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Expression of the cancer-associated DNA polymerase ε P286R in fission yeast leads to translesion synthesis polymerase dependent hypermutation and defective DNA replication
No full textSomatic and germline mutations in the proofreading domain of the replicative DNA polymerase ε (POLE-exonuclease domain mutations, POLE-EDMs) are frequently found in colorectal and endometrial cancers and, occasionally, in other tumours. POLE-associated cancers typically display hypermutation, and a unique mutational signature, with a predominance of C > A transversions in the context TCT and C > T transitions in the context TCG. To understand better the contribution of hypermutagenesis to tumour development, we have modelled the most recurrent POLE-EDM (POLE-P286R) in Schizosaccharomyces pombe. Whole-genome sequencing analysis revealed that the corresponding pol2-P287R allele also has a strong mutator effect in vivo, with a high frequency of base substitutions and relatively few indel mutations. The mutations are equally distributed across different genomic regions, but in the immediate vicinity there is an asymmetry in AT frequency. The most abundant base-pair changes are TCT > TAT transversions and, in contrast to human mutations, TCG > TTG transitions are not elevated, likely due to the absence of cytosine methylation in fission yeast. The pol2-P287R variant has an increased sensitivity to elevated dNTP levels and DNA damaging agents, and shows reduced viability on depletion of the Pfh1 helicase. In addition, S phase is aberrant and RPA foci are elevated, suggestive of ssDNA or DNA damage, and the pol2-P287R mutation is synthetically lethal with rad3 inactivation, indicative of checkpoint activation. Significantly, deletion of genes encoding some translesion synthesis polymerases, most notably Pol κ, partially suppresses pol2-P287R hypermutation, indicating that polymerase switching contributes to this phenotype
The changing epidemiology of Plasmodium vivax: insights from conventional and novel surveillance tools
No full text
Evaluation of a digital system to predict unplanned admissions to the intensive care unit: A mixed-methods approach
No full textBackground
We have developed the Hospital Alerting Via Electronic Noticeboard (HAVEN) which aims to identify hospitalised patients most at risk of reversible deterioration. HAVEN combines patients’ vital-sign measurements with laboratory results, demographics and comorbidities using a machine learnt algorithm.
Objectives
The aim of this study was to identify variables or concepts that could improve HAVEN predictive performance.
Methods
This was an embedded, mixed methods study. Eligible patients with the five highest HAVEN scores in the hospital (i.e., ‘HAVEN Top 5′) had their medical identification details recorded. We conducted a structured medical note review on these patients 48 hours post their identifiers being recorded. Methods of constant comparison were used during data collection and to analyse patient data.
Results
The 129 patients not admitted to ICU then underwent constant comparison review, which produced three main groups. Group 1 were patients referred to specialist services (n = 37). Group 2 responded to ward-based treatment, (n = 38). Group 3 were frail and had documented treatment limitations (n = 47).
Conclusions
Digital-only validation methods code the cohort not admitted to ICU as ‘falsely positive’ in sensitivity analyses however this approach limits the evaluation of model performance. Our study suggested that coding for patients referred to other specialist teams, those with treatment limitations in place, along with those who are deteriorating but then respond to ward-based therapies, would give a more accurate measure of the value of the scores, especially in relation to cost-effectiveness of resource utilisation
Mental health professionals’ experiences of working with parents with psychosis and their families: a qualitative study
No full textBackground
Healthcare service users who are parents with psychosis form part of the caseload of most community mental health teams. Mental health professionals can experience uncertainty about how to work with and ask about the children of these parents, and often report difficulties when collaborating with other agencies. This study focused on professionals’ experiences of working with parents with psychosis and their families to gain an understanding of these parents’ needs from a service-level perspective, and to identify barriers that professionals may experience in meeting those needs.
Methods
Qualitative focus groups were conducted with four to eight mental health professionals per group. Data were analysed using reflexive thematic analysis. JR familiarised herself with the transcripts and then coded each salient unit within the text. Themes were then identified and discussed amongst all authors until there was agreement.
