Hunting imaging biomarkers in pulmonary fibrosis: Benchmarks of the AIIB23 challenge.

Airway-related quantitative imaging biomarkers are crucial for examination, diagnosis, and prognosis in pulmonary diseases. However, the manual delineation of airway structures remains prohibitively time-consuming. While significant efforts have been made towards enhancing automatic airway modelling, current public-available datasets predominantly concentrate on lung diseases with moderate morphological variations. The intricate honeycombing patterns present in the lung tissues of fibrotic lung disease patients exacerbate the challenges, often leading to various prediction errors. To address this issue, the 'Airway-Informed Quantitative CT Imaging Biomarker for Fibrotic Lung Disease 2023' (AIIB23) competition was organized in conjunction with the official 2023 International Conference on Medical Image Computing and Computer Assisted Intervention (MICCAI). The airway structures were meticulously annotated by three experienced radiologists. Competitors were encouraged to develop automatic airway segmentation models with high robustness and generalization abilities, followed by exploring the most correlated QIB of mortality prediction. A training set of 120 high-resolution computerised tomography (HRCT) scans were publicly released with expert annotations and mortality status. The online validation set incorporated 52 HRCT scans from patients with fibrotic lung disease and the offline test set included 140 cases from fibrosis and COVID-19 patients. The results have shown that the capacity of extracting airway trees from patients with fibrotic lung disease could be enhanced by introducing voxel-wise weighted general union loss and continuity loss. In addition to the competitive image biomarkers for mortality prediction, a strong airway-derived biomarker (Hazard ratio>1.5, p < 0.0001) was revealed for survival prognostication compared with existing clinical measurements, clinician assessment and AI-based biomarkers.

LncRNAway: a web-based sgRNA design tool for precise and effective suppression of long noncoding RNAs.

Thousands of long noncoding RNAs (lncRNAs) have been annotated via high-throughput RNA sequencing, yet only a small fraction have been functionally investigated. Genomic knockout is the mainstream strategy for studying the biological function of protein-coding genes and lncRNAs, whereas the complexity of the lncRNA locus, especially the natural antisense lncRNAs (NAT-lncRNAs), presents great challenges. Knocking out lncRNAs often results in unintended disruptions of neighboring protein-coding genes and small RNAs, leading to ambiguity in observing phenotypes and interpreting biological function. To address this issue, we launched LncRNAway, a user-friendly web tool based on the BESST (branchpoint to 3' splicing site targeting) method, to design sgRNAs for lncRNA knockout. LncRNAway not only provides specific and effective lncRNA knockout guidelines but also integrates genotyping primers and quantitative PCR primers designing, thereby streamlining experimental procedures of lncRNA function study. LncRNAway is freely available at https://www.lncrnaway.com.

Deep learning for automatic organ and tumor segmentation in nanomedicine pharmacokinetics.

Rationale: Multimodal imaging provides important pharmacokinetic and dosimetry information during nanomedicine development and optimization. However, accurate quantitation is time-consuming, resource intensive, and requires anatomical expertise. Methods: We present NanoMASK: a 3D U-Net adapted deep learning tool capable of rapid, automatic organ segmentation of multimodal imaging data that can output key clinical dosimetry metrics without manual intervention. This model was trained on 355 manually-contoured PET/CT data volumes of mice injected with a variety of nanomaterials and imaged over 48 hours. Results: NanoMASK produced 3-dimensional contours of the heart, lungs, liver, spleen, kidneys, and tumor with high volumetric accuracy (pan-organ average %DSC of 92.5). Pharmacokinetic metrics including %ID/cc, %ID, and SUVmax achieved correlation coefficients exceeding R = 0.987 and relative mean errors below 0.2%. NanoMASK was applied to novel datasets of lipid nanoparticles and antibody-drug conjugates with a minimal drop in accuracy, illustrating its generalizability to different classes of nanomedicines. Furthermore, 20 additional auto-segmentation models were developed using training data subsets based on image modality, experimental imaging timepoint, and tumor status. These were used to explore the fundamental biases and dependencies of auto-segmentation models built on a 3D U-Net architecture, revealing significant differential impacts on organ segmentation accuracy. Conclusions: NanoMASK is an easy-to-use, adaptable tool for improving accuracy and throughput in imaging-based pharmacokinetic studies of nanomedicine. It has been made publicly available to all readers for automatic segmentation and pharmacokinetic analysis across a diverse array of nanoparticles, expediting agent development.

Calponin 1 inhibits agonist-induced ERK activation and decreases calcium sensitization in vascular smooth muscle.

Smooth muscle cell (SMC) contraction and vascular tone are modulated by phosphorylation and multiple modifications of the thick filament, and thin filament regulation of SMC contraction has been reported to involve extracellular regulated kinase (ERK). Previous studies in ferrets suggest that the actin-binding protein, calponin 1 (CNN1), acts as a scaffold linking protein kinase C (PKC), Raf, MEK and ERK, promoting PKC-dependent ERK activation. To gain further insight into this function of CNN1 in ERK activation and the regulation of SMC contractility in mice, we generated a novel Calponin 1 knockout mouse (Cnn1 KO) by a single base substitution in an intronic CArG box that preferentially abolishes expression of CNN1 in vascular SMCs. Using this new Cnn1 KO mouse, we show that ablation of CNN1 has two effects, depending on the cytosolic free calcium level: (1) in the presence of elevated intracellular calcium caused by agonist stimulation, Cnn1 KO mice display a reduced amplitude of stress and stiffness but an increase in agonist-induced ERK activation; and (2) during intracellular calcium depletion, in the presence of an agonist, Cnn1 KO mice exhibit increased duration of SM tone maintenance. Together, these results suggest that CNN1 plays an important and complex modulatory role in SMC contractile tone amplitude and maintenance.

Tissue-specific Cre driver mice to study vascular diseases.

Vascular diseases, including atherosclerosis and abdominal aneurysms, are the primary cause of mortality and morbidity among the elderly worldwide. The life quality of patients is significantly compromised due to inadequate therapeutic approaches and limited drug targets. To expand our comprehension of vascular diseases, gene knockout (KO) mice, especially conditional knockout (cKO) mice, are widely used for investigating gene function and mechanisms of action. The Cre-loxP system is the most common method for generating cKO mice. Numerous Cre driver mice have been established to study the main cell types that compose blood vessels, including endothelial cells, smooth muscle cells, and fibroblasts. Here, we first discuss the characteristics of each layer of the arterial wall. Next, we provide an overview of the representative Cre driver mice utilized for each of the major cell types in the vessel wall and their most recent applications in vascular biology. We then go over Cre toxicity and discuss the practical methods for minimizing Cre interference in experimental outcomes. Finally, we look into the future of tissue-specific Cre drivers by introducing the revolutionary single-cell RNA sequencing and dual recombinase system.

Functional knockout of long non-coding RNAs with genome editing.

An effective loss-of-function study is necessary to investigate the biological function of long non-coding RNA (lncRNA). Various approaches are available, including RNA silencing, antisense oligos, and CRISPR-based genome editing. CRISPR-based genome editing is the most widely used for inactivating lncRNA function at the genomic level. Knocking out the lncRNA function can be achieved by removing the promoter and the first exon (PE1), introducing pre-termination poly(A) signals, or deleting the entire locus, unlike frameshift strategies used for messenger RNA (mRNA). However, the intricate genomic interplay between lncRNA and neighbor genes makes it challenging to interpret lncRNA function accurately. This article discusses the advantages and disadvantages of each lncRNA knockout method and envisions the potential future directions to facilitate lncRNA functional study.

Translating radiology reports into plain language using ChatGPT and GPT-4 with prompt learning: results, limitations, and potential.

