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Mutations in the progranulin gene (GRN) are a major cause of frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions (FTLD-U) but the distinguishing clinical and anatomical features of this subgroup remain unclear. In a large UK cohort of FTLD (n=227), we found 5 different frameshift and premature termination mutations likely to be causative of FTLD in 27 affected family members. A four base pair insertion mutation in GRN exon 2 comprised the majority of British cases across multiple unrelated families, although microsatellite haplotype analysis supports a recent common ancestor. Additional novel missense changes were discovered of uncertain pathogenicity but deletion of the entire gene was not detected. The age of onset of disease in GRN mutation carriers was later when compared with tau gene (MAPT) mutation carriers, and duration of disease shorter than both MAPT carriers and patients with FTLD-U without mutation. Common presenting features were a behavioural syndrome, normally dominated by apathy, and language output impairment which was either a dynamic aphasia or a progressive non-fluent aphasia. Neurological and neuropsychological assessment also suggests that parietal lobe dysfunction is a characteristic feature of GRN mutation and may differentiate this group from other patients with FTLD. MR imaging showed evidence of strikingly asymmetrical atrophy with the frontal, temporal and parietal lobes all affected. GRN carriers showed more asymmetry and more posterior involvement compared to MAPT carriers or FTLD-U without mutation. Finally, we confirmed a modifying effect of APOE genotype on clinical phenotype with later onset in the GRN carriers. [ABSTRACT FROM AUTHOR]

Background: Physical activity (PA) has been associated with benefits for cognitive function (CF), but previous estimates of the strength of this relationship may have been biased due to limitations in statistical modelling practices that are common among observational studies. We aimed to address this by using a rigorously constructed conceptual causal model to guide an empirical analysis estimating the effect of PA on CF in the UK Biobank cohort of middle-aged and older adults., Methods: This study analysed a subsample of 334 227 adults from the UK Biobank prospective cohort study. PA was measured subjectively by self-report and by device using accelerometry, and CF was measured using objective cognitive tests. Composite CF measures were derived to represent general and domain-specific performance. Effect coefficients were estimated using regression models, adjusting for a wide range of confounders specified by the assumed causal model, including genetic risk factors, and relevant health, sociodemographic and behavioural variables from across the lifespan., Results: Results indicated very small effect sizes (standardized mean difference estimates all <0.01) of inconsistent direction, for both cross-sectional and longitudinal analyses., Conclusions: The expected protective effect of PA on CF was not observed. This may reflect selection bias within UK Biobank, or the relatively young age of the sample at follow-up., (© The Author(s) 2023. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Inherited prion diseases (IPD) are a set of rare neurodegenerative diseases that are always caused by mutation of the prion protein gene (PRNP). These are highly heterogeneous in clinical presentation and best described by the specific gene mutation, but traditionally include the canonical syndromes familial Creutzfeldt-Jakob disease, Gerstamann-Straussler-Scheinker syndrome, and fatal familial insomnia. In the UK, care of IPD patients and clinical PRNP sequencing have been carried out almost exclusively by the National Prion Clinic and affiliated laboratories since the disease gene was discovered in 1989. Using data obtained over 30 years (1990-2019), this study aimed to provide a greater understanding of the genetic prevalence of IPD using multiple complementary methods. A key source of bias in rare disorders is ascertainment, so we included an analysis based on capture-recapture techniques that may help to minimise ascertainment bias. 225 patients, with 21 different IPD mutations were identified, varying in frequency (with 8/21 mutations comprising over 90% observed cases), derived from 116 kindreds and 151 3-generation families. We estimated a total of 303 UK families (95% CI = 222, 384) segregate IPD mutations, 1091 (95% CI = 720, 1461) UK mutation carriers and a lifetime risk of approximately 1 in 60,000. Simpler methods of measuring prevalence based on extrapolation from the annual incidence of disease, and large scale genomic studies, result in similar estimates of prevalence. These estimates may be of value for planning preventive trials of therapeutics in IPD mutation carriers, prevention of prion disease transmission and provision of specialist services., (© 2022. The Author(s).)

It is critical that academic opinion of pandemic pedagogy is comprehensively quantified in order to inform future practices. Thus, this study examines how anatomists in the United Kingdom (UK) and Republic of Ireland (ROI) perceive the teaching adaptations made in response to COVID-19, and how these adaptations have impacted their experiences teaching, their online work environment and community. Data was collected via a questionnaire from 24 anatomists across 15 universities in the UK (11) and ROI (4). With regards to teaching, 95.6% of academics have upskilled in new technologies to meet the demands of distance teaching. Academics (95.8%) preferred face-to-face delivery of practical sessions. Most universities (80.0%) reported that practical sessions will continue in a new form that ensures social distancing. However, 50.0% of academics are uncertain if these adaptations will improve student learning. Many anatomists believe that the new adaptations may hinder student-student (66.7%) and student-tutor (45.8%) interactions. Regarding assessment, 52.6% of academics preferred traditional methods to online. Remote online assessment was difficult to protect against collusion, but provided time saving opportunities for academics. Finally, in terms of working environment, 83.3% of academics stated that their workload increased; 54.2% preferred working on site rather than remotely and 79.2% think that staff interactions are better when working on site. These results demonstrate a widespread concern amongst anatomists regarding the pandemic-induced adaptations to teaching, assessment and working environment. However, important opportunities were also identified that could ultimately serve to benefit students and educators alike., (© 2021 The Authors. Clinical Anatomy published by Wiley Periodicals LLC on behalf of American Association of Clinical Anatomists.)

