Sustained Effect of Clinical Decision Support for Heart Failure: A Natural Experiment Using Implementation Science.

OBJECTIVES: In a randomized controlled trial, we found that applying implementation science (IS) methods and best practices in clinical decision support (CDS) design to create a locally customized, "enhanced" CDS significantly improved evidence-based prescribing of ß blockers (BB) for heart failure compared with an unmodified commercially available CDS. At trial conclusion, the enhanced CDS was expanded to all sites. The purpose of this study was to evaluate the real-world sustained effect of the enhanced CDS compared with the commercial CDS. METHODS: In this natural experiment of 28 primary care clinics, we compared clinics exposed to the commercial CDS (preperiod) to clinics exposed to the enhanced CDS (both periods). The primary effectiveness outcome was the proportion of alerts resulting in a BB prescription. Secondary outcomes included patient reach and clinician adoption (dismissals). RESULTS: There were 367 alerts for 183 unique patients and 171 unique clinicians (pre: March 2019-August 2019; post: October 2019-March 2020). The enhanced CDS increased prescribing by 26.1% compared with the commercial (95% confidence interval [CI]: 17.0-35.1%), which is consistent with the 24% increase in the previous study. The odds of adopting the enhanced CDS was 81% compared with 29% with the commercial (odds ratio: 4.17, 95% CI: 1.96-8.85). The enhanced CDS adoption and effectiveness rates were 62 and 14% in the preperiod and 92 and 10% in the postperiod. CONCLUSION: Applying IS methods with CDS best practices was associated with improved and sustained clinician adoption and effectiveness compared with a commercially available CDS tool.

Victors: a web-based knowledge base of virulence factors in human and animal pathogens.

Virulence factors (VFs) are molecules that allow microbial pathogens to overcome host defense mechanisms and cause disease in a host. It is critical to study VFs for better understanding microbial pathogenesis and host defense mechanisms. Victors (http://www.phidias.us/victors) is a novel, manually curated, web-based integrative knowledge base and analysis resource for VFs of pathogens that cause infectious diseases in human and animals. Currently, Victors contains 5296 VFs obtained via manual annotation from peer-reviewed publications, with 4648, 179, 105 and 364 VFs originating from 51 bacterial, 54 viral, 13 parasitic and 8 fungal species, respectively. Our data analysis identified many VF-specific patterns. Within the global VF pool, cytoplasmic proteins were more common, while adhesins were less common compared to findings on protective vaccine antigens. Many VFs showed homology with host proteins and the human proteins interacting with VFs represented the hubs of human-pathogen interactions. All Victors data are queriable with a user-friendly web interface. The VFs can also be searched by a customized BLAST sequence similarity searching program. These VFs and their interactions with the host are represented in a machine-readable Ontology of Host-Pathogen Interactions. Victors supports the 'One Health' research as a vital source of VFs in human and animal pathogens.

Quality assurance processes for standardized patient programs.

OUR PROBLEM: As the pharmacy profession evolves to include non-dispensing services and collaborative care, greater emphasis is placed on communication skills building through standardized patient programs. Best practices for assuring the quality of standardized patient (SP) programs, however, remains unclear. The objective of this manuscript is to summarize quality assurance processes for standardized patient programs from health professions education literature. METHODOLOGICAL LITERATURE REVIEW: A search of PubMed and Scopus between 2011 and 2016 was conducted and 22 articles were retained for thematic analysis. Articles were screened for relevance to quality assurance. OUR RECOMMENDATIONS AND THEIR APPLICATIONS: The thematic analysis revealed four themes: (1) enhanced SP training programs, (2) structured feedback to students, (3) statistical measurements to ensure inter-rater reliability, and (4) observation and evaluation of the SP to improve SP performance. Specific methods to assure the quality of an SP program were identified, including training program content and feedback techniques. POTENTIAL IMPACT: Although SP programs varied widely in their implementation, there were several common strategies used to evaluate the consistency of performance, effectiveness of feedback to students, and reliability of grading. Additional research is necessary to establish standards for SP programs across professional healthcare disciplines.

Myocardial perfusion quantification using simultaneously acquired 13 NH3 -ammonia PET and dynamic contrast-enhanced MRI in patients at rest and stress.