The large language model called ChatGPT has drawn extensively attention because of its human-like expression and reasoning abilities. In this study, we investigate the feasibility of using ChatGPT in experiments on translating radiology reports into plain language for patients and healthcare providers so that they are educated for improved healthcare. Radiology reports from 62 low-dose chest computed tomography lung cancer screening scans and 76 brain magnetic resonance imaging metastases screening scans were collected in the first half of February for this study. According to the evaluation by radiologists, ChatGPT can successfully translate radiology reports into plain language with an average score of 4.27 in the five-point system with 0.08 places of information missing and 0.07 places of misinformation. In terms of the suggestions provided by ChatGPT, they are generally relevant such as keeping following-up with doctors and closely monitoring any symptoms, and for about 37% of 138 cases in total ChatGPT offers specific suggestions based on findings in the report. ChatGPT also presents some randomness in its responses with occasionally over-simplified or neglected information, which can be mitigated using a more detailed prompt. Furthermore, ChatGPT results are compared with a newly released large model GPT-4, showing that GPT-4 can significantly improve the quality of translated reports. Our results show that it is feasible to utilize large language models in clinical education, and further efforts are needed to address limitations and maximize their potential.

INKILN is a Novel Long Noncoding RNA Promoting Vascular Smooth Muscle Inflammation via Scaffolding MKL1 and USP10.

BACKGROUND: Activation of vascular smooth muscle cell (VSMC) inflammation is vital to initiate vascular disease. The role of human-specific long noncoding RNAs in VSMC inflammation is poorly understood. METHODS: Bulk RNA sequencing in differentiated human VSMCs revealed a novel human-specific long noncoding RNA called inflammatory MKL1 (megakaryoblastic leukemia 1) interacting long noncoding RNA (INKILN). INKILN expression was assessed in multiple in vitro and ex vivo models of VSMC phenotypic modulation as well as human atherosclerosis and abdominal aortic aneurysm. The transcriptional regulation of INKILN was verified through luciferase reporter and chromatin immunoprecipitation assays. Loss-of-function and gain-of-function studies and multiple RNA-protein and protein-protein interaction assays were used to uncover a mechanistic role of INKILN in the VSMC proinflammatory gene program. Bacterial artificial chromosome transgenic mice were used to study INKILN expression and function in ligation injury-induced neointimal formation. RESULTS: INKILN expression is downregulated in contractile VSMCs and induced in human atherosclerosis and abdominal aortic aneurysm. INKILN is transcriptionally activated by the p65 pathway, partially through a predicted NF-κB (nuclear factor kappa B) site within its proximal promoter. INKILN activates proinflammatory gene expression in cultured human VSMCs and ex vivo cultured vessels. INKILN physically interacts with and stabilizes MKL1, a key activator of VSMC inflammation through the p65/NF-κB pathway. INKILN depletion blocks interleukin-1ß-induced nuclear localization of both p65 and MKL1. Knockdown of INKILN abolishes the physical interaction between p65 and MKL1 and the luciferase activity of an NF-κB reporter. Furthermore, INKILN knockdown enhances MKL1 ubiquitination through reduced physical interaction with the deubiquitinating enzyme USP10 (ubiquitin-specific peptidase 10). INKILN is induced in injured carotid arteries and exacerbates ligation injury-induced neointimal formation in bacterial artificial chromosome transgenic mice. CONCLUSIONS: These findings elucidate an important pathway of VSMC inflammation involving an INKILN/MKL1/USP10 regulatory axis. Human bacterial artificial chromosome transgenic mice offer a novel and physiologically relevant approach for investigating human-specific long noncoding RNAs under vascular disease conditions.

Noise Suppression With Similarity-Based Self-Supervised Deep Learning.

Image denoising is a prerequisite for downstream tasks in many fields. Low-dose and photon-counting computed tomography (CT) denoising can optimize diagnostic performance at minimized radiation dose. Supervised deep denoising methods are popular but require paired clean or noisy samples that are often unavailable in practice. Limited by the independent noise assumption, current self-supervised denoising methods cannot process correlated noises as in CT images. Here we propose the first-of-its-kind similarity-based self-supervised deep denoising approach, referred to as Noise2Sim, that works in a nonlocal and nonlinear fashion to suppress not only independent but also correlated noises. Theoretically, Noise2Sim is asymptotically equivalent to supervised learning methods under mild conditions. Experimentally, Nosie2Sim recovers intrinsic features from noisy low-dose CT and photon-counting CT images as effectively as or even better than supervised learning methods on practical datasets visually, quantitatively and statistically. Noise2Sim is a general self-supervised denoising approach and has great potential in diverse applications.

BESST: a novel LncRNA knockout strategy with less genome perturbance.

Long noncoding RNAs (lncRNAs) are >200 nt RNA transcripts without protein-coding potential. LncRNAs can be categorized into intergenic, intronic, bidirectional, sense, and antisense lncRNAs based on the genomic localization to nearby protein-coding genes. The current CRISPR-based lncRNA knockout strategy works efficiently for lncRNAs distant from the protein-coding gene, whereas it causes genomic perturbance inevitably due to technical limitations. In this study, we introduce a novel lncRNA knockout strategy, BESST, by deleting the genomic DNA fragment from the branch point to the 3' splicing site in the last intron of the target lncRNA. The BESST knockout exhibited comparable or superior repressive efficiency to RNA silencing or conventional promoter-exon1 deletion. Significantly, the BESST knockout strategy minimized the intervention of adjacent/overlap protein-coding genes by removing an average of ∼130 bp from genomic DNA. Our data also found that the BESST knockout strategy causes lncRNA nuclear retention, resulting in decapping and deadenylation of the lncRNA poly(A) tail. Further study revealed that PABPN1 is essential for the BESST-mediated decay and subsequent poly(A) deadenylation and decapping. Together, the BESST knockout strategy provides a versatile tool for investigating gene function by generating knockout cells or animals with high specificity and efficiency.

[Network Meta-analysis of Chinese patent medicine containing Hirudo in treatment of atherosclerosis].

This study aimed to evaluate the efficacy and safety of Chinese patent medicines containing Hirudo in the treatment of atherosclerosis(AS) by network Meta-analysis, and to provide evidence-based reference for clinical treatment of AS. The clinical randomized controlled trial(RCT) on the treatment of atherosclerosis with Chinese patent medicines containing Hirudo were searched in CNKI, Wanfang, VIP, SinoMed, PubMed and EMbase from the establishment of the databases to July 1, 2022. And data extraction and quality assessment of the included RCT was performed according to the Cochrane standards. Stata 17 and ADDIS 1.16.5 were then used for Bayesian model network Meta-analysis. Finally, 67 RCTs with a total sample size of 6 826 cases were included, 3 569 cases in the experimental group and 3 257 cases in the control group, involving three oral Chinese patent medicines. Network Meta-analysis showed that in terms of reducing intima-media thickness(IMT), the top three Chinese patent medicines were Tongxinluo Capsules+sta-tins>Maixuekang Capsules+statins>Maixuekang Capsules. In terms of reducing plaque area, the top one was Maixuekang Capsules+sta-tins, and the other Chinese patent medicines had similar efficacy. For lowering AS Crouse scores, the top three were Maixuekang Capsules>Tongxinluo Capsules+statins>Naoxintong Capsules. For decreasing plaque number, the top three were Naoxintong Capsules+sta-tins>Tongxinluo Capsules+statins>Tongxinluo Capsules. With regard to adverse reactions/events, Naoxintong Capsules+statins had the lo-west incidence. In conclusion, in Chinese patent medicines containing Hirudo for the treatment of AS, Tongxinluo Capsules+statins, Maixuekang Capsules, Maixuekang Capsules+statins, and Naoxintong Capsules+statins were the primary choices to reduce IMT, AS Crouse scores, plaque area, and plaque number, respectively. The efficacy of Chinese patent medicines containing Hirudo with or without statins was more significant than that of statins alone in the four outcome indexes. Additionally, the treatment of AS should be evaluated comprehensively, and attention should be paid to Chinese patent medicines or their combination with western medicine, to optimize the treatment effect and minimize adverse reactions as the benchmark.

PGC-1α senses the CBC of pre-mRNA to dictate the fate of promoter-proximally paused RNAPII.

