Mavacamten, a First-in-Class Cardiac Myosin Inhibitor for Obstructive Hypertrophic Cardiomyopathy.

OBJECTIVE: To assess mavacamten's role in hypertrophic cardiomyopathy treatment. DATA SOURCES: In addition to clinical guidelines, package inserts, and general reviews, we searched PubMed using the term mavacamten from inception to June 11, 2022. STUDY SELECTION AND DATA EXTRACTION: English language studies describing mavacamten's mechanism of action, pharmacokinetics, drug interactions, clinical and economic outcomes, and adverse events. DATA SYNTHESIS: Mavacamten reduces left ventricular outflow obstruction and New York Heart Association functional class while improving Kansas City Cardiomyopathy Questionnaire-Clinical Summary Scores in patients with obstructive hypertrophic cardiomyopathy. With an acquisition cost of $245.20 per capsule, it would cost $1.2 million for every additional quality-adjusted life year. In those with unobstructive hypertrophic cardiomyopathy, there were improvements in N-terminal probrain natriuretic peptide and high-sensitivity cardiac troponin biochemical markers. Mavacamten is a substrate for CYP2C19 and CYP3A4, and a CYP enzyme inducer. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Patients with obstructive hypertrophic cardiomyopathy and an ejection fraction ≥55% have a new option if they remain symptomatic despite maximally tolerated ß-blocker or non-dihydropyridine calcium channel blocker therapy. It is an alternative to disopyramide therapy, which has poor patient tolerance, or septal reduction therapies, which are invasive. However, mavacamten is not cost-effective and its role in nonobstructive hypertrophic cardiomyopathy is not well established. CONCLUSIONS: Mavacamten is a new option for patients with refractory obstructive hypertrophic cardiomyopathy and an ejection fraction ≥55% but its pricing makes therapy not cost-effective. Final health outcomes are not fully elucidated and additional studies are needed to determine long-term effects.

Bistable self-assembly in homogeneous colloidal systems for flexible modular architectures.

This paper presents a homogeneous system of magnetic colloidal particles that self-assembles via two structural patterns of different symmetry. Based on a qualitative comparison between a real magnetic particles system, analytical calculations and molecular dynamics simulations, it is shown that bistability can be achieved by a proper tailoring of an anisotropic magnetization distribution inside the particles. The presented bistability opens new possibilities to form two-dimensionally extended and flexible structures where the connectivity between the particles can be changed in vivo.

Magnetic coupling of vortices in a two dimensional lattice.

We investigated the magnetization reversal of magnetic vortex structures in a two-dimensional lattice. The structures were formed by permalloy (Py) film deposition onto large arrays of self assembled spherical SiO(2)-particles with a diameter of 330 nm. We present the dependence of the nucleation and annihilation field of the vortex structures as a function of the Py layer thickness(aspect ratio) and temperature. By increasing the Py thickness up to 90 nm or alternatively by lowering the temperature the vortex structure becomes more stable as expected. However, the increase of the Py thickness results in the onset of strong exchange coupling between neighboring Py caps due to the emergence of Py bridges connecting them. In particular, we studied the influence of magnetic coupling locally by in-field scanning magne to-resistive microscopy and full-field magnetic soft x-ray microscopy, revealing a domain-like nucleation process of vortex states, which arises via domain wall propagation due to exchange coupling of the closely packed structures. By analyzing the rotation sense of the reversed areas, large connected domains are present with the same circulation sense. Furthermore, the lateral core displacements when an in-plane field is applied were investigated, revealing spatially enlarged vortex cores and a broader distribution with increasing Py layer thickness. In addition, the presence of some mixed states, vortices and c-states, is indicated for the array with the thickest Py layer.

Co/Pd-Based synthetic antiferromagnetic thin films on Au/resist underlayers: towards biomedical applications.

