Quantification of morpho-hemodynamic changes in unruptured intracranial aneurysms with irregular pulsation during the cardiac cycle using 4D-CTA.

Background and purpose: Previous studies predicting the rupture risk of intracranial aneurysms (IAs) have predominantly utilized static imaging data, overlooking the dynamic blood flow and biomechanical properties of the aneurysm wall. Irregular pulsation detected by 4D-CTA is a potential predictor of aneurysm rupture, albeit with uncertain clinical significance. This study aimed to analyze the changes in morpho-hemodynamic characteristics of IAs during the cardiac cycle to elucidate the dynamic changes and the associated hemodynamic mechanisms. Methods: A retrospective review was conducted on the 4D-CTA data of IA patients between January 2017 and September 2019. R-R intervals were segmented into 20-time phases, reconstructing 20 CT datasets to identify irregular pulsation and extract 3D aneurysm models. Computational fluid dynamics (CFD) simulations analyzed hemodynamic parameters such as oscillatory shear index (OSI) and relative residence time (RRT). Changes in morpho-hemodynamic characteristics were quantified in terms of the absolute change (parameter*) and relative change rate (parameter%). Rupture risk was assessed using the rupture resemblance model (RRS). Results: Eleven UIAs from 10 patients were finally included, with five aneurysms showing irregular pulsation (45.45%). No significant differences in morpho-hemodynamic characteristics were observed between aneurysms with or without irregular pulsation. More remarkable changes in aneurysm size (size*: 0.59 ± 0.14 mm vs. 0.32 ± 0.12 mm, p = 0.010; size%: 10.49% ± 1.43% vs. 3.95% ± 1.79%, p < 0.001), volume (volume%: 13.72% vs. 6.39%, p = 0.009), OSI (OSI*: 0.02 ± 0.01 vs. 0.004 ± 0.005, p = 0.004; OSI%: 200% vs. 12.50%, p = 0.004) and RRT (RRT%: 97.14% vs. 43.95, p = 0.052) over the cardiac cycle were significantly linked to irregular pulsation. Aneurysms with irregular pulsation demonstrated a more unfavorable hemodynamic environment during the cardiac cycle, irrespective of the predicted rupture risk. Furthermore, irregular pulsation at the aneurysm dome exhibited higher hemodynamic instability than at the sidewall. Conclusion: Irregular pulsation may indicate hemodynamic instability within the aneurysm, leading to an increased rupture risk in the area where irregular pulsation occurs. This proof-of-concept study could enhance understanding of dynamic changes in UIAs during the cardiac cycle and the underlying hemodynamic mechanisms.

Identifying novel risk genes in intracranial aneurysm by integrating human proteomes and genetics.

Genome-wide association studies (GWAS) have become increasingly popular for detecting numerous loci associated with intracranial aneurysm (IA), but how these loci function remains unclear. In this study, we employed an integrative analytical pipeline to efficiently transform genetic associations and identify novel genes for IA. Using multidimensional high-throughput data, we integrated proteome-wide association studies (PWAS), transcriptome-wide association studies (TWAS), Mendelian randomization (MR) and Bayesian co-localization analyses to prioritize genes that can increase IA risk by altering their expression and protein abundances in the brain and blood. Moreover, single-cell RNA sequencing (scRNA-seq) of the circle of Willis was performed to enrich filtered genes in cells, and gene set enrichment analysis (GSEA) was conducted for each gene using bulk RNA-seq data for IA. No significant genes with cis-regulated plasma protein levels were proven to be associated with IA. The protein abundances of five genes in the brain were found to be associated with IA. According to cellular enrichment analysis, these five genes were expressed mainly in the endothelium, fibroblasts and vascular smooth muscle cells. Only three genes, CNNM2, GPRIN3 and UFL1, passed MR and Bayesian co-localization analyses. While UFL1 was not validated in confirmation PWAS as it was not profiled, it was validated in TWAS. GSEA suggested these three genes are associated with the cell cycle. In addition, the protein abundance of CNNM2 was found to be associated with IA rupture (based on PWAS, MR and co-localization analyses). Our findings indicated that CNNM2, GPRIN3 and UFL1 (CNNM2 correlated with IA rupture) are potential IA risk genes that may provide a broad hint for future research on possible mechanisms and therapeutic targets for IA.

Intracranial Aneurysms Managed by Parent Artery Reconstruction Using Tubridge Flow Diverter study: 1-year outcomes.

OBJECTIVE: Previous randomized controlled trials have reported a significantly higher occlusion rate of large and giant aneurysms when utilizing the Tubridge flow diverter (FD). In the present trial, the safety and efficacy of the Tubridge FD in treating unruptured internal carotid artery (ICA) or vertebral artery (VA) aneurysms were assessed in a real-world setting. METHODS: The Intracranial Aneurysms Managed by Parent Artery Reconstruction Using Tubridge Flow Diverter (IMPACT) study is a prospective, multicenter, single-arm clinical trial assessing the efficacy of the Tubridge FD in the management of unruptured aneurysms located in the ICA or VA. The primary endpoint was the complete occlusion (Raymond-Roy class 1) rate at the 1-year follow-up. The secondary endpoints included the technical success rate, the successful occlusion rate of the aneurysm, which is the degree of aneurysm embolization scored as Raymond-Roy class 1 or 2, major (> 50%) in-stent stenosis, and incidence of disabling stroke or neurological death associated with the target aneurysms. RESULTS: This study included 14 interventional neuroradiology centers, with 200 patients and 240 aneurysms. According to angiographic core laboratory assessment, 205 (85.4%) aneurysms were located in the ICA, 34 (14.2%) in the VA, and 1 (0.4%) in the middle cerebral artery. Additionally, 189 (78.8%) aneurysms were small (< 10 mm). At the 12-month follow-up, the total occlusion rate was 79.0% (166/210, 95% CI 72.91%-84.34%). Additionally, the occurrence of disabling stroke or neurological death related to the specified aneurysms was 1% (2/200). CONCLUSIONS: The 1-year results from the IMPACT trial affirm the safety record of use of the Tubridge FD in the treatment of intracranial aneurysms in real-world scenarios. These results reveal low morbidity and mortality rates of 3.5% and 1.5%, respectively. Furthermore, they provide evidence of the effectiveness of the Tubridge FD, as demonstrated by the complete occlusion achieved in 166 of 210 (79%) cases.

Treatment with Sacubitril/Valsartan Effectively Manages Hypertension and Ameliorates Left Ventricular Hypertrophy in Hemodialysis Patients.

INTRODUCTION: The aim of this study was to investigate the role of sacubitril/valsartan in managing hypertension and cardiac remodeling in patients undergoing hemodialysis. METHODS: Hemodialysis patients with stable blood pressure control were enrolled in the study. Sacubitril/valsartan was prescribed to replace previously used angiotensin-converting enzyme inhibitor/angiotensin receptor blocker or other antihypertensive drugs. During a 6-month follow-up period, pre-dialysis blood pressure, routine biochemical markers, and N-terminal pro-brain natriuretic peptide levels were measured. Volume status was assessed using bioelectrical impedance analysis. Endothelial damage was evaluated by measuring asymmetric dimethylarginine expression, while echocardiography and life quality assessed by Short Form-12 Health Survey were conducted at baseline and after treatment. RESULTS: The median daily dose of sacubitril/valsartan in 32 participants was 200 mg, and no obvious adverse reactions were reported. The defined daily dose of other antihypertensive drugs (baseline 2.00 ± 1.18, end point 1.46 ± 1.30, t = 3.216, p = 0.003) reduced significantly. After treatment with sacubitril/valsartan, left ventricular ejection fraction significantly increased from 64.81 ± 8.16% to 67.55 ± 5.85% (t = -4.022, p ≤ 0.001) and the thickness of posterior wall of the left ventricle reduced from 1.05 ± 0.14 cm to 1.00 ± 0.11 cm (t = 2.063, p = 0.048). The interventricular septal thickness (baseline 1.08 ± 0.16 cm, endpoint 1.02 ± 0.12 cm, t = 2.260, p = 0.031) remarkably reduced by the end of follow-up. The tricuspid regurgitation pressure gradient decreased from 28.47 ± 8.26 mm Hg at baseline to 23.79 ± 6.61 mm Hg (t = 2.531, p = 0.020) after treatment. CONCLUSION: Sacubitril/valsartan effectively manages hypertension in hemodialysis patients and may also independently improve left ventricular hypertrophy and systolic function, regardless of changes in the blood pressure or the volume load.

Cardiac sympathetic overdrive, M2 macrophage activation and fibroblast heterogeneity are associated with cardiac remodeling in a chronic pressure overload rat model of HFpEF.

