Impact of the 10-valent pneumococcal conjugate vaccine on antimicrobial prescriptions in young children: a whole population study.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadAntimicrobial resistance is a public-health threat and antimicrobial consumption is the main contributor. The ten-valent pneumococcal conjugate vaccine (PHiD-CV10) was introduced into the Icelandic vaccination program in 2011. The aim was to estimate the vaccine impact of PHiD-CV10 on outpatient antimicrobial prescriptions in children. Eleven Icelandic birth-cohorts (2005-2015) were followed from birth until three years of age or to the end of the study period (December 31, 2016). Birth-cohorts were grouped as vaccine non-eligible (VNEC, 2005-2010) or vaccine eligible (VEC, 2011-2015). Data on primary care visits for respiratory infections and antimicrobial prescriptions were extracted from two national registers. Using national identification numbers, prescriptions were linked to physician visits if filled within three days of the visit. Incidence rates and incidence rate ratios between VNEC and VEC were calculated. An Andersen-Gill model was used to model the individual level data, accounting for repeated events and censoring. Vaccine impact was calculated as (1 - Hazard Ratio) × 100%. Included were 53,510 children who contributed 151,992 person-years of follow-up and filled 231,660 antimicrobial prescriptions. The incidence rate was significantly lower in the VEC compared to the VNEC, 144.5 and 157.2 prescriptions per 100 person-years respectively (IRR 0.92, 95%CI 0.91-0.93). Children in VEC were more likely to have filled zero (IRR 1.16 (95%CI 1.10-1.23) and 1-4 (IRR 1.08 95%CI 1.06-1.11) prescriptions compared to children in VNEC. The vaccine impact of PHiD-CV10 against all-cause antimicrobial prescriptions was 5.8% (95%CI 1.6-9.8%).When only considering acute otitis media-associated prescriptions, the vaccine impact was 21.8% (95%CI 11.5-30.9%). The introduction of PHiD-CV10 lead to reduced antimicrobial use in children, mainly by reducing acute otitis media episodes. This intervention therefore reduces both disease burden and could slow the spread of antimicrobial resistance.GlaxoSmithKline Biologicals SA Landspitali University Hospital Research Fun

Impact of the 10-valent pneumococcal conjugate vaccine on hospital admissions in children under three years of age in Iceland.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadIntroduction: Pneumococcus is an important respiratory pathogen. The 10-valent pneumococcal vaccine (PHiD-CV) was introduced into the Icelandic vaccination programme in 2011. The aim was to estimate the impact of PHiD-CV on paediatric hospitalisations for respiratory tract infections and invasive disease. Methods: The 2005-2015 birth-cohorts were followed until three years of age and hospitalisations were recorded for invasive pneumococcal disease (IPD), meningitis, sepsis, pneumonia and otitis media. Hospitalisations for upper- and lower respiratory tract infections (URTI, LRTI) were used as comparators. The 2005-2010 birth-cohorts were defined as vaccine non-eligible cohorts (VNEC) and 2011-2015 birth-cohorts as vaccine eligible cohorts (VEC). Incidence rates (IR) were estimated for diagnoses, birth-cohorts and age groups, and incidence rate ratios (IRR) between VNEC and VEC were calculated assuming Poisson variance. Cox regression was used to estimate the hazard ratio (HR) of hospitalisation between VNEC and VEC. Results: 51,264 children were followed for 142,315 person-years, accumulating 1,703 hospitalisations for the respective study diagnoses. Hospitalisations for pneumonia decreased by 20% (HR 0.80, 95%CI:0.67-0.95) despite a 32% increase in admissions for LRTI (HR 1.32, 95%CI:1.14-1.53). Hospital admissions for culture-confirmed IPD decreased by 93% (HR 0.07, 95%CI:0.01-0.50) and no hospitalisations for IPD with vaccine-type pneumococci were observed in the VEC. Hospitalisations for meningitis and sepsis did not change. A decrease in hospital admissions for otitis media was observed, but did not coincide with PHiD-CV introduction. Conclusion: Following the introduction of PHiD-CV in Iceland, hospitalisations for pneumonia and culture confirmed IPD decreased. Admissions for other LRTIs and URTIs increased during this period.GlaxoSmithKline Landspitali University Hospital Research Fun

Current status of intestinal transplantation in children

Purpose: A clinical trial of intestinal transplantation (Itx) under tacrolimus and prednisone immunosuppression was initiated in June 1990 in children with irreversible intestinal failure and who were dependent on total parenteral nutrition (TPN). Methods: Fifty-five patients (28 girls, 27 boys) with a median age of 3.2 years (range, 0.5 to 18 years) received 58 intestinal transplants that included isolated small bowel (SB) (n = 17), liver SB (LSB) (n = 33), and multivisceral (MV) (n = 8) allografts. Nine patients also received bone marrow infusion, and there were 20 colonic allografts. Azathioprine, cyclophosphamide, or mycophenolate mofetil were used in different phases of the series. Indications for Itx included: gastroschisis (n = 14), volvulus (n = 13), necrotizing enterocolitis (n = 6), intestinal atresia (n = 8), chronic intestinal pseudoobstruction (n = 5), Hirschsprung's disease (n = 4), microvillus inclusion disease (n = 3), multiple polyposis (n = 1), and trauma (n = 1). Results: Currently, 30 patients are alive (patient survival, 55%; graft survival, 52%). Twenty-nine children with functioning grafts are living at home and off TPN, with a mean follow-up of 962 (range, 75 to 2,424) days. Immunologic complications have included liver allograft rejection (n = 18), intestinal allograft rejection (n = 52), posttransplant lymphoproliferative disease (n = 16), cytomegalovirus (n = 16) and graft-versus-host disease (n = 4). A combination of associated complications included intestinal perforation (n = 4), biliary leak (n = 3), bile duct stenosis (n = 1), intestinal leak (n = 6), dehiscence with evisceration (n = 4), hepatic artery thrombosis (n = 3), bleeding (n = 9), portal vein stenosis (n = 1), intraabdominal abscess (n = 11), and chylous ascites (n = 4). Graft loss occurred as a result of rejection (n = 8), infection (n = 12), technical complications (n = 8), and complications of TPN after graft removal (n = 3). There were four retransplants (SB, n = 1; LSB n = 3). Conclusions: Intestinal transplantation is a valid therapeutic option for patients with intestinal failure suffering complications of TPN. The complex clinical and immunologic course of these patients is reflected in a higher complication rate as well as patient and graft loss than seen after heart, liver, and kidney transplantation, although better than after lung transplantation

Gravitational Waves from a Compact Star in a Circular, Inspiral Orbit, in the Equatorial Plane of a Massive, Spinning Black Hole, as Observed by LISA

Results are presented from high-precision computations of the orbital evolution and emitted gravitational waves for a stellar-mass object spiraling into a massive black hole in a slowly shrinking, circular, equatorial orbit. The focus of these computations is inspiral near the innermost stable circular orbit (isco)---more particularly, on orbits for which the angular velocity Omega is 0.03 < Omega/Omega_{isco} < 1. The computations are based on the Teukolsky-Sasaki-Nakamura formalism, and the results are tabulated in a set of functions that are of order unity and represent relativistic corrections to low-orbital-velocity formulas. These tables can form a foundation for future design studies for the LISA space-based gravitational-wave mission. A first survey of applications to LISA is presented: Signal to noise ratios S/N are computed and graphed as functions of the time-evolving gravitational-wave frequency for representative values of the hole's mass M and spin a and the inspiraling object's mass \mu, with the distance to Earth chosen to be r_o = 1 Gpc. These S/N's show a very strong dependence on the black-hole spin, as well as on M and \mu. A comparison with predicted event rates shows strong promise for detecting these waves, but not beyond about 1Gpc if the inspiraling object is a white dwarf or neutron star. This argues for a modest lowering of LISA's noise floor. A brief discussion is given of the prospects for extracting information from the observed wavesComment: Physical Review D, in press; 21 pages, 9 figures, 10 tables it is present in the RevTeX fil

