Eliciting patient-important outcomes through group brainstorming: when is saturation reached?

Purpose: Group brainstorming is a technique for the elicitation of patient input that has many potential uses, however no data demonstrate concept saturation. In this study we explore concept saturation in group brainstorming performed in a single session as compared to two or three sessions.

Methods: Fifty-two predominately African American adults patients with moderately to poorly controlled Diabetes Mellitus participated in three separate group brainstorming sessions as part of a PCORI-funded group concept mapping study examining comparing methods for the elicitation of patient important outcomes (PIOs).

The power of the group: comparison of interviews and group concept mapping for identifying patient-important outcomes of care.

Background: Data are limited regarding how to effectively and efficiently identify patient priorities for research or clinical care. Our goal was to compare the comprehensiveness and efficiency of group concept mapping (GCM), a group participatory method, to interviews for identifying patient goals when seeking care.

Methods: We engaged patients with moderately- to poorly-controlled diabetes mellitus in either GCM or an individual interview.

Insulin receptor plays a central role in skin carcinogenesis by regulating cytoskeleton assembly.

Diabetes mellitus prevalence is increasing rapidly and is a major cause of mortality and morbidity worldwide. In addition to the known severe complications associated with the disease, in recent years diabetes has been recognized as a major risk factor for cancer. Patients with diabetes experience significantly higher incidence of and higher mortality rates from many types of cancer.

Thirty-Second Walk Test: Expansion of Normative Data.

Purpose: To collect 30-second walk test (30sWT) normative data on a large, diverse sample of school children developing typically, ages 5 to 13 years, and describe the influences of gender, body mass index, and path shape on distance walked.

Methods: Five physical therapists administered the 30sWT on 1223 children developing typically (boys = 517, girls = 706) from 20 urban schools.

Results: Average distances (standard deviation) ranged from 139.

Adapting Conceptual Frameworks for Patient Engagement in Emergency Department Research.

For many people the emergency department (ED) is the first point of access to healthcare for acute needs and a recurring location for many with chronic healthcare needs. While the ED is well placed to identify unmet needs it can also be a net that people slip through when faced with uncoordinated and expensive healthcare challenges. Thus the ED has a responsibility to set patients on a safe and meaningful care trajectory, which can only be done in consultation and partnership with the patients themselves.

The 2016 Academic Emergency Medicine Consensus Conference, "Shared Decision Making in the Emergency Department: Development of a Policy-relevant Patient-centered Research Agenda" Diagnostic Testing Breakout Session Report.

Diagnostic testing is an integral component of patient evaluation in the emergency department (ED). Emergency clinicians frequently use diagnostic testing to more confidently exclude "worst-case" diagnoses rather than to determine the most likely etiology for a presenting complaint. Increased utilization of diagnostic testing has not been associated with reductions in disease-related mortality but has led to increased overall healthcare costs and other unintended consequences (e.

Timed Floor to Stand-Natural: Reference Data for School Age Children.

Purpose: To collect reference data for the Timed Floor to Stand-Natural (TFTS-N) on a large, diverse sample of school children who are typically developing, taking into account age, sex, and body mass index (BMI).

Methods: Five physical therapists administered the TFTS-N on a sample of convenience of 1476 school children who were typically developing, aged 5 to 14 years (male = 637, female = 839), using previously tested, standardized reliable procedures.

Results: The average time ranged from 7.

Timed Up and Go: Reference Data for Children Who Are School Age.

Purpose: To collect normative data for the Timed Up and Go (TUG) on a large, diverse sample of urban school children who are typically developing, accounting for age, sex, and body mass index.

Methods: Physical therapists administered the TUG with natural walking speeds on 1481 children (M = 635, F = 846), ages 5 to 13 years representing 29.60% whites, 24.

Insulin analogues display atypical differentiative activities in skin keratinocytes.

Background: We have previously shown that both insulin and IGF1 lead to increased proliferation of keratinocytes. However, whereas insulin supports keratinocytes differentiation, IGF1 inhibits this process. The aim of the present study was to examine the proliferative and differentiative effects of insulin analogues (glargine, detemir, lispro and aspart) in primary keratinocytes in comparison with insulin and IGF1.

