Chromosome-level organization of the regulatory genome in the Drosophila nervous system.

Previous studies have identified topologically associating domains (TADs) as basic units of genome organization. We present evidence of a previously unreported level of genome folding, where distant TAD pairs, megabases apart, interact to form meta-domains. Within meta-domains, gene promoters and structural intergenic elements present in distant TADs are specifically paired. The associated genes encode neuronal determinants, including those engaged in axonal guidance and adhesion. These long-range associations occur in a large fraction of neurons but support transcription in only a subset of neurons. Meta-domains are formed by diverse transcription factors that are able to pair over long and flexible distances. We present evidence that two such factors, GAF and CTCF, play direct roles in this process. The relative simplicity of higher-order meta-domain interactions in Drosophila, compared with those previously described in mammals, allowed the demonstration that genomes can fold into highly specialized cell-type-specific scaffolds that enable megabase-scale regulatory associations.

Modular antibodies reveal DNA damage-induced mono-ADP-ribosylation as a second wave of PARP1 signaling.

PARP1, an established anti-cancer target that regulates many cellular pathways, including DNA repair signaling, has been intensely studied for decades as a poly(ADP-ribosyl)transferase. Although recent studies have revealed the prevalence of mono-ADP-ribosylation upon DNA damage, it was unknown whether this signal plays an active role in the cell or is just a byproduct of poly-ADP-ribosylation. By engineering SpyTag-based modular antibodies for sensitive and flexible detection of mono-ADP-ribosylation, including fluorescence-based sensors for live-cell imaging, we demonstrate that serine mono-ADP-ribosylation constitutes a second wave of PARP1 signaling shaped by the cellular HPF1/PARP1 ratio. Multilevel chromatin proteomics reveals histone mono-ADP-ribosylation readers, including RNF114, a ubiquitin ligase recruited to DNA lesions through a zinc-finger domain, modulating the DNA damage response and telomere maintenance. Our work provides a technological framework for illuminating ADP-ribosylation in a wide range of applications and biological contexts and establishes mono-ADP-ribosylation by HPF1/PARP1 as an important information carrier for cell signaling.

Five million years of Antarctic Circumpolar Current strength variability.

The Antarctic Circumpolar Current (ACC) represents the world's largest ocean-current system and affects global ocean circulation, climate and Antarctic ice-sheet stability1-3. Today, ACC dynamics are controlled by atmospheric forcing, oceanic density gradients and eddy activity4. Whereas palaeoceanographic reconstructions exhibit regional heterogeneity in ACC position and strength over Pleistocene glacial-interglacial cycles5-8, the long-term evolution of the ACC is poorly known. Here we document changes in ACC strength from sediment cores in the Pacific Southern Ocean. We find no linear long-term trend in ACC flow since 5.3 million years ago (Ma), in contrast to global cooling9 and increasing global ice volume10. Instead, we observe a reversal on a million-year timescale, from increasing ACC strength during Pliocene global cooling to a subsequent decrease with further Early Pleistocene cooling. This shift in the ACC regime coincided with a Southern Ocean reconfiguration that altered the sensitivity of the ACC to atmospheric and oceanic forcings11-13. We find ACC strength changes to be closely linked to 400,000-year eccentricity cycles, probably originating from modulation of precessional changes in the South Pacific jet stream linked to tropical Pacific temperature variability14. A persistent link between weaker ACC flow, equatorward-shifted opal deposition and reduced atmospheric CO2 during glacial periods first emerged during the Mid-Pleistocene Transition (MPT). The strongest ACC flow occurred during warmer-than-present intervals of the Plio-Pleistocene, providing evidence of potentially increasing ACC flow with future climate warming.

PARP14 and PARP9/DTX3L regulate interferon-induced ADP-ribosylation.

PARP-catalysed ADP-ribosylation (ADPr) is important in regulating various cellular pathways. Until recently, PARP-dependent mono-ADP-ribosylation has been poorly understood due to the lack of sensitive detection methods. Here, we utilised an improved antibody to detect mono-ADP-ribosylation. We visualised endogenous interferon (IFN)-induced ADP-ribosylation and show that PARP14 is a major enzyme responsible for this modification. Fittingly, this signalling is reversed by the macrodomain from SARS-CoV-2 (Mac1), providing a possible mechanism by which Mac1 counteracts the activity of antiviral PARPs. Our data also elucidate a major role of PARP9 and its binding partner, the E3 ubiquitin ligase DTX3L, in regulating PARP14 activity through protein-protein interactions and by the hydrolytic activity of PARP9 macrodomain 1. Finally, we also present the first visualisation of ADPr-dependent ubiquitylation in the IFN response. These approaches should further advance our understanding of IFN-induced ADPr and ubiquitin signalling processes and could shed light on how different pathogens avoid such defence pathways.

Histone ADP-ribosylation promotes resistance to PARP inhibitors by facilitating PARP1 release from DNA lesions.

Poly(ADP-ribose) polymerase 1 (PARP1) has emerged as a central target for cancer therapies due to the ability of PARP inhibitors to specifically kill tumors deficient for DNA repair by homologous recombination. Upon DNA damage, PARP1 quickly binds to DNA breaks and triggers ADP-ribosylation signaling. ADP-ribosylation is important for the recruitment of various factors to sites of damage, as well as for the timely dissociation of PARP1 from DNA breaks. Indeed, PARP1 becomes trapped at DNA breaks in the presence of PARP inhibitors, a mechanism underlying the cytotoxitiy of these inhibitors. Therefore, any cellular process influencing trapping is thought to impact PARP inhibitor efficiency, potentially leading to acquired resistance in patients treated with these drugs. There are numerous ADP-ribosylation targets after DNA damage, including PARP1 itself as well as histones. While recent findings reported that the automodification of PARP1 promotes its release from the DNA lesions, the potential impact of other ADP-ribosylated proteins on this process remains unknown. Here, we demonstrate that histone ADP-ribosylation is also crucial for the timely dissipation of PARP1 from the lesions, thus contributing to cellular resistance to PARP inhibitors. Considering the crosstalk between ADP-ribosylation and other histone marks, our findings open interesting perspectives for the development of more efficient PARP inhibitor-driven cancer therapies.

The loss of DNA polymerase epsilon accessory subunits POLE3-POLE4 leads to BRCA1-independent PARP inhibitor sensitivity.

The clinical success of PARP1/2 inhibitors (PARPi) prompts the expansion of their applicability beyond homologous recombination deficiency. Here, we demonstrate that the loss of the accessory subunits of DNA polymerase epsilon, POLE3 and POLE4, sensitizes cells to PARPi. We show that the sensitivity of POLE4 knockouts is not due to compromised response to DNA damage or homologous recombination deficiency. Instead, POLE4 loss affects replication speed leading to the accumulation of single-stranded DNA gaps behind replication forks upon PARPi treatment, due to impaired post-replicative repair. POLE4 knockouts elicit elevated replication stress signaling involving ATR and DNA-PK. We find POLE4 to act parallel to BRCA1 in inducing sensitivity to PARPi and counteracts acquired resistance associated with restoration of homologous recombination. Altogether, our findings establish POLE4 as a promising target to improve PARPi driven therapies and hamper acquired PARPi resistance.

An altered extracellular matrix-integrin interface contributes to Huntington's disease-associated CNS dysfunction in glial and vascular cells.

Astrocytes and brain endothelial cells are components of the neurovascular unit that comprises the blood-brain barrier (BBB) and their dysfunction contributes to pathogenesis in Huntington's disease (HD). Defining the contribution of these cells to disease can inform cell-type-specific effects and uncover new disease-modifying therapeutic targets. These cells express integrin (ITG) adhesion receptors that anchor the cells to the extracellular matrix (ECM) to maintain the integrity of the BBB. We used HD patient-derived induced pluripotent stem cell (iPSC) modeling to study the ECM-ITG interface in astrocytes and brain microvascular endothelial cells and found ECM-ITG dysregulation in human iPSC-derived cells that may contribute to the dysfunction of the BBB in HD. This disruption has functional consequences since reducing ITG expression in glia in an HD Drosophila model suppressed disease-associated CNS dysfunction. Since ITGs can be targeted therapeutically and manipulating ITG signaling prevents neurodegeneration in other diseases, defining the role of ITGs in HD may provide a novel strategy of intervention to slow CNS pathophysiology to treat HD.

