Combined image-guided radiofrequency and iodine-125 seeds implantation in the treatment of recurrent hepatocellular carcinoma after hepatectomy.

BACKGROUND: Currently, there is no consensus on the treatment of recurrent hepatocellular carcinoma (HCC) after hepatectomy. It is necessary to assess the efficacy and safety of radiofrequency ablation (RFA) combined with iodine-125 seeds implantation (RFA-125I) in the treatment of recurrent HCC. METHODS: This study retrospectively analyzed the clinical data of patients with postoperative recurrence of HCC receiving RFA-125I or RFA treatment from January 2013 to January 2023. Both RFA and 125I seeds implantation were performed under dual guidance of ultrasound and CT. Overall survival (OS), progression-free survival (PFS), recurrence, and complications were compared between the two groups. RESULTS: A total of 210 patients with recurrent HCC were enrolled in this study, including 125 patients in the RFA-125I group and 85 patients in the RFA group. The RFA-125I group showed a significantly better survival benefit than RFA group (median OS: 37 months vs. 16 months, P < 0.001; median PFS: 15 months vs. 10 months, P = 0.001). The uni- and multivariate analysis showed that RFA-125I was a protective factor for OS and PFS. There were no procedure-related deaths and no grade 3 or higher adverse events in both groups. CONCLUSIONS: RFA combined with 125I seeds implantation under dual guidance of ultrasound and CT is effective and safe for the treatment of HCC patients with recurrence after hepatectomy.

Characteristics and patient-reported outcomes of long-term cancer survivors after apatinib-based therapy: an online survey.

BACKGROUND: Data on long-term cancer survivors treated with apatinib are lacking. This study aimed to describe the characteristics of long-term cancer survivors after apatinib-based therapy, and to know about their satisfaction degree with apatinib and severity of depression and insomnia. METHODS: Patients with solid tumors who had received apatinib-based therapy for at least 5 years were invited to complete an online questionnaire. Characteristics of patients and treatment, knowledge of apatinib, satisfaction degree, and severity of depression and insomnia assessed by Patient Health Questionnaire-9 and Insomnia Severity Index were collected. RESULTS: Between December 8, 2023 and March 1, 2024, a total of 436 patients completed the online questionnaire. Most patients were satisfied with the efficacy (96.6%) and safety (93.1%) of apatinib, were willing to continue apatinib treatment (99.5%), and would recommend apatinib to other patients (93.3%). Continuous apatinib treatment resulted in significant negative impact on daily life, work, or study in only two (0.5%) patients. Almost all patients currently had no or mild depression (97.0%) and insomnia (97.9%) problems. The most common patient-reported adverse events were hand-foot syndrome (21.3%) and hypertension (18.3%). CONCLUSIONS: Our survey showed a high satisfaction degree with apatinib in long-term cancer survivors. Long-term apatinib treatment resulted in almost no negative impact on patient's quality of life.

A Transformer-Based microvascular invasion classifier enhances prognostic stratification in HCC following radiofrequency ablation.

BACKGROUND & AIMS: We aimed to develop a Transformer-based deep learning (DL) network for prognostic stratification in hepatocellular carcinoma (HCC) patients undergoing RFA. METHODS: A Swin Transformer DL network was trained to establish associations between magnetic resonance imaging (MRI) datasets and the ground truth of microvascular invasion (MVI) based on 696 surgical resection (SR) patients with solitary HCC ≤3 cm, and was validated in an external cohort (n = 180). The multiphase MRI-based DL risk outputs using an optimal threshold of .5 was employed as a MVI classifier for prognosis stratification in the RFA cohort (n = 180). RESULTS: Over 90% of all enrolled patients exhibited hepatitis B virus infection. Liver cirrhosis was significantly more prevalent in the RFA cohort compared to the SR cohort (72.2% vs. 44.1%, p < .001). The MVI risk outputs exhibited good performance (area under the curve values = .938 and .883) for predicting MVI in the training and validation cohort, respectively. The RFA patients at high risk of MVI classified by the MVI classifier demonstrated significantly lower recurrence-free survival (RFS) and overall survival rates at 1, 3 and 5 years compared to those classified as low risk (p < .001). Multivariate cox regression modelling of a-fetoprotein > 20 ng/mL [hazard ratio (HR) = 1.53; 95% confidence interval (95% CI): 1.02-2.33, p = .047], high risk of MVI (HR = 3.76; 95% CI: 2.40-5.88, p < .001) and unfavourable tumour location (HR = 2.15; 95% CI: 1.40-3.29, p = .001) yielded a c-index of .731 (bootstrapped 95% CI: .667-.778) for evaluating RFS after RFA. Among the three risk factors, MVI was the most powerful predictor for intrahepatic distance recurrence. CONCLUSIONS: The proposed MVI classifier can serve as a valuable imaging biomarker for prognostic stratification in early-stage HCC patients undergoing RFA.

