How do gut feelings feature in tutorial dialogues on diagnostic reasoning in GP traineeship?

Diagnostic reasoning is considered to be based on the interaction between analytical and non-analytical cognitive processes. Gut feelings, a specific form of non-analytical reasoning, play a substantial role in diagnostic reasoning by general practitioners (GPs) and may activate analytical reasoning. In GP traineeships in the Netherlands, trainees mostly see patients alone but regularly consult with their supervisors to discuss patients and problems, receive feedback, and improve their competencies. In the present study, we examined the discussions of supervisors and their trainees about diagnostic reasoning in these so-called tutorial dialogues and how gut feelings feature in these discussions. 17 tutorial dialogues focussing on diagnostic reasoning were video-recorded and transcribed and the protocols were analysed using a detailed bottom-up and iterative content analysis and coding procedure. The dialogues were segmented into quotes. Each quote received a content code and a participant code. The number of words per code was used as a unit of analysis to quantitatively compare the contributions to the dialogues made by supervisors and trainees, and the attention given to different topics. The dialogues were usually analytical reflections on a trainee's diagnostic reasoning. A hypothetico-deductive strategy was often used, by listing differential diagnoses and discussing what information guided the reasoning process and might confirm or exclude provisional hypotheses. Gut feelings were discussed in seven dialogues. They were used as a tool in diagnostic reasoning, inducing analytical reflection, sometimes on the entire diagnostic reasoning process. The emphasis in these tutorial dialogues was on analytical components of diagnostic reasoning. Discussing gut feelings in tutorial dialogues seems to be a good educational method to familiarize trainees with non-analytical reasoning. Supervisors need specialised knowledge about these aspects of diagnostic reasoning and how to deal with them in medical education.

DNA copy number profiling reveals extensive genomic loss in hereditary BRCA1 and BRCA2 ovarian carcinomas.

BACKGROUND: Few studies have attempted to characterise genomic changes occurring in hereditary epithelial ovarian carcinomas (EOCs) and inconsistent results have been obtained. Given the relevance of DNA copy number alterations in ovarian oncogenesis and growing clinical implications of the BRCA-gene status, we aimed to characterise the genomic profiles of hereditary and sporadic ovarian tumours. METHODS: High-resolution array Comparative Genomic Hybridisation profiling of 53 familial (21 BRCA1, 6 BRCA2 and 26 non-BRCA1/2) and 15 sporadic tumours in combination with supervised and unsupervised analysis was used to define common and/or specific copy number features. RESULTS: Unsupervised hierarchical clustering did not stratify tumours according to their familial or sporadic condition or to their BRCA1/2 mutation status. Common recurrent changes, spanning genes potentially fundamental for ovarian carcinogenesis, regardless of BRCA mutations, and several candidate subtype-specific events were defined. Despite similarities, greater contribution of losses was revealed to be a hallmark of BRCA1 and BRCA2 tumours. CONCLUSION: Somatic alterations occurring in the development of familial EOCs do not differ substantially from the ones occurring in sporadic carcinomas. However, some specific features like extensive genomic loss observed in BRCA1/2 tumours may be of clinical relevance helping to identify BRCA-related patients likely to respond to PARP inhibitors.

Workplace-based assessment: raters' performance theories and constructs.

Weaknesses in the nature of rater judgments are generally considered to compromise the utility of workplace-based assessment (WBA). In order to gain insight into the underpinnings of rater behaviours, we investigated how raters form impressions of and make judgments on trainee performance. Using theoretical frameworks of social cognition and person perception, we explored raters' implicit performance theories, use of task-specific performance schemas and the formation of person schemas during WBA. We used think-aloud procedures and verbal protocol analysis to investigate schema-based processing by experienced (N = 18) and inexperienced (N = 16) raters (supervisor-raters in general practice residency training). Qualitative data analysis was used to explore schema content and usage. We quantitatively assessed rater idiosyncrasy in the use of performance schemas and we investigated effects of rater expertise on the use of (task-specific) performance schemas. Raters used different schemas in judging trainee performance. We developed a normative performance theory comprising seventeen inter-related performance dimensions. Levels of rater idiosyncrasy were substantial and unrelated to rater expertise. Experienced raters made significantly more use of task-specific performance schemas compared to inexperienced raters, suggesting more differentiated performance schemas in experienced raters. Most raters started to develop person schemas the moment they began to observe trainee performance. The findings further our understanding of processes underpinning judgment and decision making in WBA. Raters make and justify judgments based on personal theories and performance constructs. Raters' information processing seems to be affected by differences in rater expertise. The results of this study can help to improve rater training, the design of assessment instruments and decision making in WBA.

Small bowel adenocarcinoma copy number profiles are more closely related to colorectal than to gastric cancers.

BACKGROUND: Small bowel adenocarcinoma (SBA) is a rare cancer and consequently, the options for clinical trials are limited. As they are treated according to either a colorectal or a gastric cancer regimen and the molecular biology of a tumor is a pivotal determinant for therapy response, chromosomal copy number aberrations were compared with the colorectal and gastric adenocarcinomas. MATERIALS AND METHODS: A total of 85 microsatellite stable (MSS) adenocarcinomas from the stomach, colorectum and small bowel were selected from existing array comparative genomic hybridization (aCGH) datasets. We compared the aCGH profiles of the three tumor sites by supervised analysis and hierarchical clustering. RESULTS: Hierarchical clustering revealed substantial overlap of 27 SBA copy number profiles with matched colorectal adenocarcinomas but less overlap with profiles of gastric adenocarcinomas. DNA copy number aberrations located at chromosomes 1p36.3-p34.3, 4p15.3-q35.2, 9p24.3-p11.1, 13q13.2-q31.3 and 17p13.3-p13.2 were the strongest features discriminating SBAs and colorectal adenocarcinomas from gastric adenocarcinomas. CONCLUSIONS: We show that MSS SBAs are more similar to colorectal than to gastric cancer, based on the 27 genome-wide DNA copy number profiles that are currently available. These molecular similarities provide added support for treatment of MSS small bowel cancers according to colorectal cancer regimens.

The effect of guiding questions on students' performance and attitude towards statistics.

BACKGROUND: In this study, the effect of guidance on students' performance was investigated. This effect was hypothesized to be manifested through a reduction of cognitive load and enhancement of self-explanations. AIM: The goal of this study was to investigate the effect of guiding questions on students' understanding of statistics. SAMPLE AND METHOD: In an experimental setting, two randomly selected groups of students (N= 49) answered achievement and transfer questions on statistics as a measure of performance. Students in the intervention condition were given guiding questions to direct their way of reasoning before they answered the achievement questions. The students in the control condition were asked to write down their way of thinking before they answered the same achievement questions. In this way, both groups were stimulated to self-explain, but only the reasoning processes of the students in the intervention condition were guided. RESULTS AND CONCLUSION: It was found that students in the intervention condition performed significantly better on achievement and transfer questions and that this effect of guidance was mediated by self-explanations. Attitude towards statistics was positively related to performance.

Patients' gut feelings seem useful in primary care professionals' decision making.

BACKGROUND: Family physicians' diagnostic gut feelings have proved to be valuable. But what about patients' gut feelings? Research has shown that patients' gut feelings may contribute to their physicians' clinical reasoning. Dutch medical tribunals consider patients' worry useful for doctors' diagnostic process. However, how general practitioners and other primary care professionals recognize gut feelings of patients and deal with them in their decision making is yet unclear. We aim to explore how primary care professionals perceive patients' gut feelings and use this information in their decision-making. METHODS: We interviewed 30 Dutch and Belgian primary care professionals, exploring how they recognize and value patients' gut feelings. We coded all interviews using a descriptive content analysis in an iterative process. Data sufficiency was achieved. RESULTS: Primary care professionals acknowledged gut feelings in their patients, and most participants found them a useful source of information. Patients' gut feelings might alert them to possible hidden problems and might provide quicker insight into patients' perceptions. Primary care professionals listed a whole series of wordings relating to trusting or distrusting the situation or to any changes in normal patterns. A patient's gut feeling was often a reason for the professionals to explore patients' worries and to reconsider their own clinical reasoning. CONCLUSIONS: Primary care professionals regularly considered patients' gut feelings useful, as they might contribute to their clinical reasoning and to a deeper understanding of the patient's problem. The next step could be to ask patients themselves about their gut feelings and explore their diagnostic value.

Fecal amine metabolite analysis before onset of severe necrotizing enterocolitis in preterm infants: a prospective case-control study.

Infants developing necrotizing enterocolitis (NEC) have a different metabolomic profile compared to controls. The potential of specific metabolomics, i.e. amino acids and amino alcohols (AAA), as early diagnostic biomarkers for NEC is largely unexplored. In this multicenter prospective case-control study, longitudinally collected fecal samples from preterm infants (born <30 weeks of gestation) from 1-3 days before diagnosis of severe NEC (Bell's stage IIIA/IIIB), were analyzed by targeted high-performance liquid chromatography (HPLC). Control samples were collected from gestational and postnatal age-matched infants. Thirty-one NEC cases (15 NEC IIIA;16 NEC IIIB) with 1:1 matched controls were included. Preclinical samples of infants with NEC were characterized by five increased essential amino acids-isoleucine, leucine, methionine, phenylalanine and valine. Lysine and ethanolamine ratios were lower prior to NEC, compared to control samples. A multivariate model was rendered based on isoleucine, lysine, ethanolamine, tryptophan and ornithine, modestly discriminating cases from controls (AUC 0.67; p < 0.001). Targeted HPLC pointed to several specific AAA alterations in samples collected 1-3 days before NEC onset, compared to controls. Whether this reflects metabolic alterations and has a role in early biomarker development for NEC, has yet to be elucidated.

[General practitioners' recognition and management of child abuse: what is going well and what could be improved?] / Kindermishandeling herkennen en aanpakken.

In the Netherlands, child abuse affects about 100.000 children resulting in at least 17 child fatalities a year. General practitioners' (GPs) health care position is of vital importance for recognising and managing child abuse. In this Clinical Lesson, using three illustrating cases, we discuss how GPs' suspicion of child abuse may arise including the role of gut feelings, and what the mandatory national guideline on child abuse means for the follow-up. We also clarify the role of the Dutch Child Abuse Counselling and Reporting Centre (CACRC) in the process. A first lesson is that any doubts about child abuse should lead to action because diagnostic failure has serious consequences for vulnerable children. A second lesson is that asking CACRC for anonymous advice how to deal with a situation may certainly have added value. Finally, we advise CACRC to invest in building a relationship of trust with the collaborating partners.

Detection of colorectal cancer in urine using DNA methylation analysis.

Colorectal cancer (CRC) is the second leading cause for cancer-related death globally. Clinically, there is an urgent need for non-invasive CRC detection. This study assessed the feasibility of CRC detection by analysis of tumor-derived methylated DNA fragments in urine. Urine samples, including both unfractioned and supernatant urine fractions, of 92 CRC patients and 63 healthy volunteers were analyzed for DNA methylation levels of 6 CRC-associated markers (SEPT9, TMEFF2, SDC2, NDRG4, VIM and ALX4). Optimal marker panels were determined by two statistical approaches. Methylation levels of SEPT9 were significantly increased in urine supernatant of CRC patients compared to controls (p < 0.0001). Methylation analysis in unfractioned urine appeared inaccurate. Following multivariate logistic regression and classification and regression tree analysis, a marker panel consisting of SEPT9 and SDC2 was able to detect up to 70% of CRC cases in urine supernatant at 86% specificity. First evidence is provided for CRC detection in urine by SEPT9 methylation analysis, which combined with SDC2 allows for an optimal differentiation between CRC patients and controls. Urine therefore provides a promising liquid biopsy for non-invasive CRC detection.

Multiple putative oncogenes at the chromosome 20q amplicon contribute to colorectal adenoma to carcinoma progression.

OBJECTIVE: This study aimed to identify the oncogenes at 20q involved in colorectal adenoma to carcinoma progression by measuring the effect of 20q gain on mRNA expression of genes in this amplicon. METHODS: Segmentation of DNA copy number changes on 20q was performed by array CGH (comparative genomic hybridisation) in 34 non-progressed colorectal adenomas, 41 progressed adenomas (ie, adenomas that present a focus of cancer) and 33 adenocarcinomas. Moreover, a robust analysis of altered expression of genes in these segments was performed by microarray analysis in 37 adenomas and 31 adenocarcinomas. Protein expression was evaluated by immunohistochemistry on tissue microarrays. RESULTS: The genes C20orf24, AURKA, RNPC1, TH1L, ADRM1, C20orf20 and TCFL5, mapping at 20q, were significantly overexpressed in carcinomas compared with adenomas as a consequence of copy number gain of 20q. CONCLUSION: This approach revealed C20orf24, AURKA, RNPC1, TH1L, ADRM1, C20orf20 and TCFL5 genes to be important in chromosomal instability-related adenoma to carcinoma progression. These genes therefore may serve as highly specific biomarkers for colorectal cancer with potential clinical applications.

MiR-17-92 cluster is associated with 13q gain and c-myc expression during colorectal adenoma to adenocarcinoma progression.

BACKGROUND: MicroRNAs are small non-coding RNA molecules, which regulate central mechanisms of tumorigenesis. In colorectal tumours, the combination of gain of 8q and 13q is one of the major factors associated with colorectal adenoma to adenocarcinoma progression. Functional studies on the miR-17-92 cluster localised on 13q31 have shown that its transcription is activated by c-myc, located on 8q, and that it has oncogenic activities. We investigated the contribution of the miR-17-92 cluster during colorectal adenoma to adenocarcinoma progression. METHODS: Expression levels of the miR-17-92 cluster were determined in 55 colorectal tumours and in 10 controls by real-time RT-PCR. Messenger RNA c-myc expression was also determined by real-time RT-PCR in 48 tumours with array comparative genomic hybridisation (aCGH) data available. RESULTS: From the six members of the miR-17-92 cluster, all except miR-18a, showed significant increased expression in colorectal tumours with miR-17-92 locus gain compared with tumours without miR-17-92 locus gain. Unsupervised cluster analysis clustered the tumours based on the presence of miR-17-92 locus gain. Significant correlation between the expression of c-myc and the six miRNAs was also found. CONCLUSION: Increased expression of miR-17-92 cluster during colorectal adenoma to adenocarcinoma progression is associated to DNA copy number gain of miR17-92 locus on 13q31 and c-myc expression.

Expression of Pla2g2a prevents carcinogenesis in Muc2-deficient mice.

Goblet cell depletion and down-regulation of MUC2 expression are observed in a significant percentage of human non-mucinous colorectal adenocarcinomas. Direct evidence for the role of MUC2 in gastrointestinal tumor formation was demonstrated by a knockout of Muc2 in mice that resulted in the development of adenocarcinomas in the small and large intestine. The secretory phospholipase Pla2g2a is a protein that confers resistance to Apc(Min/+)-induced intestinal tumorigenesis. Like Muc2, in the large intestine Pla2g2a is exclusively expressed by the goblet cells and Pla2g2a's tumor resistance is also strongest in the large intestine. Possible genetic interactions between Muc2 and Pla2g2a were examined by creating C57BL/6-Muc2(-/-)Pla2g2a transgenic mice. Expression of a Pla2g2a transgene reduced tumorigenesis in the large intestine by 90% in male Muc2(-/-) mice and by nearly 100% in female Muc2(-/-) mice. Expression of Pla2g2a also inhibited tumor progression. Microarray gene expression studies revealed Pla2g2a target genes that modulate intestinal energy metabolism, differentiation, inflammation, immune responses and proliferation. Overall, results of the present study demonstrate an Apc-independent role for Pla2g2a in tumor resistance and indicate that Pla2g2a plays an important role, along with Muc2, in protection of the intestinal mucosa.

Genome-wide DNA copy number alterations in head and neck squamous cell carcinomas with or without oncogene-expressing human papillomavirus.

Oncogene-expressing human papillomavirus type 16 (HPV16) is found in a subset of head and neck squamous cell carcinomas (HNSCC). HPV16 drives carcinogenesis by inactivating p53 and pRb with the viral oncoproteins E6 and E7, paralleled by a low level of mutations in TP53 and allelic loss at 3p, 9p, and 17p, genetic changes frequently found in HNSCCs of nonviral etiology. We hypothesize that two pathways to HNSCC exist: one determined by HPV16 and the other by environmental carcinogens. To define the critical genetic events in these two pathways, we now present a detailed genome analysis of HNSCC with and without HPV16 involvement by employing high-resolution microarray comparative genomic hybridization. Four regions showed alterations in HPV-negative tumors that were absent in HPV-positive tumors: losses at 3p11.2-26.3, 5q11.2-35.2, and 9p21.1-24, and gains/amplifications at 11q12.1-13.4. Also, HPV16-negative tumors demonstrated loss at 18q12.1-23, in contrast to gain in HPV16-positive tumors. Seven regions were altered at high frequency (>33%) in both groups: gains at 3q22.2-qter, 5p15.2-pter, 8p11.2-qter, 9q22-34.1, and 20p-20q, and losses at 11q14.1-qter and 13q11-33. These data show that HNSCC arising by environmental carcinogens are characterized by genetic alterations that differ from those observed in HPV16-induced HNSCC, and most likely occur early in carcinogenesis. A number of genetic changes are shared in both tumor groups and can be considered crucial in the later stages of HNSCC progression.

Evaluating the Reliability of Expert Evidence in Compensation Procedures: Are Diagnosticians Influenced by the Narrative Fallacy when Assessing the Psychological Injuries of Trauma Victims?

The current study investigated whether mental health practitioners are influenced by the narrative fallacy when assessing the psychological injuries of trauma victims. The narrative fallacy is associated with our tendency to establish logical links between different facts. In psychodiagnostic assessments, this tendency may result in overdiagnosis of mental disorders when psychological symptoms can be attributed to a traumatic event. Consequently, legal decision makers may be at risk of awarding compensation for psychological injuries which are not severe enough to justify financial reimbursement. To explore this topic, we asked Dutch mental health practitioners whether they would assign a diagnosis of mental disorder to fictitious symptoms of psychological injury. Each participant was presented with two vignettes. The first vignette described symptoms in terms of a generalized anxiety disorder; the second in terms of a major depressive episode. The vignettes varied in the cause (trauma versus cause not specified) and severity (near threshold of DSM diagnosis versus below threshold of DSM diagnosis) of the symptoms. Results indicated that participants more often assigned a diagnosis of mental disorder if the psychological symptoms had been caused by a traumatic event than if that had not been the case. Further analysis of the data suggested that this difference was due to the high numbers of assigned diagnoses of posttraumatic stress and acute stress disorder in the trauma conditions. It was speculated that participants filled in missing information to justify the assignment of such diagnoses, for example by imagining symptoms of intrusion and avoidance.

MiR expression profiles of paired primary colorectal cancer and metastases by next-generation sequencing.

