The effect of health care working conditions on patient safety.
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Evidence-Based Medicine↗
Biomedical subjects
P Gorman
Publications and source records attributed to P Gorman.
Analysis of chromosomal instability in human colorectal adenomas with two mutational hits at APC.
In vitro data show that the adenomatous polyposis coli (APC) protein associates with the mitotic spindle and that mouse embryonic stem cells with biallelic Apc mutations are karyotypically unstable. These findings led to suggestions that APC acts in chromosomal segregation and that APC inactivation leads to chromosomal instability (CIN). An alternative hypothesis based on allelic loss studies in colorectal adenomas proposes that CIN precedes and contributes to genetic changes at APC. We determined whether colorectal adenomas with two mutations at APC show features consistent with these models by studying 55 lesions (average size 5 mm; range 1-13 mm) from patients with familial adenomatous polyposis. A variety of methods was used depending on available material, including flow cytometry, comparative genomic hybridization, and loss of heterozygosity (LOH) analysis. Selected adenomas were assessed for proliferative activity by Ki-67 immunocytochemistry. Seventeen of 20 (85%) tumors were diploid, two were near-diploid, and one was hypotetraploid. Just one (near-diploid) tumor showed increased proliferative activity. LOH was found occasionally on chromosome 15q (2 of 49 tumors), but not on chromosome 18q (0 of 48). In 20 adenomas, LOH at APC was associated with loss at 5q but not 5p markers, with the former encompassing a minimum of 20 Mb. However, three of these lesions analyzed by comparative genomic hybridization displayed normal profiles, suggesting, together with other data, that the mechanism of LOH at APC is probably somatic recombination. Our results therefore do not support the hypothesis that CIN precedes APC mutations in tumorigenesis. Regarding the model in which APC mutations lead directly to CIN, if APC mutations do have this effect in vivo, it must be subtle. Alternatively, CIN associated with APC mutations might be essentially an in vitro phenomenon.
Adenoma↗
Molecular characteristics of serrated adenomas of the colorectum.
BACKGROUND: Serrated adenomas (SAs) of the colorectum combine architectural features of hyperplastic polyps and cytological features of classical adenomas. Molecular studies comparing SAs and classical adenomas suggest that each may be a distinct entity; in particular, it has been proposed that microsatellite instability (MSI) distinguishes SAs from classical adenomas and that SAs and the colorectal cancers arising from them develop along a pathway driven by low level microsatellite instability (MSI-L). AIMS: To define the molecular characteristics of SAs of the colorectum. MATERIALS AND METHODS: We analysed 39 SAs from 27 patients, including eight SAs from patients with familial adenomatous polyposis (FAP). We screened these polyps for selected molecular changes, including loss of heterozygosity (LOH) close to APC (5q21) and CRAC1 (15q13-q22), MSI, and mutations of K-ras, APC, p53, and beta-catenin. Expression patterns of beta-catenin, p53, MLH1, MSH2, E-cadherin, and O(6)-methylguanine DNA methyltransferase (MGMT) were assessed by immunohistochemistry. Comparative genomic hybridisation was performed on several polyps. RESULTS: MSI was rare (<5% cases) and there was no loss of expression of mismatch repair proteins. Wnt pathway abnormalities (APC mutation/LOH, beta-catenin mutation/nuclear expression) occurred in 11 SAs, including 6/31 (19%) non-FAP tumours. CRAC1 LOH occurred in 23% of tumours. K-ras mutations and p53 mutations/overexpression were found in 15% and 8% of SAs, respectively. Loss of MGMT expression occurred in 18% of polyps and showed a borderline association with K-ras mutations. Aberrant E-cadherin expression was found in seven polyps. Comparative genomic hybridisation detected no gains or deletions of chromosomal material. CONCLUSIONS: The serrated pathway of colorectal tumorigenesis appears to be heterogeneous. In common with classical adenomas, some SAs develop along pathways involving changes in APC/beta-catenin. SAs rarely show MSI or any evidence of chromosomal-scale genetic instability. K-ras mutations may however be less common in SAs than in classical adenomas. Some SAs may harbour changes in the CRAC1 gene. Changes in known genes do not account for the growth of the majority of SAs.
Adenoma↗
SMAD4 mutations in colorectal cancer probably occur before chromosomal instability, but after divergence of the microsatellite instability pathway.
