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Background: Despite a major research focus on clinical reasoning over the last several decades, a method of evaluating the clinical reasoning process that is both objective and comprehensive is yet to be developed.The aim of this study was to test whether a dual approach, using two measures of clinical reasoning, the Clinical Reasoning Problem (CRP) and the Script Concordance Test (SCT), provides a valid, reliable and targeted analysis of clinical reasoning characteristics to facilitate the development of diagnostic thinking in medical students., Methods: Three groups of participants, general practitioners, and third and fourth (final) year medical students completed 20 on-line clinical scenarios -10 in CRP and 10 in SCT format. Scores for each format were analysed for reliability, correlation between the two formats and differences between subject-groups., Results: Cronbach's alpha coefficient ranged from 0.36 for SCT 1 to 0.61 for CRP 2, Statistically significant correlations were found between the mean f-score of the CRP 2 and total SCT 2 score (0.69); and between the mean f-score for all CRPs and all mean SCT scores (0.57 and 0.47 respectively). The pass/fail rates of the SCT and CRP f-score are in keeping with the findings from the correlation analysis (i.e. 31% of students (11/35) passed both, 26% failed both, and 43% (15/35) of students passed one but not the other test), and suggest that the two formats measure overlapping but not identical characteristics. One-way ANOVA showed consistent differences in scores between levels of expertise with these differences being significant or approaching significance for the CRPs., Conclusion: SCTs and CRPs are overlapping and complementary measures of clinical reasoning. Whilst SCTs are more efficient to administer, the use of both measures provides a more comprehensive appraisal of clinical skills than either single measure alone, and as such could potentially facilitate the customised teaching of clinical reasoning for individuals. The modest reliability of SCTs and CRPs in this study suggests the need for an increased number of items for testing. Further work is needed to determine the suitability of a combined approach for assessment purposes.

The aim of this study was to identify and describe the clinical reasoning characteristics of diagnostic experts. A group of 21 experienced general practitioners were asked to complete the Diagnostic Thinking Inventory (DTI)and a set of 10 clinical reasoning problems (CRP) to evaluate their clinical reasoning. Both the DTI and the CRPs were scored, and the CRP response patterns of each GP examined in terms of the number and type of errors contained in them. Analysis of these data showed that six GPs were able to reach the correct diagnosis using significantly less clinical information than their colleagues. These GPs also made significantly fewer interpretation errors but scored lower on both the DTI and the CRPs. Additionally, this analysis showed that more than 20% of misdiagnoses occurred despite no errors being made in the identification and interpretation of relevant clinical information. These rests indicate that these six GPs diagnose efficiently,effectively and accurately using relatively few clinical data and can therefore be classified as diagnostic experts. They also indicate that a major cause of misdiagnoses is failure to properly integrate clinical data. We suggest that increased emphasis on this step in the reasoning process should prove beneficial to the development of clinical reasoning skill in undergraduate medical students.

The practice of clinical medicine needs to be a very flexible discipline which can adapt promptly to continuously changing surrounding events. Despite the huge advances and progress made in recent decades, clinical reasoning to achieve an accurate diagnosis still seems to be the most appropriate and distinctive feature of clinical medicine. This is particularly evident in internal medicine where diagnostic boundaries are often blurred. Making a diagnosis is a multi-stage process which requires proper data collection, the formulation of an illness script and testing of the diagnostic hypothesis. To make sense of a number of variables, physicians may follow an analytical or an intuitive approach to clinical reasoning, depending on their personal experience and level of professionalism. Intuitive thinking is more typical of experienced physicians, but is not devoid of shortcomings. Particularly, the high risk of biases must be counteracted by de-biasing techniques, which require constant critical thinking. In this review, we discuss critically the current knowledge regarding diagnostic reasoning from an internal medicine perspective.

In this paper, we present a novel Artificial Intelligence (AI) -empowered system that enhances large language models and other machine learning tools with rules to provide primary care diagnostic advice to patients. Specifically, we introduce a novel methodology, represented through a process diagram, which allows the definition of generative AI processes and functions with a focus on the rule-augmented approach. Our methodology separates various components of the generative AI process as blocks that can be used to generate an implementation data flow diagram. Building upon this framework, we utilize the concept of a dialogue process as a theoretical foundation. This is specifically applied to the interactions between a user and an AI-empowered software program, which is called "Med|Primary AI assistant" (Alpha Version at the time of writing), and provides symptom analysis and medical advice in the form of suggested diagnostics. By leveraging current advancements in natural language processing, a novel approach is proposed to define a blueprint of domain-specific knowledge and a context for instantiated advice generation. Our approach not only encompasses the interaction domain, but it also delves into specific content that is relevant to the user, offering a tailored and effective AI–user interaction experience within a medical context. Lastly, using an evaluation process based on rules, defined by context and dialogue theory, we outline an algorithmic approach to measure content and responses. [ABSTRACT FROM AUTHOR]

Breast cancer is among the most frequent malignancies in women worldwide. While early detection and effective treatment provide many women with a cure and prevent their cancer from spreading, metastases to distant sites still occur in around 20% of women suffering from breast cancer. These relapses occur in many forms and locations and are as varied as the primary breast tumors. Metastatic spread makes a cancer incurable and potentially lethal, but new, targeted treatments can offer control of the cancer cells if the features of new targets are unlocked by advanced diagnostic testing. The article offers an overview of the pathomechanisms of metastatic progression and describes the types of metastases, such as hormone-receptor-positive and -negative breast cancers, and HER2-overexpressing or triple-negative types. Once distant metastatic spread occurs, cytology allows a precise diagnosis to confirm the breast origin. Other molecular targets include ESR1 and PIK3CA mutations, MSI, NTRK fusion, PD-L1 expression and others, which can be obtained also from cytology material and used to determine eligibility for emerging targeted therapeutic options. We outline the diagnostic features of metastatic breast cancer in cytology samples, together with validated and emergent biomarkers that may provide new, targeted treatment options. [ABSTRACT FROM AUTHOR]

Background: Dancing is an engaging physical activity for people living with Parkinson's disease (PD). We conducted a process evaluation for a PD trial on online dancing. Methods: "ParkinDANCE Online" was co-produced by people with PD, healthcare professionals, dance instructors, and a PD organisation. The evaluation mapped the following inputs: (i) stakeholder steering group to oversee program design, processes, and outcomes; (ii) co-design of online classes, based on a research evidence synthesis, expert advice, and stakeholder recommendations; (iii) trial fidelity. The key activities were (i) the co-design of classes and instruction manuals, (ii) the education of dance teachers, (iii) fidelity checking, (iv) online surveys, (v) and post-trial focus groups and interviews with participants. The outputs pertained to: (i) recruitment, (ii) retention, (iii) adverse events, (iv) fidelity, (v) protocol variations, and (vi) participant feedback. Results: Twelve people with PD, four dance instructors and two physiotherapists, participated in a 6-week online dance program. There was no attrition, nor were there any adverse events. Program fidelity was strong with few protocol variations. Classes were delivered as planned, with 100% attendance. Dancers valued skills mastery. Dance teachers found digital delivery to be engaging and practical. The safety of online testing was facilitated by careful screening and a home safety checklist. Conclusions: It is feasible to deliver online dancing to people with early PD. [ABSTRACT FROM AUTHOR]

