Citations

AbstractBiallelic loss‐of‐function variants in the thrombospondin‐type laminin G domain and epilepsy‐associated repeats (TSPEAR) gene have recently been associated with ectodermal dysplasia and hearing loss. The first reports describing a TSPEAR disease association identified this gene is a cause of nonsyndromic hearing loss, but subsequent reports involving additional affected families have questioned this evidence and suggested a stronger association with ectodermal dysplasia. To clarify genotype–phenotype associations for TSPEAR variants, we characterized 13 individuals with biallelic TSPEAR variants. Individuals underwent either exome sequencing or panel‐based genetic testing. Nearly all of these newly reported individuals (11/13) have phenotypes that include tooth agenesis or ectodermal dysplasia, while three newly reported individuals have hearing loss. Of the individuals displaying hearing loss, all have additional variants in other hearing‐loss‐associated genes, specifically TMPRSS3, GJB2, and GJB6, that present competing candidates for their hearing loss phenotype. When presented alongside previous reports, the overall evidence supports the association of TSPEAR variants with ectodermal dysplasia and tooth agenesis features but creates significant doubt as to whether TSPEAR variants are a monogenic cause of hearing loss. Further functional evidence is needed to evaluate this phenotypic association.

Abstract Rationale Chronic obstructive pulmonary disease (COPD) is a well-established independent risk factor for lung cancer; however, the literature on the association between asthma and lung cancer is mixed. Whether asthma–COPD overlap (ACO) is associated with lung cancer has not been studied. Objectives We aimed to compare lung cancer risk among patients with ACO versus COPD and other conditions associated with airway obstruction. Methods We studied 13,939 smokers from the National Lung Cancer Screening Trial who had baseline spirometry and used spirometric indices and history of childhood asthma to categorize participants into five specific airway disease subgroups. We used Poisson regression to compare unadjusted and adjusted lung cancer risk. Results The incidence rate of lung cancer per 1,000 person-years was as follows: ACO, 13.2 (95% confidence interval [CI], 8.1–21.5); COPD, 11.7 (95% CI, 10.5–13.1); asthmatic smokers, 1.8 (95% CI, 0.6–5.4); Global Initiative for Chronic Obstructive Lung Disease–Unclassified, 7.7 (95% CI, 6.4–9.2); and normal spirometry smokers, 4.1 (95% CI, 3.5–4.8). Patients with ACO had increased adjusted risk of lung cancer compared with patients with asthma (incidence rate ratio [IRR], 4.5; 95% CI, 1.3–15.8) and normal spirometry smokers (IRR, 2.3; 95% CI, 1.3–4.2) in models adjusting for other risk factors. Adjusted lung cancer incidence in patients with ACO and COPD were not found to be different (IRR, 1.2; 95% CI, 0.7–2.1). Conclusions The risk of lung cancer among patients with ACO is similar to those with COPD and higher than other groups of smokers. These results provide further evidence that COPD, with or without a history of childhood asthma, is an independent risk factor for lung cancer.

Abstract Embolic protection devices (EPDs) have become a standard of care during internal carotid artery revascularization. 1,2 This video is about a 57-yr-old-male who presented with a wake-up stroke with a left hemispheric syndrome. Head computed tomography angiography (CTA) revealed tandem occlusions of the proximal left internal carotid artery (ICA) and of the distal left middle cerebral artery (MCA) with an ASPECT (Alberta Stroke Program Early CT Score) score of 6. The patient underwent a cerebral angiogram and was treated with balloon angioplasty with a distal EPD and mechanical thrombectomy. The EPD became occluded with thrombus from the ICA and was retrieved through a 6-Fr Sofia (MicroVention) under continuous aspiration. Successful revascularization of the proximal ICA and distal MCA was achieved. No procedure-related complications occurred, and the patient's neurological exam improved. Tandem occlusions can occur in up to 15% of strokes. The optimal treatment can be controversial, but mechanical thrombectomy and ICA revascularization with a distal EPD appear to be safe and effective in selected patients. 3 Consent was obtained for the procedure and for the video production.

Introduction: Spontaneous coronary artery dissection (SCAD) is an uncommon but increasingly recognized cause of acute coronary syndrome and sudden cardiac death. We aim to review the occurrence of atrial fibrillation and atrial flutter in the Mayo Clinic SCAD Registry (MCSR) to gain insight into the association of SCAD and atrial arrhythmias. Methods: Atrial arrhythmias were queried amongst patients in the MCSR using diagnostic codes and text contained in both a large data repository known as the Advanced Cohort Explorer as well as a clinical database maintained by nurse abstractors for patients in the MCSR. All positive were manually verified using available medical records. Univariable logistic regression analysis was performed using JMP to investigate associations with classic cardiovascular risk factors. Results: A total of 1,215 patients from the Mayo SCAD registry were included. Six patients had a pre SCAD atrial arrhythmia, 19 had an atrial arrhythmia during a SCAD event, and 11 had a post SCAD atrial arrhythmia. Univariable analysis did not reveal significant associations with diabetes, hypertension, hyperlipidemia, or smoking. Conclusion: Atrial arrhythmias were not uncommonly seen in patients at the time of or after SCAD, especially after cardiac arrest or coronary artery bypass grafting. No significant associations with traditional cardiovascular risk factors were observed. Further investigation into the mechanism of atrial arrhythmia development as well as its management in the setting of SCAD is warranted.

Introduction: Mycobacterium Chimaera (MC) infections following cardiovascular surgery are challenging to diagnose given their insidious presentation. We therefore reviewed the various imaging modalities used to diagnose these infections at Mayo Clinic. Methods: Cases from 01/01/2010-06/01/2020 were identified using electronic medical records. Demographics and clinical history were collected. Imaging studies, including transthoracic echocardiogram (TTE), transesophageal echocardiogram (TEE), positron emission tomography / computed tomography (PET/CT), cardiac CT (CCT), and cardiac magnetic resonance (CMR) were reviewed. Results: A total of 7 patients (85.7% male) were found. 6 underwent aortic valve replacement and 1 received an aortic composite valve conduit. Surgical dates ranged from 01/2010-12/2018. Mean age at presentation was 63.3 years. Mean time from surgery to symptom onset was 28.0 months. All patients underwent TTE and TEE; prosthetic valve endocarditis was identified in 6 cases between both, while CMR established the diagnosis in 1 case. TTE showed prosthetic valve obstruction in 2 cases and an anterior pseudoaneurysm in 1 case. TEE findings included thickened prosthesis and/or vegetations (n=5), thickened posterior root (n=4), and root abscess (n=3). Among the 3 patients who underwent PET/CT, 2 demonstrated increased fluorodeoxyglucose (FDG) uptake around the aortic prosthesis; in addition, 1 had elevated FDG uptake in the myocardium suggesting myocarditis. 1 patient did not have aortic prosthesis FDG uptake. In the 2 patients who had CCT, 1 showed a pseudoaneurysm that prompted suspicion for endocarditis, and the other revealed a fluid collection adjacent to the aortic valve conduit. 2 patients underwent CMR; 1 had aortic prosthesis thickening and patchy areas of myocardial delayed enhancement suspicious for myocarditis, whereas the other showed vegetation and an aortic root abscess. Conclusion: TTE plus TEE successfully identified MC prosthetic valve endocarditis in most cases with TEE having higher specificity. Advanced imaging techniques are helpful to support the diagnosis and assess for myocardial and/or aortic involvement. Combining these modalities is therefore crucial in unveiling this elusive organism.

Abstract Intracranial atherosclerotic disease (ICAD) is a common cause of stroke. Antiplatelet therapy is the mainstay for symptomatic ICAD treatment. Endovascular management with submaximal angioplasty and/or intracranial stenting is reserved for patients with repeated ischemic events despite optimal medical therapy. We demonstrate intracranial angioplasty and stenting technique, technique indications, and sizing of stent and target vessel diameter. Stenting and angioplasty have been described in the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis and Wingspan Stent System Post Market Surveillance trials. 1,2 Submaximal angioplasty has also been described. 3 This patient, who had been on dual antiplatelet therapy for several months, initially presented with occlusion of the left middle cerebral artery M2 inferior division and underwent mechanical thrombectomy with successful reperfusion. Postoperatively, the patient's symptoms did not improve. Medical management was optimized with heparin infusion. However, repeat stroke study demonstrated M2 inferior division reocclusion. A decision was made to proceed with intracranial angioplasty and stenting. P2Y12 levels were therapeutic. Under moderate conscious sedation, submaximal angioplasty of up to 80% of the normal M2 caliber was attempted. However, we observed persistent high-grade stenosis of the M2 inferior division. The major risk of crossing the lesion for angioplasty is vessel perforation. To safely perform this maneuver, we used a J-configured Synchro-2 microwire (Stryker). Because of the patient's recent thrombectomy, we also had prior tactile feedback about how much resistance was encountered while crossing the occlusion. We then deployed a balloon-mounted intracranial stent for optimal radial force across the stenotic area to restore perfusion. Postoperative computed tomography perfusion showed resolution of the previously noticed perfusion deficit. The patient gave informed consent for the procedures and video recording. Institutional review board approval was deemed unnecessary. Video. ©University at Buffalo Neurosurgery, September 2020. With permission.

Abstract Background Across complex traits, common variants explain only a modest amount of variance, with SNP-heritability consistently below heritability estimates from close relatives. Here, we examined the contribution of rare variant to tobacco use risk in up to 26,000 individuals of European ancestry in the Trans-Omics for Precision Medicine (TOPMed) program with whole genome sequence (WGS;~30X coverage).Method We grouped about 35 million genetic variants by their minor allele frequencies (MAF) and linkage disequilibrium (LD) and estimated SNP-heritability for age of smoking initiation (N = 14,747), cigarettes smoked per day (N = 15,425), smoking cessation (N = 17,871) and initiation (N = 26,340) using linear mixed model. Rare variant population structure is detected and adjusted for by permutation procedure. We estimated an upper bound for narrow-sense heritability for tobacco use using available pedigrees consisting of close relatives in TOPMed.Results Rare variants with MAF 0.1–0.01%, mostly from non-protein altering region, accounted for 26% of variation in age of initiation and 15% for cessation. Follow-up analysis indicated that about one-third of these rare variants contribtion is potentially confounded with rare variants structure even after adjusting for principal components. After further conservative adjustment of population structure, we estimated SNP-based heritability to be 0.21 (SE = 0.08) for age of initiation, 0.15 (0.06) for cigarettes per day, 0.21 (0.09) for cessation, and 0.24 (0.07) for initiation, 1.8–4.5 times higher than previous SNP-based estimates. Our pedigree-based upper-bound for SNP-based heritability ranged from 0.18–0.35.Conclusion The substantial contribution of rare variants for several smoking phenotypes sheds light on the missing heritability and genetic etiology of tobacco use. It also informs fine-mapping strategies since the majority of the rare variant contribution was located in non-coding regulatory regions.