Reliability and validity of the Timed Floor To Stand Test-Natural in school-aged children.

Purpose: To establish reliability for the Timed Floor to Stand-Natural (TFTS-N) test as a stand-alone measure for schoolchildren with typical development (TD) in preparation for normative data collection.

Methods: Five physical therapists working in schools standardized testing procedures for a "natural" pace version of the TFTS. Time data were collected using a repeated-measures design.

Two novel mutations identified in familial cases with Donohue syndrome.

Donohue syndrome (DS) is a rare and lethal autosomal recessive disease caused by mutations in the insulin receptor (INSR) gene, manifesting marked insulin resistance, severe growth retardation, hypertrichosis, and characteristic dysmorphic features. We report the clinical, molecular, and biochemical characterization of three new patients with DS, and address genotype-phenotype issues playing a role in the pathophysiology of DS. A female infant born to first-degree cousins Muslim Arab parents and two brothers born to first-degree cousins Druze parents presented classical features of DS with hypertrophic cardiomyopathy and died in infancy.

Discovery of GSK143, a highly potent, selective and orally efficacious spleen tyrosine kinase inhibitor.

The lead optimisation of the diaminopyrimidine carboxamide series of spleen tyrosine kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over liability kinases and hERG activity. GSK143 is a potent and highly selective SYK inhibitor showing good efficacy in the rat Arthus model.

Aryl aminopyrazole benzamides as oral non-steroidal selective glucocorticoid receptor agonists.

Aryl aminopyrazole amides capped with N-alkylbenzamides 13-16 are selective glucocorticoid receptor agonists. 2,6-Disubstituted benzamides have prednisolone-like potency or better in vitro. Good oral exposure was demonstrated in the rat, with compounds with lower lipophilicity, for example N-hydroxyethyl benzamides (e.

The first X-ray crystal structure of the glucocorticoid receptor bound to a non-steroidal agonist.

The amino-pyrazole 2,6-dichloro-N-ethyl benzamide 1 is a selective GR agonist with dexamethasone-like in vitro potency. Its X-ray crystal structure in the GR LBD (Glucocorticoid ligand-binding domain) is described and compared to other reported structures of steroidal GR agonists in the GR LBD (3E7C).

Convergent, regiospecific synthesis of quinolines from o-aminophenylboronates.

A direct convergent two-component synthesis of quinolines from alpha,beta-unsaturated ketones and o-aminophenylboronic acid derivatives is reported. The reaction is regiocomplementary to the traditional Skraup-Doebner-Von Miller synthesis and proceeds under basic rather than strongly acidic conditions. Quinolines substituted in the benzenoid ring can be accessed by using substituted o-aminophenylboronates prepared by direct palladium-catalyzed borylation of the corresponding o-bromoanilines.

Nonsteroidal glucocorticoid agonists: tetrahydronaphthalenes with alternative steroidal A-ring mimetics possessing dissociated (transrepression/transactivation) efficacy selectivity.

The synthesis and biological activity of tetrahydronaphthalene derivatives coupled to various heterocycles are described. These compounds are potent glucocorticoid receptor agonists with efficacy selectivity in an NFkappaB glucocorticoid receptor (GR) agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). Quinolones, indoles, and C- and N-linked quinolines are some of the heterocycles that provide efficacy selectivity.

Insulin receptor substrate 1 (IRS-1) plays a unique role in normal epidermal physiology.

Insulin receptor substrate (IRS) proteins play a central role in insulin signaling. Previously we have demonstrated that insulin is essential for normal skin development and function. In the present study we investigated the involvement of the IRS-1 and IRS-2 proteins in skin physiology and in mediating insulin action in skin.

Insulin-like growth factor 1 receptor signaling regulates skin development and inhibits skin keratinocyte differentiation.

The insulin-like growth factor 1 receptor (IGF-1R) is a multifunctional receptor that mediates signals for cell proliferation, differentiation, and survival. Genetic experiments showed that IGF-1R inactivation in skin results in a disrupted epidermis. However, because IGF-1R-null mice die at birth, it is difficult to study the effects of IGF-1R on skin.

Insulin receptor substrate 2 plays diverse cell-specific roles in the regulation of glucose transport.

