Exome Sequencing in Individuals with Isolated Biliary Atresia.

Biliary atresia (BA) is a severe pediatric liver disease resulting in necroinflammatory obliteration of the extrahepatic biliary tree. BA presents within the first few months of life as either an isolated finding or with additional syndromic features. The etiology of isolated BA is unknown, with evidence for infectious, environmental, and genetic risk factors described. However, to date, there are no definitive causal genes identified for isolated BA in humans, and the question of whether single gene defects play a major role remains open. We performed exome-sequencing in 101 North American patients of European descent with isolated BA (including 30 parent-child trios) and considered several experimental designs to identify potentially deleterious protein-altering variants that may be involved in the disease. In a case-only analysis, we did not identify genes with variants shared among more than two probands, and burden tests of rare variants using a case-case control design did not yield significant results. In the trio analysis of 30 simplex families (patient and parent trios), we identified 66 de novo variants in 66 genes including potentially deleterious variants in STIP1 and REV1. STIP1 is a co-chaperone for the heat-shock protein, HSP90, and has been shown to have diverse functions in yeast, flies and mammals, including stress-responses. REV1 is known to be a key player in DNA repair pathway and to interact with HSP90. In conclusion, our results do not support the hypothesis that a simple genetic model is responsible for the majority of cases of isolated BA. Our finding of de novo variants in genes linked to evolutionarily conserved stress responses (STIP1 and REV1) suggests that exploration of how genetic susceptibility and environmental exposure may interact to cause BA is warranted.

Methods to Improve Sustainability of a Large Academic Biorepository.

This article discusses the evolution of the University of Pittsburgh (UPitt) Health Sciences Tissue Bank (HSTB) operation and how it has successfully positioned itself, manages to sustain its value, and remains viable in today's research landscape. We describe the various components of our biobanking operation, which are valued by our researchers, thus leading to sustainability for our biorepository. Operating within the infrastructure of a large academic university, we have access to the most cutting-edge database resources for collecting, tracking, and annotating thousands of specimens. We are constantly improving upon our ability to provide real-time longitudinal follow-up data for our collections, thus providing researchers with valuable, highly annotated research specimens. We believe the combination of all that is described within this article helps to create a biobank that will remain sustainable well into the future.

Tissue adequacy for ancillary studies beyond frozen section: a potential method for improving diagnostic and therapeutic results.

The evolving nature of medicine has created new challenges in numerous aspects of the practice of pathology. The development of less invasive procedures, the generation of better diagnostic tools, and the recognition of prognostic markers have contributed to these challenges. Between 42.7% and 65.0% of intraoperative consultations are performed to identify or type a neoplastic process. We instituted a reporting requirement on our intraoperative consultations to provide an assessment of adequacy. The assessment of adequacy was subjective by its very nature and was based on the possible uses for the submitted tissue. A total of 3086 intraoperative consultations were performed over a 13-month period. Sixty-two cases were determined to be insufficient for ancillary studies; 52 of these cases were remedied by the surgeon during the original diagnostic procedure. We have instituted a new assessment for intraoperative consultations to optimize the tissue obtained and reduce the need for additional procedures.

Frozen section diagnosis: is there discordance between what pathologists say and what surgeons hear?

OBJECTIVES: Communication in various medical settings is subject to misinterpretation. The frozen section (FS) diagnosis in patient care is dependent on successful communication between pathologists and surgeons. However, very few studies looking at FS errors analyzed postanalytic communication issues. METHODS: A total of 300 consecutive cases, in which an FS was performed and corresponding surgical note was available, were studied. The FS diagnosis and surgeon's interpretation were recorded for all cases. Discrepancies were classified as major (clinical impact) or minor (no clinical impact). RESULTS: We found 8 (2.7%) miscommunications, all with only minor clinical impact. These were attributed mainly to the surgeon's misinterpretation of a deferred diagnosis. Also contributing to miscommunication was the pathologist's use of nonspecific terminology such as "favor" or "scattered." CONCLUSIONS: We found that the rate of miscommunicated FS diagnoses was low at our institution during the period of our study. However, the rate of miscommunication was similar to the much more widely recognized problem of sampling error.

Use of a laboratory information system driven tool for pre-signout quality assurance of random cytopathology reports.

