bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human circadian phase–response curves for exercise
Authors: Youngstedt Shawn D. , Elliott Jeffrey A. , Kripke Daniel F. 
Published: February 2019

Key points
Exercise elicits circadian phase‐shifting effects, but additional information is needed.
The phase–response curve describing the magnitude and direction of circadian rhythm phase shifts, depending on the time of the zeigeber (time cue) stimulus, is the most fundamental chronobiological tool for alleviating circadian misalignment and related morbidity.
Fifty‐one older and 48 young adults followed a circadian rhythms measurement protocol for up to 5.5 days, and performed 1 h of moderate treadmill exercise for 3 consecutive days at one of eight times of the day/night.
Temporal changes in the phase of 6‐sulphatoxymelatonin (aMT6s) were measured from evening onset, cosine acrophase, morning offset and duration of excretion. Significant phase–response curves were established for aMT6 onset and acrophase with large phase delays from 7:00 pm to 10:00 pm and large phase advances at both 7:00 am and from 1:00 pm to 4:00 pm. Delays or advances would be desired, for example, for adjustment to westward or eastward air travel, respectively.
Along with known synergism with bright light, the above PRCs with a second phase advance region (afternoon) could support both practical and clinical applications.
AbstractAlthough bright light is regarded as the primary circadian zeitgeber, its limitations support exploring alternative zeitgebers. Exercise elicits significant circadian phase‐shifting effects, but fundamental information regarding these effects is needed. The primary aim of the present study was to establish phase–response curves (PRCs) documenting the size and direction of phase shifts in relation to the circadian time of exercise. Aerobically fit older (n = 51; 59–75 years) and young adults (n = 48; 18–30 years) followed a 90 min laboratory ultrashort sleep–wake cycle (60 min wake/30 min sleep) for up to 5½ days. At the same clock time on three consecutive days, each participant performed 60 min of moderate treadmill exercise (65–75% of heart rate reserve) at one of eight times of day/night. To describe PRCs, phase shifts were measured for the cosine‐fitted acrophase of urinary 6‐sulphatoxymelatonin (aMT6s), as well as for the evening rise, morning decline and change in duration of aMT6s excretion. Significant PRCs were found for aMT6s acrophase, onset and duration, with peak phase advances corresponding to clock times of 7:00 am and from 1:00 pm to 4:00 pm, delays from 7:00 pm to 10:00 pm, and minimal shifts around 4:00 pm and 2:00 am. There were no significant age or sex differences. The amplitudes of the aMT6s onset and acrophase PRCs are comparable to expectations for bright light of equal duration. The phase advance to afternoon exercise and the exercise‐induced PRC for change in aMT6s duration are novel findings. The results support further research exploring additive phase‐shifting effects of bright light and exercise and health benefits.
Costs and effects of higher turnover of nurses and Aboriginal health practitioners and higher use of short-term nurses in remote Australian primary care services: an observational cohort study
Authors: Zhao Yuejen , Russell Deborah Jane , Guthridge Steven , Ramjan Mark , Jones Michael P , Humphreys John S , Wakerman John 
Published: February 2019

ObjectivesTo compare the costs and effects of higher turnover of resident nurses and Aboriginal health practitioners and higher use of agency-employed nurses in remote primary care (PC) services and quantify associations between staffing patterns and health outcomes in remote PC clinics in the Northern Territory (NT) of Australia.DesignObservational cohort study, using hospital admission, financial and payroll data for the period 2013–2015.Setting53 NT Government run PC clinics in remote communities.Outcome measuresIncremental cost-effectiveness ratios were calculated for higher compared with lower turnover and higher compared with lower use of agency-employed nurses. Costs comprised PC, travel and hospitalisation costs. Effect measures were total hospitalisations and years of life lost per 1000 person-months. Multiple regression was performed to investigate associations between overall health costs and turnover rates and use of agency-employed nurses, after adjusting for key confounders.ResultsHigher turnover was associated with significantly higher hospitalisation rates (p<0.001) and higher average health costs (p=0.002) than lower turnover. Lower turnover was always more cost-effective. Average costs were significantly (p<0.001) higher when higher proportions of agency-employed nurses were employed. The probability that lower use of agency-employed nurses was more cost-effective was 0.84. Halving turnover and reducing use of a short-term workforce have the potential to save $32 million annually in the NT.ConclusionHigh turnover of health staff is costly and associated with poorer health outcomes for Aboriginal peoples living in remote communities. High reliance on agency nurses is also very likely to be cost-ineffective. Investment in a coordinated range of workforce strategies that support recruitment and retention of resident nurses and Aboriginal health practitioners in remote clinics is needed to stabilise the workforce, minimise the risks of high staff turnover and over-reliance on agency nurses and thereby significantly reduce expenditure and improve health outcomes.
Development and external validation of new nomograms by adding ECG changes (ST depression or tall T wave) and age to conventional scoring systems to improve the predictive capacity in patients with subarachnoid haemorrhage: a retrospective, observational study in Korea
Authors: Hong Ju young , You Je Sung , Kim Min Joung , Lee Hye Sun , Park Yoo Seok , Chung Sung Phil , Park Incheol 
Published: February 2019

