Bayesian inference of a new Mallows model for characterising symptom sequences applied in primary progressive aphasia

Machine learning models offer the potential to understand diverse datasets in a data-driven way, powering insights into individual disease experiences and ensuring equitable healthcare. In this study, we explore Bayesian inference for characterising symptom sequences, and the associated modelling challenges. We adapted the Mallows model to account for partial rankings and right-censored data, employing custom MCMC fitting. Our evaluation, encompassing synthetic data and a primary progressive aphasia dataset, highlights the model's efficacy in revealing mean orderings and estimating ranking variance. This holds the potential to enhance clinical comprehension of symptom occurrence. However, our work encounters limitations concerning model scalability and small dataset sizes.Comment: Extended Abstract presented at Machine Learning for Health (ML4H) symposium 2023, December 10th, 2023, New Orleans, United States, 8 page

Polygenic and socioeconomic risk for high body mass index:69 years of follow-up across life

Genetic influences on body mass index (BMI) appear to markedly differ across life, yet existing research is equivocal and limited by a paucity of life course data. We thus used a birth cohort study to investigate differences in association and explained variance in polygenic risk for high BMI across infancy to old age (2-69 years). A secondary aim was to investigate how the association between BMI and a key purported environmental determinant (childhood socioeconomic position) differed across life, and whether this operated independently and/or multiplicatively of genetic influences. Data were from up to 2677 participants in the MRC National Survey of Health and Development, with measured BMI at 12 timepoints from 2-69 years. We used multiple polygenic indices from GWAS of adult and childhood BMI, and investigated their associations with BMI at each age. For polygenic liability to higher adult BMI, the trajectories of effect size (β) and explained variance (R2) diverged: explained variance peaked in early adulthood and plateaued thereafter, while absolute effect sizes increased throughout adulthood. For polygenic liability to higher childhood BMI, explained variance was largest in adolescence and early adulthood; effect sizes were marginally smaller in absolute terms from adolescence to adulthood. All polygenic indices were related to higher variation in BMI; quantile regression analyses showed that effect sizes were sizably larger at the upper end of the BMI distribution. Socioeconomic and polygenic risk for higher BMI across life appear to operate additively; we found little evidence of interaction. Our findings highlight the likely independent influences of polygenic and socioeconomic factors on BMI across life. Despite sizable associations, the BMI variance explained by each plateaued or declined across adulthood while BMI variance itself increased. This is suggestive of the increasing importance of chance ('non-shared') environmental influences on BMI across life

The Holocene Geoarchaeology of the Desert Nile in Northern Sudan

Invited Paper Forty years ago Colin Renfrew declared that "every archaeological problem starts as a problem in geoarchaeology" (Renfrew, 1976 p. 2). With this assertion in mind, this paper draws upon the findings from field research in two sectors of the Nile Valley of Northern Sudan dedicated to the exploration of human-environment interactions during the middle and late Holocene. This part of the Nile corridor contains a rich cultural record and an exceptionally well preserved Holocene fluvial archive. A distinctive feature of these records is the variety of evidence for interaction between desert and river over a range of spatial and temporal scales. This interaction presented both challenges and opportunities for its ancient inhabitants. This paper will present evidence for large-scale landscape changes driven by shifts in global climate. It will also show how we have integrated the archaeological and geological records in the Northern Dongola Reach and at Amara West - where long-term field projects led by archaeologists from the British Museum have recognised the importance of a sustained commitment to interdisciplinary research to achieve a fully integrated geoarchaeological approach across a range of scales. The former project is a large-scale landscape survey with multiple sites across an 80 km reach of the Nile whilst the latter has a strong focus on a single New Kingdom town site and changes in its environmental setting. By combining multiple archaeological and geological datasets - and pioneering the use of OSL dating and strontium isotope analysis in the Desert Nile - we have developed a new understanding of human responses to Holocene climate and landscape change in this region. Renfrew, C. (1976) Archaeology and the earth sciences. In: D.A. Davidson and M.I. Shackley (eds) Geoarchaeology: Earth Science and the Past, Duckworth, London, 1-5

Multiplex ligation-dependent probe amplification (MLPA) analysis is an effective tool for the detection of novel intragenic PLA2G6 mutations: Implications for molecular diagnosis

