bluuebunny/crossref_metadata_2025 huggingface dataset:
The ‘Rights’ Way to Democratize the Science–Policy Interface in International Environmental Law? A Reply to Anna-Maria Hubert
Authors: Peel Jacqueline
Published: May 2020

Science is widely regarded as being necessary for effective international environmental decision-making and risk assessment processes. However, it is equally well recognized that uncertainties or the complexity of phenomena under study mean that science may only offer partial knowledge for environmental problems in many circumstances. ‘Democratization’ of science is often proposed as a solution to this dilemma. This may involve incorporating a wider spectrum of expert views and public inputs in risk assessments of new technologies, public participation in science through so-called ‘citizen science’ initiatives or the application of the precautionary principle. This reply reviews these approaches and contrasts them with another tantalizing possibility offered by Anna-Maria Hubert’s article; a human rights-based approach drawing on the ‘oft-neglected’ right to science. It assesses the extent to which a rights-based approach, utilizing the right to science, offers a way to bridge the gap between science and democracy in contested international environmental legal decision-making processes. While it concludes that there are important potential benefits to the application of the right to science in international environmental law, it is far from clear that it provides a panacea given the limitations on the right expressed in the international human rights instruments in which it is found, such as the International Covenant on Economic, Social and Cultural Rights. Instead, the right to science can be seen as placing another thumb on the scales – alongside the precautionary and participatory approaches – in favour of enabling broader, more democratically accountable decision-making in cases of uncertain science and contested environmental risks.
Optimization strategies for the organization of mental healthcare
Authors: Rabrenovic Mihajlo , Simonovic Perisa , Cogoljevic Dusan
Published: May 2020

Aim

The aim of this paper is to analyse the main issues and obstacles to optimizing the organization of mental healthcare and the strategies that should be applied by presenting the examples from practice.

Results

Outcomes of mental healthcare are in relation with ‘improved legislation’ and the introduction of up-to-date management and economic concepts including continuous treatment model, in addition to the advantages and disadvantages in the provision of mental healthcare within primary and secondary inpatient and outpatient healthcare. Some of these lessons are learned from reforms implemented in Serbia.
A whole-genome screen identifies Salmonella enterica serovar Typhi genes involved in fluoroquinolone susceptibility
Authors: Turner A Keith , Eckert Sabine E , Turner Daniel J , Yasir Muhammud , Webber Mark A , Charles Ian G , Parkhill Julian , Wain John
Published: May 2020

Objectives

A whole-genome screen at sub-gene resolution was performed to identify candidate loci that contribute to enhanced or diminished ciprofloxacin susceptibility in Salmonella enterica serovar Typhi.

Methods

A pool of over 1 million transposon insertion mutants of an S. Typhi Ty2 derivative were grown in a sub-MIC concentration of ciprofloxacin, or without ciprofloxacin. Transposon-directed insertion site sequencing (TraDIS) identified relative differences between the mutants that grew following the ciprofloxacin treatment compared with the untreated mutant pool, thereby indicating which mutations contribute to gain or loss of ciprofloxacin susceptibility.

Results

Approximately 88% of the S. Typhi strain’s 4895 annotated genes were assayed, and at least 116 were identified as contributing to gain or loss of ciprofloxacin susceptibility. Many of the identified genes are known to influence susceptibility to ciprofloxacin, thereby providing method validation. Genes were identified that were not known previously to be involved in susceptibility, and some of these had no previously known phenotype. Susceptibility to ciprofloxacin was enhanced by insertion mutations in genes coding for efflux, other surface-associated functions, DNA repair and expression regulation, including phoP, barA and marA. Insertion mutations that diminished susceptibility were predominantly in genes coding for surface polysaccharide biosynthesis and regulatory genes, including slyA, emrR, envZ and cpxR.

Conclusions

A genomics approach has identified novel contributors to gain or loss of ciprofloxacin susceptibility in S. Typhi, expanding our understanding of the impact of fluoroquinolones on bacteria and of mechanisms that may contribute to resistance. The data also demonstrate the power of the TraDIS technology for antibacterial research.
DNA binds to a specific site of the adhesive blood-protein von Willebrand factor guided by electrostatic interactions
Authors: Sandoval-Pérez Angélica , Berger Ricarda M L , Garaizar Adiran , Farr Stephen E , Brehm Maria A , König Gesa , Schneider Stefan W , Collepardo-Guevara Rosana , Huck Volker , Rädler Joachim O , Aponte-Santamaría Camilo
Published: May 2020

Neutrophils release their intracellular content, DNA included, into the bloodstream to form neutrophil extracellular traps (NETs) that confine and kill circulating pathogens. The mechanosensitive adhesive blood protein, von Willebrand Factor (vWF), interacts with the extracellular DNA of NETs to potentially immobilize them during inflammatory and coagulatory conditions. Here, we elucidate the previously unknown molecular mechanism governing the DNA–vWF interaction by integrating atomistic, coarse-grained, and Brownian dynamics simulations, with thermophoresis, gel electrophoresis, fluorescence correlation spectroscopy (FCS), and microfluidic experiments. We demonstrate that, independently of its nucleotide sequence, double-stranded DNA binds to a specific helix of the vWF A1 domain, via three arginines. This interaction is attenuated by increasing the ionic strength. Our FCS and microfluidic measurements also highlight the key role shear-stress has in enabling this interaction. Our simulations attribute the previously-observed platelet-recruitment reduction and heparin-size modulation, upon establishment of DNA–vWF interactions, to indirect steric hindrance and partial overlap of the binding sites, respectively. Overall, we suggest electrostatics—guiding DNA to a specific protein binding site—as the main driving force defining DNA–vWF recognition. The molecular picture of a key shear-mediated DNA–protein interaction is provided here and it constitutes the basis for understanding NETs-mediated immune and hemostatic responses.
A Young Diabetic Patient With Sepsis After Gardening
Authors: Camargo Nataly , Casadiego Giovanna K , Fernandez Dinno A , Millan Lina V , Hernandez Angie K , Vargas Sandra , Rios Rafael , Marin-Osorio Adriana , Salcedo Soraya , Rodriguez Deisy L , Bayuelo-Charris Ilich V , Arias Cesar A , Diaz Lorena , Reyes Jinnethe
Published: May 2020

