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.

Development and validation of a clinical prediction rule for chest wall syndrome in primary care

Le "Chest wall syndrome" (CWS) est défini comme étant une source bénigne de douleurs thoraciques, localisées sur la paroi thoracique antérieure et provoquées par une affection musculosquelettique. Le CWS représente la cause la plus fréquente de douleurs thoraciques en médecine de premier recours. Le but de cette étude est de développer et valider un score de prédiction clinique pour le CWS. Une revue de la littérature a d'abord été effectuée, d'une part pour savoir si un tel score existait déjà, et d'autre part pour retrouver les variables décrites comme étant prédictives d'un CWS. Le travail d'analyse statistique a été effectué avec les données issues d'une cohorte clinique multicentrique de patients qui avaient consulté en médecine de premier recours en Suisse romande avec une douleur thoracique (59 cabinets, 672 patients). Un diagnostic définitif avait été posé à 12 mois de suivi. Les variables pertinentes ont été sélectionnées par analyses bivariées, et le score de prédiction clinique a été développé par régression logistique multivariée. Une validation externe de ce score a été faite en utilisant les données d'une cohorte allemande (n= 1212). Les analyses bivariées ont permis d'identifier 6 variables caractérisant le CWS : douleur thoracique (ni rétrosternale ni oppressive), douleur en lancées, douleur bien localisée, absence d'antécédent de maladie coronarienne, absence d'inquiétude du médecin et douleur reproductible à la palpation. Cette dernière variable compte pour 2 points dans le score, les autres comptent pour 1 point chacune; le score total s'étend donc de 0 à 7 points. Dans la cohorte de dérivation, l'aire sous la courbe sensibilité/spécificité (courbe ROC) est de 0.80 (95% de l'intervalle de confiance : 0.76-0.83). Avec un seuil diagnostic de > 6 points, le score présente 89% de spécificité et 45% de sensibilité. Parmi tous les patients qui présentaient un CWS (n = 284), 71% (n = 201) avaient une douleur reproductible à la palpation et 45% (n= 127) sont correctement diagnostiqués par le score. Pour une partie (n = 43) de ces patients souffrant de CWS et correctement classifiés, 65 investigations complémentaires (30 électrocardiogrammes, 16 radiographies du thorax, 10 analyses de laboratoire, 8 consultations spécialisées, et une tomodensitométrie thoracique) avaient été réalisées pour parvenir au diagnostic. Parmi les faux positifs (n = 41), on compte trois angors stables (1.8% de tous les positifs). Les résultats de la validation externe sont les suivants : une aire sous la courbe ROC de 0.76 (95% de l'intervalle de confiance : 0.73-0.79) avec une sensibilité de 22% et une spécificité de 93%. Ce score de prédiction clinique pour le CWS constitue un complément utile à son diagnostic, habituellement obtenu par exclusion. En effet, pour les 127 patients présentant un CWS et correctement classifiés par notre score, 65 investigations complémentaires auraient pu être évitées. Par ailleurs, la présence d'une douleur thoracique reproductible à la palpation, bien qu'étant sa plus importante caractéristique, n'est pas pathognomonique du CWS.

Ruling out coronary artery disease in primary care: development and validation of a simple prediction rule.

