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Captain Cold's arctic eruption
\"Within hours, a monstrous volcano will destroy a Pacific island and all of its citizens. The Flash has done everything he can, but there's only one way to stop the disaster . . . cool the volcano's magma chamber. Unfortunately, only one man is capable of such a task . . . his archenemy, Captain Cold. The Scarlet Speedster cuts a deal with this frosty felon, and they're off to save the day. But Captain Cold cannot be trusted. While firing his freeze gun into the volcano, this sneaky super-villain sees an opportunity. He'll turn the tropical paradise into his personal tundra!\"--P. [4] of cover.
Book
The Role of TEG Analysis in Patients with COVID-19-Associated Coagulopathy: A Systematic Review
Coronavirus disease 2019 (COVID-19)-associated coagulopathy (CAC), characterized by hypercoagulability and an increased risk of thrombotic complications, is an important consideration in the management of patients with COVID-19. As COVID-19 is a new disease, no standard of care for the diagnosis or management of its associated coagulopathy is yet established. Whole blood viscoelastic tests, such as thromboelastography (TEG® hemostasis analyzer), analyze whole blood to provide a complete overview of the coagulation status. We conducted a systematic review of thromboelastography for management of patients with COVID-19, using MEDLINE (PubMed) and Cochrane databases. TEG® parameter measurements and clinical outcomes data were extracted for analysis. Our review found 15 publications, with overall results showing thromboelastography can identify and assess a hypercoagulable state in patients with COVID-19. Furthermore, utilization of thromboelastography in this patient population was shown to predict thrombotic complications. The benefits of thromboelastography presented here, in addition to advantages compared with laboratory coagulation tests, position thromboelastography as an important opportunity for optimizing diagnosis of CAC and improving patient management in COVID-19. Given that the benefits of thromboelastography have already been demonstrated in several other clinical applications, we anticipate that clinical data from future studies in patients with COVID-19 will further elucidate the optimal use of thromboelastography in this patient population.
Journal Article
Fine-scale population structure and demographic history of British Pakistanis
Previous genetic and public health research in the Pakistani population has focused on the role of consanguinity in increasing recessive disease risk, but little is known about its recent population history or the effects of endogamy. Here, we investigate fine-scale population structure, history and consanguinity patterns using genotype chip data from 2,200 British Pakistanis. We reveal strong recent population structure driven by the biraderi social stratification system. We find that all subgroups have had low recent effective population sizes (N
e
), with some showing a decrease 15‒20 generations ago that has resulted in extensive identity-by-descent sharing and homozygosity, increasing the risk of recessive disorders. Our results from two orthogonal methods (one using machine learning and the other coalescent-based) suggest that the detailed reporting of parental relatedness for mothers in the cohort under-represents the true levels of consanguinity. These results demonstrate the impact of cultural practices on population structure and genomic diversity in Pakistanis, and have important implications for medical genetic studies.
Little is known about the recent population history or the effects of endogamy on the Pakistani population. Here the authors examine the impact of the biraderi social stratification system on the population structure of individuals of British Pakistani ancestry in the Born in Bradford cohort.
Journal Article
Estimating the human mutation rate from autozygous segments reveals population differences in human mutational processes
Heterozygous mutations within homozygous sequences descended from a recent common ancestor offer a way to ascertain de novo mutations across multiple generations. Using exome sequences from 3222 British-Pakistani individuals with high parental relatedness, we estimate a mutation rate of 1.45 ± 0.05 × 10
−8
per base pair per generation in autosomal coding sequence, with a corresponding non-crossover gene conversion rate of 8.75 ± 0.05 × 10
−6
per base pair per generation. This is at the lower end of exome mutation rates previously estimated in parent–offspring trios, suggesting that post-zygotic mutations contribute little to the human germ-line mutation rate. We find frequent recurrence of mutations at polymorphic CpG sites, and an increase in C to T mutations in a 5ʹ CCG 3ʹ to 5ʹ CTG 3ʹ context in the Pakistani population compared to Europeans, suggesting that mutational processes have evolved rapidly between human populations.
Estimates of human mutation rates differ substantially based on the approach. Here, the authors present a multi-generational estimate from the autozygous segment in a non-European population that gives insight into the contribution of post-zygotic mutations and population-specific mutational processes.
Journal Article
Identification of autosomal cis expression quantitative trait methylation (cis eQTMs) in children’s blood
Cells can fine-tune which genes they activate, when and at which levels using a range of chemical marks on the DNA and certain proteins that help to organise the genome. One well-known example of such ‘epigenetic tags’ is DNA methylation, whereby a methyl group is added onto particular positions in the genome. Many factors – including environmental effects such as diet – control DNA methylation, allowing an organism to adapt to ever-changing conditions. An expression quantitative trait methylation (eQTM) is a specific position of the genome whose DNA methylation status regulates the activity of a given gene. A catalogue of eQTMs would be useful in helping to reveal how the environment and disease impacts the way cells work. Yet, currently, the relationships between most epigenetic tags and gene activity remains unclear, especially in children. To fill this gap, Ruiz-Arenas et al. studied DNA methylation in blood samples from over 800 healthy children across Europe. Amongst all tested DNA methylation sites, 22,000 (5.7% of total) were associated with the expression of a gene – and therefore were eQTMs; reciprocally, 9,000 genes (15.3% of all tested genes) were linked to at least one methylation site, leading to a total of 40,000 pairs of DNA methylation sites and genes. Most often, eQTMs regulated the expression of nearby genes – but only half controlled the gene that was the closest to them. Age and the genetic background of the individuals influenced the nature of eQTMs. This catalogue is a useful resource for the scientific community to start understanding the relationship between epigenetics and gene activity. Similar studies are now needed for other tissues and age ranges. Overall, extending our knowledge of eQTMs may help reveal how life events lead to illness, and could inform prevention efforts.