We report a case of soft tissue infection, sepsis, and bacteremia due to Burkholderia pseudomallei (melioidosis) in a diabetic young patient and the genomic characterization of Burkholderia pseudomallei isolate (COL-5428).
A novel design for sampling benthic zooplankton communities in disparate Gulf of Alaska habitats using an autonomous deep-water plankton pump
Authors: Wilborn Rachel E , Rooper Christopher N , Goddard Pam , Williams Kresimir , Towler Rick
Published: May 2020

Deep-water larval fish and zooplankton utilize structurally complex, cold-water coral and sponge (CWCS) habitats as refuges, nurseries and feeding grounds. Fine-scale sampling of these habitats for larval fish and zooplankton has proven difficult. This study implemented a newly designed, autonomous, noninvasive plankton pump sampler that collected large mesozooplankton within 1 m of the seafloor. It was successfully deployed in the western Gulf of Alaska between the Shumagin Islands (~158°W) and Samalga Pass (−170°W), and collected in situ zooplankton from diverse benthic communities (coral, sponge and bare substrates) at depths in excess of 100 m. Key design parameters of the plankton pump were its ability to be deployed from ships of opportunity, be untethered from the vessel during sampling and be deployed and retrieved in high-relief, rocky areas where CWCS are typically present. The plankton pump remains stationary while collecting from the water column, rests within 1 m of the seafloor and captures images of the surrounding habitat and substrate. This plankton pump design is a low-cost, highly portable solution for assessing the role of benthic habitat in the life cycle of mesozooplankton, a linkage that has been relatively underexplored due to the difficulty in obtaining near-bottom samples.
0005 Cataplexy Triggered by Social Cues: A Role for Oxytocin in the Amygdala
Authors: Mahoney C E , Zhao W , Coffey A , Woods C , Kroeger D , Scammell T
Published: May 2020

Introduction

People with narcolepsy type 1 report that cataplexy is triggered most often by positive social experiences such as laughing with friends, yet the mechanisms through which social interaction promotes cataplexy are unknown. We hypothesize a subpopulation of central amygdala neurons that are sensitive to the prosocial neuropeptide, oxytocin (CeAOTR), respond to positive valence and trigger cataplexy.

Methods

We have used in vivo calcium imaging, chemogenetic and optogenetic approaches to characterize the activity pattern of these neurons and to manipulate their activity state.

Results

Cre-dependent anterograde tracing of the CeAOTR neurons of the central amygdala indicate a moderate to dense projection to the REM sleep-regulatory region of the ventral lateral periaqueductal gray (vlPAG). Additionally, Channel Rhodopsin Assisted Circuit Mapping (CRACM) experiments show that CeAOTR neurons inhibit vlPAG neurons that innervate the REM atonia-promoting region, the sublaterodorsal nucleus. Targeted photostimulation (15Hz (10ms) for 20sec every hour) of the CeAOTR fibers in the vlPAG doubled the amount of cataplexy. Preliminary in vivo calcium imaging indicates that the CeAOTR are active just prior to the onset of cataplexy. Chemogenetic and optogenetic activation of CeAOTR neurons increased cataplexy.

Conclusion

We conclude that the CeAOTR subpopulation is sufficient to promote cataplexy. Our future directions include determining the necessity of these oxytocin sensitive neurons in cataplexy under different conditions of positive valence.

Support

R01 NS106032 and WakeUp Narcolepsy.
0007 Daytime Sleep in Night Shift Workers: Quantifying the Role of Circadian Misalignment
Authors: Mann E , Sagong C , Cuamatzi Castelan A , Singh M , Roth T , Drake C L , Cheng P
Published: May 2020

Introduction

Circadian misalignment is commonly cited as a culprit of daytime sleep disturbances in night shift workers; however, the specific impact and magnitude that circadian misalignment has on daytime sleep has not been well-characterized in larger samples of night shift workers.

Methods

Participants included fixed-night shift workers (n=52, ages 18–50) who completed an 8-hour daytime polysomnography (PSG) in the lab following a night shift. Measures of sleep disturbances included: difficulty falling asleep (sleep onset latency [SOL], latency to persistent sleep [LPS]), difficulty staying asleep (sleep efficiency [SE], wake after sleep onset [WASO]), and sleep duration (total sleep time [TST]). Melatonin samples were collected hourly for 24 hours under dim light (<10 lux) and used to determine dim light melatonin offset (DLMOff). Circadian misalignment (CM) was calculated as the time difference between bedtime and DLMOff (higher values represented sleeping after DLMOff), and correlated with PSG sleep variables.

Results

CM was significantly associated with difficulty staying asleep (WASO: r=0.48, p<0.001; SE: r=-0.45, p<0.001), and sleep duration (TST: r=-0.38, p<0.01). Specifically, every 3 hours of CM on average added 19.2 minutes of WASO and reduced TST by 15 minutes. In contrast, CM was not significantly correlated with sleep onset difficulties (SOL: r=-0.27; LPS: r=-0.02).

