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.

Adverse events following immunization (AEFIs) with anti-meningococcus type B vaccine (4CMenB): Data of post-marketing active surveillance program. Apulia Region (Italy), 2019-2023.

The four-component recombinant-DNA anti-meningococcus B vaccine (4CMenB) has been approved by the European Medicines Agency in 2013. In Italy, 4CMenB is recommended since 2017 for use in infants under one year of age. Due to the strong evidence of increased risk of fever after administration, surveillance of adverse events following immunization (AEFIs) is a priority for 4CMenB. This cross-sectional prospective study aims at investigating 4CMenB's safety profile. The study population is represented by infants under twelve months of age vaccinated with 4CMenB in selected ambulatories in Apulia, a region in South-Eastern Italy, from October 1st, 2020, to March 31st, 2023. Parents were provided with a post-vaccination diary covering up to seven days after immunization and were contacted one week after the vaccination day. Information about AEFIs was collected, and reactions were classified following World Health Organization guidelines. For serious AEFIs, causality assessment was carried out. AEFI risk determinants were investigated via logistic regression. A total of 4,773 diaries were completed, with 78.13 % of them (3,729/4,773) containing one or more AEFI reports. Systemic reactions such as malaise, drowsiness/insomnia and fatigue were the most common ones, followed by fever and local pain, tenderness, redness and swelling. Twenty-three cases of serious AEFIs were reported. Following causality assessment, 78.26 % of serious adverse events (18/23) were deemed to have a consistent causal association with the administration of 4CMenB (reporting rate: 0.38 %). Three infants were hospitalized following vaccination, but no cases of death or permanent/severe impairment were reported. Prophylactic paracetamol administration showed a significant protective effect against the risk of manifesting fever within the first 24 h after administration (OR: 0.75; p < 0.005). Our data confirms existing evidence regarding the safety of 4CMenB vaccination in babies under 2 years of age, but also highlight a significant risk of fever after vaccination. Prophylactic paracetamol administration could represent a protective factor against fever, especially during the first 24 h after vaccination.

Chronic treatment of COPD: state of the art and real-world analysis of healthcare costs based on medication adherence data.

INTRODUCTION: Chronic Obstructive Pulmonary Disease (COPD), represents a serious and growing health problem worldwide. Healthcare should be conceived and structured in a proactive logic mode predicting to promote prevention and supporting the patient in the path of care. This desirable approach could reduce the impact of chronicity on patient' quality of life and health care costs. In this context, the theme of therapeutic adherence represents one of the priorities on which to intervene. OBJECTIVE: To show a real life picture of the health expenditure and economics consequences due to non-adherent COPD therapy. MATERIALS AND METHODS: Patients with a COPD diagnosis were selected from the Regional Health Information System Edotto; consumption data was also obtained from the same patients and was based on data relating to prescriptions dispensed by affiliated pharmacies belonging to the Local Health Agency of the province of Barletta-Andria-Trani (LHA BT) in a time period including 2017 and 2018. The assisted patients not adhering to COPD treatment (medication possession ratio between 20% and 80%) in 2017 were included in the analysis. The system Edotto was used to verify how many of them had become adherent in 2018. For both groups of patients, the average cost per patient was assessed, both in terms of pharmaceutical expenditure and hospitalizations due to COPD. RESULTS: Of the 66 patients not adhering to the treatment in 2017, 66.67% (44 patients) became adherent to therapy and 33.33% (22 patients) remained non-adherent to treatment during 2018. The total cost (pharmaceutical expenditure ATC-R03 and the cost derived from hospitalizations due to COPD) for non-adherent patient during 2018 was 73% increase compared to the cost of the patient adhering to treatment (p=.000317), thus resulting a saving of € 992.56 per adherent patient. CONCLUSIONS: Adherence to COPD therapy can improve patient health and reduce healthcare costs.

