Evaluation of area under the concentration curve adjusted by the terminal-phase as a metric to reduce the impact of variability in bioequivalence testing.

AIM: To quantify the utility of a terminal-phase adjusted area under the concentration curve method in increasing the probability of a correct and conclusive outcome of a bioequivalence (BE) trial for highly variable drugs when clearance (CL) varies more than the volume of distribution (V). METHODS: Data from a large population of subjects were generated with variability in CL and V, and used to simulate a two-period, two-sequence crossover BE trial. The 90% confidence interval for formulation comparison was determined following BE assessment using the area under the concentration curve (AUC) ratio test, and the proposed terminal-phase adjusted AUC ratio test. An outcome of bioequivalent, nonbioequivalent or inconclusive was then assigned according to predefined BE limits. RESULTS: When CL varied more than V, the proposed approach enhanced the probability of correctly assigning bioequivalent or nonbioequivalent and reduced the risk of an inconclusive trial. For a hypothetical drug with between-subject variability of 35% for CL and 10% for V, when the true test-reference ratio of bioavailability was 1.15, a crossover study of n = 14 subjects analysed by the proposed method would have 80% or 20% probability of claiming bioequivalent or nonbioequivalent, compared to 22%, 46% or 32% probability of claiming bioequivalent, nonbioequivalent or inconclusive using the standard AUC ratio test. CONCLUSIONS: The terminal-phase adjusted AUC ratio test represents a simple and readily applicable approach to enhance the BE assessment of drug products when CL varies more than V.

Repeated Critical Illness and Unplanned Readmissions Within 1 Year to PICUs.

OBJECTIVES: To determine the occurrence rate of unplanned readmissions to PICUs within 1 year and examine risk factors associated with repeated readmission. DESIGN: Retrospective cohort analysis. SETTING: Seventy-six North American PICUs that participated in the Virtual Pediatric Systems, LLC (VPS, LLC, Los Angeles, CA). PATIENTS: Ninety-three thousand three hundred seventy-nine PICU patients discharged between 2009 and 2010. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Index admissions and unplanned readmissions were characterized and their outcomes compared. Time-to-event analyses were performed to examine factors associated with readmission within 1 year. Eleven percent (10,233) of patients had 15,625 unplanned readmissions within 1 year to the same PICU; 3.4% had two or more readmissions. Readmissions had significantly higher PICU mortality and longer PICU length of stay, compared with index admissions (4.0% vs 2.5% and 2.5 vs 1.6 d; all p < 0.001). Median time to readmission was 30 days for all readmissions, 3.5 days for readmissions during the same hospitalization, and 66 days for different hospitalizations. Having more complex chronic conditions was associated with earlier readmission (adjusted hazard ratio, 2.9 for one complex chronic condition; hazard ratio, 4.8 for two complex chronic conditions; hazard ratio, 9.6 for three or more complex chronic conditions; all p < 0.001 compared no complex chronic condition). Most specific complex chronic condition conferred a greater risk of readmission, and some had considerably higher risk than others. CONCLUSIONS: Unplanned readmissions occurred in a sizable minority of PICU patients. Patients with complex chronic conditions and particular conditions were at much higher risk for readmission.

Children and Young Adults Who Received Tracheostomies or Were Initiated on Long-Term Ventilation in PICUs.

OBJECTIVES: To characterize patients who received tracheostomies for airway compromise or were initiated on long-term ventilation for chronic respiratory failure in PICUs and to examine variation in the incidence of initiation, patient characteristics, and modalities across sites. DESIGN: Retrospective cross-sectional analysis. SETTINGS: Seventy-three North American PICUs that participated in the Virtual Pediatric Systems, LLC. PATIENTS: PICU patients admitted between 2009 and 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 115,437 PICU patients, 1.8% received a tracheostomy or were initiated on long-term ventilation; 1,034 received a tracheostomy only, 717 were initiated on invasive ventilation, and 381 were initiated on noninvasive ventilation. Ninety percent had substantial chronic conditions and comorbidities, including more than 50% with moderate or worse cerebral disability upon discharge. Seven percent were initiated after a catastrophic injury/event. Across sites, there was variation in incidence of tracheotomy and initiation of long-term ventilation, ranging from 0% to 4.6%. There also was variation in patient characteristics, time to tracheotomy, number of extubations prior to tracheostomy, and the use of invasive ventilation versus noninvasive ventilation. CONCLUSIONS: Although the PICU incidence of initiation of tracheostomies and long-term ventilation was relatively uncommon, it suggests that thousands of children and young adults receive these interventions each year in North American PICUs. The majority of them have conditions and comorbidities that impose on-going care needs, beyond those required by artificial airways and long-term ventilation themselves.

