bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endocannabinoid degradation inhibitors ameliorate neuronal and synaptic alterations following traumatic brain injury
Authors: Fucich Elizabeth A. , Stielper Zachary F. , Cancienne Heather L. , Edwards Scott , Gilpin Nicholas W. , Molina Patricia E. , Middleton Jason W. 
Published: January 2020

Our previous work showed that lateral fluid percussion injury to the sensorimotor cortex (SMC) of anesthetized rats increased neuronal synaptic hyperexcitability in layer 5 (L5) neurons in ex vivo brain slices 10 days postinjury. Furthermore, endocannabinoid (EC) degradation inhibition via intraperitoneal JZL184 injection 30 min postinjury attenuated synaptic hyperexcitability. This study tested the hypothesis that traumatic brain injury (TBI) induces synaptic and intrinsic neuronal alterations of L5 SMC pyramidal neurons and that these alterations are significantly attenuated by in vivo post-TBI treatment with EC degradation inhibitors. We tested the effects of systemically administered EC degradation enzyme inhibitors (JZL184, MJN110, URB597, or JZL195) with differential selectivity for fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on electrophysiological parameters in SMC neurons of TBI- and sham-treated rats 10 days post-TBI. We recorded intrinsic neuronal properties, including resting membrane voltage, input resistance, spike threshold, spiking responses to current input, voltage “sag” (rebound response to hyperpolarization-activated inward current), and burst firing. We also measured the frequency and amplitude of spontaneous excitatory postsynaptic currents. We then used the aggregate parameter sets (intrinsic + synaptic properties) to apply a machine learning classification algorithm to quantitatively compare neural population responses from each experimental group. Collectively, our electrophysiological and computational results indicate that sham neurons are the most distinguishable from TBI neurons. Administration of EC degradation inhibitors post-TBI exerted varying degrees of rescue, approximating the neuronal phenotype of sham neurons, with neurons from TBI/JZL195 (a dual MAGL/FAAH inhibitor) being most similar to neurons from sham rats. NEW & NOTEWORTHY This study elucidates neuronal properties altered by traumatic brain injury (TBI) in layer 5 of sensorimotor cortex, which may be implicated in post-TBI circuit dysfunction. We compared effects of systemic administration of four different endocannabinoid degradation inhibitors within a clinically relevant window postinjury. Electrophysiological measures and using a machine learning classification algorithm collectively suggest that pharmacological inhibitors targeting both monoacylglycerol lipase and fatty acid amide hydrolase (e.g., JZL195) may be most efficacious in attenuating TBI-induced neuronal dysfunction at site of injury.
Tumor Cell–Derived IL1β Promotes Desmoplasia and Immune Suppression in Pancreatic Cancer
Authors: Das Shipra , Shapiro Beny , Vucic Emily A. , Vogt Sandra , Bar-Sagi Dafna 
Published: January 2020

AbstractPancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy typified by a highly stromal and weakly immunogenic tumor microenvironment that promotes tumor evolution and contributes to therapeutic resistance. Here, we demonstrate that PDA tumor cell–derived proinflammatory cytokine IL1β is essential for the establishment of the protumorigenic PDA microenvironment. Tumor cell–derived IL1β promoted the activation and secretory phenotype of quiescent pancreatic stellate cells and established an immunosuppressive milieu mediated by M2 macrophages, myeloid-derived suppressor cells, CD1dhiCD5+ regulatory B cells, and Th17 cells. Loss of tumor cell–derived IL1 signaling in tumor stroma enabled intratumoral infiltration and activation of CD8+ cytotoxic T cells, attenuated growth of pancreatic neoplasia, and conferred survival advantage to PDA-bearing mice. Accordingly, antibody-mediated neutralization of IL1β significantly enhanced the antitumor activity of α-PD-1 and was accompanied by increased tumor infiltration of CD8+ T cells. Tumor cell expression of IL1β in vivo was driven by microbial-dependent activation of toll-like receptor 4 (TLR4) signaling and subsequent engagement of the NLRP3 inflammasome. Collectively, these findings identify a hitherto unappreciated role for tumor cell–derived IL1β in orchestrating an immune-modulatory program that supports pancreatic tumorigenesis.Significance:These findings identify a new modality for immune evasion in PDA that depends on IL1β production by tumor cells through TLR4-NLRP3 inflammasome activation. Targeting this axis might provide an effective PDA therapeutic strategy.
Shift Work and Working at Night in Relation to Breast Cancer Incidence
Authors: Sweeney Marina R. , Sandler Dale P. , Niehoff Nicole M. , White Alexandra J. 
Published: January 2020

Abstract

Background:
Night shift work has been classified by the International Agency for Research on Cancer as a probable carcinogen in humans. Several studies have assessed night shift work in relation to breast cancer risk, with inconsistent results.

