Supreme Court Brief Amicus Curiae of Administrative Law Scholars in Support of Neither Party

This brief on behalf of 29 administrative law scholars takes no position on whether Administrative Law Judges (ALJs) are employees or inferior officers. It urges the Court to issue an opinion that respects the decision that Congress made unanimously in 1946 to enact numerous statutory safeguards that assure that ALJs have decisional independence from the agencies where they work while assuring that agencies retain control over the policy content and legal basis for any decision made in an adjudication in which an ALJ presides. The brief describes the fifteen years of study and deliberation that led to the unanimous decision of Congress to enact the Administrative Procedure Act (APA) in 1946. It describes the particular attention that Congress devoted to the critical task of providing ALJs with the combination of statutory safeguards that minimize the risk that they will favor the agencies for whom they adjudicate cases while assuring that the agencies retain control of the policy content of any decision made in such an adjudication. It then describes the series of opinions the Supreme Court issued during the 1950s in which the Justices unanimously praised the provisions of the APA that assure that ALJs conduct adjudicatory hearings in an unbiased manner, explained the importance of those statutory provisions in protecting the values reflected in the Due Process Clause, and urged Congress to make those safeguards applicable to all agency adjudications. It concludes by urging the Court to issue an opinion that respects the decision that Congress made in 1946 to insulate ALJs from potential sources of pro-agency bias by including in the APA a combination of provisions that confer decisional independence on ALJs

Premature mortality in people affected by co-occurring homelessness, justice involvement, opioid dependence, and psychosis: a retrospective cohort study using linked administrative data.

BACKGROUND: Homelessness, opioid dependence, justice involvement, and psychosis are each associated with an increased risk of poor health and commonly co-occur in the same individuals. Most existing studies of mortality associated with this co-occurrence rely on active follow-up methods prone to selection and retention bias, and focus on a limited set of specific exposures rather than taking a population-based approach. To address these limitations, we did a retrospective cohort study using linked administrative data. METHODS: In this retrospective cohort study, we linked a population register of adults resident in Glasgow, UK, to administrative datasets from homelessness and criminal justice services; community pharmacies; and a clinical psychosis registry with data from April 1, 2010 to March 31, 2014. Linkage to death registrations from April 1, 2014 to March 31, 2019 provided follow-up data on premature mortality (age <75 years) from all causes, non-communicable diseases, and causes considered potentially avoidable through health-care or public health intervention. We estimated hazard ratios (HR) using Poisson regression, adjusting for age, gender, socioeconomic deprivation, and calendar time. FINDINGS: Of 536 653 cohort members, 11 484 (2·1%) died during follow-up. All-cause premature mortality was significantly higher among people with multiple exposures than among people with single exposures, and among people with any exposure than among people with none (eg, homelessness plus other exposures vs no exposures: HR 8·4 [95% CI 7·3-9·5]; homelessness alone vs no exposures: HR 2·2 [1·9-2·5]). Avoidable premature mortality was highest among those with multiple exposures (eg, imprisonment plus other exposures vs no exposures: HR 10·5 [9·1-12·3]; imprisonment alone vs no exposures: HR 3·8 [3·0-4·8]). Premature mortality from non-communicable disease was higher among those with any exposures than among those with none, despite accounting for a lower proportion of deaths in the exposed group; although in some cases there was little difference between estimates for single versus multiple exposures. INTERPRETATION: The co-occurrence of at least two of homelessness, opioid dependence, justice involvement, or psychosis is associated with very high rates of premature mortality, particularly from avoidable causes of death, including non-communicable disease. Responding to these findings demands wide-ranging efforts across health-care provision, public health, and social policy. Future work should examine the timing and sequencing of exposures to better understand the causal pathways underlying excess mortality

Mutations in CHMP2B in lower motor neuron predominant amyotrophic lateral sclerosis (ALS)

