HyGAnno: hybrid graph neural network-based cell type annotation for single-cell ATAC sequencing data.

Reliable cell type annotations are crucial for investigating cellular heterogeneity in single-cell omics data. Although various computational approaches have been proposed for single-cell RNA sequencing (scRNA-seq) annotation, high-quality cell labels are still lacking in single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq) data, because of extreme sparsity and inconsistent chromatin accessibility between datasets. Here, we present a novel automated cell annotation method that transfers cell type information from a well-labeled scRNA-seq reference to an unlabeled scATAC-seq target, via a parallel graph neural network, in a semi-supervised manner. Unlike existing methods that utilize only gene expression or gene activity features, HyGAnno leverages genome-wide accessibility peak features to facilitate the training process. In addition, HyGAnno reconstructs a reference-target cell graph to detect cells with low prediction reliability, according to their specific graph connectivity patterns. HyGAnno was assessed across various datasets, showcasing its strengths in precise cell annotation, generating interpretable cell embeddings, robustness to noisy reference data and adaptability to tumor tissues.

Transjugular approach in aspiration thrombectomy and angioplasty of a thrombosed straight arteriovenous graft compared to the direct hemodialysis access approach.

PURPOSE: To evaluate the efficacy and outcome of the transjugular approach in endovascular recanalization of a thrombosed straight arteriovenous graft (AVG) compared to those of the direct hemodialysis access approach (conventional approach). MATERIALS AND METHODS: We retrospectively assessed patients who underwent aspiration thrombectomy and percutaneous transluminal angioplasty for thrombosed straight AVG performed at a single institution between October 2006 and October 2021. A total of 138 thrombosed AVGs in 83 patients (39 male and 44 females) were divided into the transjugular approach group (Group A) and the conventional approach group (Group B). Technical and clinical success, postintervention primary patency, cumulative patency, and periprocedural complications were compared. RESULTS: There was no statistical difference in demographic data between groups A and B. The technical success rate of group A and B was 96.4% (80/83) and 98.2% 54/55, respectively (p > 0.05). The mean procedure time was 61.4 min (Group A) and 70.5 min (Group B) (p > 0.05). There was no statistically significant difference between the two groups in postintervention primary patency. The cumulative patency of Groups A and B was 911.9 days (range 122-6277) and 1062.3 days (range 72-2302 days), respectively (p > 0.05). One patient in Group B experienced a major graft rupture. Pseudoaneurysm formation at the sheath insertion site occurred in two patients in Group B. No cases of stenosis or thrombosis of the IJV or hematoma at the puncture site were observed in Group A. CONCLUSION: The transjugular approach is as safe and effective as the conventional approach for aspiration thrombectomy and percutaneous transluminal angioplasty of thrombosed straight AVGs.

A deep learning model of tumor cell architecture elucidates response and resistance to CDK4/6 inhibitors.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) have revolutionized breast cancer therapy. However, <50% of patients have an objective response, and nearly all patients develop resistance during therapy. To elucidate the underlying mechanisms, we constructed an interpretable deep learning model of the response to palbociclib, a CDK4/6i, based on a reference map of multiprotein assemblies in cancer. The model identifies eight core assemblies that integrate rare and common alterations across 90 genes to stratify palbociclib-sensitive versus palbociclib-resistant cell lines. Predictions translate to patients and patient-derived xenografts, whereas single-gene biomarkers do not. Most predictive assemblies can be shown by CRISPR-Cas9 genetic disruption to regulate the CDK4/6i response. Validated assemblies relate to cell-cycle control, growth factor signaling and a histone regulatory complex that we show promotes S-phase entry through the activation of the histone modifiers KAT6A and TBL1XR1 and the transcription factor RUNX1. This study enables an integrated assessment of how a tumor's genetic profile modulates CDK4/6i resistance.

Genome-wide ATAC-see screening identifies TFDP1 as a modulator of global chromatin accessibility.

