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Objectives: Previously, web-based tools for cross-sectional antimicrobial point prevalence surveys (PPSs) have been used in adults to develop indicators of quality improvement. We aimed to determine the feasibility of developing similar quality indicators of improved antimicrobial prescribing focusing specifically on hospitalized neonates and children worldwide. Methods: A standardized antimicrobial PPS method was employed. Included were all inpatient children and neonates receiving an antimicrobial at 8:00 am on the day of the PPS. Denominators included the total number of inpatients. A web-based application was used for data entry, validation and reporting. We analysed 2012 data from 226 hospitals (H) in 41 countries (C) from Europe (174H; 24C), Africa (6H; 4C), Asia (25H; 8C), Australia (6H), Latin America (11H; 3C) and North America (4H). Results: Of 17693 admissions, 6499 (36.7%) inpatients received at least one antimicrobial, but this varied considerably between wards and regions. Potential indicators included very high broad-spectrum antibiotic prescribing in children of mainly ceftriaxone (ranked first in Eastern Europe, 31.3%; Asia, 13.0%; Southern Europe, 9.8%), cefepime (ranked third in North America, 7.8%) and meropenem (ranked first in Latin America, 13.1%). The survey identified worryingly high use of critically important antibiotics for hospital-acquired infections in neonates (34.9%; range from 14.2% in Africa to 68.0% in Latin America) compared with children (28.3%; range from 14.5% in Africa to 48.9% in Latin America). Parenteral administration was very common among children in Asia (88%), Latin America (81%) and Europe (67%). Documentation of the reasons for antibiotic prescribing was lowest in Latin America (52%). Prolonged surgical prophylaxis rates ranged from 78% (Europe) to 84% (Latin America). Conclusions: Simple web-based PPS tools provide a feasible method to identify areas for improvement of antibiotic use, to set benchmarks and to monitor future interventions in hospitalized neonates and children. To our knowledge, this study has derived the first global quality indicators for antibiotic use in hospitalized neonates and children., peer-reviewed

OBJECTIVES: The objective of this study was to evaluate the ability of weighted-incidence syndromic combination antibiograms (WISCAs) to inform the selection of empirical antibiotic regimens for suspected paediatric bloodstream infections (BSIs) by comparing WISCAs derived using data from single hospitals and from a multicentre surveillance dataset. METHODS: WISCAs were developed by estimating the coverage of five empirical antibiotic regimens for childhood BSI using a Bayesian decision tree. The study used microbiological data on ∼2000 bloodstream isolates collected over 2 years from 19 European hospitals. We evaluated the ability of a WISCA to show differences in regimen coverage at two exemplar hospitals. For each, a WISCA was first calculated using only their local data; a second WISCA was calculated using pooled data from all 19 hospitals. RESULTS: The estimated coverage of the five regimens was 72%-86% for Hospital 1 and 79%-94% for Hospital 2, based on their own data. In both cases, the best regimens could not be definitively identified because the differences in coverage were not statistically significant. For Hospital 1, coverage estimates derived using pooled data gave sufficient precision to reveal clinically important differences among regimens, including high coverage provided by a narrow-spectrum antibiotic combination. For Hospital 2, the hospital and pooled data showed signs of heterogeneity and the use of pooled data was judged not to be appropriate. CONCLUSIONS: The Bayesian WISCA provides a useful approach to pooling information from different sources to guide empirical therapy and could increase confidence in the selection of narrow-spectrum regimens.

ObjectiveTo assess the availability and source of guidelines for common infections in European paediatric hospitals and determine their content and characteristics.DesignParticipating hospitals completed an online questionnaire on the availability and characteristics of antibiotic prescribing guidelines and on empirical antibiotic treatment including duration of therapy for 5 common infection syndromes: respiratory tract, urinary tract, skin and soft tissue, osteoarticular and sepsis in neonates and children.Results84 hospitals from 19 European countries participated in the survey of which 74 confirmed the existence of guidelines. Complete guidelines (existing guidelines for all requested infection syndromes) were reported by 20% of hospitals and the majority (71%) used a range of different sources. Guidelines most commonly available were those for urinary tract infection (UTI) (74%), neonatal sepsis (71%) and sepsis in children (65%). Penicillin and amoxicillin were the antibiotics most commonly recommended for respiratory tract infections (RTIs) (up to 76%), cephalosporin for UTI (up to 50%) and for skin and soft tissue infection (SSTI) and bone infection (20% and 30%, respectively). Antistaphylococcal penicillins were recommended for SSTIs and bone infections in 43% and 36%, respectively. Recommendations for neonatal sepsis included 20 different antibiotic combinations. Duration of therapy guidelines was mostly available for RTI and UTI (82%). A third of hospitals with guidelines for sepsis provided recommendations for length of therapy.ConclusionsComprehensive antibiotic guideline recommendations are generally lacking from European paediatric hospitals. We documented multiple antibiotics and combinations for most infections. Considerable improvement in the quality of guidelines and their evidence base is required, linking empirical therapy to resistance rates.

Item does not contain fulltext BACKGROUND: Surveillance of antimicrobial resistance (AMR) is central for defining appropriate strategies to deal with changing AMR levels. It is unclear whether childhood AMR patterns differ from those detected in isolates from adult patients. METHODS: Resistance percentages of nonduplicate Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa bloodstream isolates from children less than 18 years of age reported to the Antibiotic Resistance and Prescribing in European Children (ARPEC) project were compared with all-age resistance percentages reported by the European Antimicrobial Resistance Surveillance Network (EARS-Net) for the same pathogen-antibiotic class combinations, period and countries. In addition, resistance percentages were compared between ARPEC isolates from children less than 1 year of age and children greater than or equal to1 year of age. RESULTS: Resistance percentages for many important pathogen-antibiotic class combinations were different for ARPEC isolates compared with EARS-Net. E. coli and K. pneumoniae fluoroquinolone resistance percentages were substantially lower in ARPEC (13.4% and 17.9%) than in EARS-Net (23.0% and 30.7%), whereas the reverse was true for all pathogen-antibiotic class combinations in P. aeruginosa (for example, 27.3% aminoglycoside resistance in ARPEC, 19.3% in EARS-Net, 32.8% carbapenem resistance in ARPEC and 20.5% in EARS-Net), and for S. pneumoniae and macrolide resistance. For many Gram-negative pathogen-antibiotic class combinations, isolates from children greater than or equal to 1 year of age showed higher resistance percentages than isolates from children less than 1 year of age. CONCLUSIONS: Age-stratified presentation of resistance percentage estimates by surveillance programs will allow identification of important variations in resistance patterns between different patient groups for targeted intervention. 01 juli 2015

Background The neonatal and pediatric antimicrobial point prevalence survey (PPS) of the Antibiotic Resistance and Prescribing in European Children project (http://www.arpecproject.eu/) aims to standardize a method for surveillance of antimicrobial use in children and neonates admitted to the hospital within Europe. This article describes the audit criteria used and reports overall country-specific proportions of antimicrobial use. An analytical review presents methodologies on antimicrobial use. Methods A 1-day PPS on antimicrobial use in hospitalized children was organized in September 2011, using a previously validated and standardized method. The survey included all inpatient pediatric and neonatal beds and identified all children receiving an antimicrobial treatment on the day of survey. Mandatory data were age, gender, (birth) weight, underlying diagnosis, antimicrobial agent, dose and indication for treatment. Data were entered through a web-based system for data-entry and reporting, based on the WebPPS program developed for the European Surveillance of Antimicrobial Consumption project. Results There were 2760 and 1565 pediatric versus 1154 and 589 neonatal inpatients reported among 50 European (n = 14 countries) and 23 non-European hospitals (n = 9 countries), respectively. Overall, antibiotic pediatric and neonatal use was significantly higher in non-European (43.8%; 95% confidence interval [CI]: 41.3-46.3% and 39.4%; 95% CI: 35.5-43.4%) compared with that in European hospitals (35.4; 95% CI: 33.6-37.2% and 21.8%; 95% CI: 19.4-24.2%). Proportions of antibiotic use were highest in hematology/oncology wards (61.3%; 95% CI: 56.2-66.4%) and pediatric intensive care units (55.8%; 95% CI: 50.3-61.3%). Conclusions An Antibiotic Resistance and Prescribing in European Children standardized web-based method for a 1-day PPS was successfully developed and conducted in 73 hospitals worldwide. It offers a simple, feasible and sustainable way of data collection that can be used globally.

Objective: To investigate the effect of parity on Down syndrome (DS). Methods: The study was conducted on data from Northeast Italy (NEI) (1981–1996) and Sicily (ISMAC) (1991–1996) Congenital Malformation Registries. In these areas, all DS births are recorded and confirmed by chromosomal analysis; the NEI Registry also registers pregnancy terminations (TOPs) after prenatal diagnosis of DS. In order to estimate the effect of parity independently of the mother’s age and to reduce the truncation effect, different age classes and three classes of parity (1, 2–4, >4) were defined. Results: The study sample consisted of 1,088 consecutive newborns and 169 consecutive fetuses affected by DS. In both NEI and ISMAC samples, we found a significantly increased risk of having a DS child for multiparas ≥35 years of age. In the NEI sample, the inclusion of TOP data did not seem to modify this finding. In the ISMAC sample, a significantly reduced risk for primiparas was found at all ages. Conclusions: Our data confirm a higher risk of having a DS child in women with parity >4. As this effect is evident only in women ≥35 years age, its practical impact is null because these women are usually offered prenatal diagnosis in any case. However, the mechanisms involved, if this association is true, are very intriguing and the observation should stimulate scientific studies allowing a better knowledge of the nondisjunction mechanism.

Molecular defects altering the expression of the imprinted genes of the 11p15.5 cluster are responsible for the etiology of two congenital disorders characterized by opposite growth disturbances, Silver–Russell syndrome (SRS), associated with growth restriction, and Beckwith–Wiedemann syndrome (BWS), associated with overgrowth. At the molecular level, SRS and BWS are characterized by defects of opposite sign, including loss (LoM) or gain (GoM) of methylation at the H19/IGF2:intergenic differentially methylated region (H19/IGF2:IG-DMR), maternal or paternal duplication (dup) of 11p15.5, maternal (mat) or paternal (pat) uniparental disomy (upd), and gain or loss of function mutations of CDKN1C. However, while upd(11)pat is found in 20% of BWS cases and in the majority of them it is segmental, upd(11)mat is extremely rare, being reported in only two SRS cases to date, and in both of them is extended to the whole chromosome. Here, we report on two novel cases of mosaic upd(11)mat with SRS phenotype. The upd is mosaic and isodisomic in both cases but covers the entire chromosome in one case and is restricted to 11p14.1-pter in the other case. The segmental upd(11)mat adds further to the list of molecular defects of opposite sign in SRS and BWS, making these two imprinting disorders even more specular than previously described.

Contains fulltext : 231702.pdf (Publisher’s version ) (Closed access) Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.

