A high-resolution protein architecture of the budding yeast genome.

The genome-wide architecture of chromatin-associated proteins that maintains chromosome integrity and gene regulation is not well defined. Here we use chromatin immunoprecipitation, exonuclease digestion and DNA sequencing (ChIP-exo/seq)1,2 to define this architecture in Saccharomyces cerevisiae. We identify 21 meta-assemblages consisting of roughly 400 different proteins that are related to DNA replication, centromeres, subtelomeres, transposons and transcription by RNA polymerase (Pol) I, II and III. Replication proteins engulf a nucleosome, centromeres lack a nucleosome, and repressive proteins encompass three nucleosomes at subtelomeric X-elements. We find that most promoters associated with Pol II evolved to lack a regulatory region, having only a core promoter. These constitutive promoters comprise a short nucleosome-free region (NFR) adjacent to a +1 nucleosome, which together bind the transcription-initiation factor TFIID to form a preinitiation complex. Positioned insulators protect core promoters from upstream events. A small fraction of promoters evolved an architecture for inducibility, whereby sequence-specific transcription factors (ssTFs) create a nucleosome-depleted region (NDR) that is distinct from an NFR. We describe structural interactions among ssTFs, their cognate cofactors and the genome. These interactions include the nucleosomal and transcriptional regulators RPD3-L, SAGA, NuA4, Tup1, Mediator and SWI-SNF. Surprisingly, we do not detect interactions between ssTFs and TFIID, suggesting that such interactions do not stably occur. Our model for gene induction involves ssTFs, cofactors and general factors such as TBP and TFIIB, but not TFIID. By contrast, constitutive transcription involves TFIID but not ssTFs engaged with their cofactors. From this, we define a highly integrated network of gene regulation by ssTFs.

Association of race/ethnicity and socioeconomic status with COVID-19 30-day mortality at a Philadelphia medical center using a retrospective cohort study.

COVID-19 has disproportionately affected low-income communities and people of color. Previous studies demonstrated that race/ethnicity and socioeconomic status (SES) are not independently correlated with COVID-19 mortality. The purpose of our study is to determine the effect of race/ethnicity and SES on COVID-19 30-day mortality in a diverse, Philadelphian population. This is a retrospective cohort study in a single-center tertiary care hospital in Philadelphia, PA. The study includes adult patients hospitalized with polymerase-chain-reaction-confirmed COVID-19 between March 1, 2020 and June 6, 2020. The primary outcome was a composite of COVID-19 death or hospice discharge within 30 days of discharge. The secondary outcome was intensive care unit (ICU) admission. The study included 426 patients: 16.7% died, 3.3% were discharged to hospice, and 20.0% were admitted to the ICU. Using multivariable analysis, race/ethnicity was not associated with the primary nor secondary outcome. In Model 4, age greater than 75 (odds ratio [OR]: 11.01; 95% confidence interval [CI]: 1.96-61.97) and renal disease (OR: 2.78; 95% CI: 1.31-5.90) were associated with higher odds of the composite primary outcome. Living in a "very-low-income area" (OR: 0.29; 95% CI: 0.12-0.71) and body mass index (BMI) 30-35 (OR: 0.24; 95% CI: 0.08-0.69) were associated with lower odds of the primary outcome. When controlling for demographics, SES, and comorbidities, race/ethnicity was not independently associated with the composite primary outcome. Very-low SES, as extrapolated from census-tract-level income data, was associated with lower odds of the composite primary outcome.

Comparing reliability of ICD-10-based COVID-19 comorbidity data to manual chart review, a retrospective cross-sectional study.

International Statistical Classification of Disease and Related Health Problems, 10th Revision codes (ICD-10) are used to characterize cohort comorbidities. Recent literature does not demonstrate standardized extraction methods. OBJECTIVE: Compare COVID-19 cohort manual-chart-review and ICD-10-based comorbidity data; characterize the accuracy of different methods of extracting ICD-10-code-based comorbidity, including the temporal accuracy with respect to critical time points such as day of admission. DESIGN: Retrospective cross-sectional study. MEASUREMENTS: ICD-10-based-data performance characteristics relative to manual-chart-review. RESULTS: Discharge billing diagnoses had a sensitivity of 0.82 (95% confidence interval [CI]: 0.79-0.85; comorbidity range: 0.35-0.96). The past medical history table had a sensitivity of 0.72 (95% CI: 0.69-0.76; range: 0.44-0.87). The active problem list had a sensitivity of 0.67 (95% CI: 0.63-0.71; range: 0.47-0.71). On day of admission, the active problem list had a sensitivity of 0.58 (95% CI: 0.54-0.63; range: 0.30-0.68)and past medical history table had a sensitivity of 0.48 (95% CI: 0.43-0.53; range: 0.30-0.56). CONCLUSIONS AND RELEVANCE: ICD-10-based comorbidity data performance varies depending on comorbidity, data source, and time of retrieval; there are notable opportunities for improvement. Future researchers should clearly outline comorbidity data source and validate against manual-chart-review.

External validation of the COVID-19 4C mortality score in an urban United States cohort.

BACKGROUND: Identifying patients at risk for mortality from COVID-19 is crucial to triage, clinical decision-making, and the allocation of scarce hospital resources. The 4C Mortality Score effectively predicts COVID-19 mortality, but it has not been validated in a United States (U.S.) population. The purpose of this study is to determine whether the 4C Mortality Score accurately predicts COVID-19 mortality in an urban U.S. adult inpatient population. METHODS: This retrospective cohort study included adult patients admitted to a single-center, tertiary care hospital (Philadelphia, PA) with a positive SARS-CoV-2 PCR from 3/01/2020 to 6/06/2020. Variables were extracted through a combination of automated export and manual chart review. The outcome of interest was mortality during hospital admission or within 30 days of discharge. RESULTS: This study included 426 patients; mean age was 64.4 years, 43.4% were female, and 54.5% self-identified as Black or African American. All-cause mortality was observed in 71 patients (16.7%). The area under the receiver operator characteristic curve of the 4C Mortality Score was 0.85 (95% confidence interval, 0.79-0.89). CONCLUSIONS: Clinicians may use the 4C Mortality Score in an urban, majority Black, U.S. inpatient population. The derivation and validation cohorts were treated in the pre-vaccine era so the 4C Score may over-predict mortality in current patient populations. With stubbornly high inpatient mortality rates, however, the 4C Score remains one of the best tools available to date to inform thoughtful triage and treatment allocation.