PAttern of drug use in PEdiatrics: An observational study in Italian hOSpitals (the PAPEOS study).

AIMS: To assess the extent of off-label drug use and the occurrence of suspected adverse drug reactions (ADRs) among paediatric patients in Italian hospitals. METHODS: We conducted a 2-year prospective cohort study across 22 Italian hospital wards from September 2020 to September 2022. As part of the surveillance project, we performed a 6-month retrieval of all reported ADRs and evaluated all drug prescriptions for their possible off-label use. Following an educational project on pharmacovigilance addressed to healthcare professionals in participating wards, the same data collection was performed. RESULTS: Among the 892 patients included in the study, 64% were admitted to paediatric wards and 36% to neonatal wards. Fifty per cent of all drugs prescribed were used off-label and mainly concerned the administration of a different dose from the one authorized. In neonatal wards, off-label prescriptions occurred slightly more often, with antibacterials being the most frequently used off-label drugs. A total of 35 reports of suspected ADRs were collected, five before the educational project and 30 afterwards. Based on product licence, 10 of the total 35 reports concerned at least one off-label drug use. CONCLUSIONS: The off-label use of drugs in treating paediatric patients was extensive in Italian hospitals. Regulatory interventions are needed to promote the use of drugs based on the latest available literature and improve ADR reporting on children. Paediatric indications and dosages of the drugs most commonly used in children should be supported by appropriate ad hoc studies.

The Impact of GLP-1 RAs and DPP-4is on Hospitalisation and Mortality in the COVID-19 Era: A Two-Year Observational Study.

Novel antidiabetic drugs have the ability to produce anti-inflammatory effects regardless of their glucose-lowering action. For this reason, these molecules (including GLP-1 RAs and DPP-4is) were hypothesized to be effective against COVID-19, which is characterized by cytokines hyperactivity and multiorgan inflammation. The aim of our work is to explore the potential protective role of GLP-1 RAs and DPP-4is in COVID-19 (with the disease intended to be a model of an acute stressor) and non-COVID-19 patients over a two-year observation period. Retrospective and one-versus-one analyses were conducted to assess the impact of antidiabetic drugs on the need for hospitalization (in both COVID-19- and non-COVID-19-related cases), in-hospital mortality, and two-year mortality. Logistic regression analyses were conducted to identify the variables associated with these outcomes. Additionally, log-rank tests were used to plot survival curves for each group of subjects, based on their antidiabetic treatment. The performed analyses revealed that despite similar hospitalization rates, subjects undergoing home therapy with GLP-1 RAs exhibited significantly lower mortality rates, even over a two-year period. These individuals demonstrated improved survival estimates both within hospital and non-hospital settings, even during a longer observation period.

Postmarketing observational study on the safety of 2021/2022 and 2022/2023 influenza vaccination campaigns in Italy: TheShinISS-Vax|Flu study protocol.

INTRODUCTION: The purpose of TheShinISS-Vax|Flu study is to examine the association between influenza vaccines and adverse events requiring hospital admission or emergency care during the influenza vaccination campaigns 2021/2022 and 2022/2023 in Italy. METHODS AND ANALYSIS: This is a Self-Controlled Case Series multiregional study using linked routinely collected data from regional healthcare databases of the participating regions. Study participants will be persons aged ≥6 months, unvaccinated or who have received influenza vaccine during the influenza vaccination campaigns in the seasons 2021/2022 and 2022/2023 in Italy and who have experienced the outcome of interest for the first time during the study period (1 September 2021-30 June 2022 and 1 September 2022-30 June 2023 for the first and second vaccination campaigns, respectively). Risk periods will be specifically defined for each outcome and further subdivided into periods of 7 days. The exposures will be the first or second dose of the influenza vaccines administered during the two vaccination campaigns. Statistical analysis will be conducted separately for the data of the two campaigns. Exposure risk period will be compared with baseline risk period defined as any time of observation out of the risk periods. The modified SCCS method will be applied to handle event-dependent exposure and mortality and fitted using unbiased estimating equations to estimate relative incidences and excess of cases per 100 000 vaccinated by dose, age, sex and type of vaccine. Calendar period will be included as time-varying confounder in the model, where appropriate. ETHICS AND DISSEMINATION: The study received the approval from the National ethics committee for clinical trials of public research bodies and other national public institutions (PRE BIO CE n.0036723, 23/09/2022). Results will be published in peer-reviewed journals and reports in accordance with the publication policies of the Italian National Institute of Health and of the Italian Medicines Agency.

