Comparing clinical trial population representativeness to real-world users of 17 biologics approved for immune-mediated inflammatory diseases: An external validity analysis of 66,639 biologic users from the Italian VALORE project.

To date, no population-based studies have specifically explored the external validity of pivotal randomized clinical trials (RCTs) of biologics simultaneously for a broad spectrum of immuno-mediated inflammatory diseases (IMIDs). The aims of this study were, firstly, to compare the patients' characteristics and median treatment duration of biologics approved for IMIDs between RCTs' and real-world setting (RW); secondly, to assess the extent of biologic users treated for IMIDs in the real-world setting that would not have been eligible for inclusion into pivotal RCT for each indication of use. Using the Italian VALORE distributed database (66,639 incident biologic users), adult patients with IMIDs treated with biologics in the Italian real-world setting were substantially older (mean age ± SD: 50 ± 15 years) compared to those enrolled in pivotal RCTs (45 ± 15 years). In the real-world setting, certolizumab pegol was more commonly used by adult women with psoriasis/ankylosing spondylitis (F/M ratio: 1.8-1.9) compared to RCTs (F/M ratio: 0.5-0.6). The median treatment duration (weeks) of incident biologic users in RW was significantly higher than the duration of pivotal RCTs in almost all indications for use and most biologics (4-100 vs. 6-167). Furthermore, almost half (46.4%) of biologic users from RW settings would have been ineligible for inclusion in the respective indication-specific pivotal RCTs. The main reasons were: advanced age, recent history of cancer and presence of other concomitant IMIDs. These findings suggest that post-marketing surveillance of biologics should be prioritized for those patients.

Large-Scale Postmarketing Surveillance of Biological Drugs for Immune-Mediated Inflammatory Diseases Through an Italian Distributed Multi-Database Healthcare Network: The VALORE Project.

BACKGROUND: Biological drugs have improved the management of immune-mediated inflammatory diseases (IMIDs) despite being associated with important safety issues such as immunogenicity, infections, and malignancies in real-world settings. OBJECTIVE: The aim of this study was to explore the potential of a large Italian multi-database distributed network for use in the postmarketing surveillance of biological drugs, including biosimilars, in patients with IMID. METHODS: A retrospective cohort study was conducted using 13 Italian regional claims databases during 2010-2019. A tailor-made R-based tool developed for distributed analysis of claims data using a study-specific common data model was customized for this study. We measured the yearly prevalence of biological drug users and the frequency of switches between originator and biosimilars for infliximab, etanercept, and adalimumab separately and stratified them by calendar year and region. We then calculated the cumulative number of users and person-years (PYs) of exposure to individual biological drugs approved for IMIDs. For a number of safety outcomes (e.g., severe acute respiratory syndrome coronavirus 2 [SARS-COV-2] infection), we conducted a sample power calculation to estimate the PYs of exposure required to investigate their association with individual biological drugs approved for IMIDs, considering different strengths of association. RESULTS: From a total underlying population of almost 50 million inhabitants from 13 Italian regions, we identified 143,602 (0.3%) biological drug users, with a cumulative exposure of 507,745 PYs during the entire follow-up. The mean age ± standard deviation of biological drug users was 49.3 ± 16.3, with a female-to-male ratio of 1.2. The age-adjusted yearly prevalence of biological drug users increased threefold from 0.7 per 1000 in 2010 to 2.1 per 1000 in 2019. Overall, we identified 40,996 users of biosimilars of tumor necrosis factor (TNF)-α inhibitors (i.e., etanercept, adalimumab, and infliximab) in the years 2015-2019. Of these, 46% (N = 18,845) switched at any time between originator and biosimilars or vice versa. To investigate a moderate association (incidence rate ratio 2) between biological drugs approved for IMIDs and safety events of interest, such as optic neuritis (lowest background incidence rate 10.4/100,000 PYs) or severe infection (highest background incidence rate 4312/100,000 PYs), a total of 43,311 PYs and 104 PYs of exposure to individual biological drugs, respectively, would be required. As such, using this network, of 15 individual biological drugs approved for IMIDs, the association with those adverse events could be investigated for four (27%) and 14 (93%), respectively. CONCLUSION: The VALORE project multi-database network has access to data on more than 140,000 biological drug users (and > 0.5 million PYs) from 13 Italian regions during the years 2010-2019, which will be further expanded with the inclusion of data from other regions and more recent calendar years. Overall, the cumulated amount of person-time of exposure to biological drugs approved for IMIDs provides enough statistical power to investigate weak/moderate associations of almost all individual compounds and the most relevant safety outcomes. Moreover, this network may offer the opportunity to investigate the interchangeability of originator and biosimilars of several TNFα inhibitors in different therapeutic areas in real-world settings.