Outcomes from a 12-Week, Open-Label, Multicenter Clinical Trial of Teduglutide in Pediatric Short Bowel Syndrome

Objective To determine safety and pharmacodynamics/efficacy of teduglutide in children with intestinal failure associated with short bowel syndrome (SBS-IF). Study design This 12-week, open-label study enrolled patients aged 1-17 years with SBS-IF who required parenteral nutrition (PN) and showed minimal or no advance in enteral nutrition (EN) feeds. Patients enrolled sequentially into 3 teduglutide cohorts (0.0125 mg/kg/d [n = 8], 0.025 mg/kg/d [n = 14], 0.05 mg/kg/d [n = 15]) or received standard of care (SOC, n = 5). Descriptive summary statistics were used. Results All patients experienced ≥1 treatment-emergent adverse event; most were mild or moderate. No serious teduglutide-related treatment-emergent adverse events occurred. Between baseline and week 12, prescribed PN volume and calories (kcal/kg/d) changed by a median of −41% and −45%, respectively, with 0.025 mg/kg/d teduglutide and by −25% and −52% with 0.05 mg/kg/d teduglutide. In contrast, PN volume and calories changed by 0% and −6%, respectively, with 0.0125 mg/kg/d teduglutide and by 0% and −1% with SOC. Per patient diary data, EN volume increased by a median of 22%, 32%, and 40% in the 0.0125, 0.025, and 0.05 mg/kg/d cohorts, respectively, and by 11% with SOC. Four patients achieved independence from PN, 3 in the 0.05 mg/kg/d cohort and 1 in the 0.025 mg/kg/d cohort. Study limitations included its short-term, open-label design, and small sample size. Conclusions Teduglutide was well tolerated in pediatric patients with SBS-IF. Teduglutide 0.025 or 0.05 mg/kg/d was associated with trends toward reductions in PN requirements and advancements in EN feeding in children with SBS-IF

Effect of Vaccination on Pneumococci Isolated from the Nasopharynx of Healthy Children and the Middle Ear of Children with Otitis Media in Iceland.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadVaccination with pneumococcal conjugate vaccines (PCVs) disrupts the pneumococcal population. Our aim was to determine the impact of the 10-valent PCV on the serotypes, genetic lineages, and antimicrobial susceptibility of pneumococci isolated from children in Iceland. Pneumococci were collected between 2009 and 2017 from the nasopharynges of healthy children attending 15 day care centers and from the middle ears (MEs) of children with acute otitis media from the greater Reykjavik capital area. Isolates were serotyped and tested for antimicrobial susceptibility. Whole-genome sequencing (WGS) was performed on alternate isolates from 2009 to 2014, and serotypes and multilocus sequence types (STs) were extracted from the WGS data. Two study periods were defined: 2009 to 2011 (PreVac) and 2012 to 2017 (PostVac). The overall nasopharyngeal carriage rate was similar between the two periods (67.3% PreVac and 61.5% PostVac,GlaxoSmithKline Biologicals SA Landspitali University Hospital Research Fund Eimskip University Fund Wellcome Trust John Fell Fund Wellcome core fundin

Pneumococcal vaccination: Direct and herd effect on carriage of vaccine types and antibiotic resistance in Icelandic children

