A scheme of hiding large-size image into small-size image based on FCdDNet.

The hiding capacity of the current information hiding field has reached a relatively high level, which can hide two color images into one color image. In order to explore a larger hidden capacity, an information hiding scheme based on an improved FCdDNet is proposed, which can hide large-size color images into small-size color images. An improved FCdDNet network is used as the main structure shared by the hidden network and the extraction network. These two networks promote and improve each other during the confrontation training process and are used in pairs. It can be seen that the proposed scheme achieves a larger information hiding capacity, and the hidden information is four times larger than the scale of the carrier image. At the same time, the visual effect after hiding is guaranteed, and the image extracted from the hidden image also has a high degree of restoration. The scheme can be applied to image authentication, secret image transmission, and other fields.

Deletion of GPR81 activates CREB/Smad7 pathway and alleviates liver fibrosis in mice.

BACKGROUND: Enhanced glycolysis is a crucial metabolic event that drives the development of liver fibrosis, but the molecular mechanisms have not been fully understood. Lactate is the endproduct of glycolysis, which has recently been identified as a bioactive metabolite binding to G-protein-coupled receptor 81 (GPR81). We then questioned whether GPR81 is implicated in the development of liver fibrosis. METHODS: The level of GPR81 was determined in mice with carbon tetrachloride (CCl4)-induced liver fibrosis and in transforming growth factor beta 1 (TGF-ß1)-activated hepatic stellate cells (HSCs) LX-2. To investigate the significance of GPR81 in liver fibrosis, wild-type (WT) and GPR81 knockout (KO) mice were exposed to CCl4, and then the degree of liver fibrosis was determined. In addition, the GPR81 agonist 3,5-dihydroxybenzoic acid (DHBA) was supplemented in CCl4-challenged mice and TGF-ß1-activated LX-2 cells to further investigate the pathological roles of GPR81 on HSCs activation. RESULTS: CCl4 exposure or TGF-ß1 stimulation significantly upregulated the expression of GPR81, while deletion of GPR81 alleviated CCl4-induced elevation of aminotransferase, production of pro-inflammatory cytokines, and deposition of collagen. Consistently, the production of TGF-ß1, the expression of alpha-smooth muscle actin (α-SMA) and collagen I (COL1A1), as well as the elevation of hydroxyproline were suppressed in GPR81 deficient mice. Supplementation with DHBA enhanced CCl4-induced liver fibrogenesis in WT mice but not in GPR81 KO mice. DHBA also promoted TGF-ß1-induced LX-2 activation. Mechanistically, GPR81 suppressed cAMP/CREB and then inhibited the expression of Smad7, a negative regulator of Smad3, which resulted in increased phosphorylation of Smad3 and enhanced activation of HSCs. CONCLUSION: GPR81 might be a detrimental factor that promotes the development of liver fibrosis by regulating CREB/Smad7 pathway.

Targeting Neuronal GPR65 With Delayed BTB09089 Treatment Improves Neurorehabilitation Following Ischemic Stroke.

BACKGROUND: GPR65 (G protein-coupled receptor 65) can sense extracellular acidic environment to regulate pathophysiological processes. Pretreatment with the GPR65 agonist BTB09089 has been proven to produce neuroprotection in acute ischemic stroke. However, whether delayed BTB09089 treatment and neuronal GPR65 activation promote neurorestoration remains unknown. METHODS: Ischemic stroke was induced in wild-type (WT) or GPR65 knockout (GPR65-/-) mice by photothrombotic ischemia. Male mice were injected intraperitoneally with BTB09089 every other day at days 3, 7, or 14 poststroke. AAV-Syn-GPR65 (adenoassociated virus-synapsin-GPR65) was utilized to overexpress GPR65 in the peri-infarct cortical neurons of GPR65-/- and WT mice. Motor function was monitored by grid-walk and cylinder tests. The neurorestorative effects of BTB09089 were observed by immunohistochemistry, Golgi-Cox staining, and Western blotting. RESULTS: BTB09089 significantly promoted motor outcomes in WT but not in GPR65-/- mice, even when BTB09089 was delayed for 3 to 7 days. BTB09089 inhibited the activation of microglia and glial scar progression in WT but not in GPR65-/- mice. Meanwhile, BTB09089 reduced the decrease in neuronal density in WT mice, but this benefit was abolished in GPR65-/- mice and reemerged by overexpressing GPR65 in peri-infarct cortical neurons. Furthermore, BTB09089 increased the GAP43 (growth-associated protein-43) and synaptophysin puncta density, dendritic spine density, dendritic branch length, and dendritic complexity by overexpressing GPR65 in the peri-infarct cortical neurons of GPR65-/- mice, which was accompanied by increased levels of p-CREB (phosphorylated cAMP-responsive element-binding protein). In addition, the therapeutic window of BTB09089 was extended to day 14 by overexpressing GPR65 in the peri-infarct cortical neurons of WT mice. CONCLUSIONS: Our findings indicated that delayed BTB09089 treatment improved neurological functional recovery and brain tissue repair poststroke through activating neuronal GRP65. GPR65 overexpression may be a potential strategy to expand the therapeutic time window of GPR65 agonists for neurorehabilitation after ischemic stroke.

