147 research outputs found
The Magnetism of the Human Rights Act 1998
Anthony Lester QC discusses the impact of the UK Human Rights Act 1998 ('UK Act') in the United Kingdom and compares its aspects to the New Zealand Bill of Rights Act 1990. The article begins with an overview of constitutional developments in the United Kingdom, and a brief political background to the UK Act. The author discusses section 3 of the UK Act, which imposes a duty on courts and tribunals to strive to avoid incompatibility between domestic legislation and the European Convention on Human Rights ('Convention'), and section 4, which empowers the Court to make a declaration of incompatibility as a last resort. The article also explores the principle of proportionality, the impact of the UK Act on private law relationships, and section 19 of the UK Act which requires the Minister in charge of Bills to show declare whether a new bill is consistent with the Convention. The author concludes that the UK Act weaves Convention rights into the very fabric of UK common law and legislation, and the judiciary will have a key role in developing the constitutional principles of public law in both the UK and New Zealan
Apparently synonymous substitutions in FGFR2affect splicing and result in mild Crouzon syndrome
BACKGROUND: Mutations of fibroblast growth factor receptor 2 (FGFR2) account for a higher proportion of genetic cases of craniosynostosis than any other gene, and are associated with a wide spectrum of severity of clinical problems. Many of these mutations are highly recurrent and their associated features well documented. Crouzon syndrome is typically caused by heterozygous missense mutations in the third immunoglobulin domain of FGFR2. CASE PRESENTATION: Here we describe two families, each segregating a different, previously unreported FGFR2 mutation of the same nucleotide, c.1083A>G and c.1083A>T, both of which encode an apparently synonymous change at the Pro361 codon. We provide experimental evidence that these mutations affect normal FGFR2 splicing and document the clinical consequences, which include a mild Crouzon syndrome phenotype and reduced penetrance of craniosynostosis. CONCLUSIONS: These observations add to a growing list of FGFR2 mutations that affect splicing and provide important clinical information for genetic counselling of families affected by these specific mutations
Judicial Review, Irrationality, and the Limits of Intervention by the Courts
When exercising judicial review, the courts, on occasions, have intervened in circumstances where administrative decisions were not irrational. However, these low standards of judicial intervention are arguably constitutional, especially since the enactment of the Human Rights Act 1998 (HRA). To this end, this article seeks to establish a zone of executive decision-making, for reasons of democracy, where the courts are clearly excluded. But it is unable to do so. Does this mean, therefore, that judicial intervention on the grounds of irrationality exists without limit? Assuming this to be the case, it is suggested that the courts should show greater respect to the administrative branch of the state where it has genuinely sought to engage with the legal process in arriving at its decisions
Apparently synonymous substitutions in FGFR2 affect splicing and result in mild Crouzon syndrome
Background: Mutations of fibroblast growth factor receptor 2 (FGFR2) account for a higher proportion of genetic cases of craniosynostosis than any other gene, and are associated with a wide spectrum of severity of clinical problems. Many of these mutations are highly recurrent and their associated features well documented. Crouzon syndrome is typically caused by heterozygous missense mutations in the third immunoglobulin domain of FGFR2.Case presentation: Here we describe two families, each segregating a different, previously unreported FGFR2 mutation of the same nucleotide, c.1083A>G and c.1083A>T, both of which encode an apparently synonymous change at the Pro361 codon. We provide experimental evidence that these mutations affect normal FGFR2 splicing and document the clinical consequences, which include a mild Crouzon syndrome phenotype and reduced penetrance of craniosynostosis.Conclusions: These observations add to a growing list of FGFR2 mutations that affect splicing and provide important clinical information for genetic counselling of families affected by these specific mutations
Chitayat syndrome: hyperphalangism, characteristic facies, hallux valgus and bronchomalacia results from a recurrent c.266A>G p.(Tyr89Cys) variant in the ERF gene.
