Orthodeoxia Platypnea Syndrome in the Setting of Cholangiocarcinoma: A Case Report.

Platypnea-orthodeoxia syndrome is a rare cause of positional hypoxemia and dyspnea. We present the case of a 54-year-old man with right-to-left shunting through a patent foramen ovale in the setting of metastatic cholangiocarcinoma resulting in platypnea-orthodeoxia syndrome. The shunt was originally not visualized on cardiac magnetic resonance imaging but later detected with transesophageal echocardiography. This case highlights the importance of complimentary multimodality cardiac imaging in the diagnosis of both common and uncommon disorders.

Durvalumab-Associated Myocarditis Initially Presenting With Sinus Bradycardia Progressing Into Complete Heart Block.

Durvalumab is a monoclonal antibody that blocks programmed cell death ligand-1 (PD-L1). It has been recently approved for the treatment of advanced urothelial and non-small cell lung cancer (NSCLC) with a more favorable side effect profile compared to traditional chemotherapy agents. We present a case of durvalumab-induced myocarditis complicated by complete heart block (CHB). A 71-year-old male with a history of atrial flutter status post ablation, type 2 diabetes mellitus, hypertension, and non-small cell lung carcinoma (NSCLC) recently started on durvalumab, presented with new sinus bradycardia on electrocardiogram (EKG). His initial labs were notable for a troponin T of 207 ng/L (normal range ≤50). Transthoracic echo (TTE) and computed tomography angiography (CTA) of the coronaries were unremarkable. The hospital course was complicated by CHB on telemetry for 15 minutes. Given hemodynamic instability, cardiac magnetic resonance imaging (MRI) could not be obtained. The patient received transvenous pacing. Electrophysiology and cardiology-oncology were consulted to evaluate for pacemaker implantation as well as management for durvalumab-induced myocarditis. Methylprednisolone 1000 mg intravenous (IV) was started with an improvement in troponin levels but without improvement in CHB. His course was further complicated by polymorphic ventricular tachycardia prompting the placement of a permanent dual-chamber pacemaker. The patient was discharged on a prednisone taper, and durvalumab was discontinued. A diagnosis of durvalumab-induced myocarditis was made based on elevated troponin levels, with the exclusion of coronary artery disease with CTA of the coronaries. The persistence of conduction abnormalities despite treatment with steroids leads to the placement of a permanent pacemaker. Durvalumab falls under the category of immune checkpoint inhibitor (ICI) therapy which are novel agents that have more favorable side effect profiles compared to traditional chemotherapeutic agents. A review of the literature shows myocarditis with arrhythmias as a potentially rare side effect of ICI therapy. Corticosteroid therapy seems to be promising as a potential therapy.

Development of High-Grade Sarcoma After Second Dose of Moderna Vaccine.

Coronavirus disease 2019 (COVID-19) is a disease characterized by predominantly respiratory symptoms, which can progress to respiratory failure. Due to the novelty of the vaccines, it is difficult to assess if there are any associated long-term side effects. Here, we present a case of an elderly female who received the Moderna COVID-19 vaccine and developed a high-grade sarcoma at the site of the injection. A 73-year-old female with a past medical history of hypertension, hyperlipidemia, and renal angiomyolipoma status post resection in 2019 presented with worsening right upper arm swelling for the past two weeks. She noticed the swelling two to four days after receiving her second dose of the Moderna vaccine within 1 cm from the prior injection site. Physical examination was remarkable for a 6 cm, circular, mobile, soft mass present in the right upper arm. MRI with and without contrast revealed a 5.2 cm soft tissue mass overlying the triceps region with irregular features concerning for malignancy. Fine needle aspiration revealed pathologic characteristics indicative of high-grade sarcoma. The patient ultimately had resection of the mass four months after the initial visit and was diagnosed as having grade 3, stage IIIA undifferentiated, pleomorphic high-grade sarcoma. Herein, we present a case demonstrating the development of high-grade sarcoma at the injection site in an elderly female patient within days of receiving the second dose of the Moderna COVID-19 vaccine. Currently, it is unclear whether there is a true association between the vaccines and malignancy or inflammatory response exacerbating underlying malignancy. This case highlights the necessity to investigate and be aware of such rare, adverse complications that may be associated with the novel COVID-19 vaccinations to guide physicians in their differential diagnosis.