PURPOSE: Systematic differences with respect to myocardial perfusion quantification exist between DCE-MRI and PET. Using the potential of integrated PET/MRI, this study was conceived to compare perfusion quantification on the basis of simultaneously acquired 13 NH3 -ammonia PET and DCE-MRI data in patients at rest and stress. METHODS: Twenty-nine patients were examined on a 3T PET/MRI scanner. DCE-MRI was implemented in dual-sequence design and additional T1 mapping for signal normalization. Four different deconvolution methods including a modified version of the Fermi technique were compared against 13 NH3 -ammonia results. RESULTS: Cohort-average flow comparison yielded higher resting flows for DCE-MRI than for PET and, therefore, significantly lower DCE-MRI perfusion ratios under the common assumption of equal arterial and tissue hematocrit. Absolute flow values were strongly correlated in both slice-average (R2 = 0.82) and regional (R2 = 0.7) evaluations. Different DCE-MRI deconvolution methods yielded similar flow result with exception of an unconstrained Fermi method exhibiting outliers at high flows when compared with PET. CONCLUSION: Thresholds for Ischemia classification may not be directly tradable between PET and MRI flow values. Differences in perfusion ratios between PET and DCE-MRI may be lifted by using stress/rest-specific hematocrit conversion. Proper physiological constraints are advised in model-constrained deconvolution.

Improved spatial localization in magnetic resonance spectroscopic imaging with two-dimensional PSF-Choice encoding.

PURPOSE: Magnetic resonance spectroscopic imaging (MRSI), under low-spatial resolution settings, often suffers signal contamination from neighboring voxels due to ringing artifacts. Spatial localization can be improved by constraining the point-spread-function (PSF). Here the effectiveness of the two-dimensional PSF-Choice technique in providing improved spatial localization for MRSI is demonstrated. THEORY AND METHODS: The PSF-Choice technique constrains the PSF to a desired shape by manipulating the weighting of RF excitation pulse throughout phase-encode steps. Based on a Point REsolved SpectroScopy (PRESS)-type sequence, PSF-Choice encoding was implemented along two dimensions to excite a two-dimensional Gaussian profile, by replacing the usual RF excitation pulse with a train of pulses that is modified at each phase-encoding step. The method was proven mathematically, and demonstrated experimentally in phantoms containing prostate relevant metabolic compounds of choline, creatine and citrate. RESULTS: Using a dedicated prostate-mimicking spectroscopy phantom surrounded by oil, it was found that there is significantly less signal contamination from oil for PSF-Choice encoding compared with standard phase encoding. In particular, with standard phase encoding, there was a significant difference (p = 0.014) between ratios of Choline + Creatine to Citrate for voxels well within the phantom compared to voxels within the phantom but near the boundary with oil. The ratios in boundary voxels were also significantly different (p = 0.035) from reference values obtained using the prostate phantom with no oil present. In contrast, no significant differences were found in comparisons of these ratios when encoding with PSF-Choice. CONCLUSION: The PSF-Choice scheme applied along two dimensions produces MR spectroscopic images with substantially reduced truncation artifacts and spectral contamination.

Linking MedDRA(®)-Coded Clinical Phenotypes to Biological Mechanisms by the Ontology of Adverse Events: A Pilot Study on Tyrosine Kinase Inhibitors.