Safety profile of MenB-FHBp vaccine among adolescents: data from surveillance of Adverse Events Following Immunization in Puglia (Italy), 2018-2020.

MenB-FHBp was licensed in Europe in 2017 from the age of 10. In the "postmarketing life" of a new vaccine, surveillance of Adverse Events Following Immunization (AEFI) is crucial, to better understand the pattern of safety and the effectiveness. This paper describes the MenB-FHBp AEFIs notified in Puglia in 2018-2021, to take a picture of the safety profile of this vaccine in the real life, four years after its introduction in Italy. This is a retrospective observational study. Data were collected from the list of AEFIs notified after MenB-FHBp vaccine administration in Puglia in 2018-2020, and the number of doses of this vaccine administered in the same period. AEFIs were classified according to WHO's algorithm, and causality assessment was carried out for serious AEFIs. From January 2018 to December 2020, in Puglia, 43,061 doses of MenB-FHBp were administered and 42 MenB-FHBp AEFIs (reporting rate: 97.5 per 100,000 doses administered) were reported. Among these, 12 were classified as severe (28.6%; reporting rate 27.9 per 100,000 doses). Overall, the male/female ratio in AEFIs was 1:1. The median age of people who suffered from AEFIs was 12 years (range 11-13). For the 11 serious AEFIs for which the classification was "consistent causal association," the diagnosis was hyperpyrexia (reporting rate 13.9 per 100,000 doses), fainting (rate 4.6 per 100,000 doses), urticaria (rate 2,3 per 100,000 doses), convulsions (rate 2,3 per 100,000 doses), and vomit (rate 2,3 per 100,000 doses). No deaths or impairment were notified in studied AEFIs. The picture of MenB-FHBp vaccine supports that the risk of AEFIs is in line with previous published data and in general acceptable.

Postmarketing surveillance of adverse events following meningococcal B vaccination: data from Apulia Region, 2014-19.

Since the multicomponent meningococcal B vaccine introduction, the Apulian Regional Health Authority implemented postmarketing surveillance program, as provided by Italian laws.From National Pharmacovigilance Network, we selected 4CMenB AEFIs reported in Apulia from 01 January 2014 to 31 December 2019, while the number of 4 cMen B doses administered per year was obtained from the regional immunization database (GIAVA).For each subject who experienced an adverse event following meningococcal B vaccine (AEFIs), a predefined form was filled in.A total of 214 AEFIs (26.5 × 100.000 doses) were reported after any dose of MenB-4 c vaccination of which 58/214 (27.1%) were classified as serious (7.2 × 100,000 doses), 145/214 (67.8%) as not serious (180 × 100,000 doses), and 11/214 (5.1%) as undefined (1.3 × 100,000 doses).The average age of subjects who experimented and AEFI was 30 months. The majority of serious AEFIs were reported in 2- to 11-month-old children (44/57; 77.2%). A total of 31/58 (3.8 × 100,000 doses; 53.4%) serious AEFIs were reported as having a 'consistent causal association' with vaccination. Of these, fever/hyperpyrexia was reported in 21/31 (2.6 × 100,000 doses; 67.7%); hypotonic-hyporesponsive episode was reported in 7/31 (0.9 × 100,000 doses [add %-age]) and was the most frequent adverse event with neurological symptoms. A total of 13/31 (41.9%) serious AEFIs classified as 'consistent causal association' were reported after the first dose of 4cMenB, of these 5/13 (38.5%) children did not complete the vaccination schedule.Our data seemed to confirm, in a large population, the a good safety profile of the universal mass vaccination with 4CMENB.

Medication prescriptions before, during and after pregnancy in Italy: a population-based study.