Within-host evolutionary dynamics and tissue compartmentalization during acute SARS-CoV-2 infection.

The global evolution of SARS-CoV-2 depends in part upon the evolutionary dynamics within individual hosts with varying immune histories. To characterize the within-host evolution of acute SARS-CoV-2 infection, we sequenced saliva and nasal samples collected daily from vaccinated and unvaccinated individuals early during infection. We show that longitudinal sampling facilitates high-confidence genetic variant detection and reveals evolutionary dynamics missed by less-frequent sampling strategies. Within-host dynamics in both unvaccinated and vaccinated individuals appeared largely stochastic; however, in rare cases, minor genetic variants emerged to frequencies sufficient for forward transmission. Finally, we detected significant genetic compartmentalization of viral variants between saliva and nasal swab sample sites in many individuals. Altogether, these data provide a high-resolution profile of within-host SARS-CoV-2 evolutionary dynamics.IMPORTANCEWe detail the within-host evolutionary dynamics of SARS-CoV-2 during acute infection in 31 individuals using daily longitudinal sampling. We characterized patterns of mutational accumulation for unvaccinated and vaccinated individuals, and observed that temporal variant dynamics in both groups were largely stochastic. Comparison of paired nasal and saliva samples also revealed significant genetic compartmentalization between tissue environments in multiple individuals. Our results demonstrate how selection, genetic drift, and spatial compartmentalization all play important roles in shaping the within-host evolution of SARS-CoV-2 populations during acute infection.

Identification of key residues of the DNA glycosylase OGG1 controlling efficient DNA sampling and recruitment to oxidized bases in living cells.

The DNA-glycosylase OGG1 oversees the detection and clearance of the 7,8-dihydro-8-oxoguanine (8-oxoG), which is the most frequent form of oxidized base in the genome. This lesion is deeply buried within the double-helix and its detection requires careful inspection of the bases by OGG1 via a mechanism that remains only partially understood. By analyzing OGG1 dynamics in the nucleus of living human cells, we demonstrate that the glycosylase constantly samples the DNA by rapidly alternating between diffusion within the nucleoplasm and short transits on the DNA. This sampling process, that we find to be tightly regulated by the conserved residue G245, is crucial for the rapid recruitment of OGG1 at oxidative lesions induced by laser micro-irradiation. Furthermore, we show that residues Y203, N149 and N150, while being all involved in early stages of 8-oxoG probing by OGG1 based on previous structural data, differentially regulate the sampling of the DNA and recruitment to oxidative lesions.

Breast density knowledge and willingness to delay treatment for pre-operative breast cancer imaging among women with a personal history of breast cancer.

BACKGROUND: Following a breast cancer diagnosis, it is uncertain whether women's breast density knowledge influences their willingness to undergo pre-operative imaging to detect additional cancer in their breasts. We evaluated women's breast density knowledge and their willingness to delay treatment for pre-operative testing. METHODS: We surveyed women identified in the Breast Cancer Surveillance Consortium aged ≥ 18 years, with first breast cancer diagnosed within the prior 6-18 months, who had at least one breast density measurement within the 5 years prior to their diagnosis. We assessed women's breast density knowledge and correlates of willingness to delay treatment for 6 or more weeks for pre-operative imaging via logistic regression. RESULTS: Survey participation was 28.3% (969/3,430). Seventy-two percent (469/647) of women with dense and 11% (34/322) with non-dense breasts correctly knew their density (p < 0.001); 69% (665/969) of all women knew dense breasts make it harder to detect cancers on a mammogram; and 29% (285/969) were willing to delay treatment ≥ 6 weeks to undergo pre-operative imaging. Willingness to delay treatment did not differ by self-reported density (OR:0.99 for non-dense vs. dense; 95%CI: 0.50-1.96). Treatment with chemotherapy was associated with less willingness to delay treatment (OR:0.67; 95%CI: 0.46-0.96). Having previously delayed breast cancer treatment more than 3 months was associated with an increased willingness to delay treatment for pre-operative imaging (OR:2.18; 95%CI: 1.26-3.77). CONCLUSIONS: Understanding of personal breast density was not associated with willingness to delay treatment 6 or more weeks for pre-operative imaging, but aspects of a woman's treatment experience were. CLINICALTRIALS: GOV : NCT02980848 registered December 2, 2016.

