Transformation of metallo-elastomer grafts in a carotid artery interposition model over a year.

Current vascular grafts, primarily Gore-Tex® and Dacron®, don't integrate with the host and have low patency in small-diameter vessels (<6 mm). Biomaterials that possess appropriate viscoelasticity, compliance, and high biocompatibility are essential for their application in small blood vessels. We have developed metal ion crosslinked poly(propanediol-co-(hydroxyphenyl methylene)amino-propanediol sebacate) (M-PAS), a biodegradable elastomer with a wide range of mechanical properties. We call these materials metallo-elastomers. An initial test on Zn-, Fe-, and Cu-PAS grafts reveals that Cu-PAS is the most suitable because of its excellent elastic recoil and well-balanced polymer degradation/tissue regeneration rate. Here we report host remodeling of Cu-PAS vascular grafts in rats over one year. 76 % of the grafts remain patent and >90 % of the synthetic polymer is degraded by 12 months. Extensive cell infiltration leads to a positive host remodeling. The remodeled grafts feature a fully endothelialized lumen. Circumferentially organized smooth muscle cells, elastin fibers, and widespread mature collagen give the neoarteries mechanical properties similar to native arteries. Proteomic analysis further reveals the presence of important vascular proteins in the neoarteries. Evidence suggests that Cu-PAS is a promising material for engineering small blood vessels.

Tirzepatide Immunogenicity on Pharmacokinetics, Efficacy, and Safety: Analysis of Data From Phase 3 Studies.

CONTEXT: Antidrug antibodies (ADA) can potentially affect drug pharmacokinetics, safety, and efficacy. OBJECTIVE: This work aimed to evaluate treatment-emergent (TE) ADA in tirzepatide (TZP)-treated participants across 7 phase 3 trials and their potential effect on pharmacokinetics, efficacy, and safety. METHODS: ADA were assessed at baseline and throughout the study until end point, defined as week 40 (SURPASS-1, -2, and -5) or week 52 (SURPASS-3, -4, Japan-Mono, and Japan-Combo). Samples for ADA characterization were collected at SURPASS trial sites. Participants included ADA-evaluable TZP-treated patients with type 2 diabetes (N = 5025). Interventions included TZP 5, 10, or 15 mg. ADA were detected and characterized for their ability to cross-react with native glucose-dependent insulinotropic polypeptide (nGIP) and glucagon-like peptide-1 (nGLP-1), neutralize tirzepatide activity on GIP and GLP-1 receptors, and neutralize nGIP and nGLP-1. RESULTS: TE ADA developed in 51.1% of tirzepatide-treated patients. Proportions were similar across dose groups. Maximum ADA titers ranged from 1:20 to 1: 81 920 among TE ADA+ patients. Neutralizing antibodies (NAb) against TZP activity on GIP and GLP-1 receptors were observed in 1.9% and 2.1% of patients, respectively. Less than 1.0% of patients had cross-reactive NAb against nGIP or nGLP-1. TE ADA status, ADA titer, and NAb status had no effect on the pharmacokinetics or efficacy of TZP. More TE ADA+ patients experienced hypersensitivity reactions or injection site reactions than TE ADA- patients. The majority of hypersensitivity and injection site reactions were nonserious and nonsevere, and most events occurred and/or resolved irrespective of TE ADA status or titer. CONCLUSION: Immunogenicity did not affect TZP pharmacokinetics or efficacy. The majority of hypersensitivity or injection site reactions experienced by TE ADA+ patients were mild to moderate in severity.

Left Atrial Appendage Occlusion as an Alternative to Anticoagulants in Ibrutinib-Induced Hemorrhagic Pericardial Effusion.

Bleeding tendency increases with concomitant use of ibrutinib and anticoagulants. Our patient presented with shortness of breath and was found to have a nonmalignant hemorrhagic pericardial effusion. Ibrutinib was resumed, and percutaneous left atrial appendage occlusion was performed as a substitute for the chemical anticoagulation to decrease the drug-drug interaction. (Level of Difficulty: Intermediate.).

Recreational Nitrous Oxide-Induced Subacute Combined Degeneration.

Subacute combined degeneration (SCD) is myelopathy caused by vitamin B12 deficiency, leading to demyelination of the dorsal column located in the posterior spinal cord. Despite the high prevalence of recreational nitrous oxide use, its detrimental effects, including significant nerve dysfunction, are insufficiently recognized. We present the case of a 32-year-old male who was brought to the emergency department with complaints of paresthesia of his four extremities and lower extremity weakness. He was found to have B12 deficiency from chronic nitrous oxide abuse and responded positively to intramuscular B12 supplementation. It is important to consider possible nitrous oxide abuse while investigating suspected B12 deficiency, especially in patients presenting with nonspecific myeloneuropathy. Elevated methylmalonic acid (MMA) level is specific for diagnosing B12 deficiency. Prompt diagnosis and treatment can lead to the resolution of the symptoms and prevent further nerve damage.

