The burden of human disease related to medically important fungal pathogens is substantial. An improved understanding of antifungal pharmacology and antifungal pharmacokinetics-pharmacodynamics has ...resulted in therapeutic drug monitoring (TDM) becoming a valuable adjunct to the routine administration of some antifungal agents. TDM may increase the probability of a successful outcome, prevent drug-related toxicity and potentially prevent the emergence of antifungal drug resistance. Much of the evidence that supports TDM is circumstantial. This document reviews the available literature and provides a series of recommendations for TDM of antifungal agents.
Prior to the SARS-CoV-2 pandemic, antibiotic resistance was listed as the major global health care priority. Some analyses, including the O'Neill report, have predicted that deaths due to ...drug-resistant bacterial infections may eclipse the total number of cancer deaths by 2050. Although fungal infections remain in the shadow of public awareness, total attributable annual deaths are similar to, or exceeds, global mortalities due to malaria, tuberculosis or HIV. The impact of fungal infections has been exacerbated by the steady rise of antifungal drug resistant strains and species which reflects the widespread use of antifungals for prophylaxis and therapy, and in the case of azole resistance in Aspergillus, has been linked to the widespread agricultural use of antifungals. This review, based on a workshop hosted by the Medical Research Council and the University of Exeter, illuminates the problem of antifungal resistance and suggests how this growing threat might be mitigated.
1 Pathology and Physiology Research Branch and 2 Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health (NIOSH), and 3 ...Physiology and Pharmacology, West Virginia University, Morgantown, West Virginia; 4 Lockheed Martin, Engineering Directorate, Materials and Processes Branch, and 5 Nanotube Team, GB Tech, National Aeronautics and Space Administration Johnson Space Center, Houston, Texas; 6 Monitoring Research and Statistical Activity, Division of Applied Research and Technology, NIOSH, Cincinnati, Ohio; 7 Woodrow Wilson International Center for Scholars, Washington, District of Columbia; and 8 Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania
Submitted 23 April 2008
; accepted in final form 18 July 2008
Nanomaterials are frontier technological products used in different manufactured goods. Because of their unique physicochemical, electrical, mechanical, and thermal properties, single-walled carbon nanotubes (SWCNT) are finding numerous applications in electronics, aerospace devices, computers, and chemical, polymer, and pharmaceutical industries. SWCNT are relatively recently discovered members of the carbon allotropes that are similar in structure to fullerenes and graphite. Previously, we (47) have reported that pharyngeal aspiration of purified SWCNT by C57BL/6 mice caused dose-dependent granulomatous pneumonia, oxidative stress, acute inflammatory/cytokine responses, fibrosis, and decrease in pulmonary function. To avoid potential artifactual effects due to instillation/agglomeration associated with SWCNT, we conducted inhalation exposures using stable and uniform SWCNT dispersions obtained by a newly developed aerosolization technique (2). The inhalation of nonpurified SWCNT (iron content of 17.7% by weight) at 5 mg/m 3 , 5 h/day for 4 days was compared with pharyngeal aspiration of varying doses (5–20 µg per mouse) of the same SWCNT. The chain of pathological events in both exposure routes was realized through synergized interactions of early inflammatory response and oxidative stress culminating in the development of multifocal granulomatous pneumonia and interstitial fibrosis. SWCNT inhalation was more effective than aspiration in causing inflammatory response, oxidative stress, collagen deposition, and fibrosis as well as mutations of K- ras gene locus in the lung of C57BL/6 mice.
nanoparticles; lung disease
Address for reprint requests and other correspondence: A. A. Shvedova, Health Effects Laboratory Div., NIOSH, Morgantown, WV 26505 (e-mail: ats1{at}cdc.gov )
Simvastatin is among the most commonly used prescription medications for cholesterol reduction. A single coding single‐nucleotide polymorphism, rs4149056T>C, in SLCO1B1 increases systemic exposure to ...simvastatin and the risk of muscle toxicity. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for simvastatin based on SLCO1B1 genotype. This article is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium guideline for SLCO1B1 and simvastatin‐induced myopathy.
Clinical Pharmacology & Therapeutics (2014); 96 4, 423–428. doi:10.1038/clpt.2014.125
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The survey description and the near-, mid-, and far-infrared flux properties are presented for the 258 galaxies in the Local Volume Legacy (LVL). LVL is a Spitzer Space Telescope legacy program that ...surveys the local universe out to 11 Mpc, built upon a foundation of ultraviolet, H Delta *a, and Hubble Space Telescope imaging from 11HUGS (11 Mpc H Delta *a and Ultraviolet Galaxy Survey) and ANGST (ACS Nearby Galaxy Survey Treasury). LVL covers an unbiased, representative, and statistically robust sample of nearby star-forming galaxies, exploiting the highest extragalactic spatial resolution achievable with Spitzer. As a result of its approximately volume-limited nature, LVL augments previous Spitzer observations of present-day galaxies with improved sampling of the low-luminosity galaxy population. The collection of LVL galaxies shows a large spread in mid-infrared colors, likely due to the conspicuous deficiency of 8 Delta *mm polycyclic aromatic hydrocarbon emission from low-metallicity, low-luminosity galaxies. Conversely, the far-infrared emission tightly tracks the total infrared emission, with a dispersion in their flux ratio of only 0.1 dex. In terms of the relation between the infrared-to-ultraviolet ratio and the ultraviolet spectral slope, the LVL sample shows redder colors and/or lower infrared-to-ultraviolet ratios than starburst galaxies, suggesting that reprocessing by dust is less important in the lower mass systems that dominate the LVL sample. Comparisons with theoretical models suggest that the amplitude of deviations from the relation found for starburst galaxies correlates with the age of the stellar populations that dominate the ultraviolet/optical luminosities.