Active surveillance of adverse events after immunization (AEFI) from the Local Health Unitof Ferrara, Italy.

Introduction: Vaccine vigilance implies the collection, evaluation, analysis and communication of adverse events following immunization (AEFI) and is a useful tool for vaccine monitoring allowing, even after approval and marketing, to check its safety/tolerability. The multiregional project "Active surveillance of adverse vaccine reactions", joined by the AUSL of Ferrara, is aimed at making parents of children, who have undergone at least one vaccination provided by the regional vaccination calendar in the first 24 months of life, aware of the reporting of any AEFI via mobile phone-SMS. Methods: An analysis of the project data, collected in the period March 2018 - May 2019, was carried out, to evaluate the effectiveness of the reporting tool and the type and frequency of AEFI. Anonymized data were analyzed by number, gender, distribution by age, type of vaccine, adverse event, severity and outcome. Results: A total of 1,494 consents and 983 SMS messages were obtained from parents. The vaccine doses carried out were 1,984 (28.3% hexavalent, 28% PCV13, 17% anti-rotavirus, 14.3% Men-B). Almost all (99.5%) AEFI were classified as "not serious". Based on the Organ System Class (SOC), most reports are related to "General Disorders and Administration Site Conditions" (52.3%), followed by "Psychiatric Disorders" (26.5%) and "Metabolic and nutrition disorders" (12.5%). Conclusions: The reported AEFI are in line with the ones reported in the literature. Reporting via SMS is a valid vaccine surveillance tool contributing to the qualitative and quantitative improvement of the information transmitted.

Postmarketing active surveillance of myocarditis and pericarditis following vaccination with COVID-19 mRNA vaccines in persons aged 12 to 39 years in Italy: A multi-database, self-controlled case series study.

BACKGROUND: Myocarditis and pericarditis following the Coronavirus Disease 2019 (COVID-19) mRNA vaccines administration have been reported, but their frequency is still uncertain in the younger population. This study investigated the association between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mRNA vaccines, BNT162b2, and mRNA-1273 and myocarditis/pericarditis in the population of vaccinated persons aged 12 to 39 years in Italy. METHODS AND FINDINGS: We conducted a self-controlled case series study (SCCS) using national data on COVID-19 vaccination linked to emergency care/hospital discharge databases. The outcome was the first diagnosis of myocarditis/pericarditis between 27 December 2020 and 30 September 2021. Exposure risk period (0 to 21 days from the vaccination day, subdivided in 3 equal intervals) for first and second dose was compared with baseline period. The SCCS model, adapted to event-dependent exposures, was fitted using unbiased estimating equations to estimate relative incidences (RIs) and excess of cases (EC) per 100,000 vaccinated by dose, age, sex, and vaccine product. Calendar period was included as time-varying confounder in the model. During the study period 2,861,809 persons aged 12 to 39 years received mRNA vaccines (2,405,759 BNT162b2; 456,050 mRNA-1273); 441 participants developed myocarditis/pericarditis (346 BNT162b2; 95 mRNA-1273). Within the 21-day risk interval, 114 myocarditis/pericarditis events occurred, the RI was 1.99 (1.30 to 3.05) after second dose of BNT162b2 and 2.22 (1.00 to 4.91) and 2.63 (1.21 to 5.71) after first and second dose of mRNA-1273. During the [0 to 7) days risk period, an increased risk of myocarditis/pericarditis was observed after first dose of mRNA-1273, with RI of 6.55 (2.73 to 15.72), and after second dose of BNT162b2 and mRNA-1273, with RIs of 3.39 (2.02 to 5.68) and 7.59 (3.26 to 17.65). The number of EC for second dose of mRNA-1273 was 5.5 per 100,000 vaccinated (3.0 to 7.9). The highest risk was observed in males, at [0 to 7) days after first and second dose of mRNA-1273 with RI of 12.28 (4.09 to 36.83) and RI of 11.91 (3.88 to 36.53); the number of EC after the second dose of mRNA-1273 was 8.8 (4.9 to 12.9). Among those aged 12 to 17 years, the RI was of 5.74 (1.52 to 21.72) after second dose of BNT162b2; for this age group, the number of events was insufficient for estimating RIs after mRNA-1273. Among those aged 18 to 29 years, the RIs were 7.58 (2.62 to 21.94) after first dose of mRNA-1273 and 4.02 (1.81 to 8.91) and 9.58 (3.32 to 27.58) after second dose of BNT162b2 and mRNA-1273; the numbers of EC were 3.4 (1.1 to 6.0) and 8.6 (4.4 to 12.6) after first and second dose of mRNA-1273. The main study limitations were that the outcome was not validated through review of clinical records, and there was an absence of information on the length of hospitalization and, thus, the severity of the outcome. CONCLUSIONS: This population-based study of about 3 millions of residents in Italy suggested that mRNA vaccines were associated with myocarditis/pericarditis in the population younger than 40 years. According to our results, increased risk of myocarditis/pericarditis was associated with the second dose of BNT162b2 and both doses of mRNA-1273. The highest risks were observed in males of 12 to 39 years and in males and females 18 to 29 years vaccinated with mRNA-1273. The public health implication of these findings should be considered in the light of the proven mRNA vaccine effectiveness in preventing serious COVID-19 disease and death.

Disentangling a Thorny Issue: Myocarditis and Pericarditis Post COVID-19 and Following mRNA COVID-19 Vaccines.

Considering the clinical significance for myocarditis and pericarditis after immunization with mRNA COVID-19 vaccines, the present pharmacovigilance study aimed to describe these events reported with mRNA COVID-19 vaccines in the Vaccine Adverse Events Reporting System (VAERS). From 1990 to July 2021, the mRNA vaccines were the most common suspected vaccines related to suspected cases of myocarditis and/or pericarditis (myocarditis: N = 1,165; 64.0%; pericarditis: N = 743; 55.1%), followed by smallpox vaccines (myocarditis: N = 222; 12.2%; pericarditis: N = 200; 14.8%). We assessed all suspected cases through the case definition and classification of the Brighton Collaboration Group, and only definitive, probable, and possible cases were included in the analysis. Our findings suggested that myocarditis and pericarditis mostly involve young male, especially after the second dose with a brief time to onset. Nevertheless, this risk is lower (0.38/100,000 vaccinated people; 95% CI 0.36-0.40) than the risk of developing myocarditis after SARS-CoV-2 infection (1000-4000 per 100,000 people) and the risk of developing "common" viral myocarditis (1-10 per 100,000 people/year). Comparing with the smallpox vaccine, for which is already well known the association with myocarditis and pericarditis, our analysis showed a lower probability of reporting myocarditis (ROR 0.12, 95% CI 0.10-0.14) and pericarditis (ROR 0.06, 95% CI 0.05-0.08) following immunization with mRNA COVID-19 vaccines.

Co-Infections in Critically Ill Patients with or without COVID-19: A Comparison of Clinical Microbial Culture Findings.

Co-infections in critically ill patients hospitalized for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have an important impact on the outcome of coronavirus disease 2019 (COVID-19). We compared the microbial isolations found in COVID-19 patients hospitalized in an intensive care unit (ICU) with those in a non-COVID-19 ICU from 22 February to 30 April 2020 and in the same period of 2019. We considered blood, urine or respiratory specimens obtained with bronchoalveolar lavage (BAL) or bronchial aspirate (BASP), collected from all patients admitted in ICUs with or without COVID-19 infection. We found a higher frequency of infections due to methicillin-resistant (MR) staphylococci, vancomycin-resistant Enterococcus faecium, carbapenem-resistant Acinetobacter baumannii and Candida parapsilosis in COVID-19-positive patients admitted in ICUs compared to those who were COVID-19 negative. Carbapenem-resistant Pseudomonas aeruginosa was more frequently isolated from patients admitted in non-COVID-19 ICUs. Several conditions favor the increased frequency of these infections by antibiotic-resistant microorganisms. Among all, the severity of the respiratory tracts was definitely decisive, which required assisted ventilation with invasive procedures. The turnover in the ICU of a large number of patients in a very short time requiring urgent invasive interventions has favored the not always suitable execution of assistance procedures. No less important is the increased exposure to infectious risk from bacteria and fungi in patients with severe impairment due to ventilation. The highest costs for antifungal drugs were shown in the ICU-COVID group.

Analysis of fatal adverse drug events recorded in several Italian emergency departments (the MEREAFaPS study).

Fatal Adverse Events (FADEs) are a major public health problem, and some FADEs could be preventable. The aim of the present study is to describe the frequency, the drugs involved and the preventability in the FADEs collected through the MEREAFaPS Study between 2012 and 2018. All cases including the outcome "death" have been examined. We excluded cases with vaccine-related ADEs, overdose or suicide, and ADEs occurred during the hospitalisation. Two trained assessors evaluated all cases fulfilling the inclusion criteria. ADEs' preventability was evaluated applying the Schumock and Thornton algorithm. During the study period, we observed 429 cases of death, 92 of which were excluded. The remaining 337 cases involved 187 women and 150 men, with a mean age of 79 and of 77 years, respectively. For each report, the suspected drugs and concomitant ones were 1.26 and 4.20, respectively. Anticoagulants and antiplatelet agents account for more than 40% of FADE cases and the most frequent reactions are haemorrhages (37.5%). The 25% of the FADEs were preventable. This study confirms that FADEs are still a relevant clinical occurrence, and are often caused by widely used old drugs associated with adverse events. The death of one in four patients was preventable. Further efforts should be done to improve the appropriateness of the therapy, especially in older patients who are treated with anticoagulants.

Secondary Metabolite Production from Industrially Relevant Bacteria is Enhanced by Organic Nanofibers.

Streptomycetes are exploited for the production of a wide range of secondary metabolites, including antibiotics. Therefore, both academic and industrial research efforts are focused on enhancing production of these precious metabolites. So far, this has been mostly achieved by classical or recombinant genetic techniques, in association with process optimization for either submerged or solid state fermentation. New cultivation approaches addressing the natural mycelial growth and life cycle would allow the biosynthetic potential of filamentous strains to be much better exploited. We developed a cultivation system for antibiotic-producing microorganisms which involves electrospun organic nanofibers deposited onto agar plates or immersed in liquid media. Dense filamentous networks of branched hyphae formed by bacterial colonies were found to wrapped around the fibers. We analyzed the effects of fibers on growth and antibiotic production in Streptomyces lividans, and found that the actinorhodin, undecylprodigiosin and calcium dependent antibiotic productions were positively modulated, with a two- to sixfold enhancement compared to standard culture conditions. Highlighting the secondary metabolism-promoting role of nanofibers in bacterial cultures, these results open a route to the design of improved culture systems for microorganisms based on organic nanostructures.

Hypofractionation and concomitant boost to deliver adjuvant whole-breast radiation in ductal carcinoma in situ (DCIS): a subgroup analysis of a prospective case series.

To report the four-year outcomes of accelerated hypofractionated whole-breast radiotherapy (WBRT) with a concomitant boost (CB) to the tumor bed in ductal carcinoma in situ (DCIS), we performed a subgroup analysis of 103 patients affected with DCIS within a cohort of 960 early breast cancer patients treated with breast conservation and hypofractionated WBRT. Prescription dose to the whole breast was 45 Gy (2.25 Gy/20 fractions) with an additional daily CB of 0.25 Gy to the surgical cavity (2.5 Gy/20 fractions up to 50 Gy). With a median follow-up of 48 months (range 12-91), no local recurrence was observed. Maximum detected acute skin toxicity was as follows: G0 in 35 % of patients, G1 in 54 %, G2 in 9 % and G3 in 2 %. Late skin and subcutaneous toxicity were generally mild with only 1 % of patients experiencing ≥G3 events (telangiectasia). No major lung and heart toxicity were detected. Cosmetic results were excellent in 50 % of patients, good in 37 %, fair in 9 % and poor in 4 %. Quality of life had a generally favorable profile both within the functioning and symptoms domains. The present result supports the hypothesis that DCIS patients could be safely treated with a hypofractionated schedule employing a CB to the lumpectomy cavity.

Five-year results of a prospective case series of accelerated hypofractionated whole breast radiation with concomitant boost to the surgical bed after conserving surgery for early breast cancer.