Aims: Diagnostic Reasoning (DR) is an essential competency requiring mastery for safe, independent Nurse Practitioner (NP) practice, but little is known about DR content included in NP education programs. The aims of this study were to identify whether and how the concept of DR is addressed in NP education. Design: We conducted a scoping review on DR‐related content and teaching innovations in U.S. primary care NP education programs, with implications for NP education programs worldwide. Concepts and principles with global applicability include: conducting focused and hypothesis‐directed histories and exams, generating the problem statement, formulating the differential diagnosis, appropriate and relevant diagnostic testing, determining the working diagnosis and developing evidence‐based, patient‐centred management plans. Data sources N = 1115 articles retrieved from Medline, Embase, PsycINFO, and CINAHL for the period 2005–2021. Forty‐one scholarly articles met inclusion/exclusion criteria. Review methods: Data were extracted, synthesized and grouped by theoretical frameworks, content included, educational interventions and assessment measures. Results: Most articles provided descriptions of approaches for teaching NP clinical or diagnostic reasoning. Ten papers directly referenced the current science and theory of DR. Conclusion: The US NP education literature addressing DR is limited and demonstrates a lack of shared conceptualizations of DR. Whilst numerous components of DR are identifiable in the literature, a robust teaching/learning scholarship for DR has not yet been established in the US NP education literature. Impact Whilst primary care NP education programs are beginning to incorporate DR education into their curricula, little research has been conducted to demonstrate the effectiveness of educational outcomes. Increased integration of DR content into NP education is needed, including increased educational research on teaching DR competencies. Patient or public contribution: No patient or public contribution was included in this review, as the public is generally not familiar with DR or its teaching approaches. [ABSTRACT FROM AUTHOR]

Neurofilament proteins (Nf) have been validated and established as a reliable body fluid biomarker for neurodegenerative pathology. This review covers seven Nf isoforms, Nf light (NfL), two splicing variants of Nf medium (NfM), two splicing variants of Nf heavy (NfH), α‐internexin (INA) and peripherin (PRPH). The genetic and epigenetic aspects of Nf are discussed as relevant for neurodegenerative diseases and oncology. The comprehensive list of mutations for all Nf isoforms covers Amyotrophic Lateral Sclerosis, Charcot–Marie Tooth disease, Spinal muscular atrophy, Parkinson Disease and Lewy Body Dementia. Next, emphasis is given to the expanding field of post‐translational modifications (PTM) of the Nf amino acid residues. Protein structural aspects are reviewed alongside PTMs causing neurodegenerative pathology and human autoimmunity. Molecular visualisations of NF PTMs, assembly and stoichiometry make use of Alphafold2 modelling. The implications for Nf function on the cellular level and axonal transport are discussed. Neurofilament aggregate formation and proteolytic breakdown are reviewed as relevant for biomarker tests and disease. Likewise, Nf stoichiometry is reviewed with regard to in vitro experiments and as a compensatory mechanism in neurodegeneration. The review of Nf across a spectrum of 87 diseases from all parts of medicine is followed by a critical appraisal of 33 meta‐analyses on Nf body fluid levels. The review concludes with considerations for clinical trial design and an outlook for future research. [ABSTRACT FROM AUTHOR]

Background. Chemical exchange saturation transfer (CEST) is a novel imaging modality in clinical practice and scientific research. Angiopep-2 is an artificial peptide that can penetrate blood-brain barrier. The aim of this study was to explore the feasibility of Angiopep-2 serving as an exogenous CEST contrast. Methods. Phantoms of Angiopep-2 with different concentrations were prepared and then scanned using the 7.0T small animal MRI scanner. Different parameters including saturation powers and saturation duration were used to achieve the optimal CEST effect, and the optimal parameters were finally selected based on Z-spectra, asymmetric spectra, and phantom CEST imaging. CEST scanning of dimethyl sulfoxide (DMSO), the substance helping Angiopep-2 to be dissolved in water, was performed to exclude its contribution for the CEST effect. Results. A broad dip was observed from 2.5 to 3.5 ppm in the Z-spectra of Angiopep-2 phantoms. The most robust CEST was generated at 3.2 ppm when using formula (M–3.2ppm − M+3.2ppm)/M–3.2ppm. The CEST effect of Angiopep-2 was concentration dependent; the effect increased as the concentration increased. In addition, the CEST effect was more obvious as the saturation power increased and peaked at 5.5 µT, and the CEST effect increased as the saturation duration increased. DMSO showed nearly 0% of the CEST effect at 3.2 ppm. Conclusions. Our results demonstrate that Angiopep-2 can act as an excellent exogenous CEST contrast. As it can penetrate blood-brain barrier and bind amyloid-β protein, amyloid-β targeting CEST, with Angiopep-2 as an exogenous contrast agent, can be potentially used as a novel imaging modality for early diagnosis of Alzheimer's disease. Collectively, Angiopep-2 may play a critical role in early diagnosis of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

To compare the efficacy and safety of treatments based on the Stupp protocol for adult patients with newly diagnosed glioblastoma and to determine the optimal treatment option for patients with different O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation statuses. We estimated hazard ratios (HRs) for overall survival (OS) and odds ratios (ORs) for adverse events of grade 3 or higher (AEs ≥ 3). Twenty-one randomized controlled trials involving 6478 patients treated with 21 different treatment strategies were included. Results of the pooled HRs indicated tumor-treating fields (TTF) combined with the Stupp protocol resulted in the most favorable OS for patients with and without MGMT promoter methylation. Subgroup analyses by the two MGMT promoter statuses indicated that lomustine-temozolomide plus radiotherapy or TTF combination therapy was associated with the best OS for patients with methylated MGMT promoter (HR, 1.03; 95% credible interval [CI], 0.54–1.97), and standard cilengitide combination therapy or TTF combination treatment was associated with the best OS for patients with unmethylated MGMT promoter (HR, 1.05; 95% CI, 0.67–1.64). Regarding AEs ≥ 3, there were no significant differences in pooled ORs. However, Bayesian ranking profiles that demonstrated intensive cilengitide combination therapy and TTF combination therapy have a similar possibility to cause the least toxicity. These results indicated that TTF combination therapy was associated with increased survival, irrespective of the MGMT promoter methylation status, and a relatively tolerated safety profile compared with other combination treatments. The optimal treatment option for glioblastoma patients with different MGMT promoter methylation statuses was different. [ABSTRACT FROM AUTHOR]