BACKGROUND: Monitoring medicine prescriptions in pregnancy is an aspect of extreme interest in term of public health. METHODS: A retrospective prevalence study using administrative healthcare databases was performed in order to evaluate medication prescriptions in Italy. A cohort of 274,938 pregnant women (15-49 years) residing in three Italian regions (Emilia-Romagna, Lazio, Puglia), who delivered in 2014-2017, were enrolled. The prevalence of medication use was estimated as the proportion of pregnant women with any medication prescription in each of the following five trimesters: 1 before pregnancy (pre-T), 3 during pregnancy (1st TP, 2nd TP, 3rd TP) and 1 after pregnancy (post-T). RESULTS: About 80% of enrolled pregnant women received at least one prescription during pregnancy, 36.5% before pregnancy and 50.7% in the post-partum. The most prescribed medicine was folic acid (42%), mostly used in 1st TP (35%). Progesterone use was concentrated in 1st TP (19%) and increased as the number of previous abortions. Pregnancy use of antidiabetics, antihypertensives, and thyroid preparations were 24.1‰, 21.5‰, 101.8‰, respectively. CONCLUSIONS: At the national level, this study confirmed the prescriptive trend observed in other European studies, but a regional variability for all medication groups was found. Further studies are needed in order to identify determinants of medication prescriptions during pregnancy in Italy.

Post-Marketing Active Surveillance of Adverse Reactions Following Influenza Cell-Based Quadrivalent Vaccine: An Italian Prospective Observational Study.

Since the influenza season 2018/19, the Italian Ministry of Health recommended a dose of cell-based quadrivalent vaccine (Flucelvax Tetra) for HCWs (healthcare workers), because this vaccine seemed more efficacious in the prevention of AH3N2 virus. Due to the lack of pre-registration data, the safety profile of this new vaccine must be investigated in post-marketing surveillance. The aim of our study is to evaluate, through a post-marketing active surveillance program developed during the 2019/20 influenza season, any Adverse Events Following Immunization (AEFIs) that happened in the 7 days after immunization with Flucelvax Tetra. The study was carried out in a sample of HCWs of Policlinico General University-Hospital (Apulia, South Italy). AEFIs were classified as 'serious' or 'not serious' according to the WHO (World Health Organization) guidelines; the WHO causality assessment algorithm was applied to classify serious AEFIs. A total of 741 HCWs were enrolled, and 430 AEFIs (reporting rate: 58.0 (95%CI: 54.4-61.6) × 100 enrolled) were recorded. Of these, 429 of 430 (99.8%; reporting rate: 57.8 (95%CI: 54.2-61.5) × 100 enrolled) were classified as not serious and one (0.2%; reporting rate: 0.13 (0.03-0.75) × 100 enrolled) was classified as serious. Local reactions were the adverse reaction reported most frequently (88%); regarding the serious AEFI, causality assessment excluded the causal link with the administration of the vaccine. All the AEFIs resolved without sequelae. Flucelvax Tetra showed a profile of high safety. Due to their characteristics of greater sensitivity than passive surveillance, active surveillance programs can be useful in defining the safety profiles of a given vaccine/drug in certain population subgroups.

Analysis of the Introduction in Clinical Practice of New Oral Anticoagulants in Local Health Agency BT: Translation of the Clinical Trial Data to a Local Health Care Area.

The commercial release of the New Oral Anticoagulants (NOACs) has been the most significant change in anticoagulant therapy in recent years. The work aimed to evaluate the economic and health impact for the Local Health Agency Barletta-Andria-Trani (BT). Through the Regional Information System data about naïve patients on NOAC treatment and patients on anti-vitamin-k (VKA), treatments were extrapolated. We assessed therapeutic continuity, pharmaceutical expenditure, hospitalizations, and deaths in 2017 and 2018. Therapeutic continuity was similar in the two groups. The number and the average cost of hospitalizations for a patient treated with VKAs were almost constant, while those of patients treated with NOACs decreased. The treatment of adult-aged naïve patients with NOACs, compared to VKAs therapy, involves an increase in expenditure of about 100€ for a patient, but the reduced hospitalizations could generate, in the long term, saving for the Health System. Clinical data, according to the Real-World Data, confirmed the safety and effectiveness of these drugs. However, attention to the special population is necessary to improve the safety and effectiveness of NOACs. Innovative formulations for pediatric patients are being developed. The challenge for Health Systems is the appropriate use of available resources through health interventions with transversal competences.

