Identification of ADME genes polymorphic variants linked to trastuzumab-induced cardiotoxicity in breast cancer patients: Case series of mono-institutional experience.

BACKGROUND: Long-term survival induced by anticancer treatments discloses emerging frailty among breast cancer (BC) survivors. Trastuzumab-induced cardiotoxicity (TIC) is reported in at least 5% of HER2+BC patients. However, TIC mechanism remains unclear and predictive genetic biomarkers are still lacking. Interaction between systemic inflammation, cytokine release and ADME genes in cancer patients might contribute to explain mechanisms underlying individual susceptibility to TIC and drug response variability. We present a single institution case series to investigate the potential role of genetic variants in ADME genes in HER2+BC patients TIC experienced. METHODS: We selected data related to 40 HER2+ BC patients undergone to DMET genotyping of ADME constitutive variant profiling, with the aim to prospectively explore their potential role in developing TIC. Only 3 patients ("case series"), who experienced TIC, were compared to 37 "control group" matched patients cardiotoxicity-sparing. All patients underwent to left ventricular ejection fraction (LVEF) evaluation at diagnosis and during anti-HER2 therapy. Each single probe was clustered to detect SNPs related to cardiotoxicity. RESULTS: In this retrospective analysis, our 3 cases were homogeneous in terms of clinical-pathological characteristics, trastuzumab-based treatment and LVEF decline. We identified 9 polymorphic variants in 8 ADME genes (UGT1A1, UGT1A6, UGT1A7, UGT2B15, SLC22A1, CYP3A5, ABCC4, CYP2D6) potentially associated with TIC. CONCLUSION: Real-world TIC incidence is higher compared to randomized clinical trials and biomarkers with potential predictive value aren't available. Our preliminary data, as proof of concept, could suggest a predictive role of pharmacogenomic approach in the identification of cardiotoxicity risk biomarkers for anti-HER2 treatment.

Surveillance of clinical research integrity in medically assisted reproduction: a systematic review of retracted publications.

Background and purpose: Retraction is a significant consequence of scientific research, resulting from various factors ranging from unintentional errors to intentional misconduct. Previous reviews on retracted publications in obstetrics and gynecology have identified "article duplication," "plagiarism," and "fabricated results" as the main reasons for retraction. However, the extent of retracted articles in the literature on medically assisted reproduction (MAR) remains unclear. This systematic review aimed to assess the number and characteristics of retracted articles in the field of MAR. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed for this study. A comprehensive literature search was conducted on the PubMed database from 1993 to February 2023, limited to English articles and including all 283 terms from the International Glossary on Infertility and Fertility Care. To identify retracted studies, a specific query combining the 283 terms from the glossary with a retraction-related keyword was used. Only studies focused on MAR and involving human subjects were included. Results: The electronic search yielded a total of 523,067 records in the field of infertility and fertility care. Among these, a total of 2,458 records were identified as retracted. The citation retraction rate was found to be 0.47% (2,458/523,067; 95%CI 0.45-0.49), and the citation retraction rate for randomized controlled trials (RCTs) was 0.20% (93/45,616; 95%CI 0.16-0.25). A total of 39 retracted articles specifically related to MAR were identified. Among these, 41.0% were RCTs (n = 16), 15.4% were reviews (n = 6), and 10.3% were retrospective studies (n = 4) or prospective studies (n = 4). Most of the retractions occurred shortly after publication, with "plagiarism" being the most common reason for retraction, followed by "duplicate publication." Discussion: The issue of retraction exists within the field of infertility and fertility care, including MAR. Our findings indicate that scientific misconduct, particularly plagiarism and duplicate publication, are the primary causes of retraction in MAR. Despite finding that the proportion of retracted citations is low, promoting scientific integrity should be a priority. The consequences of article retractions have significant implications for patient care and the scientific community. Hence, it is crucial to prioritize thorough screening of manuscripts before publication to maintain research integrity. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=185769, PROSPERO, identifier: CRD42020185769.

Characterization of Nutritional Quality Traits of a Common Bean Germplasm Collection.