INTRODUCTION: A translational bioinformatics challenge exists in connecting population and individual clinical phenotypes in various formats to biological mechanisms. The Medical Dictionary for Regulatory Activities (MedDRA(®)) is the default dictionary for adverse event (AE) reporting in the US Food and Drug Administration Adverse Event Reporting System (FAERS). The ontology of adverse events (OAE) represents AEs as pathological processes occurring after drug exposures. OBJECTIVES: The aim of this work was to establish a semantic framework to link biological mechanisms to phenotypes of AEs by combining OAE with MedDRA(®) in FAERS data analysis. We investigated the AEs associated with tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) targeting tyrosine kinases. The five selected TKIs/mAbs (i.e., dasatinib, imatinib, lapatinib, cetuximab, and trastuzumab) are known to induce impaired ventricular function (non-QT) cardiotoxicity. RESULTS: Statistical analysis of FAERS data identified 1053 distinct MedDRA(®) terms significantly associated with TKIs/mAbs, where 884 did not have corresponding OAE terms. We manually annotated these terms, added them to OAE by the standard OAE development strategy, and mapped them to MedDRA(®). The data integration to provide insights into molecular mechanisms of drug-associated AEs was performed by including linkages in OAE for all related AE terms to MedDRA(®) and the existing ontologies, including the human phenotype ontology (HP), Uber anatomy ontology (UBERON), and gene ontology (GO). Sixteen AEs were shared by all five TKIs/mAbs, and each of 17 cardiotoxicity AEs was associated with at least one TKI/mAb. As an example, we analyzed "cardiac failure" using the relations established in OAE with other ontologies and demonstrated that one of the biological processes associated with cardiac failure maps to the genes associated with heart contraction. CONCLUSION: By expanding the existing OAE ontological design, our TKI use case demonstrated that the combination of OAE and MedDRA(®) provides a semantic framework to link clinical phenotypes of adverse drug events to biological mechanisms.

Gradient-induced voltages on 12-lead ECGs during high duty-cycle MRI sequences and a method for their removal considering linear and concomitant gradient terms.

PURPOSE: To restore 12-lead electrocardiographic (ECG) signal fidelity inside MRI by removing magnetic field gradient-induced voltages during high gradient duty cycle sequences. THEORY AND METHODS: A theoretical equation was derived to provide first- and second-order electrical fields induced at individual ECG electrodes as a function of gradient fields. Experiments were performed at 3T on healthy volunteers using a customized acquisition system that captured the full amplitude and frequency response of ECGs, or a commercial recording system. The 19 equation coefficients were derived via linear regression of data from accelerated sequences and were used to compute induced voltages in real-time during full resolution sequences to remove ECG artifacts. Restored traces were evaluated relative to ones acquired without imaging. RESULTS: Measured induced voltages were 0.7 V peak-to-peak during balanced steady state free precession (bSSFP) with the heart at the isocenter. Applying the equation during gradient echo sequencing, three-dimensional fast spin echo, and multislice bSSFP imaging restored nonsaturated traces and second-order concomitant terms showed larger contributions in electrodes further from the magnet isocenter. Equation coefficients are evaluated with high repeatability (ρ = 0.996) and are dependent on subject, sequence, and slice orientation. CONCLUSION: Close agreement between theoretical and measured gradient-induced voltages allowed for real-time removal. Prospective estimation of sequence periods in which large induced voltages occur may allow hardware removal of these signals.

Reduced NADPH oxidase type 2 activity mediates sleep fragmentation-induced effects on TC1 tumors in mice.

The molecular mechanisms underlying how sleep fragmentation (SF) influences cancer growth and progression remain largely elusive. Here, we present evidence that SF reduced ROS production by downregulating gp91phox expression and activity in TC1 cell tumor associated macrophages (TAMs), while genetic ablation of phagocytic Nox2 activity increased tumor cell proliferation, motility, invasion, and extravasation in vitro. Importantly, the in vivo studies using immunocompetent syngeneic murine tumor models suggested that Nox2 deficiency mimics SF-induced TAMs infiltration and subsequent tumor growth and invasion. Taken together, these studies reveal that perturbed sleep could adversely affect innate immunity within the tumor by altering Nox2 expression and activity, and indicate that selective potentiation of Nox2 activity may present a novel therapeutic strategy in the treatment of cancer.

Adipose tissue macrophage polarization by intermittent hypoxia in a mouse model of OSA: effect of tumor microenvironment.

