The economic burden of pediatric growth hormone deficiency in Italy: a cost of illness study.

PURPOSE: Growth hormone deficiency (GHD) is a rare condition with a worldwide prevalence of 1 patient in 4000 to 10,000 live births, placing a significant economic burden on healthcare systems. The aim of this study is to generate evidence on the economic burden of children and adolescents with GHD treated with rhGH and their parents in Italy. METHODS: A cost of illness analysis, adopting the prevalence approach, has been developed, producing evidence on the total annual cost sustained by the Italian National Health System (NHS) and by the society. The study is based on original data collected from a survey conducted among Italian children and adolescents with GHD and their parents. RESULTS: 143 children/adolescents with GHD and their parents participated to the survey, conducted from May to October 2021. Patients had a mean age of 12.2 years (SD: 3.1) and were mostly males (68.5%). The average direct healthcare cost sustained by the NHS was € 8,497.2 per patient/year; adding the out-of-pocket expenses (co-payments and expenses for private healthcare service), the total expense was € 8,568.6. The indirect costs, assessed with the human capital approach, were € 847.9 per patient/year. The total of direct and indirect cost is € 9,345.1 from the NHS perspective, and € 9,416.5 from a social perspective. The total cost incurred by the Italian NHS for children with GHD (range: 5,708-8,354) was estimated in € 48.5-71.0 million, corresponding to 0.04-0.06% of the total Italian public health expense in the year 2020. CONCLUSIONS: The total annual cost for GHD children is close to € 10,000, and is mainly due to the cost of rhGH treatment. This cost is almost entirely sustained by the NHS, with negligible out-of-pocket expenses. The economic burden on the Italian NHS for the health care of established GHD children is fourfold higher than the prevalence of the disease in the overall Italian population.

Quality of life in children and adolescents with growth hormone deficiency and their caregivers: an Italian survey.

PURPOSE: The aim of this study was to produce evidence on quality of life (QoL) among Italian growth hormone deficiency (GHD) children and adolescents treated with growth hormone (GH) and their parents. METHODS: A survey was conducted among Italian children and adolescents aged 4-18 with a confirmed diagnosis of GHD and treated with GH therapy and their parents. The European Quality of Life 5 Dimensions 3 Level Version (EQ-5D-3L) and the Quality of Life in Short Stature Youth (QoLISSY) questionnaires were administered between May and October 2021 through the Computer-Assisted Personal Interview (CAPI) method. Results were compared with national and international reference values. RESULTS: The survey included 142 GHD children/adolescents and their parents. The mean EQ-5D-3L score was 0.95 [standard deviation (SD) 0.09], while the mean visual analogue scale (VAS) score was 86.2 (SD 14.2); the scores are similar to those of a reference Italian population aged 18-24 of healthy subjects. As for the QoLISSY child-version, compared to the international reference values for GHD/ idiopathic short stature (ISS) patients, we found a significantly higher score for the physical domain, and lower scores for coping and treatment; compared to the specific reference values for GHD patients, our mean scores were significantly lower for all domains except the physical one. As for the parents, we found a significantly higher score for the physical domain, and a lower score for treatment; compared to reference values GHD-specific, we found lower score in the social, emotional, treatment, parental effects, and total score domains. CONCLUSIONS: Our results suggest that the generic health-related quality of life (HRQoL) in treated GHD patients is high, comparable to that of healthy people. The QoL elicited by a disease specific questionnaire is also good, and comparable with that of international reference values of GHD/ISS patients.

Are glucose and insulin levels at all time points during OGTT a reliable marker of diabetes mellitus risk in pediatric obesity?

PURPOSE: Childhood overweight and obesity associated with insulin resistance and metabolic syndrome represent the new global pandemic and the main causative factors for dysglycemia, prediabetes, and Type 2 Diabetes Mellitus (T2DM). Predictors, such as HOMA-IR, HOMA-ß%, and QUICKI lack specific reference values in children. OGTT is a gold standard for glycometabolic assessment. Recently, a glycemic level higher than 155 mg/dl at + 60' after glucose ingestion has been defined as a risk factor for T2DM in obese adolescents. We aim to analyze and correlate fasting insulin-resistance markers with OGTT results in overweight/obese children and adolescents. METHODS: We retrospectively evaluated glucose and insulin values during a 2-h OGTT every 30 min in 236 overweight/obese patients. Glucose values and insulin sum during OGTT were compared to glycometabolic indexes and different cut-off values for insulin sum. RESULTS: A 1-h glucose > 155 mg/dl and insulin sum > 535 microU/ml at all times during OGTT are the best predictors of diabetes risk in obese youths. A1-h glucose > 155 mg/dl is significantly associated with HbA1c > 5.7%, while no association was observed between HbA1c > 5.7% and glucose levels at baseline and 2 h. The ability of the standardized HOMA-IR to predict the prediabetes status is clearly lower than the total insulin sum at OGTT. CONCLUSION: Our study demonstrates that also 1-h post-OGTT glucose, together with HbA1c, is an effective diabetes predictor.

Multicentric Italian case-control study on 25OH vitamin D levels in children and adolescents with Prader-Willi syndrome.

PURPOSE: 25OHD levels in patients with Prader-Willi Syndrome (PWS), the most frequent cause of genetic obesity with a peculiar fat mass distribution, are still debated. Insulin resistance (IR), Body Mass Index-SDS (BMI-SDS), Growth Hormone Therapy (GHT), and puberty onset seem to interact with 25OHD levels. The objectives of the study are: (1) To analyze 25OHD levels in pediatric PWS patients in comparison with a control group (CNT) (2) To evaluate a possible correlation between BMI-SDS, HOMA-IR, puberty, GHT, and 25OHD levels. METHODS: This is a retrospective case-control, multicenter study. Data were collected among 8 different Italian Hospitals (outpatient clinics), over a period of four years (2016-2020). We included 192 genetically confirmed PWS and 192 CNT patients, aged 3-18 years, matched 1:1 for age, gender, BMI-SDS, Tanner stage, sun exposure, and month of recruitment. RESULTS: No statistically significant differences in 25OHD levels were observed between the PWS population and the CNT (PWS 24.0 ng/mL vs CNT 22.5 ng/mL, p > 0.05), OR = 0.89 (95% CI 0.58-1.35). We observed a slight, although non-significant, reduction in 25OHD levels comparing NW and OB populations. HOMA-IR, puberty onset, genotype and GHT (previous or ongoing) did not show statistically significant correlation with 25OHD levels. CONCLUSIONS: Our findings could be useful for clinicians to optimize the therapeutic management as well as to increase awareness of PWS.

Kounis syndrome: an underestimated emergency.

Summary: Background. Kounis syndrome (KS) is defined as a rare cause of an acute coronary syndrome associated with systemic allergic reactions. To establish the prevalence of KS among the patients with diagnosis of anaphylaxis, we described clinical features, cardiological and allergological outcomes of patients evaluated in our allergy outpatient clinic. Methods. A retrospective study was carried out in the Allergy Unit of Novara hospital, from January 2008 to March 2020. Skin tests and in vitro tests were performed with suspected etiological agents. Results. We found 9 adults with KS (2%) out of 444 subjects who had experienced anaphylactic reactions (4/9 to Hymenoptera stings, 5/9 to drugs). Conclusions. The present study highlights the importance of suspicion of KS that appears not so uncommon in patients with anaphylaxis. KS seems to be a rare disease because unrecognized in diagnosis of anaphylaxis.

"Did you wash your hands?": a prospective study of patient empowerment to prompt hand washing by healthcare providers.

BACKGROUND: Hand hygiene is paramount in preventing the spread of healthcare-associated infections especially during disease epidemics. Compliance rates with hand hygiene policies remain below 50% internationally and may be lower in the outpatient care setting. This study assessed the impact of the patient empowerment model on hand hygiene compliance among healthcare providers. METHODS: From October 2016 to May 2017, patients from a large ambulatory oncology centre were prospectively enrolled. Patients were instructed to observe healthcare providers for hand hygiene compliance and to remind healthcare providers where it was not observed during at least three consecutive encounters. Healthcare provider reactions to this intervention were rated by patients. Patients' hand hygiene knowledge and beliefs were objectively elicited pre and post-study. RESULTS: Thirty patients with a median age of 52 years (range 5-91) completed the study for a total of 190 healthcare provider encounters. When initial hand hygiene was not observed, patients offered a reminder in 71 (37.4%) encounters, did not offer a reminder in 73 (38.4%) encounters and forgot to offer a reminder in 24 (14.2%) encounters. Patients perceived positive or neutral reactions in 76.8% of encounters and negative or surprised reactions in 23.2% of encounters. Healthcare provider compliance improved from 11.6% to 48.9% with intervention. Patient hand hygiene knowledge improved by 16% following the study. CONCLUSIONS: Patient-empowered hand hygiene may be a useful adjunct for improving hand hygiene compliance among healthcare providers and improving patient hand hygiene knowledge, although it may confer an emotional burden on patients.

A clinical-in silico study on the effectiveness of multipoint bicathodic and cathodic-anodal pacing in cardiac resynchronization therapy.

Up to one-third of patients undergoing cardiac resynchronization therapy (CRT) are nonresponders. Multipoint bicathodic and cathodic-anodal left ventricle (LV) stimulations could overcome this clinical challenge, but their effectiveness remains controversial. Here we evaluate the performance of such stimulations through both in vivo and in silico experiments, the latter based on computer electromechanical modeling. Seven patients, all candidates for CRT, received a quadripolar LV lead. Four stimulations were tested: right ventricular (RVS); conventional single point biventricular (S-BS); multipoint biventricular bicathodic (CC-BS) and multipoint biventricular cathodic-anodal (CA-BS). The following parameters were processed: QRS duration; maximal time derivative of arterial pressure (dPdtmax); systolic arterial pressure (Psys); and stroke volume (SV). Echocardiographic data of each patient were then obtained to create an LV geometric model. Numerical simulations were based on a strongly coupled Bidomain electromechanical coupling model. Considering the in vivo parameters, when comparing S-BS to RVS, there was no significant decrease in SV (from 45 ± 11 to 44 ± 20 ml) and 6% and 4% increases of dPdtmax and Psys, respectively. Focusing on in silico parameters, with respect to RVS, S-BS exhibited a significant increase of SV, dPdtmax and Psys. Neither the in vivo nor in silico results showed any significant hemodynamic and electrical difference among S-BS, CC-BS and CA-BS configurations. These results show that CC-BS and CA-BS yield a comparable CRT performance, but they do not always yield improvement in terms of hemodynamic parameters with respect to S-BS. The computational results confirmed the in vivo observations, thus providing theoretical support to the clinical experiments.

Medical Student Attitudes toward USMLE Step 1 and Health Systems Science - A Multi-Institutional Survey.

Phenomenon: Because of its importance in residency selection, the United States Medical Licensing Examination Step 1 occupies a critical position in medical education, stimulating national debate about appropriate score use, equitable selection criteria, and the goals of undergraduate medical education. Yet, student perspectives on these issues and their implications for engagement with health systems science-related curricular content are relatively underexplored. Approach: We conducted an online survey of medical students at 19 American allopathic medical schools from March-July, 2019. Survey items were designed to elicit student opinions on the Step 1 examination and the impact of the examination on their engagement with new, non-test curricular content related to health systems science. Findings: A total of 2856 students participated in the survey, representing 23.5% of those invited. While 87% of students agreed that doing well on the Step 1 exam was their top priority, 56% disagreed that studying for Step 1 had a positive impact on engagement in the medical school curriculum. Eighty-two percent of students disagreed that Step 1 scores should be the top item residency programs use to offer interviews. When asked whether Step 1 results should be reported pass/fail with no numeric score, 55% of students agreed, while 33% disagreed. The majority of medical students agreed that health systems science topics were important but disagreed that studying for Step 1 helped learn this content. Students reported being more motivated to study a topic if it was on the exam, part of a course grade, prioritized by residency program directors, or if it would make them a better physician in the future. Insights: These results confirm the primacy of the United States Medical Licensing Examination Step 1 exam in preclinical medical education and demonstrate the need to balance the objectives of medical licensure and residency selection with the goals of the broader medical profession. The survey responses suggest several potential solutions to increase student engagement in health systems science curricula which may be especially important after Step 1 examination results are reported as pass/fail.

