Search

ImportanceElder mistreatment is common and has serious health consequences. Little is known, however, about patterns of health care utilization among older adults experiencing elder mistreatment.ObjectiveTo examine emergency department (ED) and hospital utilization of older adults experiencing elder mistreatment in the period surrounding initial mistreatment identification compared with other older adults.Design, Setting, and ParticipantsThis retrospective case-control study used Medicare insurance claims to examine older adults experiencing elder mistreatment initially identified between January 1, 2003, and December 31, 2012, and control participants matched on age, sex, race and ethnicity, and zip code. Statistical analysis was performed in April 2022.Main Outcomes and MeasuresWe used multiple measures of ED and hospital utilization patterns (eg, new and return visits, frequency, urgency, and hospitalizations) in the 12 months before and after mistreatment identification. Data were adjusted using US Centers for Medicare and Medicaid Services Hierarchical Condition Categories risk scores. Chi-squared tests and conditional logistic regression models were used for data analyses.ResultsThis study included 114 case patients and 410 control participants. Their median age was 72 years (IQR, 68-78 years), and 340 (64.9%) were women. Race and ethnicity were reported as racial or ethnic minority (114 [21.8%]), White (408 [77.9%]), or unknown (2 [0.4%]). During the 24 months surrounding identification of elder mistreatment, older adults experiencing mistreatment were more likely to have had an ED visit (77 [67.5%] vs 179 [43.7%]; adjusted odds ratio [AOR], 2.95 [95% CI, 1.78-4.91]; P < .001) and a hospitalization (44 [38.6%] vs 108 [26.3%]; AOR, 1.90 [95% CI, 1.13-3.21]; P = .02) compared with other older adults. In addition, multiple ED visits, at least 1 ED visit for injury, visits to multiple EDs, high-frequency ED use, return ED visits within 7 days, ED visits for low-urgency issues, multiple hospitalizations, at least 1 hospitalization for injury, hospitalization at multiple hospitals, and hospitalization for ambulatory care sensitive conditions were substantially more likely for individuals experiencing elder mistreatment. The rate of ED and hospital utilization for older adults experiencing elder mistreatment was much higher in the 12 months after identification than before, leading to more pronounced differences between case patients and control participants in postidentification utilization. During the 12 months after identification of elder mistreatment, older adults experiencing mistreatment were particularly more likely to have had high-frequency ED use (12 [10.5%] vs 8 [2.0%]; AOR, 8.23 [95% CI, 2.56-26.49]; P < .001) and to have visited the ED for low-urgency issues (12 [10.5%] vs 8 [2.0%]; AOR, 7.33 [95% CI, 2.54-21.18]; P < .001).Conclusions and RelevanceIn this case-control study of health care utilization, older adults experiencing mistreatment used EDs and hospitals more frequently and with different patterns during the period surrounding mistreatment identification than other older adults. Additional research is needed to better characterize these patterns, which may be helpful in informing early identification, intervention, and prevention of elder mistreatment.

Numerous recent works highlight the limited utility of established tumor cell lines in recapitulating the heterogeneity of tumors in patients. More realistic preclinical cancer models are thought to be provided by transplantable, patient-derived xenografts (PDXs). The inter- and intratumor heterogeneity of PDXs, however, presents several challenges in developing optimal quantitative pipelines to assess response to therapy. The objective of this work was to develop and optimize image metrics for

