The minimally important difference in the Rhinoconjunctivitis Total Symptom Score in grass-pollen-induced allergic rhinoconjunctivitis.

BACKGROUND: The minimally important difference (MID) has been defined as the smallest improvement considered worthwhile by a patient. The MID has not been estimated for the Rhinoconjunctivitis Total Symptom Score (RTSS). METHODS: In a prospective multicentre study, patients consulting for grass-pollen-induced allergic rhinitis (AR) recorded a 15-point global rating of change scale (GRCS) score and the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score on a weekly basis and the individual symptom scores comprising the RTSS on a daily basis over two consecutive weeks. The MID in the RTSS was determined with anchor-based methods (using the GRCS and the RQLQ) and a distribution-based method [based on the RTSS' standard deviation (SD)]. RESULTS: The study population comprised 806 patients (253 children, 250 adolescents and 303 adults). During the first week of the study, the mean ± SD RTSSs for these age groups were 6.5 ± 3.3, 6.8 ± 3.4 and 7.0 ± 3.4, respectively. For an improvement of 2 points in the GRCS or 0.5 points in the RQLQ score, the regression analysis yielded MIDs in the RTSS of 1.24 ± 0.17 and 1.12 ± 0.14 in children, 1.33 ± 0.14 and 1.20 ± 0.13 in adolescents and 1.13 ± 0.14 and 0.89 ± 0.12 in adults, respectively. When applying distribution-based methods, the MID ranged from 1.09 to 1.13 (based on 0.33 SDs of the first-week RTSS) and from 1.22 to 1.40 (based on 0.5 SDs of the difference in RTSSs between the first and second weeks). CONCLUSION: The MID in the RTSS was consistently estimated as 1.1-1.3 (and could conceivably be rounded to 1) in patients with grass-pollen-induced AR.

Validation of a self-questionnaire for assessing the control of allergic rhinitis.

BACKGROUND: Allergic rhinitis affects the lives of patients for whom discomfort is, in most cases, significantly improved by pharmacological treatment. OBJECTIVE: To develop and validate a self-assessment global score for allergic rhinitis control (five items scored from 1 to 5 assessing the rhinitis over the 2 previous weeks). METHODS: Study of acceptability, reliability, validity and sensitivity to change during a prospective observational study in 902 patients selected by 411 general practitioners or allergists. RESULTS: The score correlated significantly to the clinical picture and to the impact of the rhinitis on social and sports activities at inclusion (P<0.0001). A significant improvement in the score was observed after 15 days of treatment: 14.9 ± 4.0 at inclusion and 21.5 ± 2.9 at re-evaluation after 15 days of treatment (P<0.0001). Using receiver operating characteristics curve, a score of 20 was the cut-off for poor vs. well-controlled rhinitis; a score strictly higher than 20 (best being 25) had a sensitivity of 67%, a specificity of 82%, a negative predictive value of 32% and a positive predictive value of 95%. CONCLUSION AND CLINICAL RELEVANCE: The self-assessment score for allergic rhinitis control appeared to be sensitive to change and correlated to the clinical expression of rhinitis and also to its involvement with treatment. These results suggest that this self-completion questionnaire could be used in daily practice at each consultation to determine, in a standardized manner, the level of control of the allergic rhinitis of an individual patient.

[COVID-19 and medical publications: How three articles have influenced the media and public decisions in France]. / Littérature médicale et COVID-19 : comment trois articles ont influencé les médias et la décision publique en France.

The present article details the publication process and the vicissitudes of three articles about SARS-CoV-2 and its related disease (COVID-19). The three articles were published one month apart between March and May 2020. Their mediatization led French health authorities to intervene. Our article does not focus on and does not assess the scientific quality of the articles presented, but only aims to open the reflection on medical publication. Beyond the description of these three specific cases, this article raises issues about article retraction, peer-reviewing, preprints, authorship and the dissemination of scientific medical information, including through the mass media. It discusses new publishing modes and the dissemination of published information in clinical research.

