The Association of Prenatal Diagnoses with Mortality and Long-Term Morbidity in Children with Specific Isolated Congenital Anomalies: A European Register-Based Cohort Study.

OBJECTIVES: To compare 5-year survival rate and morbidity in children with spina bifida, transposition of great arteries (TGA), congenital diaphragmatic hernia (CDH) or gastroschisis diagnosed prenatally with those diagnosed postnatally. METHODS: Population-based registers' data were linked to hospital and mortality databases. RESULTS: Children whose anomaly was diagnosed prenatally (n = 1088) had a lower mean gestational age than those diagnosed postnatally (n = 1698) ranging from 8 days for CDH to 4 days for TGA. Children with CDH had the highest infant mortality rate with a significant difference (p < 0.001) between those prenatally (359/1,000 births) and postnatally (116/1,000) diagnosed. For all four anomalies, the median length of hospital stay was significantly greater in children with a prenatal diagnosis than those postnatally diagnosed. Children with prenatally diagnosed spina bifida (79% vs 60%; p = 0.002) were more likely to have surgery in the first week of life, with an indication that this also occurred in children with CDH (79% vs 69%; p = 0.06). CONCLUSIONS: Our findings do not show improved outcomes for prenatally diagnosed infants. For conditions where prenatal diagnoses were associated with greater mortality and morbidity, the findings might be attributed to increased detection of more severe anomalies. The increased mortality and morbidity in those diagnosed prenatally may be related to the lower mean gestational age (GA) at birth, leading to insufficient surfactant for respiratory effort. This is especially important for these four groups of children as they have to undergo anaesthesia and surgery shortly after birth. Appropriate prenatal counselling about the time and mode of delivery is needed.

Higher risk of cerebral palsy, seizures/epilepsy, visual- and hearing impairments, cancer, injury and child abuse in children with congenital anomalies: Data from the EUROlinkCAT study.

AIM: The aim is to examine the risk of cerebral palsy, seizures/epilepsy, visual- and hearing impairments, cancer, injury/poisoning and child abuse in children with and without a congenital anomaly up to age 5 and 10 years. METHODS: This is a population-based data linkage cohort study linking information from the European Surveillance of Congenital Anomalies network (EUROCAT) and birth registries to hospital discharge databases. We included 91 504 live born children with major congenital anomalies born from 1995 to 2014 from nine EUROCAT registries in five countries and 1 960 727 live born children without congenital anomalies (reference children). Prevalence and relative risk (RR) were estimated for each of the co-morbidities using Kaplan-Meier survival estimates. RESULTS: Children with congenital anomalies had higher risks of the co-morbidities than reference children. The prevalences in the reference children were generally very low. The RR was 13.8 (95% CI 12.5-15.1) for cerebral palsy, 2.5 (95% CI 2.4-2.6) for seizures/epilepsy, 40.8 (95% CI 33.2-50.2) for visual impairments, 10.0 (95% CI 9.2-10.9) for hearing loss, 3.6 (95% CI 3.2-4.2) for cancer, 1.5 (95% CI 1.4-1.5) for injuries/poisoning and 2.4 (95% CI 1.7-3.4) for child abuse. CONCLUSION: Children with congenital anomalies were more likely to be diagnosed with the specified co-morbidities compared to reference children.

Medication use during pregnancy and the risk of gastroschisis: a systematic review and meta-analysis of observational studies.

OBJECTIVES: The aetiology of gastroschisis is considered multifactorial. We conducted a systematic review and meta-analysis to assess whether the use of medications during pregnancy, is associated with the risk of gastroschisis in offspring. METHODS: PubMed, EMBASE, and Scopus were searched from 1st January 1990 to 31st December 2020 to identify observational studies examining the association between medication use during pregnancy and the risk of gastroschisis. The Newcastle-Ottawa Scale was used for the quality assessment of the individual studies. We pooled adjusted measures using a random-effect model to estimate relative risk [RR] and the 95% confidence interval [CI]. I2 statistic for heterogeneity and publication bias was calculated. RESULTS: Eighteen studies providing data on 751,954 pregnancies were included in the meta-analysis. Pooled RRs showed significant associations between aspirin (RR 1.66, 95% CI 1.16-2.38; I2 = 58.3%), oral contraceptives (RR 1.52, 95% CI 1.21-1.92; I2 = 22.0%), pseudoephedrine and phenylpropanolamine (RR 1.51, 95% CI 1.16-1.97; I2 = 33.2%), ibuprofen (RR 1.42, 95% CI 1.26-1.60; I2 = 0.0%), and gastroschisis. No association was observed between paracetamol and gastroschisis (RR 1.16, 95% CI 0.96-1.41; I2 = 39.4%). CONCLUSIONS: These results suggest that the exposure in the first trimester of pregnancy to over the counter medications (OTC) such as aspirin, ibuprofen, pseudoephedrine and phenylpropanolamine as well as to oral contraceptives, was associated with an increased risk of gastroschisis. However, these associations are significant only in particular subgroups defined by geographic location, adjustment variables and type of control. Therefore, further research is needed to investigate them as potential risk factors for gastroschisis, to assess their safety in pregnancy and to develop treatment strategies to reduce the risk of gastroschisis in offspring. PROSPERO registration number: CRD42021287529.