ObjectivesTo develop new nomograms by adding ECG changes (ST depression or tall T wave) and age to three conventional scoring systems, namely, World Federation of Neurosurgical Societies (WFNS) scale, Hunt and Hess (HH) system and Fisher scale, that can predict prognosis in patients with subarachnoid haemorrhage (SAH) using our preliminary research results and to perform external validation of the three new nomograms.DesignRetrospective, observational studySettingEmergency departments (ED) of two university-affiliated tertiary hospital between January 2009 and March 2015.ParticipantsAdult patients with SAH were enrolled. Exclusion criteria were age <19 years, no baseline ECG, cardiac arrest on arrival, traumatic SAH, referral from other hospital and referral to other hospitals from the ED.Primary outcome measuresThe 6 month prognosis was assessed using the Glasgow Outcome Scale (GOS). We defined a poor outcome as a GOS score of 1, 2 or 3.ResultsA total of 202 patients were included for analysis. From the preliminary study, age, ECG changes (ST depression or tall T wave), and three conventional scoring systems were selected to predict prognosis in patients with SAH using multi-variable logistic regression. We developed simplified nomograms using these variables. Discrimination of the developed nomograms including WFNS scale, HH system and Fisher scale was superior to those of WFNS scale, HH system and Fisher scale (0.912 vs 0.813; p<0.001, 0.913 vs 0.826; p<0.001, and 0.885 vs 0.746; p<0.001, respectively). The calibration plots showed excellent agreement. In the external validation, the discrimination of the newly developed nomograms incorporating the three scoring systems was also good, with an area under the receiver-operating characteristic curve value of 0.809, 0.812 and 0.772, respectively.ConclusionsWe developed and externally validated new nomograms using only three independent variables. Our new nomograms were superior to the WFNS scale, HH systems, and Fisher scale in predicting prognosis and are readily available.
Protocol for a systematic literature review and network meta-analysis of the clinical benefit of inhaled maintenance therapies in chronic obstructive pulmonary disease
Authors: Lewis Adam , Axson Eleanor L , Potts James , Tarnowska Renelle , Vioix Helene , Quint Jennifer K 
Published: February 2019

IntroductionChronic obstructive pulmonary disease (COPD) exacerbations progress the course of disease and impair lung function. Inhaled maintenance therapy reduces exacerbations. It is not yet established which inhaled therapy combination is best to reduce exacerbations, lung function decline and symptom burden.Methods and analysisMEDLINE, EMBASE and the Cochrane Library will be searched for articles between January 2011 and May 2018 using a pre-specified search strategy. Conference proceedings will be searched. Systematic reviews (with or without meta-analysis), randomised controlled trials (RCTs), cohort studies and case controlled studies comparing six interventions comprising different combinations of long-acting bronchodilators and inhaled corticosteroids in unison or on their own. The primary outcome is the reduction in moderate-to-severe exacerbations. Secondary outcomes include: lung function, quality of life, mortality and other adverse events. Titles and abstracts will screened by the primary researcher. A second reviewer will repeat this on a proportion of records. The Population, Intervention, Comparator, Outcomes and Study framework will be used for data extraction. A network meta-analyses of outcomes from RCTs and real-world evidence will be integrated if feasible. The 95% credible interval will be used to assess the statistical significance of each summary effect. Ranking of interventions will be based on their surface under cumulative ranking area.Ethics and disseminationCOPD exacerbations are burdensome to patients. We aim to report results that provide clinicians with a more informed choice of which inhaled therapy combinations are best to reduce exacerbations, improve disease burden and reduce lung function and exercise capacity decline, compared with the potential harms, in certain populations with COPD.PROSPERO registration numberCRD42018088013.
Cardiovascular, antidepressant and immunosuppressive drug use in relation to risk of cutaneous melanoma: a protocol for a prospective case–control study
Authors: Berge Leon Alexander Mclaren , Andreassen Bettina Kulle , Stenehjem Jo Steinson , Larsen Inger Kristin , Furu Kari , Juzeniene Asta , Roscher Ingrid , Heir Trond , Green Adele , Veierød Marit Bragelien , Robsahm Trude Eid 
Published: February 2019

