The Requirements of Managing Phase I Clinical Trials Risks: The British and Italian Case Studies.

Phase I clinical trials represent a critical point in drug development because the investigational medicinal product is being tested in humans for the first time. For this reason, it is essential to evaluate and identify the Maximum Tolerated Dose (MTD) and the safety of the new compound. To mitigate the possible risks associated with drug administration and treatment, the European Competent Authority issued various guidelines to provide provisions and harmonize risk management processes. In the UK and Italy, particular attention should be paid to the Medicines & Healthcare Products Regulatory Agency (MHRA) phase I accreditation scheme and the specific rules set by the Italian Drug Authority through the AIFA Determination no. 809/2015. Both reference documents are based on the concept of quality risk management while conducting phase I clinical studies. Moreover, the AIFA determination outlines specific requirements for those sites that want to conduct non-profit phase I clinical trials. Indeed, the document reports peculiar activities to the "Clinical Trial Quality Team", which is a team that should support the clinical site researchers in designing, starting, performing, and closing non-profit phase I studies. In this paper, we provide a general overview of the main European guidelines concerning the management of risks during phase I trials, focusing on the main peculiarities of the schemes and rules set by the MHRA and AIFA.

More Children Means More Tumours? We Can Do More to Protect the Health of Our Kids-A Call for a New Epidemiology That Can Change the World.

In encyclopaedic dictionaries published until 1955, the word "tumour" was defined as an "occupational disease suffered by the workers of chemical industries", thus referring to a very specific cause [...].

Trends of Phase I Clinical Trials in the Latest Ten Years across Five European Countries.

BACKGROUND: Phase 1 clinical trials represent a critical phase of drug development because new candidate therapeutic agents are tested for the first time on humans. Therefore, international guidelines and local laws have been released to mitigate and control possible risks for human health in agreement with the declaration of Helsinki and the international Good Clinical Practice principles. Despite numerous scientific works characterizing the registered clinical trials on ClinicalTrials.gov, the main features and trends of registered phase 1 clinical trials in Europe have not been investigated. This study is aimed at assessing the features and the temporal trend of distribution of phase 1 clinical studies, carried out in the five largest European countries over a ten-year period (2012-2021), and to evaluate the impact of the Italian regulatory framework on the activation of such studies. METHODS: The main data and characteristics of phase 1 clinical studies registered on the ClinicalTrials.gov database for France, Germany, Italy, Spain and the United Kingdom have been investigated and subsequently compared. The above-mentioned countries were selected based on similarities in terms of demographic and Gross Domestic Product (GDP) data available on official government websites. (3) Results: A total number of 6878 phase 1 clinical trials were registered for the five selected countries in the ClinicalTrials.gov database during the ten years analyzed; the studies were predominantly randomized (39.33%) and for-profit (76.64%). The most represented area of investigations was oncology (52.15%), followed by hematology (24.99%) and immunology (12.04%). The variability observed between the analyzed countries showed that the UK, Germany and France presented the highest reduction in the number of phase 1 clinical trials, while for Spain and Italy, a stable/increased trend was observed, although with a lower number of trials registered on the ClinicalTrials.gov database. (4) Conclusions: Italy displayed the lowest number of registered phase 1 clinical trials, even though it showed a stable trend over the years. In this regard, the Italian regulatory framework must urgently be adapted to that of other European countries (Spain has been the first country to implement the new Regulation (EU) No 536/2014) and streamline the process of clinical trial application to increase the attractiveness of the country. Moreover, nonprofit phase 1 clinical trials (which represent 19.81% of the total number of phase 1 clinical trials registered in Italy vs. 80.19% of profit phase 1 clinical studies) should be promoted and supported by the institutions, even from a financial point of view, to allow independent researchers to develop new therapeutic drugs.

Use of official municipal demographics for the estimation of mortality in cities suffering from heavy environmental pollution: Results of the first study on all the neighborhoods of Taranto from 2011 to 2020.

BACKGROUND: In cities suffering from heavy environmental pressure or pollution, it is extremely important to rapidly access municipal demographics that can be used as indicators of population health status. Among those, mortality rates represent the most reliable data as they are officially retained and available to municipality with high level of details, thus allowing epidemiological comparison between different neighborhoods of the city across several years. Our study was aimed at validating and propose as universally applicable approach the use of municipal demographics as first-line tool to rapidly assess population health and drive health policies or urban planning in cities characterized by heavy environmental pressure. The case study of Taranto has been chosen due to the presence of the biggest European steel plant since 1960s resulting in heavy burden on environment and population health. METHODS: We have performed an ecological study on general mortality data due to all causes, specific by gender, age groups and disaggregated at sub-municipal level (highest data granularity) into neighborhoods from 2011 to 2020 by using official demographics related to all people living in Taranto available at General Registry Office of the municipality. A preliminary analysis comparing data available at Municipality and those provided by the Italian National Institute of Statistics (ISTAT) was performed and confirmed the high level of reliability of the municipal source of data. For comparative analyses, we used Regional demographics and mortality from ISTAT. Indirect age-standardized mortality ratios (SMR; CI 90% and 95%), specific for gender and neighborhoods, were calculated in reference to the city of Taranto and Apulia Region; direct age-standardized and neighborhoods mortality rates were computed on city population. RESULTS: The city of Taranto shows relevant inequalities in terms of mortality between the northern neighborhoods, closest to the industrial area (Paolo VI, Tamburi and Città Vecchia-Borgo), with excess mortality highlighted across 10 years described by SMRs always higher than those of the entire Apulia region, with peaks exceeding 50% between 2015 and 2017 both in women and men. The significant excesses of mortality have increased from 2011 to 2020 and progressively extended across several neighborhoods of Taranto city. Compared to the Apulia region, in the 3 Northern neighborhoods of the city (Paolo VI, Tamburi and Città Vecchia-Borgo) a total of 1020 excess deaths were recorded from 2011 to 2019 in both males and females (showing statistical significance), with a peak of 68% mortality excess in 2019 for men living in Paolo VI district. CONCLUSION: The use of official mortality data allows a timely, reliable and costless assessment of population health in cities heavily impacted by environmental pollution like Taranto.

Differential Glycosylation Levels in Saliva from Patients with Lung or Breast Cancer: A Preliminary Assessment for Early Diagnostic Purposes.

Glycans play a fundamental role in several biological processes, such as cell-cell adhesion, signaling, and recognition. Similarly, abnormal glycosylation is involved in many pathological processes, among which include tumor growth and progression. Several highly glycosylated proteins found in blood are currently used in clinical practice as cancer biomarkers (e.g., CA125, PSA, and CA19-9). The development of novel non-invasive diagnostic procedures would greatly simplify the screening and discovery of pathologies at an early stage, thus also allowing for simpler treatment and a higher success rate. In this observational study carried out on 68 subjects diagnosed with either breast or lung cancer and 34 healthy volunteers, we hydrolyzed the glycoproteins in saliva and quantified the obtained free sugars (fucose, mannose, galactose, glucosamine, and galactosamine) by using high-performance anion-exchange chromatography with pulsed-amperometric detection (HPAEC-PAD). The glycosidic profiles were compared by using multivariate statistical analysis, showing differential glycosylation patterns among the three categories. Furthermore, Receiver Operating Characteristics (ROC) analysis allowed obtaining a reliable and minimally invasive protocol able to discriminate between healthy and pathological subjects.

Personalized paths for physical activity: developing a person-centered quantitative function to determine a customized amount of exercise and enhancing individual commitment.

