Somatic development long after the Fontan operation: Factors influencing catch-up growth

ObjectiveAs mortality and morbidity after the Fontan operation has improved, long-term outcome, including developmental aspects, have become more important. To understand the long-term effects of this operation, we followed somatic development for up to 15 years.MethodsWe evaluated 90 patients who underwent the Fontan operation between 1984 and 2004 (mean follow-up, 11.8 ± 4.2 years). The modified Fontan operations were atriopulmonary anastomosis (n = 19) and total cavopulmonary connection (n = 71). Mean age at the time of surgical intervention was 5.5 ± 4.8 years. Weight, height, and body mass index were evaluated preoperatively and postoperatively and given as percentiles on a normal growth curve.ResultsPostoperative weight, height, and body mass index reached the 47.2 ± 35.6, 37.9 ± 30.4, and 41.6 ± 31.2 percentiles, which were significantly better than preoperative values (the 21.6 ± 25.9, 25.9 ± 25.7, and 20.0 ± 25.1 percentiles). Although neither early surgical intervention nor anatomic features affected postoperative growth, early Fontan completion demonstrated better somatic development in subgroups of tricuspid atresia. Prior bidirectional Glenn shunting provided better weight gain before the Fontan operation. Prior atrioseptectomy, central shunt, and pulmonary artery reconstruction were associated with impaired somatic development. Reoperation and catheter-based intervention improved somatic development.ConclusionsLong-term catch-up growth can be observed in patients after the Fontan operation. Early volume-unloading procedures might lead to better somatic growth. Prior atrioseptectomy, central shunt, and pulmonary artery reconstruction are associated with impaired weight and height gain, implying that the severity of the underlying diseases affects postoperative somatic development

Risk factors for sporadic domestically acquired Campylobacter infections in Norway 2010–2011: A national prospective case-control study

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: https://creativecommons.org/licenses/by/4.0/"Background: Campylobacteriosis is the most frequently reported food- and waterborne infection in Norway. We investigated the risk factors for sporadic Campylobacter infections in Norway in order to identify areas where control and prevention measures could be improved."Funds were provided for the preparation of data collection materials by the Norwegian Food Safety Authority and the Norwegian Veterinary Institut

Mutations in the Genes for Interphotoreceptor Matrix Proteoglycans, IMPG1 and IMPG2, in Patients with Vitelliform Macular Lesions

A significant portion of patients diagnosed with vitelliform macular dystrophy (VMD) do not carry causative mutations in the classic VMD genes BEST1 or PRPH2. We therefore performed a mutational screen in a cohort of 106 BEST1/PRPH2-negative VMD patients in two genes encoding secreted interphotoreceptor matrix proteoglycans-1 and -2 (IMPG1 and IMPG2). We identified two novel mutations in IMPG1 in two simplex VMD cases with disease onset in their early childhood, a heterozygous p.(Leu238Pro) missense mutation and a homozygous c.807 + 5G > A splice site mutation. The latter induced partial skipping of exon 7 of IMPG1 in an in vitro splicing assay. Furthermore, we found heterozygous mutations including three stop [p.(Glu226*), p.(Ser522*), p.(Gln856*)] and five missense mutations [p.(Ala243Pro), p.(Gly1008Asp), p.(Phe1016Ser), p.(Tyr1042Cys), p.(Cys1077Phe)] in the IMPG2 gene, one of them, p.(Cys1077Phe), previously associated with VMD. Asymptomatic carriers of the p.(Ala243Pro) and p.(Cys1077Phe) mutations show subtle foveal irregularities that could characterize a subclinical stage of disease. Taken together, our results provide further evidence for an involvement of dominant and recessive mutations in IMPG1 and IMPG2 in VMD pathology. There is a remarkable similarity in the clinical appearance of mutation carriers, presenting with bilateral, central, dome-shaped foveal accumulation of yellowish material with preserved integrity of the retinal pigment epithelium (RPE). Clinical symptoms tend to be more severe for IMPG1 mutations

Oxygen fluxes beneath Arctic land-fast ice and pack ice: towards estimates of ice productivity