Cancer is an urgent public health issue with a very huge number of cases all over the world expected to increase by 2040. Despite improved diagnosis and therapeutic protocols, it remains the main leading cause of death in the world. Cancer stem cells (CSCs) constitute a tumor subpopulation defined by ability to self-renewal and to generate the heterogeneous and differentiated cell lineages that form the tumor bulk. These cells represent a major concern in cancer treatment due to resistance to conventional protocols of radiotherapy, chemotherapy and molecular targeted therapy. In fact, although partial or complete tumor regression can be achieved in patients, these responses are often followed by cancer relapse due to the expansion of CSCs population. The aberrant activation of developmental and oncogenic signaling pathways plays a relevant role in promoting CSCs therapy resistance. Although several targeted approaches relying on monotherapy have been developed to affect these pathways, they have shown limited efficacy. Therefore, an urgent need to design alternative combinatorial strategies to replace conventional regimens exists. This review summarizes the preclinical studies which provide a proof of concept of therapeutic efficacy of combinatorial approaches targeting the CSCs. [ABSTRACT FROM AUTHOR]

Background: Rheumatoid arthritis (RA) and the genetic risk landscape of autoimmune disorders and Parkinson's disease (PD) overlap. Additionally, anti-inflammatory medications used to treat RA might influence PD risk. Objective: To use a population-based approach to determine if there is an association between pre-occurring rheumatoid arthritis (RA) and later-life risk of PD. Methods: The study population was 3.6 million residents of Sweden, who were alive during part or all of the follow-up period; 1997–2016. We obtained diagnoses from the national patient registry and identified 30,032 PD patients, 8,256 of whom each was matched to ten controls based on birth year, sex, birth location, and time of follow-up. We determined the risk reduction for PD in individuals previously diagnosed with RA. We also determined if the time (in relation to the index year) of the RA diagnosis influenced PD risk and repeated the analysis in a sex-stratified setting. Results: Individuals with a previous diagnosis of RA had a decreased risk of later developing PD by 30–50% compared to individuals without an RA diagnosis. This relationship was strongest in our conservative analysis, where the first PD diagnosis occurred close to the earliest PD symptoms (odds ratio 0.47 (CI 95% 0.28–0.75, p = 0.0006); with the greatest risk reduction in females (odds ratio 0.40 (CI 95% 0,19–0.76, p = 0.002). Discussion: Our findings provide evidence that individuals diagnosed with RA have a significantly lower risk of developing PD than the general population. Our data should be considered when developing or repurposing therapies aimed at modifying the course of PD. [ABSTRACT FROM AUTHOR]

Background: Development of clinical reasoning is an essential aspect in musculoskeletal physiotherapy practice that is linked to better outcomes. The measurement of clinical reasoning has placed an emphasis on diagnostic reasoning using different types of examinations. The Diagnostic Thinking Inventory (DTI) is a self‐assessment tool developed to measure two aspects of diagnostic reasoning: flexibility in thinking (FT) and structure in memory (SM). DTI is valid and reliable that has been used extensively in medical field. Objective: To investigate the validity and reliability of DTI in musculoskeletal physiotherapy practice. Methods: Two groups of musculoskeletal physiotherapists completed DTI. Expert musculoskeletal physiotherapists assessed face and content validity. Data from the second group of musculoskeletal physiotherapists were used to assess test–retest reliability. Internal consistency was calculated using Cronbach's alpha. Construct validity was assessed by comparing both groups. Data were analyzed using the IBM SPSS statistics 25.0 version. Results: The experts agreed that DTI measures diagnostic reasoning. For test–retest reliability, average intraclass correlation coefficient was 0.91, 0.92 and 0.90 (p < 0.001) for DTI, FT and SM scores, respectively. Cronbach's alpha was 0.909, 0.919 and 0.897 (p < 0.001) for DTI, FT and SM, respectively. The independent samples t‐test demonstrated that the experts group achieved higher and statistically significant score (p < 0.001). Conclusion: DTI is valid and reliable in measuring diagnostic reasoning in the context of musculoskeletal physiotherapy practice. It can be used to assess the impact of continuing education on musculoskeletal physiotherapists' diagnostic reasoning. [ABSTRACT FROM AUTHOR]

The success of clinical treatments is highly dependent on early detection and much research has been conducted to develop fast, efficient, and precise methods for this reason. Conventional methods relying on nonspecific and targeting probes are being outpaced by so‐called nanosensors. Over the last two decades a variety of activatable sensors have been engineered, with a great diversity concerning the operating principle. Therefore, this review delineates the achievements made in the development of nanosensors designed for diagnosis of diseases. [ABSTRACT FROM AUTHOR]

While multiple theories exist to explain the diagnostic process, there are few available assessments that reliably determine diagnostic competence in trainees. Most methods focus on aspects of the process of diagnostic reasoning, such as the relation between case features and diagnostic hypotheses. Inevitably, detailed elucidation of aspects of the process requires substantial time per case and limits the number of cases that can be examined given a limited testing time. Shifting assessment to the outcome of diagnostic reasoning, accuracy of the diagnosis, may serve as a reliable measure of diagnostic competence and would allow increased sampling across cases. The present study is a retrospective analysis of 7 large studies, conducted by 3 research teams, that all used a series of brief written cases to examine the outcome of diagnostic reasoning-the diagnosis. The studies involved over 600 clinicians ranging from final year medical students to practicing emergency physicians. For 4 studies with usable reliability data, reliability for a 2 h test ranged from .63 to .94. On average speeded tests were more reliable (.85 vs. .73).To achieve a reliability of .75 required an average test time of 1.11 h for speeded tests and 1.99 for unspeeded tests. The measure was shown to be positively correlated with both written knowledge tests and measures of problem solving derived from OSCE performance tests. This retrospective analysis provides evidence to support the implementation of outcome-based assessments of clinical reasoning. [ABSTRACT FROM AUTHOR]

Artificial intelligence is a growing phenomenon that is driving major changes to how we deliver healthcare. One of its most significant and challenging contributions is likely to be in diagnosis. Artificial intelligence is challenging the physician's exclusive role in diagnosis and in some areas, its diagnostic accuracy exceeds that of humans. We argue that we urgently need to consider how we will incorporate AI into our teaching of clinical reasoning in the undergraduate curriculum; students need to successfully navigate the benefits and potential issues of new and developing approaches to AI in clinical diagnosis. We offer a pedagogical framework for this challenging change to our curriculum. [ABSTRACT FROM AUTHOR]

