Comparison of the diagnostic performance of human whole genome microarrays using mixed-tissue RNA reference samples

Universal approaches for assessing the diagnostic performance of microarray assays are essential for the application of microarray technology to clinical and regulatory settings. Reference systems for diagnostic assays in laboratory medicine typically involve the utilization of reference samples, metrics, and reference datasets to ensure that measurements are comparable and true. For microarray performance evaluation and process improvement, reference samples can be composed of mixes of different tissue or cell line RNAs that contain tissue-selective analytes at defined target ratios. The diagnostic accuracy of detected changes in expression, measured as the area under the curve from receiver-operating characteristic plots, can provide a single commutable value for comparing assay specificity and sensitivity. Examples of applying this method for assessing overall performance are provided using public datasets generated on five commercial human whole genome microarray platforms for the MicroArray Quality Control project, a community-wide effort to address issues surrounding microarray data reliability.     

Carcinoma broncogénico en pacientes con trasplante de órgano sólido. Papel de la cirugía

Background

The incidence of neoplastic diseases is higher in patients undergoing solid organ transplant. However, the incidence of bronchogenic carcinoma (BC) is controversial. The objective of our study was to determine the incidence of BC in a large cohort of transplant patients and the role of surgery.

Material and methods

Until December 2006, 3596 patients underwent solid organ transplant at our institution; 24 (0.7%) patients subsequently developed BC, of which 6 (24%) were classified as clinical stage I and submitted to surgical treatment. Survival was estimated by the Kaplan-Meier method.

Results

Three patients received a liver transplant, two a kidney transplant and one a heart transplant. All were male and all had a smoking history. Mean age was 58.6 years. Two patients had cough, one accompanied by bloody expectoration, and BC was an incidental finding in the remaining cases. The interval between transplant and diagnosis of BC was 38.1 months. Epidermoid carcinoma was the most frequent histological type. Mean tumour size was 3.6 cm (range, 1.3-6). One tumour was classified as pathological stage IA, four as stage IB and one as IIB due to parietal pleural invasion. No patient died during the perioperative period and only one had a haemothorax which resolved with chest tube drainage. Mean hospital stay was 8.5 days (range, 7-11). The immunosuppression regimen was maintained continuously. In subsequent follow-up, one patient died from BC metastasis, one from sepsis, one from chronic renal failure, and three remained alive. The probability of survival at 5 years was 40%, and median survival was established at 5 years.

Conclusions

The incidence of BC in patients undergoing solid organ transplant and the proportion of patients diagnosed in early stages does not differ from non-transplant patients diagnosed with BC, which questions the role of immunosuppression in the genesis and aggressiveness of BC in transplant patients. Surgery may offer acceptable results in early stages, with acceptable rates of perioperative morbidity and mortality.     

Safety is part of quality: a proposal for a continuum in performance measurement

Objectives Safer care is a strategic priority for health care organizations worldwide. Yet, the measurement and evaluation of key processes and outcomes associated with safer care remains challenging, even with existing performance measurement indicators. The multi‐national Quality Indicator Project (QI Project^®) data are analysed to [ 1 ] document the patterns of safety indicators used between 1999 and 2006 among hospitals in Asia, Europe and the USA; and [ 2 ] to identify trends in using both organization‐level and patient‐level data in hospital performance improvement. Design and setting Retrospective data are used to ascertain how the use of safety indicators has changed in comparison to other QI Project^® indicators. ‘Continent’ rather than ‘hospital’ is used as the unit of analysis and P‐values of the differences in use percentages across Asia, Europe and the USA are calculated. Results There was a significant increase in the use of QI Project^® indicators in Asia between 1999 and 2006. Measured as the mean percentage of usage, the safety versus ‘all other’ indicators' increase in Asia was 43.7% versus 27% (P < 0.05) and 37.2% versus 24.4% (P < 0.05), respectively, during the study's time period. The European participants used both safety and all other indicators less frequently, 14.7% versus 18% (P < 0.05) and 9.5% versus 19.8% (P < 0.05), respectively. Finally, USA hospitals demonstrated a larger difference in the decrease of QI Project^® indicator use than European hospitals between the ‘safety’ and ‘all other’ indicators, 12.7% decrease for safety indicators and 7.1% for all others (P < 0.05). These findings are consistent with trends reported in a previous study. Conclusion Traditional performance measures continue to assist hospitals in identifying crucial aspects of safety in the delivery of care. Building on the findings of a previous study, there are emerging trends in the type of measures used in hospitals in Asia, Europe and the USA pursuing the improvement of overall performance. The increasing use of patient‐level data specifically, in tandem with organizational level indicators, may signal the continuum of measurement strategies, now still predominately in the USA but anticipated to be adopted both in Europe and Asia.     