Predicting in vivo therapeutic efficacy of CelTrac1000-labeled hair follicle epidermal neural crest stem cells in models of repairing rat facial nerve defects via second near-infrared fluorescence imaging.

AIMS: To detect the therapeutic efficacy of CelTrac1000-labeled hair follicle epidermal neural crest stem cells (EPI-NCSCs) on repairing facial nerve defects by second near-infrared (NIR-II) fluorescence imaging. MATERIALS AND METHODS: Firstly, CelTrac1000-labeled EPI-NCSCs were microinjected into the acellular nerve allografts (ANAs) to bridge a 10-mm-long gap in the buccal branch of facial nerve in adult rats. Then, Celtrac1000-labeled EPI-NCSCs were detected by NIR-II fluorescence imaging system to visualize the behavior of the transplanted cells in vivo. Additionally, the effect of the transplanted EPI-NCSCs on repairing facial nerve defect was examined. KEY FINDINGS: Through 14 weeks of dynamic observation, the transplanted EPI-NCSCs survived in the ANAs in vivo after surgery. Meanwhile, the region of the NIR-II fluorescence signals was gradually limited to be consistent with the direction of the regenerative nerve segment. Furthermore, the results of functional and morphological analysis showed that the transplanted EPI-NCSCs could promote the recovery of facial paralysis and neural regeneration after injury. SIGNIFICANCE: Our research provides a novel way to track the transplanted cells in preclinical studies of cell therapy for facial paralysis, and demonstrates the therapeutic potential of EPI-NCSCs combined with ANAs in bridging rat facial nerve defects.

Ultrasound -Induced Thermal Effect Enhances the Efficacy of Chemotherapy and Immunotherapy in Tumor Treatment.

Background: The inadequate perfusion, frequently resulting from abnormal vascular configuration, gives rise to tumor hypoxia. The presence of this condition hinders the effective delivery of therapeutic drugs and the infiltration of immune cells into the tumor, thereby compromising the efficacy of treatments against tumors. The objective of this study is to exploit the thermal effect of ultrasound (US) in order to induce localized temperature elevation within the tumor, thereby facilitating vasodilation, augmenting drug delivery, and enhancing immune cell infiltration. Methods: The selection of US parameters was based on intratumor temperature elevation and their impact on cell viability. Vasodilation and hypoxia improvement were investigated using enzyme-linked immunosorbent assay (ELISA) and immunofluorescence examination. The distribution and accumulation of commercial pegylated liposomal doxorubicin (PLD) and PD-L1 antibody (anti-PD-L1) in the tumor were analyzed through frozen section analysis, ELISA, and in vivo fluorescence imaging. The evaluation of tumor immune microenvironment was conducted using flow cytometry (FCM). The efficacy of US-enhanced chemotherapy in combination with immunotherapy was investigated by monitoring tumor growth and survival rate after various treatments. Results: The US irradiation condition of 0.8 W/cm2 for 10 min effectively elevated the tumor temperature to approximately 40 °C without causing any cellular or tissue damage, and sufficiently induced vasodilation, thereby enhancing the distribution and delivery of PLD and anti-PD-L1 in US-treated tumors. Moreover, it effectively mitigated tumor hypoxia while significantly increasing M1-phenotype tumor-associated macrophages (TAMs) and CD8+ T cells, as well as decreasing M2-phenotype TAMs. By incorporating US irradiation, the therapeutic efficacy of PLD and anti-PD-L1 was substantially boosted, leading to effective suppression of tumor growth and prolonged survival in mice. Conclusion: The application of US (0.8 W/cm2 for 10 min) can effectively induce vasodilation and enhance the delivery of PLD and anti-PD-L1 into tumors, thereby reshaping the immunosuppressive tumor microenvironment and optimizing therapeutic outcomes.

A fluorescence aptamer sensor utilizing WS2 nanosheets for sensitive detection of patulin: enhanced specificity and wide applicability.

