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Carlota Mestres Gonzalvo,1 Kim PGM Hurkens,2 Hugo AJM de Wit,3 Brigit PC van Oijen,1 Rob Janknegt,1 Jos MGA Schols,4 Wubbo J Mulder,5 Frans R Verhey,6 Bjorn Winkens,7 Paul-Hugo M van der Kuy1 1Department of Clinical Pharmacology and Toxicology, Orbis Medical Centre, Sittard, 2Department of Internal Medicine, Section of Geriatric Medicine, Academic Medical Centre, Amsterdam, 3Department of Clinical Pharmacy and Toxicology, Atrium Medical Centre, Heerlen, 4Department of Family Medicine and Department of Health Services Research, School for Public Health and Primary Care, Maastricht University, 5Department of Internal Medicine, Maastricht University Medical Centre, 6Department of Psychiatry and Neuropsychology, Alzheimer Centre Limburg/School for Mental Health and Neurosciences, 7Department of Methodology and Statistics, School for Public Health and Primary Care, Maastricht University, Maastricht, the Netherlands Background: The aim of this study was to evaluate to what extent laboratory data, actual medication, medical history, and/or drug indication influence the quality of medication reviews for nursing home patients. Methods: Forty-six health care professionals from different fields were requested to perform medication reviews for three different cases. Per case, the amount of information provided varied in three subsequent stages: stage 1, medication list only; stage 2, adding laboratory data and reason for hospital admission; and stage 3, adding medical history/drug indication. Following a slightly modified Delphi method, a multidisciplinary team performed the medication review for each case and stage. The results of these medication reviews were used as reference reviews (gold standard). The remarks from the participants were scored, according to their potential clinical impact, from relevant to harmful on a scale of 3 to -1. A total score per case and stage was calculated and expressed as a percentage of the total score from the expert panel for the same case and stage. Results: The overall mean percentage over all cases, stages, and groups was 37.0% when compared with the reference reviews. For one of the cases, the average score decreased significantly from 40.0% in stage 1, to 30.9% in stage 2, and 27.9% in stage 3; no significant differences between stages was found for the other cases. Conclusion: The low performance, against the gold standard, of medication reviews found in the present study highlights that information is incorrectly used or wrongly interpreted, irrespective of the available information. Performing medication reviews without using the available information in an optimal way can have potential implications for patient safety. Keywords: polypharmacy, medication therapy management, decision support systems management, aged, medication review

Recanalization therapy after acute ischemic stroke enables restoration of cerebral perfusion. However, a significant subset of patients has poor outcome, which may be caused by disruption of cerebral energy metabolism. To assess changes in glucose metabolism subacutely and chronically after recanalization, we applied two complementary imaging techniques, fluorodeoxyglucose (FDG) positron emission tomography (PET) and deuterium ( 2 H) metabolic imaging (DMI), after 60-minute transient middle cerebral artery occlusion (tMCAO) in C57BL/6 mice. Glucose uptake, measured with FDG PET, was reduced at 48 hours after tMCAO and returned to baseline value after 11 days. DMI revealed effective glucose supply as well as elevated lactate production and reduced glutamate/glutamine synthesis in the lesion area at 48 hours post-tMCAO, of which the extent was dependent on stroke severity. A further decrease in oxidative metabolism was evident after 11 days. Immunohistochemistry revealed significant glial activation in and around the lesion, which may play a role in the observed metabolic profiles. Our findings indicate that imaging (altered) active glucose metabolism in and around reperfused stroke lesions can provide substantial information on (secondary) pathophysiological changes in post-ischemic brain tissue.

Objectives: The objectives of the study are to study daily hospital practice regarding detection and management and to study hyperactive and hypoactive delirium of older patients during their hospitalization., Methods: A retrospective cohort study evaluating care as usual for older hospitalized patients with delirium at Maastricht University Medical Center+, a university hospital in the Netherlands, was performed. Inclusion criteria were older hospitalized patients (65+ years), diagnosed with delirium between 1 January and 31 December 2014. Data were retrieved from the patients' medical files. Delirium was categorized as hyperactive or hypoactive. Primary outcome measures were prevalence and management (pharmacological, reorientation, screening for delirium and delirium consultations, and physical restraints). Secondary outcomes were short-term adverse outcomes., Results: Prevalence of delirium was 5% (N = 401), of which 77% (n = 307) was hyperactive and 23% (n = 94) was hypoactive. Significantly, more patients with a hyperactive delirium received medication to manage the delirium than patients with a hypoactive delirium (89% vs. 77%, respectively, p = 0.004). No other significant differences between the subtypes were found., Conclusion: There was probably a strong under-recognition of delirium. Drugs were the main intervention of choice, especially for patients with hyperactive delirium. The two subtypes did not differ on non-pharmacological management. The retrospective nature of this study sheds light on the status quo of recognition, management, and care as usual for the different delirium subtypes in daily hospital practice, which may help in forming new guidelines and protocols for the detection and treatment of delirium for older patients in hospitals., (© 2017 The Authors. International Journal of Geriatric Psychiatry Published by John Wiley & Sons Ltd.)

Background: Delirium is a common and serious complication of hospitalisation in older adults. It can lead to prolonged hospital stay, institutionalisation, and even death. However, it often remains unrecognised or is not managed adequately. The aim of this study was to evaluate the effects of an educational intervention for nursing staff on three aspects of clinical practice concerning delirium in older hospitalised patients: the frequency and correctness of screening for delirium using the 13-item Delirium Observation Screening score (DOS), and the frequency of geriatric consultations requested for older patients. The a priori expectations were that there would be an increase in all three of these outcomes., Methods: We designed an educational intervention and implemented this on two inpatient hospital units. Before providing the educational session, the nursing staff was asked to fill out two questionnaires about delirium in older hospitalised patients. The educational session was then tailored to each unit based on the results of these questionnaires. Additionally, posters and flyers with information on the screening and management of delirium were provided and participants were shown where to find additional information. Relevant data (outcomes, demographics and background patient data) were collected retrospectively from digital medical files. Data was retrospectively collected for four different time points: three pre-test and one post-test., Results: There was a significant increase in frequency of delirium screening (P = 0.001), and both units showed an increase in the correctness of the screening. No significant effect of the educational intervention was found for the proportion of patients who received a geriatric consultation (P = 0.083)., Conclusion: The educational intervention was fairly successful in making positive changes in clinical practice: after the educational session an improvement in the frequency and correctness of screening for delirium was observed. A trend, though not significant, towards an increase in the proportion of geriatric consultations for older hospitalised patients was also observed.