Loss of chromosome 18q21 is well documented in colorectal cancer, and it has been suggested that this loss targets the DCC, DPC4/SMAD4, and SMAD2 genes. Recently, the importance of SMAD4, a downstream regulator in the TGF-beta signaling pathway, in colorectal cancer has been highlighted, although the frequency of SMAD4 mutations appears much lower than that of 18q21 loss. We set out to investigate allele loss, mutations, protein expression, and cytogenetics of chromosome 18 copy number in a collection of 44 colorectal cancer cell lines of known status with respect to microsatellite instability (MSI). Fourteen of thirty-two MSI(-) lines showed loss of SMAD4 protein expression; usually, one allele was lost and the other was mutated in one of a number of ways, including deletions of various sizes, splice site changes, and missense and nonsense point mutations (although no frameshifts). Of the 18 MSI(-) cancers with retained SMAD4 expression, four harbored missense mutations in the 3' part of the gene and showed allele loss. The remaining 14 MSI(-) lines had no detectable SMAD4 mutation, but all showed allele loss at SMAD4 and/or DCC. SMAD4 mutations can therefore account for about 50-60% of the 18q21 allele loss in colorectal cancer. No MSI(+) cancer showed loss of SMAD4 protein or SMAD4 mutation, and very few had allelic loss at SMAD4 or DCC, although many of these MSI(+) lines did carry TGFBIIR changes. Although SMAD4 mutations have been associated with late-stage or metastatic disease, our combined molecular and cytogenetic data best fit a model in which SMAD4 mutations occur before colorectal cancers become aneuploid/polyploid, but after the MSI(+) and MSI(-) pathways diverge. Thus, MSI(+) cancers may diverge first, followed by CIN(+) (chromosomal instability) cancers, leaving other cancers to follow a CIN(-)MSI(-) pathway.
Adenocarcinoma↗
Strategic management simulations is a novel way to measure resident competencies.
BACKGROUND: The Strategic Management Simulation (SMS) has been used extensively to test and train higher cognitive functions in persons who occupy professional and leadership positions (i.e., skills like those needed by a surgeon). METHODS: The SMS was used to predict surgical residents' competency in decision making. Skills required for integrative surgical decision making including critical thinking, crisis management, flexibility, factual knowledge, and team building were assessed. Surgical residents with at least 2 years of experience participated. In additional, attending faculty familiar with the residents' work evaluated each resident with a standard comprehensive rating scale. Simulation performance on multiple measures was compared with faculty ratings. RESULTS: A number of measures obtained on simulation performance (eg, activity level, response speed, initiative, adequate usage of and appropriate search for relevant information) generated high correlations with comprehensive faculty assessment (eg, measures of crisis management, team interactions, flexibility of approach). CONCLUSION: The simulation technique is able to accurately assess performance of surgical residents (on a number of parameters) in a relatively brief time period. Simulation data were highly similar to faculty ratings that were based on at least 2 years of experience with the resident.
Clinical Competence↗
Efficacy of an implanted neuroprosthesis for restoring hand grasp in tetraplegia: a multicenter study.
OBJECTIVE: To evaluate an implanted neuroprosthesis that allows tetraplegic users to control grasp and release in 1 hand. DESIGN: Multicenter cohort trial with at least 3 years of follow-up. Function for each participant was compared before and after implantation, and with and without the neuroprosthesis activated. SETTING: Tertiary spinal cord injury (SCI) care centers, 8 in the United States, 1 in the United Kingdom, and 1 in Australia. PARTICIPANTS: Fifty-one tetraplegic adults with C5 or C6 SCIs. INTERVENTION: An implanted neuroprosthetic system, in which electric stimulation of the grasping muscles of 1 arm are controlled by using contralateral shoulder movements, and concurrent tendon transfer surgery. Assessed participants' ability to grasp, move, and release standardized objects; degree of assistance required to perform activities of daily living (ADLs), device usage; and user satisfaction. MAIN OUTCOME MEASURES: Pinch force; grasp and release tests; ADL abilities test and ADL assessment test; and user satisfaction survey. RESULTS: Pinch force was significantly greater with the neuroprosthesis in all available 50 participants, and grasp-release abilities were improved in 49. All tested participants (49/49) were more independent in performing ADLs with the neuroprosthesis than they were without it. Home use of the device for regular function and exercise was reported by over 90% of the participants, and satisfaction with the neuroprosthesis was high. CONCLUSIONS: The grasping ability provided by the neuroprosthesis is substantial and lasting. The neuroprosthesis is safe, well accepted by users, and offers improved independence for a population without comparable alternatives.
Adult↗
Peculiar velocity surveys: optimal moments analysis.
A new formalism to analyze peculiar velocity surveys is presented. Results from these surveys are shown to be dominated by small-scale noise, aliasing, and incomplete cancellations. The formalism allows us to filter out the signal from scales that are not of interest and thus provides us with a clean signal that probe large scales. We use maximum likelihood techniques to analyze the filtered data and compare it to the analysis of the full dataset. The filtered analysis gives a much better parameter estimation than the full analysis, leading us to conclude that, indeed, the large-scale signal is obscured by small-scale noise.
Journal Article↗
Policy implications for implementing evidence-based practices.
