Citations

Background: Ultrasound-guided percutaneous fasciotomy and debridement (USPFD) is a minimally invasive treatment for patients with plantar fasciopathy refractory to conservative management. Previous studies have shown clinical improvement with USPFD, but pain relief and patient satisfaction have not been demonstrated beyond 2 years. Methods: This retrospective case series included patients who underwent USPFD at a quaternary academic medical center between April 2013 and January 2018, with refractory plantar fasciopathy and at least 4 years’ follow-up. Patient outcomes were assessed through electronic surveys and telephone interviews. Primary outcome measures included mean changes in visual analog scale pain (VAS-Pain) scores and patient satisfaction via Likert scale. Secondary measures included VAS-Pain with the first 5 steps, VAS-Pain during daily weightbearing, and procedural complications. Results: Seventy unique procedures were identified among 62 patients. Follow-up data were obtained from 51 of 62 patients (82%) who responded to surveys or phone calls. This corresponded to 58 of 70 procedures (83%) at a mean postprocedure follow-up of 6.6 ± 1.4 years. Patients had a mean duration of symptoms of 2.1 ± 3.0 years prior to the procedure. Baseline VAS-Pain was 6.8 ± 2.2 and final follow-up VAS-Pain was 0.7 ± 1.1. At the last follow-up, patient-reported VAS-Pain with first 5 steps was 0.9 ± 1.6 and VAS-Pain with weightbearing through the day was 1.3 ± 1.8. Overall, 91% (53/58) of the procedures were considered successful, where patients responded they were “satisfied” or “very satisfied” and 52 of 58 (90%) procedural responses indicated that based on the outcome, they would recommend the procedure to others. Final follow-up VAS-Pain, VAS-first 5 steps, and VAS-weightbearing, were all improved in the success vs failure groups ( P ≤ .002). No complications were reported. Conclusion: USPFD was associated with high patient satisfaction and durable pain relief for chronic plantar fasciopathy at an average follow-up of 6.6 ± 1.4 years.

Background: Cardiac fibrosis is a central pathological process that leads to worse outcomes in various cardiomyopathies. Recent evidence shows that CDCP1 (CUB domain-containing protein 1) modulates myocardial recovery by attenuating human cardiac fibroblast (HCF) proliferation. This study investigates the hypothesis that selective targeting of the CDCP1 cleavage domain can mitigate fibroblast proliferation, thereby offering a novel therapeutic approach to reducing cardiac fibrosis. Methods: A high-throughput in silico screening was performed using the Enamine compound library, focusing on structural regions that include the cleavage and adjacent sites of CDCP1 . A total of 147 candidate compounds were prioritized based on docking scores and binding stability profiles. Selected compounds were subsequently evaluated in vitro using HCF cultures seeded at 3,000 cells/well in 96-well plates. Each compound was administered at 10 μM concentration, and cell proliferation and viability were assessed by time-lapse imaging in the Incucyte® system at 24 and 96 hours. All experiments were done in triplicate with appropriate DMSO vehicle controls. Results: Compound C3 significantly reduced HCF proliferation (Fig B) to 27.3±2.4% relative to DMSO controls (99.9±0.5%, P <0.001) at 96 hours. Detailed structural modeling indicated that C3 binds to the CDCP1 cleavage site (Fig C) with a favorable Glide XP docking score of -7.66 kcal/mol. The interaction is stabilized by hydrogen bonds with Lys365 and Cys374 (Fig D), and supplementary hydrophobic interactions between aromatic rings and aliphatic groups, which contribute to a strong inhibitory effect. Conclusion: Targeting the CDCP1 cleavage domain with compound C3 effectively diminishes HCF proliferation in vitro. Therefore, these results substantiate the therapeutic potential of CDCP1 inhibition in cardiac fibrosis. Ongoing in vivo studies will explore the translational relevance of these findings.

