Supporting Fair and Efficient Emergency Medical Services in a Large Heterogeneous Region.

Emergency Medical Services (EMS) are crucial in delivering timely and effective medical care to patients in need. However, the complex and dynamic nature of operations poses challenges for decision-making processes at strategic, tactical, and operational levels. This paper proposes an action-driven strategy for EMS management, employing a multi-objective optimizer and a simulator to evaluate potential outcomes of decisions. The approach combines historical data with dynamic simulations and multi-objective optimization techniques to inform decision-makers and improve the overall performance of the system. The research focuses on the Friuli Venezia Giulia region in north-eastern Italy. The region encompasses various landscapes and demographic situations that challenge fairness and equity in service access. Similar challenges are faced in other regions with comparable characteristics. The Decision Support System developed in this work accurately models the real-world system and provides valuable feedback and suggestions to EMS professionals, enabling them to make informed decisions and enhance the efficiency and fairness of the system.

Introducing Virtual Reality in a STEMI Coronary Syndrome Course: Qualitative Evaluation with Nurses and Doctors.

In the increasing number of medical education topics taught with virtual reality (VR), the prehospital management of ST-segment elevation myocardial infarction (STEMI) had not been considered. This article proposes an implemented VR system for STEMI training and introduces it in an institutional course addressed to emergency nurses and case manager (CM) doctors. The system comprises three different applications to, respectively, allow (a) the course instructor to control the conditions of the virtual patient, (b) the CM to communicate with the nurse in the virtual field and receive from him/her the patient's parameters and electrocardiogram, and (c) the nurse to interact with the patient in the immersive VR scenario. We enrolled 17 course participants to collect their perceptions and opinions through a semistructured interview. The thematic analysis showed the system was appreciated (n = 17) and described as engaging (n = 4), challenging (n = 5), useful to improve self-confidence (n = 4), innovative (n = 5), and promising for training courses (n = 10). Realism was also appreciated (n = 13), although with some drawbacks (e.g., oversimplification; n = 5). Overall, participants described the course as an opportunity to share opinions (n = 8) and highlight issues (n = 4) and found it useful for novices (n = 5) and, as a refresh, for experienced personnel (n = 6). Some participants suggested improvements in the scenarios' type (n = 5) and variability (n = 5). Although most participants did not report usage difficulties with the VR system (n = 13), many described the need to get familiar with it (n = 13) and the specific gestures it requires (n = 10). Three suffered from cybersickness.

Vaccination against human papilloma virus in a Northeastern Italian area.

OBJECTIVES: Vaccination against human papilloma virus (HPV) in adolescents and persons at increased risk of infection and related consequences is an effective strategy to prevent genital cancers. The objective of this study was to assess vaccination activity and coverages in a Northeastern Italian area. METHODS: Anonymous data from various health administrative databases of the Italian 530,000-inhabitant Health Authority "Azienda Sanitaria Universitaria Friuli Centrale" were deterministically linked at the individual level through an anonymous stochastic key. Doses of HPV vaccine administered by year and coverages in different birth cohorts were calculated. Vaccinations of women treated for a CIN2+ lesion were also identified. RESULTS: The number of doses administered by year followed the evolution of national and regional laws. A steep drop was observed in 2020 and 2021 in both males and females (from 6,907 in 2019 to 5,027 in 2020 in males and from 6,989 in 2019 to 4,348 in 2020 in females). Coverages in adolescents were variable across Vaccination Services located in different sub-areas (complete cycle coverage in the 2008 cohort ranged from <40% in some Districts to >70% in others). Vaccination doses administered in adult women have increased almost steadily since 2018. One third of women treated for a CIN2+ were vaccinated. CONCLUSIONS: In this area, efforts must be done to catch-up with doses missed during the pandemic and to overcome differences among different sub-areas.

[A&F: obstacles to implementing interventions in the health system.] / A&F: gli ostacoli nell'implementare interventi nel sistema sanitario.

Understanding how well a clinician or health care team is performing provides an essential foundation for improvement. If done well, Audit and Feedback (A&F) provides data in non-judgemental, motivating insights and leads to changes in clinical processes that benefit patients. This article will explore obstacles to optimizing the potential positive effects of A&F to improve patient care and outcomes by examining three interrelated steps in the process: the audit; the feedback; and the action. The audit requires data that will be perceived as both valid and actionable. Acquiring and using such data properly often requires partnerships. Feedback recipients need to know how to turn data into action. The A&F, therefore, should include components that direct the recipient toward feasible next steps to undertake the change that will lead to improvement. The proposed actions may be individual (learning new diagnostic or therapeutic strategies, trying a more patient-centered approach, etc.) or organizational (more proactive approaches often including the involvement of additional team members). The ability to turn feedback into action will depend on the culture of the recipient-group, and its level of experience with these change processes. Feedback facilitation or coaching may be useful for some groups or certain kinds of desired changes in practice. Inadequate leadership and support for health professionals, as they try to respond to A&F, is also often a barrier. Finally, with the final focus on the challenges of the individual Work Packages (WP) within the Easy-Net network program, the article focuses on what were the facilitating and hindering factors, the obstacles encountered, and the resistance to change overcome, useful considerations in support of the increasingly widespread implementation of A&F activities in our Healthcare System in the future.

[The EASY-NET research programme: background, structure, and methodology]. / Il programma di rete EASY-NET: razionale, struttura e metodologie.

This is the first contribution of a series of interventions describing the EASY-NET research program (Bando Ricerca Finalizzata 2016, funds 2014-2015; NET-2016-02364191). Here, the objective is to illustrate the background and the research question, the structure and organization, the methodologies and the expected results of the programme. The main theme is audit&feedback (A&F), a proven and widespread technique for improving the quality of health care. EASY-NET, funded by the Italian Ministry of Health and by the governments of the participating Italian Regions, starts its research activities in 2019 with the aim of evaluating the effectiveness of A&F in improving care for different clinical conditions in various organizational and legislative contexts. The research network involves seven Italian Regions, each conducting specific research activities described by as many work packages (WP): Lazio (the leading Region, coordinator of the research activities), Friuli Venezia Giulia, Piedmont, Lombardy, Emilia-Romagna, Calabria, and Sicily. The involved clinical areas include the management of chronic diseases, emergency care for acute conditions, surgery in the oncological area, the treatment of heart disease, obstetrics, and the use of caesarean section and post-acute rehabilitation. The involved settings concern the community, the hospital, the emergency room, and the rehabilitation facilities. Different experimental or quasi-experimental study designs are applied in each WP to achieve specific objectives of the specific clinical and organizational context. In all WPs, the process and outcome indicators are calculated on the basis of the Health Information Systems (HIS) and, in some cases, they are integrated with measures obtained from ad hoc data collections. The programme aims to contribute to the scientific evidence on A&F also exploring the obstacles and favourable factors for its effectiveness and to promote its implementation in the health service, with the ultimate aim of improving the access to healthcare and the health outcomes for citizens.

[A&F: integrating research into practice and practice into research.] / A&F: integrare la ricerca nella pratica e la pratica nella ricerca.

This article proposes a focus on Audit & Feedback (A&F)'s sustainability. If on one side, it is essential to ask how to bring A&F interventions out of research programs into clinical practices and contexts of care. On the other, it is fundamental to ensure that the experiences gained within care contexts can inform research, helping to define the research objectives and questions whose development can support paths of change. The reflection starts from two research programs on A&F carried out in the United Kingdom, respectively, at the regional level (Aspire) in the field of primary care and at the national level (Affinitie and Enact) in the field of the transfusion system. Aspire raised awareness of the importance of establishing a primary care implementation laboratory, which randomizes practices to different types of feedback to evaluate the effectiveness, also to improve patient care. The national Affinitie and Enact programs served to 'inform' recommendations to improve the conditions for sustainable collaboration between A&F researchers and audit programs. They represent an example to understand how to incorporate research results within a national clinical audit program. Finally, starting from the complex experience of the Easy-Net research program, the reflection moves on to how it was possible to make A&F interventions sustainable in Italy beyond research projects, in clinical-care contexts in which the resources provisions make continuous and structured interventions difficult and impractical. The Easy-Net program envisages different clinical care settings, study designs, interventions, and recipients, which require different actions to adapt research results to the specific realities to which A&F's interventions are addressed.

[How to optimize Audit&Feedback: experience from the EASY-NET programme]. / Come rendere più efficace l'Audit&Feedback: riflessioni dal programma di rete EASY-NET.

This is the second of a series of papers dedicated to the EASY-NET research programme (NET-2016-02364191). The rationale, structure and methodologies are described in the previous contribution. Scientific literature demonstrated that Audit & Feedback (A&F) is an effective strategy for continuous quality improvement and its effectiveness varies considerably according to factors that are currently little known. Some recent publication pointed out, with the contribution of an international group of experts, 15 suggestions to optimize A&F and developed a tool to evaluate their application. This tool, called REFLECT-52, includes 52 items related to the 15 suggestions and organized into four categories relating to the "Nature of the desired action", to the "Nature of the data available for feedback", to the "Feedback Display" and to the "Intervention delivery". Then, the aim of this work was to evaluate the level of adherence of A&F interventions tested in EASY-NET to suggestions from the literature by using a slightly adapted version of the REFLECT-52 tool, in its original language. In EASY-NET, 14 A&F interventions with different characteristics and in different clinical and organizational contexts were tested in seven Italian regions, each of these was evaluated by the respective research groups. Overall, the level of adherence was high in three of the four categories analysed, with some difficulties reported regarding the nature of the data available for feedback. In fact, contrary to what the literature suggests, it was not possible to send repeated feedback for some interventions and, in some cases, the data available for feedback presented a delay longer than one year. In summary, this analysis has confirmed a high level of compliance of the interventions tested with the suggestions from the literature, but it has also allowed researchers to identify critical aspects that need to be addressed for the future development of these strategies.

Type A acute aortic dissection with ≥40-mm aortic root: results of conservative and replacement strategies at long-term follow-up.

OBJECTIVES: We evaluated the long-term results of aortic root (AR) preservation and replacement in patients operated on for acute type A aortic dissection. METHODS: Out of 302 patients discharged after repair of acute aortic dissection (1977-2019), 124 patients had an AR ≥40 mm, which was preserved in 84 (68%, group A) patients and replaced in 40 (32%, group B) patients. Group B patients were younger (mean age 57 ± 12 vs 62 ± 11 years, P = 0.07), with a mean AR of 47 vs 43 mm and ≥moderate aortic insufficiency in 65% vs 30%. Survival, causes of death and reoperations were analysed at mean follow-up of 9 ± 8 years (6 months to 40 years). RESULTS: Actuarial survival of discharged patients at 5, 10 and 15 years was 97% (0.89-0.99), 78% (0.67-0.90) and 75% (0.64-0.88) in group A, and 85% (0.71-0.95), 62% (0.44-0.78) and 57% (0.39-0.76) in group B (log-rank test P = 0.2). Nine patients in group A (7 patients for aortic insufficiency and dilatation of the root and 2 patients for pseudoaneurysm) and 1 patient of group B (pseudoaneurysm of the right coronary button) required proximal reoperation without deaths. At 5, 10 and 15 years, the cumulative incidence of proximal aortic reoperations was 5%, 9% and 25% in group A, and 0%, 3% and 3% in group B (P = 0.02). At multivariable analysis AR >45 mm [hazard ratio (HR) 6.8, P = 0.026] and age (HR 0.9, P = 0.016) were independently associated with proximal reoperation. CONCLUSIONS: AR preservation in acute type A dissection showed acceptable long-term outcomes. Nevertheless, a more aggressive approach appears a valid option, especially in patients with AR diameter >45 mm.

[Emergency department visits for interpersonal violence injuries in Udine (Friuli Venezia Giulia Region, Northern Italy)]. / Gli accessi al Pronto soccorso dell'Azienda sanitaria universitaria integrata di Udine per traumatismi causati da violenza interpersonale.

OBJECTIVES: to describe frequency, characteristics, and consequences of intentional injuries due to interpersonal violence visited at the Emergency Rooms of Udine and Cividale del Friuli (Friuli Venezia Giulia Region, North-Eastern Italy). DESIGN: analysis of the administrative database of the Emergency Department. SETTING AND PARTICIPANTS: in the two Emergency Departments of Udine and Cividale del Friuli, serving a 250,000-inhabitant area, all the visits due to injuries from interpersonal violence in the years 2015-2017 were analysed. MAIN OUTCOME MEASURES: number of visits because of injuries from interpersonal violence, distribution of demographic characteristics of patients, of characteristics of the events (place of occurrence, mechanism, relation with patient's occupation, involvement of persons known to the victims), of consequences (discharge diagnosis, Emergency Department management times). RESULTS: in three years, 1,741 visits of violence victims were recorded in the Emergency Department of the Udine area; 8.7% of patients were assigned a triage yellow tag and 1.0% a red tag. Almost one third of victims were non-Italian citizens; 14.2% of events were work-related; more than one third occurred in the home; in one third of cases, the aggressor was known to the victim; 96 people were diagnosed with fractures. The average time from start of medical care and Emergency Room discharge ranged from half an hour among white triage tags to more than three hours among yellow tags. More than 100 people experiences more than one violent episode. CONCLUSIONS: this is the first description of frequency, characteristics, and health impact of violence in the area of Udine, providing information useful for a targeted prevention. It also highlights the central role of the Emergency Department not only for the registration of the phenomenon, but also for the management of the acute episodes and for the prevention of recurrent events.

Value of the Rare Disease Registry of the Italian Region Friuli Venezia Giulia.

BACKGROUND: The lack of epidemiological and clinical data is a major obstacle in health service planning for rare diseases. Patient registries are examples of real-world data that may fill the information gap. OBJECTIVE: We describe the Rare Disease Registry of the Friuli Venezia Giulia region of Italy and its potential for research and health planning. METHODS: The Rare Disease Registry data were linked with information on mortality, hospital discharges, ambulatory care, and drug prescriptions contained in administrative databases. All information is anonymous, and data linkage was based on a stochastic key univocal for each patient. Average annual costs owing to hospitalizations, outpatient care, and medications were estimated. RESULTS: Implementation of the Registry started in 2010, and 4250 participants were registered up to 2017. A total of 2696 patients were living in the region as of January 1, 2017. The overall raw prevalence of rare diseases was 22 per 10,000 inhabitants, with higher prevalence in the pediatric population. The most common disease groups were congenital malformations, chromosomal and genetic syndromes, and circulatory and nervous diseases. In 2017, 30 patients died, 648 were hospitalized, and 2355 received some type of ambulatory care. The total annual estimated cost was approximately €6.5 million, with great variability in the average patient cost across diseases. CONCLUSIONS: The possibility of following the detailed real-world care experience of patients with each specific rare disease and assessing the costs related to each step in their care path represents a unique opportunity to identify inefficiencies, optimize care, and reduce waste of resources.

Hospital discharge diagnoses in patients with positive blood cultures in an Italian academic hospital.

OBJECTIVE: To assess the sensitivity of hospital discharge diagnoses for identifying sepsis in patients with blood culture confirmation. METHODS: A cross-sectional study was conducted at the Italian 1000-bed University Hospital of Udine. The administrative databases of the Hospital were used as the source of information. Laboratory data were linked with hospital discharge data. We estimated the proportion of hospitalizations with at least 2 positive blood culture tests in which at least one discharge diagnosis indicated bloodstream infection. RESULTS: From 2011 to 2017, 3571 hospitalizations (1.2%) had positive blood culture tests. Of them, only 49.5% had at least one ICD-9-CM discharge diagnosis code of sepsis, with lower proportions in surgical than in medical wards. CONCLUSIONS: The sensitivity of ICD-9-CM discharge codes for sepsis is low as compared with the blood culture gold standard. Using discharge codes for epidemiological estimates of sepsis, health planning and risk management may yield biased results. Audits and ICD coding training are needed.

[Pharmaceutical prescription of proton pump inhibitors and ranitidine in the general population living in the area of the Healthcare Authority and University of Udine (Friuli Venezia Giulia, Northeastern Italy)]. / La prescrizione farmaceutica territoriale di inibitori di pompa protonica e ranitidina nella popolazione residente nell'area della Azienda sanitaria universitaria integrata di Udine.

OBJECTIVES: to describe the use of proton pump inhibitors (PPI) and ranitidine in the general population living in the area of the Healthcare Authority and University of Udine (Friuli Venezia Giulia, Northeastern Italy) and to evaluate whether there are any cases of co-prescription of medications in those classes. DESIGN: analysis of health-related administrative databases (list of potential healthcare beneficiaries, prescriptions of medications, exemption from medical charges because of chronic conditions, list of general practitioners). SETTING AND PARTICIPANTS: population of the Italian area of the Healthcare Authority and University of Udine (approximately 250,000 inhabitants) ≥1 year of age as of January 1st, 2016. MAIN OUTCOME MEASURES: prevalence of PPI or H2RA use (>1 prescription in 2016), overall and stratified by drug, age class and sex; duration of the theoretical period covered by prescriptions; prevalence of co-prescriptions; association of co-prescriptions and clinical and demographic characteristics of patients (odds ratio and 95% confidence intervals). RESULTS: in 2016, 162 persons per 1,000 used those medications; in particular, 158/1,000 used PPIs. Prevalence of use increased with age, as did the median treatment duration with PPIs. Co-prescription of two medications of the same class were observed in 0.43% of antacid users. The likelihood of receiving co-prescriptions was higher among non-elderly subjects, long-term PPI users, and those with chronical diseases, such asthma. CONCLUSION: in the considered Italian area, PPIs and ranitidine were frequently used, although less than in the rest of Italy. We observed occasionally non-recommended practices, such as the co-prescription of different medications of the same class or with the same indications.

Recipient age impact on outcome after cardiac transplantation: should it still be considered in organ allocation?

OBJECTIVES: Improvement of clinical results in heart transplantation (HTx) has favoured the expansion of indication criteria towards aged population. The impact of increasing recipient age is controversial and, owing to donor shortage, the debate still remains whether HTx is justified for older patients. We analysed age as a prognostic factor at long-term after HTx and if it should be a determinant in organ allocation. METHODS: Data of 364 consecutive patients who underwent cardiac transplantation between 1999 and 2014 at the University Hospital of Udine were analysed. Patients were divided into three groups according to age (Group 1: 18-40, Group 2: 41-59, Group 3: ≥ 60 years) and survival and major complications were evaluated at long-term (mean follow-up 6.7 ± 4.5 years, range 1-15.7 years). RESULTS: Preoperatively, renal failure (2.9, 16.1, 39.5%, P < 0.01) and cardiovascular factors such as diabetes (1.2, 17.1, 36.4%, P < 0.01), systemic hypertension (5.9, 31.5, 40.8%, P < 0.01) and dyslipidaemia (5.9, 40.3, 42.9%, P < 0.01) were more common in older patients (Group 3), as well as ischaemic cardiopathy (0, 42.6, 49.7%, P < 0.01). Donor age was lower in younger recipients (Group 1) (33 ± 15, 39 ± 14, 45 ± 14 years, P < 0.01). Older patients showed a worse long-term survival (hazard ratio 1.7; 1.1-2.5), also after adjusting for major cardiovascular risk factors, renal failure and donor age. In fact, 15-year survival was 100% in Group 1, while at 1, 5, 10 and 15 years survival was 88, 78, 69 and 56% in Group 2, and 87, 68, 49 and 43% in Group 3, respectively. Even major long-term complications were less frequent in younger patients in terms of neoplasms (P < 0.01), rehospitalizations (P < 0.01) and a tendency to higher freedom from other complications such as cytomegalovirus infections, renal failure and dialysis. CONCLUSIONS: Our results showed a significantly different outcome according to recipient age, even when adjusted for major risk factors. Notably, patients younger than 40 years showed 100% long-term survival, and apparent lower rate of complications due to immunosuppression. Since 15-year survival in patients ≤40 years is twice that of patients ≥60 years, recipient age should be taken into account in organ allocation.

Comprehensive Evaluation of Plasma 7-Ketocholesterol and Cholestan-3ß,5α,6ß-Triol in an Italian Cohort of Patients Affected by Niemann-Pick Disease due to NPC1 and SMPD1 Mutations.

Niemann-Pick C disease (NPCD) is a rare autosomal recessive neurovisceral disorder with a heterogeneous clinical presentation. Cholestan-3ß,5α,6ß-triol and 7-ketocholesterol have been proposed as biomarkers for the screening of NPCD. In this work, we assessed oxysterols levels in a cohort of Italian patients affected by NPCD and analyzed the obtained results in the context of the clinical, biochemical and molecular data. In addition, a group of patients affected by Niemann-Pick B disease (NPBD) were also analyzed. NPC patients presented levels of both oxysterols way above the cut off value, except for 5 siblings presenting the variant biochemical phenotype who displayed levels of 3ß,5α,6ß-triol below or just above the cut-off value; 2 of them presented also normal levels of 7-KC. Both oxysterols were extremely high in a patient presenting the neonatal systemic lethal phenotype. All NPB patients showed increased oxysterols levels. In conclusion, the reported LC-MS/MS assay provides a robust non-invasive screening tool for NPCD. However, false negative results can be obtained in patients expressing the variant biochemical phenotype. These data strengthen the concept that the results should always be interpreted in the context of the patients' clinical picture and filipin staining and/or genetic studies might still be undertaken in patients with normal levels of oxysterols if symptoms are highly suggestive of NPCD. Both oxysterols are significantly elevated in NPB patients; thus a differential diagnosis should always be performed in patients presenting isolated hepatosplenomegaly, a common clinical sign of both NPCD and NPBD.

Bicuspid aortic valve disease and ascending aortic aneurysm: should an aortic root replacement be mandatory?†.