Conclusion

These data suggest that circadian misalignment in shift workers may be a better predictor of difficulties staying asleep and sleep duration during the day relative to difficulties falling asleep. Because longer work hours (10–12 hours) are common in night shift worker, it may be that sleep initiation difficulties associated with circadian misalignment is masked by elevated fatigue or an increased homeostatic drive from prolonged wakefulness. These results may help guide decisions about the magnitude of phase shifts required (e.g., with light therapy) for the desired improvement in daytime sleep.

Support

Support for this study was provided to PC by the NHLBI (K23HL138166)
0014 Reduced Cortical Thickness as a Biomarker of Daytime Sleepiness in Mild Traumatic Brain Injury
Authors: Dailey N S , Raikes A C , Alkozei A , Grandner M A , Killgore W D
Published: May 2020

Introduction

Sleep disruptions, including the increase of daytime sleepiness, are reported in roughly 70% of all individuals who have suffered a mild traumatic brain injury (mTBI). Prior research using magnetic resonance imaging (MRI) has identified associations between functional brain changes and daytime sleepiness following mTBI. In the present study, we aimed to identify whether structural differences in cortical thickness are associated with increased daytime sleepiness in adults with mTBI.

Methods

A total of 58 adults between 18 and 45 years of age (M=23.58±5.31) participated in the study, including 19 healthy controls and 39 individuals with a documented mTBI. Individuals with mTBI were further divided based on time-since-injury into a sub-acute (n=22) or chronic (n=17) group. Daytime sleepiness was assessed using the Epworth Sleepiness Scale (ESS) and cortical thickness was measured using high-resolution T1-weighted structural MRI. Whole-brain vertex-wise estimations of cortical thickness were calculated using FreeSurfer (v.6.0) and entered into a GLM to identify between-group differences in cortical thickness and the association with ESS.

Results

Significant differences in cortical thickness were found between the two mTBI groups (cluster-forming threshold p<.01; cluster-wise threshold p<.05; two-tailed; FWE-corrected). Specifically, lower cortical thickness in the left hemisphere was found in the inferior parietal lobule (p=.01), precuneus (p=.03), and pars triangularis (p=.04) for the sub-acute, compared to chronic group. Furthermore, a significant negative correlation was found between ESS and cortical thickness in the inferior parietal lobule (r=-.55, p=.009) for the sub-acute mTBI group.

Conclusion

More daytime sleepiness was associated with reduced inferior parietal cortical thickness in those 2 to 12-weeks post-injury, an association not observed in those 6 to 12-months post-injury or healthy controls. The inferior parietal lobule is part of the frontoparietal attention network and has been associated with vulnerability to sleep loss. Our findings suggest structural damage to the attention network following mTBI may be one factor affecting daytime sleepiness in mTBI. These findings may reflect a potential biomarker of sleep disturbances in mTBI.

Support

USAMRMC grant (W81XWH-12–0386).
0031 Photoperiodic Effects on Diurnal Rhythms in the Immune System, Rest-Activity Behavior, and Cortisol Revealed in a Diurnally Active Large Animal Model - The Domestic Pig
Authors: Engert L C , Weiler U , Pfaffinger B , Stefanski V , Schmucker S S
Published: May 2020

Introduction

Diurnal variations in immune cell number and function are regarded important for immune competence and are thought to be mediated by rest-activity rhythms and hormones. Moreover, the photoperiod is also known to modulate the immune system and considered to affect seasonal disease susceptibility. Whereas few studies investigated seasonal effects, the present study is the first investigating the specific effect of the photoperiod on diurnal rhythms in cell numbers of peripheral leukocyte types in any species.

Methods

Domestic pigs were held either under long day (LD, 16L:8D, lights-on 07:00-23:00, n=9) or short day conditions (SD, 8L:16D, lights-on 07:00-15:00, n=11) and fed concentrate at 07:30 + 14:00 (ad libitum hay/water). Blood samples were taken every 2 h over periods of 50 h via indwelling vein catheters. Rest-activity behavior of the pigs was analyzed using continuous camera recordings.

Results

Cosinor analyses (p<.05) revealed photoperiodic differences in diurnal rhythms of cell numbers of various peripheral leukocyte subtypes, rest-activity behavior, and cortisol concentration. Cell numbers of total leukocytes, NK cells, T cells, and eosinophils in blood, rest-activity behavior, and cortisol concentration peaked earlier relative to lights-on under SD (p<.05). Relative amplitudes in rest-activity behavior and cell counts of total leukocytes, NK cells, T cells, and monocytes were higher under SD (p<.05). However, there was no photoperiodic effect on diurnal rhythms in neutrophil counts and mesor in any leukocyte type. Generalized linear mixed models revealed associations of leukocyte counts with rest-activity behavior and cortisol concentration in most cell types (p<.05). Moreover, the found photoperiodic effects on diurnal rhythms in rest-activity behavior and cortisol concentration are in agreement with research in humans and primates.

Conclusion

The present study revealed photoperiodic effects on diurnal rhythms in the immune system, rest-activity behavior, and cortisol concentration in pigs and strengthens the importance of the domestic pig as suitable model for chronoimmunology.

