Rasch Analysis of Joint Replacement Version for Hip Disability and Osteoarthritis Outcome in Individuals With Advanced Osteoarthritis of Hip Awaiting Total Hip Arthroplasty Surgery.

OBJECTIVE: The objective of this study was to examine measurement properties of the Joint replacement version for Hip Disability and Osteoarthritis Outcome Score (HOOS-JR) using Rasch analysis in patients with osteoarthritis of hip (HOA). DESIGN: Cross-sectional clinical measurement SETTING: Patient outcomes database at a tertiary care hospital PARTICIPANTS: Convenience sampling of patients with HOA scheduled for total hip arthroplasty (N=327) OUTCOME MEASURES AND ANALYSIS: The data for pre-surgery assessments for patients with HOA were extracted from an existing database. Variables extracted included HOOS-JR scores, demographic information (age, sex), health-related data, and anthropometric variables. The assumptions of Rasch model such as the test of fit, fit residuals, ordering of item thresholds, factor structure, DIF, internal consistency and Pearson separation index were examined for the HOOS-JR scores. RESULTS: The HOOS-JR showed adequate overall fit to the Rasch model, logically ordered response thresholds, no floor or ceiling effects, and high internal consistency (Cronbach's alpha of 0.91). The HOOS-JR did not satisfy the assumption of unidimensionality, albeit the violation of this assumption was marginal (6.12% over 5%). Person-item threshold distribution (difference between person and item means were equal to 0.92 which was less than 1 logit unit) confirmed that the HOOS-JR scores were well targeted. CONCLUSIONS: Given that the violation of unidimensionality for HOOS-JR was marginal, we recommend further studies to validate this finding. Results broadly support the use of HOOS-JR for assessing hip health in patients with HOA.

Influence of reagent lots and multiple measuring systems on estimating the coefficient of variation from quality control data; implications for uncertainty estimation and interpretation of QC results.

Background Clinical laboratories use internal quality control (QC) data to calculate standard deviation (SD) and coefficient of variation (CV) to estimate uncertainty of results and to interpret QC results. We examined the influence of different instruments, and QC and reagent lots on the CV calculated from QC data. Methods Results for BioRad Multiqual frozen liquid QC samples over a 2-year interval were partitioned by QC and reagent lots. The mean and CV were calculated for each partition for each of three Abbott Architect c8000 instruments for measuring serum alanine amino transferase (ALT), creatinine (enzymatic), glucose and sodium. Results CVs differed among partitions and instruments for two QC levels by 5.8- and 3.3-fold for ALT, by 4.7- and 2.1-fold for creatinine, by 2.0- and 2.6-fold for glucose, and by 2.1- and 2.0-fold for sodium. Pooled CVs for two QC levels varied among instruments by 1.78- and 1.11-fold for ALT, by 1.63- and 1.11-fold for creatinine, by 1.08- and 1.06-fold for glucose, and by 1.24- and 1.31-fold for sodium. Conclusions The CVs from QC data varied substantially among QC and reagent lots and for different identical specification instruments. The CV used to estimate uncertainty for a measurement result or as the basis for interpreting individual QC results must be derived over a sufficient time interval to obtain a pooled CV that represents "typical" performance of a measuring system. An estimate of uncertainty provided to users of laboratory results will itself have uncertainty that can influence medical decisions.

Identifying cases of heroin toxicity where 6-acetylmorphine (6-AM) is not detected by toxicological analyses.