Risk factors for mortality in infancy and childhood in children with major congenital anomalies: A European population-based cohort study.

BACKGROUND: Preterm birth and young maternal age are known risk factors for infant and childhood mortality. There is limited knowledge of the impact of these risk factors in children born with major congenital anomalies (CAs), who have inherently higher risks of death compared with other children. OBJECTIVES: To investigate the risk factors for mortality up to age 10 years in children born with specific major CAs. METHODS: This population-based cohort study involved 150,198 livebirths from 1995 to 2014 in 13 European CA registries linked to mortality data. Cox proportional hazards models estimated the association of gestational age, maternal age and child's sex with death <1 year and 1-9 years for the whole cohort and by CA subgroup. Hazard ratios (HR) from each registry were pooled using multivariate meta-analysis. RESULTS: Preterm birth had a dose-response association with mortality; compared with infants born at 37+ weeks gestation, those born at <28, 28-31 and 32-36 weeks had 14.88 (95% CI 12.57, 17.62), 8.39 (95% CI 7.16, 9.85) and 3.88 (95% CI 3.40, 4.43) times higher risk of death <1 year, respectively. The corresponding risks at 1-9 years were 4.99 (95% CI 2.94, 8.48), 3.09 (95% CI 2.28, 4.18) and 2.04 (95% CI 1.69, 2.46) times higher, respectively. Maternal age <20 years (versus 20-34 years) was a risk factor for death <1 year (HR 1.30, 95% CI 1.09, 1.54) and 1-9 years (HR 1.58, 95% CI 1.19, 2.10). Females had 1.22 (95% CI 1.07, 1.39) times higher risk of death between 1 and 9 years than males. CONCLUSION: Preterm birth was associated with considerably higher infant and childhood mortality in children with CAs, comparable to estimates reported elsewhere for the background population. Additional risk factors included young maternal age and female sex. Information on risk factors could benefit clinical care and guide counselling of parents following CA diagnoses.

Creating a population-based cohort of children born with and without congenital anomalies using birth data matched to hospital discharge databases in 11 European regions: Assessment of linkage success and data quality.

Linking routinely collected healthcare administrative data is a valuable method for conducting research on morbidity outcomes, but linkage quality and accuracy needs to be assessed for bias as the data were not collected for research. The aim of this study was to describe the rates of linking data on children with and without congenital anomalies to regional or national hospital discharge databases and to evaluate the quality of the matched data. Eleven population-based EUROCAT registries participated in a EUROlinkCAT study linking data on children with a congenital anomaly and children without congenital anomalies (reference children) born between 1995 and 2014 to administrative databases including hospital discharge records. Odds ratios (OR), adjusted by region, were estimated to assess the association of maternal and child characteristics on the likelihood of being matched. Data on 102,654 children with congenital anomalies were extracted from 11 EUROCAT registries and 2,199,379 reference children from birth registers in seven regions. Overall, 97% of children with congenital anomalies and 95% of reference children were successfully matched to administrative databases. Information on maternal age, multiple birth status, sex, gestational age and birthweight were >95% complete in the linked datasets for most regions. Compared with children born at term, those born at ≤27 weeks and 28-31 weeks were less likely to be matched (adjusted OR 0.23, 95% CI 0.21-0.25 and adjusted OR 0.75, 95% CI 0.70-0.81 respectively). For children born 32-36 weeks, those with congenital anomalies were less likely to be matched (adjusted OR 0.78, 95% CI 0.71-0.85) while reference children were more likely to be matched (adjusted OR 1.28, 95% CI 1.24-1.32). Children born to teenage mothers and mothers ≥35 years were less likely to be matched compared with mothers aged 20-34 years (adjusted ORs 0.92, 95% CI 0.88-0.96; and 0.87, 95% CI 0.86-0.89 respectively). The accuracy of linkage and the quality of the matched data suggest that these data are suitable for researching morbidity outcomes in most regions/countries. However, children born preterm and those born to mothers aged <20 and ≥35 years are less likely to be matched. While linkage to administrative databases enables identification of a reference group and long-term outcomes to be investigated, efforts are needed to improve linkages to population groups that are less likely to be linked.

Causes of death in children with congenital anomalies up to age 10 in eight European countries.

BACKGROUND: Congenital anomalies (CAs) increase the risk of death during infancy and childhood. This study aimed to evaluate the accuracy of using death certificates to estimate the burden of CAs on mortality for children under 10 years old. METHODS: Children born alive with a major CA between 1 January 1995 and 31 December 2014, from 13 population-based European CA registries were linked to mortality records up to their 10th birthday or 31 December 2015, whichever was earlier. RESULTS: In total 4199 neonatal, 2100 postneonatal and 1087 deaths in children aged 1-9 years were reported. The underlying cause of death was a CA in 71% (95% CI 64% to 78%) of neonatal and 68% (95% CI 61% to 74%) of postneonatal infant deaths. For neonatal deaths the proportions varied by registry from 45% to 89% and by anomaly from 53% for Down syndrome to 94% for tetralogy of Fallot. In children aged 1-9, 49% (95% CI 42% to 57%) were attributed to a CA. Comparing mortality in children with anomalies to population mortality predicts that over 90% of all deaths at all ages are attributable to the anomalies. The specific CA was often not reported on the death certificate, even for lethal anomalies such as trisomy 13 (only 80% included the code for trisomy 13). CONCLUSIONS: Data on the underlying cause of death from death certificates alone are not sufficient to evaluate the burden of CAs on infant and childhood mortality across countries and over time. Linked data from CA registries and death certificates are necessary for obtaining accurate estimates.

Survival, hospitalisation and surgery in children born with Pierre Robin sequence: a European population-based cohort study.

OBJECTIVE: To evaluate survival, hospitalisations and surgical procedures for children born with Pierre Robin sequence (PRS) across Europe. DESIGN: Multicentre population-based cohort study. SETTING: Data on 463 live births with PRS from a population of 4 984 793 from 12 EUROCAT congenital anomaly registries. METHODS: Data on children with PRS born 1995-2014 were linked electronically to data on mortality, hospitalisations and surgical procedures up to 10 years of age. Each registry applied a common data model to standardise the linked data and ran common syntax scripts to produce aggregate tables. Results from each registry were pooled using random-effect meta-analyses. MAIN OUTCOME MEASURES: Probability of survival, proportion of children hospitalised and undergoing surgery, and median length of hospital stay. RESULTS: The majority of deaths occurred in the first year of life with a survival rate of 96.0% (95% CI 93.5% to 98.5%); 95.1% (95% CI 92.7% to 97.7%) survived to age 10. In the first year of life, 99.2% (95% CI 95.0% to 99.9%) of children were hospitalised with a median stay of 21.4 days (95% CI 15.6 to 27.2), and 67.6% (95% CI 46.6% to 81.8%) underwent surgery. In the first 5 years of life, 99.2% of children underwent a median of two surgical procedures. Between ages 5 and 9, 58.3% (95% CI 44.7% to 69.7%) were hospitalised with a median annual stay of 0.3 days. CONCLUSIONS: Children with PRS had high mortality and morbidity with long hospital stays in the first year of life, and almost all had surgery before 5 years of age. Survival improved after infancy with fewer hospitalisations after age 5. This study provides reliable estimates of the survival and morbidity of children with PRS for families and healthcare providers.

Giardia duodenalis Colonization Slightly Affects Gut Microbiota and Hematological Parameters in Clinically Healthy Dogs.

Giardia duodenalis (Giardia) is a worldwide cause of acute diarrheal disease both in humans and animals. The primary aim of this study was to investigate possible variations in gut microbiota in a population of asymptomatic dogs (n = 31), naturally infected or not by Giardia. Gut microbiota and the hematological, biochemical, and fecal parameters related to intestinal function were investigated. Giardia infection was associated with a significant shift of beta diversity, showing a relevant reduction of Gammaproteobacteria and an increase of Fusobacteria in male-positive dogs if compared with negatives. A significant imbalance of different bacterial taxa, with particular reference to the Erysipelotrichales, Lactobacillales, Clostridiales, and Burkholderiales orders, was observed, with the first two being higher in Giardia-positive dogs. Giardia-positive males displayed significantly higher values of cCRP than negative males as well as positive females, supporting the presence of a pro-inflammatory state. Taken together, these results indicate that the presence of Giardia does not substantially modify the microbial ecology of the intestine nor the hematological markers of disease. Thus treatments against Giardia should be considered with caution in asymptomatic subjects.

Accuracy of congenital anomaly coding in live birth children recorded in European health care databases, a EUROlinkCAT study.

Electronic health care databases are increasingly being used to investigate the epidemiology of congenital anomalies (CAs) although there are concerns about their accuracy. The EUROlinkCAT project linked data from eleven EUROCAT registries to electronic hospital databases. The coding of CAs in electronic hospital databases was compared to the (gold standard) codes in the EUROCAT registries. For birth years 2010-2014 all linked live birth CA cases and all children identified in the hospital databases with a CA code were analysed. Registries calculated sensitivity and Positive Predictive Value (PPV) for 17 selected CAs. Pooled estimates for sensitivity and PPV were then calculated for each anomaly using random effects meta-analyses. Most registries linked more than 85% of their cases to hospital data. Gastroschisis, cleft lip with or without cleft palate and Down syndrome were recorded in hospital databases with high accuracy (sensitivity and PPV ≥ 85%). Hypoplastic left heart syndrome, spina bifida, Hirschsprung's disease, omphalocele and cleft palate showed high sensitivity (≥ 85%), but low or heterogeneous PPV, indicating that hospital data was complete but may contain false positives. The remaining anomaly subgroups in our study, showed low or heterogeneous sensitivity and PPV, indicating that the information in the hospital database was incomplete and of variable validity. Electronic health care databases cannot replace CA registries, although they can be used as an additional ascertainment source for CA registries. CA registries are still the most appropriate data source to study the epidemiology of CAs.

[SENTIERI - Epidemiological Study of Residents in National Priority Contaminated Sites. Sixth Report]. / SENTIERI - Studio epidemiologico nazionale dei territori e degli insediamenti esposti a rischio da inquinamento. Sesto Rapporto.

INTRODUCTION ADN OBJECTIVES: The Sixth Report presents the results of the "SENTIERI Project: implementation of the permanent epidemiological surveillance system of populations residing in Italian Sites of Remediation Interest", promoted and financed by the Italian Ministry of Health (Centre for Disease Control and Prevention - CCM Project 2018). The aim of this study is to update the mortality and hospitalization analyses concerning the 6,227,531 inhabitants (10.4% of the Italian population) residing in 46 contaminated sites (39 of national interest and 7 of regional interest). The sites include 316 municipalities distributed as follows: 15 in the North-East (20.3% of the investigated population); 104 in the North-West (12% of the investigated population), 32 in the Centre (12.6% of the investigated population), 165 in the South and Islands (55.5% of the investigated population). Analyses were carried out on the paediatric-adolescent (1,128,396 residents) and youth (665,284 residents) population, and a study on congenital anomalies (CA) was carried out at sites covered by congenital malformation registers. Accompanying the epidemiological assessments, site-specific socioeconomic conditions were examined and an overall estimate of excess risk for populations residing at contaminated sites was drawn up. By means of a systematic review of the scientific literature, the epidemiological evidence on causal links between sources of environmental exposure and health effects was updated to identify pathologies of a priori interest. METHODOLOGY: In the 46 sites included in the SENTIERI Project, mortality (time window: 2013-2017) and hospital admissions (time window: 2014-2018) of the general population of all ages, divided by gender, and of the paediatric-adolescent (0-1 year, 0-14 years, 0-19 years), youth (20-29 years), and overall (0-29 years) age groups, divided by gender, were analysed. In 21 sites, CA diagnosed within the first year of life were studied. Standardised mortality ratios (SMR) and hospitalization ratios (SHR) were calculated with reference to the rates in the regions to which the sites belong. The reference population was calculated net of residents in the sites. CA were studied by calculating the prevalence per 10,000 births and the ratio, multiplied by 100, between the cases observed at the site and those expected on the basis of the prevalences observed in the reference area (region or sub-regional area of belonging, according to the geographical coverage of the registry). The socioeconomic condition studied in the 46 sites is based on the convergence of three deprivation indicators with respect to the reference region: deprivation index at municipal level, deprivation index at census section level, premature mortality indicator (age range 30-69 years) for chronic non-communicable diseases. For the estimation of excess risk for the entire study population, meta-analysis of the mortality and hospitalization risk estimates for each site was carried out and the number of excess deaths estimated for the sites as a whole. The epidemiological evidence was updated through a systematic literature review (January 2009-May 2020), following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The search was carried out on the search engines MEDLINE, EMBASE and Web of Science; the quality of the studies included in the review was assessed using the AMSTAR 2 checklist for systematic reviews and the NewCastle-Ottawa Scale for observational studies in the case of cohort and case-control studies and a modified version thereof for ecological and cross-sectional studies. The update was based on the selection of 14 systematic reviews, 15 primary studies, 6 monographs/reports from international scientific organisations on health effects due to the presence of environmental exposure sources. RESULTS: Mortality. The a priori causes of interest that occur most frequently in excess are, in descending order: malignant lung cancer, malignant mesothelioma of the pleura, malignant bladder cancer, respiratory diseases, non-Hodgkin lymphomas, malignant liver cancer, all malignant tumours, malignant colorectal cancer, malignant stomach cancer, total mesotheliomas, malignant breast cancer, and asbestosis. Hospitalization. The a priori causes of interest that occur most frequently in excess are represented in descending order by: respiratory diseases, malignant lung cancer, malignant tumours of the pleura, malignant bladder cancer, malignant breast cancer, malignant liver cancer, asthma, malignant colorectal cancer, all malignant tumours, malignant stomach cancer, non-Hodgkin's lymphomas, acute respiratory diseases, leukaemias. The differences observed between mortality and hospitalization can be attributed to the intrinsic characteristics of the diseases (higher or lower lethality, gender differences in incidence), lifestyles, and occupational phenomena. Age classes. Excesses of general mortality were observed in the first year of life at the Manfredonia, Basso Bacino Fiume Chienti, Litorale Domizio Flegreo and Agro Aversano sites; in the 0-1 year and 0-19 year age groups at Casale Monferrato; in the paediatric age group at Serravalle Scrivia and at the Trento Nord site; in the 0-19 year age group at Sassuolo Scandiano; in the young age group (0-29 years) at the two municipalities of Cerchiara and Cassano (Crotone-Cassano-Cerchiara site). With regard to hospitalization due to natural causes, risk excesses in both genders are found in the first year of life in 35% of the sites (Porto Torres industrial areas, Bari-Fibronit, Basso bacino fiume Chienti, Bolzano, Crotone-Cassano-Cerchiara, Cerro al Lambro, Bologna ETR large repair workshop, Gela, Manfredonia, Massa Carrara, Pioltello Rodano, Pitelli, Priolo, Sesto San Giovanni, Trento Nord, and Trieste). These same sites, with the addition of Casale Monferrato, Cengio e Saliceto, Serravalle Scrivia, and Sulcis-Iglesiente-Guspinese (total: 43% of sites), show excesses for all natural causes, in both genders, even in the paediatric-adolescent age group (0-19 years). Among young adults (20-29 years), the analyses show excesses of hospitalization for all natural causes in both genders in the Bolzano, Crotone-Cassano-Cerchiara, Gela, Manfredonia, Pitelli, Priolo, and