PGC-1α is well established as a metazoan transcriptional coactivator of cellular adaptation in response to stress. However, the mechanisms by which PGC-1α activates gene transcription are incompletely understood. Here, we report that PGC-1α serves as a scaffold protein that physically and functionally connects the DNA-binding protein estrogen-related receptor α (ERRα), cap-binding protein 80 (CBP80), and Mediator to overcome promoter-proximal pausing of RNAPII and transcriptionally activate stress-response genes. We show that PGC-1α promotes pausing release in a two-arm mechanism (1) by recruiting the positive transcription elongation factor b (P-TEFb) and (2) by outcompeting the premature transcription termination complex Integrator. Using mice homozygous for five amino acid changes in the CBP80-binding motif (CBM) of PGC-1α that destroy CBM function, we show that efficient differentiation of primary myoblasts to myofibers and timely skeletal muscle regeneration after injury require PGC-1α binding to CBP80. Our findings reveal how PGC-1α activates stress-response gene transcription in a previously unanticipated pre-mRNA quality-control pathway.

INKILN is a novel long noncoding RNA promoting vascular smooth muscle inflammation via scaffolding MKL1 and USP10.

Background: Activation of vascular smooth muscle cells (VSMCs) inflammation is vital to initiate vascular disease. However, the role of human-specific long noncoding RNAs (lncRNAs) in VSMC inflammation is poorly understood. Methods: Bulk RNA-seq in differentiated human VSMCs revealed a novel human-specific lncRNA called IN flammatory M K L1 I nteracting L ong N oncoding RNA ( INKILN ). INKILN expression was assessed in multiple in vitro and ex vivo models of VSMC phenotypic modulation and human atherosclerosis and abdominal aortic aneurysm (AAA) samples. The transcriptional regulation of INKILN was determined through luciferase reporter system and chromatin immunoprecipitation assay. Both loss- and gain-of-function approaches and multiple RNA-protein and protein-protein interaction assays were utilized to uncover the role of INKILN in VSMC proinflammatory gene program and underlying mechanisms. Bacterial Artificial Chromosome (BAC) transgenic (Tg) mice were utilized to study INKLIN expression and function in ligation injury-induced neointimal formation. Results: INKILN expression is downregulated in contractile VSMCs and induced by human atherosclerosis and abdominal aortic aneurysm. INKILN is transcriptionally activated by the p65 pathway, partially through a predicted NF-κB site within its proximal promoter. INKILN activates the proinflammatory gene expression in cultured human VSMCs and ex vivo cultured vessels. Mechanistically, INKILN physically interacts with and stabilizes MKL1, a key activator of VSMC inflammation through the p65/NF-κB pathway. INKILN depletion blocks ILIß-induced nuclear localization of both p65 and MKL1. Knockdown of INKILN abolishes the physical interaction between p65 and MKL1, and the luciferase activity of an NF-κB reporter. Further, INKILN knockdown enhances MKL1 ubiquitination, likely through the reduced physical interaction with the deubiquitinating enzyme, USP10. INKILN is induced in injured carotid arteries and exacerbates ligation injury-induced neointimal formation in BAC Tg mice. Conclusions: These findings elucidate an important pathway of VSMC inflammation involving an INKILN /MKL1/USP10 regulatory axis. Human BAC Tg mice offer a novel and physiologically relevant approach for investigating human-specific lncRNAs under vascular disease conditions.

Generation and Comparative Analysis of an Itga8-CreER T2 Mouse with Preferential Activity in Vascular Smooth Muscle Cells.

All current smooth muscle cell (SMC) Cre mice similarly recombine floxed alleles in vascular and visceral SMCs. Here, we present an Itga8-CreER T2 knock-in mouse and compare its activity with a Myh11-CreER T2 mouse. Both Cre drivers demonstrate equivalent recombination in vascular SMCs. However, Myh11-CreER T2 mice, but not Itga8-CreER T2 mice, display high activity in visceral SMC-containing tissues such as intestine, show early tamoxifen-independent activity, and produce high levels of CreERT2 protein. Whereas Myh11-CreER T2 -mediated knockout of serum response factor (Srf) causes a lethal intestinal phenotype precluding analysis of the vasculature, loss of Srf with Itga8-CreER T2 (Srf Itga8 ) yields viable mice with no evidence of intestinal pathology. Male and female Srf Itga8 mice exhibit vascular contractile incompetence, and angiotensin II causes elevated blood pressure in wild type, but not Srf Itga8 , male mice. These findings establish the Itga8-CreER T2 mouse as an alternative to existing SMC Cre mice for unfettered phenotyping of vascular SMCs following selective gene loss.