Background Since the introduction of pneumococcal conjugate vaccines, vaccine type pneumococcal carriage and disease has decreased world-wide. The aim was to monitor changes in the nasopharyngeal carriage of pneumococci, the distribution of serotypes and antimicrobial resistance in children before and after initiation of the 10-valent pneumococcal vaccination in 2011, in a previously unvaccinated population. Methods Repeated cross-sectional study at 15 day-care centres in greater Reykjavik area. Nasopharyngeal swabs were collected yearly in March from 2009 to 2015. The swabs were selectively cultured for pneumococci, which were serotyped using latex agglutination and/or PCR and antimicrobial susceptibility determined. Two independent studies were conducted. In study 1, on total impact, isolates from children aged <4 years were included. The vaccine-eligible-cohort (birth-years: 2011–2013, sampled in 2013–2015) was compared with children at the same age born in 2005–2010 and sampled in 2009–2012. In study 2 on herd effect, isolates from older non-vaccine-eligible children (3.5–6.3 years) were compared for the periods before and after the vaccination (2009–2011 vs 2013–2015. Vaccine impact was determined using 1-odds-ratio. Results Following vaccination, the vaccine impact on vaccine type acquisition was 94% (95% CI: 91–96%) in study 1 and 56% (95% CI: 44–65%) in study 2. The impact on serotype 6 A was 33% (95% CI: −9%; 59%) in study 1 and 42% (95% CI: 10–63%) in study 2 with minimal effect on 19A. The non-vaccine serotypes/groups 6C, 11, 15 and 23B were the most common serotypes/groups after vaccination. Isolates from the vaccine-eligible-cohort had lower penicillin MICs, less resistance to erythromycin and co-trimoxazole and less multi resistance than isolates from the control-group. Conclusions The efficacy of the vaccination on vaccine serotypes was high, and a milder effect on vaccine-associated-serotype 6A was observed for the vaccine-eligible-cohort. There was a significant herd effect on vaccine types in older non-vaccine-eligible children. Overall antimicrobial non-susceptibility was reduced.Funding for this study was provided by GlaxoSmithKline Biologicals SA and a grant was received from the Landspitali University Hospital Research Fund. GlaxoSmithKline Biologicals SA was provided the opportunity to review a draft version of this manuscript but the authors are solely responsible for final content and interpretation. The authors received no financial support or other form of compensation related to the development of the manuscript.Peer Reviewe

Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects.

Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course

A sub-Neptune sized planet transiting the M2.5-dwarf G 9-40: Validation with the Habitable-zone Planet Finder

We validate the discovery of a 2 Earth radii sub-Neptune-size planet around the nearby high proper motion M2.5-dwarf G 9-40 (EPIC 212048748), using high-precision near-infrared (NIR) radial velocity (RV) observations with the Habitable-zone Planet Finder (HPF), precision diffuser-assisted ground-based photometry with a custom narrow-band photometric filter, and adaptive optics imaging. At a distance of $d=27.9\mathrm{pc}$, G 9-40b is the second closest transiting planet discovered by K2 to date. The planet's large transit depth ($\sim$3500ppm), combined with the proximity and brightness of the host star at NIR wavelengths (J=10, K=9.2) makes G 9-40b one of the most favorable sub-Neptune-sized planet orbiting an M-dwarf for transmission spectroscopy with JWST, ARIEL, and the upcoming Extremely Large Telescopes. The star is relatively inactive with a rotation period of $\sim$29 days determined from the K2 photometry. To estimate spectroscopic stellar parameters, we describe our implementation of an empirical spectral matching algorithm using the high-resolution NIR HPF spectra. Using this algorithm, we obtain an effective temperature of $T_{\mathrm{eff}}=3404\pm73$K, and metallicity of $\mathrm{[Fe/H]}=-0.08\pm0.13$. Our RVs, when coupled with the orbital parameters derived from the transit photometry, exclude planet masses above $11.7 M_\oplus$ with 99.7% confidence assuming a circular orbit. From its radius, we predict a mass of $M=5.0^{+3.8}_{-1.9} M_\oplus$ and an RV semi-amplitude of $K=4.1^{+3.1}_{-1.6}\mathrm{m\:s^{-1}}$, making its mass measurable with current RV facilities. We urge further RV follow-up observations to precisely measure its mass, to enable precise transmission spectroscopic measurements in the future.Comment: Accepted for publication in AJ, 22 pages, 15 figure

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe