Population pharmacokinetic modeling of ceftriaxone in cerebrospinal fluid in children: should we be using once- or twice-daily dosing for meningitis?

Guidelines for bacterial meningitis in children recommend intravenous ceftriaxone 50 mg/kg (max 2 g) twice daily (BD) or 100 mg/kg (max 4 g) once daily (OD), leaving the decision regarding the dose frequency to the prescriber. We investigated the cerebrospinal fluid (CSF) penetration of ceftriaxone to evaluate whether one dosing regimen is superior. Unbound ceftriaxone concentrations were measured in serum and CSF samples from children aged 0-18 years treated with ceftriaxone if there was a sample remaining after clinical tests were performed. A serum-CSF population pharmacokinetic model was developed using non-linear mixed-effects modeling. The once- and twice-daily dosing regimens were simulated, and the probability of target attainment (PTA) was determined for maintaining a CSF concentration above a minimum inhibitory concentration (MIC) of 1 mg/L for common meningitis pathogens and 4 mg/L for Staphylococcus aureus for 100% of the dosing interval. Sixteen serum and 87 CSF samples were collected from 98 children (age range 0.1-18.5 years). The final two-compartment serum-CSF model included a renal maturation function with weight scaling on clearance and volume of distribution. The estimated serum:CSF uptake was 20.1%. For MIC 1 mg/L, the 24 h PTA was higher for OD (88%) compared with BD (53%) dosing, although both achieved a 100% PTA at steady state. For S. aureus (MIC 4 mg/L), neither dosing regimen was sufficient. Our findings support the use of a 100 mg/kg once daily regimen for empirical treatment of bacterial meningitis due to earlier achievement of the pharmacodynamic target. Neither dosing regimen was adequate for S. aureus meningitis.

Safety and efficacy of odronextamab in patients with relapsed or refractory follicular lymphoma.

BACKGROUND: Odronextamab, a CD20×CD3 bispecific antibody that engages cytotoxic T cells to destroy malignant B cells, has demonstrated encouraging activity across multiple subtypes of relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma. PATIENTS AND METHODS: This phase II study (ELM-2; NCT03888105) evaluated odronextamab in patients with R/R follicular lymphoma after two or more lines of systemic therapy. Patients received intravenous odronextamab in 21-day cycles, with step-up dosing in cycle 1 to help mitigate the risk of cytokine release syndrome, until disease progression or unacceptable toxicity. The primary endpoint was objective response rate by independent central review. RESULTS: Among 128 patients evaluated, 95% completed cycle 1, and 85% completed four or more cycles. At 20.1 months' efficacy follow-up, objective response rate was 80.0% and complete response rate was 73.4%. Median duration of complete response was 25.1 months. Median progression-free survival was 20.7 months, and median overall survival was not reached. Discontinuation of odronextamab due to adverse events occurred in 16% of patients. The most common treatment-emergent adverse events were cytokine release syndrome [56%; grade ≥3 1.7% (1/60) with 0.7/4/20 mg step-up], neutropenia (39%), and pyrexia (38%). CONCLUSIONS: Odronextamab achieved high complete response rates with generally manageable safety in patients with heavily pretreated R/R follicular lymphoma.

Neoadjuvant short-course radiotherapy followed by camrelizumab and chemotherapy in locally advanced rectal cancer (UNION): early outcomes of a multicenter randomized phase III trial.

BACKGROUND: Neoadjuvant short-course radiotherapy (SCRT) followed by CAPOX and camrelizumab (a programmed cell death protein 1 monoclonal antibody) has shown potential clinical activity for locally advanced rectal cancer (LARC) in a phase II trial. This study aimed to further confirm the efficacy and safety of SCRT followed by CAPOX and camrelizumab compared to long-course chemoradiotherapy (LCRT) followed by CAPOX alone as neoadjuvant treatment for LARC. PATIENTS AND METHODS: In this randomized, phase III trial, patients with T3-4/N+ rectal adenocarcinoma were randomly assigned (1 : 1) to receive SCRT or long-course chemoradiotherapy (LCRT), followed by two cycles of camrelizumab and CAPOX or CAPOX alone, respectively. After surgery, each arm underwent either six cycles of camrelizumab and CAPOX, followed by up to 17 doses of camrelizumab, or six cycles of CAPOX. The primary endpoint was pathological complete response (pCR) rate (ypT0N0) assessed by a blinded independent review committee. Key secondary endpoints tested hierarchically were 3-year event-free survival (EFS) rate and overall survival (OS). RESULTS: Between July 2021 and March 2023, the intention-to-treat population comprised 113 patients in the experimental arm and 118 patients in the control arm, with surgery carried out in 92% and 83.9%, respectively. At data cut-off (11 July 2023), the pCR rates were 39.8% [95% confidence interval (CI) 30.7% to 49.5%] in the experimental arm compared to 15.3% (95% CI 9.3% to 23.0%) in the control arm (difference, 24.6%; odds ratio, 3.7; 95% CI 2.0-6.9; P < 0.001). In each arm, surgical complication rates were 40.0% and 40.8%, and grade ≥3 treatment-related adverse events were 29.2% and 27.2%. Three-year EFS rate and OS continue to mature. CONCLUSIONS: In LARC patients, neoadjuvant SCRT followed by camrelizumab plus CAPOX demonstrated a significantly higher pCR rate than LCRT followed by CAPOX, with a well-tolerated safety profile. SCRT followed by camrelizumab and chemotherapy can be recommended as a neoadjuvant treatment modality for these patients.

Generation of attosecond electron bunches of tunable duration and density by relativistic vortex lasers in near-critical density plasma.

Attosecond electron bunches have wide application prospects in free-electron laser injection, attosecond X/γ-ray generation, ultrafast physics, etc. Nowadays, there is one notable challenge in the generation of high-quality attosecond electron bunch, i.e., how to enhance the electron bunch density. Using theoretical analysis and three-dimensional particle-in-cell simulations, we discovered that a relativistic vortex laser pulse interacting with near-critical density plasma can not only effectively concentrate the attosecond electron bunches to over critical density, but also control the duration and density of the electron bunches by tuning the intensity and carrier-envelope phase of the drive laser. It is demonstrated that this method can efficiently produce attosecond electron bunches with a density up to 300 times of the original plasma density, peak divergence angle of less than 0.5 ∘, and duration of less than 67 attoseconds. Furthermore, by using near-critical density plasma instead of solid targets, our scheme is potential for the generation of high-repetition-frequency attosecond electron bunches, thus reducing the requirements for experiments, such as the beam alignment or target supporter.

Early-Time Harmonic Generation from a Single-Mode Perturbation Driven by X-Ray Ablation.

X-ray ablation dynamics of the planar foil with preimposed sinusoidal ripples is investigated at the SG 100 kJ Laser Facility. A significant fraction of the second harmonics is observed and identified at the beginning of the ablative drive when the amplitude of the perturbation is within the linear regime. With radiation-hydrodynamic simulations and a developed simple model, we can reveal that such a novel phenomenon is due to the fact that a sustained deformation of the ablation front is initiated since the ablation pressure is directed to the normal direction of the perturbation surface. We find that this deformation dominates the early-time perturbation evolution and results in a specific stage in addition to the traditional ablative Richtmyer-Meshkov instability phase. Our results can be applicable to various regions such as implosions in inertial confinement fusion and the dynamics of molecular clouds in astrophysics.

Intratumoural and peritumoural CT-based radiomics for diagnosing lepidic-predominant adenocarcinoma in patients with pure ground-glass nodules: a machine learning approach.

