IMPORTANCE Early-life factors may be important for later dementia risk. The association between a more advantaged early-life environment, as reflected through an individual's height and socioeconomic status indicators, and decreases in dementia incidence by birth cohort is unknown. OBJECTIVES To examine the association of birth cohort and early-life environment with dementia incidence among participants in the Adult Changes in Thought study from 1994 to 2015. DESIGN, SETTING, AND PARTICIPANTS This prospective cohort study included 4277 participants from the Adult Changes in Thought study, an ongoing longitudinal population-based study of incident dementia in a random sample of adults 65 years and older who were born between 1893 and 1949 and are members of Kaiser Permanente Washington in the Seattle region. Participants in the present analysis were followed up from 1994 to 2015. At enrollment, all participants were dementiafree and completed a baseline evaluation. Subsequent study visits were held every 2 years until a diagnosis of dementia, death, or withdrawal from the study. Participants were categorized by birth period (defined by historically meaningful events) into 5 cohorts: pre-World War I (1893-1913), World
Background: Acute kidney injury (AKI) is common in patients hospitalized with coronavirus disease 2019 (COVID-19). Risk factors for AKI requiring dialysis (AKI-D) are not fully understood. We aimed to identify risk factors associated with AKI-D and AKI not requiring dialysis (AKI-ND). Methods: We reviewed electronic health records of 3186 patients aged > 18 years old hospitalized with COVID-19 across six hospitals. Patient characteristics, urinalysis findings, and inflammatory markers were analyzed for association with in-hospital AKI status (AKI-D, AKI-ND, or no AKI), and we subsequently evaluated mortality. Results: After adjustment for multiple covariates, higher baseline eGFR was associated with 30% lower odds of AKI-D and 11% lower odds of AKI-ND (OR 0.70, 95% CI 0.64-0.77 for AKI-D; OR 0.89, 95% CI 0.85-0.92 for AKI-ND). Patients with obesity and Latino patients had increased odds of AKI-D, whereas those with congestive heart failure or diabetes with complications had increased odds of AKI-ND. Females had lower odds of in-hospital AKI (OR 0.28, 95% CI 0.17-0.46 for AKI-D; OR 0.83, 95% CI 0.70-0.99 for AKI-ND). After adjustment for covariates and baseline eGFR, 1-4+ protein on initial urinalysis was associated with a 9-fold increase in odds of AKI-D (OR 9.00, 95% CI 2.16-37.38) and > 2-fold higher odds of AKI-ND (OR 2.28, 95% CI 1.66-3.13). 1-3+ blood and trace glucose on initial urinalysis were also associated with increased odds of both AKI-D and AKI-ND. AKI-D and AKI-ND were associated with in-hospital death (OR 2.64, 95% CI 1.13-6.17 for AKI-D; OR 2.44, 95% CI 1.77-3.35 for AKI-ND). Conclusions: Active urine sediments, even after adjustment for baseline kidney function, and reduced baseline eGFR are significantly associated with increased odds of AKI-D and AKI-ND. In-hospital AKI was associated with in-hospital death. These findings may help prognosticate patients hospitalized with COVID-19.
Tyrosine kinase inhibitors (TKIs) are used to treat non-small cell lung cancers (NSCLC) driven by epidermal growth factor receptor (EGFR) mutations in the tyrosine kinase domain (TKD). TKI responses vary across tumors driven by the heterogeneous group of exon 19 deletions and mutations, but the molecular basis for these differences is not understood. Using purified TKDs, we compared kinetic properties of several exon 19 variants. Although unaltered for the second generation TKI afatinib, sensitivity varied significantly for both the first and third generation TKIs erlotinib and osimertinib. The most sensitive variants showed reduced ATP-binding affinity, whereas those associated with primary resistance retained wild type ATP-binding characteristics (and low KM, ATP). Through crystallographic and hydrogen-deuterium exchange mass spectrometry (HDX-MS) studies, we identify possible origins for the altered ATP-binding affinity underlying TKI sensitivity and resistance, and propose a basis for classifying uncommon exon 19 variants that may have predictive clinical value.
There is a need for prognostic markers to select patients most likely to benefit from antibody–drug conjugate (ADC) therapy. We quantified the relationship between pretreatment PET imaging of glycoprotein nonmetastatic melanoma B (gpNMB) with 89Zr-labeled anti-gpNMB antibody ([89Zr]ZrDFO-CR011) and response to ADC therapy (CDX-011) in triple-negative breast cancer. First, we compared different PET imaging metrics and found that standardized uptake values (SUV) and tumor-to-heart SUV ratios were sufficient to delineate differences in radiotracer uptake in the tumor of four different cell- and patient-derived tumor models and achieved high standardized effect sizes. These tumor models with varying levels of gpNMB expression were imaged with [89Zr]ZrDFO-CR011 followed by treatment with a single bolus injection of CDX-011. The percent change in tumor volume relative to baseline (% CTV) was then correlated with SUVmean of [89Zr]ZrDFO-CR011 uptake in the tumor. All gpNMB-positive tumor models responded to CDX-011 over 6 weeks of treatment, except one patient-derived tumor regrew after 4 weeks of treatment. As expected, the gpNMB-negative tumor increased in volume by 130 ± 59% at endpoint. The magnitude of pretreatment SUV had the strongest inverse correlation with the % CTV at 2–4 weeks after treatment with CDX-011 (Spearman ρ = −0.8). However, pretreatment PET imaging with [89Zr]ZrDFO-CR011 did not inform on which tumor types will regrow over time. Other methods will be needed to predict resistance to treatment.
Purpose: The uncommon EGFR exon 19 deletion (ex19del), L747_A750>P, demonstrates reduced sensitivity to osimertinib compared to the common ex19del, E746_A750del in preclinical models. The clinical efficacy of osimertinib in patients with non-small cell lung cancer (NSCLC) harboring L747_A750>P and other uncommon ex19dels is not known. Design: The AACR GENIE database was interrogated to characterize the frequency of individual ex19dels relative to other variants, and a multi-center retrospective cohort was used to compare clinical outcomes for patients with tumors harboring E746_A750del, L747_A750>P, and other uncommon ex19dels who received osimertinib in the first line (1L) or in second or later lines of therapy and were T790M+ (≥2L). Results: Ex19dels comprised 45% of EGFR mutations, with 72 distinct variants ranging in frequency from 28.1% (E746_A750del) to 0.03%, with L747_A750>P representing 1.8% of the EGFR mutant cohort. In our multi-institution cohort (N=200), E746_A750del was associated with significantly prolonged progression free survival (PFS) with 1L osimertinib vs. L747_A750>P (median 21.3 months [95% CI 17.0-31.7] vs. 11.7 months [10.8-29.4], adjusted hazard ratio [HR] 0.52 [0.28-0.98] p=0.043). Osimertinib efficacy in patients with other uncommon ex19dels varied based on the specific mutation present. Conclusions: The ex19del L747_A750>P is associated with inferior PFS compared to the common E746_A750del mutation in patients treated with 1L osimertinib. Understanding differences in osimertinib efficacy among EGFR ex19del
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