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The investigational ticagrelor‐neutralizing antibody fragment, MEDI2452, is developed to rapidly and specifically reverse the antiplatelet effects of ticagrelor. However, the dynamic interaction of ticagrelor, the ticagrelor active metabolite (TAM), and MEDI2452, makes pharmacokinetic (PK) analysis nontrivial and mathematical modeling becomes essential to unravel the complex behavior of this system. We propose a mechanistic PK model, including a special observation model for post‐sampling equilibration, which is validated and refined using mouse in vivo data from four studies of combined ticagrelor‐MEDI2452 treatment. Model predictions of free ticagrelor and TAM plasma concentrations are subsequently used to drive a pharmacodynamic (PD) model that successfully describes platelet aggregation data. Furthermore, the model indicates that MEDI2452‐bound ticagrelor is primarily eliminated together with MEDI2452 in the kidneys, and not recycled to the plasma, thereby providing a possible scenario for the extrapolation to humans. We anticipate the modeling work to improve PK and PD understanding, experimental design, and translational confidence.

Nonlinear mixed effects (NLME) modeling based on stochastic differential equations (SDEs) have evolved into a promising approach for analysis of PK/PD data. SDE-NLME models go beyond the realm of standard population modeling as they consider stochastic dynamics, thereby introducing a probabilistic perspective on the state variables. This article presents a summary of the main contributions to SDE-NLME models found in the literature. The aims of this work were to develop an exact gradient version of the first-order conditional estimation (FOCE) method for SDE-NLME models and to investigate whether it enabled faster estimation and better gradient precision/accuracy compared to the use of gradients approximated by finite differences. A simulation-estimation study was set up whereby finite difference approximations of the gradients of each level were interchanged with the exact gradients. Following previous work, the uncertainty of the state variables was accounted for using the extended Kalman filter (EKF). The exact gradient FOCE method was implemented in Mathematica 11 and evaluated on SDE versions of three common PK/PD models. When finite difference gradients were replaced by exact gradients at both FOCE levels, relative runtimes improved between 6- and 32-fold, depending on model complexity. Additionally, gradient precision/accuracy was significantly better in the exact gradient case. We conclude that parameter estimation using FOCE with exact gradients can successfully be applied to SDE-NLME models.

A central question in drug discovery is how to select drug candidates from a large number of available compounds. This analysis presents a model-based approach for comparing and ranking combinations of radiation and radiosensitizers. The approach is quantitative and based on the previously-derived Tumor Static Exposure (TSE) concept. Combinations of radiation and radiosensitizers are evaluated based on their ability to induce tumor regression relative to toxicity and other potential costs. The approach is presented in the form of a case study where the objective is to find the most promising candidate out of three radiosensitizing agents. Data from a xenograft study is described using a nonlinear mixed-effects modeling approach and a previously-published tumor model for radiation and radiosensitizing agents. First, the most promising candidate is chosen under the assumption that all compounds are equally toxic. The impact of toxicity in compound selection is then illustrated by assuming that one compound is more toxic than the others, leading to a different choice of candidate.

Oral corticosteroids such as prednisolone are potent anti-inflammatory drugs but their use is limited by side effects caused by unwanted actions on the glucocorticoid receptor (GR), such as increased insulin resistance, and off-target actions on the mineralocorticoid receptor (MR) that disrupt electrolyte balance and increase water retention. AZD9567 is an oral, selective, non-steroidal glucocorticoid receptor modulator being developed to treat inflammatory diseases. Pre-clinical and phase 1 clinical data indicate that AZD9567 is the first GR modulator with an improved efficacy–dysglycaemic side effect profile versus prednisolone. To compare the efficacy, safety and tolerability of AZD9567 with prednisolone in patients with active rheumatoid arthritis (RA), at doses with predicted equivalent anti-inflammatory activity. In this phase 2a, randomised, double-blind, parallel-group, multicentre study in RA patients with DAS28-CRP ≥ 3.2 despite stable treatment with conventional disease-modifying anti-rheumatic therapies (NCT03368235), patients were randomised 1:1 to AZD9567 40 mg or prednisolone 20 mg orally once daily for 14 days. The primary endpoint was change from baseline in DAS28-CRP at day 15. Secondary outcomes included components of DAS28-CRP, TJC68, SJC66, ACR response (ACR20, ACR50, ACR70) and safety outcomes, including serum electrolytes. All 21 randomised patients (AZD9567, n = 11; prednisolone, n = 10) completed the study. There was a slight imbalance between the treatment groups at baseline, with higher age (mean ± SD: 64.5 ± 8.4 vs 55.5 ± 13.6 years), more women (8 vs 5) and greater disease severity (DAS28-CRP, mean ± SD: 5.26 ± 0.98 vs 4.90 ± 0.74) in the AZD9567 group versus the prednisolone group. There was no statistically significant or clinically meaningful (i.e. > 1.2) difference in change from baseline to day 15 in DAS28-CRP between AZD9567 and prednisolone, although this was numerically lower with AZD9567 (Table 1). Similar results were observed for TJC68, SJC66, CRP and GH (Table 1). The proportions of patients achieving ACR20, 50 and 70 response criteria were similar in both groups, albeit numerically lower with AZD9567. Similar numbers of patients in each group reported treatment-emergent adverse events (AZD9567, n = 10, prednisolone, n = 9); most were mild in severity. One serious adverse event, suicidal depression, was reported after completing AZD9567 treatment. Morning fasting serum sodium/potassium ratio at day 15 was not altered with AZD9567 but was increased from baseline with prednisolone (Figure 1). AZD9567 40 mg had a similar efficacy profile to prednisolone 20 mg in patients with active RA. Both drugs were well tolerated, with no new safety signals. Unlike prednisolone, AZD9567 had no effect on serum sodium/potassium ratio, suggesting selectivity of AZD9567 for the GR over the MR. These results support further trials of AZD9567 in patients with inflammatory disease. [Display omitted] Medical writing support was provided by Richard Claes PhD of PharmaGenesis London, London, UK, funded by AstraZeneca, Gothenburg, Sweden in accordance with Good Publication Practice 3 (GPP3) guidelines (http://www.ismpp.org/gpp3). This study was funded by AstraZeneca. AZD9567 is an investigational medical product with no approved indication. Jacob M. van Laar Consultant of: Honoraria from - Abbvie, Arxx Tx, Galapagos, Gesyntha, Leadiant, Magenta, Roche, Sanofi Genzyme, Grant/research support from: AstraZeneca, Pfizer, Roche, Alejhandra Lei Shareholder of: AstraZeneca., Grant/research support from: Boehringer Ingelheim in 1998, Bristol-Myers Squibb in 1999, Employee of: AstraZeneca. Past employee of Almirall, Grünenthal, Boehringer Ingelheim, CESIF Pharma, Mary Safy-Khan Grant/research support from: Student grant from AstraZeneca 2015-2018., Joachim Almquist Shareholder of: AstraZeneca, Consultant of: AstraZeneca., Employee of: AstraZeneca., Carol Astbury Shareholder of: AstraZeneca., Employee of: AstraZeneca., Maria Belvisi Shareholder of: AstraZeneca., Grant/research support from: AstraZeneca and Chiesi, Employee of: AstraZeneca., Adam Platt Shareholder of: AstraZeneca., Employee of: AstraZeneca., Susanne Prothon Shareholder of: AstraZeneca., Employee of: AstaZeneca., Sara Samuelsson Shareholder of: AstraZeneca, Employee of: AstraZeneca, Petter Svanberg Employee of: AstraZeneca, Christina Keen Shareholder of: AstraZeneca., Employee of: AstraZeneca. Table 1Change from baseline to day 15 in clinical disease activity measures.AZD9567 (n = 11)Prednisolone (n = 10)Comparison(AZD9567 – prednisolone)LSM CFB (SE)95% CILSM CFB (SE)95% CILSMD (SE)95% CIp valueDAS28−CRP score−1.93 (0.35)−2.66, −1.21−2.40 (0.34)−3.11, −1.700.47 (0.46)−0.49, 1.430.315TJC28 score−6.12 (1.25)−8.76, −3.49−6.07 (1.21)−8.61, −3.52−0.05 (1.60)−3.43, 3.320.973SJC28 score−5.14 (0.65)−6.51, −3.76−5.40 (0.63)−6.73, −4.080.26 (0.84)−1.50, 2.030.757GH score−27.7 (7.3)−42.8, −12.5−37.4 (7.1)−52.3, −22.69.8 (9.7)−10.5, 30.10.325CRP, mg/L−10.8 (2.4)−15.9, −5.8−15.6 (2.5)−20.9, −10.34.8 (3.5)−2.5, 12.00.187TJC68 score−9.02 (2.46)−14.21, −3.82−7.90 (2.36)−12.88, −2.91−1.12 (3.12)−7.69, 5.460.724SJC66 score−6.24 (0.89)−8.13, −4.36−6.66 (0.86)−8.48, −4.850.42 (1.14)−1.98, 2.810.717CFB, change from baseline; CRP, C-reactive protein; DAS28, 28-joint disease activity score; GH, global health; LSM(D), least-squares mean (difference); SJC, swollen joint count; TJC, tender joint count.