BACKGROUND: Quality assurance (QA) programs in cytopathology laboratories in the USA currently primarily involve the review of Pap tests per clinical laboratory improvement amendments of 1988 federal regulations. A pre-signout quality assurance tool (PQAT) at our institution allows the laboratory information system (LIS) to also automatically and randomly select an adjustable percentage of non-gynecological cytopathology cases for review before release of the final report. The aim of this study was to review our experience and the effectiveness of this novel PQAT tool in cytology. MATERIALS AND METHODS: Software modifications in the existing LIS application (CoPathPlus, Cerner) allow for the random QA of 8% of cases prior to signout. Selected cases are assigned to a second QA cytopathologist for review and all agreement and disagreements tracked. Detected errors are rectified before the case is signed out. Data from cases selected for PQAT over an 18-month period were collected and analyzed. RESULTS: The total number of non-gynecological cases selected for QA review was 1339 (7.45%) out of 17,967 cases signed out during this time period. Most (1304) cases (97.4%) had an agreement in diagnosis. In 2.6% of cases, there were disagreements, including 34 minor and only 1 major disagreement. Average turnaround time of cases selected for review was not significantly altered. CONCLUSION: The PQAT provides a prospective QA mechanism in non-gynecological cytopathology to prevent diagnostic errors from occurring. This LIS-driven tool allows for peer review and corrective action to be taken prior to reporting without delaying turnaround time, thereby improving patient safety.

Initial experience with a novel pre-sign-out quality assurance tool for review of random surgical pathology diagnoses in a subspecialty-based university practice.

We recently implemented a novel pre-sign-out quality assurance tool in our subspecialty-based surgical pathology practice at the University of Pittsburgh Medical Center. It randomly selects an adjustable percentage of cases for review by a second pathologist at the time the originating pathologist's electronic signature is entered and requires that the review be completed within 24 hours, before release of the final report. The tool replaced a retrospective audit system and it has been in successful use since January 2009. We report our initial experience for the first 14 months of its service. During this time, the disagreement numbers and levels were similar to those identified using the retrospective system, case turnaround time was not significantly affected, and the number of case amendments generated decreased. The tool is a useful quality assurance instrument and its prospective nature allows for the potential prevention of some serious errors.

The development and testing of a laboratory information system-driven tool for pre-sign-out quality assurance of random surgical pathology reports.

We describe the development and testing of a novel pre-sign-out quality assurance tool for case diagnoses that allows for the random review of a percentage of cases by a second pathologist before case verification and release of the final report. The tool incorporates the ability to record and report levels of diagnostic disagreement, reviewers' comments, and steps taken to resolve any discrepancies identified. It is expandable to allow for the review of any percentage of cases in any number of subspecialty or general pathology "benches" and provides a prospective instrument for preventing some serious errors from occurring, thereby potentially affecting patient care in addition to identifying and documenting more general process issues. It can also be used to augment other more conventional methods of quality control such as frozen section/final diagnosis correlation, conference review, and case review before interdisciplinary clinicopathologic sessions. There has been no significant delay in case turnaround time since implementation. Further assessment of the tool's function after full departmental application is underway.

Clinical outcomes of exercise in the management of subacromial impingement syndrome: a systematic review.

OBJECTIVE: To assess the clinical outcomes of types of exercise in the management of subacromial impingement syndrome. DESIGN: Systematic review of randomized controlled trials. METHODS: Studies were identified from databases searched to May 2009: MEDLINE, EMBASE, CINAHL, Sports Discus, PEDro, AMED, Cochrane Library, National Research Register, Index Chiropractic Literature. Two reviewers selected studies meeting inclusion criteria. The methodological quality of the included studies was independently assessed by two reviewers using the PEDro quality assessment tool. RESULTS: Eight studies with sample sizes ranging from 14 to 125 were included in the systematic review and appraised for content. Four papers achieved a score of 6 or above indicating good quality, with the remaining four achieving 4 or lower, indicating poor quality. Synthesis showed only limited evidence to support the use of exercise in the treatment of subacromial impingement syndrome. CONCLUSION: There is a need for further well-defined clinical trials on specific exercise interventions for the treatment of shoulder dysfunction including subacromial impingement syndrome.

The value of physical tests for subacromial impingement syndrome: a study of diagnostic accuracy.

