Cell competition constitutes a barrier for interspecies chimerism.

Cell competition involves a conserved fitness-sensing process during which fitter cells eliminate neighbouring less-fit but viable cells1. Cell competition has been proposed as a surveillance mechanism to ensure normal development and tissue homeostasis, and has also been suggested to act as a barrier to interspecies chimerism2. However, cell competition has not been studied in an interspecies context during early development owing to the lack of an in vitro model. Here we developed an interspecies pluripotent stem cell (PSC) co-culture strategy and uncovered a previously unknown mode of cell competition between species. Interspecies competition between PSCs occurred in primed but not naive pluripotent cells, and between evolutionarily distant species. By comparative transcriptome analysis, we found that genes related to the NF-κB signalling pathway, among others, were upregulated in less-fit 'loser' human cells. Genetic inactivation of a core component (P65, also known as RELA) and an upstream regulator (MYD88) of the NF-κB complex in human cells could overcome the competition between human and mouse PSCs, thereby improving the survival and chimerism of human cells in early mouse embryos. These insights into cell competition pave the way for the study of evolutionarily conserved mechanisms that underlie competitive cell interactions during early mammalian development. Suppression of interspecies PSC competition may facilitate the generation of human tissues in animals.

Prognostic significance of PET/CT and its association with immuno-genomic profiling in oesophageal squamous cell carcinoma treated with immunotherapy plus chemoradiotherapy: results from a phase II study.

BACKGROUND: A phase II trial (EC-CRT-001) demonstrated the promising efficacy of combining toripalimab (an anti-PD-1 antibody) with definitive chemoradiotherapy (CRT) for locally advanced oesophageal squamous cell carcinoma (ESCC). Biomarkers are key to identifying patients who may benefit from this therapeutic approach. METHODS: Of the 42 patients with ESCC who received toripalimab combined with definitive CRT, 37 were included in this analysis. Baseline assessments included PET/CT metabolic parameters (SUVmax, SUVmean, SUVpeak, MTV, and TLG), RNA sequencing of tumour biopsies to quantify the tissue mutational burden (TMB), and multiplex immunofluorescence staining to estimate immune cell infiltration in the tumour microenvironment (TME). Frozen neoplastic samples were procured for RNA sequencing to further explore the immune-related TME. RESULTS: Among the 37 patients, high baseline SUVmax (≥12.0; OR = 6.5, 95% CI 1.4-48.2, p = 0.032) and TLG (≥121.8; OR = 6.8, 95% CI 1.6-33.5, p = 0.012) were significantly correlated with lower complete response rates. All five PET/CT parameters were notably associated with overall survival; only SUVmax and TLG were associated with a significantly worse progression-free survival. A trend towards an inverse correlation was observed between SUVmax and TMB (R = -0.33, p = 0.062). PD-1 + CD8 + T cell infiltration was negatively correlated with MTV (R = -0.355, p = 0.034) and TLG (R = -0.385, p = 0.021). Moreover, RNA sequencing revealed that the high TLG subgroup exhibited low immune cell infiltration, indicating an immunosuppressive landscape. CONCLUSIONS: High baseline SUVmax and TLG might predict poorer treatment response and worse survival in patients with ESCC undergoing immunotherapy combined with CRT. In addition, high PET/CT metabolic parameters, particularly TLG, were correlated with an immunosuppressive TME, which warrants further exploration.

Pharmacokinetics and safety of EVER206, a novel polymyxin antimicrobial, in healthy Chinese subjects.

EVER206 (also known as SPR206) is a novel polymyxin analog that has shown in vitro potency and in vivo efficacy against multidrug-resistant (MDR) Gram-negative pathogens. This randomized, double-blinded, placebo-controlled, Phase I study evaluated the safety, tolerability, and pharmacokinetics of EVER206 in healthy Chinese subjects. After single administration of 50-300 mg EVER206, the Cmax ranged from 3.94 to 25.82 mg/L, and the AUC0-inf ranged from 12.42 to 101.67 h·mg/L. The plasma exposure displayed a linear relationship with the dose administered. After administration of 75 and 100 mg of EVER206 every 8 hours (q8 hour), a steady state was achieved on Day 2. The accumulation ratios of Cmax and AUC from Day 1 to Day 7 were in the range of 1.12 to 1.3. The elimination half-lives ranged from 2.86 to 4.32 hours in the single-ascending-dose (SAD) study and 4.71 to 6.18 hours in the multiple-ascending-dose (MAD) study. The urinary excretion of unchanged EVER206 increased with the dose, with the mean cumulative fraction ranging from 23.70% to 47.10%. EVER206 was safe and well-tolerated in Chinese healthy subjects. No severe treatment emerging adverse events (TEAEs), serious adverse events, or TEAEs leading to discontinuation were reported. The results of the present study demonstrated a similar safety profile of EVER206 with data reported in an earlier study on SPR206-101. The exposure of EVER206 in Chinese healthy subjects was higher than that in Australian healthy subjects. These results could enable further clinical development of EVER206 in Chinese patients with severe MDR Gram-negative pathogen infections.CLINICAL TRIALSThis study was registered at the Chinese Clinical Trial Registry under identifier ChiCTR2200056692.

First-in-human study to evaluate the safety, tolerability, and population pharmacokinetic/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects.

FL058 is a novel diazabicyclooctane ß-lactamase inhibitor. This first-in-human study evaluated the safety, tolerability, and population pharmacokinetic (PK)/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects. The results showed that the maximum tolerated dose of FL058 was 3,000 mg after single-dose infusion. FL058 in combination with meropenem did not cause any grade 3 or higher adverse event when the dose was escalated up to 1,000 mg/2,000 mg. FL058 exposure PK parameters showed dose proportionality. FL058 was excreted primarily in urine. No significant PK interaction was found between FL058 and meropenem. Population PK model analysis indicated that the PK profiles of FL058 and meropenem were consistent with the two-compartment model. The impact of covariates, creatinine clearance, concomitant use of meropenem, body weight, sex, and FL058 dose, on FL058 exposure was less than 10%. FL058/meropenem combination was safe and well tolerated up to a 1,000-mg/2,000-mg dose in healthy adults. The recommended minimum dose of FL058/meropenem combination was 500 mg/1,000 mg by intravenous infusion over 2 h every 8 h based on target attainment analysis. The good safety, tolerability, and satisfactory PK profiles of FL058 alone and in combination with meropenem in this first-in-human study will support further clinical development of FL058 in combination with meropenem in patients with target infections (ClinicalTrials.gov identifiers: NCT05055687, NCT05058118, and NCT05058105).

The effect of shikonin on the metabolism of lapatinib in vitro, and in vivo.

PURPOSE: The purpose of this study was to develop an assay for simultaneous determination of lapatinib and its metabolites (N-dealkylated lapatinib and O-dealkylated lapatinib) by ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS), and to determine the interaction between shikonin and lapatinib in vitro, in vivo, in silico and its mechanism of action. METHODS: A new UPLC-MS/MS method for the determination of the concentrations of lapatinib and its metabolites was developed. In vivo, Sprague-Dawley (SD) rats were given lapatinib with or without shikonin. In vitro, to study the interaction mechanism, rat liver microsomes (RLMs), human liver microsomes (HLMs) and recombinant human CYP3A4.1 were used for determining enzyme kinetics. Lastly, we used in silico molecular docking to investigate the molecular mechanism of inhibition. RESULTS: The selectivity, precision, accuracy, stability, matrix effect and recovery of UPLC-MS/MS all met the requirements of quantitative analysis of biological samples. Administration of lapatinib combined with shikonin resulted in significantly increased pharmacokinetic parameters (AUC(0-t) and Cmax) of lapatinib, indicating that shikonin increased the exposure of lapatinib in rats. Moreover, in vitro kinetic measurements indicated that shikonin was a time-independent inhibitor, which inhibited the metabolism of lapatinib through a competitive mechanism in RLMs, while noncompetitive inhibition type in both HLMs and CYP3A4.1. Molecular docking analysis further verified the non-competitive inhibition of shikonin on lapatinib in CYP3A4.1. CONCLUSION: We developed an UPLC-MS/MS assay for simultaneous determination of lapatinib and its metabolites. It could be successfully applied to the study of pharmacokinetic interaction of shikonin on the inhibition of lapatinib metabolism in vivo and in vitro. In the end, further studies are needed to determine if such interactions are indeed valid in humans and if the interaction is clinically relevant.