Stewart-Treves Syndrome in Obesity-Associated Chronic Lymphedema: A Case Report.

Stewart-Treves syndrome (STS) is defined as the development of cutaneous angiosarcoma in the presence of long-standing lymphedema and is a rare disease with only about 400 cases reported in world literature. We report a case of a 63-year-old morbidly obese woman with a long-standing history of lymphedema who developed angiosarcoma of the right lower extremity with metastasis and presented with acute respiratory distress. The patient underwent a thorough laboratory workup with a chest X-ray showing bilateral effusions. The hematology-oncology service was consulted and found the patient to have significant progression of angiosarcoma causing respiratory failure and cardiac instability. A decision to transition to hospice care was made and the patient eventually passed away in the intensive care unit. We present this case to raise awareness of STS in medical literature to understand its clinical manifestations better. Early detection is imperative as angiosarcoma is commonly an aggressive disease.

Nivolumab, a Double-Edged Sword: A Case Report of Nivolumab-Induced Myasthenia Gravis.

Nivolumab is a checkpoint inhibitor approved to treat various solid organs malignancies. Although checkpoint inhibitors are very efficacious, these medications are also associated with a variety of side effects that could be life-threatening. We present a case of nivolumab-induced myasthenia gravis in a patient with stage IV esophageal cancer, who was found to have generalized weakness, blurry vision, diplopia, and later developed acute hypoxic respiratory failure with subsequent intubation. The patient was treated with intravenous immunoglobulin and plasmapheresis, and later started on pyridostigmine and high-dose steroids with minimal improvement. Goals of care were discussed with the patient and family, and the decision was made to discharge the patient home with hospice care. Nivolumab-induced myasthenia gravis is very aggressive with a poor prognosis if not appropriately managed in time. Hence we strongly recommend a multidisciplinary approach, including neurologists, to monitor patients on nivolumab therapy to reduce morbidity and mortality associated with it.

A Rare Case of Cavernous Hemangioma of the Mitral Valve Presenting As Multifocal Embolic Brain Infarcts.

Primary cardiac tumors (PCTs) are rare and represent a heterogeneous group of tumors, potentially arising from various parts of the heart. The majority of these tumors are benign (90%), with myxoma being the most common subtype. Cardiac hemangiomas are rare vascular tumors that constitute 1-2% of all benign heart neoplasms. We present a rare case of a 79-year-old woman presented with multifocal embolic brain infarcts secondary to cavernous hemangioma of the mitral valve (MV). Cavernous hemangioma was successfully resected with follow-up imaging at six months, demonstrating no regrowth. There are no pathognomonic signs or findings to suggest cavernous hemangioma of the MV on clinical examination or imaging studies. Surgical resection and histopathologic analysis remain the gold standard for diagnosis and treatment, respectively. Following complete resection, the prognosis is generally favorable with a low recurrence rate, but periodic echocardiography is recommended to detect any potential recurrence.

Syncope as the Initial Manifestation of a Late-Stage Renal Cell Carcinoma With Metastasis to the Brain.

Renal cell carcinoma (RCC) is the most common neoplasm that arises from renal parenchyma. About one-third of patients with RCC develop metastatic spread, with common sites including the lung, liver, bone, adrenal gland, and brain. Distant metastases can be difficult to detect unless symptoms appear. We report a case of a 56-year-old female who presented to the emergency department with the unresponsiveness of unknown duration. She underwent a thorough laboratory workup, and the computed tomography (CT) scan revealed a retroperitoneal mass originating from the right kidney and a large hemorrhagic brain mass in the left frontal lobe. The patient underwent emergent full craniotomy for tumor removal, and histology confirmed metastatic RCC. Since several patients with RCC are asymptomatic, the slow growth of tumors leading to distant metastasis can be overlooked. Thus, this case demonstrates the importance of early detection of RCC to help prevent or delay further disease progression.

Chronic Idiopathic Intestinal Pseudo-Obstruction.

Chronic intestinal pseudo-obstruction (CIPO) is a rare, potentially debilitating gastrointestinal (GI) condition characterized by symptoms of intestinal obstruction with the absence of anatomic lesions. In this report, we present a case of an 86-year-old female who presented with severe abdominal discomfort, nausea, and vomiting for two weeks prior to presentation. Imaging studies revealed severe gastric distension with a lack of anatomic lesions. The patient was ultimately diagnosed with chronic idiopathic intestinal pseudo-obstruction (CIIP). The purpose of this case report is to raise awareness of this condition in the medical literature and discuss the epidemiology, pathophysiology, clinical manifestations, diagnostic workup, and treatment options of this disorder.

Deglutition Syncope Due to Exaggerated Vagal Reflex.

Swallow or deglutition syncope is an uncommon cause of syncope associated with bradyarrhythmia and hypotension during food swallowing. Early recognition of this condition is imperative but challenging. We report a case of a 60-year-old female who presented with a complaint of intermittent lightheadedness after swallowing food. An episode of presyncope was observed and a reduced pulse rate from baseline was noted when she was instructed to eat a candy bar in the clinic. Further workup revealed normal in-office electrocardiogram, bilateral carotid ultrasound, transthoracic echocardiogram, and videofluoroscopic swallow study. Our goal in presenting this case is to raise awareness of the condition in medical literature and provide a good understanding of its clinical manifestation to prevent life-threatening events.

Acute Pancreatitis: A Possible Side Effect of COVID-19 Vaccine.

For the first time, the mRNA technology was utilized to produce a vaccine against COVID-19 after the unprecedented pandemic equally affected every part of the world. Pfizer-BioNTech (BNT162b2) mRNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was granted emergency use authorization (EUA) by Food and Drug Administration (FDA) in December 2020. EUA has been widely discussed in the medical literature and the general public. The safety of the BNT162b2 vaccine has been investigated in short-term trials with data available for three months. We present a case of a 96-year-old female with a past surgical history of cholecystectomy who presented with acute onset severe abdominal pain a few days after getting the first dose of Pfizer-BioNTech COVID-19 vaccine. She was diagnosed with acute pancreatitis with a lipase level of 4036 U/L. Extensive history and investigations were unable to find any etiology. The patient was conservatively managed and discharged home without any complications. There has been some data available in medical literature showing an association between acute pancreatitis and COVID-19 infection. Trial data of Pfizer COVID-19 also shows one case of acute pancreatitis in the treatment group. There have also been individual cases of unexplained acute pancreatitis shared by medical professionals on online forums. Our main goal to write this case is to make medical literature aware of possible emerging side effects of the COVID-19 vaccine, one of such side effects being self-resolving uncomplicated acute pancreatitis.

Gastric Epithelioid Angiosarcoma: An Unexpected Tumor in an Unexpected Location.

Angiosarcomas are aggressive neoplasms that arise from endothelial cells and can develop in any part of the body. Gastrointestinal angiosarcomas are very uncommon and can have a variable clinical presentation. We report a case of an 84-year-old female who presented with acute blood loss anemia. She underwent a gastrointestinal workup with esophagogastroduodenoscopy (EGD), which revealed two polyps in the stomach. Histologic evaluation of the polyps was indicative of angiosarcoma, and the diagnosis was eventually confirmed by immunohistochemical analysis with positive CD31, ERG, and FLI1 stains. This case is reported to demonstrate the importance of considering angiosarcoma in the differential for patients presenting with gastrointestinal bleeding.

SARS-CoV-2 Myocarditis Due to Severe Obesity.

Myocarditis is defined as a myocardial injury concomitant with myocardial dysfunction. Several causes are associated with it, including infectious versus inflammatory and inherited cardiomyopathies. It can be acute, subacute, or chronic, and it can present as focal versus diffuse myocardial dysfunction. Viruses diseases, including the Coxsackie B3 virus, have been a well-established cause of viral myocarditis. It is a significant cause of mortality typically among young individuals due to lymphocytic or granulomatous inflammation of the myocardium. At present, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a detrimental cause of myocarditis with significant mortality and morbidity. Literature has revealed that most of the individuals affected by SARS-CoV-2 have significant other comorbidities, including cardiovascular, renal, or endocrine system-related comorbidities. It is noticed worldwide that patients with hypertension, diabetes mellitus, chronic obstructive pulmonary disease, and obesity are at a higher risk of developing severe infection. Obesity itself is related to chronic low-grade inflammation, and SARS-CoV-2 infection creates an environment of an inflammatory storm by excessive activation of cytokines, thus creating a vicious cycle of injury and organ damage. We present the case of a 33-year-old Hispanic morbidly obese male without other comorbidities diagnosed with SARS-CoV-2 pneumonia, complicated by severe systolic heart failure due to SARS-CoV-2 myocarditis.

