Site-Specific Silencing of Regulatory Elements as a Mechanism of X Inactivation

The inactive X chromosome’s (Xi) physical territory is microscopically devoid of transcriptional hallmarks and enriched in silencing-associated modifications. How these microscopic signatures relate to specific Xi sequence is unknown. Therefore, we profiled Xi gene expression and chromatin states at high resolution via allele-specific sequencing in mouse trophoblast stem cells. Most notably, X-inactivated transcription start sites harbored distinct epigenetic signatures relative to surrounding Xi DNA. These sites displayed H3-lysine27-trimethylation enrichment and DNaseI hypersensitivity, similar to autosomal Polycomb targets, yet excluded Pol II and other transcriptional hallmarks, similar to non-transcribed genes. CTCF bound X-inactivated and escaping genes, irrespective of measured chromatin boundaries. Escape from X-inactivation occurred within, and X-inactivation was maintained exterior to, the area encompassed by Xist in cells subject to imprinted and random X-inactivation. The data support a model whereby inactivation of specific regulatory elements, rather than a simple chromosome-wide separation from transcription machinery, governs gene silencing over the Xi

Tsx Produces a Long Noncoding RNA and Has General Functions in the Germline, Stem Cells, and Brain

The Tsx gene resides at the X-inactivation center and is thought to encode a protein expressed in testis, but its function has remained mysterious. Given its proximity to noncoding genes that regulate X-inactivation, here we characterize Tsx and determine its function in mice. We find that Tsx is actually noncoding and the long transcript is expressed robustly in meiotic germ cells, embryonic stem cells, and brain. Targeted deletion of Tsx generates viable offspring and X-inactivation is only mildly affected in embryonic stem cells. However, mutant embryonic stem cells are severely growth-retarded, differentiate poorly, and show elevated cell death. Furthermore, male mice have smaller testes resulting from pachytene-specific apoptosis and a maternal-specific effect results in slightly smaller litters. Intriguingly, male mice lacking Tsx are less fearful and have measurably enhanced hippocampal short-term memory. Combined, our study indicates that Tsx performs general functions in multiple cell types and links the noncoding locus to stem and germ cell development, learning, and behavior in mammals

Optimal tax policy and expected longevity: a mean and variance approach

This paper studies the normative problem of redistribution between agents who can influence their survival probability through private health spending, but who differ in their attitude towards the risks involved in the lotteries of life to be chosen. For that purpose, we develop a two-period model where agents's preferences on lotteries of life can be represented by a mean and variance utility function allowing, unlike the expected utility form, some – agent-specific – sensitivity to what Allais (1953) calls the 'dispersion of psychological values'. It is shown that if agents ignore the impact of their health expenditures on the return of their savings, the decentralization of the first-best optimum requires not only intergroup lump-sum transfers, but, also, group-specific taxes on health spending. Under asymmetric information, we find that a subsidy on savings is optimal, whereas group-specific taxes on health spending are of ambiguous signs

Clinical characteristics of Aboriginal and Torres Strait Islander emergency department patients with suspected acute coronary syndrome

Objectives: To describe the demographics, presentation characteristics, clinical features and cardiac outcomes for Aboriginal and Torres Strait Islander patients who present to a regional cardiac referral centre ED with suspected acute coronary syndrome (ACS). Methods: This was a single-centre observational study conducted at a regional referral hospital in Far North Queensland, Australia from November 2017 to September 2018 and January 2019 to December 2019. Study participants were 278 Aboriginal and Torres Strait Islander people presenting to an ED and investigated for suspected ACS. The main outcome measure was the proportion of patients with ACS at index presentation and differences in characteristics between those with and without ACS. Results: ACS at presentation was diagnosed in 38.1% of patients (n = 106). The mean age of patients with ACS was 53.5 years (SD 9.5) compared with 48.7 years (SD 12.1) in those without ACS (P = 0.001). Patients with ACS were more likely to be male (63.2% vs 39.0%, P < 0.001), smokers (70.6% vs 52.3%, P = 0.002), have diabetes (56.6% vs 38.4%, P = 0.003) and have renal impairment (24.5% vs 10.5%, P = 0.002). Conclusions: Aboriginal and Torres Strait Islander patients with suspected ACS have a high burden of traditional cardiac risk factors, regardless of whether they are eventually diagnosed with ACS. These patients may benefit from assessment for coronary artery disease regardless of age at presentation.</p

BIOSOLVE-IV-registry: Safety and performance of the Magmaris scaffold: 12-month outcomes of the first cohort of 1,075 patients

OBJECTIVES: We aimed to assess the safety and performance of the Magmaris sirolimus-eluting bioresorbable magnesium scaffold in a large patient population. BACKGROUND: Magmaris has shown good outcomes in small-sized controlled trials, but further data are needed to confirm its usability, safety, and performance. METHODS: BIOSOLVE-IV is an international, single arm, multicenter registry including patients with a maximum of two single de novo lesions. Follow-up is scheduled up to 5 years; the primary outcome is target lesion failure (TLF) at 12 months. RESULTS: A total of 1,075 patients with 1,121 lesions were enrolled. Mean patient age was 61.3 ± 10.5 years and 19.2% (n = 206) presented with non-ST-elevation myocardial infarction (NSTEMI). Lesions were 3.2 ± 0.3 mm in diameter and 14.9 ± 4.2 mm long; 5.1% (n = 57) were bifurcation lesions. Device success was 97.3% (n = 1,129) and procedure success 98.9% (n = 1,063). The Kaplan-Meier estimate of TLF at 12 months was 4.3% [95% confidence interval, CI: 3.2, 5.7] consisting of 3.9% target lesion revascularizations, 0.2% cardiac death, and 1.1% target-vessel myocardial infarction. Definite/probable scaffold thrombosis occurred in five patients (0.5% [95% CI: 0.2, 1.1]), thereof four after early discontinuation of antiplatelet/anticoagulation therapy. CONCLUSION: BIOSOLVE-IV confirms the safety and performance of the Magmaris scaffold in a large population with excellent device and procedure success and a very good safety profile up to 12 months in a low-risk population.status: publishe

I-PASS Mentored Implementation Handoff Curriculum: Implementation Guide and Resources

IntroductionCommunication failures during shift-to-shift handoffs of patient care have been identified as a leading cause of adverse events in health care institutions. The I-PASS Handoff Program is a comprehensive handoff program that has been shown to decrease rates of medical errors and adverse events. As part of the spread and adaptation of this program, a comprehensive implementation guide was created to assist individuals in the implementation process.MethodsThe I-PASS Mentored Implementation Guide grew out of materials created for the original I-PASS Study, Society of Hospital Medicine (SHM) mentored implementation programs, and the experience of members of the I-PASS Study Group. The guide provides a comprehensive framework of all elements required to implement the large-scale I-PASS Handoff Program and contains detailed information on generating institutional support, training activities, a campaign, measuring impact, and sustaining the program.ResultsThirty-two sites across North America utilized the guide as part of the SHM program. The guide served as a main reference for 477 hours of mentoring phone calls between site leads and their mentors. Postprogram surveys from wave 2 sites revealed that 85% (N = 34) of respondents felt the quality of the guide was very good/excellent. Site leads noted that they referenced the guide most often during the early part of the program and that they referenced the sections on the curriculum and handoff observations most often.DiscussionThe I-PASS Mentored Implementation Guide is an essential resource for those looking to implement the large-scale I-PASS Handoff Program at their institution