AdipoRon Ameliorates Synaptic Dysfunction and Inhibits tau Hyperphosphorylation through the AdipoR/AMPK/mTOR Pathway in T2DM Mice.

There is growing evidence showing that adiponectin (APN) can improve Alzheimer's disease(AD)-like pathological changes by improving insulin resistance. However, the role of AdipoRon (an Adiponectin receptor agonist) on synaptic plasticity and cognitive dysfunction in the early stages of type 2 diabetes mellitus(T2DM) remains unknown. In this study, we investigated the neuroprotective effect and the molecular mechanism underlying the effect of AdipoRon in T2DM mice. We found that AdipoRon significantly restored the cognitive deficits in T2DM mice, including shorter escape latency, more crossing times, increased distances, and percentage of time in the target quadrant. In addition, AdipoRon treatment up-regulated synaptic proteins (PSD95, SYN, GAP43, and SYP), increased the number of hippocampal synapses and attenuated synaptic damage, including the length, the number and the density of dendritic spines in CA1 and DG regions. Furthermore, AdipoRon attenuated Tau phosphorylation at multiple AD-related sites (p-tau 205, p-tau 396, p-tau 404) by promoting AdipoR expression and activating the AMPK/mTOR pathway. Our data suggests that AdipoRon exerts neuroprotective effects on the T2DM mice, which may be mediated by the activation of the AdipoR/AMPK/mTOR signaling pathway.

Celastrol ameliorates hypoxic-ischemic brain injury in neonatal rats by reducing oxidative stress and inflammation.

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is caused by perinatal hypoxia and subsequent reductions in cerebral blood flow and is one of the leading causes of severe disability or death in newborns. Despite its prevalence, we currently lack an effective drug therapy to combat HIE. Celastrol (Cel) is a pentacyclic triterpene extracted from Tripterygium Wilfordi that can protect against oxidative stress, inflammation, and cancer. However, whether Cel can alleviate neonatal hypoxic-ischemic (HI) brain damage remains unclear. METHODS: Here, we established both in vitro and in vivo models of HI brain damage using CoCl2-treated PC12 cells and neonatal rats, respectively, and explored the neuroprotective effects of Cel in these models. RESULTS: Analyses revealed that Cel administration reduced brain infarction size, microglia activation, levels of inflammation factors, and levels of oxidative stress markers by upregulating levels of p-AMPKα, Nrf2, HO-1, and by downregulating levels of TXNIP and NLRP3. Conversely, these beneficial effects of Cel on HI brain damage were largely inhibited by AMPKα inhibitor Compound C and its siRNA. CONCLUSIONS: We present compelling evidence that Cel decreases inflammation and oxidative stress through the AMPKα/Nrf2/TXNIP signaling pathway, thereby alleviating neonatal HI brain injury. Cel therefore represents a promising therapeutic agent for treating HIE. IMPACT: We firstly report that celastrol can ameliorate neonatal hypoxic-ischemic brain injury both in in vivo and in vitro, which represents a promising therapeutic agent for treating related brain injuries. Celastrol activates the AMPKα/Nrf2/TXNIP signaling pathway to relieve oxidative stress and inflammation and thereby alleviates neonatal hypoxic-ischemic brain injury.

Constructing a Ready-to-Use mRNA Vaccine Delivery System for the Prevention of Influenza A virus, Utilizing FDA-Approved Raw Materials.

Messenger ribonucleic acid (mRNA) vaccines, serving as a rapid and easily scalable emergency preventive measure, have played a pivotal role in preventing infectious diseases. The effectiveness of mRNA vaccines heavily relies on the delivery carrier, but the current market options are predominantly lipid nanoparticles. Their intricate preparation process and high transportation costs pose challenges for widespread use in remote areas. In this study, we harnessed FDA-approved polymer PLGA and lipid components widely employed in clinical experiments to craft a ready-to-use mRNA vaccine delivery system known as lipid-polymer hybrid nanoparticles (LPP). Following formulation optimization, the PDCD nanoparticles emerged as the most effective, showcasing exceptional mRNA delivery capabilities both in vitro and in vivo. Loading PDCD nanoparticles with mRNA encoding the H1N1 influenza virus HA antigen-fused M2e peptide enabled the successful induction of M2e-specific antibodies and T cell immune responses in immunized mice. After three rounds of vaccine immunization, the mice demonstrated weight recovery to normal levels and maintained a survival rate exceeding 80% following an encounter with the H1N1 influenza virus. The innovative mRNA delivery system that we designed demonstrates outstanding effectiveness in preventing infectious diseases, with the potential to play an even more significant role in future clinical applications.