Is the Renal Resistive Index a Marker for Revascularization in Atherosclerotic Renal Artery Stenosis?

Renal artery stenosis (RAS) is one of the major causes of resistant/malignant hypertension. It can be described as atherosclerotic or non-atherosclerotic. Atherosclerotic RAS comprises almost 90% of all RAS cases and is a prevalent disease of the elderly. Multiple risk factors contribute to atherosclerosis development, which leads to the release of renin and aldosterone, causing resistant/malignant hypertension. Early recognition is prudent but challenging as there are no early clinical signs. We believe that renal resistive index with supportive clinical, laboratory, and imaging modalities can help select revascularization patients.

A Unique Case of Bannwarth Syndrome in Early Disseminated Lyme Disease.

Lyme borreliosis is a multisystem inflammatory disease caused by the spirochete Borrelia burgdorferi (B. burgdorferi) and transmitted through the Ixodes tick. Nervous system involvement is known as Lyme neuroborreliosis; it only occurs in disseminated Lyme disease and is manifested by the classic triad of meningitis, cranial neuritis, and radiculoneuritis. Timeline is a significant factor when staging Lyme manifestations. However, certain cases do not follow the typical presentation timelines described in most literature. We report a case of a 66-year-old male who presented with progressively worsening generalized body aches, severe fatigue, and new-onset urine retention for two weeks. Physical examination revealed severe pain with neck flexion and lying supine and diminished deep tendon reflexes bilaterally. Laboratory data revealed a positive Lyme immunoglobulin (Ig) M antibody with lymphocytic pleocytosis on lumbar puncture. He was treated with intravenous (IV) ceftriaxone for early disseminated Lyme disease. His radicular pain responded well to therapy, and he regained full bladder function. Bannwarth syndrome (BWS) is a term applied to the constellation of painful radiculoneuritis characterized as severe, burning, often dermatomal pain. In most cases, BWS affects the limbs, with only a few reported cases of sacral radiculitis causing neurogenic urinary dysfunction. Early recognition of this rare presentation associated with Lyme disease and treatment with antibiotics can prevent disease progression and detrimental neurological sequelae.

A Rare Case of RYR2 Mutation Causing Sudden Cardiac Arrest Due to Catecholaminergic Polymorphic Ventricular Tachycardia.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a complex disorder that can induce lethal ventricular arrhythmias, secondary to activation of the sympathetic nervous system. This disease is often diagnosed in childhood but can also manifest in adulthood (the early 40s). Gene mutations such as CALM1, RYR2 (ryanodine receptor-2), CASQ2, and TRDN have been identified as common causes of CPVT. Those affected can present with episodes of syncope, sudden cardiac arrest, or sudden cardiac death due to either fast polymorphic ventricular tachycardia (VT) or bidirectional VT. Diagnosing and managing CPVT can often be challenging as patients are often asymptomatic and may present after a sudden cardiac arrest. Exercise stress testing and genetic testing play a pivotal role in the workup of CPVT. Avoidance of strenuous activities and pharmacological therapy with beta-blockers are the mainstays of treatment. Here, we report a case of CPVT in a patient with RYR2 gene mutation, causing sudden cardiac arrest.

COVID-19-Induced Diabetic Ketoacidosis in an Adult with Latent Autoimmune Diabetes.

Latent autoimmune diabetes in adults (LADA) is a type of slow-onset, immune-mediated insulin deficiency involving progressive destruction of beta-cell function. Despite sharing some similarities with both type 1 and type 2 diabetes, LADA is a separate entity that should be given equal attention as patients with this condition are subject to severe complications and preventable hospitalizations without proper medical management if not diagnosed in a timely manner. Herein, we describe the case of a 45-year-old Hispanic female with a past medical history of presumed noninsulin-dependent type 2 diabetes managed with metformin for six years who presented with fatigue, dry cough, and intermittent presyncope for one week. Laboratory data revealed evidence of diabetic ketoacidosis. She also tested positive for coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although her respiratory status was stable and did not require treatment for COVID-19, she required high doses of insulin to normalize hyperglycemia and spent two days in the intensive care unit (ICU). Further evaluation revealed positive islet autoantibodies and decreased C-peptide levels, leading to a diagnosis of LADA. SARS-CoV-2 has been shown to enter islet cells via the angiotensin-converting enzyme-2 (ACE2), causing damage and inducing acute diabetes and associated complications, including ketoacidosis. It is conceivable that this patient had acute worsening of her diabetes through this mechanism. Recognition of this association may contribute to the timely diagnosis of LADA and prevention of medical complications due to inappropriate diabetes therapy.

