Citations

Purpose To develop a standardized method for tibial tunnel volumetric bone mineral density (BMD) analysis with quantitative computed tomography (qCT) using cadaveric specimens to provide validation of this technique on a healthy control population and to determine whether osteopenia occurs following an anterior cruciate ligament (ACL) injury. Methods: qCT was used to develop a volumetric BMD (mg/cm 3 ) measurement technique throughout the region of a standard tibial tunnel. This method was applied to 90 lower extremities, including 10 matched cadaveric knees, 10 matched healthy knees, 25 ACL‐injured knees, and 25 contralateral ACL‐uninjured knees. The mean total and segmental (proximal, middle, and distal) tibial tunnel BMD were analyzed. Results The mean entire tibial tunnel BMD measured 165.8 ± 30.5 mg/cm 3 (cadaver), 255.9 ± 28.2 mg/cm 3 (healthy control), 290.3 ± 36.4 mg/cm 3 (ACL‐injured), and 300.1 ± 35.1 (ACL‐uninjured). Segmental tibial tunnel BMD demonstrated distal one‐third segments as the greatest areas of BMD, followed by proximal one‐third, and middle one‐third for all cohorts with all pairwise comparisons ( P < .001). The mean BMD was significantly greater in the uninjured extremity compared with the injured extremity in the entire tunnel (290.3 vs 300.1; P < .001), proximal (271.2 vs 279.1; P = .002), middle (167.6 vs 179.6; P < .001), and distal segments (432.7 vs 441.7; P = .004) at an average of 8 weeks following ACL injury. Conclusions A standardized method to quantitatively measure the volumetric BMD within the region of a standard tibial tunnel for ACL reconstruction was successfully developed and validated. Significant osteopenia of the injured knee occurs following ACL injury when compared with the contralateral uninjured knee. This observation has potential clinical implications for ACL graft tibial fixation and healing. Level of Evidence Descriptive diagnostic study, Level III.

Background: Among patients receiving percutaneous coronary intervention (PCI), the role of a genotype-guided approach for antiplatelet therapy compared with usual care is unclear. We conducted a Bayesian analysis of the entire TAILOR-PCI (Tailored Antiplatelet Initiation to Lessen Outcomes Due to Decreased Clopidogrel Response After Percutaneous Coronary Intervention) randomized clinical trial population to evaluate the effect of the genotype-guided antiplatelet therapy post-PCI compared with the usual care on the risk of major adverse cardiovascular events (MACE). Methods: The primary outcome for our study was the composite of MACE (myocardial infarction, stroke, and cardiovascular death). Secondary outcomes included cardiovascular death, stroke, myocardial infarction, stent thrombosis, and major/minor bleeding. Bayesian modeling was used to estimate the probability of clinical benefit of genotype-guided therapy using (1) noninformative priors (ie, analyzing the TAILOR-PCI trial) and (2) informative priors derived from the ADAPT, POPular Genetics, IAC-PCI, and PHARMCLO trials (ie, analyzing TAILOR-PCI trial in the context of prior evidence). Risk ratio (RR: ratio of cumulative outcome incidence between genotype-guided and conventional therapy group) and 95% credible interval (CrI) were estimated for the study outcomes, and probability estimates for RR <1 were computed. Results: Using noninformative priors, in TAILOR-PCI the RR for MACE was 0.78 (95% CrI, 0.55–1.07) in genotype-guided therapy after PCI, and the probability of RR <1 was 94%. Using noninformative priors, the probability of RR <1 for cardiovascular death (RR, 0.95 [95% CrI, 0.52–1.74]), stroke (RR, 0.68 [95% CrI, 0.44–1.06]), myocardial infarction (RR, 0.84 [95% CrI, 0.37–1.89]), stent thrombosis (RR, 0.75 [95% CrI, 0.37–1.45]), and major or minor bleeding (RR, 1.22 [95% CrI, 0.84–1.77]) were 57%, 96%, 67%, 81%, and 15%, respectively. Using informative priors, the posterior probability of RR <1 for MACE, from genotype-guided therapy, was 99% (RR, 0.69 [95% CrI, 0.57–0.84]). Using informative priors, the posterior probability of RR <1 for cardiovascular death (RR, 0.86 [95% CrI, 0.61–1.19]), stroke (RR, 0.69 [95% CrI, 0.48–0.99]), myocardial infarction (RR:0.56 [95% CrI, 0.40–0.78]), stent thrombosis (RR, 0.59 [95% CrI, 0.38–0.94]), and major or minor bleeding (RR, 0.84 [95% CrI, 0.70–0.99]) were 81%, 99%, 99%, 99%, and 99%, respectively. Conclusions: Bayesian analysis of the TAILOR-PCI trial provides clinically meaningful data on the posterior probability of reducing MACE using genotype-guided P2Y 12 inhibitor therapy after PCI.

Abstract Synucleinopathies are clinically and pathologically heterogeneous disorders characterized by pathologic aggregates of α-synuclein in neurons and glia, in the form of Lewy bodies, Lewy neurites, neuronal cytoplasmic inclusions, and glial cytoplasmic inclusions (GCIs). Synucleinopathies can be divided into two major disease entities: Lewy body disease (LBD) and multiple system atrophy (MSA). Common clinical presentations of LBD are Parkinson's disease (PD), PD with dementia (PDD), and dementia with Lewy bodies (DLB), while MSA has two major clinical subtypes, MSA with predominant cerebellar ataxia (MSA-C) and MSA with predominant parkinsonism (MSA-P). There are currently no disease-modifying therapies for the synucleinopathies, but elucidation of genetics and mechanisms of α-synuclein conversion to pathologic oligomers and insoluble fibrils offer hope for eventual therapies. It remains unclear how α-synuclein can be associated with distinct cellular pathologies (e.g., Lewy bodies and GCI) and what factors determine neuroanatomical and cell type vulnerability. Accumulating evidence from in vitro and in vivo experiments suggests that α-synuclein species derived from LBD and MSA are distinct "strains" having different seeding properties. Recent advancements in in vitro seeding assays, such as real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA), not only demonstrate distinct seeding activity in the synucleinopathies, but also offer exciting opportunities for molecular diagnosis using readily accessible peripheral tissues. Cryogenic electron microscopy (cryo-EM) structural studies of α-synuclein derived from recombinant or brain-derived filaments provide new insight into mechanisms of seeding in synucleinopathies. In this review, we describe clinical, genetic and neuropathologic features of synucleinopathies, including a review of classification and staging schemes for LBD. We also review evidence supporting the existence of distinct α-synuclein strains in LBD and MSA.

Background: Individuals with spinal cord injury (SCI) who use manual wheelchairs (MWCs) have a higher rate of rotator cuff pathology progression than able-bodied individuals. Objectives: This study aimed to test the ability of risk and recovery metrics of arm use to differentiate between (1) MWC users with SCI and matched able-bodied participants (cross-sectional matched-sample study) and (2) MWC users with rotator cuff pathology progression over 1 year from those without pathology progression (longitudinal study). Methods: Thirty-four MWC users and 34 age- and sex-matched able-bodied individuals were recruited. Upper arm risk (humeral elevation >60°) and recovery (static ≥5 seconds and humeral elevation <40°) metrics were calculated from wireless inertial measurement units (IMUs) worn on the upper arms and torso in the free-living environment. Two separate magnetic resonance imaging studies were completed and assessed for a subset of 16 MWC users approximately 1 year apart. Results: The frequency of risk events ( p = .019), summated duration of recovery events ( p = .025), and duration of each recovery event ( p = .003) were higher for MWC users than able-bodied participants. The summated duration of risk events ( p = .047), frequency of risk events ( p = .027), and risk to recovery ratio ( p = .02) were higher and the summated duration of recovery events ( p = .036) and frequency of recovery events ( p = .047) were lower for MWC users with rotator cuff pathology progression ( n = 5) compared to those without progression ( n = 11). Conclusion: IMU-derived metrics quantifying arm use at postures >60° and risk to recovery ratios may provide insights of potential risk factors for rotator cuff pathology progression.

Introduction: Phenome-wide association studies (PheWAS) using electronic medical record (EMR)-linked biobanks have been used not only to identify and replicate known associations of genetic variants with disease phenotypes but have also resulted in the discovery of potentially novel genotype-phenotype relationships. The natriuretic peptide (NP) system plays an important role in a broad range of disease processes including cardiovascular and inflammatory diseases. We hypothesized that performing a PheWAS using previously known functional genetic variants of the NP system may result in novel disease associations that could provide mechanistic insights in an unbiased manner. Methods: We scanned for associations between 9 single-nucleotide polymorphisms (SNPs) in the NP system and 27 EMR-derived chronic disease phenotypes in 3,025 individuals participating in a case-control study of peripheral arterial disease. The EMR phenotypes were identified using two or more ICD-9-CM diagnosis codes based on the AHRQ Clinical Classifications Software (CCS). The relationship of SNPs and phenotypes were modeled using logistic regression adjusting for gender. Results: We identified rs5065, a SNP located in the stop codon of exon 3 of the NPPA gene, to be the strongest associated SNP with rheumatoid arthritis (RA) (OR=0.78, p=0.0008, q-value=0.11). The SNP leads to the extension of atrial natriuretic peptide (ANP) by 2 additional arginines at the C terminus. Cardiovascular disease is known to be the leading cause of death in patients with RA and ANP plays an important immunomodulatory role by inhibiting inducible nitric oxide synthase, reducing TNF-α production and attenuating prostaglandin E2 production in macrophages. Circulating NPs have been used to screen for occult cardiac disease and are associated with mortality in RA. This study demonstrates for the first time the importance of the relationship between genetic variation in the NP system and RA. Conclusions: PheWAS was successfully used as a tool to identify a novel association of functional genetic variation in the NPPA gene with RA. The observation is hypothesis generating and further replication studies are required to determine the role of rs5065 in cardiovascular outcomes of RA.

Background: Galectin-3 (Gal-3) may promote cardiac and renal fibrosis in heart failure (HF). Plasma Gal-3 levels predict outcome in HF but are tightly correlated with renal function. The source of Gal-3 in human HF, chronic kidney disease (CKD) or cardio-renal failure (HF+CKD) is unclear. Objective: To assess Gal-3 presence and location in human heart or kidney tissue from patients with HF, CKD or HF+CKD. Methods: Plasma Gal-3 levels and LV tissue explanted at time of cardiac transplant in systolic HF (n=15) and autopsy renal sections from patients with normal kidneys (n=4), CKD (n=17) or CKD+HF (n=14) were examined (H&E, Masson’s trichrome and CD-68 and Gal-3 immunohistochemistry). In the systolic HF patients, we quantified the number of Gal-3+/CD-68+ cells per HPF in LV tissue and assessed the correlation with plasma Gal-3 levels. In autopsy renal tissue, we derived a Composite Gal-3 Score (CG3S) incorporating the % of Gal-3+ tubules per HPF, % of Gal-3+ cells/tubule per HPF, and intensity of Gal-3 staining and assessed the correlation of the CG3S with ante-mortem estimated glomerular filtration rate(eGFR). Renal macrophage Gal-3 staining was also assessed. Results: In systolic HF LV tissue, Gal-3 was present in macrophages rather than myocytes but Gal-3+/CD-68+ cells per HPF was not correlated with plasma Gal-3 levels (p> 0.9) which correlated inversely with eGFR (r = -0.89 for log Gal-3 vs eGFR, p<0.0001). In the kidney, Gal-3 was not present in macrophages but was localized to renal tubular cells (Figure). The CG3S increased exponentially as eGFR decreased (r = - 0.88 for log CG3S versus eGFR; p<0.0001) and this relationship was not different (p=0.44) in patients with or without HF (Figure). The log CG3S correlated with the degree of fibrosis (tubulointerstitial scarring) in the kidney (r=0.88; p<0.0001). Conclusion: Collectively, these data suggest that plasma Gal-3 is predominantly of renal tubular epithelial origin in human HF, CKD, and CKD+HF.

Introduction: Endovascular procedures are traditionally performed for a variety of indications. However, guidewire/catheter manipulation and hazardous radiation exposure are limitations to manual interventions. Thus, significant work has been done to develop robotic approaches to therapies. These devices have FDA clearance for performing procedures like cardiac arrhythmias, angioplasty, aneurysm repair and stenting etc. With the increasing usage of robotic assistance in endovascular procedures, it is essential to understand the adverse events that may occur. This study aims to provide an understanding of adverse events with currently available robotic systems. Methods: The analysis of adverse events is performed with the FDA MAUDE (Manufacturer and User Facility Device Experience) database. MAUDE database is a collection of reports on medical devices reported by manufacturers, distributors, users, volunteers. In case of occurrence of adverse events, FDA regulations requires that event to be reported for further investigation. Based on the impact of events on the patient’s outcome, the reported events were grouped into 3 categories death (patient death), injury (patient injury) or device malfunction. Results: A total of 71 different events were reported collectively for all the four robotic devices (Hansen Medical- 37, Corindus Inc.-27, Stereotaxis Inc.-5 & Catheter Robotics Inc.-2). The major adverse events included death and common injuries such as perforation, pseudo-aneurysm / blockage/ tamponade/ clot, blood pressure dropped or an effusion, or hemodynamic instability. The table summarizes the events by brand of system. Conclusions: While robotic approaches to intervention reflect a potentially useful means to improve outcomes of endovascular procedures by optimizing catheter manipulation with finer robotic motions or limiting radiation exposure, there are potentially significant risks. Whether these reflect higher or lower risk than traditional manual approaches requires randomized studies. Use of robotic technologies may present additional risks in light of potential malfunctions that occur from system errors that a human system may not be prone to. Future studies will be needed to better understand incremental benefit.

Aims The outcomes of patients presenting with acute myocarditis and life‐threatening ventricular arrhythmias (LT‐VA) are unclear. The aim of this study was to assess the incidence and predictors of recurrent major arrhythmic events (MAEs) after hospital discharge in this patient population. Methods and results We retrospectively analysed 156 patients (median age 44 years; 77% male) discharged with a diagnosis of acute myocarditis and LT‐VA from 16 hospitals worldwide. Diagnosis of myocarditis was based on histology or the combination of increased markers of cardiac injury and cardiac magnetic resonance (CMR) Lake Louise criteria. MAEs were defined as the relapse, after discharge, of sudden cardiac death or successfully defibrillated ventricular fibrillation, or sustained ventricular tachycardia (sVT) requiring implantable cardioverter‐defibrillator therapy or synchronized external cardioversion. Median follow‐up was 23 months [first to third quartile (Q1–Q3) 7–60]. Fifty‐eight (37.2%) patients experienced MAEs after discharge, at a median of 8 months (Q1–Q3 2.5–24.0 months; 60.3% of MAEs within the first year). At multivariable Cox analysis, variables independently associated with MAEs were presentation with sVT [hazard ratio (HR) 2.90, 95% confidence interval (CI) 1.38–6.11]; late gadolinium enhancement involving ≥2 myocardial segments (HR 4.51, 95% CI 2.39–8.53), and absence of positive short‐tau inversion recovery (STIR) (HR 2.59, 95% CI 1.40–4.79) at first CMR. Conclusions Among patients discharged with a diagnosis of myocarditis and LT‐VA, 37.2% had recurrences of MAEs during follow‐up. Initial CMR pattern and sVT at presentation stratify the risk of arrhythmia recurrence.