Limited waterpower contributed to rise of steam power in British "Cottonopolis".

The Industrial Revolution precipitated a pivotal shift from waterpower to coal-fueled steam power in British textile mills. Although it is now widely accepted that steam was chosen to power factories despite the availability of sufficient waterpower resources across most of Britain, the location and suitability of that waterpower during the early 19th century remain underexplored. Here, we employ quantitative fluvial geomorphology alongside historical climate data, factory records, and a catalog of over 26,000 mill sites to reveal that waterpower was abundant for most of early 19th century Britain, except in the central hub of British cotton production: Greater Manchester in the Mersey Basin. Our findings show that surging factory mechanization and overcrowding on key waterways in the Mersey Basin compounded waterpower scarcity arising from a drier 19th century climate. Widespread adoption of coal-fueled steam engines in certain key industrial centers of Britain was a strategy aimed at ameliorating some of the reduced reliability of waterpower. The fact that steam engines were frequently used in water-powered factories in many industrial regions until the third quarter of the 19th century to recirculate water to provide that power, or as a power supplement when waterpower availability was restricted, adds further weight to our argument. Rapid adoption of coal-powered steam engines reshaped the social and structural landscape of industrial work, firmly established Britain's prominence as an industrial powerhouse, and had lasting global industrial and environmental impacts.

Frequency, risk factors, and outcomes of early unplanned readmissions to PICUs.

OBJECTIVES: To determine the rate of unplanned PICU readmissions, examine the characteristics of index admissions associated with readmission, and compare outcomes of readmissions versus index admissions. DESIGN: Retrospective cohort analysis. SETTING: Ninety North American PICUs that participated in the Virtual Pediatric Intensive Care Unit Systems. PATIENTS: One hundred five thousand four hundred thirty-seven admissions between July 2009 and March 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Unplanned PICU readmission within 48 hours of index discharge was the primary outcome. Summary statistics, bivariate analyses, and mixed-effects logistic regression model with random effects for each hospital were performed.There were 1,161 readmissions (1.2%). The readmission rate varied among PICUs (0-3.3%), and acute respiratory (56%), infectious (35%), neurological (28%), and cardiovascular (20%) diagnoses were often present on readmission. Readmission risk increased in patients with two or more complex chronic conditions (adjusted odds ratio, 1.72; p < 0.001), unscheduled index admission (adjusted odds ratio, 1.37; p < 0.001), and transfer to an intermediate unit (adjusted odds ratio, 1.29; p = 0.004, compared with ward). Trauma patients had a decreased risk of readmission (adjusted odds ratio, 0.67; p = 0.003). Gender, race, insurance, age more than 6 months, perioperative status, and nighttime transfer were not associated with readmission. Compared with index admissions, readmissions had longer median PICU length of stay (3.1 vs 1.7 d, p < 0.001) and higher mortality (4% vs 2.5%, p = 0.002). CONCLUSIONS: Unplanned PICU readmissions were relatively uncommon, but were associated with worse outcomes. Several patient and admission characteristics were associated with readmission. These data help identify high-risk patient groups and inform risk-adjustment for standardized readmission rates.

Parent and Provider Perspectives on Primary Continuity Intensivists and Nurses for Long-Stay Pediatric Intensive Care Unit Patients.