A tungsten disulfide (WS2) nanosheet-based aptamer sensor was developed to detect patulin (PAT). The 5'-end of the PAT aptamer was modified with a cyanine 3 (Cy3) fluorophore, which self-assembled on WS2 nanosheets. The interaction between the Cy3 fluorophore at the 5'-end of the PAT aptamer and the WS2 nanosheets resulted in reduced fluorescence (FL) intensity due to fluorescence resonance energy transfer (FRET). The introduction of PAT into this sensing system led to hybridization with the PAT aptamer, forming a G-quadruplex/PAT complex with low affinity for the WS2 nanosheet surface. This hybridization increased the distance between the Cy3 fluorophore and the WS2 nanosheets, inhibiting FRET and producing a strong FL signal. Under optimal experimental conditions, the FL intensity of the sensing system demonstrated an excellent linear correlation with PAT concentrations ranging from 0.5 to 40.0 ng mL-1, and it achieved a detection limit (S/N = 3) of 0.23 ng mL-1. This sensing system offers enhanced specificity for PAT detection and has the potential for broad application in detecting other toxins by substituting the sequence of the recognition aptamer.

A prospective study of vitamin D, proinflammatory cytokines, and risk of fragility fractures in women on aromatase inhibitors for breast cancer.

BACKGROUND: Vitamin D is critical to bone health by regulating intestinal absorption of calcium, whereas proinflammatory cytokines, including IL-1, IL-6, IL-12, and TNF-α, are known to increase bone resorption. We hypothesized that vitamin D and these cytokines at the time of breast cancer diagnosis were predictive for fragility fractures in women receiving aromatase inhibitors (AIs). METHODS: In a prospective cohort of 1,709 breast cancer patients treated with AIs, we measured the levels of 25-hydroxyvitamin D (25OHD), IL-1ß, IL-6, IL-12, and TNF-α from baseline blood samples. The associations of these biomarkers were analyzed with bone turnover markers (BALP and TRACP), bone regulatory markers (OPG and RANKL), bone mineral density (BMD) close to cancer diagnosis, and risk of fragility fractures during a median of 7.5 years of follow up. RESULTS: Compared to patients with vitamin D deficiency, patients with sufficient levels had higher bone turnover, lower BMD, and higher fracture risk; the latter became non-significant after controlling for covariates including BMD and no longer existed when patients taking vitamin D supplement or bisphosphonates or with history of fracture or osteoporosis were excluded. There was a non-significant trend of higher levels of IL-1ß and TNF-α associated with higher risk of fracture (highest vs. lowest tertile, IL-1ß: adjusted HR=1.37, 95% CI=0.94-1.99; TNF-α: adjusted HR=1.38, 95% CI=0.96-1.98). CONCLUSIONS: Our results do not support proinflammatory cytokines or vitamin D levels as predictors for risk of fragility fractures in women receiving AIs for breast cancer.

Elucidating the role of angiogenesis-related genes in colorectal cancer: a multi-omics analysis.

Background: Angiogenesis plays a pivotal role in colorectal cancer (CRC), yet its underlying mechanisms demand further exploration. This study aimed to elucidate the significance of angiogenesis-related genes (ARGs) in CRC through comprehensive multi-omics analysis. Methods: CRC patients were categorized according to ARGs expression to form angiogenesis-related clusters (ARCs). We investigated the correlation between ARCs and patient survival, clinical features, consensus molecular subtypes (CMS), cancer stem cell (CSC) index, tumor microenvironment (TME), gene mutations, and response to immunotherapy. Utilizing three machine learning algorithms (LASSO, Xgboost, and Decision Tree), we screen key ARGs associated with ARCs, further validated in independent cohorts. A prognostic signature based on key ARGs was developed and analyzed at the scRNA-seq level. Validation of gene expression in external cohorts, clinical tissues, and blood samples was conducted via RT-PCR assay. Results: Two distinct ARC subtypes were identified and were significantly associated with patient survival, clinical features, CMS, CSC index, and TME, but not with gene mutations. Four genes (S100A4, COL3A1, TIMP1, and APP) were identified as key ARCs, capable of distinguishing ARC subtypes. The prognostic signature based on these genes effectively stratified patients into high- or low-risk categories. scRNA-seq analysis showed that these genes were predominantly expressed in immune cells rather than in cancer cells. Validation in two external cohorts and through clinical samples confirmed significant expression differences between CRC and controls. Conclusion: This study identified two ARG subtypes in CRC and highlighted four key genes associated with these subtypes, offering new insights into personalized CRC treatment strategies.

Assessment of metabolomic variations among individuals returning to plain areas after exposure to high altitudes: a metabolomic analysis of human plasma samples with high-altitude de-acclimatization syndrome.