Methods:
In the prospective Sister Study cohort, current and past occupational history was collected for 48,451 participants. We used Cox proportional hazards models to estimate adjusted HRs and 95% confidence intervals (CI) for the association between baseline work schedule characteristics and incident breast cancer.

Results:
During follow-up (mean = 9.1 years), 3,191 incident cases were diagnosed. We observed little to no increase in risk associated with work schedule characteristics (ever working rotating shifts: HR = 1.04, 95% CI, 0.91–1.20; ever working rotating night shifts: HR = 1.08, 95% CI, 0.92–1.27; ever working at night: HR = 1.01, 95% CI, 0.94–1.10; and ever working irregular hours: HR = 0.98, 95% CI, 0.91–1.06). Although short-term night work (&gt;0 to 5 years vs. never: HR = 1.12; 95% CI, 1.00–1.26) and rotating shift work at night (&gt;0 to 5 years vs. never: HR = 1.30; 95% CI, 1.05–1.61) were associated with increased breast cancer risk, working nights for more than 5 years was not associated with risk.

Conclusions:
Overall, we observed little evidence that rotating shift work or work at night was associated with a higher risk of breast cancer, except possibly among those who participated in such work for short durations of time.

Impact:
This study indicates that if night shift work is associated with breast cancer, the increase in risk is small.
BMX Represses Thrombin-PAR1–Mediated Endothelial Permeability and Vascular Leakage During Early Sepsis
Authors: Li Zhao , Yin Mingzhu , Zhang Haifeng , Ni Weiming , Pierce Richard W. , Zhou Huanjiao Jenny , Min Wang 
Published: January 2020

Rationale:
BMX (bone marrow kinase on the X chromosome) is highly expressed in the arterial endothelium from the embryonic stage to the adult stage in mice. It is also expressed in microvessels and the lymphatics in response to pathological stimuli. However, its role in endothelial permeability and sepsis remains unknown.

Objective:
We aimed to delineate the function of BMX in thrombin-mediated endothelial permeability and the vascular leakage that occurs with sepsis in cecal ligation and puncture models.

Methods and Results:
The cecal ligation and puncture model was applied to WT (wild type) and BMX-KO (BMX global knockout) mice to induce sepsis. Meanwhile, the electric cell-substrate impedance sensing assay was used to detect transendothelial electrical resistance in vitro and, the modified Miles assay was used to evaluate vascular leakage in vivo. We showed that BMX loss caused lung injury and inflammation in early cecal ligation and puncture–induced sepsis. Disruption of BMX increased thrombin-mediated permeability in mice and cultured endothelial cells by 2- to 3-fold. The expression of BMX in macrophages, neutrophils, platelets, and lung epithelial cells was undetectable compared with that in endothelial cells, indicating that endothelium dysfunction, rather than leukocyte and platelet dysfunction, was involved in vascular permeability and sepsis. Mechanistically, biochemical and cellular analyses demonstrated that BMX specifically repressed thrombin-PAR1 (protease-activated receptor-1) signaling in endothelial cells by directly phosphorylating PAR1 and promoting its internalization and deactivation. Importantly, pretreatment with the selective PAR1 antagonist SCH79797 rescued BMX loss-mediated endothelial permeability and pulmonary leakage in early cecal ligation and puncture–induced sepsis.