Support

German Research Foundation DFG (grant provided to SS, grant number SCHM3162/1-1), Federal Ministry of Education and Research, Germany (grant number 01PL16003), Faculty of Agricultural Sciences, University of Hohenheim (scholarship provided to LE).
0038 The Effects of Morning Blue Light Therapy on Insomnia Severity and PTSD Symptoms in a Clinical Sample
Authors: Jecmen D , King R , Gould J , Mitchell J , Ralston K , Burns A I , Bullock A , Grandner M A , Alkozei A , Killgore W D
Published: May 2020

Introduction

Individuals with Post Traumatic Stress Disorder (PTSD) often present with insomnia, which may exacerbate other symptoms of the disorder. Morning Blue Light Therapy (BLT) can regulate circadian rhythms and may even improve sleep and mood in individuals with major depressive disorder. However, it is unclear whether morning BLT could also be an effective treatment for the insomnia associated with PTSD. We investigated whether 6 weeks of daily morning BLT would improve insomnia severity and symptom presentation in individuals with PTSD in comparison to a placebo condition of amber light (ALT). We hypothesized that changes in insomnia severity would correlate with improvement in PSTD symptom severity.

Methods

Forty-one participants with a clinical diagnosis of PTSD were randomized to receive 6 weeks of either daily morning BLT (n=22) or ALT (n=19). Insomnia and PTSD symptom severity were evaluated at pre- and post-treatment using the Insomnia Severity Index (ISI) and the Clinician-Administered PTSD Scale (CAPS) for DSM-5, respectively.

Results

Both groups showed a significant decrease in their PTSD symptom severity (p<0.001) and insomnia severity (p<0.001) over the 6-week treatment period. However, improvement in insomnia severity significantly predicted improvements in PTSD symptom severity for the BLT group only (BLT: r =0.542, p=0.009; ALT: r=-0.095, p=0.699). The difference between the two correlation coefficients was significant (Z=-2.07, p=0.039).

Conclusion

The results suggest that morning BLT may be effective in improving PTSD symptoms by regulating the circadian rhythm and improving sleep. While ALT also led to improved PTSD symptom severity, it appears that those changes cannot be explained by improved sleep and may have other underlying mechanisms (e.g., placebo effect). Morning BLT may be a promising adjunctive method to bolster current treatment approaches for PTSD. Because of its ease of administration, it could be easily added to ongoing treatment as usual. This approach warrants further research.

Support

US Army Medical Research and Materiel Command: W81XWH-14-1-0570
0042 Stroke Volume and Cardiac Index are Differentially Altered by Total Sleep Deprivation and Psychological Stress in Resilient vs. Vulnerable Individuals and Predict Cognitive Performance
Authors: Yamazaki E M , Rosendahl-Garcia K M , MacMullen L E , Ecker A J , Kirkpatrick J N , Goel N
Published: May 2020

Introduction

Individuals show robust resilience and vulnerability in neurobehavioral performance to sleep loss and stress. For the first time, we investigated the time course of two cardiovascular measurements, stroke volume (SV) and cardiac index (CI), both derived from echocardiography, across baseline, total sleep deprivation (TSD), the combination of TSD+psychological stress, and recovery. We also determined whether these variables differ in resilient vs. vulnerable individuals and whether they predict differential vulnerability in cognitive performance.

Methods

Thirty-one healthy adults (ages 27–53; mean±SD, 35.4±7.1y; 14 females) participated in a five-day experiment consisting of two 8h time-in-bed (TIB) baseline nights, 39h TSD, and two 8h-10h TIB recovery nights. A modified Trier Social Stress Test (TSST) was conducted on the TSD day to induce psychological stress. Echocardiographic measures of SV and CI were obtained at six time points (pre-study, baseline, during TSD, during TSD after the TSST, after recovery, and post-study). A median split of TSD performance [total lapses (>500 ms response time) and errors] on the 10-minute Psychomotor Vigilance Test (PVT), defined cognitively resilient (n=15) and vulnerable (n=16) groups. Repeated measures ANOVA and post-hoc comparisons corrected for multiple testing, examined SV and CI across time points between groups.

Results

There was a significant time*group interaction for SV: cognitively resilient individuals had greater SV during the five-day experiment. In addition, in both resilient and vulnerable individuals, SV increased with TSD and with TSD+psychological stress compared with baseline. Like SV, there was a significant time*group interaction for CI: resilient individuals had greater CI at all points of the experiment.

Conclusion

SV and CI differed between resilient and vulnerable individuals across TSD, psychological stress and recovery sleep. Greater SV and greater CI at baseline predicted resilience to TSD and TSD+psychological stress. CI and SV are novel physiological biomarkers of sleep loss, stress, and individual differences in cognitive performance.

Support

NASA NNX14AN49G.
0062 Improved Circadian Data Ordering in the Presence of Biological and Technical Confounds
Authors: Hammarlund J , Anafi R
Published: May 2020

Introduction

We recently used unsupervised machine learning to order genome scale data along a circadian cycle. CYCLOPS (Anafi et al PNAS 2017) encodes high dimensional genomic data onto an ellipse and offers the potential to identify circadian patterns in large data-sets. This approach requires many samples from a wide range of circadian phases. Individual data-sets often lack sufficient samples. Composite expression repositories vastly increase the available data. However, these agglomerated datasets also introduce technical (e.g. processing site) and biological (e.g. age or disease) confounders that may hamper circadian ordering.

Methods

Using the FLUX machine learning library we expanded the CYCLOPS network. We incorporated additional encoding and decoding layers that model the influence of labeled confounding variables. These layers feed into a fully connected autoencoder with a circular bottleneck, encoding the estimated phase of each sample. The expanded network simultaneously estimates the influence of confounding variables along with circadian phase.

We compared the performance of the original and expanded networks using both real and simulated expression data. In a first test, we used time-labeled data from a single-center describing human cortical samples obtained at autopsy. To generate a second, idealized processing center, we introduced gene specific biases in expression along with a bias in sample collection time. In a second test, we combined human lung biopsy data from two medical centers.