MicroRNAs (miRs) have been recognized as promising biomarkers. It is unknown to what extent tumor-derived miRs are differentially expressed between primary colorectal cancers (pCRCs) and metastatic lesions, and to what extent the expression profiles of tumor tissue differ from the surrounding normal tissue. Next-generation sequencing (NGS) of 220 fresh-frozen samples, including paired primary and metastatic tumor tissue and non-tumorous tissue from 38 patients, revealed expression of 2245 known unique mature miRs and 515 novel candidate miRs. Unsupervised clustering of miR expression profiles of pCRC tissue with paired metastases did not separate the two entities, whereas unsupervised clustering of miR expression profiles of pCRC with normal colorectal mucosa demonstrated complete separation of the tumor samples from their paired normal mucosa. Two hundred and twenty-two miRs differentiated both pCRC and metastases from normal tissue samples (false discovery rate (FDR) <0.05). The highest expressed tumor-specific miRs were miR-21 and miR-92a, both previously described to be involved in CRC with potential as circulating biomarker for early detection. Only eight miRs, 0.5% of the analysed miR transcriptome, were differentially expressed between pCRC and the corresponding metastases (FDR <0.1), consisting of five known miRs (miR-320b, miR-320d, miR-3117, miR-1246 and miR-663b) and three novel candidate miRs (chr 1-2552-5p, chr 8-20656-5p and chr 10-25333-3p). These results indicate that previously unrecognized candidate miRs expressed in advanced CRC were identified using NGS. In addition, miR expression profiles of pCRC and metastatic lesions are highly comparable and may be of similar predictive value for prognosis or response to treatment in patients with advanced CRC.

A failure to reproduce the intermediate effect in clinical case recall.

PURPOSE: To investigate the differences between experts, intermediates, and novices in diagnosing and representing clinical cases under various time constraints. METHOD: Second-, fourth-, and sixth-year medical students, and internists studied, diagnosed, and recalled four clinical cases from internal medicine. Participants were allowed to study each case for either 3 minutes, 1 minute 15 seconds, or 30 seconds. The study replicated in most ways the 1993 clinical case recall study of Schmidt and Boshuizen. RESULTS: As expected, diagnostic accuracy increased with level of expertise. However, this study failed to disclose the intermediate effect in clinical case recall that was found in the original study. Instead, a positive linear relation between expertise level and case recall was found. The discrepancy resulted from more elaborate recall by experts in the present study. Constraining processing time did not effect diagnostic accuracy, but equally affected the recall performances of the participants of all expertise levels. This contrasts with the earlier finding that experts' recall is independent of processing time. CONCLUSION: Although it is unclear why the experts' case processing was more elaborate in the present study than in the earlier study, it must be concluded that expert medical knowledge is so flexibly organized that experts can easily represent clinical cases in either the encapsulated or the elaborated mode.

The effect of familiality on clinical presentation and survival in mammary carcinoma.

In a series of 467 patients treated for mammary carcinoma 96 (20%) had a family history for this tumour. Sixty-eight (71%) had at least one first degree, 28 (29%) a second or third degree family member. Only the mean age of the second degree relative group differed significantly from that of the non-familial group. The size of the primary tumour at first presentation did not differ significantly in the familial and non-familial group, as the estimated survival. So patients with a family history for mammary carcinoma did not present themselves in an earlier stage of disease. Because of the higher risk of developing this type of tumour in female relatives we have to instruct this potential patient group more explicitly.

Fountain syndrome: further delineation of the clinical syndrome and follow-up data.

We present five patients with the clinical diagnosis of Fountain's syndrome, an autosomal recessive entity with mental retardation, deafness, skeletal abnormalities and coarse face with full lips as cardinal features and review all cases reported so far. We report two new isolated cases, and present follow-up data on three previously reported patients. The clinical features of all these patients are presented to further delineate the clinical picture and the natural course of this rare syndrome. We propose that epilepsy, short stature, large head circumference, broad, plump hands and the remarkable behavior are important accessory findings of this syndrome. The clinical features of this syndrome become more evident with advancing age.