Nanomedicine holds great potential for revolutionizing medical treatment. Ongoing research and advancements in nanotechnology are continuously expanding the possibilities, promising significant advancements in healthcare. To fully harness the potential of nanotechnology in medical applications, it is crucial to conduct safety evaluations for the nanomedicines that offer effective benefits in the preclinical stage. Our recent efficacy studies indicated that rapamycin perfluorocarbon (PFC) nanoparticles showed promise in mitigating cisplatin-induced acute kidney injury (AKI). As cisplatin is routinely administered to ovarian cancer patients as their first-line chemotherapy, in this study, we focused on evaluating the safety of rapamycin PFC nanoparticles in mice bearing ovarian tumor xenografts. Specifically, this study evaluated the effects of repeat-dose rapamycin PFC nanoparticle treatment on vital organs, the immune system, and tumor growth and assessed pharmacokinetics and biodistribution. Our results indicated that rapamycin PFC nanoparticle treatment did not cause any detectable adverse effects on cardiac, renal, or hepatic functions or on splenocyte populations, but it reduced the splenocyte secretion of IL-10, TNFα, and IL12p70 upon IgM stimulation. The pharmacokinetics and biodistribution results revealed a significant enhancement in the delivery of rapamycin to tumors by rapamycin PFC nanoparticles, which, in turn, led to a significant reduction in ovarian tumor growth. Therefore, rapamycin PFC nanoparticles have the potential to be clinically beneficial in cisplatin-treated ovarian cancer patients.

Background: Transthyretin (ATTR) cardiac amyloidosis is associated with an apical-sparing strain pattern on TTE. We hypothesize that strain indices derived from myocardial perfusion imaging (MPI) can identify this abnormality. Methods: A group with ATTR amyloidosis was compared to age-matched controls with LVH but without amyloidosis who underwent PET or SPECT MPI. Strain values were used to calculate the apical strain index (ASI), apex-to-base ratio (ABR), and ejection fraction to global strain ratio in multiple planes. Results: A direct comparison using Welch's t-tests reveals 6 statistically significant metrics. After regression analysis, the circumferential ASI and ABR at rest remain significantly greater in the ATTR group compared to controls. Conclusion: MPI-derived strain from the circumferential plane at rest may distinguish cardiac amyloidosis from other forms of LVH. If these findings are confirmed with validation studies, routine MPI-derived strain analysis could identify patients with subclinical amyloidosis who may benefit from further testing.

Myocardial ischemia reperfusion injury (IRI) in acute coronary syndromes is a condition in which ischemic/hypoxic injury to cells subtended by the occluded vessel continues despite successful resolution of the thrombotic obstruction. For decades, most efforts to attenuate IRI have focused on interdicting singular molecular targets or pathways, but none have successfully transitioned to clinical use. In this work, we investigate a nanoparticle-based therapeutic strategy for profound but local thrombin inhibition that may simultaneously mitigate both thrombosis and inflammatory signaling pathways to limit myocardial IRI. Perfluorocarbon nanoparticles (PFC NP) were covalently coupled with an irreversible thrombin inhibitor, PPACK (Phe[D]-Pro-Arg-Chloromethylketone), and delivered intravenously to animals in a single dose prior to ischemia reperfusion injury. Fluorescent microscopy of tissue sections and 19F magnetic resonance images of whole hearts ex vivo demonstrated abundant delivery of PFC NP to the area at risk. Echocardiography at 24 h after reperfusion demonstrated preserved ventricular structure and improved function. Treatment reduced thrombin deposition, suppressed endothelial activation, inhibited inflammasome signaling pathways, and limited microvascular injury and vascular pruning in infarct border zones. Accordingly, thrombin inhibition with an extraordinarily potent but locally acting agent suggested a critical role for thrombin and a promising therapeutic strategy in cardiac IRI.