AIM: To develop and validate a diagnostic model utilising machine-learning algorithms that differentiates lepidic predominant adenocarcinoma (LPA) from other pathological subtypes in patients with pure ground-glass nodules (pGGNs). MATERIALS AND METHODS: This bicentric study was conducted across two medical centres and included 151 patients diagnosed with lung adenocarcinoma based on histopathological confirmation of pGGNs. The training cohort consisted of 99 patients from Institution 1, while the test cohort included 52 patients from Institution 2. Radiomics features were extracted from both tumours and the 2 mm peritumoural parenchyma. The tumoural and peritumoural radiomics were designated as Modeltumoural and Modelperitumoural, respectively. The diagnostic efficacy of various models was evaluated through the receiver operating characteristic (ROC) curve analysis. Subsequently, a machine-learning-based prediction model that combined Modeltumoural, Modelperitumoural, and Modelclinical-radiological was developed to differentiate LPA from other pathological subtypes in patients with pGGNs. RESULTS: Modeltumoural achieved area under the curve (AUC) values of 0.762 and 0.783 in the training and validation sets, respectively. Modelperitumoural attained AUCs of 0.742 and 0.667, and Modelclinical-radiological generated an AUC of 0.727 and 0.739 in the training and validation sets, respectively. Among the machine-learning models evaluated, gradient boosting machines demonstrated the best diagnostic efficacy, with accuracy, AUC, F1 score, and log loss values of 0.885, 0.956, 0.943, and 0.260, respectively. CONCLUSION: The combined model based on machine learning that incorporated tumour and peritumoural parenchyma, as well as clinical and imaging characteristics, may offer benefits in assessing the pathological subtype of pGGNs.

Value of spectral CT parameters in predicting the efficacy of neoadjuvant chemotherapy for gastric cancer.

AIM: To investigate the value of pre-chemotherapy spectral computed tomography (CT) parameters in predicting neoadjuvant chemotherapy (NAC) response in gastric cancer (GC). MATERIALS AND METHODS: Sixty patients with GC who received NAC and underwent spectral CT examination before chemotherapy were enrolled retrospectively and divided into a responsive group and a non-responsive group according to the postoperative pathological tumour regression grade. Clinical characteristics were collected. The iodine concentration (IC), water concentration (WC), and effective atomic number (Eff-Z) of the portal venous phases were measured before chemotherapy, and IC was normalised to that of the aorta to provide the normalised IC (NIC). An independent samples t-test, Mann-Whitney U-test, or chi-square test was used to analyse the differences between the two groups, and the receiver operating curve (ROC) was used to evaluate the predictive performance of different variables. RESULTS: The neutrophil-to-lymphocyte ratio (NLR) was lower in the responsive group than in the non-responsive group (p<0.05). IC, NIC, and Eff-Z values were significantly higher in the responsive group than in the non-responsive group (p<0.01). The areas under the ROC curves for the NLR, IC, NIC, and Eff-Z were 0.694, 0.688, 0.799, and 0.690, respectively. The combination of NIC, Eff-Z, and NLR values showed good diagnostic performance in predicting response to NAC in GC, with an area under the ROC curve of 0.857, 76.92% sensitivity, 80% accuracy, and 85.71% specificity. CONCLUSION: Spectral CT parameters may serve as non-invasive tools for predicting the response to NAC in patients with GC.

Metabolic habitat imaging with hemodynamic heterogeneity predicts individual progression-free survival in high-grade glioma.

AIM: We design a feasibility study to obtain a set of metabolic-hemodynamic habitats for tackling tumor spatial metabolic patterns with hemodynamic information. MATERIALS AND METHODS: Preoperative data from 69 high-grade gliomas (HGG) patients with subsequent histologic confirmation of HGG were prospectively collected (January 2016 to March 2020) after concurrent chemoradiotherapy (CCRT). Four vascular habitats were automatically segmented by multiparametric magnetic resonance imaging (MRI). The metabolic information, either at enhancing or edema tumor regions, was obtained by two neuroradiologists. The relative habitat volumes were used for weight estimation procedures for computing the coefficients of a linear regression model using weighted least squares (WLS) for metabolite semiquantifications (i.e. the Cho/NAA ratio and the Cho/Cr ratio) at vascular habitats. Multivariate Cox proportional hazard regression analyses are used to obtain the odds ratio (OR) and develop a nomogram using weighted estimators corresponding to each covariate derived from Cox regression coefficients. RESULTS: There was a strongly correlation between perfusion indexes and the Cho/Cr ratio (rCBV, r=0.71) or Cho/NAA ratio (rCBV, r=0.66) at high-angiogenic enhancing tumor habitats (HAT) habitat. Compared isocitrate dehydrogenase (IDH) mutation to their wild type, the IDH wild type had significantly decreased Cho/Cr ratio (IDH mutation: Cho/Cr ratio = 2.44 ± 0.33, IDH wildtype: Cho/Cr ratio = 2.66 ± 0.36, p=0.02) and Cho/NAA ratio (IDH mutation: Cho/Cr ratio = 4.59 ± 0.61, IDH wildtype: Cho/Cr ratio = 4.99 ± 0.66, p=0.022) at the HAT. The C-index for the median progression-free survival (PFS) prediction was 0.769 for the Cho/NAA nomogram and 0.747 for the Cho/Cr nomogram through 1000 bootstrapping validation. CONCLUSIONS: Our findings suggest that spatial metabolism combined with hemodynamic heterogeneity is associated with individual PFS to HGG patients post-CCRT.