PURPOSE: Heroin has a half-life of 2-6 min and is metabolized too quickly to be detected in autopsy samples. The presence of 6-acetylmophine (6-AM) in urine, blood, or other samples is convincing evidence of heroin use by a decedent, but 6-AM itself has a half-life of 6-25 min before it is hydrolyzed to morphine, so 6-AM may not be present in sufficient concentration to detect in postmortem samples. Codeine is often present in heroin preparations as an impurity and is not a metabolite of heroin. Studies report that a ratio of morphine to codeine greater than one indicates heroin use. We hypothesize that the ratio of morphine to codeine in our decedents abusing drugs intravenously will be no different in individuals with 6-AM present than in individuals where no 6-AM is detected, and we report our study of this hypothesis. METHODS: All accidental deaths investigated by the Jefferson County Coroner/Medical Examiner Office from 2010 to 2013 with morphine detected in blood samples collected at autopsy were reviewed. Five deaths where trauma caused or contributed to death were excluded from the review. The presence or absence of 6-AM and the concentrations of morphine and codeine were recorded for each case. The ratio of morphine to codeine was calculated for all decedents. Any individual in whom no morphine or codeine was detected in a postmortem sample was excluded from further study. Absence or presence of drug paraphernalia or evidence of intravascular (IV) drug use was documented in each case to identify IV drug users. The proportion of the IV drug users with and without 6-AM present in a postmortem sample was compared to the M/C ratio for the individuals. RESULTS: Of the 230 deaths included in the analysis, 103 IV drug users with quantifiable morphine and codeine in a postmortem sample were identified allowing for calculation of an M/C ratio. In these IV drug users, the M/C ratio was greater than 1 in 98 % of decedents. When controlling for the absence or presence of 6-AM there was no statistically significant difference in the proportion of IV drug users when compared to non IV drug users with an M/C ratio of greater than 1 (p = 1.000). CONCLUSION: The M/C ratio in IV drug users, if greater than 1, is seen in deaths due to heroin toxicity where 6-AM is detected in a postmortem sample. This study provides evidence that a M/C ratio greater than one in an IV drug user is evidence of a death due to heroin toxicity even if 6-AM is not detected in the blood. Using the M/C ratio, in addition to scene and autopsy findings, provides sufficient evidence to show heroin is the source of the morphine and codeine. Listing heroin as a cause or contributing factor in deaths with evidence of IV drug abuse and where the M/C ratio exceeds 1 will improve identification of heroin fatalities, which will allow better allocation of resources for public health initiatives.

The Tennessee Heart Health Network effectiveness study: A stepped wedge cluster randomized controlled trial to assess the effectiveness of statewide quality improvement cooperative participation on cardiovascular outcomes.

BACKGROUND: Cardiovascular disease (CVD) is the primary cause of premature morbidity and mortality in the United States and Tennessee ranks among the highest in CVD events. While patient-centered outcomes research (PCOR) evidence-based approaches that reach beyond the traditional doctor-patient visit hold promise to improve CVD care and prevent serious complications, most primary care providers lack time, knowledge, and infrastructure to implement these proven approaches. Statewide primary care quality improvement (QI) collaboratives hold potential to help address primary care needs, however, little is known regarding their effectiveness in improving uptake of PCOR evidence-based population health approaches and improving CVD outcomes. This study describes the design and implementation of a stepped-wedge cluster randomized controlled trial to assess the effectiveness of participation in a statewide quality improvement cooperative (The Tennessee Heart Health Network [TN-HHN]) on cardiovascular outcomes. METHODS/DESIGN: The TN-HHN Effectiveness Study randomized 77 practices to 4 waves (i.e., clusters), with each wave beginning three months after the start of the prior wave and lasting for 18 months. All practice clusters received one of three Network interventions, and outcomes are measured for each three months both in the control phase and the intervention phase. Primary outcomes include Center for Medicare and Medicaid Services measures for aspirin use, blood pressure control, cholesterol control, and smoking cessation (ABCS). CONCLUSIONS: This trial, upon its conclusion, will allow us to assess the effect of participation in a statewide quality improvement cooperative on cardiovascular outcomes as well as key contributors to successful practice transformation.

Delineating the Clinical Phenotype of Patients With the c.629C>G, p.Pro210Arg Mutation in Peripherin-2.

