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Summary: This open-label, phase 1/1b study was conducted to evaluate the safety, tolerability, and pharmacokinetics (PK) of fruquintinib in United States (U.S.) patients to confirm the recommended phase 2 dose (RP2D) established in China. Patients with advanced solid tumors who had progressed on approved systemic therapy, were enrolled into 2 successive dose escalation cohorts, fruquintinib 3 mg (n = 7) or 5 mg (n = 7), orally, once daily (QD), 3 weeks on and 1 week off (3/1) with a 3 + 3 design followed by a dose expansion cohort at the RP2D 5 mg dose (n = 6). PK samples were collected on Days 1, 14, and 21 (Cycle 1). One of 6 dose-limiting toxicity (DLT)-evaluable patients in the 3 mg cohort had a DLT of grade 4 hypertension; there were no DLTs in the 5 mg cohort. The RP2D was confirmed to be 5 mg QD 3/1. All 20 patients experienced a treatment-emergent adverse event; grade ≥ 3 in 5 (71.4%; 3 mg dose) and 12 (92.3%; 5 mg dose) patients. Two patients had a confirmed partial response. After single and multiple doses, median peak plasma concentrations occurred at 2 h post-dose. Steady-state was achieved after 14 days of QD dosing with systemic exposure four-fold higher than that after a single dose. Fruquintinib was well tolerated, and the safety and PK profile at the 5 mg RP2D in U.S. patients with advanced solid tumors was consistent with dose-finding studies in China. Preliminary anticancer activity was observed. This study is registered at Clinicaltrials.gov NCT03251378. [ABSTRACT FROM AUTHOR]

Prior research indicates that land use and land cover change (LULCC) in the central United States has led to significant changes in surface climate. The spatial resolution of simulations is particularly relevant in this region due to its influence on model skill in capturing mesoscale convective systems (MCSs) and on representing the spatial heterogeneity. Recent advances in Earth system models (ESMs) make it feasible to use variable resolution (VR) meshes to study regional impacts of LULCC while avoiding inconsistencies introduced by lateral boundary conditions typically seen in limited area models. Here, we present numerical experiments using the Community Earth System Model version 2–VR to evaluate (1) the influence of resolution and land use on model skill and (2) impacts of LULCC over the central United States at different resolutions. These simulations are configured either on the 1° grid or a VR grid with grid refinement to 1/8° over the contiguous United States for the period of 1984–2010 with two alternative land use data sets corresponding to the preindustrial and present day states. Our results show that skill in simulating precipitation over the central United States is primarily dependent on resolution, whereas skill in simulating 2‐m temperature is more dependent on accurate land use. The VR experiments show stronger LULCC‐induced precipitation increases over the Midwest in May and June, corresponding to an increase in the number of MCS‐like features and a more conductive thermodynamic environment for convection. Our study demonstrates the potential of using VR ESMs for hydroclimatic simulations in regions with significant LULCC. Plain Language Summary: Land use and land cover change (LULCC) in the central United States has likely affected the historical climate of this region, along with other global and regional factors. Experiments using Earth system models can be used to understand how LULCC has affected the regional climate. But such studies are limited by model resolution used for the experiments. Recent developments in Earth system modeling allow for higher regional resolution simulations over areas of focused interest in global simulations. In this study, we perform model experiments using the Community Earth System Model at a high resolution over the central United States to understand how resolution affects the model skill and the simulated LULCC impacts. The warm‐season precipitation over the central United States shows lower biases in the high‐resolution simulations. We also find stronger precipitation increases over the Midwest during May and June due to LULCC in experiments at high resolution. This is because the environmental conditions over the Midwest become more favorable for convective activities as a result of LULCC in the high‐resolution experiments. Key Points: Precipitation and temperature biases over the central United States are reduced with more accurate land use and higher resolution in VR‐CESMThe high‐resolution model shows stronger LULCC‐induced precipitation increases over the Midwest in May and JuneVariable resolution model demonstrates great potential to be used for regional hydroclimatic applications in areas of major LULCC [ABSTRACT FROM AUTHOR]