MRI radiomics for predicting intracranial progression in non-small-cell lung cancer patients with brain metastases treated with epidermal growth factor receptor tyrosine kinase inhibitors.

AIM: To identify clinical and magnetic resonance imaging (MRI) radiomics predictors specialised for intracranial progression (IP) after first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment in non-small-cell lung cancer (NSCLC) patients with brain metastases (BMs). MATERIALS AND METHODS: Seventy EGFR-mutated NSCLC patients with a total of 212 BMs who received first-line EGFR-TKI therapy were enrolled. Radiomics features were extracted from the BM regions on the pretreatment contrast-enhanced T1-weighted images, and the radiomics score (rad-score) of each BM was established based on the selected features. Furthermore, the mean rad-score derived from the average rad-score of all included BMs in each patient was calculated. Univariate and multivariate logistic regression analyses were performed to identify potential predictors of IP. Prediction models based on different predictors and their combinations were constructed, and nomogram based on the optimal prediction model was evaluated. RESULTS: Thirty-three (47.1 %) patients developed IP, and the remaining 37 (52.9 %) patients were IP-free. EGFR-19del mutation (OR 0.19, 95 % CI 0.05-0.69), third-generation TKI treatment (OR 0.33, 95 % CI 0.16-0.67) and mean rad-score (OR 5.71, 95 % CI 1.65-19.68) were found to be independent predictive factors. Models based on these three predictors alone and in combination (combined model) achieved AUCs of 0.64, 0.64, 0.74, and 0.86 and 0.64, 0.64, 0.75, and 0.84 in the training and validation sets, respectively, and the combined model demonstrated optimal performance for predicting IP. CONCLUSIONS: The model integrating EGFR-19del mutation, third-generation TKI treatment and mean rad-score had good predictive value for IP after EGFR-TKI treatment in NSCLC patients with BM.

Multimodel habitats constructed by perfusion and/or diffusion MRI predict isocitrate dehydrogenase mutation status and prognosis in high-grade gliomas.

AIM: To determine whether tumour vascular and cellular heterogeneity of high-grade glioma (HGG) is predictive of isocitrate dehydrogenase (IDH) mutation status and overall survival (OS) by using tumour habitat-based analysis constructed by perfusion and/or diffusion magnetic resonance imaging (MRI). MATERIALS AND METHODS: Seventy-eight HGG patients that met the 2021 World Health Organization WHO Classification of Tumors of the Central Nervous System, 5th edition (WHO CNS5), were enrolled to predict IDH mutation status, of which 32 grade 4 patients with unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter were enrolled for prognostic analysis. The deep-learning-based model nnU-Net and K-means clustering algorithm were applied to construct the Traditional Habitat, Vascular Habitat (VH), Cellular Density Habitat (DH), and their Combined Habitat (CH). Quantitative parameters were extracted and compared between IDH-mutant and IDH-wild-type patients, respectively, and the prediction potential was evaluated by receiver operating characteristic (ROC) curve analysis. OS was analysed using Kaplan-Meier survival analysis and the log-rank test. RESULTS: Compared with IDH-mutants, median relative cerebral blood volume (rCBVmedian) values in the whole enhancing tumour (WET), VH1, VH3, CH1-4 habitats were significantly increased in IDH-wild-type HGGs (all p<0.05). Additionally, the accuracy of rCBVmedian values in CH1 outperformed other habitats in identifying IDH mutation status (p<0.001) at a cut-off value of 4.83 with AUC of 0.815. Kaplan-Meier survival analysis highlighted significant differences in OS between the populations dichotomised by the median of rCBVmedian in WET, VH1, CH1-3 habitats (all p<0.05). CONCLUSIONS: The habitat imaging technique may improve the accuracy of predicting IDH mutation status and prognosis, and even provide a new direction for subsequent personalised precision treatment.

