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Vaishnavi Kundel,1 Daniel Lehane,2 Sarayu Ramachandran,3 Zahi Fayad,3 Philip Robson,3 Neomi Shah,1 Venkatesh Mani3 1Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 2University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; 3Department of Radiology, BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USACorrespondence: Vaishnavi KundelAssistant Professor of Medicine, Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1232, New York, NY, 10029, USATel +1 212-241-6564Email Vaishnavi.kundel@mssm.eduPurpose: Visceral adipose tissue (VAT) is proinflammatory and is associated with cardiovascular (CV) disease. We investigated the relationship between obstructive sleep apnea (OSA) and visceral adipose tissue (VAT) metabolic activity in a pilot group of patients using positron-emission tomography/magnetic resonance imaging (PET/MRI) with 18F-fluorodeoxyglucose (FDG) tracer as a novel marker of adipose tissue inflammation.Patients and Methods: We analyzed patients from an ongoing study, recruiting those with newly diagnosed, untreated OSA (Respiratory Disturbance Index [RDI] ≥ 5), using home sleep apnea testing (WatchPAT-200 Central-Plus). PET/MRI scans were acquired before continuous positive airway pressure (CPAP)-initiation, and after 3 months of CPAP therapy. Adipose tissue metabolic activity (18F-FDG-uptake) was measured using standardized uptake values (SUV) within the adipose tissue depots. The primary outcome was VAT SUVmean, and secondary outcomes included VAT volume, and subcutaneous adipose tissue (SAT) volume/SUVmean. Reproducibility and reliability of outcome measures were analyzed using intraclass correlation coefficients (ICC). Multivariable linear regression was used to evaluate the association betw

Nanomedicine research produces hundreds of studies every year, yet very few formulations have been approved for clinical use. This is due in part to a reliance on murine studies, which have limited value in accurately predicting translational efficacy in larger animal models and humans. Here, we report the scale-up of a nanoimmunotherapy from mouse to large rabbit and porcine atherosclerosis models, with an emphasis on the solutions we implemented to overcome production and evaluation challenges. Specifically, we integrated translational imaging readouts within our workflow to both analyze the nanoimmunotherapeutic's in vivo behavior and assess treatment response in larger animals. We observed our nanoimmunotherapeutic's anti-inflammatory efficacy in mice, as well as rabbits and pigs. Nanoimmunotherapy-mediated reduction of inflammation in the large animal models halted plaque progression, supporting the approach's translatability and potential to acutely treat atherosclerosis.

Psoriasis increases the risk of cardiovascular (CV) disease. Secukinumab, a fully human monoclonal antibody against IL-17A, shows significant efficacy in psoriasis, but effects on CV markers are unknown. CARIMA (Evaluation of Cardiovascular Risk Markers in Psoriasis Patients Treated with Secukinumab) was a 52-week, randomized, double-blind, placebo-controlled, exploratory trial in patients with moderate to severe plaque psoriasis without clinical CV disease. Patients were randomly assigned to receive 300 mg or 150 mg secukinumab until week 52 or to receive placebo until week 12 and then 300 mg or 150 mg secukinumab until week 52. The primary outcome was endothelial function measured by flow-mediated dilation (FMD). Baseline FMD was significantly lower in psoriasis patients than healthy volunteers (4.4 +/- 3.9% vs. 6.1 +/- 3.3%, P = 0.01). At week 12, baseline-adjusted mean FMD was numerically higher in patients receiving secukinumab versus those receiving placebo, but this difference (300-mg group, +1.2%; 150-mg group, +0.76%; P = 0.223 and P = 0.403 by analysis of covariance) did not reach significance. At week 52, FMD increased across groups. FMD was significantly higher than baseline in patients receiving the label dose of 300 mg secukinumab for 52 weeks (+2.1%, 95% confidence interval = 0.8-3.3; P = 0.0022). Other relevant CV markers were unchanged. CARIMA indicates that secukinumab might have a beneficial effect on CV risk by improving the endothelial function of patients with plaque psoriasis.

