Profiling quality of care: Is there a role for peer review?

BACKGROUND: We sought to develop a more reliable structured implicit chart review instrument for use in assessing the quality of care for chronic disease and to examine if ratings are more reliable for conditions in which the evidence base for practice is more developed. METHODS: We conducted a reliability study in a cohort with patient records including both outpatient and inpatient care as the objects of measurement. We developed a structured implicit review instrument to assess the quality of care over one year of treatment. 12 reviewers conducted a total of 496 reviews of 70 patient records selected from 26 VA clinical sites in two regions of the country. Each patient had between one and four conditions specified as having a highly developed evidence base (diabetes and hypertension) or a less developed evidence base (chronic obstructive pulmonary disease or a collection of acute conditions). Multilevel analysis that accounts for the nested and cross-classified structure of the data was used to estimate the signal and noise components of the measurement of quality and the reliability of implicit review. RESULTS: For COPD and a collection of acute conditions the reliability of a single physician review was quite low (intra-class correlation = 0.16–0.26) but comparable to most previously published estimates for the use of this method in inpatient settings. However, for diabetes and hypertension the reliability is significantly higher at 0.46. The higher reliability is a result of the reviewers collectively being able to distinguish more differences in the quality of care between patients (p < 0.007) and not due to less random noise or individual reviewer bias in the measurement. For these conditions the level of true quality (i.e. the rating of quality of care that would result from the full population of physician reviewers reviewing a record) varied from poor to good across patients. CONCLUSIONS: For conditions with a well-developed quality of care evidence base, such as hypertension and diabetes, a single structured implicit review to assess the quality of care over a period of time is moderately reliable. This method could be a reasonable complement or alternative to explicit indicator approaches for assessing and comparing quality of care. Structured implicit review, like explicit quality measures, must be used more cautiously for illnesses for which the evidence base is less well developed, such as COPD and acute, short-course illnesses

Haptic Edge Detection Through Shear

Most tactile sensors are based on the assumption that touch depends on measuring pressure. However, the pressure distribution at the surface of a tactile sensor cannot be acquired directly and must be inferred from the deformation field induced by the touched object in the sensor medium. Currently, there is no consensus as to which components of strain are most informative for tactile sensing. Here, we propose that shape-related tactile information is more suitably recovered from shear strain than normal strain. Based on a contact mechanics analysis, we demonstrate that the elastic behavior of a haptic probe provides a robust edge detection mechanism when shear strain is sensed. We used a jamming-based robot gripper as a tactile sensor to empirically validate that shear strain processing gives accurate edge information that is invariant to changes in pressure, as predicted by the contact mechanics study. This result has implications for the design of effective tactile sensors as well as for the understanding of the early somatosensory processing in mammals

Possible mechanisms of host resistance to Haemonchus contortus infection in sheep breeds native to the Canary Islands

Haemonchus contortus appears to be the most economically important helminth parasite for small ruminant production in many regions of the world. The two sheep breeds native to the Canary Islands display distinctly different resistant phenotypes under both natural and experimental infections. Canaria Hair Breed (CHB) tends to have significantly lower worm burden and delayed and reduced egg production than the susceptible Canaria Sheep (CS). To understand molecular mechanisms underlying host resistance, we compared the abomasal mucosal transcriptome of the two breeds in response to Haemonchus infection using RNAseq technology. The transcript abundance of 711 and 50 genes were significantly impacted by infection in CHB and CS, respectively (false discovery rate <0.05) while 27 of these genes were significantly affected in both breeds. Likewise, 477 and 16 Gene Ontology (GO) terms were significantly enriched in CHB and CS, respectively (P < 1.0 × 10(−4)). A broad range of mechanisms have evolved in resistant CHB to provide protection against the parasite. Our findings suggest that readily inducible acute inflammatory responses, complement activation, accelerated cell proliferation and subsequent tissue repair, and immunity directed against parasite fecundity all contributed to the development of host resistance to parasitic infection in the resistant breed

A new implicit review instrument for measuring quality of care delivered to pediatric patients in the emergency department

BackgroundThere are few outcomes experienced by children receiving care in the Emergency Department (ED) that are amenable to measuring for the purposes of assessing of quality of care. The purpose of this study was to develop, test, and validate a new implicit review instrument that measures quality of care delivered to children in EDs.MethodsWe developed a 7-point structured implicit review instrument that encompasses four aspects of care, including the physician's initial data gathering, integration of information and development of appropriate diagnoses; initial treatment plan and orders; and plan for disposition and follow-up. Two pediatric emergency medicine physicians applied the 5-item instrument to children presenting in the highest triage category to four rural EDs, and we assessed the reliability of the average summary scores (possible range of 5-35) across the two reviewers using standard measures. We also validated the instrument by comparing this mean summary score between those with and without medication errors (ascertained independently by two pharmacists) using a two-sample t-test.ResultsWe reviewed the medical records of 178 pediatric patients for the study. The mean and median summary score for this cohort of patients were 27.4 and 28.5, respectively. Internal consistency was high (Cronbach's alpha of 0.92 and 0.89). All items showed a significant (p &lt; 0.005) positive correlation between reviewers using the Spearman rank correlation (range 0.24 to 0.39). Exact agreement on individual items between reviewers ranged from 70.2% to 85.4%. The Intra-class Correlation Coefficient for the mean of the total summary score across the two reviewers was 0.65. The validity of the instrument was supported by the finding of a higher score for children without medication errors compared to those with medication errors which trended toward significance (mean score = 28.5 vs. 26.0, p = 0.076).ConclusionThe instrument we developed to measure quality of care provided to children in the ED has high internal consistency, fair to good inter-rater reliability and inter-rater correlation, and high content validity. The validity of the instrument is supported by the fact that the instrument's average summary score was lower in the presence of medication errors, which trended towards statistical significance

