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Background: We have previously reported that Sorbs2 (sorbin and SH3 domain 2) knockout mice have significant cardiac structural and electrical remodeling, including atrial enlargement and fibrosis. The mechanisms of such changes were unknown. Hypothesis: We hypothesized that loss of Sorbs2 in cardiac fibroblasts promotes profibrotic signaling pathways and alters the balance between matrix metalloproteinases (MMPs), and their inhibitors (TIMPs) resulting in excessive collagen deposition in the atria. Methods: We used Sorbs2 global knockout ( Sorbs2 KO) mice and age-matched wild-type (WT) controls at 4 to 5 months of age. Left atrial fibrosis was quantitated by Masson's trichrome staining in serial sections. Scratch wound healing assays and transwell migration assays were performed in isolated Sorbs2 KO and WT atrial fibroblasts. Protein expression was determined by Western blots. Interleukin-6 (IL-6) production in cultured fibroblast supernatants was measured by ELISA. Results: Sorbs2 KO mice showed significant increase in atrial diameter (16.6 ± 1.5 mm vs 12.0 ± 1.1 mm in WT; n=3, p < 0.05) and atrial fibrosis (fraction of fibrotic areas: 18.6± 2.9 % vs. 7.6 ± 0.9 % in WT; p < 0.01). Collagen 1 and collagen 3 protein levels in Sorbs2 KO mouse atria were 1.8-fold and 1.7-fold higher than those of WT respectively. Sorbs2 KO atrial fibroblasts showed impaired function with significantly reduced migration and slower scratch-wound closure (migration area after 24h: 18.5 ± 3.8 % vs 70.1 ± 6.7 % in WT; n=6, p < 0.01).Moreover, transforming growth factor β1 (TGF-β1), α-smooth muscle actin, and periostin expression levels were significantly reduced in isolated fibroblasts and atrial myocardia from Sorbs2 KO mice, suggesting that fibrosis is not caused by TGF-b1-dependent mechanisms or from myofibroblast transformation. Analysis of ECM proteins showed significant downregulation of MMP1 and MMP3 but upregulation of TIMP1, while TIMP3 was unchanged. Consistent with a pro-inflammatory phenotype, Sorbs2 KO atrial fibroblasts secreted higher IL-6 levels at baseline (3303± 463 pg/mL vs. 2075 ± 731 pg/mL in WT; n=6, p < 0.01) and with LPS stimulation (7791 ± 604 pg/mL vs. 5588 ± 763 pg/mL in WT; n=6, p < 0.01). Conclusion: Sorbs2 deficiency is associated with abnormal atrial fibroblast function showing impaired migration and scratch wound healing, as well as increased IL-6 production and imbalanced MMP/TIMP. These changes result in collagen accumulation and enhanced fibrosis.

Background: Voltage-gated Nav1.5 channel, encoded by SCN5A , is essential for initiation and propagation of action potentials (AP) in atria. Nav1.5 channelopathy is strongly associated with arrhythmogenesis, including atrial fibrillation. Sorbin and SH3 domain-containing protein 2 (Sorbs2), encoded by SORBS2 , is an important cytoskeletal protein for maintaining atrial structural and electrical integrity. However, the specific mechanisms through which Sorbs2 modulates Nav1.5 function in atria is unknown. Hypothesis: Sorbs2 modulates atrial Nav1.5 expression and function through direct protein-protein interaction. Methods: We created the cardiac-specific Sorbs2 knockout ( c-Sorbs2 KO) mice. We determined the mechanisms by which Sorbs2 regulates Nav1.5 channel expression and function by performing electrophysiological experiments using atrial cells and tissues from control and c-Sorbs2 KO mice, in conjunction with molecular biological studies and in silico analysis. Results: c-Sorbs2 KO mice at 8-10 months showed marked left atrial (LA) enlargement, and ECG showed significantly prolonged P-R durations. Compared to wild-type controls, intracellular recordings in LA tissues isolated from c-Sorbs2 KO mice showed reduced AP amplitude, decreased upstroke velocity, prolonged AP duration at 90% repolarization and effective refractory period, spontaneous atrial tachycardias and triggered activity. Patch-clamp recordings in freshly isolated atrial cardiomyocytes showed a significantly reduced peak sodium current density in c-Sorbs2 KO mice (-12.0 ± 1.6 pA/pF at -45 mV, n = 10), compared to controls (-21.3 ± 4.0 pA/pF at -45 mV, n = 12, p < 0.05). Also, the steady-state activation and inactivation curves of Nav1.5 channel were rightward shifted in c-Sorbs2 KO atrial cardiomyocytes. Molecular docking analysis showed that the Sorbs2 SH3 domain interacts directly with the voltage-sensing domain of Nav1.5. Co-immunoprecipitation assays confirmed the physical interactions between Nav1.5 and the C-terminal SH3 domain of Sorbs2. Furthermore, results from membrane biotinylation study demonstrated that deletion of the SH3 domains of Sorbs2 significantly reduced Nav1.5 surface expression in HEK293 cells. Sorbs2 interacts directly with Nav1.5 through its SH3 domain, playing a key role in regulating Nav1.5 channel gating kinetics and surface expression in atrial cardiomyocytes. Loss of Sorbs2 results in Nav1.5 channelopathy and contributes to atrial electrical remodeling.

Background: Cardiac myosin-binding protein C (cMyBP-C, encoded by MYBPC3 ) and Sorbin and SH3 domain-containing protein 2 (Sorbs2, encoded by SORBS2 ) are critical sarcomeric components that maintain cardiac structure and function. MYBPC3 and SORBS2 are linked to hypertrophic and dilated cardiomyopathies. But the relationship between Sorbs2 and cMyBP-C regulation, and their roles in the pathogenesis of atrial fibrotic cardiomyopathy (AFCM), remains unclear. Hypothesis: Sorbs2 acts as a cytoskeletal and RNA-binding protein that regulates cMyBP-C expression in atrial myocardium. Methods: We created the cardiac-specific Sorbs2 knockout ( c-Sorbs2 KO mice. We used next-generation RNA sequencing, molecular biology techniques, and in silico analysis to study how Sorbs2 regulates cMyBP-C expression in the atria of c-Sorbs2 KO mice. Results: Compared to age-matched wild-type (WT) mice at 8-9 months of age, the c-Sorbs2 KO male exhibited significant left atrial (LA) enlargement (diameter: 2.41±0.11 mm vs 1.82 ± 0.05 mm in WT; n = 8; p < 0.001) and severe atrial fibrosis (fibrotic area: 12.29±1.73 vs 2.83 ± 0.41% in WT; p < 0.001), accompanied by marked reductions in both mRNA and protein levels of cMyBP-C in LA. In vitro knock-down of Sorbs2 by 60% via shRNA led to an 86.3% decrease in cMyBP-C protein levels, while a 3-fold Sorbs2 overexpression via adenoviral transduction resulted in a 1.4-fold increase in cMyBP-C protein levels in HL-1 cells . cMyBP-C mRNAs were identified in the ribonucleoprotein complexes immunoprecipitated with anti-Sorbs2 antibodies from cardiomyocyte lysates. Loss of Sorbs2 significantly reduced the half-life of cMyBP-C mRNA (from 2.1 hrs in WT to 1.2 hrs in KO). Co-immunoprecipitation with truncated Sorbs2 constructs showed that the C-terminal SH3 domains of Sorbs2, but not the N-terminal SoHo domain, interacted with cMyBP-C protein. Molecular docking and modeling showed hydrophobic interactions and hydrogen bonds between residues H906 and G907 in the SH3 domain of Sorbs2 and residue A954, P955 and T957 in the SH3-binding motif (949-MA P GA P VT-957) of cMyBP-C with a weighted score of -1036 using ClusPro online service. Conclusions: Sorbs2 regulates cMyBP-C expression through direct interaction with both cMyBP-C mRNA and protein. Loss of Sorbs2 results in reduced cMyBP-C expression, atrial fibrosis, and chamber enlargement, revealing a novel Sorbs2/cMyBP-C axis underlying AFCM pathogenesis.

Background Older adults undergoing percutaneous coronary intervention (PCI) face unique challenges due to complex anatomy and comorbidities. Intravascular imaging [including intravascular ultrasound (IVUS) and optical coherence tomography (OCT)] has been shown to improve PCI outcomes, but its benefits in older adults are less well established. We conducted a meta-analysis of randomized controlled trials (RCTs) to compare intravascular imaging with angiography alone to guide PCI in older adults. Methods Cochrane, PubMed, and Scopus were searched for RCTs comparing intravascular imaging (IVUS or OCT) vs. angiography alone in adults aged ≥65 years. The outcome of interest was major adverse cardiovascular events (MACE) at the longest follow-up, as defined by each trial. Subgroup analyses were performed based on intravascular imaging modality, age group, and lesion complexity. Data were pooled using random-effects models, and heterogeneity was assessed using Higgins’ I ² statistic. Results Nine RCTs ( n = 7164, intravascular imaging = 3703, angiography alone = 3461) met the inclusion criteria. Intravascular imaging significantly reduced MACE compared with angiography alone [relative risk (RR) 0.66, 95% confidence interval (CI) 0.56–0.77; P < 0.001; I ² = 0%]. IVUS demonstrated superiority over angiography alone (RR 0.55, 95% CI 0.43–0.72; P < 0.001; I ² = 0%), while OCT demonstrated only a trend toward MACE reduction (RR 0.80, 95% CI 0.62–1.02). Subgroup analyses indicated consistent benefits with intravascular imaging for adults aged ≥65 and ≥70 years, respectively, and among those with complex coronary lesions (RR 0.65, 95% CI 0.53–0.79; P < 0.001). Conclusion Intravascular imaging guidance, especially IVUS, reduces MACE in older adults undergoing PCI compared with angiography alone.

Objectives: To determine the feasibility of reduced-dose chest computed tomographic angiography (CTA) with convolutional neural network (CNN) denoising for detecting pulmonary arteriovenous malformations (pAVMs) in children with hereditary hemorrhagic telangiectasia (cwHHT). Methods: Fifteen cwHHT underwent a chest CTA (ie, a controlled “study” dose). Noise was inserted to simulate a quarter dose (QD) exam. Images were reconstructed using iterative reconstruction (IR) and our self-trained CNN denoising model. For each case, 3 sets of images were created: study dose (SD)+IR, QD+IR, and QD+CNN. Two thoracic radiologists independently scored each set to assess quality, spatial resolution, artifacts, and the presence of pAVMs using 4-level ordinal scales. Quantitative assessments of image quality were performed using contrast-to-noise ratios (CNRs) with comparisons made between the experimental conditions. Results: Thirteen of the 15 patients recruited with hereditary hemorrhagic telangiectasia (mean age: 9.3±4.5 y) were positive for pAVM by transthoracic contrast echocardiography. The sensitivities using QD+CNN were 0.85 and 1.00 for readers 1 and 2, respectively. This was compared with 0.69 and 0.84 using QD+IR versus 0.85 and 0.92 for SD+IR. Inter-reader agreement for pAVM detection utilizing QD+CNN was moderate and resulted in kappa=0.59 ( P =0.012). The subjective assessments for QD+CNN were comparable to the SD technique. Regression analysis of reader scores revealed improved quality in QD+CNN versus QD+IR ( P =0.001). Similarly, the QD+CNN condition demonstrated the highest CNRs. Conclusions: Reduced-dose chest CTA with CNN denoising provides a level of sensitivity comparable to standard dose CTA and high CNRs for the detection of pAVMs in cwHHT.