BACKGROUND: Chest pain can be caused by various conditions, with life-threatening cardiac disease being of greatest concern. Prediction scores to rule out coronary artery disease have been developed for use in emergency settings. We developed and validated a simple prediction rule for use in primary care. METHODS: We conducted a cross-sectional diagnostic study in 74 primary care practices in Germany. Primary care physicians recruited all consecutive patients who presented with chest pain (n = 1249) and recorded symptoms and findings for each patient (derivation cohort). An independent expert panel reviewed follow-up data obtained at six weeks and six months on symptoms, investigations, hospital admissions and medications to determine the presence or absence of coronary artery disease. Adjusted odds ratios of relevant variables were used to develop a prediction rule. We calculated measures of diagnostic accuracy for different cut-off values for the prediction scores using data derived from another prospective primary care study (validation cohort). RESULTS: The prediction rule contained five determinants (age/sex, known vascular disease, patient assumes pain is of cardiac origin, pain is worse during exercise, and pain is not reproducible by palpation), with the score ranging from 0 to 5 points. The area under the curve (receiver operating characteristic curve) was 0.87 (95% confidence interval [CI] 0.83-0.91) for the derivation cohort and 0.90 (95% CI 0.87-0.93) for the validation cohort. The best overall discrimination was with a cut-off value of 3 (positive result 3-5 points; negative result <or= 2 points), which had a sensitivity of 87.1% (95% CI 79.9%-94.2%) and a specificity of 80.8% (77.6%-83.9%). INTERPRETATION: The prediction rule for coronary artery disease in primary care proved to be robust in the validation cohort. It can help to rule out coronary artery disease in patients presenting with chest pain in primary care.

A quantitative test of Hamilton's rule for the evolution of altruism.

The evolution of altruism is a fundamental and enduring puzzle in biology. In a seminal paper Hamilton showed that altruism can be selected for when rb - c > 0, where c is the fitness cost to the altruist, b is the fitness benefit to the beneficiary, and r is their genetic relatedness. While many studies have provided qualitative support for Hamilton's rule, quantitative tests have not yet been possible due to the difficulty of quantifying the costs and benefits of helping acts. Here we use a simulated system of foraging robots to experimentally manipulate the costs and benefits of helping and determine the conditions under which altruism evolves. By conducting experimental evolution over hundreds of generations of selection in populations with different c/b ratios, we show that Hamilton's rule always accurately predicts the minimum relatedness necessary for altruism to evolve. This high accuracy is remarkable given the presence of pleiotropic and epistatic effects as well as mutations with strong effects on behavior and fitness (effects not directly taken into account in Hamilton's original 1964 rule). In addition to providing the first quantitative test of Hamilton's rule in a system with a complex mapping between genotype and phenotype, these experiments demonstrate the wide applicability of kin selection theory.

Prevalence of Acute Coronary Syndrome in Patients Suspected for Pulmonary Embolism or Acute Aortic Syndromes: Rational for "Double" and "Triple" Rule-Out Concepts

PURPOSE To evaluate the prevalence of acute coronary syndrome (ACS) in patients presenting initially with atypical chest pain and suspected to have pulmonary embolism (PE) or acute aortic syndromes (AAS). To evaluate the overlap between ACS, PE and AAS in routine practice and determine how many patients could have benefit from a single CT protocol to rule out ACS at the same time as PE and AAS. METHOD AND MATERIALS Our electronic hospital database revealed 1122 consecutive patients who underwent a thoracic CT angiography for PE or AAS from 2004 to 2006 (mean age, 63±13 years). Patients without chest pain were excluded from this study. Thus, 447 patients presented with isolated atypical chest were included in the analysis. All patients who underwent a thoracic CT scan previously received standard clinical care and were initially considered as non ACS. The final diagnosis was obtained by the hospital stay report. RESULTS Among the 447 patients with atypical chest pain, 25 (5.5%) were finally found to have ACS: 19 patients (4.2%) were suspected for PE and 6 (1. 3%) were suspected for AAS. There were 90 patients diagnosed to have PE, 89 (98.8%) of them were suspected for PE while only 1 (1%) was suspected for AAS. Eleven patients diagnosed to have AAS, 9 (82%) of them were suspected for AAS while 2 (18%) were suspected for PE. CONCLUSION In clinical practice, the overlap between PE, AAS and ACS is limited which make the triple rule-out studies less recommended to be done at the time being because of the high dose radiation. A double rule-out investigation is suggested to be done for patients being evaluated for atypical chest pain and suspected of having AAS or PE because of a significant overlap between the two entities as well it doesn't implicate any increment in radiation dose. CLINICAL RELEVANCE/APPLICATION With 64-slice CT, coronary circulation and total chest can be evaluated at the same time offering new opportunitie for the evaluation of three major life-threatening conditions :ACS,PE and AAS.

Ruling out coronary heart disease in primary care: external validation of a clinical prediction rule.

BACKGROUND: The Marburg Heart Score (MHS) aims to assist GPs in safely ruling out coronary heart disease (CHD) in patients presenting with chest pain, and to guide management decisions. AIM: To investigate the diagnostic accuracy of the MHS in an independent sample and to evaluate the generalisability to new patients. DESIGN AND SETTING: Cross-sectional diagnostic study with delayed-type reference standard in general practice in Hesse, Germany. METHOD: Fifty-six German GPs recruited 844 males and females aged ≥ 35 years, presenting between July 2009 and February 2010 with chest pain. Baseline data included the items of the MHS. Data on the subsequent course of chest pain, investigations, hospitalisations, and medication were collected over 6 months and were reviewed by an independent expert panel. CHD was the reference condition. Measures of diagnostic accuracy included the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, likelihood ratios, and predictive values. RESULTS: The AUC was 0.84 (95% confidence interval [CI] = 0.80 to 0.88). For a cut-off value of 3, the MHS showed a sensitivity of 89.1% (95% CI = 81.1% to 94.0%), a specificity of 63.5% (95% CI = 60.0% to 66.9%), a positive predictive value of 23.3% (95% CI = 19.2% to 28.0%), and a negative predictive value of 97.9% (95% CI = 96.2% to 98.9%). CONCLUSION: Considering the diagnostic accuracy of the MHS, its generalisability, and ease of application, its use in clinical practice is recommended.

The pulmonary embolism rule-out criteria (PERC) rule does not safely exclude pulmonary embolism.

Background: The Pulmonary Embolism Rule-out Criteria (PERC) rule is a clinical diagnostic rule designed to exclude pulmonary embolism (PE) without further testing. We sought to externally validate the diagnostic performance of the PERC rule alone and combined with clinical probability assessment based on the revised Geneva score. Methods: The PERC rule was applied retrospectively to consecutive patients who presented with a clinical suspicion of PE to six emergency departments, and who were enrolled in a randomized trial of PE diagnosis. Patients who met all eight PERC criteria [PERC(-)] were considered to be at a very low risk for PE. We calculated the prevalence of PE among PERC(-) patients according to their clinical pretest probability of PE. We estimated the negative likelihood ratio of the PERC rule to predict PE. Results: Among 1675 patients, the prevalence of PE was 21.3%. Overall, 13.2% of patients were PERC(-). The prevalence of PE was 5.4% [95% confidence interval (CI): 3.1-9.3%] among PERC(-) patients overall and 6.4% (95% CI: 3.7-10.8%) among those PERC(-) patients with a low clinical pretest probability of PE. The PERC rule had a negative likelihood ratio of 0.70 (95% CI: 0.67-0.73) for predicting PE overall, and 0.63 (95% CI: 0.38-1.06) in low-risk patients. Conclusions: Our results suggest that the PERC rule alone or even when combined with the revised Geneva score cannot safely identify very low risk patients in whom PE can be ruled out without additional testing, at least in populations with a relatively high prevalence of PE.

A generalization of Cope's rule

For numerous shelly invertebrates, Cope's rule is shown in this paper to merely describe the particular case where volume increase is strictly coupled with diameter or length. Allometries, which are frequently observed in the evolution of the shells' geometry, mean that their size, volume and surface can vary independently. The consequences of this can be summarized as follows : 1) volume increase not coupled with an increase of diameter or length of the organisms generates increasing involution and/or lateral width in the shell of cephalopods, foraminifera and radiolarians; 2) an increase of the biomineralizing surface, not coupled with volume increase, generates increasing apparent complexity in the sutures and growth lines in ammonites, and an increase in the complexity and number of chambers in foraminifera.

Development and validation of a clinical prediction rule for chest wall syndrome in primary care.

ABSTRACT: BACKGROUND: Chest wall syndrome (CWS), the main cause of chest pain in primary care practice, is most often an exclusion diagnosis. We developed and evaluated a clinical prediction rule for CWS. METHODS: Data from a multicenter clinical cohort of consecutive primary care patients with chest pain were used (59 general practitioners, 672 patients). A final diagnosis was determined after 12 months of follow-up. We used the literature and bivariate analyses to identify candidate predictors, and multivariate logistic regression was used to develop a clinical prediction rule for CWS. We used data from a German cohort (n = 1212) for external validation. RESULTS: From bivariate analyses, we identified six variables characterizing CWS: thoracic pain (neither retrosternal nor oppressive), stabbing, well localized pain, no history of coronary heart disease, absence of general practitioner's concern, and pain reproducible by palpation. This last variable accounted for 2 points in the clinical prediction rule, the others for 1 point each; the total score ranged from 0 to 7 points. The area under the receiver operating characteristic (ROC) curve was 0.80 (95% confidence interval 0.76-0.83) in the derivation cohort (specificity: 89%; sensitivity: 45%; cut-off set at 6 points). Among all patients presenting CWS (n = 284), 71% (n = 201) had a pain reproducible by palpation and 45% (n = 127) were correctly diagnosed. For a subset (n = 43) of these correctly classified CWS patients, 65 additional investigations (30 electrocardiograms, 16 thoracic radiographies, 10 laboratory tests, eight specialist referrals, one thoracic computed tomography) had been performed to achieve diagnosis. False positives (n = 41) included three patients with stable angina (1.8% of all positives). External validation revealed the ROC curve to be 0.76 (95% confidence interval 0.73-0.79) with a sensitivity of 22% and a specificity of 93%. CONCLUSIONS: This CWS score offers a useful complement to the usual CWS exclusion diagnosing process. Indeed, for the 127 patients presenting CWS and correctly classified by our clinical prediction rule, 65 additional tests and exams could have been avoided. However, the reproduction of chest pain by palpation, the most important characteristic to diagnose CWS, is not pathognomonic.

Allergy to betalactam antibiotics in children: results of a 20-year study based on clinical history, skin and challenge tests.

To cite this article: Ponvert C, Perrin Y, Bados-Albiero A, Le Bourgeois M, Karila C, Delacourt C, Scheinmann P, De Blic J. Allergy to betalactam antibiotics in children: results of a 20-year study based on clinical history, skin and challenge tests. Pediatr Allergy Immunol 2011; 22: 411-418. ABSTRACT: Studies based on skin and challenge tests have shown that 12-60% of children with suspected betalactam hypersensitivity were allergic to betalactams. Responses in skin and challenge tests were studied in 1865 children with suspected betalactam allergy (i) to confirm or rule out the suspected diagnosis; (ii) to evaluate diagnostic value of immediate and non-immediate responses in skin and challenge tests; (iii) to determine frequency of betalactam allergy in those children, and (iv) to determine potential risk factors for betalactam allergy. The work-up was completed in 1431 children, of whom 227 (15.9%) were diagnosed allergic to betalactams. Betalactam hypersensitivity was diagnosed in 50 of the 162 (30.9%) children reporting immediate reactions and in 177 of the 1087 (16.7%) children reporting non-immediate reactions (p < 0.001). The likelihood of betalactam hypersensitivity was also significantly higher in children reporting anaphylaxis, serum sickness-like reactions, and (potentially) severe skin reactions such as acute generalized exanthematic pustulosis, Stevens-Johnson syndrome, and drug reaction with systemic symptoms than in other children (p < 0.001). Skin tests diagnosed 86% of immediate and 31.6% of non-immediate sensitizations. Cross-reactivity and/or cosensitization among betalactams was diagnosed in 76% and 14.7% of the children with immediate and non-immediate hypersensitivity, respectively. The number of children diagnosed allergic to betalactams decreased with time between the reaction and the work-up, probably because the majority of children with severe and worrying reactions were referred for allergological work-up more promptly than the other children. Sex, age, and atopy were not risk factors for betalactam hypersensitivity. In conclusion, we confirm in numerous children that (i) only a few children with suspected betalactam hypersensitivity are allergic to betalactams; (ii) the likelihood of betalactam allergy increases with earliness and/or severity of the reactions; (iii) although non-immediate-reading skin tests (intradermal and patch tests) may diagnose non-immediate sensitizations in children with non-immediate reactions to betalactams (maculopapular rashes and potentially severe skin reactions especially), the diagnostic value of non-immediate-reading skin tests is far lower than the diagnostic value of immediate-reading skin tests, most non-immediate sensitizations to betalactams being diagnosed by means of challenge tests; (iv) cross-reactivity and/or cosensitizations among betalactams are much more frequent in children reporting immediate and/or anaphylactic reactions than in the other children; (v) age, sex and personal atopy are not significant risk factors for betalactam hypersensitivity; and (vi) the number of children with diagnosed allergy to betalactams (of the immediate-type hypersensitivity especially) decreases with time between the reaction and allergological work-up. Finally, based on our experience, we also propose a practical diagnostic approach in children with suspected betalactam hypersensitivity.

