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.

Long-Term Spinal Cord Stimulation Alleviates Mechanical Hypersensitivity and Increases Peripheral Cutaneous Blood Perfusion in Experimental Painful Diabetic Polyneuropathy.

OBJECTIVES: This study utilizes a model of long-term spinal cord stimulation (SCS) in experimental painful diabetic polyneuropathy (PDPN) to investigate the behavioral response during and after four weeks of SCS (12 hours/day). Second, we investigated the effect of long-term SCS on peripheral cutaneous blood perfusion in experimental PDPN. METHODS: Mechanical sensitivity was assessed in streptozotocin induced diabetic rats (n = 50) with von Frey analysis. Hypersensitive rats (n = 24) were implanted with an internal SCS battery, coupled to an SCS electrode covering spinal levels L2-L5. The effects of four weeks of daily conventional SCS for 12 hours (n = 12) or Sham SCS (n = 12) were evaluated with von Frey assessment, and laser Doppler imaging (LDI). RESULTS: Average paw withdrawal thresholds (PWT) increased during long-term SCS in the SCS group, in contrast to a decrease in the Sham group (Sham vs. SCS; p = 0.029). Twenty-four hours after long-term SCS average PWT remained higher in the SCS group. Furthermore, the SCS group showed a higher cutaneous blood perfusion during long-term SCS compared to the Sham group (Sham vs. SCS; p = 0.048). Forty-eight hours after long-term SCS, no differences in skin perfusion were observed. DISCUSSION: We demonstrated that long-term SCS results in decreased baseline mechanical hypersensitivity and results in increased peripheral blood perfusion during stimulation in a rat model of PDPN. Together, these findings indicate that long-term SCS results in modulation of the physiological circuitry related to the nociceptive system in addition to symptomatic treatment of painful symptoms.

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.

Fifty-one full-length major histocompatibility complex class II alleles in the olive baboon (Papio anubis).

Here we report 51 novel major histocompatibility complex (MHC) class II alleles in a group of related olive baboons.

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.

Novel DRA alleles extracted from seven macaque cohorts.

In this document, we report the detection of 37 DRA alleles in macaque cohorts.

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.

Altered microRNA expression associated with chromosomal changes contributes to cervical carcinogenesis.

Little is known about the alterations in microRNA (miRNA) expression patterns during the consecutive stages of cervical cancer development and their association with chromosomal instability. In this study, miRNA expression in normal cervical squamous epithelium, high-grade precancerous lesions (cervical intraepithelial neoplasia (CIN2-3)), squamous cell carcinomas (SCCs) and adenocarcinomas (AdCAs) was integrated with previously generated chromosomal profiles of the same samples. Significantly differential expression during the consecutive stages of cervical SCC development was observed for 106 miRNAs. Of these differentially expressed miRNAs, 27 showed early transiently altered expression in CIN2-3 lesions only, 46 miRNAs showed late altered expression in SCCs only and 33 showed continuously altered expression in both CIN2-3 and SCCs. Altered expression of five significantly differentially expressed miRNAs, hsa-miR-9 (1q23.2), hsa-miR-15b (3q25.32), hsa-miR-28-5p (3q27.3), hsa-miR-100 and hsa-miR-125b (both 11q24.1), was directly linked to frequent chromosomal alterations. Functional analyses were performed for hsa-miR-9, representing a potential oncogene with increased expression linked to a chromosomal gain of 1q. Hsa-miR-9 overexpression was found to increase cell viability, anchorage-independent growth and migration in vitro. Upon organic raft culturing, hsa-miR-9 hampered differentiation and induced proliferation in all strata of the epithelial layer. These findings support a potential oncogenic function of hsa-miR-9 in cervical cancer. In summary, differential expression of 106 miRNAs, partly associated with chromosomal alterations, was observed during cervical SCC development. Altered expression of hsa-miR-9 associated with a chromosomal gain of chromosome 1q was shown to be functionally relevant, underlining the importance of deregulated miRNA expression in cervical carcinogenesis.

[Are postgraduate courses for GPs relevant to diagnostics?]. / Nascholing van huisartsen relevant voor diagnostiek?

Correctly predicting the course of a patient's pattern of symptoms, even if no diagnosis has (yet) been established, is a core task of the general practitioner (GP). This is a complex task requiring extensive knowledge and experience, as the presentation of diseases in primary care regularly deviates from what doctors learn at medical school. In addition, knowledge among GPs about clinical pictures requiring immediate action is not always sufficient. Finally, GPs' context and experiential knowledge are decreasing due to changes in the organization of care. In the authors' opinion, postgraduate courses for GPs insufficiently address these issues. Postgraduate courses should teach them about serious diseases that must not be missed, about uncommon presentations of common diseases and about the role of gut feelings in diagnostic thinking and the way to act on these feelings. GPs should be obliged to devote part of their compulsory postgraduate training to these subjects.

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.

Modelling river history and evolution.

Over the last few decades, a suite of numerical models has been developed for studying river history and evolution that is almost as diverse as the subject of river history itself. A distinction can be made between landscape evolution models (LEMs), alluvial architecture models, meander models, cellular models and computational fluid dynamics models. Although these models share some similarities, there also are notable differences between them, which make them more or less suitable for simulating particular aspects of river history and evolution. LEMs embrace entire drainage basins at the price of detail; alluvial architecture models simulate sedimentary facies but oversimplify flow characteristics; and computational fluid dynamics models have to assume a fixed channel form. While all these models have helped us to predict erosion and depositional processes as well as fluvial landscape evolution, some areas of prediction are likely to remain limited and short-term owing to the often nonlinear response of fluvial systems. Nevertheless, progress in model algorithms, computing and field data capture will lead to greater integration between these approaches and thus the ability to interpret river history more comprehensively.

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.

Functional recovery, serotonergic sprouting, and endogenous progenitor fates in response to delayed environmental enrichment after spinal cord injury.

Environmental enrichment (EE) is a way to induce voluntary locomotor training that positively affects locomotor recovery after acute spinal cord injury (SCI). The beneficial effect on SCI outcome is thought to be based on enhanced plasticity in motor pathways, triggered by locomotor-specific sensory feedback to the spinal cord circuitry for locomotion (central pattern generators [CPGs]). In view of chronic SCI, we tested the hypothesis that EE improves motor outcome after SCI in the rat when started after a clinically relevant delay of 3 weeks. At the CPG level (i.e., the spinal L1-L2 level), where EE-related sensory feedback is processed, two key mechanisms of anatomical plasticity were examined: (1) serotonergic innervation, and (2) survival and differentiation of spinal cord progenitor cells. Delayed EE improved interlimb coordination, which was associated with an increased serotonergic innervation of the ventro-lateral grey matter within the L1-L2 segments. Although spinal cord progenitor cells were found to differentiate into both neurons and glial cells, EE did not affect their survival. These results show that EE induces a substantial improvement of motor outcome after SCI when commenced after a clinically-relevant delay. Increased serotonergic innervation of the lumbar CPG area is therefore suggested to play an important role in the EE-induced recovery of interlimb coordination.