Sulcis-Iglesiente-Guspinese sites. Among young women only, excesses for all natural causes are also found in Brescia Caffaro, Brindisi, Broni, Casale Monferrato, Crotone-Cassano-Cerchiara, Falconara Marittima, Fidenza, and Massa Carrara. Congenital anomalies. In the 21 sites investigated for CA, 10,126 cases of CA, validated by participating registers, were analysed out of 304,620 resident births. Genital CA is the subgroup for which the greatest number of excesses was observed (in 6 out of 21 sites). The available evidence does not allow a causal link to be established between the excesses observed for specific subgroups of ACs and exposure to industrial sources, but the results suggest further action. The interpretation of the results appears, in fact, particularly complex as the scientific literature on the association between exposure to industrial sources and AC is very limited. Socioeconomic status. The sites in which the indicators converge to show the presence of fragility are: Litorale Vesuviano area, Val Basento industrial areas, Basso Bacino fiume Chienti, Biancavilla, Crotone-Cassano-Cerchiara, Litorale Domizio Flegreo and Agro Aversano, Livorno, Massa Carrara, Trieste. Global impact. Over the period 2013-2017, an estimated 8,342 excess deaths (CI90% 1,875-14,809) or approximately 1,668 excess cases/year, 4,353 excess deaths among males (CI90% 334-8,372) and 3,989 among females (CI90% -1,122;9,101). The pooled excess risk of general mortality is 2% in both genders (pooled SMR 1.02; CI90% 1.00-1.04). The proportion of excess deaths to total observed deaths is almost constant over time, rising from 2.5% in 1995-2002 to 2.6% in 2013-2017. The number of deaths in absolute value is also very similar between the periods analysed. Deaths from all malignant tumours contribute the most by accounting for 56% of the observed excesses, the excess risk of mortality from malignant tumours across all sites, compared to the reference populations, is 4% in the male population (pooled SMR 1.04; CI90% 1.01-1.06) and 3% among the female population (pooled SMR 1.03; CI90% 1.01-1.05). Hospitalization (2014-2018) in the 46 sites as a whole was in excess of 3% for all causes, in both genders, for all major disease groups (males: SHR pooled 1.03; CI90% 1.01-1.04 - females: SHR pooled 1.03; CI90% 1.01-1.05). The results for the pooled estimates at the 46 sites on the general population, both with regard to mortality and hospitalization, are consistent in indicating excess risk in both genders for all the diseases considered and, in particular, for all malignancies. A total of 1,409 paediatric-adolescent deaths and 999 young adult deaths were observed, and the pooled analysis of mortality across the 46 sites showed no critical issues, with pooled estimates for all causes, perinatal morbid conditions and all malignancies falling short of expectations. The analysis of hospitalizations, on the other hand, showed an excess risk of 8% (males: SHR pooled 1.08; CI90% 1.03-1.13 - females: SHR pooled 1.08; CI90% 1.03-1.14) for all causes in the first year of life, and in paediatric-adolescent and juvenile age of 3-4% among males (age 0-19 years: SHR pooled 1.04; CI90% 1.02-1.06 - age 20-29 years: SHR pooled 1.03; CI90% 1.00-1.05) and 5% among females (in both age groups; SHR pooled 1.05; CI90% 1.02-1.08). The pooled analysis of mortality for the a priori identified diseases reported excesses for specific diseases in the group of sites with sources of exposure associated with them. Mortality from total mesotheliomas is three times higher at sites with asbestos present (males:pooled SMR 3.02; CI90% 2.18-3.87 - females: pooled SMR 3.61; CI90% 2.33-4.88) and that from pleural mesotheliomas more than two times higher at the group of sites with asbestos and port areas (males: pooled SMR 2.47; CI90% 1.94-3.00 - females: pooled SMR 2.43; CI90% 1.67-3.19). Lung cancer was in excess by 6% among males (pooled SMR 1.06; CI90% 1.03-1.10) and 7% among females (pooled SMR 1.07; CI90% 1.00-1.13). In addition, there are excess mortalities for colorectal cancer at sites with chemical plants, by 4 % among males (SMR pooled 1.04; CI90% 1.01-1.08) and 3 % among females (SMR pooled 1.03; CI90% 1.00-1.07) and for bladder cancer among the male population of sites with landfills (+6 %: SMR pooled 1.06; CI90% 1.02-1.11). Among the diseases of a priori interest, stomach and soft tissue cancers are at fault as a cause of death among all the sites considered. LITERATURE REVIEW: The update of the epidemiological evidence underlying the Sixth SENTIERI Report has highlighted in the general population a possible association, previously undiscovered, between certain diseases and residence near petrochemical and steel plants, landfills, coal mines and asbestos sources. CONCLUSIONS AND PERSPECTIVES: Despite the fact that this is an ecological study, and the excesses of pathologies with multifactorial aetiology can never be mechanically attributed solely to the environmental pressure factors that exist or existed in the areas studied, the ability to identify the excesses found in the contaminated sites investigated by the SENTIERI Project confirms the validity of this method of assessing the site-specific health profile, based on the use of epidemiological evidence to identify pathologies of interest a priori. In interpreting the data and lending robustness to what has been observed, comparison with the results obtained in previous Reports is essential. The global estimates give an overall picture that shows excess mortality and hospitalization in these populations compared to the rest of the population, and show how, for specific pathologies, comparable effects are produced at sites with similar contamination characteristics. The themes developed in the in-depth chapters broaden the vision and understanding of the complex interactions between environment and health, describe the possibilities offered by new ways of communicating the results, and confirm the modernity of a Project that began way back in 2006, and that could be grafted onto the objectives of the National Recovery and Resilience Plan within the framework of the Operational Programme Health, Environment, Biodiversity and Climate.