Heart failure with preserved ejection fraction (HFpEF) is a multifaceted pathogenesis disease and the exact mechanisms driving HFpEF have not been completely elucidated. Pressure overload hypertrophy (POH) related fibroblasts and M2 macrophages in HFpEF myocardium have been recently identified and are now of great interest. Sympathetic overdrive has also been implicated in HFpEF. This study is designed to dynamically observe the potential roles of aforementioned mechanisms in pathological remodeling and cardiac dysfunction in chronic PO rats. Surgical constriction of the abdominal aorta was used for induction of HFpEF. Echocardiography, electrocardiogram, hemodynamic measurement, hematoxylin and eosin staining, Masson staining, immunohistochemistry and immunofluorescence were performed to assess the changes in heart dysfunction, cardiac remodeling and driving mechanisms at different time points (2, 18, 24 weeks). The PO induced HFpEF model was well established, which was confirmed by the persistent increase in carotid artery systolic and diastolic blood pressure, and left ventricle hypertrophy at the corresponding postoperative stage. Meanwhile, PO hypertrophy gradually developed into HFpEF, associated with QT and QTc intervals prolongation, normal systolic (EF was maintained at >50%) but impaired diastolic function (increasing LVEDP and LV -dP/dtmin, abnormal E/A ratio), increased myocytes size, and observed relatively slight inflammatory infiltration but robust reactive fibrosis. IHC staining further confirmed that macrophages (CD68) but not neutrophils (MPO) or T cells (CD3) accounted for a predominant proportion of infiltrating cells. Mechanistically, we found that the infiltrating macrophages in the heart expressed high levels of CD206 which was simultaneously adjacent to POH fibroblasts appeared to overexpression of α-SMA in PO rats at late stages. Interestingly, we distinguished two different POHF sub-populations during PO induced HFpEF development, according to non overlapping signals of α-SMA and PDGFRα/ß proteins. Additionally, PO led to a pronounced exaggeration in sympathetic fibers at all time points. These findings suggest that the establishing model here begins with cardiac sympathetic overdrive, subsequently along with immune cells especially M2 macrophage accumulation and fibroblast heterogeneity at later stages is associated with the development of cardiac maladaptive remodeling and diastolic dysfunction thus further progression to HFpEF.

Study of a PST-trained voice-enabled artificial intelligence counselor for adults with emotional distress (SPEAC-2): Design and methods.

BACKGROUND: Novel and scalable psychotherapies are urgently needed to address the depression and anxiety epidemic. Leveraging artificial intelligence (AI), a voice-based virtual coach named Lumen was developed to deliver problem solving treatment (PST). The first pilot trial showed promising changes in cognitive control measured by functional neuroimaging and improvements in depression and anxiety symptoms. METHODS: To further validate Lumen in a 3-arm randomized clinical trial, 200 participants with mild-to-moderate depression and/or anxiety will be randomly assigned in a 2:1:1 ratio to receive Lumen-coached PST, human-coached PST as active treatment comparison, or a waitlist control condition where participants can receive Lumen after the trial period. Participants will be assessed at baseline and 18 weeks. The primary aim is to confirm neural target engagement by testing whether compared with waitlist controls, Lumen participants will show significantly greater improvements from baseline to 18 weeks in the a priori neural target for cognitive control, right dorsal lateral prefrontal cortex engaged by the go/nogo task (primary superiority hypothesis). A secondary hypothesis will test whether compared with human-coached PST participants, Lumen participants will show equivalent improvements (i.e., noninferiority) in the same neural target from baseline to 18 weeks. The second aim is to examine (1) treatment effects on depression and anxiety symptoms, psychosocial functioning, and quality of life outcomes, and (2) relationships of neural target engagement to these patient-reported outcomes. CONCLUSIONS: This study offers potential to improve the reach and impact of psychotherapy, mitigating access, cost, and stigma barriers for people with depression and/or anxiety. CLINICALTRIALS: gov #: NCT05603923.

Exome sequencing reveals genetic heterogeneity and clinically actionable findings in children with cerebral palsy.

Cerebral palsy (CP) is the most common motor disability in children. To ascertain the role of major genetic variants in the etiology of CP, we conducted exome sequencing on a large-scale cohort with clinical manifestations of CP. The study cohort comprised 505 girls and 1,073 boys. Utilizing the current gold standard in genetic diagnostics, 387 of these 1,578 children (24.5%) received genetic diagnoses. We identified 412 pathogenic and likely pathogenic (P/LP) variants across 219 genes associated with neurodevelopmental disorders, and 59 P/LP copy number variants. The genetic diagnostic rate of children with CP labeled at birth with perinatal asphyxia was higher than the rate in children without asphyxia (P = 0.0033). Also, 33 children with CP manifestations (8.5%, 33 of 387) had findings that were clinically actionable. These results highlight the need for early genetic testing in children with CP, especially those with risk factors like perinatal asphyxia, to enable evidence-based medical decision-making.

Subpocket-Based Analysis Approach for the Protein Pocket Dynamics.