BACKGROUND: Non-Communicable Diseases (NCDs) are leading causes of mortality. These conditions are also known as chronic diseases of long duration and generally slow progression. Physical activity (PA) is a main factor to delay symptoms and consequences of NCDs. In last decades, reduced physical exercise has been observed across all ages. Despite educational campaigns aimed at modifying unhealthy habits, it is difficult to promote healthy lifestyles in general population. Poor interest, lack of motivation, as well as career and family commitments hinder people's participation in regular PA programs. In this study we propose a theoretical person-centred approach to actively involve general population in enhancing their opportunity to perform PA based on personalized needs and targets. METHODS: We defined four profiles of baseline PA levels (inactive, moderately inactive, moderately active, and active people) by referring to Metabolic equivalents (METs) based on individual answers to General Practice Physical Activity Questionnaire (GPPAQ). RESULTS: Based on the answers to the GPPAQ and by computing the related METs for each profile of baseline exercise levels, we developed an innovative person-centered web-based algorithm/function for enhancing and measuring PA participation in community settings. This function can compute evidence-based standardized profiles of participants, personalized goals of PA being functional to the purpose of maintaining or gaining health benefits, as well as the type and duration of PA needed to reach these goals. CONCLUSION: It might be speculated that this approach would be a reliable method for increasing people's self-efficacy and population adherence to recommended levels of PA. However, this theoretical proposal requires to be implemented in further research.

Updated incidence and costs of hip fractures in elderly Italian population.

PURPOSE: We aimed at updating our previous researches about the burden of hip fractures in elderly Italian population. METHODS: We analyzed national hospitalizations records from 2000 to 2014 to compute age- and sex-specific standardized rates. RESULTS: 1,335,375 hospitalizations were recorded in people ≥ 65 (1,031,816 women: 77.27% and 303,559 men: 22.73%) over 15 years, passing from 73,493 in year 2000 to 94,525 in 2014, with an overall increase of 28.62% over the 15-year period (females: + 25.1%; males: + 41.2%). About 84.9% of total hip fractures were suffered by patients aged ≥ 75 years old. Direct hospitalization costs and rehabilitation costs increased from 343 to 457 million Euros and from 392 to 504 million Euros from year 2000 to 2014, respectively. Overall costs of hip fractures raised from 735 to 961 million Euros (+ 30.74% from 2000 to 2014). CONCLUSION: The number of hip fractures and related hospitalizations costs in Italian elderly population is still increasing due to the absolute number of fractures occurring in people ≥ 65 years old and particularly over 75 years old.

Incidence and costs of hip fractures in elderly Italian population: first regional-based assessment.

We analyzed for the first-time hospitalizations and costs for hip fractures in the elderly Italian population at the regional level from 2007 to 2014. The number of fractures and the overall costs increased, mainly due to people aged > 85 in all the Italian regions, although at different rates. OBJECTIVE: We aimed at evaluating the burden of hip fractures in elderly Italian population at the regional level. METHODS: We analyzed national hospitalizations records 2007-2014 to compute standardized hospitalizations rates (SHR) due to hip fractures per 10,000 inhabitants at the regional level and average annual percent change (AAPC), along with related costs. RESULTS: Hip fractures occurred in people over 65 years increased from 89,601 to 94,525 over 8 years. The overall increase in the number of hospitalizations is attributable only to people aged ≥85. Actually, in the 65-74 and 74-84 age groups, total hospitalizations decreased from 13,396 to 12,268 and from 40,733 to 37,786 respectively, while they increased from 35,472 to 44,471 in people aged ≥85 (women = 28,605 and men = 6,867 in 2007; women = 34,636 and men = 9,835 in 2014). Almost 50% of hip fractures were found to have been experienced by patients aged 85 or older in 2014 (with women ≥ 85 representing 36.6% of total fractures), in accordance with the higher prevalence of osteoporosis in this age group. Fractures increase in people aged ≥ 85 was two-folds higher in males (AAPC: + 5.0%; P > 0.05) than in females (AAPC: + 2.6%; P > 0.05). Increases in the number of hospitalizations and related costs were observed for all the regions, with the only exception of Lazio (AAPC: - 4.6%; P < 0.05) and Friuli Venezia Giulia (hip fractures AAPC: - 1.9%; P < 0.05). The most significant increases in hip fractures and related costs were recorded in Calabria (+ 2.7%), Campania (+ 2.2%), and Lombardia (+ 2.0%). At the national level, SHR per 10,000 inhabitants due to hip fractures decreased in all three examined age groups (65-74, 75-84, and ≥ 85), both in males and females during the 8-year period (P < 0.05). This reduction was confirmed also when looking at the regional dataset, with few exceptions concerning female population (AAPC not statistically significant). When looking at the SHR per 10,000 inhabitants for the entire nation, we recorded a decreasing trend also in females aged 85 years old and over but not in males ≥ 85. Actually, men aged ≥ 85 showed increased HR per 10,000 in 10 regions out of 20. Direct hospitalization and rehabilitation costs increased in all the regions over the 8-year period (although at different rates), except for Friuli Venezia Giulia (where costs decreased from 21 to 19 million Euros) and Lazio (from 107 to 87 million Euros). Lombardia and Piemonte were the regions spending the highest amount of money to treat hip fractures in elderly people (151 and 95 million Euros in the year 2014, respectively). CONCLUSION: Hip fractures in the elderly population remain a major public health issue in all Italian regions, especially in people aged 85 years old and over, although the problem is starting to become more controlled compared with the past. Women represent the majority of hip fractures, but the highest increasing rate has been observed in men. Pilot projects at regional level targeting elderly people at higher risk of fractures and treatment compliance are needed.