Purpose: The chronic use of benzodiazepines and benzodiazepine-related drugs (BZ/Z) in older people is common and not without risks. The objective of this study was to evaluate whether the implementation of a clinical rule promotes the discontinuation of chronically used BZ/Z for insomnia., Methods: A clinical rule, generating an alert in case of chronic BZ/Z use, was created and applied to the nursing home (NH) setting. The clinical rule was a one-off intervention, and alerts did not occur over time. Reports of the generated alerts were digitally sent to NH physicians with the advice to phase out and eventually stop the BZ/Z. In cases where the advice was adopted, a follow-up period of 4 months on the use of BZ/Z was taken into account in order to determine whether the clinical rule alert led to a successful discontinuation of BZ/Z., Results: In all, 808 NH patients were screened. In 161 (19.1%) of the patients, BZ/Z use resulted in a clinical rule alert. From these, the advice to phase out and stop the BZ/Z was adopted for 27 patients (16.8%). Reasons for not following the advice consisted of an unsuccessful attempt in the past (38 patients), patients family and/or patient resistance (37 patients), the non-continuous use of BZ/Z (32 patients) and indication still present (27 patients). Of the 12 NH physicians, seven adopted the advice., Conclusions: The success rate of a clinical rule for discontinuation of chronically used BZ/Z for insomnia was low, as reported in the present study. Actions should be taken to help caregivers, patients and family members understand the importance of limiting BZ/Z use to achieve higher discontinuation rates.

Background: Delirium in older hospitalised patients is a common and serious disorder. Polypharmacy and certain medications are risk factors for developing delirium. A medication review could benefit older hospitalised patients with delirium., Objectives: (1) Evaluate the effects of medication review on length of delirium, length of hospital stay, mortality, and discharge destination; and (2) describe and analyse the proposed changes to medication and its implementation by the treating physician., Setting: The study was conducted at Maastricht University Medical Centre+., Methods: We compared two cohorts of older patients with delirium: the first cohort from before introducing the medication review, and a second cohort 5 months after introduction of the medication review. Data were extracted from the patients' digital medical records., Results: A significant interaction effect of cohort and number of medications taken by the patient was found for duration of delirium: patients from the second cohort taking between zero and six medications had significantly shorter delirious episodes than patients in the first cohort. This effect bordered on significance for patients taking between seven and 11 medications, but disappeared for patients taking 12 or more medications. No other statistically significant differences were found between the cohorts. The proposed changes in medication were implemented for 71% of the patients., Conclusion: A medication review seems to significantly decrease the length of an older patient's delirious episode. Given the clinical relevance of these findings, we advise medication reviews for all older patients who are delirious or are at risk of developing delirium.

Objectives: Delirium is an underdiagnosed, severe and costly disorder, and 30%-40% of cases can be prevented. A fully automated model to predict delirium (DEMO) in older people has been developed, and the objective of this study is to validate the model in a hospital setting., Setting: Secondary care, one hospital with two locations., Design: Observational study., Participants: The study included 450 randomly selected patients over 60 years of age admitted to Zuyderland Medical Centre. Patients who presented with delirium on admission were excluded., Primary Outcome Measures: Development of delirium through chart review., Results: A total of 383 patients were included in this study. The analysis was performed for delirium within 1, 3 and 5 days after a DEMO score was obtained. Sensitivity was 87.1% (95% CI 0.756 to 0.939), 84.2% (95% CI 0.732 to 0.915) and 82.7% (95% CI 0.734 to 0.893) for 1, 3 and 5 days, respectively, after obtaining the DEMO score. Specificity was 77.9% (95% CI 0.729 to 0.882), 81.5% (95% CI 0.766 to 0.856) and 84.5% (95% CI 0.797 to 0.884) for 1, 3 and 5 days, respectively, after obtaining the DEMO score., Conclusion: DEMO is a satisfactory prediction model but needs further prospective validation with in-person delirium confirmation. In the future, DEMO will be applied in clinical practice so that physicians will be aware of when a patient is at an increased risk of developing delirium, which will facilitate earlier recognition and diagnosis, and thus will allow the implementation of prevention measures., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: The Maastricht frailty screening tool for hospitalised patients (MFST-HP) is a frailty screening tool that is fully integrated in the nursing assessment at admission. This study aims to determine the predictive value of the MFST-HP for the health outcomes length of hospital stay, discharge destination, readmission and mortality., Methods: Data of 2691 hospitalised patients (70+), admitted between 01-01-2013 and 31-12-2013, were included in the study. The predictive value of the MFST-HP was analysed by means of receiver operating characteristics curves. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for different MFST-HP cut-off scores were examined., Results: Mean age of the population was 78.9 years (SD 6.4) and their average length of stay was 10.2 days (SD 9.7). Nearly 75.0% of the patients were discharged to their home and around. Approximately 25% of the patients were readmitted within 120 days. Mortality rates were 4.3% and 9.5% (within 30 or 120 days postdischarge, respectively). The area under the curve was moderate and varied from 0.50 to 0.69 for the different outcomes. As a result of high values on negative predictive value (between 73.5% and 96.7%) the MFST-HP is able to rule out a large proportion of non-frail patients. In this study 84% of the patients had a MFST-HP score of ≥ 6, suggested as most favourable cut off., Conclusions: The MFST-HP seems to operate more strongly as a non-frailty indicator than as a frailty indicator and may in this respect help professionals to decide upon subsequent care. The MFST-HP is able to rule out 84% of the non-frail population in this study. The remaining 16% need to be assessed by means of a comprehensive geriatric assessment or rapid geriatric assessment, to gain more insight in the level of vulnerability in the frail-group., (© 2017 John Wiley & Sons Ltd.)

Several cell disruption methods were tested on Nannochloropsis gaditana, to evaluate their efficiency in terms of cell disintegration, energy input and release of soluble proteins. High-pressure homogenization (HPH) and bead milling were the most efficient with >95% cell disintegration, ±50% (w/w) release of total proteins and low energy input (<0.5kWh.kg -1 biomass ). Enzymatic treatment required low energy input (<0.34kWh.kg -1 biomass ), but it only released ±35% protein (w/w). Pulsed Electric Field (PEF) was neither energy-efficient (10.44kWh.kg -1 biomass ) nor successful for protein release (only 10% proteins w/w) and cell disintegration. The release of proteins after applying HPH and bead milling always required less intensive operating conditions for cell disruption. The energy cost per unit of released protein ranged from 0.15-0.25 €.kg Protein -1 in case of HPH, and up to 2-20 €.kg Protein -1 in case of PEF., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Understanding the formation process of nanoparticles is of the utmost importance to improve their design and production. This especially holds true for self-assembled nanoparticles whose formation processes have been largely overlooked. Herein, we present a new technology that integrates a microfluidic-based nanoparticle synthesis method and Förster resonance energy transfer (FRET) microscopy imaging to visualize nanoparticle self-assembly in real time. Applied to different nanoparticle systems, for example, nanoemulsions, drug-loaded block-copolymer micelles, and nanocrystal-core reconstituted high-density lipoproteins, we have shown the approach's unique ability to investigate key parameters affecting nanoparticle formation., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Inspired by the success of previous cancer nanomedicines in the clinic, researchers have generated a large number of novel formulations in the past decade. However, only a small number of nanomedicines have been approved for clinical use, whereas the majority of nanomedicines under clinical development have produced disappointing results. One major obstacle to the successful clinical translation of new cancer nanomedicines is the lack of an accurate understanding of their in vivo performance. This article features a rigorous procedure to characterize the in vivo behavior of nanomedicines in tumor-bearing mice at systemic, tissue, single-cell, and subcellular levels via the integration of positron emission tomography-computed tomography (PET-CT), radioactivity quantification methods, flow cytometry, and fluorescence microscopy. Using this approach, researchers can accurately evaluate novel nanoscale formulations in relevant mouse models of cancer. These protocols may have the ability to identify the most promising cancer nanomedicines with high translational potential or to aid in the optimization of cancer nanomedicines for future translation.