Introduction: Educators have theorized that interventions grounded in dual process theory (DPT) and script theory (ST) may improve the diagnostic reasoning process of physicians but little empirical evidence exists. Methods: In this quasi-experimental study, we assessed the impact of a clinical reasoning (CR) curriculum grounded in DPT and ST on medicine residents participating in one of three groups during a 6-month period: no, partial, or full intervention. Residents completed the diagnostic thinking inventory (DTI) at baseline and 6 months. At 6 months, participants also completed a post-survey assessing application of concepts to cases. Results: There was a significant difference between groups in application of concepts (no intervention 1.6 (0.65) compared to partial 2.3 (0.81) and full 2.2 (0.91), p = 0.05), as well as describing cases in problem representation format (no intervention 1.2 (0.38) and partial 1.5 (0.55) compared to full 2.1 (0.93), p = 0.004). There was no significant difference in change in DTI scores (no intervention 7.0 (16.3), partial 8.8 (9.8), full 7.8 (12.0)). Conclusions: Residents who participated in a CR curriculum grounded in DPT and ST were effective in applying principles of CR in cases from their practice. To our knowledge, this is the first workplace-based CR educational intervention study showing differences in the reasoning process residents apply to patients. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus is an opportunistic pathogen of humans and warm-blooded animals and presents a growing threat in terms of multi-drug resistance. Despite numerous studies, the basis of staphylococcal virulence and switching between commensal and pathogenic phenotypes is not fully understood. Using genomics, we show here that S. aureus strains exhibiting virulent (VIR) and non-virulent (NVIR) phenotypes in a chicken embryo infection model genetically fall into two separate groups, with the VIR group being much more cohesive than the NVIR group. Significantly, the genes encoding known staphylococcal virulence factors, such as clumping factors, are either found in different allelic variants in the genomes of NVIR strains (compared to VIR strains) or are inactive pseudogenes. Moreover, the pyruvate carboxylase and gamma-aminobutyrate permease genes, which were previously linked with virulence, are pseudogenized in NVIR strain ch22. Further, we use comprehensive proteomics tools to characterize strains that show opposing phenotypes in a chicken embryo virulence model. VIR strain CH21 had an elevated level of diapolycopene oxygenase involved in staphyloxanthin production (protection against free radicals) and expressed a higher level of immunoglobulin-binding protein Sbi on its surface compared to NVIR strain ch22. Furthermore, joint genomic and proteomic approaches linked the elevated production of superoxide dismutase and DNA-binding protein by NVIR strain ch22 with gene duplications. [ABSTRACT FROM AUTHOR]

Objective: There is pressure domestically and internationally to abandon the “4 + 2” pathway in order to more closely align with other western countries. Yet there is limited empirical evidence to support the benefits of the “postgraduate” pathway above that of the internship model. This study examined the training pathways to qualify for registration as a psychologist in Australia and their relationship to years of practice experience, the anchoring effect, and diagnostic accuracy. Method: A total of 121 psychologists in Australia completed the study requirements via an online questionnaire. The participants were randomly allocated to conditions with those in the experimental groups receiving an introductory statement suggesting a diagnosis (depression or anxiety). The control group received no statement. All participants then reviewed the same de‐identified case material of a real client and formulated a diagnosis based on the information presented. The data were examined using hierarchical binary logistic regression. Results: The study found that endorsement significantly predicted more accurate diagnosis but that additional practice experience did not further increase diagnostic skills in the specialist group. Additional years of practice experience did improve accuracy in those without endorsement. An anchoring effect was not consistently observed. Conclusions: The results suggest that endorsement appears beneficial for improving diagnostic accuracy; however, a similar level of improvement can be acquired through practice experience if endorsement is not pursued. While the endorsement pathway appears advantageous, practice experience also has its merits as an alternative to develop clinical skills. [ABSTRACT FROM AUTHOR]

Leukemic cells often carry chromosome aberrations which generate chimeric genes of pathogenetic, diagnostic, and prognostic importance. New rearrangements giving rise to novel fusion genes define hitherto unrecognized genetic leukemia subgroups. G-banding, fluorescence in situ hybridization (FISH), and molecular genetic analyses were done on bone marrow cells from a patient with chronic lymphocytic leukemia (CLL) and secondary myelodysplasia. The G-banding analysis revealed the karyotype 46,XX,del(21)(q22)[9]/46,XX[2]. FISH on metaphase spreads with a RUNX1 break apart probe demonstrated that part of RUNX1 (from 21q22) had moved to chromosome band 5p15. RNA sequencing showed in-frame fusion of RUNX1 with PDCD6 (from 5p15), something that was verified by RT-PCR together with Sanger sequencing. Further FISH analyses with PDCD6 and RUNX1 home-made break apart/double fusion probes showed a red signal (PDCD6) on chromosome 5, a green signal on chromosome 21 (RUNX1), and two yellow fusion signals, one on der(5) and the other on der(21). Reassessment of the G-banding preparations in light of the FISH and RNA-sequencing data thus yielded the karyotype 46,XX,t(5;21)(p15;q22)[9]/46,XX[2]. The t(5;21)(p15;q22)/RUNX1-PDCD6 was detected only by performing molecular studies of the leukemic cells, but should be sought after also in other leukemic/myelodysplastic cases with del(21q). [ABSTRACT FROM AUTHOR]

Problem/Background: The ability to accurately diagnose patients based on symptom profiles is a vital yet challenging skill that Nurse Practitioners (NPs) undertake frequently. Purpose: This integrative literature review highlights a variety of evidence based, practical educational strategies that foster the development of diagnostic reasoning. Methods: An integrative literature review was conducted in order to identify original research focusing on diagnostic reasoning educational interventions. Results: Eighteen primary sources met inclusion and exclusion criteria. Results are synthesized in terms of sample and setting, methodological features, interventions, and outcomes. Interventions broadly fit into five educational themes: testing strategies, cognitive biases, simulation programs, course formats, and instructional approaches. Discussion: Interventions are simple and can be implemented in multiple educational settings. Future research should occur in populations of NP students. Validated, easy-to-use measurement tools as well as more precise diagnostic reasoning concept development should occur. [ABSTRACT FROM AUTHOR]

Self-explanation while diagnosing clinical cases fosters medical students' diagnostic performance. In previous studies on self-explanation, students were free to self-explain any aspect of the case, and mostly clinical knowledge was used. Elaboration on knowledge of pathophysiological mechanisms of diseases has been largely unexplored in studies of strategies for teaching clinical reasoning. The purpose of this two-phase experiment was to investigate the effect of self-explanation of pathophysiology during practice with clinical cases on students' diagnostic performance. In the training phase, 39 4th-year medical students were randomly assigned to solve 6 criterion cases (3 of jaundice; 3 of chest pain), either self-explaining the pathophysiological mechanisms of the findings (n = 20) or without self-explaining (n = 19). One-week later, in the assessment phase, all students solved 6 new cases of the same syndromes. A repeated-measures analysis of variance on the mean diagnostic accuracy scores showed no significant main effects of study phase (p = 0.34) and experimental condition (p = 0.10) and no interaction effect (p = 0.42). A post hoc analysis found a significant interaction (p = 0.022) between study phase and syndrome type. Despite equal familiarity with jaundice and chest pain, the performance of the self-explanation group (but not of the non-self-explanation group) on jaundice cases significantly improved between training and assessment phases (p = 0.035) whereas no differences between phases emerged on chest pain cases. Self-explanation of pathophysiology did not improve students' diagnostic performance for all diseases. Apparently, the positive effect of this form of self-explanation on performance depends on the studied diseases sharing similar pathophysiological mechanisms, such as in the jaundice cases. [ABSTRACT FROM AUTHOR]