BACKGROUND: In 1993, Chitayat et al., reported a newborn with hyperphalangism, facial anomalies, and bronchomalacia. We identified three additional families with similar findings. Features include bilateral accessory phalanx resulting in shortened index fingers; hallux valgus; distinctive face; respiratory compromise. OBJECTIVES: To identify the genetic aetiology of Chitayat syndrome and identify a unifying cause for this specific form of hyperphalangism. METHODS: Through ongoing collaboration, we had collected patients with strikingly-similar phenotype. Trio-based exome sequencing was first performed in Patient 2 through Deciphering Developmental Disorders study. Proband-only exome sequencing had previously been independently performed in Patient 4. Following identification of a candidate gene variant in Patient 2, the same variant was subsequently confirmed from exome data in Patient 4. Sanger sequencing was used to validate this variant in Patients 1, 3; confirm paternal inheritance in Patient 5. RESULTS: A recurrent, novel variant NM_006494.2:c.266A>G p.(Tyr89Cys) in ERF was identified in five affected individuals: de novo (patient 1, 2 and 3) and inherited from an affected father (patient 4 and 5). p.Tyr89Cys is an aromatic polar neutral to polar neutral amino acid substitution, at a highly conserved position and lies within the functionally important ETS-domain of the protein. The recurrent ERF c.266A>C p.(Tyr89Cys) variant causes Chitayat syndrome. DISCUSSION: ERF variants have previously been associated with complex craniosynostosis. In contrast, none of the patients with the c.266A>G p.(Tyr89Cys) variant have craniosynostosis. CONCLUSIONS: We report the molecular aetiology of Chitayat syndrome and discuss potential mechanisms for this distinctive phenotype associated with the p.Tyr89Cys substitution in ERF
The origin of the [C II] emission in the S140 PDRs - new insights from HIFI
Using Herschel's HIFI instrument we have observed [C II] along a cut through
S140 and high-J transitions of CO and HCO+ at two positions on the cut,
corresponding to the externally irradiated ionization front and the embedded
massive star forming core IRS1. The HIFI data were combined with available
ground-based observations and modeled using the KOSMA-tau model for photon
dominated regions. Here we derive the physical conditions in S140 and in
particular the origin of [C II] emission around IRS1. We identify three
distinct regions of [C II] emission from the cut, one close to the embedded
source IRS1, one associated with the ionization front and one further into the
cloud. The line emission can be understood in terms of a clumpy model of
photon-dominated regions. At the position of IRS1, we identify at least two
distinct components contributing to the [C II] emission, one of them a small,
hot component, which can possibly be identified with the irradiated outflow
walls. This is consistent with the fact that the [C II] peak at IRS1 coincides
with shocked H2 emission at the edges of the outflow cavity. We note that
previously available observations of IRS1 can be well reproduced by a
single-component KOSMA-tau model. Thus it is HIFI's unprecedented spatial and
spectral resolution, as well as its sensitivity which has allowed us to uncover
an additional hot gas component in the S140 region.Comment: accepted for publication in Astronomy and Astrophysics (HIFI special
issue
SMAD6 variants in craniosynostosis : genotype and phenotype evaluation
PURPOSE: Enrichment of heterozygous missense and truncating SMAD6 variants was previously reported in nonsyndromic sagittal and metopic synostosis, and interaction of SMAD6 variants with a common polymorphism near BMP2 (rs1884302) was proposed to contribute to inconsistent penetrance. We determined the occurrence of SMAD6 variants in all types of craniosynostosis, evaluated the impact of different missense variants on SMAD6 function, and tested independently whether rs1884302 genotype significantly modifies the phenotype. METHODS: We performed resequencing of SMAD6 in 795 unsolved patients with any type of craniosynostosis and genotyped rs1884302 in SMAD6-positive individuals and relatives. We examined the inhibitory activity and stability of SMAD6 missense variants. RESULTS: We found 18 (2.3%) different rare damaging SMAD6 variants, with the highest prevalence in metopic synostosis (5.8%) and an 18.3-fold enrichment of loss-of-function variants comparedwith gnomAD data (Pâ<â10-7). Combined with eight additional variants, â„20/26 were transmitted from an unaffected parent but rs1884302 genotype did not predict phenotype. CONCLUSION: Pathogenic SMAD6 variants substantially increase the risk of both nonsyndromic and syndromic presentations of craniosynostosis, especially metopic synostosis. Functional analysis is important to evaluate missense variants. Genotyping of rs1884302 is not clinically useful. Mechanisms to explain the remarkable diversity of phenotypes associated with SMAD6 variants remain obscure
