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Background Age at presentation with primary biliary cholangitis ( PBC) is associated with differential response to ursodeoxycholic acid ( UDCA) therapy. Younger-presenting patients are less likely to respond to treatment and more likely to need transplant or die from the disease. PBC has a complex impact on quality of life (QoL), with systemic symptoms often having significant impact. Aim To explain the impact of age at presentation on perceived QoL and the inter-related symptoms which impact upon it. Methods Using the UK- PBC cohort, symptoms were assessed using the PBC-40 and other validated tools. Data were available on 2055 patients. Results Of the 1990 patients reporting a global PBC-QoL score, 66% reported good/neutral scores and 34% reported poor scores. Each 10-year increase in age at presentation was associated with a 14% decrease in risk of poor perceived QoL ( OR = 0.86, 95% CI: 0.75-0.98, P < 0.05). All symptom domains were similarly age-associated ( P < 0.01). Social dysfunction was the symptom factor with the greatest impact on QoL. Median (interquartile range) PBC-40 social scores for patients with good perceived QoL were 18 (14-23) compared with 34 (29-39) for those with poor QoL. Conclusion The majority of patients with primary biliary cholangitis do not feel their QoL is impaired, although impairment is reported by a sizeable minority. Age at presentation is associated with impact on perceived QoL and the symptoms impairing it, with younger patients being more affected. Social dysfunction makes the greatest contribution to QoL impairment, and it should be targeted in trials aimed at improving life quality. [ABSTRACT FROM AUTHOR]

The educational technology research field has been at the heart of debates about the future of education for the last quarter century. This paper explores the socio-technical developments that the next 25 years might bring and the implications of such developments for educators and for educational technology research. The paper begins by outlining the diverse approaches to educational futures that are currently visible in the field, and suggests four principles to underpin future thinking in educational technology. It then describes the methods used to inquire into long-term socio-technical futures in the 2-year Beyond Current Horizons Programme. These included a foresight and scenario development process bringing together evidence reviews and insights from over 100 researchers from disciplines as diverse as computer science, demography and sociology of childhood, as well as consultation with over 130 organizations and individuals from industry, practice and educational beneficiary groups. The outcomes of this programme are then presented, including a set of future scenarios for education and a set of socio-technical developments that might underpin such scenarios. The scenarios emerge from three future worlds (‘Trust Yourself’, ‘Loyalty Points’ and ‘Only Connect’), and from projections including: changing demography, new human–machine relations and a weakening of institutional boundaries. The paper then argues that the next 25 years will challenge our current organization of education around the unit of the individual child, the school and the discourses of the knowledge economy; and will require the development of new approaches to curriculum, cross-institutional relationships, workforce development and decision-making in education. Finally, the paper argues that these developments challenge educational technology research to move beyond pedagogy to curriculum; beyond the school to the community, home and workplace; and beyond social sciences to collaborations with medical and bio-ethics fields. [ABSTRACT FROM AUTHOR]

Biallelic mutations in SNORD118, encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given the difficulty in interpreting the functional consequences of variants in nonprotein encoding genes, and the high allelic polymorphism across SNORD118 in controls, we set out to provide a description of the molecular pathology and clinical spectrum observed in a cohort of patients with LCC. We identified 64 affected individuals from 56 families. Age at presentation varied from 3 weeks to 67 years, with disease onset after age 40 years in eight patients. Ten patients had died. We recorded 44 distinct, likely pathogenic, variants in SNORD118. Fifty two of 56 probands were compound heterozygotes, with parental consanguinity reported in only three families. Forty nine of 56 probands were either heterozygous (46) or homozygous (three) for a mutation involving one of seven nucleotides that facilitate a novel intramolecular interaction between the 5' end and 3' extension of precursor-U8. There was no obvious genotype-phenotype correlation to explain the marked variability in age at onset. Complementing recently published functional analyses in a zebrafish model, these data suggest that LCC most often occurs due to combinatorial severe and milder mutations, with the latter mostly affecting 3' end processing of precursor-U8., (© 2020 Wiley Periodicals LLC.)