Evolution, Perfection, and Theories of Language

In this article it is argued that evolutionary plausibility must be made an important constraining factor when building theories of language. Recent suggestions that presume that language is necessarily a perfect or optimal system are at odds with this position, evolutionary theory showing us that evolution is a meliorizing agent often producing imperfect solutions. Perfection of the linguistic system is something that must be demonstrated, rather than presumed. Empirically, examples of imperfection are found not only in nature and in human cognition, but also in language — in the form of ambiguity, redundancy, irregularity, movement, locality conditions, and extra-grammatical idioms. Here it is argued that language is neither perfect nor optimal, and shown how theories of language which place these proper-ties at their core run into both conceptual and empirical problems

Deriving a mutation index of carcinogenicity using protein structure and protein interfaces

With the advent of Next Generation Sequencing the identification of mutations in the genomes of healthy and diseased tissues has become commonplace. While much progress has been made to elucidate the aetiology of disease processes in cancer, the contributions to disease that many individual mutations make remain to be characterised and their downstream consequences on cancer phenotypes remain to be understood. Missense mutations commonly occur in cancers and their consequences remain challenging to predict. However, this knowledge is becoming more vital, for both assessing disease progression and for stratifying drug treatment regimes. Coupled with structural data, comprehensive genomic databases of mutations such as the 1000 Genomes project and COSMIC give an opportunity to investigate general principles of how cancer mutations disrupt proteins and their interactions at the molecular and network level. We describe a comprehensive comparison of cancer and neutral missense mutations; by combining features derived from structural and interface properties we have developed a carcinogenicity predictor, InCa (Index of Carcinogenicity). Upon comparison with other methods, we observe that InCa can predict mutations that might not be detected by other methods. We also discuss general limitations shared by all predictors that attempt to predict driver mutations and discuss how this could impact high-throughput predictions. A web interface to a server implementation is publicly available at http://inca.icr.ac.uk/

Osteoarthritis Preoperative Package for care of Orthotics, Rehabilitation, Topical and oral agent Usage and Nutrition to Improve ouTcomes at a Year (OPPORTUNITY); a feasibility study protocol for a randomised controlled trial

BackgroundPatients’ pre-operative health and physical function is known to influence their post-operative outcomes. In patients with knee osteoarthritis, pharmacological and non-pharmacological options are often not optimised prior to joint replacement. This results in some patients undergoing surgery when they are not as fit as they could be. The aim of this study is to assess the feasibility and acceptability of a pre-operative package of non-operative care versus standard care prior to joint replacement.Methods/designThis is a multicentre, randomised controlled feasibility trial of patients undergoing primary total knee replacement for osteoarthritis. Sixty patients will be recruited and randomised (2:1) to intervention or standard care arms. Data will be collected at baseline (before the start of the intervention), around the end of the intervention period and a minimum of 90 days after the planned date of surgery. Adherence will be reviewed each week during the intervention period (by telephone or in person). Participants will be randomised to a pre-operative package of non-operative care or standard care. The non-operative care will consist of (1) a weight-loss programme, (2) a set of exercises, (3) provision of advice on analgesia use and (4) provision of insoles. The intervention will be started as soon as possible after patients have been added to the waiting list for joint replacement surgery to take advantage of the incentive for behavioural change that this will create. The primary outcomes of this study are feasibility outcomes which will indicate whether the intervention and study protocol is feasible and acceptable and whether a full-scale effectiveness trial is warranted.The following will be measured and used to inform study feasibility: rate of recruitment, rate of retention at 90-day follow-up review after planned surgery date, and adherence to the intervention estimated through review questionnaires and weight change (for those receiving the weight-loss aspect of intervention). In addition the following information will be assessed qualitatively: analysis of qualitative interviews exploring acceptability, feasibility, adherence and possible barriers to implementing the intervention, and acceptability of the different outcome measures.DiscussionThe aims of the study specifically relate to testing the feasibility and acceptability of the proposed effectiveness trial intervention and the feasibility of the trial methods.This study forms the important first step in developing and assessing whether the intervention has the potential to be assessed in a future fully powered effectiveness trial. The findings will also be used to refine the design of the effectiveness trial.Trial registrationISRCTN registry, ID: ISRCTN96684272. Registered on 18 April 2018