The authors describe the policy and administrative-practice implications of implementing evidence-based services, particularly in public-sector settings. They review the observations of the contributors to the evidence-based practices series published throughout 2001 in Psychiatric Services. Quality and accountability have become the watchwords of health and mental health services; evidence-based practices are a means to both ends. If the objective of accountable, high-quality services is to be achieved by implementing evidence-based practices, the right incentives must be put in place, and systemic barriers must be overcome. The authors use the framework from the U.S. Surgeon General's 1999 report on mental health to describe eight courses of action for addressing the gap between science and practice: continue to build the science base; overcome stigma; improve public awareness of effective treatments; ensure the supply of mental health services and providers; ensure delivery of state-of-the-art treatments; tailor treatment to age, sex, race, and culture; facilitate entry into treatment; and reduce financial barriers to treatment.
Ethnicity↗
Information needs in primary care: a survey of rural and nonrural primary care physicians.
OBJECTIVE: To compare the self-reported information needs of rural and nonrural primary care physicians. DESIGN AND PARTICIPANTS: Mail survey of active non-academic primary care physicians. DATA COLLECTION: A 60 item questionnaire regarding 1) demographic and practice setting data; 2) medical information needs; 3) medical knowledge resource availability and use; and 4) physician information seeking behavior. MAIN RESULTS: The response rate was higher among rural than non-rural physicians (55% vs. 42%, p< 0.001) and among Family Physicians than others (Family Medicine 53%, Internal Medicine 43%, Pediatrics 48%, p=0.015.) Rural physicians reported working more hours per week (45.3 vs. 42.7, p=0.033,) and seeing more patients per day (24.6 vs. 22.3, p=0.005) than their nonrural counterparts. Both groups reported a median of about 1 question for every 10 patients they see, with great variance among responses. Both groups reported pursuing answers to about 57% of their questions, and finding answers to about 70% of those they pursue. Knowledge resource preferences of the two groups were similar. Both groups reported frequent use of consultants, drug compendia, colleagues, and textbooks, and little use of library- or computer-based sources. Compared to nonrural physicians, rural physicians reported less frequent use of consultants, colleagues, librarians, and bound journals. These differences were small, and paralleled differences in availability. The two groups had equal access to textbooks and drug compendia, but for rural physicians, other resources were locally available significantly less often. CONCLUSIONS: Rural and nonrural primary care physicians reported equal information needs, similar information seeking, and similar resource preferences. Rural physicians reported less access to some information resources, but little difference in use of resources. Further studies are needed to determine how these differences impact rural practitioners and their patients.
Data Collection↗
Investigating physician order entry in the field: lessons learned in a multi-center study.
The progress of studies by this team of researchers concerning computerized physician order entry (POE), beginning with a mail survey and moving to qualitative multi-center studies, is reviewed, with emphases on lessons learned and future directions. While mail surveys were appropriate to answer initial research questions about diffusion of POE in the U.S., multiple qualitative methods became the methods of choice for answering more complex questions. Results of the latter include articulation of multiple perspectives on both positive and negative aspects of POE and a description of what may be important for successful implementation of POE in the future. The present economic environment of hospitals may be inhibiting widespread diffusion of POE, not only because of the direct cost, but also indirectly by affecting relations with practitioners. Analysis of successful past implementations can provide guidance when the time is right.
Attitude to Computers↗
Colorectal carcinomas arising in the hyperplastic polyposis syndrome progress through the chromosomal instability pathway.
The hyperplastic polyposis syndrome is characterized by the presence within the colon of multiple large hyperplastic polyps. We describe a case of hyperplastic polyposis syndrome associated with two synchronous carcinomas, one of which arises within a pre-existing hyperplastic lesion. Comparative genomic hybridization was used to determine genetic changes in both carcinomas and several associated hyperplastic lesions. Microsatellite analysis at five loci was performed on carcinomas and representative hyperplastic polyps, and p53 status was analyzed by immunohistochemistry. Both carcinomas showed multiple genetic aberrations, including high level gains of 8q and 13q, and loss of 5q. These changes were not seen in the hyperplastic polyps. Microsatellite instability was not seen in the carcinomas, four separate hyperplastic polyps, the hyperplastic polyp with mild adenomatous change associated with the carcinoma, or a separate serrated adenoma. Allelic imbalance in the cancers at D5S346 and D17S938 suggested allelic loss of both p53 and APC, as well as at the loci D13S263, D13S174, D13S159, and D18S49. An early invasive carcinoma in one hyperplastic polyp stained for p53 protein, but the associated hyperplastic polyp was negative. In this case, neoplastic progression followed the typical genetic pathway of common colorectal carcinoma and occurred synchronously with mutation of p53.
Adenomatous Polyps↗
Excellent information is needed for excellent care, but so is good communication.
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Communication↗
A prototype haptic lumbar puncture simulator.