Chromatin accessibility is a hallmark of active regulatory regions and is functionally linked to transcriptional networks and cell identity. However, the molecular mechanisms and networks that govern chromatin accessibility have not been thoroughly studied. Here we conducted a genome-wide CRISPR screening combined with an optimized ATAC-see protocol to identify genes that modulate global chromatin accessibility. In addition to known chromatin regulators like CREBBP and EP400, we discovered a number of previously unrecognized proteins that modulate chromatin accessibility, including TFDP1, HNRNPU, EIF3D and THAP11 belonging to diverse biological pathways. ATAC-seq analysis upon their knockouts revealed their distinct and specific effects on chromatin accessibility. Remarkably, we found that TFDP1, a transcription factor, modulates global chromatin accessibility through transcriptional regulation of canonical histones. In addition, our findings highlight the manipulation of chromatin accessibility as an approach to enhance various cell engineering applications, including genome editing and induced pluripotent stem cell reprogramming.

Association between arterial stiffness and autonomic dysfunction in participants underwent treadmill exercise testing: a cross-sectional analysis.

Data on the impact of arterial stiffness on autonomic function are limited. We sought to investigate whether heart rate recovery (HRR), a predictor of autonomic function, is impaired in patients with increased arterial stiffness. A total of 475 participants (mean age 55.8 ± 11.1 years, 34.3% women) who underwent a treadmill exercise test (TET) for the evaluation of chest pain were retrospectively analyzed. All patients underwent brachial-ankle pulse wave velocity (baPWV) measurement on the same day. HRR was defined as the difference in heart rate from maximal exercise to 1 min of recovery. Participants with the lowest HRR tertile were older and had more cardiovascular risk factors than those with the highest HRR tertile. Simple correlation analysis showed that baPWV was negatively correlated with HRR (r = - 0.327, P < 0.001). In multiple linear regression analysis, there was a significant association between baPWV and HRR, even after adjusting for potential confounders (ß = - 0.181, P < 0.001). In participants who underwent TET, baPWV was negatively correlated with HRR. The results of our study indicate a potential relationship between arterial stiffness and the autonomic nervous system.

Association of epicardial adipose tissue with metabolic risk factors on cardiovascular outcomes: serial coronary computed tomography angiography study.

BACKGROUND/AIMS: Epicardial adipose tissue (EAT) shares pathophysiological properties with other visceral fats and potentially triggers local inflammation. However, the association of EAT with cardiovascular disease (CVD) is still debatable. The study aimed to observe the changes and associations in EAT and risk factors over time, as well as to investigate whether EAT was associated with CVD. METHODS: A total of 762 participants from Seoul National University Hospital (SNUH) and SNUH Gangnam Center were included in this study. EAT was measured using coronary computed tomography angiography. RESULTS: Baseline EAT level was positively associated with body mass index (BMI), calcium score, atherosclerotic cardiovascular disease (ASCVD) 10-year risk score, glucose, triglycerides (TG)/high-density lipoprotein (HDL), but not with total cholesterol, low-density lipoprotein (LDL). At follow-up, EAT levels increased in all groups, with low EAT groups demonstrating a significant increase in EAT per year. Change in EAT was associated with a change in BMI, TG/HDL, and glucose, while changes in LDL, calcium score, and ASCVD 10-year risk score were not associated. Although calcium score and ASCVD 10-year risk score were associated with CVD events, baseline information of EAT, baseline EAT/body surface area, or EAT change was not available. CONCLUSION: Metabolic risks, e.g., BMI, TG/HDL, and glucose, were associated with EAT change per year, whereas classical CVD risks, e.g., LDL, calcium score, and ASCVD 10-year risk score, were not. The actual CVD event was not associated with EAT volume, warranting future studies combining qualitative assessments with quantitative ones.

Efficacy and Safety of Triple Therapy of Telmisartan/Amlodipine/Rosuvastatin in Patients with Dyslipidemia and Hypertension: A Multicenter Randomized Clinical Trial.