The NOvA experiment has seen a 4.4σ signal of ν¯e appearance in a 2 GeV ν¯μ beam at a distance of 810 km. Using 12.33×1020 protons on target delivered to the Fermilab NuMI neutrino beamline, the ...experiment recorded 27 ν¯μ→ν¯e candidates with a background of 10.3 and 102 ν¯μ→ν¯μ candidates. This new antineutrino data are combined with neutrino data to measure the parameters |Δm322|=2.48−0.06+0.11×10−3 eV2/c4 and sin2θ23 in the ranges from (0.53–0.60) and (0.45–0.48) in the normal neutrino mass hierarchy. The data exclude most values near δCP=π/2 for the inverted mass hierarchy by more than 3σ and favor the normal neutrino mass hierarchy by 1.9σ and θ23 values in the upper octant by 1.6σ.
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Heavy-ion data suggest that a common mechanism is responsible for single-event burnout (SEB) in 1200-V power MOSFETs and junction barrier Schottky (JBS) diodes. Similarly, heavy-ion data suggest a ...common mechanism is also responsible for leakage current degradation in both devices. This mechanism, based on ion-induced, highly localized energy pulses, is demonstrated in simulations and shown to be capable of causing degradation and SEB for both the MOSFETs and JBS diodes.
The SERCA-LVAD trial was a phase 2a trial assessing the safety and feasibility of delivering an adeno-associated vector 1 carrying the cardiac isoform of the sarcoplasmic reticulum calcium ATPase ...(AAV1/SERCA2a) to adult chronic heart failure patients implanted with a left ventricular assist device. The SERCA-LVAD trial was one of a program of AAV1/SERCA2a cardiac gene therapy trials including CUPID1, CUPID 2 and AGENT trials. Enroled subjects were randomised to receive a single intracoronary infusion of 1 × 10
DNase-resistant AAV1/SERCA2a particles or a placebo solution in a double-blinded design, stratified by presence of neutralising antibodies to AAV. Elective endomyocardial biopsy was performed at 6 months unless the subject had undergone cardiac transplantation, with myocardial samples assessed for the presence of exogenous viral DNA from the treatment vector. Safety assessments including ELISPOT were serially performed. Although designed as a 24 subject trial, recruitment was stopped after five subjects had been randomised and received infusion due to the neutral result from the CUPID 2 trial. Here we describe the results from the 5 patients at 3 years follow up, which confirmed that viral DNA was delivered to the failing human heart in 2 patients receiving gene therapy with vector detectable at follow up endomyocardial biopsy or cardiac transplantation. Absolute levels of detectable transgene DNA were low, and no functional benefit was observed. There were no safety concerns in this small cohort. This trial identified some of the challenges of performing gene therapy trials in this LVAD patient cohort which may help guide future trial design.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
A deeper understanding of the role of autophagy, literally 'self-eating', in normal and cancer cell biology has emerged over the last few years. Autophagy serves as a vehicle for cells to respond to ...various stressors including genomic, hypoxic and nutrient stress, and to oppose mechanisms of 'programmed' cell death. Here, we review not only mechanisms of cell death and cell survival but also the early successes in applying autophagy inhibition strategies in solid tumors using the only currently available clinical inhibitor, oral hydroxychloroquine. In acute leukemia, currently available chemotherapy drugs promote cell death and demonstrate clinical benefit, but relapse and subsequent chemotherapy resistance is common. Increasing preclinical data suggest that autophagy is active in leukemia as a means of promoting cell survival in response to chemotherapy. We propose coupling autophagy inhibition strategies with current cytotoxic chemotherapy and discuss synergistic combinations of available anti-leukemic therapies with autophagy inhibition. Furthermore, novel autophagy inhibitors are in development and promise to provide new therapeutic opportunities for patients with leukemia.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Peripartum cardiomyopathy (PPCM) is a potentially life‐threatening condition typically presenting as heart failure with reduced ejection fraction (HFrEF) in the last month of pregnancy or in the ...months following delivery in women without another known cause of heart failure. This updated position statement summarizes the knowledge about pathophysiological mechanisms, risk factors, clinical presentation, diagnosis and management of PPCM. As shortness of breath, fatigue and leg oedema are common in the peripartum period, a high index of suspicion is required to not miss the diagnosis. Measurement of natriuretic peptides, electrocardiography and echocardiography are recommended to promptly diagnose or exclude heart failure/PPCM. Important differential diagnoses include pulmonary embolism, myocardial infarction, hypertensive heart disease during pregnancy, and pre‐existing heart disease. A genetic contribution is present in up to 20% of PPCM, in particular titin truncating variant. PPCM is associated with high morbidity and mortality, but also with a high probability of partial and often full recovery. Use of guideline‐directed pharmacological therapy for HFrEF is recommended in all patients respecting contraindications during pregnancy/lactation. The oxidative stress‐mediated cleavage of the hormone prolactin into a cardiotoxic fragment has been identified as a driver of PPCM pathophysiology. Pharmacological blockade of prolactin release using bromocriptine as a disease‐specific therapy in addition to standard therapy for heart failure treatment has shown promising results in two clinical trials. Thresholds for devices (implantable cardioverter‐defibrillators, cardiac resynchronization therapy and implanted long‐term ventricular assist devices) are higher in PPCM than in other conditions because of the high rate of recovery. The important role of education and counselling around contraception and future pregnancies is emphasised.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
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