Epstein-Barr virus: clinical and epidemiological revisits and genetic basis of oncogenesis

Epstein-Barr virus (EBV) is classified as a member in the order herpesvirales, family herpesviridae, subfamily gammaherpesvirinae and the genus lymphocytovirus. The virus is an exclusively human pathogen and thus also termed as human herpesvirus 4 (HHV4). It was the first oncogenic virus recognized and has been incriminated in the causation of tumors of both lymphatic and epithelial nature. It was reported in some previous studies that 95% of the population worldwide are serologically positive to the virus. Clinically, EBV primary infection is almost silent, persisting as a life-long asymptomatic latent infection in B cells although it may be responsible for a transient clinical syndrome called infectious mononucleosis. Following reactivation of the virus from latency due to immunocompromised status, EBV was found to be associated with several tumors. EBV linked to oncogenesis as detected in lymphoid tumors such as Burkitt's lymphoma (BL), Hodgkin's disease (HD), post-transplant lymphoproliferative disorders (PTLD) and T-cell lymphomas (e.g. Peripheral T-cell lymphomas; PTCL and Anaplastic large cell lymphomas; ALCL). It is also linked to epithelial tumors such as nasopharyngeal carcinoma (NPC), gastric carcinomas and oral hairy leukoplakia (OHL). In vitro, EBV many studies have demonstrated its ability to transform B cells into lymphoblastoid cell lines (LCLs). Despite these malignancies showing different clinical and epidemiological patterns when studied, genetic studies have suggested that these EBV- associated transformations were characterized generally by low level of virus gene expression with only the latent virus proteins (LVPs) upregulated in both tumors and LCLs. In this review, we summarize some clinical and epidemiological features of EBV- associated tumors. We also discuss how EBV latent genes may lead to oncogenesis in the different clinical malignancie

A novel approach to the determination of clinical decision thresholds

Our objective was to determine the test and treatment thresholds for common acute primary care conditions. We presented 200 clinicians with a series of web-based clinical vignettes, describing patients with possible influenza, acute coronary syndrome (ACS), pneumonia, deep vein thrombosis (DVT) and urinary tract infection (UTI). We randomly varied the probability of disease and asked whether the clinician wanted to rule out disease, order tests or rule in disease. By randomly varying the probability, we obtained clinical decisions across a broad range of disease probabilities that we used to create threshold curves. For influenza, the test (4.5% vs 32%, p<0.001) and treatment (55% vs 68%, p=0.11) thresholds were lower for US compared with Swiss physicians. US physicians had somewhat higher test (3.8% vs 0.7%, p=0.107) and treatment (76% vs 58%, p=0.005) thresholds for ACS than Swiss physicians. For both groups, the range between test and treatment thresholds was greater for ACS than for influenza (which is sensible, given the consequences of incorrect diagnosis). For pneumonia, US physicians had a trend towards higher test thresholds and lower treatment thresholds (48% vs 64%, p=0.076) than Swiss physicians. The DVT and UTI scenarios did not provide easily interpretable data, perhaps due to poor wording of the vignettes. We have developed a novel approach for determining decision thresholds. We found important differences in thresholds for US and Swiss physicians that may be a function of differences in healthcare systems. Our results can also guide development of clinical decision rules and guidelines

Correlation of clinical decision-making with probability of disease: A web-based study among general practitioners.

Medical decision-making relies partly on the probability of disease. Current recommendations for the management of common diseases are based increasingly on scores that use arbitrary probability thresholds. To assess decision-making in pharyngitis and appendicitis using a set of clinical vignettes, and the extent to which management is congruent with the true probability of having the disease. We developed twenty-four clinical vignettes with clinical presentations corresponding to specific probabilities of having disease defined by McIsaac (pharyngitis) or Alvarado (appendicitis) scores. Each participant answered four randomly selected web-based vignettes. General practitioners (GP) working in primary care structures in Switzerland and the USA. A comparison between the GP's management decision according to the true probability of having the disease and to the GP's estimated probability, investigating the GP's ability to estimate probability of disease. The mean age of the GPs was 48 years (SD 12) and 66% were men. The correlation between the GP's clinical management decision based on the vignette and the recommendations was stronger for appendicitis than pharyngitis (kw = 0.74, 95% CI 0.70-0.78 vs. kw = 0.66, 95% CI 0.62-0.71). On the other hand, the association between the clinical management decision and the probability of disease estimated by GPs was more congruent with recommendations for pharyngitis than appendicitis (kw = 0.70, 95% CI 0.66-0.73 vs. 0.61, 95% CI 0.56-0.66). Only a minority of GPs correctly estimated the probability of disease (29% for appendicitis and 39% for pharyngitis). Despite the fact that general practitioners often misestimate the probability of disease, their management decisions are usually in line with recommendations. This means that they use other approaches, perhaps more subjective, to make decisions, such as clinical judgment or reasoning that integrate factors other than just the risk of the disease

Diagnosis and treatment of community-acquired pneumonia in patients with acute cough: a quantitative study of decision thresholds in primary care.