Results
We developed two overarching themes: 1) Diversity of need in parents with psychosis and 2) Role boundaries. The first explored mental health professionals’ perceived range of experiences that parents with psychosis and their families have, and the range of potential effects of parental psychosis on a child. The second theme described how some mental health professionals emphasised the importance of supporting service users in terms of their parenting status and others felt it was more critical to treat the person’s symptomatic expression. This theme also included issues with communication both with their service users and with other agencies.
Conclusions
Mental health professionals identified that the needs of parents with psychosis were diverse and reflected significant variation in the experiences of service users. Mental health professionals across different types of team (early intervention and community mental health) expressed contrasting viewpoints about how achievable it was to respond to a service user’s parenting status in an adult mental health setting. Future research should aim to determine where training is needed to enhance mental health professionals’ ability to work holistically with families in an adult mental health setting, and how to enhance collaboration with other agencies
Exploring interactions between trust, anthropomorphism, and relationship development in voice assistants
No full textModern conversational agents such as Alexa and Google Assistant represent significant progress in speech recognition, natural language processing, and speech synthesis. But as these agents have grown more realistic, concerns have been raised over how their social nature might unconsciously shape our interactions with them. Through a survey of 500 voice assistant users, we explore whether users' relationships with their voice assistants can be quantified using the same metrics as social, interpersonal relationships; as well as if this correlates with how much they trust their devices and the extent to which they anthropomorphise them. Using Knapp's staircase model of human relationships, we find that not only can human-device interactions be modelled in this way, but also that relationship development with voice assistants correlates with increased trust and anthropomorphism
Is SGD a Bayesian sampler? Well, almost
No full textDeep neural networks (DNNs) generalise remarkably well in the overparameterised regime, suggesting a strong inductive bias towards functions with low generalisation error. We empirically investigate this bias by calculating, for a range of architectures and datasets, the probability PSGD(f∣S) that an overparameterised DNN, trained with stochastic gradient descent (SGD) or one of its variants, converges on a function f consistent with a training set S. We also use Gaussian processes to estimate the Bayesian posterior probability PB(f∣S) that the DNN expresses f upon random sampling of its parameters, conditioned on S. Our main findings are that PSGD(f∣S) correlates remarkably well with PB(f∣S) and that PB(f∣S) is strongly biased towards low-error and low complexity functions. These results imply that strong inductive bias in the parameter-function map (which determines PB(f∣S)), rather than a special property of SGD, is the primary explanation for why DNNs generalise so well in the overparameterised regime. While our results suggest that the Bayesian posterior PB(f∣S) is the first order determinant of PSGD(f∣S), there remain second order differences that are sensitive to hyperparameter tuning. A function probability picture, based on PSGD(f∣S) and/or PB(f∣S), can shed light on the way that variations in architecture or hyperparameter settings such as batch size, learning rate, and optimiser choice, affect DNN performance
Pregnancy outcomes following different types of bariatric surgery: a national cohort study
No full textOBJECTIVE: To assess the impact of type of bariatric surgery on pregnancy outcomes.
STUDY DESIGN: This is a national prospective observational study using the UK Obstetric Surveillance System (UKOSS). Data collection was undertaken in 200 consultant-led NHS maternity units between November 2011 and October 2012 (gastric banding), and April 2014 and March 2016 (gastric bypass and sleeve gastrectomy). Participants were pregnant women following gastric banding (n = 127), gastric bypass (n = 134) and sleeve gastrectomy (n = 29). Maternal and perinatal outcomes were compared using generalised linear and linear mixed models. Maternal outcomes included gestational weight gain, pre-eclampsia, gestational diabetes, anaemia, surgical complications. Perinatal outcomes included birthweight, small/large for gestational age (SGA/LGA), preterm birth, stillbirth.
