On the normativity of evidence - Lessons from philosophy of science and the "VALIDATE" project.

"Evidence" is a key term in medicine and health services research, including Health Technology Assessment (HTA). Randomized clinical trials (RCTs) have undoubtedly dominated the scene of generating evidence for a long period of time, becoming the hallmark of evidence-based medicine (EBM). However, due to a number of misunderstandings, the lay audience and some researchers have sometimes placed too much trust in RCTs compared to other methods of investigation. One of the principal misunderstandings is to consider RCTs findings as isolated and self-apparent pieces of information. In other words, what has been essentially lacking was the awareness of the value-context of the evidence and, in particular, the value- and theory-ladenness (normativity) of scientific knowledge. This paper aims to emphasize the normativity that exists in the production of scientific knowledge, and in particular in the conduct of RCTs as well as in the performance of HTA. The work is based on some lessons learned from Philosophy of Science and the European project "VALIDATE" (VALues In Doing Assessments of healthcare TEchnologies"). VALIDATE was a three-year EU Erasmus+ strategic partnerships project (2018-2021), in which training in the field of HTA was further optimized by using insights from political science and ethics (in accordance with the recent definition of HTA). Our analysis may reveal useful insights for addressing some challenges that HTA is going to face in the future.

Food and nutrient intakes in a group of 11 to 16 year old Swiss teenagers.

Better knowledge of the dietary intake of teenagers is necessary to help health professionals to provide better advice on an individual and data for prevention and health programme. We carried out a dietary survey by 3-day records technique in a group of adolescents living in the Canton of Vaud, Switzerland. Food habits were traditional but rich in refined products and poor in plant food. Mean daily energy intake, which was 8025 kJ for the girls and 9350 kJ for boys, was lower than the recommended dietary allowances, especially for girls. Independently of the gender, breakfast represented 19% of the total daily energy intake, lunch 31% and dinner 29%. Total energy provided by snacks was 23.0% for girls and 20.4% for boys. The percentage of energy supplied by the afternoon snack was 15.8% for the girls and 13.3% for the boys. The source of energy was 14% from protein, 37% from fat and 49% from carbohydrates. A high percentage of adolescents had low micronutrient intakes (vitamins A, E, B1, B6, C, folates and for minerals magnesium, calcium and iron). An increase intake of vegetables and fruit should thus be strongly encouraged; snacking could offer a target vector to improve dietary nutritional quality.

Food habits and sport activity during adolescence: differences between athletic and non-athletic teenagers in Switzerland.

OBJECTIVE: To describe food habits and dietary intakes of athletic and non-athletic adolescents in Switzerland. SETTING: College, high schools and professional centers in the Swiss canton of Vaud. METHOD: A total of 3,540 subjects aged 9-19 y answered a self-reported anonymous questionnaire to assess lifestyles, physical plus sports activity and food habits. Within this sample, a subgroup of 246 subjects aged 11-15 also participated in an in-depth ancillary study including a 3 day dietary record completed by an interview with a dietician. RESULTS: More boys than girls reported engaging in regular sports activities (P<0.001). Adolescent food habits are quite traditional: up to 15 y, most of the respondents have a breakfast and eat at least two hot meals a day, the percentages decreasing thereafter. Snacking is widespread among adolescents (60-80% in the morning, 80-90% in the afternoon). Food habits among athletic adolescents are healthier and also are perceived as such in a higher proportion. Among athletic adolescents, consumption frequency is higher for dairy products and ready to eat (RTE) cereals, for fruit, fruit juices and salad (P<0.05 at least). Thus the athletic adolescent's food brings more micronutrients than the diet of their non-athletic counterparts. Within the subgroup (ancillary study), mean energy intake corresponds to requirements for age/gender group. CONCLUSIONS: Athletic adolescents display healthier food habits than non-athletic adolescents: this result supports the idea that healthy behavior tends to cluster and suggests that prevention programs among this age group should target simultaneously both sports activity and food habits.

Isoniazid-induced crescentic glomerulonephritis in a child with a positive tuberculin skin test.

Acute nonoliguric renal failure developed in a 13-year-old girl, 1 month after the institution of isoniazid therapy because of a positive tuberculin test at school screening. A renal biopsy demonstrated severe crescentic glomerulonephritis with focal interstitial changes. Discontinuation of isoniazid and a short course of steroids and cyclophosphamide therapy were followed by complete recovery. Whereas isoniazid has been shown to induce a lupus-like syndrome and antihistone antinuclear antibodies, our patient displayed none of the clinical or immunological features that are characteristic of drug-induced lupus. Furthermore, none of the identifiable causes for crescentic glomerulonephritis was evident in this girl. To the best of our knowledge this is the first report suggesting a possible association of crescentic glomerulonephritis to isoniazid treatment.

Ocular melanomas and melanocytic lesions of the eye.

This article describes several melanocytic lesions of the eye. Benign and malignant lesions will be discussed as well as a review of the dysplastic nevus syndrome and its proposed association with ocular melanoma. Ocular melanomas arise from the same embryologically derived melanocytes as their cutaneous counterparts. However, ocular and cutaneous melanomas differ in many respects. The diagnosis and management of these ocular tumors rely heavily on the ophthalmologist. However, knowledge of melanocytic lesions will aid the dermatologist in detection and in proper referral of these patients.

[Mechanisms involved in the antiarrhythmic and proarrhythmic effects of magnesium]. / Mecanismos involucrados en el efecto antiarrítmico y proarrítmico del magnesio.

This paper reports an electrophysiological study on the antiarrhythmic and proarrhythmic actions of magnesium chloride and magnesium sulphate intravenous infusions. Magnesium kinetics in control dogs, following a pulse of magnesium chloride or magnesium sulphate, was not affected by the accompanying anion. The experiments were performed with mongrel dogs divided into three groups fed either a normal diet (group I), a low magnesium diet plus chlortalidone treatment and potassium supplementation (group IIA) or a low magnesium diet plus chlortalidone treatment and magnesium sulphate infusion (group II B). In group I, infusion of magnesium sulphate solution decreased plasma sodium, potassium and ventricular fibrillation threshold (VFT), prolonged the ventricular effective refractory period (VERP) and increased the urinary excretion of potassium. The infusion of magnesium chloride solution did not affect VFT, prolonged VERP, QTc, AH and PQ. In this group, sodium chloride or sulphate infusion did not affect the electrophysiological variables but sodium sulphate decreased plasma potassium levels. The group II A was characterized by the decreased levels of potassium and magnesium contents of plasma, lymphocytes and myocardium, decreased VERP and VFT and prolonged QTc. The intravenous infusion of magnesium sulphate solution depressed further VFT and plasma potassium and increased VERP. The acute infusion of potassium chloride solution increased plasma potassium and VFT. In group II B, plasma electrolyte levels and electrophysiological variables were not affected. We conclude that the clinically demonstrable, antiarrhythmic effect of magnesium infusion can be attributed to prolonged VERP. Magnesium sulphate infusion, however, produced potassium depletion and decreased VFT (a pro-arrhythmic effect). These adverse effects can be avoided infusing magnesium chloride solutions.

Clinical usefulness of ambulatory blood pressure monitoring.

During the last decade, ambulatory blood pressure monitoring (ABPM) made a transition from a method reserved for clinical investigators to a technique considered useful by practicing physicians in assessing certain problems in hypertension. Recent recommendations of the National High Blood Pressure Education Program (NHBPEP) Working Group on Ambulatory Blood Pressure Monitoring suggested using ABPM for a number of clinical problems, including borderline hypertension without target organ damage, evaluation of drug resistance, and white-coat hypertension. We evaluated the clinical indications for ordering ABPM by Connecticut physicians both in hospital and community-based practices. Through specific questionnaires, the clinical indications used by referring physicians to order ABPM and their inclinations for future use of the methodology were assessed. Forty-seven of 70 physicians (65%) responded to the questionnaire, basing their answers on 237 patients. The majority of physicians were internists (57%) or cardiologists (25%). Leading indications for patient referral for ABPM included borderline hypertension (27%), assessment of drug therapy/BP control (25%), and possible white-coat hypertension (22%). Far fewer referrals were observed for severe hypertension or as a routine test for the diagnosis of hypertension. These data suggest that practicing physicians have become aware of the usefulness of ambulatory blood pressure recordings and are following the NHBPEP guidelines on referral for the study.

Management of hypertension after ambulatory blood pressure monitoring.

OBJECTIVE: To study the test-ordering behavior of practicing physicians regarding ambulatory monitoring of blood pressure and to assess changes in patient management after this study. DESIGN: Cross-sectional assessment of physicians' practice habits regarding the ordering of ambulatory blood pressure monitoring and a longitudinal study of patient management after monitoring. SETTING: Physicians' offices in central Connecticut. PARTICIPANTS: Two hundred thirty-seven consecutive patients referred by 65 community- and hospital-based physicians. MEASUREMENTS: Indications for ambulatory blood pressure monitoring, changes in diagnosis and therapy, and office blood pressures before and after the ambulatory blood pressure study. RESULTS: The main indications for ordering the test included borderline hypertension (27% of studies ordered), assessment of blood pressure control during drug therapy (25%), evaluation for "white coat" or "office" hypertension (22%), and drug-resistant hypertension (16%). After the ambulatory blood pressure study, only 13% of the patients had further testing (for example, echocardiography); the diagnosis was changed in 41% of the patients, and antihypertensive therapy was changed in 46%. In 122 patients for whom data were complete, office blood pressure measured by the referring physician decreased from 161/96 +/- 22/12 mm Hg before the ambulatory blood pressure study to 151/86 +/- 27/12 mm Hg 3 months after the study (P = 0.004 for systolic blood pressure and P < 0.001 for diastolic blood pressure). One to 2 years after the study, office blood pressure was 149/86 +/- 24/12 mm Hg (P > 0.2 compared with 3 months after the study). Seventy-two percent of the patients had a lower office blood pressure within 3 months of the ambulatory blood pressure study. CONCLUSIONS: Practicing physicians use ambulatory blood pressure recordings for appropriate indications, and data from the monitoring studies affected the management of patients with hypertension.

[Effect of chlorpromazine on the graft versus host reaction]. / Effecto de la cloropromacina sobre la reacción injerto contra huesped.

The effect of chlorpromazine (CLZ) on the graft vs. host reaction (G.vs.H.r.) induced by the injection of parental immunocompetent cells to F1 hybrids was studied. Rats of one parental strain were immunized with 3 X 10(7) splenic nucleated cells from the other parental strain. The injection of 3 X 10(6) and 6 X 10(6) nucleated cells obtained from the spleen of these previously immunized rats to 21-day-old F1 hybrids induced a typical G.vs.H.r. The degree of the G.vs. H.r. was estimated 10 days after the injection of the parental cells by the splenic index (S.I.) and histological studies of the spleen. The administration of CLZ (30 mg/kg/day i.p. during 10 days) either to the donor or to the host inhibited the G. vs.H.r. The effect of CLZ was partially antagonized by the simultaneous administration of Bromocriptine (10 mg/kg/day i.p.) to F1 hybrids. An effect similar, although quantitatively smaller to that of CLZ was caused by the injection of Prolactin (Pro) 100 I.U./kg/day, i.p. to F1 hybrids. None of these drugs modified neither the lymphatic structure nor the S.I. of hybrids not inoculated with lymphoid cells. The rectification of the functions number of injected cells vs. S.I. allowed us to apply the statistical method of covariance to the different treatments used and to establish the degree of significance of the modifications produced by the drugs. In contrast to the profound inhibition of the G.vs.H.r. obtained when CLZ was administered to previously immunized donors, the effect of this drug was minor if the treatment was performed in nonimmunized donors. Splenic cells obtained from rats previously immunized with the other parental strain were incubated in vitro during two hours with different concentrations of CLZ (10(-6), 10(-5) and 10(-4) M) or Pro (15,30,50,75,100,200 and 500 ng/ml). This treatment did not modify the capacity of these cells to induce G.vs.H.r. when injected into F1 hybrids. We postulate that the inhibitory action of CLZ on the G.vs.H.reaction is mediated, at least in part, by the capacity of this drug to increase the plasmatic levels of PRO. The effect of CLZ and PRO is observed mainly in lymphoid clones in expansion because of the stimulation by histocompatibility antigens.

Effecto de la cloropromacina sobre la reacción injerto contra huesped. / [Effect of chlorpromazine on the graft versus host reaction]

The effect of chlorpromazine (CLZ) on the graft vs. host reaction (G.vs.H.r.) induced by the injection of parental immunocompetent cells to F1 hybrids was studied. Rats of one parental strain were immunized with 3 X 10(7) splenic nucleated cells from the other parental strain. The injection of 3 X 10(6) and 6 X 10(6) nucleated cells obtained from the spleen of these previously immunized rats to 21-day-old F1 hybrids induced a typical G.vs.H.r. The degree of the G.vs. H.r. was estimated 10 days after the injection of the parental cells by the splenic index (S.I.) and histological studies of the spleen. The administration of CLZ (30 mg/kg/day i.p. during 10 days) either to the donor or to the host inhibited the G. vs.H.r. The effect of CLZ was partially antagonized by the simultaneous administration of Bromocriptine (10 mg/kg/day i.p.) to F1 hybrids. An effect similar, although quantitatively smaller to that of CLZ was caused by the injection of Prolactin (Pro) 100 I.U./kg/day, i.p. to F1 hybrids. None of these drugs modified neither the lymphatic structure nor the S.I. of hybrids not inoculated with lymphoid cells. The rectification of the functions number of injected cells vs. S.I. allowed us to apply the statistical method of covariance to the different treatments used and to establish the degree of significance of the modifications produced by the drugs. In contrast to the profound inhibition of the G.vs.H.r. obtained when CLZ was administered to previously immunized donors, the effect of this drug was minor if the treatment was performed in nonimmunized donors. Splenic cells obtained from rats previously immunized with the other parental strain were incubated in vitro during two hours with different concentrations of CLZ (10(-6), 10(-5) and 10(-4) M) or Pro (15,30,50,75,100,200 and 500 ng/ml). This treatment did not modify the capacity of these cells to induce G.vs.H.r. when injected into F1 hybrids. We postulate that the inhibitory action of CLZ on the G.vs.H.reaction is mediated, at least in part, by the capacity of this drug to increase the plasmatic levels of PRO. The effect of CLZ and PRO is observed mainly in lymphoid clones in expansion because of the stimulation by histocompatibility antigens.