Structural and dynamic characteristics of protein pockets remarkably influence their biological functions and are also important for enzyme engineering and new drug research and development. To date, several softwares have been developed to analyze the dynamic properties of protein pockets. However, due to the complexity and diversity of the pocket information during the kinetic relaxation, further improvement and capacity expansion of current tools are required. Here, we developed a platform software AlphaTraj in which a computational strategy that divides the whole protein pocket into subpockets and examines various properties of the subpockets such as survival time, stability, and correlation was proposed and implemented. We also proposed a scoring function for the subpockets as well as the whole pocket to visualize the quality of the pocket. Furthermore, we implemented automated conformational search functions for ligand docking and ligand optimization. These functions may help us to gain a deep understanding of the dynamic properties of protein pockets and accelerate the protein engineering and the design of inhibitors and small-molecule drugs. The software is freely available at https://github.com/dooo12332/AlphaTraj.git under the GNU GPL license.

Relationships between irregular pulsation and variations in morphological characteristics during the cardiac cycle in unruptured intracranial aneurysms by 4D-CTA.

Background and purpose: Irregular pulsation of the aneurysmal wall has been suggested as a novel predictor for aneurysm rupture. Aneurysm volume variations during the cardiac cycle and the association between irregular pulsation and morphological features have been discussed, but the clinical significance remains unclear. The purpose of this study was to quantify changes in morphological characteristics over the cardiac cycle and examine their correlation with irregular pulsation to facilitate comprehension of aneurysm dynamics. Materials and methods: Fourteen unruptured intracranial aneurysms (UIAs) from 11 patients were included in this study, and each of them underwent 4D-CTA after diagnosis by DSA. The R-R intervals were divided into 20-time phases at 5% intervals to determine whether an aneurysm had irregular pulsation throughout the cardiac cycle. CT images from the 20-time phases were used to reconstruct 3D aneurysm models, measure 14 morphological parameters, and quantify each parameter's absolute change and relative rates of change during the cardiac cycle. Results: Seven of 14 UIAs exhibited irregular pulsation over the cardiac cycle by 4D-CTA, 5 of which were small aneurysms (< 7 mm). The UIAs with irregular pulsation exhibited greater changes in morphological characteristics. As aneurysm size increased, the absolute change in aneurysm volume increased (p = 0.035), but the relative rates of change in aneurysm size (p = 0.013), height (p = 0.014), width (p = 0.008), height-to-width ratio (p = 0.009), dome-to-neck ratio (p = 0.019) and bottleneck factor (p = 0.012) decreased. Conclusion: Although the larger the aneurysm, the greater the amplitude of its volumetric variation, small aneurysms are prone to irregular pulsation during the cardiac cycle and have more pronounced and dramatic morphological changes during the cardiac cycle that may increase the risk of rupture. This proof-of-concept study could help to explain the importance of dynamic changes using 4D-CTA in assessing the rupture risk of UIAs.

IV Flat Detector CT Angiography in Flat Detector CT Image-Guided Minimally Invasive Surgery for the Treatment of Intracerebral Hypertensive Hemorrhage.

BACKGROUND AND PURPOSE: Spontaneous intracerebral hemorrhage is a serious stroke subtype with high mortality and morbidity. Minimally invasive surgery plus thrombolysis is a promising treatment option, but it requires accurate catheter placement and real-time monitoring. The authors introduced IV flat detector CT angiography (ivFDCTA) into the minimally invasive surgery procedure for the first time, to provide vascular information and guidance for hematoma evacuation. MATERIALS AND METHODS: Thirty-six patients with hypertensive intracerebral hemorrhage were treated with minimally invasive surgery under the guidance of ivFDCTA and flat detector CT (FDCT) in the angiography suite. The needle path and puncture depth were planned and calculated using software on the DSA workstation. The hematoma volume reduction, operation time, complications, and clinical outcomes were recorded and evaluated. RESULTS: The mean preoperative hematoma volume of 36 patients was 35 (SD, 12) mL, the mean intraoperative volume reduction was 19 (SD, 11) mL, and the mean postoperative residual hematoma volume was 15 (SD, 8) mL. The average operation time was 59 (SD, 22) minutes. One patient had an intraoperative epidural hematoma, which improved after conservative treatment. The mean Glasgow Outcome Scale score at discharge was 4.3 (SD, 0.8), and the mean mRS score at 90 days was 2.4 (SD, 1.1). CONCLUSIONS: The use of ivFDCTA in the evacuation of an intracerebral hemorrhage hematoma could improve the safety and efficiency of minimally invasive surgery and has shown great potential in hemorrhagic stroke management in selected patients.

Clinical Outcomes On Tubridge Flow Diverter in Treatmenting Intracranial Aneurysms: a Retrospective Multicenter Registry Study.