Odor and taste characteristics, transduction mechanism, and perceptual interaction in fermented foods: a review.

Fermentation is a critical technological process for flavor development in fermented foods. The combination of odor and taste, known as flavor, is crucial in enhancing people's perception and psychology toward fermented foods, thereby increasing their acceptance among consumers. This review summarized the determination and key flavor compound screening methods in fermented foods and analyzed the flavor perception, perceptual interactions, and evaluation methods. The flavor compounds in fermented foods could be separated, purified, and identified by instrument techniques, and a molecular sensory science approach could identify the key flavor compounds. How flavor compounds bind to their respective receptors determines flavor perception, which is influenced by their perceptual interactions, including odor-odor, taste-taste, and odor-taste. Evaluation methods of flavor perception mainly include human sensory evaluation, electronic sensors and biosensors, and neuroimaging techniques. Among them, the biosensor-based evaluation methods could facilitate the investigation of the flavor transduction mechanism and the neuroimaging technique could explain the brain's signals that relate to the perception of flavor and how they compare to signals from other senses. This review aims to elucidate the flavor profile of fermented foods and highlight the significance of comprehending the interactions between various flavor compounds, thus improving the healthiness and sensory attributes.

Predictors of mortality and poor outcome for patients with severe infectious encephalitis in the intensive care unit: a cross-sectional study.

BACKGROUND: There are few thorough studies assessing predictors of severe encephalitis, despite the poor prognosis and high mortality associated with severe encephalitis. The study aims to evaluate the clinical predictors of mortality and poor outcomes at hospital discharge in patients with severe infectious encephalitis in intensive care units. METHOD: In two Chinese hospitals, a retrospective cohort study comprising 209 patients in intensive care units suffering from severe infectious encephalitis was carried out. Univariate and multivariate logistic regression analyses were used to identify the factors predicting mortality in all patients and poor outcomes in all survivors with severe infectious encephalitis. RESULTS: In our cohort of 209 patients with severe encephalitis, 22 patients died, yielding a mortality rate of 10.5%. Cerebrospinal fluid pressure ≥ 400mmH2O (OR = 7.43), abnormal imaging (OR = 3.51), abnormal electroencephalogram (OR = 7.14), and number of rescues (OR = 1.12) were significantly associated with an increased risk of mortality in severe infectious encephalitis patients. Among the 187 survivors, 122 (65.2%) had favorable outcomes, defined as the modified Rankine Scale (mRS) score (0 ~ 3), and 65(34.8%) had poor outcomes (mRS scores 4 ~ 5). Age (OR = 1.02), number of rescues (OR = 1.43), and tubercular infection (OR = 10.77) were independent factors associated with poor outcomes at discharge in all survivors with severe infectious encephalitis. CONCLUSIONS: Multiple clinical, radiologic, and electrophysiological variables are independent predictive indicators for mortality and poor outcomes in patients with severe encephalitis in intensive care units. Identifying these outcome predictors early in patients with severe encephalitis may enable the implementation of appropriate medical treatment and help reduce mortality rates.

Investigation of metabolite alterations in the kidneys of methionine-choline-deficient mouse by mass spectrometry imaging.

Methionine and choline both are essential nutrients which are needed for methyl group metabolism. A methionine-choline-deficient (MCD) diet leads to pathological changes in the kidney. The mechanism of the MCD diet is complex, and fundamental research is still required to provide a better understanding of the driving forces behind it. We evaluated the regional effects of the MCD diet on the metabolites of mouse kidney tissue using desorption electrospray ionization mass spectrometry imaging technology. A total of 20, 17, and 13 metabolites were significantly changed in the cortex, outer medulla, and inner medulla, respectively, of the mouse kidney tissue after the administration of the MCD diet. Among the discriminating metabolites, only three metabolites (guanidoacetic acid, serine, and nicotinamide riboside) were significantly increased, and all the other metabolites showed a significant decrease. The results showed that there were significant region-specific changes in the serine metabolism, carnitine metabolism, choline metabolism, and arginine metabolism. This study presents unique regional metabolic data, providing a more comprehensive understanding of the molecular characteristics of the MCD diet in the kidney.