Background Low back pain is the leading cause of disability worldwide. Multidisciplinary approaches to chronic pain can support resilience in recovery of functioning. The ancient arts of t’ai chi and qigong have been touted for centuries as multimodal approaches to health and healing. An RCT of an on-line t’ai chi and qigong program for individuals with chronic low back pain found clinically significant improvements in pain, physical function, and quality of life. The program consisted of the integrated practice of t’ai chi movement and the stillness of qigong practice. Meditations in the program focused on developing positive mental attitudes to support resilience in managing the emotional challenges of pain and disease. Objective The purpose of the current qualitative study aimed to better understand participants’ experiences during the online Heal and Strengthen the Spine with T’ai Chi and Qigong (HSSTQ) program. Methods Written feedback was received from 96 program participants, and semi-structured interviews were completed with 20 participants. Interviews were transcribed and coded based upon the written feedback and interview questions. A thematic narrative was developed from the coded segments of texts and reviewed by participants in a member check. Results Three interlocking themes characterized the experiences of participants in the program: (1) participants learned skills to relieve back pain including moderation in movement; (2) the holistic nature of the program enabled a range of benefits for participants beyond pain reduction; and (3) personal healing experience, the enthusiasm of the instructor, the program itself, and available staff resources motivated individuals to participate. Conclusion The conclusion from this study and the initial RCT is that a virtually delivered integrated tai chi, qigong, and meditation program may be a viable treatment option for adults with low back pain.

The NCCN Clinical Practice Guidelines (NCCN Guidelines) for Wilms Tumor (WT; nephroblastoma) cover strategies for the screening, diagnosis, and treatment of WT, which is the most frequent primary kidney tumor in children. WT can generally be separated into 2 histology types: favorable histology WT and anaplastic WT. Five-year survival is high for children with favorable histology WT who receive appropriate treatment; however, survival rates are much lower for patients who present with higher stage diffuse anaplastic WT. Treatment of WT can range from surgery alone to surgery plus intensive chemotherapy and radiation depending on whether the tumor is unilateral or bilateral, histology, and local stage. The goal of therapy is to maximize cure while minimizing long-term toxicities. The content featured in this issue covers the NCCN panel’s recommendations for overall management of both favorable histology WT and anaplastic WT.

ImportanceIdentification of factors associated with variation in outpatient surgery may further quality improvement efforts to safely reduce postoperative hospital length of stay nationally.ObjectivesTo explore variation in the use of outpatient surgery, incorporating patient, geographic, and hospital factors.Design, Setting, and ParticipantsThis retrospective cross-sectional study used deidentified administrative claims data from OptumLabs Data Warehouse. Participants included adults who underwent 1 of 10 general, urological, or gynecological operations between January 1, 2015, and June 30, 2021, in the US. Patients who underwent combined procedures or reoperations or had at least 15 Elixhauser comorbidities were excluded. Data were analyzed from July 26 to December 16, 2023.ExposureInpatient or outpatient surgical procedures.Main Outcomes and MeasuresMultilevel logistic regression assessed variation in the use of outpatient surgery rates by hospital characteristics (bed size, presence of trainees, and rural referral center status) and hospital census division, adjusting for patient factors (age, sex, number of Elixhauser comorbidities, year, and rural-urban commuting area). This multilevel model allowed for the sources of variability to be quantitatively attributed to patient characteristics, geography, and hospital characteristics.ResultsA total of 330 424 (72.3%) of 456 954 included patients