Family cascade screening for equitable identification of familial hypercholesterolemia: study protocol for a hybrid effectiveness-implementation type III randomized controlled trial.

BACKGROUND: Familial hypercholesterolemia (FH) is a heritable disorder affecting 1.3 million individuals in the USA. Eighty percent of people with FH are undiagnosed, particularly minoritized populations including Black or African American people, Asian or Asian American people, and women across racial groups. Family cascade screening is an evidence-based practice that can increase diagnosis and improve health outcomes but is rarely implemented in routine practice, representing an important care gap. In pilot work, we leveraged best practices from behavioral economics and implementation science-including mixed-methods contextual inquiry with clinicians, patients, and health system constituents-to co-design two patient-facing implementation strategies to address this care gap: (a) an automated health system-mediated strategy and (b) a nonprofit foundation-mediated strategy with contact from a foundation-employed care navigator. This trial will test the comparative effectiveness of these strategies on completion of cascade screening for relatives of individuals with FH, centering equitable reach. METHODS: We will conduct a hybrid effectiveness-implementation type III randomized controlled trial testing the comparative effectiveness of two strategies for implementing cascade screening with 220 individuals with FH (i.e., probands) per arm identified from a large northeastern health system. The primary implementation outcome is reach, or the proportion of probands with at least one first-degree biological relative (parent, sibling, child) in the USA who is screened for FH through the study. Our secondary implementation outcomes include the number of relatives screened and the number of relatives meeting the American Heart Association criteria for FH. Our secondary clinical effectiveness outcome is post-trial proband cholesterol level. We will also use mixed methods to identify implementation strategy mechanisms for implementation strategy effectiveness while centering equity. DISCUSSION: We will test two patient-facing implementation strategies harnessing insights from behavioral economics that were developed collaboratively with constituents. This trial will improve our understanding of how to implement evidence-based cascade screening for FH, which implementation strategies work, for whom, and why. Learnings from this trial can be used to equitably scale cascade screening programs for FH nationally and inform cascade screening implementation efforts for other genetic disorders. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05750667. Registered 15 February 2023-retrospectively registered, https://clinicaltrials.gov/study/NCT05750667 .

Unconsciousness as the main nonfocal symptom of anterior circulation transient ischemic attack: A case report.

RATIONALE: Unconsciousness is a nonfocal symptom of transient ischemic attack (TIA) that is frequently observed in patients with vertebrobasilar artery stenosis or occlusion. Conversely, loss of consciousness due to anterior circulation involvement (e.g., middle cerebral artery [MCA]) is a rare occurrence in TIA. PATIENT CONCERNS: This report describes a rare case in a 59-year-old woman who experienced recurrent episodes of altered consciousness because of the occlusion or stenosis of her MCAs. DIAGNOSES: The diagnosis of the case was updated from TIA to acute cerebral infarction, finally. Following initial loss of consciousness, cranial magnetic resonance imaging (MRI) did not reveal any evidence of acute cerebral infarction. However, following the second and third episodes of unconsciousness, the MRI revealed multiple new acute cerebral infarcts affecting both the cerebral hemispheres. Further evaluation through digital subtraction angiography disclosed complete occlusion of the left MCA and severe stenosis of the right MCA. INTERVENTIONS: Early in her illness, the patient was treated with vasodilators, aspirin and atorvastatin. Finally, 2 stents in her right and left MCAs were placed respectively, followed by treatment with aspirin, clopidogrel, and double-dosed atorvastatin calcium. Meanwhile, the patient focused on avoiding conditions which may lead to dehydration in her daily life routine. OUTCOMES: The episodes of unconsciousness of this patient were completely resolved. During the 1-year postoperative follow-up, the patient remained clinically stable without any symptoms of unconsciousness, limb numbness or weakness, or dizziness. LESSONS: These findings suggested that hypoperfusion in the bilateral cerebral hemispheres played a pivotal role in precipitating the patient episodes of unconsciousness. This case underscores the possibility that occlusion or severe stenosis in both MCAs can contribute to recurrent episodes of unconsciousness due to hypoperfusion. Moreover, it emphasizes the association between these episodes of unconsciousness and an increased risk of subsequent ischemic stroke.

