The Right to Know and the Right Not to Know Revisited: Part One

Prompted by developments in human genetics, a recurrent bioethical question concerns a person’s ‘right to know’ and ‘right not to know’ about genetic information held that is intrinsically related to or linked to them. In this paper, we will revisit the claimed rights in relation to two particular test cases. One concerns the rights of the 500,000 participants in UK Biobank (UKB) whose biosamples, already having been genotyped, will now be exome sequenced; and the other concerns the rights of pregnant women (and their children) who undergo non-invasive prenatal testing (NIPT)—a simple blood test that can reveal genetic information about both a fetus and its mother. This two-part paper is in four principal sections. First, we sketch the relevant features of our two test cases. Secondly, we consider the significance of recent legal jurisprudence in the UK and Singapore. Thirdly, we consider how, the jurisprudence apart, the claimed rights might be grounded. Fourthly, we consider the limits on the rights. We conclude with some short remarks about the kind of genetically aware society that we might want to be and how far there is still an opportunity meaningfully to debate the claimed rights

Alzheimer's pathology targets distinct memory networks in the ageing brain

Alzheimer’s disease researchers have been intrigued by the selective regional vulnerability of the brain to amyloid-β plaques and tau neurofibrillary tangles. Post-mortem studies indicate that in ageing and Alzheimer’s disease tau tangles deposit early in the transentorhinal cortex, a region located in the anterior-temporal lobe that is critical for object memory. In contrast, amyloid-β pathology seems to target a posterior-medial network that subserves spatial memory. In the current study, we tested whether anterior-temporal and posterior-medial brain regions are selectively vulnerable to tau and amyloid-β deposition in the progression from ageing to Alzheimer’s disease and whether this is reflected in domain-specific behavioural deficits and neural dysfunction. 11C-PiB PET and 18F-flortaucipir uptake was quantified in a sample of 131 cognitively normal adults (age: 20–93 years; 47 amyloid-β-positive) and 20 amyloid-β-positive patients with mild cognitive impairment or Alzheimer’s disease dementia (65–95 years). Tau burden was relatively higher in anterior-temporal regions in normal ageing and this difference was further pronounced in the presence of amyloid-β and cognitive impairment, indicating exacerbation of ageing-related processes in Alzheimer’s disease. In contrast, amyloid-β deposition dominated in posterior-medial regions. A subsample of 50 cognitively normal older (26 amyloid-β-positive) and 25 young adults performed an object and scene memory task while functional MRI data were acquired. Group comparisons showed that tau-positive (n = 18) compared to tau-negative (n = 32) older adults showed lower mnemonic discrimination of object relative to scene images [t(48) = −3.2, P = 0.002]. In a multiple regression model including regional measures of both pathologies, higher anterior-temporal flortaucipir (tau) was related to relatively worse object performance (P = 0.010, r = −0.376), whereas higher posterior-medial PiB (amyloid-β) was related to worse scene performance (P = 0.037, r = 0.309). The functional MRI data revealed that tau burden (but not amyloid-β) was associated with increased task activation in both systems and a loss of functional specificity, or dedifferentiation, in posterior-medial regions. The loss of functional specificity was related to worse memory. Our study shows a regional dissociation of Alzheimer’s disease pathologies to distinct memory networks. While our data are cross-sectional, they indicate that with ageing, tau deposits mainly in the anterior-temporal system, which results in deficits in mnemonic object discrimination. As Alzheimer’s disease develops, amyloid-β deposits preferentially in posterior-medial regions additionally compromising scene discrimination and anterior-temporal tau deposition worsens further. Finally, our findings propose that the progression of tau pathology is linked to aberrant activation and dedifferentiation of specialized memory networks that is detrimental to memory function

Neonatal-onset multisystem inflammatory disease responsive to interleukin-1 beta inhibition

BACKGROUND:Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. Many patients have mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, encoding cryopyrin, a protein that regulates inflammation.METHODS:We selected 18 patients with neonatal-onset multisystem inflammatory disease (12 with identifiable CIAS1 mutations) to receive anakinra, an interleukin-1-receptor antagonist (1 to 2 mg per kilogram of body weight per day subcutaneously). In 11 patients, anakinra was withdrawn at three months until a flare occurred. The primary end points included changes in scores in a daily diary of symptoms, serum levels of amyloid A and C-reactive protein, and the erythrocyte sedimentation rate from baseline to month 3 and from month 3 until a disease flare.RESULTS:All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 (all P<0.001), and remained low at month 6. Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline. Withdrawal of anakinra uniformly resulted in relapse within days; retreatment led to rapid improvement. There were no drug-related serious adverse events.CONCLUSIONS:Daily injections of anakinra markedly improved clinical and laboratory manifestations in patients with neonatal-onset multisystem inflammatory disease, with or without CIAS1 mutations