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Attention-deficit/hyperactivity disorder (ADHD) in the adult population is frequently associated with comorbid psychiatric diseases that complicate its recognition, diagnosis and management. The prevalence of ADHD in the general adult population is 2.5% and it is associated with substantial personal and individual burden. The most frequent comorbid psychopathologies include mood and anxiety disorders, substance use disorders, and personality disorders. There are strong familial links and neurobiological similarities between ADHD and the various associated psychiatric comorbidities. The overlapping symptoms between ADHD and comorbid psychopathologies represent challenges for diagnosis and treatment. Guidelines recommend that when ADHD coexists with other psychopathologies in adults, the most impairing condition should generally be treated first. Early recognition and treatment of ADHD and its comorbidities has the potential to change the trajectory of psychiatric morbidity later in life. The use of validated assessment scales and high-yield clinical questions can help identify adults with ADHD who could potentially benefit from evidence-based management strategies. [ABSTRACT FROM AUTHOR]

Introduction: The purpose of the current study was to examine the painful elbow, and in particular enthesitis, in psoriatic arthritis (PsA) and rheumatoid arthritis (RA) using clinical examination, ultrasonography (US) and magnetic resonance imaging (MRI). Methods: Patients with elbow pain (11 with PsA and 9 with RA) were recruited. Clinical examination, US and MRI studies were performed on the same day. For enthesitis, the common extensor and flexor insertions and the triceps insertion were imaged (20 patients, giving a total of 60 sites with comparative data). Imaging was performed with the radiologists blinded to the diagnosis and clinical findings. US was used to assess 'inflammatory activity' (Power Doppler signal, oedema, tendon thickening and bursal swelling) and 'damage' (erosions, cortical roughening and enthesophytes). MRI was used to assess 'inflammation' (fluid in paratenon, peri-entheseal soft-tissue oedema, entheseal enhancement with gadolinium, entheseal oedema and bone oedema) and 'damage' (erosion, cortical roughening and enthesophyte). Results: Complete scan data were not available for all patients as one patient could not tolerate the MRI examination. No significant differences in imaging scores were found between PsA and RA. Analysis of damage scores revealed complete agreement between US and MRI data in 43/55 (78%) comparisons; in 10/55 (18%) cases the US data were abnormal but the MRI data normal; in 2/55 (4%) cases, the MRI data were abnormal and the US data normal. Analysis of the inflammation scores revealed complete agreement between US and MRI data in 33/55 (60%) comparisons; in 3/55 (5%) cases US data were abnormal but MRI data normal; in 19/55 (35%) cases the MRI data were abnormal and the US data normal. There was a poor relationship between assessments based on clinical examination and imaging studies. Readers could not accurately identify the disease from imaging findings. Conclusion: Based on our results, at the elbow, US and MR have different roles in assessing enthesitis, with US apparently the better diagnostic tool for assessing damage and MR the better tool for assessing inflammation. In this study enthesitis and synovitis in the painful elbow were found equally in cases of established RA and PsA. [ABSTRACT FROM AUTHOR]

Recurrent pneumonia (RP), i.e., at least two episodes of pneumonia in one year or three episodes ever with intercritical radiographic clearing of densities, occurs in 7.7%-9% of children with community-acquired pneumonia. In RP, the challenge is to discriminate between children with self-limiting or minor problems, that do not require a diagnostic work-up, and those with an underlying disease. The aim of the current review is to discuss a reasoned diagnostic approach to RP in childhood. Particular emphasis has been placed on which children should undergo a diagnostic work-up and which tests should be performed. A pediatric case series is also presented, in order to document a single centre experience of RP. A management algorithm for the approach to children with RP, based on the evidence from a literature review, is proposed. Like all algorithms, it is not meant to replace clinical judgment, but it should drive physicians to adopt a systematic approach to pediatric RP and provide a useful guide to the clinician. [ABSTRACT FROM AUTHOR]

The article presents a study on the utilization and role of the Think Aloud (TA) qualitative research tool in script concordance testing (SCT) conducted by Alyssa Power, Jean-Francois Lemay, and Suzette Cooke of Alberta Children's Hospital in Calgary, Alberta.

Objectives: The aim of this study was to assess the use of muscle biopsy for histopathological confirmation of small vessel vasculitis (SVV) or medium vessel vasculitis (MVV).Method: Muscle biopsies were performed for all consecutive cases of suspected SVV or MVV seen at Tokyo Metropolitan Tama Medical Centre between February 2012 and May 2014 except those for which a skin or renal biopsy was indicated.Results: Forty-nine patients underwent muscle biopsies. All patients were followed for a minimum of 6 months. Diagnosis of SVV or MVV was made in 35 patients. An unrelated condition was diagnosed in 11 patients and no diagnoses were made in three patients. Of the 35 patients in whom SVV or MVV was diagnosed, positive muscle biopsies were obtained in 20 patients [15 microscopic polyangiitis (MPA), three polyarteritis nodosa (PAN), and two eosinophilic granulomatosis with polyangiitis (EGPA)], while other findings led to the same diagnosis in 15 (seven MPA, four GPA, three PAN, and one rheumatoid vasculitis). The sensitivity of the muscle biopsy was 57% [20/35; 95% confidence interval (CI) 50-57]. Of 13 patients presenting with peripheral neuropathy, the muscle biopsy demonstrated vasculitis in nine patients, with 75% sensitivity (9/12; 95% CI 69-75). There were no complications in the procedure apart from delayed wound healing in one patient.Conclusions: Muscle biopsy is a safe method that offers a high diagnostic yield for SVV or MVV, especially in patients with vasculitic neuropathy. [ABSTRACT FROM AUTHOR]

Epithelial-to-mesenchymal transition (EMT) is an essential biological process involved in embryonic development, cancer progression, and metastatic diseases. EMT has often been used as a model for elucidating the mechanisms that underlie bladder cancer progression. However, no study to date has addressed the quantitative global variation of proteins in EMT using normal and non-malignant bladder cells. We treated normal bladder epithelial HCV29 cells and low grade nonmuscle invasive bladder cancer KK47 cells with transforming growth factor-beta (TGF-β) to establish an EMT model, and studied non-treated and treated HCV29 and KK47 cells by the stable isotope labeling amino acids in cell culture (SILAC) method. Labeled proteins were analyzed by 2D ultrahigh-resolution liquid chromatography/LTQ Orbitrap mass spectrometry. Among a total of 2994 unique identified and annotated proteins in HCV29 and KK47 cells undergoing EMT, 48 and 56 proteins, respectively, were significantly upregulated, and 106 and 24 proteins were significantly downregulated. Gene ontology (GO) term analysis and pathways analysis indicated that the differentially regulated proteins were involved mainly in enhancement of DNA maintenance and inhibition of cell-cell adhesion. Proteomes were compared for bladder cell EMT vs. bladder cancer cells, revealing 16 proteins that displayed similar changes in the two situations. Studies are in progress to further characterize these 16 proteins and their biological functions in EMT. [ABSTRACT FROM AUTHOR]