While academic librarians have long engaged in marketing, it has typically been in the limited sense of promotion and advertising. Application of the marketing concept, with the realization of a marketing orientation as a long term goal, redirects the library to actively seek out user needs and then to design and provide services and resources that will meet those needs. When fully realized, marketing is a bidirectional process in which user needs are determined, services developed, and feedback obtained to assess how effectively the library has addressed the needs. This eliminates the necessity to \"sell\" services, allowing the library to spend the majority of its efforts on further innovation. The article provides an explanation of the marketing concept and orientation contrasted with the much more common production orientation. The concepts are illustrated through models and a description of the marketing effort as it has developed in the W. Frank Steely Library at Northern Kentucky University.

The impact of waterfowl herbivory on the macrophyte Potamogeton pectinatus was tested at six shallow sites adjacent to Askö island, in the northern Baltic proper. Protection by means of floating nets affected P. pectinatus at the three most sheltered sites but had no influence on the more wave-exposed sites. Ramet density in July of the first study year was 10-23 times higher in protected plots than in unprotected plots, at the sheltered sites. The density at two of the sites was constantly low in unprotected plots and remained much higher (10-80 times) in the protected plots throughout the 3-year study. At the third very sheltered site the impact of waterfowl was more variable. Additional studies of permanent plots and pot experiments revealed that waterfowl mainly suppressed P. pectinatus, not by grazing on shoots, but by eating subterranean tubers between late April and early June. This study suggests that waterfowl herbivory can constrain submerged macrophyte populations in shallow sheltered areas.

Oral corticosteroid use is limited by side effects, some caused by off‐target actions on the mineralocorticoid receptor that disrupt electrolyte balance. AZD9567 is a selective, nonsteroidal glucocorticoid receptor modulator. The efficacy, safety, and tolerability of AZD9567 and prednisolone were assessed in a phase IIa study. Anti‐inflammatory mechanism of action was also evaluated in vitro in monocytes from healthy donors. In this randomized, double‐blind, parallel‐group, multicenter study, patients with active rheumatoid arthritis were randomized 1:1 to AZD9567 40 mg or prednisolone 20 mg once daily orally for 14 days. The primary end point was change from baseline in DAS28‐CRP at day 15. Secondary end points included components of DAS28‐CRP, American College of Rheumatology (ACR) response criteria (ACR20, ACR50, and ACR70), and safety end points, including serum electrolytes. Overall, 21 patients were randomized to AZD9567 (n = 11) or prednisolone (n = 10), and all completed the study. As anticipated, AZD9567 had a similar efficacy profile to prednisolone, with no clinically meaningful (i.e., >1.0) difference in change from baseline to day 15 in DAS28‐CRP between AZD9567 and prednisolone (least‐squares mean difference: 0.47, 95% confidence interval: −0.49 to 1.43). Similar results were observed for the secondary efficacy end points. In vitro transcriptomic analysis showed that anti‐inflammatory responses were similar for AZD9567, prednisolone, and dexamethasone. Unlike prednisolone, AZD9567 had no effect on the serum sodium:potassium ratio. The safety profile was not different from that of prednisolone. Larger studies of longer duration are required to determine whether AZD9567 40 mg may in the future be an alternative to prednisolone in patients with inflammatory disease.