Peripheral arterial disease has a strong impact on cardiovascular outcome in patients with acute coronary syndromes: from the START Antiplatelet registry.

BACKGROUND: Peripheral arterial disease (PAD) was reported to increase the risk of new cardiovascular events in patients with acute coronary syndromes (ACS). However, most of the evidence comes from randomized clinical trials. We aimed to assess the impact of PAD on cardiovascular outcome and treatment decisions in ACS patients in a current real-life setting. METHODS: START-ANTIPLATELET is a multicenter registry enrolling ACS patient. Baseline clinical characteristics and treatment at discharge were recorded and follow-up was repeated at 6-months and 1-year. PAD was defined as intermittent claudication and/or previous revascularization. RESULTS: Among 1442 patients enrolled, 103 (7.1%) had PAD. PAD patients were older (71.8 ± 10.6vs66.2 ± 12.6 yrs., p < 0.0001), more frequently hypertensive (90.3vs68.6%, p< 0.0001), hypercholesterolemic (66vs52%, p= 0.037), diabetic (51.5vs24%, p= 0.0001), obese (28.2vs19.3%, p= 0.029) and with previous TIA (7.8vs2.8%, p= 0.005) or stroke (11.7vs3.1%, p< 0.0001). Clinical presentation and acute treatment were similar in non-PAD and PAD patients, but the latter were discharged significantly less frequently on dual antiplatelet therapy (DAPT) (68.9vs85%, p= 0.005). After a median follow-up time of 11.1 months, major cardio/cerebrovascular event-free survival [MACCE, including cardiovascular death, MI, TIA and stroke, target-vessel revascularization (TVR) and major arterial ischemic events] was significantly shorter (9.0vs11.2 months, p= 0.02; HR 3.2, 2.4-8.4) in PAD patients and net adverse cardiovascular events (NACE = MACCE plus major hemorrhages) were significantly more frequent (19.1%vs10.5%, p = 0.049). CONCLUSIONS: PAD identifies a subgroup of ACS patients at significantly increased cardiovascular risk, but these patients tend to be undertreated. Patients admitted for ACS should be screened for PAD and optimal medical therapy at discharge should be implemented.

Patient motivational dialogue: A novel approach to improve hand hygiene through patient empowerment in ambulatory care.

A novel patient empowerment strategy called Patient Motivational Dialogue purposed to improve hand hygiene compliance is described. Two barriers to sustainability of patients asking health care providers (HCP) to clean their hands were noted in this study: (1) the HCP responding negatively to the patient asking, and (2) the patient misunderstanding that wearing gloves does not replace hand hygiene. Both barriers may be addressed through education of HCP and of consumer.

Environmental Infection Prevention: Priorities of Patient Safety Collaboration.

Although progress has been made in decreasing health care-associated infections (HAI) in intensive care unit (ICU) patients, there has been an increase in HAI caused by drug-resistant pathogens, particularly those that contaminate the environment such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, Pseudomonas spp, Acinetobacter spp, and Clostridium difficile. The ICU environment including sinks and medical equipment has been identified as being at risk for contamination and associated with cross-transmission of pathogens between the health care provider, the environment, and the patient. This article addresses the role of the ICU nurse as a team facilitator collaborating with environmental services, infection preventionists, and others to influence ICU design during preconstruction planning and unit environmental hygiene after construction to promote patient safety and prevent HAI associated with contaminated environments and equipment.

A new H2 (+) source: Conceptual study and experimental test of an upgraded version of the VIS-Versatile ion source.

The versatile ion source is an off-resonance microwave discharge ion source which produces a slightly overdense plasma at 2.45 GHz of pumping wave frequency extracting more than 60 mA proton beams and 50 mA He(+) beams. DAEδALUS and IsoDAR experiments require high intensities for H2 (+) beams to be accelerated by high power cyclotrons for neutrinos generation. In order to fulfill the new requirements, a new plasma chamber and injection system has been designed and manufactured for increasing the H2 (+) beam intensity. In this paper the studies for the increasing of the H2 (+)/p ratio and for the design of the new plasma chamber and injection system will be shown and discussed together with the experimental tests carried out at Istituto Nazionale di Fisica Nucleare-Laboratori Nazionali del Sud (INFN-LNS) and at Best Cyclotron Systems test-bench in Vancouver, Canada.

The new ECR charge breeder for the Selective Production of Exotic Species project at INFN--Laboratori Nazionali di Legnaro.

The Selective Production of Exotic Species (SPES) project is an ISOL facility under construction at Istituto Nazionale di Fisica Nucleare-Laboratori Nationali di Legnaro (INFN-LNL). 1+ radioactive ions, produced and extracted from the target-ion-source system, will be charge bred to high charge states by an ECR charge breeder (SPES-CB): the project will adopt an upgraded version of the PHOENIX charge breeder, developed since about twenty years by the Laboratoire de Physique Subatomique et de Cosmologie (LPSC). The collaboration between LNL and LPSC started in 2010 with charge breeding experiments performed on the LPSC test bench and led, in June 2014, to the signature of a Research Collaboration Agreement for the delivery of a complete charge breeder and ancillaries, satisfying the SPES requirements. Important technological aspects were tackled during the construction phase, as, for example, beam purity issues, electrodes alignment, and vacuum sealing. This phase was completed in spring 2015, after which the qualification tests were carried out at LPSC on the 1+/q+ test stand. This paper describes the characteristics of the SPES-CB, with particular emphasis on the results obtained during the qualification tests: charge breeding of Ar, Xe, Rb, and Cs satisfied the SPES requirements for different intensities of the injected 1+ beam, showing very good performances, some of which are "best ever" for this device.

Electromagnetic analysis of the plasma chamber of an ECR-based charge breeder.

The optimization of the efficiency of an ECR-based charge breeder is a twofold task: efforts must be paid to maximize the capture of the injected 1+ ions by the confined plasma and to produce high charge states to allow post-acceleration at high energies. Both tasks must be faced by studying in detail the electrons heating dynamics, influenced by the microwave-to-plasma coupling mechanism. Numerical simulations are a powerful tools for obtaining quantitative information about the wave-to-plasma interaction process: this paper presents a numerical study of the microwaves propagation and absorption inside the plasma chamber of the PHOENIX charge breeder, which the selective production of exotic species project, under construction at Legnaro National Laboratories, will adopt as charge breeder. Calculations were carried out with a commercial 3D FEM solver: first, all the resonant frequencies were determined by considering a simplified plasma chamber; then, the realistic geometry was taken into account, including a cold plasma model of increasing complexity. The results gave important information about the power absorption and losses and will allow the improvement of the plasma model to be used in a refined step of calculation reproducing the breeding process itself.

Optimizing charge breeding techniques for ISOL facilities in Europe: Conclusions from the EMILIE project.

The present paper summarizes the results obtained from the past few years in the framework of the Enhanced Multi-Ionization of short-Lived Isotopes for Eurisol (EMILIE) project. The EMILIE project aims at improving the charge breeding techniques with both Electron Cyclotron Resonance Ion Sources (ECRIS) and Electron Beam Ion Sources (EBISs) for European Radioactive Ion Beam (RIB) facilities. Within EMILIE, an original technique for debunching the beam from EBIS charge breeders is being developed, for making an optimal use of the capabilities of CW post-accelerators of the future facilities. Such a debunching technique should eventually resolve duty cycle and time structure issues which presently complicate the data-acquisition of experiments. The results of the first tests of this technique are reported here. In comparison with charge breeding with an EBIS, the ECRIS technique had lower performance in efficiency and attainable charge state for metallic ion beams and also suffered from issues related to beam contamination. In recent years, improvements have been made which significantly reduce the differences between the two techniques, making ECRIS charge breeding more attractive especially for CW machines producing intense beams. Upgraded versions of the Phoenix charge breeder, originally developed by LPSC, will be used at SPES and GANIL/SPIRAL. These two charge breeders have benefited from studies undertaken within EMILIE, which are also briefly summarized here.

