bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deciphering the Complexity of MEK Mutations in the Clinic
Authors: Whitehead Christopher E. , Sebolt-Leopold Judith S. 
Published: October 2020

Abstract
Significant advances in tumor sequencing have led to an explosion in our knowledge of the genetic complexity of cancer. For many cancers, the selection of a targetable alteration is not readily apparent, especially when confronted with mutational variants of unknown significance. The complex clinical landscape of MEK mutations illustrates the need for improved methods to identify those patients, independent of tumor histology, who would benefit from treatment with a MAP kinase pathway inhibitor. In this issue of Cancer Research, Hanrahan and colleagues adopt an in silico platform to attempt to distinguish benign MEK mutations from those that are functional and, therefore, most likely to be therapeutically actionable.
See related article by Hanrahan et al., p. 4233
BRCA1 and PALB2 in a Messy Breakup
Authors: Her Joonyoung , Bunting Samuel F. 
Published: October 2020

Abstract
Mutations in the BRCA1 gene cause an extremely high lifetime risk of breast and ovarian cancer, but the exact mechanism by which the BRCA1 protein acts to prevent cancer onset remains unclear. In this edition of Cancer Research, Park and colleagues describe a new mouse model featuring a single amino acid substitution in the coiled-coil motif of BRCA1. This change prevents BRCA1 from interacting with PALB2 (partner and localizer of BRCA2), causing rapid cancer onset and a loss of blood cells similar to Fanconi anemia.
See related article by Park et al., p. 4172
Ion Channels and Their Role in the Pathophysiology of Gliomas
Authors: Takayasu Takeshi , Kurisu Kaoru , Esquenazi Yoshua , Ballester Leomar Y. 
Published: October 2020

Abstract
Malignant gliomas are the most common primary central nervous system tumors and their prognosis is very poor. In recent years, ion channels have been demonstrated to play important roles in tumor pathophysiology such as regulation of gene expression, cell migration, and cell proliferation. In this review, we summarize the current knowledge on the role of ion channels on the development and progression of gliomas. Cell volume changes through the regulation of ion flux, accompanied by water flux, are essential for migration and invasion. Signaling pathways affected by ion channel activity play roles in cell survival and cell proliferation. Moreover, ion channels are involved in glioma-related seizures, sensitivity to chemotherapy, and tumor metabolism. Ion channels are potential targets for the treatment of these lethal tumors. Despite our increased understanding of the contributions of ion channels to glioma biology, this field remains poorly studied. This review summarizes the current literature on this important topic.
Safely Administering Potential QTc Prolonging Therapy Across a Large Health Care System in the COVID-19 Era
Authors: Saleh Moussa , Gabriels James , Chang David , Fishbein Joanna , Qiu Michael , Mountantonakis Stavros E. , Epstein Laurence M. ,   on behalf of the Northwell COVID-19 Research Consortium
Published: October 2020

Background:
The severe acute respiratory syndrome coronavirus 2 (SARs-CoV-2) has resulted in a global pandemic. Hydroxychloroquine±azithromycin have been widely used to treat coronavirus disease 2019 (COVID-19) despite a paucity of evidence regarding efficacy. The incidence of torsade de pointes remains unknown. Widespread use of these medications forced overwhelmed health care systems to search for ways to effectively monitor these patients while simultaneously trying to minimize health care provider exposure and use of personal protective equipment.

Methods:
Patients with COVID-19 positive who received hydroxychloroquine±azithromycin across 13 hospitals between March 1 and April 15 were included in this study. A comprehensive search of the electronic medical records was performed using a proprietary python script to identify any mention of QT prolongation, ventricular tachy-arrhythmias and cardiac arrest.

Results:
The primary outcome of torsade de pointes was observed in 1 (0.015%) out of 6476 hospitalized patients with COVID-19 receiving hydroxychloroquine±azithromycin. Sixty-seven (1.03%) had hydroxychloroquine±azithromycin held or discontinued due to an average QT prolongation of 60.5±40.5 ms from a baseline QTc of 473.7±35.9 ms to a peak QTc of 532.6±31.6 ms. Of these patients, hydroxychloroquine±azithromycin were discontinued in 58 patients (86.6%), while one or more doses of therapy were held in the remaining nine (13.4%). A simplified approach to monitoring for QT prolongation and arrythmia was implemented on April 5. There were no deaths related to the medications with the simplified monitoring approach and health care provider exposure was reduced.

Conclusions:
The risk of torsade de pointes is low in hospitalized patients with COVID-19 receiving hydroxychloroquine±azithromycin therapy.
Timing of the evening emergence of Hilgendorf’s tube-nosed bat (Murina hilgendorfi) in relation to roost type and season
Authors: Takada Hayato 
Published: October 2020

Abstract
Like for many species, the timing of evening emergence of bats is an important behavioral aspect that affects their fitness and has been studied in various bat species. However, little is known about emergence timing of solitary bats that frequently switch day roosts, because they are difficult to observe. In this study, I examined the emergence timing of Hilgendorf’s tube-nosed bats (Murina hilgendorfi), which are solitary and frequently switch roosts, in relation to roost type and season over six years in Hayakawa, central Japan. The results show that the bats emerged after dusk when the light was weak. Later emergence may be related to the habits of this species, such as their solitary lifestyle, slow flight speed, and gleaning foraging strategy, which may enhance predation risk. Individuals roosting in dead foliage and on the outer wall of a building situated in closed forests emerged significantly earlier than those roosting in an old mine and tunnel located in open environments, suggesting that vegetation cover and/or lower predictability of roost location provide security for bats. Bats emerged progressively earlier from late spring (preparturition) to early autumn (late lactation or post-lactation), suggesting that the reproductive status of females or the growth stage of pups may influence emergence timing. To my knowledge, this study provides the first record of the emergence timing of Hilgendorf’s tube-nosed bat, and suggests that predation risk may impact the bats’ emergence behavior.
Influence of River Discharge and Tides on the Summertime Discontinuity of Western Boundary Current in the Bay of Bengal
Authors: Das Bijan Kumar , Anandh T. S. , Kuttippurath J. , Chakraborty Arun 
Published: October 2020

AbstractThe East India Coastal Current (EICC), the western boundary current (WBC) in the Bay of Bengal (BOB), is continuous and well directed during pre- and postmonsoon season but is discontinuous during summer monsoon season (June–September). This study examines the individual and combined effects of river discharge and tidal forcing on the EICC discontinuity using high-resolution (1/12°) Regional Ocean Modeling System simulations. Four climatological experiments, a control simulation with normal boundary conditions and three other sensitivity simulations with the same boundary conditions but with river input, tidal forcing, and both together, are conducted. The analysis shows that, during summer monsoon, the southward reversal of EICC from head bay is enhanced with the river input while the tide forcing strengthens the northward EICC from north of Sri Lanka. High horizontal-salinity-gradient flow in the stratified upper ocean caused by the river discharge increases the surface currents. High vertical mixing in tide forcing suppresses the surface features. The strong horizontal diffusivity due to river discharge promotes the eddy genesis and propagation throughout the western BOB. Conversely, tidal oscillation contributes high turbulent buoyancy, which makes the upper ocean relatively unstable, and the discontinuity remains confined to the western boundary. The combined-forcing simulation indicates the dominance of river discharge in the upper layers with suppressed surface features due to tides, which intensify the discontinuity at subsurface. Therefore, the results of this numerical study suggest that the river input and tidal forcing both play important and complementary roles in maintaining the realistic summertime discontinuity in the BOB.
Subseasonal Statistical Forecasts of Eastern U.S. Hot Temperature Events
Authors: Vijverberg Sem , Schmeits Maurice , van der Wiel Karin , Coumou Dim 
Published: October 2020

AbstractExtreme summer temperatures can cause severe societal impacts. Early warnings can aid societal preparedness, but reliable forecasts for extreme temperatures at subseasonal-to-seasonal (S2S) time scales are still missing. Earlier work showed that specific sea surface temperature (SST) patterns over the northern Pacific Ocean are precursors of high temperature events in the eastern United States, which might provide skillful forecasts at long leads (~50 days). However, the verification was based on a single skill metric, and a probabilistic forecast was missing. Here, we introduce a novel algorithm that objectively extracts robust precursors from SST linked to a binary target variable. When applied to reanalysis (ERA-5) and climate model data (EC-Earth), we identify robust precursors with the clearest links over the North Pacific. Different precursors are tested as input for a statistical model to forecast high temperature events. Using multiple skill metrics for verification, we show that daily high temperature events have no predictive skill at long leads. By systematically testing the influence of temporal and spatial aggregation, we find that noise in the target time series is an important bottleneck for predicting extreme events on S2S time scales. We show that skill can be increased by a combination of 1) aggregating spatially and/or temporally, 2) lowering the threshold of the target events to increase the base rate, or 3) adding additional variables containing predictive information (soil moisture). Exploiting these skill-enhancing factors, we obtain forecast skill for moderate heat waves (i.e., 2 or more hot days closely clustered together in time) with up to 50 days of lead time.
Half a Loaf for the Destitute
Authors: Lone Razi Allah , Zahid Adnan 
Published: October 2020