Psoriasis increases the risk of cardiovascular (CV) disease. Secukinumab, a fully human monoclonal antibody against IL-17A, shows significant efficacy in psoriasis, but effects on CV markers are unknown. CARIMA (Evaluation of Cardiovascular Risk Markers in Psoriasis Patients Treated with Secukinumab) was a 52-week, randomized, double-blind, placebo-controlled, exploratory trial in patients with moderate to severe plaque psoriasis without clinical CV disease. Patients were randomly assigned to receive 300 mg or 150 mg secukinumab until week 52 or to receive placebo until week 12 and then 300 mg or 150 mg secukinumab until week 52. The primary outcome was endothelial function measured by flow-mediated dilation (FMD). Baseline FMD was significantly lower in psoriasis patients than healthy volunteers (4.4 +/- 3.9% vs. 6.1 +/- 3.3%, P = 0.01). At week 12, baseline-adjusted mean FMD was numerically higher in patients receiving secukinumab versus those receiving placebo, but this difference (300-mg group, +1.2%; 150-mg group, +0.76%; P = 0.223 and P = 0.403 by analysis of covariance) did not reach significance. At week 52, FMD increased across groups. FMD was significantly higher than baseline in patients receiving the label dose of 300 mg secukinumab for 52 weeks (+2.1%, 95% confidence interval = 0.8-3.3; P = 0.0022). Other relevant CV markers were unchanged. CARIMA indicates that secukinumab might have a beneficial effect on CV risk by improving the endothelial function of patients with plaque psoriasis.

Nanomedicine research produces hundreds of studies every year, yet very few formulations have been approved for clinical use. This is due in part to a reliance on murine studies, which have limited value in accurately predicting translational efficacy in larger animal models and humans. Here, we report the scale-up of a nanoimmunotherapy from mouse to large rabbit and porcine atherosclerosis models, with an emphasis on the solutions we implemented to overcome production and evaluation challenges. Specifically, we integrated translational imaging readouts within our workflow to both analyze the nanoimmunotherapeutic's in vivo behavior and assess treatment response in larger animals. We observed our nanoimmunotherapeutic's anti-inflammatory efficacy in mice, as well as rabbits and pigs. Nanoimmunotherapy-mediated reduction of inflammation in the large animal models halted plaque progression, supporting the approach's translatability and potential to acutely treat atherosclerosis.

Nanomedicine research produces hundreds of studies every year, yet very few formulations have been approved for clinical use. This is due in part to a reliance on murine studies, which have limited value in accurately predicting translational efficacy in larger animal models and humans. Here, we report the scale-up of a nanoimmunotherapy from mouse to large rabbit and porcine atherosclerosis models, with an emphasis on the solutions we implemented to overcome production and evaluation challenges. Specifically, we integrated translational imaging readouts within our workflow to both analyze the nanoimmunotherapeutic's in vivo behavior and assess treatment response in larger animals. We observed our nanoimmunotherapeutic's anti-inflammatory efficacy in mice, as well as rabbits and pigs. Nanoimmunotherapy-mediated reduction of inflammation in the large animal models halted plaque progression, supporting the approach's translatability and potential to acutely treat atherosclerosis.

Inflammation and neovascularization in vulnerable atherosclerotic plaques are key features for severe clinical events. Dynamic contrast-enhanced (DCE) MRI and FDG PET are two noninvasive imaging techniques capable of quantifying plaque neovascularization and inflammatory infiltrate, respectively. However, their mutual role in defining plaque vulnerability and their possible overlap has not been thoroughly investigated. We studied the relationship between DCE-MRI and [supersript 18]F-FDG PET data from the carotid arteries of 40 subjects with coronary heart disease (CHD) or CHD risk equivalent, as a substudy of the dal-PLAQUE trial (NCT00655473).

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 63. h (LN-PLP 1.5. mg/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.