Single-pixel imaging based on metasurface fuzzy coding.

Single-pixel imaging, renowned for its high sensitivity, robustness against interference, and superior resolution, has become increasingly prominent in the field of optical research. Over recent years, a diverse array of light modulation devices and methodologies has been devised to accomplish megahertz modulations rates. This work presents a single-pixel imaging scheme based on the fuzzy coding of metasurfaces. This unique encoding technique manipulates the quality of the mask pattern by adjusting the pixel count within the metasurface units. Notably, we expand the metasurface units to effectively mitigate the position sensitivity during movement or rotations, thus easing the challenge for the detector in collecting the correct light intensity during sub-mask transitions. A detailed analysis is drawn of the reconstruction quality of fuzzy masks. Simultaneously, we provide simulations of single-pixel imaging under the condition where the fuzzy-coded metasurface is moving. This work provides a new, to the best of our knowledge, mask generation mode for high-speed spatial light modulation.

Half-Space Sound Field Reconstruction Based on the Combination of the Helmholtz Equation Least-Squares Method and Equivalent Source Method.

In practical conditions, near-field acoustic holography (NAH) requires the measurement environment to be a free sound field. If vibrating objects are located above the reflective ground, the sound field becomes non-free in the presence of a reflecting surface, and conventional NAH may not identify the sound source. In this work, two types of half-space NAH techniques based on the Helmholtz equation least-squares (HELS) method are developed to reconstruct the sound field above a reflecting plane. The techniques are devised by introducing the concept of equivalent source in HELS-method-based NAH. Two equivalent sources are tested. In one technique, spherical waves are used as the equivalent source, and the sound reflected from the reflecting surface is regarded as a linear superposition of orthogonal spherical wave functions of different orders located below the reflecting surface. In the other technique, some monopoles are considered equivalent sources, and the reflected sound is considered a series of sounds generated by simple sources distributed under the reflecting surface. The sound field is reconstructed by matching the pressure measured on the holographic surface with the orthogonal spherical wave source in the vibrating object and replacing the reflected sound with an equivalent source. Therefore, neither technique is related to the surface impedance of the reflected plane. Compared with the HELS method, both methods show higher reconstruction accuracy for a half-space sound field and are expected to broaden the application range of HELS-method-based NAH techniques.

A phase I study of the safety, tolerability, and pharmacokinetics of contezolid acefosamil after intravenous and oral administration in healthy Chinese subjects.

Contezolid acefosamil (also known as MRX-4), a prodrug of contezolid, is under development for treatment of multidrug-resistant Gram-positive bacterial infections. A phase I single ascending dose (SAD) and multiple-dose placebo-controlled study was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of contezolid acefosamil in healthy Chinese subjects following intravenous (IV) and oral administration. Adverse events (AEs) and PK parameters were assessed appropriately. All subjects (n = 70) completed the trial. Overall, 67 cases of treatment-emergent adverse events (TEAEs) were observed in 49.1% (27 of 55) of the subjects receiving contezolid acefosamil. All TEAEs were mild in severity. No serious AEs or deaths were reported. After IV SAD (500-2,000 mg), the corresponding C max of the active drug contezolid increased from 1.95 ± 0.57 to 15.61 ± 4.88 mg/L, AUC0-inf from 40.25 ± 10.12 to 129.41 ± 38.30 h·mg/L, median T max from 2.00 to 2.75 h, and mean t 1/2 from 13.33 to 16.74 h. Plasma contezolid reached steady state on day 6 after multiple IV doses, with an accumulation ratio of 2.20-2.96. Oral SAD of 500 and 1,500 mg resulted in contezolid C max of 8.66 ± 2.60 and 37.10 ± 8.66 mg/L, AUC0-inf of 30.44 ± 7.33 and 162.36 ± 47.08 h·mg/L, and median T max of 2.50 and 2.98 h. Contezolid reached steady state on day 5 after multiple oral doses of 1,500 mg without significant accumulation. Contezolid C max and AUC0-inf increased with the dose of contezolid acefosamil. The good safety and PK profiles in this SAD and multiple-dose study can support further clinical development of contezolid acefosamil.