Consistency, completeness and external validity of ethnicity recording in NHS primary care records: a cohort study in 25 million patients' records at source using OpenSAFELY.

BACKGROUND: Ethnicity is known to be an important correlate of health outcomes, particularly during the COVID-19 pandemic, where some ethnic groups were shown to be at higher risk of infection and adverse outcomes. The recording of patients' ethnic groups in primary care can support research and efforts to achieve equity in service provision and outcomes; however, the coding of ethnicity is known to present complex challenges. We therefore set out to describe ethnicity coding in detail with a view to supporting the use of this data in a wide range of settings, as part of wider efforts to robustly describe and define methods of using administrative data. METHODS: We describe the completeness and consistency of primary care ethnicity recording in the OpenSAFELY-TPP database, containing linked primary care and hospital records in > 25 million patients in England. We also compared the ethnic breakdown in OpenSAFELY-TPP with that of the 2021 UK census. RESULTS: 78.2% of patients registered in OpenSAFELY-TPP on 1 January 2022 had their ethnicity recorded in primary care records, rising to 92.5% when supplemented with hospital data. The completeness of ethnicity recording was higher for women than for men. The rate of primary care ethnicity recording ranged from 77% in the South East of England to 82.2% in the West Midlands. Ethnicity recording rates were higher in patients with chronic or other serious health conditions. For each of the five broad ethnicity groups, primary care recorded ethnicity was within 2.9 percentage points of the population rate as recorded in the 2021 Census for England as a whole. For patients with multiple ethnicity records, 98.7% of the latest recorded ethnicities matched the most frequently coded ethnicity. Patients whose latest recorded ethnicity was categorised as Other were most likely to have a discordant ethnicity recording (32.2%). CONCLUSIONS: Primary care ethnicity data in OpenSAFELY is present for over three quarters of all patients, and combined with data from other sources can achieve a high level of completeness. The overall distribution of ethnicities across all English OpenSAFELY-TPP practices was similar to the 2021 Census, with some regional variation. This report identifies the best available codelist for use in OpenSAFELY and similar electronic health record data.

Annexin A2 modulates phospholipid membrane composition upstream of Arp2 to control angiogenic sprout initiation.

The intersection of protein and lipid biology is of growing importance for understanding how cells address structural challenges during adhesion and migration. While protein complexes engaged with the cytoskeleton play a vital role, support from the phospholipid membrane is crucial for directing localization and assembly of key protein complexes. During angiogenesis, dramatic cellular remodeling is necessary for endothelial cells to shift from a stable monolayer to invasive structures. However, the molecular dynamics between lipids and proteins during endothelial invasion are not defined. Here, we utilized cell culture, immunofluorescence, and lipidomic analyses to identify a novel role for the membrane binding protein Annexin A2 (ANXA2) in modulating the composition of specific membrane lipids necessary for cortical F-actin organization and adherens junction stabilization. In the absence of ANXA2, there is disorganized cortical F-actin, reduced junctional Arp2, excess sprout initiation, and ultimately failed sprout maturation. Furthermore, we observed reduced filipin III labeling of membrane cholesterol in cells with reduced ANXA2, suggesting there is an alteration in phospholipid membrane dynamics. Lipidomic analyses revealed that 42 lipid species were altered with loss of ANXA2, including an accumulation of phosphatidylcholine (16:0_16:0). We found that supplementation of phosphatidylcholine (16:0_16:0) in wild-type endothelial cells mimicked the ANXA2 knock-down phenotype, indicating that ANXA2 regulated the phospholipid membrane upstream of Arp2 recruitment and organization of cortical F-actin. Altogether, these data indicate a novel role for ANXA2 in coordinating events at endothelial junctions needed to initiate sprouting and show that proper lipid modulation is a critical component of these events.

The impact of COVID-19 on medication reviews in English primary care. An OpenSAFELY-TPP analysis of 20 million adult electronic health records.

AIMS: The COVID-19 pandemic caused significant disruption to routine activity in primary care. Medication reviews are an important primary care activity ensuring safety and appropriateness of prescribing. A disruption could have significant negative implications for patient care. Using routinely collected data, our aim was first to describe codes used to record medication review activity and then to report the impact of COVID-19 on the rates of medication reviews. METHODS: With the approval of NHS England, we conducted a cohort study of 20 million adult patient records in general practice, in-situ using the OpenSAFELY platform. For each month, between April 2019 and March 2022, we report the percentage of patients with a medication review coded monthly and in the previous 12 months with breakdowns by regional, clinical and demographic subgroups and those prescribed high-risk medications. RESULTS: In April 2019, 32.3% of patients had a medication review coded in the previous 12 months. During the first COVID-19 lockdown, monthly activity decreased (-21.1% April 2020), but the 12-month rate was not substantially impacted (-10.5% March 2021). The rate of structured medication review in the last 12 months reached 2.9% by March 2022, with higher percentages in high-risk groups (care home residents 34.1%, age 90+ years 13.1%, high-risk medications 10.2%). The most used medication review code was Medication review done 314530002 (59.5%). CONCLUSIONS: There was a substantial reduction in the monthly rate of medication reviews during the pandemic but rates recovered by the end of the study period. Structured medication reviews were prioritized for high-risk patients.

Inferring condition in wild mammals: body condition indices confer no benefit over measuring body mass across ecological contexts.

Many studies assume that it is beneficial for individuals of a species to be heavier, or have a higher body condition index (BCI), without accounting for the physiological relevance of variation in the composition of different body tissues. We hypothesized that the relationship between BCI and masses of physiologically important tissues (fat and lean) would be conditional on annual patterns of energy acquisition and expenditure. We studied three species with contrasting ecologies in their respective natural ranges: an obligate hibernator (Columbian ground squirrel, Urocitellus columbianus), a facultative hibernator (black-tailed prairie dog, Cynomys ludovicianus), and a food-caching non-hibernator (North American red squirrel, Tamiasciurus hudsonicus). We measured fat and lean mass in adults of both sexes using quantitative magnetic resonance (QMR). We measured body mass and two measures of skeletal structure (zygomatic width and right hind foot length) to develop sex- and species-specific BCIs, and tested the utility of BCI to predict body composition in each species. Body condition indices were more consistently, and more strongly correlated, with lean mass than fat mass. The indices were most positively correlated with fat when fat was expected to be very high (pre-hibernation prairie dogs). In all cases, however, BCI was never better than body mass alone in predicting fat or lean mass. While the accuracy of BCI in estimating fat varied across the natural histories and annual energetic patterns of the species considered, measuring body mass alone was as effective, or superior in capturing sufficient variation in fat and lean in most cases.

OpenSAFELY: A platform for analysing electronic health records designed for reproducible research.

Electronic health records (EHRs) and other administrative health data are increasingly used in research to generate evidence on the effectiveness, safety, and utilisation of medical products and services, and to inform public health guidance and policy. Reproducibility is a fundamental step for research credibility and promotes trust in evidence generated from EHRs. At present, ensuring research using EHRs is reproducible can be challenging for researchers. Research software platforms can provide technical solutions to enhance the reproducibility of research conducted using EHRs. In response to the COVID-19 pandemic, we developed the secure, transparent, analytic open-source software platform OpenSAFELY designed with reproducible research in mind. OpenSAFELY mitigates common barriers to reproducible research by: standardising key workflows around data preparation; removing barriers to code-sharing in secure analysis environments; enforcing public sharing of programming code and codelists; ensuring the same computational environment is used everywhere; integrating new and existing tools that encourage and enable the use of reproducible working practices; and providing an audit trail for all code that is run against the real data to increase transparency. This paper describes OpenSAFELY's reproducibility-by-design approach in detail.

