Determination of an optimal response cut-off able to predict progression-free survival in patients with well-differentiated advanced pancreatic neuroendocrine tumours treated with sunitinib: an alternative to the current RECIST-defined response.

BACKGROUND: Sunitinib prolongs progression-free survival (PFS) in patients with advanced pancreatic neuroendocrine tumours (pNET). Response Evaluation Criteria in Solid Tumors (RECIST)-defined partial responses (PR; classically defined as ⩾30% size decrease from baseline) are infrequent. METHODS: Individual data of pNET patients from the phase II [NCT00056693] and pivotal phase III [NCT00428597] trials of sunitinib were analysed in this investigator-initiated, post hoc study. The primary objective was to determine the optimal RECIST (v.1.0) response cut-off value to identify patients who were progression-free at 11 months (median PFS in phase III trial); and the most informative time-point (highest area under the curve (AUC) by receiver operating characteristic (ROC) analysis and logistic regression) for prediction of benefit (PFS) from sunitinib. RESULTS: Data for 237 patients (85 placebo; 152 sunitinib (n=66.50 mg \u274-weeks on/2-weeks off\u27 schedule; n=86 \u2737.5 mg continuous daily dosing (CDD)\u27)) and 788 scans were analysed. The median PFS for sunitinib and placebo were 9.3 months (95% CI 7.6-12.2) and 5.4 months (95% CI 3.5-6.01), respectively (hazard ratio (HR) 0.43 (95% CI 0.29-0.62); P CONCLUSIONS: A 10% reduction within marker lesions identifies pNET patients benefiting from sunitinib treatment with implications for maintenance of dose intensity and future trial design

Using a summary measure for multiple quality indicators in primary care: the Summary QUality InDex (SQUID)

BACKGROUND: Assessing the quality of primary care is becoming a priority in national healthcare agendas. Audit and feedback on healthcare quality performance indicators can help improve the quality of care provided. In some instances, fewer numbers of more comprehensive indicators may be preferable. This paper describes the use of the Summary Quality Index (SQUID) in tracking quality of care among patients and primary care practices that use an electronic medical record (EMR). All practices are part of the Practice Partner Research Network, representing over 100 ambulatory care practices throughout the United States. METHODS: The SQUID is comprised of 36 process and outcome measures, all of which are obtained from the EMR. This paper describes algorithms for the SQUID calculations, various statistical properties, and use of the SQUID within the context of a multi-practice quality improvement (QI) project. RESULTS: At any given time point, the patient-level SQUID reflects the proportion of recommended care received, while the practice-level SQUID reflects the average proportion of recommended care received by that practice's patients. Using quarterly reports, practice- and patient-level SQUIDs are provided routinely to practices within the network. The SQUID is responsive, exhibiting highly significant (p < 0.0001) increases during a major QI initiative, and its internal consistency is excellent (Cronbach's alpha = 0.93). Feedback from physicians has been extremely positive, providing a high degree of face validity. CONCLUSION: The SQUID algorithm is feasible and straightforward, and provides a useful QI tool. Its statistical properties and clear interpretation make it appealing to providers, health plans, and researchers

A systematic review of high-fibre dietary therapy in diverticular disease

The exact pathogenesis of diverticular disease of the sigmoid colon is not well established. However, the hypothesis that a low-fibre diet may result in diverticulosis and a high-fibre diet will prevent symptoms or complications of diverticular disease is widely accepted. The aim of this review is to assess whether a high-fibre diet can improve symptoms and/or prevent complications of diverticular disease of the sigmoid colon and/or prevent recurrent diverticulitis after a primary episode. Clinical studies were eligible for inclusion if they assessed the treatment of diverticular disease or the prevention of recurrent diverticulitis with a high-fibre diet. The following exclusion criteria were used for study selection: studies without comparison of the patient group with a control group. No studies concerning prevention of recurrent diverticulitis with a high-fibre diet met our inclusion criteria. Three randomised controlled trials (RCT) and one case-control study were included in this systematic review. One RCT of moderate quality showed no difference in the primary endpoints. A second RCT of moderate quality and the case-control study found a significant difference in favour of a high-fibre diet in the treatment of symptomatic diverticular disease. The third RCT of moderate quality found a significant difference in favour of methylcellulose (fibre supplement). This study also showed a placebo effect. High-quality evidence for a high-fibre diet in the treatment of diverticular disease is lacking, and most recommendations are based on inconsistent level 2 and mostly level 3 evidence. Nevertheless, high-fibre diet is still recommended in several guideline

