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We previously estimated that 42% of patients with severe developmental disorders carry pathogenic de novo mutations in coding sequences. The role of de novo mutations in regulatory elements affecting genes associated with developmental disorders, or other genes, has been essentially unexplored. We identified de novo mutations in three classes of putative regulatory elements in almost 8,000 patients with developmental disorders. Here we show that de novo mutations in highly evolutionarily conserved fetal brain-active elements are significantly and specifically enriched in neurodevelopmental disorders. We identified a significant twofold enrichment of recurrently mutated elements. We estimate that, genome-wide, 1-3% of patients without a diagnostic coding variant carry pathogenic de novo mutations in fetal brain-active regulatory elements and that only 0.15% of all possible mutations within highly conserved fetal brain-active elements cause neurodevelopmental disorders with a dominant mechanism. Our findings represent a robust estimate of the contribution of de novo mutations in regulatory elements to this genetically heterogeneous set of disorders, and emphasize the importance of combining functional and evolutionary evidence to identify regulatory causes of genetic disorders.

Introduction Acute exacerbations of COPD (AE-COPD) are a leading cause of health service utilisation and are associated with morbidity and mortality. Identifying the prodrome of AE-COPD by monitoring symptoms and physiological parameters (telemonitoring) has proven disappointing and false alerts limit clinical utility. We report objective monitoring of cough counts around AE-COPD and the performance of a novel alert system identifying meaningful change in cough frequency. Methods This prospective longitudinal study of cough monitoring included chronic obstructive pulmonary disease (COPD) patients experienced in telemonitoring that had two or more AE-COPD in the past year. Participants underwent cough monitoring and completed a daily questionnaire for 90 days. The automated system identified deteriorating trends in cough and this was compared with alerts generated by an established telemonitoring questionnaire. Results 28 patients [median age 66 (range 46-86), mean FEV-1% predicted 36% (SD 18%)] completed the study and had a total of 58 exacerbations (43 moderate and 15 severe). Alerts based on cough monitoring were generated mean 3.4 days before 45% of AE-COPD with one false alert every 100 days. In contrast, questionnaire-based alerts occurred in the prodrome of 88% of AE-COPD with one false alert every 10 days. Conclusion An alert system based on cough frequency alone predicted 45% AE-COPD; the low false alert rate with cough monitoring suggests it is a practical and clinically relevant tool. In contrast, the utility of questionnaire-based symptom monitoring is limited by frequent false alerts., Author(s): Michael G. Crooks [sup.1] [sup.3], Albertus C. den Brinker [sup.2], Susannah Thackray-Nocera [sup.1], Ralph van Dinther [sup.2], Caroline E. Wright [sup.1], Alyn H. Morice [sup.1] Author Affiliations: (1) grid.413631.2, [...]

Paralytic polio once afflicted almost half a million children each year. The attenuated oral polio vaccine (OPV) has enabled world-wide vaccination efforts, which resulted in nearly complete control of the disease. However, poliovirus eradication is hampered globally by epidemics of vaccine-derived polio. Here, we describe a combined theoretical and experimental strategy that describes the molecular events leading from OPV to virulent strains. We discover that similar evolutionary events occur in most epidemics. The mutations and the evolutionary trajectories driving these epidemics are replicated using a simple cell-based experimental setup where the rate of evolution is intentionally accelerated. Furthermore, mutations accumulating during epidemics increase the replication fitness of the virus in cell culture and increase virulence in an animal model. Our study uncovers the evolutionary strategies by which vaccine strains become pathogenic and provides a powerful framework for rational design of safer vaccine strains and for forecasting virulence of viruses. VIDEO ABSTRACT.

Patterns of participation in higher education (HE) in the UK, as elsewhere, have been marked by social inequalities for decades. UK Governments have responded with a plethora of policies and agendas aimed at addressing this broad social issue. However, little is known about how higher education institutions (HEIs) interpret and 'enact' these policies in relation to institution-specific contexts. Drawing on concepts from policy sociology this paper examines how HEIs in one nation state, Wales, enact its Government's policy on 'widening access' to higher education. Interviews with a range of 'policy actors' along with analyses of institutional 'widening access' policy documents, reveal divergences between HEIs in how this policy agenda is interpreted and delivered. These differences reflect institution-specific contexts -- not least their internal politics and assumptions about the type of students they admit, but also their interests and priorities in relation to their positions within a global, marketised, HE system. The implications of this for the reproduction of university hierarchies in the UK, as well as social inequalities more generally are brought to the fore.

Background: Higher levels of pre-operative anxiety are associated with adverse outcomes according to the cardiothoracic and orthopedic literature on emergent surgeries. There are limited data on pre-operative anxiety levels in the gynecologic setting. This study sought to identify predictive variables for high pre-operative anxiety levels in patients undergoing major urogynecologic surgery. Methods: Pre- and post-operative surveys that included demographic data, a modification of the Amsterdam Pre-Operative Anxiety and Information Scale, and open-ended questions regarding anxiety were administered. Descriptive, univariate and multivariate analyses were used to analyze the quantitative elements of the survey data. The qualitative components of the survey data were coded and analyzed using thematic analyses. Results: A total of 54 participants completed the pre-operative survey. The median age was 62 years old, and the majority were employed (n = 34, 60.7%). Roughly 1/3 had been diagnosed with a mental health condition (n = 19, 33.9%) and nearly all had other health conditions (n = 51, 91%). The baseline APAIS score ranged from 9 to 40, with higher scores reflecting higher levels of pre-operative anxiety. The median APAIS score was 24, with a score equal to or greater than 30 being in the highest tertile. Conclusion: No associations were made between the variables and pre-operative anxiety levels. However, useful insights into our patient population were made. [ABSTRACT FROM AUTHOR]