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"Because Western medicine has remained largely unsuccessful at treating tinnitus symptoms, many physicians as well as patients have turned to alternative treatment options to decrease patients' suffering and improve their quality of life. Although research in complementary/integrative medicine continues to be scarce and inconclusive, studies are pointing toward the positive effects of acupuncture, herbal remedies, dietary supplements, antioxidants, melatonin, and hypnosis on tinnitus. Although the efficacies of these treatments are inconsistent and may depend on a patient's unique circumstances, studies acknowledge that each treatment is worth trying in light of the potential benefits while being both noninvasive and well tolerated."

To test the feasibility and impact of a simulation training program for myringotomy and tube (MT) placement.Prospective randomized controlled.Multi-institutional.An MT simulator was used to assess the impact of simulation training vs no simulation training on the rate of achieving competency. Novice trainees were assessed using posttest simulator Objective Structured Assessment of Technical Skills (OSATS) scores, OSATS score for initial intraoperative tube insertion, and number of procedures to obtain competency. The effect of simulation training was analyzed using χA total of 101 residents and 105 raters from 65 institutions were enrolled; however, just 63 residents had sufficient data to be analyzed due to substantial breaches in protocol. There was no difference in simulator pretest scores between intervention and control groups; however, the intervention group had better OSATS global scores on the simulator (17.4 vs 13.7,A multi-institutional simulation study is feasible. Novices trained using the MT simulator achieved higher scores on simulator but not initial intraoperative OSATS, and they did not reach

Objective In individuals with chronic tinnitus, our interest was to determine whether daily low-level electrical stimulation of the vagus nerve paired with tones (paired-VNSt) for tinnitus suppression had any adverse effects on motor-speech production and physiological acoustics of sustained vowels. Similarly, we were also interested in evaluating for changes in pure-tone thresholds, word-recognition performance, and minimum-masking levels. Both voice and hearing functions were measured repeatedly over a period of 1 year. Study design Longitudinal with repeated-measures. Methods Digitized samples of sustained frontal, midline, and back vowels (/e/, /o/, /ah/) were analyzed with computer software to quantify the degree of jitter, shimmer, and harmonic-to-noise ratio contained in these waveforms. Pure-tone thresholds, monosyllabic word-recognition performance, and MMLs were also evaluated for VNS alterations. Linear-regression analysis was the benchmark statistic used to document change over time in voice and hearing status from a baseline condition. Results Most of the regression functions for the vocal samples and audiometric variables had slope values that were not significantly different from zero. Four of the nine vocal functions showed a significant improvement over time, whereas three of the pure tone regression functions at 2-4 kHz showed some degree of decline; all changes observed were for the left ear, all were at adjacent frequencies, and all were ipsilateral to the side of VNS. However, mean pure-tone threshold changes did not exceed 4.29 dB from baseline and therefore, would not be considered clinically significant. In some individuals, larger threshold shifts were observed. No significant regression/slope effects were observed for word-recognition or MMLs. Conclusion Quantitative voice analysis and assessment of audiometric variables showed minimal if any evidence of adverse effects using paired-VNSt over a treatment period of 1 year. Therefore, we conclude that paired-VNSt is a safe tool for tinnitus abatement in humans without significant side effects. Level of evidence Level IV.

Post-explant (ex vivo) evaluation of medical devices is an essential part of quality assurance, quality improvement, and further device development. Central to this is detailed pathological analysis. Here, we provide the first such evaluation of an explanted Tiara transcatheter mitral valve prosthesis. (Level of Difficulty: Advanced.), Graphical abstract, Post-explant (ex vivo) evaluation of medical devices is an essential part of quality assurance, quality improvement, and further device development…

Patients with restrictive cardiomyopathy due to Fabry disease are often deemed ineligible for left ventricular assist device (LVAD) support due to the risk of suction events with a small LV cavity. We describe the first case series of LVAD support for Fabry disease. LVAD therapy can improve survival, quality of life, and provide clinical stability to start enzyme replacement therapy. Precautions at the time of surgery include rapid treatment of fever to avoid Fabry crises, involvement of a multidisciplinary team, and early initiation of rehabilitation. We describe LVAD support for both bridging and destination therapy.

Supplemental Digital Content is available in the text., Background: Major uncertainties remain regarding disease activity within the retained native aortic valve, and regarding bioprosthetic valve durability, after transcatheter aortic valve implantation (TAVI). We aimed to assess native aortic valve disease activity and bioprosthetic valve durability in patients with TAVI in comparison with subjects with bioprosthetic surgical aortic valve replacement (SAVR). Methods: In a multicenter cross-sectional observational cohort study, patients with TAVI or bioprosthetic SAVR underwent baseline echocardiography, computed tomography angiography, and 18F-sodium fluoride (18F-NaF) positron emission tomography. Participants (n=47) were imaged once with 18F-NaF positron emission tomography/computed tomography either at 1 month (n=9, 19%), 2 years (n=22, 47%), or 5 years (16, 34%) after valve implantation. Patients subsequently underwent serial echocardiography to assess for changes in valve hemodynamic performance (change in peak aortic velocity) and evidence of structural valve dysfunction. Comparisons were made with matched patients with bioprosthetic SAVR (n=51) who had undergone the same imaging protocol. Results: In patients with TAVI, native aortic valves demonstrated 18F-NaF uptake around the outside of the bioprostheses that showed a modest correlation with the time from TAVI (r=0.36, P=0.023). 18F-NaF uptake in the bioprosthetic leaflets was comparable between the SAVR and TAVI groups (target-to-background ratio, 1.3 [1.2–1.7] versus 1.3 [1.2–1.5], respectively; P=0.27). The frequencies of imaging evidence of bioprosthetic valve degeneration at baseline were similar on echocardiography (6% versus 8%, respectively; P=0.78), computed tomography (15% versus 14%, respectively; P=0.87), and positron emission tomography (15% versus 29%, respectively; P=0.09). Baseline 18F-NaF uptake was associated with a subsequent change in peak aortic velocity for both TAVI (r=0.7, P