Understanding non-compliance to colorectal cancer screening: a case control study, nested in a randomised trial [ISRCTN83029072]

BACKGROUND: The major limit to colorectal cancer screening effectiveness is often low compliance. We studied the reasons for non compliance and determinants of compliance to faecal occult blood tests in Lazio, Italy. METHODS: This is a case-control study nested within a trial that tested the effect of type of test and provider on colorectal cancer screening compliance. Non compliant trial subjects were classified as cases, and compliant subjects were classified as controls. We sampled 600 cases and 600 controls matched by their general practitioner, half were invited for screening at the hospital, and the other half directly at their general practitioner's office. Cases and controls answered questions on: distance from test provider, logistical problems, perception of colorectal cancer risk, confidence in screening efficacy, fear of results, presence of colorectal cancer in the family, and gastrointestinal symptoms. RESULTS: About 31% of cases never received the letter offering free screening, and 17% of the sampled population had already been screened. The first reported reason for non-compliance was "lack of time" (30%); the major determinant of compliance was the distance from the test provider: odds ratio >30 minutes vs <15 minutes 0.3 (95%CI = 0.2–0.7). The odds ratio for lack of time was 0.16 (95% IC 0.1–0.26). The effect was stronger if the hospital (0.03 95%CI = 0.01–0.1) rather than the general practitioner (0.3 95%CI = 0.2–0.6) was the provider. Twenty-two percent of controls were accompanied by someone to the test. CONCLUSION: To increase compliance, screening programmes must involve test providers who are geographically close to the target population

Controversies in the Surgical Management of Sigmoid Diverticulitis

The timing and appropriateness of surgical treatment of sigmoid diverticular disease remain a topic of controversy. We have reviewed the current literature on this topic, focusing on issues related to the indications and types of surgery. Current evidence would suggest that elective surgery for diverticulitis can be avoided in patients with uncomplicated disease, regardless of the number of recurrent episodes. Furthermore, the need for elective surgey should not be influenced by the age of the patient. Operation should be undertaken in patients with severe attacks, as determined by their clinical and radiological evaluation

Proteomic Comparison of Entamoeba histolytica and Entamoeba dispar and the Role of E. histolytica Alcohol Dehydrogenase 3 in Virulence

The protozoan intestinal parasite Entamoeba histolytica infects millions of people worldwide and is capable of causing amebic dysentery and amebic liver abscess. The closely related species Entamoeba dispar colonizes many more individuals, but this organism does not induce disease. To identify molecular differences between these two organisms that may account for their differential ability to cause disease in humans, we used two-dimensional gel-based (DIGE) proteomic analysis to compare whole cell lysates of E. histolytica and E. dispar. We observed 141 spots expressed at a substantially (>5-fold) higher level in E. histolytica HM-1∶IMSS than E. dispar and 189 spots showing the opposite pattern. Strikingly, 3 of 4 proteins consistently identified as different at a greater than 5-fold level between E. histolytica HM-1∶IMSS and E. dispar were identical to proteins recently identified as differentially expressed between E. histolytica HM-1∶IMSS and the reduced virulence strain E. histolytica Rahman. One of these was E. histolytica alcohol dehydrogenase 3 (EhADH3). We found that E. histolytica possesses a higher level of NADP-dependent alcohol dehydrogenase activity than E. dispar and that some EhADH3 can be localized to the surface of E. histolytica. Episomal overexpression of EhADH3 in E. histolytica trophozoites resulted in only subtle phenotypic differences in E. histolytica virulence in animal models of amebic colitis and amebic liver abscess, making it difficult to directly link EhADH3 levels to virulence differences between E. histolytica and less-pathogenic Entamoeba

Proteome analysis of human gastric cardia adenocarcinoma by laser capture microdissection

<p>Abstract</p> <p>Background</p> <p>The incidence of gastric cardiac adenocarcinoma (GCA) has been increasing in the past two decades in China, but the molecular changes relating to carcinogenesis have not been well characterised.</p> <p>Methods</p> <p>In this study, we used a comparative proteomic approach to analyse the malignant and nonmalignant gastric cardia epithelial cells isolated by navigated laser capture microdissection (LCM) from paired surgical specimens of human GCA.</p> <p>Results</p> <p>Twenty-seven spots corresponding to 23 proteins were consistently differentially regulated. Fifteen proteins were shown to be up-regulated, while eight proteins were shown to be down-regulated in malignant cells compared with nonmalignant columnar epithelial cells. The identified proteins appeared to be involved in metabolism, chaperone, antioxidation, signal transduction, apoptosis, cell proliferation, and differentiation. In addition, expressions of HSP27, 60, and Prx-2 in GCA specimens were further confirmed by immunohistochemical and western blot analyses.</p> <p>Conclusion</p> <p>These data indicate that the combination of navigated LCM with 2-DE provides an effective strategy for discovering proteins that are differentially expressed in GCA. Such proteins may contribute in elucidating the molecular mechanisms of GCA carcinogenesis. Furthermore, the combination provides potential clinical biomarkers that aid in early detection and provide potential therapeutic targets.</p

Do electronic health records affect the patient-psychiatrist relationship? A before & after study of psychiatric outpatients

<p>Abstract</p> <p>Background</p> <p>A growing body of literature shows that patients accept the use of computers in clinical care. Nonetheless, studies have shown that computers unequivocally change both verbal and non-verbal communication style and increase patients' concerns about the privacy of their records. We found no studies which evaluated the use of Electronic Health Records (EHRs) specifically on psychiatric patient satisfaction, nor any that took place exclusively in a psychiatric treatment setting. Due to the special reliance on communication for psychiatric diagnosis and evaluation, and the emphasis on confidentiality of psychiatric records, the results of previous studies may not apply equally to psychiatric patients.</p> <p>Method</p> <p>We examined the association between EHR use and changes to the patient-psychiatrist relationship. A patient satisfaction survey was administered to psychiatric patient volunteers prior to and following implementation of an EHR. All subjects were adult outpatients with chronic mental illness.</p> <p>Results</p> <p>Survey responses were grouped into categories of "Overall," "Technical," "Interpersonal," "Communication & Education,," "Time," "Confidentiality," "Anxiety," and "Computer Use." Multiple, unpaired, two-tailed t-tests comparing pre- and post-implementation groups showed no significant differences (at the 0.05 level) to any questionnaire category for all subjects combined or when subjects were stratified by primary diagnosis category.</p> <p>Conclusions</p> <p>While many barriers to the adoption of electronic health records do exist, concerns about disruption to the patient-psychiatrist relationship need not be a prominent focus. Attention to communication style, interpersonal manner, and computer proficiency may help maintain the quality of the patient-psychiatrist relationship following EHR implementation.</p

Selected heterozygosity at cis-regulatory sequences increases the expression homogeneity of a cell population in humans

Background: Examples of heterozygote advantage in humans are scarce and limited to protein-coding sequences. Here, we attempt a genome-wide functional inference of advantageous heterozygosity at cis-regulatory regions. Results: The single-nucleotide polymorphisms bearing the signatures of balancing selection are enriched in active cis-regulatory regions of immune cells and epithelial cells, the latter of which provide barrier function and innate immunity. Examples associated with ancient trans-specific balancing selection are also discovered. Allelic imbalance in chromatin accessibility and divergence in transcription factor motif sequences indicate that these balanced polymorphisms cause distinct regulatory variation. However, a majority of these variants show no association with the expression level of the target gene. Instead, single-cell experimental data for gene expression and chromatin accessibility demonstrate that heterozygous sequences can lower cell-to-cell variability in proportion to selection strengths. This negative correlation is more pronounced for highly expressed genes and consistently observed when using different data and methods. Based on mathematical modeling, we hypothesize that extrinsic noise from fluctuations in transcription factor activity may be amplified in homozygotes, whereas it is buffered in heterozygotes. While high expression levels are coupled with intrinsic noise reduction, regulatory heterozygosity can contribute to the suppression of extrinsic noise. Conclusions: This mechanism may confer a selective advantage by increasing cell population homogeneity and thereby enhancing the collective action of the cells, especially of those involved in the defense systems in humansope