Relationships between sociocultural factors (gender, immigrant and socioeconomic background), peer relatedness and positive affect in adolescents.

INTRODUCTION: During adolescence, experiencing positive emotions at school is important for motivation as well as for academic success and psychological well-being. In the present study, on the basis of Self-Determination Theory (SDT), we investigated the relationships between sociocultural factors (gender, immigrant and socioeconomic background), peer relatedness (acceptance and friendship) and positive affect at school. METHODS: Data was based on a random sample of 36,712 tenth grade Italian adolescents. Their average age was 15.6 years (SD = 0.77), 50.6% were males, while 6.1% were first-generation immigrants and 3.8% were second-generation immigrants. Firstly, comparing latent means, we established peer relatedness and positive affect profiles of adolescents with different sociocultural backgrounds. Subsequently, we tested a structural equation model, based on SDT, according to which the effects of sociocultural factors on experiencing positive affect at school are mediated by peer relatedness dimensions. RESULTS: Latent mean comparisons showed that immigrant adolescents, students with a lower-SES and girls had fewer friendships with their classmates, lower levels of positive affect at school and were less accepted by their peers. A well-fitting structural equation model corroborated the mediating role of acceptance and friendship, which accounted for 16% of variance in positive affect. CONCLUSIONS: Due to sociocultural factors, some groups of adolescents proved to be more at risk of being socially excluded and of experiencing less positive affect at school. Moreover, our findings support the claim of SDT that the satisfaction of basic psychological needs, such as relatedness, is more important than sociocultural factors in determining adolescents' psychological well-being.

The Effectiveness of a New School-Based Media Literacy Intervention on Adolescents' Doping Attitudes and Supplements Use.

The aim of the study was to evaluate the effectiveness of a media literacy intervention targeting, for the first time, the specific topic of Performance and Appearance Enhancing Substances (PAESs) use in high-school students. Overall, 389 students (52% male) aged between 13 and 19 years (mean = 16.56 year; SD = 1.26) participated to a media literacy intervention (i.e., "intervention group") while 103 students aged between 14 and 19 year (mean = 16.10 year; SD = 1.38) were considered as the control group (i.e., "control group"). In two separate occasions over the course of six consecutive months, students in both groups filled out a set of questionnaires which included measures of social-cognitive beliefs (i.e., attitudes, subjective norms, intentions) and a self-reported measure of retrospective use of doping (Yes/No) and supplements (Yes/No). Compared to students in the control group (Mean(time1) = 1.96; SD(time1) = 0.85; and Mean(time2) = 2.09; SD(time2) = 0.94), intervention students on average expressed relatively stronger attitudes against doping use over time (Mean(time1) = 2.2; SD(time1) = 0.85; and Mean(time2) = 2.05; SD(time2) = 0.82). Students in the latter group also showed a statistically significant decrease in self-reported supplement use (Use(time1) = 6.7%; Use(time2) = 3.8%; p = 0.05, McNemar Test). Interestingly, albeit marginally significant, students in the control group showed a relative increment in the self-reported use of supplements over time (Use(time1) = 4.9%; Use(time2) = 8.7%; p = 0.22, McNemar Test). Overall, the media literacy intervention investigated in the present study was effective in decreasing adolescent student's positive attitudes toward doping use and in reducing the use of legal PAES. These findings supported the generalizability and the usefulness of a media literacy approach in the specific field of PAES.

(Mal)Adaptive Psychological Functioning of Students Utilizing University Counseling Services.

Background: University students confront psychological difficulties that can negatively influence their academic performance. The present study aimed to assess several areas of adaptive and maladaptive psychological functioning among university students who request counseling services. Method: One hundred eighty-four young female students seeking professional psychological help (Counseling seekers) and 185 young female students who have never asked for psychological help (Non-counseling seekers) were asked to complete the Adult Self-Report (ASR) to evaluate both their internalizing and externalizing problems through DSM-oriented scales as well as their adaptive functioning. Results: ANOVA results indicated worse psychological functioning for the students who sought counseling. They reported lower score in ASR Adaptive Functioning Scales (i.e., friends, jobs, family, education), and higher scores in DSM-oriented scales (i.e., Depressive, Anxiety, Somatic, Avoidant Personality, Attention Deficit/Hyperactivity symptoms) than the students who never asked psychological help. Furthermore, discriminant analysis successfully discriminated between the two groups of students on the basis of the ASR's adaptive and DSM-oriented scales. Conclusion: The study findings could be useful to guide university counseling services in their screening activities as well as useful for clinical practice.