This study aimed to develop a measure of longitudinal, radial, and circumferential myocardial strain at rest and regadenoson during pharmacologic stress using 82Rb PET electrocardiography-gated myocardial perfusion imaging (MPI). Methods: We retrospectively identified 80 patients who underwent rest and regadenoson-stress CT attenuation-corrected 82Rb PET and had a standard resting transthoracic echocardiogram (TTE) with global longitudinal strain (GLS) analysis within 3 mo. A method was developed to compute longitudinal, radial, and circumferential strain from PET MPI at stress and rest. PET MPI-derived strain and left ventricular function were compared with resting TTE measures as the clinical reference standard. Interobserver agreement of PET MPI strain and left ventricular ejection fraction processing was reported. Results: Longitudinal strain assessed with resting TTE GLS showed good correlation with PET MPI at stress (r = 0.68, P < 0.001) and rest (r = 0.58, P < 0.001). Resting TTE GLS also correlated with PET MPI radial strain at stress (r = -0.70, P < 0.001) and rest (r = -0.59, P < 0.001) and circumferential strain at stress (r = 0.67, P < 0.001) and rest (r = 0.69, P < 0.001). The left ventricular ejection fraction showed good correlation between resting TTE and PET MPI at stress (r = 0.83, P < 0.001) and rest (r = 0.80, P < 0.001). Bland-Altman analysis indicated positive bias of TTE GLS compared with PET MPI longitudinal strain at stress (mean difference = 5.1%, 95% CI = [-2.5, 12.7]) and rest (mean difference = 4.2%, 95% CI = [-4.3, 12.8]). Reproducibility of PET MPI longitudinal strain showed good agreement at stress (concordance correlation coefficient = 0.73, P < 0.001) and rest (concordance correlation coefficient = 0.74, P < 0.001), with Bland-Altman analysis showing a small bias in the longitudinal direction at stress (mean difference = -0.2%) and rest (mean difference = -1.0%). Conclusion: Strain measured with PET MPI using an automated technique correlated well with resting GLS strain obtained by TTE, and the measure is reproducible. Strain from PET MPI should be investigated further to establish reference ranges and assess its value in routine clinical practice.

ABSTRACT The complex pathophysiology underlying biological aging creates challenges for identifying biomarkers associated with frailty. This longitudinal, nontargeted proteomics study aimed to identify proteins associated with frailty, particularly the change from nonfrail to frail. The population‐based Osteoporosis Prospective Risk Assessment cohort includes women all of whom are 75 years old at inclusion ( n = 1044) and reassessed at 80 years ( n = 715) and 85 years ( n = 382). A deficits in health frailty index (FI) and 92 plasma proteins (Olink CVD‐II panel) were available at all ages. The identical age facilitated differentiating chronological and biological aging. Bidirectional analyses, performed cross‐sectionally and longitudinally, used regression models controlled for false discovery rate (FDR), across 5‐ and 10‐year time windows and longitudinal mixed models. Frailty outcomes were frailty index, frailty status (frail defined as FI ≥ 0.25), change in frailty index, and change in frailty status, together with protein expression or change in protein expression. Elevated levels of 32 proteins were positively associated with the FI, cross‐sectionally at all ages (range: β‐coefficients 0.22–2.06; FDR 0.021–0.024), of which 18 were also associated with frailty status (range: odds ratios 1.40–5.77; FDR 0.022–0.016). Based on the accrued data, eight core proteins (CD4, FGF23, Gal‐9, PAR‐1, REN, TNFRSF10A TNFRSF11A, and TNFRSF10B) are proposed. A one‐unit change in the FI was additively associated with increased protein expression over 5 and 10 years (range: β‐coefficients 0.52–1.59; p < 0.001). Increments in baseline FI consistently associated with a change in protein expression over time (5 years, β‐range 0.05–1.35; 10 years, β‐range 0.51–1.48; all p < 0.001). A one‐unit increase in protein expression was also associated with an increased probability of being frail (FI ≥ 0.25) (β‐range: 0.14–0.61). Mirroring the multisystem deterioration that typifies frailty, the proteins and their associated biological pathways reflect pathologies, including the renal system, skeletal homeostasis, and TRAIL‐activated apoptotic signaling. The core proteins are compelling candidates for understanding the development and progression of frailty with advancing age, including the intrinsic musculoskeletal component. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

The complex pathophysiology underlying biological aging creates challenges for identifying biomarkers associated with frailty. This longitudinal, nontargeted proteomics study aimed to identify proteins associated with frailty, particularly the change from nonfrail to frail. The population-based Osteoporosis Prospective Risk Assessment cohort includes women all of whom are 75 years old at inclusion ( n  = 1044) and reassessed at 80 years ( n  = 715) and 85 years ( n  = 382). A deficits in health frailty index (FI) and 92 plasma proteins (Olink CVD-II panel) were available at all ages. The identical age facilitated differentiating chronological and biological aging. Bidirectional analyses, performed cross-sectionally and longitudinally, used regression models controlled for false discovery rate (FDR), across 5- and 10-year time windows and longitudinal mixed models. Frailty outcomes were frailty index, frailty status (frail defined as FI ≥ 0.25), change in frailty index, and change in frailty status, together with protein expression or change in protein expression. Elevated levels of 32 proteins were positively associated with the FI, cross-sectionally at all ages (range: β-coefficients 0.22–2.06; FDR 0.021–0.024), of which 18 were also associated with frailty status (range: odds ratios 1.40–5.77; FDR 0.022–0.016). Based on the accrued data, eight core proteins (CD4, FGF23, Gal-9, PAR-1, REN, TNFRSF10A TNFRSF11A, and TNFRSF10B) are proposed. A one-unit change in the FI was additively associated with increased protein expression over 5 and 10 years (range: β-coefficients 0.52–1.59; p  < 0.001). Increments in baseline FI consistently associated with a change in protein expression over time (5 years, β-range 0.05–1.35; 10 years, β-range 0.51–1.48; all p  < 0.001). A one-unit increase in protein expression was also associated with an increased probability of being frail (FI ≥ 0.25) (β-range: 0.14–0.61). Mirroring the multisystem deterioration that typifies frailty, the proteins and their associated biological pathways reflect pathologies, including the renal system, skeletal homeostasis, and TRAIL-activated apoptotic signaling. The core proteins are compelling candidates for understanding the development and progression of frailty with advancing age, including the intrinsic musculoskeletal component. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

OBJECTIVE:Focal lesions within the subchondral bone, termed subchondral bone cysts (SBCs), are clinically accepted radiographic markers of advanced osteoarthritis (OA), but their etiology in the hip is not well understood. DESIGN:This study used micro-computed tomography (μCT), and histological and immunocytological analysis to examine the prevalence, size, location, and morphological and cellular features of SBCs found within 34 femoral heads (14 male, 20 female; age range = 43-80 years) obtained from total hip arthroplasty procedures. RESULTS:SBCs were common-present in 91% of the femoral heads examined-and frequently commuted with the surface of the femoral head, but otherwise showed no preferred anatomical location. Few associations were found between SBC features and patient characteristics such as BMI, age and sex. SBCs were also heterogenous in composition, ranging from fibrous (most common) to predominantly fatty (least common) and often containing vasculature, nerve fibers, cartilage islands, and bony spicules. Despite this heterogeneity, focal abnormalities in bone density and cartilage thickness were consistently observed. Bone adjacent to SBCs was denser than that in the primary compressive group, and cartilage thickness in regions overlying SBCs was lower than in non-overlying regions. In contrast to these local bony changes, μCT-based finite element analyses indicated that the stiffness of the primary compressive group was only mildly affected by SBCs. CONCLUSIONS:These findings indicate that SBCs in the femoral head involve extensive perturbations in cellular activity, culminating in myriad skeletal tissue types and spatially heterogenous changes in bone and cartilage morphology that are likely to affect OA progression.

Introduction: Global longitudinal strain (GLS) by two-dimensional (2D) transthoracic echocardiography (TTE) is a robust index for identifying early left ventricular (LV) myocardial dysfunction. Positron emission tomography (PET) myocardial perfusion imaging (MPI) is widely used in the assessment of ischemic heart disease (IHD) but has not been used for strain analysis. Hypothesis: Longitudinal, radial, and circumferential myocardial strain measures at rest and at pharmacologic stress by Rb-82 ECG-gated PET MPI are correlated to those measured by resting 2D TTE. Methods: We developed a novel PET MPI method to track the LV myocardium throughout the cardiac cycle processed in the Emory Cardiac Toolbox, to measure LV strain from longitudinal, radial, and circumferential direction at regadenoson-stress and at rest. We retrospectively identified 80 patients who underwent Rb-82 PET MPI and also had TTE with strain analysis within 3 months. The agreement between LV strain and LVEF derived from PET MPI and resting TTE was assessed with Bland-Altman analysis, Pearson’s correlation, and the concordance correlation coefficient (CCC). Results: PET MPI derived measurements of longitudinal (Figure 1A-1B: Bland-Altman analysis; 1C-1D: Pearson’s correlations), circumferential (Figure 1E-1F: Pearson’s correlations) and radial (Figure 1G-1H: Pearson’s correlations) strain measures at rest and stress were strongly correlated to resting TTE derived GLS (p<.001). LVEF showed strong correlations at stress (0.83, p<.001) and rest (0.80, p<.001). Inter-observer agreements of PET MPI strain measures showed high correlation between 2 independent observers for all 3 directions (p<.001). Conclusions: LV strain measures by PET MPI using a novel automated technique correlated strongly with GLS by TTE. PET MPI measures are highly reproducible. Strain by PET MPI should be investigated further to establish its value in routine clinical practice.