Effectiveness of a computer assisted learning (CAL) package to raise awareness of autism
<p>Abstract</p> <p>Background</p> <p>Promoting awareness of autism in populations who work with children may result in an earlier diagnosis of the condition. In this study, a computer assisted learning (CAL) package, containing educationally appropriate knowledge about autism was developed; and the effectiveness of this CAL package was evaluated.</p> <p>Methods</p> <p>The CAL package was developed using computer software, "Xerte" and "Flash Macromedia". The effectiveness of the CAL package was evaluated in 32 childcare students in the UK, who were randomised to watch the CAL package or to read the information leaflet containing the same information (n = 16 in each group). Retention performance, level of enjoyment, and level of confidence to identify a child with autism, after the interventions, were evaluated. The data obtained from two studied groups was analysed using unpaired Student's t-test, 95% confidence interval, and effect size.</p> <p>Results</p> <p>Students who watched the CAL package had superior retention performance percentage scores (p = 0.02, 95% CI = 0.83â12.19, effect size = 0.8) and level of enjoyment (p = 0.04, 95% CI = 0.03â2.75, effect size = 0.7) compared with students who read the information leaflet. However, there was no significant difference in level of confidence to identify a child with autism (p = 0.39, 95% CI = -1.80â0.72, effect size = -0.3).</p> <p>Conclusion</p> <p>The CAL package developed was an effective method of educating people who work with children about autism.</p
CONFIRM: a double-blind, placebo controlled phase III clinical trial investigating the effect of nivolumab in patients with relapsed mesothelioma: study protocol for a randomised controlled trial
Background: Mesothelioma is an incurable, apoptosis-resistant cancer caused in most cases by previous exposure
to asbestos and is increasing in incidence. It represents a growing health burden but remains under-researched,
with limited treatment options. Early promising signals of activity relating to both PD-L1- and PD-1-targeted
treatment in mesothelioma implicate a dependency of mesothelioma on this immune checkpoint. There is a need
to evaluate checkpoint inhibitors in patients with relapsed mesothelioma where treatment options are limited.
Methods: The addition of 12 months of nivolumab (anti-PD1 antibody) to standard practice will be conducted in
the UK using a randomised, placebo-controlled phase III trial (the Cancer Research UK CONFIRM trial). A total of 336
patients with pleural or peritoneal mesothelioma who have received at least two prior lines of therapy will be
recruited from UK secondary care sites. Patients will be randomised 2:1 (nivolumab:placebo), stratified according to
epithelioid/non-epithelioid, to receive either 240 mg nivolumab monotherapy or saline placebo as a 30-min
intravenous infusion. Treatment will be for up to 12 months. We will determine whether the use of nivolumab
increases overall survival (the primary efficacy endpoint). Secondary endpoints will include progression-free
survival, objective response rate, toxicity, quality of life and cost-effectiveness. Analysis will be performed
according to the intention-to-treat principle using a Cox regression analysis for the primary endpoint (and
for other time-to-event endpoints).
Discussion: The outcome of this trial will provide evidence of the potential benefit of the use of nivolumab
in the treatment of relapsed mesothelioma. If found to be clinically effective, safe and cost-effective it is likely
to become the new standard of care in the UK
SMAD6 variants in craniosynostosis: genotype and phenotype evaluation
Purpose: Enrichment of heterozygous missense and truncating SMAD6 variants was previously reported in nonsyndromic sagittal and metopic synostosis, and interaction of SMAD6 variants with a common polymorphism near BMP2 (rs1884302) was proposed to contribute to inconsistent penetrance. We determined the occurrence of SMAD6 variants in all types of craniosynostosis, evaluated the impact of different missense variants on SMAD6 function, and tested independently whether rs1884302 genotype significantl
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