Background: Amyotrophic lateral sclerosis (ALS), a common late-onset neurodegenerative disease, is associated with fronto-temporal dementia (FTD) in 3-10% of patients. A mutation in CHMP2B was recently identified in a Danish pedigree with autosomal dominant FTD. Subsequently, two unrelated patients with familial ALS, one of whom also showed features of FTD, were shown to carry missense mutations in CHMP2B. The initial aim of this study was to determine whether mutations in CHMP2B contribute more broadly to ALS pathogenesis. Methodology/Principal Findings: Sequencing of CHMP2B in 433 ALS cases from the North of England identified 4 cases carrying 3 missense mutations, including one novel mutation, p. Thr104Asn, none of which were present in 500 neurologically normal controls. Analysis of clinical and neuropathological data of these 4 cases showed a phenotype consistent with the lower motor neuron predominant (progressive muscular atrophy (PMA)) variant of ALS. Only one had a recognised family history of ALS and none had clinically apparent dementia. Microarray analysis of motor neurons from CHMP2B cases, compared to controls, showed a distinct gene expression signature with significant differential expression predicting disassembly of cell structure; increased calcium concentration in the ER lumen; decrease in the availability of ATP; down-regulation of the classical and p38 MAPK signalling pathways, reduction in autophagy initiation and a global repression of translation. Transfection of mutant CHMP2B into HEK-293 and COS-7 cells resulted in the formation of large cytoplasmic vacuoles, aberrant lysosomal localisation demonstrated by CD63 staining and impairment of autophagy indicated by increased levels of LC3-II protein. These changes were absent in control cells transfected with wild-type CHMP2B. Conclusions/Significance: We conclude that in a population drawn from North of England pathogenic CHMP2B mutations are found in approximately 1% of cases of ALS and 10% of those with lower motor neuron predominant ALS. We provide a body of evidence indicating the likely pathogenicity of the reported gene alterations. However, absolute confirmation of pathogenicity requires further evidence, including documentation of familial transmission in ALS pedigrees which might be most fruitfully explored in cases with a LMN predominant phenotype

Effect of HSV-1 Infection on the Exercise-induced Mobilization of T-cell Subsets

Acute exercise mobilizes highly-differentiated memory and senescent T-cells into the blood compartment, which could have important implications for post-exercise immune surveillance. This response differs in individuals with latent cytomegalovirus (CMV) infection (a herpesvirus), but it is unknown if other latent herpesviruses, such as herpes simplex virus type 1 (HSV-1), also influence this exercise-induced immune response. As HSV-1 infects 50% of the US population, this could have implications for many athletes. PURPOSE: To examine the effects of an acute bout of exercise on the frequency and relative proportion of naïve, memory, and senescent T-cells in the peripheral blood in HSV-1 infected and non-infected participants. METHODS: Eleven HSV-1-infected and twelve non-infected men (mean±SD: Age: 28±5 yrs; VO2max: 40.64±10.15 ml/kg/min) cycled at 85% of their estimated maximum power for 30 min. Blood samples were collected before and immediately after exercise, and mononuclear cells were isolated using density gradient centrifugation. Cells were labeled with monoclonal antibodies to identify naïve (CD28+CD57-KLRG1- or CD45RA+CCR7+), memory (CD28+CD57-KLRG1+, CD45RA+CCR7-, CD45RA-CCR7+, or CD45RA-CCR7-), and senescent (CD28-CD57+KLRG1+) subsets of CD3+CD4+ and CD3+CD8+ T-cells using four-color flow cytometry. HSV-1 serostatus was determined by an ELISA test. Main effects for exercise and serostatus, and exercise x serostatus interaction effects, were detected using maximum likelihood linear mixed models. RESULTS: A main effect for exercise was found on proportions of naïve (-8.82±8.49%), memory (+35.04±26.48%), and senescent (+64.12±56.12%) CD4+ T-cells, as well as on naïve (-21.02±11.56%) and senescent (+53.89±53.26%) CD8+ T-cells (p\u3c0.05). There were main effects for serostatus on proportions of memory CD4+ and CD8+ T-cells, with decreased levels in HSV-1+ subjects in all memory phenotypes examined (p\u3c0.05). Interaction effects between HSV-1 serostatus and exercise were found. HSV-1+ subjects had lower naïve cell counts, and a greater increase in the proportion of senescent cells, post-exercise (p\u3c0.05) than HSV-1-non-infected subjects. CONCLUSIONS: HSV-1 infection led to a decrease of memory T-cell subsets found in peripheral blood. It also influenced the relative response of naïve and senescent T-cells to acute exercise, although this effect was not nearly as great as that seen with other herpesviruses (i.e. CMV). This indicates that individuals with and without latent HSV-1 infection may have a different lymphocyte mobilization in response to exercise

Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens.