Background: Loss of muscle mass and muscle strength are natural consequences of the aging process, accompanied by an increased prevalence of chronic health conditions. Research suggests that in the elderly, the presence of comorbidities may impact the muscle mass/strength relationship. The objectives of this study were to characterize the muscle mass/strength relationship in older adults in the USA and to examine the impact of a variety of comorbidities on this relationship. Methods: Data were obtained from the National Health and Nutrition Examination Survey 1999-2002 databases. Subjects aged 50 years and older were included in the present study. Muscle mass was assessed by height-adjusted appendicular skeleton muscle mass (aASM) in kg/m², as measured by dual-energy x-ray absorptiometry. Muscle strength was assessed via isokinetic quadriceps strength (IQS) in newton as measured by a dynamometer. The relationship between aASM and IQS was assessed adjusting for age and gender. The effects of a variety of comorbidities on IQS and/or on the relationship between IQS and aASM were assessed using multiple regression models. Results: This study included 2,647 individuals, with a mean age of 62.6 years and 52.9% of whom were female. The mean (SE) aASM (kg/m²) was 7.3 (0.04), and the mean (SE) IQS (newton) was 365.0 (3.00). After adjusting for age and gender, the correlation coefficient between aASM and IQS was 0.365 (P < 0.001). Diabetes, coronary heart disease/congestive heart failure (CHD/CHF), and vision problems were significant predictors of lower muscle strength (P < 0.05) in the multiple regression models that adjusted for age, gender, and aASM, and obesity significantly modified the relationship between aASM and IQS (P < 0.05). Conclusions: Among individuals aged 50 and older in the US, muscle mass and muscle strength are positively correlated, independent of the associations of age and gender with muscle mass and strength. A variety of comorbid medical conditions serve as independent predictors of lower muscle strength (e.g., diabetes, CHD/CHF, vision problems) and/or modify the relationship between muscle mass and muscle strength (e.g., obesity). [ABSTRACT FROM AUTHOR]

Background: Osteoarthritis is a chronic and costly condition affecting 14% of adults in the US, and has a significant impact on patient quality of life. This retrospective cohort study compared direct health care utilization and costs between patients with osteoarthritis and a matched control group without osteoarthritis. Methods: MarketScan® databases were used to identify adult patients with an osteoarthritis claim (ICD-9-CM, 715.xx) in 2007, and the date of first diagnosis served as the index. Patients were excluded if they did not have 12 months of continuous health care benefit prior to and following the index date, were aged ,18 years, or lacked a second diagnosis code for osteoarthritis between 15 and 365 days pre-index or post-index. Osteoarthritis patients were matched 1:1 to patients without osteoarthritis for age group, gender, geographic region, health plan type, and Medicare eligibility. Multivariate analyses were conducted to assess for differences in utilization and costs, controlling for differences between cohorts. Results: The study sample included 258,237 patients with osteoarthritis and 258,237 matched controls without osteoarthritis. Most patients were women and over 55 years of age. Patients with osteoarthritis had significantly higher pre-index rates of comorbidity than controls. Mean total adjusted direct costs for osteoarthritis patients were more than double those for the control group at US$18,435 (95% confidence interval [CI]: US$18,318-US$18,560) versus US$7494 (95% CI: US$7425-US$7557). Osteoarthritis patients incurred significantly higher inpatient costs at US$6668 (95% CI: US$6587-US$6744) versus US$1756 (95% CI: US$1717- US$1794), outpatient costs at US$7840 (95% CI: US$7786-US$7902) versus US$3675 (95% CI: US$3637-US$3711), and prescription drug costs at US$3213 (95% CI: US$3195-US$3233) versus US$2245 (95% CI: US$2229-US$2262) compared with the controls. Conclusion: The direct health care costs of osteoarthritis patients were over two times higher than those of similar patients without the condition. The primary drivers of the cost difference were comorbidities and inpatient costs. [ABSTRACT FROM AUTHOR]

