35 research outputs found
Implementing the U.N. Convention on the Rights of the Child
The United Nations Convention on the Rights of the Child, adopted by the General Assembly on November 20, 1989, articulates a comprehensive scheme of rights specifically tailored to children. International recognition of children\u27s rights is only the first step, however. The effectiveness of the Convention on the Rights of the Child depends on the signatories\u27 efforts to comply with its provisions and to incorporate children\u27s rights into existing schemes of established rights. The 1996 Constitution of the Republic of South Africa includes specific rights for children resembling those articulated in the Convention on the Rights of the Child. Although South Africa has incorporated children\u27s rights into its Constitution, there are still substantial numbers of children in South Africa who do not enjoy the protection that the Convention on the Rights of the Child demands. In this Note, the Author examines the experience of South Africa to illustrate that the constitutionalization of children\u27s rights does not alone ensure that the rights of the Convention are accessible to children. The Author addresses the barriers to South Africa\u27s compliance with the Convention on the Rights of the Child and offers possible solutions to them. The Author\u27s conclusion is that implementation of the Convention on the Rights of the Child requires legislative reform and increased participation of community-based organizations, as well as constitutionalization of children\u27s rights
Comparison of \nu\mu-Ar multiplicity distributions observed by MicroBooNE to GENIE model predictions
We measure a large set of observables in inclusive charged current muon
neutrino scattering on argon with the MicroBooNE liquid argon time projection
chamber operating at Fermilab. We evaluate three neutrino interaction models
based on the widely used GENIE event generator using these observables. The
measurement uses a data set consisting of neutrino interactions with a final
state muon candidate fully contained within the MicroBooNE detector. These data
were collected in 2016 with the Fermilab Booster Neutrino Beam, which has an
average neutrino energy of 800 MeV, using an exposure corresponding to 5E19
protons-on-target. The analysis employs fully automatic event selection and
charged particle track reconstruction and uses a data-driven technique to
separate neutrino interactions from cosmic ray background events. We find that
GENIE models consistently describe the shapes of a large number of kinematic
distributions for fixed observed multiplicity.Comment: 31 pages, 39 figures, 10 table
Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome
To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases
Detectable clonal mosaicism and its relationship to aging and cancer
In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases
Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome
To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP
microarray intensity data of 38,303 women from cancer genome-wide association studies
(20,878 cases and 17,425 controls) and detected 124 mosaic X events42Mb in 97 (0.25%)
women. Here we show rates for X-chromosome mosaicism are four times higher than mean
autosomal rates; X mosaic events more often include the entire chromosome and participants
with X events more likely harbour autosomal mosaic events. X mosaicism frequency
increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and
autosomes. Methylation array analyses of 33 women with X mosaicism indicate events
preferentially involve the inactive X chromosome. Our results provide further evidence that
the sex chromosomes undergo mosaic events more frequently than autosomes, which could
have implications for understanding the underlying mechanisms of mosaic events and their
possible contribution to risk for chronic diseases
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Extracorporeal Membrane Oxygenation: Rescue Therapy in Pediatric Bupropion Cardiotoxicity
Abstract:
Objective Our objective was to describe clinical characteristics and course of pediatric bupropion ingestions requiring extracorporeal membrane oxygenation (ECMO) life support.
Desgin The study included a retrospective cohort of patients ≤18 years of age reported to a regional poison control (PC) system covering three states in the upper Midwest United States. All bupropion exposures ≤18 years of age, coded as receiving ECMO to treat toxicity, were included. Clinical presentation and management including ECMO are presented as descriptive statistics.
Results During the study period, 4,951 bupropion exposures were reported; 1,145 (23.1%) were children. Nine patients were coded as undergoing ECMO; four (44.4%) were ≤18 years of age (median 16, range 14–17). All were treated with venoarterial ECMO. The median time from ingestion to presentation was 2.25 hours (range: 1–3.5). Median first systolic blood pressure and pulse were 100 mm Hg (range: 70–124) and 119.5 (range: 70–175). The median time from ingestion to ECMO was 17.63 hours (range: 7.25–33.75); median number of vasopressors was 2.5 (range: 2–3). All experienced multiple seizures, ventricular dysrhythmias, and hypotension. Three of four sustained cardiac arrest. All but one required transfer to an ECMO-capable facility for definitive care. Three patients survived with full neurologic recovery; one died.
Conclusion Pediatric bupropion cases requiring ECMO were rare in this study. Time to initiation and duration of EMCO suggest that the variable onset of hemodynamic instability may delay ECMO initiation. It is incumbent on PCs and medical toxicologists to educate prescribers and pediatricians about bupropion's potential lethality and to consider early transfer to an ECMO center
Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition.
Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis
Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition
Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis