[Codes, guidelines and guidance of ethics of research: the issue of quality]. / Codici, linee guida e commentari di etica della ricerca: la questione della qualità

After an overview of the evolution of ethics laws for medical activities, we suggest a possible classification of documents regarding the ethical conduct of scientific research with human beings. The authors outline the necessity to define formal criteria for the development and the implementation of ethics standards.

A post-trial survey to assess the impact of dissemination of results and unmasking on participants in a 13-year randomised controlled trial on age-related cataract.

BACKGROUND: The Italian-American Clinical Trial of Nutritional Supplements and Age-Related Cataract was designed to assess the impact of a multivitamin-mineral supplement on age-related cataract. Trial results showed evidence of a beneficial effect of the supplement on all types of cataract combined, opposite effects on two of the three types of cataract (beneficial for nuclear opacities and harmful for posterior sub-capsular opacities) and no statistically significant effect on cortical opacities. No treatment recommendations were made. A post-trial survey was conducted on 817 surviving elderly participants to assess their satisfaction, their understanding of treatment assignment to supplement or placebo and the success of masking. METHODS: Trial results were communicated by letter and the level of satisfaction and of understanding of the results was assessed by a questionnaire. Participants were offered the option of being unmasked: a second questionnaire was administered to this subset to assess their understanding of the randomisation process and the success of masking. RESULTS: 610 participants (74.7%) responded to the survey:94.6% thought the description of the results was "very clear" or "quite clear", 5.4% "not clear" or "do not know"; 89.8% considered the results "very interesting" or "quite interesting", 10.2% "not interesting" or "do not know"; 60.3% expressed "satisfaction", 17.2% "both satisfaction and concern", 2.6% "concern", 19.9% "indifference" or "do not know".480 participants (78.7%) accepted the offer to be unmasked to their treatment assignment: 395 (82.3%) recalled/understood the possibility of assignment to vitamins or placebo, 85 (17.7%) did not. 68 participants (17.2%) thought they had taken vitamins (79.4% were correct; p = 0.0006), 47 (11.9%) thought they had taken placebo (59.6% were correct; p = 0.46) and 280 (70.9%) declared they did not know. CONCLUSIONS: The results were made difficult to explain to study participants by the qualitatively different effect of treatment on the two most visually significant types of cataract. Although the study did not lead to a recommendation to use the dietary supplement, the vast majority of participants reported satisfaction after they received the results but almost 20% of the participants expressed some concern. Masking to treatment assignment was successful in the majority of participants.

Body mass index, cardiovascular risk factors, and carotid intima-media thickness in a pediatric population in southern Italy.

OBJECTIVES: Obesity and exposure to cardiovascular risk factors during adolescence may be associated with the development of atherosclerosis and cardiovascular diseases later in life. The objective of the study was to investigate whether any excess body weight, including moderate overweight, is associated with a more severe cardiovascular risk profile and signs of early atherosclerosis in a pediatric population. PATIENTS AND METHODS: A cross-sectional study was conducted among 646 adolescents ages 11 to 13 years from several primary schools of Reggio Calabria, Italy. Body mass index, waist circumference, blood pressure, glucose, insulin, homeostatic model assessment of insulin resistance, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and C-reactive protein (CRP) were determined. All of the subjects underwent carotid ultrasonography for the measurement of intima-media thickness. Complete clinical data were available from 575 subjects. RESULTS: Overweight was similarly frequent in boys and girls (31.2% vs 31.0%), whereas prevalence of obesity was higher in boys (18.4% vs 10.1%). Subjects with lower levels of HDL and higher levels of triglycerides, insulin, and CRP plasma were observed more frequently among overweight and obese subjects than nonoverweight. At multivariate analysis, HDL cholesterol, insulin, and CRP were associated (P < 0.05) with overweight and obesity in girls, whereas in boys, insulin and CRP were associated (P < 0.05) with overweight and obesity, and LDL cholesterol with obesity. The association between overweight or obesity and increased intima-media thickness, a sign of early atherosclerosis, was present in girls (P < 0.05) and was close to statistical significance in obese boys (P = 0.07). CONCLUSIONS: Overweight and obese adolescents have a higher prevalence of cardiovascular risk factors and show signs of early atherosclerosis. In girls, in particular, overweight is sufficient to determine a more severe cardiovascular risk profile.