Conclusions:
Acting as a negative regulator of PAR1, BMX promotes PAR1 internalization and signal inactivation through PAR1 phosphorylation. Moreover, BMX-mediated PAR1 internalization attenuates endothelial permeability to protect vascular leakage during early sepsis.
Human Dignity in an Age of Autonomous Weapons: Are We in Danger of Losing an ‘Elementary Consideration of Humanity’?
Authors: Ulgen Ozlem 
Published: January 2020

Military investment in robotics technology is leading to development and use of autonomous weapons, which are machines with varying degrees of autonomy in target, attack, and infliction of lethal harm (that is, injury, suffering or death). Examples of autonomous weapons include weapons systems involving levels of automation and remotely controlled human input, unmanned armed aerial vehicles (uav), remotelycontrolled robotic soldiers, bio-augmentation, and 3D printed weapons. Autonomous weapons generally fall into one of two categories: semi-autonomous, involving some degree of autonomy in certain critical functions such as acquiring, tracking, selecting, and attacking targets, along with a degree of human input or remote control (for example, uav or ‘drones’); and autonomous, involving higher levels of independent thinking as regards critical functions without the need for human input or control (for example, US Navy X-47B uav with autonomous take-off, landing, and aerial refuelling capability). The trend is clearly towards developing autonomous weapons. Development of new weapons aimed at reducing costs and casualties is not a new phenomenon in warfare. Technological advances have created greater distance between the soldier and the battlefield. A bullet fired from a rifle handled by a human has been superseded by a missile fired from a remotely controlled or autonomous machine. So what makes autonomous weapons different? What particular challenge do they pose international law? Although autonomous weapons may be employed to attack nonhuman targets, such as state infrastructure, here I am primarily concerned with their use for lethal attacks against humans.
In this chapter I focus on autonomous weapons (both semi-autonomous and fully autonomous) and their impact on human dignity under two of Kant’s conceptual strands: (1) human dignity as a status entailing rights and duties; and (2) human dignity as respectful treatment. Under the first strand I explore how use of autonomous weapons denies the right of equality of persons and diminishes the duty not to harm others. In the second strand I consider how replacing human combatants with autonomous weapons debases human life and does not provide respectful treatment. Reference is made to contemporary development of Kant’s conceptual strands in icj and other international jurisprudence recognising human dignity as part of ‘elementary considerations of humanity’ in war and peace.
Importance of Orography for Greenland Cloud and Melt Response to Atmospheric Blocking
Authors: Hahn L. C. , Storelvmo T. , Hofer S. , Parfitt R. , Ummenhofer C. C. 
Published: January 2020

AbstractMore frequent high pressure conditions associated with atmospheric blocking episodes over Greenland in recent decades have been suggested to enhance melt through large-scale subsidence and cloud dissipation, which allows more solar radiation to reach the ice sheet surface. Here we investigate mechanisms linking high pressure circulation anomalies to Greenland cloud changes and resulting cloud radiative effects, with a focus on the previously neglected role of topography. Using reanalysis and satellite data in addition to a regional climate model, we show that anticyclonic circulation anomalies over Greenland during recent extreme blocking summers produce cloud changes dependent on orographic lift and descent. The resulting increased cloud cover over northern Greenland promotes surface longwave warming, while reduced cloud cover in southern and marginal Greenland favors surface shortwave warming. Comparison with an idealized model simulation with flattened topography reveals that orographic effects were necessary to produce area-averaged decreasing cloud cover since the mid-1990s and the extreme melt observed in the summer of 2012. This demonstrates a key role for Greenland topography in mediating the cloud and melt response to large-scale circulation variability. These results suggest that future melt will depend on the pattern of circulation anomalies as well as the shape of the Greenland Ice Sheet.
Is It Time to Go Positive? Assessing the Positively Worded System Usability Scale (SUS)
Authors: Kortum Philip , Acemyan Claudia Ziegler , Oswald Frederick L. 
Published: January 2020