Lumbar punctures (LP) are complex, precise procedures done to obtain cerebro-spinal fluid from a patient for diagnostic purposes. Incorrect techniques resulting from inadequate training or supervision can result in sub-optimal outcomes. As tactile feedback is crucial for a successful lumbar puncture, this procedure serves as an ideal candidate for the development of a haptic training simulator. The intent of this project is to engineer a force feedback LP simulator that provides a safe method of training students (medical students, residents, or trained physicians) for an actual LP procedure on a patient.
Computer Graphics↗
Environmental Dependence of the Fundamental Plane of Galaxy Clusters.
Galaxy clusters approximate a planar distribution in a three-dimensional parameter space that can be characterized, for example, by an optical luminosity, half-light radius, and X-ray luminosity. We find the nearest neighbor clusters for those common to either of two previous fundamental-plane studies and a high-quality cluster redshift catalog. Examining scatter about one plane in parameter space, we find a 2 sigma result that it is dependent on the nearest neighbor distance. Study of another sample of X-ray clusters shows that those with high central gas densities are systematically (2.5 sigma) closer to neighbor clusters. These results suggest a possible explanation for recent evidence that X-ray cooling flow clusters reside in crowded environments.
Journal Article↗
Comparative genomic hybridization of breast tumors stratified by histological grade reveals new insights into the biological progression of breast cancer.
How does breast cancer progress? There is evidence both to support (S. W. Duffy et al., Br. J. Cancer, 64: 1133-1138, 1991; R. Rajakariar et al., Br. J. Cancer, 71: 150-154, 1995) and refute (M. Hakama et al., Lancet, 345: 221-224, 1995; R. R. Millis et al., Eur. J. Cancer, 34: 548-553, 1998) the hypothesis of dedifferentiation; the theory that as breast cancers grow they evolve from well differentiated (grade I) to poorly differentiated (grade III) tumors. We provide evidence to support the view that the majority of grade I tumors do not progress to grade III tumors. Comparative genomic hybridization was used to screen entire genomes of a large sample (40 grade I and 50 grade III) of invasive ductal breast carcinomas, stratified by grade. We found distinct genetic differences between grade I and grade III tumors. Significantly, we found that 65% of grade I tumors lost the long arm of chromosome 16 compared with only 16% of grade III tumors. This pattern of loss leads us to conclude that the majority of grade I tumors do not progress to grade III tumors. These findings have important implications because they suggest that different breast tumor grades may have distinct molecular origins, pathogenesis, and behavior and, therefore, potentially present distinct molecular targets for research and treatment.
Breast Neoplasms↗
The type of somatic mutation at APC in familial adenomatous polyposis is determined by the site of the germline mutation: a new facet to Knudson's 'two-hit' hypothesis.
APC is often cited as a prime example of a tumor suppressor gene. Truncating germline and somatic mutations (or, infrequently, allelic loss) occur in tumors in FAP (familial adenomatous polyposis). Most sporadic colorectal cancers also have two APC mutations. Clues from attenuated polyposis, missense germline variants with mild disease and the somatic mutation cluster region (codons 1,250-1,450) indicate, however, that APC mutations might not result in simple loss of protein function. We have found that FAP patients with germline APC mutations within a small region (codons 1,194-1,392 at most) mainly show allelic loss in their colorectal adenomas, in contrast to other FAP patients, whose 'second hits' tend to occur by truncating mutations in the mutation cluster region. Our results indicate that different APC mutations provide cells with different selective advantages, with mutations close to codon 1,300 providing the greatest advantage. Allelic loss is selected strongly in cells with one mutation near codon 1,300. A different germline-somatic APC mutation association exists in FAP desmoids. APC is not, therefore, a classical tumor suppressor. Our findings also indicate a new mechanism for disease severity: if a broader spectrum of mutations is selected in tumors, the somatic mutation rate is effectively higher and more tumors grow.
Adenoma↗
Incidence of operative procedures on cleft lip and palate patients.
The incidence of operative procedures in a group of 374 cleft lip and palate patients was determined by a chart review. These patients were part of a long term study funded by the National Institute of Dental Research at the Lancaster Cleft Palate Clinic. The chart review provided a breakdown of the primary and secondary procedures performed on the patients. Although the secondary procedures carried out were underestimated in this study, it is clear that these operations comprise a major component of the successful treatment of these patients. The results of the study and the implications in today's managed care environment are discussed.
Child↗
The usefulness of handheld computers in a surgical group practice.
We designed a system using hand-held computers allowing physicians in the hospital setting to access their surgical schedules, to track patients in multiple hospitals, and to quickly enter billing information. The physicians would then update their schedules and pass billing information electronically when they returned to the office. The system was successfully implemented, it was well accepted by clinicians and staff users, and it showed an increased capture of charges. Whether an economically important effect on the number of days to post hospital charges will be evident after follow-up data has been collected.
Appointments and Schedules↗