Quality of life utility values for hereditary haemochromatosis in Australia

Background: Hereditary hemochromatosis (HH) is a common autosomal recessive disorder amongst persons of northern European heritage. If untreated, iron accumulates in parenchymal tissues causing morbidity and mortality. As diagnosis often follows irreversible organ damage, screening programs have been suggested to increase early diagnosis. A lack of economic evidence has been cited as a barrier to establishing such a program. Previous analyses used poorly estimated utility values. This study sought to measure utilities directly from people with HH in Australia. Methods: Volunteers with HH were recruited to complete a web-based survey. Utility was assessed using the Assessment of Quality of Life 4D (AQOL-4D) instrument. Severity of HH was graded into four categories. Multivariable regression analysis was performed to identify parameters associated with HSUV. Results: Between November 2013 and November 2014, 221 people completed the survey. Increasing severity of HH was negatively associated with utility. Mean (standard deviation) utilities were 0.76 (0.21), 0.81 (0.18), 0.60 (0.27), and 0.50 (0.27) for categories 1-4 HH respectively. Lower mean utility was found for symptomatic participants (categories 3 and 4) compared with asymptomatic participants (0.583 v. 0.796). Self-reported HH-related symptoms were negatively associated with HSUV (r = -0.685). Conclusions: Symptomatic stages of HH and presence of multiple self-reported symptoms were associated with decreasing utility. Previous economic analyses have used higher utilities which likely resulted in underestimates of the cost effectiveness of HH interventions. The utilities reported in this paper are the most robust available, and will contribute to improving the validity of future economic models for HH

Etiology of Bacterial Meningitis Among Children < 5 Years Old in Cote d'Ivoire: Findings of Hospital-based Surveillance Before and After Pneumococcal Conjugate Vaccine Introduction

Background: Bacterial meningitis remains a major disease affecting children in Côte d’Ivoire. Thus, with support from the World Health Organization (WHO), Côte d’Ivoire has implemented pediatric bacterial meningitis (PBM) surveillance at 2 sentinel hospitals in Abidjan, targeting the main causes of PBM: Streptococcus pneumoniae (pneumococcus), Haemophilus influenzae, and Neisseria meningitidis (meningococcus). Herein we describe the epidemiological characteristics of PBM observed in Côte d’Ivoire during 2010–2016. Methods: Cerebrospinal fluid (CSF) was collected from children aged <5 years admitted to the Abobo General Hospital or University Hospital Center Yopougon with suspected meningitis. Microbiology and polymerase chain reaction (PCR) techniques were used to detect the presence of pathogens in CSF. Where possible, serotyping/grouping was performed to determine the specific causative agents. Results: Overall, 2762 cases of suspected meningitis were reported, with CSF from 39.2% (1083/2762) of patients analyzed at the WHO regional reference laboratory in The Gambia. In total, 82 (3.0% [82/2762]) CSF samples were positive for bacterial meningitis. Pneumococcus was the main pathogen responsible for PBM, accounting for 69.5% (52/82) of positive cases. Pneumococcal conjugate vaccine serotypes 5, 18C, 19F, and 6A/B were identified post–vaccine introduction. Emergence of H. influenzae nontypeable meningitis was observed after H. influenzae type b vaccine introduction. Conclusions: Despite widespread use and high coverage of conjugate vaccines, pneumococcal vaccine serotypes and H. influenzae type b remain associated with bacterial meningitis among children aged <5 years in Côte d’Ivoire. This reinforces the need for enhanced surveillance for vaccine-preventable diseases to determine the prevalence of bacterial meningitis and vaccine impact across the country

Selective amplification of Brucella melitensis mRNA from a mixed host-pathogen total RNA