The advances of genome-wide 'discovery platforms' and the increasing affordability of the analysis of significant sample sizes have led to the identification of novel mutations in brain tumours that became diagnostically and prognostically relevant. The development of mutation-specific antibodies has facilitated the introduction of these convenient biomarkers into most neuropathology laboratories and has changed our approach to brain tumour diagnostics. However, tissue diagnosis will remain an essential first step for the correct stratification for subsequent molecular tests, and the combined interpretation of the molecular and tissue diagnosis ideally remains with the neuropathologist. This overview will help our understanding of the pathobiology of common intrinsic brain tumours in adults and help guiding which molecular tests can supplement and refine the tissue diagnosis of the most common adult intrinsic brain tumours. This article will discuss the relevance of 1p/19q codeletions, IDH 1/2 mutations, BRAF V600 E and BRAF fusion mutations, more recently discovered mutations in ATRX, H3F3A, TERT, CIC and FUBP 1, for diagnosis, prognostication and predictive testing. In a tumour-specific topic, the role of mitogen-activated protein kinase pathway mutations in the pathogenesis of pilocytic astrocytomas will be covered. [ABSTRACT FROM AUTHOR]

Context The development of clinical reasoning ( CR) in students has traditionally been left to clinical rotations, which, however, often offer limited practice and suboptimal supervision. Medical schools begin to address these limitations by organising pre-clinical CR courses. The purpose of this paper is to review the variety of approaches employed in the teaching of CR and to present a proposal to improve these practices. Methods We conducted a narrative review of the literature on teaching CR. To that end, we searched PubMed and Web of Science for papers published until June 2014. Additional publications were identified in the references cited in the initial papers. We used theoretical considerations to characterise approaches and noted empirical findings, when available. Results Of the 48 reviewed papers, only 24 reported empirical findings. The approaches to teaching CR were shown to vary on two dimensions. The first pertains to the way the case information is presented. The case is either unfolded to students gradually - the 'serial-cue' approach - or is presented in a 'whole-case' format. The second dimension concerns the purpose of the exercise: is its aim to help students acquire or apply knowledge, or is its purpose to teach students a way of thinking? The most prevalent approach is the serial-cue approach, perhaps because it tries to directly simulate the diagnostic activities of doctors. Evidence supporting its effectiveness is, however, lacking. There is some empirical evidence that whole-case, knowledge-oriented approaches contribute to the improvement of students' CR. However, thinking process-oriented approaches were shown to be largely ineffective. Conclusions Based on research on how expertise develops in medicine, we argue that students in different phases of their training may benefit from different approaches to the teaching of CR. [ABSTRACT FROM AUTHOR]

Objective Combined nerve/muscle biopsy is widely carried out to improve the diagnostic sensitivity for vasculitic neuropathy. However, an additional yield of muscle biopsy is modest. Therefore, we investigated whether skin biopsy in combination with nerve/muscle biopsy increases the detection rate of vasculitis. Methods A total of 25 combined nerve/muscle/skin biopsy samples from patients with biopsy-proven necrotizing vasculitis ( n = 16) or clinically probable vasculitic neuropathy ( n = 9) were reviewed. Specimens from the sural nerve, peroneus brevis muscle and skin were obtained simultaneously by a single incision. Results Skin biopsy substantially contributed to diagnosis of vasculitic neuropathy. Additional skin biopsy enhanced diagnostic sensitivity from 88% to 100% in patients with pathologically confirmed vasculitis ( n = 16). Vasculitis was detected only in skin specimens from two of the entire cohort ( n = 25). There were no complications related to skin collection, such as anastomotic leakage or wound infection. Conclusion Combined nerve/muscle/skin biopsy could be a less invasive option to improve the diagnostic sensitivity for vasculitis. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction The clinical diagnosis of amyotrophic lateral sclerosis (ALS) relies on exclusion of mimic syndromes, but there are no specific guidelines regarding the extent of laboratory testing required. Methods A survey was sent to 274 physicians listed in the Neuromuscular Section of the American Academy of Neurology. The survey asked how often they order 21 different laboratory tests in patients suspected of having ALS. Results Ninety-nine responses were received (36% response rate). Greater than 75% ordered serum creatine kinase, chemistry panel, and thyroid functions often or always. Fewer than 25% tested for serum complement, hexosaminidase A, spinal muscular atrophy, Kennedy disease, heavy metals, or human T-cell lymphotrophic virus often or always. Twelve other tests had intermediate responses. Conclusions There is a lack of consensus among respondents regarding the laboratory evaluation of suspected ALS. Prospective studies are needed to define the diagnostic yield and cost-effectiveness of laboratory testing in this population. Muscle Nerve 52: 83-87, 2015 [ABSTRACT FROM AUTHOR]

Myeloid malignancies including acute myeloid leukemia ( AML) and myelodysplastic syndromes ( MDS) are a heterogeneous group of disorders that share a common biology and are a major source of morbidity and mortality. In the last several years, studies using next-generation sequencing ( NGS) have identified a core set of recurrently mutated myeloid malignancy genes in the majority of patients with AML and MDS, including those with normal cytogenetics. DNA-level mutations in several of these genes including NPM1, FLT3, and CEBPA in AML and ASXL1, ETV6, EZH2, RUNX1, and TP53 in MDS are associated with changes in patient outcomes and are now tested for in clinical laboratories. In addition to providing prognostic information, these gene mutations can be used to monitor patient disease burden through the use of ultrasensitive detection techniques. In this review, we will focus on the clinical utility of various NGS-based methods including whole-genome sequencing, exome sequencing, and targeted panel-based sequencing in the initial diagnosis and management of AML and MDS and cover recent methodological advances for the molecular monitoring of AML and MDS. [ABSTRACT FROM AUTHOR]

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Currently there is no guideline for the screening, diagnosis and treatment of adult attention deficit/hyperactivity disorder (ADHD) in patients with a substance use disorder (SUD). The aim was to develop such a guideline, starting out from a systematic review and based on the methodology of the Scottish Intercollegiate Guideline Network (SIGN). Due to the lack of scientific evidence on some of the topics, the guideline is a combination of evidence based and practice based recommendations. Given the high prevalence of ADHD in treatment seeking SUD patients and the availability of valid screening instruments, all treatment seeking SUD patients should be screened for ADHD. Diagnosis of ADHD should be based on clinical observation and history taking, including informant data. Integrated treatment of ADHD and SUD is recommended, including pharmacotherapy, psycho-education, coaching, and cognitive behavioral therapy (CBT). The lack of scientific data and the overall lack of expertise in the field are significant obstacles to the implementation of the guideline. Intensive training programs in the substance abuse sector need to be organized to implement these guidelines. [ABSTRACT FROM AUTHOR]

Brugia malayi is a filarial nematode, which causes lymphatic filariasis in humans. In 1995, the disease has been identified by the World Health Organization (WHO) as one of the second leading causes of permanent and long-term disability and thus it is targeted for elimination by year 2020. Therefore, accurate filariasis diagnosis is important for management and elimination programs. A recombinant antigen (BmR1) from the Bm17DIII gene product was used for antibody-based filariasis diagnosis in "Brugia Rapid". However, the structure and dynamics of BmR1 protein is yet to be elucidated. Here we study the three dimensional structure and dynamics of BmR1 protein using comparative modeling, threading and ab initio protein structure prediction. The best predicted structure obtained via an ab initio method (Rosetta) was further refined and minimized. A total of 5 ns molecular dynamics simulation were performed to investigate the packing of the protein. Here we also identified three epitopes as potential antibody binding sites from the molecular dynamics average structure. The structure and epitopes obtained from this study can be used to design a binder specific against BmR1, thus aiding future development of antigen-based filariasis diagnostics to complement the current diagnostics. [ABSTRACT FROM AUTHOR]