Purpose: More than 200 different mutations in peripherin-2 (PRPH2) are associated with multiple subtypes of inherited retinal diseases (IRDs), including retinitis pigmentosa and cone or macular diseases. Our goal was to understand how the poorly characterized PRPH2 mutation p.Pro210Arg (P210R) affects visual function and retinal structure as well as gain insight into the mechanism driving the clinical pathology. Methods: Eleven patients had clinical assessments including best-corrected visual acuity (BCVA), full field and multifocal electroretinography (ERG), static (spot size V) and kinetic perimetry (Octopus 900), and dark-adapted chromatic (DAC; Medmont; spot size V) perimetry. Images were acquired with the Optos ultra-wide field camera and spectral-domain optical coherence tomography (SD-OCT). Molecular characteristics of the P210R mutant protein were evaluated in vitro. Results: Patients with the P210R mutation had BCVA (Snellen) ranging from 20/15 to 20/80. Perimetry showed a reduction in sensitivity, while ERG findings suggested that cone function was more impaired than rod function. Scotomas were identified corresponding to atrophic retinal lesions. Imaging revealed heterogeneous outer retinal changes such as hyperfluorescent flecks, hypo-autofluorescence (AF) regions of atrophy, and thinning of the photoreceptor layer on SD-OCT. In vitro findings suggested that P210R-Prph2 retains the ability to interact with binding partner Rom1 but abnormally accumulates in the endoplasmic reticulum (ER), suggesting the protein does not fold properly. Conclusions: Rod and cone sensitivities were decreased in subjects with the P210R mutation in PRPH2. There was scotomatous vision loss that occurred within the macula, likely due to atrophy that occurs after drusen have formed and have begun to resolve. This suggests that although rod and cone photoreceptors are dependent on PRPH2, preventing blindness in this specific subgroup of patients could involve therapeutics that impede the formation or lifecycle of drusen.

Neuroprotection mediated by ST266 requires full complement of proteins secreted by amnion-derived multipotent progenitor cells.

ST266 is the biological secretome of cultured Amnion-derived Multipotent Progenitor cells containing multiple growth factors and cytokines. While intranasally-administered ST266 improves the phenotype in experimental optic neuritis, specific ST266 components mediating these effects are not known. We compared the effects of ST266 with and without removal of large molecular weight proteins both in vitro and in the multiple sclerosis model experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice. Mice were treated daily with intranasal vehicle, ST266 or lower molecular weight fraction of ST266. Retinal ganglion cells were counted in isolated retinas, and optic nerves were assessed for inflammation and demyelination. ST266 treatment significantly improved retinal ganglion cell survival and reduced optic nerve demyelination in EAE mice. The lower molecular weight ST266 fraction significantly improved optic nerve demyelination, but only showed a trend towards improved retinal ganglion cell survival. ST266 fractions below 50kDa increased Schwann cell proliferation in vitro, but were less effective than non-fractionated ST266. Demyelination attenuation was partially associated with the lower molecular weight ST266 fraction, but removal of higher molecular weight biomolecules from ST266 diminishes its neuroprotective effects, suggesting at least some high molecular weight proteins play a role in ST266-mediated neuroprotection.

BCL9/STAT3 regulation of transcriptional enhancer networks promote DCIS progression.

The molecular processes by which some human ductal carcinoma in situ (DCIS) lesions advance to the more aggressive form, while others remain indolent, are largely unknown. Experiments utilizing a patient-derived (PDX) DCIS Mouse INtraDuctal (MIND) animal model combined with ChIP-exo and RNA sequencing revealed that the formation of protein complexes between B Cell Lymphoma-9 (BCL9), phosphoserine 727 STAT3 (PS-727-STAT3) and non-STAT3 transcription factors on chromatin enhancers lead to subsequent transcription of key drivers of DCIS malignancy. Downregulation of two such targets, integrin ß3 and its associated metalloproteinase, MMP16, resulted in a significant inhibition of DCIS invasive progression. Finally, in vivo targeting of BCL9, using rosemary extract, resulted in significant inhibition of DCIS malignancy in both cell line and PDX DCIS MIND animal models. As such, our studies provide compelling evidence for future testing of rosemary extract as a chemopreventive agent in breast cancer.

High prevalence of discordant human papillomavirus and p16 oropharyngeal squamous cell carcinomas in an African American cohort.