Validation of a questionnaire for assessment of asthma patient knowledge and behaviour.

BACKGROUND: For several years, educational programmes have been highlighted because care success depends on patient's knowledge and patient's asthma management. However, no tool is available to assess change in patient knowledge and behaviour before and after completing an educational programme. OBJECTIVE: To validate a questionnaire measuring the knowledge and behaviour of asthmatics participating in an educational programme and to gauge the benefit of such a programme. METHODS: The Asthma Behaviour Change (ABC) questionnaire was generated from literature, patient surveys and clinical situations. It was organized in eight dimensions assessing patient behaviour in seven different clinical situations and two assessing patient (pathophysiology and therapeutic) knowledge. A total of 139 asthmatics filled out the questionnaire before, during and after the educational programme. RESULTS: The principal component analysis confirmed the structure empirically made by clinical situations. Internal consistency analysis yielded high Cronbach's alpha values. Different dimensions and the two global scores were able to discriminate patients according to asthma severity. Finally, the effect size of difference before and after educational programme was at least 0.47, and was larger than 0.74 for both global behaviour and knowledge scores. The difference between visit 1 and 3 for global behaviour and knowledge scores reached 18.84 +/- 20.83 (P < 0.001, 95% CI: 13.18-24.43) and 11.06 +/- 14.98 (P < 0.001, 95% CI: 7.10-15.03), respectively. CONCLUSION: ABC questionnaire is a valid tool to assess asthmatics' knowledge and behaviour. Furthermore, this study confirmed that educational programmes lead to better awareness of asthma by patients.

[How can an effective drug to treat irritable bowel syndrome be successfully developed?]. / Développer un médicament dans le syndrome de l'intestin irritable : une mission impossible ?

BACKGROUND: Irritable bowel syndrome (IBS) is a prevalent disorder, and although the pharmaceutical industry knows the potential fallout of a successful drug launch in this area, effective drug treatments are rare. AIM: To give an overview of the main factors interfering with the development of IBS drugs and to provide pertinent methodological indications to improve their investigation in clinical trials. RESULTS: Developing IBS drugs remains a major challenge, as numerous factors, related or unrelated to the nature of the disease itself, interfere with the demonstration of efficacy : the multiplicity of physiopathological mechanisms, wide variation in symptoms across patients and over time, associated psychological traits and environmental aspects, and a very significant placebo effect. There can be no question of developing drugs to target a single receptor in the hope of thereby impacting the whole range of factors involved in the genesis of IBS symptoms. Drug safety is, moreover, a prime consideration, given that this pathology, while certainly disabling, is not life-threatening. If a significant difference between a new treatment and placebo is to be demonstrated on a clinical trial, inclusion and efficacy criteria and study treatment duration must be predefined very precisely. The primary endpoint is abdominal pain, but the assessment of relief of the patient's symptoms has been also recommended, even if there is as yet no consensus as to its definition. The impact of a new IBS drug on patient's quality of life is an important secondary endpoint. CONCLUSION: In IBS more, perhaps, than in other pathologies, study design needs very careful consideration if new IBS drug trials are to be conclusive. However, some critical methodological issues (e.g., definite primary endpoint, interpretation of results, and definition of responders) are still unresolved.

Effect of a fermented milk containing Bifidobacterium animalis DN-173 010 on the health-related quality of life and symptoms in irritable bowel syndrome in adults in primary care: a multicentre, randomized, double-blind, controlled trial.

BACKGROUND: Health-related quality of life (HRQoL) has been rarely evaluated as a primary endpoint in the assessment of the effect of probiotics on the irritable bowel syndrome (IBS). AIM: To study the effects of fermented milk containing Bifidobacterium animalis DN-173 010 and yoghurt strains on the IBS in a multicentre, double-blind, controlled trial. METHODS: A total of 274 primary care adults with constipation-predominant IBS (Rome II) were randomized to consume for 6 weeks either the test fermented milk or a heat-treated yoghurt (control). HRQoL and digestive symptoms were assessed after 3 and 6 weeks on an intention-to-treat population of 267 subjects. RESULTS: The HRQoL discomfort score, the primary endpoint, improved (P < 0.001) in both groups at weeks 3 and 6. The responder rate for the HRQoL discomfort score was higher (65.2 vs. 47.7%, P < 0.005), as was the decrease in bloating score [0.56 +/- (s.d.)1.01 vs. 0.31 +/- 0.87, P = 0.03], at week 3 in the test vs. the control group. In those subjects with <3 stools/week, stool frequency increased (P < 0.001) over 6 weeks in the test vs. control group. CONCLUSIONS: This study suggests a beneficial effect of a probiotic food on discomfort HRQoL score and bloating in constipation-predominant IBS, and on stool frequency in subjects with <3 stools/week.

Acute exacerbation of pain in irritable bowel syndrome: efficacy of phloroglucinol/trimethylphloroglucinol. A randomized, double-blind, placebo-controlled study.

BACKGROUND: Abdominal pain is the predominant symptom in irritable bowel syndrome patients. Phloroglucinol and its methylated derivative are antispasmodic agents acting on smooth muscle. AIM: To evaluate the efficacy of phloroglucinol/trimethylphloroglucinol on pain intensity during an acute exacerbation of pain of irritable bowel syndrome over a 1-week period treatment. METHODS: Irritable bowel syndrome Rome II patients seeking medical advice for an acute exacerbation of abdominal pain were randomized to phloroglucinol/trimethylphloroglucinol (62.2 mg P + 80 mg TMP) two pills three times daily or placebo for 7 days. Patients were included if they had a pain with a minimal intensity of 40 on a 100-mm visual analogue scale, and if pain occurred at least 2 days during the week previous inclusion. RESULTS: Three hundred and seven patients were included by 78 general practitioners. The intent-to-treat population included 300 patients, aged of 46.9 +/- 14.8 years (73% female). The relative decrease of pain intensity at day 7 was 57.8 +/- 31.7% vs. 46.3 +/- 34.7% (Delta = 11.5 +/- 3.8%, [CI(95%): 4.0 ; 19.1], P = 0.0029) and the percentage of patients with at least a 50% decrease of pain intensity was 62% vs. 47% (Delta = 15.3 +/- 5.7%, [CI(95%): 4.1 ; 26.5], P = 0.0078) in phloroglucinol/trimethylphloroglucinol and placebo groups, respectively. CONCLUSIONS: A 1-week phloroglucinol/trimethylphloroglucinol treatment significantly reduces pain intensity in irritable bowel syndrome patients consulting their general practitioners for pain exacerbation.

Validation of French version of the Scleroderma Health Assessment Questionnaire (SSc HAQ).

The modified Scleroderma Health Assessment Questionnaire (SSc HAQ) is a functional score to assess systemic sclerosis (SSc) comprising the HAQ disease index (HAQ-DI) plus five specific visual analogue scales (VAS). Since it was validated in English-speaking patients only, its general use in any other language necessitates prior cross-cultural adaptation and validation. We designed this study to assess its value in French-speaking patients and to validate the French version according to international recommendations. We elaborated a French version using the "forward-backward" method. We then validated its psychometric properties with 100 consecutive SSc French-speaking patients who had undergone simultaneous clinical and paraclinical examination. In addition, we calculated the SSc HAQ score, a new outcome measure, which is obtained by pooling the eight domains from the HAQ-DI with the five organ VAS. Our study confirmed the psychometric properties of the SSc HAQ in non-English-speaking patients with (a) structural validity: the major component analysis, performed on the HAQ-DI and the five VAS, yielding a two-factor structure; (b) convergent validity: with high correlation coefficients between the SSc HAQ score and the physical component score of the SF-36 (r=-0.74, p<0.0001); (c) discriminant validity: the SSc HAQ score was better in patients with limited than with diffuse SSc (0.5+/-0.5 vs 1.1+/-0.7, respectively, p<0.0001) in relation to the number of clinical involvements; (d) reproducibility was high using the test-retest procedure (r=0.98). This study showed the value of the SSc HAQ, which is a simple, discriminant, reproducible self-administered questionnaire to evaluate French-speaking SSc patients. In addition, we suggest the use of a new outcome measure, the SSc HAQ score, to assess this systemic disease more accurately.