Results

The performance of the original CYCLOPS network degraded with the introduction of increasing, non-circadian confounds. The expanded network was able to more accurately assess circadian phase over a wider range of confounding influences.

Conclusion

The addition of labeled confounding variables into the network architecture improves circadian data ordering. The use of the expanded network should facilitate the application of CYCLOPS to multi-center data and expand the data available for circadian analysis.

Support

This work was supported by the National Cancer Institute (1R01CA227485-01)
0063 Age Related Changes in Central Autonomic Couplings During Sleep
Authors: Chen P , Naji M , Sattari N , Whitehurst L N , Mednick S C
Published: May 2020

Introduction

Studies show coupling between central nervous system (CNS) and autonomic nervous system (ANS) activity during sleep. We reported on a novel central/autonomic coupling event (ACE) during non-rapid eye movement (NREM) sleep, in which bursts in heart rate (HRBs) coincide with increased slow-wave activity (SWA) 5 seconds prior to the HRB, followed by a surge in vagal high-frequency activity in the RR signal (HFRR) 5 seconds after the HRB. ACEs predicted sleep-related explicit memory improvement. Aging is characterized with impaired sleep and autonomic loss. We, therefore, investigated ACE activity in older adults.

Methods

We compared ACEs during a daytime nap between youngers (18-25yrs, N=49) and olders (60-75yrs, N=32). Subjects took an EEG-monitored, 90-minute nap. We measured SWA and HFRR in a 20-sec window around the HRB peak separately for Stage 2 and slow-wave sleep (SWS). EEG were binned into 5-sec intervals around the HRB: -10, -5, +5, +10 bins. For Stage 2 and SWS, repeated-measure ANOVAs with two factors (age and windows) were performed on SWA and HFRR. Corrections used Greenhouse-Geisser and Bonferroni methods.

Results

For SWA, we found an interaction between age and windows during Stage 2 (p<.001), and SWS (p=.001). SWA during the -5bin was greater in youngers than olders during both Stage 2 and SWS (ps < .001). The ACE profile in youngers showed highest SWA in the -5bin in Stage 2 and SWS (ps < .001) and highest HFRR in the +5bin in Stage 2 (ps < .001) The ACE profile in olders, however, showed no clear pattern for SWA in either sleep stage. Olders showed greater HFRR during the +5bin compared to the -10bin (p=.041) during Stage 2 but no HFRR modulations were found during SWS.

Conclusion

Our results replicated the ACE profile in daytime naps first reported by Naji et al (2018). In youngers, heart rate bursts were coupled with increased SWA and vagal activity. In contrast, olders demonstrated a lack of boost in SWA and HFRR, which provides implications in cognitive aging. Future research is needed to further understand the impact of decreased coupling between ANS/CNS activity on cognitive decline.

Support
0072 Preclinical Characterization of SUVN-G3031, a Histamine H3 Receptor Inverse Agonist for the Treatment of Narcolepsy
Authors: Jayarajan P , Subramanian R , Kamuju V , Muddana N , Palacharla R , Mekala V , Abraham R , Reballi V , Achanta P , Nirogi R
Published: May 2020

Introduction

Narcolepsy is a chronic sleep disorder characterized by overwhelming daytime drowsiness, sudden attacks of sleep and sometimes accompanied by cataplexy. Although the orexin deficiency is considered to be the primary cause of this disorder, lot of attention has been focused recently on targeting histaminergic neurotransmission by blockade of histamine H3 receptor (H3R). SUVN-G3031 is one of the potent and selective H3R inverse agonist currently being evaluated in a Phase 2 study as monotherapy for the treatment of narcolepsy with and without cataplexy (ClinicalTrials.gov Identifier: NCT04072380).

Methods

Binding of SUVN-G3031 in human and rat histamine H3R was evaluated in in vitro radioligand binding assay and functionality was assessed in GTPγS assay. Pharmacokinetic properties were evaluated after oral administration in rat and dog. Neurotransmitters like histamine, dopamine and norepinephrine were estimated in rat cortex using microdialysis.

Results

SUVN-G3031 is an inverse agonist at histamine H3R with hKi of 8.7 nM and showed minimal binding against over 70 target sites. SUVN-G3031 exhibited desired pharmacokinetic properties in rat and dog with excellent brain penetration in rats. SUVN-G3031 produced significant increase in histamine, dopamine and norepinephrine levels in cortex. SUVN-G3031 produced no change in the striatal and accumbal dopamine levels in rats, suggesting no propensity to induce abuse liability. SUVN-G3031 blocked R-α-methylhistamine induced water intake and produced dose dependent increase in tele-methylhistamine levels in various brain regions and in cerebrospinal fluid of male Wistar rats.

Conclusion

SUVN-G3031 is an inverse agonist at histamine H3 receptor and results from the preclinical studies presented here provide a strong evidence for the potential utility of SUVN-G3031 in the treatment of narcolepsy with and without cataplexy.

Support

None
1008 Brain Age Based on Sleep Encephalography is Elevated in HIV+ Adults on ART
Authors: Leone M J , Sun H , Boutros C , Sullivan L , Thomas R J , Robbins G , Mukerji S , Westover M
Published: May 2020

Introduction

Sleep EEG is a promising tool to measure brain aging in vulnerable populations such as people with HIV, who are high risk of brain aging due to co-morbidities, increased inflammation, and antiretroviral neurotoxicity. Our lab previously developed a machine learning model that estimates age from sleep EEG (brain age, BA), which reliably predicts chronological age (CA) in healthy adults. The difference between BA and CA, the brain age index (BAI), independently predicts mortality, and is increased by cardiovascular co-morbidities. Here, we assessed BAI in HIV+ compared to matched HIV- adults.

