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Objective: To assess seizure and developmental outcomes, their predictors, and complications in 160 children who, between 1998 and 2022, underwent surgery for lesional epilepsy with curative intent before the age of 3 years. To compare trends in epilepsy surgery in this age group before and after the year 2014., Methods: Retrospective multicenter study. Descriptive and univariate analyses, and multivariable models for all outcomes., Results: These 160 patients (76 F; 47.5%) underwent 169 surgeries (age at surgery 20.4 ± 9.4 months). At the last follow-up (77 ± 57.4 months), 121 patients (75.6%) were in Engel class I, 106 (66.2%) of whom were in Engel class Ia. Antiseizure medications were stopped in 84 patients (52.5%). Complications requiring reoperations were observed in 16 patients (10%; 9.5% of surgeries) and unexpected permanent deficits in 12 (7.5%; 7.1% of surgeries). Postoperative cognitive functions remained unchanged in 56 patients (44.4%), improved in 51 (40.5%), and worsened in 19 (15.1%). Multivariable analyses showed that the probability of achieving Engel class Ia was lower when the duration of epilepsy was longer, patients underwent preoperative video-EEG, and unexpected postoperative permanent deficits occurred. Cognitive improvement after surgery was associated with lower preoperative seizure frequency, better preoperative developmental level, and a longer postoperative follow-up. FCDII and tumors were the histopathologies carrying a higher probability of achieving seizure freedom, while polymicrogyria was associated with a lower probability of cognitive improvement. The number of patients operated on after 2014 was higher than before (61.3% vs. 38.7%), with stable outcomes., Significance: Epilepsy surgery is effective and safe in infants and toddlers, although the complication rate is higher than seen in older patients. Shorter duration of epilepsy, lower seizure frequency, no need for video-EEG, tumors, and some malformations of cortical development are robust predictors of seizure and cognitive outcome that may be exploited to increase earlier referral., Plain Language Summary: This study analyzed the results of epilepsy surgery in 160 children who had been operated on before the age of 3 years at four Italian centers between 1998 and 2022. At the last follow-up (77 ± 57.4 months), 121 patients (75.6%) were free from disabling seizures, of which 106 (66.2%) were completely seizure-free since surgery. Major surgical complications occurred in 28 patients (17.5%), which is higher than observed with epilepsy surgery in general, but similar to hemispheric/multilobar surgery. Postoperative cognitive function remained unchanged in 56 patients (44.4%), improved in 51 (40.5%), and worsened in 19 (15.1%). Epilepsy surgery is effective and safe in infants and toddlers., (© 2024 The Author(s). Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background and Objectives: The SLC35A2 gene, located at chromosome Xp11.23, encodes for a uridine diphosphate-galactose transporter. We describe clinical, genetic, neuroimaging, EEG, and histopathologic findings and assess possible predictors of postoperative seizure and cognitive outcome in 47 patients with refractory epilepsy and brain somatic SLC35A2 gene variants., Methods: This is a retrospective multicenter study where we performed a descriptive analysis and classical hypothesis testing. We included the variables of interest significantly associated with the outcomes in the generalized linear models., Results: Two main phenotypes were associated with brain somatic SLC35A2 variants: (1) early epileptic encephalopathy (EE, 39 patients) with epileptic spasms as the predominant seizure type and moderate to severe intellectual disability and (2) drug-resistant focal epilepsy (DR-FE, 8 patients) associated with normal/borderline cognitive function and specific neuropsychological deficits. Brain MRI was abnormal in all patients with EE and in 50% of those with DR-FE. Histopathology review identified mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy in 44/47 patients and was inconclusive in 3. The 47 patients harbored 42 distinct mosaic SLC35A2 variants, including 14 (33.3%) missense, 13 (30.9%) frameshift, 10 (23.8%) nonsense, 4 (9.5%) in-frame deletions/duplications, and 1 (2.4%) splicing variant. Variant allele frequencies (VAFs) ranged from 1.4% to 52.6% (mean VAF: 17.3 ± 13.5). At last follow-up (35.5 ± 21.5 months), 30 patients (63.8%) were in Engel Class I, of which 26 (55.3%) were in Class IA. Cognitive performances remained unchanged in most patients after surgery. Regression analyses showed that the probability of achieving both Engel Class IA and Class I outcomes, adjusted by age at seizure onset, was lower when the duration of epilepsy increased and higher when postoperative EEG was normal or improved. Lower brain VAF was associated with improved postoperative cognitive outcome in the analysis of associations, but this finding was not confirmed in regression analyses., Discussion: Brain somatic SLC35A2 gene variants are associated with 2 main clinical phenotypes, EE and DR-FE, and a histopathologic diagnosis of MOGHE. Additional studies will be needed to delineate any possible correlation between specific genetic variants, mutational load in the epileptogenic tissue, and surgical outcomes., (© 2022 American Academy of Neurology.)

