Comparative efficacy of antiepileptic drugs in children and adolescents: A network meta-analysis.

OBJECTIVE: To estimate the comparative efficacy among antiepileptic drugs in the pediatric population (0-18 years). METHODS: Using the Embase and MEDLINE databases, we updated to February 2017 the search strategy of the National Institute for Health and Care Excellence guidelines for epilepsy. We only included randomized clinical trials conducted in children and mixed-age populations. According to the PRISMA network meta-analysis guideline, the study-level quality assessment was made with the Cochrane risk-of-bias tool. Three investigators independently selected articles. The efficacy outcome was considered to be seizure freedom or ≥50% seizure reduction. RESULTS: We selected 46 randomized clinical trials. A total of 5652 individuals were randomized to 22 antiepileptic drugs and placebo. The point estimates of carbamazepine and lamotrigine efficacy showed their superiority with respect to all comparator antiepileptic drugs for the treatment of newly diagnosed focal epilepsy. In refractory focal epilepsy, levetiracetam (odds ratio [OR] = 3.3, 95% credible interval [CrI] = 1.3-7.6) and perampanel (OR = 2.5, 95% CrI = 1.1-5.8) were more effective compared to placebo. Ethosuximide and valproic acid were both superior to lamotrigine against absence seizures. The OR point estimate showed the superiority of adrenocorticotropic hormone over all comparators in infantile spasms. A wide heterogeneity in the length of follow-up was observed among the studies. SIGNIFICANCE: This network meta-analysis suggests that the quality of studies should be improved through the use of comparative designs, relevant outcomes, appropriate follow-up length, and more reliable inclusion criteria.

Fetal programming and systemic sclerosis.

OBJECTIVE: This study investigated whether birthweight is linked to an increased risk of the development of systemic sclerosis. STUDY DESIGN: This was a multicenter case-control study with perinatal data that were obtained from 332 cases with systemic sclerosis and 243 control subjects. Birthweight was treated as a dichotomous variable (<2500 g vs ≥2500 g); low birthweight was defined as a weight <2500 g; small for gestational age was defined as birthweight <10th percentile for gestational age adjusted for sex. The relationship between systemic sclerosis and both low birthweight and small for gestational age was expressed with the crude (univariate analysis) and adjusted (multivariate analysis) odds ratio (OR). RESULTS: Significantly increased ORs were observed in the univariate analysis for low birthweight (OR, 2.59; 95% confidence interval [CI], 1.39-5.05) and small for gestational age (OR, 2.60; 95% CI, 1.34-5.32) subjects. Similarly increased risks were confirmed for both conditions in the multivariate analysis (OR, 3.93; 95% CI, 1.92-8.07; and OR, 2.58; 95% CI, 1.28-5.19), respectively. CONCLUSION: Low birthweight and small for gestational age at birth are risk factors for the adult onset of systemic sclerosis.

HyM3D: A hybrid method for the automatic 3D reconstruction of a defective cranial vault.

BACKGROUND AND OBJECTIVE: The ability to accomplish a consistent restoration of a missing or deformed anatomical area is a fundamental step for defining a custom implant, especially in the maxillofacial and cranial reconstruction where the aesthetical aspect is crucial for a successful surgical outcome. At the same time, this task is also the most difficult, time-consuming, and complicated across the whole reconstruction process. This is mostly due to the high geometric complexity of the anatomical structures, insufficient references, and significant interindividual anatomical heterogeneity. Numerous solutions, specifically for the neurocranium, have been put forward in the scientific literature to address the reconstruction issue, but none of them has yet been persuasive enough to guarantee an easily automatable approach with a consistent shape reconstruction. METHODS: This work aims to present a novel reconstruction method (named HyM3D) for the automatic restoration of the exocranial surface by ensuring both the symmetry of the resulting skull and the continuity between the reconstructive patch and the surrounding bone. To achieve this goal, the strengths of the Template-based methods are exploited to provide knowledge of the missing or deformed region and to guide a subsequent Surface Interpolation-based algorithm. HyM3D is an improved version of a methodology presented by the authors in a previous publication for the restoration of unilateral defects. Differently from the first version, the novel procedure applies to all kinds of cranial defects, whether they are unilateral or not. RESULTS: The presented method has been tested on several test cases, both synthetic and real, and the results show that it is reliable and trustworthy, providing a consistent outcome with no user intervention even when dealing with complex defects. CONCLUSIONS: HyM3D method proved to be a valid alternative to the existing approaches for the digital reconstruction of a defective cranial vault; furthermore, with respect to the current alternatives, it demands less user interaction since the method is landmarks-independent and does not require any patch adaptation.