A transformer-based deep-learning approach for classifying brain metastases into primary organ sites using clinical whole-brain MRI images.

Treatment decisions for brain metastatic disease rely on knowledge of the primary organ site and are currently made with biopsy and histology. Here, we develop a deep-learning approach for accurate non-invasive digital histology with whole-brain magnetic resonance imaging (MRI) data. Contrast-enhanced T1-weighted and fast spoiled gradient echo brain MRI exams (n = 1,582) were preprocessed and input to the proposed deep-learning workflow for tumor segmentation, modality transfer, and primary site classification into one of five classes. Tenfold cross-validation generated an overall area under the receiver operating characteristic curve (AUC) of 0.878 (95% confidence interval [CI]: 0.873,0.883). These data establish that whole-brain imaging features are discriminative enough to allow accurate diagnosis of the primary organ site of malignancy. Our end-to-end deep radiomic approach has great potential for classifying metastatic tumor types from whole-brain MRI images. Further refinement may offer an invaluable clinical tool to expedite primary cancer site identification for precision treatment and improved outcomes.

LncRNA PSR Regulates Vascular Remodeling Through Encoding a Novel Protein Arteridin.

RATIONALE: Vascular smooth muscle cells (VSMCs) phenotype switch from contractile to proliferative phenotype is a pathological hallmark in various cardiovascular diseases. Recently, a subset of long noncoding RNAs was identified to produce functional polypeptides. However, the functional impact and regulatory mechanisms of long noncoding RNAs in VSMCs phenotype switching remain to be fully elucidated. OBJECTIVES: To illustrate the biological function and mechanism of a VSMC-enriched long noncoding RNA and its encoded peptide in VSMC phenotype switching and vascular remodeling. RESULTS: We identified a VSMC-enriched transcript encoded by a previously uncharacterized gene, which we called phenotype switching regulator (PSR), which was markedly upregulated during vascular remodeling. Although PSR was annotated as a long noncoding RNA, we demonstrated that the lncPSR (PSR transcript) also encoded a protein, which we named arteridin. In VSMCs, both arteridin and lncPSR were necessary and sufficient to induce phenotype switching. Mechanistically, arteridin and lncPSR regulate downstream genes by directly interacting with a transcription factor YBX1 (Y-box binding protein 1) and modulating its nuclear translocation and chromatin targeting. Intriguingly, the PSR transcription was also robustly induced by arteridin. More importantly, the loss of PSR gene or arteridin protein significantly attenuated the vascular remodeling induced by carotid arterial injury. In addition, VSMC-specific inhibition of lncPSR using adeno-associated virus attenuated Ang II (angiotensin II)-induced hypertensive vascular remodeling. CONCLUSIONS: PSR is a VSMC-enriched gene, and its transcript IncPSR and encoded protein (arteridin) coordinately regulate transcriptional reprogramming through a shared interacting partner, YBX1. This is a previously uncharacterized regulatory circuit in VSMC phenotype switching during vascular remodeling, with lncPSR/arteridin as potential therapeutic targets for the treatment of VSMC phenotype switching-related vascular remodeling.

Early administration of hydrocortisone, vitamin C, and thiamine in adult patients with septic shock: a randomized controlled clinical trial.