Objective: Temporal plus epilepsy (TPE) represents a rare type of epilepsy characterized by a complex epileptogenic zone including the temporal lobe and the close neighboring structures. We investigated whether the complete resection of temporal plus epileptogenic zone as defined through stereoelectroencephalography (SEEG) might improve seizure outcome in 38 patients with TPE., Methods: Inclusion criteria were as follows: epilepsy surgery performed between January 1990 and December 2001, SEEG defining a temporal plus epileptogenic zone, unilobar temporal operations ("temporal lobe epilepsy [TLE] surgery") or multilobar interventions including the temporal lobe ("TPE surgery"), magnetic resonance imaging either normal or showing signs of hippocampal sclerosis, and postoperative follow-up of at least 12 months. For each assessment of postoperative seizure outcome, at 1, 2, 5, and 10 years, we carried out descriptive analysis and classical tests of hypothesis, namely, Pearson χ 2 test or Fisher exact test of independence on tables of frequency for each categorical variable of interest and Student t-test for each continuous variable of interest, when appropriate., Results: Twenty-one patients underwent TPE surgery and 17 underwent TLE surgery with a follow-up of 12.4 ± 8.16 years. In the multivariate models, there was a significant effect of the time from surgery on Engel Class IA versus IB-IV outcome, with a steadily worsening trend from 5-year follow-up onward. TPE surgery was associated with better results than TLE surgery., Significance: This study suggests that surgical outcome in patients with TPE can be improved by a tailored, multilobar resection and confirms that SEEG is mandatory when a TPE is suspected., (© 2022 International League Against Epilepsy.)

Objective: To assess seizure and cognitive outcomes and their predictors in children (<16 years at surgery) and adults undergoing temporal lobe epilepsy (TLE) surgery in eight Italian centers., Methods: This is a retrospective multicenter study. We performed a descriptive analysis and subsequently carried out multivariable mixed-effect models corrected for multiple comparisons., Results: We analyzed data from 511 patients (114 children) and observed significant differences in several clinical features between adults and children. The possibility of achieving Engel class IA outcome and discontinuing antiepileptic drugs (AEDs) at last follow-up (FU) was significantly higher in children (P = .006 and < .0001). However, percentages of children and adults in Engel class I at last FU (mean ± SD, 45.9 ± 17 months in children; 45.9 ± 20.6 months in adults) did not differ significantly. We identified different predictors of seizure outcome in children vs adults and at short- vs long-term FU. The only variables consistently associated with class I outcome over time were postoperative electroencephalography (EEG) in adults (abnormal, improved,odds ratio [OR] = 0.414, P = .023, Q = 0.046 vs normal, at 2-year FU and abnormal, improved, OR = 0.301, P = .001, Q = 0.002 vs normal, at last FU) and the completeness of resection of temporal magnetic resonance (MR) abnormalities other than hippocampal sclerosis in children (OR = 7.93, P = .001, Q = 0.003, at 2-year FU and OR = 45.03, P < .0001, Q < 0.0001, at last FU). Cognitive outcome was best predicted by preoperative performances in either age group., Significance: Clinical differences between adult and pediatric patients undergoing TLE surgery are reflected in differences in long-term outcomes and predictors of failures. Children are more likely to achieve sustained seizure freedom and withdraw AEDs after TLE surgery. Earlier referral should be encouraged as it can improve surgical outcome., (© 2020 International League Against Epilepsy.)

Hypertensive disorders are common complications during pregnancy (HDP) with substantial public health impact. Acute and chronic particulate matter (PM) exposure during pregnancy increases the risk of HDP, although the underlying molecular mechanisms remain unclear. Extracellular vesicles (EVs) may be the ideal candidates for mediating the effects of PM exposure in pregnancy as they are released in response to environmental stimuli. The INSIDE project aims to investigate this mechanism in pregnancy outcomes. The study population is enrolled at the Fetal Medicine Unit of Fondazione IRCCS Ca'Granda-Ospedale Maggiore Policlinico at 10-14 weeks of gestation. Exposure to PM 10 and PM 2.5 is assessed using the flexible air quality regional model (FARM) and Bayesian geostatistical models. Each woman provides a blood sample for EV analysis and circulating biomarker assessment. Moreover, a subgroup of recruited women (n = 85) is asked to participate in a cardiovascular screening program including a standard clinical evaluation, a non-invasive assessment of right ventricular function, and pulmonary circulation at rest and during exercise. These subjects are also asked to wear a personal particulate sampler, to measure PM 10 , PM 2.5 , and PM 1 . The INSIDE study is expected to identify the health impacts of PM exposure on pregnancy outcomes.