Effect of frequency difference on sensitivity of beats perception

Two vibrations with slightly different frequencies induce the beats phenomenon. In tactile perception, when two pins of different frequencies stimulate the fingertips, an individual perceives a beats caused by a summation stimulus of the two vibrations. The present study demonstrates experimentally that humans can perceive another vibration based on the beats phenomenon when two tactile stimuli with slightly different frequencies are stimulated on the finger pad with a small contactor in different locations at the same time. Moreover, we examined the amplitude of the detection threshold to be able to perceive beats phenomenon on the index finger with 5 carrier frequency (63.1, 100, 158.5, 251.2, and 398.1 Hz) and 4 beats frequency (2.5, 3.98, 6.31, and 10 Hz) when two stimuli 1 mm distance apart are vibrated at a slightly different frequency. From the experiments, it is concluded that the amplitude threshold to be able to perceive beats decreases as the standard frequency increases under 398 Hz. Furthermore, from comparing the absolute detection threshold and beats detection threshold, as the carrier frequency increases, the required amplitude at two pins for the detection of beats decreases compared to absolute vibration

Detection of Functional Modes in Protein Dynamics

Proteins frequently accomplish their biological function by collective atomic motions. Yet the identification of collective motions related to a specific protein function from, e.g., a molecular dynamics trajectory is often non-trivial. Here, we propose a novel technique termed “functional mode analysis” that aims to detect the collective motion that is directly related to a particular protein function. Based on an ensemble of structures, together with an arbitrary “functional quantity” that quantifies the functional state of the protein, the technique detects the collective motion that is maximally correlated to the functional quantity. The functional quantity could, e.g., correspond to a geometric, electrostatic, or chemical observable, or any other variable that is relevant to the function of the protein. In addition, the motion that displays the largest likelihood to induce a substantial change in the functional quantity is estimated from the given protein ensemble. Two different correlation measures are applied: first, the Pearson correlation coefficient that measures linear correlation only; and second, the mutual information that can assess any kind of interdependence. Detecting the maximally correlated motion allows one to derive a model for the functional state in terms of a single collective coordinate. The new approach is illustrated using a number of biomolecules, including a polyalanine-helix, T4 lysozyme, Trp-cage, and leucine-binding protein

Validation of pharmacodynamic assays to evaluate the clinical efficacy of an antisense compound (AEG 35156) targeted to the X-linked inhibitor of apoptosis protein XIAP

The inhibitor of apoptosis protein, XIAP, is frequently overexpressed in chemoresistant human tumours. An antisense oligonucleotide (AEG 35156/GEM 640) that targets XIAP has recently entered phase I trials in the UK. Method validation data are presented on three pharmacodynamic assays that will be utilised during this trial. Quantitative RT-PCR was based on a Taqman assay and was confirmed to be specific for XIAP. Assay linearity extended over four orders of magnitude. MDA-MB-231/U6-E1 cells and clone X-G4 stably expressing an RNAi vector against XIAP were chosen as high and low XIAP expression quality controls (QCs). Within-day and between-day coefficients of variation (CVs) in precision for cycle threshold (CT) and delta CT values (employing GAPDH and beta 2 microglobulin as housekeepers) were always less than 10%. A Western blotting technique was validated using a GST–XIAP fusion protein as a standard and HeLa cells and SF268 (human glioblastoma) cells as high and low XIAP expression QCs. Specificity of the final choice of antibody for XIAP was evaluated by analysing a panel of cell lines including clone X-G4. The assay was linear over a 29-fold range of protein concentration and between-day precision was 29% for the low QC and 23% for the high QC when normalised to GAPDH. XIAP protein was also shown to be stable at −80°C for at least 60 days. M30-Apoptosense™ plasma Elisa detects a caspase-cleaved fragment of cytokeratin 18 (CK18), believed to be a surrogate marker for tumour cell apoptosis. Generation of an independent QC was achieved through the treatment of X-G4 cells with staurosporine and collection of media. Measurements on assay precision and kit-to-kit QC were always less than 10%. The M30 antigen (CK18-Asp396) was stable for 3 months at −80°C, while at 37°C it had a half-life of 80–100 h in healthy volunteer plasma. Results from the phase I trial are eagerly awaited