Background: Emotional stress is associated with increased risk of cardiovascular disease. We imaged the amygdala, a brain region involved in stress, to determine whether its resting metabolic activity predicts risk of subsequent cardiovascular events., Methods: Individuals aged 30 years or older without known cardiovascular disease or active cancer disorders, who underwent 18 F-fluorodexoyglucose PET/CT at Massachusetts General Hospital (Boston, MA, USA) between Jan 1, 2005, and Dec 31, 2008, were studied longitudinally. Amygdalar activity, bone-marrow activity, and arterial inflammation were assessed with validated methods. In a separate cross-sectional study we analysed the relation between perceived stress, amygdalar activity, arterial inflammation, and C-reactive protein. Image analyses and cardiovascular disease event adjudication were done by mutually blinded researchers. Relations between amygdalar activity and cardiovascular disease events were assessed with Cox models, log-rank tests, and mediation (path) analyses., Findings: 293 patients (median age 55 years [IQR 45·0-65·5]) were included in the longitudinal study, 22 of whom had a cardiovascular disease event during median follow-up of 3·7 years (IQR 2·7-4·8). Amygdalar activity was associated with increased bone-marrow activity (r=0·47; p<0·0001), arterial inflammation (r=0·49; p<0·0001), and risk of cardiovascular disease events (standardised hazard ratio 1·59, 95% CI 1·27-1·98; p<0·0001), a finding that remained significant after multivariate adjustments. The association between amygdalar activity and cardiovascular disease events seemed to be mediated by increased bone-marrow activity and arterial inflammation in series. In the separate cross-sectional study of patients who underwent psychometric analysis (n=13), amygdalar activity was significantly associated with arterial inflammation (r=0·70; p=0·0083). Perceived stress was associated with amygdalar activity (r=0·56; p=0·0485), arterial inflammation (r=0·59; p=0·0345), and C-reactive protein (r=0·83; p=0·0210)., Interpretation: In this first study to link regional brain activity to subsequent cardiovascular disease, amygdalar activity independently and robustly predicted cardiovascular disease events. Amygdalar activity is involved partly via a path that includes increased bone-marrow activity and arterial inflammation. These findings provide novel insights into the mechanism through which emotional stressors can lead to cardiovascular disease in human beings., Funding: None., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Cerenkov luminescence (CL) is an emerging imaging modality that utilizes the light generated during the radioactive decay of many clinical used isotopes. Although it is increasingly used for background-free imaging and deep tissue photodynamic therapy, in vivo applications of CL suffer from limited tissue penetration. Here, we propose to use quantum dots (QDs) as spectral converters that can transfer the CL UV-blue emissions to near-infrared light that is less scattered or absorbed in vivo. Experiments on tissue phantoms showed enhanced penetration depth and increased transmitted intensity for CL in the presence of near-infrared (NIR) QDs. To realize this concept for in vivo imaging applications, we developed three types of NIR QDs and 89 Zr dual-labeled nanoparticles based on lipid micelles, nanoemulsions, and polymeric nanoplatforms, which enable codelivery of the radionuclide and the QDs for maximized spectral conversion efficiency. We finally demonstrated the application of these self-illuminating nanoparticles for imaging of lymph nodes and tumors in a prostate cancer mouse model.

A mild biorefinery process was investigated on the microalga Nannochloropsis gaditana, to obtain an enriched fraction of water soluble proteins free from chlorophyll. After harvesting, a 100g.L -1 solution of cells was first subjected to cell disruption by either high-pressure homogenization (HPH) or enzymatic treatment (ENZ). HPH resulted in a larger release of proteins (49%) in the aqueous phase compared to the Alcalase incubation (35%). In both cases, an ultrafiltration/diafiltration (UF/DF) was then performed on the supernatant obtained from cell disruption by testing different membrane cut-off (1000kDa, 500kDa and 300kDa). After optimising the process conditions, the combination of ENZ→UF/DF ended in a larger overall yield of water soluble proteins (24.8%) in the permeate compared to the combination of HPH→UF/DF (17.4%). A gel polarization model was implemented to assess the maximum achievable concentration factor during ultrafiltration and the mass transfer coefficient related to the theoretical permeation flux rate., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In the nursing home population, it is estimated that 1 in every 3 patients is polymedicated and given their considerable frailty, these patients are especially prone to adverse drug reactions. Clinical pharmacist-led medication reviews are considered successful interventions to improve medication safety in the inpatient setting. Due to the limited available evidence concerning the benefits of medication reviews performed in the nursing home setting, we propose a study aiming to demonstrate a positive effect that a clinical decision support system, as a health care intervention, may have on the target population. The primary objective of this study is to reduce the number of patients with at least one event when using the clinical decision support system compared to the regular care. These events consist of hospital referrals, delirium, falls, and/or deaths., Method/design: This study is a multicentre, prospective, randomised study with a cluster group design. The randomisation will be per main nursing home physician and stratified per ward (somatic and psychogeriatric). In the intervention group the clinical decision support system will be used to screen medication list, laboratory values and medical history in order to obtain potential clinical relevant remarks. The remarks will be sent to the main physician and feedback will be provided whether the advice was followed or not. In the control group regular care will be applied., Discussion: We strongly believe that by using a clinical decision support system, medication reviews are performed in a standardised way which leads to comparable results between patients. In addition, using a clinical decision support system eliminates the time factor to perform medication reviews as the major problems related to medication, laboratory values, indications and/or established patient characteristics will be directly available. In this way, and in order to make the medication review process complete, consultation within healthcare professionals and/or the patient itself will be time effective and the medication surveillance could be performed around the clock., Trial Registration: The Netherlands National Trial Register NTR5165 . Registered 2nd April 2015.

Tissue macrophage numbers vary during health versus disease. Abundant inflammatory macrophages destruct tissues, leading to atherosclerosis, myocardial infarction and heart failure. Emerging therapeutic options create interest in monitoring macrophages in patients. Here we describe positron emission tomography (PET) imaging with 18 F-Macroflor, a modified polyglucose nanoparticle with high avidity for macrophages. Due to its small size, Macroflor is excreted renally, a prerequisite for imaging with the isotope flourine-18. The particle's short blood half-life, measured in three species, including a primate, enables macrophage imaging in inflamed cardiovascular tissues. Macroflor enriches in cardiac and plaque macrophages, thereby increasing PET signal in murine infarcts and both mouse and rabbit atherosclerotic plaques. In PET/magnetic resonance imaging (MRI) experiments, Macroflor PET imaging detects changes in macrophage population size while molecular MRI reports on increasing or resolving inflammation. These data suggest that Macroflor PET/MRI could be a clinical tool to non-invasively monitor macrophage biology., Competing Interests: R.W., N.K. and M.N. are inventors on a related patent application. The remaining authors declare no competing financial interests.

Immunological complexity in atherosclerosis warrants targeted treatment of specific inflammatory cells that aggravate the disease. With the initiation of large phase III trials investigating immunomodulatory drugs for atherosclerosis, cardiovascular disease treatment enters a new era. We here propose a radically different approach: implementing and evaluating in vivo a combinatorial library of nanoparticles with distinct physiochemical properties and differential immune cell specificities. The library's nanoparticles are based on endogenous high-density lipoprotein, which can preferentially deliver therapeutic compounds to pathological macrophages in atherosclerosis. Using the apolipoprotein E-deficient (Apoe -/- ) mouse model of atherosclerosis, we quantitatively evaluated the library's immune cell specificity by combining immunological techniques and in vivo positron emission tomography imaging. Based on this screen, we formulated a liver X receptor agonist (GW3965) and abolished its liver toxicity while still preserving its therapeutic function. Screening the immune cell specificity of nanoparticles can be used to develop tailored therapies for atherosclerosis and other inflammatory diseases., Competing Interests: The authors declare no conflict of interest.

High-density lipoprotein (HDL) nanoparticles doped with gadolinium lipids can be used as magnetic resonance imaging diagnostic agents for atherosclerosis. In this study, HDL nanoparticles with different molar fractions of gadolinium lipids (0 < x Gd-lipids < 0.33) were prepared, and the MR relaxivity values ( r 1 and r 2) for all compositions were measured. Both r 1 and r 2 parameters reached a maximal value at a molar fraction of approximately x Gd-lipids = 0.2. Higher payloads of gadolinium did not significantly increase relaxivity values but induced changes in the structure of HDL, increasing the size of the particles from d H = 8.2 ± 1.6 to 51.7 ± 7.3 nm. High payloads of gadolinium lipids trigger conformational changes in HDL, with potential effects on the in vivo behavior of the nanoparticles., Competing Interests: The authors declare no competing financial interest.

Objective: Delirium is a serious and common complication among older hospitalized patients and is a predictor of many adverse outcomes. However, up to 72% of delirium incidents are unrecognized or misdiagnosed. The aim of this systematic review is to determine the validity, reliability, and feasibility of instruments for the detection of delirium in older hospitalized patients., Methods: A systematic literature search was conducted. The inclusion criteria were a mean or median age of 65+ years, the use of the Diagnostic and Statistical Manual of Mental Disorders or International Classification of Diseases-10 as a reference standard, and publication in English. All included studies underwent a quality assessment (QUADAS-2)., Results: Forty-three of the 3.790 identified studies were relevant to the review, describing 28 instruments. Quality assessment resulted in 37 studies with a positive quality assessment, describing 23 instruments. Five instruments (Delirium Observation Scale (DOS), Nursing Delirium Screening Scale (Nu-DESC), Confusion Assessment Method (CAM), CAM-Intensive Care Unit (ICU), and Delirium Rating Scale-Revised-98) were described in three or more methodologically sound studies. The Delirium Observation Screening Scale (DOS) and Nu-DESC are observational instruments with good psychometric properties, but the Nu-DESC is shorter and has been validated in more languages. The CAM, CAM-ICU, and Delirium Rating Scale-Revised-98 (DRS-R-98) are instruments with both observational and interactive components. The CAM is the most widely studied and demonstrates the best psychometric properties., Conclusion: Timely detection of delirium might reduce the negative outcomes of delirium in the long term. The Nu-DESC and CAM appear to be the most adequate instruments for detecting delirium. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

As nurses in hospitals are confronted with increasing numbers of older patients, their geriatric nursing skills and knowledge must be integrated into daily clinical practice. Early risk identification via screening tools may help improve geriatric care. To reduce the assessment burden of nurses, the Maastricht Frailty Screening Tool for Hospitalized Patients (MFST-HP) was developed. The aim of the current study was to explore aspects of reliability, validity, and feasibility of the MFST-HP. Intrarater reliability was assessed by measuring patients two times within 24 hours. Interrater reliability was assessed by having patients screened by two different nurses. Construct validity was studied by the associations between the MFST-HP scores and age and comorbidities. Intraclass correlation coefficients for both intra- and interrater reliability were good (>0.93). Older patients and those with more comorbidity showed higher scores on the MFST-HP compared to younger patients and those with less comorbidity. The MFST-HP shows promise as a reliable, valid, and feasible screening tool for frailty among hospitalized older adults. [Res Gerontol Nurs. 2016; 9(5):243-251.]., (Copyright 2016, SLACK Incorporated.)

Background A delirium is common in hospital settings resulting in increased mortality and costs. Prevention of a delirium is clearly preferred over treatment. A delirium risk prediction model can be helpful to identify patients at risk of a delirium, allowing the start of preventive treatment. Current risk prediction models rely on manual calculation of the individual patient risk. Objective The aim of this study was to develop an automated ward independent delirium riskprediction model. To show that such a model can be constructed exclusively from electronically available risk factors and thereby implemented into a clinical decision support system (CDSS) to optimally support the physician to initiate preventive treatment. Setting A Dutch teaching hospital. Methods A retrospective cohort study in which patients, 60 years or older, were selected when admitted to the hospital, with no delirium diagnosis when presenting, or during the first day of admission. We used logistic regression analysis to develop a delirium predictive model out of the electronically available predictive variables. Main outcome measure A delirium risk prediction model. Results A delirium risk prediction model was developed using predictive variables that were significant in the univariable regression analyses. The area under the receiver operating characteristics curve of the "medication model" model was 0.76 after internal validation. Conclusions CDSSs can be used to automatically predict the risk of a delirium in individual hospitalised patients' by exclusively using electronically available predictive variables. To increase the use and improve the quality of predictive models, clinical risk factors should be documented ready for automated use.