Patlak-Ki derived from ultra-high sensitivity dynamic total body [18F]FDG PET/CT correlates with the response to induction immuno-chemotherapy in locally advanced non-small cell lung cancer patients.

PURPOSE: This study aimed to investigate the predictive value of metabolic features in response to induction immuno-chemotherapy in patients with locally advanced non-small cell cancer (LA-NSCLC), using ultra-high sensitivity dynamic total body [18F]FDG PET/CT. METHODS: The study analyzed LA-NSCLC patients who received two cycles of induction immuno-chemotherapy and underwent a 60-min dynamic total body [18F]FDG PET/CT scan before treatment. The primary tumors (PTs) were manually delineated, and their metabolic features, including the Patlak-Ki, Patlak-Intercept, maximum SUV (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were evaluated. The overall response rate (ORR) to induction immuno-chemotherapy was evaluated according to RECIST 1.1 criteria. The Patlak-Ki of PTs was calculated from the 20-60 min frames using the Patlak graphical analysis. The best feature was selected using Laplacian feature importance scores, and an unsupervised K-Means method was applied to cluster patients. ROC curve was used to examine the effect of selected metabolic feature in predicting tumor response to treatment. The targeted next generation sequencing on 1021 genes was conducted. The expressions of CD68, CD86, CD163, CD206, CD33, CD34, Ki67 and VEGFA were assayed through immunohistochemistry. The independent samples t test and the Mann-Whitney U test were applied in the intergroup comparison. Statistical significance was considered at P < 0.05. RESULTS: Thirty-seven LA-NSCLC patients were analyzed between September 2020 and November 2021. All patients received two cycles of induction chemotherapy combined with Nivolumab/ Camrelizumab. The Laplacian scores showed that the Patlak-Ki of PTs had the highest importance for patient clustering, and the unsupervised K-Means derived decision boundary of Patlak-Ki was 2.779 ml/min/100 g. Patients were categorized into two groups based on their Patlak-Ki values: high FDG Patlak-Ki (H-FDG-Ki, Patlak-Ki > 2.779 ml/min/100 g) group (n = 23) and low FDG Patlak-Ki (L-FDG-Ki, Patlak-Ki ≤ 2.779 ml/min/100 g) group (n = 14). The ORR to induction immuno-chemotherapy was 67.6% (25/37) in the whole cohort, with 87% (20/23) in H-FDG-Ki group and 35.7% (5/14) in L-FDG-Ki group (P = 0.001). The sensitivity and specificity of Patlak-Ki in predicting the treatment response were 80% and 75%, respectively [AUC = 0.775 (95%CI 0.605-0.945)]. The expression of CD3+/CD8+ T cells and CD86+/CD163+/CD206+ macrophages were higher in the H-FDG-Ki group, while Ki67, CD33+ myeloid cells, CD34+ micro-vessel density (MVD) and tumor mutation burden (TMB) were comparable between the two groups. CONCLUSIONS: The total body [18F]FDG PET/CT scanner performed a dynamic acquisition of the entire body and clustered LA-NSCLC patients into H-FDG-Ki and L-FDG-Ki groups based on the Patlak-Ki. Patients with H-FDG-Ki demonstrated better response to induction immuno-chemotherapy and higher levels of immune cell infiltration in the PTs compared to those with L-FDG-Ki. Further studies with a larger patient cohort are required to validate these findings.

Significant CT dose reduction of 2-[18F]FDG PET/CT in pretreatment pediatric lymphoma without compromising the diagnostic and staging efficacy.