This case describes an ethical dilemma faced by an employee of an established business organization. Working in a business environment rife with unethical practices, Zafar came to believe that some of these practices were acceptable for the business to survive, particularly in the context of dysfunctional state institutions. Where he drew the line was when an act became detrimental to the interest of his organization. Also, he chose not to become directly involved in such practices. In his personal life, a cause close to his heart was helping the poor for which purpose, in addition to other things, he started a school for children of poor families in a low-income area with the help of a friend named Qasim. Funds were needed to run this school, which he generated from his income and through the support of his family and friends. He also convinced Qasim to secure business from his organization, ZSP, even if it required using commissions, and use the funds generated through this venture to further their charitable causes. The dilemma Zafar faced was when a company, FEP, contacted him to help it materialize a deal with ZSP in exchange for a handsome commission. Being a reputable name, FEP had all the ingredients of a valuable partner. While Zafar believed that taking a commission for a deal of this kind would not harm his organization, he could not bring himself to benefit from the financial gain personally. One way out was to utilize the funds for the poor children who attended his school. Refusing to take the commission would not have any impact on this practice since someone else in his organization would be quite willing to accept it. It would also mean the loss of a good opportunity to support an important cause. Zafar was unable to decide.
Minimally Invasive Lower Leg Fasciotomy for Chronic Exertional Compartment Syndrome—How Safe Is It? A Cadaveric Study
Authors: Grechenig Peter , Valsamis Epaminondas Markos , Müller Tom , Gänsslen Axel , Hohenberger Gloria 
Published: October 2020

Background: Chronic exertional compartment syndrome (CECS) is a recognized clinical diagnosis in running athletes and military recruits. Minimally invasive fasciotomy techniques have become increasingly popular, but with varied results and small case numbers. Although decompression of the anterior and peroneal compartments has demonstrated a low rate of iatrogenic injury, little is known about the safety of decompressing the deep posterior compartment. Purpose: To evaluate the risk of iatrogenic injury when using minimally invasive techniques to decompress the anterior, peroneal, and deep posterior compartments of the lower leg. Study Design: Descriptive laboratory study. Methods: A total of 60 lower extremities from 30 adult cadavers were subject to fasciotomy of the anterior, peroneal, and deep posterior compartments using a minimally invasive technique. Two common variations in surgical technique were employed to decompress each compartment. Anatomical dissection was subsequently carried out to identify incomplete division of the fascia, muscle injury, neurovascular injury, and the anatomical relationship of key neurovascular structures to the incisions. Results: Release of the anterior and peroneal compartments was successful in all but 2 specimens. There was no injury to the superficial peroneal nerve or any vessel in any specimen. A transverse incision crossing the anterior intermuscular septum resulted in muscle injury in 20% of the cases. Release of the deep posterior compartment was successful in all but 1 specimen when a longitudinal skin incision was used, without injury to neurovascular structures. Compared with a longitudinal incision, a transverse skin incision resulted in fewer complete releases of the deep posterior compartment and a significantly higher rate of injury to the saphenous nerve (16.7%; P = .052) and long saphenous vein (23.3%; P = .011). Conclusion: Minimally invasive fasciotomy of the anterior, peroneal, and deep posterior compartments using longitudinal incisions had a low rate of iatrogenic injury in a cadaveric model. Complete compartment release was achieved in 97% to 100% of specimens when employing this technique. Clinical Relevance: Minimally invasive fasciotomy techniques for CECS have become increasingly popular with purported low recurrence rates, improved cosmesis, and faster return to sport. It is important to determine whether this technique is safe, particularly given the variable rates of neurovascular injury reported in the literature.
Trends in mediastinal nodal staging and its impact on unforeseen N2 and survival in lung cancer
Authors: Bousema Jelle E. , Aarts Mieke J. , Dijkgraaf Marcel G.W. , Annema Jouke T. , van den Broek Frank J.C. 
Published: October 2020