OBJECTIVES: The higher risk of adverse aortic events in patients with bicuspid aortic valve (BAV) disease and ascending aorta aneurysm is known, but the management of moderate aortic root dilatation in younger patients is a controversial issue. The aim of the study was to compare survival in patients with or without root replacement. METHODS: We reviewed 166 consecutive patients with BAV disease and concomitant ascending aorta aneurysm (mean ascending aorta diameter: 51.4 ± 7.2 mm) undergoing cardiac surgery from 1994 to 2010. A total of 77 patients underwent Bentall procedure (90.9% male, mean age: 55.7 ± 12.7 years, Bentall group), whereas the remaining 89 patients underwent aortic valve replacement with supracoronary ascending aorta replacement (SAAR 71.9% male, mean age: 60.5 ± 11.2 years, SAAR group, P = 0.002). The preoperative mean diameter of the root was 44.0 ± 7.2 mm in the Bentall, and 38.5 ± 4.8 mm in the SAAR group (P < 0.0001). RESULTS: In-hospital mortality was 2.6% in the Bentall, and 2.3% in the SAAR groups. Overall survival was 84 and 81% in the Bentall (median follow-up: 105 months) versus 89 and 88% in the SAAR (median follow-up: 73 months) groups at 10 and 15 years (P = 0.36), respectively. The mean cardiopulmonary bypass (CPB) time was 201 ± 56 min and 174 ± 58 min (P = 0.0016), the mean cross-clamp time 156 ± 42 min and 132 ± 38 min (P = 0.0008) in the Bentall and SAAR groups, respectively. Four sudden deaths have occurred in the Bentall group and in 2 in the SAAR group. Progressive dilatation of the aortic root in the SAAR group was not significat (postoperative mean diameter: 36.3 ± 4.4 mm). Neither subgroup of patients in the SAAR with preoperative moderate dilatation of aortic root had significat aortic dilatation at the mean follow-up of 73 ± 39 months (preoperative diameter: 43.5 ± 2.3 mm versus postoperative: 39.1 ± 4.2 mm). One patient in Bentall and 1 in the SAAR groups were reoperated for tubular graft infection. CONCLUSIONS: In patients with BAV disease, ascending aorta aneurysm and moderate dilatation of the root, the significat reduction of CPB and cross-clamp times, the stability of the residual root at long term and the low risk of adverse aortic events associated with SAAR compared with the Bentall procedure have led us to consider the isolated aortic valve replacement with supracoronary aorta replacement an alternative strategy to the Bentall procedure, especially in high-risk and older patients.

The influence of patients' complexity and general practitioners' characteristics on referrals to outpatient health services in an Italian region.

BACKGROUND: Patient referrals to outpatient health services may affect both health outcomes and health expenditures. General practitioners (GP) have a crucial role in driving the use of outpatient services and recognizing factors which affect referrals is important for health managers and planners. OBJECTIVES: We investigated patient- and physician-related determinants of patient referrals in an Italian region. METHODS: This was cross-sectional study based on the individual linkage of administrative databases from the health information system of the Friuli Venezia Giulia region. For each GP of the region, the association of the number of patient referrals to different types of outpatient services with the proportion of patients with chronic conditions, with the number of hospital admissions and drug prescriptions in 2012, and with GP's characteristics was investigated through multilevel multivariable Poisson regression models. RESULTS: Some chronic conditions (e.g., cancer, autoimmune diseases, endocrine diseases, digestive system diseases) were positively associated with the number of referrals, as were hospital admissions and drug prescriptions. Time since GP's graduation was inversely related with referrals. CONCLUSION: Patient complexity and GP's experience affect referral rates. These factors should be considered in case of a reorganization of the general practice structure in Friuli Venezia Giulia.

Enzyme replacement and substrate reduction therapy for Gaucher disease.