A preoperative package of care for osteoarthritis, consisting of weight loss, orthotics, rehabilitation, topical and oral analgesia (OPPORTUNITY): A two centre open label randomised controlled feasibility trial

Background Osteoarthritis of the knee is a major cause of disability worldwide. Non-operative treatments can reduce the morbidity but adherence is poor. We hypothesised that adherence could be optimised if behavioural change was established in the preoperative period. Therefore, we aimed to assess feasibility, acceptability, and recruitment and retention rates of a preoperative package of non-operative care in patients awaiting knee replacement surgery. Methods We did an open-label, randomised controlled, feasibility trial in two secondary care centres in the UK. Eligible participants were aged 15–85 years, on the waiting list for a knee arthroplasty for osteoarthritis, and met at least one of the thresholds for one of the four components of the preoperative package of non-operative care intervention (ie, weight loss, exercise therapy, use of insoles, and analgesia adjustment). Participants were randomly assigned (2:1) to either the intervention group or the standard of care (ie, control) group. All four aspects of the intervention were delivered weekly over 12 weeks. Participants in the intervention group were reviewed regularly to assess adherence. The primary outcome was acceptability and feasibility of delivering the intervention, as measured by recruitment rate, retention rate at follow-up review after planned surgery, health-related quality of life, joint-specific scores, and adherence (weight change and qualitative interviews). This study is registered with ISRCTN, ISRCTN96684272. Findings Between Sept 3 2018, and Aug 30, 2019, we screened 233 patients, of whom 163 (73%) were excluded and 60 (27%) were randomly assigned to either the intervention group (n=40) or the control group (n=20). 34 (57%) of 60 participants were women, 26 (43%) were men, and the mean age was 66·8 years (SD 8·6). Uptake of the specific intervention components varied: 31 (78%) of 40 had exercise therapy, 28 (70%) weight loss, 22 (55%) analgesia adjustment, and insoles (18 [45%]). Overall median adherence was 94% (IQR 79·5–100). At the final review, the intervention group lost a mean of 11·2 kg (SD 5·6) compared with 1·3 kg (3·8) in the control group (estimated difference –9·8 kg [95% CI –13·4 to –6·3]). A clinically significant improvement in health-related quality o life (mean change 0·078 [SD 0·195]) were reported, and joint-specific scores showed greater improvement in the intervention group than in the control group. No adverse events attributable to the intervention occurred. Interpretation Participants adhered well to the non-operative interventions and their health-related quality of life improved. Participant and health professional feedback were extremely positive. These findings support progression to a full-scale effectiveness trial

Mother-infant interactions and regional brain volumes in infancy: an MRI study

Background: It is generally agreed that the human brain is responsive to environmental influences, and that the male brain may be particularly sensitive to early adversity. However, this is largely based on retrospective studies of older children and adolescents exposed to extreme environments in childhood. Less is understood about how normative variations in parent-child interactions are associated with the development of the infant brain in typical settings. Method: To address this, we used magnetic resonance imaging to investigate the relationship between observational measures of mother-infant interactions and regional brain volumes in a community sample of 3-6 month old infants (N=39). In addition, we examined whether this relationship differed in male and female infants. Results: We found that lower maternal sensitivity was correlated with smaller subcortical grey matter volumes in the whole sample, and that this was similar in both sexes. However, male infants who showed greater levels of positive communication and engagement during early interactions had smaller cerebellar volumes. Conclusion These preliminary findings suggest that variations in mother-infant interaction dimensions are associated with differences in infant brain development. Although the study is cross-sectional and causation cannot be inferred, the findings reveal a dynamic interaction between brain and environment that may be important when considering interventions to optimize infant outcomes

Emergence of polarized opinions from free association networks

We developed a method that can identify polarized public opinions by finding modules in a network of statistically related free word associations. Associations to the cue “migrant” were collected from two independent and comprehensive samples in Hungary (N1 = 505, N2 = 505). The co-occurrence-based relations of the free word associations reflected emotional similarity, and the modules of the association network were validated with well-established measures. The positive pole of the associations was gathered around the concept of “Refugees” who need help, whereas the negative pole associated asylum seekers with “Violence”. The results were relatively consistent in the two independent samples. We demonstrated that analyzing the modular organization of association networks can be a tool for identifying the most important dimensions of public opinion about a relevant social issue without using predefined constructs