The insulin receptor substrate 2 (IRS-2) protein is one of the major insulin-signaling substrates. In the present study, we investigated the role of IRS-2 in skin epidermal keratinocytes and dermal fibroblasts. Although skin is not a classical insulin target tissue, we have previously demonstrated that insulin, via the insulin receptor, is essential for normal skin cell physiology.

Design and synthesis of pyrrolidine-5,5'-trans-lactams (5-oxo-hexahydropyrrolo[3,2-b]pyrroles) as novel mechanism-based inhibitors of human cytomegalovirus protease. 4. Antiviral activity and plasma stability.

A series of chiral, (S)-proline-alpha-methylpyrrolidine-5,5-trans-lactam serine protease inhibitors has been developed as antivirals of human cytomegalovirus (HCMV). The SAR of the functionality on the proline nitrogen has shown that derivatives of para-substituted phenyl ureas > para-substituted phenyl sulfonamides > para-substituted phenyl carboxamide for activity against HCMV deltaAla protease, producing para-substituted phenyl ureas with single figure nM potency (K(i)) against the viral enzyme. The SAR of the functionality on the lactam nitrogen has defined the steric and electronic requirements for high human plasma stability while retaining good activity against HCMV protease.

Pyrrolidine-5,5-trans-lactams as novel mechanism-based inhibitors of human cytomegalovirus protease. Part 3: potency and plasma stability.

Mechanism-based inhibitors of HCMV protease, which are stable to human plasma (> or = 20 h) and have single-figure potency in the microM range against HCMV protease, have been developed based on the dansylproline alpha-methyl pyrrolidine-5,5-trans-lactam nucleus.

Identification of potent and selective oxytocin antagonists. Part 2: further investigation of benzofuran derivatives.

The paper covers continuing efforts to discover novel, potent and selective oxytocin antagonists. Further benzofuran derivatives with potent oxytocin antagonist activity and good pharmacokinetic parameters are reported. Efforts to improve the in vivo activity of the series are described.

Design and synthesis of pyrrolidine-5,5-trans-lactams (5-oxohexahydropyrrolo[3,2-b]pyrroles) as novel mechanism-based inhibitors of human cytomegalovirus protease. 2. Potency and chirality.

The stereospecific synthesis of a series of alpha-methylpyrrolidine-5,5-trans-lactam inhibitors of human cytomegalovirus (HCMV) protease is described. Examination of the SAR in this series has defined the size and chirality of the alpha-substituent, optimized the acyl substituent on the lactam nitrogen, and defined the steric constraint of this functionality. The SAR of the functionality on the pyrrolidine nitrogen of the trans-lactam has been investigated, and this has led to the discovery of potent serine protease inhibitors that are highly selective for the viral enzyme over the mammalian enzymes elastase, thrombin, and acetylcholine esterase.

Design and synthesis of pyrrolidine-5,5-trans-lactams (5-oxo-hexahydro-pyrrolo[3,2-b]pyrroles) as novel mechanism-based inhibitors of human cytomegalovirus protease. 1. The alpha-methyl-trans-lactam template.

Mechanism-based inhibitors of human cytomegalovirus (HCMV) protease have been designed based on the pyrrolidine-5,5-trans-lactam ring system. New routes to the beta-methyl-, desmethyl-, and alpha-methyl-pyrrolidine-5,5-trans-lactam templates have been developed from 2,4-diaminobutyric acid. ESI/MS studies have shown that these inhibitors can bind covalently and reversibly to the viral enzyme in a time-dependent manner by a mechanism which is consistent with acylation of HCMV deltaAla protease at the active site nucleophile Ser 132.

Design and synthesis of monocyclic beta-lactams as mechanism-based inhibitors of human cytomegalovirus protease.

Mechanism based inhibitors of HCMV protease have been designed based on the monocyclic beta-lactam nucleus, which have been shown to acylate the viral enzyme in a time dependent manner. SAR in a series of monocyclic beta-lactam N-ureas, has defined the size and relative stereochemistry of the C-3 substituent producing a low micromolar inhibitor 17b with good aqueous stability and selectivity over the mammalian serine proteases.