IntroductionGuidelines for invasive mediastinal nodal staging in resectable nonsmall cell lung cancer (NSCLC) have changed over the years. The aims of this study were to describe trends in invasive staging and unforeseen N2 (uN2) and to assess a potential effect on overall survival.MethodsA nationwide Dutch cohort study included all clinical stage IA–IIIB NSCLC patients primarily treated by surgical resection between 2005 and 2017 (n=22 555). We assessed trends in invasive nodal staging (mediastinoscopy 2005–2017; endosonography 2011–2017), uN2 and overall survival and compared outcomes in the entire group and in clinical nodal stage (cN)1–3 patients with or without invasive staging.ResultsAn overall increase in invasive nodal staging from 26% in 2005 to 40% in 2017 was found (p<0.01). Endosonography increased from 19% in 2011 to 32% in 2017 (p<0.01), while mediastinoscopy decreased from 24% in 2011 to 21% in 2017 (p=0.08). Despite these changes, uN2 was stable over the years at 8.7%. 5-year overall survival rate was 41% for pN1 compared to 37% in single node uN2 (p=0.18) and 26% with more than one node uN2 (p<0.01). 5-year overall survival rate of patients with cN1–3 with invasive staging was 44%versus39% in patients without invasive staging (p=0.12).ConclusionA significant increase in invasive mediastinal nodal staging in patients with resectable NSCLC was found between 2011 and 2017 in the Netherlands. Increasing use of less invasive endosonography prior to (or as a substitute for) surgical staging did not lead to more cases of uN2. Performance of invasive staging indicated a possible overall survival benefit in patients with cN1–3 disease.
Response inhibition alterations in migraine: evidence from event-related potentials and evoked oscillations
Authors: Chen Guoliang , Li Yansong , Dong Zhao , Wang Rongfei , Zhao Dengfa , Obeso Ignacio , Yu Shengyuan 
Published: October 2020

Abstract
Background
Migraine is characterized by a hypersensitivity to environmental stimulation which climaxes during headache attacks but persists during attack-free period. Despite ongoing debates about the nature of the mechanisms giving rise to this abnormality, the presence of deficient inhibitory cortical processes has been proposed to be one possible mechanism underlying its pathogenesis. Empirical evidence supporting this claim is mainly based on previous accounts showing functional cortical disexcitability in the sensory domain. Considering that a general inhibitory control process can play an important role across early to later stage of information processing, this may indicate the important role other dimensions of inhibitory control can play in migraine disability. The present study examined the pathophysiological features of inhibitory control that takes place during suppression of prepotent responses in migraineurs.

Methods
Twenty-two patients with migraine without aura (mean age = 30.86 ± 5.69 years; 19 females) during the interictal period and 25 healthy controls (mean age = 30.24 ± 3.52 years; 18 females) were recruited. We used a stop signal task in combination with event-related potentials (ERPs) to examine participants’ neural activity supporting response inhibition.

Results
Behaviorally, migraineurs exhibited prolonged stop signal reaction times relative to healthy controls. At the neural level, the amplitude of the stop-N2 over fronto-central, central and centro-parietal scalp regions, a component of the ERPs related to conflict monitoring during early, non-motoric stages of inhibition, was significantly increased in migraineurs. Meanwhile, the amplitude of the stop-P3 over central and centro-parietal scalp regions, a component of the ERPs reflecting late-stage inhibition of the motor system and cognitive evaluation of motor inhibition, was also significantly increased in migraineurs. Ultimately, our time-frequency analysis further revealed increased delta activity in migraineurs.