The authors report a 27-year-old woman with a remote left femoral osteosarcoma and amputation above the left knee who presented with a large right ventricular mass. Initial evaluation with thoracic CT was inconclusive regarding thrombus versus tumor, but metastatic osteosarcoma was suggested by findings at transthoracic echocardiography, cardiac CT, and cardiac MRI. The patient underwent tumor debulking, and osteosarcoma was confirmed with pathologic examination. She responded to chemotherapy, which resulted in reduction in size of the residual right ventricular tumor and of a few pulmonary metastases. Following induction chemotherapy, patient remains well undergoing maintenance therapy with an oral tyrosine kinase inhibitor. Keywords: CT, Echocardiography, MR Imaging, Intraoperative, Cardiac, Heart, Right Ventricle, Imaging Sequences, Metastases, Oncology Supplemental material is available for this article. © RSNA, 2021

Valve replacement using bioprosthetic heart valves (BPVs) is considered an intervention for severe tricuspid or pulmonic valvular disease. However, there is a lack of understanding of the mechanisms and features of structural valve degeneration (SVD) of tricuspid and pulmonic BPVs. This is in

Objective— Smooth muscle cells (SMCs) are the most abundant cells in human atherosclerotic lesions and are suggested to contribute at least 50% of atheroma foam cells. In mice, SMCs contribute fewer total lesional cells. The purpose of this study was to determine the contribution of SMCs to total foam cells in apolipoprotein E-deficient (ApoE −/− ) mice, and the utility of these mice to model human SMC foam cell biology and interventions. Approach and Results— Using flow cytometry, foam cells in the aortic arch of ApoE −/− mice were characterized based on the expression of leukocyte-specific markers. Nonleukocyte foam cells increased from 37% of total foam cells in 27-week-old to 75% in 57-week-old male ApoE −/− mice fed a chow diet and were ≈70% in male and female ApoE −/− mice following 6 weeks of Western diet feeding. A similar contribution to total foam cells by SMCs was found using SMC-lineage tracing ApoE −/− mice fed the Western diet for 6 or 12 weeks. Nonleukocyte foam cells contributed a similar percentage of total atheroma cholesterol and exhibited lower expression of the cholesterol exporter ABCA1 (ATP-binding cassette transporter A1) when compared with leukocyte-derived foam cells. Conclusions— Consistent with previous studies of human atheromas, we present evidence that SMCs contribute the majority of atheroma foam cells in ApoE −/− mice fed a Western diet and a chow diet for longer periods. Reduced expression of ABCA1, also seen in human intimal SMCs, suggests a common mechanism for formation of SMC foam cells across species, and represents a novel target to enhance atherosclerosis regression.

Introduction Iatrogenic embolization following cardiac investigative procedures may result from hydrophilic polymer emboli (HPE) from catheter valve and vessel wall calcifications, and air embolism from open heart surgery. This retrospective clinical pathologic analysis was undertaken to ascertain the frequency and extent of these potentially fatal complications. Methods This retrospective clinical pathologic autopsy analysis with premortem diagnostic imaging correlation identified 110 individuals who had undergone endovascular procedures between 2010 and 2016 within 90 days of death and followed by hospital autopsy. Clinical outcomes, radiologic studies, and autopsy materials were reviewed. Results Iatrogenic emboli were assessed as causing death in 9/110 autopsy cases (8.2%) and 9/34 (26.5%) cases with proven iatrogenic emboli. Iatrogenic emboli caused strokes in 10/110 (9.1%) autopsy cases including calcified emboli (CE, n=6), HPE (n=2), cardiac valvular tissue (n=1), and air embolism (n=1). Seven cases of calcified emboli complicating endovascular procedures were identified: four of the CE were thought to be the cause of death due to fatal strokes (n=2) and fatal myocardial (n=1) and colonic infarction (n=1). The CE likely originated from calcified aortic valves and atherosclerotic aortic plaques. Histologic evidence of HPE was found in 23% (25/110) of cases; 54% (26/48) showed evidence of infarction in postprocedural imaging, with radiologic evidence of infarction in 32% (8/25) of cases with HPE histology. Endovascular aortic repair was associated with the greatest density/distribution of HPE. HPE material showed degradation with time and was often associated with an inflammatory response. HPE directly contributed to death in three cases. One fatal air embolism followed open heart surgery, and one cardiac tissue embolus resulted in a major stroke. Conclusions We advocate for greater awareness of these underrecognized and occasionally fatal complications of endovascular procedures. Targeted postprocedural imaging has a role in the identification of iatrogenic embolic infarcts.

Marfan syndrome (MFS) is a genetic disorder that results in accelerated aortic root widening and aneurysm. However, management of MFS patients with blood pressure (BP)‐lowering medications, such as angiotensin II (AngII) receptor blocker (ARB) losartan, continues to pose challenges due to their questionable efficacy at attenuating the rate of aortic root widening in patients. Herein we investigate the anti‐aortic root widening effects of a sub‐BP‐lowering dose valsartan, an ARB previously linked to non‐BP lowering anti‐remodeling effects. Despite absence of BP‐lowering effects, valsartan attenuated MFS aortic root widening by 75.9%, which was similar to a hypotensive dose of losartan (79.4%) when assessed by ultrasound echocardiography. Medial thickening, elastic fiber fragmentation, and phospho‐ERK signaling were also inhibited to a similar degree with both treatments. Valsartan and losartan decreased vascular contractility ex vivo between 60% and 80%, in a nitric oxide (NO)‐sensitive fashion. Valsartan increased acetylcholine (Ach)‐induced vessel relaxation and phospho‐eNOS levels in the aortic vessel supporting BP‐independent activation of protective endothelial function, which is critical to ARB‐mediated aortic root stability. This study supports the concept of achieving aortic root stability with valsartan in absence of BP‐lowering effects, which may help address efficacy and compliance issues with losartan‐based MFS patient management., Inhibition of Marfan aortic root remodeling and widening with blood pressure lowering medications losartan and valsartan. However, valsartan was used at sub‐blood pressure lowering dose, therefore implying blood pressure independence.

Early microcalcification is a feature of coronary plaques with an increased propensity to rupture and to cause acute coronary syndromes. In this ex vivo imaging study of coronary artery specimens, the non-invasive imaging radiotracer, 18F-fluoride, was highly selective for hydroxyapatite deposition in atherosclerotic coronary plaque. Specifically, coronary 18F-fluoride uptake had a high signal to noise ratio compared with surrounding myocardium that makes it feasible to identify coronary mineralisation activity. Areas of 18F-fluoride uptake are associated with osteopontin, an inflammation-associated glycophosphoprotein that mediates tissue mineralisation, and Runt-related transcription factor 2, a nuclear protein involved in osteoblastic differentiation. These results suggest that 18F-fluoride is a non-invasive imaging biomarker of active coronary atherosclerotic mineralisation.