The Cardiac Rehabilitation Psychodynamic Group Intervention (CR-PGI): An Explorative Study.

Objective: An explorative study focusing on the process of a Cardiac Rehabilitation Psychodynamic Group Intervention (CR-PGI) addressed to myocardial infarction (MI) patients is discussed. The study aimed at analyzing whether the treatment based on CR-PGI serves as a communicational context within which MI patients are enabled to explore new interpretations of their post-infarction condition. Methods: The intervention, divided into 12 weekly one-hour group sessions, was addressed to MI patients recruited within a Public Hospital of southern Italy. Each session was audio-recorded and lexical correspondence analysis (LCA) was applied to the verbatim transcripts, in order to provide a map of the evolution of the communication exchange occurring over the 12 sessions. Results: The findings showed that the discourses associated to the first eight sessions differed from the discourses of the last four sessions. Two main transitions occurred. The first concerns the response to the infarction, first interpreted as a process of affective elaboration and afterwards as practical management of the functional aspects associated with the condition of MI patients. The second concerns the nature of the change and contrasts a lifestyle-oriented model with a social role approach, which refers to social, legal, and medical practices related to the acknowledgment of being an MI patient. Conclusion: The findings offer preliminary support to the capacity of CR-PGI to work as a context where new meanings for the biographical rupture of the MI can be explored. Consistently with the rationale of the model, the intervention seems to have promoted the emergence of new ways of feeling and understanding one's condition.

Reply to the Letter of Terracini B. et al. "Comment on Piscitelli et al. Hospitalizations in Pediatric and Adult Patients for All Cancer Type in Italy: The EPIKIT Study under the E.U. COHEIRS Project on Environment and Health". Int. J. Environ. Res. Public Health 2017, 14, 495.

A letter to the IJERPH Editor was submitted by Terracini B. et al. as a comment to our latest paper "Hospitalizations in Pediatric and Adult Patients for all Cancer Type in Italy:[...].

Hospitalizations in Pediatric and Adult Patients for All Cancer Type in Italy: The EPIKIT Study under the E.U. COHEIRS Project on Environment and Health.

Background: Cancer Registries (CRs) remain the gold standard for providing official epidemiological estimations. However, due to CRs' partial population coverage, hospitalization records might represent a valuable tool to provide additional information on cancer occurrence and expenditures at national/regional level for research purposes. The Epidemiology of Cancer in Italy (EPIKIT) study group has been built up, within the framework of the Civic Observers for Health and Environment: Initiative of Responsibility and Sustainability (COHEIRS) project under the auspices of the Europe for Citizens Program, to assess population health indicators. Objective: To assess the burden of all cancers in Italian children and adults. Methods: We analyzed National Hospitalization Records from 2001 to 2011. Based on social security numbers (anonymously treated), we have excluded from our analyses all re-hospitalizations of the same patients (n = 1,878,109) over the entire 11-year period in order to minimize the overlap between prevalent and incident cancer cases. To be more conservative, only data concerning the last five years (2007-2011) have been taken into account for final analyses. The absolute number of hospitalizations and standardized hospitalization rates (SHR) were computed for each Italian province by sex and age-groups (0-19 and 20-49). Results: The EPIKIT database included a total of 4,113,169 first hospital admissions due to main diagnoses of all tumors. The annual average number of hospital admissions due to cancer in Italy has been computed in 2362 and 43,141 hospitalizations in pediatric patients (0-19 years old) and adults (20-49 years old), respectively. Women accounted for the majority of cancer cases in adults aged 20-49. As expected, the big city of Rome presented the highest average annual number of pediatric cancers (n = 392, SHR = 9.9), followed by Naples (n = 378; SHR = 9.9) and Milan (n = 212; SHR = 7.3). However, when we look at SHR, minor cities (i.e., Imperia, Isernia and others) presented values >10 per 100,000, with only 10 or 20 cases per year. Similar figures are shown also for young adults aged 20-49. Conclusions: In addition to SHR, the absolute number of incident cancer cases represents a crucial piece of information for planning adequate healthcare services and assessing social alarm phenomena. Our findings call for specific risk assessment programs at local level (involving CRs) to search for causal relations with environmental exposures.

Who benefits from a dietary online intervention? Evidence from Italy, Spain and Greece.

OBJECTIVE: The traditional Mediterranean diet includes high consumption of fruits, vegetables, olive oil, legumes, cereals and nuts, moderate to high intake of fish and dairy products, and low consumption of meat products. Intervention effects to improve adoption of this diet may vary in terms of individuals' motivational or volitional prerequisites. In the context of a three-country research collaboration, intervention effects on these psychological constructs for increasing adoption of the Mediterranean diet were examined. DESIGN: An intervention was conducted to improve Mediterranean diet consumption with a two-month follow-up. Linear multiple-level models examined which psychological constructs (outcome expectancies, planning, action control and stage of change) were associated with changes in diet scores. SETTING: Web-based intervention in Italy, Spain and Greece. SUBJECTS: Adults (n 454; mean age 42·2 (sd 10·4) years, range 18-65 years; n 112 at follow-up). RESULTS: Analyses yielded an overall increase in the Mediterranean diet scores. Moreover, there were interactions between time and all four psychological constructs on these changes. Participants with lower levels of baseline outcome expectancies, planning, action control and stage of change were found to show steeper slopes, thus greater behavioural adoption, than those who started out with higher levels. CONCLUSIONS: The intervention produced overall improvements in Mediterranean diet consumption, with outcome expectancies, planning, action control and stage of change operating as moderators, indicating that those with lower motivational or volitional prerequisites gained more from the online intervention. Individual differences in participants' readiness for change need to be taken into account to gauge who would benefit most from the given treatment.

Diabetes and Obesity as Independent Risk Factors for Osteoporosis: Updated Results from the ROIS/EMEROS Registry in a Population of Five Thousand Post-Menopausal Women Living in a Region Characterized by Heavy Environmental Pressure.

Objectives: We aimed to analyze bone mineralization and the effect of different risk factors for osteoporosis in postmenopausal women. Methods: We found 4909 postmenopausal subjects within ≥10,000 records from the ROIS/EMEROS (Ionian and Salento Osteoporosis Registry/Euro Mediterranean Registry of Osteoporosis) registry, a population study carried out in an area characterized by heavy environmental pressure between Brindisi and Taranto from 2009 to 2016. All subjects were assessed via phalangeal quantitative ultrasound (QUS) to evaluate their bone mineralization (assessed via amplitude dependent speed of sound (AD-SoS)) and the association between demineralization and the presence of other conditions or risk factors. Results: Mean age was 64 ± 9.5 years and mean body mass index (BMI) was 28.7 ± 3.5 kg/m². Pearson correlation analyses revealed a negative association between bone mineralization (AD-SoS) and BMI (p < 0.001). By using multivariate logistic regression analysis, we observed significant values of odds ratios (ORs) of osteoporosis (adjusted for age, physical activity, and the use of drugs known to increase the risk of fractures) in subjects with diabetes and obesity: 1.39 (confidence interval (CI): 1.05-1.83) and 1.46 (CI: 1.20-1.78), respectively. A statistically significant linear trend of higher ORs of osteoporosis was found for increasing values of BMI. Conclusions: Our study confirmed the high impact of obesity and type 1 and type 2 diabetes on osteoporosis.

Melanoma in the Italian Population and Regional Environmental Influences: A National Retrospective Survey on 2001-2008 Hospitalization Records.

OBJECTIVE: To assess the burden of regional environmental factors influencing the incidence of Melanoma in the Italian population and overcome the problem of partial population coverage by local cancer registries and thematic archives. METHODS: We analyzed the Italian national hospitalization records from 2001 to 2008 provided by the Ministry of Health, excluding hospital re-admissions of the same patients, in order to assess the occurrence of Melanoma over a 8-year period. Data were presented by age groups (absolute number of cases from 20 to ≥80 years old) and per Region (rates per 100,000 inhabitants) for each year. RESULTS: The overall number of new hospitalizations due to malignant Melanoma increased by 16.8% from 2001 (n = 4846) to 2008 (n = 5823), with the rate per 100,000 inhabitants passing from 10.5 to almost 12.0 at a national level. The majority of new diagnoses of malignant Melanoma was observed in two age groups: 61-70 years old (from 979 in 2001 up to 2109 in 2008, corresponding to 15.1 and 18.1 new cases per 100,000 inhabitants, respectively) and 71-80 years old (from 954 in 2001 up to 1141 in 2008, corresponding to 19.5 and 21.8 new cases per 100,000 inhabitants, respectively). The number of hospitalizations due to Melanoma increased in all age groups with the only exception of the youngest patients aged 20-30 years old. The highest increases over the 8-year period were observed in people aged ≥81 years old (+34%), 61-70 years old (+20%) and surprisingly in the age group 31-40 years old (+17%). Southern Regions showed lower hospitalization rates compared to Northern Italy and Region Lazio. The highest increases between 2001 and 2008 were observed in Trentino/Alto Adige, Friuli Venezia Giulia, Valla d'Aosta and Veneto Region. CONCLUSIONS: Hospitalizations due to malignant Melanoma in Italy seem to be influenced by environmental or population-related factors showing a decreasing incidence rate from the Northern to Southern Regions.

[Pharmacogenetic algorithms for predicting the appropriate dose of vitamin K antagonists: are they still useful?]. / Algoritmi farmacogenetici per la predizione della dose degli anticoagulanti anti-vitamina K: ancora utili?

The severity of side effects that may occur with vitamin K antagonists due to their narrow therapeutic window requires great attention in finding out the most appropriate dose for these drugs. Pharmacogenetic research has now considerably helped clarifying the relationships between genetic variants and sensitivity to such therapy, paving the ground to predictive algorithms that include clinical and genetic variables to establish the best doses to start and maintain an adequate anticoagulation. Pharmacogenetic algorithms indeed aim at identifying tailored regimens, reducing adverse drug reactions and subsequent hospitalizations, optimizing therapeutic efficacy and containing costs. Here we describe the results so far achieved in pharmacogenetic research with vitamin K antagonists, analyzing studies that have assessed the usefulness of such algorithms.