Rationale: Primary continuity intensivists and nurses for long-stay patients (LSPs) in pediatric intensive care units (PICUs) are understudied strategies used to mitigate the fragmented care of typical rotating care models. Objectives: To investigate the advantages and disadvantages of primary continuity intensivists and nurses for LSPs as perceived by their parents and PICU providers. Methods: We conducted a prospective cross-sectional mixed-methods study of the perspectives of parents whose children were admitted to a PICU for >10 days and had one or more complex chronic conditions regarding the care provided by their PICU intensivists and nurses. As part of a trial, patients had been randomized to care provided by a rotating on-service intensivist who changed weekly and by PICU nurses who changed every 12 hours (usual care group) or to care provided by the same on-service intensivist plus a primary continuity intensivist and primary nurses (primary group). In addition, PICU providers (intensivists, fellows, and nurses) were queried for their perspectives on primary intensivists and nurses. Novel questionnaires, assessed for content and face validity and for readability, were used. The parental questionnaire involved indicating their degree of agreement with 16 statements about their children's care. The provider questionnaire involved rating potential advantages of primary continuity intensivists and nurses and estimating the frequency of disadvantages. Descriptive statistics and divergent stack bar charts were used; parents' and providers' responses were compared, stratified by their children's group (usual care or primary) and provider role, respectively. Results: The parental response rate was 71% (120 completed questionnaires). For 10 of 16 statements, parents whose children had primary continuity intensivists and nurses indicated significantly more positive perceptions of care (e.g., communication, listening, decision making, problems due to changing providers). The provider response rate was 61% (117 completed questionnaires); more than 80% believed that primary intensivists and nurses were highly or very highly beneficial for LSPs. Providers perceived more benefits for patients/families (e.g., informational continuity, facilitating and expediting decision making) than for staff/institutions (e.g., staff satisfaction). Providers reported associated stress, expenditure of time and effort, and decreased staffing flexibility with primary practices. Conclusions: Perceived benefits of primary continuity intensivists and nurses by both parents and providers support more widespread adoption and study of these continuity strategies.

Potentiation of the anticonvulsant efficacy of sodium channel inhibitors by an NK1-receptor antagonist in the rat.

PURPOSE: Many patients with epilepsy are refractory to anticonvulsant drugs or do not tolerate side effects associated with the high doses required to fully prevent seizures. Antagonists of neurokinin-1 (NK1) receptors have the potential to reduce seizure severity, although this potential has not been fully explored in animals or humans. The present study was designed to evaluate the efficacy of the NK1-receptor antagonist, vofopitant, alone and in combination with different anticonvulsant drugs. METHODS: Studies were conducted in rats using a model of generalized seizure induced by electroshock. Drug concentrations in blood and brain were determined in parallel to distinguish pharmacodynamic from pharmacokinetic interactions. RESULTS: The NK1-receptor antagonist, GR205171 (vofopitant) had no anticonvulsant efficacy by itself, but could potentiate the anticonvulsant efficacy of lamotrigine and other sodium channel blockers. However, GR205171 had no effect on the anticonvulsant potency of either valproate or gabapentin. GR205171 did not produce central nervous system (CNS) side effects at the doses tested, and it did not potentiate side effects induced by high doses of lamotrigine. The NK1-receptor inactive enantiomer of GR205171, GR226206 did not potentiate the efficacy of lamotrigine, suggesting that effects observed with GR205171 were mediated by NK1 receptors. Analysis of the dose-effect relationship for GR205171 indicated that a high (>99%) occupancy of NK1 receptors is required for effect, consistent with previous behavioral and human clinical studies with this pharmacologic class. DISCUSSION: These results suggest that there may be benefit in adding treatment with a suitable NK1-receptor antagonist to treatment with a sodium channel blocker in patients with refractory epilepsy.

2' biaryl amides as novel and subtype selective M1 agonists. Part II: Further optimization and profiling.

Further optimization of the biaryl amide series via extensively exploring structure-activity relationships resulted in potent and subtype selective M(1) agonists exemplified by compounds 9a and 9j with good rat PK properties including CNS penetration. Synthesis, structure-activity relationships, subtype selectivity for M(1) over M(2-5), and DMPK properties of these novel compounds are described.

The discovery of a series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles as highly brain penetrant, selective muscarinic M1 agonists.

A series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles are reported which were found to be potent and selective muscarinic M1 agonists. By control of the physicochemical characteristics of the series, particularly the lipophilicity, compounds with good metabolic stability and excellent brain penetration were identified. An exemplar of the series was shown to be pro-cognitive in the novel object recognition rat model of temporal induced memory deficit.

Receptor occupancy and brain free fraction.

This study was designed to investigate whether brain unbound concentration (C(u,brain)) is a better predictor of dopamine D(2) receptor occupancy than total brain concentration, cerebrospinal fluid concentration (C(CSF)), or blood unbound concentration (C(u,blood)). The ex vivo D(2) receptor occupancy and concentration-time profiles in cerebrospinal fluid, blood, and brain of six marketed antipsychotic drugs were determined after oral administration in rats at a range of dose levels. The C(u,brain) was estimated from the product of total brain concentration and unbound fraction, which was determined using a brain homogenate method. In conclusion, the C(u,brain) of selected antipsychotic agents is a good predictor of D(2) receptor occupancy in rats. Furthermore, C(u,brain) seems to provide a better prediction of D(2) receptor occupancy than C(CSF) or C(u,blood) for those compounds whose mechanism of entry into brain tissue is influenced by factors other than simple passive diffusion.

Estimating human ADME properties, pharmacokinetic parameters and likely clinical dose in drug discovery.

Introduction: Prediction of human absorption, distribution, metabolism, and excretion (ADME) properties, therapeutic dose and exposure has become an integral part of compound optimization in discovery. Incorporation of drug metabolism and pharmacokinetics into discovery projects has largely tempered historical drug failure due to sub-optimal ADME. In the current era, inadequate safety and efficacy are leading culprits for attrition; both of which are dependent upon drug exposure. Therefore, prediction of human pharmacokinetics (PK) and dose are core components of de-risking strategies in discovery. Areas covered: The authors provide an overview of human dose prediction methods and present a toolbox of PK parameter prediction models with a proposed framework for a consensus approach valid throughout the discovery value chain. Mechanistic considerations and indicators for their application are discussed which may impact the dose prediction approach. Examples are provided to illustrate how implementation of the proposed strategy throughout discovery can assist project progression. Expert opinion: Anticipation of human ADME, therapeutic dose and exposure must be deliberated throughout drug discovery from virtual/initial synthesis where key properties are considered and similar molecules ranked, into development where advanced compounds can be subject to prediction with greater mechanistic understanding and data-driven model selection.

A multi-institutional analysis of children on long-term non-invasive respiratory support and their outcomes.

OBJECTIVES: To characterize a multi-institutional cohort of children with chronic respiratory failure that use long-term, non-invasive respiratory support, perform a time-to-event analysis of transitions to transtracheal ventilation and identify factors associated with earlier transition to transtracheal ventilation. STUDY DESIGN: A retrospective cohort study of patients less than 21 years of age with diagnoses associated with chronic respiratory failure and discharged on non-invasive respiratory support was performed using data from the Pediatric Health Information System (PHIS) between 2007 and 2015. Demographic and clinical characteristics, as well as times from index discharge on non-invasive support to transtracheal ventilation were presented. A competing risk regression model was fitted to estimate factors associated with earlier transition to transtracheal ventilation. RESULTS: A total of 3802 patients were identified. Their median age at index discharge was 10.4 years (interquartile range [IQR] 4.1-14.9). Of these patients, 337 (8.9%) transitioned to transtracheal ventilation and transitioned at a median of 11.5 months (IQR 4.6-26) post-index discharge, or a median age of 9.3 years (IQR 4.2-14.5). Competing risk modeling demonstrated that patients who were older or whose discharge occurred later in the study period had lower hazards of earlier transition to transtracheal ventilation, whereas patients with anoxia/encephalopathy and quadriplegia had higher hazards of earlier transitioning. CONCLUSIONS: Most patients on long-term, non-invasive respiratory support who progress to transtracheal ventilation transition do so within a few years of support initiation. Various characteristics were associated with earlier risk of transitioning to transtracheal ventilation. This information may enhance anticipatory guidance for this population.