PURPOSE: In China, the application of nitinol Tubridge flow diverter (TFD) has become popular for treating intracranial aneurysms (IAs). In this study, we investigated the safety outcomes of the application of TFD for treating IAs in real-world scenarios. METHODS: We retrospectively analyzed aneurysms treated with TFD in 235 centers throughout China between April 2018 and April 2020. The primary endpoint was the event-free survival rate at 12 months, defined as the occurrence of morbidity (spontaneous rupture, intraparenchymal hemorrhage (IPH), ischemic stroke, and permanent cranial neuropathy) or death. Univariate and multivariate analyses were performed to assess the risk factors. A good outcome was defined as a modified Rankin Score (mRS) of 0-2. RESULTS: We included 1281 unruptured aneurysms treated with TFD. The overall neurological morbidity and death rates after 12 months were 5.4 and 2.8%, respectively. Ischemic strokes were the most common complication (4.2%, P < 0.001). Cranial neuropathy, IPH, and spontaneous rupture occurred in 0.3%, 0.3%, and 0.5% of aneurysms, respectively. Univariate and multivariate analyses indicated that the male gender, older age, larger aneurysm diameter, and aneurysm located on BA were the independent risk factors for neurologic events. Aneurysm located on BA was the independent risk factor for ischemic strokes. Most patients (1222) had access to the mRS, and 93.2% of them achieved good outcomes. CONCLUSION: Treatment of IAs with TFD was associated with low morbidity and mortality, most of which were ischemic events. Large posterior aneurysms might be associated with a higher complication rate. TRIAL REGISTRATION: Retrospectively registered.

Antioxidants and the risk of stroke: results from NHANES and two-sample Mendelian randomization study.

BACKGROUND: Stroke is the second leading cause of death worldwide, and observational studies have suggested a correlation between antioxidants and reduced stroke risk. However, it remains unclear whether causal relationships exist. METHODS: This study first performed a cross-sectional study of the association between the Composite Dietary Antioxidant Index (CDAI) and stroke using data from the National Health and Nutrition Examination Survey (NHANES) 2007-2018. Second, a two-sample univariable Mendelian Randomization (MR) was performed to analyze the causal effect of circulating levels of antioxidants on different subtypes of stroke. RESULTS: The cross-sectional study included a total of 24,892 participants representing more than 200 million US non-institutionalized residents, a multivariable logistic regression model revealed that the risk of stroke decreased by 3.4% for each unit increase in CDAI (P = 0.017), with a non-linear association found, indicating a reduction in stroke risk before an inflection point of 3.078. MR analysis revealed that genetically determined levels of retinol had a suggestive protective effect on subarachnoid hemorrhage (SAH) (OR = 0.348, P = 0.025), and genetically determined levels of selenium had a suggestive protective effect against SAH (OR = 0.826, P = 0.007). However, no causal relationship was found between antioxidants and ischemic stroke or intracranial hemorrhage risk. CONCLUSIONS: Evidence suggests that diet-derived antioxidants may reduce the risk of stroke, as indicated by the protective effects of retinol and selenium against SAH. However, more research is needed to fully understand how antioxidants prevent stroke.

Platelet Membrane-Encapsulated Nanocomplexes Based on Profundity Scavenging ROS Strategy for Myocardial Infarction Therapy.

Ischemia-induced myocardial injury has become a serious threat to human health, and its treatment remains a challenge. The occurrence of ischemic events leads to a burst release of reactive oxygen species (ROS), which triggers extensive oxidative damage and leads to dysfunctional autophagy, making it difficult for cells to maintain homeostasis. Antioxidants and modulation of autophagy have thus become promising strategies for the treatment of ischemic myocardial injury. This study proposes an antioxidant-activated autophagy therapeutic regimen based on combining melanin (Mel), an excellent antioxidant with metformin mimetic ploymetformin via electrostatic interactions, to obtain a nanocomplex (Met-Mel). The nanocomplex is finally encapsulated with platelet membranes (PMN) to construct a biomimetic nanoparticle (PMN@Met-Mel) capable of targeting injured myocardium. The prepared PMN@Met-Mel has good Mel loading capacity and optimal biosafety. It exhibits excellent antioxidant activity and autophagy activation, rapidly restoring mitochondrial function. Moreover, RNA sequencing (RNA-seq) analysis reveals that PMN@Met-Mel operates mechanistically by triggering the activation of the autophagy pathway. Subsequent in vivo experiments showcase promising cardioprotective effects of these nanoparticles. These discoveries present a newly devised nanoplatform with promising potential for the effective treatment of myocardial infarction.

ROS-Suppression Nanoplatform Combined Activation of STAT3/Bcl-2 Pathway for Preventing Myocardial Infarction in Mice.