Regional differences in prostaglandin E₂ metabolism in human colorectal cancer liver metastases

Background: Prostaglandin (PG) E₂ plays a critical role in colorectal cancer (CRC) progression, including epithelial-mesenchymal transition (EMT). Activity of the rate-limiting enzyme for PGE₂ catabolism (15-hydroxyprostaglandin dehydrogenase [15-PGDH]) is dependent on availability of NAD+. We tested the hypothesis that there is intra-tumoral variability in PGE₂ content, as well as in levels and activity of 15-PGDH, in human CRC liver metastases (CRCLM). To understand possible underlying mechanisms, we investigated the relationship between hypoxia, 15-PGDH and PGE₂ in human CRC cells in vitro. Methods: Tissue from the periphery and centre of 20 human CRCLM was analysed for PGE₂ levels, 15-PGDH and cyclooxygenase (COX)-2 expression, 15-PGDH activity, and NAD+/NADH levels. EMT of LIM1863 human CRC cells was induced by transforming growth factor (TGF) β. Results: PGE₂ levels were significantly higher in the centre of CRCLM compared with peripheral tissue (P = 0.04). There were increased levels of 15-PGDH protein in the centre of CRCLM associated with reduced 15-PGDH activity and low NAD+/NADH levels. There was no significant heterogeneity in COX-2 protein expression. NAD+ availability controlled 15-PGDH activity in human CRC cells in vitro. Hypoxia induced 15-PGDH expression in human CRC cells and promoted EMT, in a similar manner to PGE₂. Combined 15-PGDH expression and loss of membranous E-cadherin (EMT biomarker) were present in the centre of human CRCLM in vivo.Conclusions: There is significant intra-tumoral heterogeneity in PGE₂ content, 15-PGDH activity and NAD+ availability in human CRCLM. Tumour micro-environment (including hypoxia)-driven differences in PGE₂ metabolism should be targeted for novel treatment of advanced CRC

Effects of the 5-HT2C receptor agonist meta-chlorophenylpiperazine on appetite, food intake and emotional processing in healthy volunteers

RATIONALE: The treatment of obesity is an increasing global health priority, yet few effective drug treatments are currently available. The discovery of novel anti-obesity therapies could be assisted by the validation of experimental (translational) medicine models in healthy volunteers that assess efficacy and safety at an early stage of drug development. OBJECTIVES: The aim of this study was to examine the effects of the 5-HT2C receptor agonist meta-chlorophenylpiperazine (mCPP) in an experimental medicine model assessing both appetite and mood. METHODS: Using a between-subjects, double-blind, placebo-controlled design, 24 male and 24 female participants were randomly assigned to either placebo, 15- or 30-mg mCPP treatment groups. Lunch was eaten from a Universal Eating Monitor (UEM) that measured eating rate, and the participants completed the P1vital® Oxford Emotional Test Battery (ETB) and a series of appetite and mood ratings. RESULTS: mCPP reduced appetite and, in women, enhanced measures of satiation. The drug also enhanced memory for emotional material in the word recall and recognition memory tasks of the ETB. CONCLUSIONS: The results provide new insight into the effects of mCPP on appetite, satiety and memory in humans. In addition, our data provide an illustration of the value of measuring changes in appetite and mood in healthy volunteers to determine the potential efficacy and safety of novel anti-obesity drugs

Destabilizing Protein Polymorphisms in the Genetic Background Direct Phenotypic Expression of Mutant SOD1 Toxicity

Genetic background exerts a strong modulatory effect on the toxicity of aggregation-prone proteins in conformational diseases. In addition to influencing the misfolding and aggregation behavior of the mutant proteins, polymorphisms in putative modifier genes may affect the molecular processes leading to the disease phenotype. Mutations in SOD1 in a subset of familial amyotrophic lateral sclerosis (ALS) cases confer dominant but clinically variable toxicity, thought to be mediated by misfolding and aggregation of mutant SOD1 protein. While the mechanism of toxicity remains unknown, both the nature of the SOD1 mutation and the genetic background in which it is expressed appear important. To address this, we established a Caenorhabditis elegans model to systematically examine the aggregation behavior and genetic interactions of mutant forms of SOD1. Expression of three structurally distinct SOD1 mutants in C. elegans muscle cells resulted in the appearance of heterogeneous populations of aggregates and was associated with only mild cellular dysfunction. However, introduction of destabilizing temperature-sensitive mutations into the genetic background strongly enhanced the toxicity of SOD1 mutants, resulting in exposure of several deleterious phenotypes at permissive conditions in a manner dependent on the specific SOD1 mutation. The nature of the observed phenotype was dependent on the temperature-sensitive mutation present, while its penetrance reflected the specific combination of temperature-sensitive and SOD1 mutations. Thus, the specific toxic phenotypes of conformational disease may not be simply due to misfolding/aggregation toxicity of the causative mutant proteins, but may be defined by their genetic interactions with cellular pathways harboring mildly destabilizing missense alleles