Securing Our Economic Future

The American economy is in the midst of a wrenching crisis, one caused by the COVID-19 pandemic and aggravated further by a series of climate-driven natural disasters. While the economy has made some steps towards recovery, the pandemic has laid bare the reality that too many Americans are unable to meet many of their urgent and basic needs. At the same time, it has become painfully clear that American society is not equipped to deal with the risks emerging from our changing climate. This book is a contribution towards policy options for addressing these challenges. Although it was largely written before the pandemic crises beset our country, the analyses, diagnoses, and prescriptions contained within all shed new light on the underlying fragilities that have since been exposed. The volume is composed of nine commissioned chapters and is divided into three sections, covering the 'Economics of the American Middle Class'; the 'Geographic Disparities in Economic Opportunity'; and the 'Geopolitics of the Climate and Energy Challenge and the US Policy Response.' Part I focuses on the economic wellbeing of the American middle class and the chapters in this section evaluate the prevailing narrative of its decline. The chapters in part II investigate the large variation in income and economic opportunities across places, and include a specific policy proposal for emergency rental assistance. Part III is devoted to the global climate crisis. The chapters in this final section emphasize the mounting social and economic costs of inaction and discuss potential policy approaches for tackling the climate challenge

De novo point mutations in patients diagnosed with ataxic cerebral palsy

Cerebral palsy is a sporadic disorder with multiple likely aetiologies, but frequently considered to be caused by birth asphyxia. Genetic investigations are rarely performed in patients with cerebral palsy and there is little proven evidence of genetic causes. As part of a large project investigating children with ataxia, we identified four patients in our cohort with a diagnosis of ataxic cerebral palsy. They were investigated using either targeted next generation sequencing or trio-based exome sequencing and were found to have mutations in three different genes, KCNC3, ITPR1 and SPTBN2. All the mutations were de novo and associated with increased paternal age. The mutations were shown to be pathogenic using a combination of bioinformatics analysis and in vitro model systems. This work is the first to report that the ataxic subtype of cerebral palsy can be caused by de novo dominant point mutations, which explains the sporadic nature of these cases. We conclude that at least some subtypes of cerebral palsy may be caused by de novo genetic mutations and patients with a clinical diagnosis of cerebral palsy should be genetically investigated before causation is ascribed to perinatal asphyxia or other aetiologies.peer-reviewe

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Space and Poverty: The Effect of Concentrated Poverty on Employment in Large Urban Areas

From 1970 to 1980, the percent of poor living in high poverty census tracts (poverty rates of forty percent or greater) increased by 27 percent (Jargowsky and Bane, 1991). This increase in the concentration of poverty has occurred almost exclusively in large urban areas and among minorities (Massey and Eggers, 1989). For minority poor living in such areas, the 'area-poverty' experienced by the poor has increased quite dramatically. A greater proportion of the people with whom poor residents come into contact are also poor; fewer are nonpoor. If living in such areas of concentrated poverty affects the chances of escaping poverty, then this increase has profound social and policy implications.In the following, we refer to the impact of the spatial concentration of poverty on the life chances of the poor as a "concentration effect." This paper is an empirical exploration of the presence and magnitude of a concentration effect on employment

Teenage Employment and the Spatial Isolation of Minority and Poverty Households

Using micro data from the US Census, this paper tests the importance of the spatial isolation of minority and poverty households for youth employment in the largest US metropolitan areas. We first estimate a model relating youth employment probabilities to individual and family characteristics, race, and metropolitan location. We then investigate the determinants of the systematic differences in employment probabilities by race and metropolitan area. We find that a substantial fraction of differences in youth employment can be attributed to the isolation of minorities and poor households. Minority youth residing in cities in which minorities are more segregated or in which minorities have less contact with non-poor household have lower employment probabilities than otherwise identical youth living in similar but less segregated metropolitan areas. Simulations suggest that the magnitude of these spatial effects is not small. It may explain a substantial fraction of the existing differences in youth employment rates for white, black, and hispanic youth

Where Youth Live: Economic Effects of Urban Space on Employment Prospects

This paper summarizes and synthesizes a series of empirical analyses investigating the role of urban space in affecting minority employment outcomes. It adds to the considerable (but inconclusive) literature by broadening the focus beyond transportation and the “friction of space,” and by expanding the data available for spatial research. The empirical analyses share a common framework linking “access” to youth labor market performance. The first set of results is based on aggregate data relating access to employment outcomes for black youth at the metropolitan level. Access is broadly defined to include traditional measures of geographic distance, as well as measures of social isolation or social access. Metropolitan areas in which the black poor are more spatially isolated are also found to have higher black youth unemployment rates. The second body of evidence relies on the same type of metropolitan measures, combined with individual data on youth living with at least one parent. When individual and family characteristics are controlled for, and white and Hispanic youth are also considered, metropolitan measures of social access exert distinguishable effects upon youth employment -- youth living in urban areas in which they have less residential contact with whites or the non poor are less likely to be employed. The final piece of analysis links the individual records of such youth to tract level measures of access, both social (neighborhood composition variables) and geographic (job access measures). This is accomplished through the creation of a unique data set at the Bureau of the Census. Again, after controlling for individual and family characteristics, the residential conditions of youth affect their employment. Ceteris paribus, youth living in census tracts with fewer employed adults, with fewer whites, and which are further from jobs are less likely to be employed. Results suggest that the overall effects of space on employment outcomes are substantial, explaining between ten and forty percent of the observed racial differences in employment in four urban areas examined. Of this “spatial” effect, the bulk arises from social/informational measures; job access appears to play a much smaller role. However, when measured more precisely, at the census tract level, job access does have a significant effect on youth employment. This effect is less important than other spatial influences. Spatial influences are less important in explaining outcomes than are differences in human capital