Intermittent hypoxia (IH)-induces alterations in tumor-associated macrophages (TAMs) that are associated with adverse cancer outcomes, as reported in patients suffering from sleep apnea. Adipose tissues (AT) and bone-marrow (BM)-derived cells are the inferred sources of macrophages infiltrating malignant tumors. Here, the sources of TAMs and the phenotypic changes induced by IH in the ipsilateral and contralateral AT were investigated by using a syngeneic murine solid tumor model (TC1). C57/B6 male mice were exposed to either IH or room air (RA) for 6 weeks, with TC1 cells being inoculated in the 2nd week. Macrophage content, phenotype and tissue origin were assessed in tumors, and ipsilateral and contralateral AT. IH induced a ~2.2-fold increase in TAM tumor infiltration. However, differential responses in the tumor ipsilateral and contralateral AT emerged: IH increased infiltration of preferentially M1 macrophages in contralateral AT, while reductions in macrophages emerged in ipsilateral AT and primarily consisted of the M2 phenotype. These changes were accompanied by reciprocal increases in resident and BM-derived TAMs in the tumor. IH-induced phenotypic alterations in AT macrophages surrounding the tumor and their increased infiltration within the tumor may contribute to the accelerated tumor progression associated with IH.

Resveratrol attenuates intermittent hypoxia-induced macrophage migration to visceral white adipose tissue and insulin resistance in male mice.

Chronic intermittent hypoxia during sleep (IH), as occurs in sleep apnea, promotes systemic insulin resistance. Resveratrol (Resv) has been reported to ameliorate high-fat diet-induced obesity, inflammation, and insulin resistance. To examine the effect of Resv on IH-induced metabolic dysfunction, male mice were subjected to IH or room air conditions for 8 weeks and treated with either Resv or vehicle (Veh). Fasting plasma levels of glucose, insulin, and leptin were obtained, homeostatic model assessment of insulin resistance index levels were calculated, and insulin sensitivity tests (phosphorylated AKT [also known as protein kinase B]/total AKT) were performed in 2 visceral white adipose tissue (VWAT) depots (epididymal [Epi] and mesenteric [Mes]) along with flow cytometry assessments for VWAT macrophages and phenotypes (M1 and M2). IH-Veh and IH-Resv mice showed initial reductions in food intake with later recovery, with resultant lower body weights after 8 weeks but with IH-Resv showing better increases in body weight vs IH-Veh. IH-Veh and IH-Resv mice exhibited lower fasting glucose levels, but only IH-Veh had increased homeostatic model assessment of insulin resistance index vs all 3 other groups. Leptin levels were preserved in IH-Veh but were significantly lower in IH-Resv. Reduced VWAT phosphorylated-AKT/AKT responses to insulin emerged in both Mes and Epi in IH-Veh but normalized in IH-Resv. Increases total macrophage counts and in M1 to M2 ratios occurred in IH-Veh Mes and Epi compared all other 3 groups. Thus, Resv ameliorates food intake and weight gain during IH exposures and markedly attenuates VWAT inflammation and insulin resistance, thereby providing a potentially useful adjunctive therapy for metabolic morbidity in the context of sleep apnea.

Chronic sleep fragmentation induces endothelial dysfunction and structural vascular changes in mice.

STUDY OBJECTIVES: Sleep fragmentation (SF) is a common occurrence and constitutes a major characteristic of obstructive sleep apnea (OSA). SF has been implicated in multiple OSA-related morbidities, but it is unclear whether SF underlies any of the cardiovascular morbidities of OSA. We hypothesized that long-term SF exposures may lead to endothelial dysfunction and altered vessel wall structure. METHODS AND RESULTS: Adult male C57BL/6J mice were fed normal chow and exposed to daylight SF or control sleep (CTL) for 20 weeks. Telemetric blood pressure and endothelial function were assessed weekly using a modified laser-Doppler hyperemic test. Atherosclerotic plaques, elastic fiber disruption, lumen area, wall thickness, foam cells, and macrophage recruitment, as well as expression of senescence-associated markers were examined in excised aortas. Increased latencies to reach baseline perfusion levels during the post-occlusive period emerged in SF mice with increased systemic BP values starting at 8 weeks of SF and persisting thereafter. No obvious atherosclerotic plaques emerged, but marked elastic fiber disruption and fiber disorganization were apparent in SF-exposed mice, along with increases in the number of foam cells and macrophages in the aorta wall. Senescence markers showed reduced TERT and cyclin A and increased p16INK4a expression, with higher IL-6 plasma levels in SF-exposed mice. CONCLUSIONS: Long-term sleep fragmentation induces vascular endothelial dysfunction and mild blood pressure increases. Sleep fragmentation also leads to morphologic vessel changes characterized by elastic fiber disruption and disorganization, increased recruitment of inflammatory cells, and altered expression of senescence markers, thereby supporting a role for sleep fragmentation in the cardiovascular morbidity of OSA.

