Clinical Outcomes of a Pharmacy-Led Blood Factor Stewardship Program

To report the results of a pharmacist-directed blood factor stewardship program targeting off-label utilization designed to limit use to established organizational guidelines in high-risk populations. Prospective evaluation of recombinant factor VIIa and prothrombin complex concentrate orders beginning June 2013 through May 2014 and a matched retrospective cohort from June 2012 to May 2013. Matched cohorts were evaluated for 28-day mortality, change in international normalized ratio (INR), adverse events, concurrent blood product use, and cost savings. Forty-two orders for blood factor were ordered between June 2013 and May 2014, 70 orders in the year before (N = 112). Twenty eight-day mortality was not different between the cohorts: 53.9% versus 50% (P = 0.77). Blood factor use with underlying liver failure and active bleeding was strongly associated with 28-day mortality: odds ratio (95% confidence interval), 2.9 (1.5-7.14) and 2.91 (0.01-2.91), respectively. Blood products dispensed increased over the year with plasma products the most significant (1 vs. 4 P = 0.004). All other clinical outcomes were nonsignificant. An annual cost savings of $375,539 was achieved, primarily through a significant reduction in recombinant factor VIIa and avoidance in high-risk patients. Use of off-label blood factors can be controlled through a pharmacist-led stewardship program. Twenty eight-day mortality was not different between the 2 cohorts; however, identification of risk factors for death associated with blood factor use allows for restriction in high-risk populations, creates a discussion of futile care, and yields cost savings

Efficacy of Different Leuprolide Administration Schedules in Premenopausal Breast Cancer: A Retrospective Review

Background Leuprolide is a safe and effective treatment of estrogen receptor–positive premenopausal breast cancer. Data from the SOFT/TEXT trials solidified leuprolide in combination with an aromatase inhibitor as an effective hormonal treatment for premenopausal breast cancer. However, the efficacy of monthly leuprolide depot compared to leuprolide depot every 3 months in combination with an aromatase inhibitor in this patient population is unclear. Patients and Methods In this single center retrospective study, 201 patients were enrolled between January 1, 2015, and October 1, 2016; 100 were included in the 7.5 mg leuprolide monthly injection plus aromatase inhibitor group and 101 in the 22.5 mg leuprolide injection every 3 months plus aromatase inhibitor group. The primary end point was the proportion of patients who experienced ovarian ablation, defined as an estradiol concentration less than 40 pg/mL and a follicle-stimulating hormone concentration of 23 to 116 mU/mL after 3 months of treatment. Significance threshold was P < .05 (2 sided). Secondary end points included disease-free survival and overall survival at 1-year follow-up, as well as adverse events reported during treatment. Results All patients in the monthly leuprolide arm experienced ovarian ablation compared to 100 (99%) of 101 patients in the arm treated every 3 months ( P = 1). The disease-free survival rate at 1 year was 95% in the monthly leuprolide arm and 97% in the arm treated every 3 months ( P = .75). The overall survival rate at 1 year was 100% in the monthly leuprolide arm and 99% in the arm treated every 3 months ( P = 1). The most common treatment-related adverse events between the 2 groups were musculoskeletal pain, hot flashes, fatigue, and insomnia. Conclusion Leuprolide acetate depot administered every 3 months is as efficacious and tolerable as a monthly injection in combination with an aromatase inhibitor for premenopausal patients with hormone receptor–positive breast cancer

Precision Genomic Practice in Oncology: Pharmacist Role and Experience in an Ambulatory Care Clinic

Recent advancements in molecular testing, the availability of cost-effective technology, and novel approaches to clinical trial design have facilitated the implementation of tumor genome sequencing into standard of care oncology practices. Current models of precision oncology practice include specialized clinics or consultation services based on a molecular tumor board (MTB) approach. MTBs are comprised of interprofessional teams of clinicians and scientists who evaluate tumors at the molecular level to guide patient-specific targeted therapy. The practice of precision oncology utilizing MTB-based models is an emerging approach, transforming precision genomics from a novel concept into clinical practice. This rapid shift in practice from cytotoxic therapy to targeted medicine poses challenges, yet brings exciting opportunities to clinical pharmacists practicing in hematology and oncology. Only a few precision genomics programs in the United States have a strong pharmacy presence with oncology pharmacists serving in leadership roles in research, interpreting genomic sequencing, making treatment recommendations, and facilitating off-label drug procurement. This article describes the experience of the precision medicine clinic at the Indiana University Health Simon Cancer Center, with emphasis on the role of the pharmacist in the precision oncology initiative

Exceptional Response with Immunotherapy in a Patient with Anaplastic Thyroid Cancer

Chemotherapy with or without radiation is the standard therapy for anaplastic thyroid cancer (ATC), although the response rate is not high and not durable. We describe a 62-year-old male who was diagnosed with ATC and initially treated with a thyroidectomy and lymph node dissection, followed by chemotherapy. Next generation sequencing was then performed to guide therapy and the tumor was found to have BRAF and programmed death-ligand 1 (PD-L1) positivity that was subsequently treated with vemurafenib and nivolumab. This led to substantial regression of tumor nodules. Genomic sequencing-based approaches to identify therapeutic targets has potential for improving outcomes. Currently, the patient continues to be in complete radiographic and clinical remission 20 months after beginning treatment with nivolumab. KEY POINTS: Programmed death-1 (PD-1)/PD-L1 immunotherapy has shown evidence of durable responses in certain malignancies such as melanoma, lung cancer, and renal cell carcinoma.PD-L1 positive tumors promote autoimmunity against the tumor; therefore, PD-1/PD-L1 blockade may be beneficial.Molecular profiling could possibly result in improved targeted therapy for certain malignancies

