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Jonathan P Wisor, 1 Nils Henrik Holmedahl, 2 Ingvild West Saxvig, 3 Odd-Magne Fjeldstad, 2 Eddie Weitzberg, 4 Janne Grønli, 5 Harald Kåre Engan 6 1Sleep and Performance Research Center and Department of Biomedical Sciences, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, USA; 2Section of Lung Rehabilitation, Department of Rehabilitation and Lifestyle Medicine, LHL-Hospital Gardermoen, Jessheim, Norway; 3Norwegian Competence Center for Sleep Disorders, Haukeland University Hospital, Bergen, Norway; 4Department of Physiology and Pharmacology, Karolinska Institutet and Department of Perioperative Medicine and Intensive Care, Karolinska Hospital, Stockholm, Sweden; 5Department of Biological and Medical Psychology, Faculty of Psychology, University of Bergen, Bergen, Norway; 6Unicare Rehabilitation, Oslo, NorwayCorrespondence: Jonathan P WisorWashington State University, 412 E. Spokane Falls Blvd, Spokane, WA, 99202, USATel +1 509358-7577Email Jonathan.Wisor@wsu.eduPurpose: Poor sleep quality in chronic obstructive pulmonary disease (COPD) is a result of oxygen desaturation secondary to compromised lung function. Nitrate supplementation with dietary beetroot juice is known to elevate plasma nitrate and to increase the efficiency of oxygen utilization in non-COPD individuals; whether it is of therapeutic benefit for sleep quality in COPD has not been reported.Patients and Methods: In a counterbalanced within-subjects design involving 15 COPD patients as subjects, the subjects consumed either beetroot juice containing nitrate (BJ; ∼ 6.2 mmol NO 3–) or placebo (NO 3– -depleted juice) immediately before a night of polysomnographic monitoring. Nitrate was measured in plasma collected immediately after waking.Results: While BJ consumption had no effect on the amount of time spent in any sleep stages, wake-to-N2 transitions and direct wake-to-rapid eye movement sleep (REMS) transitions, hallmarks of disordered sleep, were less frequent on the BJ night than on the placebo night. In the last two hours of the BJ night, percent time in REMS increased and delta power during deep (N3) non-REMS decreased, relative to the placebo night. Collectively, the reduced frequency of atypical transitions and the normalization of non-REMS/REMS dynamics after BJ are indicative of an improvement of sleep quality. BJ also resulted in sustained elevation of peripheral oxygen saturation (SpO 2), during episodes of wake after sleep onset. Plasma nitrate was elevated nearly tenfold on the morning after BJ relative to placebo.Conclusion: BJ has a normalizing effect on disordered sleep in COPD, which may be related to improved oxygen delivery.Clinical Trial Registration: The activities of the Regional Committees for Medical and Health Research Ethics (REC) are founded on the Norwegian law on research ethics and medical research. This study was approved by NTNU/REK midt, Det medisinske fakultet, Postboks 8905, 7491 Trondheim (REK midt 2016/1360).Keywords: polysomnography, oxygen saturation, beetroot juice, hypoxia

Dmitry Grishenkov,1–3 Adrian Gonon,3,4 Eddie Weitzberg,5 Jon O Lundberg,5 Johan Harmark,6 Barbara Cerroni,7 Gaio Paradossi,7 Birgitta Janerot-Sjoberg1–3 1Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden; 2Department of Medical Engineering, KTH, Royal Institute of Technology, School of Technology and Health, Stockholm, Sweden; 3Department of Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden; 4Department of Medicine, Karolinska Institutet, Stockholm, Sweden; 5Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; 6Department of Biosciences and Nutrition, Karolinska Institutet, KTH, Royal Institute of Technology, School of Technology and Health, Stockholm, Sweden; 7Department of Chemical Sciences and Technologies, University of Rome Tor Vergata, Rome, Italy Abstract: The current study describes novel multifunctional polymer-shelled microbubbles (MBs) loaded with nitric oxide (NO) for integrated therapeutic and diagnostic applications (ie, theranostics) of myocardial ischemia. We used gas-filled MBs with an average diameter of 4 µm stabilized by a biocompatible shell of polyvinyl alcohol. In vitro acoustic tests showed sufficient enhancement of the backscattered power (20 dB) acquired from the MBs’ suspension. The values of attenuation coefficient (0.8 dB/cm MHz) and phase velocities (1,517 m/s) were comparable with those reported for the soft tissue. Moreover, polymer MBs demonstrate increased stability compared with clinically approved contrast agents with a fracture threshold of about 900 kPa. In vitro chemiluminescence measurements demonstrated that dry powder of NO-loaded MBs releases its gas content in about 2 hours following an exponential decay profile with an exponential time constant equal to 36 minutes. The application of high-power ultrasound pulse (mechanical index =1.2) on the MBs resuspended in saline decreases the exponential time constant from 55 to 4 minutes in air-saturated solution and from 17 to 10 minutes in degassed solution. Thus, ultrasound-triggered release of NO is achieved. Cytotoxicity tests indicate that phagocytosis of the MBs by macrophages starts within 6–8 hours. This is a suitable time for initial diagnostics, treatment, and monitoring of the therapeutic effect using a single injection of the proposed multifunctional MBs. Keywords: microbubbles, contrast agent, ultrasound, nitric oxide, myocardial ischemia

Abstract Background Cerebral microdialysis (MD) is used to monitor local brain chemistry of patients with traumatic brain injury (TBI). Despite an extensive literature on cerebral MD in the clinical setting, it remains unclear how individual levels of real-time MD data are to be interpreted. Intracranial pressure (ICP) and cerebral perfusion pressure (CPP) are important continuous brain monitors in neurointensive care. They are used as surrogate monitors of cerebral blood flow and have an established relation to outcome. The purpose of this study was to investigate the relations between MD parameters and ICP and/or CPP in patients with TBI. Methods Cerebral MD, ICP and CPP were monitored in 90 patients with TBI. Data were extensively analyzed, using over 7,350 samples of complete (hourly) MD data sets (glucose, lactate, pyruvate and glycerol) to seek representations of ICP, CPP and MD that were best correlated. MD catheter positions were located on computed tomography scans as pericontusional or nonpericontusional. MD markers were analyzed for correlations to ICP and CPP using time series regression analysis, mixed effects models and nonlinear (artificial neural networks) computer-based pattern recognition methods. Results Despite much data indicating highly perturbed metabolism, MD shows weak correlations to ICP and CPP. In contrast, the autocorrelation of MD is high for all markers, even at up to 30 future hours. Consequently, subject identity alone explains 52% to 75% of MD marker variance. This indicates that the dominant metabolic processes monitored with MD are long-term, spanning days or longer. In comparison, short-term (differenced or Δ) changes of MD vs. CPP are significantly correlated in pericontusional locations, but with less than 1% explained variance. Moreover, CPP and ICP were significantly related to outcome based on Glasgow Outcome Scale scores, while no significant relations were found between outcome and MD. Conclusions The multitude of highly perturbed local chemistry seen with MD in patients with TBI predominately represents long-term metabolic patterns and is weakly correlated to ICP and CPP. This suggests that disturbances other than pressure and/or flow have a dominant influence on MD levels in patients with TBI.