Targeted long-read sequencing for comprehensive detection of CYP21A2 mutations in patients with 21-hydroxylase deficiency.

BACKGROUND: 21-Hydroxylase deficiency (21-OHD) is caused by pathogenic CYP21A2 variations. CYP21A2 is arranged in tandem with its highly homologous pseudogene CYP21A1P; therefore, it is prone to mismatch and rearrangement, producing different types of complex variations. There were few reports on using only one method to detect different CYP21A2 variants simultaneously. AIMS: Targeted long-read sequencing method was used to detect all types of CYP21A2 variants in a series of patients with 21-OHD. METHODS: A total of 59 patients with 21-OHD were enrolled from Peking Union Medical College Hospital. Long-range locus-specific PCR and long-read sequencing (LRS) were performed to detect the pathogenic variants in CYP21A2. RESULTS: Copy-number variants of CYP21A2 were found in 25.4% of patients, including 5.1% with 3 copies of CYP21A2, 16.9% with 1 copy of CYP21A2, and 3.4% with 0 copy of CYP21A2. The remaining 74.6% of patients had 2 copies of CYP21A2. Pathogenic variants were identified in all 121 alleles of 59 patients. Specifically, single-nucleotide variants and small insertions/deletions (< 50 bp) were detected in 79 alleles, of which conversed from CYP21A1P were detected in 63 alleles, and rare variants were found in the other 16 alleles. Large gene conversions (> 50 bp) from pseudogene were detected in 10 alleles, and different chimeric genes (CYP21A1P/CYP21A2 or TNXA/TNXB) formed by large deletions were detected in 32 alleles. Of all variants, p.I173N was the most common variant (19.0%). CONCLUSIONS: Our study demonstrated that targeted long-read sequencing is a comprehensive method for detecting CYP21A2 variations, which is helpful for genetic diagnosis in 21-OHD patients.

Single-cell and bulk RNA sequencing reveal heterogeneity and diagnostic markers in papillary thyroid carcinoma lymph-node metastasis.

PURPOSE: Papillary thyroid carcinoma (PTC) is characterized by lymph-node metastasis (LNM), which affects recurrence and prognosis. This study analyzed PTC LNM by single-cell RNA sequencing (scRNA-seq) data and bulk RNA sequencing (RNA-seq) to find diagnostic markers and therapeutic targets. METHODS: ScRNA-seq data were clustered and malignant cells were identified. Differentially expressed genes (DEGs) were identified in malignant cells of scRNA-seq and bulk RNA-seq, respectively. PTC LNM diagnostic model was constructed based on intersecting DEGs using glmnet package. Next, PTC samples from 66 patients were used to validate the two most significant genes in the diagnostic model, S100A2 and type 2 deiodinase (DIO2) by quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and immunohistochemical (IHC). Further, the inhibitory effect of DIO2 on PTC cells was verified by cell biology behavior, western blot, cell cycle analysis, 5-ethynyl-2'-deoxyuridine (EdU) assay, and xenograft tumors. RESULTS: Heterogeneity of PTC LNM was demonstrated by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis. A total of 19 differential genes were used to construct the diagnostic model. S100A2 and DIO2 differ significantly at the RNA (p < 0.01) and protein level in LNM patient tissues (p < 0.001). And differed in PTC tissues with different pathologic typing (p < 0.001). Further, EdU (p < 0.001) and cell biology behavior revealed that PTC cells overexpressed DIO2 had reduced proliferative capacity. Cell cycle proteins were reduced and cells are more likely to be stuck in G2/M phase (p < 0.001). CONCLUSIONS: This study explored the heterogeneity of PTC LNM using scRNA-seq. By combining with bulk RNA-seq data, diagnostic markers were explored and the model was established. Clinical diagnostic efficacy of S100A2 and DIO2 was validated and the treatment potential of DIO2 was discovered.