Purpose: To investigate whether longitudinal functional PET imaging of mammary tumors using the radiopharmaceuticals [18F]FDG (to measure glucose uptake), [18F]FES [to measure estrogen receptor (ER) levels], or [18F]FFNP [to measure progesterone receptor (PgR) levels] is predictive of response to estrogen-deprivation therapy. Experimental Design: [18F]FDG, [18F]FES, and [18F]FFNP uptake in endocrine-sensitive and -resistant mammary tumors was quantified serially by PET before ovariectomy or estrogen withdrawal in mice, and on days 3 and 4 after estrogen-deprivation therapy. Specificity of [18F]FFNP uptake in ERα+ mammary tumors was determined by competition assay using unlabeled ligands for PgR or glucocorticoid receptor (GR). PgR expression was also assayed by immunohistochemistry (IHC). Results: The levels of [18F]FES and [18F]FDG tumor uptake remained unchanged in endocrine-sensitive tumors after estrogen-deprivation therapy compared with those at pretreatment. In contrast, estrogen-deprivation therapy led to a reduction in PgR expression and [18F]FFNP uptake in endocrine-sensitive tumors, but not in endocrine-resistant tumors, as early as 3 days after treatment; the changes in PgR levels were confirmed by IHC. Unlabeled PgR ligand R5020 but not GR ligand dexamethasone blocked [18F]FFNP tumor uptake, indicating that [18F]FFNP bound specifically to PgR. Therefore, a reduction in FFNP tumor to muscle ratio in mammary tumors predicts sensitivity to estrogen-deprivation therapy. Conclusions: Monitoring the acute changes in ERα activity by measuring [18F]FFNP uptake in mammary tumors predicts tumor response to estrogen-deprivation therapy. Longitudinal noninvasive PET imaging using [18F]FFNP is a robust and effective approach to predict tumor responsiveness to endocrine treatment. Clin Cancer Res; 21(5); 1063–70. ©2014 AACR.

Overall survival of patients with newly diagnosed glioblastoma (GBM) remains dismal at 16 months with state-of-the-art treatment that includes surgical resection, radiation, and chemotherapy. GBM tumors are highly heterogeneous, and mechanisms for overcoming tumor resistance have not yet fully been elucidated. An injectable chitosan hydrogel capable of releasing chemotherapy (temozolomide [TMZ]) while retaining radioactive isotopes agents (iodine, [ 131 I]) was used as a vehicle for localized radiation and chemotherapy, within the surgical cavity. Release from hydrogels loaded with TMZ or 131 I was characterized in vitro and in vivo and their efficacy on tumor progression and survival on GBM tumors was also measured. The in vitro release of 131 I was negligible over 42 days, whereas the TMZ was completely released over the first 48 h. 131 I was completely retained in the tumor bed with negligible distribution in other tissues and that when delivered locally, the chemotherapy accumulated in the tumor at 10-fold higher concentrations than when delivered systemically. We found that the tumors were significantly decreased, and survival was improved in both treatment groups compared to the control group. Novel injectable chemo-radio-hydrogel implants may potentially improve the local control and overall outcome of aggressive, poor prognosis brain tumors.

Dietary conditions may affect liver [(18)F]FDG kinetics due to arterial and portal vein (PV) input. The purpose of this study was to evaluate kinetic models of [(18)F]FDG metabolism under a wide range of dietary interventions taking into account variations in arterial (HA) and portal vein (PV) input.The study consisted of three groups of rats maintained under different diet interventions: 12 h fasted, 24 h fasted and those fed with high fructose diet. [(15)O]H₂O PET imaging was used to characterize liver flow contribution from HA and PV to the liver's dual input function (DIF). [(18)F]FDG PET imaging was used to characterize liver metabolism. Differences in [(18)F]FDG kinetics in HA, PV and liver under different diet interventions were investigated. An arterial to PV Transfer Function (TF) was optimized in all three dietary states to noninvasively estimate PV activity. Finally, two compartment 3-parameter (2C3P), two compartment 4-parameter (2C4P), two compartment 5-parameter (2C5P), and three compartment 5-parameter (3C5P) models were evaluated and compared to describe the kinetics of [(18)F]FDG in the liver across diet interventions. Sensitivity of the compartmental models to ratios of HA to PV flow fractions was further investigated.Differences were found in HA and PV [(18)F]FDG kinetics across 12h fasted, 24h fasted and high fructose fed diet interventions. A two exponential TF model was able to estimate portal activity in all the three diet interventions. Statistical analysis suggests that a 2C3P model configuration was adequate to describe the kinetics of [(18)F]FDG in the liver under wide ranging dietary interventions. The net influx of [(18)F]FDG was lowest in the 12h fasted group, followed by 24 h fasted group, and high fructose diet.A TF was optimized to non-invasively estimate PV time activity curve in different dietary states. Several kinetic models were assessed and a 2C3P model was sufficient to describe [(18)F]FDG liver kinetics despite differences in HA and PV kinetics across wide ranging dietary interventions. The observations have broader implications for the quantification of liver metabolism in metabolic disorders and cancer, among others.