Nontypeable Haemophilus influenzae strain INTl was isolated from the blood of a young child with clinical signs of meningitis following acute otitis media. No immunologicor anatomic predisposition of this child for invasive bacterial infection with an unusual organism was documented. Sensitive ELISA proved the absence of intra- or extracellular capsular polysaccharide production by INTl, and Southern blot analysis confirmed the lack of an intact capsulation (cap) gene locus within the chromosome. Nevertheless, INTl established bacteremia and meningitis in infant and weanling rat models of invasive H. influenzae infection. High-molecular-weight DNA isolated from INT1 was shown to confer an invasive phenotype on transformation of a nonencapsulated, avirulent laboratory strain of H. influenzae. Together these findings imply the presence of one or more asyet-undiscovered, noncapsular virulence factors of H. influenzae that are capable of mediating invasive disease and resistance to immunologic clearance.

In most hospitals there is a protocol to follow so that a colonized patient can be retested, and if he or she is found to have an acceptable amount of the organism or to have eliminated (ie, cleared) it, they will no longer need precautions. [...]that happens, these patients are considered carriers of the organism and should not be placed with vulnerable patients (eg, postoperative patients) to reduce the chance of transmission. Type of isolation Personal protective equipment required and room required Hand hygiene Cleaning of equipment Examples of diseases requiring isolation Criteria for discontinuing isolation Contact Gown and gloves when entering patient's roomPrivate room (this will vary per hospital policy) Hand hygiene upon entering and leaving patient's room--if hands are visibly soiled, use soap and water Hospital-approved disinfectant to clean equipment between patients (stethoscopes, noncritical equipment) MRSAVREExtended-spectrum β-lactamaseCarbapenem-resistant Enterobacteriaceaerespiratory syncytial virus and scabies MRSA and VRE: varies according to hospital policyExtended-spectrum β-lactamase and carbapenem-resistant Enterobacteriaceae: most hospitals do not have criteria for discontinuing theserespiratory syncytial viruses: duration of illnessScabies: until 24 h after start of effective therapy Airborne Particulate respiratorRespirator maskNegative-pressure room Hand hygiene upon entering and leaving patient's room Hospital-approved disinfectant to clean equipment between patients TB pulmonary and laryngealZoster, disseminated--requires airborne and contact precautionsVaricella--requires airborne and contact precautions TB pulmonary and laryngeal: discontinue only when patient is receiving effective therapy and improving clinically and has 3 consecutive sputum smears negative for acid-fast bacilli collected on separate daysZoster, disseminated: until lesions are dry and crustedVaricella: until lesions are dry and crusted Droplet Surgical mask within 3 ft of patientPrivate roomMay cohort patients with same type influenza Hand hygiene upon entering and leaving patient's room Hospital-approved disinfectant to clean equipment between patients InfluenzaGroup A streptococcus major wound/skin infection--requires contact precautions in additionMeningococcal disease (sepsis, pneumonia, meningitis)Pertussis Influenza: 5 d except for duration of illness in immunocompromised patientsGroup A streptococcus: until 24 h after initiation of effective therapyMeningococcal disease: until 24 h after initiation of effective therapyPertussis: until 5 d after start of effective therapy Enteric contact precautions Gown and gloves when entering patient's roomPrivate roomMay cohort patients with C difficile or norovirus if absolutely necessary Soap and water (not alcohol hand gel) when entering and leaving patient's room Equipment wiped with 1:10 bleach disinfectant to water before removing from room C difficile Norovirus C difficile: CDC guidelines discontinue isolation if patient has been treated and has had no diarrhea for 24 h; some hospitals continue isolation (check hospital policy)Norovirus: isolation may be discontinued after no diarrhea for 72 h (this will vary per hospital policy) Table 1 Transmission-based precautions quick reference guidelines

Intradermal delivery of AZD8601, an mRNA designed to produce vascular endothelial growth factor A (VEGF‐A), has previously been shown to accelerate cutaneous wound healing in a murine diabetic model. Here, we develop population pharmacokinetic and pharmacodynamic models aiming to quantify the effect of AZD8601 injections on the dynamics of wound healing. A dataset of 584 open wound area measurements from 131 mice was integrated from 3 independent studies encompassing different doses, dosing timepoints, and number of doses. Evaluation of several candidate models showed that wound healing acceleration is not likely driven directly by time‐dependent VEGF‐A concentration. Instead, we found that administration of AZD8601 induced a sustained acceleration of wound healing depending on the accumulated dose, with a dose producing 50% of the maximal effect of 92 µg. Simulations with this model showed that a single dose of 200 µg AZD8601 can reduce the time to reach 50% wound healing by up to 5 days.