Association between dizziness and future falls and fall-related injuries in older adults: a systematic review and meta-analysis.

BACKGROUND: Dizziness is common in older adults, especially in those attending falls services. Yet, the extent to which dizziness is associated with future falls has not been reviewed. This systematic review and meta-analysis assessed the association between dizziness and future falls and related injuries in older adults. METHODS: EMBASE, CINAHL Plus, SCOPUS and PsycINFO databases were searched from inception to 5 February 2024. The review was registered on PROSPERO (registration ID: CRD42022371839). Meta-analyses were conducted for the associations of dizziness with future falls (including recurrent and injurious falls). Three meta-analyses were performed on different outcomes: any-type falls (≥1 falls), recurrent falls (≥2 falls) and injurious falls. RESULTS: Twenty-nine articles were included in the systematic review (N = 103 306 participants). In a meta-analysis of 14 articles (N = 46 795 participants), dizziness was associated with significantly higher odds of any-type future falls (OR = 1.63, 95% CI = 1.44-1.84). In another meta-analysis involving seven articles (N = 5630 participants), individuals with dizziness also had significantly higher odds of future recurrent falls (OR = 1.98, 95% CI = 1.62-2.42). For both meta-analyses, significant overall associations were observed even when adjusted for important confounding variables. In contrast, a meta-analysis (three articles, N = 46 631 participants) revealed a lack of significant association between dizziness and future injurious falls (OR = 1.12, 95% CI = 0.87-1.45). CONCLUSIONS: Dizziness is an independent predictor of future falls in older adults. These findings emphasise the importance of recognising dizziness as a risk factor for falls and implementing appropriate interventions.

Experiences with home monitoring technology in older adults with traumatic brain injury: a qualitative study.

BACKGROUND: Home monitoring systems utilising artificial intelligence hold promise for digitally enhanced healthcare in older adults. Their real-world use will depend on acceptability to the end user i.e. older adults and caregivers. We explored the experiences of adults over the age of 60 and their social and care networks with a home monitoring system installed on hospital discharge after sustaining a moderate/severe Traumatic Brain Injury (TBI), a growing public health concern. METHODS: A qualitative descriptive approach was taken to explore experiential data from older adults and their caregivers as part of a feasibility study. Semi-structured interviews were conducted with 6 patients and 6 caregivers (N = 12) at 6-month study exit. Data were analysed using Framework analysis. Potential factors affecting acceptability and barriers and facilitators to the use of home monitoring in clinical care and research were examined. RESULTS: Home monitoring was acceptable to older adults with TBI and their caregivers. Facilitators to the use of home monitoring were perceived need for greater support after hospital discharge, the absence of sound and video recording, and the peace of mind provided to care providers. Potential barriers to adoption were reliability, lack of confidence in technology and uncertainty at how data would be acted upon to improve safety at home. CONCLUSIONS: Remote monitoring approaches are likely to be acceptable, especially if patients and caregivers see direct benefit to their care. We identified key barriers and facilitators to the use of home monitoring in older adults who had sustained TBI, which can inform the development of home monitoring for research and clinical use. For sustained use in this demographic the technology should be developed in conjunction with older adults and their social and care networks.

Lawmakers' use of scientific evidence can be improved.

Core to the goal of scientific exploration is the opportunity to guide future decision-making. Yet, elected officials often miss opportunities to use science in their policymaking. This work reports on an experiment with the US Congress-evaluating the effects of a randomized, dual-population (i.e., researchers and congressional offices) outreach model for supporting legislative use of research evidence regarding child and family policy issues. In this experiment, we found that congressional offices randomized to the intervention reported greater value of research for understanding issues than the control group following implementation. More research use was also observed in legislation introduced by the intervention group. Further, we found that researchers randomized to the intervention advanced their own policy knowledge and engagement as well as reported benefits for their research following implementation.