Conclusions
Consistent with the theory that alterations in cognitive cortical processes are a key signature of migraine, our findings revealed an abnormal state of suppressing prepotent responses in migraineurs, which can be attributed to cortical disexcitability of the pre-frontal executive network and centro-parietal sensorimotor network. These novel findings extend to show the existence of dysfunctional inhibition control that occurs during suppression of prepotent responses in migraneurs.
Peritumoral ductular reaction can be a prognostic factor for intrahepatic cholangiocarcinoma
Authors: Shen Zhenyang , Xiao Jingbo , Wang Junjun , Lu Lungen , Wan Xinjian , Cai Xiaobo 
Published: October 2020

AbstractBackgroundPeritumoral ductular reaction (DR) was reported to be related to the prognosis of combined hepatocellular-cholangiocarcinoma and hepatocellular carcinoma. Non-mucin-producing intrahepatic cholangiocarcinoma (ICC) which may be derived from small bile duct cells or liver progenitor cells (LPCs) was known to us. However, whether peritumoral DR is also related to non-mucin-producing ICCs remains to be investigated.MethodsForty-seven patients with non-mucin-producing ICC were eventually included in the study and clinicopathological variables were collected. Immunohistochemical analysis and immunofluorescence staining for cytokeratin 19, proliferating cell nuclear antigen, and α-smooth muscle actin were performed in tumor and peritumor liver tissues.ResultsA significant correlation existed between peritumoral DR and local inflammation and fibrosis. (r = 0.357, 95% CI, 0.037–0.557;P = 0.008 andr = 0.742, 95% CI, 0.580–0.849;P < 0.001, respectively). Patients with obvious peritumoral DR had high recurrence rate (81.8% vs 56.0%,P = 0.058) and poor overall and disease-free survival time (P = 0.01 andP = 0.03, respectively) comparing with mild peritumoral DR. Compared with the mild peritumoral DR group, the proliferation activity of LPCs/ cholangiocytes was higher in obvious peritumoral DR, which, however, was not statistically significant. (0.43 ± 0.29 vs 0.28 ± 0.31,P = 0.172). Furthermore, the correlation analysis showed that the DR grade was positively related to the portal/septalα-SMA level (r = 0.359,P = 0.001).ConclusionsPeritumoral DR was associated with local inflammation and fibrosis. Patients with non-mucin-producing ICC having obvious peritumoral DR had a poor prognosis. Peritumoral DR could be a prognostic factor for ICC. However, the mechanism should be further investigated.
Inflammatory phenotyping predicts clinical outcome in COVID-19
Authors: Burke H. , Freeman A. , Cellura D. C. , Stuart B. L. , Brendish N. J. , Poole S. , Borca F. , Phan H. T. T. , Sheard N. , Williams S. , Spalluto C. M. , Staples K. J. , Clark T. W. , Wilkinson T. M. A. ,   on behalf of the REACT COVID investigators, Wilkinson Tom , Freeman Anna , Burke Hannah , Dushianthan Ahilanadan , Celinski Michael , Batchelor James , Faust Saul N. , Thomas Gareth , Kipps Christopher 
Published: October 2020

Abstract
Background
The COVID-19 pandemic has led to more than 760,000 deaths worldwide (correct as of 16th August 2020). Studies suggest a hyperinflammatory response is a major cause of disease severity and death. Identitfying COVID-19 patients with hyperinflammation may identify subgroups who could benefit from targeted immunomodulatory treatments. Analysis of cytokine levels at the point of diagnosis of SARS-CoV-2 infection can identify patients at risk of deterioration.

Methods
We used a multiplex cytokine assay to measure serum IL-6, IL-8, TNF, IL-1β, GM-CSF, IL-10, IL-33 and IFN-γ in 100 hospitalised patients with confirmed COVID-19 at admission to University Hospital Southampton (UK). Demographic, clinical and outcome data were collected for analysis.

Results
Age > 70 years was the strongest predictor of death (OR 28, 95% CI 5.94, 139.45). IL-6, IL-8, TNF, IL-1β and IL-33 were significantly associated with adverse outcome. Clinical parameters were predictive of poor outcome (AUROC 0.71), addition of a combined cytokine panel significantly improved the predictability (AUROC 0.85). In those ≤70 years, IL-33 and TNF were predictive of poor outcome (AUROC 0.83 and 0.84), addition of a combined cytokine panel demonstrated greater predictability of poor outcome than clinical parameters alone (AUROC 0.92 vs 0.77).

Conclusions
A combined cytokine panel improves the accuracy of the predictive value for adverse outcome beyond standard clinical data alone. Identification of specific cytokines may help to stratify patients towards trials of specific immunomodulatory treatments to improve outcomes in COVID-19.