Abstract
Purpose
Direct-acting antivirals (DAAs) used to treat hepatitis C virus (HCV) infection are associated with significant drug-drug interactions (DDIs). Pharmacists are well positioned to ...identify and mitigate these DDIs. Data to guide assessment of the impact of HCV specialty pharmacy services on identifying and addressing DDIs with DAAs are lacking. The overall purpose of the study described here was to determine the incidence and severity of DDIs identified by specialty pharmacists among patients treated with DAAs prior to and 1 month into therapy.
Methods
An observational, retrospective study was conducted to evaluate the impact of specialty pharmacy services in mitigating DDIs associated with use of DAAs. Adult patients with HCV infection (n = 200) who received DAAs and were enrolled with a specialty pharmacy service over a 1-year period were included. Endpoints included number, severity, and type of DDIs and DDIs per patient at baseline and 1 month into therapy, pharmacists’ interventions, and safety and clinical outcomes.
Results
Fifty-nine percent of patients had at least 1 DDI. A total of 170 DDIs were identified (137 at baseline and 33 at 1-month follow-up), and the mean number of DDIs per patient significantly decreased from baseline to 1-month follow-up (from 1.38 to 0.16, P < 0.0001). The rate of “potentially clinically significant” or “critical” interactions was significantly lower at 1-month follow-up vs baseline assessment (69.6% vs 81.7%, P < 0.0001). The most commonly identified DDIs involved acid suppressive medications (49.6% and 66.6% of DDIs at baseline and follow-up assessment, respectively) and cardiovascular medications (26.2% and 21.2%, respectively). Total number of DDI interventions was 131, with an acceptance rate of 85%. Most common intervention was patient education and monitoring.
Conclusion
Approximately 60% of patients had DDIs with DAAs. Implementing HCV specialty pharmacy services significantly decreased DDIs while maintaining SVR12.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
The philosophy of chemistry has emerged in recent years as a new and autonomous field within the Anglo-American philosophical tradition. With the development of this new discipline, Eric Scerri and ...Grant Fisher's "Essays in Philosophy of Chemistry" is a timely and definitive guide to all current thought in this field. One of the themes of this collection is how philosophy of chemistry can make a contributions to problems of philosophy more generally, such as how chemistry and quantum chemistry contribute to the philosophy of the mind.
This paper aims to contribute to the study of practical pursuit-worthiness in science by engaging with a case in therapeutic stem cell biology. Induced pluripotent stem cell (iPSC) research emerged ...from research in developmental biology and the molecular biology of cell fate conversion. It took on practical significance when proposed as an alternative to therapeutic stem cell research that used human embryonic stem cells. The supposed ability of iPSC research to tackle ethical and regulatory constraints on research at the beginning of the twentieth century was a central part of the heuristic assessment of iPSC. However, the development and transfer of knowledge from experimental and theoretical biology to preclinical pursuit conflicted with the framing of biomedical innovation in public policy. The framing of innovation operated as part of the heuristic assessment of the pursuit-worthiness of iPSCs in the United States and was characterized by attempts to underdetermine conflicting ethical and socio-economic values – to seek innovations that are “incompletely theorized” in the sense that they purportedly allow stakeholders to refrain from engagement with the divisive values that created impediments to research in stem cell biology. When conflict arose with the epistemic standards in preclinical pursuit required to ensure the safety and efficacy of biomedical innovations, it resulted in the critical appraisal of the values used to rationalize policies for the distribution of federal resources for biomedical research. The case demonstrates how non-epistemic values impinge on standards of assessment in translational science, how background assumptions about innovation can drive practical pursuit, and how conflicting values and goals in research creates an important context for the appraisal of emerging science, technology and policy.
This case report documents a patient with a Class II skeletal malocclusion and suspected obstructive sleep apnea who underwent a combined mandibular inverted L osteotomy and total subapical ...osteotomy. The surgery involved a single-piece Lefort 1 osteotomy of the maxilla, bilateral inverted L osteotomies of the mandible, and a total mandibular subapical osteotomy. After the patient's pre-surgical orthodontic phase was completed, a traditional bilateral sagittal split osteotomy (BSSO) was initially planned to achieve mandibular advancement. However, the large horizontal and yaw correction required for the patient's mandibular teeth made a BSSO alone unrealistic. The virtual surgical plan (VSP) indicated that a subapical osteotomy was necessary, and due to the extension of the total subapical segment, an inverted L osteotomy was added to benefit the subapical osteotomy. The patient's surgery was successful, and the results were satisfactory.
The aim of this paper is to engage with the interplay between representational content and design in chemistry and to explore some of its epistemological consequences. Constraints on representational ...content arising from the aspectual structure of representation can be manipulated by design. Designs are epistemologically important because representational content, hence our knowledge of target systems in chemistry, can change with design. The significance of this claim is that while it has been recognised that the way one conveys information makes a difference to the inferences one can draw from representations in spite of the invariance of informational content, the present paper argues that in chemistry and biochemistry it is often the case that designs have cognitive priority relative to informational content.
Focusing on computational studies of pericyclic reactions from the late twentieth century into the twenty-first century, this paper argues that computational diagnostics is a key methodological ...development that characterize the management and coordination of plural approximation methods in computational organic chemistry. Predictive divergence between semi-empirical and ab initio approximation methods in the study of pericyclic reactions has issued in epistemic dissent. This has resulted in the use of diagnostics to unpack computational greyboxes in order to critically assess the effect of specific misrepresentations on predictive accuracy given that approximations and idealizations must be made to render computational models tractable. Furthermore, benchmarking is used to determine the applicability of approximation methods depending on how accurate the results need to be in a given research context. The epistemology of benchmarking consists of the co-generation of data sets in a hybrid computational–experimental form used to standardize computational methods but does not determine a unique quantitative method to be used across computational organic chemistry.