The environmental and socioeconomic effects of tuberculosis patients in the southwest of China: a population-based study.

OBJECTIVE: The objective of this study was to assess the incidence of tuberculosis (TB) and find the risk factors of TB patients with a high burden of TB in socioeconomic level, the high level of TB incidence and the great changes of economic and social factors, explore the possible factors, construct scientific and robust prediction model, and analyse whether the task of stopping TB can be accomplished by the expected global deadline. STUDY DESIGN: This was an ecological study. METHODS: Descriptive analysis, spatial and space-time scan, correlation analysis, and regression analysis were carried out, based on cases of TB in Sichuan Province and ecological data from 2006 to 2017, to explore the characters of TB and ecological factors, using the transfer function-noise model to forecast the trend of TB until 2035. RESULTS: Factors affecting the incidence of TB, increasing per capita green area, reporting status of TB among Tibetans and Yi minorities, comprehensive treatment management, total cost of TB per capita for urban residents, proportion of males with high school education, 20 to 20 h of 24-h accumulated precipitation, reducing HIV at the same time as AIDS deaths, the increase in the proportion of males in junior high school education, and the increase in the number of registered TB cases can reduce the incidence of TB. CONCLUSIONS: There was concentration mainly on enhanced control of the environment and society measures, helpful in guiding government planning to control TB. Reinforcement is required to reduce the TB of population aged 15-24 and aged 25-64 in socioeconomic level by 2035.

Clinical application of endoscopic submucosal dissection for superficially invasive squamous cell carcinoma/high-grade squamous intraepithelial lesion involving the canal anal.

BACKGROUND: Superficially invasive squamous cell carcinoma (SISCC) and high-grade squamous intraepithelial lesions (HSIL) involving the anal canal are rare, and their surgical management involves local excision. Endoscopic submucosal dissection (ESD) has recently emerged as a promising treatment. This study aimed to evaluate the feasibility and safety of ESD for SISCC and HSIL in the anal canal. METHODS: All patients diagnosed with SISCC or HSIL in the anal canal who underwent ESD between November 2018 and May 2023 were included. Patient age, sex, pathology, human immunodeficiency virus (HIV) status, human papillomavirus (HPV) status, T stage, en bloc rate, and R0 resection rate were analyzed. RESULTS: Ten patients, including two men and eight women, with a median age of 61 (51-68) years were enrolled. All patients were HIV-negative, but five (50%) were HPV-positive. Pathological examination showed tumor stage of two patients as T2, one as T0 of SISCC, and seven as Tis of HSIL. The median specimen and tumor sizes were 24 (6-65) mm and 18 (6-55) mm, respectively. The en bloc and R0 resection rates were 100% and 80%, respectively. No severe complications occurred and no recurrence was observed at the follow-up (median follow-up period, 9 (1-35) months). CONCLUSIONS: ESD is a reliable and minimally invasive procedure that enables more individualized treatment options for specific groups. As we were limited by the length of the observation period, the long-term performance of ESD for SISCC and HSIL involving the anal canal requires further investigation.

Evidence for a role of metformin in preventing olfactory dysfunction among older adults.

