Author Correction: Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening.

This corrects the article DOI: 10.1038/ncomms16081.

Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening.

The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins. This concept was further explored by screening 42 targets from Mycobacterium tuberculosis. Active chemical series for six targets from our initial effort as well as three chemotypes for DHFR from M. tuberculosis are reported. The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery.

Effect of coexisting chronic obstructive pulmonary disease and cognitive impairment on health outcomes in older adults.

OBJECTIVES: To determine the extent to which the co-occurrence of chronic obstructive pulmonary disease (COPD) and cognitive impairment affect adverse health outcomes in older adults. DESIGN: Multicenter longitudinal cohort study. SETTING: California, Pennsylvania, Maryland, and North Carolina. PARTICIPANTS: Three thousand ninety-three community-dwelling adults aged 65 and older from the Cardiovascular Health Study. Four hundred thirty-one had chronic obstructive pulmonary disease (COPD) at study baseline. MEASUREMENTS: Follow-up began at the second CHS visit and continued for 3 years. Spirometric criteria for airflow limitation served to establish COPD using the Lambda-Mu-Sigma method, which accounts for age-related changes in lung function. Cognitive impairment was evaluated using the modified Mini-Mental State Examination and claims data. Outcomes were respiratory-related and all-cause hospitalizations and death. RESULTS: Participants with coexisting COPD and cognitive impairment had the highest rates of respiratory-related (adjusted hazard ratio (aHR) = 4.10, 95% confidence interval (CI) = 1.86-9.05) and all-cause hospitalizations (aHR = 1.34, 95% CI = 1.00-1.80) and death (aHR = 2.29, 95% CI = 1.18-4.45). In particular, individuals with both conditions had a 48% higher rate of all-cause hospitalizations (adjusted synergy index (aSI) = 1.48, 95% CI = 0.19-11.31) and a rate of death nearly three times as high (aSI = 2.74, 95% CI = 0.43-17.32) as the sum of risks for each respective outcome associated with having COPD or cognitive impairment alone. Nevertheless, tests for interaction were not statistically significant for the presence of synergism between the two conditions contributing to each of the outcomes. Therefore, it cannot be concluded that the combined effect of COPD and cognitive impairment is greater than additive. CONCLUSION: Coexisting COPD and cognitive impairment have an additive effect on respiratory-related and all-cause hospitalizations and death. Optimizing outcomes in older adults with COPD and cognitive impairment will require that how to improve concurrent management of both conditions be determined.

Association between inflammatory-related disease burden and frailty: results from the Women's Health and Aging Studies (WHAS) I and II.

Frailty is associated with a pro-inflammatory state, which has been characterized by elevated levels of systemic inflammatory biomarkers, but has not been related to the number of co-existing chronic diseases associated with inflammation. We sought to determine the extent to which a higher number of inflammatory-related diseases is associated with frailty and to identify the most common disease patterns associated with being frail in older adults. We performed binomial regression analyses to assess whether a higher count of inflammatory-related diseases increases the probability of frailty using data from the WHAS I and II, companion cohorts composed of 70-79-year-old community-dwelling older women in Baltimore, Maryland (n=620). An increase of one inflammatory-related disease was associated log-linearly with frailty (Prevalence Ratio (PR)=2.28, 95% Confidence Interval (CI)=1.81-2.87). After adjusting for age, race, education, and smoking status, the probability of frailty remained significant (PR=1.97, 95%CI=1.52-2.55). In the frail population, chronic kidney disease (CKD) and depressive symptoms (Prevalence=22.9%, 95%CI=14.2-34.8%); CVD and depressive symptoms (21.7%, 95%CI=13.2-33.5%); CKD and anemia (18.7%, 95%CI=11.1-29.7%); cardiovascular disease (CVD), CKD, and pulmonary disease (10.7%, 95%CI=5.2-21.0%); CKD, anemia, and depressive symptoms (8.7%, 95%CI=3.9-18.2%); and CVD, anemia, pulmonary disease, and depressive symptoms (5.0%, 95%CI=1.6-14.4%) were among the most frequent disease combinations. Their prevalence percentages were significantly higher in the frail versus non-frail women. A higher inflammatory-related disease count, perhaps reflecting a greater pro-inflammatory burden, increases the likelihood of frailty. Shared mechanisms among specific disease combinations may further contribute to this risk.