Rationale and Objectives Non-invasive longitudinal imaging of tumor vasculature could provide new insights into the development of solid tumors, facilitating efficient delivery of therapeutics. In this study, we report three-dimensional imaging and characterization of tumor vascular architecture using a nanoparticle contrast agent and high-resolution computed tomography (CT) imaging. Materials and Methods Five Balb/c mice implanted with 4T1/Luc syngeneic breast tumors cells were used for the study. The nanoparticle contrast agent was systemically administered and longitudinal CT imaging was performed pre-contrast and at serial time points post-contrast, for up to 7 days for studying the characteristics of tumor-associated blood vessels. Gene expression of tumor angiogenic biomarkers was measured using quantitative real-time polymerase chain reaction. Results Early-phase imaging demonstrated the presence of co-opted and newly developed tumor vessels. The co-opted vessels demonstrated wall-permeability and “leakiness” characteristics evident by an increase in extravascular nanoparticle-based signal enhancement visible well beyond the margins of tumor. Diameters of tumor-associated vessels were larger than the contralateral normal vessels. Delayed-phase imaging also demonstrated significant accumulation of nanoparticle contrast agent both within and in areas surrounding the tumor. A heterogeneous pattern of signal enhancement was observed both within and among individual tumors. Gene-expression profiling demonstrated significant variability in several angiogenic biomarkers both within and among individual tumors. Conclusions The nanoparticle contrast agent and high-resolution CT imaging facilitated visualization of co-opted and newly developed tumors vessels as well as imaging of nanoparticle accumulation within tumors. The use of this agent could provide novel insights into tumor vascular biology and could have implications on the monitoring of tumor status.

Progesterone receptors (PRs) are present in many breast tumors, and their levels are increased by certain endocrine therapies. They can be used as targets for diagnostic imaging and radiotherapy.16alpha,17alpha-[(R)-1'-alpha-(5-[(76)Br]Bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione ([(76)Br]16alpha,17alpha-[(R)-1'-alpha-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione (3)), a PR ligand with relative binding affinity (RBA)=65 and log P(o/w)=5.09+/-0.84, was synthesized via a two-step reaction, and its tissue biodistribution and metabolic stability were evaluated in estrogen-primed immature female Sprague-Dawley rats.[(76)Br]16alpha,17alpha-[(R)-1'-alpha-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione 3 was synthesized in 5% overall yield with specific activity being 200-1250 Ci/mmol. [(76)Br]16alpha,17alpha-[(R)-1'-alpha-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione 3 demonstrated high PR-mediated uptake in the target tissue uterus (8.72+/-1.84 %ID/g at 1 h) that was reduced by a blocking dose of unlabeled progestin R5020, but the nonspecific uptake in blood and muscle (2.11+/-0.14 and 0.89+/-0.16 %ID/g at 1 h, respectively) was relatively high. [(76)Br]16alpha,17alpha-[(R)-1'-alpha-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione 3 was stable in whole rat blood in vitro, but it was not stable in vivo due to the fast metabolism that occurred in the liver, resulting in the formation of a more polar radioactive metabolite and free [(76)Br]bromide. The level of free [(76)Br]bromide in blood remained high during the experiment (2.11+/-0.14 %ID/g at 1 h and 1.52+/-0.24 %ID/g at 24 h). The tissue distribution of [(76)Br]16alpha,17alpha-[(R)-1'-alpha-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione 3 at 1 and 3 h was compared with that of the (18)F analogs, [(18)F]FFNP fluoro furanyl norprogesterone (FFNP) 1 and ketal 2.[(76)Br]16alpha,17alpha-[(R)-1'-alpha-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione 3 may have potential for imaging PR-positive breast tumors at early time points, but it is not suitable for imaging at later times or for radiotherapy.