Atherosclerosis is a lipid-driven inflammatory disease, for which nanomedicinal interventions are under evaluation. Previously, we showed that liposomal nanoparticles loaded with prednisolone (LN-PLP) accumulated in plaque macrophages, however, induced proatherogenic effects in patients. Here, we confirmed in low-density lipoprotein receptor knockout (LDLr(-/-)) mice that LN-PLP accumulates in plaque macrophages. Next, we found that LN-PLP infusions at 10mg/kg for 2weeks enhanced monocyte recruitment to plaques. In follow up, after 6weeks of LN-PLP exposure we observed (i) increased macrophage content, (ii) more advanced plaque stages, and (iii) larger necrotic core sizes. Finally, in vitro studies showed that macrophages become lipotoxic after LN-PLP exposure, exemplified by enhanced lipid loading, ER stress and apoptosis. These findings indicate that liposomal prednisolone may paradoxically accelerate atherosclerosis by promoting macrophage lipotoxicity. Hence, future (nanomedicinal) drug development studies are challenged by the multifactorial nature of atherosclerotic inflammation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: The goal of this study was to develop and validate a noninvasive imaging tool to visualize the in vivo behavior of high-density lipoprotein (HDL) by using positron emission tomography (PET), with an emphasis on its plaque-targeting abilities., Background: HDL is a natural nanoparticle that interacts with atherosclerotic plaque macrophages to facilitate reverse cholesterol transport. HDL-cholesterol concentration in blood is inversely associated with risk of coronary heart disease and remains one of the strongest independent predictors of incident cardiovascular events., Methods: Discoidal HDL nanoparticles were prepared by reconstitution of its components apolipoprotein A-I (apo A-I) and the phospholipid 1,2-dimyristoyl-sn-glycero-3-phosphocholine. For radiolabeling with zirconium-89 ((89)Zr), the chelator deferoxamine B was introduced by conjugation to apo A-I or as a phospholipid-chelator (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-deferoxamine B). Biodistribution and plaque targeting of radiolabeled HDL were studied in established murine, rabbit, and porcine atherosclerosis models by using PET combined with computed tomography (PET/CT) imaging or PET combined with magnetic resonance imaging. Ex vivo validation was conducted by radioactivity counting, autoradiography, and near-infrared fluorescence imaging. Flow cytometric assessment of cellular specificity in different tissues was performed in the murine model., Results: We observed distinct pharmacokinetic profiles for the two (89)Zr-HDL nanoparticles. Both apo A-I- and phospholipid-labeled HDL mainly accumulated in the kidneys, liver, and spleen, with some marked quantitative differences in radioactivity uptake values. Radioactivity concentrations in rabbit atherosclerotic aortas were 3- to 4-fold higher than in control animals at 5 days' post-injection for both (89)Zr-HDL nanoparticles. In the porcine model, increased accumulation of radioactivity was observed in lesions by using in vivo PET imaging. Irrespective of the radiolabel's location, HDL nanoparticles were able to preferentially target plaque macrophages and monocytes., Conclusions: (89)Zr labeling of HDL allows study of its in vivo behavior by using noninvasive PET imaging, including visualization of its accumulation in advanced atherosclerotic lesions. The different labeling strategies provide insight on the pharmacokinetics and biodistribution of HDL's main components (i.e., phospholipids, apo A-I)., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: First, to estimate the added value of a clinical decision support system (CDSS) in the performance of medication reviews in hospitalised elderly. Second, to identify the limitations of the current CDSS by analysing generated drug-related problems (DRPs)., Methods: Medication reviews were performed in patients admitted to the geriatric ward of the Zuyderland medical centre. Additionally, electronically available patient information was introduced into a CDSS. The DRP notifications generated by the CDSS were compared with those found in the medication review. The DRP notifications were analysed to learn how to improve the CDSS., Results: A total of 223 DRP strategies were identified during the medication reviews. The CDSS generated 70 clinically relevant DRP notifications. Of these DRP notifications, 63 % (44) were also found during the medication reviews. The CDSS generated 10 % (26) new DRP notifications and conveyed 28 % (70) of all 249 clinically relevant DRPs that were found. Classification of the CDSS generated DRP notifications related to 'medication error type' revealed that 'contraindications/interactions/side effects' and 'indication without medication' were the main categories not identified during the manual medication review. The error types 'medication without indication', 'double medication', and 'wrong medication' were mostly not identified by the CDSS., Conclusions: The CDSS used in this study is not yet sufficiently advanced to replace the manual medication review, though it does add value to the manual medication review. The strengths and weaknesses of the current CDSS can be determined according to the medication error types.

A major goal of cancer nanotherapy is to use nanoparticles as carriers for targeted delivery of anti-tumour agents. The drug-carrier association after intravenous administration is essential for efficient drug delivery to the tumour. However, a large number of currently available nanocarriers are self-assembled nanoparticles whose drug-loading stability is critically affected by the in vivo environment. Here we used in vivo FRET imaging to systematically investigate how drug-carrier compatibility affects drug release in a tumour mouse model. We found the drug's hydrophobicity and miscibility with the nanoparticles are two independent key parameters that determine its accumulation in the tumour. Next, we applied these findings to improve chemotherapeutic delivery by augmenting the parent drug's compatibility; as a result, we achieved better antitumour efficacy. Our results help elucidate nanomedicines' in vivo fate and provide guidelines for efficient drug delivery.

Background: The majority of dialysis patients are elderly, and the trend towards even more elderly people with end-stage renal disease (ESRD) will further determine the dialysis field in the future., Method: If these elderly ESRD patients do not opt for conservative ESRD care, they may still qualify for peritoneal dialysis (PD), which may be assisted or unassisted., Results: Although they may be more frail and have a greater co-morbidity burden compared to their younger counterparts, elderly patients with ESRD may still be able to maintain a good functionality level with adequate quality of life by performing PD, which may be assisted (treatment performed or supported e.g. by partner or nurse) or unassisted (without support). PD may indeed further contribute to maintaining autonomy, and enhance quality of life compared to in-center conventional hemodialysis. In order to illustrate this strategy, we hereby describe a centenarian patient with ESRD who received assisted PD successfully., Conclusions: With appropriate management and infrastructure, (very) high age is not a contra-indication for PD.

Background: The objective of this study is to identify and review screening tools for frailty in older adults admitted to inpatient hospital care with respect to their validity, reliability and feasibility., Methods: Studies were identified through systematically searching PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase and PsycINFO and screening reference lists till June 2014. Papers dealing with screening tools aimed at identifying frail older patients in in-hospital care, and including information about validity, reliability or feasibility, were included in the review. The quality of the included studies was critically appraised via the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)., Results: From the originally identified 2001 studies 32 studies met the inclusion criteria, in which 16 screening tools were presented. The screening tools showed different characteristics with respect to the number of items, the method of administration and the domains included. The most frequently studied tools with respect to predictive validity were the Identification Seniors At Risk (ISAR) and Triage Risk Stratification Tool (TRST). Studies retrieved poorer information about reliability and feasibility. Overall sensitivity was fairly good. The ISAR, ISAR-HP (Identification Seniors At Risk Hospitalized Patients) and Multidimensional Prognostic Index (MPI) generally had the best sensitivity., Conclusions: Many screening tools are available for daily practice. These tools to identify frail older patients in inpatient hospital care could be useful. For no tool, however, is clear evidence available yet regarding validity, reliability and feasibility. The overall sensitivity of the included screening tools was fairly good, whereas information on reliability and feasibility was lacking for most tools. In future research more attention should be given to the latter items.

The endothelium lines the internal surfaces of blood and lymphatic vessels and has a critical role in maintaining homeostasis. Endothelial dysfunction is involved in the pathology of many diseases and conditions, including disorders such as diabetes, cardiovascular diseases, and cancer. Given this common etiology in a range of diseases, medicines targeting an impaired endothelium can strengthen the arsenal of therapeutics. Nanomedicine - the application of nanotechnology to healthcare - presents novel opportunities and potential for the treatment of diseases associated with an impaired endothelium. This review discusses therapies currently available for the treatment of these disorders and highlights the application of nanomedicine for the therapy of these major disease complications.