Serum 25-hydroxyvitamin D and pulmonary function in older disabled community-dwelling women.

BACKGROUND: Recent studies have expanded the functions of vitamin D to a possible role in pulmonary function. Our objective was to examine the relationship between serum 25-hydroxyvitamin D (25[OH]D), serum parathyroid hormone, and pulmonary function in older women. METHODS: We examined the relationship of serum 25(OH)D and parathyroid hormone with pulmonary function (forced expiratory volume in one second [FEV(1)], forced vital capacity [FVC], and FEV(1)/FVC ratio) in a cross-sectional study of 646 moderately to severely disabled women, 65 years or more, living in the community in Baltimore, Maryland, who participated in the Women's Health and Aging Study I. RESULTS: Overall, median (25th, 75th percentile) serum 25-hydroxyvitamin D concentrations were 19.9 (14.7, 26.7) ng/mL. Serum 25(OH)D was positively associated with FEV(1) (p = .03), FVC (p = .18), and FEV(1)/FVC (p = .04) in multivariable linear regression models adjusting for age, race, education, smoking, height, physical activity, cognition, interleukin-6, chronic diseases, and other potential confounders. In the same models, serum parathyroid hormone was not significantly associated with FEV(1), FVC, or FEV(1)/FVC. CONCLUSIONS: These findings support the idea that vitamin D deficiency is independently associated with poor pulmonary function in older disabled women.

Contribution of multiple chronic conditions to universal health outcomes.

OBJECTIVES: To determine the relative effect of five chronic conditions on four representative universal health outcomes. DESIGN: Cross-sectional. SETTING: Cardiovascular Health Study. PARTICIPANTS: Five thousand two hundred and ninety-eight community-living participants aged 65 and older. MEASUREMENTS: Multiple regression and Cox models were used to determine the effect of heart failure (HF), chronic obstructive pulmonary disease (COPD), osteoarthritis, depression, and cognitive impairment on self-rated health, 12 basic and instrumental activities of daily living (ADLs and IADLs), six-item symptom burden scale, and death. RESULTS: Each condition adversely affected self-rated health (P < .001) and ADLs and IADLs (P < .001). For example, persons with HF performed 0.70 ± 0.08 fewer ADLs and IADLs than those without; persons with depression and persons with cognitive impairment performed 0.59 ± 0.04 and 0.58 ± 0.06 fewer activities, respectively, than those without these conditions. Depression, HF, COPD, and osteoarthritis were associated with 1.18 ± 0.04, 0.40 ± 0.08, 0.40 ± 0.05, and 0.57 ± 0.03 more symptoms, respectively, in individuals with these conditions than in those without. HF (hazard ratio (HR) = 2.84, 95% confidence interval (CI) = 1.97-4.10), COPD (2.62, 95% CI = 1.94-3.53), cognitive impairment (2.05, 95% CI = 1.47-2.85), and depression (1.47, 95% CI = 1.08-2.01) were each associated with death within 2 years. Several paired combinations of conditions had synergistic effects on ADLs and IADLs. For example, individuals with HF plus depression performed 2.0 fewer activities than persons with neither condition, versus the 1.3 fewer activities expected from adding the effects of the two conditions together. CONCLUSION: Universal health outcomes may provide a common metric for measuring the effects of multiple conditions and their treatments. The varying effects of the conditions across universal outcomes could inform care priorities.

Effect of chronic disease-related symptoms and impairments on universal health outcomes in older adults.

OBJECTIVES: To determine the extent to which disease-related symptoms and impairments, which constitute measures of disease severity or targets of therapy, account for the associations between chronic diseases and universal health outcomes. DESIGN: Cross-sectional. SETTING: The Cardiovascular Health Study (CHS) and the Health, Aging and Body Composition Study (Health ABC). PARTICIPANTS: Five thousand six hundred fifty-four CHS members and 2,706 Health ABC members. MEASUREMENTS: Diseases included heart failure (HF), chronic obstructive pulmonary disease (COPD), osteoarthritis, and cognitive impairment. The universal health outcomes included self-rated health, basic and instrumental activities of daily living (ADLs and IADLs), and death. Disease-related symptoms and impairments included HF symptoms and ejection fraction (EF) for HF, Dyspnea Scale and forced expiratory volume in 1 second for COPD, joint pain for osteoarthritis, and executive function for cognitive impairment. RESULTS: The diseases were associated with the universal health outcomes (P<.001) except osteoarthritis with death (both cohorts) and cognitive impairment with self-rated health (Health ABC). Symptoms and impairments accounted for 30% or more of each disease's effect on the universal health outcomes. In CHS, for example, HF was associated with one fewer (0.918) ADL and IADL performed without difficulty than no HF; HF symptoms accounted for 27% of this effect and EF for only 5%. The hazard ratio for death with HF was 6.5 (95% confidence interval=4.7-8.9) with EF accounting for 40% and HF symptoms for only 14%. CONCLUSION: Disease-related symptoms and impairments accounted for much of the significant associations between the four chronic diseases and the universal health outcomes. Results support considering universal health outcomes as common metrics across diseases in clinical decision-making, perhaps by targeting the disease-related symptoms and impairments that contribute most strongly to the effect of the disease on the universal health outcomes.

Association between combined interleukin-6 and C-reactive protein levels and pulmonary function in older women: results from the Women's Health and Aging Studies I and II.

OBJECTIVES: To determine whether combined higher interleukin-6 (IL-6) and C-reactive protein (CRP) levels are associated with lower pulmonary function levels in older women, accounting for chronic inflammatory diseases, physical function, and other factors associated with inflammation. DESIGN: Cross-sectional study using data from two prospective cohorts. SETTING: Baltimore, Maryland. PARTICIPANTS: Eight hundred forty disabled and 332 higher-functioning community-dwelling women aged 65 and older from the Women's Health and Aging Studies (WHAS) I and II, respectively. MEASUREMENTS: IL-6 and CRP, combined according to their tertile concentrations, and pulmonary function measures, assessed according to forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC). RESULTS: In WHAS I and II, similar dose-response trends were observed between combined higher IL-6 and CRP levels and lower pulmonary function levels. In WHAS I (disabled women), the combined highest IL-6 and CRP levels were associated with the lowest levels of FEV1 (mean 137.0 mL, 95% confidence interval (CI)=128.4-145.7 mL) and FVC (mean 191.7 mL, 95% CI=180.4-202.9 mL). Similarly, in WHAS II (higher-functioning women), the combined highest IL-6 and CRP levels were associated with the lowest levels of FEV1 (mean 1,543 mL, [corrected] 95% CI=146.3-170.4 mL) and FVC (mean 224.2 mL, 95% CI=209.9-238.5 mL). CONCLUSION: Combined elevations in IL-6 and CRP were associated with the lowest pulmonary function levels in older women. These findings suggest that high IL-6 and CRP levels may be an indication of prevalent impaired pulmonary function. Future studies should determine whether measurement of IL-6 and CRP could enhance current methods of monitoring respiratory diseases beyond that provided by pulmonary function measures.

Patterns of comorbid inflammatory diseases in frail older women: the Women's Health and Aging Studies I and II.

BACKGROUND: Developing interventions to prevent frailty in older adults is a priority as it increases the risk for disability, institutionalization, and death. Single chronic inflammatory diseases are known to increase the risk of frailty. Identification of comorbid inflammatory diseases that synergistically might heighten this risk would provide further insight into therapeutic approaches to prevent frailty. The study aims were to characterize whether there are specific inflammatory disease pairs that are associated with frailty and to determine whether the risk of frailty is affected by synergistic interactions between these inflammatory diseases. METHODS: Data were from the Women's Health and Aging Studies I and II and complementary cohorts of community-dwelling women aged 70-79 years from Baltimore, Maryland (n = 620). Multivariable logistic regression analyses were performed to evaluate the relationships between these diseases and frailty. RESULTS: Among the frail (11.3%), 15.2% had both depressive symptoms and anemia and 14.5% had pulmonary disease and anemia. The risk of frailty was synergistically increased in those with depressive symptoms and anemia (adjusted risk ratios = 11.93, 95% confidence interval [CI] 4.10-34.76) and those with pulmonary disease and anemia (risk ratios = 5.57, 95% CI 2.14-14.48), compared with those without either disease in each pair. The attributable proportions of frail cases due to interaction between the diseases of each pair were 0.56 (95% CI 0.07-1.05) and 0.61 (95% CI 0.18-1.05), respectively. CONCLUSIONS: Synergistic interactions between specific inflammatory diseases may heighten the risk of frailty. These findings suggest that a common etiologic pathway may exist among co-occurring inflammatory diseases and that their improved comanagement may be an approach to reducing frailty.