Early HELLP Syndrome or Catastrophic Antiphospholipid Syndrome? A Diagnostic Dilemma.

Hypertensive disorders of pregnancy typically occur in the third trimester, with earlier presentations associated with underlying disorders such as antiphospholipid syndrome (APLS). We describe a case of a young primigravida presenting at 15 weeks 6 days gestation with epigastric pain, vomiting, new-onset severe-range hypertension, and subsequent development of anemia, thrombocytopenia, and transaminitis. Antiphospholipid antibodies (aPL) were triple-positive and imaging was negative for thrombosis. She was treated with aspirin, therapeutic anticoagulation, and ultimately dilatation and evacuation with initial postoperative improvement. Her symptoms returned postoperative day 3 and resolved following re-initiation of therapeutic anticoagulation. The differential diagnosis for hypertensive disorders of pregnancy is wide, particularly in second-trimester gestation, and includes catastrophic antiphospholipid syndrome (CAPS), lupus flare, microangiopathic anemias, and acute fatty liver of pregnancy. This case was an atypical presentation not clearly explained by any of the above diagnoses and required a multidisciplinary approach. Obstetric patients with high-risk aPL must be meticulously investigated with a broad differential to guide diagnosis and treatment.

Expanding a single­lead mobile electrocardiographic device to multiple­lead recordings improves diagnostic accuracy and confidence.

BACKGROUND: Mobile electrocardiographic (mECG) devices that record ECG lead I have been used to detect atrial fibrillation. Other arrhythmias may not be readily diagnosed with one lead. Obtaining multi­lead tracings from an mECG (MLmECG) to simulate a 12­lead ECG may lead to more accurate diagnoses. METHODS: We developed a method to generate multi­lead ECGs using a mECG device by attaching it with alligator clips connected to an insulated copper wire to adhesive electrodes on the patient's limbs and torso according to standard lead configurations. Different rhythm and conduction abnormalities from a sample of inpatients were collected. Arrhythmias were recorded in three ways (single lead, MLmECG, and standard 12­lead) and grouped by category. Recordings were sent to cardiology fellows in the form of a multiple choice survey. Participants were asked for their diagnosis and confidence in their decision. RESULTS: Survey response rate was 100%. Single­lead, MLmECG, and 12­lead yielded 48.2%, 81.6%, and 88.6% of agreement with the correct diagnosis, respectively (single­lead vs. MLmECG or 12­lead; p < 0.01). Overall mean confidence scores were 3.34, 4.35, and 4.53 out of 5, for single­lead, MLmECG, and 12­lead ECG, respectively (single­lead vs. MLmECG or 12­lead; p < 0.01, MLmECG vs. 12­lead; p = 0.09). CONCLUSION: The diagnostic accuracy of MLmECGs were similar to that of a standard 12­lead ECG. Fellows' confidence in their diagnosis were similar between MLmECG or 12­lead ECG, and higher with both modalities compared to a single­lead tracing. The ability to recreate, as fully as possible, a standard 12­lead ECG is a reasonable goal for mobile technology.

Improved accuracy and confidence with multiple-lead recordings from a single-lead mobile electrocardiographic device.

BACKGROUND: Mobile electrocardiograms (mECGs) utilizing smartphone applications are an emerging technology. Typically, a Lead I rhythm strip is recorded. However, interpretation can be difficult in patients with sinus rhythm and low amplitude P-waves (SR-LAP) or atrial flutter (AFL). We hypothesized that patients could independently obtain multi-lead tracings using a commercial mECG device, and that cardiologists who interpreted the multi-lead tracings would make more accurate diagnoses and have more confidence in their interpretation compared to a single lead only. METHODS: Thirty sets of recordings were obtained from 10 patients with either SR-LAP or AFL that was not apparent on Lead I on a standard ECG. Patients recorded Lead I, Lead II, and Lead V1 tracings using AliveCor's KardiaMobile mECG device. Twenty-nine cardiologists reviewed each patient's Lead I tracing, multi-lead tracings (Leads I, II, V1), and 12-lead ECG. Accuracy was noted and each cardiologist rated their level of confidence in their interpretation. RESULTS: All patients were able to record their own single and multi-lead tracings. Single lead, multi-lead, and the 12-lead ECG yielded 36.4%, 84.3%, and 97.7% agreement with the established diagnosis, respectively (P < .01 for each comparison). Overall mean confidence scores (out of a score of 5) were 2.95, 3.50, and 4.47 for single lead, multi-lead, and the 12-lead ECG, respectively (P < .01 for each comparison). CONCLUSIONS: Patients were able to record their own multi-lead mECG tracings. Compared to a single lead recording, multi-lead mECGs significantly improved cardiologists' diagnostic accuracy and confidence in their interpretation approaching that of a standard 12-lead ECG.

