Refining Cardiovascular Calcification in the Appraisal of Ischemic Heart.

BACKGROUND: Even in asymptomatic patients, there is a high association of ischemia on myocardial perfusion scans in those with coronary artery calcification or valvular calcifications. Patients without coronary artery calcifications have exceeding-low rates of cardiovascular events. The absence of cardiovascular calcification, including coronary artery, valvular, and thoracic aorta is a strong negative predictor of myocardial ischemia. In individuals with suspected ischemia who had chest computed tomography imaging, evaluation for cardiovascular calcification (coronary artery, valves, and thoracic aorta) is an invaluable tool to guide management for further diagnostic imaging. We hypothesize that the complete absence of cardiovascular calcification has a high negative predictive value for defects in myocardial perfusion imaging such as single-photon emission computed tomography (SPECT) or positron emission tomography (PET). METHODS: Non-contrast computed tomography performed for SPECT/PET CT attenuation correction from March 1, 2017, to September 30, 2017, were retrospectively reviewed for the absence of cardiovascular calcification by a cardiologist and radiologist who were blinded to patients' medical history. Medical records were reviewed to include patient demographics and medical history. A total of 132 patients were analyzed. RESULTS: Of the 132 patients without calcifications, seven patients had small myocardial perfusion defects suggestive of ischemia or infarct, but none were considered significant defects. Of these seven patients, six were managed medically and one was from an outside institution with no follow-up data. Two of the seven patients had follow-up invasive angiography or coronary CTA that did not show significant atherosclerotic coronary artery disease. CONCLUSION: A complete absence of cardiovascular calcification indicates a 100% negative predictive value for a significant perfusion defect on same-day confirmatory nuclear stress testing. Patients with suspected ischemia but absent cardiovascular calcifications can be safely managed medically without further testing for ischemia.

Case Illustration of the Natural History of Left Dominant Arrhythmogenic Cardiomyopathy.

Background: Arrhythmogenic left ventricular cardiomyopathy is an increasingly recognized cause of recurrent myocarditis, a mimicker of acute coronary syndrome, and an important cause of malignant ventricular arrythmias and heart failure. Desmoplakin is a protein that is critical to maintaining the structural integrity of the myocardium. Disruption of desmoplakin leads to fibrofatty infiltration of the myocardium which leads to congestive heart failure, cardiac arrhythmias, and sudden cardiac death. However, desmoplakin cardiomyopathy is often misdiagnosed, resulting in significant morbidity and mortality. We report 2 contrasting cases illustrating the natural history-hot and cold phases-of arrhythmogenic left ventricular cardiomyopathy. Case Series: The first case demonstrates a common phenotypic presentation of desmoplakin cardiomyopathy manifested as recurrent myocarditis and myocardial injury representing the hot phase. The second case is an undulating course of chronic systolic heart failure and ventricular arrhythmias representing the cold phase. Conclusion: Arrhythmogenic cardiomyopathy manifests as a spectrum of disease processes that involve the right, left, or both ventricles. Mutations in the desmoplakin gene are often associated with a left dominant ventricular cardiomyopathy. Diagnosis remains difficult as the condition has no signature clinical presentation, and imaging findings are variable.

COVID-19 online medical education and outcomes on Internal Medicine In-Training Examination scores.

Background: COVID-19 presented a unique opportunity to explore new methods to deliver medical education virtually due to requirements for social distancing. We provided webcams and microphones in each of our core teaching team rooms. We used existing teleconferencing systems with share screen, polling, and audio/video capabilities to continue fostering a group learning environment. Methods: The Internal Medicine In-Training Examination (IM-ITE) was used as a surrogate measurement of the effectiveness of virtual medical education, comparing composite scores from 2015 to 2019 (pre-COVID, in-person conference) to 2020 (post-COVID, virtual conference) for each postgraduate class. Results: No statistically significant differences between the mean or median scores on the IM-ITE were noted for all three classes. Conclusion: Although COVID-19 presented many challenges to residency programs across the United States, our pilot study demonstrated that virtual medical education did not result in lower IM-ITE scores and may be an innovative solution to bridge the education gap during COVID-19.

Mechanical nanosurgery of chemoresistant glioblastoma using magnetically controlled carbon nanotubes.

Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Despite multimodal treatment including surgery, radiotherapy, and chemotherapy, median patient survival has remained at ~15 months for decades. This situation demands an outside-the-box treatment approach. Using magnetic carbon nanotubes (mCNTs) and precision magnetic field control, we report a mechanical approach to treat chemoresistant GBM. We show that GBM cells internalize mCNTs, the mobilization of which by rotating magnetic field results in cell death. Spatiotemporally controlled mobilization of intratumorally delivered mCNTs suppresses GBM growth in vivo. Functionalization of mCNTs with anti-CD44 antibody, which recognizes GBM cell surface-enriched antigen CD44, increases mCNT recognition of cancer cells, prolongs mCNT enrichment within the tumor, and enhances therapeutic efficacy. Using mouse models of GBM with upfront or therapy-induced resistance to temozolomide, we show that mCNT treatment is effective in treating chemoresistant GBM. Together, we establish mCNT-based mechanical nanosurgery as a treatment option for GBM.

Mechanosensitive brain tumor cells construct blood-tumor barrier to mask chemosensitivity.

Major obstacles in brain cancer treatment include the blood-tumor barrier (BTB), which limits the access of most therapeutic agents, and quiescent tumor cells, which resist conventional chemotherapy. Here, we show that Sox2+ tumor cells project cellular processes to ensheathe capillaries in mouse medulloblastoma (MB), a process that depends on the mechanosensitive ion channel Piezo2. MB develops a tissue stiffness gradient as a function of distance to capillaries. Sox2+ tumor cells perceive substrate stiffness to sustain local intracellular calcium, actomyosin tension, and adhesion to promote cellular process growth and cell surface sequestration of ß-catenin. Piezo2 knockout reverses WNT/ß-catenin signaling states between Sox2+ tumor cells and endothelial cells, compromises the BTB, reduces the quiescence of Sox2+ tumor cells, and markedly enhances the MB response to chemotherapy. Our study reveals that mechanosensitive tumor cells construct the BTB to mask tumor chemosensitivity. Targeting Piezo2 addresses the BTB and tumor quiescence properties that underlie treatment failures in brain cancer.

Ion Channels in Cancer: Orchestrators of Electrical Signaling and Cellular Crosstalk.

Ion channels are pore-forming transmembrane proteins that govern ion flux to regulate a myriad of biological processes in development, physiology, and disease. Across various types of cancer, ion channel expression and activity are often dysregulated. We review the contribution of ion channels to multiple stages of tumorigenesis based on data from in vivo model systems. As intertumoral and intratumoral heterogeneities are major obstacles in developing effective therapies, we provide perspectives on how ion channels in tumor cells and their microenvironment represent targetable vulnerabilities in the areas of tumor-stromal cell interactions, cancer neuroscience, and cancer mechanobiology.

Castleman Disease Presenting as a Mediastinal Mass.

Castleman disease is a complex benign lymphoproliferative disorder characterized by the enlargement of a single lymph node or a group of lymph nodes. Its etiology is unclear, with the mechanism of action of IL-6 and HHV-8 implicated as possibly associated with the development of the disease. Diagnosis depends on the histopathological findings of the involved lymph nodes. Surgical resection can be curative, but a small number of cases may be unresectable and need radiation and chemotherapy with subsequent resection if possible.

Association of Maximum Troponin Levels With Diagnosis of Acute Myocardial Infarction and Elevated Risk of Mortality.

Background: Cardiac troponins I and T are highly sensitive and specific markers for acute myocardial infarction (AMI). However, a wide range of non-AMI conditions can also cause significant elevations in cardiac troponins. Given the deleterious impact of misdiagnosis of AMI, the ability to risk-stratify patients who present with an elevated troponin is paramount. We hypothesized that the maximum troponin level would be more predictive of mortality and the diagnosis of AMI than the initial troponin level or change in troponin level. Methods: Patient records from a 9-hospital system (n=30,173) in Texas were reviewed during a 24-month period in 2016-2017. Data collected for patients aged ≥40 years included International Classification of Diseases, Tenth Revision diagnoses, troponin I, demographic data (age, sex, smoking history, and chronic medical conditions), and death during hospitalization. We used logistic regression with the Firth penalized likelihood approach to determine the predictive ability of initial, maximum, and change in troponin level for mortality and the diagnosis of AMI. Results: Demographic characteristics of our cohort included a median age of 70 years, with 48.05% male and 51.95% female. The most common preexisting risk factor was hypertension in 78.81% of the cohort. Notable findings from the logistic regression include the predictive ability of maximum troponin on the odds of death by 0.7% for each unit of increase in troponin value. Also, the odds of AMI increased by 3.1% for each unit of increase in the maximum troponin value. Conclusion: Regardless of the level, a detectable amount of troponin in the serum results in a significantly elevated risk of mortality. Many patients with elevated troponin levels leave the hospital without a specific diagnosis, which can lead to poor outcomes because a detectable troponin does not represent a no-risk population. Our study demonstrates that maximum troponin level is a more sensitive and specific predictor of mortality than initial or change in troponin. Similarly, maximum troponin is the most predictive of AMI vs other causes of troponin elevation, likely because of the correlation between rising troponin levels and cardiomyocyte damage. Further studies are needed to correlate maximum troponin levels and clinical manifestations, which may be helpful in redefining AMI so that AMI can be distinguished more easily from non-AMI diagnoses.

