Time and motion study of pharmacist prescribing of oral hormonal contraceptives in Oregon community pharmacies.

OBJECTIVES: The aim of this time and motion study was to evaluate the procedural time and steps of performing an oral hormonal contraceptive pharmacist prescribing service in an Oregon community pharmacy. METHODS: A standardized patient seeking oral hormonal contraception visited 13 community pharmacies throughout February 2018 in the tri-county Portland, Oregon, metropolitan area for pharmacist-prescribed hormonal contraception services for a total of 26 patient encounters. An observer was present at each encounter to record the time for each step and the total encounter time. Each pharmacist was asked to perform assessment procedures and prescribing for each of 2 standardized patient presentations: in cohort 1 (n = 13), the pharmacist's assessment resulted in a hormonal contraception prescription written; in cohort 2 (n = 13), pharmacist's assessment detected contraindications and resulted in a medical referral to another health care prescriber. RESULTS: The average total patient time from arrival at the pharmacy to the generation of either a written prescription for hormonal contraception or referral to another health care provider was 17.9 and 14.1 minutes, respectively. Without accounting for documentation or dispensing the prescription, the average total pharmacist time to perform the service and issue a prescription, or refer the patient, was 7.8 and 5.4 minutes, respectively. CONCLUSION: The results indicate that the pharmacist prescribing service for oral hormonal contraception requires a modest amount of pharmacist time. Incorporation of practice into regular workflow appears to have an impact similar to other clinical services, such as immunizations and point-of-care testing. The patient time spent with the pharmacist was similar to other health care provider visits.

Health Analytics as a Service with Artemis Cloud: Service Availability.

Critical care units internationally contain medical devices that generate Big Data in the form of high speed physiological data streams. Great opportunities exist for systemic and reliable approaches for the analysis of high speed physiological data for clinical decision support. This paper presents the instantiation of a Big Data analytics based Health Analytics as-a-Service model. The availability results of the deployment of two instances of Artemis Cloud to support two neonatal ICUs (NICUs) in Ontario Canada are presented.

Adaptive API for Real-Time Streaming Analytics as a Service.

A significant amount of physiological data is generated from bedside monitors and sensors in neonatal intensive units (NICU) every second, however facilitating the ingestion of such data into multiple analytical processes in a real time streaming architecture remains a central challenge for systems that seek effective scaling of real-time data streams. In this paper we demonstrate an adaptive streaming application program interface (API) that provides real time streams of data for consumption by multiple analytics services enabling real-time exploration and knowledge discovery from live data streams. We have designed, developed and evaluated an adaptive API with multiple ingestion of data streamed out of bedside monitors that is passed to a middleware for standardization and structuring and finally distributed as a service for multiple analytical services to consume and perform further processing. This approach allows, (a) multiple applications to process the same data streams using multiple algorithms, (b) easy scalability to manage diverse data streams, (c) processing of analytics for each patient monitored at the NICU, (d) ability to integrate analytics that seek to evaluate multiple patients at the same point in time, and (e) a robust automated process with no manual interruptions that effectively adapts to changing data volumes when bedside monitors increases or the amount of data emitted by a monitor changes. The proposed architecture has been instantiated within the Artemis Platform which provides a framework for real-time high speed physiological data collection from multiple and diverse bed side monitors and sensors in NICUs from multiple hospitals. Results indicate this is a robust approach that can scale effectively as data volumes increase or data sources change.

Hypercapnic acidosis modulates inflammation, lung mechanics, and edema in the isolated perfused lung.

OBJECTIVE: Low tidal volume (V(T)) ventilation strategies may be associated with permissive hypercapnia, which has been shown by ex vivo and in vivo studies to have protective effects. We hypothesized that hypercapnic acidosis may be synergistic with low V(T) ventilation; therefore, we studied the effects of hypercapnia and V(T) on unstimulated and lipopolysaccharide-stimulated isolated perfused lungs. MATERIALS AND METHODS: Isolated perfused rat lungs were ventilated for 2 hours with low (7 mL/kg) or moderately high (20 mL/kg) V(T) and 5% or 20% CO(2), with lipopolysaccharide or saline added to the perfusate. RESULTS: Hypercapnia resulted in reduced pulmonary edema, lung stiffness, tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) in the lavage and perfusate. The moderately high V(T) did not cause lung injury but increased lavage IL-6 and perfusate IL-6 as well as TNF-alpha. Pulmonary edema and respiratory mechanics improved, possibly as a result of a stretch-induced increase in surfactant turnover. Lipopolysaccharide did not induce significant lung injury. CONCLUSIONS: We conclude that hypercapnia exerts a protective effect by modulating inflammation, lung mechanics, and edema. The moderately high V(T) used in this study stimulated inflammation but paradoxically improved edema and lung mechanics with an associated increase in surfactant release.