What Imaging-Detected Pathologies Are Associated With Shoulder Symptoms and Their Persistence? A Systematic Literature Review.

OBJECTIVE: Shoulder symptoms are common, and imaging is being increasingly used to help with management. However, the relationship between imaging and symptoms remains unclear. This review aims to understand the relationship between imaging-detected pathologies, symptoms, and their persistence. METHODS: A systematic review using Medline, EMBASE, Cochrane, and grey literature was conducted to April 2017. The cross-sectional and longitudinal relationships between imaging-detected abnormalities and symptoms were analyzed and associations qualitatively characterized by a best-evidence synthesis based on study design, covariate adjustment, and the Grade of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. Modalities included ultrasound, magnetic resonance imaging (MRI), radiographs, positron emission tomography (PET), bone scintigraphy, and computed tomography. RESULTS: A total of 6,569 abstracts was screened and 56 articles were included. In total, 50 studies did not adjust for covariates and 36 analyzed individual pathologies only. The majority of studies showed conflicting results. There was no significant association between most imaging features and symptoms among high-quality, cross-sectional studies. There was low-quality evidence that enhancement of the joint capsule on MRI and increased uptake on PET were associated with symptoms in adhesive capsulitis. Based on high-quality longitudinal studies, enlarging rotator cuff tears were associated with an increased incidence of symptoms. CONCLUSION: There were conflicting results on the association of imaging features with shoulder symptoms and their persistence. The existing evidence was very low in quality, based on the GRADE methodology. Further high-quality studies are required to understand the relationship between imaging and shoulder symptoms and to determine the appropriate role of imaging in care pathways.

Homogeneous detection of unamplified genomic DNA sequences based on colorimetric scatter of gold nanoparticle probes.

Nucleic acid diagnostics is dominated by fluorescence-based assays that use complex and expensive enzyme-based target or signal-amplification procedures. Many clinical diagnostic applications will require simpler, inexpensive assays that can be done in a screening mode. We have developed a 'spot-and-read' colorimetric detection method for identifying nucleic acid sequences based on the distance-dependent optical properties of gold nanoparticles. In this assay, nucleic acid targets are recognized by DNA-modified gold probes, which undergo a color change that is visually detectable when the solutions are spotted onto an illuminated glass waveguide. This scatter-based method enables detection of zeptomole quantities of nucleic acid targets without target or signal amplification when coupled to an improved hybridization method that facilitates probe-target binding in a homogeneous format. In comparison to a previously reported absorbance-based method, this method increases detection sensitivity by over four orders of magnitude. We have applied this method to the rapid detection of mecA in methicillin-resistant Staphylococcus aureus genomic DNA samples.

Pediatric intermediate care and pediatric intensive care units: PICU metrics and an analysis of patients that use both.

PURPOSE: To examine how intermediate care units (IMCUs) are used in relation to pediatric intensive care units (PICUs), characterize PICU patients that utilize IMCUs, and estimate the impact of IMCUs on PICU metrics. MATERIALS & METHODS: Retrospective study of PICU patients discharged from 108 hospitals from 2009 to 2011. Patients admitted from or discharged to IMCUs were characterized. We explored the relationships between having an IMCU and several PICU metrics: physical length-of-stay (LOS), medical LOS, discharge wait time, admission severity of illness, unplanned PICU admissions from wards, and early PICU readmissions. RESULTS: Thirty-three percent of sites had an IMCU. After adjusting for known confounders, there was no association between having an IMCU and PICU LOS, mean severity of illness of PICU patients admitted from general wards, or proportion of PICU readmissions or unplanned ward admissions. At sites with an IMCU, patients waited 3.1h longer for transfer from the PICU once medically cleared (p<0.001). CONCLUSIONS: There was no association between having an IMCU and most measures of PICU efficiency. At hospitals with an IMCU, patients spent more time in the PICU once they were cleared for discharge. Other ways that IMCUs might affect PICU efficiency or particular patient populations should be investigated.