The Intestinal Gas Questionnaire: development of a new instrument for measuring gas-related symptoms and their impact on daily life.

BACKGROUND: Although gas-related symptoms (GRS) are common and intrusive, there are no questionnaires to quantitate this problem. This study aimed to develop an instrument to rectify this gap in our knowledge. METHODS: Concepts were initially identified from the literature and interviews with gastroenterologists. Exploratory one-to-one interviews and focus groups with irritable bowel syndrome (IBS) patients (n = 28) and non-IBS subjects (n = 27) with GRS were conducted in UK, France, and Spain leading to a conceptual framework for the questionnaire. Last, iterative rounds of cognitive debriefing were performed with IBS (n = 16) and non-IBS subjects (n = 14). KEY RESULTS: From the first three steps, nine GRS (bloating, distension, flatulence, odorous flatulence, difficult gas evacuation, stomach rumbling, belching, bad breath, and abdominal movement) were identified although abdominal movement was subsequently excluded. Twelve quality of life domains affected by these symptoms were identified as: Clothing, emotional, physical appearance, diet, daily living, work, social life, physical activity, relationships, sex life, sleep, and cognitive function. A 24-h recall for symptoms and a 7-day recall for impact assessment were supported by the qualitative findings. Cognitive debriefing confirmed the understanding of the instrument. Across the three languages, the instrument was conceptually and linguistically consistent. CONCLUSIONS & INFERENCES: The International Gas Questionnaire is a 2-part instrument, developed rigorously and simultaneously in three languages assessing seven symptoms (17 items) and their impact on 12 domains (26 items) in IBS and general population. It is now undergoing psychometric validation and should provide a unique tool for epidemiological surveys and clinical trials for developing new treatments for these symptoms.

Study design in osteoporosis: a European perspective.

The advent of effective agents for the treatment of osteoporosis has led to the view that placebo-controlled trials to test new agents for efficacy are no longer appropriate. Rather, studies of superiority, equivalence, or non-inferiority have been recommended. Such studies require very large sample sizes, and the burden of osteoporotic fracture in a trial setting is substantially increased. Studies of equivalence cannot be unambiguously interpreted because the variance in effect of active comparator agents is too large in osteoporosis. If fracture studies are required by regulatory agencies, there is still a requirement for placebo-controlled studies, although perhaps of shorter duration than demanded at present.

Orocecal transit time in humans assessed by sulfapyridine appearance in saliva after sulfasalazine intake.

PURPOSE: We propose a noninvasive method for the measurement of orocecal transit time assessed by the sulfapyridine appearance time in saliva after ingestion of sulfasalazine. METHOD: In 12 healthy volunteers, we studied the correlation between plasma and saliva sulfapyridine appearance times and then the sulfapyridine appearance times in saliva under various experimental conditions to assess the reproducibility, the effects of meals, and the role of the formulation, and the effects of gastrointestinal kinetic drugs. RESULTS: The correlation between saliva and plasma sulfapyridine appearance times was strong (r = 0.84; p = 0.0004). The sulfapyridine saliva appearance time was significantly delayed by the meal. Compared with placebo, the saliva sulfapyridine appearance time was reduced by cisapride (312 +/- 128 versus 551 +/- 97 minutes; p = 0.0001) and increased by loperamide (674 +/- 267 versus 501 +/- 131 minutes; p = 0.044). CONCLUSION: We propose the salivary sample method as a validated simplification of the plasma sulfasalazine-sulfapyridine test for the measurement of orocecal transit time.

Protection against aspirin-induced gastric lesions by lansoprazole: simultaneous evaluation of functional and morphologic responses.

The protective effect of lansoprazole, a new proton pump inhibitor, against aspirin-induced gastric lesions was studied in a double-blind crossover trial with a simultaneous measure of the functional capacities of the mucosal barrier (by a recording of the gastric potential difference) and of the morphologic changes in the mucosa (by gastric endoscopy). After 1 week of treatment with lansoprazole (30 mg per day) or placebo, each healthy volunteer received 1 gm aspirin by mouth. Recording of the gastric potential difference lasted for 3 hours and was followed by gastric endoscopy. Morphologic lesions induced by aspirin were effectively prevented by lansoprazole: Lanza score was 0.67 +/- 0.98 (mean +/- SD) versus 2.25 +/- 1.1 with placebo (p < 0.005, ANOVA). Conversely, the decrease in the gastric potential difference was similar. The inhibition of acid secretion induced by lansoprazole was therefore sufficient to prevent aspirin-induced mucosal lesions without reinforcing the defense capacities of the mucosa. This simple pharmacologic model makes it possible to simultaneously evaluate the functional and morphologic effects of aspirin intake on the gastric mucosa.

Analysis of free fatty acid effect on methotrexate binding to albumin.

The binding of methotrexate to human serum albumin and the inhibitory effect of serum free fatty acids (FFA) have been studied by equilibrium dialysis with radiolabeled methotrexate. Methotrexate was bound to albumin via a single site (1.03 +/- 0.02) with a low affinity (1350 +/- 60 M-1). The effect of FFA on binding by albumin of methotrexate was analysed according to the classical inhibition models with computation of the free inhibitor concentration and was ascribed to an uncompetitive type of inhibition. These results were in agreement with the observed serum binding of methotrexate (45-50%) and allowed the simulation of the effect of various concentrations of FFA on methotrexate albumin binding in human serum.

Drug-induced diarrhoea.

Diarrhoea is a relatively frequent adverse event, accounting for about 7% of all drug adverse effects. More than 700 drugs have been implicated in causing diarrhoea; those most frequently involved are antimicrobials, laxatives, magnesium-containing antacids, lactose- or sorbitol-containing products, nonsteroidal anti-inflammatory drugs, prostaglandins, colchicine, antineoplastics, antiarrhythmic drugs and cholinergic agents. Certain new drugs are likely to induce diarrhoea because of their pharmacodynamic properties; examples include anthraquinone-related agents, alpha-glucosidase inhibitors, lipase inhibitors and cholinesterase inhibitors. Antimicrobials are responsible for 25% of drug-induced diarrhoea. The disease spectrum of antimicrobial-associated diarrhoea ranges from benign diarrhoea to pseudomembranous colitis. Several pathophysiological mechanisms are involved in drug-induced diarrhoea: osmotic diarrhoea, secretory diarrhoea, shortened transit time, exudative diarrhoea and protein-losing enteropathy, and malabsorption or maldigestion of fat and carbohydrates. Often 2 or more mechanisms are present simultaneously. In clinical practice, 2 major types of diarrhoea are seen: acute diarrhoea, which usually appears during the first few days of treatment, and chronic diarrhoea, lasting more than 3 or 4 weeks and which can appear a long time after the start of drug therapy. Both can be severe and poorly tolerated. In a patient presenting with diarrhoea, the medical history is very important, especially the drug history, as it can suggest a diagnosis of drug-induced diarrhoea and thereby avoid multiple diagnostic tests. The clinical examination should cover severity criteria such as fever, rectal emission of blood and mucus, dehydration and bodyweight loss. Establishing a relationship between drug consumption and diarrhoea or colitis can be difficult when the time elapsed between the start of the drug and the onset of symptoms is long, sometimes up to several months or years.

Comparative serum protein binding of anthracycline derivatives.