Identification of Appropriate Endogenous Controls for Circulating miRNA Quantification in Working Dogs under Physiological Stress Conditions.

Cell-free miRNAs, called circulating miRNAs (cmiRNAs), can act in a paracrine manner by facilitating a diversity of signaling mechanisms between cells. Real-time qPCR is the most accepted method for quantifying miRNA expression levels. The use of stable miRNA endogenous control (EC) for qPCR data normalization allows an accurate cross-sample gene expression comparison. The appropriate selection of EC is a crucial step because qPCR data can change drastically when normalization is performed using an unstable versus a stable EC. To find EC cmiRNA with stable expression in search and rescue (SAR) working dogs, we explored the serum miRNome by Next-Generation Sequencing (NGS) at T0 (resting state) and T1 immediately after SAR performance (state of physiologically recovered stress). The cmiRNAs selected in the NGS circulating miRNome as probable ECs were validated by qPCR, and miRNA stability was evaluated using the Delta Ct, BestKeeper, NormFinder, and GeNorm algorithms. Finally, RefFinder was used to rank the stability orders at both T0 and T1 by establishing miR-320 and miR-191 as the best-circulating ECs. We are confident that this study not only provides a helpful result in itself but also an experimental design for selecting the best endogenous controls to normalize gene expression for genes beyond circulating miRNAs.

European study showed that children with congenital anomalies often underwent multiple surgical procedures at different ages across Europe.

AIM: Children with congenital anomalies often require surgery but data on the burden of surgery for these children are limited. METHODS: A population-based record-linkage study in Finland, Wales and regions of Denmark, England, Italy and Spain. A total of 91 504 children with congenital anomalies born in 1995-2014 were followed to their tenth birthday or the end of 2015. Electronic linkage to hospital databases provided data on inpatient surgical procedures and meta-analyses of surgical procedures were performed by age groups. RESULTS: The percentage of children having surgery in the first year was 38% with some differences across regions and 14% also underwent surgery at age 1-4 years. Regional differences in age at the time of their first surgical procedure were observed for children with cleft palate, hydronephrosis, hypospadias, clubfoot and craniosynostosis. The children had a median of 2.0 (95% CI 1.98, 2.02) surgical procedures before age 5 years with children with oesophageal atresia having the highest median number of procedures (4.5; 95% CI 3.3, 5.8). CONCLUSION: A third of children with congenital anomalies required surgery during infancy and often more than one procedure was needed before age 5 years. There was no European consensus on the preferred age for surgery for some anomalies.

Profile of Drug Utilization in Patients with Rare Diseases in Tuscany, Italy: A Population-Based Study.

Patients with rare diseases (RDs) generally have delayed diagnosis and misdiagnosis, which lead to inappropriate care or the need to modify treatment during the course of the disease. The medical care of RD patients can be further complicated by the presence of comorbidities. In this population-based study, we evaluated the prevalence, intensity of use, and consumption of drugs prescribed to RD patients residing in Tuscany (Italy) in the years 2008-2018. Data from the Registry of Rare Diseases of Tuscany were integrated with information retrieved from regional pharmaceutical prescription databases. The overall prevalence of drug use in the RD patients was 85.4%. Drugs for the alimentary tract and metabolism and antiinfectives for systemic use showed the highest prevalence of use, while drugs for the nervous system had the highest intensity of use only in the pediatric patients. The adults exhibited a female preponderance in terms of the prevalence of use and drug consumption in almost all the age groups and therapeutic categories. Conversely, a higher prevalence of use was observed in the male children. These results provide relevant insights into drug profiles in RD patients, representing a first step for future analyses to monitor changes in drug utilization in patients with RDs over time.

Epidemiology of aplasia cutis congenita: A population-based study in Europe.

BACKGROUND: Aplasia cutis congenita (ACC) is a rare congenital anomaly characterized by localized or widespread absence of skin at birth, mainly affecting the scalp. Most information about ACC exists as individual case reports and medium-sized studies. OBJECTIVES: This study aimed to investigate the epidemiology of ACC, using data from a large European network of population-based registries for congenital anomalies (EUROCAT). METHODS: Twenty-eight EUROCAT population-based registries in 16 European countries were involved. Poisson regression models were exploited to estimate the overall and live birth prevalence, to test time trends in prevalence between four 5-year periods and to evaluate the impact of the change of coding for ACC from the unspecific ICD9-BPA code to the specific ICD10 code. Proportions of ACC cases associated with other anomalies were reported. RESULTS: Five hundred cases were identified in the period 1998-2017 (prevalence: 5.10 per 100,000 births). Prevalence across 5-year periods did not differ significantly and no significant differences were evident due to the change from ICD9 to ICD10 in ACC coding. Heterogeneity in prevalence was observed across registries. The scalp was the most common site for ACC (96.4%) and associated congenital anomalies were present in 33.8% of cases. Patau and Adams-Oliver syndromes were the most frequent among the associated chromosomal anomalies (88.3%) and the associated genetic syndromes (57.7%), respectively. 16% of cases were associated with limb anomalies and 15.4% with congenital heart defects. A family history of ACC was found in 2% of cases. CONCLUSION: To our knowledge, this is the only population-based study on ACC. The EUROCAT methodologies provide reliable prevalence estimates and proportions of associated anomalies.

Small intestinal submucosa-derived extracellular matrix as a heterotopic scaffold for cardiovascular applications.

Structural cardiac lesions are often surgically repaired using prosthetic patches, which can be biological or synthetic. In the current clinical scenario, biological patches derived from the decellularization of a xenogeneic scaffold are gaining more interest as they maintain the natural architecture of the extracellular matrix (ECM) after the removal of the native cells and remnants. Once implanted in the host, these patches can induce tissue regeneration and repair, encouraging angiogenesis, migration, proliferation, and host cell differentiation. Lastly, decellularized xenogeneic patches undergo cell repopulation, thus reducing host immuno-mediated response against the graft and preventing device failure. Porcine small intestinal submucosa (pSIS) showed such properties in alternative clinical scenarios. Specifically, the US FDA approved its use in humans for urogenital procedures such as hernia repair, cystoplasties, ureteral reconstructions, stress incontinence, Peyronie's disease, penile chordee, and even urethral reconstruction for hypospadias and strictures. In addition, it has also been successfully used for skeletal muscle tissue reconstruction in young patients. However, for cardiovascular applications, the results are controversial. In this study, we aimed to validate our decellularization protocol for SIS, which is based on the use of Tergitol 15 S 9, by comparing it to our previous and efficient method (Triton X 100), which is not more available in the market. For both treatments, we evaluated the preservation of the ECM ultrastructure, biomechanical features, biocompatibility, and final bioinductive capabilities. The overall analysis shows that the SIS tissue is macroscopically distinguishable into two regions, one smooth and one wrinkle, equivalent to the ultrastructure and biochemical and proteomic profile. Furthermore, Tergitol 15 S 9 treatment does not modify tissue biomechanics, resulting in comparable to the native one and confirming the superior preservation of the collagen fibers. In summary, the present study showed that the SIS decellularized with Tergitol 15 S 9 guarantees higher performances, compared to the Triton X 100 method, in all the explored fields and for both SIS regions: smooth and wrinkle.

Correlation between retinal vessel rarefaction and psychometric measures in an older Southern Italian population.

Objective: To explore the linear association between inner retinal layers thickness and macular capillary density compared to variations of global cognition evaluated by psychometric measures in a cohort of Mediterranean subjects aged 65+ years. Materials and methods: We performed a cross-sectional analysis of 574 participants aged 65 years+ drawn from a population-based Southern Italian study. All subjects underwent neurological evaluations, including global cognitive screening, the Mini-Mental State Examination (MMSE) and frontal assessment battery (FAB), together with an ophthalmic examination including optical coherence tomography (OCT) and OCT-Angiography. We assessed the average thickness of the ganglion cell complex (GCC) and the retinal nerve fiber layer (RNFL), the foveal avascular zone area, and vascular density (VD) of superficial (SVD) and deep (DVD) capillary plexi at the foveal and parafoveal area. Linear regression was applied to assess associations of ocular measurements with MMSE and FAB scores. Results: In the linear regression model, foveal DVD (beta = 0.01, 95% CI:0.004-0.052), whole DVD (beta = 0.04, 95% CI:0.02-0.08), and whole SVD (beta = 0.04, 95% CI:0.02-0.07) showed a positive association with MMSE. In addition, foveal SVD (beta = 0.01, 95% CI:0.003-0.05) and whole SVD (beta = 0.03, 95% CI:0.004-0.08) were positively associated with the FAB score. We found no further significant association between the MMSE score or the FAB score and the average thickness of the GCC and RNFL, and FAZ area. Conclusion: A direct linear association between the VD of the macular capillary plexi with global and frontal cognitive functions was observed in elderly subjects.

Intravenous Magnesium Sulfate Reduces the Need for Antiarrhythmics during Acute-Onset Atrial Fibrillation in Emergency and Critical Care.

Several studies have suggested the potential role of Magnesium Sulfate (MgSO4) for the treatment of Atrial Fibrillation (AF) but, in clinical practice, the use of magnesium is not standardized although it is largely used for the treatment of supraventricular arrhythmias. Objectives. We evaluated the role of MgSO4 infusion in association with flecainide in cardioversion of patients presenting in ED with symptomatic AF started less than 48 h before. We retrospectively searched for all patients presented in ED from 1 January 2019 to 31 December 2019 requiring pharmacological cardioversion with flecainide 2 mg/kg. Ninety-seven patients met these criteria, 46 received the administration of intravenous MgSO4 2 gr (Group A), and 51 did not (Group B). Among the 97 patients, the overall cardioversion rate was 85.6%, 91.3% in Group A and 80.4% in Group B. In 27 patients out of 97, the Flecainide was not administered because of spontaneous restoration of sinus rhythm of 9 pts (Group B) and 18 pts (Group A). We also found a statistical significance in the HR at the time of cardioversion between Group A (77.8 ± 19.1 bpm) and Group B (87 ± 21.7 bpm). No complications emerged. The association between MgSO4 and Flecainide has not yielded statistically significant results. However, in consideration of its high safety profile, MgSO4 administration may play a role in ED cardioversion of acute onset AF, reducing the need for antiarrhythmic medications and electrical cardioversion procedures, relieving symptoms reducing heart rate, and reducing the length of stay in the ED.