3D-Printed Patient-Specific Casts for the Distal Radius in Children: Outcome and Pre-Market Survey.

BACKGROUND: Orthopaedic and Trauma surgery is expected to undergo profound transformation as a result of the adoption of 3D technology. Among the various applications, patient specific manufacturing of splints and casts would appear to be, particularly in children, an interesting implementation. This study aims to assess the safety of patient specific 3D casts obtained with a newly developed 3D-scanning devise in a small case series. We therefore conducted a clinical outcome and pre-marketing study in 10 consecutive patients with distal radius fractures treated at an Academic Level I Pediatric Trauma Center. After the application of the 3D cast, patients underwent three consecutive evaluations in the following 21 days. The main outcome measurements were: pain, skin lesions and general comfort, and acceptance of the cast. The three domains were measured with the Visual Analogue Scale (VAS), the NPUAP/EPUAP classification and the Positive affect-Negative affect Scale for Children (PANAS-C), the Self-Assessment Manikin (SAM) clinical psychology tests and a Likert-type five item questionnaire, respectively. A final mechanical analysis of the cast was carried out to confirm product integrity. RESULTS: The results obtained were consistently positive in the investigated domains of general comfort, efficacy of contention and mechanical integrity of the 3D-printed cast as well as in the practicability of the supply chain. CONCLUSIONS: This study provides Level IV evidence that patient specific 3D printed casts obtained with a specifically designed software were safe in the management of "buckle" fractures of the distal radius in children. These results encourage to extend the technology to the treatment of more demanding fractures.

Impact of SARS-CoV-2 Pandemic and Strategies for Resumption of Activities During the Second Wave of the Pandemic: A Report From Eight Paediatric Hospitals From the ECHO Network.

The Severe Acute Respiratory Syndrome CoronaVirus type 2 (SARS-CoV-2) pandemic impacted the organization of paediatric hospitals. This study aimed to evaluate the preparedness for the pandemic among a European network of children's hospitals and to explore the strategies to restart health care services. A cross-sectional, web-based survey was distributed in May 2020 to the 13 children's tertiary care hospitals belonging to the European Children's Hospitals Organisation. Responses were obtained from eight hospitals (62%). Significant reductions were observed in accesses to the emergency departments (41.7%), outpatient visits (35.7%), intensive and non-intensive care unit inpatient admissions (16.4 and 13%, respectively) between February 1 and April 30, 2020 as compared with the same period of 2019. Overall, 93 children with SARS CoV-2 infection were admitted to inpatient wards. All the hospitals created SARS-CoV-2 preparedness plans for the diagnosis and management of infected patients. Routine activities were re-scheduled. Four hospitals shared their own staff with adult units, two designated bed spaces for adults and only one admitted adults to inpatient wards. The three main components for the resumption of clinical activities were testing, source control, and reorganization of spaces and flows. Telemedicine and telehealth services were used before the SARS-CoV-2 pandemic by three hospitals and by all the hospitals during it. Conclusion: The present study provides a perspective on preparedness to SARS-CoV-2 pandemic among eight large European children's hospitals, on the impact of the pandemic on the hospital activities and on the strategies adopted to restart clinical activities.

Molecular recognition in copper trafficking.

From the basic export of unwanted metal ions in simple organisms to the complex orchestration of metal handling and usage in higher eukaryotes, cellular systems are based on a variety of molecular mechanisms that constrain the right metal to bind to the right protein partner at the right time when needed. A failure to overcome the challenges inherent in this task can lead to pathological states that compromise the life of the cell. This is indeed the case with copper, a metal ion that is essential but which can however also create toxic effects when its intracellular concentration and distribution are not properly controlled. Research in this field increasingly indicates that a subtle interplay between metal coordination chemistry and protein-protein interactions finely tunes molecular recognition.

Ear Reconstruction Simulation: From Handcrafting to 3D Printing.

Microtia is a congenital malformation affecting one in 5000 individuals and is characterized by physical deformity or absence of the outer ear. Nowadays, surgical reconstruction with autologous tissue is the most common clinical practice. The procedure requires a high level of manual and artistic techniques of a surgeon in carving and sculpting of harvested costal cartilage of the patient to recreate an auricular framework to insert within a skin pocket obtained at the malformed ear region. The aesthetic outcomes of the surgery are highly dependent on the experience of the surgeon performing the surgery. For this reason, surgeons need simulators to acquire adequate technical skills out of the surgery room without compromising the aesthetic appearance of the patient. The current paper aims to describe and analyze the different materials and methods adopted during the history of autologous ear reconstruction (AER) simulation to train surgeons by practice on geometrically and mechanically accurate physical replicas. Recent advances in 3D modelling software and manufacturing technologies to increase the effectiveness of AER simulators are particularly described to provide more recent outcomes.