Food legumes are at the crossroads of many societal challenges that involve agriculture, such as climate change and food sustainability and security. In this context, pulses have a crucial role in the development of plant-based diets, as they represent a very good source of nutritional components and improve soil fertility, such as by nitrogen fixation through symbiosis with rhizobia. The main contribution to promotion of food legumes in agroecosystems will come from plant breeding, which is guaranteed by the availability of well-characterized genetic resources. Here, we analyze seeds of 25 American and European common bean purified accessions (i.e., lines of single seed descent) for different morphological and compositional quality traits. Significant differences among the accessions and superior genotypes for important nutritional traits are identified, with some lines showing extreme values for more than one trait. Heritability estimates indicate the importance of considering the effects of environmental growth conditions on seed compositional traits. They suggest the need for more phenotypic characterization in different environments over different years to better characterize combined effects of environment and genotype on nutritional trait variations. Finally, adaptation following the introduction and spread of common bean in Europe seems to have affected its nutritional profile. This finding further suggests the relevance of evolutionary studies to guide breeders in the choice of plant genetic resources.

Real-world data on patients with metastatic non-small-cell lung cancer treated with checkpoint inhibitors in an Italian Teaching Hospital in 2015-2018.

BACKGROUND: Non-small-cell lung carcinoma (NSCLC) accounts for 85-90% of all forms of lung cancer. Immuno-oncology represents a valid new approach but the high cost requires a specific evaluation of the health outcomes. This study describes the real-world efficacy, safety and cost profiles of the new anti-PD-1 immune-checkpoint inhibitors nivolumab and pembrolizumab on a cohort of 56 selected patients with advanced NSCLC. METHODS: A retrospective, observational analysis was conducted on patients treated with immune checkpoint inhibitors from September 2015 to September 2018 at Azienda Ospedaliera Universitaria "Mater Domini" in Catanzaro, Italy. Data sources were medical records, internal prescription cards and reports of adverse reactions. RESULTS: Fifty-six patients were diagnosed with advanced NSCLC, 64.3% characterized by a non-squamous histology, 30.3% squamous and 5.4% not specified. First-line treatment with pembrolizumab was administered to 11 patients for an average of 4.4 months, while 45 patients were treated with nivolumab for an average of 8.6 months. Data showed a survival rate of 95% after 6 months and 88% after 12 months. Most patients received immunotherapy as a second-line or subsequent treatment. In terms of prior therapy among all the patients, 43 had received platinum-based treatments. Indirect comparison with other real-world data studies showed variability in methodologies and an alignment in terms of results. CONCLUSION: This study, based on real-world data, was a first step in the assessment of the impact of the introduction of a significant new class of treatments, i.e. immunotherapy, and covers patients, treatments and outcomes, as well as organizational and economic variables.

Pattern of triptans use: a retrospective prescription study in Calabria, Italy.

Triptans are 5-hydroxytryptamine 1B/1D receptor agonists used in moderate to severe migraine attacks as first line when non-specific, symptomatic, nonsteroidal anti-inflammatory drugs are not effective. To gain insight in the treatment of migraine in the regional context, this retrospective (from January to August of the years 2017 and 2018) study aimed at monitoring the use of triptans approved by the regional health authority in Calabria. The data demonstrate that the overall treatment of migraine with triptans in the different provinces of Calabria falls in the average regional prescription/dispensation. Interestingly, Crotone showed a trend to an increased amount of defined daily dose/1000 inhabitants per day. The present analysis might stand for homogeneity of treatment of migraineurs in Calabria and highlights the need for better understanding the apparent differences in the local pattern of almotriptan use to improve the appropriateness.

Evidence for accuracy of pain assessment and painkillers utilization in neuropsychiatric symptoms of dementia in Calabria region, Italy.

During the clinical course of dementia, beside cognitive impairment and memory loss, a very complex challenge is posed by the neuropsychiatric symptoms (NPSs). Accurate evaluation and treatment of pain impacts positively the agitation of demented patients aged ≥ 65 years. To gather information on the utilization of pain killers in demented patients a preliminary survey has been conducted in collaboration with the Calabrian Pharmacovigilance Territorial Service of the health district of Catanzaro (Italy). The study has taken into consideration the prescriptions of acetylcholinesterase inhibitors and memantine during the period ranging from July 2015 to June 2016 and the percentage of patients treated against pain with non steroidal antinflammatory drugs, opioids, and anticonvulsants have been monitored. The latter have been evaluated statistically for difference between the treatment before (pre) and after (post) the settlement of acetylcholinesterase inhibitors (AChEI) or memantine therapy. The results do support accuracy in painkillers utilization in the course of dementia in the regional population of Calabria (Italy).