Methods

Sleep EEGs from 43 treated HIV+ adults were gathered and matched to controls (HIV-, n=284) by age, gender, race, alcoholism, smoking and substance use history. We compared BAI between groups and used additional causal interference methods to ensure robustness. Individual EEG features that underlie BA prediction were also compared. We performed a sub-analysis of BAI between HIV+ with or without a history of AIDS.

Results

After matching, mean CA of HIV+ vs HIV- adults were 49 and 48 years, respectively (n.s.). The mean HIV+ BAI was 3.04 years higher than HIV- (4.4 vs 1.4 yr; p=0.048). We found consistent and significant results with alternative causal inference methods. Several EEG features predictive of BA were different in the HIV+ and HIV- cohorts. Most notably, non-REM stage 2 sleep (N2) delta power (1-4Hz) was decreased in HIV+ vs. HIV- adults, while theta (4-8Hz) and alpha (8-12Hz) power were increased. Those with AIDS (n=19, BAI=4.40) did not have significantly different BAI than HIV+ without AIDS (n=23, BAI=5.22). HIV+ subjects had higher rates of insomnia (56% vs 29%, p<0.001), obstructive apnea (47% vs 30%, p=0.03), depression (49% vs 23%, p<0.001), and bipolar disorder (19% vs 4%, p<0.001).

Conclusion

HIV+ individuals on ART have excess sleep-EEG based brain age compared to matched controls. This excess brain age is partially due to reduction in delta power during N2, suggesting decreased sleep depth. These results suggest sleep EEG could be a valuable brain aging biomarker for the HIV population.

Support

This research is supported by the Harvard Center for AIDS Research HU CFAR NIH/NIAID 5P30AI060354-16.
1016 Multiple Sleep Disturbances and Hypertension Risk Among White, Black, and Hispanic/Latina Women
Authors: Lunyera J , Park Y M , Ward J B , Gaston S A , Bhavsar N A , Muntner P , Sandler D P , Jackson C L
Published: May 2020

Introduction

Poor sleep has been associated with a higher risk of hypertension, but few prospective studies have included multiple sleep dimensions and few have investigated age differences or racial/ethnic disparities in this relationship among pre- and post-menopausal women.

Methods

To investigate the association between sleep disturbances and hypertension risk, we used data from women in the United States enrolled in the Sister Study who were aged 35 to 74 years at baseline (2003 to 2009) and did not have hypertension at enrollment. Participants were followed through September 2017. Sleep duration, inconsistent weekly sleep patterns, sleep debt, frequent napping, and insomnia symptoms were reported at baseline. During follow-up, participants reported whether they were diagnosed by a healthcare provider with hypertension. Adjusting for sociodemographic characteristics, health behaviors, and health conditions including diabetes and depression, we used Cox Proportional Hazards regression to estimate hypertension risk among women with vs. without unfavorable sleep characteristics. We also investigated potential modification by race/ethnicity, age,and menopausal status.

Results

Of 33,175 women without hypertension at baseline (mean age ± standard deviation: 53.9 ±8.8 years; 88.8% White, 6.4% Black, and 4.9% Hispanic/Latina), 19.9% developed hypertension over a median follow-up of 9.2 years (interquartile range: 7.6 to 10.9). After adjustment, insomnia symptoms (hazard ratio[HR]=1.08 (95% Confidence Interval [CI]: 1.03-1.15)) and insomnia symptoms combined with short sleep (HR=1.14 (95% CI: 1.06-1.23)) were associated with incident hypertension. While similar across race/ethnicity, these associations were stronger in younger (age <54 vs. ≥54 years) and premenopausal vs. postmenopausal women (p-values for interaction <0.05).

Conclusion

Sleep disturbances related to insomnia were associated with an increased risk of hypertension, especially among younger and premenopausal women.

Support

This work was funded by the Intramural Program at the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS, Z1AES103325-01 [CLJ] and Z01 ES044005 [DPS]).
1022 Association Between Homocysteine and Sleep in Postmenopausal Women
Authors: Banzoli C V , Bezerra A G , D’Almeida V , Andersen M L , Tufik S V , Hachul H V
Published: May 2020

Introduction

Homocysteine (Hcy) is a sulfur amino acid, considered an independent risk factor for cardiovascular disease. Excessive Hcy directly harms the endothelium and can lead to premature atherosclerosis, with progression to stroke and acute myocardial infarction. One of the causes of hyperhomocysteinemia (Hhcy) is known to be hypoestrogenism. Hypoestrogenism increases the cardiovascular risk as well as the occurrence of sleep disorders. Hhcy prevalence varies by population and its value in postmenopausal women in Brazil is unknown. Objective: To evaluate the prevalence of hyperhomocysteinemia in postmenopausal women in the city of São Paulo. Check if there is an association between the variables: Hcy and lipid profile; Hcy and hot flushes; Hcy and subjective sleep parameters

Methods

A population-based cross-sectional study was conducted that included a total of 1,042 volunteers living in the city of São Paulo in 2007. This research is part of the São Paulo Sleep Epidemiological Study (EPISONO). Study approved by the Ethics Committee (CEP # 0593/06) and registered with ClinicalTrials.gov (NCT00596713). Hcy, total cholesterol, HDL, LDL, triglycerides were measured. Sleep questionnaires PSQI, IGI, Epworth Sleepiness Scale were used. The GLzM (Generalized Linear Model) was used to verify the association between the different variables. Dependent variables were used in binominal and gama distribution when needed

Results

The sample consisted of 193 postmenopausal women, with a mean age of 58 years (SD ± 9). The prevalence of Hhcy in this sample was 4.7%, while 14.7% had dyslipidemia 22.8% with hypertriglyceridemia and 29% with low HDL levels. There was an association between Hcy and HDL. There was no association between Hcy and hot flushes, Hcy and LDL, nor with Hcy and sleep parameters.

Conclusion

The studied population presented low prevalence of Hhcy and there was no association between Hcy and sleep parameters.

Support

This research was support by fellowships from Associação Fundo de Incentivo à Pesquisa (AFIP) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) - Finance Code 001.
1025 Sleep Patterns In Head Neck Cancer Patients During Radiotherapy
Authors: Gu F , Jungquist C , Sonia A , Liu L , Repasky E , Schlecht N , Reid M , Ambrosone C , Andrew R , Singh A
Published: May 2020

Introduction

Sleep disturbances are reported to be highly prevalent in head and neck cancer (HNC) patients, but no carefully assessed sleep data exists in patients with HNC undergoing concurrent chemoradiotherapy (CRT).

Methods

To objectively assess sleep patterns in this study population, we conducted a pilot study in 15 patients and 13 non-cancer healthy volunteers. Patients wore the wrist Actiwatch Spectrum (Philips Respironics) at week 1, 3, and 6/7 during the 7-week treatment period. Volunteers wore the Actiwatch for one week. We used the Actiware software to calculate sleep parameters. A sleep log was used as a complement to define participants’ bedtime and rise-up time. Any sleep episode scored by the software during daytime was considered as a nap.

Results

Compared to healthy volunteers, patients had lower overnight sleep efficiency, longer sleep onset latency and more waking time after sleep onset (WASO), indicating more difficulty falling asleep and maintaining sleep. During CRT, patients’ sleep efficiency decreased whereas latency and WASO increased, indicating possible the decrease of sleep quality. Sleep efficiency of <85% has been used previously as a cut-off for poor sleep; based on this criteria, 45% of HNC patients had poor sleep at treatment baseline, compared to 31% in non-cancer volunteers, and this proportion increased to 51% by the end of treatment. Patients had longer napping time: compared to healthy volunteers, the napping time was on average 2 hours longer at baseline, and 3 hours longer at the end of treatment, indicating unhealthy sleep habits of these patients.

Conclusion

Our data suggested HNC patients had severe sleep disturbances and unhealthy sleep habits, which were aggravated during CRT treatment.

Support

This study was supported by UL1TR001412-04, a Clinical and Translational Research Award under SUNY-Buffalo.
1030 An Exploration of the Impact of Cognitive Behavioural Therapy of Insomnia (CBT-I) on Perceived Cognitive Impairment in Breast Cancer Survivors
Authors: Walsh N , Garland S , Lester R , McCarthy J , Laing K
Published: May 2020

Introduction

Insomnia and cognitive impairment are prevalent and persistent symptoms in cancer survivors. Cognitive Behavior Therapy is effective for improving insomnia and comorbid symptoms in cancer survivors but there are very few empirically supported treatments that can improve cognitive impairment. This feasibility study explored the impact of CBT-I on perceived cognitive impairment in breast cancer survivors.

Methods

We enrolled 10 early stage breast cancer survivors with insomnia disorder and perceived cognitive impairment. Participants received 7 individual sessions of CBT-I over the course of 8 weeks and completed the Insomnia Severity Index (ISI), the Functional Assessment of Cancer Therapy - Cognitive Function (FACT-Cog) questionnaires and The Hospital Anxiety and Depression Scale (HADS) at baseline and post-treatment. Paired samples t-tests were used to assess change over time.

Results

The sample was predominantly diagnosed with stage II breast cancer (60%). Women were an average age of 50.8 (SD 6.84) and 18.2 (SD 3.62) years of education. CBT-I significantly reduced insomnia severity [19.4 to 7.1; t(9)= 6.56, p < .001] and improved perceived cognitive impairment [t(9)= -3.55, p < .01], perceived cognitive ability [t(9)= -2.87, p < .05], quality of life [t(9)= -3.14, p < .05], and overall subjective cognitive function [t(9)= -3.67, p < .01]. Although participants began treatment with low levels of mood disturbance, CBT-I further decreased symptoms of anxiety (baseline: M= 10.10, SD= 4.34; post-treatment M= 8.20, SD= 3.91) and depression (baseline: M= 7.90, SD= 3.45; post-treatment M= 5.30, SD= 2.83), although not statistically significant.

Conclusion

This study suggests CBT-I may improve perceived cognitive impairment in cancer survivors, in addition to insomnia and mood. Future randomized controlled trials with larger samples and objective measurements of cognition are needed.

Support

Nyissa Walsh is a trainee in the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute (BHCRI). Dr. Sheila Garland is supported by a Scotiabank New Investigator Award from BHCRI.
1056 Perceived Financial Difficulty Predicts Sleep Quality In Participants With Type 2 Diabetes And Obstructive Sleep Apnea
Authors: Morris J L , Baniak L , Belcher S M , Imes C , Luyster F , Scott P W , Sereika S , Chasens E R
Published: May 2020

Introduction

People with multiple chronic conditions such as type 2 diabetes (T2D) and obstructive sleep apnea (OSA) are at increased risk for poor sleep quality. It is unclear if social determinants of health (SDoH) such as race, perceived financial difficulty, education, gender, and marital status are associated with sleep quality in this population. The purpose of this cross-sectional secondary analysis of data from the Diabetes Sleep Treatment Trial was to explore SDoH and disease severity as predictors of sleep quality in persons with both OSA and T2D.

Methods

Disease severity was measured by Apnea-Hypopnea Index [(AHI) ≥ 5] and A1C for glycemic control. SDoH included perceived financial difficulty (none/moderate-severe), race (White/African American), sex (f/m), marital status (no/yes), education (≤ or > 2 years post high school), and age. Sleep quality was measured by Pittsburgh Sleep Quality Index (PSQI). Correlations and linear regression modeling investigated associations between SDoH and disease severity on sleep quality. Post-hoc correlations were explored for significant relations among SDoH.

Results

The sample (N = 229) was middle-aged (57.6 ± 10.0; 66 % White and 34% African American; and 54 % men vs. 46% women. Participants carried a high burden of disease (mean AHI = 20.7±18.1, mean A1C = 7.9 %±1.7%). Disease severity was not significantly associated with sleep quality (all p >.05). The perception of worse financial difficulty was the only SDoH that predicted worse sleep quality (b=-1.54, p=.015). Characteristics significantly associated with worse financial difficulty were being African American, female, ≤ 2 years post high school, and younger (all p<.01).

Conclusion

Financial difficulty may be a more important predictor of subjective measures of sleep quality than disease severity in patients with OSA and T2D. Researchers and clinicians should be aware of these characteristics as potential markers of vulnerability to poor sleep quality in this population.

Support

The National Institute of Diabetes and Digestive and Kidney Diseases (R01DK096028) and through the Clinical +Translational Research Institute grants UL1TR001857 and UL1TR000005.
1060 Screening For Obstructive Sleep Apnea In Severe Gastroesophageal Reflux Disease Patients: A Forgotten Association?
Authors: De A , Gharib H , Frenia D , Velpari S
Published: May 2020

Introduction

Obstructive sleep apnea (OSA) is an emerging epidemic in the USA and remains underdiagnosed. Investigations of Gastroesophageal reflux disease (GERD) poses a substantial burden on patient-welfare and costs to the health system. Current literature has highlighted the association between severe GERD and OSA, and other sleep disorders. We conducted a retrospective analysis of patient records undergoing Bravo pH monitoring for refractory GERD to measure the prevalence of OSA and screening.

Methods

Records of patients who underwent outpatient Bravo pH monitoring at a teaching hospital were reviewed from August 2018 to May 2019. 72 records were reviewed in our analysis. Analysis variables included age, gender, body mass index, history of hypertension and OSA. Outpatient records were reviewed for documentation for OSA or screening and demographics were obtained for calculation of a partial STOP-BANG score (a validated OSA screening tool).

Results

8 out of 72 (11%) were excluded due to incomplete documentation regarding their history. Of the remaining 64, 2 had a known diagnosis of OSA (3%) and 1 was due a sleep study for maintenance insomnia. Of the remaining 61 patients, none had documentation of a history pertaining to sleep complaints or full screening for OSA. 4 of the 8 components to the STOP-BANG criteria were documented and used to measure risk of OSA in these patients. 23 (39%) patients had a score of 3 or above characterizing them as intermediate risk. The other 4 components were not used due to a lack of clinical information. 13 of these patients had a positive Bravo test, 2 had an inconclusive result and 8 had a negative result. Of the 61 patients in total, 31 had a positive Bravo result and 9 had an inconclusive result.

Conclusion

In our study, we found that 39% of patients based on demographic data were of intermediate risk of OSA. Over half of these patients had a positive result for GERD. Despite the increased awareness of sleep disorders it is still neglected despite prevalent associated comorbid conditions. This study highlights the failure to screen for this modifiable risk factor within a teaching environment.

Support

None
1063 Depression Moderates the Association Between Posttraumatic Stress Disorder and Nightmare Severity in Nurses
Authors: Shapiro T , Messman B , Slavish D C , Alkire C , Wardle-Pinkston S , Dietch J , Kelly K , Ruggero C , Taylor D
Published: May 2020

Introduction

Nurses report a higher prevalence of posttraumatic stress disorder (PTSD) than the general population, and approximately 18% of nurses report having depression. Nightmares are a common symptom of PTSD, and both nightmares and PTSD are correlated with depression. Nightmares may represent a possible clinical target for improving outcomes in both disorders. This study assessed associations between PTSD and depressive symptoms with nightmare severity, and whether depressive symptoms moderated associations between PTSD and nightmare severity.

Methods

Participants were 461 nurses (91% female; 77% white, mean age = 38.39 years) recruited from two hospitals for a parent study. Participants completed the Patient Health Questionnaire (PHQ-9), Post-traumatic Stress Disorder Checklist (PCL-5), and 14 days of sleep diaries to assess daily nightmare frequency and severity (on a scale of 0 = not at all severe to 3 = very severe).

Results

22.1% of participants reported at least one nightmare across the 14 days, with a mean daily nightmare frequency of 1.17 (SD = 2.15) and a mean severity of 0.11 (SD = 0.18). PCL-5 and PHQ-9 scores were significantly correlated with nightmare severity (r = 0.27; r = 0.24, respectively) and each other (r = 0.69). PHQ-9 scores moderated the association between PCL-5 scores and nightmare severity (β = -.01, SE = <0.01, p = 0.015). For individuals 1 SD below the PHQ-9 mean, higher PCL-5 scores were associated with higher nightmare severity. For individuals 1 SD above the PHQ-9 mean, higher PCL-5 scores were associated with higher nightmare severity, but to a lesser degree.

Conclusion

Both depressive and PTSD symptoms were associated with more severe nightmares. Surprisingly, the association between PTSD symptoms and nightmare severity was stronger for those with lower depressive symptoms. Results suggest depression, PTSD, and nightmares may represent a partially overlapping symptom cluster. Research should investigate how nightmare treatment may reduce PTSD and depressive symptoms.

Support

NIAID R01AI128359-01