Diabetic cardiomyopathy is associated with abnormalities in glucose metabolism. We evaluated myocardial glucose metabolism in a rodent model of type 2 diabetes, namely the Zucker diabetic fatty (ZDF) rat, and validated PET measurements of glucose uptake against gene and protein expression of glucose transporters (GLUTs).Six lean and ZDF rats underwent small-animal PET at the age of 14 wk and at the age of 19 wk. The imaging protocol consisted of a 60-min dynamic acquisition with 18F-FDG (18.5-29.6 MBq). Dynamic images were reconstructed using filtered backprojection with a 2.5 zoom on the heart and 40 frames per imaging session. PET measurements of myocardial glucose uptake (MGUp) rate and utilization were determined with an input function derived by the hybrid image-blood-sampling algorithm on recovery-corrected anterolateral myocardial regions of interest. After the PET session at week 19 (W19), hearts were extracted for gene and protein expression analysis of GLUT-1 and GLUT-4. The dependence of MGUp on gene expression of GLUT-1 and GLUT-4 was characterized by multiple-regression analysis.MGUp in ZDF rats at both week 14 (W14) and W19 (P0.006) was significantly lower than MGUp in lean littermate control rats. Moreover, lean rats at W19 displayed significantly higher MGUp than they did at W14 (P = 0.007). Consistent with a diminished MGUp result, gene expression of GLUT-4 was significantly (P = 0.004) lower in ZDF rats. Finally, MGUp significantly (P = 0.0003) correlated with gene expression of GLUT-4.Using small-animal PET, we confirmed alterations in myocardial glucose utilization and validated PET measurement of MGUp against gene and protein expression of GLUTs in the diabetic heart of an animal model of type 2 diabetes.

Estrogen receptor-α (ERα) is expressed in most human breast cancers and is an important predictive factor for directing therapy. Compared with patients with ERα-negative tumors, patients with ERα-positive (ERα+) tumors typically have longer overall survival and are more likely to respond to hormone-based therapies designed to decrease endogenous estrogens or block ER transcriptional activity, such as aromatase inhibitors, tamoxifen, or fulvestrant. However, some patients with ERα+ tumors do not respond to endocrine therapy (1). The progesterone receptor gene (PGR) is a classic estrogen-stimulated target gene, and currently both ERα and progesterone receptor (PR) are routinely measured using immunohistochemistry as part of the pathologic assessment of breast cancer (2). Although immunohistochemistry is the current gold standard for detecting steroid hormone receptor expression, noninvasive imaging offers several advantages. For instance, imaging can assess the entire lesion, which is advantageous for tumors with heterogeneous receptor expression that could lead to biopsy sample error. Furthermore, noninvasive imaging is useful for metastatic lesions that may be technically difficult to biopsy or for patients at high risk for biopsy-related complications. Repeated imaging can assess whole-body disease burden over time, as one cannot presume that recurrent or metastatic lesions retain the same steroid hormone expression profile as the primary tumor and discordance occurs in up to 30% of the patients who ultimately have a decreased response to hormonal therapy (3,4). The ability of these nuclear receptors to bind ligand provides a convenient target for the development of imaging agents (5). The estrogen-based radiopharmaceutical 18F-fluoroestradiol (18F-FES) has high specific activity, binding affinity, and selectivity for ERα over the ERβ subtype (6) and has been shown to exhibit high specific uptake by ER-rich target tissues and ERα+ mammary tumors using small-animal models (7,8). For human breast cancer patients, use of 18F-FES PET as a measure of tumoral ERα expression has been validated by the gold standards of immunohistologic and biochemical receptor assays with significant concordance (9–11). 18F-FES imaging has also been shown to be a predictive assay for endocrine therapy since patients with pretreatment 18F-FES standardized uptake values greater than 1.5–2.0 correlate with a positive response to therapy (12,13). Although not as well studied as 18F-FES, progestin-based radiopharmaceuticals such as 18F-fluoro furanyl norprogesterone (18F-FFNP) have been developed for PR imaging as an indicator of a functionally intact ERα signaling pathway (14). Preclinical studies have demonstrated high 18F-FFNP uptake in the uterus and ovaries of estrogen-primed immature female rats (14), and initial results for 18F-FFNP imaging of human breast cancer patients have recently been published (15). The goal of this study was to determine whether changes in tumoral steroid hormone receptor expression as assessed by molecular imaging after endocrine therapy are of predictive value using a preclinical animal model of human luminal breast cancer. Disruption of the gene for the signal transducer and activator of transcription-1 (STAT1) in mice results in a complete lack of responsiveness to interferons and, interestingly, spontaneous development of mammary tumors (16). These adenocarcinomas are remarkably similar to human luminal breast cancers since they express ERα and PR, require ovarian hormones for growth, and have significantly overlapping gene expression profiles (17). Furthermore, the tumors are HER2/neu-negative (17) and have no detectable epidermal growth factor receptor or ERβ protein expression (Szeman Ruby Chan and Robert D. Schreiber, unpublished data, May 29, 2012). In the current study, we performed 18F-FES and 18F-FFNP PET of primary and implanted STAT1-deficient (STAT1−/−) mammary tumors at baseline and in response to fulvestrant, a pure ERα antagonist, to determine whether changes in these imaging bio-markers can serve as an early predictive indicator of the ultimate response to therapy. An imaging approach that successfully predicts tumor response to standard endocrine therapy would be a useful tool for the further evaluation of novel breast cancer treatments.