Sleep habits, circadian preference, and school performance in early adolescents.

OBJECTIVE: This study aimed to cast light on the relationships between sleep habits, perceived sleep problems and school performance in Evening-type (E-type) compared with Morning-type (M-type) early adolescents. METHODS: Comparison of questionnaire data of E-type and M-type adolescents random-selected from a large sample of eight-grade adolescents who took part in a national survey of competence in mathematics and science. RESULTS: The proportions of sleep problems that were observed to occur more than once per week and the frequency of struggling to fall asleep and/or falling asleep in distinct everyday situations were much higher in E-type than in M-type adolescents. Moreover, E-type adolescents showed more disturbed and poorer sleep during both school and weekend days and reported lower grades in mathematics, science and Italian. CONCLUSIONS: E-type adolescents showed a partial recovery of sleep debt during weekend days. This finding suggests that they could improve their school performance if tests and classwork would be scheduled on their most alert school days, namely the post-weekend ones.

[Budget impact analysis of efavirenz daily dose reduction at the Verona University Hospital]. / La riduzione del dosaggio giornaliero di efavirenz nella terapia antiretrovirale: impatto sul budget nell'Azienda Ospedaliera Universitaria Integrata di Verona.

Efavirenz is a non-nucleoside-reverse-transcriptase-inhibitor used as part of highly-active-antiretroviral-therapy for the treatment of the human immunodeficiency virus (HIV) type 1 infection. The present paper aims to describing the impact of efavirenz dose reduction on the pharmaceutical budget at the Verona University Hospital. A budget impact analysis comparing two prescribing scenarios was conducted: all patients treated with the efavirenz full dose (600 mg per day) vs. a proportion of patients treated with a reduced dose (200-400 mg per day). All outpatients referring to the Infectious Disease Clinic in the period November 2009-October 2011 were selected. Out of 132 patients treated with efavirenz, 25 were not considered, mainly due to a too short treatment period. Of the remaining 107 patients, 68 received the full dose, while 39 received a reduced dosage. The analysis included the cost of the drug and of diagnostic tests, from the National Health Service perspective. The daily dose reduction of efavirenz saved 54,664 euros (a 30% expenditure reduction). In sum, new strategies for pharmaceutical system sustainability are necessary; despite forthcoming expiring patents of several drugs, spending on antiretroviral drugs is expected to rise. This paper suggests a way of linking clinical benefits and cost reduction.

Pulse pressure and mortality from cerebrovascular diseases in type 2 diabetic patients: the Verona Diabetes Study.

BACKGROUND/OBJECTIVE: Previous studies conducted both in the general and diabetic population have shown that pulse pressure (PP) can predict mortality from cardiovascular diseases. The aim of the present study was to investigate the relationship between PP and specific cardiovascular mortality, i.e. from cerebrovascular and ischemic heart diseases, in a well-characterized cohort of type 2 diabetic patients. METHODS: A cohort of 1,128 known type 2 diabetic patients 56 to 74 years of age with at least 2 blood pressure measurements for each year between 1984-1986 was followed-up for ten years to assess specific causes of death. The analyses were carried out by using the mean and the coefficient of variation (CV) of PP. RESULTS: By the end of the 10-year follow-up period, 375 patients (178 male, 197 female) had died (33%). The mean PP resulted as an independent predictor of all causes and cardiovascular mortality. Remarkably, the mean PP, but not the CV of PP, was highly predictive of mortality from cerebrovascular diseases. The risk of cerebrovascular mortality rose by 86% with a 10 mm Hg increase in mean PP. PP turned out to be the most important predictor of cerebrovascular mortality among various pressure indexes (mean, systolic and diastolic pressure). CONCLUSION: The mean pulse pressure, but not the coefficient of variation is a strong predictor of cardiovascular mortality, mainly from cerebrovascular diseases, in type 2 diabetic patients.