Advancing the 3Rs in regulatory ecotoxicology: A pragmatic cross-sector approach.

The ecotoxicity testing of chemicals for prospective environmental safety assessment is an area in which a high number of vertebrates are used across a variety of industry sectors. Refining, reducing, and replacing the use of animals such as fish, birds, and amphibians for this purpose addresses the ethical concerns and the increasing legislative requirements to consider alternative test methods. Members of the UK-based National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) Ecotoxicology Working Group, consisting of representatives from academia, government organizations, and industry, have worked together over the past 6 y to provide evidence bases to support and advance the application of the 3Rs in regulatory ecotoxicity testing. The group recently held a workshop to identify the areas of testing, demands, and drivers that will have an impact on the future of animal use in regulatory ecotoxicology. As a result of these discussions, we have developed a pragmatic approach to prioritize and realistically address key opportunity areas, to enable progress toward the vision of a reduced reliance on the use of animals in this area of testing. This paper summarizes the findings of this exercise and proposes a pragmatic strategy toward our key long-term goals-the incorporation of reliable alternatives to whole-organism testing into regulations and guidance, and a culture shift toward reduced reliance on vertebrate toxicity testing in routine environmental safety assessment. Integr Environ Assess Manag 2016;12:417-421. © 2015 SETAC.

Plasma surfactant protein-B: a novel biomarker in chronic heart failure.

BACKGROUND: In chronic heart failure (CHF), elevated pulmonary microvascular pressure (P(mv)) results in pulmonary edema. Because elevated P(mv) may alter the integrity of the alveolocapillary barrier, allowing leakage of surfactant protein-B (SP-B) from the alveoli into the circulation, we aimed to determine plasma levels of SP-B in CHF and their relation to clinical status. METHODS AND RESULTS: Fifty-three outpatients with CHF had plasma SP-B and N-terminal proBNP (NT-proBNP) assayed, in addition to a formalized clinical assessment at each clinic review over a period of 18 months. The control group comprised 19 normal volunteers. Plasma SP-B was elevated in CHF (P<0.001), and levels increased with New York Heart Association classification (P<0.001). SP-B correlated with objective clinical status parameters and NT-proBNP. During follow-up, major cardiovascular events occurred in patients with higher plasma SP-B (P<0.01) and NT-proBNP (P<0.05). Furthermore, on conditional logistic regression analysis, only SP-B was independently associated with CHF hospitalization (P=0.005). The 53 patients underwent a total of 210 outpatient visits. When the diuretic dosage was increased on clinical grounds, SP-B had increased 39% (P<0.001) and NT-proBNP had increased 32% (P<0.001). Conversely, at the next visit, SP-B fell 12% (P<0.001), whereas NT-proBNP fell 39% (P<0.001). CONCLUSIONS: Plasma SP-B is increased in CHF, and levels are related to clinical severity. Furthermore, within individual patients, SP-B levels vary with dynamic clinical status and NT-proBNP levels. Because plasma SP-B is independently associated with CHF hospitalization, it may, by virtue of its differing release mechanism to NT-proBNP, be a clinically useful biomarker of the pulmonary consequences of raised P(mv).

Assessing pharmacologic and nonpharmacologic risks in candidates for kidney transplantation.

PURPOSE: Pharmacotherapy concerns and other factors with a bearing on patient selection for kidney transplantation are discussed. SUMMARY: The process of selecting appropriate candidates for kidney transplantation involves multidisciplinary assessment to evaluate a patient's mental, social, physical, financial, and medical readiness for successful surgery and good posttransplantation outcomes. Transplantation pharmacists can play important roles in the recognition and stratification of pharmacologic and nonpharmacologic risks in prospective kidney transplant recipients and the identification of issues that require a mitigation strategy. Key pharmacotherapy-related issues and considerations during the risk assessment process include (1) anticoagulation concerns, (2) cytochrome P-450 isoenzyme-mediated drug interactions, (3) mental health-related medication use, (4) chronic pain-related medication use, (5) medication allergies, (6) use of hormonal contraception and replacement therapy, (7) prior or current use of immunosuppressants, (8) issues with drug absorption, (9) alcohol use, (10) tobacco use, (11) active use of illicit substances, and (12) use of herbal supplements. Important areas of nonpharmacologic risk include vaccine delivery, infection prophylaxis and treatment, and socially related factors such as nonadherent behavior, communication barriers, and financial, insurance, or transportation challenges that can compromise posttransplantation outcomes. CONCLUSION: Consensus opinions of practitioners in transplantation pharmacy regarding the pharmacologic and nonpharmacologic factors that should be considered in assessing candidates for kidney transplantation are presented.