Mapping brain functions is crucial for neurosurgical planning in patients with drug-resistant seizures. However, presurgical language mapping using either functional or structural networks can be challenging, especially in children. In fact, most of the evidence on this topic derives from cross-sectional or retrospective studies in adults submitted to anterior temporal lobectomy. In this prospective study, we used fMRI and DTI to explore patterns of language representation, their predictors and impact on cognitive performances in 29 children and young adults (mean age at surgery: 14.6 ± 4.5 years) with focal lesional epilepsy. In 20 of them, we also assessed the influence of epilepsy surgery on language lateralization. All patients were consecutively enrolled at a single epilepsy surgery center between 2009 and 2015 and assessed with preoperative structural and functional 3T brain MRI during three language tasks: Word Generation (WG), Rhyme Generation (RG) and a comprehension task. We also acquired DTI data on arcuate fasciculus in 24 patients. We first assessed patterns of language representation (relationship of activations with the epileptogenic lesion and Laterality Index (LI)) and then hypothesized a causal model to test whether selected clinical variables would influence the patterns of language representation and the ensuing impact of the latter on cognitive performances. Twenty out of 29 patients also underwent postoperative language fMRI. We analyzed possible changes of fMRI and DTI LIs and their clinical predictors. Preoperatively, we found atypical language lateralization in four patients during WG task, in one patient during RG task and in seven patients during the comprehension task. Diffuse interictal EEG abnormalities predicted a more atypical language representation on fMRI (p = 0.012), which in turn correlated with lower attention (p = 0.036) and IQ/GDQ scores (p = 0.014). Postoperative language reorganization implied shifting towards atypical language representation. Abnormal postoperative EEG (p = 0.003) and surgical failures (p = 0.015) were associated with more atypical language lateralization, in turn correlating with worsened fluency. Neither preoperative asymmetry nor postoperative DTI LI changes in the arcuate fasciculus were observed. Focal lesional epilepsy associated with diffuse EEG abnormalities may favor atypical language lateralization and worse cognitive performances, which are potentially reversible after successful surgery., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Describing and monitoring socioeconomic inequalities in health are the prerequisite for planning equity policies. In Italy, some cities have integrated personal information from the municipal registries with Census data and with data from healthcare information systems to set up Longitudinal Metropolitan Studies (LMS). Under the coordination of the Italian National Institute for Health, Migration, and Poverty (NIHMP), six cities in the LMS network have contributed to the present monograph: Turin, Venice, Reggio Emilia, Modena, Bologna, and Rome. MORTALITY RESULTS. Significant socioeconomic differences by level of education were seen in all the participating centres. People who live alone or in single-parent households are more likely to die, as are those living in a substandard dwelling. Immigrants resident in the six cities included in the study showed lower all-cause mortality than Italians (males: MRR 0.83; 95%CI 0.78-0.90 - females: MRR 0.70; 95%CI 0.64-0.77). Sub-Saharan Africans experienced a significant higher mortality than Italians (males: MRR 1.33; 95%CI 1.12-1.59 - females: MMR 1.69; 95%CI 1.31-2.17). Immigrants had a neonatal and post-neonatal mortality risk about 1.5 times higher than Italians (neonatal: OR 1.71; 95%CI 1.22-2.39 - post-neonatal: OR 1.63; 95%CI 1.03-2.57). A difference between Italians and immigrants was also observed for mortality in children aged 1-4 years, though less marked (OR 1.24; 95%CI 0.73-2.11). Excesses concerned particularly immigrants from North Africa and from sub-Saharan Africa as well as those residing in Italy for >5 years. HOSPITALISATION RESULTS. Hospitalisation rates are lower for immigrants than for Italians, except when due to infectious diseases, blood disorders, and, among women, for reasons linked to pregnancy and childbirth. Avoidable hospitalisation rates of adults from low migratory pressure Countries are lower than or equal to those of Italians. On the contrary, adults from low migratory pressure Countries show higher avoidable hospitalisation rates compared to Italians in every cohort, with the exception of Rome (RR 0.81; 95%CI 0.78-0.85), with RR ranging from 1.08 (95%CI 0.96-1.22) in Venice to 1.64 (95%CI 1.47-1.83) in Modena., Conclusions: Maternal and child health is the most critical area of health for immigrant population. Considering the importance that the issue of health equity has taken on in the political agenda, the data presented in this volume are a great asset, particularly in light of the long recession and the social crisis that have impacted the Country.