In this work we present a methodology to extract information from medical imaging and use it for hemodynamical simulation in arteries. Based on in-vivo magnetic resonance images (MRI), the velocity of the blood flow has been measured at different positions and times. Also, the anatomy of the vessel has been converted into a volume mesh suitable for numerical modeling. This data has been used to solve computationally the dynamics of the fluid inside the artery in healthy and pathologic cases. As an application, we have developed a computational model within the carotids. The next step in the pipeline will be to extend the simulation to fluidstructure interaction (FSI) to find the parameters in an atherosclerotic plaque that could lead to rupture., Peer Reviewed

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.

Heat stress compromises intestinal integrity which may partially explain its negative effects on animal health and productivity. Research suggests that challenged intestinal barrier function improves with dietary dairy products in various models. Thus, the study objective was to evaluate the effects of bovine milk whey protein (WP) and colostral whey protein (CWP) on intestinal integrity in heat-stressed pigs. Crossbred gilts (39 ± 3 kg body weight) were fed 1 of 4 diets (n = 8 pigs/diet): control (Ct), control diet containing an 80% WP and 20% CWP product (WP80), control diet containing a 98% WP and 2% CWP product (WP98), and control diet containing a 100% WP product (WP100). After 7d on experimental diets, pigs were exposed to constant heat stress conditions (32 °C) for 24h. There were no treatment differences in growth or body temperature indices prior to heat stress. During heat exposure, both rectal temperature and respiration rate increased (+0.85 °C and 3-fold, respectively; P < 0.01), and feed intake and body weight decreased (44% and -0.5kg, respectively; P < 0.01), but neither variable was affected by dietary treatments. Plasma L-lactate and D-lactate concentrations increased (36%; P < 0.01) and tended to increase (19%; P = 0.09) with heat stress. After 24h of heat exposure, WP100-fed pigs had lower plasma D-lactate relative to Ct-fed pigs. Ileal transepithelial electrical resistance was decreased (37%; P = 0.02) in WP80 pigs, compared with controls. No differences were detected in other intestinal integrity ex vivo measurements. These data demonstrate that dietary WP and CWP did not mitigate intestinal integrity dysfunction during severe heat stress.

Heat stress compromises intestinal integrity which may partially explain its negative effects on animal health and productivity. Research suggests that challenged intestinal barrier function improves with dietary dairy products in various models. Thus, the study objective was to evaluate the effects of bovine milk whey protein (WP) and colostral whey protein (CWP) on intestinal integrity in heat-stressed pigs. Crossbred gilts (39 ± 3 kg body weight) were fed 1 of 4 diets (n = 8 pigs/diet): control (Ct), control diet containing an 80% WP and 20% CWP product (WP80), control diet containing a 98% WP and 2% CWP product (WP98), and control diet containing a 100% WP product (WP100). After 7d on experimental diets, pigs were exposed to constant heat stress conditions (32 °C) for 24h. There were no treatment differences in growth or body temperature indices prior to heat stress. During heat exposure, both rectal temperature and respiration rate increased (+0.85 °C and 3-fold, respectively; P < 0.01), and feed intake and body weight decreased (44% and -0.5kg, respectively; P < 0.01), but neither variable was affected by dietary treatments. Plasma L-lactate and D-lactate concentrations increased (36%; P < 0.01) and tended to increase (19%; P = 0.09) with heat stress. After 24h of heat exposure, WP100-fed pigs had lower plasma D-lactate relative to Ct-fed pigs. Ileal transepithelial electrical resistance was decreased (37%; P = 0.02) in WP80 pigs, compared with controls. No differences were detected in other intestinal integrity ex vivo measurements. These data demonstrate that dietary WP and CWP did not mitigate intestinal integrity dysfunction during severe heat stress.