Rationale: Local plaque macrophage proliferation and monocyte production in hematopoietic organs promote progression of atherosclerosis. Therefore, noninvasive imaging of proliferation could serve as a biomarker and monitor therapeutic intervention., Objective: To explore (18)F-FLT positron emission tomography-computed tomography imaging of cell proliferation in atherosclerosis., Methods and Results: (18)F-FLT positron emission tomography-computed tomography was performed in mice, rabbits, and humans with atherosclerosis. In apolipoprotein E knock out mice, increased (18)F-FLT signal was observed in atherosclerotic lesions, spleen, and bone marrow (standardized uptake values wild-type versus apolipoprotein E knock out mice, 0.05 ± 0.01 versus 0.17 ± 0.01, P<0.05 in aorta; 0.13 ± 0.01 versus 0.28 ± 0.02, P<0.05 in bone marrow; 0.06 ± 0.01 versus 0.22 ± 0.01, P<0.05 in spleen), corroborated by ex vivo scintillation counting and autoradiography. Flow cytometry confirmed significantly higher proliferation of macrophages in aortic lesions and hematopoietic stem and progenitor cells in the spleen and bone marrow in these mice. In addition, (18)F-FLT plaque signal correlated with the duration of high cholesterol diet (r(2)=0.33, P<0.05). Aortic (18)F-FLT uptake was reduced when cell proliferation was suppressed with fluorouracil in apolipoprotein E knock out mice (P<0.05). In rabbits, inflamed atherosclerotic vasculature with the highest (18)F-fluorodeoxyglucose uptake enriched (18)F-FLT. In patients with atherosclerosis, (18)F-FLT signal significantly increased in the inflamed carotid artery and in the aorta., Conclusions: (18)F-FLT positron emission tomography imaging may serve as an imaging biomarker for cell proliferation in plaque and hematopoietic activity in individuals with atherosclerosis., (© 2015 American Heart Association, Inc.)

Atherosclerotic plaques that cause stroke and myocardial infarction are characterized by increased microvascular permeability and inflammation. Dynamic contrast-enhanced MRI (DCE-MRI) has been proposed as a method to quantify vessel wall microvascular permeability in vivo. Until now, most DCE-MRI studies of atherosclerosis have been limited to two-dimensional (2D) multi-slice imaging. Although providing the high spatial resolution required to image the arterial vessel wall, these approaches do not allow the quantification of plaque permeability with extensive anatomical coverage, an essential feature when imaging heterogeneous diseases, such as atherosclerosis. To our knowledge, we present the first systematic evaluation of three-dimensional (3D), high-resolution, DCE-MRI for the extensive quantification of plaque permeability along an entire vascular bed, with validation in atherosclerotic rabbits. We compare two acquisitions: 3D turbo field echo (TFE) with motion-sensitized-driven equilibrium (MSDE) preparation and 3D turbo spin echo (TSE). We find 3D TFE DCE-MRI to be superior to 3D TSE DCE-MRI in terms of temporal stability metrics. Both sequences show good intra- and inter-observer reliability, and significant correlation with ex vivo permeability measurements by Evans Blue near-infrared fluorescence (NIRF). In addition, we explore the feasibility of using compressed sensing to accelerate 3D DCE-MRI of atherosclerosis, to improve its temporal resolution and therefore the accuracy of permeability quantification. Using retrospective under-sampling and reconstructions, we show that compressed sensing alone may allow the acceleration of 3D DCE-MRI by up to four-fold. We anticipate that the development of high-spatial-resolution 3D DCE-MRI with prospective compressed sensing acceleration may allow for the more accurate and extensive quantification of atherosclerotic plaque permeability along an entire vascular bed. We foresee that this approach may allow for the comprehensive and accurate evaluation of plaque permeability in patients, and may be a useful tool to assess the therapeutic response to approved and novel drugs for cardiovascular disease., (Copyright © 2015 John Wiley & Sons, Ltd.)

Unlabelled: Tumor-associated macrophages (TAMs) are increasingly investigated in cancer immunology and are considered a promising target for better and tailored treatment of malignant growth. Although TAMs also have high diagnostic and prognostic value, TAM imaging still remains largely unexplored. Here, we describe the development of reconstituted high-density lipoprotein (rHDL)-facilitated TAM PET imaging in a breast cancer model., Methods: Radiolabeled rHDL nanoparticles incorporating the long-lived positron-emitting nuclide (89)Zr were developed using 2 different approaches. The nanoparticles were composed of phospholipids and apolipoprotein A-I (apoA-I) in a 2.5:1 weight ratio. (89)Zr was complexed with deferoxamine (also known as desferrioxamine B, desferoxamine B), conjugated either to a phospholipid or to apoA-I to generate (89)Zr-PL-HDL and (89)Zr-AI-HDL, respectively. In vivo evaluation was performed in an orthotopic mouse model of breast cancer and included pharmacokinetic analysis, biodistribution studies, and PET imaging. Ex vivo histologic analysis of tumor tissues to assess regional distribution of (89)Zr radioactivity was also performed. Fluorescent analogs of the radiolabeled agents were used to determine cell-targeting specificity using flow cytometry., Results: The phospholipid- and apoA-I-labeled rHDL were produced at 79% ± 13% (n = 6) and 94% ± 6% (n = 6) radiochemical yield, respectively, with excellent radiochemical purity (>99%). Intravenous administration of both probes resulted in high tumor radioactivity accumulation (16.5 ± 2.8 and 8.6 ± 1.3 percentage injected dose per gram for apoA-I- and phospholipid-labeled rHDL, respectively) at 24 h after injection. Histologic analysis showed good colocalization of radioactivity with TAM-rich areas in tumor sections. Flow cytometry revealed high specificity of rHDL for TAMs, which had the highest uptake per cell (6.8-fold higher than tumor cells for both DiO@Zr-PL-HDL and DiO@Zr-AI-HDL) and accounted for 40.7% and 39.5% of the total cellular DiO@Zr-PL-HDL and DiO@Zr-AI-HDL in tumors, respectively., Conclusion: We have developed (89)Zr-labeled TAM imaging agents based on the natural nanoparticle rHDL. In an orthotopic mouse model of breast cancer, we have demonstrated their specificity for macrophages, a result that was corroborated by flow cytometry. Quantitative macrophage PET imaging with our (89)Zr-rHDL imaging agents could be valuable for noninvasive monitoring of TAM immunology and targeted treatment., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Elderly patients with diffuse large B-cell lymphoma (DLBCL) are frequently not treated with standard immunochemotherapy, and this influences survival negatively. The purpose of this study was to gain more insight into treatment decision-making by hematologists. Case vignettes concerning patients with DLBCL were presented to hematologists in the Netherlands. Patient characteristics (age, comorbidity) differed per case. Respondents were asked in each case if they would treat the patient with curative intent by means of full-dose chemotherapy or chemotherapy with dose reduction or if they would not treat the patient with curative intent. The vast majority of respondents would treat an elderly patient diagnosed with DLBCL without a relevant medical history with full-dose chemotherapy irrespective of age. In the presence of comorbidity, lack of social support, cognitive disorders, and untreated depression dose reductions in advance are frequently applied or patients are not treated with curative intent. This is most pronounced for patients aged older than 80 years. Respondents working in a university hospital more frequently refrain form full-dose chemotherapy with curative intent compared to respondents working in tertiary medical teaching hospitals or general hospitals. Patients without a relevant medical history are generally treated with curative intent irrespective of age. Cognitive disorders, comorbidity, and depression reduce the change of being treated with curative intent. This is most prominent in the eldest patient category.

The globally increasing protein demands require additional resources to those currently available. Furthermore, the optimal usage of protein fractions from both traditional and new protein resources, such as algae and leaves, is essential. Here, we present an overview on alkaline plant protein extraction including the potentials of enzyme addition in the form of proteases and/or carbohydrolases. Strategic biomass selection, combined with the appropriate process conditions can increase protein yields after extraction. Enzyme addition, especially of proteases, can be useful when alkaline protein extraction yields are low. These additions can also be used to enable processing at a pH closer to 7 to avoid the otherwise severe conditions that denature proteins. Finally, a protein biorefinery concept is presented that aims to upcycle residual biomass by separating essential amino acids to be used for food and feed, and non-essential amino acids for production of bulk chemicals., (Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Drug delivery to atherosclerotic plaques via liposomal nanoparticles may improve therapeutic agents' risk-benefit ratios. Our paper details the first clinical studies of a liposomal nanoparticle encapsulating prednisolone (LN-PLP) in atherosclerosis. First, PLP's liposomal encapsulation improved its pharmacokinetic profile in humans (n=13) as attested by an increased plasma half-life of 63h (LN-PLP 1.5mg/kg). Second, intravenously infused LN-PLP appeared in 75% of the macrophages isolated from iliofemoral plaques of patients (n=14) referred for vascular surgery in a randomized, placebo-controlled trial. LN-PLP treatment did however not reduce arterial wall permeability or inflammation in patients with atherosclerotic disease (n=30), as assessed by multimodal imaging in a subsequent randomized, placebo-controlled study. In conclusion, we successfully delivered a long-circulating nanoparticle to atherosclerotic plaque macrophages in patients, whereas prednisolone accumulation in atherosclerotic lesions had no anti-inflammatory effect. Nonetheless, the present study provides guidance for development and imaging-assisted evaluation of future nanomedicine in atherosclerosis., From the Clinical Editor: In this study, the authors undertook the first clinical trial using long-circulating liposomal nanoparticle encapsulating prednisolone in patients with atherosclerosis, based on previous animal studies. Despite little evidence of anti-inflammatory effect, the results have provided a starting point for future development of nanomedicine in cardiovascular diseases., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The present study describes the development of a good manufacturing practice (GMP)-grade liposomal nanotherapy containing prednisolone phosphate for the treatment of inflammatory diseases. After formulation design, GMP production was commenced which yielded consistent, stable liposomes sized 100nm±10nm, with a prednisolone phosphate (PLP) incorporation efficiency of 3%-5%. Pharmacokinetics and toxicokinetics of GMP-grade liposomal nanoparticles were evaluated in healthy rats, which were compared to daily and weekly administration of free prednisolone phosphate, revealing a long circulatory half-life with minimal side effects. Subsequently, non-invasive multimodal clinical imaging after liposomal nanotherapy's intravenous administration revealed anti-inflammatory effects on the vessel wall of atherosclerotic rabbits. The present program led to institutional review board approval for two clinical trials with patients with atherosclerosis., From the Clinical Editor: In drug discovery, bringing production to industrial scale is an essential process. In this article the authors describe the development of an anti-inflammatory nanoparticle according to good manufacturing practice. As a result, this paves the way for translating laboratory studies to clinical trials in humans., (Copyright © 2015 Elsevier Inc. All rights reserved.)

While acute myocardial infarction mortality declines, patients continue to face reinfarction and/or heart failure. The immune system, which intimately interacts with healthy and diseased tissues through resident and recruited leukocytes, is a central interface for a global host response to ischemia. Pathways that enhance the systemic leukocyte supply may be potential therapeutic targets. Pre-clinically, imaging helps to identify immunity's decision nodes, which may serve as such targets. In translating the rapidly-expanding pre-clinical data on immune activity, the difficulty of obtaining multiple clinical tissue samples from involved organs is an obstacle that whole-body imaging can help overcome. In patients, molecular and cellular imaging can be integrated with blood-based diagnostics to assess the translatability of discoveries, including the activation of hematopoietic tissues after myocardial infarction, and serve as an endpoint in clinical trials. In this review, we discuss these concepts while focusing on imaging immune activity in organs involved in ischemic heart disease., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Inflammation drives atherosclerotic plaque progression and rupture, and is a compelling therapeutic target. Consequently, attenuating inflammation by reducing local macrophage accumulation is an appealing approach. This can potentially be accomplished by either blocking blood monocyte recruitment to the plaque or increasing macrophage apoptosis and emigration. Because macrophage proliferation was recently shown to dominate macrophage accumulation in advanced plaques, locally inhibiting macrophage proliferation may reduce plaque inflammation and produce long-term therapeutic benefits. To test this hypothesis, we used nanoparticle-based delivery of simvastatin to inhibit plaque macrophage proliferation in apolipoprotein E deficient mice ( Apoe -/- ) with advanced atherosclerotic plaques. This resulted in rapid reduction of plaque inflammation and favorable phenotype remodeling. We then combined this short-term nanoparticle intervention with an eight-week oral statin treatment, and this regimen rapidly reduced and continuously suppressed plaque inflammation. Our results demonstrate that pharmacologically inhibiting local macrophage proliferation can effectively treat inflammation in atherosclerosis.

High-density lipoprotein (HDL) is a natural nanoparticle that exhibits an intrinsic affinity for atherosclerotic plaque macrophages. Its natural targeting capability as well as the option to incorporate lipophilic payloads, e.g., imaging or therapeutic components, in both the hydrophobic core and the phospholipid corona make the HDL platform an attractive nanocarrier. To realize controlled release properties, we developed a hybrid polymer/HDL nanoparticle composed of a lipid/apolipoprotein coating that encapsulates a poly(lactic-co-glycolic acid) (PLGA) core. This novel HDL-like nanoparticle (PLGA-HDL) displayed natural HDL characteristics, including preferential uptake by macrophages and a good cholesterol efflux capacity, combined with a typical PLGA nanoparticle slow release profile. In vivo studies carried out with an ApoE knockout mouse model of atherosclerosis showed clear accumulation of PLGA-HDL nanoparticles in atherosclerotic plaques, which colocalized with plaque macrophages. This biomimetic platform integrates the targeting capacity of HDL biomimetic nanoparticles with the characteristic versatility of PLGA-based nanocarriers.