Test and treatment thresholds have not yet been described for decision-making regarding the likelihood of pneumonia in patients with acute cough. To determine decision thresholds in the management of patients with acute cough. Set among primary care physicians attending meetings in the US and Switzerland, using data from a prospective cohort of primary care patients. Clinical vignettes were used to study the clinical decisions of physicians regarding eight patients with cough that varied by six signs and symptoms. The probability of community-acquired pneumonia (CAP) was determined for each vignette based on a multivariate model. A previously published approach based on logistic regression was used to determine test and treatment thresholds. In total, 256 physicians made 764 clinical decisions. Initial physician estimates systematically overestimated the likelihood of CAP; 75% estimating a higher probability than that predicted by the multivariate model. Given the probability of CAP from a multivariate model, 16.7% (125 of 749) changed their decision from 'treat' to 'test' or 'test' to 'rule out', whereas only 3.5% (26/749) changed their decision from 'rule out' to 'test' or 'test' to 'treat'. Test and treatment thresholds were 9.5% (95% confidence interval (CI) = 8.7 to 10.5) and 43.1% (95% CI = 40.1 to 46.4) and were updated to 12.7% (95% CI = 11.7 to 13.8) and 51.3% (95% CI = 48.3 to 54.9) once the true probability of CAP was given. Test thresholds were consistent between subgroups. Treatment thresholds were higher if radiography was available, for Swiss physicians, and for non-primary care physicians. Test and treatment thresholds for CAP in patients with acute cough were 9.5% and 43.1%, respectively. Physicians tended to overestimate the likelihood of CAP, and providing information from a clinical decision rule (CDR) changed about 1 in 6 clinical decisions

Raisonnement clinique : de la théorie à la pratique… et retour [Clinical decision making : from theory to practice… and backward]

Being able to analyze all the successive steps of decision making from the first contact with the patient to the final diagnosis is complex because it refers sometimes to intuitive elements proper to each clinician. However, understanding how they integrate probabilities of diseases into their clinical practice and manage diagnostic uncertainties is crucial. This allows a more rational practice of medicine and identifying factors related to the patient, physician or context that may modify the clinical decision making. Furthermore, the use of tools such as clinical scores has taken an important place with the evidence based medicine. Given the fact that they are partly theoretical, it is necessary to assess whether these recommendations are in line with clinical practice

Development and validation of a clinical decision rule for the diagnosis of influenza.

INTRODUCTION: A clinical decision rule to improve the accuracy of a diagnosis of influenza could help clinicians avoid unnecessary use of diagnostic tests and treatments. Our objective was to develop and validate a simple clinical decision rule for diagnosis of influenza. METHODS: We combined data from 2 studies of influenza diagnosis in adult outpatients with suspected influenza: one set in California and one in Switzerland. Patients in both studies underwent a structured history and physical examination and had a reference standard test for influenza (polymerase chain reaction or culture). We randomly divided the dataset into derivation and validation groups and then evaluated simple heuristics and decision rules from previous studies and 3 rules based on our own multivariate analysis. Cutpoints for stratification of risk groups in each model were determined using the derivation group before evaluating them in the validation group. For each decision rule, the positive predictive value and likelihood ratio for influenza in low-, moderate-, and high-risk groups, and the percentage of patients allocated to each risk group, were reported. RESULTS: The simple heuristics (fever and cough; fever, cough, and acute onset) were helpful when positive but not when negative. The most useful and accurate clinical rule assigned 2 points for fever plus cough, 2 points for myalgias, and 1 point each for duration <48 hours and chills or sweats. The risk of influenza was 8% for 0 to 2 points, 30% for 3 points, and 59% for 4 to 6 points; the rule performed similarly in derivation and validation groups. Approximately two-thirds of patients fell into the low- or high-risk group and would not require further diagnostic testing. CONCLUSION: A simple, valid clinical rule can be used to guide point-of-care testing and empiric therapy for patients with suspected influenza