IntroductionThe incidence of cutaneous melanoma (hereafter melanoma) has increased dramatically among fair-skinned populations worldwide. In Norway, melanoma is the most rapidly growing type of cancer, with a 47% increase among women and 57% among men in 2000–2016. Intermittent ultraviolet exposure early in life and phenotypic characteristics like a fair complexion, freckles and nevi are established risk factors, yet the aetiology of melanoma is multifactorial. Certain prescription drugs may have carcinogenic side effects on the risk of melanoma. Some cardiovascular, antidepressant and immunosuppressive drugs can influence certain biological processes that modulate photosensitivity and immunoregulation. We aim to study whether these drugs are related to melanoma risk.Methods and analysisA population-based matched case–control study will be conducted using nation-wide registry data. Cases will consist of all first primary, histologically verified melanoma cases diagnosed between 2007 and 2015 identified in the Cancer Registry of Norway (14 000 cases). Ten melanoma-free controls per case (on date of case melanoma diagnosis) will be matched based on sex and year of birth from the National Registry of Norway. For the period 2004—2015, and by using the unique personal identification numbers assigned to all Norwegian citizens, the case–control data set will be linked to the Norwegian Prescription Database for information on drugs dispensed prior to the melanoma diagnosis, and to the Medical Birth Registry of Norway for data regarding the number of child births. Conditional logistic regression will be used to estimate associations between drug use and melanoma risk, taking potential confounding factors into account.Ethics and disseminationThe project is approved by the Regional Committee for Medical Research Ethics in Norway and by the Norwegian Data Protection Authority. The study is funded by the Southeastern Norway Regional Health Authority. Results will be published in peer-reviewed journals and disseminated further through scientific conferences, news media and relevant patient interest groups.
L-sepiapterin restores SLE serum-induced markers of endothelial function in endothelial cells
Authors: Jones Buie Joy N , Pleasant Jenkins Dorea , Muise-Helmericks Robin , Oates Jim C 
Published: February 2019

ObjectiveSLE serves as an independent risk factor` for endothelial dysfunction (ED) not explained by Framingham risk factors. We sought to understand the development of SLE-induced ED on a cellular level in order to develop strategies aimed at reversing cellular abnormalities. This study assessed the impact of SLE patient serum on endothelial nitric oxide synthase (eNOS), nitric oxide (NO) production and functional changes in the cell.MethodsHuman umbilical vein endothelial cells (HUVECs) cultured in serum of either SLE (n=25) or healthy patients (n=14) or endothelial basal medium 2 (EBM-2) culture media supplemented with fetal bovine serum with or without L-sepiapterin were used for our studies. We applied the fluorescent probe DAF-FM diacetate for intracellular NO detection using flow cytometry. Total RNA isolates were analysed using reverse transcription PCR for eNOS mRNA expression. Oxygen consumption rate was determined using seahorse analysis. Neutrophil adhesion and migration were determined using a calcein AM microscopy assay.ResultsThe mRNA expression of eNOS was increased in SLE cultured HUVECs compared with healthy control (p<0.05). The SLE eNOS mRNA level correlated with SLE patient age (p=0.008); however, this trend was not observed with healthy patients. SLE serum reduced NO production in HUVECs compared with EBM-2 cultured cells (p<0.05). Co-treatment of endothelial cells with L-sepiapterin preserved HUVEC capacity to produce NO in SLE conditions (p<0.01). SLE serum enhanced neutrophil migration (p<0.01) but not neutrophil adhesion compared with healthy controls. The bioenergetic health index was not different.ConclusionsSLE likely causes disruption of endothelial cell eNOS function and NO modulated pathways.
Impaired posture, movement preparation, and execution during both paretic and nonparetic reaching following stroke
Authors: Yang Chieh-ling , Creath Robert A. , Magder Laurence , Rogers Mark W. , McCombe Waller Sandy 
Published: February 2019