Association between tea consumption and risk of kidney stones: results from dose-response meta-analysis of prospective studies and Mendelian randomization analysis.

PURPOSE: The association between tea consumption and kidney stones is inconsistent in observational studies. Thus, we performed a dose-response meta-analysis of prospective cohort studies and a two-sample Mendelian randomization (MR) analysis to identify this association. METHODS: The prospective cohort studies reporting the relationship between tea consumption and kidney stones were searched from PubMed, the Cochrane Library, EMBASE, and Web of Science from inception to December 1, 2023. For MR analysis, the summary-level data for tea consumption and kidney stones were extracted from the UK Biobank available data and the 8th release of the FinnGen consortium, respectively. The inverse-variance weighted (IVW) method was the primary analytical method. RESULTS: In our dose-response meta-analysis, four prospective cohort studies involving 1,263,008 participants were included, and tea consumption was found to have significant associations with kidney stones (RR: 0.80, 95% CI: 0.73-0.87). We also observed a substantially linear negative relationship between tea consumption and the risk of kidney stones. In MR analysis, the IVW method indicated that tea consumption was inversely associated with kidney stones (OR: 0.71, 95% CI: 0.53-0.94). CONCLUSION: Our study confirmed a causal relationship between tea consumption and kidney stones, and higher tea consumption may reduce the risk of kidney stones.

Impact response of lightweight steel foam concrete composite slabs: Experimental, numerical and analytical studies.

This paper presents a study on the low-velocity impact response of lightweight steel foam concrete (LSFC) composite slabs. The LSFC composite slab consisted of a W-shaped steel plate, foam concrete and oriented strand board (OSB). Low-velocity impact tests on the LSFC composite slabs were conducted by employing an ultra-high heavy-duty drop hammer testing machine. The tests revealed the failure mode, impact force and displacement response of LSFC composite slabs. The effects of density and thickness of foam concrete and drop height on the peak impact force and energy absorption ratio were investigated. A finite element (FE) model was set up to predict the impact resistance of the LSFC composite slabs, and a good agreement between simulation and test results was achieved. In addition, an equivalent-single-degree-of-freedom (ESDOF) model was set up to predict the displacement response of the LSFC composite slabs under impact loading.

Clinical correlates of CT imaging-derived phenotypes among lean and overweight patients with hepatic steatosis.

The objective of this study is to define CT imaging derived phenotypes for patients with hepatic steatosis, a common metabolic liver condition, and determine its association with patient data from a medical biobank. There is a need to further characterize hepatic steatosis in lean patients, as its epidemiology may differ from that in overweight patients. A deep learning method determined the spleen-hepatic attenuation difference (SHAD) in Hounsfield Units (HU) on abdominal CT scans as a quantitative measure of hepatic steatosis. The patient cohort was stratified by BMI with a threshold of 25 kg/m2 and hepatic steatosis with threshold SHAD ≥ - 1 HU or liver mean attenuation ≤ 40 HU. Patient characteristics, diagnoses, and laboratory results representing metabolism and liver function were investigated. A phenome-wide association study (PheWAS) was performed for the statistical interaction between SHAD and the binary characteristic LEAN. The cohort contained 8914 patients-lean patients with (N = 278, 3.1%) and without (N = 1867, 20.9%) steatosis, and overweight patients with (N = 1863, 20.9%) and without (N = 4906, 55.0%) steatosis. Among all lean patients, those with steatosis had increased rates of cardiovascular disease (41.7 vs 27.8%), hypertension (86.7 vs 49.8%), and type 2 diabetes mellitus (29.1 vs 15.7%) (all p < 0.0001). Ten phenotypes were significant in the PheWAS, including chronic kidney disease, renal failure, and cardiovascular disease. Hepatic steatosis was found to be associated with cardiovascular, kidney, and metabolic conditions, separate from overweight BMI.

Polygenic risk scores for cardiometabolic traits demonstrate importance of ancestry for predictive precision medicine.

