system. Cutaneous acanthamoebiasis often occurs in immunocompromised patients and is likely overlooked or even misdiagnosed only by cutaneous biopsy tissue histopathological analysis. Here, we report a HIV-infected 63-year-old female with oral leukoplakia for 4 months and scattered large skin ulcers all over the body for 2 months. The cause of the cutaneous lesions was unclear through cutaneous specimens histopathological analysis, and subsequently Acanthamoeba were detected by metagenomic next-generation sequencing (mNGS), which may be the cause of cutaneous lesions. Based on the mNGS results, a pathologist subsequently reviewed the previous pathological slides and found trophozoites of Acanthamoeba so that the cause was identified, and the skin ulcers improved significantly after treatment with multi-drug combination therapy. Acanthamoeba is also a host of pathogenic microorganisms. The presence of endosymbionts enhances the pathogenicity of Acanthamoeba, and no other pathogens were reported in this case. mNGS is helpful for rapidly diagnosing the etiology of rare skin diseases and can indicate the presence or absence of commensal microorganisms.

A systematic review of ginsenoside biosynthesis, spatiotemporal distribution, and response to biotic and abiotic factors in American ginseng.

American ginseng (Panax quinquefolius) has gained recognition as a medicinal and functional food homologous product with several pharmaceutical, nutritional, and industrial applications. However, the key regulators involved in ginsenoside biosynthesis, the spatiotemporal distribution characteristics of ginsenosides, and factors influencing ginsenosides are largely unknown, which make it challenging to enhance the quality and chemical extraction processes of the cultivated American ginseng. This review presents an overview of the pharmacological effects, biosynthesis and spatiotemporal distribution of ginsenosides, with emphasis on the impacts of biotic and abiotic factors on ginsenosides in American ginseng. Modern pharmacological studies have demonstrated that American ginseng has neuroprotective, cardioprotective, antitumor, antidiabetic, and anti-obesity effects. Additionally, most genes involved in the upregulation of ginsenoside biosynthesis have been identified, while downstream regulators (OSCs, CYP450, and UGTs) require further investigation. Futhermore, limited knowledge exists regarding the molecular mechanisms of the impact of biotic and abiotic factors on ginsenosides. Notably, the nonmedicinal parts of American ginseng, particularly its flowers, fibrous roots, and leaves, exhibit higher ginsenoside content than its main roots and account for a considerable amount of weight in the whole plant, representing promising resources for ginsenosides. Herein, the prospects of molecular breeding and metabolic engineering based on multi-omics to improve the unstable quality of cultivated American ginseng and the shortage of ginsenosides are proposed. This review highlights the gaps in the current research on American ginseng and proposes solutions to address these limitations, providing a guide for future investigations into American ginseng ginsenosides.

Combination of MRI-based prediction and CRISPR/Cas12a-based detection for IDH genotyping in glioma.

Early identification of IDH mutation status is of great significance in clinical therapeutic decision-making in the treatment of glioma. We demonstrate a technological solution to improve the accuracy and reliability of IDH mutation detection by combining MRI-based prediction and a CRISPR-based automatic integrated gene detection system (AIGS). A model was constructed to predict the IDH mutation status using whole slices in MRI scans with a Transformer neural network, and the predictive model achieved accuracies of 0.93, 0.87, and 0.84 using the internal and two external test sets, respectively. Additionally, CRISPR/Cas12a-based AIGS was constructed, and AIGS achieved 100% diagnostic accuracy in terms of IDH detection using both frozen tissue and FFPE samples in one hour. Moreover, the feature attribution of our predictive model was assessed using GradCAM, and the highest correlations with tumor cell percentages in enhancing and IDH-wildtype gliomas were found to have GradCAM importance (0.65 and 0.5, respectively). This MRI-based predictive model could, therefore, guide biopsy for tumor-enriched, which would ensure the veracity and stability of the rapid detection results. The combination of our predictive model and AIGS improved the early determination of IDH mutation status in glioma patients. This combined system of MRI-based prediction and CRISPR/Cas12a-based detection can be used to guide biopsy, resection, and radiation for glioma patients to improve patient outcomes.