The role of overexpressed DYRK1A protein in the early onset of neurofibrillary degeneration in Down syndrome

The gene encoding the minibrain kinase/dual-specificity tyrosine phosphorylated and regulated kinase 1A (DYRK1A) is located in the Down syndrome (DS) critical region of chromosome 21. The third copy of DYRK1A is believed to contribute to abnormal brain development in patients with DS. In vitro studies showing that DYRK1A phosphorylates tau protein suggest that this kinase is also involved in tau protein phosphorylation in the human brain and contributes to neurofibrillary degeneration, and that this contribution might be enhanced in patients with DS. To explore this hypothesis, the brain tissue from 57 subjects including 16 control subjects, 21 patients with DS, and 20 patients with sporadic Alzheimer's disease (AD) was examined with two antibodies to the amino-terminus of DYRK1A (7F3 and G-19), as well as two polyclonal antibodies to its carboxy-terminus (X1079 and 324446). Western blots demonstrated higher levels of full-length DYRK1A in the brains of patients with DS when compared to control brains. Immunocytochemistry revealed that DYRK1A accumulates in neurofibrillary tangles (NFTs) in subjects with sporadic AD and in subjects with DS/AD. Overexpression of DYRK1A in patients with DS was associated with an increase in DYRK1A-positive NFTs in a gene dosage-dependent manner. Results support the hypothesis that overexpressed DYRK1A contributes to neurofibrillary degeneration in DS more significantly than in subjects with two copies of the DYRK1A gene and sporadic AD. Immunoreactivity with antibodies against DYRK1A not only in NFTs but also in granules in granulovacuolar degeneration and in corpora amylacea suggests that DYRK1A is involved in all three forms of degeneration and that overexpression of this kinase may contribute to the early onset of these pathologies in DS.     

The utility of knee releases in arthrogryposis

BACKGROUND: Knee contractures are difficult deformities to manage in arthrogryposis. There is little information regarding the long-term functional outcomes. METHODS: Patients with a diagnosis of arthrogryposis who had knee releases performed at a single institution with at least 2 years of follow-up were identified retrospectively. Patients were called back prospectively for a clinical examination and administration of the Pediatric Outcomes Data Collection Instrument (PODCI), Pediatric Evaluation of Disability Inventory (PEDI), and the WeeFIM instruments. Functional mobility was quantified using the Functional Mobility Scale (FMS). RESULTS: Thirty-two patients were identified with a total of 50 knees. There were 45 flexion contractures and 5 extension contractures. Average length of follow-up was 11.9 years (range, 2.2-23.6 years). Amount of extension on final follow-up correlated with all final FMS scores (P < 0.02). The FMS demonstrated decreases in mobility as distance increased. Twenty-two of 32 patients completed functional outcomes measures. Pediatric Evaluation of Disability Inventory Mobility scores, Functional Independence Measure for Children (WeeFIM) Mobility, and WeeFIM Self-Care scores were decreased compared with norms, and Normative PODCI scores at final follow-up showed significant impairment in Upper Extremity Function, Transfers/Mobility, Sports/Physical Function, and Global Function Domains. When patients were subdivided by length of follow-up, patients showed decline in scores for all FMS distances; PEDI Mobility Domains; WeeFIM Self-Care and Mobility Domains; and Transfer/Mobility, Sports/Physical Function, and Global Function Domains, as length of follow-up increased. CONCLUSIONS: Whereas knee releases may improve function in the short term, function and outcomes decline as patients age. Patients with arthrogryposis demonstrated significant impairment in normative scores for Upper Extremity/Physical Function, Transfers/Mobility, Sports/Physical Function, and Global Function Domains. In addition, function as measured by the PODCI, WeeFIM, and PEDI showed decreased scores as length of follow-up increased. We strongly advise that when counseling parents on this surgical intervention, parents are made aware that ambulatory ability may improve short term but may decline as patients age and contractures recur. LEVEL OF EVIDENCE: Therapeutic Level 4.     

The effect of the annular ligament on kinematics of the radial head

PURPOSE: There is evidence that the radial head translates during pronation and supination. This study measured radial head movement and the location of the pronation-supination axis of the forearm with and without the annular ligament. METHODS: Thirteen cadaveric arms were attached to a custom-built frame. Pronation and supination were achieved by actuation of the pronator teres and biceps tendons, respectively. Motion was captured by video cameras via marker arrays attached to the distal radius, distal ulna, humerus, and radial head. Three pronation-supination trials were performed with the annular ligament intact and the elbow positioned at 90 degrees . The sequence was repeated after transection of the annular ligament. RESULTS: The radial head traveled an average of 2.1 mm in the anteroposterior direction and 1.6 mm in the mediolateral direction during forearm rotation. After annular ligament resection, travel of the radial head increased by an average of 44% in the mediolateral direction and by 24% in the anteroposterior direction. On average, the mean pronation-supination axis (screw displacement axis) passed 1.4 mm +/- 1.9 medial to the center of the capitellum and through the center of the ulnar head. Loss of the annular ligament did not change the location of the pronation-supination axis. CONCLUSIONS: During forearm rotation, the radial head travels to a greater extent in the anteroposterior direction than in the mediolateral direction. Loss of the stabilizing effect of the annular ligament increases the travel mediolaterally more than anteroposteriorly. The pronation-supination axis of the forearm is nearly constant and is not affected by annular ligament transection.