Background: Few studies, based on a limited number of patients using non-uniform therapeutic protocols, have analyzed Methicillin-resistant Staphylococcus aureus (MRSA) eradication., Methods: In a randomized multicenter trial conducted on patients with new-onset MRSA infection we evaluated the efficacy of an early eradication treatment (arm A) compared with an observational group (B). Arm A received oral rifampicin and trimethoprim/sulfamethoxazole (21 days). Patients' microbiological status, FEV1, BMI, pulmonary exacerbations and use of antibiotics were assessed., Results: Sixty-one patients were randomized. Twenty-nine (47.5%) patients were assigned to active arm A and 32 (52.5%) patients to observational arm B. Twenty-nine (47.5%) patients, 10 patients in arm A and 19 in arm B, dropped out of the study. At 6 months MRSA was eradicated in 12 (63.2%) out of 19 patients in arm A while spontaneous clearance was observed in 5 (38.5%) out of 13 patients in arm B. A per-protocol analysis showed a 24.7% difference in the proportion of MRSA clearance between the two groups (z = 1.37, P(Z>z) = 0.08). Twenty-seven patients, 15 (78.9%) out of 19 in arm A and 12 (92.3%) out of 13 in arm B, were able to perform spirometry. The mean (±SD) FEV1 change from baseline was 7.13% (±14.92) in arm A and -1.16% (±5.25) in arm B (p = 0.08). In the same period the BMI change (mean ±SD) from baseline was 0.54 (±1.33) kg/m2 in arm A and -0.38 (±1.56) kg/m2 in arm B (p = 0.08). At 6 months no statistically significant differences regarding the number of pulmonary exacerbations, days spent in hospital and use of antibiotics were observed between the two arms., Conclusions: Although the statistical power of the study is limited, we found a 24.7% higher clearance of MRSA in the active arm than in the observational arm at 6 months. Patients in the active arm A also had favorable FEV1 and BMI tendencies., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To determine the accuracy of skull point-of-care ultrasound (POCUS) for identifying fractures in children younger than 2 years of age with signs of head trauma, and the ability of POCUS to identify the type and depth of fracture depression., Study Design: This was a multicenter, prospective, observational study of children younger than 2 years of age with nontrivial mechanisms of injury and signs of scalp/skull trauma. Patients were enrolled if they underwent computed tomography (CT). Patients underwent clinical evaluation, in addition to a cranial POCUS in the emergency department (ED). From the POCUS examinations, we documented whether fractures were present or absent, their location, characteristics, and depth. POCUS and CT findings were compared to calculate the diagnostic accuracy., Results: We enrolled a convenience sample of 115 of 151 (76.1%) eligible patients. Of the 115 enrolled, 88 (76.5%) had skull fractures. POCUS had a sensitivity of 80 of 88 (90.9%; 95% CI 82.9-96.0) and a specificity of 23 of 27 (85.2%; 95% CI 66.3-95.8) for identifying skull fractures. Agreement between POCUS and CT to identify the type of fracture as linear, depressed, or complex was 84.4% (97 of 115) with a kappa of 0.75 (95% CI 0.70-0.84)., Conclusions: POCUS performed by emergency physicians may identify the type and depth of fractures in infants with local physical signs of head trauma with substantial accuracy. Emergency physicians should consider POCUS as an adjunct to clinical evaluation and prediction rules for traumatic brain injuries in children younger than 2 years of age., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: The Italian Network of Longitudinal Metropolitan Studies (IN-LiMeS) is a system of integrated data on health outcomes, demographic and socioeconomic information, and represents a powerful tool to study health inequalities., Participants: IN-LiMeS is a multicentre and multipurpose pool of metropolitan population cohorts enrolled in nine Italian cities: Turin, Venice, Reggio Emilia, Modena, Bologna, Florence, Leghorn, Prato and Rome. Data come from record linkage of municipal population registries, the 2001 population census, mortality registers and hospital discharge archives. Depending on the source of enrolment, cohorts can be closed or open. The census-based closed cohort design includes subjects resident in any of the nine cities at the 2001 census day; 4 466 655 individuals were enrolled in 2001 in the nine closed cohorts. The open cohort design includes subjects resident in 2001 or subsequently registered by birth or immigration until the latest available follow-up (currently 31 December 2013). The open cohort design is available for Turin, Venice, Reggio Emilia, Modena, Bologna, Prato and Rome. Detailed socioeconomic data are available for subjects enrolled in the census-based cohorts; information on demographic characteristics, education and citizenship is available from population registries., Findings to Date: The first IN-LiMeS application was the study of differentials in mortality between immigrants and Italians. Either using a closed cohort design (nine cities) or an open one (Turin and Reggio Emilia), individuals from high migration pressure countries generally showed a lower mortality risk. However, a certain heterogeneity between the nine cities was noted, especially among men, and an excess mortality risk was reported for some macroareas of origin and specific causes of death., Future Plans: We are currently working on the linkage of the 2011 population census data, the expansion of geographical coverage and the implementation of the open design in all the participating cohorts., Competing Interests: Competing interests: All authors declare support from National Institute for Health, Migration and Poverty (INMP) in the form of a grant that has funded the study., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: To explore the prognostic value of initial clinical and mutational findings in infants with SCN1A mutations., Methods: Combining sex, age/fever at first seizure, family history of epilepsy, EEG, and mutation type, we analyzed the accuracy of significant associations in predicting Dravet syndrome vs milder outcomes in 182 mutation carriers ascertained after seizure onset. To assess the diagnostic accuracy of all parameters, we calculated sensitivity, specificity, receiver operating characteristic (ROC) curves, diagnostic odds ratios, and positive and negative predictive values and the accuracy of combined information. We also included in the study demographic and mutational data of the healthy relatives of mutation carrier patients., Results: Ninety-seven individuals (48.5%) had Dravet syndrome, 49 (23.8%) had generalized/genetic epilepsy with febrile seizures plus, 30 (14.8%) had febrile seizures, 6 (3.5%) had focal epilepsy, and 18 (8.9%) were healthy relatives. The association study indicated that age at first seizure and frameshift mutations were associated with Dravet syndrome. The risk of Dravet syndrome was 85% in the 0- to 6-month group, 51% in the 6- to 12-month range, and 0% after the 12th month. ROC analysis identified onset within the sixth month as the diagnostic cutoff for progression to Dravet syndrome (sensitivity = 83.3%, specificity = 76.6%)., Conclusions: In individuals with SCN1A mutations, age at seizure onset appears to predict outcome better than mutation type. Because outcome is not predetermined by genetic factors only, early recognition and treatment that mitigates prolonged/repeated seizures in the first year of life might also limit the progression to epileptic encephalopathy., (© 2017 American Academy of Neurology.)