Myocardial infarction (MI) is the leading cause of death worldwide. The most effective way to treat myocardial infarction is to rescue ischemic cardiomyocytes. After an ischemic event, the overproduction of reactive oxygen species (ROS) is a key driver of myocardial injury. The produced ROS affects mitochondrial function and induces apoptosis in cardiomyocytes. This was accomplished by constructing platelet-membrane-encapsulated ROS-responsive drug-releasing nanoparticles (PMN@NIC-MalNPs) to deliver malonate and niclosamide (NIC). The results revealed that PMN@NIC-MalNPs degraded and released malonate and niclosamide in a high-level ROS microenvironment, effectively reducing the oxidative stress and apoptosis rate. By enhancing basal mitochondrial oxygen consumption rate (OCR), adenosine triphosphate (ATP) production, and spare respiratory capacity (SRC) in vitro, reduced the oxidative stress levels and restored mitochondrial function. In vivo studies revealed that the PMN@NIC-MalNPs improved cardiac dysfunction, inhibited succinate dehydrogenase (SDH) activity, increased ATP production, and reduced the myocardial infarct size in myocardial infarction model mice. Further, transcriptome analysis and Western blot revealed that PMN@NIC-MalNPs prevented apoptosis by activating the expressions of the signal transducer and activator of transcription 3 (STAT3) and Bcl-2, and inhibiting the expression of Bax. Thus, this study provides a novel therapeutic solution for treating myocardial infarction and predicting the viability of an antioxidant and antiapoptotic therapeutic solution in the treatment of myocardial injury.

The occurrence characteristics, removal efficiency, and risk assessment of polycyclic aromatic hydrocarbons in sewage sludges from across China.

Sewage sludge is considered to be an important sink for polycyclic aromatic hydrocarbons (PAHs) in wastewater treatment plants and the potential risks from sludge contaminated with PAHs during land application has attracted attention. To identify the priority PAHs for control and enhance their removal from sludge, the occurrence characteristics, removal efficiency, and risk assessment of PAHs in sewage sludges from across China were analyzed. Data collection was from 2001 to 2023. Results showed that 16 PAHs were widely detected in Chinese sewage sludge with total amounts (∑16PAHs) between 0.06 and 34.93 mg kg dw-1. Fossil fuel, coal, and biomass combustion are main anthropogenic sources of PAHs in China. In general, phenanthrene (PHE), anthracene (ANT), fluorescein (FL), chrysene (CHR), pyrene (PYR), and benzo[b]fluoranthene (BbF) are regarded as the main components and PAHs with 3-5 rings dominate (84.01%-91.53%) sewage sludge in China. Although aerobic composting and anaerobic treatment significantly improve ∑16PAHs removal, sludge stabilization treatment only reduced the risk by a small amount, especially for high-molecular-weight (HMW) PAHs. The benzo[a]anthracene (BaA), benzo[a]pyrene (BaP), and dibenzo[a,h]anthracene (DahA) are proposed as the priority control contaminants for sewage sludge in China because they have consistently high-risk quotient (RQ) values of 2.42-7.47, 1.28-3.16, 1.06-1.83 before and after sludge stabilization, respectively. More attention should be paid to BaA, BbF, benzo[k]fluoranthene (BkF), BaP, DahA, and indeno[1,2,3-cd]pyrene (IcdP) in Beijing; ANT, BaA, and BaP in Shanghai; and BaA and BaP in Guanghzou. Although the toxic equivalent quotient (TEQ) for PAHs met the limit concentration requirements of the national standard, the potential health risks due to long-term exposure to HMW PAHs cannot be ignored because the incremental lifetime cancer risk (ILCR) was consistently in the risk threshold range (>1 × 10-6). Some suggestions on enhanced treatment approaches and land use standards are proposed to further alleviate the risk from HMW PAHs.

Association Between User Interaction and Treatment Response of a Voice-Based Coach for Treating Depression and Anxiety: Secondary Analysis of a Pilot Randomized Controlled Trial.