<p>Abstract</p> <p>Background</p> <p>Brucellosis is a worldwide anthropozoonotic disease caused by an in vivo intracellular pathogen belonging to genus <it>Brucella</it>. The characterization of brucelae transcriptome's during host-pathogen interaction has been limited due to the difficulty of obtaining an adequate quantity of good quality eukaryotic RNA-free pathogen RNA for downstream applications.</p> <p>Findings</p> <p>Here, we describe a combined protocol to prepare RNA from intracellular <it>B. melitensis </it>in a quantity and quality suitable for pathogen gene expression analysis. Initially, <it>B. melitensis </it>total RNA was enriched from a host:pathogen mixed RNA sample by reducing the eukaryotic RNA..Then, to increase the <it>Brucella </it>RNA concentration and simultaneously minimize the contaminated host RNA in the mixed sample, a specific primer set designed to anneal to all <it>B. melitensis </it>ORF allows the selective linear amplification of sense-strand prokaryotic transcripts in a previously enriched RNA sample.</p> <p>Conclusion</p> <p>The novelty of the method we present here allows analysis of the gene expression profile of <it>B. melitensis </it>when limited amounts of pathogen RNA are present, and is potentially applicable to both <it>in vivo </it>and <it>in vitro </it>models of infection, even at early infection time points.</p

What are we measuring? A critique of range of motion methods currently in use for Dupuytren's disease and recommendations for practice

Background: Range of motion is the most frequently reported measure used in practice to evaluate outcomes. A goniometer is the most reliable tool to assess range of motion yet, the lack of consistency in reporting prevents comparison between studies. The aim of this study is to identify how range of motion is currently assessed and reported in Dupuytren’s disease literature. Following analysis recommendations for practice will be made to enable consistency in future studies for comparability. This paper highlights the variation in range of motion reporting in Dupuytren’s disease. Methods: A Participants, Intervention, Comparison, Outcomes and Study design format was used for the search strategy and search terms. Surgery, needle fasciotomy or collagenase injection for primary or recurrent Dupuytren’s disease in adults were included if outcomes were monitored using range of motion to record change. A literature search was performed in May 2013 using subject heading and free-text terms to also capture electronic publications ahead of print. In total 638 publications were identified and following screening 90 articles met the inclusion criteria. Data was extracted and entered onto a spreadsheet for analysis. A thematic analysis was carried out to establish any duplication, resulting in the final range of motion measures identified. Results: Range of motion measurement lacked clarity, with goniometry reportedly used in only 43 of the 90 studies, 16 stated the use of a range of motion protocol. A total of 24 different descriptors were identified describing range of motion in the 90 studies. While some studies reported active range of motion, others reported passive or were unclear. Eight of the 24 categories were identified through thematic analysis as possibly describing the same measure, ‘lack of joint extension’ and accounted for the most frequently used. Conclusions: Published studies lacked clarity in reporting range of motion, preventing data comparison and meta-analysis. Percentage change lacks context and without access to raw data, does not allow direct comparison of baseline characteristics. A clear description of what is being measured within each study was required. It is recommended that range of motion measuring and reporting for Dupuytren’s disease requires consistency to address issues that fall into 3 main categories:- Definition of terms Protocol statement Outcome reportin

Permissivity of the NCI-60 cancer cell lines to oncolytic Vaccinia Virus GLV-1h68

<p>Abstract</p> <p>Background</p> <p>Oncolytic viral therapy represents an alternative therapeutic strategy for the treatment of cancer. We previously described GLV-1h68, a modified Vaccinia Virus with exclusive tropism for tumor cells, and we observed a cell line-specific relationship between the ability of GLV-1h68 to replicate in vitro and its ability to colonize and eliminate tumor in vivo.</p> <p>Methods</p> <p>In the current study we surveyed the in vitro permissivity to GLV-1h68 replication of the NCI-60 panel of cell lines. Selected cell lines were also tested for permissivity to another Vaccinia Virus and a vesicular stomatitis virus (VSV) strain. In order to identify correlates of permissity to viral infection, we measured transcriptional profiles of the cell lines prior infection.</p> <p>Results</p> <p>We observed highly heterogeneous permissivity to VACV infection amongst the cell lines. The heterogeneity of permissivity was independent of tissue with the exception of B cell derivation. Cell lines were also tested for permissivity to another Vaccinia Virus and a vesicular stomatitis virus (VSV) strain and a significant correlation was found suggesting a common permissive phenotype. While no clear transcriptional pattern could be identified as predictor of permissivity to infection, some associations were observed suggesting multifactorial basis permissivity to viral infection.</p> <p>Conclusions</p> <p>Our findings have implications for the design of oncolytic therapies for cancer and offer insights into the nature of permissivity of tumor cells to viral infection.</p