Alcohol use in early adolescence: findings from a survey among middle school students in Italy.

BackgroundThe aims of this study were to measure the extent of alcohol use among a sample of early adolescents and to provide information on the factors influencing the consumption.MethodsData were collected via self-administered anonymous questionnaires from 1,520 middle school students (mean age of 13.1 years (range 12-15 years)), who were recruited from a random sample of public schools in Calabria Region, Italy.ResultsA total of 1,032 participants completed the survey for a response rate of 68%. Nearly 70% of the respondents had drunk at least once during their lifetime, and 16.7% reported consuming alcohol during 30 days before the survey. Multivariate analysis showed that the factors associated with the consumption of alcohol were being male (odds ratio (OR) 0.58, 95% confidence interval (CI) 0.41-0.80), being older (OR 1.88, 95% CI 1.37-2.56), living in an urban area (OR 0.29, 95% CI 0.21-0.40), reporting a sad self-perceived mood (OR 2.76, 95% CI 1.87-4.48), reporting parental drinking habits (OR 7.11, 95% CI 5.02-10.08), and not considering alcohol use as an unhealthy behavior (OR 2.43, 95% CI 1.11-5.31).ConclusionAlcohol use among early adolescents is widespread. Multicomponent interventions are required in order to reduce the average levels of alcohol drinking among early adolescents.

Adverse drug reactions reporting in Calabria (Southern Italy) in the four-year period 2011-2014: impact of a regional pharmacovigilance project in light of the new European Legislation.

BACKGROUND: The number of suspected adverse drug reactions (ADRs) yearly submitted to the Italian Network of Pharmacovigilance (RNF) has progressively increased after the new European Pharmacovigilance legislation (July 2012). These results have mostly reflected the agreements between Italian Medicines Agency (AIFA) and Italian Regions, enabling the implementation of active pharmacovigilance projects. A project was funded by the AIFA in Calabria region (Southern Italy) in 2010 to increase ADRs reporting and promote a safer medicines' use. Based on this background, we investigated the trend of ADRs in Calabria in 2011-2014, trying to analyze the possible entailments of the new law. METHODS: Quantitative and descriptive analysis of ADRs submitted by Calabrian healthcare professionals and patients to the RNF database between 2011 and 2014. RESULTS: A sharp rise in regional reporting rate was observed over study period. Calabrian Pharmacovigilance system completely fulfilled the World Health Organization gold standard for ADR reporting rate, both in 2013 and 2014. However, heterogeneity was observed regarding reporting health facilities, healthcare professionals and patients among the study years. CONCLUSIONS: These findings reflect the success of the project performed in Calabria. However, this initiative should go on in the next future to obtain better and more homogeneous reporting behavior.

Spelling errors among children with ADHD symptoms: the role of working memory.

Research has shown that children with attention deficit/hyperactivity disorder (ADHD) may present a series of academic difficulties, including spelling errors. Given that correct spelling is supported by the phonological component of working memory (PWM), the present study examined whether or not the spelling difficulties of children with ADHD are emphasized when children's PWM is overloaded. A group of 19 children with ADHD symptoms (between 8 and 11 years of age), and a group of typically developing children matched for age, schooling, gender, rated intellectual abilities, and socioeconomic status, were administered two dictation texts: one under typical conditions and one under a pre-load condition that required the participants to remember a series of digits while writing. The results confirmed that children with ADHD symptoms have spelling difficulties, produce a higher percentages of errors compared to the control group children, and that these difficulties are enhanced under a higher load of PWM. An analysis of errors showed that this holds true, especially for phonological errors. The increased errors in the PWM condition was not due to a tradeoff between working memory and writing, as children with ADHD also performed more poorly in the PWM task. The theoretical and practical implications are discussed.

Hypericum perforatum: pharmacokinetic, mechanism of action, tolerability, and clinical drug-drug interactions.

Hypericum perforatum (HP) belongs to the Hypericaceae family and is one of the oldest used and most extensively investigated medicinal herbs. The medicinal form comprises the leaves and flowering tops of which the primary ingredients of interest are naphthodianthrones, xanthones, flavonoids, phloroglucinols (e.g. hyperforin), and hypericin. Although several constituents elicit pharmacological effects that are consistent with HP's antidepressant activity, no single mechanism of action underlying these effects has thus far been found. Various clinical trials have shown that HP has a comparable antidepressant efficacy as some currently used antidepressant drugs in the treatment of mild/moderate depression. Interestingly, low-hyperforin-content preparations are effective in the treatment of depression. Moreover, HP is also used to treat certain forms of anxiety. However, HP can induce various cytochrome P450s isozymes and/or P-glycoprotein, of which many drugs are substrates and which are the main origin of HP-drug interactions. Here, we analyse the existing evidence describing the clinical consequence of HP-drug interactions. Although some of the reported interactions are based on findings from in vitro studies, the clinical importance of which remain to be demonstrated, others are based on case reports where causality can, in some cases, be determined to reveal clinically significant interactions that suggest caution, consideration, and disclosure of potential interactions prior to informed use of HP.

Pharmacovigilance in Italy: An overview.

INTRODUCTION: Spontaneous reporting of adverse drug reactions (ADRs) is the basis of pharmacovigilance. In fact, ADRs are associated with a high degree of morbidity and mortality. However, underreporting by all healthcare professionals remains the major problem in Italy and in the rest of the world. The dissemination of pharmacovigilance knowledge among Italian healthcare professionals, and the new pharmacovigilance regulations may promote the early detection and reporting of ADRs. This review examines the legislative framework concerning the pharmacovigilance in Italy. MATERIALS AND METHODS: The information was collected from scientific articles and the websites of the Italian Ministry of Health and the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA). RESULTS: The pharmacovigilance system, both in Italy and Europe, has undergone profound changes. European legislation on pharmacovigilance has been changed in 2010 according to the EU Regulation 1235/2010 and Directive 2010/84/EU. Basically, the changes tend to increase the efficiency, speed and transparency of pharmacovigilance activities. The new Regulation (1235/2010) and the Directive (2010/84/EU) aim to strengthen the system of pharmacovigilance, establish more precisely who is obliged to do what, and allow faster and easier circulation and retrieval of information about ADRs. CONCLUSION: A greater knowledge on what is the Italian pharmacovigilance legislation will be useful to improve the status of ADRs reporting and spread the culture of spontaneous reporting.

Informatics applied to pharmacovigilance: Future perspectives.

Spontaneous adverse drugs reaction (ADRs) reporting represents a precious resource for control and information about the drug's safety and pharmacovigilance. The current reporting system is mainly based on handwritten forms and later manually loaded into a national electronic database by few local pharmacovigilance centers. This reporting system is complicated for both reporters and pharmacovigilance centers which often avoid reporting ADRs for several reasons such as the lack of data on the report. The reporting system might be implemented by improving online platform for ADRs upload; this could allow inspecting all ADRs loaded. Currently, the database is only accessible by the Italian Medicine Agency (AIFA) and local pharmacovigilance centers; neither reporters nor other healthcare professionals can access the database. Finally, it would be right to implement pharmacovigilance centers with specific professional figures qualified in the pharmacovigilance to support both citizens and reporters on various aspects of ADRs reporting.

Pharmacovigilance and drug safety in Calabria (Italy): 2012 adverse events analysis.