The optimal coronary artery disease surveillance strategy for end-stage renal disease patients being evaluated for kidney transplantation is unknown. It is unclear what risk factors are associated with the development of new-onset perfusion abnormalities on serial myocardial perfusion imaging. Potential kidney transplant recipients who underwent 2 myocardial perfusion imaging studies at Emory University Hospital between January 2010 and December 2019 were identified. We assessed the frequency of development of any new perfusion defect and development of moderate to severe ischemia (reversible perfusion defect >10%) on serial imaging. Finally, we identified the clinical and imaging factors associated with new perfusion defects and explored the association between new perfusion defects and all-cause mortality. History of myocardial infarction (MI) and peripheral artery disease was associated with an increased risk of developing a new perfusion defect. History of MI was also associated with the risk of developing moderate-severe ischemia. Female patients were less likely to develop new perfusion defects or moderate-severe ischemia. There was no association between either outcome and all-cause mortality. In conclusion, a history of MI, peripheral artery disease, and male gender are risk factors for developing new perfusion defects, although only the history of MI and male gender predict moderate to severe ischemia. Interval development of any abnormal perfusion is not associated with increased mortality.

Abstract Context In a cross-sectional study, we found an association between type 2 diabetes mellitus (T2DM) and smaller bone area together with greater bone mineral density (BMD) at the total hip. Objective This work aims to investigate these associations longitudinally, by studying T2DM status (no T2DM n = 1521, incident T2DM n = 119, or prevalent T2DM n = 106) in relation to changes in total hip bone area and BMD. Methods In 3 cohorts, the Swedish Mammography Cohort Clinical (SMCC; n = 1060), Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; n = 483), and Uppsala Longitudinal Study of Adult Men (ULSAM; n = 203), with repeat assessment of T2DM status and dual energy x-ray absorptiometry (DXA) measurements of total hip bone area and BMD on average 8 years apart, a linear regression model was used to assess the effect of T2DM status on change in bone area and BMD at the total hip. Results After meta-analysis, the change in bone area at the total hip was 0.5% lower among those with incident T2DM compared to those without T2DM (–0.18 cm2; 95% CI, –0.30 to –0.06). The change in bone area was similar among those with prevalent T2DM compared to those without (0.00 cm2; 95% CI, –0.13 to 0.13). For BMD, the combined estimate was 0.004 g/cm2 (95% CI, –0.006 to 0.014) among those with incident T2DM and 0.010 g/cm2 (95% CI, –0.000 to 0.020) among those with prevalent T2DM, compared to those without T2DM. Conclusion Those with incident T2DM have a lower expansion in bone area at the total hip compared to those without T2DM.

Aims/hypothesis Observational studies indicate that type 2 diabetes mellitus and fasting glucose levels are associated with a greater risk for hip fracture, smaller bone area and higher bone mineral density (BMD). However, these findings may be biased by residual confounding and reverse causation. Mendelian randomisation (MR) utilises genetic variants as instruments for exposures in an attempt to address these biases. Thus, we implemented MR to determine whether fasting glucose levels in individuals without diabetes are causally associated with bone area and BMD at the total hip. Methods We selected 35 SNPs strongly associated with fasting glucose ( p < 5 × 10 −8 ) in a non-diabetic European-descent population from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) ( n = 133,010). MR was used to assess the associations of genetically predicted fasting glucose concentrations with total hip bone area and BMD in 4966 men and women without diabetes from the Swedish Mammography Cohort, Prospective Investigation of Vasculature in Uppsala Seniors and Uppsala Longitudinal Study of Adult Men. Results In a meta-analysis of the three cohorts, a genetically predicted 1 mmol/l increment of fasting glucose was associated with a 2% smaller total hip bone area (−0.67 cm 2 [95% CI −1.30, −0.03; p = 0.039]), yet was also associated, albeit without reaching statistical significance, with a 4% higher total hip BMD (0.040 g/cm 2 [95% CI −0.00, 0.07; p = 0.060]). Conclusions/interpretation Fasting glucose may be a causal risk factor for smaller bone area at the hip, yet possibly for greater BMD. Further MR studies with larger sample sizes are required to corroborate these findings. Graphical abstract