Ubiquitin Ligases of the N-End Rule Pathway: Assessment of Mutations in UBR1 That Cause the Johanson-Blizzard Syndrome.

Background: Johanson-Blizzard syndrome (JBS; OMIM 243800) is an autosomal recessive disorder that includes congenital exocrine pancreatic insufficiency, facial dysmorphism with the characteristic nasal wing hypoplasia, multiple malformations, and frequent mental retardation. Our previous work has shown that JBS is caused by mutations in human UBR1, which encodes one of the E3 ubiquitin ligases of the N-end rule pathway. The N-end rule relates the regulation of the in vivo half-life of a protein to the identity of its N-terminal residue. One class of degradation signals (degrons) recognized by UBR1 are destabilizing N-terminal residues of protein substrates.Methodology/Principal Findings: Most JBS-causing alterations of UBR1 are nonsense, frameshift or splice-site mutations that abolish UBR1 activity. We report here missense mutations of human UBR1 in patients with milder variants of JBS. These single-residue changes, including a previously reported missense mutation, involve positions in the RING-H2 and UBR domains of UBR1 that are conserved among eukaryotes. Taking advantage of this conservation, we constructed alleles of the yeast Saccharomyces cerevisiae UBR1 that were counterparts of missense JBS-UBR1 alleles. Among these yeast Ubr1 mutants, one of them (H160R) was inactive in yeast-based activity assays, the other one (Q1224E) had a detectable but weak activity, and the third one (V146L) exhibited a decreased but significant activity, in agreement with manifestations of JBS in the corresponding JBS patients.Conclusions/Significance: These results, made possible by modeling defects of a human ubiquitin ligase in its yeast counterpart, verified and confirmed the relevance of specific missense UBR1 alleles to JBS, and suggested that a residual activity of a missense allele is causally associated with milder variants of JBS.

Respiratory viruses in HIV-infected patients with suspected respiratory opportunistic infection.

OBJECTIVE: To assess the incidence and epidemiological pattern of respiratory viruses in HIV-infected patients and to evaluate their potential clinical impact. DESIGN AND METHODS: A prospective population-based cohort study was conducted at three Swiss university hospitals. Study participants were HIV-infected patients who underwent a bronchoalveolar lavage to rule out an opportunistic event. All bronchoalveolar lavage specimens were screened using a set of real-time reverse transcriptase-polymerase chain reaction assays targeting 17 different respiratory viruses. RESULTS: Between November 2003 and November 2006, 59 bronchoalveolar episodes from 55 HIV-infected patients were analysed. Eleven of 59 episodes (18.6%) were positive for at least one respiratory virus. Coronavirus OC43 was identified in three cases (27.3%) followed by influenza A in two (18.2%). Parainfluenza virus (PIV) 2, PIV 3, PIV 4, bocavirus, human rhinovirus A and human metapneumovirus were each identified in one case (9%). In the majority of these cases (63.6%) no other concomitant microorganism was isolated. CONCLUSIONS: Clinical investigation of respiratory viral infections in HIV-infected patients should not be restricted to prototype viruses and also need to target all the different family of viruses as it seems likely that these viruses contribute to pulmonary complications and morbidity in this population.