Postmarketing safety profile of brexanolone: a pharmacovigilance analysis based on FDA Adverse Event Reporting System (FAERS).

OBJECTIVE: Brexanolone (Zulresso®) that was approved for the USA in March 2019 is indicated for the treatment of postpartum depression (PPD), but information on adverse drug reactions (ADRs) associated with its use is limited. The main aim of this study was to explore the postmarketing safety profile of brexanolone. METHODS: In our case/non-case pharmacovigilance study based on the FDA Adverse Event Reporting System (FAERS), the reporting odds ratio and information component with 95% confidence intervals were estimated as measures of disproportionate reporting. Primary disproportionality analyses were performed by comparing brexanolone with all other drugs or selective serotonin reuptake inhibitors (SSRIs). Sensitivity analyses were performed on a subset of perinatal depression. RESULTS: We identified 267 cases using brexanolone. Brexanolone was reported as a primary or secondary suspect drug in most cases (n = 260, 97.38%). Of the total brexanolone cases, positive dechallenge and discontinuation accounted for 12.36% (n = 33) and 26.22% (n = 70), respectively. Serious outcomes were reported in 11.61% (n = 31) patients. Compared to all the other drugs or SSRIs within the same time window, the reporting risks of brexanolone were mainly from psychiatric and nervous systems. Sensitivity analyses indicated that these significant disproportionalities were mostly retained. CONCLUSION: Our pharmacovigilance analysis showed a high reporting frequency of psychiatric and nervous system ADRs associated with the use of brexanolone. In additional prospective research, these signals urgently need to be clarified.

Improved clinical outcomes in advanced hepatocellular carcinoma treated with transarterial chemoembolization plus atezolizumab and bevacizumab: a bicentric retrospective study.

PURPOSE: The aim of the present study was to assess the efficacy and safety of transarterial chemoembolization (TACE) combined with atezolizumab and bevacizumab (hereafter, TACE-Atez/Bev) in the treatment of advanced hepatocellular carcinoma (HCC) patients. MATERIALS AND METHODS: Clinical information was collected from consecutive patients with advanced HCC who received treatment with TACE-Atez/Bev or Atez/Bev from April 2021 and October 2022. Treatment response, overall survival (OS), and progression-free survival (PFS) were the primary outcomes of this study. Adverse events (AEs) were the secondary outcomes. Propensity score matching (PSM) analysis was applied to reduce bias between two groups. RESULTS: This study included 62 patients in the TACE-Atez/Bev group and 77 patients in the Atez/Bev group. The objective response rate (ORR) of the TACE-Atez/Bev group and the Atez/Bev group were 38.7% and 16.9% (P=0.004). However, there was no statistical difference in disease control rate between the two groups (69.4% vs 63.6%, P=0.479). Before PSM, the median OS was 14 months in the TACE-Atez/Bev group and 10 months in the Atez/Bev group (P=0.014). The median PFS in the TACE-Atez/Bev and Atez/Bev groups was 10 months and 6 months, respectively (P=0.001). After PSM, the median OS in the two groups was 14 months and 9 months, respectively (P=0.01). The median PFS was 7 months and 6 months, respectively (P=0.036). Multivariable analysis showed that treatment method was independent prognostic factors affecting OS. CONCLUSIONS: Compared with Atez/Bev treatment, TACE-Atez/Bev showed better OS, PFS, and ORR for Chinese patients with advanced HCC, with an acceptable safety profile.

Relationship between caffeine intake and thyroid function: results from NHANES 2007-2012.