Background: Chronic hepatitis C is a global health problem. Although new, highly effective and safe direct-acting antivirals have been approved for adults, the only drugs currently registered for children are pegylated interferon and ribavirin. The timelines for the pediatric approval of the new treatment regimens are far off. Three phase II-III pediatric trials with direct-acting antivirals are recruiting, and the estimated dates of completion of these studies range between April 2018 and January 2023., Methods: The aim of this study was to evaluate the value of on-treatment virologic response (VR) as predictor of sustained virologic response (SVR) in a cohort of Italian children with chronic hepatitis C and to establish possible stopping rules., Results: Sixty-four children were enrolled (January 2012 to December 2015). SVR rate was 79.7% (51/64). VR at weeks 2 to 12 were shown to be robust predictors for the attainment of SVR. The positive predictive values of VR at weeks 8 and 12 were 98% and 92.7%, respectively. The negative predictive values at the same treatment weeks were 92.9% and 100%, indicating that no child who did not achieve VR at week 12 obtained SVR and that the likelihood of achieving SVR if still positive at week 8 was very low., Conclusions: Our results suggest for the first time that VR at week 8 could be considered a reliable predictor of SVR. Monitoring viral kinetics is useful for predicting the success of pegylated interferon and ribavirin therapy in children.

Objective: To assess factors associated with favorable seizure outcome after surgery for symptomatic epileptic spasms and improve knowledge on pathophysiology of this seizure type., Methods: Inclusion criteria were: (1) age between 6 months and 15 years at surgery; (2) active epileptic spasms; (3) follow-up after surgery >1 year., Results: We retrospectively studied 80 children (aged 1.3 ± 2 years at seizure onset; 5.8 ± 4 years at surgery, 11.7 ± 5.7 years at last follow up). Magnetic resonance imaging (MRI) revealed structural abnormalities in 77/80 patients (96.3%; unilateral in 69: 89.6%). We performed invasive recordings in 24 patients (30%). In 21 patients in whom MRI or histopathology detected a lesion, electrodes exploring it constantly captured initial ictal activity at spasm onset. Fifty-eight patients (72.5%) underwent unilobar and 22 (27.5%) multilobar or hemispheric procedures. At last follow-up, 49 patients (61.3%) were in Engel class I. Multivariate logistic models showed completeness of resection of the seizure onset zone (OR = 0.016, 95%CI: 0.002, 0.122) and of the MRI visible lesion (OR = 0.179, 95% CI: 0.032, 0.999) to be significantly associated with Engel class IA outcome. Unfavorable outcome was associated with an older age at surgery, when it reflected a longer duration of epilepsy (OR = 1.383, 95% CI: 0.994,1.926)., Interpretation: Data emerging from invasive recordings and the good seizure outcome following removal of discrete epileptogenic lesions support a focal cortical origin of spasms. In patients with discrete epileptogenic lesions, the pragmatic approach to surgery should follow the same principles applied to focal epilepsy favoring, whenever possible, unilobar, one-stage resections.

Background: Pectus excavatum (PE) is known to be associated with adolescent idiopathic scoliosis (AIS). The correction of severe PE requires a mini-invasive procedure (MIRPE), with a metal bar positioned and left in the chest for 3 years. Adolescence seems to be the more appropriate time not only for MIRPE but also for AIS peak progression. This study was designed to answer the question whether, in adolescents, MIRPE could affect mild/moderate AIS., Methods: We carried out a meta-analysis focused on defining the natural progression of untreated AIS. Inclusion criteria were as follows: AIS patients -age 10-18 years old -Cobb angle <40°-none treated as orthotics/electrostimulation/surgery. The expected outcome was the percentage of patients who improved, worsened, or hold steady of their condition at follow-up. Between 2008 and 2014, we followed up a cohort of 67 adolescents with severe PE treated with MIRPE, assessing whether AIS underwent a modification in the period between bar insertion and removal., Results: Meta-analysis included 9 studies with 1641 AIS patients. Although heterogeneous (I(2) = 99.5%, P < .0001), the overall percentage of progression for untreated AIS was 42.5% (CI 18.2%-72.2%). In our follow-up group who underwent MIRPE, 34 out of 67 patients had concurrent AIS with a Cobb angle >10° (range 10°-45°). We demonstrated that MIRPE had a favorable effect on AIS, with a mean improvement of 1.5° (CI 0.64-2.44; P = .0011)., Conclusion: In our PE patients with AIS, MIRPE had a beneficial effect also on the spine. From our preliminary results, it seems that MIRPE should be offered during puberty as a timely option for treating PE and stabilizing mild/moderate scoliosis progression, when concurrent.