Gastrostomy and congenital anomalies: a European population-based study.

OBJECTIVE: To report and compare the proportion of children with and without congenital anomalies undergoing gastrostomy for tube feeding in their first 5 years. METHODS: A European, population-based data-linkage cohort study (EUROlinkCAT). Children up to 5 years of age registered in nine EUROCAT registries (national and regional) in six countries and children without congenital anomalies (reference children) living in the same geographical areas were included. Data on hospitalisation and surgical procedures for all children were obtained by electronic linkage to hospital databases. RESULTS: The study included 91 504 EUROCAT children and 1 960 272 reference children. Overall, 1200 (1.3%, 95% CI 1.2% to 1.6%) EUROCAT children and 374 (0.016%, 95% CI 0.009% to 0.026%) reference children had a surgical code for gastrostomy within the first 5 years of life. There were geographical variations across Europe with higher rates in Northern Europe compared with Southern Europe. Around one in four children with Cornelia de Lange syndrome and Wolf-Hirschhorn syndrome had a gastrostomy. Among children with structural anomalies, those with oesophageal atresia had the highest proportion of gastrostomy (15.9%). CONCLUSIONS: This study including almost 2 million reference children in Europe found that only 0.016% of these children had a surgery code for gastrostomy before age 5 years. The children with congenital anomalies were on average 80 times more likely to need a gastrostomy before age 5 years than children without congenital anomalies. More than two-thirds of gastrostomy procedures performed within the first 5 years of life were in children with congenital anomalies.

Hospital length of stay among children with and without congenital anomalies across 11 European regions-A population-based data linkage study.

BACKGROUND: Congenital anomalies are a leading cause of childhood morbidity, but little is known about the long-term outcomes. OBJECTIVE: To quantify the burden of disease in childhood for children with congenital anomalies by assessing the risk of hospitalisation, the number of days spent in hospital and proportion of children with extended stays (≥10 days). METHODS: European population-based record-linkage study in 11 regions in eight countries including children with congenital anomalies (EUROCAT children) and without congenital anomalies (reference children) living in the same regions. The children were born between 1995 and 2014 and were followed to their tenth birthday or 31/12/2015. European meta-analyses of the outcome measures were performed by two age groups, <1 year and 1-4 years. RESULTS: 99,416 EUROCAT children and 2,021,772 reference children were linked to hospital databases. Among EUROCAT children, 85% (95%-CI: 79-90%) were hospitalised in the first year and 56% (95%-CI: 51-61%) at ages 1-4 years, compared to 31% (95%-CI: 26-37%) and 25% (95%-CI: 19-31%) of the reference children. Median length of stay was 2-3 times longer for EUROCAT children in both age groups. The percentages of children with extended stays (≥10 days) in the first year were 24% (95%-CI: 20-29%) for EUROCAT children and 1% (95%-CI: 1-2%) for reference children. The median length of stay varied greatly between congenital anomaly subgroups, with children with gastrointestinal anomalies and congenital heart defects having the longest stays. CONCLUSIONS: Children with congenital anomalies were more frequently hospitalised and median length of stay was longer. The outlook improves after the first year. Parents of children with congenital anomalies should be informed about the increased hospitalisations required for their child's care and the impact on family life and siblings, and they should be adequately supported.

Healthcare Burden of Rare Diseases: A Population-Based Study in Tuscany (Italy).

Patients with rare diseases (RDs) need tailored, continuous, and multidisciplinary hospital care. This retrospective cohort study aimed to analyse the healthcare burden of RD patients using a multi-database approach, by linking the data of the Rare Diseases Registry of Tuscany with the regional hospital discharge database. The study population included 21,354 patients diagnosed with a RD between 1 January 2000 and 31 December 2017. The healthcare burden was evaluated for all the RDs during 2009-2018 period. The hospitalisation rate (per 1000) decreased over the years, ranging from 606.9 in 2009 (95% CI: 589.2-625.0) to 443.0 in 2018 (95% CI: 433.2-453.0). A decrease in the average length of stay (LOS) was observed in the earlier years, followed by an increase up to a steady trend (8.3 days in 2018). The patients with RDs of metabolism and the genitourinary system showed the highest hospitalisation rate (903.3 and 644.0 per 1000, respectively). The patients with rare immune system disorders and diseases of the skin and subcutaneous tissue showed the highest LOS (9.7 and 9.5 days, respectively). The methodological approach presented in this population-based study makes it possible to estimate the healthcare burden of RDs, which is crucial in the decision-making and planning aimed at improving patient care.