Polygenic risk scores (PRS) have predominantly been derived from genome-wide association studies (GWAS) conducted in European ancestry (EUR) individuals. In this study, we present an in-depth evaluation of PRS based on multi-ancestry GWAS for five cardiometabolic phenotypes in the Penn Medicine BioBank (PMBB) followed by a phenome-wide association study (PheWAS). We examine the PRS performance across all individuals and separately in African ancestry (AFR) and EUR ancestry groups. For AFR individuals, PRS derived using the multi-ancestry LD panel showed a higher effect size for four out of five PRSs (DBP, SBP, T2D, and BMI) than those derived from the AFR LD panel. In contrast, for EUR individuals, the multi-ancestry LD panel PRS demonstrated a higher effect size for two out of five PRSs (SBP and T2D) compared to the EUR LD panel. These findings underscore the potential benefits of utilizing a multi-ancestry LD panel for PRS derivation in diverse genetic backgrounds and demonstrate overall robustness in all individuals. Our results also revealed significant associations between PRS and various phenotypic categories. For instance, CAD PRS was linked with 18 phenotypes in AFR and 82 in EUR, while T2D PRS correlated with 84 phenotypes in AFR and 78 in EUR. Notably, associations like hyperlipidemia, renal failure, atrial fibrillation, coronary atherosclerosis, obesity, and hypertension were observed across different PRSs in both AFR and EUR groups, with varying effect sizes and significance levels. However, in AFR individuals, the strength and number of PRS associations with other phenotypes were generally reduced compared to EUR individuals. Our study underscores the need for future research to prioritize 1) conducting GWAS in diverse ancestry groups and 2) creating a cosmopolitan PRS methodology that is universally applicable across all genetic backgrounds. Such advances will foster a more equitable and personalized approach to precision medicine.

ALA-PDT promotes the death and contractile capacity of hypertrophic scar fibroblasts through inhibiting the TGF-ß1/Smad2/3/4 signaling pathway.

BACKGROUND: Hypertrophic scars, an abnormal wound-healing response to burn injuries, are characterized by massive fibroblast proliferation and excessive deposition of extracellular matrix and collagen. 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT) is a promising therapy for hypertrophic scar, details of the mechanisms remain to be elucidated. In this study, we aimed to investigate the molecular mechanisms involved in ALA-PDT against hypertrophic scar fibroblasts. METHODS: The morphologies of hypertrophic scar fibroblasts (HSFs) treated with ALA-PDT were observed under a light microscopy. The viability of HSFs was detected using the CCK-8 assay. HSFs-populated collagen gel contraction assays were conducted to examine the fibroblast contractility and the cytotoxicity of HSFs in 3D collagen tissues were observed using confocal microscopy. The effect of ALA-PDT on TGF-ß1/Smad2/3/4 signaling pathway activation and effector gene expression were verified by immunoprecipitation, western blot and real-time quantitative PCR analysis. RESULTS: We observed significant changes in cell morphology after ALA-PDT treatment of HSFs. As ALA concentration and light dose increased, the viability of HSFs significantly decreased. ALA-PDT can significantly alleviate the contractile capacity and promote the death of HSFs induced by TGF-ß1 treatment in a three-dimensional collagen culture model. TGF-ß1 treatment of HSFs can significantly induce phosphorylation of Smad2/3 (p-Smad2/3) in whole cells, as well as p-Smad2/3 and Smad4 proteins into the nucleus and increase the mRNA levels of collagen 1/3 and α-SMA. ALA-PDT hampers the TGF-ß1-Smad2/3/4 signaling pathway activation by inducing K48-linked ubiquitination and degradation of Smad4. CONCLUSIONS: Our results provide evidence that ALA-PDT can inhibit fibroblast contraction and promote cell death by inhibiting the activation of the TGF-ß1 signaling pathway that mediates hypertrophic scar formation, which may be the basis for the efficacy of ALA-PDT in the treatment of hypertrophic scars.

KDM3B Single-Nucleotide Polymorphisms Impact Radiation Therapy Toxicity Through Circular RNA-Mediated KDM3B Expression and Inflammatory Responses.

