Potentials and pitfalls of clinical peptidomics and metabolomics

Clinical peptidomics and metabolomics are two emerging "-omics" technologies with the potential not only to detect disease-specific markers, but also to give insight into the disease dependency of degradation processes and metabolic pathway alterations. However, despite their rapid evolution and major investments, a clinical breakthrough, such as the approval of a major cancer biomarker, is still out of sight. What are the reasons for this failure? In this review we focus on three important factors: sensitivity, specificity and the avoidance of bias. The way to clinical implementation of peptidomics and metabolomics is still hampered by many of the problems that had to be solved for genomics and proteomics in the past, as well as new ones that require the creation of new analytic, computational and interpretative techniques. The greatest challenge, however, will be the integration of information from different "-omics" subdisciplines into straightforward answers to clinical questions, for example, in the form of new, superior "meta-markers".

Computer-based summative assessment of clinical reasoning in clerkships: A mixed-method comparison of key feature problems with case-based multiple choice questions

Background: It is yet unclear if there are differences between using electronic key feature problems (KFPs) or electronic case-based multiple choice questions (cbMCQ) for the assessment of clinical decision making. Summary of Work: Fifth year medical students were exposed to clerkships which ended with a summative exam. Assessment of knowledge per exam was done by 6-9 KFPs, 9-20 cbMCQ and 9-28 MC questions. Each KFP consisted of a case vignette and three key features (KF) using “long menu” as question format. We sought students’ perceptions of the KFPs and cbMCQs in focus groups (n of students=39). Furthermore statistical data of 11 exams (n of students=377) concerning the KFPs and (cb)MCQs were compared. Summary of Results: The analysis of the focus groups resulted in four themes reflecting students’ perceptions of KFPs and their comparison with (cb)MCQ: KFPs were perceived as (i) more realistic, (ii) more difficult, (iii) more motivating for the intense study of clinical reasoning than (cb)MCQ and (iv) showed an overall good acceptance when some preconditions are taken into account. The statistical analysis revealed that there was no difference in difficulty; however KFP showed a higher discrimination and reliability (G-coefficient) even when corrected for testing times. Correlation of the different exam parts was intermediate. Conclusions: Students perceived the KFPs as more motivating for the study of clinical reasoning. Statistically KFPs showed a higher discrimination and higher reliability than cbMCQs. Take-home messages: Including KFPs with long menu questions into summative clerkship exams seems to offer positive educational effects.

Endocarditis due to Tropheryma whipplei: rapid detection, limited genetic diversity, and long-term clinical outcome in a local experience

The characteristic features of Whipple's disease include abdominal pain, diarrhoea, wasting, and arthralgias, with the causative agent, Tropheryma whipplei, being detected mainly in intestinal biopsies. PCR technology has led to the identification of T. whipplei in specimens from various other locations, including the central nervous system and the heart. T. whipplei is now recognized as one of the causes of culture-negative endocarditis, and endocarditis can be the only manifestation of the infection with T. whipplei. Although it is considered a rare disease, the true incidence of endocarditis due to T. whipplei is not clearly established. With the increasing use of molecular methods, it is likely that T. whipplei will be more frequently identified. Questions also remain about the genetic variability of T. whipplei strains, optimal diagnostic procedures and therapeutic options. In the present study, we provide clinical data on four new patients with documented endocarditis due to T. whipplei in the context of the available published literature. There was no clinical involvement of the gastrointestinal tract. Genetic analysis of the T. whipplei strains with DNA isolated from the excised heart valves revealed little to no genetic variability. In a selected case, we describe acridine orange staining for early detection of the disease, prompting early adaptation of the antibiotic therapy. We provide long-term follow-up data on the patients. In our hands, an initial 2-week course of intravenous antibiotics followed by cotrimoxazole for at least 1 year was a suitable treatment option for T. whipplei endocarditis.

[Early genetic testing in nephrology - a diagnostic aid in ambiguous clinical situations]

Despite a growing number of identified genetic causes of monogenetic disorders, early molecular testing is rarely applied in daily nephrologic practice. In selected cases and to answer specific questions, molecular testing however can be helpful for the specialist. The future significance of genetic testing most likely lies in the area of individual risk profiling for polygenetic disorders. The basis for this testing however has yet to be established.

Pharmacological treatment of primary chronic venous disease: rationale, results and unanswered questions

The aim of this article was first to review the complex pathophysiological mechanisms responsible for symptoms and signs of primary chronic venous disease (CVD) that allow the identification of targets for pharmacological treatment. The results of CVD treatment with venoactive drugs (VADs) were emphasised and presented in the form of recommendations. The last section raises key questions to be answered to improve protocols for good clinical trials and to draw up future guidelines on these agents.

Postoperative radiotherapy after radical prostatectomy: indications and open questions

Biochemical relapse after radical prostatectomy occurs in approximately 15-40% of patients within 5 years. Postoperative radiotherapy is the only curative treatment for these patients. After radical prostatectomy, two different strategies can be offered, adjuvant or salvage radiotherapy. Adjuvant radiotherapy is defined as treatment given directly after surgery in the presence of risk factors (R1 resection, pT3) before biochemical relapse occurs. It consists of 60-64 Gy and was shown to increase biochemical relapse-free survival in three randomized controlled trials and to increase overall survival after a median followup of 12.7 years in one of these trials. Salvage radiotherapy, on the other hand, is given upon biochemical relapse and is the preferred option, by many centers as it does not include patients who might be cured by surgery alone. As described in only retrospective studies the dose for salvage radiotherapy ranges from 64 to 72 Gy and is usually dependent on the absence or presence of macroscopic recurrence. Randomized trials are currently investigating the role of adjuvant and salvage radiotherapy. Patients with biochemical relapse after prostatectomy should at the earliest sign of relapse be referred to salvage radiotherapy and should preferably be treated within a clinical trial.

European Working Group on Clinical Cell Analysis: Consensus protocol for the flow cytometric characterisation of platelet function

An increased or disturbed activation and aggregation of platelets plays a major role in the pathophysiology of thrombosis and haemostasis and is related to cardiovascular disease processes. In addition to qualitative disturbances of platelet function, changes in thrombopoiesis or an increased elimination of platelets, (e. g., in autoimmune thrombocytopenia), are also of major clinical relevance. Flow cytometry is increasingly used for the specific characterisation of phenotypic alterations of platelets which are related to cellular activation, haemostatic function and to maturation of precursor cells. These new techniques also allow the study of the in vitro response of platelets to stimuli and the modification thereof under platelet-targeted therapy as well as the characterisation of platelet-specific antibodies. In this protocol, specific flow cytometric techniques for platelet analysis are recommended based on a description of the current state of flow cytometric methodology. These recommendations are an attempt to promote the use of these new techniques which are at present broadly evaluated for diagnostic purposes. Furthermore, the definition of the still open questions primarily related to the technical details of the method should help to promote the multi-center evaluation of procedures with the goal to finally develop standardized operation procedures as the basis of interlaboratory reproducibility when applied to diagnostic testing.

The SAKK cancer-specific geriatric assessment (C-SGA): a pilot study of a brief tool for clinical decision-making in older cancer patients

BACKGROUND Recommendations from international task forces on geriatric assessment emphasize the need for research including validation of cancer-specific geriatric assessment (C-SGA) tools in oncological settings. The objective of this study was to evaluate the feasibility of the SAKK Cancer-Specific Geriatric Assessment (C-SGA) in clinical practice. METHODS A cross sectional study of cancer patients >=65 years old (N = 51) with pathologically confirmed cancer presenting for initiation of chemotherapy treatment (07/01/2009-03/31/2011) at two oncology departments in Swiss canton hospitals: Kantonsspital Graubunden (KSGR N = 25), Kantonsspital St. Gallen (KSSG N = 26). Data was collected using three instruments, the SAKK C-SGA plus physician and patient evaluation forms. The SAKK C-SGA includes six measures covering five geriatric assessment domains (comorbidity, function, psychosocial, nutrition, cognition) using a mix of medical record abstraction (MRA) and patient interview. Five individual domains and one overall SAKK C-SGA score were calculated and dichotomized as below/above literature-based cut-offs. The SAKK C-SGA was evaluated by: patient and physician estimated time to complete, ease of completing, and difficult or unanswered questions. RESULTS Time to complete the patient questionnaire was considered acceptable by almost all (>=96%) patients and physicians. Patients reported slightly shorter times to complete the questionnaire than physicians (17.33 +/- 7.34 vs. 20.59 +/- 6.53 minutes, p = 0.02). Both groups rated the patient questionnaire as easy/fairly easy to complete (91% vs. 84% respectively, p = 0.14) with few difficult or unanswered questions. The MRA took on average 8.32 +/- 4.72 minutes to complete. Physicians (100%) considered time to complete MRA acceptable, 96% rated it as easy/fairly easy to complete. Individual study site populations differed on health-related characteristics (excellent/good physician-rated general health KSGR 71% vs. KSSG 32%, p = 0.007). The overall mean C-SGA score was 2.4 +/- 1.12. Patients at KSGR had lower C-SGA scores (2.00 +/- 1.19 vs. 2.81 +/- 0.90, p = 0.009) and a smaller proportion (28% vs.65%, p = 0.008) was above the C-SGA cut-off score compared to KSSG. CONCLUSIONS These results suggest the SAKK C-SGA is a feasible practical tool for use in clinical practice. It demonstrated discriminative ability based on objective geriatric assessment measures, but additional investigations on use for clinical decision-making are warranted. The SAKK C-SGA also provides important usable domain information for intervention to optimize outcomes in older cancer patients.

Exploring the validity and reliability of a questionnaire for evaluating virtual patient design with a special emphasis on fostering clinical reasoning

Background: The design of Virtual Patients (VPs) is essential. So far there are no validated evaluation instruments for VP design published. Summary of work: We examined three sources of validity evidence of an instrument to be filled out by students aimed at measuring the quality of VPs with a special emphasis on fostering clinical reasoning: (1) Content was examined based on theory of clinical reasoning and an international VP expert team. (2) Response process was explored in think aloud pilot studies with students and content analysis of free text questions accompanying each item of the instrument. (3) Internal structure was assessed by confirmatory factor analysis (CFA) using 2547 student evaluations and reliability was examined utilizing generalizability analysis. Summary of results: Content analysis was supported by theory underlying Gruppen and Frohna’s clinical reasoning model on which the instrument is based and an international VP expert team. The pilot study and analysis of free text comments supported the validity of the instrument. The CFA indicated that a three factor model comprising 6 items showed a good fit with the data. Alpha coefficients per factor were 0,74 - 0,82. The findings of the generalizability studies indicated that 40-200 student responses are needed in order to obtain reliable data on one VP. Conclusions: The described instrument has the potential to provide faculty with reliable and valid information about VP design. Take-home messages: We present a short instrument which can be of help in evaluating the design of VPs.

An investigation into the mechanical and aesthetic properties of new generation coated nickel-titanium wires in the as-received state and after clinical use.

BACKGROUND/OBJECTIVES The purpose of this study was to compare the mechanical, structural, and aesthetic properties of two types of aesthetic coated nickel-titanium (NiTi) wires compared with comparable regular NiTi wires in the as-received state and after clinical use. MATERIALS/METHODS Sixty one subjects were randomly assigned to four groups (N = 61), two groups of coated wires and two groups of comparable, non-coated controls (n = 15/group). The period in the mouth ranged from 4 to 12 weeks after insertion. In total, 121 wires (61 retrieved and 60 as-received) were used in the study. The percentages of coating retention and loss were extrapolated from scans. A brief survey of five questions with three choices was given to all patients. Differential scanning calorimetry (DSC) and three-point bending tests were done on as-received and used wires. RESULTS The surface characterization by the percentage of resin remaining indicated that most wires in both test groups lost a significant amount of coating. A patient survey indicated that this was a noticeable feature for patients. DSC analysis of the wires indicated that the metallurgical properties of the coated wires were not similar to the uncoated wires in the as-received condition. Three-point bending results indicate a wide variation in test results with large standard deviations among all the groups. LIMITATIONS The extent of coating loss requires investigating, as do the biological properties of the detached coating. CONCLUSIONS Both wires lost a significant amount of aesthetic coating after varying periods in the mouth. The metallurgical testing of these findings may indicate that these wires perform differently in the mouth.

The mini-clinical evaluation exercise during medical clerkships: are learning needs and learning goals aligned?

OBJECTIVES The generation of learning goals (LGs) that are aligned with learning needs (LNs) is one of the main purposes of formative workplace-based assessment. In this study, we aimed to analyse how often trainer–student pairs identified corresponding LNs in mini-clinical evaluation exercise (mini-CEX) encounters and to what degree these LNs aligned with recorded LGs, taking into account the social environment (e.g. clinic size) in which the mini-CEX was conducted. METHODS Retrospective analyses of adapted mini-CEX forms (trainers’ and students’ assessments) completed by all Year 4 medical students during clerkships were performed. Learning needs were defined by the lowest score(s) assigned to one or more of the mini-CEX domains. Learning goals were categorised qualitatively according to their correspondence with the six mini-CEX domains (e.g. history taking, professionalism). Following descriptive analyses of LNs and LGs, multi-level logistic regression models were used to predict LGs by identified LNs and social context variables. RESULTS A total of 512 trainers and 165 students conducted 1783 mini-CEXs (98% completion rate). Concordantly, trainer–student pairs most often identified LNs in the domains of ‘clinical reasoning’ (23% of 1167 complete forms), ‘organisation/efficiency’ (20%) and ‘physical examination’ (20%). At least one ‘defined’ LG was noted on 313 student forms (18% of 1710). Of the 446 LGs noted in total, the most frequently noted were ‘physical examination’ (49%) and ‘history taking’ (21%). Corresponding LNs as well as social context factors (e.g. clinic size) were found to be predictors of these LGs. CONCLUSIONS Although trainer–student pairs often agreed in the LNs they identified, many assessments did not result in aligned LGs. The sparseness of LGs, their dependency on social context and their partial non-alignment with students’ LNs raise questions about how the full potential of the mini-CEX as not only a ‘diagnostic’ but also an ‘educational’ tool can be exploited.

Exploring the validity and reliability of a questionnaire for evaluating virtual patient design with a special emphasis on fostering clinical reasoning

Background: Virtual patients (VPs) are increasingly used to train clinical reasoning. So far, no validated evaluation instruments for VP design are available. Aims: We examined the validity of an instrument for assessing the perception of VP design by learners. Methods: Three sources of validity evidence were examined: (i) Content was examined based on theory of clinical reasoning and an international VP expert team. (ii) The response process was explored in think-aloud pilot studies with medical students and in content analyses of free text questions accompanying each item of the instrument. (iii) Internal structure was assessed by exploratory factor analysis (EFA) and inter-rater reliability by generalizability analysis. Results: Content analysis was reasonably supported by the theoretical foundation and the VP expert team. The think-aloud studies and analysis of free text comments supported the validity of the instrument. In the EFA, using 2547 student evaluations of a total of 78 VPs, a three-factor model showed a reasonable fit with the data. At least 200 student responses are needed to obtain a reliable evaluation of a VP on all three factors. Conclusion: The instrument has the potential to provide valid information about VP design, provided that many responses per VP are available.

Translation of ERC resuscitation guidelines into clinical practice by emergency physicians

PURPOSE Austrian out-of-hospital emergency physicians (OOHEP) undergo mandatory biannual emergency physician refresher courses to maintain their licence. The purpose of this study was to compare different reported emergency skills and knowledge, recommended by the European Resuscitation Council (ERC) guidelines, between OOHEP who work regularly at an out-of-hospital emergency service and those who do not currently work as OOHEP but are licenced. METHODS We obtained data from 854 participants from 19 refresher courses. Demographics, questions about their practice and multiple-choice questions about ALS-knowledge were answered and analysed. We particularly explored the application of therapeutic hypothermia, intraosseous access, pocket guide use and knowledge about the participants' defibrillator in use. A multivariate logistic regression analysed differences between both groups of OOHEP. Age, gender, years of clinical experience, ERC-ALS provider course attendance and the self-reported number of resuscitations were control variables. RESULTS Licenced OOHEP who are currently employed in emergency service are significantly more likely to initiate intraosseous access (OR = 4.013, p < 0.01), they initiate mild-therapeutic hypothermia after successful resuscitation (OR = 2.550, p < 0.01) more often, and knowledge about the used defibrillator was higher (OR = 2.292, p < 0.01). No difference was found for the use of pocket guides.OOHEP who have attended an ERC-ALS provider course since 2005 have initiated more mild therapeutic hypothermia after successful resuscitation (OR = 1.670, p <0.05) as well as participants who resuscitated within the last year (OR = 2.324, p < 0.01), while older OOHEP initiated mild therapeutic hypothermia less often, measured per year of age (OR = 0.913, p <0.01). CONCLUSION Licenced and employed OOHEP implement ERC guidelines better into clinical practice, but more training on life-saving rescue techniques needs to be done to improve knowledge and to raise these rates of application.

Clinical Practice Recommendations on Genetic Testing of CYP2C9 and VKORC1 Variants in Warfarin Therapy

OBJECTIVE To systematically review evidence on genetic variants influencing outcomes during warfarin therapy and provide practice recommendations addressing the key questions: (1) Should genetic testing be performed in patients with an indication for warfarin therapy to improve achievement of stable anticoagulation and reduce adverse effects? (2) Are there subgroups of patients who may benefit more from genetic testing compared with others? (3) How should patients with an indication for warfarin therapy be managed based on their genetic test results? METHODS A systematic literature search was performed for VKORC1 and CYP2C9 and their association with warfarin therapy. Evidence was critically appraised, and clinical practice recommendations were developed based on expert group consensus. RESULTS Testing of VKORC1 (-1639G>A), CYP2C9*2, and CYP2C9*3 should be considered for all patients, including pediatric patients, within the first 2 weeks of therapy or after a bleeding event. Testing for CYP2C9*5, *6, *8, or *11 and CYP4F2 (V433M) is currently not recommended. Testing should also be considered for all patients who are at increased risk of bleeding complications, who consistently show out-of-range international normalized ratios, or suffer adverse events while receiving warfarin. Genotyping results should be interpreted using a pharmacogenetic dosing algorithm to estimate the required dose. SIGNIFICANCE This review provides the latest update on genetic markers for warfarin therapy, clinical practice recommendations as a basis for informed decision making regarding the use of genotype-guided dosing in patients with an indication for warfarin therapy, and identifies knowledge gaps to guide future research.