Objective The goal of the research presented in this paper was to determine if the positively worded System Usability Scale (SUS) can be used in place of the positively and negatively worded standard SUS instrument for the subjective assessment of usability, and whether the results found here replicate those of Sauro and Lewis. Background Sauro and Lewis’ previous study found no evidence that responses to SUS items differed across the standard SUS and the modified, positively worded version of the SUS when participants assessed websites. This study replicates and extends this work by examining a large number of different systems with larger sample sizes to add to the generalizability of previous findings. Methods So that participants could retrospectively assess 20 products, the standard SUS was administered to 268 participants and the positive SUS to 698 participants. SUS scores were computed and the data analyzed using psychometric methods to explore how the two versions of the SUS differed. Results The standard and positive versions of the SUS yielded similar SUS scores. In addition, both versions of the scale demonstrated evidence in support of reliability and validity. Conclusion Either version of the SUS can be used with confidence to measure subjective usability. Furthermore, the scores generated from both versions of the SUS can be directly compared. Applications In situations where cognitive load, participants’ spoken language, or item consistency with other surveys being given may be a factor, the positive SUS is a viable alternative to the standard SUS.
Association of regulatory variants of dopamine β-hydroxylase with cognition and tardive dyskinesia in schizophrenia subjects
Authors: Punchaichira Toyanji J , Mukhopadhyay Anirban , Kukshal Prachi , Bhatia Triptish , Deshpande Smita N , Thelma BK 
Published: January 2020

Background: Dopamine-β-hydroxylase (DBH, EC 1.14.17.1), which converts dopamine to norepinephrine, is a candidate gene in neuropsychiatric diseases. Aim: To assess the effect of regulatory variants in DBH on schizophrenia and its endophenotypes –cognition and tardive dyskinesia. Methods: We tested association of functional variants 19bp Ins/Del, rs1989787 and rs1611115 in DBH with i) schizophrenia (1236 cases, 1136 controls), ii) tardive dyskinesia (83 positive, 162 negative) and iii) performance functions of cognition (357 cases, 306 controls) estimated by the Penn Computerized Neurocognitive Battery. Results: A modest haplotypic ( Ins-C; 19bp Ins/Del – rs1989787 C>T; p=0.04) association was observed with schizophrenia. We observed ~39% reduction in activity of 19bp Del allele on luciferase assay. Analysis of covariance revealed interactions of tardive dyskinesia status and: i) 19bp Ins/Del (genotypic, p=0.04) and ii) rs1989787 and rs1611115 (combined genotypic, p=0.004) on Abnormal Involuntary Movement Scale total score. Association of rs1611115 with positive and negative syndrome scale (PANSS) total score ( p=0.05) and allelic/genotypic association with lower positive ( p=0.03/0.04), general psychopathology ( p=0.01/0.01) PANSS scales in tardive dyskinesia-positive; and allelic/genotypic ( p=0.02/0.05) with higher score of depressive factors in tardive dyskinesia-negative subgroups were observed. Analysis of covariance with continuous variable of cognition showed interaction of health status with: i) rs1989787 on accuracy and efficiency ( p=0.03) of abstraction and mental ﬂexibility; ii) rs1611115 on accuracy of working memory and emotion ( p=0.05); iii) 19bp Ins/Del on processing speed of emotion ( p=0.03). Allelic/genotypic association of rs1989787 with spatial ability ( p=0.02–0.05) among healthy controls; association of rs1611115 with Global Assessment Scale scores in the past month ( p=0.05) among schizophrenia subjects of cognition cohort was also observed. Conclusions: With modest genotype–phenotype correlations available for DBH variants, personalized treatment regimens based on DBH activity for ameliorating tardive dyskinesia and cognitive symptoms may be plausible.
The Influence of Donor Milk Supplementation on Duration of Parenteral Nutrition in Preterm Infants
Authors: Chinea Jiménez Bibiana , Cabrera Lafuente Marta , Couce María L. , Madero Rosario , Vento Maximo , Villarino Marín Antonio , Saenz de Pipaon Miguel 
Published: January 2020