Background: Hypertension and dyslipidemia significantly contribute to cardiovascular disease development. Their coexistence poses challenges in managing multiple medications, influencing treatment adherence. Objective: This study aimed to assess the efficacy and safety of a combined treatment approach using a fixed-dose combination therapy. Methods: This multicenter, 8-week, randomized, double-blind, Phase IV trial was named Telmisartan/Amlodipine/Rosuvastatin from Samjin Pharmaceuticals and evaluated the efficacy and safety of fixed-dose combination treatment in patients with essential hypertension and dyslipidemia. They were randomly assigned to 2 fixed-dose combination therapy groups, telmisartan 40 mg/amlodipine 5 mg/rosuvastatin 10 mg (TEL/ALD/RSV) or amlodipine 5 mg/atorvastatin 10 mg (ALD/ATV) after washout/run-in period. The primary outcomes were the change in mean sitting systolic blood pressure and the percentage change of LDL-C after 8 weeks of medical treatment. Adverse drug reactions and events were assessed. Results: Of a total of 304 patients who underwent screening, 252 were randomized to the TEL/ALD/RSV group (125 patients) and the ALD/ATV group (127 patients). The mean (SD) ages of the TEL/ALD/RSV group and the ALD/ATV group were 67.4 (11.3) and 68.2 (10.6) years, respectively (P = 0.563). The least-squares mean (SE) in mean sitting systolic blood pressure changes between the 2 groups were -16.27 (0.93) mm Hg in the TEL/ALD/RSV group, -6.85 (0.92) mm Hg in the ALD/ATV group (LSM difference = -9.42 mm Hg; 95% CI, -11.99 to -6.84; P < .001). For LDL-C level changes, a significant difference was noted between the 2 groups: -50.03% (1.18%) in the TEL/ALD/RSV group, -39.60% (1.17%) in the ALD/ATV group (LSM difference = -10.43%; 95% CI, -13.70 to -7.16; P < .001). No severe adverse events were observed. Conclusions: TEL/ALD/RSV proved to be more efficient than ALD/ATV in lowering blood pressure and reducing LDL-C levels among patients with hypertension and dyslipidemia, with no notable safety concerns. (Curr Ther Res Clin Exp. 2024; XX:XXX-XXX). ClinicalTrials.gov identifier: NCT03860220.

Cancer Mutations Converge on a Collection of Protein Assemblies to Predict Resistance to Replication Stress.

Rapid proliferation is a hallmark of cancer associated with sensitivity to therapeutics that cause DNA replication stress (RS). Many tumors exhibit drug resistance, however, via molecular pathways that are incompletely understood. Here, we develop an ensemble of predictive models that elucidate how cancer mutations impact the response to common RS-inducing (RSi) agents. The models implement recent advances in deep learning to facilitate multidrug prediction and mechanistic interpretation. Initial studies in tumor cells identify 41 molecular assemblies that integrate alterations in hundreds of genes for accurate drug response prediction. These cover roles in transcription, repair, cell-cycle checkpoints, and growth signaling, of which 30 are shown by loss-of-function genetic screens to regulate drug sensitivity or replication restart. The model translates to cisplatin-treated cervical cancer patients, highlighting an RTK-JAK-STAT assembly governing resistance. This study defines a compendium of mechanisms by which mutations affect therapeutic responses, with implications for precision medicine. SIGNIFICANCE: Zhao and colleagues use recent advances in machine learning to study the effects of tumor mutations on the response to common therapeutics that cause RS. The resulting predictive models integrate numerous genetic alterations distributed across a constellation of molecular assemblies, facilitating a quantitative and interpretable assessment of drug response. This article is featured in Selected Articles from This Issue, p. 384.

Feasibility and Effectiveness of a Ring-Type Blood Pressure Measurement Device Compared With 24-Hour Ambulatory Blood Pressure Monitoring Device.

BACKGROUNDS AND OBJECTIVES: This study aimed to evaluate the applicability and precision of a ring-type cuffless blood pressure (BP) measurement device, CART-I Plus, compared to conventional 24-hour ambulatory BP monitoring (ABPM). METHODS: Forty patients were recruited, and 33 participants were included in the final analysis. Each participant wore both CART-I Plus and ABPM devices on the same arm for approximately 24 hours. BP estimation from CART-I Plus, derived from photoplethysmography (PPG) signals, were compared with the corresponding ABPM measurements. RESULTS: The CART-I Plus recorded systolic blood pressure (SBP)/diastolic blood pressure (DBP) values of 131.4±14.1/81.1±12.0, 132.7±13.9/81.9±11.9, and 128.7±14.6/79.3±12.2 mmHg for 24-hour, daytime, and nighttime periods respectively, compared to ABPM values of 129.7±11.7/84.4±11.2, 131.9±11.6/86.3±11.1, and 124.5±13.6/80.0±12.2 mmHg. Mean differences in SBP/DBP between the two devices were 1.74±6.69/-3.24±6.51 mmHg, 0.75±7.44/-4.41±7.42 mmHg, and 4.15±6.15/-0.67±5.23 mmHg for 24-hour, daytime, and nighttime periods respectively. Strong correlations were also observed between the devices, with r=0.725 and r=0.750 for transitions in SBP and DBP from daytime to nighttime, respectively (both p<0.001). CONCLUSIONS: The CART-I Plus device, with its unique ring-type design, shows promising accuracy in BP estimation and offers a potential avenue for continuous BP monitoring in clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06084065.

Dual Representation Learning for Predicting Drug-side Effect Frequency using Protein Target Information.

Knowledge of unintended effects of drugs is critical in assessing the risk of treatment and in drug repurposing. Although numerous existing studies predict drug-side effect presence, only four of them predict the frequency of the side effects. Unfortunately, current prediction methods (1) do not utilize drug targets, (2) do not predict well for unseen drugs, and (3) do not use multiple heterogeneous drug features. We propose a novel deep learning-based drug-side effect frequency prediction model. Our model utilized heterogeneous features such as target protein information as well as molecular graph, fingerprints, and chemical similarity to create drug embeddings simultaneously. Furthermore, the model represents drugs and side effects into a common vector space, learning the dual representation vectors of drugs and side effects, respectively. We also extended the predictive power of our model to compensate for the drugs without clear target proteins using the Adaboost method. We achieved state-of-the-art performance over the existing methods in predicting side effect frequencies, especially for unseen drugs. Ablation studies show that our model effectively combines and utilizes heterogeneous features of drugs. Moreover, we observed that, when the target information given, drugs with explicit targets resulted in better prediction than the drugs without explicit targets. The implementation is available at https://github.com/eskendrian/sider.

Ultrasound-guided genitofemoral nerve block for femoral arterial access gain and closure: a randomized controlled trial.

OBJECTIVES: This study aimed to compare the analgesic efficacy and safety of the femoral branch block of the genitofemoral nerve (FBB) versus local infiltration anesthesia (LIA) for femoral arterial access gain and closure. METHODS: Eighty-two patients (age, 64.8 ± 10.9 years; female, 30.5%) undergoing endovascular procedures using 5-Fr femoral sheath were assigned to either FBB (n = 41) or LIA (n = 41). In both groups, 2% lidocaine HCL with 1:100,000 epinephrine was used as an anesthetic solution. Pain scores during access gain and closure were evaluated using a visual analog scale (score 0-10), patient satisfaction levels with the quality of anesthesia were scored on a 7-point Likert scale, and adverse events were recorded. RESULTS: The primary endpoint, pain scores during access closure, was significantly lower in the FBB group than in the LIA group (0.1 ± 0.37 vs 1.73 ± 0.92; p < 0.001). The FBB group also had significantly lower pain scores during access gain compared to the LIA group (0.83 ± 0.83 vs 2.78 ± 1.26; p < 0.001). There was an inverse relationship between pain scores and FBB after adjustment for age, gender, and body mass index (p < 0.001). FBB group reported significantly higher satisfaction with anesthesia quality compared to the LIA group (6.49 ± 0.64 vs 4.05 ± 1.05; p < 0.001). No complications were recognized in either group. CONCLUSIONS: Ultrasound-guided genitofemoral nerve blocks offered better acute pain relief and higher patient satisfaction than LIA during femoral arterial access gain and closure. CLINICAL RELEVANCE STATEMENT: In this prospective randomized controlled trial, ultrasound-guided genitofemoral nerve blocks offered better acute pain relief than local infiltration anesthesia, resulting in enhanced patient satisfaction. KEY POINTS: • FBB provided better pain relief during access gain and closure than LIA. • FBB offered higher patient satisfaction with the quality of anesthesia than LIA. • No anesthesia-related or access site complications were recognized in either treatment group.

Subcellular expression pattern and clinical significance of CBX2 and CBX7 in breast cancer subtypes.

Chromobox (CBX)2 and CBX7, members of CBX family protein, show diverse expression patterns and contrasting roles in certain cancers. We aimed to investigate the subcellular expression patterns and clinical significances of CBXs in breast cancer (BC) subtypes, which have heterogeneous clinical course and therapeutic responses. Among the subtypes, the triple-negative BC (TNBC) is a heterogeneous group that lacks specific markers. We categorized TNBC into quadruple-negative BC (QNBC) and TNBC, based on androgen receptor (AR) status, to make the groups more homogeneous. Immunohistochemistry for CBX proteins was performed on 323 primary invasive BC tissues and their clinical significances were analyzed. Cytoplasmic CBX2 (CBX2-c) was linked to adverse clinicopathological factors and TNBC and QNBC subtypes. In contrast, nuclear CBX7 (CBX7-n) was associated with favorable parameters and luminal A subtype. CBX2-c expression increased progressively from that in benign lesions to that in in situ carcinomas and invasive cancers, whereas CBX7-n and AR expressions showed sequential downregulation. AR was lower in metastatic tissues compared to matched primary cancer tissues. We speculate that the upregulation of CBX2-c and downregulation of CBX7-n could play a role in breast oncogenesis and an adverse clinical course, suggesting them as potential prognostic markers and therapeutic targets in invasive BCs.

Practical Application of Coronary Physiologic Assessment: Asia-Pacific Expert Consensus Document: Part 1.

Coronary physiologic assessment is performed to measure coronary pressure, flow, and resistance or their surrogates to enable the selection of appropriate management strategy and its optimization for patients with coronary artery disease. The value of physiologic assessment is supported by a large body of evidence that has led to major recommendations in clinical practice guidelines. This expert consensus document aims to convey practical and balanced recommendations and future perspectives for coronary physiologic assessment for physicians and patients in the Asia-Pacific region based on updated information in the field that including both wire- and image-based physiologic assessment. This is Part 1 of the whole consensus document, which describes the general concept of coronary physiology, as well as practical information on the clinical application of physiologic indices and novel image-based physiologic assessment.

Practical Application of Coronary Physiologic Assessment: Asia-Pacific Expert Consensus Document: Part 2.

Coronary physiologic assessment is performed to measure coronary pressure, flow, and resistance or their surrogates to enable the selection of appropriate management strategy and its optimization for patients with coronary artery disease. The value of physiologic assessment is supported by a large body of clinical data that has led to major recommendations in all practice guidelines. This expert consensus document aims to convey practical and balanced recommendations and future perspectives for coronary physiologic assessment for physicians and patients in the Asia-Pacific region, based on updated information in the field that includes both wire- and image-based physiologic assessment. This is Part 2 of the whole consensus document, which provides theoretical and practical information on physiologic indexes for specific clinical conditions and patient statuses.

Brachial plexus block using only 1% lidocaine to reduce pain during the endovascular treatment of dysfunctional arteriovenous access.

BACKGROUND: Interventional endovascular treatments of dysfunctional arteriovenous (AV) access for hemodialysis can cause pain and discomfort to the patients. Ultrasound-guided brachial plexus block (BPB) is an alternative regional anesthesia method, but conventional BPB using ropivacaine or bupivacaine may cause long-lasting motor power loss, significantly reducing patient satisfaction. This study aimed to introduce BPB using only 1% lidocaine, which induces sensory loss while minimizing motor block, and evaluate the efficacy and safety of this procedure. METHODS: This retrospective study was conducted on 277 consecutive patients with dysfunctional AV access requiring percutaneous transluminal angioplasty (PTA). Of these, 174 patients underwent the BPB procedure using 1% lidocaine. Time data were recorded, and the motor strength grade (MRC scale, grade 0-5) was evaluated. Numeric rating pain score (NRPS, grade 0-10) was asked during every PTA, and overall NRPS and satisfaction scores (scale 1-3) were asked after the procedure was completed. RESULTS: Of the 174 patients who received BPB, the success rate was 100%, and there were no significant complications related to BPB. The MRC scale measured at the time when the complete sensory loss was achieved was 1.99 ± 0.63, and that at the point of sensory recovery when the block effect expired was 3.93 ± 0.62, indicating a good grade of motor strength. The average NRPS during PTA in the BPB group was significantly lower than that of the control group without BPB (1.04 ± 2.04vs 6.30 ± 2.71, p < 0.001). The overall satisfaction score was significantly higher in the BPB group than in the control group (2.79 ± 0.50vs 2.00 ± 0.81, p < 0.001). CONCLUSIONS: BPB using only 1% lidocaine can induce a sensory block while minimizing the effect on motor function. It can be applied safely in an outpatient clinic setting with relatively higher satisfaction.