The binding of doxorubicin, iododoxorubicin, daunorubicin, epirubicin, pirarubicin, zorubicin, aclarubicin, and mitoxantrone to 600 microM human serum albumin and 50 microM alpha 1-acid glycoprotein was studied by ultrafiltration at 37 degrees C and pH 7.4. Anthracycline concentrations (total and free) were determined by high-performance liquid chromatography (HPLC) with fluorometric detection. Binding to albumin (600 microM) varied from 61% (daunorubicin) to 94% (iododoxorubicin). The binding to alpha 1-acid glycoprotein (50 microM) was more variable, ranging from 31% (epirubicin) to 64% (zorubicin), and was essentially related to the hydrophobicity of the derivatives. Simulations showed that the total serum binding varied over a broad range from 71% (doxorubicin) to 96% (iododoxorubicin). We recently reported that the binding to lipoproteins of a series of eight anthracycline analogues could be ascribed to chemicophysical determinants of lipophilicity [2]. The present study was conducted to evaluate in vitro the contribution of albumin and alpha 1-acid glycoprotein to the total serum binding of these drugs.

D-dimer: a characteristic of the coagulation state of each patient with chronic atrial fibrillation.

BACKGROUND AND OBJECTIVE: It is accepted that patients with atrial fibrillation (AF) are characterised by increased levels of plasmatic D-dimers, with a wide inter-individual variability depending on the patients and therapeutic characteristics, but it has not been established if this level was predictive of the risk of arterial thromboembolic event. In order to answer such a question, it has to be established if the D-dimer level in a given patient is characteristic of such a patient (stable over time) if also fluctuating with time (and useless to characterise the patient). METHODS AND RESULTS: One hundred thirty clinically stable patients with chronic AF were recruited (anticoagulant: group 1, antiaggregant aspirin: group 2, no antithrombotic: group 3). During the follow-up of patients without clinical events (n=63), it is notable that in patients with D-dimer levels <500 ng/ml, these remained <1000 ng/ml, in patients with levels between 500 and 1000 ng/ml, these did not reach 1590 ng/ml, and in those with D-dimers >1000 ng/ml, the levels remained relatively stable. Mean age and D-dimer levels were lower in group 1 (74.4 years and 509.1 ng/ml, respectively) than in group 2 (82.4 years, p=0.0003 and 1015.7 ng/ml, p<0.0001, respectively) and in group 3 (79.3 years and 1289.3 ng/ml, p<0.0001, respectively). The effect of the antithrombotic therapy was independent of the age of patients (p=0.017). CONCLUSION: D-dimer levels in patients with chronic AF remain in the same range over time. They are lower on anticoagulant therapy than on antiaggregant or no antithrombotic therapy, irrespective of age. Thus, D-dimers appear to be a useful parameter for assessing the degree of hypercoagulability of patients whatever their age.

Ethics and clinical trials.

The current reference guideline about ethics in clinical trials is the Declaration of Helsinki of human rights in medical research. Three major principles are emphasised: respect of the patient to accept or not to participate in a trial, the constraints and the presumed risks must be acceptable for patients included in a study, and vulnerable subjects should not participate in studies. The investigator is responsible for obtaining a free and well-informed consent from patients before their inclusion in a study. Where possible, a new drug should always first be compared to placebo in order to prove its superiority. Else, a small-sized trial comparing a new drug versus a reference treatment can lead to an erroneous conclusion of absence of difference. Moreover, good results or improvement are obtained in at least 30% of cases with placebo, whatever the disease. The use of placebo is unethical in life-threatening diseases and when an effective proved drug exists. The use of placebo is ethical in severe diseases with no efficient drug, in some severe diseases even when an active reference treatment is available, and in all moderate and functional diseases. In order to detect flawed studies, most journals now ask for any manuscript submitted and reporting results of a randomised clinical trial to join a checklist in order to verify the quality of the trial. Finally, it remains the responsibility of the doctor to decide whether or not a protocol is ethical, to participate or not and to include patients or not.