Background: High altitude de-acclimatization (HADA) is gradually becoming a public health concern as millions of individuals of different occupations migrate to high-altitude areas for work due to economic growth in plateau areas. HADA affects people who return to lower elevations after exposure to high altitudes. It causes significant physiological and functional changes that can negatively impact health and even endanger life. However, uncertainties persist about the detailed mechanisms underlying HADA. Methods: We established a population cohort of individuals with HADA and assessed variations in metabolite composition. Plasm samples of four groups, including subjects staying at plain (P) and high altitude (H) as well as subjects suffering from HADA syndrome with almost no reaction (r3) and mild-to-moderate reaction (R3) after returning to plain from high altitude, were collected and analyzed by Liquid Chromatography-Mass Spectrometry metabolomic. Multivariate statistical analyses were used to explore significant differences and potential clinical prospect of metabolites. Result: Although significantly different on current HADAS diagnostic symptom score, there were no differences in 17 usual clinical indices between r3 and R3. Further multivariate analyses showed isolated clustering distribution of the metabolites among the four groups, suggesting significant differences in their metabolic characteristics. Through K-means clustering analysis, we identified 235 metabolites that exhibited patterns of abundance change consistent with phenotype of HADA syndrome. Pathway enrichment analysis indicated a high influence of polyunsaturated fatty acids under high-altitude conditions. We compared the metabolites between R3 and r3 and found 107 metabolites with differential abundance involved in lipid metabolism and oxidation, suggesting their potential role in the regulation of oxidative stress homeostasis. Among them, four metabolites might play a key role in the occurrence of HADA, including 11-beta-hydroxyandrosterone-3-glucuronide, 5-methoxyindoleacetate, 9,10-epoxyoctadecenoic acid, and PysoPC (20:5). Conclusion: We observed the dynamic variation in the metabolic process of HADA. Levels of four metabolites, which might be provoking HADA mediated through lipid metabolism and oxidation, were expected to be explore prospective indices for HADA. Additionally, metabolomics was more efficient in identifying environmental risk factors than clinical examination when dramatic metabolic disturbances underlying the difference in symptoms were detected, providing new insights into the molecular mechanisms of HADAS.

Affiliate Stigma, Resilience and Quality of Life among Parents of Children with Autism Spectrum Disorder in Two Public Hospitals in Kelantan, Malaysia.

Background: Often, the indirect impact of autism spectrum disorder (ASD) presents the family with significant challenges. One of these challenges is affiliate stigma due to parental affiliation with their child. This study aimed to explore affiliate stigma, resilience and quality of life (QoL) among parents of children with ASD. Methods: Cross-sectional study of 144 parents of children with ASD were recruited from two main tertiary hospitals in Kelantan, Malaysia, a developing country in Southeast Asia. Pearson correlation was used to examine the relationship between parental affiliate stigma, resilience and QoL. Simple and multiple linear regression analyses were used to identify the significant associated factors of affiliate stigma, resilience and QoL. Results: Correlational analyses revealed that perceived affiliate stigma demonstrated an inverse relationship with resilience and QoL. Additionally, resilience had a positive relationship with QoL. Regression analyses revealed that the father's employment status, the mother's level of education, having a disability card, the child's age at ASD diagnosis, comorbidities of the child and ASD severity perceived by parents were associated with parental affiliate stigma, resilience and QoL. Conclusion: Study findings highlight the contribution of socio-demographic characteristics of children with ASD and their families in the determination of affiliate stigma, resilience and QoL.

An intermittent fasting intervention for Black adults can be feasibly implemented in Black churches: A cluster randomized controlled pilot study.

BACKGROUND: Intensive lifestyle interventions including modest reductions in daily caloric intake (i.e., continuous calorie energy reduction (CER)), are recommended by U.S. national professional health organizations (e.g. American Heart Association). However, they are less effective in Black communities. A burgeoning literature has reported the promise of intermittent fasting (IF) as an alternative strategy for weight loss. However, IF studies have been conducted with predominately White participants and provided participants resources not readily available in real-world situations. OBJECTIVE: Weight loss and weight-related outcomes of a scalable (able to be widely disseminated and implemented) IF intervention developed with and for Black adults were compared to a CER intervention for the purpose of determining IF's feasibility (initial effectiveness, adherence, acceptance) in a Black community. DESIGN: A cluster randomized controlled pilot study was conducted. PARTICIPANTS/SETTING: A total of 42 Black adults with a BMI≥25 were recruited from five Black churches (3 IF churches, 2 CER churches) in Western New York State from September 2021 until May 2022. Participants were free of medical conditions that might have contraindicated participation in a weight reduction program and other factors that might affect weight loss. INTERVENTIONS: Community health workers delivered the 6-month, 16-session faith-based IF and CER interventions. MAIN OUTCOME MEASURES: The primary outcome was feasibility, consisting of initial effectiveness on body weight (percent body weight lost from baseline to 6-month follow-up), adherence, and acceptability. STATISTICAL ANALYSES PERFORMED: Descriptive statistics and linear mixed models accounting for within-church clustering were used. A baseline covariate corresponding to the outcome variable was included in the model. Intent-to-treat analysis was used. RESULTS: There was statistically significant weight loss within both arms [IF: -3.5 (-6, -0.9)]; [CER: -2.9 (-5.1, -0.8) kg], from baseline to 6-month follow-up. Compared to CER, IF led to significantly lower daily energy intake [414.2 (55.2, 773.2) kcal] and fat intake [16.1 (2.4, 29.8) g]. IF may result in lower fruit and vegetable intake [-103.2 (-200.9, -5.5) g] and fiber intake -5.4 (-8.7, -2) compared to CER. Participants in the IF arm completed 3.8 (1.4) more self-monitoring booklets compared to those in the CER arm (p=0.02). Participants reported high levels of satisfaction with the program. CONCLUSIONS: An IF intervention developed with and for Black adults can be feasibly implemented in Black churches. Larger studies need to be conducted to ascertain the extent IF can serve as a viable weight loss alternative to CER interventions in Black communities.

Epidemiological characteristics of first-time SARS-CoV-2 Omicron infection among hospital staff in Chengdu, China.

BACKGROUND: After China ended its 'dynamic zero-COVID policy' on 7 December 2022, a large-scale outbreak of SARS-CoV-2 Omicron infections emerged across the country. We conducted a hospital-wide prospective study to document the epidemiological characteristics of the outbreak among healthcare workers in a hospital of Chengdu, where no previous staff SARS-CoV-2 infections were detected. METHODS: All hospital staff members were invited to complete an online questionnaire on COVID-19 in January 2023, and SARS-CoV-2 infection cases were followed up by telephone in June 2023 to collect data on long COVID. Univariable and multivariable logistic regression analyses were performed to evaluate factors associated with SARS-CoV-2 infection. RESULTS: A total of 2,899 hospital staff (93.5%) completed the online questionnaire, and 86.4% were infected with SARS-CoV-2 Omicron. The clinical manifestations of these patients were characterized by a high incidence of systemic symptoms. Cough (83.4%), fatigue (79.8%) and fever (74.3%) were the most frequently reported symptoms. Multivariable logistic analysis revealed that females [adjusted odds ratio (aOR): 1.42, 95% confidence interval (CI): 1.07-1.88] and clinical practitioners (aOR: 10.32, 95% CI: 6.57-16.20) were associated with an increased risk of SARS-CoV-2 infection, whereas advanced age ≥ 60 years (aOR: 0.30, 95% CI: 0.19-0.49) and a three-dose COVID-19 vaccination with the most recent dose administered within 3 months before 7 December 2022 (aOR: 0.44, 95% CI: 0.23-0.87 for within 1 month; aOR: 0.46, 95% CI: 0.22-0.97 for within 1-3 months) were associated with reduced risk. Among the cases, 4.27% experienced long COVID of fatigue, brain fog or both, with the majority reporting minor symptoms. CONCLUSION: Our findings provide a snapshot of the epidemiological situation of SARS-CoV-2 infection among healthcare workers in Chengdu after China's deregulation of COVID-19 control. Data in the study can aid in the development and implementation of effective measures to protect healthcare workers and maintain the integrity of healthcare systems during challenging times such as a rapid and widespread Omicron outbreak.

Acrosin activity negatively influences the cumulative live birth rate in patients undergoing IVF treatment.

RESEARCH QUESTION: Is acrosin activity related to cumulative live birth rate (CLBR) over 1 year after IVF, intracytoplasmic sperm injection (ICSI) treatment or both? DESIGN: Retrospective monocentric cohort study of 5704 couples who started IVF/ICSI treatments between 2016 and 2021. Acrosin activity was determined by a modified Kennedy method using a commercial kit. Patients were divided into two groups according to their acrosin activity: below 25 µIU/106 spermatozoa; and an acrosin activity 25 µIU/106 spermatozoa or above. Primary outcome was the CLBR, defined as an ongoing pregnancy leading to live birth that had arisen from all embryo transfers carried out within 1 year after the first ovum retrieval. Both conservative and optimistic methods were used for estimating CLBRs. RESULTS: The CLBRs of patients with an acrosin activity below 25 µIU/106 spermatozoa were found to be significantly lower than those of patients with an acrosin activity 25 µIU/106 spermatozoa or above by conservative (48.5% versus 55.4%, P = 0.02) and optimistic (63.7% versus 70.3%, P = 0.047) methods after adjusting for confounders. When acrosin activity was regarded as a continuous variable, significant negative relationships between acrosin activity and CLBR were identified in subgroups: young couples (men and women aged younger than 30 years) and couples from whom no more than 10 eggs were retrieved. CONCLUSION: Low acrosin activity levels were correlated with decreasing CLBRs over 1 year. These findings suggest that acrosin activity can be used as a predictor for CLBRs before starting IVF/ICSI treatment to enhance the effectiveness of counselling.

Effects of different intrusion patterns during anterior teeth retraction using clear aligners in extraction cases: an iterative finite element analysis.

Background: Overtreatment design of clear aligner treatment (CAT) in extraction cases is currently primarily based on the clinical experience of orthodontists and is not supported by robust evidence on the underlying biomechanics. This study aimed to investigate the biomechanical effects of overtreatment strategies involving different maxillary anterior teeth intrusion patterns during anterior teeth retraction by CAT in extraction cases. Materials and methods: A finite element model of the maxillary dentition with the first premolar extracted was constructed. A loading method of clear aligners (CAs) based on the initial state field was proposed. The iterative method was used to simulate the long-term orthodontic tooth movement under the mechanical load exerted by the CAs. Three groups of CAs were utilized for anterior teeth retraction (G0: control group; G1: incisors intrusion group; G2: anterior teeth intrusion group). Tooth displacement and occlusal plane rotation tendency were analyzed. Results: In G0, CAT caused lingual tipping and extrusion of the incisors, distal tipping and extrusion of the canines, mesial tipping, and intrusion of the posterior teeth. In G1, the incisors showed minimal extrusion, whereas the canines showed increased extrusion and distal tipping tendency. G2 showed the smallest degree of posterior occlusal plane angle rotation, while the inclination tendency of the canines and second premolars decreased. Conclusion: 1. In CAT, tooth displacement tendency may change with increased wear time. 2. During anterior teeth retraction, the incisor intrusion pattern can provide effective vertical control for the lateral incisors but has little effect on the central incisors. Anterior teeth intrusion patterns can alleviate the inclination of canines and second premolars, resulting in partial relief of the roller-coaster effect.

Lactobacillus rhamnosus GG ameliorates triptolide-induced liver injury through modulation of the bile acid-FXR axis.

Triptolide (TP) is the principal bioactive compound of Tripterygium wilfordii with significant anti-tumor, anti-inflammatory and immunosuppressive activities. However, its severe hepatotoxicity greatly limits its clinical use. The underlying mechanism of TP-induced liver damage is still poorly understood. Here, we estimate the role of the gut microbiota in TP hepatotoxicity and investigate the bile acid metabolism mechanisms involved. The results of the antibiotic cocktail (ABX) and fecal microbiota transplantation (FMT) experiment demonstrate the involvement of intestinal flora in TP hepatotoxicity. Moreover, TP treatment significantly perturbed gut microbial composition and reduced the relative abundances of Lactobacillus rhamnosus GG (LGG). Supplementation with LGG reversed TP-induced hepatotoxicity by increasing bile salt hydrolase (BSH) activity and reducing the increased conjugated bile acids (BA). LGG supplementation upregulates hepatic FXR expression and inhibits NLRP3 inflammasome activation in TP-treated mice. In summary, this study found that gut microbiota is involved in TP hepatotoxicity. LGG supplementation protects mice against TP-induced liver damage. The underlying mechanism was associated with the gut microbiota-BA-FXR axis. Therefore, LGG holds the potential to prevent and treat TP hepatotoxicity in the clinic.

Performance of Tumor Surveillance for Children With Cancer Predisposition.

Importance: Pediatric oncology patients are increasingly recognized as having an underlying cancer predisposition syndrome (CPS). Surveillance is often recommended to detect new tumors at their earliest and most curable stages. Data on the effectiveness and outcomes of surveillance for children with CPS are limited. Objective: To evaluate the performance of surveillance across a wide spectrum of CPSs. Design, Setting, and Participants: This cohort study reviewed surveillance outcomes for children and young adults from birth to age 23 years with a clinical and/or molecular CPS diagnosis from January 1, 2009, through September 31, 2021. Patients were monitored using standard surveillance regimens for their corresponding CPS at a specialty pediatric oncology center. Patients with hereditary retinoblastoma and bone marrow failure syndromes were excluded. Data were analyzed between August 1, 2021, and December 6, 2023. Exposure: Cancer predisposition syndrome. Main Outcomes and Measures: Outcomes of surveillance were reviewed to evaluate the incidence, spectrum, and clinical course of newly detected tumors. Surveillance modalities were classified for accuracy and assessed for common strengths and weaknesses. Results: A total of 274 children and young adults (mean age, 8 years [range, birth to 23 years]; 144 female [52.6%]) with 35 different CPSs were included, with a median follow-up of 3 years (range, 1 month to 12 years). During the study period, 35 asymptomatic tumors were detected in 27 patients through surveillance (9.9% of the cohort), while 5 symptomatic tumors were detected in 5 patients (1.8% of the cohort) outside of surveillance, 2 of whom also had tumors detected through surveillance. Ten of the 35 tumors (28.6%) were identified on first surveillance imaging. Malignant solid and brain tumors identified through surveillance were more often localized (20 of 24 [83.3%]) than similar tumors detected before CPS diagnosis (71 of 125 [56.8%]; P < .001). Of the 24 tumors identified through surveillance and surgically resected, 17 (70.8%) had completely negative margins. When analyzed across all imaging modalities, the sensitivity (96.4%), specificity (99.6%), positive predictive value (94.3%), and negative predictive value (99.6%) of surveillance were high, with few false-positive (6 [0.4%]) or false-negative (5 [0.3%]) findings. Conclusions and Relevance: These findings suggest that standardized surveillance enables early detection of new tumors across a wide spectrum of CPSs, allowing for complete surgical resection and successful treatment in the majority of patients.

Electronic symptom monitoring after lung cancer surgery: establishing a core set of patient-reported outcomes for surgical oncology care in a longitudinal cohort study.

BACKGROUND: Electronic symptom monitoring via patient-reported outcome in surgical oncology is limited owing to lengthy instruments and non-specific items in common patient-reported outcome instruments. To establish electronic symptom monitoring through a clinically relevant and fit-for-purpose core set of patient-reported outcome in patients undergoing lung cancer surgery. MATERIALS AND METHODS: One qualitative (Cohort 1) and two prospective studies (Cohorts 2 and 3) were conducted between 2018 and 2023. Patients undergoing lung cancer surgery were recruited. Items of symptoms and daily functioning were generated through extensive interviews in Cohort 1 and incorporated into a smartphone-based platform to establish the electronic Perioperative Symptom Assessment for Lung surgery (ePSA-Lung). This tool was finalized and validated in Cohort 2. Patients in Cohort 3 were longitudinally monitored for the first year post-surgery using the validated ePSA-Lung. RESULTS: In total, 1,037 patients scheduled for lung cancer surgery were recruited. The 11-item draft PSA-Lung was generated based on qualitative interview with 39 patients and input from a Delphi study involving 42 experts. A 9-item ePSA-Lung was finalized by assessing 223 patients in the validation cohort; the results supported the instrument's understandability, reliability, sensitivity, and surgical specificity. In Cohort 3 (n=775), compliance ranged from 63.21% to 84.76% during the one-year follow-up after discharge. Coughing, shortness of breath, and disturbed sleep were the most severe symptoms after discharge. Longitudinally, patients who underwent single-port video-assisted thoracic surgery had a lower symptom burden than those who underwent multi-port video-assisted thoracic surgery or thoracotomy (all symptoms, P<0.001). CONCLUSION: The ePSA-Lung is valid, concise, and clinically applicable as it supports electronic symptom monitoring in surgical oncology care. The need for long-term extensive care was identified for patients after discharge, even in early-stage cancer with potential curative treatment.

Pitfalls in Developing Machine Learning Models for Predicting Cardiovascular Diseases: Challenge and Solutions.

UNSTRUCTURED: In recent years, there has been an explosive development of artificial intelligence (AI), which has been widely applied in the healthcare field. As a typical AI technology, machine learning (ML) models have emerged as great potential in predicting cardiovascular diseases (CVDs) by leveraging large amounts of medical data for training and optimization, which are expected to play a crucial role in reducing the incidence and mortality rates of CVDs. Although the field has become a research hotspot, there are still many pitfalls that researchers need to pay close attention to. These pitfalls may affect the predictive performance, credibility, reliability, reproducibility of the studied models, ultimately reducing the value of the research and affecting the prospects for clinical application. Therefore, identifying and avoiding these pitfalls is a crucial task before implementing the research. However, there is currently a lack of comprehensive summary on this topic. This viewpoint aims to analyze the existing problems in terms of data quality, dataset characteristics, model design and statistical methods as well as clinic implication, and provide possible solutions to these problems, like gathering objective data, improving training, repeating measurements, increasing sample size, preventing overfitting using statistical methods, utilizing specific AI algorithms to address targeted issues, standardizing outcomes and evaluation criteria, as well as enhancing fairness and replicability, with the goal of offering reference and assistance to researchers, algorithm developers, policy makers, and clinical practitioners.

Association of Vitamin A and D Deficiencies with Infectious Outcomes in Children Undergoing Intensive Induction Therapy for Acute Lymphoblastic Leukemia.

OBJECTIVE: To evaluate the association between deficiency of vitamin A or D at diagnosis of pediatric acute lymphoblastic leukemia (ALL) and subsequent infectious complications during induction therapy. STUDY DESIGN: An IRB-approved, retrospective cohort study of children diagnosed with newly-diagnosed ALL from 2007 to 2017 at St. Jude Children's Research Hospital. We measured vitamin D, vitamin D binding protein, retinol binding protein as a surrogate for vitamin A, and immunoglobulin isotypes in serum obtained at ALL diagnosis, and we assessed the association between vitamin deficiencies or levels and infection-related complications during the 6-week induction phase using Cox regression models. RESULTS: Among 378 evaluable participants, vitamin A and D deficiencies were common (43% and 17% respectively). Vitamin D deficiency was associated with higher risks of febrile neutropenia (adjusted hazard ratio [aHR] 1.7; p=0.0072), clinically-documented infection (aHR 1.73; p=0.025), and likely bacterial infection (aHR 1.86; p=0.008). Conversely, vitamin A deficiency was associated solely with a reduced risk of sepsis (aHR 0.19; p=0.027). CONCLUSIONS: In this retrospective study, vitamin D deficiency was associated with an increased risk of common infection-related complications during induction therapy for ALL. Additional studies are warranted to evaluate whether vitamin D supplementation could mitigate this effect.

Clinical efficacy of CDK4/6 inhibitor plus endocrine therapy in HR-positive/HER2-0 and HER2-low-positive metastatic breast cancer: a secondary analysis of PALOMA-2 and PALOMA-3 trials.

BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with traditional endocrine therapy (ET) are now the recommended first-line treatment for hormone receptor (HR)-positive and HER2-negative metastatic breast cancer (MBC). However, the benefits of adding CDK4/6 inhibitors to ET in HER2-low-positive and HER2-0 subgroups remain unclear. We aimed to assess the effectiveness of CDK4/6 inhibitors in combination with ET in patients with HR-positive, HER2-low-positive and HER2-0 MBC. METHODS: This secondary analysis assessed progression-free survival (PFS) among HER2-low-positive and HER2-0 patients enrolled in the double-blind, placebo-controlled randomised clinical trials PALOMA-2 and PALOMA-3. The study included 1186 HER2-negative, HR-positive female patients, with available immunohistochemistry (IHC) and/or in situ hybridization (ISH) results, across 17 countries enrolled between February 2013 and August 2014. HER2-low-positive status was defined by IHC 1+ or 2+ with negative ISH, and HER2-zero by IHC 0. Data analyses were conducted between March and May 2023. In the PALOMA-2 trial, patients were randomly assigned to receive either palbociclib or placebo, in combination with letrozole in the first-line treatment for HR-positive MBC. Patients in the PALOMA-3 study, who had progression or relapse during previous ET, were randomly allocated to receive either palbociclib plus fulvestrant or placebo plus fulvestrant. The primary endpoint was investigator-assessed PFS. Kaplan-Meier approach and Cox proportional hazards model were applied to estimate the association of treatment strategies with PFS among HER2-0 and HER2-low-positive populations. The two trials are registered with ClinicalTrials.gov, number NCT01740427 and NCT01942135. FINDINGS: Of the 666 patients with MBC from the PALOMA-2 study, there were 153 HER2-0 and 513 HER2-low-positive patients. In the HER2-0 population, no significant difference in PFS was observed between the palbociclib-letrozole and placebo-letrozole groups (hazard ratio = 0.79, 95% confidence interval [CI] 0.48-1.30, p = 0.34). In the HER2-low-positive population, palbociclib-letrozole demonstrated a significantly lower risk of PFS than placebo-letrozole group (hazard ratio = 0.52, 95% CI 0.41-0.66, p < 0.0001). The PALOMA-3 study analysed 520 patients with MBC. Within the 153 HER2-0 patients, the palbociclib-fulvestrant group showed a significantly longer PFS than the placebo-fulvestrant group (hazard ratio = 0.54, 95% CI 0.30-0.95, p = 0.034). Among the 367 HER2-low-positive patients, palbociclib-fulvestrant improved PFS (hazard ratio = 0.39, 95% CI 0.28-0.54, p < 0.0001). INTERPRETATION: The combination of a CDK4/6 inhibitor with ET significantly improved PFS in HER2-low-positive patients, while for HER2-0 patients, benefits were primarily observed in patients who had progressed on previous ET. Furthermore, HER2-0 patients may derive limited benefits from first-line CDK4/6 inhibitor treatment. Further work is needed to validate these findings and to delineate patient subsets that are most likely to benefit from the combination of CDK4/6 inhibitors and ET as first-line treatments. FUNDING: None.