OBJECTIVE: To determine the diagnostic accuracy of commonly used physical tests for subacromial impingement syndrome, using ultrasound as the reference standard. DESIGN: A cross-sectional study of 59 participants with chronic shoulder pain of more than four months duration with a referral for diagnostic ultrasound scanning were invited to participate in the study. MAIN MEASURES: Thirty-four participants met the inclusion criteria and had an ultrasound scan followed immediately by application of the following tests: Neer's sign, Hawkins and Kennedy test, painful arc of abduction, empty and full can tests, resisted isometric shoulder abduction and resisted isometric shoulder external rotation. Using the two-way contingency table method sensitivity, specificity, likelihood ratios and overall accuracy were calculated for each physical test. RESULTS: Diagnostic values for each test varied considerably. The Hawkins and Kennedy test was the most accurate test for diagnosing any degree of subacromial impingement syndrome (71.0%). The most accurate tests for diagnosing subcategories of impingement were pain on resisted external rotation and weakness during the full can test (63.6%) for presence of subdeltoid fluid, pain on resisted external rotation (58.8%) for partial thickness tears and the painful arc test (62.1%) for full thickness tears. CONCLUSIONS: As the predictive values of these tests are shown to be variable in this study it indicates that the clinical tests identified have limited use in informing diagnosis. Emphasis on the management of dysfunction may be more appropriate rather than reliance on clinical tests with inconclusive sensitivity and specificity if ultrasound scanning is not available.

Effect of macronutrient composition on postprandial peptide YY levels.

BACKGROUND: Peptide YY (PYY) is released from the distal small intestine and colon after meals and reduces appetite by increasing satiety. The amount of PYY released is proportional to calories ingested. Fat ingestion has also been reported to stimulate PYY release. OBJECTIVE: The objective of the study was to determine whether macronutrient composition influences postprandial serum PYY levels by comparing 1 wk of a weight-maintenance low-carbohydrate, high-fat (LCHF) diet with a low-fat, high-carbohydrate (LFHC) diet. METHODS: In this randomized crossover study, 18 obese subjects (14 females, 4 males, mean body mass index 35.6 +/- 2.9 kg/m(2)) were randomly assigned initially to 1 wk of a weight-maintenance LCHF or LFHC diet, after which a test meal of identical composition was given and serum PYY levels were assessed for 2.5 h postprandially. After a 1-wk washout period, subjects were crossed over and retested. RESULTS: After 1 wk, mean postprandial area under the curve PYY after the LCHF test meal was 1.5-fold greater than after the LFHC test meal (P < 0.001). The LCHF diet led to 55% higher levels of postprandial serum PYY levels, compared with the LFHC diet (P = 0.005). CONCLUSIONS: These data show that a LCHF diet stimulates PYY secretion more than a LFHC diet in obese individuals.

A pilot study for a randomised controlled trial of waterbirth versus land birth.

OBJECTIVES: To assess the feasibility of undertaking an adequately powered multicentre study comparing waterbirth with land birth. To assess whether women are willing to participate in such a trial and whether participation has a negative effect on their birthing experience. DESIGN: A randomised controlled trial (RCT) with 'preference arm'. SETTING: District general hospital with 3600 deliveries annually. POPULATION: Women with no pregnancy complications and no anticipated problems for labour/delivery. METHODS: Women were recruited and randomised between 36 and 40 weeks of gestation. Comparison of randomised and 'preference arm' to assess any impact of randomisation on women's birthing experience. MAIN OUTCOME MEASURES: Data were collected at delivery concerning the labour, the pool water and baby's condition at birth and six weeks of age. The main outcome measures are means and standard deviation of cord O(2), CO(2), haemoglobin, haematocrit and base excess; medians and ranges of time to first breathe and cord pH; bacterial growth from pool water samples and neonatal swabs; and maternal satisfaction. RESULTS: Eighty women participated-60 women were randomised. Twenty women participated in a non-randomised 'preference arm'. The babies randomised to a waterbirth demonstrated a significantly lower umbilical artery pCO(2) (P= 0.003); however, it is recognised that this study is underpowered. Women were willing to participate and randomisation did not appear to alter satisfaction. CONCLUSION: This small study has shown that a RCT is feasible and demonstrated outcome measures, which can be successfully collected in an average delivery suite.