BACKGROUND: Olfactory dysfunction (OD) is increasingly recognized as a hallmark of unhealthy aging and is intimately associated with mortality, but therapies remain elusive. Recognizing the increased prevalence of OD in individuals with diabetes, and the potential anti-aging effects of metformin, we studied the association of metformin use with OD. METHODS: Cross-temporal study of participants from Waves 2 (2010-11) and 3 (2015-16) of the National Social Life, Health, and Aging Project (NSHAP), a nationally representative cohort study of community-dwelling older adults. We included participants with diabetes who had complete data on olfaction and relevant covariates at Wave 2 and were not lost to follow-up at Wave 3. Olfactory identification (OI), the ability to identify the odorant, and olfactory sensitivity (OS), the ability to detect the presence of an odorant, were tested. Weighted multivariable logistic regression was used to study the association between metformin use at Wave 2 (baseline) and odds of having impaired OI/OS at Wave 3, adjusted for age, sex, race/ethnicity, education, smoking, BMI, HbA1c, years since diabetes diagnosis, and insulin use. RESULTS: Among 228 participants with diabetes (mean age=70 years, 53% female, 21% Black), 112 (49%) used metformin at baseline. Relative to nonusers, users had 58% lower odds of impaired OI and 67% lower odds of impaired OS at Wave 3. Among participants with normal baseline OS (N=62), users had 97% lower odds of impaired OS at Wave 3. CONCLUSIONS: Metformin use is associated with lower odds of OD among individuals with diabetes, suggesting a potential protective effect on olfaction. Future work including a larger sample and additional information on metformin use is needed to establish whether these findings are independent of diabetic control.

Antiviral effect of palmatine against infectious bronchitis virus through regulation of NF-κB/IRF7/JAK-STAT signalling pathway and apoptosis.

1. Infectious bronchitis virus (IBV), a gamma-coronavirus, can infect chickens of all ages and leads to an acute contact respiratory infection. This study evaluated the anti-viral activity of palmatine, a natural non-flavonoid alkaloid, against IBV in chicken embryo kidney (CEK) cells.2. The half toxic concentration (CC50) of palmatine was 672.92 µM, the half inhibitory concentration (IC50) of palmatine against IBV was 7.76 µM and the selection index (SI) was 86.74.3. Mode of action assay showed that palmatine was able to directly inactivate IBV and inhibited the adsorption, penetration and intracellular replication of IBV.4. Palmatine significantly upregulated TRAF6, TAB1 and IKK-ß compared with the IBV-infected group, leading to the increased expressions of pro-inflammatory cytokines IL-1ß and TNF-α in the downstream NF-κB signalling pathway.5. Palmatine significantly up-regulated the levels of MDA5, MAVS, IRF7, IFN-α and IFN-ß in the IRF7 pathway, inducing type I interferon production. It up-regulated the expression of 2'5'-oligoadenylate synthase (OAS) in the JAK-STAT pathway.6. IBV infection induced cell apoptosis and palmatine-treatment delayed the process of apoptosis by regulation of the expression of apoptosis-related genes (BAX, BCL-2, CASPASE-3 and CASPASE-8).7. Palmatine could exert anti-IBV activity through regulation of NF-κB/IRF7/JAK-STAT signalling pathways and apoptosis, providing a theoretical basis for the utilisation of palmatine to treat IBV infection.

Disturbance of mitochondrial dynamics in myocardium of broilers with pulmonary hypertension syndrome.

1. The following study investigated the relationship between pulmonary hypertension syndrome (PHS) and mitochondrial dynamics in broiler cardiomyocytes.2. An animal model for PHS was established by injecting broiler chickens with CM-32 cellulose particles. Broiler myocardial cells were cultured under hypoxic conditions to establish an in vitro model. The ascites heart index, histomorphology, mitochondrial ultrastructure, and mitochondrial dynamic-related gene and protein expression were evaluated.3. The myocardial fibres from PHS broilers had wider spaces and were wavy and twisted and the number of mitochondria increased. Compared with the control group, the gene and protein expression levels were decreased for Opa1, Mfn1, and Mfn2 in the myocardium of PHS broilers. The gene and protein expression was significantly increased for Drp1 and Mff.4. This study showed that PHS in broilers may cause myocardial mitochondrial dysfunction, specifically by diminishing mitochondrial fusion and enhancing fission, causing disturbances in the mitochondrial dynamics of the heart.

Supplementing pigeon grit with acidifier improves metabolism and the reproductive performance of breeding pigeons as well as the development of growth performance of squabs.