BACKGROUND: The quality of user interaction with therapeutic tools has been positively associated with treatment response; however, no studies have investigated these relationships for voice-based digital tools. OBJECTIVE: This study evaluated the relationships between objective and subjective user interaction measures as well as treatment response on Lumen, a novel voice-based coach, delivering problem-solving treatment to patients with mild to moderate depression or anxiety or both. METHODS: In a pilot trial, 42 adults with clinically significant depression (Patient Health Questionnaire-9 [PHQ-9]) or anxiety (7-item Generalized Anxiety Disorder Scale [GAD-7]) symptoms or both received Lumen, a voice-based coach delivering 8 problem-solving treatment sessions. Objective (number of conversational breakdowns, ie, instances where a participant's voice input could not be interpreted by Lumen) and subjective user interaction measures (task-related workload, user experience, and treatment alliance) were obtained for each session. Changes in PHQ-9 and GAD-7 scores at each ensuing session after session 1 measured the treatment response. RESULTS: Participants were 38.9 (SD 12.9) years old, 28 (67%) were women, 8 (19%) were Black, 12 (29%) were Latino, 5 (12%) were Asian, and 28 (67%) had a high school or college education. Mean (SD) across sessions showed breakdowns (mean 6.5, SD 4.4 to mean 2.3, SD 1.8) decreasing over sessions, favorable task-related workload (mean 14.5, SD 5.6 to mean 17.6, SD 5.6) decreasing over sessions, neutral-to-positive user experience (mean 0.5, SD 1.4 to mean 1.1, SD 1.3), and high treatment alliance (mean 5.0, SD 1.4 to mean 5.3, SD 0.9). PHQ-9 (Ptrend=.001) and GAD-7 scores (Ptrend=.01) improved significantly over sessions. Treatment alliance correlated with improvements in PHQ-9 (Pearson r=-0.02 to -0.46) and GAD-7 (r=0.03 to -0.57) scores across sessions, whereas breakdowns and task-related workload did not. Mixed models showed that participants with higher individual mean treatment alliance had greater improvements in PHQ-9 (ß=-1.13, 95% CI -2.16 to -0.10) and GAD-7 (ß=-1.17, 95% CI -2.13 to -0.20) scores. CONCLUSIONS: The participants had fewer conversational breakdowns and largely favorable user interactions with Lumen across sessions. Conversational breakdowns were not associated with subjective user interaction measures or treatment responses, highlighting how participants adapted and effectively used Lumen. Individuals experiencing higher treatment alliance had greater improvements in depression and anxiety. Understanding treatment alliance can provide insights on improving treatment response for this new delivery modality, which provides accessibility, flexibility, comfort with disclosure, and cost-related advantages compared to conventional psychotherapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT04524104; https://clinicaltrials.gov/study/NCT04524104.

A Novel Molecular Classification Method for Glioblastoma Based on Tumor Cell Differentiation Trajectories.

The latest 2021 WHO classification redefines glioblastoma (GBM) as the hierarchical reporting standard by eliminating glioblastoma, IDH-mutant and only retaining the tumor entity of "glioblastoma, IDH-wild type." Knowing that subclassification of tumors based on molecular features is supposed to facilitate the therapeutic choice and increase the response rate in cancer patients, it is necessary to carry out molecular classification of the newly defined GBM. Although differentiation trajectory inference based on single-cell sequencing (scRNA-seq) data holds great promise for identifying cell heterogeneity, it has not been used in the study of GBM molecular classification. Single-cell transcriptome sequencing data from 10 GBM samples were used to identify molecular classification based on differentiation trajectories. The expressions of identified features were validated by public bulk RNA-sequencing data. Clinical feasibility of the classification system was examined in tissue samples by immunohistochemical (IHC) staining and immunofluorescence, and their clinical significance was investigated in public cohorts and clinical samples with complete clinical follow-up information. By analyzing scRNA-seq data of 10 GBM samples, four differentiation trajectories from the glioblastoma stem cell-like (GSCL) cluster were identified, based on which malignant cells were classified into five characteristic subclusters. Each cluster exhibited different potential drug sensitivities, pathways, functions, and transcriptional modules. The classification model was further examined in TCGA and CGGA datasets. According to the different abundance of five characteristic cell clusters, the patients were classified into five groups which we named Ac-G, Class-G, Neo-G, Opc-G, and Undiff-G groups. It was found that the Undiff-G group exhibited the worst overall survival (OS) in both TCGA and CGGA cohorts. In addition, the classification model was verified by IHC staining in 137 GBM samples to further clarify the difference in OS between the five groups. Furthermore, the novel biomarkers of glioblastoma stem cells (GSCs) were also described. In summary, we identified five classifications of GBM and found that they exhibited distinct drug sensitivities and different prognoses, suggesting that the new grouping system may be able to provide important prognostic information and have certain guiding significance for the treatment of GBM, and identified the GSCL cluster in GBM tissues and described its characteristic program, which may help develop new potential therapeutic targets for GSCs in GBM.

A novel remnant liver-first strategy for liver autotransplantation in patients with end-stage hepatic alveolar echinococcosis: a retrospective case series.