Women in leadership: Three essays

GENDER EMPOWERMENT: EFFECTS OF GODS, GEOGRAPHY, AND GDP¦Fenley, M., & Antonakis, J.¦ABSTRACT¦We examined the determinants of women's empowerment in the economy and political leadership in 178 countries. Given the androcentric nature of most religions, we hypothesized that high degrees of country-level theistic belief create social conditions that impede the progression of women to power. The dependent variable was the Gender Empowerment index of the United Nations Development Program, which captures the participation of women in political leadership, management, and their share of national income. Controlling for GDP per capita as well as the fixed-effects of the dominant type of religion and legal origin and instrumenting all endogenous variables with geographic or historical variables, our results show that atheism has a significant positive effect on gender empowerment. These results are driven by the rule of law, which in addition to being a catalyst for economic development, appears to crowd-out the informal regulation of behavior due to religious norms.¦DEVELOPING WOMEN LEADERS: COMPARING A TRANSFORMATIONAL AND A CHARISMATIC LEADERSHIP INTERVENTION¦Fenley, M., Jacquart, P., & Antonakis, J.¦ABSTRACT¦Along with a gender imbalance in leadership role occupancy, most leadership interventions have been conducted with samples of men. We conducted an experiment wherein we assigned female participants (n = 38, mean age = 35 years) to one of two conditions: Transformational (i.e., "standard") leadership training or charismatic leadership training. The two interventions were essentially equivalent, except that we also focused on developing the "charismatic leadership tactics" (e.g., rhetorical skills) of participants in the charismatic condition. After the interventions, we randomly assigned participants into problem-solving teams that required extensive interaction. Each team had an equal number of participants having received transformational training or charismatic training. At the end of the team exercises, participants rated each of their team members on a leadership prototypicality measure. Results indicated that those who received charismatic training scored higher (a) on prototypicality (standardized  = .42) and (b) on a test of declarative knowledge of charismatic rhetorical strategies (i.e., a manipulation check, standardized  = .76). Furthermore, the score on the test fully mediated the effect of the treatment on prototypicality (standardized indirect  = .32). We discuss the importance and practical implications of these results.¦CHANGING ATTITUDES TOWARDS WOMEN IN A MALE SEX-TYPE WORK ENVIRONMENT: EVIDENCE FROM A FIELD EXPERIMENT IN EUROPEAN ATHLETICS¦Fenley, M.¦ABSTRACT¦Most sports organizations have a similar gender gap in leadership as do the majority of non-sport organizations. Women's careers sputter somewhere at coaching level positions and few women obtain top leadership positions. Greater awareness of gender inequalities in general, and in leadership in particular, could decrease gender discrimination and increase women's presence at upper levels. The goal of this study was to evaluate the impact of an intervention using an online gender awareness exercise. Participants (n = 1,001 participants, n = 32 countries) were randomly assigned to one of eight conditions in a 2 (a discriminating perspective-taking story or a non-discriminating perspective-taking story) by 2 (gender quiz or no gender quiz) by 2 (diversity quiz or no diversity quiz) factorial design. The results show that the online perspective taking exercise changed initial sexist attitudes. Participants having taken a diversity quiz had less sexist attitudes (as measured by the Modern- and Old-fashioned sexism scale) than did participants who did not take the diversity quiz (irrespective of perspective-taking story). The combination of having taken a diversity quiz with a gender quiz had the biggest impact on attitudes for the non-discriminating story.