BACKGROUND: Most studies on human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (SCC) have been performed on white Americans. Our study examined the incidence of HPV in an African American oropharyngeal SCC cohort and its survival. METHODS: African American patients with oropharyngeal SCC in a combined tumor registry were identified. HPV16 testing was performed by polymerase chain reaction (PCR) from DNA extracted from tumor blocks. The p16 staining was performed using standard immunohistochemistry. RESULTS: Forty-four patients were identified for analysis. Seventy-three percent of the tumors were HPV-positive. Only 39% of the patients who were HPV-positive were also p16-positive. Survival between all 3 tumor types, patients who tested HPV-positive/p16, HPV-positive/p16-positive, and HPV-negative/p16-negative was significantly different (p = .03). HPV/p16 status was significant on univariate and multivariate analysis. CONCLUSION: HPV oropharyngeal SCC is strongly present in this African American cohort. Two thirds of the patients who were HPV-positive were p16-negative. Greater study is needed to explain the high p16 negativity among this HPV-positive oropharyngeal SCC African American cohort. © 2015 Wiley Periodicals, Inc. Head Neck 38: E867-E872, 2016.

Pathways to Improve Student Pharmacists' Experience in Research.

OBJECTIVE: To describe the implementation of a student research program and to provide outcomes from the initial 4 years' experience. DESIGN: Students conducted individual research projects in a 4-year longitudinal program (known as Pathway), with faculty member advising and peer mentoring. A prospective assessment compared perceptions of those who completed the Pathway program with those of students who did not. Descriptive statistics, t tests, and analysis of variance (ANOVA) were used. ASSESSMENT: The class of 2013 was the first to complete the Pathway program. In the Pathway assessment project, 59% (n=47) of students who responded reached self-set goals. Pathway students agreed that this research experience improved their ability to work/think independently, evaluate literature, and distinguish themselves from other students. CONCLUSION: The Pathway program helped students understand the research process and reach other self-set goals.

Structure of an Aspergillus fumigatus old yellow enzyme (EasA) involved in ergot alkaloid biosynthesis.

The Aspergillus fumigatus old yellow enzyme (OYE) EasA reduces chanoclavine-I aldehyde to dihydrochanoclavine aldehyde and works in conjunction with festuclavine synthase at the branchpoint for ergot alkaloid pathways. The crystal structure of the FMN-loaded EasA was determined to 1.8 Šresolution. The active-site amino acids of OYE are conserved, supporting a similar mechanism for reduction of the α/ß-unsaturated aldehyde. The C-terminal tail of one monomer packs into the active site of a monomer in the next asymmetric unit, which is most likely to be a crystallization artifact and not a mechanism of self-regulation.

Iloprost improves gas exchange in patients with pulmonary hypertension and ARDS.

OBJECTIVE: We hypothesized that nebulized iloprost would improve ventilation-perfusion matching in patients with pulmonary hypertension and ARDS as reflected by an improved Pao2/Fio2 ratio and Pao2 without adversely affecting lung mechanics or systemic hemodynamics. METHODS: Patients with ARDS and pulmonary hypertension were enrolled. With constant ventilator settings, hemodynamics, airway pressures, and gas exchange measured at baseline were compared with values 30 min after administration of 10 µg nebulized iloprost, and again 30 min after a second, larger, 20 µg dose of iloprost, and then a final measurement 2 h after the second dose. The primary outcome variable was Pao2; secondary outcomes were Pao2/Fio2 ratio, mean arterial BP, and lung-compliance ventilatory equivalents for oxygen and CO2. RESULTS: After informed consent was obtained, 20 patients (nine men, 11 women; median age, 59 years [interquartile range, 44-66 years]) with ARDS were enrolled. Baseline PaO2 improved from a mean (±SD) of 82 (13) mm Hg to 100 (25) mm Hg after both the first and second doses of iloprost, and the baseline mean (±SD) PaO2/FIO2 ratio of 177 (60) improved to 213 (67) and 212 (70) (all P<.01). PaCO2, peak and plateau airway pressures, systemic BP, and heart rate were not significantly changed after iloprost. CONCLUSIONS: The improvement in gas exchange without any detrimental effects on pulmonary mechanics or systemic hemodynamics suggests nebulized iloprost may be a useful therapeutic agent to improve oxygenation in patients with ARDS. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01274481; URL: www.clinicaltrials.gov.