BACKGROUND: Ex vivo liver resection combined with autotransplantation is an effective therapeutic strategy for unresectable end-stage hepatic alveolar echinococcosis (HAE). However, ex vivo liver resection combined with autotransplantation is a technically demanding and time-consuming procedure associated with significant morbidity and mortality. The authors aimed to present our novel remnant liver-first strategy of in vivo liver resection combined with autotransplantation (IRAT) technique for treating patients with end-stage HAE. METHODS: This retrospective study included patients who underwent IRAT between January 2014 and December 2020 at two institutions. Patients with end-stage HAE were carefully assessed for IRAT by a multidisciplinary team. The safety, feasibility, and outcomes of this novel technique were analyzed. RESULTS: IRAT was successfully performed in six patients, with no perioperative deaths. The median operative time was 537.5 min (range, 501.3-580.0), the median anhepatic time was 59.0 min (range, 54.0-65.5), and the median cold ischemia time was 165.0 min (range, 153.8-201.5). The median intraoperative blood loss was 700.0 ml (range, 475.0-950.0). In-hospital complications occurred in two patients. No Clavien-Dindo grade III or higher complications were observed. At a median follow-up of 18.6 months (range, 15.4-76.0) , all patients were alive. No recurrence of HAE was observed. CONCLUSION: The remnant liver-first strategy of IRAT is feasible and safe for selected patients with end-stage HAE. The widespread adoption of this novel technique requires further studies to standardize the operative procedure and identify patients who are most likely to benefit from it.

Development of a sensitive droplet digital PCR according to the HPV infection specificity in Chinese population.

HPV16 and 18 are positively correlated with cervical carcinogenesis. However, HPV prevalence tends to vary according to region, nationality, and environment. The most prevalent high-risk (HR) HPV genotypes are HPV16, 52, 58, 56, 18, 33, and 45), while the low-risk (LR) genotypes are HPV6 and 11 in the Chinese population. Importantly, undetectable low-copy HPV DNA could be an important indicator of integration into the human genome and may be a precursor to cancer progression. The HPV viral load changes dramatically, either increasing or decreasing rapidly during carcinogenesis, and traditional quantitative real-time PCR (qPCR) cannot accurately capture this subtle change. Therefore, in this study, a reliable droplet digital PCR (ddPCR) method was developed to simultaneously detect and quantify HPV genotypes. The ddPCR quantitative results showed high accuracy, sensitivity, and specificity compared to qPCR results employing the same clinical specimens and supplemented the ddPCR assay for HPV52/56/58/6 genotypes according to the infection specificity of the Chinese population. In summary, this procedure is valuable for quantifying HPV DNA, especially under conditions of low template copy number in cervical intraepithelial neoplasia (CIN) and/or cervical cancer. Additionally, this method can dynamically observe the prognosis and outcome of HPV infection and thus be used as an effective means for real-time monitoring of tumor load.

Effects of laparoscopic and choledochoscopic gallbladder-preserving cholecystolithotomy on levels of operation indicators, gallbladder function, and cholecystokinin type-A receptor in patients with gallstones.

Introduction: Gallstones are a common digestive system disease. Aim: To assess the effects of laparoscopic and choledochoscopic gallbladder-preserving cholecystolithotomy on the levels of operation indicators, gallbladder function, and cholecystokinin type-A receptor (CCKAR) in patients with gallstones. Material and methods: The medical records of 100 patients with gallstones receiving operation from July 2019 to August 2022 were collected for retrospective analysis. They were divided into a laparoscopic group (n = 48) and a laparoscopic + choledochoscopic group (n = 52). The laparoscopic group received totally laparoscopic cholecystolithotomy, while the laparoscopic + choledochoscopic group underwent laparoscopic and choledochoscopic cholecystolithotomy. Their perioperative indicators, gallbladder function, stress indicators (cortisol (Cor), norepinephrine (NE), and C-reactive protein (CRP)), serum biochemical indicators (liver receptor homologue 1 (LRH-1), CCKAR, and vasoactive intestinal peptide (VIP)), and complications were compared. Results: The fasting gallbladder volume and gallbladder contraction rate increased, and the minimum residual volume and gallbladder wall thickness decreased in the laparoscopic + choledochoscopic group in comparison with those of the laparoscopic group 6 months after operation (p < 0.05). The levels of serum Cor, NE, CRP, and CCKAR were elevated, whereas the levels of serum LRH-1 and VIP were lowered in both groups 3 d after operation compared with those before operation (p < 0.05). The levels of serum Cor, NE, CRP, LRH-1, and VIP were lower, and the level of serum CCKAR was higher in the laparoscopic + choledochoscopic group than those in the laparoscopic group 3 d after operation (p < 0.05). Conclusions: Both laparoscopic gallbladder-preserving cholecystolithotomy and laparoscopic and choledochoscopic cholecystolithotomy are effective for treating gallstones. However, the latter combination method is superior in enhancing postoperative gallbladder function, decreasing the recurrence risk, regulating the expressions of LRH-1, CCKAR, and VIP, and promoting the postoperative recovery of gastrointestinal function.