Journal Article
Born in Bradford’s Better Start: an experimental birth cohort study to evaluate the impact of early life interventions
Background
Early interventions are recognised as key to improving life chances for children and reducing inequalities in health and well-being, however there is a paucity of high quality research into the effectiveness of interventions to address childhood health and development outcomes. Planning and implementing standalone RCTs for multiple, individual interventions would be slow, cumbersome and expensive. This paper describes the protocol for an innovative experimental birth cohort: Born in Bradford’s Better Start (BiBBS) that will simultaneously evaluate the impact of multiple early life interventions using efficient study designs. Better Start Bradford (BSB) has been allocated £49 million from the Big Lottery Fund to implement 22 interventions to improve outcomes for children aged 0–3 in three key areas: social and emotional development; communication and language development; and nutrition and obesity. The interventions will be implemented in three deprived and ethnically diverse inner city areas of Bradford.
Method
The BiBBS study aims to recruit 5000 babies, their mothers and their mothers’ partners over 5 years from January 2016-December 2020. Demographic and socioeconomic information, physical and mental health, lifestyle factors and biological samples will be collected during pregnancy. Parents and children will be linked to their routine health and local authority (including education) data throughout the children’s lives. Their participation in BSB interventions will also be tracked. BiBBS will test interventions using the Trials within Cohorts (TwiCs) approach and other quasi-experimental designs where TwiCs are neither feasible nor ethical, to evaluate these early life interventions. The effects of single interventions, and the cumulative effects of stacked (multiple) interventions on health and social outcomes during the critical early years will be measured.
Discussion
The focus of the BiBBS cohort is on intervention impact rather than observation. As far as we are aware BiBBS is the world’s first such experimental birth cohort study. While some risk factors for adverse health and social outcomes are increasingly well described, the solutions to tackling them remain elusive. The novel design of BiBBS can contribute much needed evidence to inform policy makers and practitioners about effective approaches to improve health and well-being for future generations.
Journal Article
Growing up in Bradford: protocol for the age 7–11 follow up of the Born in Bradford birth cohort
Background
Born in Bradford (BiB) is a prospective multi-ethnic pregnancy and birth cohort study that was established to examine determinants of health and development during childhood and, subsequently, adult life in a deprived multi-ethnic population in the north of England. Between 2007 and 2010, the BiB cohort recruited 12,453 women who experienced 13,776 pregnancies and 13,858 births, along with 3353 of their partners. Forty five percent of the cohort are of Pakistani origin. Now that children are at primary school, the first full follow-up of the cohort is taking place. The aims of the follow-up are to investigate the determinants of children’s pre-pubertal health and development, including through understanding parents’ health and wellbeing, and to obtain data on exposures in childhood that might influence future health.
Methods
We are employing a multi-method approach across three data collection arms (community-based family visits, school based physical assessment, and whole classroom cognitive, motor function and wellbeing measures) to follow-up over 9000 BiB children aged 7–11 years and their families between 2017 and 2021. We are collecting detailed parent and child questionnaires, cognitive and sensorimotor assessments, blood pressure, anthropometry and blood samples from parents and children. Dual x-ray absorptiometry body scans, accelerometry and urine samples are collected on subsamples. Informed consent is collected for continued routine data linkage to health, social care and education records. A range of engagement activities are being used to raise the profile of BiB and to disseminate findings.
Discussion
Our multi-method approach to recruitment and assessment provides an efficient method of collecting rich data on all family members. Data collected will enhance BiB as a resource for the international research community to study the interplay between ethnicity, socioeconomic circumstances and biology in relation to cardiometabolic health, mental health, education, cognitive and sensorimotor development and wellbeing.
Journal Article
Exploring the causal effect of maternal pregnancy adiposity on offspring adiposity: Mendelian randomisation using polygenic risk scores
Background
Greater maternal adiposity before or during pregnancy is associated with greater offspring adiposity throughout childhood, but the extent to which this is due to causal intrauterine or periconceptional mechanisms remains unclear. Here, we use Mendelian randomisation (MR) with polygenic risk scores (PRS) to investigate whether associations between maternal pre-/early pregnancy body mass index (BMI) and offspring adiposity from birth to adolescence are causal.