The Script Concordance Test (SCT) has been used successfully in medical schools to assess clinical reasoning in medical students, but it has not been widely used in nursing education. The purpose of this study was to provide additional evidence of the validity and reliability of the SCT in evaluating clinical reasoning in nursing students by replicating a previous study. The test was administered to 48 first-year Bachelor of Science in Nursing students. A scoring grid was developed using the aggregate scores method based on the modal responses of 13 panel members. The reliability of the scores was measured by Cronbach's alpha coefficient, and the scores of the students and the panel were compared using a t test. The difference between the panel's and the students' scores was statistically significant, and the reliability of the scores is high. The SCT provides a reliable, standardized, and easy-to-administer method of evaluating clinical reasoning in nursing students. [J Nurs Educ. 2014;53(5):281-286.] [ABSTRACT FROM AUTHOR]

Atherosclerosis is the major underlying pathologic cause of coronary artery disease. An early detection of the disease can prevent clinical sequellae such as angina, myocardial infarction, and stroke. The different imaging techniques employed to visualize the atherosclerotic plaque provide information of diagnostic and prognostic value. Furthermore, the use of contrast agents helps to improve signal-tonoise ratio providing better images. For nuclear imaging techniques and optical imaging these agents are absolutely necessary. We report on the different contrast agents that have been used, are used or may be used in future in animals, humans, or excised tissues for the distinct imaging modalities for atherosclerotic plaque imaging. [ABSTRACT FROM AUTHOR]

The article focuses on a study which provides guidelines for the diagnosis and management of adult myelodysplastic syndromes. Topics discussed include characteristics of the syndromes such as changes in cell lineages, ineffective haematopoiesis and development of acute myeloid leukaemia, need of blood film analysis and bone marrow examination for the diagnosis, and significance of blood transfusions and antibiotics as a part of supportive care for the management of the syndromes.

Background and Purpose. Physical therapists frequently make important point-of-care decisions for musculoskeletal injuries and conditions. In the Military Health System (MHS), these decisions may occur while therapists are deployed in support of combat troops, as well as in a more traditional hospital setting. Proficiency with the musculoskeletal examination, including a fundamental understanding of the diagnostic role of musculoskeletal imaging, is an important competency for physical therapists. The purpose of this article is to present 3 cases managed by physical therapists in unique MHS settings, highlighting relevant challenges and clinical decision making. Case Description. Three cases are presented involving conditions where the physical therapist "was significantly involved in the diagnosis and clinical management plan. The physical therapist's clinical privileges, including the ability to order appropriate musculoskeletal imaging procedures, were helpful in making clinical decisions that facilitate timely management. The cases involve patients with an ankle sprain and Maisonneuve fracture, a radial head fracture, and a pelvic neoplasm referred through medical channels as knee pain. Outcomes. Clinical pathways from point of care are discussed, as well as the reasoning that led to decisions affecting definitive care for each of these patients. In each case, emergent treatment and important combat evacuation decisions were based on a combination of examination and management decisions. Discussion. Physical therapists can provide important contributions to the primary management of patients with musculoskeletal conditions in a variety of settings within the MHS. In the cases described, advanced clinical privileges contributed to the success in this role. [ABSTRACT FROM AUTHOR]

Considerable disagreements and variations exist in diagnosis and treatment planning of periodontal disease. Achieving high interrater periodontal diagnosis can prove challenging. The objectives of this study were to measure variations in periodontal diagnosis and treatment planning among predoctoral periodontics faculty members after consensus training and to compare such variation with those identified in third- and fourth-year dental students. Nine electronically stored case vignettes and survey instruments were made available to eighteen faculty members and twenty dental students under standardized conditions. A chisquare test was used to compare responses between groups, and multirater kappa tests were used to evaluate interrater agreement/ reliability. Of the nine cases, only one differed between groups significantly in terms of treatment. Also, third-year students differed from fourth-year students on the diagnosis of aggressive periodontitis versus chronic periodontitis. Most respondents were able to distinguish clearly among diagnoses of chronic periodontitis, aggressive periodontitis, and gingivitis. This study established a baseline assessment of the current status of consensus after training. We will reassess variations after addressing the specific challenges identified. Programs designed and implemented to help decrease the variation in periodontal diagnosis and treatment planning among faculty members may ultimately translate into better agreement and better standardization of dental instruction. [ABSTRACT FROM AUTHOR]

West Nile virus (WNV), first recognized in North America in 1999, was responsible for the largest arboviral epidemic of human encephalitis in history and continues to be the most frequent cause of epidemic meningoencephalitis in North America. WNV neuroinvasive disease (WNND) occurs in fewer than 1% of infected individuals, with presentations including aseptic meningitis, encephalitis, and poliomyelitis. Between 1999 and 2009, over 12,000 cases of WNND were reported in the United States, with the peak annual incidence occurring in epidemics of 2002 and 2003. In this review, we first summarize the epidemiology of WNV over the past decade and the salient clinical features of WNND, including a discussion of laboratory and radiographic findings, risk factors, morbidity, and mortality. In addition, we review recent progress in our understanding of virus and host determinants of the pathogenesis of WNND, as well as the prospects for the development of specific therapeutic targets. [ABSTRACT FROM AUTHOR]

CONTEXT Literature on diagnostic test interpretation has shown that access to clinical history can both enhance diagnostic accuracy and increase diagnostic error. Knowledge of clinical history has also been shown to enhance the more complex cognitive task of physical examination diagnosis, possibly by enabling early hypothesis generation. However, it is unclear whether clinicians adhere to these early hypotheses in the face of unexpected physical findings, thus resulting in diagnostic error. METHODS A sample of 180 internal medicine residents received a short clinical history and conducted a cardiac physical examination on a high-fidelity simulator. Resident Doctors (Residents) were randomised to three groups based on the physical findings in the simulator. The concordant group received physical examination findings consistent with the diagnosis that was most probable based on the clinical history. Discordant groups received findings associated with plausible alternative diagnoses which either lacked expected findings (indistinct discordant) or contained unexpected findings (distinct discordant). Physical examination diagnostic accuracy and physical examination findings were analysed. RESULTS Physical examination diagnostic accuracy varied significantly among groups (75 ± 44%, 2 ± 13% and 31 ± 47% in the concordant, indistinct discordant and distinct discordant groups, respectively (F2,177 = 53, p < 0.0001). Of the 115 Residents who were diagnostically unsuccessful, 33% adhered to their original incorrect hypotheses. Residents verbalised an average of 12 findings (interquartile range: 10-14); 58 ± 17% were correct and the percentage of correct findings was similar in all three groups (p = 0.44). CONCLUSIONS Residents showed substantially decreased diagnostic accuracy when faced with discordant physical findings. The majority of trainees given discordant physical findings rejected their initial hypotheses, but were still diagnostically unsuccessful. These results suggest that overcoming the bias induced by a misleading clinical history may involve two independent steps: rejection of the incorrect initial hypothesis, and selection of the correct diagnosis. Educational strategies focused solely on prompting clinicians to re-examine their hypotheses may be insufficient to reduce diagnostic error. [ABSTRACT FROM AUTHOR]