Left-ventricular mechanical activation and aortic-arch orientation recovered from magneto-hydrodynamic voltages observed in 12-lead ECGs obtained inside MRIs: a feasibility study.

To explore use of the Magnetohydrodynamic Voltage (VMHD), observed in intra-MRI 12-lead electrocardiograms (ECG), to indicate the timing of the onset of left-ventricular mechanical activation (LVMA) and the orientation of the aortic-arch (AAO). Blood flow through the aortic arch during systole, in the presence of the MRI magnetic field (B 0), generates VMHD. Since the magnitude and direction of VMHD are determined by the timing and directionality of blood flow relative to B 0, we hypothesized that clinically useful measures, LVMA and AAO, could be extracted from temporal and vectorial VMHD characteristics. VMHD signals were extracted from 12-lead ECG traces by comparing traces obtained inside and outside the MRI scanner. VMHD was converted into the Vectorcardiogram frame of reference. LVMA was quantified in 1 subject at 1.5T and 3 subjects at 3T, and the result compared to CINE MRI. AAO was inferred for 4 subjects at 3T and compared to anatomical imaging of the aortic arch orientation in the transverse plane. A < 10% error was observed in LVMA measurements, while a < 3° error was observed in aortic arch orientation measurements. The temporal and vectorial nature of VMHD is useful in estimating these clinically relevant parameters.

OAE: The Ontology of Adverse Events.

BACKGROUND: A medical intervention is a medical procedure or application intended to relieve or prevent illness or injury. Examples of medical interventions include vaccination and drug administration. After a medical intervention, adverse events (AEs) may occur which lie outside the intended consequences of the intervention. The representation and analysis of AEs are critical to the improvement of public health. DESCRIPTION: The Ontology of Adverse Events (OAE), previously named Adverse Event Ontology (AEO), is a community-driven ontology developed to standardize and integrate data relating to AEs arising subsequent to medical interventions, as well as to support computer-assisted reasoning. OAE has over 3,000 terms with unique identifiers, including terms imported from existing ontologies and more than 1,800 OAE-specific terms. In OAE, the term 'adverse event' denotes a pathological bodily process in a patient that occurs after a medical intervention. Causal adverse events are defined by OAE as those events that are causal consequences of a medical intervention. OAE represents various adverse events based on patient anatomic regions and clinical outcomes, including symptoms, signs, and abnormal processes. OAE has been used in the analysis of several different sorts of vaccine and drug adverse event data. For example, using the data extracted from the Vaccine Adverse Event Reporting System (VAERS), OAE was used to analyse vaccine adverse events associated with the administrations of different types of influenza vaccines. OAE has also been used to represent and classify the vaccine adverse events cited in package inserts of FDA-licensed human vaccines in the USA. CONCLUSION: OAE is a biomedical ontology that logically defines and classifies various adverse events occurring after medical interventions. OAE has successfully been applied in several adverse event studies. The OAE ontological framework provides a platform for systematic representation and analysis of adverse events and of the factors (e.g., vaccinee age) important for determining their clinical outcomes.

Sleep fragmentation in mice induces nicotinamide adenine dinucleotide phosphate oxidase 2-dependent mobilization, proliferation, and differentiation of adipocyte progenitors in visceral white adipose tissue.

