Citations

Abstract The significance of anterior cruciate ligament (ACL) remnants during reconstruction remains unclear. Co‐culturing ACL remnant cells and bone marrow stromal cells (BMSCs) may reduce apoptosis and enhance hamstring tendon activity. This study investigated whether extracellular vesicles (EVs), which facilitate cell–cell interactions, act as the active components, improving graft maturation in this co‐culture. The effects of EVs on cell viability, proliferation, migration and gene expression in the rabbit ACL remnant cells and BMSCs were assessed using control (BMSC‐only culture), co‐culture (ACL remnant cells and BMSCs, CM) and co‐culture without EVs (CM ∆ EVs) media. EVs were isolated from control (BMSC‐EV) and co‐culture (CM‐EV) media and characterized. CM significantly enhanced the proliferation, migration and expression of transforming growth factor ( TGF‐β )‐, vascular endothelial growth factor ( VEGF )‐, collagen synthesis‐ and tenogenesis‐related genes. However, CM‐induced effects were reversed by the CM ∆ EVs treatment. CM‐EV treatment exhibited higher potential to enhance proliferation, migration and gene expression in the ACL remnant cells and BMSCs than BMSC‐EV and non‐EV treatments. In conclusion, EVs, secreted under the coexistence of ACL remnant cells and BMSCs, primarily increase the cell viability, proliferation, migration and gene expression of collagen synthesis‐, TGF‐β ‐, VEGF ‐ and tenogenesis‐related genes in both cell types.

Previous studies have highlighted differences in the risk of periprosthetic fracture between tapered slip (TS) and composite beam (CB) stems. This biomechanical study explored periprosthetic fractures around these stems and the effect of adding a 16-gauge calcar or diaphyseal wire to TS stems on their resistance to torque.A power analysis determined a sample size of 7 specimens per group, assuming a standard deviation of 14.8 Nm in peak torque, to provide 90% power to detect a difference of at least 30 Nm between groups. Twenty-one TS stems (eight alone, six with calcar wiring, seven with diaphyseal wiring placed 2 cm distal to the lesser trochanter) and seven CB stems were cemented into standard Sawbones. A servo-hydraulic test machine applied a 1000 N load with a 1-degree rotation per second until failure. The peak torque at failure was measured, and the fracture location recorded. Comparisons were performed using two-sample t-tests.CB stems exhibited a significantly higher peak torque at failure (205.3 Nm) than TS stems (159.5 Nm, p=0.020). Calcar-wire-TS (148.2 Nm, p=0.036) and diaphyseal-wire-TS (164.9 Nm, p=0.036) were both weaker than CB stems. Wired-TS stems showed no significant difference from non-wired-TS stems. Additionally, the study could not conclude that calcar wiring is stronger than diaphyseal wiring. All TS fractures occurred at the mid-stem, simulating a B-type fracture, while the addition of the diaphyseal wire shifted the fracture location more distally in four of seven stems (p=0.0699).This biomechanical study supports the clinical evidence that CB stems have stronger resistance to torque than TS stems and may explain lower risk of periprosthetic fracture. The addition of calcar or diaphyseal wires to TS stems resulted in no significant changes in peak torque to fracture. In patients at high risk of periprosthetic fracture, CB cemented stems should be considered.

84 Background: Local therapies potentially offer a curative approach for patients with oligometastatic colorectal cancer (CRC). The effectiveness of systemic chemotherapy following definitive local treatment in this setting is not well-defined. Tumor-informed circulating tumor DNA (ctDNA) might guide management strategies after curative-intent local treatment. Methods: This is a single institution retrospective study of patients with CRC who underwent curative-intent local therapy to an isolated site of metastatic disease and had post-intervention tumor-informed ctDNA (Signatera) testing. The study was approved by the institutional review board. Clinical characteristics, including ctDNA results, were collected and evaluated. Kaplan-Meier method and log-rank test were used to calculate and compare disease-free survival (DFS). Factors associated with DFS were analyzed using multivariate Cox proportional hazards model. Results: 45 patients were included with median age of 59 years, 62% being male, 91% white, and 53% with stage IV disease at diagnosis. 37% of the patients had RAS mutations, no patient had BRAF mutation, and 2.2% patient had mismatch repair deficient disease. Isolated liver metastases were present in 80% of patients, lung metastases in 11% and other sites in 9%. 44 patients received chemotherapy prior to definitive treatment, with a median treatment duration of 16 weeks. ctDNA tests were done prior to local therapy in 23 patients, with 14 cases (61%) testing positive. Definitive treatment included resection (58%), ablation (13%), radiotherapy (4%), and multimodality (25%). Post-definitive treatment chemotherapy was administered to 24 (53%) patients. ctDNA positivity following definitive therapy was observed in 10 patients (22%), which was associated with a poorer prognosis, with a median DFS of 5.3 months compared to 21.3 months for the ctDNA-negative group (p<0.001). These findings were confirmed on multivariate analysis. In patients who had negative ctDNA after definitive local treatment, median DFS was 14.9 months for those who received post-intervention chemotherapy versus 21.3 months for those without post-intervention chemotherapy (p=0.835). Conclusions: Patients with negative ctDNA results following definitive local therapy for isolated metastatic CRC have better prognosis. Post-intervention chemotherapy in this group of patients was not associated with improved DFS. ctDNA guided omission of post-intervention chemotherapy following curative-intent local treatment of oligometastatic CRC warrants further study. [Table: see text]