ABSTRACTObjective:To examine medical conditions associated with diabetic neuropathy (DN) and to identify drivers of healthcare charges and utilization using administrative claims.Methods:The study examined commercially-insured under-age-65 individuals with 24 months continuous enrollment in a large US national health plan. DN patients were identified by having at least one claim with a DN diagnosis between July 2004 and June 2005. A demographically-matched control cohort of patients with diabetes but no DN (10: 1 ratio) was constructed using propensity scoring. Overall illness burden via a comprehensive disease classification, year 2 (July 2005 through June 2006) distribution of charges, and reasons for inpatient admissions and emergency room (ER) visits were compared between DN patients and diabetic controls. Multivariate regressions were used to assess the marginal contribution of DN to healthcare charges and utilization, and the most common reasons for ER and inpatient admissions, controlling for differences in overall illness burden.Results:Both DN patients (n  8655) and diabetic controls (n  86 550) had a mean age of 51 years, and 46 were female. Compared with controls, DN patients had more comorbid medical conditions (9.7 vs. 6.8, p < 0.05) and higher total healthcare charges. Controlling for differences in overall illness burden, DN patients had significantly more hospital days (0.67), more ER (0.09), physician office (0.62), and outpatient hospital visits (2.87), and higher total healthcare charges (5696) than controls (all p < 0.05), with majority of the difference in charges from inpatient service (3975, p < 0.05). Patients with DN were also far more likely to be hospitalized (ketoacidosis, neurological manifestation, heart disease, skin infection) or have an ER encounter (amputation) for diabetes-related complications. Due to the use of a retrospective claims database, limitations of this analysis include a lack of formal diagnostic testing of patients, inability to measure factors such as disease duration and severity that are not captured in such databases, and the possible lack of generalization from this group of patients with diabetes to other populations.Conclusions:DN patients had significantly more comorbid medical conditions and higher healthcare charges and utilization than age- and sex-matched diabetic controls. Controlling for differences in overall illness burden, DN patients incurred more ER visits and inpatient admissions. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a neurodegenerative disorder incurring significant social and economic costs. This study uses a US administrative claims database to evaluate the effect of AD on direct healthcare costs and utilization, and to identify the most common reasons for AD patients' emergency room (ER) visits and inpatient admissions. Methods: Demographically matched cohorts age 65 and over with comprehensive medical and pharmacy claims from the 2003-2004 MEDSTAT MarketScan® Medicare Supplemental and Coordination of Benefits (COB) Database were examined: 1) 25,109 individuals with an AD diagnosis or a filled prescription for an exclusively AD treatment; and 2) 75,327 matched controls. Illness burden for each person was measured using Diagnostic Cost Groups (DCGs), a comprehensive morbidity assessment system. Cost distributions and reasons for ER visits and inpatient admissions in 2004 were compared for both cohorts. Regression was used to quantify the marginal contribution of AD to health care costs and utilization, and the most common reasons for ER and inpatient admissions, using DCGs to control for overall illness burden. Results: Compared with controls, the AD cohort had more co-morbid medical conditions, higher overall illness burden, and higher but less variable costs ($13,936 s. $10,369; Coefficient of variation = 181 vs. 324). Significant excess utilization was attributed to AD for inpatient services, pharmacy, ER visits, and home health care (all p < 0.05). In particular, AD patients were far more likely to be hospitalized for infections, pneumonia and falls (hip fracture, syncope, collapse). Conclusion: Patients with AD have significantly more co-morbid medical conditions and higher healthcare costs and utilization than demographically-matched Medicare beneficiaries. Even after adjusting for differences in co-morbidity, AD patients incur excess ER visits and inpatient admissions. [ABSTRACT FROM AUTHOR]