Phospholipase associated neurodegeneration (PLAN) comprises a heterogeneous group of autosomal recessive neurological disorders caused by mutations in the PLA2G6 gene. Direct gene sequencing detects 85% mutations in infantile neuroaxonal dystrophy. We report the novel use of multiplex ligation-dependent probe amplification (MLPA) analysis to detect novel PLA2G6 duplications and deletions. The identification of such copy number variants (CNVs) expands the PLAN mutation spectrum and may account for up to 12.5% of PLA2G6 mutations. MLPA should thus be employed to detect CNVs of PLA2G6 in patients who show clinical features of PLAN but in whom both disease-causing mutations cannot be identified on routine sequencin

Two-year follow-up of infant and maternal outcomes after planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX): a randomised controlled trial

OBJECTIVE: We evaluated the best time to initiate delivery in late preterm pre-eclampsia in order to optimise long-term infant and maternal outcomes. DESIGN: Parallel-group, non-masked, randomised controlled trial SETTING: 46 UK maternity units POPULATION: Women with pre-eclampsia between 34+0 and 36+6 weeks' gestation, without severe disease, were randomised to planned delivery or expectant management. PRIMARY LONG-TERM OUTCOME: Infant neurodevelopmental outcome at 2 years of age, using the PARCA-R (Parent Report of Children's Abilities-Revised) composite score. RESULTS: Between Sept 29, 2014, and Dec 10, 2018, 901 women were enrolled in the trial, with 450 allocated to planned delivery and 451 to expectant management. At 2-year follow-up, the intention-to-treat analysis population included 276 women (290 infants) allocated to planned delivery and 251 women (256 infants) to expectant management. The mean composite standardised PARCA-R scores were 89.5 (standard deviation (SD) 18.2) in the planned delivery group and 91.9 (SD 18.4) in the expectant management group, with an adjusted mean difference of -2.4 (95% CI -5.4 to 0.5) points. CONCLUSION: In infants of women with late preterm pre-eclampsia, average neurodevelopmental assessment at 2 years lies within the normal range, regardless of whether planned delivery or expectant management is pursued. Because of lower than anticipated follow-up, there was limited power to demonstrate these scores were not different, but the small between-group difference in PARCA-R scores is unlikely to be clinically important

Effects of precompetition state anxiety interventions on performance time and accuracy among amateur soccer players: Revisiting the matching hypothesis

In this study, we tested the matching ypothesis, which contends that administration of a cognitive or somatic anxiety intervention should be matched to a participant's dominant anxiety response. Sixty-one male soccer players (mean age 31.6 years, s=6.3) were assigned to one of four groups based on their responses to the Competitive State Anxiety Inventory-2, which was modified to include a directional scale. Interventions were randomly administered in a counterbalanced order 10 min before each performance trial on a soccer skill test. The dominantly cognitive anxious group (n=17), the dominantly somatic anxious group (n=17), and the non-anxious control intervention group (n=14) completed a baseline performance trial. The second and third trials were completed with random administration of brief cognitive and somatic interventions. The non-anxious control group (n=13) completed three trials with no intervention. A mixed-model, GroupTreatment multivariate analysis of variance indicated significant (P0.05), or performance time or accuracy (P>0.05). The present findings do not provide support for the matching hypothesis for state anxiety intensity and direction, or for performance

Intracellular delivery of protein drugs with an autonomously lysing bacterial system reduces tumor growth and metastases

Critical cancer pathways often cannot be targeted because of limited efficiency crossing cell membranes. Here we report the development of a Salmonella-based intracellular delivery system to address this challenge. We engineer genetic circuits that (1) activate the regulator flhDC to drive invasion and (2) induce lysis to release proteins into tumor cells. Released protein drugs diffuse from Salmonella containing vacuoles into the cellular cytoplasm where they interact with their therapeutic targets. Control of invasion with flhDC increases delivery over 500 times. The autonomous triggering of lysis after invasion makes the platform self-limiting and prevents drug release in healthy organs. Bacterial delivery of constitutively active caspase-3 blocks the growth of hepatocellular carcinoma and lung metastases, and increases survival in mice. This success in targeted killing of cancer cells provides critical evidence that this approach will be applicable to a wide range of protein drugs for the treatment of solid tumors