Background: Percutaneous transluminal angioplasty (PTA) is the first-line treatment for arteriovenous fistula (AVF) failure and immaturation. High rate of restenosis occurs post PTA procedure caused by venous neointimal hyperplasia (VNH), and decrease the durability of it. Failed AVF showed increased gene expression of Ier3. Poly lactic- co -glycolic acid nanoparticles (PLGA) loaded with 1,25-dihydroxyvitamin D 3 (1,25 NP) can inhibit Ier3 gene expression. Hypothesis: Adventitial delivery of 1,25 NP in hydrogel will reduce venous stenosis in a murine PTA model. Methods: Male C57BL/6J mice underwent partial nephrectomy at day -42 and arteriovenous fistula (AVF) creation at day -14. At day 0, mice were randomized to vehicle group (PTA + PLGA hydrogel) or treatment group (PTA + 1,25 NP hydrogel). Mice were euthanized at day 3 for gene expression analysis and at day 21 for histopathological analysis. Doppler ultrasound was performed weekly to evaluate AVF patency and function. Results: At day 3, PTA + 1,25 NP treated vessels had a significant decrease in the gene expression of Ier3 compared to controls. At day 21, 1,25 NP treated outflow veins had increased lumen vessel area, apoptosis, and higher peak systolic velocity, but decrease in neointimal area/media area ratio, fibroblasts, pro-inflammatory macrophages (M1), fibrosis (picrosirius red staining) and cellular proliferation. Conclusion: Adventitial delivery of 1,25 NP plus PTA has the ability to reduce restenosis and VNH formation. This protective effect is related to inhibition of Ier3 gene expression which modulates vascular inflammation and fibrosis post PTA.

AbstractEpilepsy associated with high‐titer glutamic acid decarboxylase 65 (GAD65) IgG is often refractory to immunotherapies and antiseizure medication. This study sought to determine the efficacy of vagus nerve stimulation (VNS) and surgical resection in patients with drug‐resistant epilepsy associated with GAD65‐IgG. We retrospectively identified 15 patients with drug‐resistant epilepsy and high serum GAD65 antibody titers (>20 nmol·L−1) who underwent VNS implantation (n = 6), surgical resection (n = 7), or both (n = 2). A responder to VNS was defined as someone with a ≥50% reduction in seizure frequency, and a favorable surgical outcome was defined as Engel I–II. Of the eight patients who underwent VNS implantation, three (37.5%) were initially responders, but this was not sustained in two. Of the nine patients who underwent surgical resection, three (33.3%) had a favorable outcome; however, only one patient was seizure‐free at last follow‐up. Pathology was available in six patients, and only one had evidence of inflammation; this patient had seizure onset 1 year prior to surgery. Favorable seizure outcome correlated with older age at time of resective surgery, with a trend favoring later age of seizure onset. Taken together, surgical resection and VNS implantation may have limited efficacy in this patient population but can be considered in carefully selected cases.

BACKGROUND: Studies of the neurovascular contribution to dementia have largely focused on cerebral small vessel disease (CSVD), but the role of intracranial atherosclerotic disease (ICAD) remains unknown in the general population. The objective of this study was to determine the risk of incident dementia from ICAD after adjusting for CSVD and cardiovascular risk factors in a US community-based cohort. METHODS: We acquired brain magnetic resonance imaging examinations from 2011 through 2013 in 1980 Black and White participants in the ARIC study (Atherosclerosis Risk in Communities), a prospective cohort conducted in 4 US communities. Magnetic resonance imaging examinations included high-resolution vessel wall magnetic resonance imaging and magnetic resonance angiography to identify ICAD. Of these participants, 1590 without dementia, without missing covariates, and with adequate magnetic resonance image quality were followed through 2019 for incident dementia. Associations between ICAD and incident dementia were assessed using Cox proportional hazard ratios adjusted for CSVD (characterized by white matter hyperintensities, lacunar infarctions, and microhemorrhages), APOE4 genotype (apolipoprotein E gene ε4), and cardiovascular risk factors. RESULTS: The mean age (SD) of study participants was 77.4 (5.2) years. ICAD was detected in 34.6% of participants. After a median follow-up of 5.6 years, 286 participants developed dementia. Compared with participants without ICAD, the fully adjusted hazard ratios (95% CIs) for incident dementia in participants with any ICAD, with ICAD only causing stenosis ≤50%, and with ICAD causing stenosis >50% in ≥1 vessel were 1.57 (1.17–2.11), 1.41 (1.02–1.95), and 1.94 (1.32–2.84), respectively. ICAD was associated with dementia even among participants with low white matter hyperintensities burden, a marker of CSVD. CONCLUSIONS: ICAD was associated with an increased risk of incident dementia, independent of CSVD, APOE4 genotype, and cardiovascular risk factors. The increased risk of dementia was evident even among participants with low CSVD burden, a group less likely to be affected by vascular dementia, and in participants with ICAD causing only low-grade stenosis. Our results suggest that ICAD may partially mediate the effect that cardiovascular risk factors have on the brain leading to dementia. Both ICAD and CSVD must be considered to understand the vascular contributions to cognitive decline.

Background and Aims: Disruption of the epigenome is a hallmark of human disease, including liver cirrhosis and HCC. While genetic heterogeneity is an established effector of pathologic phenotypes, epigenetic heterogeneity is less well understood. Environmental exposures alter the liver-specific DNA methylation landscape and influence the onset of liver cancer. Given that currently available treatments are unable to target frequently mutated genes in HCC, there is an unmet need for novel therapeutics to prevent or reverse liver damage leading to hepatic tumorigenesis, which the epigenome may provide. Approach and Results: We performed genome-wide profiling of DNA methylation, copy number, and gene expression from multiple liver regions from 31 patients with liver disease to examine their crosstalk and define the individual and combinatorial contributions of these processes to liver disease progression. We identified epigenetic heterogeneity hotspots that are conserved across patients. Elevated epigenetic heterogeneity is associated with increased gene expression heterogeneity. Cirrhotic regions comprise 2 distinct cohorts—one exclusively epigenetic, and the other where epigenetic and copy number variations collaborate. Epigenetic heterogeneity hotspots are enriched for genes central to liver function (eg, HNF1A) and known tumor suppressors (eg, RASSF1A). These hotspots encompass genes including ACSL1, ACSL5, MAT1A, and ELFN1, which have phenotypic effects in functional screens, supporting their relevance to hepatocarcinogenesis. Moreover, epigenetic heterogeneity hotspots are linked to clinical measures of outcome. Conclusions: Substantial epigenetic heterogeneity arises early in liver disease development, targeting key pathways in the progression and initiation of both cirrhosis and HCC. Integration of epigenetic and transcriptional heterogeneity unveils putative epigenetic regulators of hepatocarcinogenesis.

ImportanceThe fecal immunochemical test (FIT) is widely used for colorectal cancer (CRC) screening, but evidence of its effectiveness is limited.ObjectiveTo evaluate whether FIT screening is associated with a lower risk of dying from CRC overall, according to cancer location, and within demographic groups.Design, Setting, and ParticipantsThis nested case-control study in a cohort of screening-eligible people was conducted in 2 large, integrated health systems of racially, ethnically, and socioeconomically diverse members with long-term programs of mailed FIT screening outreach. Eligible participants included people aged 52 to 85 years who died from colorectal adenocarcinoma between 2011 and 2017 (cases); cases were matched in a 1:8 ratio based on age, sex, health-plan membership duration, and geographic area to randomly selected persons who were alive and CRC-free on case’s diagnosis date (controls). Data analysis was conducted from January 2002 to December 2017.ExposuresCompleting 1 or more FIT screenings in the 5-year period prior to the CRC diagnosis date among cases or the corresponding date among controls; in secondary analyses, 2- to 10-year intervals were evaluated.Main Outcomes and MeasuresThe primary study outcome was CRC death overall and by tumor location. Secondary analyses were performed to assess CRC death by race and ethnicity.ResultsFrom a cohort of 2 127 128 people, a total of 10 711 participants (3529 aged 60-69 years [32.9%]; 5587 male [52.1%] and 5124 female [47.8%]; 1254 non-Hispanic Asian [11.7%]; 973 non-Hispanic Black [9.1%]; 1929 Hispanic or Latino [18.0%]; 6345 non-Hispanic White [59.2%]) was identified, including 1103 cases and 9608 controls. Among controls during the 10-year period prior to the reference date, 6101 (63.5%) completed 1 or more FITs with a cumulative 12.6% positivity rate (768 controls), of whom 610 (79.4%) had a colonoscopy within 1 year. During the 5-year period, 494 cases (44.8%) and 5345 controls (55.6%) completed 1 or more FITs. In regression analysis, completing 1 or more FIT screening was associated with a 33% lower risk of death from CRC (adjusted odds ratio [aOR], 0.67; 95% CI, 0.59-0.76) and 42% lower risk in the left colon and rectum (aOR, 0.58; 95% CI, 0.48-0.71). There was no association with right colon cancers (aOR, 0.83; 95% CI, 0.69-1.01) but the difference in the estimates between the right colon and left colon or rectum was statistically significant (P = .01). FIT screening was associated with lower CRC mortality risk among non-Hispanic Asian (aOR, 0.37; 95% CI, 0.23-0.59), non-Hispanic Black (aOR, 0.58; 95% CI, 0.39-0.85) and non-Hispanic White individuals (aOR, 0.70; 95% CI, 0.57-0.86) (P for homogeneity = .04 for homogeneity).Conclusions and RelevanceIn this nested case-control study, completing FIT was associated with a lower risk of overall death from CRC, particularly in the left colon, and the associations were observed across racial and ethnic groups. These findings support the use of FIT in population-based screening strategies.