A phase I study of the GM-CSF antagonist E21R.

PURPOSE: E21R is a competitive inhibitor of GM-CSF. This is the initial clinical study to investigate the safety, toxicity and pharmacokinetics of escalating doses of E21R. PATIENTS AND METHODS: Cohorts of three patients received doses of 10, 30, 100, 300, 600 and 1000 micro g/kg per day given subcutaneously daily for 10 days. Eligible patients had solid tumours known to express GM-CSF receptors (breast, prostate, colon and lung cancer, and melanoma). No bone marrow involvement or concomitant steroids were permitted. A total of 22 patients received doses ranging from 10 to 1000 micro g/kg per day. There were 18 males and 4 females with a median age of 60 years (range 33 to 81 years). Eight patients had an ECOG performance status of 0, seven a performance status of 1, and seven a performance status of 2. There were ten patients with colon cancer, four with prostate cancer, three with lung cancer, three with melanoma and two with breast cancer. RESULTS: E21R was in general well tolerated and the maximum tolerated dose was not reached. The most severe toxicities were WHO grade 3 injection site erythema in one patient and grade 2 in two patients, grade 2 lethargy in three patients and grade 2 muscle aches and soreness, grade 2 joint pains and grade 2 thirst in one patient each. The primary pharmacokinetic parameters were dose-independent. Dose-dependent transient eosinophilia was noted from day 3. A fall in PSA levels was recorded in two patients with prostate cancer during their initial cycles of E21R, but they subsequently rose again. Serum from patients treated at 600 and 1000 micro g/kg per day antagonized GM-CSF-mediated TF-1 cell proliferation in vitro. CONCLUSION: E21R can be safely given at doses up to 1000 micro g/kg per day.

Lucinactant (Discovery Laboratories).

Discovery Laboratories Inc (formerly Acute Therapeutics Inc (ATI) is developing lucinactant, originally identified at the Scripps Research Institute and sublicensed from Johnson & Johnson, for the potential treatment of respiratory diseases [174059], [357077], [361765], [422819]. The company anticipated filing an NDA for lucinactant in 2002, and by March 2002, lucinactant was in two pivotal phase III international trials for respiratory distress syndrome (RDS) in premature infants, a phase III trial for meconium aspiration syndrome (MAS) in full-term infants, and a phase II trial for acute lung injury/acute respiratory distress syndrome (ALI/ARDS) in adults. The company expected to complete trials by late 2003 [400846], [445166]. In February 2002, lucinactant was awarded Orphan Drug product designation in Europe for the treatment of ALI, which incorporates ARDS [440083]. By April 2001, Orphan Drug status in the US had been granted for lucinactant for MAS [301112], RDS and ARDS [404160]. The FDA also designated the drug a Fast Track product for the treatment of MAS [302120] and ARDS [301562], [302176], [404160].

Pharmacogenomic considerations in the treatment of the pediatric cardiomyopathy called Barth syndrome.

Barth syndrome (BTHS) is a genetic, X-linked, rare but often fatal, pediatric skeletal- and cardiomyopathy occurring due to mutations in the tafazzin gene (TAZ). TAZ encodes a transacylase involved in phospholipid biosynthesis, also called tafazzin, which is responsible for remodeling the inner mitochondrial membrane phospholipid, cardiolipin (CL). Tafazzin mutations lead to compositional alterations in CL molecular species, causing extensive mitochondrial aberrations and ultrastructural muscle damage. There are no specific treatments or cure for BTHS. Current therapy is largely palliative and aimed at treatment of organ-specific complications during disease progression. Polypharmacy frequently occurs during treatment and may lead to severe adverse events. Adverse reactions may originate from exogenous factors such as the inadvertent co-administration of contraindicated drugs. Theoretically, endogenous factors such as polymorphic variations in genes encoding drug metabolizing enzymes may also precipitate fatal toxicity. Investigation of the consequences of pharmacogenomic variations on BTHS therapy is lacking. To our knowledge, this review presents the first examination of the possible sources of pharmacogenomic variations that may affect BTHS therapy. We also explore BTHSspecific patents for possible treatment options. The patents discussed suggest innovative strategies for treatment, including feeding linoleic acid to patients to overcome compositional CL deficiency; or the use of 2S,4R ketoconazole formulations to augment CL levels; or the delivery of mitochondrial stabilizing cargo. Future research directions are also discussed.