'I only eat because I have to-to live': The impacts of dysphagia on quality of life from the perspectives of people with dysphagia, supporters of people with dysphagia and allied health professionals.

BACKGROUND: A recent literature review identified that past research has described the impacts of dysphagia on quality of life; but there is limited research on these impacts from the perspective of people with dysphagia, their supporters and allied health professionals. Recent qualitative research has provided details about these perspectives, but researchers have also called for verification of these findings with a larger group of participants. AIMS: To expand upon the findings of the prior qualitative research on the views of people with dysphagia, supporters of people with dysphagia, and allied health professionals on the impacts of dysphagia and texture-modified food on quality of life. METHODS & PROCEDURES: An online survey of adults with dysphagia (n = 30), supporters of people with dysphagia (n = 4) and allied health professionals (n = 18) was conducted between November 2021 and February 2022. Categorical questions were analysed descriptively and open-ended questions were analysed for content categories of meaning. OUTCOMES & RESULTS: Participants with dysphagia reported that dysphagia and texture-modified foods had a greater impact on their physical health than on their choice and control or social engagement. Supporters and allied health professionals viewed that dysphagia impacted the physical health and their choice and control of people with dysphagia. Across groups, participants considered that mealtime enjoyment, participation, and inclusion were influenced by the control the person had over their meals, the accessibility of the mealtime environment, and the attitudes of others. CONCLUSIONS & IMPLICATIONS: Dysphagia and its interventions negatively impact quality of life for people with dysphagia. People with dysphagia were the most affected by the physical impacts of dysphagia. Their perspectives contrasted with those of supporters and allied health professionals in some domains, highlighting the need for people with dysphagia to be included in research. Future research exploring how these perspectives are integrated into person-centred dysphagia management is warranted. WHAT THIS PAPER ADDS: What is already known on the subject Recent qualitative research has provided insights into the impacts of dysphagia on quality of life from the perspective of people with dysphagia, supporters of people with dysphagia, and allied health professionals. However, the small scale of these studies means that further research is needed with a larger group of people with dysphagia, supporters of people with dysphagia, and allied health professionals. What this paper adds to existing knowledge This paper verifies and extends upon the findings of prior qualitive research on the views of people with dysphagia, supporters of people with dysphagia, and allied health professionals on the impacts of dysphagia and its interventions on quality of life, participation, and inclusion. What are the potential or actual clinical implications of this work? This research shows the importance of supporters of people with dysphagia and allied health professionals discussing mealtime quality of life with the person with dysphagia so that their perspectives are considered in the mealtime decision-making process. Furthermore, people with dysphagia should be able to specify strategies they want to trial to enhance their mealtime participation and inclusion.

Closing Gaps or Holding Steady? The Affordable Care Act, Medicaid Expansion, & Racial Disparities in Coverage, 2010-2021.

CONTEXT: The Affordable Care Act's (ACA) Medicaid expansion produced major gains in coverage. However, findings on racial and ethnic disparities are mixed and may depend on how disparities are measured. This study examines both absolute and relative changes in uninsurance from 2010-2021 by race and ethnicity, stratified by Medicaid expansion status. METHODS: The sample contained all respondents under age 65 (N = 30,339,104) from the American Community Survey, 2010-2021. Absolute and relative differences in uninsurance, compared to White Non-Hispanic individuals, were calculated for Hispanic; Black; Asian-American, Pacific Islander and Native Hawaiian (AANHPI); American Indian and Alaska Native (AIAN); and multiracial individuals. States were stratified into ever-expanded vs. non-expansion status. FINDINGS: After the ACA, three patterns of coverage disparities emerge. For Hispanic and Black individuals, relative to White individuals, absolute disparities in uninsurance declined but relative disparities were largely unchanged, in both expansion and non-expansion states. For AANHPI individuals, disparities were eliminated entirely in both expansion and non-expansion states. For AIAN individuals, disparities declined in absolute terms but grew in relative terms, particularly in expansion states. CONCLUSIONS: All groups experienced coverage gains post-ACA, but with heterogeneity in changes in disparities. Focused interventions are needed to improve coverage rates for Black, Hispanic, and AIAN individuals.