Myeloid sarcoma as a manifestation of acute myeloid leukemia.

We report a case of a 43-year-old man who presented with dyspnea because of large bilateral pleural effusions and imaging findings of a large periaortic mass with compression of the esophagus and left atrium. Subsequent soft tissue biopsy was consistent with myeloid sarcoma, and bone marrow biopsy was consistent with acute myeloid leukemia. He was started on induction and subsequent consolidation chemotherapy with complete remission and shrinkage of the tumor.

Nonpenetrating trauma resulting in hemopericardium presenting as syncope.

Hemopericardium is a life-threatening condition that needs to be treated promptly to prevent serious complications. It typically results from penetrating trauma directly into the pericardial sac resulting in cardiac tamponade and death if not promptly treated. High clinical suspicion should prompt further workup even in the absence of significant injury. We present a case of a 38-year-old man who presented with blunt force trauma from a rock while mowing the lawn that resulted in syncope and hemopericardium.

Idiopathic Intracranial Hypertension and Multiple Sclerosis Overlap.

Idiopathic intracranial hypertension (IIH) and multiple sclerosis (MS) occur with a higher incidence in women of childbearing age and may be associated with other clinical entities. Both disease processes alter cerebrospinal fluid (CSF) dynamics and may present similarly with headache and visual changes. We report a case of a 33-year-old morbidly obese woman who developed progressive worsening blurry vision and unilateral temporal headache. She was found to have papilledema which prompted workup for intracranial hypertension. Her imaging and CSF findings were suggestive of a demyelinating process such as MS in addition to IIH.

Cranial nerve involvement in varicella zoster virus after renal transplantation.

This case describes a 60-year-old immunosuppressed man after renal transplant who presented to the emergency department with 1 week of generalized weakness, a 20-lb unintentional weight loss, sore throat, dysarthria, dysphagia, cough, and shortness of breath. Additionally, he developed tinnitus, headaches, photophobia, and neck stiffness. He underwent an extensive workup including a lumbar puncture with meningitis and encephalitis panel, which was positive for varicella zoster virus. He never developed a dermatomal vesicular rash but had persistent dysphagia and aspiration and was eventually diagnosed with Vernet syndrome. This case highlights theories for the increase in varicella zoster virus encephalitis cases causing neurologic symptoms and proposes that this trend is likely to continue.

Smallpox Vaccination-Associated Myopericarditis.

Myopericarditis related to a smallpox vaccination often goes unrecognized and untreated because physicians are not routinely screening for vaccination administration.

Cat scratch disease causing encephalitis.

Cat scratch disease is often a benign infection caused by Bartonella henselae, which is transmitted from scratches or bites from kittens. Presentations can vary from localized lymphadenopathy to neurologic manifestations. We present a case of a 22-year-old man with a 3-week history of an enlarged inguinal lymph node who presented with status epilepticus.

Inpatient Mortality and 30-Day Readmission Rates Associated with Troponin Testing in Patients without Acute Myocardial Infarction.