INTRODUCTION: Pharmacovigilance (PV) is designed to monitor drugs continuously after their commercialization, assessing and improving their safety profile. The main objective is to increase the spontaneous reporting of adverse drug reactions (ADRs), in order to have a wide variety of information. The Italian Drug Agency (Agenzia Italiana del Farmaco [AIFA]) is financing several projects to increase reporting. In Calabria, a PV information center has been created in 2010. MATERIALS AND METHODS: We obtained data using the database of the National Health Information System AIFA relatively to Italy and Calabria in the year 2012. Descriptive statistics were performed to analyze the ADRs. RESULTS: A total number of 461 ADRs have been reported in the year 2012 with an increase of 234% compared with 2011 (138 reports). Hospital doctors are the main source of this reporting (51.62%). Sorafenib (Nexavar(®)), the combination of amoxicillin/clavulanic acid and ketoprofen represent the drugs most frequently reported causing adverse reactions. Adverse events in female patients (61.83%) were more frequently reported, whereas the age groups "41-65" (39.07%) and "over 65" (27.9%) were the most affected. CONCLUSIONS: Calabria has had a positive increase in the number of ADRs reported, although it has not yet reached the gold standard set by World Health Organization (about 600 reports), the data have shown that PV culture is making inroads in this region and that PV projects stimulating and increasing PV knowledge are needed.

Pharmacovigilance and drug safety 2011 in Calabria (Italy): Adverse events analysis.

BACKGROUND: Pharmacovigilance assesses the safety profile of drugs. Its main aim is the increase of spontaneous reporting of adverse drug reactions (ADRs). The Italian Drug Agency (AIFA; Agenzia Italiana del Farmaco) is financing several projects to the aim of increasing reporting, and in Calabria a Pharmacovigilance Information Centre has been created. MATERIALS AND METHODS: We analyzed the AIFA database relatively to Calabria in the year 2011 and we have analyzed ADRs using descriptive statistics. We have also collected a questionnaire-based interview in order to describe the background knowledge in the field. RESULTS: Regarding the number of AIFA reported ADRs from Calabria, a 38% increase (138 vs. 100) in comparison to 2010 was evidenced. Hospital Doctors represent the main source of signaling (71.7 %). Ketoprofene and the combination amoxicillin/clavulanic acid represent the most frequently reported drugs causing ADRs. Our questionnaires indicated that despite the health professionals have met at least once an ADR only a small percentage of them was reported to the authorities (37%). There is a very good knowledge of the ADR concept and reporting system (90% of interviewed distinguish an ADR and knows how to report it), and there is a strong interest in participating to training courses in the field (95% are interested). CONCLUSIONS: Despite Calabria has had a positive increase in the number of reported ADRs, the total number is very low and the pharmacovigilance culture is far from being achieved in this region.

Histological score for cells with irregular nuclear contours for the diagnosis of reflux esophagitis in children.

Histological criteria for the diagnosis of reflux esophagitis include basal zone hyperplasia, stromal papillae elongation, and inflammatory infiltrate. However, endoscopic esophageal biopsy specimens may include little or no lamina propria. Intraepithelial T lymphocytes, seen in hematoxylin and eosin-stained sections as cells with irregular nuclear contours (CINC), may have a higher density in children with esophagitis. We evaluated the diagnostic accuracy of a numerical score built up by grading the "classical" parameters and its correlation with CINC density in grasp biopsy specimens obtained from children undergoing esophagogastroduodenoscopy with and without esophagitis. We analyzed esophageal biopsy specimens from 349 children (median age, 5 years) subdivided in 4 groups according to the previous routine histology report: group 1, 144 children with esophagitis; group 2, 65 controls; group 3, 51 children with dubious esophagitis; and group 4, 75 children with esophagitis on endoscopy but a normal histology report. A numerical value was assigned to each parameter; the sum of these values represented the histological score. We also evaluated intraepithelial CINC density (ie, number of CINC per high-power field). We separately analyzed histological sections with and without lamina propria. For both total score and for CINC density, we calculated a cutoff using a receiver operating characteristic curve. Cutoffs of 6 for score and of 4 for CINC density provided the best sensitivity and specificity. Sensitivity of the histological score was better in biopsy specimens containing lamina propria (94%) than in those without lamina propria (4%). Sensitivity of CINC density was satisfactory in both specimens with (78%) and without (75%) lamina propria. Specificity was satisfactory for both parameters. In conclusion, when lamina propria was present in sections of endoscopic esophageal biopsy specimens, histological score provided a better diagnostic accuracy for the diagnosis of esophagitis. However, when no lamina propria was present, as was the case in 67% of our children, CINC density had better sensitivity. In addition, this latter parameter showed esophageal mucosa damage in 34% of previously dubious cases or cases with esophagitis at endoscopy but a previous routine histology report of normal mucosa.