BACKGROUND: Gaucher disease, a rare disorder, is caused by inherited deficiency of the enzyme glucocerebrosidase. It is unique among the ultra-orphan disorders in that four treatments are currently approved by various regulatory authorities for use in routine clinical practice. Hitherto, because of the relatively few people affected worldwide, many of whom started therapy during a prolonged period when there were essentially no alternatives to imiglucerase, these treatments have not been systematically evaluated in studies such as randomized controlled trials now considered necessary to generate the highest level of clinical evidence. OBJECTIVES: To summarize all available randomized controlled study data on the efficacy and safety of enzyme replacement therapies and substrate reduction therapy for treating Gaucher disease. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register. Additional searches were conducted on ClinicalTrials.gov for any ongoing studies with potential interim results, and through PubMed. We also searched the reference lists of relevant articles and reviews.Date of last search: 07 August 2014. SELECTION CRITERIA: All randomized and quasi-randomized controlled studies (including open-label studies and cross-over studies) assessing enzyme replacement therapy or substrate reduction therapy, or both, in all types of Gaucher disease were included. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the risk of bias in the included studies, and extracted relevant data. MAIN RESULTS: Of the 488 studies retrieved by the electronic searches, eight met the inclusion criteria and were analysed (300 participants). Response parameters were restricted to haemoglobin concentration, platelet count, spleen and liver volume and serum biomarkers (chitotriosidase and CCL18). Only one publication reported a 'low risk of bias' score in all parameters assessed, and all studies included were randomized.Four studies reported the responses to enzyme replacement therapy of previously untreated individuals with type 1 Gaucher disease. Two studies investigated maintenance enzyme replacement therapy in people with stable type 1 Gaucher disease previously treated for at least two years. One study compared substrate reduction therapy, enzyme replacement therapy and a combination thereof as maintenance therapy in people with type 1 Gaucher disease previously treated with enzyme replacement therapy. One study examined substrate reduction therapy in people with chronic neuronopathic (type 3) Gaucher disease who continued to receive enzyme replacement therapy.Treatment-naïve participants had similar increases in haemoglobin when comparing those receiving imiglucerase or alglucerase at 60 units/kg, imiglucerase or velaglucerase alfa at 60 U/kg, taliglucerase alfa at 30 units/kg or 60 units/kg, and velaglucerase alfa at 45 units/g or 60 units/kg. For platelet count response in participants with intact spleens, a benefit for imiglucerase over velaglucerase alfa at 60 units/kg was observed, mean difference -79.87 (95% confidence interval -137.57 to -22.17). There were no other significant differences in platelet count response when comparing different doses of velaglucerase alfa and of taliglucerase alfa, and when comparing imiglucerase to alglucerase. Spleen and liver volume reductions were not significantly different in any enzyme replacement therapy product or dose comparison study. Although a dose effect on serum biomarkers was not seen after nine months, a significantly greater reduction with higher dose was reported after 12 months in the velaglucerase study, mean difference 16.70 (95% confidence intervaI 1.51 to 31.89). In the two enzyme replacement therapy maintenance studies comparing infusions every two weeks and every four weeks, there were no significant differences in haemoglobin concentration, platelet count, and spleen and liver volumes over a 6 to 12 month period when participants were treated with the same cumulative dose.A total of 25 serious adverse events were reported, nearly all deemed unrelated to treatment.There are, as yet, no randomized trials of substrate reduction therapy in treatment-naïve patients that can be evaluated. Miglustat monotherapy appeared as effective as continued enzyme replacement therapy for maintenance of hematological, organ and biomarker responses in people with type 1 Gaucher disease previously treated with imiglucerase for at least two years. In those with neuronopathic Gaucher disease, no significant improvements in haemoglobin concentration, platelet count or organ volumes occurred when enzyme replacement therapy was augmented with miglustat.One randomized controlled study assessing substrate reduction therapy was published immediately prior to producing the final version of this review, and this, along with a further ongoing study (expected to be published in the near future), will be assessed for eligibility in a future update of the review. AUTHORS' CONCLUSIONS: The results reflect the limitations of analysing evidence restricted to prospective randomized controlled trials, especially when dealing with chronic rare diseases. This analysis suggests that, during the first year of treatment, different recombinant glucocerebrosidases are bio-similar and non-inferior in safety and efficacy for surrogate biological response parameters. Enzyme replacement therapy given at 30 to 45 units/kg body weight every two to four weeks was generally as effective as the 60 unit/kg dose for the assessed clinical outcomes. The analysis emphasise the need to determine whether it is realistic to carry out multi-decade prospective clinical trials for rare diseases such as type 1 Gaucher disease. With large treatment effects on the classical manifestations of the disorder, therapeutic investigations in Gaucher disease mandate innovative trial designs and methodology to secure decisive data concerning long-term efficacy and safety - with the realization that knowledge about disease-modifying actions that are sustained are of crucial importance to people with this chronic condition.

Prescription of systemic antibiotics during pregnancy in primary care in Friuli Venezia Giulia, Northeastern Italy.