PURPOSE: Genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) associated with radiation therapy (RT) toxicities in patients with prostate cancer. SNP rs17599026 in intron 21 of KDM3B is significantly associated with the development of late urinary toxicity, specifically in the increase in urinary frequency 2 years after RT compared with pretreatment conditions. The present study aimed to provide mechanistic insights for this association. METHODS AND MATERIALS: Using human tissues and cell lines, we examined the protein expression of KDM3B and molecular mechanisms underlying the SNP modulation by variants of KDM3B SNP alleles. In animals with normal and heterozygous expressions of Kdm3b, we examined the relationship between Kdm3b expression and radiation toxicity. RESULTS: KDM3B rs17599026 lies in a motif important for circular RNA expression that is responsible for sponging miRNAs to regulate KDM3B expression. Using a murine model with heterozygous deletion of the Kdm3b gene, we found that lower Kdm3b expression is associated with altered pattern of urination after bladder irradiation, which is related to differential degrees of tissue inflammation as measured by analyses of gene expression, lymphocyte infiltration, and noninvasive ultrasound imaging. CONCLUSIONS: KDM3B SNPs can impact its expression through regulating noncoding RNA expression. Differential KDM3B expression underlies radiation toxicity through tissue inflammation at the molecular and physiological level. Our study outcome offers a foundation for mechanism-based mitigation for radiation toxicity for prostate cancer survivors.

Giant anterior scleral staphyloma caused by blunt ocular trauma: a case report.

BACKGROUND: Anterior scleral staphyloma is a relatively rare disease characterized by thinning and expansion of sclera. We described the clinical presentation, diagnosis and treatment of a case with giant anterior scleral staphyloma caused by blunt ocular trauma. CASE PRESENTATION: A 24-years-old male, presented with a black cyst-like mass protruding from the right eyeball for 9 years after a history of glass crush contusion. The ultrasound biomicroscopy examination showed two cysts in the right eyeball. The larger one was about 5.92 mm*4.69 mm in size and the scleral lacerations were connected to the posterior chamber below the cyst. For treatment, resection of the anterior scleral staphyloma and the scleral patch graft transplantation was performed. The vision of the patient was improved compared with that before surgery. There were no obvious complications. CONCLUSION: The clinical presentation, diagnosis, and treatment of the case with giant anterior scleral staphyloma can provide a reference for the management of anterior scleral staphyloma. Surgical resection and scleral patch graft should be a good option for the treatment of giant anterior scleral staphyloma.

Modified Tubeless Ureterocutaneostomy in High-Risk Patients After Radical Cystectomy and its Long-Term Clinical Outcomes.

OBJECTIVES: This work aimed to prevent stoma stenosis and achieve tubeless cutaneous ureterostomy in elderly and high-risk patients with our modified cutaneous ureterostomy. METHODS: We retrospectively analyzed 40 and 49 patients (176 renal units) who underwent Toyoda (group 1) and modified cutaneous ureterostomy (group 2) between 2012 and 2021. The average follow-up period was 44 months. The primary results of our study were the catheter-free rate and clinical outcomes, especially renal function and urinary diversion-related complications. Significant differences in catheter-free rate and urinary diversion-related complications were found between our modified method and the Toyoda technique. RESULTS: A total of 56 (71.8%) of 78 renal units in group 1 and 89 (90.8%) of 98 renal units in group 2 remained catheter free. Compared with group 1, group 2 had a higher catheter-free rate (P = .001). Multivariate analysis indicated that the surgical procedure (HR = 0.268; P = .001) and body mass index (HR = 3.127; P = .002) were the predictors independently associated with catheter insertion. During follow-up, renal deterioration was observed in 32 (36.0%) patients. Patients with catheter insertion were more likely to suffer from renal deterioration (P < .001), postoperative pyelonephritis (P < .001), and urolithiasis (P < .001) than their counterparts. CONCLUSION: Our modified cutaneous ureterostomy method may provide an effective and simple approach to tubeless cutaneous ureterostomy in elderly and high-risk patients.

Role and mechanism of PVN-sympathetic-adipose circuit in depression and insulin resistance induced by chronic stress.