Bone Marrow-Derived Mesenchymal Stem Cells as Autologous Therapy in Dogs with Naturally Occurring Intervertebral Disc Disease: Feasibility, Safety, and Preliminary Results.

The intradiscal application of mesenchymal stem cells (MSCs) is considered a promising strategy for intervertebral disc (IVD) regeneration. Although many studies have been published, the feasibility and regenerative effects of intradiscal MSC application have not been evaluated in an animal model suffering from naturally occurring degenerative disc disease. Six German Shepherd Dogs suffering from naturally occurring degenerative IVD disease were included. Autologous MSCs were isolated from bone marrow (iliac crest) and cultured for 3 weeks. After decompressive spinal surgery, three dogs received an intradiscal injection of MSCs, while the other three dogs received an intradiscal injection of saline (control). Clinical status, disc height index, Pfirrmann grading, and disc volumetry were evaluated at 1, 6, and 12 months after treatment. Autologous application of canine MSCs was feasible and successful in all dogs. No evident complication was found. Surgery resulted in an equal improvement in clinical status in the treatment and control dogs. In the MSC group, the Pfirrmann grade increased in all patients over time, whereas in the control group, the Pfirrmann grade remained stable. The volume of the L7-S1 IVD gradually increased during the 12-month study period in all dogs, with no evident difference between the MSC and control group. On the basis of this preliminary study, it can be concluded that intradiscal injection of autologous MSCs in dogs with spontaneous degenerative IVD disease is well tolerated without any adverse effects, does not affect clinical outcome, and does not have any evident regenerative effects.

Gold nanoparticle-based detection of genomic DNA targets on microarrays using a novel optical detection system.

The development of a nanoparticle-based detection methodology for sensitive and specific DNA-based diagnostic applications is described. The technology utilizes gold nanoparticles derivatized with thiol modified oligonucleotides that are designed to bind complementary DNA targets. A glass surface with arrays of immobilized oligonucleotide capture sequences is used to capture DNA targets, which are then detected via hybridization to the gold nanoparticle probes. Amplification with silver allows for detection and quantitation by measuring evanescent wave induced light scatter with low-cost optical detection systems. Compared to Cy3-based fluorescence, silver amplified gold nanoparticle probes provide for a approximately 1000-fold increase in sensitivity. Furthermore, direct detection of non-amplified genomic DNA from infectious agents is afforded through increased specificity and even identification of single nucleotide polymorphisms (SNP) in human genomic DNA appears feasible.

Biomechanical evaluation of a novel nucleus pulposus prosthesis in canine cadaveric spines.

Partial disc replacement is a new surgical technique aimed at restoring functionality to degenerated intervertebral discs (IVDs). The aim of the present study was to assess biomechanically the behaviour of a novel nucleus pulposus prosthesis (NPP) in situ and its ability to restore functionality to the canine IVD after nuclectomy alone or after combined dorsal laminectomy and nuclectomy. Nine canine T13-L5 specimens (L2L3 group) and 10 L5-Cd1 specimens (LS group) were tested biomechanically in the native state, after nuclectomy (L2L3 group) or after combined dorsal laminectomy and nuclectomy (LS group), and after insertion of the NPP. Range of motion (ROM), neutral zone (NZ), and neutral zone stiffness (NZS) were determined in flexion/extension, lateral bending, and axial rotation. Nuclectomy alone and combined dorsal laminectomy and nuclectomy caused significant instability in all motion directions. Implantation of the NPP resulted in significant restoration of the parameters (ROM, NZ, and NZS) towards the native state; however, fragmentation/herniation of the NPP occurred in 47% of the cases. In conclusion, the NPP has the ability to improve functionality of the nuclectomized canine IVD. The high rate of NPP failure requires modifications directed at the integrity of the NPP and its confinement to the nuclear cavity.