Whole-genome functional characterization of RE1 silencers using a modified massively parallel reporter assay.

Transcriptional silencers are under- studied compared with activating elements. By using MPRAduo, Mouri et al. perform a whole-genome functional characterization screen of RE1 silencers and identify REST-binding motif characteristics and cofactor localization required for a functional silencer. They also identify human genetic variants that impact RE1 activity

Functional characterization of T2D-associated SNP effects on baseline and ER stress-responsive β cell transcriptional activation.

Genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs) at \u3e250 loci in the human genome to type 2 diabetes (T2D) risk. For each locus, identifying the functional variant(s) among multiple SNPs in high linkage disequilibrium is critical to understand molecular mechanisms underlying T2D genetic risk. Using massively parallel reporter assays (MPRA), we test the cis-regulatory effects of SNPs associated with T2D and altered in vivo islet chromatin accessibility in MIN6 β cells under steady state and pathophysiologic endoplasmic reticulum (ER) stress conditions. We identify 1,982/6,621 (29.9%) SNP-containing elements that activate transcription in MIN6 and 879 SNP alleles that modulate MPRA activity. Multiple T2D-associated SNPs alter the activity of short interspersed nuclear element (SINE)-containing elements that are strongly induced by ER stress. We identify 220 functional variants at 104 T2D association signals, narrowing 54 signals to a single candidate SNP. Together, this study identifies elements driving β cell steady state and ER stress-responsive transcriptional activation, nominates causal T2D SNPs, and uncovers potential roles for repetitive elements in β cell transcriptional stress response and T2D genetics

Implementing goals of care conversations with veterans in VA long-term care setting: a mixed methods protocol

Abstract Background The program “Implementing Goals of Care Conversations with Veterans in VA LTC Settings” is proposed in partnership with the US Veterans Health Administration (VA) National Center for Ethics in Health Care and the Geriatrics and Extended Care Program Offices, together with the VA Office of Nursing Services. The three projects in this program are designed to support a new system-wide mandate requiring providers to conduct and systematically record conversations with veterans about their preferences for care, particularly life-sustaining treatments. These treatments include cardiac resuscitation, mechanical ventilation, and other forms of life support. However, veteran preferences for care go beyond whether or not they receive life-sustaining treatments to include issues such as whether or not they want to be hospitalized if they are acutely ill, and what kinds of comfort care they would like to receive. Methods Three projects, all focused on improving the provision of veteran-centered care, are proposed. The projects will be conducted in Community Living Centers (VA-owned nursing homes) and VA Home-Based Primary Care programs in five regional networks in the Veterans Health Administration. In all the projects, we will use data from context and barrier and facilitator assessments to design feedback reports for staff to help them understand how well they are meeting the requirement to have conversations with veterans about their preferences and to document them appropriately. We will also use learning collaboratives—meetings in which staff teams come together and problem-solve issues they encounter in how to get veterans’ preferences expressed and documented, and acted on—to support action planning to improve performance. Discussion We will use data over time to track implementation success, measured as the proportions of veterans in Community Living Centers (CLCs) and Home-Based Primary Care (HBPC) who have a documented goals of care conversation soon after admission. We will work with our operational partners to spread approaches that work throughout the Veterans Health Administration.http://deepblue.lib.umich.edu/bitstream/2027.42/134645/1/13012_2016_Article_497.pd

Correction to: Implementing goals of care conversations with veterans in VA long-term care setting: a mixed methods protocol

Correction The authors would like to correct errors in the original article [1] that may have lead readers to misinterpret the scope, evidence base and target population of VHA Handbook 1004.03 “Life-Sustaining Treatment (LST) Decisions: Eliciting, Documenting, and Honoring Patients’ Values, Goals, and Preferences”.https://deepblue.lib.umich.edu/bitstream/2027.42/142349/1/13012_2018_Article_724.pd

Comparative Transmissibility of SARS-CoV-2 Variants Delta and Alpha in New England, USA

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant quickly rose to dominance in mid-2021, displacing other variants, including Alpha. Studies using data from the United Kingdom and India estimated that Delta was 40-80% more transmissible than Alpha, allowing Delta to become the globally dominant variant. However, it was unclear if the ostensible difference in relative transmissibility was due mostly to innate properties of Delta\u27s infectiousness or differences in the study populations. To investigate, we formed a partnership with SARS-CoV-2 genomic surveillance programs from all six New England US states. By comparing logistic growth rates, we found that Delta emerged 37-163% faster than Alpha in early 2021 (37% Massachusetts, 75% New Hampshire, 95% Maine, 98% Rhode Island, 151% Connecticut, and 163% Vermont). We next computed variant-specific effective reproductive numbers and estimated that Delta was 58-120% more transmissible than Alpha across New England (58% New Hampshire, 68% Massachusetts, 76% Connecticut, 85% Rhode Island, 98% Maine, and 120% Vermont). Finally, using RT-PCR data, we estimated that Delta infections generate on average ∼6 times more viral RNA copies per mL than Alpha infections. Overall, our evidence indicates that Delta\u27s enhanced transmissibility could be attributed to its innate ability to increase infectiousness, but its epidemiological dynamics may vary depending on the underlying immunity and behavior of distinct populations

Comparative transmissibility of SARS-CoV-2 variants Delta and Alpha in New England, USA.

The SARS-CoV-2 Delta variant rose to dominance in mid-2021, likely propelled by an estimated 40%-80% increased transmissibility over Alpha. To investigate if this ostensible difference in transmissibility is uniform across populations, we partner with public health programs from all six states in New England in the United States. We compare logistic growth rates during each variant\u27s respective emergence period, finding that Delta emerged 1.37-2.63 times faster than Alpha (range across states). We compute variant-specific effective reproductive numbers, estimating that Delta is 63%-167% more transmissible than Alpha (range across states). Finally, we estimate that Delta infections generate on average 6.2 (95% CI 3.1-10.9) times more viral RNA copies per milliliter than Alpha infections during their respective emergence. Overall, our evidence suggests that Delta\u27s enhanced transmissibility can be attributed to its innate ability to increase infectiousness, but its epidemiological dynamics may vary depending on underlying population attributes and sequencing data availability

Genome-wide association study identifies human genetic variants associated with fatal outcome from Lassa fever

Infection with Lassa virus (LASV) can cause Lassa fever, a haemorrhagic illness with an estimated fatality rate of 29.7%, but causes no or mild symptoms in many individuals. Here, to investigate whether human genetic variation underlies the heterogeneity of LASV infection, we carried out genome-wide association studies (GWAS) as well as seroprevalence surveys, human leukocyte antigen typing and high-throughput variant functional characterization assays. We analysed Lassa fever susceptibility and fatal outcomes in 533 cases of Lassa fever and 1,986 population controls recruited over a 7 year period in Nigeria and Sierra Leone. We detected genome-wide significant variant associations with Lassa fever fatal outcomes near GRM7 and LIF in the Nigerian cohort. We also show that a haplotype bearing signatures of positive selection and overlapping LARGE1, a required LASV entry factor, is associated with decreased risk of Lassa fever in the Nigerian cohort but not in the Sierra Leone cohort. Overall, we identified variants and genes that may impact the risk of severe Lassa fever, demonstrating how GWAS can provide insight into viral pathogenesis