Posture and movement planning, preparation, and execution of a goal-directed reaching movement are impaired in individuals with stroke. No studies have shown whether the deficits are generally impaired or are specific to the lesioned hemisphere/paretic arm. This study utilized StartReact (SR) responses elicited by loud acoustic stimuli (LAS) to investigate the preparation and execution of anticipatory postural adjustments (APAs) and reach movement response during both paretic and nonparetic arm reaching in individuals with stroke and in age-matched healthy controls. Subjects were asked to get ready after receiving a warning cue and to reach at a “go” cue. An LAS was delivered at –500, –200, and 0 ms relative to the go cue. Kinetic, kinematic, and electromyographic data were recorded to characterize APA-reach movement responses. Individuals with stroke demonstrated systemwide deficits in posture and in movement planning, preparation, and execution of APA-reach sequence as shown by significant reduction in the incidence of SR response and impaired APA-reach performance, with greater deficits during paretic arm reaching. Use of trunk compensation strategy as characterized by greater involvement of trunk and pelvic rotation was utilized by individuals with stroke during paretic arm reaching compared with nonparetic arm reaching and healthy controls. Our findings have implications for upper extremity and postural control, suggesting that intervention should include training not only for the paretic arm but also for the nonparetic arm with simultaneous postural control requirements to improve the coordination of the APA-reach performance and subsequently reduce instability while functional tasks are performed during standing. NEW & NOTEWORTHY Our study is the first to show that nonparetic arm reaching also demonstrates impairment in posture and movement planning, preparation, and execution when performed during standing by individuals with stroke. In addition, we found compensatory trunk and pelvic rotations were used during a standing reach task for the paretic arms. The findings have clinical implications for upper extremity and postural rehabilitation, suggesting that training should include the nonparetic arms and incorporate simultaneous postural control demands.
Optogenetic and transcriptomic interrogation of enhanced muscle function in the paralyzed mouse whisker pad
Authors: Vajtay Thomas J. , Bandi Akhil , Upadhyay Aman , Swerdel Mavis R. , Hart Ronald P. , Lee Christian R. , Margolis David J. 
Published: February 2019

The functional state of denervated muscle is a critical factor in the ability to restore movement after injury- or disease-related paralysis. Here we used peripheral optogenetic stimulation and transcriptome profiling in the mouse whisker system to investigate the time course of changes in neuromuscular function following complete unilateral facial nerve transection. While most skeletal muscles rapidly lose functionality after lower motor neuron denervation, optogenetic muscle stimulation of the paralyzed whisker pad revealed sustained increases in the sensitivity, velocity, and amplitude of whisker movements, and reduced fatigability, starting 48 h after denervation. RNA-seq analysis showed distinct regulation of multiple gene families in denervated whisker pad muscles compared with the atrophy-prone soleus, including prominent changes in ion channels and contractile fibers. Together, our results define the unique functional and transcriptomic landscape of denervated facial muscles and have general implications for restoring movement after neuromuscular injury or disease. NEW & NOTEWORTHY Optogenetic activation of muscle can be used to noninvasively induce movements and probe muscle function. We used this technique in mice to investigate changes in whisker movements following facial nerve transection. We found unexpectedly enhanced functional properties of whisker pad muscle following denervation, accompanied by unique transcriptomic changes. Our findings highlight the utility of the mouse whisker pad for investigating the restoration of movement after paralysis.
RIPK3-Induced Inflammation by I-MDSCs Promotes Intestinal Tumors
Authors: Jayakumar Asha , Bothwell Alfred L.M. 
Published: February 2019

Abstract

Myeloid-derived suppressor cells (MDSC) promote colorectal cancer by several mechanisms, including suppression of antitumor T cells and production of tumorigenic factors. We previously showed that an intermediate MDSC subset (I-MDSC) is expanded in an intestinal tumor model (ApcMin/+ mice), but the importance of this subset in promoting tumors is unclear. Here, we show that I-MDSCs are a distinct heterogeneous subset due to differential and reduced expression of the monocytic marker, Ly6C, and granulocytic marker, Ly6G. Besides causing necroptotic cell death, receptor-interacting protein kinase 3 (RIPK3) has an alternate function as a signaling component inducing cytokine synthesis. We evaluated whether RIPK3 regulates inflammatory cytokines in I-MDSCs to assess the nonimmunosuppressive function of I-MDSCs in promoting tumors. Inhibition of RIPK3 with the commercially available small-molecule inhibitor GSK 872 showed that RIPK3-mediated inflammation promoted intestinal tumors in two intestinal tumor models, ApcMin/+ mice and an MC38 transplantable tumor model. Mechanistically, RIPK3 signaling in I-MDSC increased tumor size by expanding IL17-producing T cells in MC38 tumors. Collectively, these data suggest RIPK3 signaling as a potential therapeutic target in colorectal cancer.