underwent outpatient surgery. The median age was 54 (IQR, 41-67) years, and of those with data available, most patients were female (268 692 of 414 193 [64.9%]). The likelihood of outpatient surgery varied significantly by hospital census division for all 10 operations (eg, MIS salpingo-oophorectomy range, 29.6%-58.8%; P &amp;lt; .001). Variation in hospital census division contributed most to outpatient surgery for 8 of 10 operations compared with other patient and hospital characteristics. Hospital census division contributed the greatest degree to the variation in outpatient simple mastectomy (20.6%) and the least to outpatient open ventral hernia repair (0.7%). Multivariable analysis showed that the odds of outpatient surgery for patients from metropolitan areas were higher for minimally invasive salpingo-oophorectomy (odds ratio [OR], 1.62; 95% CI, 1.34-1.95) and open ventral hernia repair (OR, 1.16; 95% CI, 1.09-1.24). Hospitals with 400 or more beds were independently associated with decreased odds of outpatient surgery compared with hospitals with 50 to 199 beds for 4 of 7 operations (MIS paraesophageal hernia repair [OR, 0.58; 95% CI, 0.47-0.71; P &amp;lt; .001]; MIS cholecystectomy [OR, 0.73; 95% CI, 0.68-0.78; P &amp;lt; .001]; open ventral hernia [OR, 0.51; 95% CI, 0.46-0.57; P &amp;lt; .001]; MIS ventral hernia repair [OR, 0.66; 95% CI, 0.56-0.77; P &amp;lt; .001]). The presence of a residency training program was independently associated with increased odds of outpatient surgery for simple mastectomy (OR, 1.35; 95% CI, 1.16-1.58; P &amp;lt; .001) and mastectomy with reconstruction (OR, 1.50; 95% CI, 1.27-1.77; P &amp;lt; .001) and decreased odds of outpatient surgery for minimally invasive cholecystectomy (OR, 0.96; 95% CI, 0.92-1.00; P = .04), open ventral hernia repair (OR, 0.93; 95% CI, 0.86-1.00; P = .04), and total thyroidectomy (OR, 0.84; 95% CI, 0.71-1.00; P = .04).Conclusions and RelevanceIn this cross-sectional study, significant variation existed in the use of outpatient surgery in the US and appeared to be driven primarily by hospital geography. Addressing these variations may improve the use of resources.

ABSTRACTBackgroundPercutaneous transluminal angioplasty and stenting (PTAS) in patients with carotid stenosis may have potential effects on brain parenchyma. However, current studies on parenchymal changes are scarce due to the need for advanced imaging modalities. Consequently, the alterations in brain parenchyma following PTAS remain an unsolved issue.PurposeTo investigate changes to the brain parenchyma using magnetic resonance elastography (MRE).Study TypeProspective.Population13 patients (6 women and 7 men; 39 MRI imaging sessions) with severe unilateral carotid stenosis patients indicated for PTAS were recruited between 2021 and 2024.Field Strength/SequenceNoncontrast MRI sequences including MRE (spin echo) were acquired using 3 T scanners.AssessmentAll patients underwent MRE before (preprocedural), within 24 h (early postprocedural) and 3 months after (delayed postprocedural) PTAS. Preprocedural and delayed postprocedural ultrasonographic peak systolic velocity (PSV) was recorded. MRE stiffness and damping ratio were evaluated via neural network inversion of the whole brain, in 14 gray matter (GM) and 12 white matter (WM) regions.Statistical TestsStiffness and damping ratio differences between each pair of MR sessions for each subject were identified by paired sample t tests. The correlations of stiffness and damping ratio with stenosis grade and ultrasonographic PSV dynamics were evaluated by Pearson correlation coefficients. The statistical significance was defined as p < 0.05.ResultsThe stiffness of lesion side insula, deep GM, and deep WM increased significantly from preprocedural to delayed postprocedural MRE. Increasing deep GM stiffness on the lesion side was positively correlated with the DSA stenosis grade significantly (r = 0.609). The lesion side insula stiffness increments were positively correlated with PSV decrements significantly (r = 0.664).Data ConclusionRegional brain stiffness increased 3 months after PTAS. Lesion side stiffness was positively correlated with stenosis grades in deep GM and PSV decrements in the insula.Evidence Level2.Technical EfficacyStage 2.