Thin film stacks consisting of multiple repeats M of synthetic antiferromagnetic (SAF) [Co/Pd]N/Ru/[Co/Pd]N units with perpendicular magnetic anisotropy were explored as potential starting materials to fabricate free-standing micro/nanodisks, which represent a promising candidate system for theranostic applications. The films were directly grown on a sacrificial resist layer spin-coated on SiOx/Si(100) substrates, required for the preparation of free-standing disks after its dissolution. Furthermore, the film stack was sandwiched between two Au layers to allow further bio-functionalization. For M ≤ 5, the samples fulfill all the key criteria mandatory for biomedical applications, i.e., zero remanence, zero field susceptibility at small fields and sharp switching to saturation, together with the ability to vary the total magnetic moment at saturation by changing the number of repetitions of the multi-stack. Moreover, the samples show strong perpendicular magnetic anisotropy, which is required for applications relying on the transduction of a mechanical force through the micro/nano-disks under a magnetic field, such as the mechanical cell disruption, which is nowadays considered a promising alternative to the more investigated magnetic hyperthermia approach for cancer treatment. In a further step, SAF microdisks were prepared from the continuous multi-stacks by combining electron beam lithography and Ar ion milling, revealing similar magnetic properties as compared to the continuous films.

Uncompensated care provided by private practice physicians in Florida.

While a great deal of attention has been paid in recent years to establishing the magnitude and characteristics of uncompensated care in hospitals, comparatively little research has been undertaken to study physician uncompensated care. This article reports the results of a prospective patient-specific study of uncompensated care in Florida. Of 4,042 cases examined, 26.2 percent had charges voluntarily reduced below the usual and customary charge at the time of service. However, only 13.5 percent of those reductions were attributed to charity. Overall, 10.4 percent of the total billed amount was left unresolved. When payment source was considered, it was found that self-pay patients accounted for 30.6 percent of the cases but accounted for 52.0 percent of the unresolved amounts. Further analysis indicated that the self-pay patients were 35.5 times more likely to leave an outstanding balance than individuals with some type of insurance coverage. Odds of unresolved balances were also calculated as a function of income, specialty type, practice size, and type of visit.

Evaluation of IgE-sensitization to fungi in HIV-positive patients with eczematous skin reactions.

BACKGROUND: Human immunodeficiency virus infection is associated with declining immune function and polyclonal B-cell activation leading to elevated IgE-levels. In selected patient categories, increased total IgE may be associated with allergic diseases. Furthermore, a significant number of patients with low CD4+ cell numbers have various skin manifestations, eg, eczema and dermatophytosis. Patients with chronic fungal infections and a tendency to produce increased levels of specific IgE may become allergic and IgE-mediated mechanism may contribute to inflammatory reactions in the skin. OBJECTIVE: This study investigates IgE-sensitization of patients infected with human immunodeficiency virus to a panel of fungal extracts of Candida albicans, Fusarium moniliforme, Penicillium notatum, Pityrosporum ovale, and Trichophyton rubrum. METHODS: Fifteen HIV-positive patients with eczematous skin manifestations and five non-atopic healthy controls were evaluated by basophil histamine release and skin prick test with fungal extracts. The extracts were separated by sodium dodecylsulfate-polyacrylamide gel electrophoresis under reducing conditions and analyzed by IgE-immunoblotting with sera from the patients and controls. RESULTS: Thirteen of 15 patients (87%) released histamine to one or more of the fungi. Skin prick test was positive to one or more fungi in 7 (47%) patients. Patient sera revealed binding to a wide range of IgE-binding components present in the fungal extracts. The IgE response was most often directed against a 46-kD main protein in the Candida albicans extract. There was no correlation between total serum IgE, CD4+ cell counts, and frequency of IgE-sensitization to fungi. CONCLUSION: The human IgE response in HIV-infected patients appears to be polyspecific and may be directed against various fungi of which Candida albicans may be an important allergen. It is possible that the sensitization is due to frequent infections with Candida albicans in this patient population. No unspecific fungal reactions were noted among control patients. These results suggest that allergen-specific IgE-mediated mechanism may contribute to the pathogenesis of the eczematous skin reaction in HIV-infected patients.

Measurement of histamine release from human lung tissue ex vivo by microdialysis technique.