Chronic stress induces depression and insulin resistance, between which there is a bidirectional relationship. However, the mechanisms underlying this comorbidity remain unclear. White adipose tissue (WAT), innervated by sympathetic nerves, serves as a central node in the interorgan crosstalk through adipokines. Abnormal secretion of adipokines is involved in mood disorders and metabolic morbidities. We describe here a brain-sympathetic nerve-adipose circuit originating in the hypothalamic paraventricular nucleus (PVN) with a role in depression and insulin resistance induced by chronic stress. PVN neurons are labelled after inoculation of pseudorabies virus (PRV) into WAT and are activated under restraint stress. Chemogenetic manipulations suggest a role for the PVN in depression and insulin resistance. Chronic stress increases the sympathetic innervation of WAT and downregulates several antidepressant and insulin-sensitizing adipokines, including leptin, adiponectin, Angptl4 and Sfrp5. Chronic activation of the PVN has similar effects. ß-adrenergic receptors translate sympathetic tone into an adipose response, inducing downregulation of those adipokines and depressive-like behaviours and insulin resistance. We finally show that AP-1 has a role in the regulation of adipokine expression under chronic stress.

Association of serum 25-hydroxyvitamin D concentrations with all-cause mortality among individuals with kidney stone disease: the NHANES database prospective cohort study.

Background: The purpose of this study was to investigate the correlation between serum 25(OH)D concentrations and all-cause mortality in patients with kidney stone disease (KSD) as the effects of a deficiency in 25-hydroxyvitamin D on KSD patients are currently unclear. Methods: For our prospective cohort study, we included 2,916 participants from the National Health and Nutrition Examination Survey (NHANES) 2007-2018. The National Death Index (NDI) was utilized to identify all causes of death and cause-specific mortality until December 31, 2018. We calculated hazard ratios (HR) and 95% confidence intervals (CIs) using multivariate Cox regression models. Results: During the 18,859 person-years of follow-up, a total of 375 fatalities occurred, including 83 deaths from cardiovascular disease (CVD) and 79 deaths from cancer. At baseline, individuals with higher blood 25(OH)D concentrations had lower levels of glucose, glycohemoglobin, CRP, and insulin, as well as higher levels of HDL cholesterol (P < 0.01). In the fully adjusted model (Model 3), compared to the group with the lowest 25(OH)D concentrations, those with serum 25(OH)D concentrations ≥75 nmol/L had hazard ratios (HRs) and 95% confidence intervals (CIs) of 0.48 (0.26, 0.87) for all-cause mortality (P=0.02, P for trend = 0.02). The association between serum 25(OH)D concentrations and all-cause mortality in KSD patients was found to be significantly non-linear. A 7% decrease in the risk of death from all causes was observed for each unit-nmol/L increase in serum 25(OH)D concentrations when the concentrations were below 27.7 nmol/L (P < 0.05). Conclusion: Based on the findings, KSD patients with insufficient serum 25(OH)D concentrations were at a higher risk of all-cause mortality. Therefore, it is crucial to maintain sufficient blood 25(OH)D concentrations and prevent 25(OH)D insufficiency in order to extend the lifespan of KSD patients.

Lifestyle factors, serum parameters, metabolic comorbidities, and the risk of kidney stones: a Mendelian randomization study.

Background and objective: The early identification of modifiable risk factors is important for preventing kidney stones but determining causal associations can be difficult with epidemiological data. We aimed to genetically assess the causality between modifiable factors (lifestyle factors, serum parameters, and metabolic comorbidities) and the risk of kidney stones. Additionally, we aimed to explore the causal impact of education on kidney stones and its potential mediating pathways. Methods: We conducted a two-sample Mendelian randomization (MR) study to explore the causal association between 44 modifiable risk factors and kidney stones. The FinnGen dataset initially explored the causal relationship of risk factors with kidney stones and the UK Biobank dataset was used as the validation set. Then, a meta-analysis was conducted by combining discovery and validation datasets. We used two-step MR to assess potential mediators and their mediation proportions between education and kidney stones. Results: The combined results indicated that previous exposures may increase the risk of kidney stones, including sedentary behavior, urinary sodium, the urinary sodium/potassium ratio, the urinary sodium/creatinine ratio, serum calcium, 25-hydroxyvitamin D (25OHD), the estimated creatinine-based glomerular filtration rate (eGFRcrea), GFR estimated by serum cystatin C (eGFRcys), body mass index (BMI), waist circumference, type 2 diabetes mellitus (T2DM), fasting insulin, glycated hemoglobin, and hypertension. Coffee intake, plasma caffeine levels, educational attainment, and the urinary potassium/creatinine ratio may decrease the risk of kidney stones. Ranked by mediation proportion, the effect of education on the risk of kidney stones was mediated by five modifiable risk factors, including sedentary behavior (mediation proportion, 25.7%), smoking initiation (10.2%), BMI (8.2%), T2DM (5.8%), and waist circumference (3.2%). Conclusion: This study provides MR evidence supporting causal associations of many modifiable risk factors with kidney stones. Sedentary lifestyles, obesity, smoking, and T2DM are mediating factors in the causal relationship between educational attainment and kidney stones. Our results suggest more attention should be paid to these modifiable factors to prevent kidney stones.

The Eotaxin-1/CCR3 Axis and Matrix Metalloproteinase-9 Are Critical in Anti-NC16A IgE-Induced Bullous Pemphigoid.

Bullous pemphigoid (BP) is the most common autoimmune bullous skin disease of humans and is characterized by eosinophilic inflammation and circulating and tissue-bound IgG and IgE autoantibodies directed against two hemidesmosomal proteins: BP180 and BP230. The noncollagenous 16A domain (NC16A) of BP180 has been found to contain major epitopes recognized by autoantibodies in BP. We recently established the pathogenicity of anti-NC16A IgE through passive transfer of patient-derived autoantibodies to double-humanized mice that express the human high-affinity IgE receptor, FcεRI, and human NC16A domain (FcεRI/NC16A). In this model, anti-NC16A IgEs recruit eosinophils to mediate tissue injury and clinical disease in FcεRI/NC16A mice. The objective of this study was to characterize the molecular and cellular events that underlie eosinophil recruitment and eosinophil-dependent tissue injury in anti-NC16A IgE-induced BP. We show that anti-NC16A IgEs significantly increase levels of key eosinophil chemoattractants, eotaxin-1 and eotaxin-2, as well as the proteolytic enzyme matrix metalloproteinase-9 (MMP-9) in the lesional skin of FcεRI/NC16A mice. Importantly, neutralization of eotaxin-1, but not eotaxin-2, and blockade of the main eotaxin receptor, CCR3, drastically reduce anti-NC16A IgE-induced disease activity. We further show that anti-NC16A IgE/NC16A immune complexes induce the release of MMP-9 from eosinophils, and that MMP-9-deficient mice are resistant to anti-NC16A IgE-induced BP. Lastly, we find significantly increased levels of eotaxin-1, eotaxin-2, and MMP-9 in blister fluids of BP patients. Taken together, this study establishes the eotaxin-1/CCR3 axis and MMP-9 as key players in anti-NC16A IgE-induced BP and candidate therapeutic targets for future drug development and testing.

Electrical Activity and Extremes of Individual Suspended ZnO Nanowires for 3D Nanoelectronic Applications.

We explored the electrical activity and extremes inside individual suspended zinc oxide (ZnO) nanowires (NWs) (diameter: 50-550 nm, length: 5-50 µm) subjected to high forward bias-induced Joule heating using two-terminal current-voltage measurements. NWs were isolated using a reproducible nanometrology technique, employing a nanomanipulator inside a scanning electron microscope. Schottky behavior is observed between installed tips and ZnO NW. The suspended ZnO NWs exhibited an average electrical resistivity ρ (approximately 2.3 × 10-2 Ω cm) and a high electron density n (exceeding 1.89 × 1018 cm-3), comparable to that of InP NWs, GaN NWs, and InAs NWs (1018∼1019 cm-3), suggesting the potential to drive advancements in high-performance NW devices. A maximum breakdown current density (JBD) of ∼0.14 MA/cm2 and a maximum breakdown power density (PBD) of 6.93 mW/µm3 were obtained, both of which are higher than substrate-bound ZnO NWs and consistent with previously reported results obtained from probed ZnO NWs grown vertically on the substrate. Moreover, we discovered that NWs experienced thermal breakdown due to Joule heating and exploited this breakdown mechanism to further investigate the temperature distribution along the ZnO NWs, as well as its dependence on the electrical properties and thermal conductance of contact electrodes. Thermal conductance was determined to be ∼0.4 nW K-1 and ∼1.66 pW K-1 at the tungsten(W)-ZnO NW and platinum(Pt)-ZnO NW contacts, respectively. In addition, we measured the elastic modulus (130-171 GPa), which closely approximated bulk values. We also estimated the nanoindentation hardness to be between 5 and 10 GPa. This work provides valuable insights into the electrical activity and extreme mechanisms, thus providing a better understanding of the potentials and limitations associated with utilizing suspended NWs in 3D nanodevices.

LncRNA AGAP2-AS1 interacts with IGF2BP2 to promote bladder cancer progression via regulating LRG1 mRNA stability.

BACKGROUND: The long non-coding RNA (lncRNA) AGAP2-AS1 was implicated in tumorigenesis, yet with unclear mechanism in the development of Bladder Cancer (BCa). METHODS: We collected the clinicopathological features and tissue samples of 45 patients with BCa in Xiangya Hospital. Expressions of AGAP2-AS1 and LRG1 were detected by RT-qPCR in BCa tissues and normal tissues as well as in BCa cells. The roles of AGAP2-AS1 and LRG1 were investigated by CCK-8, colony formation assay, transwell assays and tube formation assay. The subcellular localization of AGAP2-AS1 was detected by Fluorescence in situ hybridization. Bioinformatics method, RNA immunoprecipitation, RNA pull-down assay and Actinomycin D test were used to predict and identify the relationships between AGAP2-AS1, LRG1 and IGF2BP2. Xenografted tumors were produced to explore the function of AGAP2-AS1 in BCa in vivo. RESULTS: AGAP2-AS1 and LRG1 were highly upregulated in BCa. AGAP2-AS1 positively correlated with T stage, grade and vascular invasion, but negatively correlated with the survival of patients. Overexpressions of AGAP2-AS1 promoted proliferation, migration, invasion, tumor angiogenesis in vitro and tumor growth, metastasis in vivo, knockdown of AGAP2-AS1 exhibited the opposite effects. AGAP2-AS1 localized mainly in the cytoplasm. AGAP2-AS1 directly bound to IGF2BP2 protein to enhance LRG1 mRNA stability. Inhibition of BCa progression by AGAP2-AS1 knockdown may be reversed by LRG1 overexpression. CONCLUSION: AGAP2-AS1 can promote BCa progression and metastasis by recruiting IGF2BP2 to stabilize LRG1.

Large-scale identification of undiagnosed hepatic steatosis using natural language processing.

Background: Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidity in people with and without diabetes, but it is underdiagnosed, posing challenges for research and clinical management. Here, we determine if natural language processing (NLP) of data in the electronic health record (EHR) could identify undiagnosed patients with hepatic steatosis based on pathology and radiology reports. Methods: A rule-based NLP algorithm was built using a Linguamatics literature text mining tool to search 2.15 million pathology report and 2.7 million imaging reports in the Penn Medicine EHR from November 2014, through December 2020, for evidence of hepatic steatosis. For quality control, two independent physicians manually reviewed randomly chosen biopsy and imaging reports (n = 353, PPV 99.7%). Findings: After exclusion of individuals with other causes of hepatic steatosis, 3007 patients with biopsy-proven NAFLD and 42,083 patients with imaging-proven NAFLD were identified. Interestingly, elevated ALT was not a sensitive predictor of the presence of steatosis, and only half of the biopsied patients with steatosis ever received an ICD diagnosis code for the presence of NAFLD/NASH. There was a robust association for PNPLA3 and TM6SF2 risk alleles and steatosis identified by NLP. We identified 234 disorders that were significantly over- or underrepresented in all subjects with steatosis and identified changes in serum markers (e.g., GGT) associated with presence of steatosis. Interpretation: This study demonstrates clear feasibility of NLP-based approaches to identify patients whose steatosis was indicated in imaging and pathology reports within a large healthcare system and uncovers undercoding of NAFLD in the general population. Identification of patients at risk could link them to improved care and outcomes. Funding: The study was funded by US and German funding sources that did provide financial support only and had no influence or control over the research process.

Corrigendum: CREB5 hypermethylation involved in the ganglioside GM1 therapy of Parkinson's disease.

[This corrects the article DOI: 10.3389/fnagi.2023.1122647.].

Corrigendum: Detection algorithm for pigmented skin disease based on classifier-level and feature-level fusion.

[This corrects the article DOI: 10.3389/fpubh.2022.1034772.].