Genetic Polymorphisms Associated with Idiopathic Short Stature and First-Year Response to Growth Hormone Treatment.

BACKGROUND/AIMS: The term idiopathic short stature (ISS) describes short stature of unknown, but likely polygenic, etiology. This study aimed to identify genetic polymorphisms associated with the ISS phenotype, and with growth response to supplemental GH. METHODS: Using a case-control analysis we compared the prevalence of "tall" versus "short" alleles at 52 polymorphic loci (17 in growth-related candidate genes, 35 identified in prior genome-wide association studies of adult height) in 94 children with ISS followed in the Genetics and Neuroendocrinology of Short Stature International Study, versus 143 controls from the Fels Longitudinal Study. RESULTS: Four variants were nominally associated with ISS using a genotypic model, confirmed by a simultaneous confident inference approach: compared with controls children with ISS had lower odds of "tall" alleles (odds ratio, 95% CI) for GHR (0.52, 0.29-0.96); rs2234693/ESR1 (0.50, 0.25-0.98); rs967417/BMP2 (0.39, 0.17-0.93), and rs4743034/ZNF462 (0.40, 0.18-0.89). Children with ISS also had lower odds of the "tall" allele (A) at the IGFBP3 -202 promoter polymorphism (rs2855744; 0.40, 0.20-0.80) in the simultaneous confident inference analysis. A significant association with 1st-year height SD score increase during GH treatment was observed with rs11205277, located near 4 known genes: MTMR11, SV2A, HIST2H2AA3, and SF3B4; the latter, in which heterozygous mutations occur in Nager acrofacial dysostosis, appears the most relevant gene. CONCLUSIONS: In children with ISS we identified associations with "short" alleles at a number of height-related loci. In addition, a polymorphic variant located near SF3B4 was associated with the GH treatment response in our cohort. The findings in our small study warrant further investigation.

In Situ Fabrication of Double-Layered Hydrogels via Spray Processes to Prevent Postoperative Peritoneal Adhesion.

Postoperative peritoneal adhesions could cause pelvic pain, infertility, and bowel obstruction. In addition, adhesiolysis makes second surgery difficult. For the first time, we fabricated double-layered hydrogels in situ on the trauma surface via sequential double spray processes to prevent peritoneal adhesions. The spray conditions were optimized for spray distance and gas flow rate to create homogeneous and seamless double-layered hydrogels. The top layer was composed of alginate (Alg)-carboxymethyl cellulose (CMC) and serves as the barrier between the wounded tissue and surrounding tissues. The bottom layer was composed of Alg-gelatin (Gela) and comes in direct contact with the wounded tissue to promote wound healing. In vitro experiments showed that the Alg-Gela hydrogel layer promoted wound healing by accelerating horizontal cell migration. In addition, the Alg-CMC layer prevented the vertical penetration of fibroblast cells. The prevention efficacy of the sprayable double-layered hydrogels was evaluated using a partial hepatectomy-induced adhesion model in rats. The double-layered hydrogels decreased the adhesion grade and extent of liver cut surface, whereas the two single-layered hydrogels, Alg-CMC and Alg-Gela, did not show any adhesion prevention efficacy.

In actio optophysiological analyses reveal functional diversification of dopaminergic neurons in the nematode C. elegans.

Many neuronal groups such as dopamine-releasing (dopaminergic) neurons are functionally divergent, although the details of such divergence are not well understood. Dopamine in the nematode Caenorhabditis elegans modulates various neural functions and is released from four left-right pairs of neurons. The terminal identities of these dopaminergic neurons are regulated by the same genetic program, and previous studies have suggested that they are functionally redundant. In this study, however, we show functional divergence within the dopaminergic neurons of C. elegans. Because dopaminergic neurons of the animals were supposedly activated by mechanical stimulus upon entry into a lawn of their food bacteria, we developed a novel integrated microscope system that can auto-track a freely-moving (in actio) C. elegans to individually monitor and stimulate the neuronal activities of multiple neurons. We found that only head-dorsal pair of dopaminergic neurons (CEPD), but not head-ventral or posterior pairs, were preferentially activated upon food entry. In addition, the optogenetic activation of CEPD neurons alone exhibited effects similar to those observed upon food entry. Thus, our results demonstrated functional divergence in the genetically similar dopaminergic neurons, which may provide a new entry point toward understanding functional diversity of neurons beyond genetic terminal identification.