Excessive heat exposure reduces intestinal integrity and post-absorptive energetics that can inhibit wellbeing and be fatal. Therefore, our objectives were to examine how acute heat stress (HS) alters intestinal integrity and metabolism in growing pigs. Animals were exposed to either thermal neutral (TN, 21°C; 35–50% humidity; n = 8) or HS conditions (35°C; 24–43% humidity; n = 8) for 24 h. Compared to TN, rectal temperatures in HS pigs increased by 1.6°C and respiration rates by 2-fold (P,0.05). As expected, HS decreased feed intake by 53% (P<0.05) and body weight (P<0.05) compared to TN pigs. Ileum heat shock protein 70 expression increased (P<0.05), while intestinal integrity was compromised in the HS pigs (ileum and colon TER decreased; P<0.05). Furthermore, HS increased serum endotoxin concentrations (P<0.05). Intestinal permeability was accompanied by an increase in protein expression of myosin light chain kinase (P<0.05) and casein kinase II-a (P = 0.06). Protein expression of tight junction (TJ) proteins in the ileum revealed claudin 3 and occludin expression to be increased overall due to HS (P,0.05), while there were no differences in claudin 1 expression. Intestinal glucose transport and blood glucose were elevated due to HS (P<0.05). This was supported by increased ileum Na+/K+ ATPase activity in HS pigs. SGLT-1 protein expression was unaltered; however, HS increased ileal GLUT-2 protein expression (P=0.06). Altogether, these data indicate that HS reduce intestinal integrity and increase intestinal stress and glucose transport.

Excessive heat exposure reduces intestinal integrity and post-absorptive energetics that can inhibit wellbeing and be fatal. Therefore, our objectives were to examine how acute heat stress (HS) alters intestinal integrity and metabolism in growing pigs. Animals were exposed to either thermal neutral (TN, 21°C; 35–50% humidity; n = 8) or HS conditions (35°C; 24–43% humidity; n = 8) for 24 h. Compared to TN, rectal temperatures in HS pigs increased by 1.6°C and respiration rates by 2-fold (P,0.05). As expected, HS decreased feed intake by 53% (P<0.05) and body weight (P<0.05) compared to TN pigs. Ileum heat shock protein 70 expression increased (P<0.05), while intestinal integrity was compromised in the HS pigs (ileum and colon TER decreased; P<0.05). Furthermore, HS increased serum endotoxin concentrations (P<0.05). Intestinal permeability was accompanied by an increase in protein expression of myosin light chain kinase (P<0.05) and casein kinase II-a (P = 0.06). Protein expression of tight junction (TJ) proteins in the ileum revealed claudin 3 and occludin expression to be increased overall due to HS (P,0.05), while there were no differences in claudin 1 expression. Intestinal glucose transport and blood glucose were elevated due to HS (P<0.05). This was supported by increased ileum Na+/K+ ATPase activity in HS pigs. SGLT-1 protein expression was unaltered; however, HS increased ileal GLUT-2 protein expression (P=0.06). Altogether, these data indicate that HS reduce intestinal integrity and increase intestinal stress and glucose transport.

The paper uniquely investigates the relationship between supply chain social sustainability practices and supply chain performance in small and medium manufacturing enterprises (SME's) in an Asian country. In this paper, we utilized semi-structured interviews of supply chain managers and practitioners to unearth the social sustainability dimensions, followed by a survey using structured questionnaire. We further tested our model using covariance-based structural equation modeling (CBSEM) using 327 samples from SME's. The results suggest a positive relationship between social sustainability practices and supply chain performance that is mediated by customer, supplier, and operational performance. Additionally, the role of firm size and investment in determining supplier performance (SP), operational performance (OP), and customer performance (CP), and supply chain performance (SCP) is established. We present an empirical model for supply chain social sustainability grounded in stakeholder's resource-based view for SME's in emerging economy setting. This study provides original evidence to SME's managers that tangible performance benefits can be realized by focusing on increasing supply chain social sustainability, supporting the case for social sustainability on economic as well as ethical grounds. The outcomes of this research have far-reaching implications for theory and practitioners (SME's) in emerging economies.