Association Between State Policies Using Medicaid Exclusions to Sanction Noncompliance With Welfare Work Requirements and Medicaid Participation Among Low-Income Adults

Twenty states have pursued community engagement requirements (ie, work requirements) as a condition for Medicaid eligibility among adults considered able-bodied. Work requirements seek to improve health by incentivizing work, but may result in coverage losses. The impact of work requirements on Medicaid coverage may extend beyond qualifying beneficiaries, by increasing confusion around benefit rules or deterring individuals from applying for coverage. However, the spillover effects of work requirements on individuals not directly subject to them are difficult to study because these programs have only recently been implemented. To examine this possibility, we studied Temporary Assistance for Needy Families (TANF), the cash welfare program enacted under welfare reform in 1996. The TANF program requires able-bodied beneficiaries to fulfill work requirements, and states can elect to terminate Medicaid benefits as a sanction for nonpregnant adult TANF participants who do not comply with them. In states adopting these sanctions, Medicaid eligibility for dual TANF-Medicaid enrollees was effectively conditional on meeting work requirements. This quasi-experimental cohort study examines whether TANF-Medicaid sanctions had spillover effects on Medicaid coverage among low-income adults who were not likely to participate in TANF and, therefore, were not directly subject to these sanctions

The Embryonic Transcriptome Of The Red-Eared Slider Turtle (Trachemys Scripta)

The bony shell of the turtle is an evolutionary novelty not found in any other group of animals, however, research into its formation has suggested that it has evolved through modification of conserved developmental mechanisms. Although these mechanisms have been extensively characterized in model organisms, the tools for characterizing them in non-model organisms such as turtles have been limited by a lack of genomic resources. We have used a next generation sequencing approach to generate and assemble a transcriptome from stage 14 and 17 Trachemys scripta embryos, stages during which important events in shell development are known to take place. The transcriptome consists of 231,876 sequences with an N-50 of 1,166 bp. GO terms and EC codes were assigned to the 61,643 unique predicted proteins identified in the transcriptome sequences. All major GO categories and metabolic pathways are represented in the transcriptome. Transcriptome sequences were used to amplify several cDNA fragments designed for use as RNA in situ probes. One of these, BMP5, was hybridized to a T. scripta embryo and exhibits both conserved and novel expression patterns. The transcriptome sequences should be of broad use for understanding the evolution and development of the turtle shell and for annotating any future T. scripta genome sequences

Identification of Functional Networks of Estrogen- and c-Myc-Responsive Genes and Their Relationship to Response to Tamoxifen Therapy in Breast Cancer

BACKGROUND: Estrogen is a pivotal regulator of cell proliferation in the normal breast and breast cancer. Endocrine therapies targeting the estrogen receptor are effective in breast cancer, but their success is limited by intrinsic and acquired resistance. METHODOLOGY/PRINCIPAL FINDINGS: With the goal of gaining mechanistic insights into estrogen action and endocrine resistance, we classified estrogen-regulated genes by function, and determined the relationship between functionally-related genesets and the response to tamoxifen in breast cancer patients. Estrogen-responsive genes were identified by transcript profiling of MCF-7 breast cancer cells. Pathway analysis based on functional annotation of these estrogen-regulated genes identified gene signatures with known or predicted roles in cell cycle control, cell growth (i.e. ribosome biogenesis and protein synthesis), cell death/survival signaling and transcriptional regulation. Since inducible expression of c-Myc in antiestrogen-arrested cells can recapitulate many of the effects of estrogen on molecular endpoints related to cell cycle progression, the estrogen-regulated genes that were also targets of c-Myc were identified using cells inducibly expressing c-Myc. Selected genes classified as estrogen and c-Myc targets displayed similar levels of regulation by estrogen and c-Myc and were not estrogen-regulated in the presence of siMyc. Genes regulated by c-Myc accounted for 50% of all acutely estrogen-regulated genes but comprised 85% (110/129 genes) in the cell growth signature. siRNA-mediated inhibition of c-Myc induction impaired estrogen regulation of ribosome biogenesis and protein synthesis, consistent with the prediction that estrogen regulates cell growth principally via c-Myc. The 'cell cycle', 'cell growth' and 'cell death' gene signatures each identified patients with an attenuated response in a cohort of 246 tamoxifen-treated patients. In multivariate analysis the cell death signature was predictive independent of the cell cycle and cell growth signatures. CONCLUSIONS/SIGNIFICANCE: These functionally-based gene signatures can stratify patients treated with tamoxifen into groups with differing outcome, and potentially identify distinct mechanisms of tamoxifen resistance

An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge

There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. RESULTS: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. CONCLUSIONS: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups

Molecular basis of USP7 inhibition by selective small-molecule inhibitors

Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells. Co-crystal structures reveal that both compounds target a dynamic pocket near the catalytic centre of the auto-inhibited apo form of USP7, which differs from other USP deubiquitinases. Consistent with USP7 target engagement in cells, FT671 destabilizes USP7 substrates including MDM2, increases levels of p53, and results in the transcription of p53 target genes, induction of the tumour suppressor p21, and inhibition of tumour growth in mice

Routine child immunizations in India during the COVID-19 pandemic

Disruptions in health service delivery and utilization during the COVID-19 pandemic may have caused many children worldwide to not receive vital preventative health services. We investigate the pandemic’s effects on routine childhood vaccinations in India, which has the world’s largest child immunization program. Using data from the Government of India’s health management information system and interrupted time series analyses, we estimate district-level changes in routine child vaccinations during the pandemic relative to typical monthly vaccinations in the pre-pandemic period. Our results indicate there were significant reductions in child vaccinations during the pandemic, with declines being extremely large in April 2020 when a strict national lockdown was in place. For example, district-level administration of the final required dose in the polio series declined by about 60% in April 2020 relative to the typical monthly vaccination levels observed prior to the pandemic. Vaccinations subsequently increased but largely remained below levels observed before the outbreak of COVID-19. Additional declines in vaccinations occurred in 2021 during the second wave of COVID-19 infections in India. Heterogeneity analyses suggest that vaccinations declined the most in districts with the strictest lockdowns and in districts with low health system capacity at baseline. There is a vital need for corrective actions, such as catch-up vaccination campaigns, to limit the deleterious consequences that will arise for the children who missed routine immunizations during the COVID-19 pandemic

Death by Robots? Automation and Working-Age Mortality in the United States

The decline of manufacturing employment is frequently invoked as a key cause of worsening U.S. population health trends, including rising mortality due to “deaths of despair.” Increasing automation—the use of industrial robots to perform tasks previously done by human workers—is one structural force driving the decline of manufacturing jobs and wages. In this study, we examine the impact of automation on age- and sex-specific mortality. Using exogenous variation in automation to support causal inference, we find that increases in automation over the period 1993–2007 led to substantive increases in all-cause mortality for both men and women aged 45–54. Disaggregating by cause, we find evidence that automation is associated with increases in drug overdose deaths, suicide, homicide, and cardiovascular mortality, although patterns differ by age and sex. We further examine heterogeneity in effects by safety net program generosity, labor market policies, and the supply of prescription opioids

Association Between State Policies Using Medicaid Exclusions to Sanction Noncompliance With Welfare Work Requirements and Medicaid Participation Among Low-Income Adults

Twenty states have pursued community engagement requirements (ie, work requirements) as a condition for Medicaid eligibility among adults considered able-bodied. Work requirements seek to improve health by incentivizing work, but may result in coverage losses. The impact of work requirements on Medicaid coverage may extend beyond qualifying beneficiaries, by increasing confusion around benefit rules or deterring individuals from applying for coverage. However, the spillover effects of work requirements on individuals not directly subject to them are difficult to study because these programs have only recently been implemented. To examine this possibility, we studied Temporary Assistance for Needy Families (TANF), the cash welfare program enacted under welfare reform in 1996. The TANF program requires able-bodied beneficiaries to fulfill work requirements, and states can elect to terminate Medicaid benefits as a sanction for nonpregnant adult TANF participants who do not comply with them. In states adopting these sanctions, Medicaid eligibility for dual TANF-Medicaid enrollees was effectively conditional on meeting work requirements. This quasi-experimental cohort study examines whether TANF-Medicaid sanctions had spillover effects on Medicaid coverage among low-income adults who were not likely to participate in TANF and, therefore, were not directly subject to these sanctions

Assessment of Medicaid Beneficiaries Included in Community Engagement Requirements in Kentucky

States are pursuing Section 1115 Medicaid demonstration waiver authority to apply community engagement (CE) requirements (eg, participation in work, volunteer activities, or training) to beneficiaries deemed able-bodied as a condition of coverage. Understanding the size and characteristics of the populations included in these requirements can help inform policy initiatives and anticipate effects

Assessment of Medicaid Beneficiaries Included in Community Engagement Requirements in Kentucky

States are pursuing Section 1115 Medicaid demonstration waiver authority to apply community engagement (CE) requirements (eg, participation in work, volunteer activities, or training) to beneficiaries deemed able-bodied as a condition of coverage. Understanding the size and characteristics of the populations included in these requirements can help inform policy initiatives and anticipate effects