1. This study evaluated the effectiveness of different types of acidifiers on reproductive performance, body weight loss and plasma biochemical indices of breeding pigeons as well as on growth performance, carcass characteristics, meat quality and plasma biochemical indices of squabs.2. In a 45 d trial, 144 pairs of European white Mimas pigeons were selected and randomly divided into three experimental groups. Three groups of pigeons were fed plain pigeon grit (NC), pigeon grit supplemented with 5% single acidifier (SAG) and pigeon grit supplemented with 5% combined acidifiers (CAG).3. Supplementing with SAG and CAG significantly increased the weight gain in male pigeons from 1-12 d of incubation. However, SAG and CAG had no significant effect on the feed intake of breeding pigeons during incubation, but significantly increased total feed intake of breeding pigeons during the lactation period. Breeder pigeons fed SAG and CAG had significantly higher egg-laying rate at 40 d. In addition, feeding SAG and CAG significantly increased growth rate and slaughter weight of squabs, but SAG reduced the diameter of pectoral muscle fibres. Biochemical indices showed that feeding SAG and CAG improved metabolism and increased the liver function of breeder pigeons and squabs.4. In conclusion, supplementing pigeon grit with acidifiers increased feed intake of breeding pigeons during lactation, protected liver function, enhanced reproductive performance and promoted the growth and development of squabs.

Supplementation with single acidifier and combined acidifier is healthy for both breeding pigeons and squabs.Supplementation with single acidifier and combined acidifier can improve the egg-laying rate of breeding pigeons.Supplementation with single acidifier and combined acidifier can improve the growth rate of squabs.Supplementation single acidifier and combined acidifier helps to protect the liver and reduce liver damage of breeding pigeons and squabs.

[The efficacy and safety of computed tomography-guided percutaneous cryoablation for malignant liver tumors at high-risk sites].

Objective: To assess the efficacy and safety of computed tomography (CT)-guided percutaneous cryoablation in treating malignant liver tumors located explicitly at high-risk sites. Methods: Data were collected retrospectively from patients with malignant liver tumors undergoing percutaneous cryoablation at Tianjin Medical University Cancer Hospital between January 2018 and December 2021. In all, 46 patients with malignant liver tumors at non-high-risk sites were matched 1∶1 according to the maximum tumor diameter. Technical success rate, complete ablation rate, and complications at 12 and 24 months post-surgery were evaluated. A statistical analysis of the ablation effect difference between the high-risk site and non-high-risk site groups was conducted. Univariate and multivariate logistic regression analyses were performed to identify risk factors. Results: Both groups demonstrated a 100% intraoperative technical success rate, and no major complications related to cryoablation were observed. The complete ablation rate was 82.6% (38/46) and 71.7% (33/46) in the high-risk group and 84.8% (39/46) and 73.9% (34/46) in the non-high-risk group at 12 and 24 months, respectively. There was no significant difference in complete ablation rates between the two groups (P>0.05). Multivariate analysis identified the distance between the tumor edge and high-risk site ≤5 mm and preoperative trans-arterial chemoembolization (TACE) treatment as independent risk factors for cryoablation effect. Conclusion: CT-guided percutaneous cryoablation is a safe and effective approach for patients with malignant liver tumor at high-risk sites. Our results emphasize the importance of proper preoperative planning and intraoperative manipulation.

[The 504th case: Multiple lymph node enlargement, renal insufficiency, blindness, and white matter lesions of the brain].

A 65-year-old male patient was admitted for recurrent lymph node enlargement for 5 years and elevated creatinine for 6 months. This patient was diagnosed with angioimmunoblastic T-cell lymphoma 5 years ago and underwent multiple lines of anti-tumor therapy, including cytotoxic chemotherapy; epigenetic modifying drugs such as chidamide and azacitidine; the immunomodulator lenalidomide; and targeted therapy such as rituximab, a CD20-targeting antibody, and brentuximab vedotin, which targets CD30. Although the tumor was considered stable, multiple virus activation (including BK virus, JC virus, and cytomegalovirus) accompanied by the corresponding organ damage (polyomavirus nephropathy, cytomegalovirus retinitis, and progressive multifocal leukoencephalopathy) occurred during anti-tumor treatment. Anti-tumor therapy was suspended and ganciclovir was used. The serum viral load decreased and organ functions were stabilized. The purpose of this report was to raise clinicians' awareness of opportunistic virus reactivation during anti-tumor treatment.