BACKGROUND: Moderate caffeine intake decreases the risk of metabolic disorders and all-cause mortality, and the mechanism may be related to its ergogenic actions. Thyroid hormones are vital in metabolic homeostasis; however, their association with caffeine intake has rarely been explored. OBJECTIVE: To investigate the association between caffeine intake and thyroid function. METHODS: We collected data on demographic background, medical conditions, dietary intake, and thyroid function from the National Health and Nutrition Examination Survey (NHANES) 2007-2012. Subgroups were classified using two-step cluster analysis, with sex, age, body mass index (BMI), hyperglycemia, hypertension, and cardio-cerebral vascular disease (CVD) being used for clustering. Restrictive cubic spline analysis was employed to investigate potential nonlinear correlations, and multivariable linear regression was used to evaluate the association between caffeine consumption and thyroid function. RESULTS: A total of 2,582 participants were included, and three subgroups with different metabolic features were clustered. In the most metabolically unhealthy group, with the oldest age, highest BMI, and more cases of hypertension, hyperglycemia, and CVD, there was a nonlinear relationship between caffeine intake and serum thyroid stimulating hormone (TSH) level. After adjusting for age, sex, race, drinking, smoking, medical conditions, and micronutrient and macronutrient intake, caffeine intake of less than 9.97 mg/d was positively associated with serum TSH (p = 0.035, standardized ß = 0.155); however, moderate caffeine consumption (9.97-264.97 mg/d) indicated a negative association (p = 0.001, standardized ß = - 0.152). CONCLUSIONS: Caffeine consumption had a nonlinear relationship with serum TSH in people with metabolic disorders, and moderate caffeine intake (9.97 ~ 264.97 mg/d) was positively associated with serum TSH.

A Multiparametric Fusion Deep Learning Model Based on DCE-MRI for Preoperative Prediction of Microvascular Invasion in Intrahepatic Cholangiocarcinoma.

BACKGROUND: Assessment of microvascular invasion (MVI) in intrahepatic cholangiocarcinoma (ICC) by using a noninvasive method is an unresolved issue. Deep learning (DL) methods based on multiparametric fusion of MR images have the potential of preoperative assessment of MVI. PURPOSE: To investigate whether a multiparametric fusion DL model based on MR images can be used for preoperative assessment of MVI in ICC. STUDY TYPE: Retrospective. POPULATION: A total of 519 patients (200 females and 319 males) with a single ICC were categorized as a training (n = 361), validation (n = 90), and an external test cohort (n = 68). FIELD STRENGTH/SEQUENCE: A 1.5 T and 3.0 T; axial T2-weighted turbo spin-echo sequence, diffusion-weighted imaging with a single-shot spin-echo planar sequence, and dynamic contrast-enhanced (DCE) imaging with T1-weighted three-dimensional quick spoiled gradient echo sequence. ASSESSMENT: DL models of multiparametric fusion convolutional neural network (CNN) and late fusion CNN were both constructed for evaluating MVI in ICC. Gradient-weighted class activation mapping was used for visual interpretation of MVI status in ICC. STATISTICAL TESTS: The DL model performance was assessed through the receiver operating characteristic curve (ROC) analysis, and the area under the ROC curve (AUC) with the accuracy, sensitivity, and specificity were measured. P value < 0.05 was considered as statistical significance. RESULTS: In the external test cohort, the proposed multiparametric fusion DL model achieved an AUC of 0.888 with an accuracy of 86.8%, sensitivity of 85.7%, and specificity of 87.0% for evaluating MVI in ICC, and the positive predictive value and negative predictive value were 63.2% and 95.9%, respectively. The late fusion DL model achieved a lower AUC of 0.866, with an accuracy of 83.8%, sensitivity of 78.6%, specificity of 85.2% for evaluating MVI in ICC. DATA CONCLUSION: Our DL model based on multiparametric fusion of MRI achieved a good diagnostic performance in the evaluation of MVI in ICC. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Development and Application of Three Steps Training Mode for Endoscopic Transnasal Transsphenoidal Approach.