OBJECTIVES: To compare the diagnostic and staging efficacy of PET/diagnostic-level CT (PET/DxCT) and PET/low-dose CT (PET/LDCT) in pretreatment pediatric lymphoma patients and to estimate the reduction of the CT effective dose in the PET/CT scan. METHODS: One hundred and five pediatric patients who underwent total-body PET/CT examination were enrolled and divided into the DxCT group (n = 47) and LDCT group (n = 58) according to their dose levels. The sensitivity, specificity, PPV, and NPV of PET/DxCT and PET/LDCT for detecting the involvement of lymph node, spleen, bone marrow, and other extranodal organs in pretreatment lymphoma were compared. ROC analysis was performed to evaluate the integral efficiency. The staging accuracies based on PET/DxCT and PET/LDCT were also evaluated. Dosimetry was calculated for DxCT and LDCT, and the reduction in the effective dose was estimated. RESULTS: In the diagnosis of nodal, splenic, bone marrow, and other extranodal involvement, the differences in sensitivity, specificity, PPV, and NPV between PET/LDCT and PET/DxCT were not significant (all p values ∈ [0.332, 1.000]). Both modalities had accuracies above 90% and the ROC analysis indicated good or high efficiency in diagnosing all patterns of lymphoma involvement. PET/LDCT and PET/DxCT each had a staging accuracy of 89.7% and 89.4%, respectively. LDCT had a comparable image quality score with DxCT, with a significant increase in noise (p < 0.001) and a 66.1% reduction in effective dose. CONCLUSIONS: PET/LDCT allowed for a 66.1% CT effective dose reduction compared to PET/DxCT in pediatric lymphoma patients without compromising the diagnostic and staging efficacy. KEY POINTS: • Pediatric lymphoma patients can benefit from a reduced effective dose of PET/CT. • This retrospective study showed that the diagnostic and staging efficacies of PET/low-dose CT are comparable to those of PET/diagnostic-level CT, both with satisfactory efficiency in diagnosing all patterns of lymphoma involvement. • PET/low-dose CT allowed for a 66.1% CT effective dose reduction compared to PET/diagnostic-level CT.

Utilization of five data mining algorithms combined with simplified preprocessing to establish reference intervals of thyroid-related hormones for non-elderly adults.

BACKGROUND: Despite the extensive research on data mining algorithms, there is still a lack of a standard protocol to evaluate the performance of the existing algorithms. Therefore, the study aims to provide a novel procedure that combines data mining algorithms and simplified preprocessing to establish reference intervals (RIs), with the performance of five algorithms assessed objectively as well. METHODS: Two data sets were derived from the population undergoing a physical examination. Hoffmann, Bhattacharya, Expectation Maximum (EM), kosmic, and refineR algorithms combined with two-step data preprocessing respectively were implemented in the Test data set to establish RIs for thyroid-related hormones. Algorithm-calculated RIs were compared with the standard RIs calculated from the Reference data set in which reference individuals were selected following strict inclusion and exclusion criteria. Objective assessment of the methods is implemented by the bias ratio (BR) matrix. RESULTS: RIs of thyroid-related hormones are established. There is a high consistency between TSH RIs established by the EM algorithm and the standard TSH RIs (BR = 0.063), although EM algorithms seems to perform poor on other hormones. RIs calculated by Hoffmann, Bhattacharya, and refineR methods for free and total triiodo-thyronine, free and total thyroxine respectively are close and match the standard RIs. CONCLUSION: An effective approach for objectively evaluating the performance of the algorithm based on the BR matrix is established. EM algorithm combined with simplified preprocessing can handle data with significant skewness, but its performance is limited in other scenarios. The other four algorithms perform well for data with Gaussian or near-Gaussian distribution. Using the appropriate algorithm based on the data distribution characteristics is recommended.

Association of solid fuel use with a risk score capturing dementia risk among middle-aged and older adults: A prospective cohort study.

OBJECTIVES: Whether household air pollution is associated with dementia risk remains unknown. This study examined the associations between solid fuel use for cooking and heating (the main source of household air pollution) and dementia risk. METHODS: This analysis included data on 11,352 participants (aged 45+ years) from the 2011 wave of China Health and Retirement Longitudinal Study, with follow-up to 2018. Dementia risk was assessed by a risk score using the Rotterdam Study Basic Dementia Risk Model (BDRM), which was subsequently standardized for analysis. Household fuel types of cooking and heating were categorized as solid (e.g., coal and crop residue) and clean (e.g., central heating and solar). Multivariable analyses were performed using generalized estimating equations. Moreover, we examined the joint associations of solid fuel use for cooking and heating with the BDRM score. RESULTS: After adjusting for potential confounders, we found an independent and significant association of solid (vs. clean) fuel use for cooking and heating with a higher BDRM score (e.g., ß = 0.17 for solid fuel for cooking; 95% confidence interval [CI]: 0.15-0.19). Participants who used solid (vs. clean) fuel for both cooking and heating had the highest BDRM score (ß = 0.32; 95% CI: 0.29-0.36). Subgroup analysis suggested stronger associations in participants living in rural areas. CONCLUSIONS: Solid fuel use for cooking and heating was independently associated with increased dementia risk in Chinese middle-aged and older adults, particularly among those living in rural areas. Our findings call for more efforts to facilitate universal access to clean energy for dementia prevention.