Significance:
The specific role of RIPK3 in intestinal tumors and MDSC function sheds light on a key inflammatory mechanism driving tumorigenesis and allows for possible therapeutic intervention.
CYR61/CCN1 Regulates dCK and CTGF and Causes Gemcitabine-resistant Phenotype in Pancreatic Ductal Adenocarcinoma
Authors: Maity Gargi , Ghosh Arnab , Gupta Vijayalaxmi , Haque Inamul , Sarkar Sandipto , Das Amlan , Dhar Kakali , Bhavanasi Sneha , Gunewardena Sumedha S. , Von Hoff Daniel D. , Mallik Sanku , Kambhampati Suman , Banerjee Sushanta K. , Banerjee Snigdha 
Published: February 2019

Abstract
Pancreatic ductal adenocarcinoma (PDAC) develops extrinsic- and intrinsic-resistant phenotypes to prevent chemotherapies from entering into the cells by promoting desmoplastic reactions (DR) and metabolic malfunctions of the drugs. It is well established that these responses are also associated with pancreatic cancer cells' gemcitabine resistance. However, the mechanism by which these resistant pathways function in the pancreatic cancer cells remains poorly understood. In these studies, we show that CYR61/CCN1 signaling plays a vital role in making pancreatic cancer cells resistant to gemcitabine in vitro and also in a tumor xenograft model. We proved that the catastrophic effect of gemcitabine could significantly be increased in gemcitabine-resistant PDAC cells when CYR61/CCN1 is depleted, while this effect can be suppressed in gemcitabine-sensitive neoplastic cells by treating them with CYR61/CCN1 recombinant protein. Ironically, nontransformed pancreatic cells, which are sensitive to gemcitabine, cannot be resistant to gemcitabine by CYR61/CCN1 protein treatment, showing a unique feature of CYR61/CCN signaling that only influences PDAC cells to become resistant. Furthermore, we demonstrated that CYR61/CCN1 suppresses the expression of the gemcitabine-activating enzyme deoxycytidine kinase (dCK) while it induces the expression of a DR-promoting factor CTGF (connective tissue growth factor) in pancreatic cancer cells in vitro and in vivo. Thus, the previously described mechanisms (dCK and CTGF pathways) for gemcitabine resistance may be two novel targets for CYR61/CCN1 to protect pancreatic cancer cells from gemcitabine. Collectively, these studies reveal a novel paradigm in which CYR61/CCN1regulates both extrinsic and intrinsic gemcitabine resistance in PDAC cells by employing unique signaling pathways.
On the Influence of Swell Propagation Angle on Surface Drag
Authors: Patton Edward G. , Sullivan Peter P. , Kosović Branko , Dudhia Jimy , Mahrt Larry , Žagar Mark , Marić Tomislav 
Published: February 2019

AbstractA combination of turbulence-resolving large-eddy simulations and observations are used to examine the influence of swell amplitude and swell propagation angle on surface drag. Based on the analysis a new surface roughness parameterization with nonequilibrium wave effects is proposed. The surface roughness accounts for swell amplitude and wavelength and its relative motion with respect to the mean wind direction. The proposed parameterization is tested in uncoupled three-dimensional Weather and Research Forecasting (WRF) simulations at grid sizes near 1 km where we explore potential implications of our modifications for two-way coupled atmosphere–wave models. Wind–wave misalignment likely explains the large scatter in observed nondimensional surface roughness under swell-dominated conditions. Andreas et al.’s relationship between friction velocity and the 10-m wind speed under predicts the increased drag produced by misaligned winds and waves. Incorporating wave-state (speed and direction) influences in parameterizations improves predictive skill. In a broad sense, these results suggest that one needs information on winds and wave state to upscale buoy measurements.