Background: Trilaciclib is an intravenous cell-cycle inhibitor that transiently maintains immune cells and haemopoietic stem and progenitor cells in G1 arrest. By protecting the immune cells and bone marrow from chemotherapy-induced damage, trilaciclib has the potential to optimise antitumour activity while minimising myelotoxicity. We report safety and activity data for trilaciclib plus gemcitabine and carboplatin chemotherapy in patients with metastatic triple-negative breast cancer., Methods: In this randomised, open-label, multicentre, phase 2 study, adult patients (aged ≥18 years) with evaluable, biopsy-confirmed, locally recurrent or metastatic triple-negative breast cancer who had no more than two previous lines of chemotherapy were recruited from 26 sites in the USA, three in Serbia, two in North Macedonia, one in Croatia, and one in Bulgaria; sites were academic and community hospitals. Availability of diagnostic samples of tumour tissue confirming triple-negative breast cancer was a prerequisite for enrolment. Eligible patients were randomly assigned (1:1:1) by an interactive web-response system, stratified by number of previous lines of systemic therapy and the presence of liver metastases, to receive intravenous gemcitabine 1000 mg/m 2 and intravenous carboplatin (area under the concentration-time curve 2 μg × h/mL) on days 1 and 8 (group 1), gemcitabine and carboplatin plus intravenous trilaciclib 240 mg/m 2 on days 1 and 8 (group 2), or gemcitabine and carboplatin on days 2 and 9 plus trilaciclib on days 1, 2, 8, and 9 (group 3) of 21-day cycles. Patients continued treatment until disease progression, unacceptable toxicity, withdrawal of consent, or discontinuation by the investigator. The primary objective was to assess the safety and tolerability of combining trilaciclib with gemcitabine and carboplatin chemotherapy. The primary endpoints were duration of severe neutropenia during cycle 1 and the occurrence of severe neutropenia during the treatment period. Overall survival was included as a key secondary endpoint. Analyses were in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with EudraCT, 2016-004466-26, and ClinicalTrials.gov, NCT02978716, and is ongoing but closed to accrual., Findings: Between Feb 7, 2017, and May 15, 2018, 142 patients were assessed for eligibility and 102 were randomly assigned to group 1 (n=34), group 2 (n=33), or group 3 (n=35). Of all patients, 38 (37%) had received one or two lines of previous chemotherapy in the metastatic setting. Median follow-up was 8·4 months (IQR 3·8-13·6) for group 1, 12·7 months (5·5-17·4) for group 2, and 12·9 months (6·7-16·8) for group 3. Data cutoff for myelosuppression endpoints was July 30, 2018, and for antitumour activity endpoints was May 17, 2019. During cycle 1, mean duration of severe neutropenia was 0·8 day (SD 2·4) in group 1, 1·5 days (3·5) in group 2, and 1·0 day (2·6) in group 3 (group 3 vs group 1 one-sided adjusted p=0·70). Severe neutropenia occurred in nine (26%) of 34 patients in group 1, 12 (36%) of 33 patients in group 2, and eight (23%) of 35 patients in group 3 (p=0·70). Overall survival was 12·6 months (IQR 5·8-15·6) in group 1, 20·1 months (9·4-not reached) in group 2, and 17·8 months (8·8-not reached) in group 3 (group 3 vs group 1 two-sided p=0·0023). The most common treatment-emergent adverse events were anaemia (22 [73%] of 34), neutropenia (21 [70%]), and thrombocytopenia (18 [60%]) in group 1; neutropenia (27 [82%] of 33), thrombocytopenia (18 [55%]) and anaemia (17 [52%]) in group 2; and neutropenia (23 [66%] of 35), thrombocytopenia (22 [63%]), and nausea (17 [49%]) in group 3. There were no treatment-related deaths., Interpretation: No significant differences were observed in myelosuppression endpoints with trilaciclib plus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer; however, the regimen was generally well tolerated and overall survival results were encouraging. Further studies of trilaciclib in this setting are warranted., Funding: G1 Therapeutics., (Copyright © 2019 Elsevier Ltd. All rights reserved.)