BACKGROUND: Chronic sleep fragmentation (SF) without sleep curtailment induces increased adiposity. However, it remains unclear whether mobilization, proliferation, and differentiation of adipocyte progenitors (APs) occurs in visceral white adipose tissue (VWAT), and whether nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (Nox2) activity plays a role. METHODS: Changes in VWAT depot cell size and AP proliferation were assessed in wild-type and Nox2 null male mice exposed to SF and control sleep (SC). To assess mobilization, proliferation, and differentiation of bone marrow mesenchymal stem cells (BM-MSC), Sca-1+ bone marrow progenitors were isolated from GFP+ or RFP+ mice, and injected intravenously to adult male mice (C57BL/6) previously exposed to SF or SC. RESULTS: In comparison with SC, SF was associated with increased weight accrual at 3 w and thereafter, larger subcutaneous and visceral fat depots, and overall adipocyte size at 8 w. Increased global AP numbers in VWAT along with enhanced AP BrDU labeling in vitro and in vivo emerged in SF. Systemic injections of GFP+ BM-MSC resulted in increased AP in VWAT, as well as in enhanced differentiation into adipocytes in SF-exposed mice. No differences occurred between SF and SC in Nox2 null mice for any of these measurements. CONCLUSIONS: Chronic sleep fragmentation (SF) induces obesity in mice and increased proliferation and differentiation of adipocyte progenitors (AP) in visceral white adipose tissue (VWAT) that are mediated by increased Nox2 activity. In addition, enhanced migration of bone marrow mesenchymal stem cells from the systemic circulation into VWAT, along with AP differentiation, proliferation, and adipocyte formation occur in SF-exposed wild-type but not in oxidase 2 (Nox2) null mice. Thus, Nox2 may provide a therapeutic target to prevent obesity in the context of sleep disorders.

3DQRS: a method to obtain reliable QRS complex detection within high field MRI using 12-lead electrocardiogram traces.

PURPOSE: To develop a technique that accurately detects the QRS complex in 1.5 Tesla (T), 3T, and 7T MRI scanners. METHODS: During early systole, blood is rapidly ejected into the aortic arch, traveling perpendicular to the MRI's main field, which produces a strong voltage (V(MHD)) that eclipses the QRS complex. Greater complexity arises in arrhythmia patients, since V(MHD) varies between sinus-rhythm and arrhythmic beats. The 3DQRS method uses a kernel consisting of 6 electrocardiogram (ECG) precordial leads (V1-V6), compiled from a 12-lead ECG performed outside the magnet. The kernel is cross-correlated with signals acquired inside the MRI to identify the QRS complex in real time. The 3DQRS method was evaluated against a vectorcardiogram (VCG)-based approach in two premature ventricular contraction (PVC) and two atrial fibrillation (AF) patients, a healthy exercising athlete, and eight healthy volunteers, within 1.5T and 3T MRIs, using a prototype MRI-conditional 12-lead ECG system. Two volunteers were recorded at 7T using a Holter recorder. RESULTS: For QRS complex detection, 3DQRS subject-averaged sensitivity levels, relative to VCG were: 1.5T (100% versus 96.7%), 3T (98.9% versus 92.2%), and 7T (96.2% versus 77.7%). CONCLUSION: The 3DQRS method was shown to be more effective in cardiac gating than a conventional VCG-based method.

Intermittent hypoxia-induced changes in tumor-associated macrophages and tumor malignancy in a mouse model of sleep apnea.

RATIONALE: An increased cancer aggressiveness and mortality have been recently reported among patients with obstructive sleep apnea (OSA). Intermittent hypoxia (IH), a hallmark of OSA, enhances melanoma growth and metastasis in mice. OBJECTIVES: To assess whether OSA-related adverse cancer outcomes occur via IH-induced changes in host immune responses, namely tumor-associated macrophages (TAMs). MEASUREMENTS AND MAIN RESULTS: Lung epithelial TC1 cell tumors were 84% greater in mice subjected to IH for 28 days compared with room air (RA). In addition, TAMs in IH-exposed tumors exhibited reductions in M1 polarity with a shift toward M2 protumoral phenotype. Although TAMs from tumors harvested from RA-exposed mice increased TC1 migration and extravasation, TAMs from IH-exposed mice markedly enhanced such effects and also promoted proliferative rates and invasiveness of TC1 cells. Proliferative rates of melanoma (B16F10) and TC1 cells exposed to IH either in single culture or in coculture with macrophages (RAW 264.7) increased only when RAW 264.7 macrophages were concurrently present. CONCLUSIONS: Our findings support the notion that IH-induced alterations in TAMs participate in the adverse cancer outcomes reported in OSA.

Fragmented sleep accelerates tumor growth and progression through recruitment of tumor-associated macrophages and TLR4 signaling.