The Covid-19 pandemic has driven the fastest changes to higher education across the globe, necessitated by social distancing measures preventing face-to-face teaching. This has led to an almost immediate switch to distance learning by higher education institutions. Anatomy faces some unique challenges. Intrinsically, anatomy is a three-dimensional subject that requires a sound understanding of the relationships between structures, often achieved by the study of human cadaveric material, models, and virtual resources. This study sought to identify the approaches taken in the United Kingdom and Republic of Ireland to deliver anatomical education through online means. Data were collected from 14 different universities in the United Kingdom and Republic of Ireland and compared adopting a thematic analysis approach. Once themes were generated, they were collectively brought together using a strength, weakness, opportunity, threat (SWOT) analysis. Key themes included the opportunity to develop new online resources and the chance to engage in new academic collaborations. Academics frequently mentioned the challenge that time constrains could place on the quality and effectiveness of these resources; especially as in many cases the aim of these resources was to compensate for a lack of exposure to cadaveric exposure. Comparisons of the actions taken by multiple higher education institutions reveal the ways that academics have tried to balance this demand. Discussions will facilitate decisions being made by higher education institutions regarding adapting the curriculum and assessment methods in anatomy., (© 2020 The Authors. Anatomical Sciences Education published by Wiley Periodicals LLC on behalf of American Association for Anatomy.)

Background: International evidence indicates relationships between pre-pregnancy body mass index (BMI) and breastfeeding behaviours. This study aims to assess associations between key points in the breastfeeding trajectory (initiation, early cessation and longevity) and pre-pregnancy BMI in a recent, nationally representative British cohort. It also aims to explore in the British context potential moderation by mothers' ethnic group., Methods: The sample comprises 17 113 mothers from the UK Millennium Cohort Study who have information on pre-pregnancy BMI. Associations between pre-pregnancy BMI categories and breastfeeding initiation, early cessation and longevity are tested using logistic regression. Directed acyclic graphics identify appropriate minimal adjustment to block biasing pathways and classify total and direct effects., Results: After adjusting for confounders, there are large differences in breastfeeding early cessation and longevity by pre-pregnancy BMI group. Differences in propensity to initiation are negligible. Having begun breastfeeding, overweight and obese mothers are more likely to cease in the first week and less likely to continue past 4 months. Observed potential mediators within pregnancy and delivery provide little explanation for relationships. Evidence for moderation by ethnicity is scant., Conclusions: The causal mechanisms underlying relationships between pre-pregnancy overweight, obesity, and breastfeeding behaviours require further research. However, this study suggests pre-pregnancy BMI as one predictive measure for targeting support to women less likely to establish breastfeeding in the early days, and to continue beyond 4 months. The nature of support should carefully be considered and developed, with mind to both intended and potential unintended consequences of intervention given the need for additional investigation into the causes of associations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Human and animal prion diseases are under genetic control, but apart from PRNP (the gene that encodes the prion protein), we understand little about human susceptibility to bovine spongiform encephalopathy (BSE) prions, the causal agent of variant Creutzfeldt-Jakob disease (vCJD)., Methods: We did a genome-wide association study of the risk of vCJD and tested for replication of our findings in samples from many categories of human prion disease (929 samples) and control samples from the UK and Papua New Guinea (4254 samples), including controls in the UK who were genotyped by the Wellcome Trust Case Control Consortium. We also did follow-up analyses of the genetic control of the clinical phenotype of prion disease and analysed candidate gene expression in a mouse cellular model of prion infection., Findings: The PRNP locus was strongly associated with risk across several markers and all categories of prion disease (best single SNP [single nucleotide polymorphism] association in vCJD p=2.5 x 10(-17); best haplotypic association in vCJD p=1 x 10(-24)). Although the main contribution to disease risk was conferred by PRNP polymorphic codon 129, another nearby SNP conferred increased risk of vCJD. In addition to PRNP, one technically validated SNP association upstream of RARB (the gene that encodes retinoic acid receptor beta) had nominal genome-wide significance (p=1.9 x 10(-7)). A similar association was found in a small sample of patients with iatrogenic CJD (p=0.030) but not in patients with sporadic CJD (sCJD) or kuru. In cultured cells, retinoic acid regulates the expression of the prion protein. We found an association with acquired prion disease, including vCJD (p=5.6 x 10(-5)), kuru incubation time (p=0.017), and resistance to kuru (p=2.5 x 10(-4)), in a region upstream of STMN2 (the gene that encodes SCG10). The risk genotype was not associated with sCJD but conferred an earlier age of onset. Furthermore, expression of Stmn2 was reduced 30-fold post-infection in a mouse cellular model of prion disease., Interpretation: The polymorphic codon 129 of PRNP was the main genetic risk factor for vCJD; however, additional candidate loci have been identified, which justifies functional analyses of these biological pathways in prion disease.