Background Data are limited on the association between the use of donor human milk and improvements in feeding tolerance. Objective To determine the influence of the duration of parenteral nutrition on the growth and morbidity of the breastfed newborn when using donated human milk in the absence of mother’s own milk. Methods We conducted a retrospective study before and after the intervention that compared two groups of newborns ( N = 284; each group n = 142). We used a convenience sample of all newborns ≤32 weeks gestation consecutively admitted in a single unit before (Group 1 between December 2012 and May 2014) or after (Group 2 between October 2014 and December 2016) the availability of donor human milk. In Group 2, donor human milk was administered at least 3 to 4 weeks or until the baby weighed 1,500 g. Weight was recorded daily and length and head circumference weekly. Parenteral nutrition was continued until enteral feeding volume reached 120 ml/kg/day. Additional variables measured were the number of days with a central venous catheter, age that the enteral feeding volume reached 150 ml/kg/day, and duration of stay. Results The duration of parenteral feeding was the same before and after: 12 (8.23) and 11 (7.19) days ( p = .822). The z scores for weight and height of newborns was lower in Group 2 = −1.8 (1.0) and −2.3 (1.1) and Group 1 = −1.2 (1.1) ( p < .001) and −1.8 (1.4) ( p = .005). Conclusion We did not find an association between the administration of donor human milk as a supplement to mother’s own milk and reduced number of days of parenteral nutrition. Back translation by Laurence Grummer-Strawn
Predictors of ICU admission and long-term outcomes in overdose presentations to Emergency Department
Authors: Savage Mark , Kung Ross , Green Cameron , Thia Brandon , Perera Dinushka , Tiruvoipati Ravindranath 
Published: January 2020

Objective: To describe the characteristics of patients presenting to an Emergency Department (ED) following overdoses; to identify risk factors for intensive care unit (ICU) admission among these patients; and to identify the rate of mortality and repeat overdose presentations over four years. Methods: Adult patients presenting to ED following drug overdose during 2014 were included. Data were collected from medical notes and hospital databases. Results: During the study period, 654 patients presented to ED 800 times following overdose. Seventy-eight (9.8%) resulted in ICU admission, and 59 (7.4%) required intubation; 57.2% had no history of overdose presentations, and 72.9% involved patients with known psychiatric illness. Overdose of atypical antipsychotics (AAP), age and history of prior overdose independently predicted ICU admission. A third of patients ( n = 196, 30%) had subsequent presentations to ED following overdose, in the four years from their index presentation, with an all-cause four-year mortality of 3.4% ( n = 22). Conclusion: A history of overdose, use of AAP and older age were risk factors for ICU admission following ED presentations. Over a third of patients had repeat overdose presentation in the four-year follow-up with a mortality of 3.4%.
Does femoral morphology and stem alignment influence outcomes of cementless total hip arthroplasty with proximally coated double-tapered titanium stems?
Authors: Narayanan Rajkishen , Elbuluk Ameer M , Chen Kevin K , Eftekhary Nima , Zuckerman Joseph D , Deshmukh Ajit J 
Published: January 2020

Introduction: Stem subsidence and thigh pain can cause significant patient dissatisfaction after cementless THA. The purpose of this study was to examine the effect of proximal-femoral morphology and stem alignment on clinical outcomes using a double-tapered, cementless titanium femoral component. Methods: We retrospectively reviewed 281 consecutive, primary THAs from 2012 to 2014 with a mean follow-up of 4 years. Preoperative radiographs were used to assess femoral neck shaft angle (FNS), canal flare index (CFI), Dorr classification, and greater trochanter (GT) overhang. Postoperative radiographs were used to determine stem alignment and 6-week follow-up radiographs were used to determine subsidence. Clinical outcomes included thigh pain, leg-length discrepancy (LLD), patient-reported outcome measures (PROMs) and revision surgeries. Results: 271 stems (96%) did not subside (<4 mm) and 10 (4%) showed evidence of subsidence (>4 mm). Subsidence was significantly associated with subsequent revision surgery ( p < 0.01). 278 stems (99%) were in neutral alignment and 3 in varus (1%). Alignment did not significantly influence subsidence, thigh pain, LLD, revisions, or PROMs. Femoral morphology measures (FNS, CFI, Dorr classification, and GT overhang) were not significantly associated with stem alignment, subsidence, LLD, or revisions. CFI was significantly associated with intraoperative calcar fractures ( p = 0.02). GT overhang was associated with thigh pain ( p = 0.03) and FNS was inversely associated with postoperative HOOS scores. Conclusions: Subsidence and proximal-femoral morphology are potential sources of postoperative morbidity in certain cementless THA patients. In accordance with prior studies, CFI was identified as a potential risk factor for intraoperative calcar fractures. More research into preoperative femoral morphologies, such as GT overhang and FNS, is warranted as these may contribute to unsatisfactory results related to cementless THA.