Sea-ice ecosystems are among the most extensive of Earth's habitats; yet its autotrophic and heterotrophic activities remain poorly constrained. We employed the in situ aquatic eddy-covariance (AEC) O-2 flux method and laboratory incubation techniques ((HCO3-)-C-14, [H-3] thymidine and [H-3] leucine) to assess productivity in Arctic sea-ice using different methods, in conditions ranging from land-fast ice during winter, to pack ice within the central Arctic Ocean during summer. Laboratory tracer measurements resolved rates of bacterial C demand of 0.003-0.166mmolCm(-2)day(-1) and primary productivity rates of 0.008-0.125mmolCm(-2)day(-1) for the different ice floes. Pack ice in the central Arctic Ocean was overall net autotrophic (0.002-0.063mmolCm(-2)day(-1)), whereas winter land-fast ice was net heterotrophic (-0.155mmol C m(-2) day(-1)). AEC measurements resolved an uptake of O-2 by the bottom-ice environment, from similar to-2mmolO(2)m(-2) day(-1) under winter land-fast ice to similar to-6mmolO(2)m(-2)day(-1) under summer pack ice. Flux of O-2-deplete meltwater and changes in water flow velocity masked potential biological-mediated activity. AEC estimates of primary productivity were only possible at one study location. Here, productivity rates of 1.3 +/- 0.9mmolO(2)m(-2)day(-1), much larger than concurrent laboratory tracer estimates (0.03mmolCm(-2)day(-1)), indicate that ice algal production and its importance within the marine Arctic could be underestimated using traditional approaches. Given careful flux interpretation and with further development, the AEC technique represents a promising new tool for assessing oxygen dynamics and sea-ice productivity in ice-covered regions.Peer reviewe

Radiation hard 3D silicon pixel sensors for use in the ATLAS detector at the HL-LHC

The High Luminosity LHC (HL-LHC) upgrade requires the planned Inner Tracker (ITk) of the ATLAS detector to tolerate extremely high radiation doses. Specifically, the innermost parts of the pixel system will have to withstand radiation fluences above 1 × 1016 neqcm-2. Novel 3D silicon pixel sensors offer a superior radiation tolerance compared to conventional planar pixel sensors, and are thus excellent candidates for the innermost parts of the ITk. This paper presents studies of 3D pixel sensors with pixel size 50 × 50 μm2 mounted on the RD53A prototype readout chip. Following a description of the design and fabrication steps, Test Beam results are presented for unirradiated as well as heavily irradiated sensors. For particles passing at perpendicular incidence, it is shown that average efficiencies above 96% are reached for sensors exposed to fluences of 1 × 1016 neqcm-2 when biased to 80 V.publishedVersio

Hepatitis C virus cell-cell transmission and resistance to direct-acting antiviral agents

Hepatitis C virus (HCV) is transmitted between hepatocytes via classical cell entry but also uses direct cell-cell transfer to infect neighboring hepatocytes. Viral cell-cell transmission has been shown to play an important role in viral persistence allowing evasion from neutralizing antibodies. In contrast, the role of HCV cell-cell transmission for antiviral resistance is unknown. Aiming to address this question we investigated the phenotype of HCV strains exhibiting resistance to direct-acting antivirals (DAAs) in state-of-the-art model systems for cell-cell transmission and spread. Using HCV genotype 2 as a model virus, we show that cell-cell transmission is the main route of viral spread of DAA-resistant HCV. Cell-cell transmission of DAA-resistant viruses results in viral persistence and thus hampers viral eradication. We also show that blocking cell-cell transmission using host-targeting entry inhibitors (HTEIs) was highly effective in inhibiting viral dissemination of resistant genotype 2 viruses. Combining HTEIs with DAAs prevented antiviral resistance and led to rapid elimination of the virus in cell culture model. In conclusion, our work provides evidence that cell-cell transmission plays an important role in dissemination and maintenance of resistant variants in cell culture models. Blocking virus cell-cell transmission prevents emergence of drug resistance in persistent viral infection including resistance to HCV DAAs

Telomere disruption results in non-random formation of de novo dicentric chromosomes involving acrocentric human chromosomes

Copyright: © 2010 Stimpson et al.Genome rearrangement often produces chromosomes with two centromeres (dicentrics) that are inherently unstable because of bridge formation and breakage during cell division. However, mammalian dicentrics, and particularly those in humans, can be quite stable, usually because one centromere is functionally silenced. Molecular mechanisms of centromere inactivation are poorly understood since there are few systems to experimentally create dicentric human chromosomes. Here, we describe a human cell culture model that enriches for de novo dicentrics. We demonstrate that transient disruption of human telomere structure non-randomly produces dicentric fusions involving acrocentric chromosomes. The induced dicentrics vary in structure near fusion breakpoints and like naturally-occurring dicentrics, exhibit various inter-centromeric distances. Many functional dicentrics persist for months after formation. Even those with distantly spaced centromeres remain functionally dicentric for 20 cell generations. Other dicentrics within the population reflect centromere inactivation. In some cases, centromere inactivation occurs by an apparently epigenetic mechanism. In other dicentrics, the size of the alpha-satellite DNA array associated with CENP-A is reduced compared to the same array before dicentric formation. Extrachromosomal fragments that contained CENP-A often appear in the same cells as dicentrics. Some of these fragments are derived from the same alpha-satellite DNA array as inactivated centromeres. Our results indicate that dicentric human chromosomes undergo alternative fates after formation. Many retain two active centromeres and are stable through multiple cell divisions. Others undergo centromere inactivation. This event occurs within a broad temporal window and can involve deletion of chromatin that marks the locus as a site for CENP-A maintenance/replenishment.This work was supported by the Tumorzentrum Heidelberg/Mannheim grant (D.10026941)and by March of Dimes Research Foundation grant #1-FY06-377 and NIH R01 GM069514

At-home use of parasacral transcutaneous electrical nerve stimulation for pediatric voiding dysfunction: a randomized controlled trial to assess its safety and feasibility

IntroductionTreating pediatric voiding dysfunction involves behavioral changes that require significant time or medications that are often avoided or discontinued due to side effects. Using parasacral transcutaneous electrical nerve stimulation (PTENS) has shown to have reasonable efficacy, but the safety and feasibility of its off-label use for pediatric voiding dysfunction are not well-established. Concerns have also been raised over treatment adherence. In-home therapy might improve adherence compared with office-based therapy; however, no studies have evaluated in-home feasibility to date. This study aims to assess the safety and feasibility of off-label use of PTENS for pediatric voiding dysfunction.Materials and methodsA single-institution prospective, randomized controlled study was conducted from March 2019 to March 2020. Participants aged 6–18 years diagnosed with voiding dysfunction, overactive bladder, or urinary incontinence were eligible for the study. Those with known neurologic disorders, implanted electrical devices, anatomic lower urinary tract abnormality, and recurrent urinary tract infections and those taking bladder medications were excluded. Children with primary monosymptomatic nocturnal enuresis were also excluded due to previous work suggesting a lack of efficacy. Participants were randomly assigned to receive 12 weeks of urotherapy alone (control) or urotherapy plus at-home PTENS treatment. Families were contacted weekly to assess for adverse events (AEs) and treatment adherence. The primary and secondary outcomes were safety, defined as the absence of AEs and treatment adherence, respectively.ResultsA total of 30 eligible participants were divided into two groups, with 15 participants in each arm. The median age was 9.4 years (interquartile range: 7.7–10.6). In total, 60% were male. Baseline demographics and urotherapy compliance were similar between the two groups. With PTENS use, two AEs were reported, including mild pruritus at the pad site and discomfort when removing pads, while no AEs were noted in the control group. In total, 60% of patients completed three 30-min sessions per week, and all participants were able to complete treatment sessions for at least 10 weeks, involving 30 min of PTENS treatment each time.ConclusionThis randomized controlled study confirms that at-home use of PTENS is feasible with reasonable treatment adherence and minimal AEs. Future collaborative, multi-institutional studies may better determine the efficacy of this treatment modality