OBJECTIVE: The model of endoscopic transnasal transsphenoidal approach (METTA) were made and the application of the 3-steps training mode in the endoscopic transnasal transsphenoidal approach (ETTA) training was discussed. METHODS: The plastic skull model was used to make a simple METTA model; the multicolor and multi-material 3D printing technology was used to make a METTA simulation model and the perfusion cadaver head specimen was used as the gold standard training model. Then 3 neurosurgeons evaluated the 3 types of models. Level 1 training group only received perfusion cadaveric head specimen training; level 2 training group with 3D printing METTA model plus cadaver head specimen training, and level 3 training group with simple model, 3D printing model and cadaver head specimen training group. The authenticity of the model and the training effect were evaluated according to the operation time and the damage degree to the surrounding structures. RESULTS: The results showed that perfusion cadaveric head specimens scored the highest in each item. The simplified model was superior to the 3D printing METTA in simulating the shape and elasticity of pituitary tumor tissue. The score of surgical skill training was the same as that of 3D printing METTA. In terms of the training effect, the doctors who had received 3 steps training had the highest score, which was better than the other 2 groups. CONCLUSIONS: The application of 3 steps training mode with simple training model, 3D printing model and perfusion cadaver head specimen can improve the effect of ETTA operation training.

LncRNA MEG8 Attenuates Cerebral Ischemia After Ischemic Stroke Through Targeting miR-130a-5p/VEGFA Signaling.

MEG8 is involved in ischemia stroke, however, its role in ischemia stroke remains unknown. The current research aimed to investigate the effects and mechanisms of MEG8 in ischemic stroke. Mouse brain microvascular endothelial cells (BMECs) were treated by oxygen-glucose deprivation (OGD). Then, the expressions of MEG8 and miR-130a-5p were detected by quantitative reverse transcription-polymerase chain reaction (q-PCR). Cell counting kit-8 (CCK-8), wound-healing, tube formation, Western blot, and q-PCR assays were performed to detect the effects of MEG8 and miR-130a-5p on cell viability, migration, and angiogenesis and VEGFA expression. Bioinformatics, dual-luciferase reporter assay, and RNA immunoprecipitation analysis were carried out to investigate the targeting relationship between MEG8 and miR-130a-5p, and between miR-130a-5p and VEGFA. Then, rat middle cerebral artery occlusion (MCAO) model and MEG8 overexpression MCAO model were established, and neurological deficit and infarct volume of the model rats were evaluated. Finally, Western blot and q-PCR were carried out to detect the expressions of MEG8, miR-130a-5p, and VEGFA. MEG8 was upregulated and miR-130a-5p was downregulated in OGD-treated BMECs. MiR-130a-5p was found to be a target of MEG8, and VEGFA was predicted to be a potential target of miR-130a-5p. Downregulation of MEG8 inhibited the cell viability, migration, and angiogenesis and the expression of VEGFA via negatively regulating miR-130a-5p of BMECs treated by OGD/non-OGD. In addition, MEG8 reduced cerebral ischemia, neurological score and miR-130a-5p expression, and increased VEGFA expression of MCAO rat. Our findings proved that MEG8 regulates angiogenesis and attenuates cerebral ischemia after ischemic stroke via miR-130a-5p/VEGFA signaling.

Electromagnetic navigation to assist with computed tomography-guided thermal ablation of liver tumors.

Purpose: To evaluate the advantages and primary technical efficacy of an electromagnetic (EM) navigation system for computed tomography (CT)-guided thermal ablation of liver tumors.Material and methods: From August 2016 to January 2018, 40 patients scheduled for CT- guided thermal ablation were prospectively enrolled and divided into two groups. Twenty patients underwent CT-guided thermal ablation with an EM navigation system (navigation group), while the other 20 patients underwent conventional CT-guided thermal ablation (control group). Data on skin punctures, instrument adjustments, puncture time to target, CT scans, CT fluoroscopy time and dose-length-product (DLP) were compared between the two groups. Any postoperative complications were recorded and the primary technical efficacy was evaluated four to six weeks after the procedure.Results: All 20 patients in the navigation group successfully underwent EM navigation. Compared to the control group, there were fewer instrument adjustments (mean 2.40 vs. 4.95; p = .003), fewer CT scans (mean 7.10 vs. 10.30; p = .006), less CT fluoroscopy time (mean 40.47 vs. 59.98 s, p = .046), and less DLP (mean 807.39 vs. 1578.67 mGy × cm; p = .001). Although not statistically significant, EM navigation resulted in fewer skin punctures (mean 1.20 vs. 1.25; p = .803) and slightly longer puncture time to target (mean 16.50 vs. 15.20 min; p = .725). No patients experienced major complications and the primary efficacy rate was 90% and 84.21% in the navigation and control groups, respectively (p = .661).Conclusions: EM navigation system optimizes the thermal ablation process and reduces radiation exposure in patients. However, further studies are warranted to determine whether an EM navigation system can improve procedure time, complication rates, and primary technical efficiacy of thermal ablation.

Multimaterial and multicolor 3D-printed model in training of transnasal endoscopic surgery for pituitary adenoma.

OBJECTIVE: The aim of the present study was to investigate the practical value of a multimaterial and multicolor 3D-printed model in anatomical teaching, surgical training, and preoperative planning of transnasal endoscopic surgery for pituitary adenoma. METHODS: Multimodality neuroimaging data were obtained in a 42-year-old healthy male volunteer and a 40-year-old female patient with an invasive nonfunctional pituitary adenoma. Three 3D-printed models were produced: a monomaterial and monocolor model, a monomaterial and multicolor model, and a multimaterial and multicolor model. The effects on anatomical teaching and surgical training for exposing the vidian nerve were assessed by 12 residents, and the training effect was validated on cadavers. The practical values for preoperative planning were evaluated by 6 experienced neurosurgeons. All evaluations were based on 5-point Likert questionnaires. RESULTS: The multimaterial and multicolor model was superior to the monomaterial models in surgical training for exposing the vidian nerve (Fisher test; p < 0.05). In addition, the multimaterial and multicolor model was superior to the monomaterial models in anatomical teaching and preoperative planning (Friedman test; p < 0.05). CONCLUSIONS: Multimaterial and multicolor 3D printing technology makes it convenient and efficient to produce a practical model for simulating individualized and complex anatomical structures in the sellar region. Furthermore, the multimaterial model can provide a more realistic manipulative experience for surgical training and facilitate the preoperative planning.

QuikLitE, a Framework for Quick Literacy Evaluation in Medicine: Development and Validation.

BACKGROUND: A plethora of health literacy instruments was developed over the decades. They usually start with experts curating passages of text or word lists, followed by psychometric validation and revision based on test results obtained from a sample population. This process is costly and it is difficult to customize for new usage scenarios. OBJECTIVE: This study aimed to develop and evaluate a framework for dynamically creating test instruments that can provide a focused assessment of patients' health literacy. METHODS: A health literacy framework and scoring method were extended from the vocabulary knowledge test to accommodate a wide range of item difficulties and various degrees of uncertainty in the participant's answer. Web-based tests from Amazon Mechanical Turk users were used to assess reliability and validity. RESULTS: Parallel forms of our tests showed high reliability (correlation=.78; 95% CI 0.69-0.85). Validity measured as correlation with an electronic health record comprehension instrument was higher (.47-.61 among 3 groups) than 2 existing tools (Short Assessment of Health Literacy-English, .38-.43; Short Test of Functional Health Literacy in Adults, .34-.46). Our framework is able to distinguish higher literacy levels that are often not measured by other instruments. It is also flexible, allowing customizations to the test the designer's focus on a particular interest in a subject matter or domain. The framework is among the fastest health literacy instrument to administer. CONCLUSIONS: We proposed a valid and highly reliable framework to dynamically create health literacy instruments, alleviating the need to repeat a time-consuming process when a new use scenario arises. This framework can be customized to a specific need on demand and can measure skills beyond the basic level.

Long non-coding RNA GAS5 aggravates hypoxia injury in PC-12 cells via down-regulating miR-124.

One important feature of cerebral ischemia is hypoxia injury in nerve cells. Growth arrest-specific transcript 5 (GAS5) is widely reported as a tumor suppressor gene; however, the investigations about its role in cerebrovascular disease are relatively rare. This study was aimed to explore the impact of GAS5 on hypoxia response in nervous cells. PC-12 cells were incubated under anoxic condition to induce hypoxia injury. Regulatory effects of GAS5 on miR-124 and miR-124 on ICAM-1 expression were assessed by qRT-PCR and/or Western blot. Targeting effect of miR-124 on ICAM-1 3'-untranslated regions (UTR) was evaluated through dual luciferase activity assay. The potential regulatory mechanism on hypoxia injury in PC-12 cells was assessed by detecting key elements of NF-κB and Notch signaling pathways using Western blot. GAS5 ectopic expression accentuated hypoxia injury in PC-12 cells. miR-124 expression was negatively regulated by GAS5 expression. Cells with overexpressions of GAS5 and miR-124 alleviated hypoxia injury as in compassion with cells only with GAS5 overexpression. ICAM-1 expression was negatively regulated by miR-124 expression. ICAM-1 was a functional target of miR-124. ICAM-1 overexpression aggravated hypoxia injury, but inversely, ICAM-1 silence diminished hypoxia damage. Besides, ICAM-1 expression was negatively related with activation of NF-κB and Notch pathways. GAS5-miR-124-ICAM-1 axis could regulate hypoxia injury in PC-12 cells. GAS5 might aggravate hypoxia injury via down-regulating miR-124, then up-regulating ICAM-1, and further enhancing activations of NF-κB and Notch pathways.

Readability Formulas and User Perceptions of Electronic Health Records Difficulty: A Corpus Study.

BACKGROUND: Electronic health records (EHRs) are a rich resource for developing applications to engage patients and foster patient activation, thus holding a strong potential to enhance patient-centered care. Studies have shown that providing patients with access to their own EHR notes may improve the understanding of their own clinical conditions and treatments, leading to improved health care outcomes. However, the highly technical language in EHR notes impedes patients' comprehension. Numerous studies have evaluated the difficulty of health-related text using readability formulas such as Flesch-Kincaid Grade Level (FKGL), Simple Measure of Gobbledygook (SMOG), and Gunning-Fog Index (GFI). They conclude that the materials are often written at a grade level higher than common recommendations. OBJECTIVE: The objective of our study was to explore the relationship between the aforementioned readability formulas and the laypeople's perceived difficulty on 2 genres of text: general health information and EHR notes. We also validated the formulas' appropriateness and generalizability on predicting difficulty levels of highly complex technical documents. METHODS: We collected 140 Wikipedia articles on diabetes and 242 EHR notes with diabetes International Classification of Diseases, Ninth Revision code. We recruited 15 Amazon Mechanical Turk (AMT) users to rate difficulty levels of the documents. Correlations between laypeople's perceived difficulty levels and readability formula scores were measured, and their difference was tested. We also compared word usage and the impact of medical concepts of the 2 genres of text. RESULTS: The distributions of both readability formulas' scores (P<.001) and laypeople's perceptions (P=.002) on the 2 genres were different. Correlations of readability predictions and laypeople's perceptions were weak. Furthermore, despite being graded at similar levels, documents of different genres were still perceived with different difficulty (P<.001). Word usage in the 2 related genres still differed significantly (P<.001). CONCLUSIONS: Our findings suggested that the readability formulas' predictions did not align with perceived difficulty in either text genre. The widely used readability formulas were highly correlated with each other but did not show adequate correlation with readers' perceived difficulty. Therefore, they were not appropriate to assess the readability of EHR notes.

Arterial compression of nerve is the primary cause of trigeminal neuralgia.

Whether arterial or venous compression or arachnoid adhesions are primarily responsible for compression of the trigeminal nerve in patients with trigeminal neuralgia is unclear. The aim of this study was to determine the causes of trigeminal nerve compression in patients with trigeminal neuralgia. The surgical findings in patients with trigeminal neuralgia who were treated by micro vascular decompression were compared to those in patients with hemifacial spasm without any signs or symptoms of trigeminal neuralgia who were treated with microvascular decompression. The study included 99 patients with trigeminal neuralgia (median age, 57 years) and 101 patients with hemifacial spasm (median age, 47 years). There were significant differences between the groups in the relationship of artery to nerve (p < 0.001) and the presence of arachnoid adhesions (p < 0.001) but no significant difference in relationship of vein to nerve. After adjustment for age, gender, and other factors, patients with vein compression of nerve or with artery compression of nerve were more likely to have trigeminal neuralgia (OR = 5.21 and 42.54, p = 0.026 and p < 0.001, respectively). Patients with arachnoid adhesions were less likely to have trigeminal neuralgia (OR = 0.15, p = 0.038). Arterial compression of the trigeminal nerve is the primary cause of trigeminal neuralgia and therefore, decompression of veins need not be a priority when performing microvascular dissection in patients with trigeminal neuralgia.

Metformin-Cimetidine Drug Interaction and Risk of Lactic Acidosis in Renal Failure: A Pharmacovigilance-Pharmacokinetic Appraisal.

OBJECTIVE: This study aimed to evaluate lactic acidosis (LA) risk when using metformin combined with histamine H2 receptor inhibitors (H2RI) in patients with renal failure (RF). RESEARCH DESIGN AND METHODS: This study analyzed FDA Adverse Event Reporting System data (2012Q4 to 2022Q4) to characterize reports of LA associated with metformin alone or combined with H2RI. Using a disproportionality approach, LA risk signal in the overall population and in patients with RF was assessed. A physiologically based pharmacokinetic (PBPK) model was developed to predict metformin and cimetidine pharmacokinetic changes following conventional doses of the combinations in patients with various degrees of RF. To explore its correlation with LA risk, a peak plasma metformin concentration of 3 mg/L was considered the threshold. RESULTS: Following the 2016 U.S. Food and Drug Administration metformin approval for mild-to-moderate RF, the percentage of patients with RF reporting LA associated with metformin combined with H2RI increased. Disproportionality analysis showed reported LA risk signal associated with metformin and cimetidine in the overall population within the study timeframe only. Furthermore, with PBPK simulations, for metformin (1,000 mg b.i.d.) with cimetidine (300 mg q.i.d. or 400 mg b.i.d.) in stage 1 of chronic kidney disease, metformin (1,000 mg b.i.d.) with cimetidine (300 mg q.i.d. or 400 mg b.i.d. or 800 mg q.d.) in stage 2, and most combinations in stage 3, the peak plasma metformin concentrations exceeded the 3 mg/L threshold. CONCLUSIONS: Metformin combined with cimetidine at conventional doses may cause LA in patients with mild-to-moderate RF.

C-reactive protein and cognitive impairment: A bidirectional Mendelian randomization study.

OBJECTIVES: While C-reactive protein (CRP) has been solidly linked as a risk factor for cognitive impairment, observational research alone cannot definitively demonstrate a causal relationship. This study therefore sought to determine whether there was an association between CRP and the development of cognitive impairment. METHODS: This study employed bidirectional Mendelian randomization (MR) to investigate the genetic association between CRP and cognitive impairment. genome-wide association studies (GWAS) summary statistics for both were sourced from IEU Open GWAS or prior reports. Cognitive GWAS's used were on tests designed to assess cognitive performance, fluid intelligence, prospective memory, and reaction time. The MR analysis applied several methods, including inverse variance-weighted (IVW), MR Egger, weighted median, simple mode, and weighted mode approaches, then use of MR sensitivity analyses to interrogate findings. RESULTS: Forward MR analysis showed that genetically proxied CRP was associated with prospective memory (P = 0.009), whereas there is little evidence to support an association between CRP and other cognitive tests. Reverse MR analysis indicated a potential association between genetic proxy cognitive performance (P = 0.002) and fluid intelligence score (P = 0.019) with CRP levels. For genetically proxied CRP on prospective memory, the level of pleiotropy (P > 0.05) and no genetic variant heterogeneity (P > 0.05) made bias unlikely, and leave-one-out tests also confirmed robust associations. CONCLUSIONS: The effect of genetically proxied CRP on prospective memory, with little evidence on other cognitive tests. The reverse MR shows some evidence of genetically proxied cognition (cognitive performance and fluid intelligence) on CRP levels.

MiR-339-5p Inhibits Ferroptosis by Promoting Autophagic Degradation of FTH1 Through Targeting ATG7 in Liver Cancer Cells.

Background: Liver cancer has a high incidence and mortality rate worldwide, and there is an urgent need to identify new therapeutic strategies and predictive targets to improve the clinical outcomes of advanced liver cancer. Ferroptosis holds promise as a novel strategy for cancer therapy. Epigenetic dysregulation is a hallmark of cancer, and noncoding RNAs are tightly involved in cell fate determination. Therefore, we aimed to identify a novel ferroptosis regulator from aberrantly expressed microRNAs that may serve as a novel biomarker and therapeutic target for liver cancer. Methods: The expression signature and prognostic value of miR-339 was assessed using TCGA data set. The role of miR-339/ATG7/FTH1 axis in liver cancer cells were evaluated through growth curve, colony formation, 7-AAD staining. The role of miR-339 in regulation of ferroptosis was determined by immunofluorescence staining, flow cytometry, and Elisa kits. Results: Here, we showed that miR-339 is aberrantly overexpressed in patients with liver cancer. In addition, miR-339 inhibition dramatically suppresses liver cancer progression. Furthermore, miR-339 silencing drives cell death and inhibits liver cancer progression, indicating that miR-339 may serve as a novel ferroptosis suppressor. Mechanistically, we demonstrated that miR-339 targets ATG7 to facilitate the autophagic degradation of FTH1 and prevent ferroptosis in liver cancer cells. Conclusions: We provide important evidence that the miR-339 inhibition activates of the autophagy pathway to promote ferroptosis by degrading FTH1 in liver cancer cells. We found that miR-339 regulates the balance between ferroptosis and autophagy in liver cancer cells.

The prognostic role of diet quality in patients with MAFLD and physical activity: data from NHANES.

BACKGROUND AND OBJECTIVES: Dietary control and increased physical activity (PA) are recommended for patients with metabolic (dysfunction-) associated fatty liver disease (MAFLD). However, not all patients can sustain both exercise and a healthy diet. This study explored the interaction between dietary quality, PA levels, and mortality in MAFLD patients. METHODS: The Third National Health and Nutrition Examination Survey and linked mortality data were used in this study. Diet quality was assessed with the Healthy Eating Index (HEI). PA level was calculated by multiply self-reported exercise frequency and its Metabolic Equivalent A high-quality diet was associated. A Cox proportional hazard model was used to explore risk factors for mortality in MAFLD patients. RESULTS: In total, 3709 participants with MAFLD were included in the final analysis. The median follow-up time was 26.2 (interquartile range 19.3-28.1) years and 1549 (41.8%) deaths were recorded over follow-up. Cox multivariate regression was used to adjust for potential confounders of mortality. The results showed both HEI score and PA level were inversely correlated with all-cause mortality (P < 0.05). In the subgroup analysis stratified by PA level, higher diet quality decreased all-cause mortality, cardiovascular-related mortality and cancer-related mortality in PA inactive of MAFLD patients (P < 0.05), but these correlations were not present in active PA groups. CONCLUSION: Healthy diet and physical activity may have different impact as lifestyle interventions for MAFLD. A high-quality diet is associated less mortality in inactive individuals with MAFLD but not in those with active PA levels. Sedentary individuals require healthier diet.

Nobiletin alleviates macrophage M2 polarization by activating AMPK-mTOR-mediated autophagy in pulmonary fibrosis mice.

Nobiletin (NOB), a polymethoxylated flavone isolated from citrus peels, is a promising dietary treatment for lung diseases, such as pulmonary fiborsis. In this work, the underlying mechanisms of NOB's preventative effect on pulmonary fibrosis were explored using bleomycin-exposed mice and IL-4-induced M2 polarization of the macrophages. Results showed that NOB treatment could significantly ameliorate lung fibrosis by suppressing pathological damages, collagen deposition, and fibroblat activation. Moreover, NOB obviously reduced the M2 macrophage-related proteins, including CD206, Arg1, and pro-fibrotic mediators such as TGF-ß and CTGF, which might contribute to the antifibrosis effect of NOB. Network analysis of the differentially expressed genes in NOB-treated M2 macrophages showed that autophagy, mTOR signaling pathway, and AMPK signaling pathway might be involved in the effects of NOB. Further exploration illustrated that autophagy was enhanced in NOB-treated lung and M2 macrophages.The addition of 3MA, an autophagy inhibitor, could significantly weaken the effect of NOB on lung fibrosis and macrophage M2 polarization. Additionally, NOB also markedly decreased the expression of p-AMPK, p-mTOR, and p-P70S6K in the M2 macrophages and lung tissues of BLM-exposed mice. Compound C, an AMPK agonist, significantly suppressed NOB-induced activation of AMPK and mTOR signals, as well as its inhibitory effect on autophagy, M2 macrophages and lung fibrosis both in vitro and in vivo, supporting the requirement of AMPK-mTOR-mediated autophagy for the NOB's antifibrosis activity. Taken together, this study suggests that NOB ameliorates pulmonary fibrosis likely involving the inhibition of M2 macrophage via activating AMPK-mTOR-mediated autophagy.