OBJECTIVE AND DESIGN: Currently no method is available for measurement of mediator release from intact human lung. In this study, a microdialysis technique was used to measure histamine release from mast cells in human lung tissue ex vivo. MATERIAL: Microdialysis fibers of 216 microm were inserted into lung tissue and perfused with Krebs Ringer buffer at a rate of 3 microl/min. After a 15 min period of steady-state perfusion, anti-IgE and vehicle were injected into the lung tissue above individual fibers. Samples from each fibre were collected for 20 min at 2 min intervals. Histamine was assayed fluorometrically. RESULTS: Anti-IgE concentrations of 40-40,000 U/ml dose-dependently released histamine, significant histamine release being demonstrated with anti-IgE concentrations of 400 U/ml and greater. The kinetics of histamine release showed peak values 2-8 min after the injection. Great individual responses were observed but data could be reproduced within individual donors. Monocyte chemoattractant protein-1, a potent basophil secretagogue, did not induce histamine release in lung tissue which indicated mast cells to be the histamine source. Substance P did not release histamine in the lung tissue. CONCLUSIONS: The microdialysis technique allowed measurements of histamine release from mast cells in intact lung ex vivo. The method may prove useful since a number of experiments can be performed in a few hours in intact lung tissue without any dispersion or enzymatic treatment.

B-chain shortening of matrix-bound insulin with pepsin, II. Preparation and properties of camel des-pentapeptide (B26-30)- and des-PheB1-des-pentapeptide (B26-30)- insulin.

Digestion of matrix-bound camel insulin with pepsin was found to be restricted to the cleavage of the peptide bond between phenylalanine(B25) and tyrosine(B26). Purification of the camel des-pentapeptide(B26-30)-insulin obtained was achieved by gel filtration and ion exchange chromatography, yielding a molecularly uniform product. In the same way, camel des-PheB1-insulin prepared according to a method described for bovine insulin was hydrolyzed with pepsin and purified to give the des-PheB1-despentapeptide(B26-30)-insulin. The biological activity of these modified camel insulins was found to be as much reduced as the corresponding bovine insulin analogues. However, the reduced biological activity of camel des-PheB1-insulin (60%) was a contrast to the fully active bovine des-PheB1-insulin.

IgE-sensitization to cellular and culture filtrates of fungal extracts in patients with atopic dermatitis.

BACKGROUND: Patients with atopic dermatitis may experience exacerbations of eczema triggered by various inflammatory stimuli. One mechanism may be IgE-mediated reactions to dermatophytes since these patients are more likely to acquire skin infections with dermatophytes and may become sensitized. OBJECTIVE: This study investigates IgE-sensitization to fungi in patients with atopic dermatitis and compares the biologic activity of culture filtrates and cellular fungal extracts. The following allergen extracts were provided as culture filtrates and cellular extracts: Candida albicans, Fusarium moniliforme, and Penicillium notatum. In addition, Pityrosporum ovale and Trichophyton rubrum cultures were included in the test panel. METHODS: Fifteen patients with clinical findings suggesting dermatophytosis and 11 controls were selected. Each subject was tested by leukocyte histamine release and skin prick test to each fungal extract. The extracts were separated and reduced by sodium dodecylsulfate polyacrylamide gel electrophoresis and analyzed by IgE-immunoblotting with sera from all study subjects. RESULTS: Fourteen patients (93%) reacted to one or several fungal extracts by releasing histamine when challenged in vitro. By immunoblotting experiments, patient sera showed binding to a wide range of components in all extracts. Patient sera recognized allergenic components shared by culture filtrates and cellular extracts but with higher frequent and greater intensity in culture filtrates. Although culture filtrates generated more frequent and potent IgE-reactions than the cellular extracts, the difference was not statistically significant. Biologic potency was similar when evaluated by skin prick tests and leukocyte histamine release. CONCLUSION: Patients with atopic dermatitis may develop specific IgE-antibodies to a number of fungi as demonstrated by IgE-immunoblotting. In selected patients, fungi may trigger an IgE-mediated reaction that may contribute to the exacerbation of eczema. Approximately, one-half of the patients, however, produced IgE-antibodies to fungal (glyco)proteins without a significant histamine release or skin test response possibly because of nonspecific interaction with carbohydrate moieties on IgE and poor biologic activity of IgE antibodies directed to cross-reactive carbohydrate determinants of fungal glycoproteins. This warrants caution when interpreting clinical relevance of serologic measurements of fungal IgE-antibodies.

Assessment of IgE allergen specificity among latex-allergic health care workers: review of IgE-binding components of various latex extracts.