Accelerated hypofractionation (HF) using larger dose per fraction, delivered in fewer fractions over a shorter overall treatment time, is presently a consistent possibility for adjuvant whole breast radiation (WBRT) after breast-conserving surgery for early breast cancer (EBC). Between 2005 and 2008, we submitted 375 consecutive patients to accelerated hypofractionated WBRT after breast-conserving surgery for EBC. The basic course of radiation consisted of 45 Gy in 20 fractions over 4 weeks to the whole breast (2.25 Gy daily) with an additional daily concomitant boost of 0.25 Gy up to 50 Gy to the surgical bed. Overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS) and local control (LC) were assessed. Late toxicity was scored according to the CTCAE v3.0; acute toxicity using the RTOG/EORTC toxicity scale. Cosmesis was assessed comparing treated and untreated breast. Quality of life (QoL) was determined using EORTC QLQ-C30/QLQ-BR23 questionnaires. With a median follow-up of 60 months (range 42-88), 5 years OS, CSS, DFS and LC were 97.6, 99.4, 96.6 and 100 %, respectively. Late skin and subcutaneous toxicity was generally mild, with few events > grade 2 observed. Cosmetic results were excellent in 75.7 % of patients, good in 20 % and fair in 4.3 %. QoL, assessed both through QLQ-C30/QLQ-BR23, was generally favorable, within the functioning and symptoms domains. Our study is another proof of principle that HF WBRT with a concurrent boost dose to the surgical cavity represents a safe and effective postoperative treatment modality with excellent local control and survival, consistent cosmetic results and mild toxicity.

Cardiovascular, ocular and bone adverse reactions associated with thiazolidinediones: a disproportionality analysis of the US FDA adverse event reporting system database.

BACKGROUND: : The risk of myocardial infarction, macular oedema and bone fractures associated with thiazolidinediones (TZDs) has been extensively investigated. OBJECTIVE: : The aim of the study was to verify if the analysis of a large spontaneous reporting database could generate early signals on these adverse drug reactions (ADRs) associated with TZDs. METHODS: : A case/non-case study, restricted to antidiabetic drugs, was performed on spontaneous reports of ADRs (2005-2008) in the US FDA Adverse Event Reporting System (AERS). The method was applied to TZDs, both as a drug class and as single agents. The reporting odds ratio (ROR) with 95% CI was calculated as a measure of disproportionality in the whole dataset and in a quarter-by-quarter analysis. RESULTS: : TZD use was registered in 49 589 out of 301 950 drug-reaction pairs (16%), with significant disproportionality for myocardial infarction (ROR 4.71; 95% CI 4.40, 5.05), macular oedema (3.88; 2.79, 5.39) and bone fractures (1.73; 1.53, 1.96). Separate analysis of the two TZDs showed that only rosiglitazone was associated with myocardial infarction (7.86; 7.34, 8.34) and macular oedema (5.55; 3.94, 7.79), whereas pioglitazone was associated with multiple site fractures (2.00; 1.70, 2.35), in particular upper and lower limb and pelvic fractures. The quarter-by-quarter analysis identified disproportionality for myocardial infarction (3.13; 2.38, 4.10) and bone fractures since January-March 2005 (2.70; 1.04, 2.78). CONCLUSIONS: : The frequency of reporting of myocardial infarction, macular oedema and fractures was significantly higher for TZDs in comparison with other antidiabetic drugs, with large intraclass differences. Both myocardial infarction and bone fracture signals appeared before major publications on these safety issues.

Pancytopenia associated with levetiracetam treatment.

Levetiracetam is a pyrrolidine derivate that is approved for the treatment of seizures. It has a favourable pharmacokinetic profile, no clearly established pharmacological interactions, good tolerability and offers the possibility of rapid treatment. We describe a case of pancytopenia and multiple infections observed in the context of levetiracetam treatment. A 65-year-old woman who underwent surgical removal of a meningioma developed progressive pancytopenia complicated by pneumonia and multiple liver abscesses after starting levetiracetam therapy. Bone marrow aspiration and biopsy confirmed the diagnosis. A gradual spontaneous recovery of normal haematopoiesis followed discontinuation of levetiracetam.