Evidence is emerging that systemic metabolic disturbances contribute to cardiac myocyte dysfunction and clinically apparent heart failure, independent of associated coronary artery disease. To test the hypothesis that perturbation of lipid homeostasis in cardiomyocytes contributes to cardiac dysfunction, we engineered transgenic mice with cardiac-specific overexpression of fatty acid transport protein 1 (FATP1) using the α-myosin heavy chain gene promoter. Two independent transgenic lines demonstrate 4-fold increased myocardial free fatty acid (FFA) uptake that is consistent with the known function of FATP1. Increased FFA uptake in this model likely contributes to early cardiomyocyte FFA accumulation (2-fold increased) and subsequent increased cardiac FFA metabolism (2-fold). By 3 months of age, transgenic mice have echocardiographic evidence of impaired left ventricular filling and biatrial enlargement, but preserved systolic function. Doppler tissue imaging and hemodynamic studies confirm that these mice have predominantly diastolic dysfunction. Furthermore, ambulatory ECG monitoring reveals prolonged QT c intervals, reflecting reductions in the densities of repolarizing, voltage-gated K + currents in ventricular myocytes. Our results show that in the absence of systemic metabolic disturbances, such as diabetes or hyperlipidemia, perturbation of cardiomyocyte lipid homeostasis leads to cardiac dysfunction with pathophysiological findings similar to those in diabetic cardiomyopathy. Moreover, the MHC-FATP model supports a role for FATPs in FFA import into the heart in vivo.

Background Cardiovascular disease is the leading cause of death among diabetic patients. Importantly, recent data highlight the apparent sexual dimorphism in the pathogenesis of cardiovascular disease in diabetics with respect to both frequency- and age-related risk factors. The disposition to cardiovascular disease among diabetic patients has been attributed, at least in part, to excess lipid supply to the heart culminating in lipotoxicity of the heart and downstream derangements. A confounding factor in obese animal models of diabetes is that increased peripheral lipid availability to the heart can induce cardio-metabolic remodeling independent of the underlying pathophysiology of diabetes, thus masking the diabetic phenotype. To that end, we hypothesized that the use of non-obese diabetic (NOD) animal models will reveal metabolic signatures of diabetes in a sex-specific manner. Methods To test this hypothesis, male and female NOD Goto-Kakizaki (GK) rats were used to assess the expression profile of 84 genes involved in lipid metabolism. In parallel, targeted lipidomics analysis was performed to characterize sex differences in homeostasis of non-esterified fatty acids (NEFA), acylcarnitines (AC), and triglycerides (TG). Results Our analysis revealed significant sex differences in the expression of a broad range of genes involved in transport, activation, and utilization of lipids. Furthermore, NOD male rats exhibited enhanced oxidative metabolism and accumulation of TG, whereas female NOD rats exhibited reduced TG content coupled with accumulation of AC species. Multi-dimensional statistical analysis identified saturated AC16:0, AC18:0, and AC20:0 as dominant metabolites in mediating sex differences in AC metabolism. Confocal microscopy of rat cardiomyocytes exposed to AC14:0, AC16:0, and AC18:0 confirmed induction of ROS with AC18:0 being more potent followed by AC14:0. Conclusion Overall, we demonstrate sex differences in myocardial AC and TG metabolism with implications for therapy and diagnosis of diabetic cardiovascular disease. Electronic supplementary material The online version of this article (doi:10.1186/s13293-016-0077-7) contains supplementary material, which is available to authorized users.