Preferential sampling refers to any situation in which the spatial process and the sampling locations are not stochastically independent. In this paper, we present two examples of geostatistical analysis in which the usual assumption of stochastic independence between the point process and the measurement process is violated. To account for preferential sampling, we specify a flexible and general Bayesian geostatistical model that includes a shared spatial random component. We apply the proposed model to two different case studies that allow us to highlight three different modeling and inferential aspects of geostatistical modeling under preferential sampling: (1) continuous or finite spatial sampling frame; (2) underlying causal model and relevant covariates; and (3) inferential goals related to mean prediction surface or prediction uncertainty., (© The Author(s) 2016.)

Despite a rapid increase in immigration from low-income countries, studies on immigrants' mortality in Italy are scarce. We aimed to describe differences in all and cause-specific mortality among immigrants and Italians residing in Turin and Reggio Emilia (Northern Italy), two cities participating in the Italian Network of Longitudinal Metropolitan Studies (IN-LiMeS). We used individual data from the municipal population registers linked to the cause of death registers. All people aged 1-64 years residing between 2001 and 2010 were enrolled (open cohort) and followed up until 2013. The mortality of citizens from high migratory pressure countries (as a whole, and for each macro-area group) was compared with that of Italians; differences were estimated by Poisson regression adjusted by age and calendar year mortality rate ratios (MRRs), and by age-standardized mortality ratios for the analysis of cause-specific mortality. Compared with Italians, immigrants had lower overall mortality (MRR for men: 0.82, 95 % CI: 0.75-0.90; for women: 0.71, 95 % CI: 0.63-0.81). Sub-Saharan Africans experienced a significant higher mortality than Italians (MRR for men 1.29, 95 % CI: 1.03-1.61; for women: 1.70, 95 % CI: 1.22-2.36). Higher mortality for immigrants compared to Italians was observed for infectious diseases, congenital anomalies, some site-specific tumours and homicide mortality. Our study showed heterogeneity in mortality across the macro-areas of origin, and in particular Sub-Saharan Africans seemed to be a vulnerable population. The extension to other cohorts of IN-LiMeS will allow the health status of immigrants and vulnerable groups to be studied and monitored in more depth.

Background: The Lombardy region in northern Italy ranks among the most air polluted areas of Europe. Previous studies showed air pollution short-term effects on all-cause mortality. We examine here the effects of particulate matter with aerodynamic diameter ≤10µm (PM10) and nitrogen dioxide (NO2) exposure on deaths and hospitalizations from specific causes, including cardiac, cerebrovascular and respiratory diseases., Methods: We considered air pollution, mortality and hospitalization data for a non-opportunistic sample of 18 highly polluted and most densely populated areas of the region in the years 2003-2006. We obtained area-specific effect estimates for PM10 and NO2 from a Poisson regression model on the daily number of total deaths or cause-specific hospitalizations and then combined them in a Bayesian random-effects meta-analysis. For cause-specific mortality, we applied a case-crossover analysis. Age- and season-specific analyses were also performed. Effect estimates were expressed as percent variation in mortality or hospitalizations associated with a 10µg/m(3) increase in PM10 or NO2 concentration., Results: Natural mortality was positively associated with both pollutants (0.30%, 90% Credibility Interval [CrI]: -0.31; 0.78 for PM10; 0.70%, 90%CrI: 0.10; 1.27 for NO2). Cardiovascular deaths showed a higher percent variation in association with NO2 (1.12%, 90% Confidence Interval [CI]: 0.14; 2.11), while the percent variation for respiratory mortality was highest in association with PM10 (1.64%, 90%CI: 0.35; 2.93). The effect of both pollutants was more evident in the summer season. Air pollution was also associated to hospitalizations, the highest variations being 0.77% (90%CrI: 0.22; 1.43) for PM10 and respiratory diseases, and 1.70% (90%CrI: 0.39; 2.84) for NO2 and cerebrovascular diseases. The effect of PM10 on respiratory hospital admissions appeared to increase with age. For both pollutants, effects on cerebrovascular hospitalizations were more evident in subjects aged less than 75 years., Conclusions: Our study provided a sound characterization of air pollution exposure and its potential effects on human health in the most polluted, and also most populated and productive, Italian region, further documenting the need for effective public health policies., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

In parasitological surveillance of livestock, prevalence surveys are conducted on a sample of farms using several sampling designs. For example, opportunistic surveys or informative sampling designs are very common. Preferential sampling refers to any situation in which the spatial process and the sampling locations are not independent. Most examples of preferential sampling in the spatial statistics literature are in environmental statistics with focus on pollutant monitors, and it has been shown that, if preferential sampling is present and is not accounted for in the statistical modelling and data analysis, statistical inference can be misleading. In this paper, working in the context of veterinary parasitology, we propose and use geostatistical models to predict the continuous and spatially-varying risk of a parasite infection. Specifically, breaking with the common practice in veterinary parasitological surveillance to ignore preferential sampling even though informative or opportunistic samples are very common, we specify a two-stage hierarchical Bayesian model that adjusts for preferential sampling and we apply it to data on Fasciola hepatica infection in sheep farms in Campania region (Southern Italy) in the years 2013-2014.

In this paper the focus is on environmental statistics, with the aim of estimating the concentration surface and related uncertainty of an air pollutant. We used air quality data recorded by a network of monitoring stations within a Bayesian framework to overcome difficulties in accounting for prediction uncertainty and to integrate information provided by deterministic models based on emissions meteorology and chemico-physical characteristics of the atmosphere. Several authors have proposed such integration, but all the proposed approaches rely on representativeness and completeness of existing air pollution monitoring networks. We considered the situation in which the spatial process of interest and the sampling locations are not independent. This is known in the literature as the preferential sampling problem, which if ignored in the analysis, can bias geostatistical inferences. We developed a Bayesian geostatistical model to account for preferential sampling with the main interest in statistical integration and uncertainty. We used PM10 data arising from the air quality network of the Environmental Protection Agency of Lombardy Region (Italy) and numerical outputs from the deterministic model. We specified an inhomogeneous Poisson process for the sampling locations intensities and a shared spatial random component model for the dependence between the spatial location of monitors and the pollution surface. We found greater predicted standard deviation differences in areas not properly covered by the air quality network. In conclusion, in this context inferences on prediction uncertainty may be misleading when geostatistical modelling does not take into account preferential sampling.

Objective: We explored the long-term follow-up of continuous spike-and-wave complexes during sleep (CSWS) in polymicrogyria and the anatomic volumetric variables that influence the risk of developing this age-related epileptic encephalopathy., Methods: We performed prospective follow-up of 27 patients with polymicrogyria/CSWS (mean follow-up 14.3 years; range 2-31 years) and comparative volumetric analysis of the polymicrogyric hemispheres and ipsilateral thalami vs 3 subgroups featuring polymicrogyria without CSWS, benign rolandic epilepsy (BRE), and headache. Receiver operator characteristic analysis of the power of volumetric values was determined to predict CSWS., Results: CSWS peaked between 5 and 7 years (mean age at onset 4.7 years). Remission occurred within 2 years from onset in 21%, within 4 years in 50%, and by age 13 years in 100%. We found smaller thalamic and hemispheric volumes in polymicrogyria/CSWS with respect to polymicrogyria without CSWS (p = 0.0021 for hemispheres; p = 0.0003 for thalami), BRE, and controls with headache (p < 0.0001). Volumes of the malformed hemispheres and ipsilateral thalami reliably identified the risk of incurring CSWS, with a 68-fold increased risk for values lower than optimal diagnostic cutoffs (436,150 mm(3) for malformed hemispheres or 4,616 mm(3) for ipsilateral thalami; sensitivity 92.54%; specificity 84.62%). The risk increased by 2% for every 1,000 mm(3) reduction of the polymicrogyric hemispheres and by 15% for every 100 mm(3) reduction of ipsilateral thalami., Conclusions: The polymicrogyria/CSWS syndrome is likely caused by a cortico-thalamic malformation complex and is characterized by remission of epilepsy within early adolescence. Early assessment of hemispheric and thalamic volumes in children with polymicrogyria and epilepsy can reliably predict CSWS., (© 2016 American Academy of Neurology.)

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., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Neurodegenerative Langerhans Cell Histiocytosis (ND-LCH) is a rare, unpredictable consequence that may devastate the quality of life of patients cured from LCH. We prospectively applied a multidisciplinary diagnostic work-up to early identify and follow-up patients with ND-LCH, with the ultimate goal of better determining the appropriate time for starting therapy., Methods: We studied 27 children and young adults with either ND-LCH verified by structural magnetic resonance imaging (MRI) (group 1) or specific risk factors for (diabetes insipidus, craniofacial bone lesions), but no evidence of, neurodegenerative MRI changes (group 2). All patients underwent clinical, neurophysiological and MRI studies., Results: Seventeen patients had MRI alterations typical for ND-LCH. Nine showed neurological impairment but only three were symptomatic; 11 had abnormal somatosensory evoked potentials (SEPs), and five had abnormal brainstem auditory evoked potentials (BAEPs). MR spectroscopy (MRS) showed reduced cerebellar NAA/Cr ratio in nine patients. SEPs showed sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for predicting ND-LCH of 70.6% (95%CI, 44.0%-89.7%), 100% (69.2%-100%), 100% (73.5%-100%), and 66.7% (38.4%-88.2%), respectively. Repeated investigations in group 1 revealed increasingly abnormal EP parameters, or neurological examination, or both, in nine of fifteen patients while MRI remained unchanged in all but one patient., Conclusion: A targeted MRI study should be performed in all patients with risk factors for ND-LCH for early identification of demyelination. The combined use of SEPs and careful neurological evaluation may represent a valuable, low-cost, well-tolerated and easily available methodology to monitor patients from pre-symptomatic to symptomatic stages. We suggest a multidisciplinary protocol including clinical, MRS, and neurophysiological investigations to identify a population target for future therapeutic trials.