Post-marketing surveillance of adverse events following measles, mumps, rubella and varicella (MMRV) vaccine: retrospecive study in apulia region (ITALY), 2009-2017.

Since 2006, some Italian Regions introduced the active offer of measles, mumps, rubella, and varicella (MMRV) vaccine for all newborns during the second years of life. In 2011, Italian Drug Authority (AIFA) recommended the discontinuation of the MMRV use for an increased risk of febrile seizures following vaccination; furthermore, some Regions (such as Apulia, that introduced MMRV offer in 2009) chose to continue the use of MMRV and Ministry of Health recommended to guarantee supplemental monitoring of safety of the vaccine. In Italy, the surveillance of Adverse Events following immunization (AEFIs) is currently carried out by AIFA and Regional Health Authorities; this paper aims to summarize the results of MMRV-vaccine surveillance of AEFIs program carried out in Apulia. From the AIFA database, we selected MMRV AEFIs that occurred in Apulia (about 4,000,000 inhabitants) from 2009 to 2017. For serious AEFIs, we applied the WHO causality assessment algorithm, using for cases hospitalized information from individual medical records. In the 8 years of observation, 155 MMRV-AEFIs (reporting rate: 37.9×100,000 doses) occurred of which 26 were classified as serious (6.3×100,000 doses) and 22 led to hospitalization. Performing causality assessment, for 10 the classification was "consistent causal association to immunization" (reporting rate: 2.4×100000 doses), for 2 indeterminate, for 13 "inconsistent causal association to immunization" and for 1 not-classifiable. No case of febrile seizure resulted consistent to vaccination. All consistent serious AEFIs were completely resolved at subsequent follow-up.

Adverse Events Following Measles-Mumps-Rubella-Varicella Vaccination and the Case of Seizures: A Post Marketing Active Surveillance in Puglia Italian Region, 2017-2018.

Since 2012, the Italian Ministry of Health has recommended to improve the surveillance of adverse events following the measles-mumps-rubella-varicella (MMRV) tetravalent vaccine that was provided in the official immunization schedule of some Italian regions for children during the second year of life. This recommendation was based on data from some surveys that showed an additional risk of seizure following the administration of this vaccine. Responding to the Ministry commitment, the Puglia Region launched, from May 2017 to November 2018, a post-marketing active surveillance program of adverse events following MMRV immunization (AEFIs). Immunized children (second year of life) were enrolled on a voluntary basis, AEFIs diaries were used, and their parents were interviewed 25 days after the immunization. There were 2540 children enrolled; 2149/2540 (84.6%) completed the post-vaccination follow-up. Of these, 992 AEFIs were registered with a reporting rate of 46.2 × 100 doses: 883/992 (89.0%) AEFIs were not serious, while 109/992 (11.0%) were serious. For serious AEFIs, the evaluation of causality assessment was performed using the algorithm proposed by the World Health Organisation (WHO): 82/109 consistent causal associations to MMRV immunization were detected (reporting rate of consistent AEFIs: 3.8 × 100 follow-up). All serious AEFIs consistently associated with immunization resulted completely resolved at the follow-up. The reporting rate of seizure consistently associated with immunization was 0.05 × 100, lower than data previous published in the literature that did not report the causality assessment. Because no emerging signals were detected, our data from the active surveillance program confirmed the safety profile of the MMRV vaccine.

Perforated vs. nonperforated acute appendicitis: evaluation of short-term surgical outcomes in an elderly population.