Atherosclerosis is a major cause of global morbidity and mortality that could benefit from novel targeted therapeutics. Recent studies have shown efficient and local drug delivery with nanoparticles, although the nanoparticle targeting mechanism for atherosclerosis has not yet been fully elucidated. Here we used in vivo and ex vivo multimodal imaging to examine permeability of the vessel wall and atherosclerotic plaque accumulation of fluorescently labeled liposomal nanoparticles in a rabbit model. We found a strong correlation between permeability as established by in vivo dynamic contrast enhanced magnetic resonance imaging and nanoparticle plaque accumulation with subsequent nanoparticle distribution throughout the vessel wall. These key observations will enable the development of nanotherapeutic strategies for atherosclerosis.

Introduction: The application of intravenously administered nanoparticle (NP) therapies is increasingly being explored for a variety of diseases. The key to their success lies in a thorough understanding of nanoparticle pharmacological behavior, specificity and elimination kinetics. Fluorescent imaging techniques provide exciting opportunities to gain insight into such NP behavior in complex biological systems, at macroscopic as well as microscopic levels., Areas Covered: In this review, we will summarize NP labeling methods in relation to their established and emerging fluorescent imaging modalities for in vitro, in vivo, and ex vivo studies of NP behavior. We will highlight novel applications and discuss recent developments in techniques such as fluorescence molecular tomography (FMT), Förster resonance energy transfer (FRET), and Raman imaging. Finally, we will provide a perspective on the challenges and future directions of NP-based fluorescent labeling and imaging in nanotherapeutics., Expert Opinion: Commonly used in preclinical applications, fluorescent imaging of NPs can be achieved with minimal invasiveness and low toxicity in a multiplex fashion. Increasingly applied in the study of NP biodistribution, dissociation, and elimination behavior, fluorescent imaging allows fluid longitudinal tracking and visualization of NP interactions at the level of the whole animal, target organs/tissues, and individual cells.

Background: Patients with familial hypercholesterolemia (FH) are characterized by elevated atherogenic lipoprotein particles, predominantly low-density lipoprotein cholesterol (LDL-C), which is associated with accelerated atherogenesis and increased cardiovascular risk., Objectives: This study used (18)F-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) to investigate whether arterial inflammation is higher in patients with FH and, moreover, whether lipoprotein apheresis attenuates arterial wall inflammation in FH patients., Methods: In total, 38 subjects were recruited: 24 FH patients and 14 normolipidemic controls. All subjects underwent FDG-PET imaging at baseline. Twelve FH patients who met the criteria for lipoprotein apheresis underwent apheresis procedures followed by a second FDG-PET imaging 3 days (range 1 to 4 days) after apheresis. Subsequently, the target-to-background ratio (TBR) of FDG uptake within the arterial wall was assessed., Results: In FH patients, the mean arterial TBR was higher compared with healthy controls (2.12 ± 0.27 vs. 1.92 ± 0.19; p = 0.03). A significant correlation was observed between baseline arterial TBR and LDL-C (R = 0.37; p = 0.03) that remained significant after adjusting for statin use (β = 0.001; p = 0.02) and atherosclerosis risk factors (β = 0.001; p = 0.03). LDL-C levels were significantly reduced after lipoprotein apheresis (284 ± 118 mg/dl vs. 127 ± 50 mg/dl; p < 0.001). There was a significant reduction of arterial inflammation after lipoprotein apheresis (TBR: 2.05 ± 0.31 vs. 1.91 ± 0.33; p < 0.02)., Conclusions: The arterial wall of FH patients is characterized by increased inflammation, which is markedly reduced after lipoprotein apheresis. This lends support to a causal role of apoprotein B-containing lipoproteins in arterial wall inflammation and supports the concept that lipoprotein-lowering therapies may impart anti-inflammatory effects by reducing atherogenic lipoproteins., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Advances in preclinical molecular imaging have generated new opportunities to noninvasively visualize the biodistribution and tumor targeting of nanoparticle therapeutics. Capitalizing on recent achievements in this area, we sought to develop an (89)Zr-based labeling strategy for liposomal nanoparticles that accumulate in tumors via passive targeting mechanisms., Methods: (89)Zr-labeled liposomes were prepared using 2 different approaches: click labeling and surface chelation. Pharmacokinetic and biodistribution studies, as well as PET/CT imaging of the radiolabeled nanoparticles, were performed on a mouse model of breast cancer. In addition, a dual PET/optical probe was prepared by incorporation of a near-infrared fluorophore and tested in vivo by PET and near-infrared fluorescence imaging., Results: The surface chelation approach proved to be superior in terms of radiochemical yield and stability, as well as in vivo performance. Accumulation of these liposomes in tumor peaked at 24 h after injection and was measured to be 13.7 ± 1.8 percentage injected dose per gram. The in vivo performance of this probe was not essentially perturbed by the incorporation of a near-infrared fluorophore., Conclusion: We have developed a highly modular and efficient strategy for the labeling of liposomal nanoparticles with (89)Zr. In xenograft and orthotopic mouse models of breast cancer, we demonstrated that the biodistribution of these nanoparticles can be visualized by PET imaging. In combination with a near-infrared dye, these liposomal nanoparticles can serve as bimodal PET/optical imaging agents. The liposomes target malignant growth, and their bimodal features may be useful for simultaneous PET and intraoperative imaging., (© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Background: Understanding how leukocytes impact atherogenesis contributes critically to our concept of atherosclerosis development and the identification of potential therapeutic targets., Objectives: The study evaluates an in vivo imaging approach to visualize peripheral blood mononuclear cell (PBMC) accumulation in atherosclerotic lesions of cardiovascular (CV) patients using hybrid single-photon emission computed tomography/computed tomography (SPECT/CT)., Methods: At baseline, CV patients and healthy controls underwent (18)fluorodeoxyglucose positron emission tomography-computed tomography and magnetic resonance imaging to assess arterial wall inflammation and dimensions, respectively. For in vivo trafficking, autologous PBMCs were isolated, labeled with technetium-99m, and visualized 3, 4.5, and 6 h post-infusion with SPECT/CT., Results: Ten CV patients and 5 healthy controls were included. Patients had an increased arterial wall inflammation (target-to-background ratio [TBR] right carotid 2.00 ± 0.26 in patients vs. 1.51 ± 0.12 in controls; p = 0.022) and atherosclerotic burden (normalized wall index 0.52 ± 0.09 in patients vs. 0.33 ± 0.02 in controls; p = 0.026). Elevated PBMC accumulation in the arterial wall was observed in patients; for the right carotid, the arterial-wall-to-blood ratio (ABR) 4.5 h post-infusion was 2.13 ± 0.35 in patients versus 1.49 ± 0.40 in controls (p = 0.038). In patients, the ABR correlated with the TBR of the corresponding vessel (for the right carotid: r = 0.88; p < 0.001)., Conclusions: PBMC accumulation is markedly enhanced in patients with advanced atherosclerotic lesions and correlates with disease severity. This study provides a noninvasive imaging tool to validate the development and implementation of interventions targeting leukocytes in atherosclerosis., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)