Does the Use of a Uterine Manipulator or Intracorporeal Colpotomy Confer an Inferior Prognosis in Minimally Invasive Surgery-Treated Early-stage Cervical Cancer?

STUDY OBJECTIVE: To identify whether the use of a uterine manipulator (UM) or intracorporeal colpotomy conferred inferior short-term survival among patients treated for early-stage cervical cancer. DESIGN: Retrospective cohort study. SETTING: Tertiary university-based hospital. PATIENTS: 1169 patients with stage IB1 to IB2 cervical cancer. INTERVENTIONS: All patients underwent minimally invasive radical hysterectomy and pelvic lymphadenectomy. MEASUREMENTS AND MAIN RESULTS: A total of 1169 patients diagnosed with preoperative stage IB1 to IB2 cervical cancer were primarily treated with surgery from 2018 to 2019. The eligible patients had a median age of 48 years (range, 23-76 years), and the median follow-up time was 34 months (range, 3.57-50.87 months). The 2-year overall survival rate of the patients with pathologic stage IB1 and IB2 was 99.8% and 98.8%, respectively, according to the 2018 International Federation of Gynecology and Obstetrics staging system. Univariable analysis revealed that the UM group had a 7.6-times higher risk of death than that of the manipulator-free group (p = .006), but multivariable analysis clarified that only tumor size (p = .016; hazard ratio, 2.285; 95% confidence interval, 1.166-4.479) and parametrial involvement (p = .003; hazard ratio, 3.556; 95% confidence interval, 1.549-8.166) were independent risk factors for overall survival. There was no statistically significant difference in survival between patients who underwent intracorporeal and protective colpotomy. CONCLUSION: Short-term survival outcomes in women undergoing minimally invasive radical hysterectomy for treatment of early-stage cervical cancer did not differ when a UM was avoided or when a protective colpotomy was performed.

BIRC5 Inhibition Is Associated with Pyroptotic Cell Death via Caspase3-GSDME Pathway in Lung Adenocarcinoma Cells.

Lung adenocarcinoma (LUAD) is a prevalent type of thoracic cancer with a poor prognosis and high mortality rate. However, the exact pathogenesis of this cancer is still not fully understood. One potential factor that can contribute to the development of lung adenocarcinoma is DNA methylation, which can cause changes in chromosome structure and potentially lead to the formation of tumors. The baculoviral IAP repeat containing the 5 (BIRC5) gene encodes the Survivin protein, which is a multifunctional gene involved in cell proliferation, migration, and invasion of tumor cells. This gene is elevated in various solid tumors, but its specific role and mechanism in lung adenocarcinoma are not well-known. To identify the potential biomarkers associated with lung adenocarcinoma, we screened the methylation-regulated differentially expressed genes (MeDEGs) of LUAD via bioinformatics analysis. Gene ontology (GO) process and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were applied to investigate the biological function and pathway of MeDEGs. A protein-protein interaction (PPI) network was employed to explore the key module and screen hub genes. We screened out eight hub genes whose products are aberrantly expressed, and whose DNA methylation modification level is significantly changed in lung adenocarcinoma. BIRC5 is a bona fide marker which was remarkably up-regulated in tumor tissues. Flow cytometry analysis, lactate dehydrogenase release (LDH) assay and Micro-PET imaging were performed in A549 cells and a mouse xenograft tumor to explore the function of BIRC5 in cell death of lung adenocarcinoma. We found that BIRC5 was up-regulated and related to a high mortality rate in lung adenocarcinoma patients. Mechanically, the knockdown of BIRC5 inhibited the proliferation of A549 cells and induced pyroptosis via caspase3/GSDME signaling. Our findings have unraveled that BIRC5 holds promise as a novel biomarker and therapeutic target for lung adenocarcinoma. Additionally, we have discovered a novel pathway in which BIRC5 inhibition can induce pyroptosis through the caspase3-GSDME pathway in lung adenocarcinoma cells.