Background Cardiac retransplantation remains the most viable option for patients with allograft heart failure; however, careful patient selection is paramount considering limited allograft resources. ...We analyzed clinical outcomes following retransplantation in an academic, tertiary care institution. Methods Between 1981 and 2011, 593 heart transplantations, including 22 retransplantations were performed at our institution. We analyzed the preoperative demographic characteristics, cause of allograft loss, short- and long-term surgical outcomes and cause of death among patients who had cardiac retransplantations. Results Twenty-two patients underwent retransplantation: 10 for graft vascular disease, 7 for acute rejection and 5 for primary graft failure. Mean age at retransplantation was 43 (standard deviation SD 15) years; 6 patients were women. Thirteen patients were critically ill preoperatively, requiring inotropes and/or mechanical support. The median interval between primary and retransplantation was 2.2 (range 0–16) years. Thirty-day mortality was 31.8%, and conditional (> 30 d) 1-, 5- and 10-year survival after retransplantation were 93%, 79% and 59%, respectively. A diagnosis of allograft vasculopathy ( p = 0.008) and an interval between primary and retransplantation greater than 1 year ( p = 0.016) had a significantly favourable impact on 30-day mortality. The median and mean survival after retransplantation were 3.3 and 5 (SD 6, range 0–18) years, respectively; graft vascular disease and multiorgan failure were the most common causes of death. Conclusion Long-term outcomes for primary and retransplantation are similar if patients survive the 30-day postoperative period. Retransplantation within 1 year of the primary transplantation resulted in a high perioperative mortality and thus may be a contraindication to retransplantation.
Whenever a volcano threatens to erupt, scientists and adventurers from around the world flock to the site in response to the irresistible allure of one of nature's most dangerous and unpredictable ...phenomena. In a unique book probing the science and mystery of these fiery features, the authors chronicle not only their geologic behavior but also their profound effect on human life. From Mount Vesuvius to Mount St. Helens, the book covers the surprisingly large variety of volcanoes, the subtle to conspicuous signs preceding their eruptions, and their far-reaching atmospheric consequences. Here scientific facts take on a very human dimension, as the authors draw upon actual encounters with volcanoes, often through firsthand accounts of those who have witnessed eruptions and miraculously survived the aftermath. The book begins with a description of the lethal May 1980 eruption of Mount St. Helens--complete with an explanation of how safety officials and scientists tried to predict events, and how unsuspecting campers and loggers miles away struggled against terrifying blasts of ash, stone, and heat. The story moves quickly to the ways volcanoes have enhanced our lives, creating mineral-rich land, clean thermal energy, and haunting landscapes that in turn benefit agriculture, recreation, mining, and commerce. Religion and psychology embroider the account, as the authors explore the impact of volcanoes on the human psyche through tales of the capricious volcano gods and attempts to appease them, ranging from simple homage to horrific ritual sacrifice. Volcanoes concludes by assisting readers in experiencing these geological phenomena for themselves. An unprecedented "tourist guide to volcanoes" outlines over forty sites throughout the world. Not only will travelers find information on where to go and how to get there, they will also learn what precautions to take at each volcano. Tourists, amateur naturalists, and armchair travelers alike will find their scientific curiosity whetted by this informative and entertaining book.
Abstract
Diffusely infiltrating gliomas feature loss-of-function mutations in the chromatin remodeler gene ATRX as defining molecular alterations delineating major adult and pediatric disease ...subtypes. We recently reported that Atrx deficiency drives glioma-relevant phenotypes, such as increased motility and astrocytic differentiation profiles, by directly modulating epigenomic landscapes and the corresponding transcriptional profiles in glioma cells of origin. In particular, Atrx deficiency was associated with disruptions in H3.3 histone content at key genetic loci. To further understand the downstream epigenomic dysfunction induced by ATRX deficiency, we compared genome-wide chromatin-state maps of Atrx+ and Atrx- primary murine neuroepithelial progenitors (mNPCs). This ChIP–seq analysis revealed major differences in the localization of heterochromatin repressive marks H3K9me3 and H3K27me3. Specifically, we identified peculiar locations in the genome displaying H3K9me3 depletion and gain of H3K27me3 upon Atrx inactivation. Interestingly, these regions were flanked by Atrx binding sites and perfectly co-localized with Lamina-Associated Domains, known to play important roles in tissue lineage specification. To better target this dysfunction, we utilized the Broad Institute Connectivity Map (CLUE analysis) to identify compounds likely to revert the unique transcriptional perturbations induced by Atrx deficiency. We found that HDAC inhibitors, as a compound class, yielded expression profiles strongly anticorrelated to those driven by Atrx deficiency in these datasets. Further integrating existing gene expression data from our mNPCs and the TCGA LGG project with our CLUE findings highlighted SIRT2, a class III HDAC, as a top potential target. SIRT2 expression was significantly upregulated in both Atrx- mNPCs and in ATRX-mutant gliomas and its specific chemical inhibition normalized cellular motility in both Atrx- mNPCs and ATRX-mutant, patient derived glioma stem cells. These findings indicate that SIRT2 inhibition represents a viable strategy to revert the epigenetic effects of ATRX deficiency on facultative heterochromatin and their transcriptional and phenotypic consequences.
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