Abstract Objectives γ‐Aminobutyric acid B receptor (GABA B R)‐IgG (immunoglobulin G) is an intermediate‐risk paraneoplastic autoantibody often associated with seizures. We aimed to assess the clinical and oncological features of GABA B R‐IgG autoimmune encephalitis (AE) and evaluate the performance of antibody testing. Methods Patients testing positive for GABA B R‐IgG in serum/cerebrospinal fluid (CSF) at Mayo Clinic Neuroimmunology Laboratory were identified. Archived sera were retested by cell‐based assay (CBA) at 1:100 and 1:200 dilutions. A live‐cell flow cytometry–based assay (LCFBA) was developed and validated using archived sera and CSF. True positivity included patients with classic presentations of GABA B R‐IgG AE or oncological explanations for antibody presence. Results Eighty‐six patients (median age 63 years; 43 female) presented with classic presentations of GABA B R‐IgG AE: encephalopathy with prominent seizures ( n = 55), status epilepticus ( n = 23), and rapidly progressive dementia ( n = 8). In addition, 44 patients (33%) had a false‐positive result for GABA B R‐IgG characterized by non‐specific symptoms/alternate diagnoses. Malignancy was identified in 78% of true‐positive patients, predominantly small cell lung carcinoma (SCLC). Testing serum at 1:100 dilution on CBA and using tissue immunofluorescence assay (IFA) in serum and CSF improved the identification of true‐positive patients ( p < 0.001). CBA at 1:100 dilution performed better than conventional CBA (at 1:10 dilution, p < 0.001) and tissue IFA ( p = 0.031). An in‐house LCFBA showed 100% sensitivity and specificity in CSF, performing similarly to conventional CBA ( p = 0.125) in CSF, but better than tissue IFA ( p = 0.031). Furthermore, serum LCFBA performed better than conventional CBA ( p = 0.022) and tissue IFA ( p = 0.006). LCFBA had the highest diagnostic accuracy and was closely followed by CBA at 1:100 dilution. Significance GABA B R‐IgG AE often presents as encephalopathy with seizures or status epilepticus in the context of an underlying SCLC. Multimodal evaluation using tissue IFA and fixed CBA at higher dilutions improves detection of true cases. LCFBA performs very well as a diagnostic test with very high sensitivity and specificity.

Background Disease‐causative variants in LMNA ‐encoded lamin A/C cause a genetic cardiomyopathy characterized by atrioventricular block, atrial fibrillation, ventricular arrhythmias, and systolic dysfunction. The influence of LMNA variant type/localization on late gadolinium enhancement (LGE) patterns and clinical outcomes remains unclear. Methods Retrospective analysis of 822 genotype‐positive patients with arrhythmogenic/dilated cardiomyopathy was used to identify those with disease‐causative variants in LMNA . Data on LGE distribution and prevalence of advanced heart failure, thromboembolic and sudden cardiac death/major ventricular arrhythmia events were extracted from the electronic record and analyzed by variant type/localization. Results Among the 72/116 (62%) LMNA variant‐positive patients with cardiac magnetic resonance imaging data, LGE was observed in 40/72 (56%) cases. Most exhibited a nonischemic, midmyocardial or subepicardial pattern (73%), and 6/40 (15%) showed a unique “pseudo‐infarct” transmural pattern, predominantly affecting the apical segments. All 6 patients with this distinct LGE pattern harbored C‐terminal IgD (immunoglobulin‐like domain) variants (p.Arg471His or p.Arg541His). In patients with clinically manifest disease (76/116), those with IgD‐localizing variants had a lower prevalence of atrioventricular block (25% versus 72%, P =0.002) and atrial fibrillation (50% versus 81%, P =0.019) but higher rates of thromboembolic events (42% versus 16%, P =0.038). During a median follow‐up of 37 months, IgD variant presence independently predicted sudden cardiac death/major ventricular arrhythmia (hazard ratio, 2.391 [95% CI, 1.046–5.464]; P =0.039). Conclusions LMNA missense variants localizing to IgD present a distinct apical pseudo‐infarct LGE pattern associated with increased risk of ventricular arrhythmias and thromboembolic events but reduced atrioventricular block and atrial fibrillation. Multicenter studies are warranted to develop variant‐specific risk‐stratification strategies in cardiac laminopathy.

Abstract Background and Aims Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv. Methods An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM. Results A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80–30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06–5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27–3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (&lt;30 years) disease (OR, 4.75; 95% CI, 2.35–9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08–.23). Conclusions Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.

Abstract RAS pathway (RASp) mutations induce proliferative features, and promote transformation in chronic myelomonocytic leukemia (CMML). However, the unique clonal landscape and hierarchy of distinct RASp mutations remain unexplored. To characterize the landscape, architecture, and implications of unique RASp mutations in CMML, we evaluated a cohort of 814 patients with CMML. We identified 461 RASp mutations among 342 patients (42%). N/KRAS and CBL mutations were the most common, frequently involved the P-loop or RING domains, respectively, and frequently appeared as dominant events (63% and 65%, respectively). BRAF, NF1, and PTPN11 mutations spanned throughout the gene structure, and frequently appeared as subclonal events (75%, 64%, and 59%, respectively). CBL mutations frequently occurred in codominance with SRSF2 and multihit TET2, and were enriched for KIT mutations. PTPN11 mutations more frequently co-occurred with SETBP1 and DNMT3A mutations, and were infrequently codominant with TET2 or ASXL1. RASp mutations predicted for shorter overall survival (hazard ratio [HR], 1.55; 95% confidence interval [CI], 1.15-2.07; P = .0075) and leukemia-free survival (LFS; HR, 1.67; 95% CI, 1.26-2.20; P = .0011), influenced outcomes of myelodysplastic and TET2 mutant CMML, and cooperated with IDH2 and RUNX1 mutations to induce shorter LFS. These data set the bases for refined genomic classifications of CMML, and underscore the need to develop RAS-directed therapies for patients with CMML.

ABSTRACTPlatelets are small, anucleate particles derived from bone marrow megakaryocytes that circulate in the blood and are central to hemostasis, atherothrombosis, and post‐angioplasty coronary restenosis. Initially thought to involve a simple process of platelet adhesion, activation, and aggregation, recent insights reveal an important interplay with genetics and other organ systems, especially in the setting of antiplatelet drug therapy. Interaction involving the hepatic cytochrome P450 enzymes, which regulate drug metabolism, and genetic variation in those enzymes affecting drug response, underscores the liver's role in modulating platelet function by attenuating circulating active drug metabolites with eventual cardiovascular implications. Circulating adhesive proteins such as von Willebrand Factor and fibronectin also significantly regulate platelet aggregation, a process that is further influenced by varying shear conditions within the vascular system. The efficacy of antiplatelet therapies can be attenuated by such individual genetic variation, which can affect multiple cellular pathways involved not only in drug metabolism and clearance but also the drug target itself. Identifying these genetic differences allows for tailored therapy, enhancing treatment outcomes and minimizing adverse effects. Genetic variation, particularly in the CYP2C19 gene, influences individual responses to the most commonly used antiplatelet drug other than aspirin, clopidogrel, with certain variants leading to reduced drug metabolism and antiplatelet effects. Therefore, genotype‐guided antiplatelet therapy has emerged as a promising approach to reduce ischemic events and minimize bleeding events. This personalized strategy requires an understanding of genetic variation, drug‐gene interaction, and the liver's role in impacting platelet function, the coagulation system, and cardiovascular systems.

Abstract Introduction: Pulmonary nodules are not uncommonly found in patients with Sjogren's disease. Although they frequently can be benign, nodules in the context of systemic autoimmune disease such as Sjogren's disease require broadened differentials including lymphoid intersitial pneumonia, follicular bronchiolitis, nodular lymphoid hyperplasia (NLH), amyloidosis and lung malignancy. Although lung carcinoma can occur, the most frequent malignant etiology is non-Hodgkin's lymphoma, including pulmonary extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT lymphoma). On the other hand, many of these differentials are benign; however, some such as NLH can progress to lymphoma while others such as nodular amyloidosis can be associated with MALT lymphoma. As pulmonary MALT lymphoma often presents with asymptomatic nodules or consolidations, the index of suspicion by pulmonologists is crucial for diagnosis. Description: A 66 year old female nonsmoker presented with incidentally found bilateral solid and subsolid pulmonary nodules, the largest being 1.3 centimeters in the left lower lobe, in the context of calcified lymph nodes and splenic and liver calcified granulomas. As she was asymptomatic, possible differentials included chronic granulomatous disease, inflammatory/autoimmune lesions and less likely multifocal pulmonary malignancy. Fungal serologies were negative. Antinuclear antibodies, SS-A, and SS-B serologies were strongly positive. Erythrocyte sedimentation rate and rheumatoid factor were also positive. Further diagnostic workup led to a diagnosis of Sjogren's disease. Repeat 3 month CT chest showed stability of the lymphadenopathy and pulmonary nodules. However, despite stability, our pre-test probability for neoplastic pulmonary nodules had increased due to her autoimmune diagnosis. PET-CT scan was completed, showing metabolically active nodules bilaterally with a SUV range of 2-3.5, with the largest nodule having the highest uptake. Transbronchial biopsy of the largest nodule was consistent with MALT lymphoma. Discussion: The diagnosis of Sjogren's disease led to more aggressive efforts towards diagnostic certainty including a PET-CT scan and ultimately transbronchial biopsy. It is postulated that autoimmune activity in the pulmonary lymphoid tissue is what gives rise to MALT lymphoma. In one retrospective study on pulmonary nodules in patients with Sjogren's disease, greater than 70% of biopsied nodules were malignant, of which half represented MALT lymphoma. MALT lymphoma is diagnosed at the stage of disseminated disease in one third of cases, frequently recurs and has potential for aggressive transformation. Therefore, in the case of multiple pulmonary nodules in patients with Sjogren's disease, the evidence of underlying autoimmunity should increase the index of suspicion for pulmonary malignancy, including MALT lymphoma.