Despite abundant expression of DNA methyltransferases (Dnmts) in brain, the regulation and behavioral role of DNA methylation remain poorly understood. We found that Dnmt3a expression was regulated in mouse nucleus accumbens (NAc) by chronic cocaine use and chronic social defeat stress. Moreover, NAc-specific manipulations that block DNA methylation potentiated cocaine reward and exerted antidepressant-like effects, whereas NAc-specific Dnmt3a overexpression attenuated cocaine reward and was pro-depressant. On a cellular level, we found that chronic cocaine use selectively increased thin dendritic spines on NAc neurons and that DNA methylation was both necessary and sufficient to mediate these effects. These data establish the importance of Dnmt3a in the NAc in regulating cellular and behavioral plasticity to emotional stimuli

Structural divergence creates new functional features in alphavirus genomes

Alphaviruses are mosquito-borne pathogens that cause human diseases ranging from debilitating arthritis to lethal encephalitis. Studies with Sindbis virus (SINV), which causes fever, rash, and arthralgia in humans, and Venezuelan equine encephalitis virus (VEEV), which causes encephalitis, have identified RNA structural elements that play key roles in replication and pathogenesis. However, a complete genomic structural profile has not been established for these viruses. We used the structural probing technique SHAPE-MaP to identify structured elements within the SINV and VEEV genomes. Our SHAPE-directed structural models recapitulate known RNA structures, while also identifying novel structural elements, including a new functional element in the nsP1 region of SINV whose disruption causes a defect in infectivity. Although RNA structural elements are important for multiple aspects of alphavirus biology, we found the majority of RNA structures were not conserved between SINV and VEEV. Our data suggest that alphavirus RNA genomes are highly divergent structurally despite similar genomic architecture and sequence conservation; still, RNA structural elements are critical to the viral life cycle. These findings reframe traditional assumptions about RNA structure and evolution: rather than structures being conserved, alphaviruses frequently evolve new structures that may shape interactions with host immune systems or co-evolve with viral proteins

Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis

The finding of TDP-43 as a major component of ubiquitinated protein inclusions in amyotrophic lateral sclerosis (ALS) has led to the identification of 30 mutations in the transactive response-DNA binding protein (TARDBP) gene, encoding TDP-43. All but one are in exon 6, which encodes the glycine-rich domain. The aim of this study was to determine the frequency of TARDBP mutations in a large cohort of motor neurone disease patients from Northern England (42 non-superoxide dismutase 1 (SOD1) familial ALS (FALS), nine ALS-frontotemporal dementia, 474 sporadic ALS (SALS), 45 progressive muscular atrophy cases). We identified four mutations, two of which were novel, in two familial (FALS) and two sporadic (SALS) cases, giving a frequency of TARDBP mutations in non-SOD1 FALS of 5% and SALS of 0.4%. Analysis of clinical data identified that patients had typical ALS, with limb or bulbar onset, and showed considerable variation in age of onset and rapidity of disease course. However, all cases had an absence of clinically overt cognitive dysfunction

Assessing Individuals’ Exposure to Environmental Conditions Using Residence-Based Measures, Activity Location-Based Measures, and Activity Path-Based Measures

Background: Many approaches are available to researchers who wish to measure individuals' exposure to environmental conditions. Different approaches may yield different estimates of associations with health outcomes. Taking adolescents' exposure to alcohol outlets as an example, we aimed to (1) compare exposure measures and (2) assess whether exposure measures were differentially associated with alcohol consumption. Methods: We tracked 231 adolescents 14-16 years of age from the San Francisco Bay Area for 4 weeks in 2015/2016 using global positioning systems (GPS). Participants were texted ecologic momentary assessment surveys six times per week, including assessment of alcohol consumption. We used GPS data to calculate exposure to alcohol outlets using three approach types: residence-based (e.g., within the home census tract), activity location-based (e.g., within buffer distances of frequently attended places), and activity path-based (e.g., average outlets per hour within buffer distances of GPS route lines). Spearman correlations compared exposure measures, and separate Tobit models assessed associations with the proportion of ecologic momentary assessment responses positive for alcohol consumption. Results: Measures were mostly strongly correlated within approach types (ρ ≥ 0.7), but weakly (ρ < 0.3) to moderately (0.3 ≤ ρ < 0.7) correlated between approach types. Associations with alcohol consumption were mostly inconsistent within and between approach types. Some of the residence-based measures (e.g., census tract: β = 8.3, 95% CI = 2.8, 13.8), none of the activity location-based approaches, and most of the activity path-based approaches (e.g., outlet-hours per hour, 100 m buffer: β = 8.3, 95% CI = 3.3, 13.3) were associated with alcohol consumption. Conclusions: Methodologic decisions regarding measurement of exposure to environmental conditions may affect study results