BACKGROUND: Allergic reactions to natural rubber latex have increased during the past 10 years, especially in many health care workers who have high exposure to latex allergens both by direct skin contact and by inhalation of latex particles from powdered gloves. Development of satisfactory diagnostic methods to verify the presence of latex allergy in health care workers requires characterization of the immunoreactive proteins in latex products and identification of specific IgE antibodies in sensitized patients. A number of different latex preparations are now available for in vitro evaluations. OBJECTIVES: Utilizing different in vitro methods, this study examines IgE sensitization to components of latex in a selected population of hospital employees, employing a raw natural latex glove extract and various commercial latex extracts. METHODS: Two hundred hospital employees exposed to latex were evaluated using an allergy history questionnaire. To further identify sensitized patients, two different specific IgE tests and leukocyte histamine release tests were performed using a panel of latex extracts obtained from different manufacturers. Sodium dodecylsulfate polyacrylamide electrophoresis (SDS-PAGE) profiles were obtained. Sera from 34 subjects suspected to be latex-sensitized were IgE immunoblotted to assess the presence of IgE antibodies directed toward specific latex proteins. RESULTS: Thirty-four participants (17%) were considered sensitized to latex by a positive clinical history in conjunction with positive specific IgE tests (18 individuals) and/or positive histamine release tests (26 individuals). Significant extract differences in both the histamine release response profile and the frequency of positive test results were noted in the histamine release test. Significant individual differences in patients' latex epitope-specificity were found by IgE immunoblotting, substantiated by sodium dodecylsulfate polyacrylamide profiles revealing differences in protein band patterns among the various extracts. The IgE immunoblots indicated that the majority of patients reacted to proteins with molecular weights of 14, 21, 30 to 35, and 42 kD; the 30 to 35 kD protein being predominant. Seven subjects (22%) of the 34 considered to be latex-sensitized did not reveal binding of specific IgE in immunoblots. One latex extract (Stallergene) with the widest IgE-reacting protein repertoire identified the majority of subjects (63%) as latex sensitive by leukocyte histamine release and also provided the best quantitative histamine release test results. CONCLUSION: Only by testing with a combination of latex extracts were all sensitized individuals identified. This study demonstrates that currently several in vitro methods may be necessary to detect IgE sensitization to latex. Latex extracts to be employed in future skin tests must contain a wide epitope repertoire of IgE-binding proteins to identify all latex-sensitized individuals.

IgE-binding components of staphylococcal enterotoxins in patients with atopic dermatitis.

BACKGROUND: The exacerbation of atopic dermatitis may be associated with infection of the skin with Staphylococcus aureus (S.aureus). S. aureus isolated from the skin of patients with atopic dermatitis secretes enterotoxin A, B, and toxic shock syndrome toxin 1. This is of interest because these patients may develop specific IgE antibodies against components from staphylococci. OBJECTIVE: The objective was to demonstrate IgE-sensitization to components of Staphylococcus aureus enterotoxins A and B (purified and partially purified), toxic shock syndrome toxin 1, and the bacterial cell component lipoteichoic acid, in patients with atopic dermatitis. METHODS: Blood samples from 34 patients with atopic dermatitis and 10 controls were tested by leukocyte histamine release to the enterotoxins and lipoteichoic acid. The toxins were separated by sodium dodecylsulfate polyacrylamide gel electrophoresis and analyzed by IgE-immunoblotting with sera from the same patients. RESULTS: The majority of patients (96%) with clinical signs of skin infection produced specific IgE-antibodies to all three toxins. Nearly half of the patients produced IgE to enterotoxin A and B. Only 63% of the patients with atopic dermatitis showed cellular response judged by the release of histamine from patient basophils when challenged in vitro with the toxins. This may indicate clinically unimportant sensitization in a number of patients. The immunoblotting revealed that the major allergens of the toxins were 24 and 28 kD proteins. Partially purified toxins showed a higher frequency of leukocyte histamine release responses than purified toxin. The only obvious difference was a difference in the content of pure toxin of the two preparations. Lipoteichoic acid showed nonspecific activity. CONCLUSION: These findings suggest that staphylococcal enterotoxins may act as specific allergens and induce IgE-antibodies to enterotoxins that may exacerbate the skin inflammation in some patients with atopic dermatitis.