RESULTS: Maternal: Women pregnant after gastric banding and sleeve gastrectomy had a lower risk of anaemia compared with gastric bypass (banding (16 %) vs bypass (39 %): p = 0.002, sleeve (21 %) vs bypass: p = 0.04). Gestational diabetes risk was lower after gastric banding compared with gastric bypass (7 % vs 16 %, p = 0.03) despite women with banding having significantly greater weight at booking as well as gestational weight gain. Women pregnant after gastric banding and sleeve gastrectomy had a lower risk of surgical complications than after gastric bypass (banding (0.9 %) vs bypass (11.4 %): p = 0.03, sleeve (0.0 %) vs bypass: p = 0.06). Perinatal: Infants born to mothers after gastric banding had a higher birthweight than those born to mothers after gastric bypass (mean difference = 260 g (125-395), p < 0.001). Infants were more likely to be LGA if their mothers had gastric banding compared with gastric bypass or sleeve gastrectomy (banding (21 %) vs bypass (5 %): p = 0.006; banding vs sleeve (3 %): p = 0.03). Risk of preterm birth was higher in women with gastric banding compared with gastric bypass (13 % vs 8 %, p = 0.04).
CONCLUSIONS: Women planning bariatric surgery should be counselled regarding the differing impacts of different types of procedure on any future pregnancy. Pre-existing gastric bypass is associated with higher rates of potentially serious surgical complications during pregnancy
Association of type 2 diabetes remission and risk of cardiovascular disease in pre-defined subgroups
No full textAim: To quantify the association between type 2 diabetes remission and 5-year incidence of cardiovascular disease outcomes, overall and in pre-defined subgroups.
Methods: Retrospective cohort analysis of 60,287 adults with type 2 diabetes from the Care and Health Information Analytics (CHIA) database. Multivariable Cox models were used to assess the association between remission within the first two years of follow-up and incidence of cardiovascular disease (CVD) outcomes including events, microvascular and macrovascular complications at 7-year follow-up. Effect modification by age, sex, diabetes duration, pre-existing CVD, baseline body mass index (BMI) and HbA1c level were assessed.
Results: 7489 (12.4%) people achieved remission during the first two years of follow-up. Overall, remission was associated with lower risk of CVD outcomes. Remission was associated with lower risk of microvascular complications for younger compared to older age groups (for example, aHR: 0.59 (0.41-0.84) and aHR: 0.78 (0.67-0.92) for those aged <45 years and 75-84 years, respectively). Among those achieving remission, those with no or 1-2 comorbidities had lower risk of microvascular complications (aHR: 0.65 (0.56-0.75) compared to those with more than 3 comorbidities (aHR: 0.83 (0.69-0.99), respectively). There were no significant interactions in the remaining subgroups or for models assessing CVD events or macrovascular complications.
Conclusions: Achieving remission of type 2 diabetes is associated with a lower risk of microvascular complications, particularly for younger groups and those with fewer comorbidities. Targeted interventions that focus on promoting remission in these groups may reduce the impact of microvascular complications and associated health costs
Prolonged Siberian heat of 2020 almost impossible without human influence
No full textOver the first half of 2020, Siberia experienced the warmest period from January to June since records began and on the 20th of June the weather station at Verkhoyansk reported 38 °C, the highest daily maximum temperature recorded north of the Arctic Circle. We present a multi-model, multi-method analysis on how anthropogenic climate change affected the probability of these events occurring using both observational datasets and a large collection of climate models, including state-of-the-art higher-resolution simulations designed for attribution and many from the latest generation of coupled ocean-atmosphere models, CMIP6. Conscious that the impacts of heatwaves can span large differences in spatial and temporal scales, we focus on two measures of the extreme Siberian heat of 2020: January to June mean temperatures over a large Siberian region and maximum daily temperatures in the vicinity of the town of Verkhoyansk. We show that human-induced climate change has dramatically increased the probability of occurrence and magnitude of extremes in both of these (with lower confidence for the probability for Verkhoyansk) and that without human influence the temperatures widely experienced in Siberia in the first half of 2020 would have been practically impossible