Differential gene expression analysis in human monocyte-derived macrophages: impact of cigarette smoke on host defence.

Alveolar macrophages have been implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD). In this setting they are routinely exposed to cigarette smoke and a range of pathogens including bacteria and viruses. The gene expression changes that result from these challenges may contribute to the initiation and progression of the disease. Understanding such changes is therefore of great interest and could aid the discovery of novel therapeutics. To study this, we stimulated monocyte-derived macrophages (MDM) from smokers and non-smokers with either cigarette smoke extract (CSE) or bacterially derived lipopolysaccharide (LPS) and profiled global transcriptional changes using Affymetrix arrays. LPS and CSE stimulation elicited markedly different transcriptome profiles with the former agent producing a larger number of significant changes. The CSE evoked changes showed some overlap with those observed when comparing habitual smokers with non-smokers, although the latter changes were generally of a more subtle nature. Detailed pathway analyses indicated that a number of genes involved in host defence were regulated following CSE stimulation and in MDM from smokers. In particular the interferon gamma (IFNgamma)-signalling pathway was significantly down-regulated following CSE stimulation, a finding that was confirmed by RT-PCR analysis. Furthermore, these changes were associated with suppressed release of the IFNgamma-induced chemokines, CXCL10 and CXCL9 from CSE treated MDM. In summary, our data provides evidence that smoking alters key mechanisms of host defence in macrophages. Such changes may explain the increased susceptibility of COPD patients to the lung infections that are associated with exacerbations of this disease.

Fractional exhaled NO and serum pneumoproteins after swimming in a chlorinated pool.

PURPOSE: The purpose of this study was to examine whether a swimming session performed in a pool sanitized with chlorine-based agents induces lung inflammation, modifies lung epithelium permeability, and alters lung function. METHODS: Eleven volunteers performed two standardized swimming sessions: one in a nonchlorinated indoor swimming pool and the other one in a chlorinated indoor pool. Lung inflammation was assessed by fractional exhaled nitric oxide (FE(NO)). Changes in lung epithelium permeability were estimated by measuring the surfactant-associated proteins Type A and Type B (SP-A and SP-B), the Clara cell protein (CC16), and the Krebs von den Lungen-6 protein (KL-6). Lung function tests were also performed. All measurements were carried out in basal conditions, after training completion and 3 h postexercise. Nitrogen trichloride (NCl3), the most concentrated gas derived from pool water chlorination, was measured in each pool during the swimming sessions. RESULTS: NCl3 ranged from 160 to 280 microg x m(-3) in the air of the chlorinated pool and was undetectable in the nonchlorinated one. Lung function was affected neither by the exercise session nor by the type of sanitation. Serum pneumoproteins were unchanged excepted SP-A which decreased by 8% after exercise in the chlorinated pool (P < 0.05). FE(NO) increased by 34% (P < 0.05) after exercise in the nonchlorinated pool, whereas it was unaffected in the chlorinated one. CONCLUSIONS: At concentrations lower than 300 microg x m(-3), NCl3 in an indoor chlorinated pool, does not produce short-term changes in lung function or in epithelial permeability. The unchanged FE(NO) found in the chlorinated pool after exercise suggests that chlorination might inhibit NO-induced vasodilation observed during exercise.

Pneumoproteins as markers of paraquat lung injury: a clinical case.