Objectives This study investigated processes causing leaflet thickening and structural valve degeneration (SVD). Background Although transcatheter aortic valve replacement (TAVR) has changed the treatment of aortic stenosis, concerns remain regarding SVD, potentially related to valve thrombosis and thickening, based on studies using computed tomography (CT). Detailed histological analyses are provided to help attain insights into these processes. Methods Explanted transcatheter heart valves (THVs) were evaluated for thrombosis, fibrosis, and calcification for quantification of leaflet thickness. Immunohistochemical and microscopy approaches were used to investigate SVD-associated mechanisms. Results THVs (n = 23) were obtained from 22 patients (median 81 years of age; 50% male) from 0 to 2,583 days post TAVR. Maximal leaflet thickness increased relative to implant duration (ρ = 0.427; p = 0.027). THVs explanted after >2 years were thicker than those explanted after Conclusions There is a time-dependent degeneration of THVs consisting of thrombus formation, endothelial hyperplasia, fibrosis, tissue remodeling, proteinase expression, and calcification. Future investigation is needed to further understand these mechanisms contributing to leaflet thickening and SVD.

OBJECTIVE To evaluate surgical findings and hearing results for patient's undergoing the described surgical approach for congenitally absent or dysplastic oval window (OW). STUDY DESIGN The Institutional Review Board approved retrospective review of patients with conductive hearing loss (CHL) operated on from 1992 to 2016. SETTING Academic tertiary center. PATIENTS Patients with CHL, an intact tympanic membrane (TM), and without history of chronic infection underwent middle ear exploration. Eleven patients and 13 ears underwent an oval window drill-out (OWD) procedure. INTERVENTION Eleven patients presented, all with dysplastic or congenitally absent oval window (CAOW). CHL was identified using audiometry and tuning forks, many patients also had preoperative computed tomography temporal bones. A transcanal approach was used and an OWD was performed with a variety of prostheses placed. MAIN OUTCOME MEASURE Audiometric studies before and after intervention were compared with 12 month and long-term follow-up (1-22 yr). RESULTS Preoperative air-bone gaps ranged from 40 to 60 dB and averaged 55.1 dB. Postoperative air-bone gaps ranged from 0 to 60 dB and averaged 24.1 dB. The preoperative pure-tone average (PTA) ranged from 55 to 99 dB and averaged 71.3 dB. Postoperative PTA ranged from 21 to 108 dB and averaged 49.6 dB. CONCLUSION Dysplastic and CAOW are uncommon congenital major ear anomalies. OWD is a viable treatment option, though careful counseling is critical, as significant complications are possible, especially with facial nerve (FN) abnormalities. This series demonstrates successful closure of the air-bone gap for many patients with this technique.

We present a case of myocarditis in a 26-year-old pregnant woman at 29 weeks gestation. Despite optimal medical therapy, she experienced a cardiac arrest 10 days postadmission. An interdisciplinary team facilitated emergency delivery of her baby by perimortem (ie, during maternal cardiac arrest) Caesarean section and initiation of emergency mechanical circulatory support. A cardiac biopsy revealed a mixed eosinophilic and histiocytic infiltrate. After a course of steroid therapy, she experienced full recovery. Both the patient and the infant are alive and well. The case highlights the success of modern interdisciplinary care, as well as ongoing gaps in our knowledge of myocarditis.

Background IgG4-related disease (IgG4-RD) is a recently recognized condition defined by characteristic histopathologic findings in affected organs. Serum IgG4 concentration is often but not always elevated. The sensitivity and specificity of serum IgG4 vary greatly across studies and has been anecdotally associated to ethnicity. Our study was conducted to investigate the difference in serum IgG4 levels between Asian and non-Asian patients with IgG4-RD. Methods This is a single-center retrospective study of 26 Asian and 10 non-Asian patients with histologically confirmed IgG4-RD. Serum IgG4 levels, clinical features and other laboratory findings were compared between the 2 groups, 31 Asian and 11 non-Asian patients with non-IgG4-RD rheumatic diseases were randomly identified to evaluate test characteristics of serum IgG4 measurement. Results Median serum IgG4 at time of diagnosis was significantly higher in Asian (median = 11.2 g/L, interquartile range: 4.6-19.7) than non-Asian patients (median = 2.9 g/L, interquartile range: 0.7-5.4, P = 0.0094), as well as the median serum IgG and total protein. Asian patients had more eosinophilia and polyclonal hypergammaglobulinemia than non-Asian patients ( P = 0.016 and 0.001, respectively). Test sensitivity was higher in Asian (96%) than non-Asian patients (67%), whereas test specificity was higher in non-Asian patients (91% versus 71%). Conclusion Asian patients with IgG4-RD have more exuberant serum IgG4, IgG and polyclonal hypergammaglobulinemia than non-Asian patients; the mechanism of this difference requires further study. These findings have significant clinical importance and must be accounted for in the diagnostic workup of patients in multiethnic settings.

BACKGROUND Organ donation after circulatory death (DCD) is increasingly being used as a means of addressing the organ supply/demand mismatch in solid organ transplantation. There is reluctance to use DCD hearts, due to an inability to precisely identify hearts that have suffered irreversible injury. We investigated novel biomarkers and clinically relevant endpoints across a spectrum of warm ischemic times, before and during ex vivo heart perfusion (EVHP), to identify features associated with a nonviable cardiac phenotype. METHODS Donor rats sustained a hypoxic cardiac arrest, followed by variable acirculatory standoff periods (DCD groups). Left ventricular function, histochemical injury, and differences in left ventricular gene expression were studied before, and during, EVHP. RESULTS As warm ischemic time exposure increased in DCD groups, fewer hearts were functional during EVHP, and ventricular function was increasingly impaired. Histochemical assessment identified severely injured hearts during EVHP. A novel gene expression signature identified severely injured hearts during EVHP (upregulation of c-Jun, 3.19 (2.84-3.60); P = 0.0014; HMOX-1, 3.87 (2.72-5.50); P = 0.0037; and Hsp90, 7.66 (6.32-9.27); P < 0.0001 in DCD20), and may be useful in identifying high-risk hearts at the point of harvest (Hsp90). CONCLUSIONS We demonstrate that our preclinical model recapitulates the cardio-respiratory decompensation observed in humans, and that EVHP appears necessary to unmask distinguishing features of severely injured DCD hearts. Furthermore, we outline a clinically relevant multimodal approach to assessing candidate DCD hearts. Novel mRNA signatures correlated with elevations in cardiac Troponin-I in severely injured hearts during EVHP, and may also detect injury at the point of harvest.

The American Academy of Otolaryngology-Head and Neck Surgery Foundation has published a supplement to this issue of Otolaryngology-Head and Neck Surgery featuring the "Clinical Practice Guideline: Benign Paroxysmal Positional Vertigo (Update)." To assist in implementing the guideline recommendations, this article summarizes the rationale, purpose, and key action statements. The 14 recommendations developed emphasize diagnostic accuracy and efficiency, reducing the inappropriate use of vestibular suppressant medications, decreasing the inappropriate use of ancillary testing, and increasing the appropriate therapeutic repositioning maneuvers. An updated guideline is needed due to new clinical trials, new systematic reviews, and the lack of consumer participation in the initial guideline development group.

The primary purpose of this multidisciplinary guideline is to identify quality improvement opportunities in the management of nosebleeds and to create clear and actionable recommendations to implement these opportunities in clinical practice. Specific goals of this guideline are to promote best practices, reduce unjustified variations in care of patients with nosebleeds, improve health outcomes, and minimize the potential harms of nosebleeds or interventions to treat nosebleeds. The target patient for the guideline is any individual aged ≥3 years with a nosebleed or history of nosebleed who needs medical treatment or seeks medical advice. The target audience of this guideline is clinicians who evaluate and treat patients with nosebleed. This includes primary care providers such as family medicine physicians, internists, pediatricians, physician assistants, and nurse practitioners. It also includes specialists such as emergency medicine providers, otolaryngologists, interventional radiologists/neuroradiologists and neurointerventionalists, hematologists, and cardiologists. The setting for this guideline includes any site of evaluation and treatment for a patient with nosebleed, including ambulatory medical sites, the emergency department, the inpatient hospital, and even remote outpatient encounters with phone calls and telemedicine. Outcomes to be considered for patients with nosebleed include control of acute bleeding, prevention of recurrent episodes of nasal bleeding, complications of treatment modalities, and accuracy of diagnostic measures. This guideline addresses the diagnosis, treatment, and prevention of nosebleed. It focuses on nosebleeds that commonly present to clinicians via phone calls, office visits, and emergency room encounters. This guideline discusses first-line treatments such as nasal compression, application of vasoconstrictors, nasal packing, and nasal cautery. It also addresses more complex epistaxis management, which includes the use of endoscopic arterial ligation and interventional radiology procedures. Management options for 2 special groups of patients-patients with hereditary hemorrhagic telangiectasia syndrome and patients taking medications that inhibit coagulation and/or platelet function-are included in this guideline. This guideline is intended to focus on evidence-based quality improvement opportunities judged most important by the guideline development group. It is not intended to be a comprehensive, general guide for managing patients with nosebleed. In this context, the purpose is to define useful actions for clinicians, generalists, and specialists from a variety of disciplines to improve quality of care. Conversely, the statements in this guideline are not intended to limit or restrict care provided by clinicians based on their experience and assessment of individual patients.The guideline development group made

Background Retroperitoneal fibrosis (RPF) is characterized by the proliferation of fibrous tissue in the retroperitoneum. The majority of RPF cases are due to idiopathic or IgG4-related disease. Recent studies on IgG4-related disease have shown rituximab to be an effective treatment. The current first-line treatment for idiopathic RPF (iRPF) is glucocorticoid therapy. Relapse rates vary widely in the literature, and DMARDs remain poorly studied. We sought to evaluate the efficacy of rituximab in idiopathic RPF by quantifying changes in iRPF diameter on imaging pre- and post-rituximab therapy and response by lab parameters in 10 iRPF patients. Methods We selected 10 patients diagnosed with iRPF and previously treated with rituximab (1000 mg) in two doses approximately 2 weeks apart. Pre- and post-therapy contrast enhanced cross-sectional abdomen and pelvis imaging were compared. In all patients, the thickest portion of the peri-aortic disease was measured in the axial and coronal planes. The presence of acute or long standing back pressure related renal findings were documented. Details of clinical visits including patient demographics and laboratory evaluations were collected pre- and post-therapy. Statistical analysis was performed using a Wilcoxon signed rank test. Results The RPF diameter around the aorta before and after therapy decreased from a mean of 15.9 ± 4.9 mm to 10.6 ± 6.1 mm, respectively (p p = 0.02). Conclusion A comparison of pre and post-rituximab imaging studies revealed a statistically significant decrease in iRPF diameter following treatment with rituximab.

While clinical donation after circulatory death (DCD) cardiac transplantation is being implemented with increasing frequency to address the supply/demand mismatch of donor grafts, no research to date has examined a strategy of donor preconditioning to optimize the viability of DCD hearts for transplantation. In our rat model of the DCD protocol, we investigate the impact of pretreating donors with phosphorothioate-linked cytosine and guanine rich oligodeoxynucleotides (CpG ODN) and their effects on cardiac function, injury, and a novel left ventricular (LV) mRNA biomarker panel.DCD rats were subjected to a withdrawal protocol, followed by 20 minutes of warm acirculatory standoff, representing a group of severely injured hearts as previously demonstrated. Beating heart controls and DCD rats were pretreated with vehicle or stimulatory CpG ODN (beating heart control and DCD stimulated with CpG ODN, BST and DST). Hearts were harvested for ex situ heart perfusion (ESHP), where LV function, histochemical injury, and differences in gene expression were characterized between groups.Donor pretreatment with CpG ODN doubled the number of functional DCD hearts at ESHP. Pretreatment was associated with improved systolic and diastolic LV function, a reduction in histological injury, and markedly reduced elaboration of cardiac troponin-I in coronary effluent during ESHP. Pretreatment was also associated with a reduction in mRNA biomarkers associated with myocardial injury.A single dose of CpG ODN was associated with reduced biomarkers of cardiac injury and a 100% increase in cardiac viability in this rodent model of marginal DCD cardiac donation.

Background: Cutaneous polyarteritis nodosa (CPAN) is a small-to-medium vessel vasculitis limited to the skin. As it is a rare condition, there is little data available to guide treatment. Previous articles have suggested that colchicine and dapsone be used in mild disease and glucocorticoids in acute flares, with DMARDs such as methotrexate or azathioprine being reserved for moderate to severe disease, or steroid-refractory disease. Objectives: Our objective was to review therapeutic regimens used to treat CPAN and to evaluate patient response. Methods: A retrospective chart review including records from January 2003 to June 2017 was performed to identify patients with both histologic and clinical features of CPAN. We extracted information regarding patient age, clinical presentation, biopsy results, and response to treatment. Results: Thirteen patients were identified who had clinical features of CPAN that were supported by histologic findings on biopsy. The majority of patients were female (92.3%). The average age at diagnosis was 44.9 years and mean duration of follow up was 53 months. All patients had involvement of the lower limbs with the most common cutaneous manifestation being subcutaneous nodules (92.3%), followed by papules (46.2%) and livedo reticularis (30.8%). Eight out of thirteen patients (61.5%) received steroids and three did not experience clinical benefit. Another patient did not respond to prednisone and hydroxychloroquine, but had significant improvement of her symptoms on prednisone and methotrexate. Seven out of nine patients (77.8%) who were treated with methotrexate had a favourable response. Three of those patients responded to methotrexate after failing other therapies such as dapsone, azathioprine, and prednisone. Conclusion: In this case series, we found that most patients had a favorable response to methotrexate and thus the role of methotrexate in treating CPAN merits further investigation. As CPAN often has a chronic relapsing and remitting course, initiating methotrexate at the same time as steroid therapy may lower overall lifetime exposure to steroids. References [1] Daoud MS, Hutton KP, Gibson LE. Cutaneous periarteritis nodosa: a clinicopathological study of 79 cases. Br J Dermatol. 1997May;136(5):706–13. [2] Ross K, Contreras J, aung-Din D, Lien M. Asymptomatic cutaneous polyarteritis nodosa: treatment options and therapeutic guidelines. Cutis. 2017Aug;100(2):125–8. [3] Maillard H, Szczesniak S, Martin L, Garot D, Machet MC, Machet L, et al. [Cutaneous periarteritis nodosa: diagnostic and therapeutic aspects of 9 cases]. Ann Dermatol Venereol. 1999Feb;126(2):125–9. [4] Khoo BP, Ng SK. Cutaneous polyarteritis nodosa: a case report and literature review. Ann acad Med Singapore. 1998Nov;27(6):868–72. [5] Schartz NEC, alaoui S, Vignon-Pennamen MD, Cordoliani F, Fermand JP, Morel P, et al. Successful treatment in two cases of steroid-dependent cutaneous polyarteritis nodosa with low-dose methotrexate. Dermatology. 2001;203(4):336–8. Disclosure of interests: Mohan Stewart: None declared, ada Lo: None declared, Kamran Shojania: None declared, Sheila au: None declared, Jan Dutz: None declared, Michael Seidman: None declared, Jon Chan Grant/research support from: Janssen, UCB, Novartis, Pfizer, Celgene, Consultant for: amgen, Celgene, Eli Lilly, Janssen, amgen, abbvie, Novartis, Pfizer, UCB, Sandoz, Merck

The Envoy Esteem and the Carina system are the 2 totally implantable hearing devices. The Esteem is designed for patients with bilateral moderate to severe sensorineural hearing loss who have an unaided speech discrimination score of greater than and equal to 40%. The Carina system is designed for patients with moderate to severe sensorineural hearing loss or those with mixed hearing loss. The Esteem offers a technologically advanced method to provide improvements in hearing and is available in the United States, whereas the Carina system is currently not available in the United States.

OBJECTIVE To compare the clinical and laboratory features of IgG4-related disease (IgG4-RD) and lymphocyte-variant hypereosinophilic syndrome (L-HES), two rare diseases that often present with lymphadenopathy, gastrointestinal symptoms, eosinophilia, and elevated immunoglobulins/IgE. METHOD Comparative case series of 31 patients with IgG4-RD and 13 patients with L-HES. RESULTS Peripheral blood eosinophilia was present in eight of 31 patients with IgG4-RD compared to 13 of 13 patients with L-HES (median eosinophils 0.4 vs 7.0 giga/L, P=.001) and 12 of 20 patients with IgG4-RD had increased serum IgE compared to eight of 13 patients with L-HES, P=.930. Twenty-seven of 30 patients with IgG4-RD had elevated serum IgG4 compared to five of 12 patients with L-HES (median IgG4 9.6 g/L vs 0.80 g/L, P=.002). Flow cytometry demonstrated an aberrant T-cell phenotype in 7 of 23 patients with IgG4-RD and 13 of 13 patients with L-HES (P

Background Polyarteritis nodosa is a small vessel to medium vessel vasculitis that frequently presents with multi-organ involvement, but can sometimes be limited to single organs such as the testes. Patients often require treatment with glucocorticoids, plus or minus additional immunosuppressive therapy depending on the severity of the disease. We describe a rare case of polyarteritis nodosa involving the right testis and urinary bladder without other systemic features of vasculitis. Case presentation A previously healthy 54-year-old First Nations Canadian man presented with intermittent gross hematuria. He underwent surgical excision of his right testis for cryptorchidism and a transurethral resection of a bladder mass. Histology showed an active medium vessel vasculitis in both organs. On extensive clinical, laboratory, and radiographic review, he had no systemic features of vasculitis. On 2-year follow-up, he has not required any systemic therapy and has not developed further symptoms. Conclusion Single organ polyarteritis nodosa can sometimes be managed with surgical excision of the involved organ alone. Although our patient had two organs involved, we extrapolated the results of our literature search to guide his care. This case highlights the potential for surgical excision to cure polyarteritis nodosa despite the involvement of two organs in the absence of symptoms and signs of systemic vasculitis.

The long-term audiological consequences of mild traumatic brain injury (mTBI) include hearing loss, tinnitus, hyperacusis, and central auditory dysfunction, and are becoming a topic of heightened regard in the medical community. Tinnitus and hearing loss are two of the most common audiological disabilities reported in the US military population. While there is currently no cure for tinnitus, a variety of treatment options exist to help patients manage their symptoms. Mechanisms underlying tinnitus, hearing loss, and hyperacusis are unknown, although proposed theories suggest a tonotopic reorganization and hyperexcitability of the auditory cortex are involved. Further research regarding behavioral, alternative, and surgical therapies is critical for helping patients who suffer from hearing disorders following brain injury.

IgG4-related disease is a fibro-inflammatory condition that can affect nearly any organ system. Common presentations include major salivary and lacrimal gland enlargement, orbital disease, autoimmune pancreatitis, retroperitoneal fibrosis and tubulointerstitial nephritis. This review focuses on the hematologic manifestations of IgG4-related disease, including lymphadenopathy, eosinophilia, and polyclonal hypergammaglobulinemia. The disease can easily be missed by unsuspecting hematologists, as patients may present with clinical problems that mimic disorders such as multicentric Castleman disease, lymphoma, plasma cell neoplasms and hypereosinophilic syndromes. When IgG4-related disease is suspected, serum protein electrophoresis and IgG subclasses are helpful as initial tests but a firm histological diagnosis is essential both to confirm the diagnosis and to rule out mimickers. The central histopathological features are a dense, polyclonal, lymphoplasmacytic infiltrate enriched with IgG4-positive plasma cells (with an IgG4/IgG ratio >40%), storiform fibrosis, and obliterative phlebitis. Importantly for hematologists, the latter two features are seen in all tissues except bone marrow and lymph nodes, making these two sites suboptimal for histological confirmation. Many patients follow an indolent course and respond well to treatment, but a significant proportion may have highly morbid or fatal complications such as periaortitis, severe retroperitoneal fibrosis or pachymeningitis. Corticosteroids are effective but cause new or worsening diabetes in about 40% of patients. Initial response rates to rituximab are high but durable remissions are rare. More intensive lymphoma chemotherapy regimens may be required in rare cases of severe, refractory disease, and targeted therapy against plasmablasts, IgE and other disease biomarkers warrant further exploration.

The purpose of this review is to describe our experience with management of chronic tinnitus and to review the recent literature on the best treatment options available for treating patients who are troubled by their tinnitus. In addition, we want to highlight our experience and approach to this very common problem.Treatment options for patients are based on the severity of the tinnitus and any associated problems. The use of nutritional supplements has a place in the treatment of mild-to-moderate tinnitus. Ginkgo biloba and B-complex vitamins may have an impact on selected patients. Treatment of underlying or accompanying anxiety disorders especially with cognitive behavior therapy can help to reduce the distress associated with tinnitus. Surgical treatment options, such as cochlear implant, have been shown to be very effective in reducing tinnitus in patients with sudden unilateral hearing loss as the cause of tinnitus. Other surgical approaches, such as repetitive transcranial magnetic stimulation and vagal stimulator, have had some limited benefits.Treatment for subjective tinnitus can range from the conventional to the investigational modalities. Best treatment options take into account the possible cause of the tinnitus and other associated symptoms.

Allergic rhinitis has a high prevalence and negatively impacts quality of life. Patients commonly use complementary and integrative modalities to help alleviate their symptoms of allergic rhinitis, with approximately one in five receiving acupuncture. This article reviews the evidence base on the efficacy/effectiveness, safety and cost-effectiveness of acupuncture for allergic rhinitis.Our review of the medical literature from January 2013 through December 2014 revealed that there is research demonstrating efficacy and effectiveness for acupuncture in the treatment of allergic rhinitis, as well as improvement of quality of life and quality-adjusted life-years.There are high-quality randomized controlled trials that demonstrate efficacy and effectiveness for acupuncture in the treatment of both seasonal and perennial allergic rhinitis. Smaller head-to-head studies also show some preliminary benefit of acupuncture when compared with antihistamines, but these had a variety of methodological limitations. Further studies of higher quality are needed, particularly with a focus on comparative effectiveness research.

Purpose of review Complementary and integrative medicine (CIM), formerly known as alternative medicine, is now part of the mainstream management for patients with a host of medical issues. This current opinion focuses on the use of CIM, more specifically, the use of nutritional and herbal therapies and homeopathic medications for patients with allergic symptoms. Recent findings The literature review revealed that naturally occurring substances when compared with placebo more often than not resulted in significant improvement of the allergic rhinitis symptoms. Summary Despite encouraging results, additional studies with greater rigor are needed.

Simulation has become a valuable tool in medical education, and several specialties accept or require simulation as a resource for resident training or assessment as well as for board certification or maintenance of certification. This study investigates current simulation resources and activities in US otolaryngology residency programs and examines interest in advancing simulation training and assessment within the specialty.Web-based survey.US otolaryngology residency training programs.An electronic web-based survey was disseminated to all US otolaryngology program directors to determine their respective institutional and departmental simulation resources, existing simulation activities, and interest in further simulation initiatives. Descriptive results are reported.Responses were received from 43 of 104 (43%) residency programs. Simulation capabilities and resources are available in most respondents' institutions (78.6% report onsite resources; 73.8% report availability of models, manikins, and devices). Most respondents (61%) report limited simulation activity within otolaryngology. Areas of simulation are broad, addressing technical and nontechnical skills related to clinical training (94%). Simulation is infrequently used for research, credentialing, or systems improvement. The majority of respondents (83.8%) expressed interest in participating in multicenter trials of simulation initiatives.Most respondents from otolaryngology residency programs have incorporated some simulation into their curriculum. Interest among program directors to participate in future multicenter trials appears high. Future research efforts in this area should aim to determine optimal simulators and simulation activities for training and assessment as well as how to best incorporate simulation into otolaryngology residency training programs.

The American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO-HNSF) has published a supplement to this issue featuring the new Clinical Practice Guideline: Allergic Rhinitis. To assist in implementing the guideline recommendations, this article summarizes the rationale, purpose, and key action statements. The 14 recommendations developed address the evaluation of patients with allergic rhinitis, including performing and interpretation of diagnostic testing and assessment and documentation of chronic conditions and comorbidities. It will then focus on the recommendations to guide the evaluation and treatment of patients with allergic rhinitis, to determine the most appropriate interventions to improve symptoms and quality of life for patients with allergic rhinitis.

BACKGROUND: Microvascular angina (MVA) is an incompletely understood clinical entity. Computational analysis of coronary Computed Tomography Angiography (CTA) has shown an association between low coronary lumen volume to myocardial mass (V/M) ratio and lower Fractional Flow Reserve values, independent of plaque measures. We hypothesized that low V/M ratio may be present in patients with MVA.METHODS: A retrospective case-control analysis was performed using patients fulfilling guideline criteria for MVA with controls matched for age, gender, coronary risk factors and atherosclerotic plaque burden. V/M was extracted off site (Heartflow Inc; Redwood City, CA) employing allometric scaling laws that allow the definition of the coronary circulation beyond the epicardium. FFRCT values were calculated in the major epicardial coronary arteries for each group.RESULTS: A total of 30 patients with MVA and 32 matched controls were included in the study. Mean total coronary lumen volume (2302 mm(3) ± 109 vs 2978 mm(3) ± 134, p < 0.001) and mean myocardial mass (90.4 g ± 13.7 vs 100.4 g ± 20.1, p = 0.029) were lower in MVA patients compared to controls. Mean V/M ratio was significantly lower in MVA compared to controls (25.6 mm(3)/g ± 5.9 vs 30.0 mm(3)/g ± 6.5, p = 0.007; c-statistic 0.69). V/M ratio did not differ significantly between subclasses of angina severity (p = 0.747). No difference in mean nadir FFRCT values was found between MVA and control groups in the LAD (0.86 ± 0.07 vs 0.83 ± 0.07, p = 0.154), LCX (0.90 ± 0.05 vs 0.90 ± 0.06, p = 0.240) and RCA (0.90 ± 0.04 vs 0.90 ± 0.03, p = 0.773) vessels.CONCLUSION: Patients with microvascular angina demonstrate a significantly lower coronary CTA-derived coronary volume/myocardial mass ratio than asymptomatic controls.

The objective is to perform a systematic review and meta-analysis of the literature on the long-term results of hearing preservation after vestibular schwannoma resection.Ovid/Medline, PubMed, Embase, and the Cochrane library from January 1980 to January 2015.Inclusion criteria: age ≥18 years, minimum 10 patients in the treatment group, hearing preserving microsurgery, no previous radiation treatment, serviceable hearing at immediate postop follow-up, hearing outcomes reported using Gardner Robinson or the American Academy of Otolaryngology-Head and Neck Surgeons hearing grading scales, and average follow-up of 5 years. Preoperative, immediate postoperative, and last follow-up audiograms were required. Exclusion criteria included neurofibromatosis type 2 patients and surgery for salvage therapy or decompression.Quality evaluated using Methodological Index for Non-Randomized Studies.Meta-analysis was performed using R v3.2.2, Metafor package v 1.9-7. Cohen's D was used to determine effect size. Ten reports had at least 5-year follow-up and used standardized hearing grading scales. The systematic review found that if hearing was preserved at Class A or B at early postop visit, the chance of preserving hearing at 5 years was excellent. Those who maintained speech discrimination score ≥ 89% at the early postoperative follow-up had better long-term hearing preservation. The meta-analysis reveals that only preoperative and postoperative pure-tone average was associated with long-term hearing preservation.Long-term (5 yr) hearing durability rates are generally very good. Most studies do not report patient and tumor characteristics, therefore precluding combining studies for meta-analysis. Only preoperative and postoperative postoperative pure-tone average was associated with long-term hearing durability.

Objective Determine if the noise levels of wind exposure experienced by cyclists reach levels that could contribute to noise-induced hearing loss. Study Design Industrial lab research. Setting Industrial wind tunnel. Subjects and Methods A commercial-grade electric wind tunnel was used to simulate different speeds encountered by a cyclist. A single cyclist was used during the simulation for audiometric measurements. Microphones attached near the ears of the cyclist were used to measure the sound (dB sound pressure level) experienced by the cyclist. Loudness levels were measured with the head positioned at 15-degree increments from 0 degrees to 180 degrees relative to the oncoming wind at different speeds (10-60 mph). Results Wind noise ranged from 84.9 dB at 10 mph and increased proportionally with speed to a maximum of 120.3 dB at 60 mph. The maximum of 120.3 dB was measured at the downwind ear when the ear was 90 degrees away from the wind. Conclusions Wind noise experienced by a cyclist is proportional to the speed and the directionality of the wind current. Turbulent air flow patterns are observed that contribute to increased sound exposure in the downwind ear. Consideration of ear deflection equipment without compromising sound awareness for cyclists during prolonged rides is advised to avoid potential noise trauma. Future research is warranted and can include long-term studies including dosimetry measures of the sound and yearly pre- and postexposure audiograms of cyclists to detect if any hearing loss occurs with long-term cycling.

While transcatheter aortic valve replacement (TAVR) has drastically changed the treatment of aortic stenosis, concerns remain regarding structural valve degeneration (SVD) potentially related to valve thrombosis and thickening. Therefore, we aimed to investigate processes causing leaflet thickening

Background We hypothesized that human perivascular and subcutaneous adipose tissues hold distinct phenotypic signatures. We also evaluated the impact of clinical parameters on the adipose phenotype. Our overall goal is to understand the determinants of adipose biology so that this tissue can be manipulated therapeutically to lessen peripheral vascular disease. Methods Perivascular and subcutaneous adipose tissues were collected from patients undergoing lower-extremity amputation (n = 27) and protein assayed for proinflammatory mediators (ie, interleukin 6, interleukin 8, leptin, tumor necrosis factor α, monocyte chemoattractant protein-1, and resistin), atheroprotective adiponectin, and the fibrinolysis inhibitor plasminogen activator inhibitor-1. Results Leptin (2.7-fold, P = .015), TNF-α (2.2-fold, P = .013), MCP-1 (1.5-fold, P = .047), and adiponectin (1.8-fold, P = .004) were more abundant in subcutaneous vs perivascular adipose tissue. Age positively correlated with perivascular adipose tissue PAI-1 expression (β = .64, P = .042), and hyperlipidemia negatively correlated with perivascular adiponectin (β = −1.18, P = .039). Conclusions Human perivascular and subcutaneous adipose tissues hold distinct phenotypic signatures. In amputation patients, the subcutaneous adipose tissue proinflammatory phenotype was relatively attenuated in perivascular adipose tissue.

Objectives/Hypothesis To determine the usefulness and the costs of computed tomography (CT) and magnetic resonance imaging (MRI) in the evaluation of patients with dizziness in the emergency department (ED). Study Design Retrospective chart review. Methods Charts of patients with a specific health maintenance insurance plan presenting with dizziness and vertigo to a large health system's ED between January 2008 and January 2011 were reviewed. Patient demographics, signs/symptoms, and CT and MRI results were assessed. CT and MRI charges were determined based on positive versus unremarkable findings. Data analysis included stepwise logistic regressions. Results Of 1681 patients identified, 810 (48%) received CT brain/head scan totaling $988,200 in charges. Of these, only 0.74% yielded clinically significant pathology requiring intervention. However, 12.2% of MRI studies yielded discovery of significant abnormalities. Logistic regression analysis revealed that older patients (P = .001) were more likely to receive a CT scan. Conclusions In the 3-year period studied, CT scans for ED patients with dizziness and vertigo yielded a low predictive value for significant pathology. These data reveal a great opportunity for cost savings by developing stricter guidelines for ordering CT scans for this set of ED patients. The use of MRI in all cases of dizziness was found to be neither practical nor useful. However, appropriately directed MRI of the brain is recommended in patients with dizziness and other neurological signs or symptoms. Level of Evidence 4. Laryngoscope, 123:2250–2253, 2013

This article discusses the mechanisms of aging and future areas of exploration, and addresses strategies to achieve successful aging given the current state of medical knowledge. The authors begin at the beginning, with mitochondrial function and cell growth and decline, then continue to present aspects over which humans have control over their health: nutrition, body posture, exercise, lifestyle choices, and Traditional Eastern medicine. The discussion concludes with the role of the physician in offering patient education regarding behaviors for a healthy life.

Background Short-term changes in preoperative nutrition can have profound effects on surgery-related outcomes such as ischemia/reperfusion injury in preclinical models. Dietary interventions that lend protection against stress in animal models (eg, fasting, dietary restriction [DR]) impact adipose tissue quality/quantity. Adipose tissue holds high surgical relevance because of its anatomic location and large tissue volume, and it is ubiquitously traumatized during surgery. Yet the response of adipose tissue to trauma under clinically relevant circumstances including dietary status remains poorly defined. We hypothesized that preoperative diet alters the adipose tissue response to surgical trauma. Methods A novel mouse model of adipose tissue surgical trauma was employed. Dietary conditions (diet-induced obesity [DIO], preoperative DR) were modulated before application of surgical adipose tissue trauma in the context of clinically common scenarios (different ages, simulated bacterial wound contamination). Local/distant adipose tissue phenotypic responses were measured as represented by gene expression of inflammatory, tissue remodeling/growth, and metabolic markers. Results Surgical trauma had a profound effect on adipose tissue phenotype at the site of trauma. Milder but significant distal effects on non-traumatized adipose tissue were also observed. DIO exacerbated the inflammatory aspects of this response, and preoperative DR tended to reverse these changes. Age and lipopolysaccharide (LPS)-simulated bacterial contamination also impacted the adipose tissue response to trauma, with young adult animals and LPS treatment exacerbating the proinflammatory response. Conclusion Surgical trauma dramatically impacts both local and distal adipose tissue biology. Short-term preoperative DR may offer a strategy to attenuate this response.

Aims The aim of this study was to examine the short- and medium-term outcomes of transcatheter aortic valve replacement (TAVR) with the self-expanding and repositionable Portico valve (St. Jude Medical, St. Paul, MN, USA). Methods and results A total of 57 patients underwent TAVR with the Portico valve between March 2012 and August 2014, representing the first-in-human experience and the entire early experience in Canada. Patients were followed up at 30 days and one year with repeat echocardiography and clinical review. Patients were 80.8±7.3 years of age, and the Society of Thoracic Surgeons predicted risk of mortality was 7.7±5.7%. All patients had a valve implanted and four patients (7%) required a second valve. At 30 days, there were two deaths (3.5%), three disabling strokes (5.3%), and new pacemakers in five (8.8%) patients. Echocardiography revealed moderate/severe aortic regurgitation in two patients (3.6%). At one year, survival was 84.2% and echocardiographic findings were unchanged. Conclusions Transcatheter aortic valve replacement with the repositionable Portico valve provides satisfactory short- and medium-term haemodynamic and clinical results.

Decorin (DCN) is a small-leucine rich proteoglycan that mediates collagen fibrillogenesis, organization, and tensile strength. Adventitial DCN is reduced in abdominal aortic aneurysm (AAA) resulting in vessel wall instability thereby predisposing the vessel to rupture. Recombinant DCN fusion protein CAR-DCN was engineered with an extended C-terminus comprised of CAR homing peptide that recognizes inflamed blood vessels and penetrates deep into the vessel wall. In the present study, the role of systemically-administered CAR-DCN in AAA progression and rupture was assessed in a murine model. Apolipoprotein E knockout (ApoE-KO) mice were infused with angiotensin II (AngII) for 28 days to induce AAA formation. CAR-DCN or vehicle was administrated systemically until day 15. Mortality due to AAA rupture was significantly reduced in CAR-DCN-treated mice compared to controls. Although the prevalence of AAA was similar between vehicle and CAR-DCN groups, the severity of AAA in the CAR-DCN group was significantly reduced. Histological analysis revealed that CAR-DCN treatment significantly increased DCN and collagen levels within the aortic wall as compared to vehicle controls. Taken together, these results suggest that CAR-DCN treatment attenuates the formation and rupture of Ang II-induced AAA in mice by reinforcing the aortic wall.

Cardiopulmonary resuscitation (CPR) is an inherently traumatic procedure. Successful resuscitations are often complicated by iatrogenic injuries to structures of the neck, thorax, or abdomen. Rib and sternal fractures are the most frequently induced injuries. However, rare and life-threatening trauma to vital organs such as the heart may also occur during CPR. We describe a novel case of CPR-associated right ventricular rupture in a woman with acute-on-chronic pulmonary embolism and no known pre-existing cardiac disease. We propose that chest compressions in the setting of elevated right ventricular pressure resulted in cardiac rupture, in this case.

Viral pathogens are well known to cause injury, inflammation, tissue destruction, and remodeling of heart muscle. Indeed, viruses are among the most common inciting agents to cause a condition termed acute myocarditis. This condition may also be provoked by bacteria, other pathogens, as well as toxins and autoimmune diseases, each of which could mimic the appearance of viral myocarditis. The reason for this phenotypic mimicry is that myocarditis is a process characterized pathologically by an inflammatory infiltrate of the myocardium with death or degeneration of adjacent myocytes, not typical of the ischemic damage associated with atherosclerotic coronary artery disease. The inflammation and damage may involve myocytes, interstitium, vascular elements, and pericardium. The inflammatory process affects cardiac function adversely, causing either ventricular dysfunction, arrhythmias, or both. The acute process may persist and manifest as chronic low-grade tissue inflammation and fibrosis associated with cardiomyopathy and frank heart failure.