OBJECTIVE: Troponin values above the threshold established to diagnose acute myocardial infarction (AMI; >99th percentile) are commonly detected in patients with diagnoses other than AMI. The objective of this study was to compare inpatient mortality and 30-day readmission rate in patients with troponin I (TnI) above and below the 99th percentile in those with type 1 AMI and type 2 myocardial injury. METHODS: Between January 1, 2016 and December 31, 2016, there were 56,895 inpatient hospitalizations; of these 14,326 (25.2%) patients received troponin testing. We evaluated mortality and readmissions in the entire cohort based on the primary discharge International Classification of Diseases, Tenth Edition (ICD-10) diagnosis and grouped into type 1 AMI versus other diagnoses comprising the type 2 AMI group (including ICD-10 codes for congestive heart failure, sepsis, and other). Among those with TnI drawn, we evaluated in-hospital mortality and 30-day readmissions based on troponin values > 99th percentile (≥ 0.1 ng/ml). RESULTS: Among the entire cohort, the inpatient mortality rate was significantly higher in those with TnI testing (5.0%, 95% CI 4.6%-5.3%) compared to those without testing (0.7%, 95% CI 0.6%-0.7%, P < 0.01). In the tested cohort 3,743 (26%) patients had troponin levels above the 99th percentile (> 0.1 ng/ml), and 10,583 (74%) had troponin levels below the 99th percentile (≤ 0.1 ng/ml). Comparing type 2 AMI with type 1 AMI and troponin testing, TnI values ≥ 0.1 ng/ml were associated with higher inpatient mortality (11.6% vs. 3.9%) and 30-day readmission rates (16.9% vs. 10.7%). CONCLUSIONS: A higher inpatient mortality and 30-day readmission rates were found in patients with type 2 AMI compared to type 1 AMI group.

Chloride intracellular channel 1 cooperates with potassium channel EAG2 to promote medulloblastoma growth.

Ion channels represent a large class of drug targets, but their role in brain cancer is underexplored. Here, we identify that chloride intracellular channel 1 (CLIC1) is overexpressed in human central nervous system malignancies, including medulloblastoma, a common pediatric brain cancer. While global knockout does not overtly affect mouse development, genetic deletion of CLIC1 suppresses medulloblastoma growth in xenograft and genetically engineered mouse models. Mechanistically, CLIC1 enriches to the plasma membrane during mitosis and cooperates with potassium channel EAG2 at lipid rafts to regulate cell volume homeostasis. CLIC1 deficiency is associated with elevation of cell/nuclear volume ratio, uncoupling between RNA biosynthesis and cell size increase, and activation of the p38 MAPK pathway that suppresses proliferation. Concurrent knockdown of CLIC1/EAG2 and their evolutionarily conserved channels synergistically suppressed the growth of human medulloblastoma cells and Drosophila melanogaster brain tumors, respectively. These findings establish CLIC1 as a molecular dependency in rapidly dividing medulloblastoma cells, provide insights into the mechanism by which CLIC1 regulates tumorigenesis, and reveal that targeting CLIC1 and its functionally cooperative potassium channel is a disease-intervention strategy.

Effect of repeat manual blood pressure measurement on blood pressure and stage of hypertension.

Hypertension management guidelines are influenced by clinical trials that utilize automated office blood pressure (BP) to measure BP. Many primary care clinics still use manual office BP, which has been shown to produce significantly higher BP values than automated office BP. In a primary care office, a manual BP was obtained by nursing staff using an aneroid sphygmomanometer. Initial BPs ≥120/80 mm Hg were repeated during the clinical encounter by the physician. A total of 1012 encounters were analyzed, with 1000 meeting inclusion criteria. The median difference between nurse and provider BP was 4 mm Hg in systolic BP and 2 mm Hg in diastolic BP (P < 0.0001), with the greatest difference seen in patients with initial BPs >150 mm Hg systolic (10 mm Hg; P < 0.0001). Repeating BP measurements resulted in 34% of patients being reclassified to a lower hypertension stage. Patients with stage 1 and 2 hypertension initially were reclassified as controlled (systolic BP <130 mm Hg) in 40% and 8% of encounters, respectively, with repeat measurements. In clinics that use manual office BP, repeating a manual BP by the physician may provide a better reflection of adherence to standard hypertension performance measures used in the primary care setting.

Eustachian valve endocarditis.

Eustachian valve infective endocarditis is rare and mostly affects intravenous drug abusers and those with implanted medical devices or indwelling central venous catheters. The most commonly identified organism is Staphylococcus aureus. Treatment includes intravenous antibiotics for approximately 6 weeks. We present a case of Staphylococcus aureus Eustachian valve endocarditis in an individual without traditional risk factors.

Not-so-benign massive cardiac lipoma.

Cardiac lipomas are rare and usually benign tumors that often remain asymptomatic throughout one's lifetime. We report a case of a 60-year-old man with a cardiac lipoma diagnosed early in childhood. However, due to the lack of surgical expertise in rural India, the lipoma was not removed. After moving to the United States, he received irregular follow-up with serial chest x-ray and computed tomography, which demonstrated an enlarging lipomatous mass occupying the pericardial space. After remaining asymptomatic for more than 37 years, he presented to the hospital with dyspnea. He underwent a surgical resection but, unfortunately, given the extension of the mass into multiple critical portions of the heart, he ultimately died.