Structure and functional composition of macroinvertebrate communities in coastal plain streams across a precipitation gradient

Climate change is expected to alter rainfall and temperature regimes across the world. The hydrology and riparian zone vegetation of lotic ecosystems are tightly linked to rainfall and a mechanistic understanding of the effects of rainfall on lotic ecosystems is needed to forecast the ecological impacts of climate change. However, it is difficult to isolate rainfall effects from other environmental variables that covary across climates. To address this, we leveraged a unique steep rainfall gradient with few covarying changes in elevation, temperature, and geology to evaluate the effects of rainfall on stream invertebrate communities. We surveyed nine streams in the Texas Gulf Coast Prairie distributed along a 550–1,350 mm/year rainfall gradient. Four sites were classified as drier semi-arid streams (\u3c750 mm annual rainfall) and five sites were classified as wetter sub-humid streams (\u3e750 mm annual rainfall). A suite of characteristics including benthic invertebrate community metrics, flow conditions, and water quality variables were assessed monthly for 14 months at each site to relate precipitation regime to stream structure and function. Precipitation regime was observed to be a master explanatory variable. As annual rainfall increased, the flow environment became more stable within seasons and predictable across seasons, influencing spatial structure and temporal variability of invertebrate community composition. Wetter streams were dominated by slower growing taxa without adaptions for desiccation resistance and strong dispersal. Wetter sites displayed seasonal variation in community composition and species richness, whereas temporal variation in communities in drier streams was controlled by stochastic variation in flow conditions. These observations show that differences in local annual rainfall correlated with major changes to community structure and functional composition. We hypothesise that this association is related to the connection of rainfall to hydrological stability, particularly the frequency of low flow disturbances, and the subsequent effects on riparian vegetation and temporally available niches to stream invertebrates. Our work adds to evidence that alterations in precipitation patterns associated with climate change have sweeping impacts on lotic fauna

Implications of Incidental Germline Findings Identified In the Context of Clinical Whole Exome Sequencing for Guiding Cancer Therapy

PURPOSE Identification of incidental germline mutations in the context of next-generation sequencing is an unintended consequence of advancing technologies. These data are critical for family members to understand disease risks and take action. PATIENTS AND METHODS A retrospective cohort analysis was conducted of 1,028 adult patients with metastatic cancer who were sequenced with tumor and germline whole exome sequencing (WES). Germline variant call files were mined for pathogenic/likely pathogenic (P/LP) variants using the ClinVar database and narrowed to high-quality submitters. RESULTS Median age was 59 years, with 16% of patients ≤ 45 years old. The most common tumor types were breast cancer (12.5%), colorectal cancer (11.5%), sarcoma (9.3%), prostate cancer (8.4%), and lung cancer (6.6%). We identified 3,427 P/LP variants in 471 genes, and 84% of patients harbored one or more variant. One hundred thirty-two patients (12.8%) carried a P/LP variant in a cancer predisposition gene, with BRCA2 being the most common (1.6%). Patients with breast cancer were most likely to carry a P/LP variant (19.2%). One hundred ten patients (10.7%) carried a P/LP variant in a gene that would be recommended by the American College of Medical Genetics and Genomics to be reported as a result of clinical actionability, with the most common being ATP7B (2.7%), BRCA2 (1.6%), MUTYH (1.4%), and BRCA1 (1%). Of patients who carried a P/LP variant in a cancer predisposition gene, only 53% would have been offered correct testing based on current clinical practice guidelines. Of 471 mutated genes, 231 genes had a P/LP variant identified in one patient, demonstrating significant genetic heterogeneity. CONCLUSION The majority of patients undergoing clinical cancer WES harbor a pathogenic germline variation. Identification of clinically actionable germline findings will create additional burden on oncology clinics as broader WES becomes common

Lingering misinterpretations of garden path sentences arise from competing syntactic representations

Recent work has suggested that readers 19 initial and incorrect interpretation of temporarily ambiguous ("garden path") sentences (e.g., Christianson, Hollingworth, Halliwell, & Ferreira, 2001) sometimes lingers even after attempts at reanalysis. These lingering effects have been attributed to incomplete reanalysis. In two eye tracking experiments, we distinguish between two types of incompleteness: the language comprehension system might not build a faithful syntactic structure, or it might not fully erase the structure built during an initial misparse. The first experiment used reflexive binding and the Gender Mismatch paradigm to show that a complete and faithful structure is built following processing of the garden-path. The second experiment used two-sentence texts to examine the extent to which the garden-path meaning from the first sentence interferes with reading of the second. Together, the results indicate that misinterpretation effects are attributable not to failure in building a proper structure, but rather to failure in cleaning up all remnants of earlier attempts to build that syntactic representation

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Accreting Black Holes

This chapter provides a general overview of the theory and observations of black holes in the Universe and on their interpretation. We briefly review the black hole classes, accretion disk models, spectral state classification, the AGN classification, and the leading techniques for measuring black hole spins. We also introduce quasi-periodic oscillations, the shadow of black holes, and the observations and the theoretical models of jets.Comment: 41 pages, 18 figures. To appear in "Tutorial Guide to X-ray and Gamma-ray Astronomy: Data Reduction and Analysis" (Ed. C. Bambi, Springer Singapore, 2020). v3: fixed some typos and updated some parts. arXiv admin note: substantial text overlap with arXiv:1711.1025