BACKGROUND: Acute appendicitis is a common acute surgical abdominal condition and despite the majority of cases are observed in children and young adults, its occurrence in the elderly seems to be increasing, with a higher risk of perforation. The aim of this study was to evaluate the surgical outcomes following appendectomy for acute appendicitis in the elderly, making a comparison between perforated and nonperforated groups regarding operative time, hospital stay and postoperative complications. METHODS: The medical records of 48 patients over the age of 60 years who had a pathologically confirmed diagnosis of acute appendicitis from January 2011 to December 2016 were retrospectively reviewed. Patients were grouped into those with perforated and those with non-perforated appendicitis (NPA) and a comparison was made between both groups regarding demography, operative time, length of hospital stay and postoperative complications. RESULTS: From 48 patients over 60 years diagnosed with acute appendicitis, a PA was removed from 10 patients (20.8%). The PA group consisted of 3 males and 7 females, and their mean age was 71.6 years (range 65-84). The NPA group included 22 males and 16 females, and their mean age was 76.5 years (range 63-96). The mean operative time was 58±18.7 minutes and 43.3±9.9 minutes in the perforated and nonperforated groups respectively, with statistically significant difference (P=0.0013). The mean length of hospital stay was similar in the PA group and in the NPA group, being 6.5±1.8 days and 5.4±1.8 days respectively, but these differences were not statistically significant (P=0.093). The frequency of postoperative complications was similar in both groups as they were observed in 3 patients (30%) of the PA group and 10 patients (26%) of the NPA group (P=0.2488). No postoperative intraabdominal abscess was observed in both groups and there was no death after the surgery. CONCLUSIONS: PA, despite requiring a longer mean operative time, in our series is not producing a longer hospital stay or more postoperative complications compared to NPA. The non-operative management of uncomplicated appendicitis is a reasonable option in frail patients in order to avoid the burden of morbidity related to operation, nevertheless surgery remains the standard of care in all age groups.

A New Surgical Device for Anterograde Intraoperative Rectal Washout.

BACKGROUND: Colorectal cancer is the fourth most diffuse cause of death in the world and local recurrence is associated with a reduced long-term life expectancy, with a reduced quality of life. Rectal washout at the anastomosis site leads to a statistically significant reduction of local recurrences. METHODS: We developed the idea of a new laparoscopic stapler with an integrated washout system that could decontaminate the rectal stump before resection, without the need to enlarge the standard surgical incision or even to distort the incision site, closing the rectal stump just below the inferior part of the cancer, and then proceeding with the resection and stapling of the distal part of the tumor. Combined with these canonical functionalities, the new device, equipped with a patented washout system (patent number EP 3103401A1) will also allow to inject in the closed bowel a physiologic saline liquid. RESULTS: In force of the mechanical action of the liquid injected, carcinogenic exfoliated cells eventually floating in the affected region of the colonic lumen will be expelled through the anal orifice. The intraoperative rectal washout, both in minimally invasive and in traditional open surgery, thus becomes a simple, effective, and reproducible procedure. CONCLUSIONS: We describe the technical features and the possible clinical applications of a potentially new surgical laparoscopic stapler coupled with an integrated irrigation system. We have patented the system and we are developing a prototype with the aim to start an experimental pilot study.

May intraperitoneal irrigation with Betadine improve cesarean delivery outcomes? Results of a 6 years' single centre experience.

PURPOSE: Cesarean presents increased risk of adverse outcomes, such as endometritis, bacteremia, peritonitis, and maternal fever. This retrospective study aims to evaluate, for the first time in Literature, the effects Betadine washing versus normal saline washing after uterine closure in women undergoing cesarean delivery (CD) at ≥36 gestational weeks. METHODS: Of the 2080 patients identified retrospectively for the analysis at Department of Obstetrics and Gynecology of San Camillo Hospital of Rome, 1042 were assigned to "Betadine group" and 1038 to "No Betadine group". There were no differences noted for maternal and obstetric characteristics. The outcomes of the present study were to evaluate the incidence of postoperative infections or fever; the reduction of blood white cells among preoperative and postoperative exams; mean and median time of intestinal recanalization, of postoperative ambulation and of 24-h post-CD pain, evaluated using VAS scale. RESULTS: Betadine group patients reported a statistically significant lower white cells increment, a lower mean time to ambulation and intestinal recanalization after CD and a lower 24-h post-CD pain and infections. CONCLUSIONS: Betadine intraperitoneal irrigation during CD seems to improve postoperative CD outcomes and patients' quality of life.

Symptomatic annular pancreas in adult: Report of two different presentations and treatments and review of the literature.

Annular pancreas (AP) in adults is a rare embryologic abnormality detected after development of complications or as incidental finding. Diagnosis and treatment strategies for symptomatic adult AP remain controversial. We describe two different presentation of AP: a woman with a specific upper abdominal pain treated with medical therapy and a man with upper gastroenteric obstructive symptoms which underwent surgical duodeno-jejunal by-pass. English language literature about annular pancreas etiology, diagnosis and treatment was reviewed. No specific guidelines and protocols exist about management of AP, therefore, treatment and operative approaches must be individualized. In consideration of the possible post-operative complications, surgical treatment should be reserved in case of failure of conservative medical therapies.

Necrotizing pancreatitis: A review of the interventions.

Acute pancreatitis may have a wide range of severity, from a clinically self-limiting to a quickly fatal course. Necrotizing pancreatitis (NP) is the most dreadful evolution associated to a poor prognosis: mortality is approximately 15% and up to 30-39% in case of infected necrosis, which is the major cause of death. Intervention is generally required for infected pancreatic necrosis and less commonly in patients with sterile necrosis who are symptomatic (gastric or duodenal outlet or biliary obstruction). Traditionally the most widely used approach to infected necrosis has been open surgical necrosectomy, but it is burdened by high morbidity (34-95%) and mortality (11-39%) rates. In the last two decades the treatment of NP has significantly evolved from open surgery towards minimally invasive techniques (percutaneous catheter drainage, per-oral endoscopic, laparoscopy and rigid retroperitoneal videoscopy). The objective of this review is to summarize the current state of the art of the management of NP and to clarify some aspects about its diagnosis and treatment.

Closed hemorrhoidectomy with linear stapler: a consecutive series of 300 patients.

BACKGROUND: Hemorrhoidectomy is one of the most commonly performed anorectal operations. The aim of this study was to evaluate the safety and the efficacy of a new technique for sutured closed hemorroidectomy with linear stapler in a consecutive series of 300 patients. PATIENTS AND METHODS: Between January 2006 and December 2009, 300 patients (117 male, 183 female) (mean age, 52 (range 21-85) years) with grade III and IV hemorrhoids were treated with our modified technique with linear stapler with 6 cm vascular recharge. This technique essentially achieves a sutured closed hemorroidectomy. The primary end-points of the study were blood loss, time to achieve complete wound healing and recurrence; the secondary end-points were postoperative pain, operative time, hospital stay, patient satisfaction, need of analgesics and morbidity. RESULTS: Post-operative bleeding occurred in 8 patients (2.7%), requiring surgical hemostasis in 2 patients (0.6%). Overall, 132 patients (44%) reported no presence of pain, 43% defined it as light, the remaining 13% reported it as moderate and required the use of painkillers for about 1 month. Eight patients (2.7%) required postoperative temporary bladder catheterization because of acute urinary retention. The mean operative time was 13 minutes and the hospital stay was one day in 282 patients (94%), two days in 12 patients (4%) and three or more days in the remaining patients. None of the patients developed anal stenosis or fecal incontinence; 1 patient reported gas incontinence. The median follow-up was 23.4 months. All patients had complete wound healing within 6 months. Two patients had recurrent disease and were re-operated on with the same technique. CONCLUSION: Our modified sutured closed hemorrhoidectomy with linear stapler is a simple and safe technique and may be successfully applied for radical treatment in patients with third-degree or fourth-degree hemorrhoids.