Charcot-Marie-Tooth (CMT) disease is the commonest inherited neuromuscular disorder affecting at least 1 in 2,500. Over the last two decades, there have been rapid advances in understanding the molecular basis for many forms of CMT with more than 30 causative genes now described. This has made obtaining an accurate genetic diagnosis possible but at times challenging for clinicians. This review aims to provide a simple, pragmatic approach to diagnosing CMT from a clinician's perspective. [ABSTRACT FROM AUTHOR]

The diagnosis of a peripheral nerve tumor can often be suggested on imaging. Direct continuity with a neural structure or location along a typical nerve distribution, shape, and intrinsic magnetic resonance (MR) signal characteristics represent the most important signs in this regard. Although several nonneoplastic nerve lesions can be specifically diagnosed by MR imaging, benign and malignant neoplasms of peripheral nerves can usually not be distinguished with confidence. This article reviews the MR imaging appearance, clinical and pathological features of schwannoma, localized neurofibroma, plexiform neurofibroma, intraneural perineurioma, fibrolipomatous hamartoma, nerve sheath ganglion, traumatic neuroma, malignant peripheral nerve sheath tumor, and secondary malignant neoplasms of peripheral nerves. Typical findings are illustrated on the basis of histologically confirmed cases. [ABSTRACT FROM AUTHOR]

Non-systemic vasculitic neuropathy (NSVN) is routinely considered in the differential diagnosis of progressive axonal neuropathies, especially those with asymmetric or multifocal features. Diagnostic criteria for vasculitic neuropathy, classification criteria for NSVN, and therapeutic approaches to NSVN are not standardized. The aim of this guideline was to derive recommendations on the classification, diagnosis, investigation, and treatment of NSVN based on the available evidence and, where evidence was not available, expert consensus. Experts on vasculitis, vasculitic neuropathy, and methodology systematically reviewed the literature for articles addressing diagnostic issues concerning vasculitic neuropathy and NSVN as well as treatment of NSVN and the small-to-medium vessel primary systemic vasculitides using MEDLINE, EMBASE, and the Cochrane Library. The selected articles were analyzed and classified. The group initially reached consensus on a classification of vasculitides associated with neuropathy. Non-diabetic radiculoplexus neuropathy was incorporated within NSVN. The consensus definition of pathologically definite vasculitic neuropathy required that vessel wall inflammation be accompanied by vascular damage. Diagnostic criteria for pathologically probable vasculitic neuropathy included five predictors of definite vasculitic neuropathy: vascular deposits of IgM, C3, or fibrinogen by direct immunofluorescence; hemosiderin deposits; asymmetric nerve fiber loss; prominent active axonal degeneration; and myofiber necrosis, regeneration, or infarcts in peroneus brevis muscle biopsy (Good Practice Points from class II/III evidence). A case definition of clinically probable vasculitic neuropathy in patients lacking biopsy proof incorporated clinical features typical of vasculitic neuropathy: sensory or sensory-motor involvement, asymmetric/multifocal pattern, lower-limb predominance, distal-predominance, pain, acute relapsing course, and non-demyelinating electrodiagnostic features (Good Practice Points from class II/III evidence). Proposed exclusionary criteria for NSVN - favoring the alternate diagnosis of systemic vasculitic neuropathy - were clinicopathologic evidence of other-organ involvement; anti-neutrophil cytoplasmic antibody (ANCAs); cryoglobulins; sedimentation rate ≥100 mm/h; and medical condition/drug predisposing to systemic vasculitis (Good Practice Points supported by class III evidence). Three class III studies on treatment of NSVN were identified, which were insufficient to permit a level C recommendation. Therefore, the group reviewed the literature on treatment of primary small-to-medium vessel systemic vasculitides prior to deriving Good Practice Points on treatment of NSVN. Principal treatment recommendations were: (1) corticosteroid (CS) monotherapy for at least 6 months is considered first-line; (2) combination therapy should be used for rapidly progressive NSVN and patients who progress on CS monotherapy; (3) immunosuppressive options include cyclophosphamide, azathioprine, and methotrexate; (4) cyclophosphamide is indicated for severe neuropathies, generally administered in IV pulses to reduce cumulative dose and side effects; (5) in patients achieving clinical remission with combination therapy, maintenance therapy should be continued for 18-24 months with azathioprine or methotrexate; and (6) clinical trials to address all aspects of treatment are needed. [ABSTRACT FROM AUTHOR]

Nerve biopsy is often the final step in the diagnostic work-up of neuropathies of unknown origin. The aim of this guideline was to prepare an evidence-based guideline on the methods for performing and evaluating nerve biopsy. The panel performed a search of MEDLINE, hand search of bibliographies of the references retrieved, review of the evidence, and reached agreement by consensus. There were not enough formal studies of diagnostic test accuracy to allow evidence-based recommendations of levels A-C for most questions. The panel summarized the class IV evidence and reached agreement by consensus on the following recommendations: (1) Nerve biopsy should not be performed before adequate clinical, electrophysiological, and laboratory investigation and only be performed with appropriate informed consent. (2) An interactive working relationship with the relevant disciplines involved and the provision of sufficient clinical information is encouraged. (3) Biopsies should be processed and read by professionals with adequate training and experience. (4) Optimal analysis of nerve biopsy is best performed by laboratories that have the facilities and expertise to prepare and evaluate frozen and fixed sections (cryostat, paraffin, and epoxy sections). (5) Immunohistochemistry, teased fiber analysis, electron microscopy, and morphometry may help clarify the diagnosis in some conditions and should be considered as additional studies. [ABSTRACT FROM AUTHOR]

This prospective study examined the value of serum neurofilament protein levels for detecting peri-operative brain damage following carotid endarterectomy. An ELISA was used for quantification of neurofilament protein heavy chain (NfHSMI35) levels from patients undergoing endarterectomy for symptomatic ( n = 17) and asymptomatic high-grade internal carotid artery stenosis ( n = 30). All patients underwent diffusion-weighted brain imaging before and after the procedure. NfHSMI35 levels were significantly higher in patients with a symptomatic carotid artery stenosis (0.131 ng/ml) if compared to asymptomatic patients (0.055 ng/ml, P = 0.01). However, serum NfHSMI35 levels were not related to signs of brain ischemia on routine brain imaging techniques. Our pilot data suggests that raised NfHSMI35 serum levels in patients with symptomatic carotid artery disease may be a sensitive biomarker for diffuse ischemic damage to the CNS. We conclude that NfHSMI35 failed to qualify as a biomarker for peri-operative brain injury in CEA and factors that may have compromised the validation of this biomarker are discussed and need to be taken into account for the design of further studies. [ABSTRACT FROM AUTHOR]