A Novel Objective Approach to the External Measurement of Pectus Excavatum Severity by Means of an Optical Device.

BACKGROUND: Current approaches to quantifying the severity of pectus excavatum require internal measurements based on cross-sectional imaging. The aim of this study is to exploit a novel index evaluated on the external surface of the chest with a three-dimensional (3D) optical scanner. METHODS: Fifty-one children (41 male, 10 female) between 2 and 17 years of age were evaluated with a 3D optical scanner. Pectus excavatum severity was calculated by using an ad hoc instant 3D scanner and defining an automatic procedure to generate an optical 3D correction index (CI3D). For the latter, an ideal threshold was derived from a statistical analysis, and five blind surveys were collected from pediatric specialists on chest wall deformities. The CI3D was then correlated with blind clinical assessments of PE severity. RESULTS: The cutoff thresholds were determined to optimally discriminate between six degrees of severity of PE patients by a correlation analysis. The correlation coefficient obtained by matching the CI3D with the average subjective severity shows that the proposed method outperforms traditional approaches. CONCLUSIONS: The optical 3D index has a good match with the average subjective assessment in distinguishing patients with mild to severe PE. This innovative approach offers several advantages over existing indices, as it is repeatable and does not require cross-sectional imaging. The index might be particularly suitable for monitoring the efficacy of nonoperative treatment and, in the future, for designing an optimal personalized usage of therapeutic devices.

The prevalence of anxiety and depression in Italian patients with cystic fibrosis and their caregivers.

BACKGROUND: Cystic fibrosis, like other chronic diseases, is a risk factor for the development of elevated symptoms of depression and anxiety. The objective of this study was to investigate the prevalence of anxiety and depression in Italian patients with CF and their parents. METHODS: The Hospital Anxiety and Depression Scale (HADS) and Center for Epidemiologic Studies Depression Scale (CES-D) questionnaires were administered to a sample of patients and their parents recruited at the cystic fibrosis centers in Italy. RESULTS: Elevated levels of anxiety were higher in mothers than in fathers, and also higher in female patients than in male patients. A correlation between elevated levels of anxiety/depression and geographical area also emerged. Patient anxiety (OR 2.33) and depression (OR 4.09) were significantly associated with forced expiratory volume in one second (FEV1) <40% and forced vital capacity (FVC) <80% (OR 1.60 and 1.61, respectively). CONCLUSIONS: Cystic fibrosis increases the risk of developing anxiety and depression in female patients and in mothers. Geographical differences were observed, with higher anxiety and depression in southern Italy for parents, but not for patients. Anxiety and depression levels also depend on clinical status. Pediatr Pulmonol. 2016;51:1311-1319. © 2016 Wiley Periodicals, Inc.

Efficacy of ketamine in refractory convulsive status epilepticus in children: a protocol for a sequential design, multicentre, randomised, controlled, open-label, non-profit trial (KETASER01).

INTRODUCTION: Status epilepticus (SE) is a life-threatening neurological emergency. SE lasting longer than 120 min and not responding to first-line and second-line antiepileptic drugs is defined as 'refractory' (RCSE) and requires intensive care unit treatment. There is currently neither evidence nor consensus to guide either the optimal choice of therapy or treatment goals for RCSE, which is generally treated with coma induction using conventional anaesthetics (high dose midazolam, thiopental and/or propofol). Increasing evidence indicates that ketamine (KE), a strong N-methyl-d-aspartate glutamate receptor antagonist, may be effective in treating RCSE. We hypothesised that intravenous KE is more efficacious and safer than conventional anaesthetics in treating RCSE. METHODS AND ANALYSIS: A multicentre, randomised, controlled, open-label, non-profit, sequentially designed study will be conducted to assess the efficacy of KE compared with conventional anaesthetics in the treatment of RCSE in children. 10 Italian centres/hospitals are involved in enrolling 57 patients aged 1 month to 18 years with RCSE. Primary outcome is the resolution of SE up to 24 hours after withdrawal of therapy and is updated for each patient treated according to the sequential method. ETHICS AND DISSEMINATION: The study received ethical approval from the Tuscan Paediatric Ethics Committee (12/2015). The results of this study will be published in peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBER: NCT02431663; Pre-results.

Comparison of a saline irrigated cooled-tip catheter to large electrode catheters with single and multiple temperature sensors for creation of large radiofrequency lesions.

