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.

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.

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.

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.

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.

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.

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.

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.

Lifestyle Intervention and Excess Weight in Chronic Obstructive Pulmonary Disease (COPD): INSIGHT COPD Randomized Clinical Trial.

Rationale: Being overweight or obese is common among patients with chronic obstructive pulmonary disease (COPD), but whether interventions targeted at weight loss improve functional impairments is unknown. Objectives: INSIGHT (Intervention Study in Overweight Patients with COPD) tested whether a pragmatic low-intensity lifestyle intervention would lead to better physical functional status among overweight or obese participants with COPD. Methods: The trial was a 12-month, multicenter, patient-level pragmatic clinical trial. Participants were recruited from April 2017 to August 2019 from 38 sites across the United States and randomized to receive usual care or usual care plus lifestyle intervention. The intervention was a self-directed video program delivering the Diabetes Prevention Program's Group Lifestyle Balance curriculum. Results: The primary outcome was 6-minute-walk test distance at 12 months. Priority secondary outcomes were postwalk modified Borg dyspnea at 12 months and weight at 12 months. Participants (N = 684; mean age, 67.0 ± 8.0 yr [standard deviation]; 41.2% female) on average were obese (body mass index, 33.0 ± 4.6 kg/m2) with moderate COPD (forced expiratory volume in 1 second % predicted, 58.1 ± 15.7%). At 12 months, participants randomized to the intervention arm walked farther (adjusted difference, 42.3 ft [95% confidence interval (CI), 7.9-76.7 ft]; P = 0.02), had less dyspnea at the end of the 6-minute-walk test (adjusted difference, -0.36 [95% CI, -0.63 to -0.09]; P = 0.008), and had greater weight loss (adjusted difference, -1.34 kg [95% CI, -2.33 to -0.34 kg]; P = 0.008) than control participants. The intervention did not improve the odds of achieving clinically meaningful thresholds of walk distance (98.4 ft) or dyspnea (1 unit) but did achieve meaningful thresholds of weight loss (3% and 5%). Conclusions: Among participants with COPD who were overweight or obese, a self-guided low-intensity video-based lifestyle intervention led to modest weight loss but did not lead to clinically important improvements in physical functional status and dyspnea. Clinical trial registered with www.clinicaltrials.gov (NCT02634268).

Mediating Effects of Neural Targets on Depression, Weight, and Anxiety Outcomes of an Integrated Collaborative Care Intervention: The ENGAGE-2 Mechanistic Pilot Randomized Clinical Trial.

Background: Integrated treatments for comorbid depression (often with anxiety) and obesity are lacking; mechanisms are poorly investigated. Methods: In a mechanistic pilot trial, adults with body mass index ≥30 and Patient Health Questionnaire-9 scores ≥10 were randomized to usual care (n = 35) or an integrated behavioral intervention (n = 71). Changes at 6 months in body mass index and Depression Symptom Checklist-20 scores were co-primary outcomes, and Generalized Anxiety Disorder Scale-7 score was a secondary outcome. Changes at 2 months in the activation and functional connectivity of regions of interest in the negative affect circuit were primary neural targets, and secondary targets were in the cognitive control, default mode, and positive affect circuits. Results: Participants were 47.0 years (SD = 11.9 years), 76% women, 55% Black, and 20% Latino. Depression Symptom Checklist-20 (between-group difference, -0.3 [95% CI: -0.6 to -0.1]) and Generalized Anxiety Disorder Scale-7 (-2.9 [-4.7 to -1.1]) scores, but not body mass index, decreased significantly at 6 months in the intervention versus usual care groups. Only Generalized Anxiety Disorder Scale-7 score changes at 6 months significantly correlated with neural target changes at 2 months in the negative affect (anterior insula, subgenual/pregenual anterior cingulate cortex, amygdala) and cognitive control circuits (dorsal lateral prefrontal cortex, dorsal anterior cingulate cortex). Effects were medium to large (0.41-1.18 SDs). Neural target changes at 2 months in the cognitive control circuit only differed by treatment group. Effects were medium (0.58-0.79 SDs). Conclusions: Compared with usual care, the study intervention led to significantly improved depression but not weight loss, and the results on neural targets were null for both outcomes. The significant intervention effect on anxiety might be mediated through changes in the cognitive control circuit, but this warrants replication.

Investigating the potential anti-inflammatory mechanism of benzophenone compounds from the leaves of Aquilaria sinensis (Lour.) Gilg based on network pharmacology and molecular docking strategies.

BACKGROUND: Aquilaria sinensis (Lour.) Gilg (ASG) has been used as traditional medicine for centuries. However, the active ingredients from leaves and their anti-inflammatory mechanism are rarely reported. The network pharmacology and molecular docking strategies were applied to explore the potential mechanisms of Benzophenone compounds from the leaves of ASG (BLASG) against inflammation. METHODS: BLASG-related targets were obtained from the SwissTargetPrediction and PharmMapper databases. Inflammation-associated targets were retrieved from GeneGards, DisGeNET, and CTD databases. Cytoscape software was used to draw a network diagram of BLASG and its corresponding targets. DAVID database was applied for enrichment analyses. A protein-protein interaction (PPI) network was constructed to identify the hub targets of BLASG. Molecular docking analyses were performed by AutoDockTools 1.5.6. Moreover, we used ELISA and qRT-PCR assays to validate the anti-inflammatory effects of BLASG by cell experiments. RESULTS: Four BLASG were extracted from ASG, and corresponding 225 potential targets were identified. PPI network analysis indicated that SRC, PIK3R1, AKT1, and other targets were the core therapeutic targets. Enrichment analyses revealed that the effects of BLASG are regulated by targets associated with apoptosis and inflammation-related pathways. In addition, molecular docking revealed that BLASG combined well with PI3K and AKT1. Furthermore, BLASG significantly decreased the inflammatory cytokines levels and down-regulated PIK3R1 and AKT1 gene expression in RAW264.7 cells. CONCLUSION: Our study predicted the potential targets and pathways of BLASG against inflammation, which offered a promising strategy to reveal the therapeutic mechanism of natural active components in the treatment of diseases.

Effects of a virtual voice-based coach delivering problem-solving treatment on emotional distress and brain function: a pilot RCT in depression and anxiety.

Consumer-based voice assistants have the ability to deliver evidence-based treatment, but their therapeutic potential is largely unknown. In a pilot trial of a virtual voice-based coach, Lumen, delivering problem-solving treatment, adults with mild-to-moderate depression and/or anxiety were randomized to the Lumen intervention (n = 42) or waitlist control (n = 21). The main outcomes included changes in neural measures of emotional reactivity and cognitive control, and Hospital Anxiety and Depression Scale [HADS] symptom scores over 16 weeks. Participants were 37.8 years (SD = 12.4), 68% women, 25% Black, 24% Latino, and 11% Asian. Activation of the right dlPFC (neural region of interest in cognitive control) decreased in the intervention group but increased in the control group, with an effect size meeting the prespecified threshold for a meaningful effect (Cohen's d = 0.3). Between-group differences in the change in activation of the left dlPFC and bilateral amygdala were observed, but were of smaller magnitude (d = 0.2). Change in right dlPFC activation was also meaningfully associated (r ≥ 0.4) with changes in self-reported problem-solving ability and avoidance in the intervention. Lumen intervention also led to decreased HADS depression, anxiety, and overall psychological distress scores, with medium effect sizes (Cohen's d = 0.49, 0.51, and 0.55, respectively), compared with the waitlist control group. This pilot trial showed promising effects of a novel digital mental health intervention on cognitive control using neuroimaging and depression and anxiety symptoms, providing foundational evidence for a future confirmatory study.

Associations between daily step count trajectories and clinical outcomes among adults with comorbid obesity and depression.

Purpose: To examine the relationship between features of daily measured step count trajectories and clinical outcomes among people with comorbid obesity and depression in the ENGAGE-2 Trial. Methods: This post hoc analysis used data from the ENGAGE-2 trial where adults (n=106) with comorbid obesity (BMI ≥30.0 or 27.0 if Asian) and depressive symptoms (Patient Health Questionnaire-9 score ≥10) were randomized (2:1) to receive the experimental intervention or usual care. Daily step count trajectories over the first 60 days (Fitbit Alta HR) were characterized using functional principal component analyses. 7-day and 30-day trajectories were also explored. Functional principal component scores that described features of step count trajectories were entered into linear mixed models to predict weight (kg), depression (Symptom Checklist-20), and anxiety (Generalized Anxiety Disorder Questionnaire-7) at 2-months (2M) and 6-months (6M). Results: Features of 60-day step count trajectories were interpreted as overall sustained high, continuous decline, and disrupted decline. Overall sustained high step count was associated with low anxiety (2M, ß=-0.78, p<.05; 6M, ß=-0.80, p<.05) and low depressive symptoms (6M, ß=-0.15, p<.05). Continuous decline in step count was associated with high weight (2M, ß=0.58, p<.05). Disrupted decline was not associated with clinical outcomes at 2M or 6M. Features of 30-day step count trajectories were also associated with weight (2M, 6M), depression (6M), and anxiety (2M, 6M); Features of 7-day step count trajectories were not associated with weight, depression, or anxiety at 2M or 6M. Conclusions: Features of step count trajectories identified using functional principal component analysis were associated with depression, anxiety, and weight outcomes among adults with comorbid obesity and depression. Functional principal component analysis may be a useful analytic method that leverages daily measured physical activity levels to allow for precise tailoring of future behavioral interventions.

Prevalence and clinical association of hyperechoic crystal deposits on ultrasonography in patients with chronic kidney disease: a cross-sectional study from a single center.

BACKGROUND: Hyperechoic crystal deposits can be detected in the kidney medulla of patients with gout by ultrasonography examination. Chronic kidney disease (CKD) is usually accompanied with hyperuricemia. Whether hyperechoic crystal deposition could be detected by ultrasonography in CKD patients, and its clinical association are unknown. METHODS: Five hundred and fifteen consecutive CKD patients were included in this observational study. Clinical, biochemical and pathological data were collected and analyzed. RESULTS: Altogether, 234 (45.4%) patients were found to have hyperuricemia and 25 patients (4.9%) had gout history. Hyperechoic crystal deposits in kidney medulla were found in forty-four (8.5%) patients, on ultrasonography. Compared with patients without hyperechoic crystal deposits, patients with deposits were more likely to be male, younger, with gout history and presenting with higher serum uric acid level, lower estimated glomerular filtration rate, lower urine pH, lower 24 h-urinary citrate and uric acid excretion, and with a higher percentage of ischemic nephropathy (all p < 0.05). On multivariable logistic analysis, the hyperechoic depositions were associated with age [0.969 (0.944, 0.994), p = 0.016], serum uric acid level [1.246 (1.027, 1.511), p = 0.026], Sqrt-transformed 24 h-urine uric acid excretion [0.923 (0.856, 0.996), p = 0.039], and ischemic nephropathy [4.524 (1.437, 14.239), p = 0.01], respectively. CONCLUSIONS: Hyperechoic crystal deposition can be detected in kidney medulla by ultrasonography; in CKD patients their presence was associated with hyperuricemia as well as with ischemic nephropathy.