Sleep fragmentation (SF) is a highly prevalent condition and a hallmark of sleep apnea, a condition that has been associated with increased cancer incidence and mortality. In this study, we examined the hypothesis that sleep fragmentation promotes tumor growth and progression through proinflammatory TLR4 signaling. In the design, we compared mice that were exposed to sleep fragmentation one week before engraftment of syngeneic TC1 or LL3 tumor cells and tumor analysis four weeks later. We also compared host contributions through the use of mice genetically deficient in TLR4 or its effector molecules MYD88 or TRIF. We found that sleep fragmentation enhanced tumor size and weight compared with control mice. Increased invasiveness was apparent in sleep fragmentation tumors, which penetrated the tumor capsule into surrounding tissues, including adjacent muscle. Tumor-associated macrophages (TAM) were more numerous in sleep fragmentation tumors, where they were distributed in a relatively closer proximity to the tumor capsule compared with control mice. Although tumors were generally smaller in both MYD88(-/-) and TRIF(-/-) hosts, the more aggressive features produced by sleep fragmentation persisted. In contrast, these more aggressive features produced by sleep fragmentation were abolished completely in TLR4(-/-) mice. Our findings offer mechanistic insights into how sleep perturbations can accelerate tumor growth and invasiveness through TAM recruitment and TLR4 signaling pathways.

Chronic sleep fragmentation promotes obesity in young adult mice.

OBJECTIVES: Short sleep confers a higher risk of obesity in humans. Restricted sleep increases appetite, promotes higher calorie intake from fat and carbohydrate sources, and induces insulin resistance. However, the effects of fragmented sleep (SF), such as occurs in sleep apnea, on body weight, metabolic rates, and adipose tissue distribution are unknown. METHODS: C57BL/6 mice were exposed to SF for 8 weeks. Their body weight, food consumption, and metabolic expenditure were monitored over time, and their plasma leptin levels measured after exposure to SF for 1 day as well as for 2 weeks. In addition, adipose tissue distribution was assessed at the end of the SF exposure using MRI techniques. RESULTS: Chronic SF-induced obesogenic behaviors and increased weight gain in mice by promoting increased caloric intake without changing caloric expenditure. Plasma leptin levels initially decreased and subsequently increased. Furthermore, increases in both visceral and subcutaneous adipose tissue volumes occurred. CONCLUSIONS: These results suggest that SF, a frequent occurrence in many disorders and more specifically in sleep apnea, is a potent inducer of obesity via activation of obesogenic behaviors and possibly leptin resistance, in the absence of global changes in energy expenditure.

Exogenous erythropoietin administration attenuates intermittent hypoxia-induced cognitive deficits in a murine model of sleep apnea.

BACKGROUND: In rodents, exposure to intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), is associated with neurobehavioral impairments, increased apoptosis in the hippocampus and cortex, as well as increased oxidant stress and inflammation. Such findings are markedly attenuated in rodents exposed to sustained hypoxia 9SH) of similar magnitude. The hypoxia-sensitive gene erythropoietin (EPO) has emerged as a major endogenous neuroprotectant, and could be involved in IH-induced neuronal dysfunction. METHODS AND RESULTS: IH induced only transiently increased expression of EPO mRNA in hippocampus, which was continued in (SH)-exposed mice. IH, but not SH, adversely affected two forms of spatial learning in the water maze, and increased markers of oxidative stress. However, on a standard place training task, mice treated with exogenously administered EPO displayed normal learning, and were protected from the spatial learning deficits observed in vehicle-treated (C) littermates exposed to IH. Moreover, anxiety levels were increased in IH as compared to normoxia, while no changes in anxiety emerged in EPO-treated mice. Additionally, C mice, but not EPO-treated IH-exposed mice had significantly elevated levels of NADPH oxidase expression, as well as increased MDA and 8-OHDG levels in cortical and hippocampal lysates. CONCLUSIONS: The oxidative stress responses and neurobehavioral impairments induced by IH during sleep are mediated, at least in part, by imbalances between EPO expression and increased NADPH oxidase activity, and thus pharmacological agents targeting EPO expression in CNS may provide a therapeutic strategy in sleep-disordered breathing.