OBJECTIVE: To describe the changes in lung-specific secretory proteins in biological fluids in a fatal case of paraquat ingestion and to present immunostaining data obtained on postmortem lung tissue specimens. METHODS: A 20-year-old man committed suicide by ingesting 100ml of a 20% paraquat solution. Surfactant associated proteins A (SP-A), B (SP-B) and Clara cell 16kDa protein (CC16) were determined in the serum and on broncho-alveloar lavage performed 18h after admission. Renal failure progressed rapidly and the patient died from refractory hypoxia. Immunostaining studies using antibodies directed against CC16, SP-A and SP-B were performed on postmortem lung tissue specimens. RESULTS: Serum CC16 seemed to increase gradually with the progression of renal impairment. Serum SP-A and SP-B levels increased before any significant changes in pulmonary gas exchanges. The immunostaining study showed that the labeling for SP-A and SP-B was reduced or absent following paraquat toxicity, while Clara cells were relatively preserved. CONCLUSIONS: The elevation of serum CC16 with paraquat toxicity is probably mainly related to a reduced renal clearance. The increase of serum SP-A and SP-B could reflect an increased lung to blood leakage, independently of the alteration of the renal function.

Intracellular storage of surfactant and proinflammatory cytokines in co-cultured alveolar epithelium and macrophages in response to increasing CO2 and cyclic cell stretch.

Cell stretch stimulates both surfactant and cytokine production. The authors proposed that stretch, through these effects, modifies the pathogenesis of lipopolysaccharide-induced acute lung injury (ALI), and that this is CO(2) dependent. Rat alveolar type II cells and macrophages were co-cultured with lipopolysaccharide in 5%, 10%, or 20% CO(2) +/- stretch (30%, 60 cycles/min) for 6 hours. Intracellular TNF-alpha and IL-6 increased whereas secreted cytokine and surfactant decreased with increasing CO(2). Stretch independently increased intracellular TNF-alpha and decreased IL-6 secretion. Elevated CO(2) may therefore diminish secretion of proinflammatory cytokines by alveolar cells, contributing to an explanation for protective hypercapnia in ALI.

Stretch and CO2 modulate the inflammatory response of alveolar macrophages through independent changes in metabolic activity.

Ventilatory-induced strain can exacerbate acute lung injury (ALI). Current ventilation strategies favour low tidal volumes and high end-expiratory volumes to 'rest' the lung, but can lead to an increase in CO2. Alveolar macrophages (AM) play a pivotal role in ALI through the release of inflammatory mediators. The effect of physical strain and CO2 on the release of pro-inflammatory mediators was examined in isolated rat AM. AM were cultured on IgG-coated silastic membranes with or without lipopolysaccharide (LPS) and 5% or 20% CO2 and subjected to a repetitive sinusoidal mechanical strain (30%, 60 cycles/min) for 4 h. Cell viability and metabolic activity were assessed. In both the presence and absence of LPS, physical strain increased metabolic activity by approximately 5%, while 20% CO2 decreased metabolic activity by approximately 40%. Twenty per cent CO2 decreased TNF-alpha secretion by approximately 45%, without affecting cell viability. Physical strain enhanced LPS-induced secretion of TNF-alpha by 1.5%, but not IL-6 or CINC-1. Hence, the effects of both CO2 and physical strain are mediated independently through changes in AM metabolic activity. Physical strain is not a major determinant of TNF-alpha, IL-6 or CINC-1 in AM. Our results confirm that high CO2 can lessen the TNF-alpha inflammatory response of AM.

Effect of CO2 on LPS-induced cytokine responses in rat alveolar macrophages.

Alveolar macrophages (AM) may be exposed to a range of CO(2) and pH levels depending on their location in the alveoli and the health of the lung. Cytokines produced by AM contribute to inflammation in acute lung injury (ALI). Current ventilatory practices for the management of ALI favor low tidal volumes, which can give rise to increases in CO(2) and changes in pH of the alveolar microenvironment. Here we examined the effect of CO(2) on cytokine release from LPS-stimulated rat AM. AM were incubated for 1-4 h under different atmospheric gas mixtures ranging from 2.5-20% CO(2). To distinguish between effects of pH and CO(2), the culture media were also buffered to pH 7.2 with NaHCO(3). Cell metabolic activity, but not cell viability, decreased and increased significantly after 4 h at 20 and 2.5% CO(2), respectively. Increasing CO(2) decreased TNF-alpha secretion but had no effect on lysate TNF-alpha. Buffering the media abated the effects of CO(2) on TNF-alpha secretion. CO(2) increased cytokine-induced neutrophil chemoattractant factor-1 secretion only when the pH was buffered to 7.2. Effects of CO(2) on cytokine responses were reversible. In conclusion, the effects of CO(2) on cytokine lysate levels and/or secretion in AM are cytokine specific and, depending on both the cytokine and the immediate microenvironment, may be beneficial or detrimental to ALI.