OBJECTIVE: To investigate the prescriptions of systemic antibiotics in a population of pregnant women in Italy, to identify socio-demographic factors associated with increased risk of being prescribed potentially unsafe medications, to compare prescriptions before and during pregnancy and to identify the prescribing General Practitioners (GPs). METHODS: A retrospective study based on administrative anonymous databases included all women resident of the Friuli Venezia Giulia Region who delivered babies in 2011 (n=9196). The antibiotic prescription risk was calculated by trimester and overall, and compared with that in the year before. Multivariate logistic regression analyses assessed the role of socio-demographic factors on the risk of being prescribed medications that should not be used as first-line. RESULTS: 6688 women (72.7%) were prescribed medicines (27363 prescriptions) during their pregnancies. Antibiotics were prescribed to 2279 women (24.8%), less commonly during pregnancy than before. Prescriptions were more frequent in the second and third trimesters. 1736 women were prescribed antibiotics other than first-line medicines (of which, seven tetracyclines and 58 quinolones, which are frankly not recommended). Those women were more frequently younger and less educated. The GPs responsible for those prescriptions were identified. CONCLUSIONS: In order to improve the prescription of antibiotics in pregnancy, an audit with the GPs is warranted to understand their motivations, discuss clinical cases and build consensus guidelines on which antibiotics should be preferred for use in pregnancy.

Long term effects of enzyme replacement therapy in an Italian cohort of type 3 Gaucher patients.

BACKGROUND: The chronic neuropathic form of Gaucher disease (GD3) is characterised by hepatosplenomegaly, anaemia, thrombocytopenia, bone alterations and central neurological involvement. Enzyme replacement therapy (ERT) has been demonstrated to be effective in non neuropathic Gaucher disease, but long term results in patients with GD3 are still limited and contrasting. A possible role of genotype in determining the response to ERT has been hypothesised. PATIENTS AND METHODS: All patients affected by GD3, treated with ERT, and followed-up in 4 different Italian centres (Udine, Catanzaro, Sassari and Florence) were included. Data on clinical conditions, laboratory values, neurological and neuropsychological examinations, radiological and electrophysiological features were collected retrospectively from clinical records. RESULTS: Ten patients (6 females, 4 males) with four different genotypes (L444P/L444P, L444P/F231I, P159T/unknown, C.115+1G>A/N188S) were identified. They received ERT infusions from 3 to 21years. Haematological parameters and organomegaly improved/normalised in all patients. Three patients showed severe progressive skeletal deformities. 6/10 patients were neurologically asymptomatic when they started ERT for systemic symptoms. During the follow-up, 2/6 developed an important central nervous system disease; 2/6 developed mild central symptoms; and 2/6 did not show any neurological symptom after 5, and 20years of treatment respectively, despite the presence of epileptiform abnormalities at the electroencephalogram. Overall, neurological involvement worsened over time in 6/10 patients, 3 of whom developed progressive myoclonic encephalopathy and died. CONCLUSIONS: ERT improved the systemic manifestations in patients with GD3, but was not able to counteract the progression of neurological symptoms in the long term.

Enzyme replacement therapy in juvenile glycogenosis type II: a longitudinal study.

UNLABELLED: Glycogenosis type II, a genetic muscle-wasting disorder, results in a spectrum of clinical phenotypes. Enzyme replacement therapy is effective in the infantile form of the disease, while little is known about its effectiveness in late-onset disease, especially in juvenile patients. The purpose of this retrospective cohort study was to assess the long-term effects of enzyme replacement therapy (ERT) in juvenile glycogenosis type II (GSDII). Eight Italian juvenile GSDII patients, receiving biweekly infusions of 20 mg/kg recombinant human α-glucosidase for at least 72 months, were enrolled (median age at therapy start was 11.8 years). Six-minute walk test (6MWT) and forced vital capacity (FVC), measured in upright position, were chosen as the principal outcome measures. Global motor disability (modified Walton scale (WS)), muscle enzymes levels [creatine phosphokinase (CK), lactate dehydrogenase (LDH), aspartate transaminase (AST), alanine transaminase (ALT)] and body mass index (BMI) were also analysed both at baseline (therapy start) and annually afterwards. At baseline, most patients (six out of eight) did not show muscle function impairment (WS ≤ 2). The performance at 6MWT showed a slight improvement during follow-up as well as FVC. Muscle enzymes levels showed a clear decrease after the 1st year of treatment while remained stable afterwards. An overall decrease in BMI was also observed during follow-up, although at the individual level, trends were variable. CONCLUSION: ERT is effective in stabilising both motor and lung functions in juvenile patients with GSDII, possibly slowing down the rate of disease progression. Randomised controlled trials are needed to understand whether early treatment allows juvenile patients to reach adulthood with a more beneficial residual muscular function than untreated patients.