Background: Absence epilepsy (AE) is etiologically heterogeneous and has at times been associated with idiopathic dystonia., Objectives: Based on the clinical observation that children with AE often exhibit, interictally, a disorder resembling writer's cramp but fully definable as dysgraphia, we tested the hypothesis that in this particular population dysgraphia would represent a subtle expression of dystonia., Methods: We ascertained the prevalence of dysgraphia in 82 children with AE (mean age 9.7) and average intelligence and compared them with 89 age-, gender- and class-matched healthy children (mean age 10.57) using tests for handwriting fluency and quality, based on which we divided patients and controls into four subgroups: AE/dysgraphia, AE without dysgraphia, controls with dysgraphia and healthy controls. We compared the blink reflex recovery cycle in children belonging to all four subgroups., Results: We identified dysgraphia in 17/82 children with AE and in 7/89 controls (20.7 vs 7.8%; P = 0.016) with the former having a 3.4-times higher risk of dysgraphia regardless of age and gender (odd ratio: 3.49; 95% CI 1.2, 8.8%). The AE/dysgraphia subgroup performed worse than controls with dysgraphia in one test of handwriting fluency (P = 0.037) and in most trials testing handwriting quality (P< 0.02). In children with AE/dysgraphia the blink reflex showed no suppression at short interstimulus intervals, with a difference for each value emerging when comparing the study group with the three remaining subgroups (P<0.001)., Conclusions: In children with AE, dysgraphia is highly prevalent and has a homogeneous, distinctive pathophysiological substrate consistent with idiopathic dystonia.

Fasciola hepatica infection challenges health, welfare and productivity of small ruminants throughout the world. The distribution of F. hepatica in sheep in Europe is usually scattered and studies are generally concerned with a single area making it difficult to compare results from different environments, climates and management regimes. In order to elucidate the current scenario in terms of prevalence and intensity of F. hepatica infection in sheep farms across Europe, a standardized cross-sectional survey was conducted in three pilot areas in Ireland, Switzerland and Italy, all part of the EU funded GLOWORM project. Two consecutive field surveys (in 2012 and 2013) were conducted in the three countries in the same period (August-October) in 361 sheep farms in total. Harmonized procedures (from farm to laboratory) based on pooled samples and the highly sensitive and accurate, diagnostic FLOTAC technique were used. The georeferenced parasitological results were modelled (at the pilot area level) following a Bayesian geostatistical approach with correction for preferential sampling and accounting for climatic and environmental covariates. The observed F. hepatica prevalence rates did not differ between the two study years in any of the three pilot areas, but they did vary between the countries showing high values in Ireland (61.6%) compared to Italy (7.9%) and Switzerland (4.0%). Spatial patterns of F. hepatica distribution were detected by the Bayesian geostatistical approach in Ireland with a high risk of infection in the south-western part of the pilot area there. The latent factor analysis highlighted the importance of year-to-year variation of mean temperature, rainfall and seasonality within a country, while long-term trends of temperature and rainfall dominated between countries with respect to prevalence of infection.

Background: Exposure to air pollution is associated with a short-term increase in mortality, and this field has begun to focus on health impact assessment., Objectives: Our aim was to estimate the impact of PM10 on mortality within 2 days from the exposure in the Italian region of Lombardy for the year 2007, at the municipality level, examining exposure entailed by daily intermunicipality commuting and accounting for uncertainty propagation., Methods: We combined data from different sources to derive probabilistic distributions for all input quantities used to calculate attributable deaths (mortality rates, PM10 concentrations, estimated PM10 effects, and commuting flows) and applied a Monte Carlo procedure to propagate uncertainty and sample the distribution of attributable deaths for each municipality., Results: We estimated that annual average PM10 concentrations above the World Health Organization-recommended threshold of 20 μg/m3 were responsible for 865 short-term deaths (80% credibility interval: 475, 1,401), 26% of which were attributable to PM10 above the European Union limit of 40 μg/m3. Reducing annual average PM10 concentrations > 20 μg/m3 by 20% would have reduced the number of attributable deaths by 36%. The largest estimated impacts were along the basin of the Po River and in the largest cities. Commuting contributed to the spatial distribution of the estimated impact., Conclusions: Our estimates, which incorporated uncertainty quantification, indicate that the short-term impact of PM10 on mortality in Lombardy in 2007 was notable, and that reduction in air pollution would have had a substantial beneficial effect on population health. Using commuting data helped to identify critical areas for prioritizing intervention.