Kinetic Evidence for a Second Ligand Binding Site on Streptococcus pneumoniae Penicillin-Binding Protein 2x.

High molecular mass penicillin-binding proteins (PBPs, DD-peptidases) of class B, such as Streptococcus pneumoniae PBP2x, catalyze the cross-linking of peptidoglycan in bacterial cell wall biosynthesis and are thus important antibiotic targets. Despite their importance in this regard, structure-function studies of ligands of these enzymes have been impeded by the absence of useful substrates. In vitro, these enzymes do not catalyze peptide hydrolysis or aminolysis, their in vivo reaction, but some, such as PBP2x, do catalyze these reactions of certain thioesters such as PhCH2CONHCH2COSCH(D-Me)CO2- (2). We have now prepared several peptidoglycan-mimetic thioesters that we expected to more closely resemble the natural substrates of these enzymes. To our surprise, however, these compounds, although indeed substrates of PBP2x, did not, unlike 2, appear to form an acyl-enzyme intermediate during hydrolysis, and their turnover was inhibited by certain peptides and N-acylamino acids much more weakly than that of 2. An inhibitor of this type, N-benzyloxycarbonyl-d-glutamic acid, also quenched the fluorescence of PBP2x that had been labeled at the DD-peptidase active site by 6-dansylamidopenicillanic acid. These results were interpreted in terms of a model where the peptidoglycan-mimetic thioesters preferentially bound to and hydrolyzed at a site other than the classical DD-peptidase active site. This second site is likely to represent part of an extended binding site that accommodates a peptidoglycan substrate or regulator in vivo. Such a site may be a target for future inhibitor/antibiotic design.

Predictors of restenosis after carotid artery stenting in 241 cases.

BACKGROUND: Variable rates of restenosis after carotid artery stenting (CAS) have been reported, and few predictors have been suggested. Because CAS is being performed with increasing frequency, more data are needed to evaluate the rate and predictors of restenosis and possibly identify new risk factors for restenosis after CAS. The aim of this study was to analyze the rate and predictors of restenosis after CAS. METHODS: 241 patients with carotid artery stenosis treated with stenting were analyzed retrospectively to identify patients who had restenosis after stenting. Univariate analysis and multivariate logistic regression were conducted to determine the predictors of restenosis. RESULTS: Mean patient age was 67.5 years. 8.3% of patients who underwent CAS had carotid restenosis of ≥50% during follow-up. 3.7% of patients required retreatment. Mean duration from CAS to retreatment was 11 months. In multivariate analysis, the predictors of restenosis included history of cardiovascular disease (OR=8.88, p<0.001) and having a cerebrovascular accident (CVA) prior to stenting (OR=1.87, p=0.034). A higher percentage of preoperative carotid stenosis was associated with higher odds of restenosis in univariate analysis (p=0.04, OR stenosis ≥80%=5.7). CONCLUSIONS: Our results suggest that the rate of carotid restenosis after stenting is low. Patients with cardiovascular disease, patients who had a CVA prior to stenting, and patients with higher percentages of preoperative stenosis had higher odds of restenosis. Higher rates of restenosis should be kept in mind when opting for CAS in these patients.

Visnagin protects against doxorubicin-induced cardiomyopathy through modulation of mitochondrial malate dehydrogenase.