Cardiovascular risk factors, nonalcoholic fatty liver disease, and carotid artery intima-media thickness in an adolescent population in southern Italy.

The objective of this study was to determine, in an adolescent population, the prevalence of nonalcoholic fatty liver disease (NAFLD) and the association of NAFLD and cardiovascular risk factors with carotid artery intima-media thickness (IMT), a marker of subclinical atherosclerosis. The authors conducted a population-based study among 642 randomly selected adolescents aged 11-13 years in Reggio Calabria, southern Italy, between November 2007 and October 2008. Prevalences of overweight and obesity were 30.5% and 13.5%, respectively. The overall prevalence of NAFLD was 12.5%, increasing to 23.0% in overweight/obese adolescents. In univariate analysis, increased IMT was positively associated with the presence of NAFLD, body mass index (BMI), waist circumference, systolic blood pressure (all P's < 0.001), diastolic blood pressure (P = 0.006), gamma-glutamyl transpeptidase (P = 0.006), alanine aminotransferase (P = 0.007), and C-reactive protein (P = 0.008) and was inversely associated with high density lipoprotein cholesterol (P < 0.001). In multivariate analysis, NAFLD (P = 0.002), BMI (P = 0.004), waist circumference (P = 0.003), and systolic blood pressure (P = 0.005) retained significant associations. The authors conclude that NAFLD, BMI, waist circumference, and systolic blood pressure are independent markers of increased IMT in a random sample of adolescents.

Effects of multivitamin/mineral supplementation on plasma levels of nutrients. Report No. 4 of the Italian-American clinical trial of nutritional supplements and age-related cataract.

The use of multivitamin-mineral supplements has become increasingly common, but whether the use of such supplements improves micronutrient status remains still unclear. The objective of this report is to investigate how a long-term vitamin-mineral supplementation following the US Recommended Daily Intake (RDI) affected the plasma levels of selected nutrients in a subset (No. = 407) of participants in the Italian-American Clinical Trial of Nutritional Supplements and Age-related Cataract (CTNS). The CTNS was a double-blind, single centre, controlled clinical trial of 1020 participants aged 55-75 years randomized to a daily tablet of Centrum(R) or placebo. A representative sample of 40% of the 1020 subjects, whom plasma level of selected vitamins was determined at the baseline, was retested throughout the treatment period that averaged 9.0 +/- 2.4 years. Participants assigned to Centrum(R) showed a significant increase (p < 0.005) in mean/median plasma levels of vitamin E, beta-carotene, folate, and vitamin B12, and an improved riboflavin status when compared with participants assigned to placebo. Differences concerning vitamin C were statistically less relevant and those concerning vitamin A were at a borderline level. In the treated group the effect of supplementation on plasma levels of vitamins A, E, and C, and on the glutathione reductase activation coefficient was significantly higher in participants with lower nutritional status at baseline.

A randomized, double-masked, placebo-controlled clinical trial of multivitamin supplementation for age-related lens opacities. Clinical trial of nutritional supplements and age-related cataract report no. 3.