BACKGROUND: Several catheter technologies for creating large radiofrequency (RF) lesions are used in clinical practice, but direct comparisons of the pathological lesions created by these technologies are unavailable. The purpose of this study was to compare the safety and efficacy of lesions created by three different large lesion RF ablation technologies. METHODS AND RESULTS: RF lesions were created in all four chambers of 15 mongrel dogs using 10 mm-tip multiple temperature sensor catheters, 10 mm tip single temperature sensor catheters, and 4 mm cooled-tip catheters. Pathological lesions were bisected, and measured after viability staining. A total of 242 (79 large-tip single sensor, 82 large-tip multiple sensor, and 81 cooled-tip) lesions were created. All atrial lesions were transmural but tended to have larger surface areas with the single thermistor large-tip catheter (73.4 +/- 24.8 mm2) compared to either the multithermistor large-tip (60.9 +/- 28.3 mm2) or the cooled-tip (61.9 +/- 28.5 mm2) catheters (p = 0.07), especially those in the IVC-TA isthmus. Depths and volumes of ventricular lesions created by the multiple-thermistor catheter (5.0 +/- 1.5 mm; 260 +/- 168 mm3) were smaller than either the single thermistor (5.7 +/- 1.5 mm; 428 +/- 290 mm3) or cooled-tip (6.1 +/- 1.8 mm; 403 +/- 217 mm3) catheters (p < 0.05). The difference in the depth and volume of lesions made by large-tip single thermistor and cooled-tip catheters was not significant. Char formation occurred during 11% of ablation with the single thermistor catheter, 6% with multithermistor and 8% of cooled-tip catheter (p = NS). There were no complications of ablation. CONCLUSIONS: All three catheters reliably created full thickness atrial lesions. For ventricular lesions, depths and volumes were similar for 10 mm-tip single thermistor and cooled-tip catheters. The multithermistor catheter lesions were smaller due to more precise temperature regulated power control. Safety was similar in all 3 groups.

Heptadecanoylcarnitine (C17) a novel candidate biomarker for newborn screening of propionic and methylmalonic acidemias.

BACKGROUND: 3-Hydroxypalmitoleoyl-carnitine (C16:1-OH) has recently been reported to be elevated in acylcarnitine profiles of patients with propionic acidemia (PA) or methylmalonic acidemia (MMA) during expanded newborn screening (NBS). High levels of C16:1-OH, combined with other hydroxylated long chain acylcarnitines are related to long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) and trifunctional protein (TFP) deficiency. METHODS: The acylcarnitine profile of two LCHADD patients was evaluated using liquid chromatography-tandem mass spectrometric method. A specific retention time was determined for each hydroxylated long chain acylcarnitine. The same method was applied to some neonatal dried blood spots (DBSs) from PA and MMA patients presenting abnormal C16:1-OH concentrations. RESULTS: The retention time of the peak corresponding to C16:1-OH in LCHADD patients differed from those in MMA and PA patients. Heptadecanoylcarnitine (C17) has been identified as the novel biomarker specific for PA and MMA patients through high resolution mass spectrometry (Orbitrap) experiments. We found that 21 out of 23 neonates (22 MMA, and 1PA) diagnosed through the Tuscany region NBS program exhibited significantly higher levels of C17 compared to controls. Twenty-three maternal deficiency (21 vitamin B12 deficiency, 1 homocystinuria and 1 gastrin deficiency) samples and 82 false positive for elevated propionylcarnitine (C3) were also analyzed. CONCLUSIONS: We have characterized a novel biomarker able to detect propionate disorders during expanded newborn screening (NBS). The use of this new biomarker may improve the analytical performances of NBS programs especially in laboratories where second tier tests are not performed.

Reducing the False-Positive Rate for Isovalerylcarnitine in Expanded Newborn Screening: The Application of a Second-Tier Test

Abstract The isodecyl neopentanoate is an ingredient used in the cosmetic industry to prepare a nipple fissure balm. We report on 12 newborns that showed elevated C5-acylcarnitine levels upon newborn screening following treatment with balm. The first 3 neonates were immediately recalled for confirmatory tests and resulted negative for both isovaleric acidemia and short/branched chain acyl-CoA dehydrogenase deficiency. In the other 9 cases, the immediate recall was avoided by applying a new second-tier test able to confirm the presence of pivaloylcarnitine. The concentration of C5-acylcarnitine was measured in the days following the suspension of balm application. Abnormal concentrations of C5-acylcarnitine did not seem to be associated with free carnitine deficiency, probably due to the short time of exposure. A direct correlation between balm ingestion and the elevation in pivaloylcarnitine has been demonstrated in 10 adult volunteers. The commercial balm containing a pivalic acid derivative is causal of false-positive results during newborn screening, and it could have the potential to cause secondary carnitine deficiency when used chronically.