FRANKLIN COUNTY, IOWA'S PROGRAM IN PUBLIC AFFAIRS

Public Economics,

High resolution time-course mapping of early transcriptomic, molecular and cellular phenotypes in Huntington\u27s disease CAG knock-in mice across multiple genetic backgrounds.

Huntington\u27s disease is a dominantly inherited neurodegenerative disease caused by the expansion of a CAG repeat in the HTT gene. In addition to the length of the CAG expansion, factors such as genetic background have been shown to contribute to the age at onset of neurological symptoms. A central challenge in understanding the disease progression that leads from the HD mutation to massive cell death in the striatum is the ability to characterize the subtle and early functional consequences of the CAG expansion longitudinally. We used dense time course sampling between 4 and 20 postnatal weeks to characterize early transcriptomic, molecular and cellular phenotypes in the striatum of six distinct knock-in mouse models of the HD mutation. We studied the effects of the HttQ111 allele on the C57BL/6J, CD-1, FVB/NCr1, and 129S2/SvPasCrl genetic backgrounds, and of two additional alleles, HttQ92 and HttQ50, on the C57BL/6J background. We describe the emergence of a transcriptomic signature in HttQ111/+  mice involving hundreds of differentially expressed genes and changes in diverse molecular pathways. We also show that this time course spanned the onset of mutant huntingtin nuclear localization phenotypes and somatic CAG-length instability in the striatum. Genetic background strongly influenced the magnitude and age at onset of these effects. This work provides a foundation for understanding the earliest transcriptional and molecular changes contributing to HD pathogenesis

Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain–gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials

SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination

BACKGROUND: Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. METHODS: In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data. FINDINGS: Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p < 0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p < 0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p = 0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R = 0.05, p = 0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination. INTERPRETATION: The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity. FUNDING: This study has been supported by ISARIC4C and PHOSP-COVID consortia. ISARIC4C is supported by grants from the National Institute for Health and Care Research and the Medical Research Council. Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research. The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute of Health and Care Research. The funders were not involved in the study design, interpretation of data or the writing of this manuscript

An integrated approach to address diabetes in the context of food insecurity: Delivering health study protocol

Background: Diabetes self-management education and support (DSMES) interventions among food insecure individuals with type 2 diabetes (T2D) have found modest improvements in nutrition and health outcomes but are limited by barriers to attendance and retention. This study applies a community-based participatory research approach, engaging community members at all levels of intervention planning, development, implementation, and dissemination, to deliver a plain-language DSMES curriculum to food insecure community members with T2D. Methods: This is a single-arm, pre-post design assessing the efficacy of a 12-week home-delivered DSMES curriculum and T2D-appropriate food box intervention to improve the nutrition and health outcomes of food insecure individuals with T2D. The intervention consists of a weekly food box delivery and handout with video links on key DSMES topics, developed and refined using community advisor feedback. Up to 100 English-, Spanish-, or Marshallese-speaking adult participants with T2D (HbA1c ≥ 7%) and food insecurity are being recruited from food pantries in northwest Arkansas. Data is collected at pre-intervention and immediately post-intervention. The primary study outcome is change in HbA1c. Secondary measures include diet quality (Healthy Eating Index-2015, calculated from 3 24-h dietary recall interviews via phone), body mass index, blood pressure, skin carotenoids, food security, T2D self-management behaviors, T2D self-efficacy, and T2D-related distress. Results: Recruitment began in August 2021 and enrollment is anticipated to be complete in March 2023. Conclusion: Findings from this study will provide a rich understanding of diabetes-related health outcomes and dietary patterns of individuals with food insecurity and T2D and inform future food-focused DSMES interventions in this setting

Toward an integrative geological and geophysical view of Cascadia subduction zone earthquakes

The Cascadia subduction zone (CSZ) is an exceptional geologic environment for recording evidence of land-level changes, tsunamis, and ground motion that reveals at least 19 great megathrust earthquakes over the past 10 kyr. Such earthquakes are among the most impactful natural hazards on Earth, transcend national boundaries, and can have global impact.Reducing the societal impacts of future events in the US Pacific Northwest and coastal British Columbia, Canada, requires improved scientific understanding of megathrust earthquake rupture, recurrence, and corresponding hazards. Despite substantial knowledge gained from decades of research, large uncertainties remain about the characteristics and frequencies of past CSZ earthquakes. In this review, we summarize geological, geophysical, and instrumental evidence relevant to understanding megathrust earthquakes along the CSZ and associated uncertainties. We discuss how the evidence constrains various models of great megathrust earthquake recurrence in Cascadia and identify potential paths forward for the earthquake science community

Non-additive degrees of belief

This paper starts from the position that belief is primarily quantitative and not categorical, i.e. we generally assume the existence of various degrees of belief. This corresponds to the observation that most human beings experience belief as a matter of degree. We follow the usual convention that such degrees of belief are values i

The United Kingdom Childhood Cancer Study: objectives, materials and methods. UK Childhood Cancer Study Investigators.

An investigation into the possible causes of childhood cancer has been carried out throughout England, Scotland and Wales over the period 1991-1998. All children known to be suffering from one or other type of the disease over periods of 4-5 years have been included, and control children matched for sex, age and area of residence have been selected at random from population registers. Information about both groups of children (with and without cancer) has been obtained from parental questionnaires, general practitioners' and hospital records, and from measurement of the extent of exposure to radon gas, terrestrial gamma radiation, and electric and magnetic fields. Samples of blood have also been obtained from the affected children and their parents and stored. Altogether 3,838 children with cancer, including 1,736 with leukaemia, and 7,629 unaffected children have been studied. Detailed accounts are given of the nature of the information obtained in sections describing the general methodology of the study, the measurement of exposure to ionizing and non-ionizing radiation, the classification of solid tumours and leukaemias, and the biological material available for genetic analysis