Doxorubicin is a highly effective anticancer chemotherapy agent, but its use is limited by its cardiotoxicity. To develop a drug that prevents this toxicity, we established a doxorubicin-induced cardiomyopathy model in zebrafish that recapitulates the cardiomyocyte apoptosis and contractility decline observed in patients. Using this model, we screened 3000 compounds and found that visnagin (VIS) and diphenylurea (DPU) rescue the cardiac performance and circulatory defects caused by doxorubicin in zebrafish. VIS and DPU reduced doxorubicin-induced apoptosis in cultured cardiomyocytes and in vivo in zebrafish and mouse hearts. VIS treatment improved cardiac contractility in doxorubicin-treated mice. Further, VIS and DPU did not reduce the chemotherapeutic efficacy of doxorubicin in several cultured tumor lines or in zebrafish and mouse xenograft models. Using affinity chromatography, we found that VIS binds to mitochondrial malate dehydrogenase (MDH2), a key enzyme in the tricarboxylic acid cycle. As with VIS, treatment with the MDH2 inhibitors mebendazole, thyroxine, and iodine prevented doxorubicin cardiotoxicity, as did treatment with malate itself, suggesting that modulation of MDH2 activity is responsible for VIS' cardioprotective effects. Thus, VIS and DPU are potent cardioprotective compounds, and MDH2 is a previously undescribed, druggable target for doxorubicin-induced cardiomyopathy.

An in vivo zebrafish screen identifies organophosphate antidotes with diverse mechanisms of action.

Organophosphates are a class of highly toxic chemicals that includes many pesticides and chemical weapons. Exposure to organophosphates, either through accidents or acts of terrorism, poses a significant risk to human health and safety. Existing antidotes, in use for over 50 years, have modest efficacy and undesirable toxicities. Therefore, discovering new organophosphate antidotes is a high priority. Early life stage zebrafish exposed to organophosphates exhibit several phenotypes that parallel the human response to organophosphates, including behavioral deficits, paralysis, and eventual death. Here, we have developed a high-throughput zebrafish screen in a 96-well plate format to find new antidotes that counteract organophosphate-induced lethality. In a pilot screen of 1200 known drugs, we identified 16 compounds that suppress organophosphate toxicity in zebrafish. Several in vitro assays coupled with liquid chromatography/tandem mass spectrometry-based metabolite profiling enabled determination of mechanisms of action for several of the antidotes, including reversible acetylcholinesterase inhibition, cholinergic receptor antagonism, and inhibition of bioactivation. Therefore, the in vivo screen is capable of discovering organophosphate antidotes that intervene in distinct pathways. These findings suggest that zebrafish screens might be a broadly applicable approach for discovering compounds that counteract the toxic effects of accidental or malicious poisonous exposures.

Substrate specificity of low-molecular mass bacterial DD-peptidases.

The bacterial DD-peptidases or penicillin-binding proteins (PBPs) catalyze the formation and regulation of cross-links in peptidoglycan biosynthesis. They are classified into two groups, the high-molecular mass (HMM) and low-molecular mass (LMM) enzymes. The latter group, which is subdivided into classes A-C (LMMA, -B, and -C, respectively), is believed to catalyze DD-carboxypeptidase and endopeptidase reactions in vivo. To date, the specificity of their reactions with particular elements of peptidoglycan structure has not, in general, been defined. This paper describes the steady-state kinetics of hydrolysis of a series of specific peptidoglycan-mimetic peptides, representing various elements of stem peptide structure, catalyzed by a range of LMM PBPs (the LMMA enzymes, Escherichia coli PBP5, Neisseria gonorrhoeae PBP4, and Streptococcus pneumoniae PBP3, and the LMMC enzymes, the Actinomadura R39 dd-peptidase, Bacillus subtilis PBP4a, and N. gonorrhoeae PBP3). The R39 enzyme (LMMC), like the previously studied Streptomyces R61 DD-peptidase (LMMB), specifically and rapidly hydrolyzes stem peptide fragments with a free N-terminus. In accord with this result, the crystal structures of the R61 and R39 enzymes display a binding site specific to the stem peptide N-terminus. These are water-soluble enzymes, however, with no known specific function in vivo. On the other hand, soluble versions of the remaining enzymes of those noted above, all of which are likely to be membrane-bound and/or associated in vivo and have been assigned particular roles in cell wall biosynthesis and maintenance, show little or no specificity for peptides containing elements of peptidoglycan structure. Peptidoglycan-mimetic boronate transition-state analogues do inhibit these enzymes but display notable specificity only for the LMMC enzymes, where, unlike peptide substrates, they may be able to effectively induce a specific active site structure. The manner in which LMMA (and HMM) DD-peptidases achieve substrate specificity, both in vitro and in vivo, remains unknown.