Abstract Background We examined whether the inverse association between adherence to a Mediterranean diet and hip fracture risk is mediated by incident type 2 diabetes mellitus (T2DM) and body mass index (BMI). Methods We included 50 755 men and women from the Cohort of Swedish Men and the Swedish Mammography Cohort who answered lifestyle and medical questionnaires in 1997 and 2008 (used for calculation of the Mediterranean diet score 9mMED; low, medium, high) and BMI in 1997, and incident T2DM in 1997–2008). The cumulative incidence of hip fracture from the National Patient Register (2009–14) was considered as outcome. Results We present conditional odds ratios (OR) 9[95% confidence interval, CI) of hip fracture for medium and high adherence to mMED, compared with low adherence. The total effect ORs were 0.82 (0.71, 0.95) and 0.75 (0.62, 0.91), respectively. The controlled direct effect of mMED on hip fracture (not mediated by T2DM, considering BMI as an exposure-induced confounder), calculated using inverse probability weighting of marginal structural models, rendered ORs of 0.82 (0.72, 0.95) and 0.73 (0.60, 0.88), respectively. The natural direct effect ORs (not mediated by BMI or T2DM, calculated using flexible mediation analysis) were 0.82 (0.71, 0.95) and 0.74(0.61, 0.89), respectively. The path-specific indirect and partial indirect natural effects ORs (through BMI or T2DM) were close to 1. Conclusions Mediterranean diet has a direct effect on hip fracture risk via pathways other than through T2DM and BMI. We cannot exclude mediating effects of T2DM or BMI, or that their effects cancel each other out.

In a previous cross-sectional study, we found an association between type 2 diabetes mellitus (T2DM) and lower bone area together with a greater bone mineral density (BMD) at the total hip. We aime ...

Introduction: Screening for coronary artery disease in patients being considered for kidney transplant is common to stratify morbidity and mortality risk, but the optimal strategy, and its impact on outcomes, remains unclear. Here we test the hypothesis that myocardial perfusion imaging (MPI) abnormalities, left ventricular ejection fraction (LVEF), or coronary artery calcium (CAC) score are associated with all-cause mortality in potential kidney transplant recipients at Emory University Hospital (EUH). Methods: In a retrospective chart review, we assessed the relationship between patient demographics, single-photon emission MPI results, and CAC scoring with post-evaluation outcomes at 5 years in consecutive patients referred for pre-transplant stress testing at EUH in 2015. Mann-Whitney U and Chi-Square tests assessed between-group differences in continuous and categorical variables, respectively. Multivariate analysis was performed using logistic regression models. Results: During the study period, 589 patients (mean age 54 years; SEM 0.512, 58% male, 65% African American) underwent MPI and 424 also underwent CAC scoring. Overall, 90 patients (15%) had abnormal MPI (defined as any fixed or reversible defect) and 54 (9%) died during follow up. Age (mean 53.2 years; SEM 0.533 vs. 57.7 years; SEM 1.73, p=0.008), previous coronary artery bypass graft (CABG) (2.06% vs. 7.41%, p=0.017), and myocardial infarction (MI) post-evaluation (4.11% vs. 18.5%, p<0.001) were associated with all-cause mortality. Age (p=0.032) and MI post-evaluation (p<0.001) remained significant in multivariate analysis. MPI abnormalities, LVEF, and CAC score were not associated with all-cause mortality. Conclusions: Age and MI post-evaluation are associated with increased mortality in potential kidney transplant recipients referred for stress testing at EUH. We found no association between MPI abnormalities, LVEF, or CAC score and all-cause mortality.