BACKGROUND: The aim of this study was to examine trends of Down syndrome (DS) in relation to maternal age and termination of pregnancies (ToP) in 20 registries of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR). METHODS: Trends of births with DS (live-born and stillborn), ToP with DS, and maternal age (percentage of mothers older than 35 years) were examined by year over a 12-year period (1993-2004). The total mean number of births covered was 1550,000 annually. RESULTS: The mean percentage of mothers older than 35 years of age increased from 10.9% in 1993 to 18.8% in 2004. However, a variation among the different registers from 4-8% to 20-25% of mothers >35 years of age was found. The total mean prevalence of DS (still births, live births, and ToP) increased from 13.1 to 18.2/10,000 births between 1993 and 2004. The total mean prevalence of DS births remained stable at 8.3/10,000 births, balanced by a great increase of ToP. In the registers from France, Italy, and the Czech Republic, a decrease of DS births and a great increase of ToP was observed. The number of DS births remained high or even increased in Canada Alberta, and Norway during the study period. CONCLUSIONS: Although an increase in older mothers was observed in most registers, the prevalence of DS births remained stable in most registers as a result of increasing use of prenatal diagnostic procedures and ToP with DS. Birth Defects Research (Part A) 88:474-479, 2010. (C) 2010 Wiley-Liss, Inc.

Rubinstein–Taybi syndrome (RSTS) is a rare malformation disorder caused by mutations in the closely related CREBBP and EP300 genes, accounting respectively for up to 60 and 3% of cases. About 10% of CREBBP mutations are whole gene deletions often extending into flanking regions. Using FISH and microsatellite analyses as a first step in the CREBBP mutation screening of 42 Italian RSTS patients, we identified six deletions, three of which were in a mosaic condition that has not been previously reported in RSTS. The use of region-specific BAC clones and small CREBBP probes allowed us to assess the extent of all of the deletions by mapping their endpoints to genomic intervals of 5–10 kb. Four of our five intragenic breakpoints cluster at the 5′ end of CREBBP, where there is a peak of breakpoints underlying rearrangements in RSTS patients and tumors. The search for genomic motifs did not reveal any low-copy repeats (LCRs) or any greater density of repetitive sequences. In contrast, the percentage of interspersed repetitive elements (mainly Alu and LINEs in the CREBBP exon 2 region) is significantly higher than that in the entire gene or the average in the genome, thus suggesting that this characteristic may be involved in the region’s vulnerability to breaking and nonhomologous pairing. The FISH analysis extended to the EP300 genomic region did not reveal any deletions. The clinical presentation was typical in all cases, but more severe in the three patients carrying constitutional deletions, raising a question about the possible underdiagnosis of a few cases of mild RSTS.

The basic genomic defect in Wolf–Hirschhorn syndrome (WHS), including isolated 4p deletions and various unbalanced de novo 4p;autosomal translocations and above all t(4p;8p), is heterogeneous. Olfactory receptor gene clusters (ORs) on 4p were demonstrated to mediate a group of WHS-associated t(4p;8p)dn translocations. The breakpoint of a 4-Mb isolated deletion was also recently reported to fall within the most distal OR. However, it is still unknown whether ORs mediate all 4p-autosomal translocations, or whether they are involved in the origin of isolated 4p deletions. Another unanswered question is whether a parental inversion polymorphism on 4p16 can act as predisposing factor in the origin of WHS-associated rearrangements. We investigated the involvement of the ORs in the origin of 73 WHS-associated rearrangements. No hotspots for rearrangements were detected. Breakpoints on 4p occurred within the proximal or the distal olfactory receptor gene cluster in 8 of 73 rearrangements (11%). These were five t(4p;8p) translocations, one t(4p;7p) translocation and two isolated terminal deletions. ORs were not involved in one additional t(4p;8p) translocation, in a total of nine different 4p;autosomal translocations and in the majority of isolated deletions. The presence of a parental inversion polymorphism on 4p was investigated in 30 families in which the 4p rearrangements, all de novo, were tested for parental origin (7 were maternal and 23 paternal). It was detected only in the mothers of 3 t(4p;8p) cases. We conclude that WHS-associated chromosome changes are not usually mediated by low copy repeats. The 4p16.3 inversion polymorphism is not a risk factor for their origin.