BACKGROUND: The combination therapy of hydrocortisone, vitamin C, and thiamine has been proposed as a potential treatment in patients with sepsis and septic shock. However, subsequent trials have reported conflicting results in relation to survival outcomes. Hence, we performed this randomized controlled trial (RCT) to evaluate the efficacy and safety of early combination therapy among adult patients with septic shock. METHODS: This single-center, double-blind RCT enrolled adult patients with diagnosis of septic shock within 12 h from Northern Jiangsu People's Hospital between February 2019 and June 2021. Recruited patients were randomized 1:1 to receive intervention (hydrocortisone 200 mg daily, vitamin C 2 g every 6 h, and thiamine 200 mg every 12 h) or placebo (0.9% saline) for 5 days or until ICU discharge. The primary endpoint was 90-day mortality. The secondary endpoints included mortality at day 28, ICU discharge, and hospital discharge; shock reversal; 72-h Delta SOFA score; ICU-free days, vasopressor-free days, and ventilator support -free days up to day 28; ICU length of stay (LOS) and hospital LOS. RESULTS: Among 426 patients randomized, a total of 408 patients with septic shock were included in the per-protocol (PP) analysis, of which 203 were assigned to the intervention group and 205 to the placebo group. In the PP population, the primary outcome of 90-day mortality was 39.9% (81/203) and 39.0% (80/205) in the intervention and the placebo groups, respectively, and was not significantly different (P = 0.86). There was no significant difference between two groups in 28-day mortality (36.5% vs. 36.1%, P = 0.94) or the ICU mortality (31.5% vs. 28.8%, P = 0.55) and hospital mortality (34.5% vs. 33.2%, P = 0.78). No other secondary outcomes showed significant differences between two groups, including shock reversal, vasopressor-free days, and ICU LOS. Intention-to-treat analysis included all the 426 patients and confirmed these results (all P > 0.05). CONCLUSION: Among adult patients with septic shock, early use of hydrocortisone, vitamin C, and thiamine combination therapy compared with placebo did not confer survival benefits. Trial registration ClinicalTrials.gov: NCT03872011 , registration date: March 12, 2019.

Vascular homeostasis in atherosclerosis: A holistic overview.

Atherosclerosis refers to the deposition of lipids and the co-existence of inflammation and impaired inflammation resolution in pan-vasculature, which causes lumen narrowing, hardening, plaque formation, and the manifestation of acute cardiovascular events. Emerging evidence has suggested that vascular circulation can be viewed as a complex homeostatic system analogous to a mini-ecosystem which consists of the vascular microenvironment (niche) and the crosstalk among phenotypically and functionally diverse vascular cell types. Here, we elucidate how cell components in the vascular wall affect vascular homeostasis, structure, function, and atherosclerosis in a holistic perspective. Finally, we discuss the potential role of vascular-stabilizing strategies including pharmacotherapies, natural substances and lifestyle modifications, in preventing cardiovascular diseases by preserving vascular integrity and homeostasis.

LKB1 suppression promotes cardiomyocyte regeneration via LKB1-AMPK-YAP axis.

The regenerative potential of cardiomyocytes in adult mammals is limited. Previous studies reported that cardiomyocyte proliferation is suppressed by AMP-activated protein kinase (AMPK). The role of liver kinase B1 (LKB1), as the major upstream kinase for AMPK, on cardiomyocyte proliferation is unclear. In this study, we found that the LKB1 levels rapidly increased after birth. With loss- and gain-of-function study, our data demonstrated that LKB1 levels negatively correlate with cardiomyocyte proliferation. We next identified Yes-associated protein (YAP) as the downstream effector of LKB1 using high-throughput RNA sequencing. Our results also demonstrated that AMPK plays an essential role in Lkb1 knockdown-induced cardiomyocyte proliferation. Importantly, deactivated AMPK abolished the LKB1-mediated regulation of YAP nuclear translocation and cardiomyocyte proliferation. Thus, our findings suggested the role of LKB1-AMPK-YAP axis during cardiomyocyte proliferation, which could be used as a potential target for inducing cardiac regeneration after injury.

Cardiac CT motion artifact grading via semi-automatic labeling and vessel tracking using synthetic image-augmented training data.

Cardiac CT provides critical information for the evaluation of cardiovascular diseases. However, involuntary patient motion and physiological movement of the organs during CT scanning cause motion blur in the reconstructed CT images, degrading both cardiac CT image quality and its diagnostic value. In this paper, we propose and demonstrate an effective and efficient method for CT coronary angiography image quality grading via semi-automatic labeling and vessel tracking. These algorithms produce scores that accord with those of expert readers to within 0.85 points on a 5-point scale. We also train a neural network model to perform fully-automatic motion artifact grading. We demonstrate, using XCAT simulation tools to generate realistic phantom CT data, that supplementing clinical data with synthetic data improves the scoring performance of this network. With respect to ground truth scores assigned by expert operators, the mean square error of grading motion of the right coronary artery is reduced by 36% by synthetic data supplementation. This demonstrates that augmentation of clinical training data with realistically synthesized images can potentially reduce the number of clinical studies needed to train the network.