Inflammation triggers production of dimethylsphingosine from oligodendrocytes.

Neuropathic pain is a chronic, refractory condition that arises after damage to the nervous system. We previously showed that an increased level of the endogenous metabolite N,N-dimethylsphingosine (DMS) in the central nervous system (CNS) is sufficient to induce neuropathic pain-like behavior in rats. However, several important questions remain. First, it has not yet been demonstrated that DMS is produced in humans and its value as a therapeutic target is therefore unknown. Second, the cell types within the CNS that produce DMS are currently unidentified. Here we provide evidence that DMS is present in human CNS tissue. We show that DMS levels increase in demyelinating lesions isolated from patients with multiple sclerosis, an autoimmune disease in which the majority of patients experience chronic pain. On the basis of these results, we hypothesized that oligodendrocytes may be a cellular source of DMS. We show that human oligodendrocytes produce DMS in culture and that the levels of DMS increase when oligodendrocytes are challenged with agents that damage white matter. These results suggest that damage to oligodendrocytes leads to increased DMS production which in turn drives inflammatory astrocyte responses involved in sensory neuron sensitization. Interruption of this pathway in patients may provide analgesia without the debilitating side effects that are commonly observed with other chronic pain therapies.

Improved design of proton source and low energy beam transport line for European Spallation Source.

The design update of the European Spallation Source (ESS) accelerator is almost complete and the construction of the prototype of the microwave discharge ion source able to provide a proton beam current larger than 70 mA to the 3.6 MeV Radio Frequency Quadrupole (RFQ) started. The source named PS-ESS (Proton Source for ESS) was designed with a flexible magnetic system and an extraction system able to merge conservative solutions with significant advances. The ESS injector has taken advantage of recent theoretical updates and new plasma diagnostics tools developed at INFN-LNS (Laboratori Nazionali del Sud, Istituto Nazionale di Fisica Nucleare). The design strategy considers the PS-ESS and the low energy beam transport line as a whole, where the proton beam behaves like an almost neutralized non-thermalized plasma. Innovative solutions have been used as hereinafter described. Thermo-mechanical optimization has been performed to withstand the chopped beam and the misaligned focused beam over the RFQ input collimator; the results are reported here.

Ionization efficiency studies with charge breeder and conventional electron cyclotron resonance ion source.

Radioactive Ion Beams play an increasingly important role in several European research facility programs such as SPES, SPIRAL1 Upgrade, and SPIRAL2, but even more for those such as EURISOL. Although remarkable advances of ECRIS charge breeders (CBs) have been achieved, further studies are needed to gain insight on the physics of the charge breeding process. The fundamental plasma processes of charge breeders are studied in the frame of the European collaboration project, EMILIE, for optimizing the charge breeding. Important information on the charge breeding can be obtained by conducting similar experiments using the gas mixing and 2-frequency heating techniques with a conventional JYFL 14 GHz ECRIS and the LPSC-PHOENIX charge breeder. The first experiments were carried out with noble gases and they revealed, for example, that the effects of the gas mixing and 2-frequency heating on the production of high charge states appear to be additive for the conventional ECRIS. The results also indicate that at least in the case of noble gases the differences between the conventional ECRIS and the charge breeder cause only minor impact on the production efficiency of ion beams.

Postadmission sepsis as a screen for quality problems: a case-control study.

The present on admission (POA) indicator used with diagnosis codes listed in hospital discharge abstracts makes it possible to screen for possible in-hospital complications, which may in turn point to quality of care problems. A case-control study was performed among 382 patients from 30 New York State hospitals to see if lapses in quality were associated with the development of postadmission sepsis. Cases with hospital-acquired sepsis (labeled not POA) were compared with matched controls without sepsis. The authors found that central venous catheters and emergently inserted peripheral intravenous catheters were associated with subsequent development of sepsis. Urethral catheters were associated with sepsis for medical patients but not for surgical patients. Adherence to several process of care guidelines was incomplete but none occurred statistically significantly more frequently among sepsis cases than controls. Using discharge abstract diagnosis codes to determine the presence of postadmission complications shows promise for identifying areas for quality improvement.