OBJECTIVE: To evaluate the effect of a multivitamin/mineral supplement on development or progression of age-related lens opacities. DESIGN: Randomized, double-masked, single center, placebo-controlled clinical trial. PARTICIPANTS: One thousand twenty participants, 55 to 75 years old and with early or no cataract, were randomly assigned to a daily tablet of a multivitamin/mineral formulation or a placebo. METHODS: Baseline and annual lens photographs were graded for severity of lens opacities according to a modification of the Age-Related Eye Disease Study system for classifying cataracts. MAIN OUTCOME MEASURES: The primary outcome was a prespecified increase from baseline in nuclear, cortical, or posterior subcapsular cataract (PSC) opacity grades or cataract surgery. Secondary outcomes included an increase in type-specific opacity grades, cataract surgery, and visual acuity (VA) loss from baseline > or =15 letters. RESULTS: Participants were observed for an average of 9.0+/-2.4 years. There was a decrease in total lens events in participants assigned to the multivitamin/mineral formulation compared with those assigned to the placebo (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.68-0.98; P = 0.03). Nuclear events were significantly less common (HR, 0.66; 95% CI, 0.50-0.88; P = 0.004) and PSC events significantly more common (HR, 2.00; 95% CI, 1.35-2.98; P<0.001) in participants taking the multivitamin/mineral formulation than in those assigned to the placebo. No statistically significant treatment effects were seen for cortical opacities, moderate VA loss, or cataract surgery. CONCLUSIONS: Lens events were less common in participants who took the multivitamin/mineral formulation, but treatment had opposite effects on the development or progression of nuclear and PSC opacities, the 2 most visually important opacity subtypes.

Scientific research on human subjects and ethics procedures at the Istituto Superiore di Sanità: a survey of the articles issued in 2001.

Principles promoting the protection of subjects involved in biomedical research are interpreted differently within the scientific community. The purpose of this paper is to describe the attitudes of researchers working at the Istituto Superiore di Sanità (ISS) regarding the ethical implications of studies involving human beings, with particular emphasis on aspects concerning informed consent (IC) and ethics committee (EC) review. In 2001, ISS researchers published a total of 733 articles, 93 (12.7%) of which were studies involving human beings. Nearly 2/3 (60/93) were epidemiological, while the remaining 35.5% were based on laboratory data. Half (47/93) reported physical or psychological interventions or treatments on study subjects. 40.9% of articles mentioned that informed consent had been obtained and only 12.9% that approval had been given by an ethics committee. The low proportion of articles on which a protocol had been submitted the EC was due in part to the type of studies, but also to the absence of an institutional EC prior to 2001. Ethical procedures were more present in laboratory than in epidemiologic studies (IC: 69.7% vs 25.0%, p < 0.001) (EC: 27.3% vs 5.0% p = 0.004). Those differences were more likely due to the less interventionist nature of the epidemiologic studies rather than in poor ethical awareness on the part of epidemiologists. Further efforts are needed to develop and enforce clear institutional policies regarding ethical procedures.

[Obtaining informed consent and resorting to ethical committee in clinical and epidemiological research in Italy. A survey]. / Indagine sull'ottenimento del consenso informato e sul ricorso al comitato etico nella ricerca clinica ed epidemiologica in Italia.

OBJECTIVES: To describe how informed consent (CIn) and ethical review (CEt) are obtained in the Italian clinical and health research. DESIGN: survey SETTING: 6 Italian and 7 foreigner journals in the years 2001 and 2002. SAMPLE: 157 original or short articles, letters and case reports for which a member of an Italian institution was the corresponding author. MAIN OUTCOME: Mention in the text of CIn and CEt procedures. RESULTS: In 42% of such studies (95% CI: 35-50%), informed consent was obtained; in 30% (95% CI: 23-37%), ethical committee approval was obtained, in 27% (95% CI: 21-35%) both had been obtained. The probability of informed consent and ethical review varied with type of data used (primary or secondary source). No significant differences, however, were noted based on the type of study population (vulnerable or non-vulnerable), the year, or the country in which the article was published (Italy or elsewhere). Keywords search in the articles text showed that ethical aspects of the study were not debated. Ethical procedures were synthetically reported as a rule, yet there were differences in their formulation. CONCLUSIONS: The limited resorting to CIn and CEt procedures and the concision and variability of their description might depend on the plethora of the ethical, legal, editorial guidelines available for Italian researchers that partially overlap and partially present specific aspects whose interpretation is not free of niceties.

[Consulting an ethics committee, when is it necessary? Two examples]. / Ricorso al comitato etico, quando è necessario? Due esempi.

