Examination of the Cell Cycle Dependence of Cytosine and Adenine Base Editors.

Base editors (BEs) are genome editing agents that install point mutations with high efficiency and specificity. Due to their reliance on uracil and inosine DNA damage intermediates (rather than double-strand DNA breaks, or DSBs), it has been hypothesized that BEs rely on more ubiquitous DNA repair pathways than DSB-reliant genome editing methods, which require processes that are only active during certain phases of the cell cycle. We report here the first systematic study of the cell cycle-dependence of base editing using cell synchronization experiments. We find that nickase-derived BEs (which introduce DNA backbone nicks opposite the uracil or inosine base) function independently of the cell cycle, while non-nicking BEs are highly dependent on S-phase (DNA synthesis phase). We found that synchronization in G1 (growth phase) during the process of cytosine base editing causes significant increases in C•G to A•T "byproduct" introduction rates, which can be leveraged to discover new strategies for precise C•G to A•T base editing. We observe that endogenous expression levels of DNA damage repair pathways are sufficient to process base editing intermediates into desired editing outcomes, and the process of base editing does not significantly perturb transcription levels. Overall, our study provides mechanistic data demonstrating the robustness of nickase-derived BEs for performing genome editing across the cell cycle.

Developing a quality measure for clinical inertia in diabetes care.

OBJECTIVE: To develop a valid quality measure that captures clinical inertia, the failure to initiate or intensify therapy in response to medical need, in diabetes care and to link this process measure with outcomes of glycemic control. DATA SOURCES: Existing databases from 13 Department of Veterans Affairs hospitals between 1997 and 1999. STUDY DESIGN: Laboratory results, medications, and diagnoses were collected on 23,291 patients with diabetes. We modeled the decision to increase antiglycemic medications at individual visits. We then aggregated all visits for individual patients and calculated a treatment intensity score by comparing the observed number of increases to that expected based on our model. The association between treatment intensity and two measures of glycemic control, change in HbA1c during the observation period, and whether the outcome glycosylated hemoglobin (HbA1c) was greater than 8 percent, was then examined. PRINCIPAL FINDINGS: Increases in antiglycemic medications occurred at only 9.8 percent of visits despite 39 percent of patients having an initial HbA1c level greater than 8 percent. A clinically credible model predicting increase in therapy was developed with the principal predictor being a recent HbA1c greater than 8 percent. There were considerable differences in the intensity of therapy received by patients. Those patients receiving more intensive therapy had greater improvements in control (p < .001). CONCLUSIONS: Clinical inertia can be measured in diabetes care and this process measure is linked to patient outcomes of glycemic control. This measure may be useful in efforts to improve clinicians management of patients with diabetes.

Identifying hypertension-related comorbidities from administrative data: what's the optimal approach?

The objective was to determine the best strategy for identifying outpatients with hypertension-related diagnoses using Veterans Affairs (VA) administrative databases. We reviewed 1176 outpatient charts from 10 VA sites in 1999, taking the presence of 11 diagnoses relevant to hypertension management as the "gold standard" for identifying the comorbidity. We calculated agreement, sensitivity, and specificity for the chart versus several administrative data-based algorithms. Using 1999 data and requiring 1 administrative diagnosis, observed agreement ranged from 0.98 (atrial fibrillation) to 0.85 (hyperlipidemia), and kappas were generally high. Sensitivity varied from 38% (tobacco use) to 97% (diabetes); specificity exceeded 91% for 10 of 11 diagnoses. Requiring 2 years of data and 2 diagnoses improved most measures, with minimal sensitivity decrease. Agreement between the database and charts was good. Administrative data varied in its ability to identify all patients with a given diagnosis but identified accurately those without. The best strategy for case-finding required 2 diagnoses in a 2-year period.

Can we use automated data to assess quality of hypertension care?

OBJECTIVE: To determine whether extractable blood pressure (BP) information available in a computerized patient record system (CPRS) could be used to assess quality of hypertension care independently of clinicians' notes. STUDY DESIGN: Retrospective cohort study of a random sample of hypertensive patients from 10 Department of Veterans Affairs (VA) sites across the country. METHODS: We abstracted BPs from electronic clinicians' notes for all medical visits of 981 hypertensive patients in 1999. We compared these with BP measurements available in a separate vitals signs file in the CPRS. We also evaluated whether assessments of performance varied by source by using patients' last documented BP reading. RESULTS: When the vital signs file and notes were combined, a BP measurement was taken for 71% of 6097 medical visits; 60% had a BP measurement only in the vital signs file. Combining sources, 43% of patients had a BP reading of less than 140/90 mm Hg; by site this varied (34%-51%). Vital signs file data alone yielded similar findings; site rankings by rates of BP control changed minimally. CONCLUSIONS: Current performance review programs collect clinical data from both clinicians' notes and automated sources as available. However, we found that notes contribute little information with respect to BP values beyond automated data alone. The VA's vital signs file is a prototypical automated data system that could make assessment of hypertension care more efficient in many settings.

Hypertension control: how well are we doing?

BACKGROUND: We compared blood pressure (BP) control in a recent cohort of hypertensive military veterans with BP control in a previous cohort and examined whether hypertension treatment practices, as defined by the frequency of antihypertensive medication dosage increases, have changed over time. METHODS: We abstracted 1999 outpatient chart data including visit type, BP measurements, comorbidities, and medication use for 981 randomly selected hypertensive veterans. We examined overall BP control and control in subgroups with diabetes mellitus and renal disease, and compared results with those of a sample of 800 veterans studied from 1990 to 1995. We also compared the frequency of antihypertensive medication dosage increases in the 2 samples. RESULTS: Mean BPs were significantly lower in 1999. The mean systolic drop was 3.1 mm Hg and reached 13.7 mm Hg for the subgroups with diabetes and renal disease. Even larger decreases were seen in mean diastolic BPs. In 1999, 57% of patients had BP measurements of 140/90 mm Hg or higher, vs 69% of patients in the 1990-1995 study (P<.001). In 1999, the BP control of patients with diabetes was similar to that of patients without diabetes, as 60% of the former had BP measurements of 140/90 mm Hg or higher. Patients with renal disease had better control than those without, however, as only 43% had BP measurements of 140/90 mm Hg or higher. When comparing samples, patients with diabetes, renal disease, or both had better BP control in 1999 than their counterparts in the 1990-1995 study (P<.003 in all cases). In 1999, more medical visits were associated with medication dosage increases than in the 1990-1995 study. CONCLUSIONS: Although overall BP control has improved, BP measurements still exceeded recommended levels in most patients. For patients with diabetes and renal disease BP was much better controlled in the more recent sample. However, BP control of patients with diabetes was similar to that of patients without diabetes, and not in agreement with the guideline-recommended tighter control. Thus, room for improvement remains, especially in this subgroup.