Costello syndrome is characterized by severe failure-to-thrive, short stature, cardiac abnormalities (heart defects, tachyarrhythmia, and hypertrophic cardiomyopathy (HCM)), distinctive facial features, a predisposition to papillomata and malignant tumors, postnatal cerebellar overgrowth resulting in Chiari 1 malformation, and cognitive disabilities. De novo germline mutations in the proto-oncogene HRAS cause Costello syndrome. Most mutations affect the glycine residues in position 12 or 13, and more than 80% of patients share p.G12S. To test the hypothesis that subtle genotype-phenotype differences exist, we report the first cohort comparison between 12 Costello syndrome individuals with p.G13C and individuals with p.G12S. The individuals with p.G13C had many typical findings including polyhydramnios, failure-to-thrive, HCM, macrocephaly with posterior fossa crowding, and developmental delay. Subjectively, their facial features were less coarse. Statistically significant differences included the absence of multifocal atrial tachycardia (P-value = 0.033), ulnar deviation of the wrist (P < 0.001) and papillomata (P = 0.003), and fewer neurosurgical procedures (P = 0.024). Fewer individuals with p.G13C had short stature (height below -2 SD) without use of growth hormone (P < 0.001). The noteworthy absence of malignant tumors did not reach statistical significance. Novel ectodermal findings were noted in individuals with p.G13C, including loose anagen hair resulting in easily pluckable hair with a matted appearance, different from the tight curls typical for most Costello syndrome individuals. Unusually long eye lashes requiring trimming are a novel finding we termed dolichocilia. These distinctive ectodermal findings suggest a cell type specific effect of this particular mutation. Additional patients are needed to validate these findings.

N-myristoylation is a common form of co-translational protein fatty acylation resulting from the attachment of myristate to a required N-terminal glycine residue(1,2). We show that aberrantly acquired N-myristoylation of SHOC2, a leucine-rich repeat-containing protein that positively modulates RAS-MAPK signal flow(3-6), underlies a clinically distinctive condition of the neuro-cardio-facial-cutaneous disorders family. Twenty-five subjects with a relatively consistent phenotype previously termed Noonan-like syndrome with loose anagen hair (MIM607721)(7) shared the 4A>G missense change in SHOC2 (producing an S2G amino acid substitution) that introduces an N-myristoylation site, resulting in aberrant targeting of SHOC2 to the plasma membrane and impaired translocation to the nucleus upon growth factor stimulation. Expression of SHOC2(S2G) in vitro enhanced MAPK activation in a cell typespecific fashion. Induction of SHOC2(S2G) in Caenorhabditis elegans engendered protruding vulva, a neomorphic phenotype previously associated with aberrant signaling. These results document the first example of an acquired N-terminal lipid modification of a protein causing human disease.

Background and aim To clarify the precise mode of inheritance of Gilbert syndrome, an unconjugated familial hyperbilirubinemia, where impaired bilirubin conjugation is caused by reduced UGT1A1 activity determined by a defective function of the A(TA)6TAA promoter region of the UGT1A1 gene. Subjects and methods Serum bilirubin levels were measured in a large, homogeneous resident population from North-Eastern Italy, consisting of 1.639 males (age 44.5 ± 13.9, range 18–89 years), and 1.420 females (age 45.1 ± 15.0, range 18–85). In 112 nuclear families from hyperbilirubinemic probands living in the same area a complex segregation analysis was then performed. In both samples we carefully excluded potentially confounding factors of bilirubin levels (alcohol abuse, excessive cigarette smoking, drug consumption, overt haemolysis and liver disease). Results Mean serum bilirubin concentrations are higher in males than in females, showing fluctuations through the different age periods in males. Complex segregation results demonstrate that unconjugated hyperbilirubinemia exhibits a precise mode of inheritance in which a major recessive gene with a frequency of 0.45 is responsible for higher serum bilirubin values. Conclusions This major recessive gene accounts only for a part of the serum bilirubin concentration, thus implying additional, environmental factors for the clinical appearance of GS.