We described the indications of laws and the commitment of researchers on the decision to submit two projects regarding observational studies to the ethics committee. Out of the two studies, the first one shows problems on data confidentiality and privacy, while the other one entails a risk, even though minimum, of physical damage for the study subjects. In Italy, the laws foreseeing the submission of research projects to the ethical committee are the Code for Personal Data Protection (Dlgs 196/2003), and the Good Clinical Practice regulations for the protection of research subjects (DM 15 luglio 1997); other provisions tied to such basic laws are also mentioned in the article. The laws on the protection of personal data tend to simplify prescriptions when the research relates to public health issues; the laws on the protection of the research subject do not almost totally pertain observational studies. We concluded that the researchers are free to submit or not both projects to the ethics committee. We underlined that the sensitivity of researchers on the endorsement of the same ethical principles can be different. We would think convenient also for epidemiological research, as well for clinic research, to establish an uniform approach. The recent issuing of the Additional Protocol on biomedical research to the Oviedo Convention may provide an opportunity.

[Italian regulation on the protection of human subjects participating to clinical studies, from the Nineties to 2004]. / La normativa sulla protezione dei soggetti partecipanti a studi clinici in Italia: dagli anni Novanta al 2004.

In chronological order, and in the light of bioethics principles, the authors describe the Italian regulation which concerns the protection of human subjects participating in clinical trials from 1990 to July 2004, the related institution of Ethical Committees and the adoption of the tool of the informed consent. The publication includes the ties that have connected the Italian regulations to the European one since the beginning. During such period, the reception of the Good Clinical Practice guidelines - which occurred in 1992 first, and finally in 1997 - has led to the establishment and the fostering of such important institutions as well as to the shaping of a network of Ethical Committees working on clinical trials and coordinated at a central level. In this paper the authors examine in particular: clinical trials of medicinal products, of medical devices and of ionizing radiations. Some implications of ethics are also discussed.

[The informed consent procedure in epidemiological research]. / Procedure di consenso informato nella ricerca epidemiologica.

After a brief introduction on the beginning and subsequent developments of informed consent (IC), this paper analyses its ethical, legal, medical and scientific implications and its specific applications to epidemiological research. The aim is to highlight how IC principles should be fulfilled through different procedures responding to the ethical and scientific requirements of epidemiological research. At least two improper applications, in fact, can deprive IC of its meaning: referring to ethical principles without discernment, or following IC guidelines without critical evaluation. Attempts to improve IC procedures adapting them to specific needs and scientific developments should be evaluated carefully and without preconceptions.

[Disease prevention and health promotion. Distinct and complementary strategies]. / Prevenzione della malattia e promozione della salute. Strategie distinte e complementari.

Health maintenance entails interventions beyond the biomedical knowledge, regarding: economic matters, education levels, improvement of work conditions, nutrition, housing, and environment; that is to say, overall well-being. According to the World Health Organization, well-being is not a health determinant but is included in the health definition. This is good from a social point of view and consistent with some economic findings, but can be misleading. The two aspects identifiable in the definition are: disease prevention and health promotion, which operate at different levels. The first one is conditioned by the sciences' reductionistic methodology and its strategies can be economically appraised; the other one is holistic and the economic and scientific evaluation of its actions is difficult. Moreover, both offer solutions to different questions of public health ethic. Thus, both are necessary and synergetic.

[Points of view in comparison on the 5ht revision of the Declaration of Helsinki]. / Punti di vista a confronto per la V revisione della Dichiarazione di Helsinki.

The horror for the scientific crimes of the nazi period led the World Medical Association (WMA), in 1964, to settle by the Helsinki declaration, an ethical code for the medical research on human beings. The code was successively modified in order to account for the developments of the medical science in the past decades. In October 2000, the last revision, the 5th one, has been approved in Edinburgh. Its preparation lasted three years and entailed a passionate, but also profitable dispute between who believes that ethical principles must be followed even though they can hamper the scientific progress, and who thinks that more articulate evaluations should prevail. The initial victory of the more intransigent party resulted in the maintenance of the norm which entails the greatest restriction in using placebo, but, after one year and half, it was partially reshaped by a more permissive interpretation of the same WMA, while waiting for a new revision that is scheduled for this year.

Hay fever and asthma in relation to markers of infection in the United States.

BACKGROUND: The hygiene hypothesis proposes that declining exposure to infections is implicated in the rising trend of allergy and asthma. OBJECTIVE: We sought to test this hypothesis by examining the relationship of hay fever, asthma, and atopic sensitization with markers of infection in a large general population sample of the United States. METHODS: We analyzed the data of 33,994 US residents recorded in a public database of a nationally representative cross-sectional survey (Third National Health and Nutrition Examination Survey, 1988-1994). The variables examined were sociodemographic information, lifetime diagnosis and age at first diagnosis of hay fever or asthma, current skin sensitization to 9 airborne allergens and peanut, and current serology for Toxoplasma gondii, herpes simplex viruses type 1 and 2, and hepatitis A, B, and C viruses. RESULTS: Hay fever (adjusted odds ratio, 0.27; 95% CI, 0.18-0.41; P <.001) and asthma (adjusted odds ratio, 0.45; 95% CI, 0.31-0.66; P <.001) were less frequent in subjects seropositive for hepatitis A virus (HAV), T gondii, and herpes simplex virus 1 versus seronegative subjects after adjusting for age, sex, race, urban residence, census region, family size, income, and education. Skin sensitization to peanut and to all the airborne allergens examined, except for cockroach, was less frequent among HAV-seropositive versus HAV-seronegative subjects younger than 40 years of age. The prevalence of hay fever and asthma diagnosed at or before 18 years of age in HAV-seronegative subjects increased progressively from 2.7% (95% CI, 0.7%-4.7%) and 0.4% (95% CI, 0.1%-1.6%), respectively, in cohorts born before 1920 to 8.5% (95% CI, 7.3%-9.7%) and 5.8% (95% CI, 4.8%-6.8%), respectively, in cohorts born in the 1960s, whereas they remained constant at around 2% in all cohorts of HAV-seropositive subjects. CONCLUSION: In the United States serologic evidence of acquisition of certain infections, mainly food-borne and orofecal infection, is associated with a lower probability of having hay fever and asthma. Third National Health and Nutrition Examination Survey data support the hypothesis that hygiene is a major factor contributing to the increase in hay fever, asthma, and atopic sensitization in westernized countries.

Baseline cataract type and 10-year mortality in the Italian-American Case-Control Study of age-related cataract.

Age-related cataract is reported to be associated with increased risk of death. The authors investigated the association of presence and type of cataract with mortality in the participants of the Italian-American Case-Control Cataract Study (Parma, Italy, 1987-1989), which included 1,008 persons aged 45-79 years who had age-related cataract and 469 who had clear lenses. Slit-lamp and retroillumination lens photographs were taken at baseline and graded with the Lens Opacities Classification System II. During 10 years of follow-up (range, 8.9-11.8 years; 11,318 person-years), the authors collected information on 1,429 participants and documented 339 deaths. After adjustment for age, sex, and other mortality risk factors, mixed cataracts with a nuclear/posterior subcapsular component were significantly associated with higher risk of death by Cox proportional hazards regression analyses. Hazard ratios were 2.26 (95% confidence interval (CI): 1.07, 4.76) for nuclear/posterior subcapsular and 1.62 (95% CI: 1.01, 2.61) for cortical/nuclear/posterior subcapsular opacities. In multivariate analysis, mixed types of opacity (any) were associated with increased mortality for malignancy (hazard ratio = 1.81, 95% CI: 1.04, 3.15) and "other" causes (hazard ratio = 2.29, 95% CI: 1.07, 4.92). These findings are compatible with the hypothesis that mixed types of cataract with a nuclear/posterior subcapsular component are indicators of accelerated aging.