The scale-up finance gap in the EU: Causes, consequences, and policy solutions.

This paper assesses the financing gap faced by innovative start-ups in the European Union (EU) when they reach the scaling-up stage of their development. It draws on data collected through a seminar involving 117 experts representing start-ups and scale-ups, financial actors, academia, and EU policymakers and aimed at investigating the causes, consequences, and policy solutions of the scale-up gap in the EU. Besides highlighting supply-side deficiencies, the seminar also emphasised weaknesses in both the demand side of the scale-up gap and the EU ecosystem for high-growth entrepreneurship. The paper offers policy recommendations, highlighting the need for policy solutions involving private actors and specifically targeting scale-ups. The paper also calls for more robust research on measuring the scale-up financing gap and its economic impact to improve the policy response.

Health Technology Assessment of Intensive Care Ventilators for Pediatric Patients.

This paper is aimed at addressing all the critical aspects linked to the implementation of intensive care ventilators in a pediatric setting, highlighting the most relevant technical features and describing the methodology to conduct health technology assessment (HTA) for supporting the decision-making process. Four ventilator models were included in the assessment process. A decision-making support tool (DoHTA method) was applied. Twenty-eight Key Performance Indicators (KPIs) were identified, defining the safety, clinical effectiveness, organizational, technical, and economic aspects. The Performance scores of each ventilator have been measured with respect to KPIs integrated with the total cost of ownership analysis, leading to a final rank of the four possible technological solutions. The final technologies' performance scores reflected a deliver valued, contextualized, and shared outputs, detecting the most performant technological solution for the specific hospital context. HTA results had informed and supported the pediatric hospital decision-making process. This study, critically identifying the pros and cons of innovative features of ventilators and the evaluation criteria and aspects to be taken into account during HTA, can be considered as a valuable proof of evidence as well as a reliable and transferable method for conducting decision-making processes in a hospital context.

Deciphering Genetic Variants of Warfarin Metabolism in Children With Ventricular Assist Devices.

Warfarin is prescribed in patients with ventricular assist devices (VADs). Dosage depends on several factors including the underlying genotype. These include polymorphisms of genes encoding cytochrome P450 enzymes, the main ones being CYP2C9, VKORC1, and CYP4F2. The objectives of this study were to evaluate the prevalence of CY2CP9 1*2*3*, VKORC1, and CYP4F2 in children with VADs and the time to reach the target international normalized ratio. We performed a retrospective/prospective study in children with VADs. We recorded polymorphisms, disease, type of VAD, ethnicity, age, gender, height, weight, INR values, bleeding, and thromboembolic episodes. Informed consent was obtained. We enrolled 34 children (19 male, 15 female), with a median age of 2 years (range 0.3-17 years) and median weight of 6.9Kg. The Berlin Heart was the most commonly implanted VAD (22/34; 64%), and the most common diagnosis was dilated cardiomyopathy. Statistical analysis confirmed a significant partial correlation with VKORC1 CC (p = 0.019). The CYP2C9*2 CT genotype showed a late rise in target INR values (p = 0.06), while the CYP2C9*2 CC showed a tendency toward an early INR rise (p = 0.024). We provide new information on the contribution of the warfarin polymorphisms in children with VAD implantation. Pharmacogenomic dosing for children using warfarin has the potential to improve clinical care in VAD patients. Patients with the CYP2C9*2 CT genotype may need more time or higher doses to reach target INR, while clinicians may need to be aware of the potential for a rapid rise in INR in patients with the CYP2C9*2 CC genotype.

Principlism and Personalism. Comparing Two Ethical Models Applied Clinically in Neonates Undergoing Extracorporeal Membrane Oxygenation Support.

Extracorporeal membrane oxygenation (ECMO) is a technology used to temporarily assist critically ill patients with acute and reversible life-threatening cardiac and/or respiratory failure. This technology can often be lifesaving but is also associated with several complications that may contribute to reduced survival. Currently, neonates supported with ECMO are complex and bear an increased risk of mortality. This means that clinicians must be particularly prepared not only to deal with complex clinical scenarios, but also ethical issues associated with ECMO. In particular, clinicians should be trained to handle unsuccessful ECMO runs with attention to high quality end of life care. Within this manuscript we will compare and contrast the application of two ethical frameworks, used in the authors' institutions (Toronto and Rome). This is intended to enhance a broader understanding of cultural differences in applied ethics which is useful to the clinician in an increasingly multicultural and diverse patient mix.

Lung ultrasound profile after cardiopulmonary bypass in paediatric cardiac surgery: first experience in a simple cohort.

