Spt6 directly interacts with Cdc73 and is required for Paf1 complex occupancy at active genes in Saccharomyces cerevisiae.

The Paf1 complex (Paf1C) is a conserved transcription elongation factor that regulates transcription elongation efficiency, facilitates co-transcriptional histone modifications, and impacts molecular processes linked to RNA synthesis, such as polyA site selection. Coupling of the activities of Paf1C to transcription elongation requires its association with RNA polymerase II (Pol II). Mutational studies in yeast identified Paf1C subunits Cdc73 and Rtf1 as important mediators of Paf1C association with Pol II on active genes. While the interaction between Rtf1 and the general elongation factor Spt5 is relatively well-understood, the interactions involving Cdc73 have not been fully elucidated. Using a site-specific protein cross-linking strategy in yeast cells, we identified direct interactions between Cdc73 and two components of the Pol II elongation complex, the elongation factor Spt6 and the largest subunit of Pol II. Both of these interactions require the tandem SH2 domain of Spt6. We also show that Cdc73 and Spt6 can interact in vitro and that rapid depletion of Spt6 dissociates Paf1 from chromatin, altering patterns of Paf1C-dependent histone modifications genome-wide. These results reveal interactions between Cdc73 and the Pol II elongation complex and identify Spt6 as a key factor contributing to the occupancy of Paf1C at active genes in Saccharomyces cerevisiae.

Black-White variation in the relationship between early educational experiences and trajectories of cognitive function among US-born older adults.

Black adults face a substantially higher risk for dementia in later life compared to their White peers. Given the critical role of educational attainment and cognitive function in later life dementia risk, this paper aims to determine if early educational experiences and educational attainment are differentially related to trajectories of cognitive status across race and if this further varies by education cohort. We use data from the Life History Mail Survey (LHMS) and prospective data on cognition from the Health and Retirement Study (HRS). We restrict our sample to Black and White US-born adults who provided at least one measure of cognitive status from 1995/6-2016. We find evidence of Black-White differences in the association between educational experiences and level of cognitive function, episodic memory, and working memory, but little evidence of Black-White differences in these associations with decline. Having a learning problem was associated with lower levels of cognitive function, episodic memory, and working memory for White and Black older adults, but was more strongly related to these outcomes among Black older adults. Further, the Black-White difference in this association was generally found in older cohorts that completed schooling after enactment of federal policies that improved educational resources for children with learning disabilities. Attending racially discordant schools was positively associated with level of these cognitive outcomes for Black older adults but not for White older adults. We also find that the educational gradient in level of cognitive function was larger for Black compared to White older adults in older cohorts not benefiting from the Brown v Board of Education decision but was similar for Black and White older adults attending school in the post-Brown era.

The organizational trauma-informed practices tool (O-TIPs): Development and preliminary validation.

The goal of the study was to develop and validate a simple, short, easy to self-administer, and cost-effective tool to assess organizational trauma-informed practices (O-TIPs), by building on existing tools. The tool was developed through a series of steps involving detailed examination, selection, and modification of existing trauma-informed (TI) frameworks and tools, which resulted in a 31-item questionnaire with three domains and eight subscales. The O-TIPs was evaluated for known-group construct validity to determine the degree to which it could discriminate between groups of organizations that were higher and lower on the extent to which they were implementing TIPs, by administering it online to staff at seven federally qualified health centers at two-time points. The domains, subscales, and the overall measure showed high internal consistency and discriminated significantly between known groups of centers at baseline and follow-up. In addition, the tool captured change over time in the extent to which the organizations were implementing TIPs. These findings provide preliminary support for the future use of the O-TIPs tool by service-delivery organizations.

Impact of Targeted Local Interventions on Tuberculosis Awareness and Screening Among Persons Experiencing Homelessness During a Large Tuberculosis Outbreak in Atlanta, Georgia, 2015-2016.