Development and validation of an updated PICC length prediction formula based on anteroposterior chest radiographs for the ultrasound-guided bedside placement.

Bedside peripherally inserted central catheter (PICC) placement is sometimes required when the patient's intrahospital transport is restricted, and the ideal catheter length prediction is needed. This study aimed to develop an updated formula that predicts the optimal length of a PICC based on anteroposterior chest radiographs (AP-CXRs). This retrospective study collected PICC procedure data as the training and validation sets in three hospitals, including cubital crease-puncture point distance (CP), the actual PICC length (aCL), and the approach side. Horizontal and vertical measurement variables were set on the AP-CXRs. Two dependent variables were ipsilateral upper arm length (AL) and ideal truncal catheter length (iTCL). Simple and multiple regression analyses were used for formula development, and it was applied to the test set to evaluate the length prediction performance. The study included 309 patients in the training and validation sets and 91 intensive care patients in the test set. The final derived formula was: (AL + iTCL = CP + estimated PICC length, cm) = 19.831 - 0.062 × (contralateral clavicle length, cm) + 0.255 × (2nd ribs horizontal distance, cm) + 0.720 × (humero-vertebral distance, cm) + 0.761 × (thoraco-carinal distance, cm) + 1.024 × (the vertical distance of two vertebral body units, cm). (If approaching from the left, add 2.843cm, and if female, subtract 0.821cm.) In the test set, there was no case of length prediction failure. Moreover, the catheter tip position was evaluated as optimal in 82 cases (90.1%). This study's results suggest an updated formula to predict the ideal PICC length using only AP-CXRs for bedside placement.

Single-Session Percutaneous Mechanical Thrombectomy for Acute and Subacute Deep Vein Thrombosis: Clinical Outcomes and Predictive Factors of Recurrence.

Objectives: To evaluate the efficacy and safety of single-session percutaneous mechanical thrombectomy (PMT) for deep vein thrombosis (DVT), to compare clinical outcomes and recurrences between acute and subacute DVT, and to identify factors predicting recurrence. Materials and Methods: From January 2018 to March 2021, 100 consecutive patients (age: 64.64 ± 17.28 years; male, 42%) with symptomatic DVT who underwent single-session PMT were enrolled for this study. These patients were divided into an acute DVT group (< 14 days, n = 75) and a subacute DVT group (15-28 days, n = 25). Results: A large-bore aspiration thrombectomy was used in 80 (80%) cases, Angiojet (Boston Scientific, Marlborough, MA, USA) device in one (1%) case, and a combination of both techniques in 19 (19%) cases. The anatomic success rate was 97% and the clinical success rate was 95%. There were no major complications. Clinical outcomes were not different between the two groups. The recurrence-free survival rate in the acute DVT group was significantly (p = 0.015) better than that in the subacute DVT group. The anatomic success (HR, 52.3; 95% CI, 3.82-715.21; p = 0.003) and symptom duration (HR, 17.58; 95% CI, 1.89-163.34; p = 0.012) were predictive factors associated with recurrence. Conclusions: Single-session PMT is safe and effective for immediate symptom relief in acute and subacute DVT patients. However, recurrence occurred more frequently in patients with subacute DVT than in those with acute DVT. Anatomic success of the procedure and duration of symptoms were independent predictors of DVT recurrence.