Objectives: To explore the association between lung ultrasound (LUS) and clinical variables in children undergoing cardiopulmonary bypass (CPB). Methods: A retrospective analysis was conducted in patients weighing <20 kg and with an Aristotle score <9, scanned with LUS on postoperative day (POD) 0, 1 and 2. We defined three LUS profiles: profile A: the prevalence of confluent B lines ("white lung"); profile B: the prevalence of B lines and profile C: the prevalence of A lines (normal lung). Results: Median (interquartile range [IRQ]) weight, age and Aristotle score were 5.6 kg [IQR 4.0-6.0], 3.2 months [IQR 3.0-7.0] and 6.75 [IQR 6.0-8.0], respectively. No profile A patients were found. At POD1, we identified statistically significant differences between profile B and C patients: CPB time was 157 [IQR138-235] vs 95 [IQR 85-183] minutes ( P < 0.005); aortic clamp duration was 104 [IQR 87-142] vs 54 [IQR 49-72] minutes ( P = 0.007); time of mechanical ventilation was 41.5 [IQR 31.0-56.0] vs 15 [IQR 15-24] hours ( P < 0.001); and ICU length of stay was 2 [IQR 2-3] vs 4 [IQR 3-4] days ( P = 0.001), respectively. No differences were found between profile B and C patients at all the other time points. No statistically significant differences were found for blood gas values, urine output and fluid balance at all time points. Conclusions: In a small cohort of children undergoing CPB, the LUS profile on POD1 was associated with CPB time, aortic cross-clamp time and mechanical ventilation duration.

Left ventricular assist device as destination therapy in cardiac end-stage dystrophinopathies: Midterm results.

OBJECTIVE: We report our experience with the use of a left ventricular assist device (LVAD) as destination therapy (DT) for the management of patients with cardiac end-stage dystrophinopathies. METHODS: From February 2011 to February 2016, 7 patients with dystrophinopathies and dilated cardiomyopathy (DCM) were treated with LVADs at our institution. Median age at surgery was 16.5 years (range, 14.2-23.4 years). All patients were preoperatively evaluated by a multidisciplinary team approach. RESULTS: All patients survived to hospital discharge. The early postoperative course was characterized by abdominal bleeding (1 patient) and retropharyngeal bleeding (1 patient). Because of abdominal or retropharyngeal bleeding, both required postoperative heparin infusion discontinuation for 35 and 33 days, respectively. Among the late complications, 1 child developed osteolysis and infection at the pedestal site of the device, which required surgical displacement; 1 patient required gastrostomy as a result of poor feeding, and another had a cerebral stroke, which was treated with percutaneous thrombus aspiration. The other 2 patients did not show early or late complications. At a median follow-up time of 21.7 months (range, 3-45 months) there have been 3 deaths: 1 patient died of a lung infection after 45 months, 1 died of tracheal bleeding after 29 months, and 1 died of cerebral hemorrhage after 14 months. CONCLUSIONS: Our experience indicates that the use of an LVAD as DT in patients with dystrophinopathies with end-stage DCM is feasible, suggesting that it may be suitable as a palliative therapy for the treatment of these patients with no other therapeutic options.

The Use of Berlin Heart EXCOR VAD in Children Less than 10 kg: A Single Center Experience.

Objective: Despite the improvement in ventricular assist device (VAD) therapy in adults and in adolescents, in infant population only Berlin Heart EXCOR (BHE) is licensed as long term VAD to bridge children to Heart Transplantation (HTx). Particularly demanding in terms of morbidity and mortality are smallest patients namely the ones implanted in the first year of life or with a lower body surface area. This work aims at retrospective reviewing a single center experience in using BHE in children with a body weight under 10 kg. Methods: Data of all pediatric patients under 10 kg undergoing BHE implantation in our institution from March 2002 to March 2016 were retrospectively reviewed. Results: Of the 30 patients enrolled in the study, 53% were male, 87% were affected by a dilated cardiomyopathy with an average weight and age at the implantation of 6.75 ± 2.16 Kg and 11.57 ± 10.12 months, respectively. Three patients (10%) required a BIVAD implantation. After the implantation, 7 patients (23%) required re-intervention for bleeding and 9 patients (30%) experienced BHE cannulas infection. A total of 56 BHE pump were changed for thrombus formation (1.86 BHE pump for patient). The average duration of VAD support was 132.8 ± 94.4 days. Twenty patients (67%) were successfully transplanted and 10 patients (33%) died: 7 for major neurological complication and 3 for sepsis. Conclusion: Mechanical support in smaller children with end stage heart failure is an effective strategy for bridging patients to HTx. The need for BIVAD was relegated, in the last years, only to restrictive cardiomiopathy. Further efforts are required in small infants to improve anticoagulation strategy to reduce neurological events and BHE pump changes.

Major discrepancies between what clinical trial registries record and paediatric randomised controlled trials publish.

BACKGROUND: Whether information from clinical trial registries (CTRs) and published randomised controlled trial (RCTs) differs remains unknown. Knowing more about discrepancies should alert those who rely on RCTs for medical decision-making to possible dissemination or reporting bias. To provide help in critically appraising research relevant for clinical practice we sought possible discrepancies between what CTRs record and paediatric RCTs actually publish. For this purpose, after identifying six reporting domains including funding, design, and outcomes, we collected data from 20 consecutive RCTs published in a widely read peer-reviewed paediatric journal and cross-checked reported features with those in the corresponding CTRs. METHODS: We collected data for 20 unselected, consecutive paediatric RCTs published in a widely read peer-reviewed journal from July to November 2013. To assess discrepancies, two reviewers identified and scored six reporting domains: funding and conflict of interests; sample size, inclusion and exclusion criteria or crossover; primary and secondary outcomes, early study completion, and main outcome reporting. After applying the Critical Appraisal Skills Programme (CASP) checklist, five reviewer pairs cross-checked CTRs and matching RCTs, then mapped and coded the reporting domains and scored combined discrepancy as low, medium and high. RESULTS: The 20 RCTs were registered in five different CTRs. Even though the 20 RCTs fulfilled the CASP general criteria for assessing internal validity, 19 clinical trials had medium or high combined discrepancy scores for what the 20 RCTs reported and the matched five CTRs stated. All 20 RCTs selectively reported or failed to report main outcomes, 9 had discrepancies in declaring sponsorship, 8 discrepancies in the sample size, 9 failed to respect inclusion or exclusion criteria, 11 downgraded or modified primary outcome or upgraded secondary outcomes, and 13 completed early without justification. The CTRs for seven trials failed to index automatically the URL address or the RCT reference, and for 12 recorded RCT details, but the authors failed to report the results. CONCLUSIONS: Major discrepancies between what CTRs record and paediatric RCTs publish raise concern about what clinical trials conclude. Our findings should make clinicians, who rely on RCT results for medical decision-making, aware of dissemination or reporting bias. Trialists need to bring CTR data and reported protocols into line with published data.

Mechanically Assisted Total Cavopulmonary Connection With an Axial Flow Pump: Computational and In Vivo Study.

A relevant number of patients undergoing total cavopulmonary connection (TCPC) experience heart failure (HF). Heart transplant is then the final option when all other treatments fail. The axial flow blood pumps are now the state of the art; however, there is little experience in low-pressure circuits, such as support of the right ventricle or even a TCPC circulation. A new T-shaped model of mechanically assisted TCPC using the "Jarvik Child 2000" axial pump, (flow rates between 1 and 3 L/m in a range of 5000-9000 rpm) was designed, simulated numerically, and then tested in animals. Eight sheep (42-45 kg) were studied: two pilot studies, four pump-supported (PS) TCPC for 3 h, and two not pump-supported (NPS) TCPC. In the PS, the axial pump was set to maintain the baseline cardiac output (CO). Pressures, CO, systemic and pulmonary vascular resistance, lactate levels, and blood gases were recorded for 3 h. Computational fluid dynamics (CFD) study allows us to set the feasible operating condition and the safety margins to minimize the venous collapse risk. In the NPS animals, a circulatory deterioration, with increasing lactate level, occurred rapidly. In the PS animals, there was a stable cardiac index of 2.7 ± 1.4 L/min/m(2), central venous pressure of 12.3 ± 1 mm Hg, and a mean pulmonary artery pressure (PAP) of 18.1 ± 6 after 3 h of support up to 9000 rpm. systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), blood gasses, and arterial lactate levels remained stable to baseline values. No caval collapse occurred. A new pediatric axial flow pump provides normal CO and physiologic stability in a new T-shaped model of TCPC in sheep, in vivo. CFD and in vivo data showed that this experimental arrangement will allow us to evaluate the potential for mechanical support in patients with Fontan failure avoiding major adverse events.

Implantation of a left ventricular assist device as a destination therapy in Duchenne muscular dystrophy patients with end stage cardiac failure: management and lessons learned.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder, characterized by progressive skeletal muscle weakness, loss of ambulation, and death secondary to cardiac or respiratory failure. End-stage dilated cardiomyopathy (DCM) is a frequent finding in DMD patients, they are rarely candidates for cardiac transplantation. Recently, the use of ventricular assist devices as a destination therapy (DT) as an alternative to cardiac transplantation in DMD patients has been described. Preoperative planning and patient selection play a significant role in the successful postoperative course of these patients. We describe the preoperative, intraoperative and postoperative management of Jarvik 2000 implantation in 4 DMD pediatric (age range 12-17 years) patients. We also describe the complications that may occur. The most frequent were bleeding and difficulty in weaning from mechanical ventilation. Our standard protocol includes: 1) preoperative multidisciplinary evaluation and selection, 2) preoperative and postoperative non-invasive ventilation and cough machine cycles, 3) intraoperative use of near infrared spectroscopy (NIRS) and transesophageal echocardiography, 4) attention on surgical blood loss, use of tranexamic acid and prothrombin complexes, 5) early extubation and 6) avoiding the use of nasogastric feeding tubes and nasal temperature probes. Our case reports describe the use of Jarvik 2000 as a destination therapy in young patients emphasizing the use of ventricular assist devices as a new therapeutic option in DMD.

Comparative evaluation of high-flow nasal cannula and conventional oxygen therapy in paediatric cardiac surgical patients: a randomized controlled trial.

OBJECTIVES: The aim of this study was to compare high-flow nasal cannula (HFNC) and conventional O2 therapy (OT) in paediatric cardiac surgical patients; the primary objective of the study was to evaluate whether HFNC was able to improve PaCO2 elimination in the first 48 h after extubation postoperatively. METHODS: We conducted a randomized, controlled trial in pediatric cardiac surgical patients under 18 months of age. At the beginning of the weaning of ventilation, patients were randomly assigned to either of the following groups: OT or HFNC. Arterial blood samples were collected before and after extubation at the following time points: 1, 6, 12, 24 and 48 h. The primary outcome was comparison of arterial PaCO2 postextubation; secondary outcomes were PaO2 and PaO2/fractional inspired oxygen (FiO2) ratio, rate of treatment failure and need of respiratory support, rate of extubation failure, rate of atelectasis, simply to complications and the length of paediatric cardiac intensive care unit stay. RESULTS: Demographic and clinical variables were comparable in the two groups. Analysis of variance for repeated measures showed that PaCO2 was not significantly different between the HFNC and OT groups (P = 0.5), whereas PaO2 and PaO2/FiO2 were significantly improved in the HFNC group (P = 0.01 and P = 0.001). The rate of reintubation was not different in the two groups (P = 1.0), whereas the need for noninvasive respiratory support was 15% in the OT group and none in the HFNC group (P = 0.008). CONCLUSIONS: HFNC had no impact on PaCO2 values. The use of HFNC appeared to be safe and improved PaO2 in paediatric cardiac surgical patients.

Inappropriate use of neurally adjusted ventilator assist.

Neurally adjusted ventilator assist (NAVA) is a ventilator mode based on providing assistance to the patient in proportion to the electrical activity of the diaphragm. NAVA may improve patient-ventilator interactions. We describe a very complex case of a child with a permanent ventricular assist device where we attempted to use NAVA during the weaning process and then realised that it was impossible to use.

Neurally adjusted ventilatory assist and lung transplant in a child: A case report.

OBJECTIVE: To report the successful application of neurally adjusted ventilatory assist to a child with cystic fibrosis who underwent single-lung transplantation. DESIGN: Case report. SETTING: Pediatric cardiac intensive care unit. PATIENT: A 15-yr-old male with cystic fibrosis was admitted to our pediatric cardiac intensive care unit after single-lung transplantation. The child had previously received two bowel resections at the age of 1 yr, right pneumonectomy at the age of 3 yrs, and endoscopic percutaneus gastrostomy at the age of 10 yrs. After transplant, the child failed several attempts of weaning off mechanical ventilation with pressure-support ventilation, due to infection, pneumothorax, and ventilator asynchrony that caused gastric distension and numerous episodes of nausea and vomiting. INTERVENTION: Use of neurally adjusted ventilatory assist to avoid patient-ventilator dyssynchrony and consequent gastric distension. CONCLUSIONS: The utilization of neurally adjusted ventilatory assist allowed to limit the risk of overassistance and prevent patient-ventilator asynchrony and to successfully wean the child off mechanical ventilation after single-lung transplant.