OBJECTIVES: Tuberculosis (TB) outbreaks disproportionately affect persons experiencing homelessness (PEH) in the United States. During 2014-2016, a resurgent TB outbreak occurred among PEH in Atlanta, Georgia. To control the outbreak, citywide policies and educational interventions were implemented in January 2015. Policy changes standardized and enforced TB screening requirements for PEH in homeless shelters. Educational campaigns informed PEH of the outbreak and encouraged TB screening. We evaluated factors associated with, and the effect policy changes and educational interventions had on, TB screening and awareness among PEH in Atlanta. METHODS: Questions related to TB screening and awareness of the outbreak were added to an annual US Department of Housing and Urban Development survey of PEH in Atlanta in 2015 (n = 296 respondents) and 2016 (n = 1325 respondents). We analyzed the 2016 survey data to determine characteristics associated with outcomes. RESULTS: From 2015 to 2016, reported TB screening increased from 81% to 86%, and awareness of the TB outbreak increased from 68% to 75%. In 2016, sheltered PEH were significantly more likely than unsheltered PEH to report being evaluated for TB in the previous 6 months (prevalence odds ratio [pOR] = 3.18; 95% confidence interval [CI], 2.28-4.47) and to report being aware of the TB outbreak (pOR = 4.00; 95% CI, 2.89-5.55). CONCLUSIONS: Implementation of required TB screening and educational interventions may reduce the incidence and severity of TB outbreaks among PEH in other communities. Furthermore, the annual survey of PEH offers an opportunity to collect data to better inform practices and policies.

Impact of GeneXpert MTB/RIF® on treatment initiation and outcomes of RIF-resistant and RIF-susceptible TB patients in Vladimir TB dispensary, Russia.

BACKGROUND: The main advantage of GeneXpert MTB/RIF® (Xpert) molecular diagnostic technology is the rapid detection of M.tuberculosis DNA and mutations associated with rifampicin (RIF) resistance for timely initiation of appropriate treatment and, consequently, preventing further transmission of the disease. We assessed time to treatment initiation and treatment outcomes of RIF-resistant and RIF-susceptible TB patients diagnosed and treated in Vladimir TB Dispensary, Russia in 2012, before and after implementation of GeneXpert MTB/RIF® diagnostic technology. METHODS: All adult patients suspected of having TB during February-December 2012 underwent a clinical examination, chest x-ray, microscopy, culture, and phenotypic drug susceptibility testing (DST). Starting August 2012 Xpert diagnostic technology became available in the facility. We used logistic regression to compare treatment outcomes in pre-Xpert and post-Xpert periods. Kaplan-Meier curves and log-rank test were used to compare the time to treatment initiation between the groups. RESULTS: Of 402 patients screened for TB during February-December 2012, 338 were diagnosed with TB (280 RIF-susceptible, 58 RIF-resistant). RIF-resistant patients in the post-Xpert group started treatment with second-line drugs (SLD) earlier than those in pre-Xpert group (median 11 vs. 37 days, Log-rank p = 0.02). The hazard ratio for time to SLD treatment initiation was significantly higher in post-Xpert group (HR:2.06; 95%CI:1.09,3.89) compared to pre-Xpert group. Among the 53/58 RIF-resistant TB patients with available treatment outcome, 28 (53%) had successful outcomes (cured/completed treatment) including 15/26 (58%) in post-Xpert group versus 13/27 (48%) in pre-Xpert group. The observed difference, however, was not statistically significant (OR:0.69; 95%CI:0.23,2.06). Among RIF-susceptible TB cases time to treatment initiation was not significantly different between the groups (2 vs. 3 days, Log-rank p = 0.73). Of 252/280 RIF-susceptible TB cases with treatment outcome, 199 (79%) cases had successful outcome including 94/114 (82%) in post-Xpert group versus 105/138 (76%) in pre-Xpert group (OR:0.68; 95%CI:0.36,1.26). CONCLUSION: We observed that availability of Xpert for initial diagnosis significantly reduced the time to SLD treatment for RIF-resistant patients in the Vladimir TB Dispensary. Although implementation of rapid diagnostics did not improve treatment outcomes, early diagnosis of MDR-TB is important for selection of appropriate treatment regimen and prevention of transmission of drug-resistant strains of TB.