Methods
We undertook confounder adjusted multivariable (MV) regression and MR using mother-offspring pairs from two UK cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) and Born in Bradford (BiB). In ALSPAC and BiB, the outcomes were birthweight (BW;
N
= 9339) and BMI at age 1 and 4 years (
N
= 8659 to 7575). In ALSPAC only we investigated BMI at 10 and 15 years (
N
= 4476 to 4112) and dual-energy X-ray absorptiometry (DXA) determined fat mass index (FMI) from age 10–18 years (
N
= 2659 to 3855). We compared MR results from several PRS, calculated from maternal non-transmitted alleles at between 29 and 80,939 single nucleotide polymorphisms (SNPs).
Results
MV and MR consistently showed a positive association between maternal BMI and BW, supporting a moderate causal effect. For adiposity at most older ages, although MV estimates indicated a strong positive association, MR estimates did not support a causal effect. For the PRS with few SNPs, MR estimates were statistically consistent with the null, but had wide confidence intervals so were often also statistically consistent with the MV estimates. In contrast, the largest PRS yielded MR estimates with narrower confidence intervals, providing strong evidence that the true causal effect on adolescent adiposity is smaller than the MV estimates (
P
difference
= 0.001 for 15-year BMI). This suggests that the MV estimates are affected by residual confounding, therefore do not provide an accurate indication of the causal effect size.
Conclusions
Our results suggest that higher maternal pre-/early-pregnancy BMI is not a key driver of higher adiposity in the next generation. Thus, they support interventions that target the whole population for reducing overweight and obesity, rather than a specific focus on women of reproductive age.
Journal Article
Characterising a healthy adult with a rare HAO1 knockout to support a therapeutic strategy for primary hyperoxaluria
By sequencing autozygous human populations, we identified a healthy adult woman with lifelong complete knockout of HAO1 (expected ~1 in 30 million outbred people). HAO1 (glycolate oxidase) silencing is the mechanism of lumasiran, an investigational RNA interference therapeutic for primary hyperoxaluria type 1. Her plasma glycolate levels were 12 times, and urinary glycolate 6 times, the upper limit of normal observed in healthy reference individuals (n = 67). Plasma metabolomics and lipidomics (1871 biochemicals) revealed 18 markedly elevated biochemicals (>5 sd outliers versus n = 25 controls) suggesting additional HAO1 effects. Comparison with lumasiran preclinical and clinical trial data suggested she has <2% residual glycolate oxidase activity. Cell line p.Leu333SerfsTer4 expression showed markedly reduced HAO1 protein levels and cellular protein mis-localisation. In this woman, lifelong HAO1 knockout is safe and without clinical phenotype, de-risking a therapeutic approach and informing therapeutic mechanisms. Unlocking evidence from the diversity of human genetic variation can facilitate drug development.
Journal Article
The association of Helicobacter pylori with adverse pregnancy outcomes in three European birth cohorts
Background
Helicobacter pylori
is a prevalent infection that may complicate pregnancy, but evidence remains limited, controversial and may not apply to all pregnant women.
Objective
This study aims to evaluate whether
Helicobacter pylori
is a risk factor for adverse pregnancy outcomes and to identify vulnerable subpopulations.
Study design
Multiplex serology was utilized to measure blood levels of immunoglobulin G against eight
Helicobacter pylori
antigens in 1372 pregnant women from three European birth cohorts: BiB (United Kingdom), Rhea (Greece) and INMA (Spain). Outcomes of interest included gestational diabetes mellitus, gestational hypertension, preeclampsia, preterm birth and small for gestational age neonates, as well as prenatal anxiety and depression. Adjusted logistic regression models were used to evaluate the association between
Helicobacter pylori
seropositivity (overall and by antigen) and antigen specific antibody levels with the outcomes. We examined effect modification of the associations by ethnicity.
Results
Helicobacter pylori
seropositivity was detected in 18.8% (258/1372) of pregnant women. Preeclampsia was the least common outcome (26/830).
Helicobacter pylori
seropositivity was associated with the development of two or more adverse pregnancy outcomes (gestational hypertension, gestational diabetes, preterm birth, small gestational age and preeclampsia) [OR:1.32 (95% CI: 1.06–1.65), p-value: 0.01], especially in women with high antibody levels to OMP antigen [OR: 2.12 (95% CI: 1.62–2.76), p-value: 0.001]. Women with high antibody levels to
Helicobacter pylori
antigens GroEL and NapA were more likely to develop preeclampsia [OR: 2.34 (95% CI: 1.10–8.82), p-value: 0.03; OR: 4.09 (95% CI: 1.4-11.93), p-value 0.01)].
Helicobacter pylori
seropositivity increased the odds of developing any hypertensive disorder during pregnancy among women of western ethnicity (948/1372) [OR:3.35 (95% CI: 1.29–8.74), p-value 0.03].
Conclusion
Our study suggests that
Helicobacter pylori
seropositivity is a risk factor for multiple adverse pregnancy outcomes and particularly in women of western origin for hypertensive disorders during pregnancy. Moreover, pathogen specific characteristics reflected in the antibody responses against OMP, GroEL and NapA seem to determine disease associations.
Journal Article