bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intranasal epinephrine effects on epinephrine pharmacokinetics and heart rate in a nasal congestion canine model
Authors: Tuttle Richard , Popescu Luca , Hill Scott , Slanczka Amber , Jankowski Jeffrey , Barre Katherine , Krueger Erika , Slade Desmond , Croutch Claire , Robben Matthew , Mesa Zack , Mesa Michael , Dretchen Kenneth L. 
Published: April 2020

Abstract
Background
Histamine release and vasodilation during an allergic reaction can alter the pharmacokinetics of drugs administered via the intranasal (IN) route. The current study evaluated the effects of histamine-induced nasal congestion on epinephrine pharmacokinetics and heart rate changes after IN epinephrine.

Methods
Dogs received 5% histamine or saline IN followed by 4 mg epinephrine IN. Nasal restriction pressure, epinephrine concentration, and heart rate were assessed. Maximum concentration (Cmax), area under plasma concentration-time curve from 1 to 90 min (AUC1–90), and time to reach Cmax (Tmax) were measured. Clinical observations were documented.

Results
In the 12 dogs in this study, nasal congestion occurred at 5–10 min after IN histamine administration versus no nasal congestion after IN saline. After administration of IN epinephrine, IN histamine-mediated nasal congestion was significantly reduced to baseline levels at 60, 80, and 100 min. There were no significant differences in Cmax and AUC1–90 between histamine and saline groups after IN epinephrine delivery (3.5 vs 1.7 ng/mL, p = 0.06, and 117 vs 59 ng/mL*minutes, p = 0.09, respectively). After receiving IN epinephrine, the histamine group had a significantly lower Tmax versus the saline group (6 vs 70 min, respectively; p = 0.02). Following IN epinephrine administration, the histamine group showed rapidly increased heart rate at 5 min, while there was a delayed increase in heart rate (occurring 30–60 min after administration) in the saline group. Clinical observations included salivation and emesis.

Conclusion
IN histamine led to more rapid epinephrine absorption and immediately increased heart rate compared with IN saline. IN epinephrine decreased histamine-induced nasal congestion.
Incarcerated Aboriginal women’s experiences of accessing healthcare and the limitations of the ‘equal treatment’ principle
Authors: Kendall S. , Lighton S. , Sherwood J. , Baldry E. , Sullivan E. A. 
Published: April 2020

AbstractBackgroundColonization continues in Australia, sustained through institutional and systemic racism. Targeted discrimination and intergenerational trauma have undermined the health and wellbeing of Australia’s Aboriginal and Torres Strait Islander population, leading to significantly poorer health status, social impoverishment and inequity resulting in the over-representation of Aboriginal people in Australian prisons. Despite adoption of the ‘equal treatment’ principle, on entering prison in Australia entitlements to the national universal healthcare system are revoked and Aboriginal people lose access to health services modelled on Aboriginal concepts of culturally safe healthcare available in the community. Incarcerated Aboriginal women experience poorer health outcomes than incarcerated non-Indigenous women and Aboriginal men, yet little is known about their experiences of accessing healthcare. We report the findings of the largest qualitative study with incarcerated Aboriginal women in New South Wales (NSW) Australia in over 15 years.MethodsWe employed a decolonizing research methodology, ‘community collaborative participatory action research’, involving consultation with Aboriginal communities prior to the study and establishment of a Project Advisory Group (PAG) of community expert Aboriginal women to guide the project. Forty-three semi-structured interviews were conducted in 2013 with Aboriginal women in urban and regional prisons in NSW. We applied a grounded theory approach for the data analysis with guidance from the PAG.ResultsWhilst Aboriginal women reported positive and negative experiences of prison healthcare, the custodial system created numerous barriers to accessing healthcare. Aboriginal women experienced institutional racism and discrimination in the form of not being listened to, stereotyping, and inequitable healthcare compared with non-Indigenous women in prison and the community.Conclusions‘Equal treatment’ is an inappropriate strategy for providing equitable healthcare, which is required because incarcerated Aboriginal women experience significantly poorer health. Taking a decolonizing approach, we unpack and demonstrate the systems level changes needed to make health and justice agencies culturally relevant and safe. This requires further acknowledgment of the oppressive transgenerational effects of ongoing colonial policy, a true embracing of diversity of worldviews, and critically the integration of Aboriginal concepts of health at all organizational levels to uphold Aboriginal women’s rights to culturally safe healthcare in prison and the community.
m6A-dependent glycolysis enhances colorectal cancer progression
Authors: Shen Chaoqin , Xuan Baoqin , Yan Tingting , Ma Yanru , Xu Pingping , Tian Xianglong , Zhang Xinyu , Cao Yingying , Ma Dan , Zhu Xiaoqiang , Zhang Youwei , Fang Jing-Yuan , Chen Haoyan , Hong Jie 
Published: April 2020

Abstract
Background
Epigenetic alterations are involved in various aspects of colorectal carcinogenesis. N6-methyladenosine (m6A) modifications of RNAs are emerging as a new layer of epigenetic regulation. As the most abundant chemical modification of eukaryotic mRNA, m6A is essential for the regulation of mRNA stability, splicing, and translation. Alterations of m6A regulatory genes play important roles in the pathogenesis of a variety of human diseases. However, whether this mRNA modification participates in the glucose metabolism of colorectal cancer (CRC) remains uncharacterized.

Methods
Transcriptome-sequencing and liquid chromatography-tandem mass spectrometry (LC-MS) were performed to evaluate the correlation between m6A modifications and glucose metabolism in CRC. Mass spectrometric metabolomics analysis, in vitro and in vivo experiments were conducted to investigate the effects of METTL3 on CRC glycolysis and tumorigenesis. RNA MeRIP-sequencing, immunoprecipitation and RNA stability assay were used to explore the molecular mechanism of METTL3 in CRC.

Results
A strong correlation between METTL3 and 18F-FDG uptake was observed in CRC patients from Xuzhou Central Hospital. METTL3 induced-CRC tumorigenesis depends on cell glycolysis in multiple CRC models. Mechanistically, METTL3 directly interacted with the 5′/3’UTR regions of HK2, and the 3’UTR region of SLC2A1 (GLUT1), then further stabilized these two genes and activated the glycolysis pathway. M6A-mediated HK2 and SLC2A1 (GLUT1) stabilization relied on the m6A reader IGF2BP2 or IGF2BP2/3, respectively.

Conclusions
METTL3 is a functional and clinical oncogene in CRC. METTL3 stabilizes HK2 and SLC2A1 (GLUT1) expression in CRC through an m6A-IGF2BP2/3- dependent mechanism. Targeting METTL3 and its pathway offer alternative rational therapeutic targets in CRC patients with high glucose metabolism.
Evidence for measurement bias of the short form health survey based on sex and metropolitan influence zone in a secondary care population
Authors: Ursenbach Jake , O’Connell Megan E. , Kirk Andrew , Morgan Debra 
Published: April 2020

Abstract
Background and objectives
The 12-item Short Form Health Survey (SF-12) is a widely used measure of health related quality of life, but has been criticized for lacking an empirically supported model and producing biased estimates of mental and physical health status for some groups. We explored a model of measurement with the SF-12 and explored evidence for measurement invariance of the SF-12.

Research design and methods
The SF-12 was completed by 429 caregivers who accompanied patients with cognitive concerns to a memory clinic designed to service rural/remote-dwelling individuals. A multi-group confirmatory factor analysis was used to compare the theoretical measurement model to two empirically identified factor models reported previously in general population studies.

Results
A model that allowed mental and physical health to correlate, and some items to cross-load provided the best fit to the data. Using that model, measurement invariance was then assessed across sex and metropolitan influence zone (MIZ; a standardized measure of degree of rurality).

Discussion
Partial scalar invariance was demonstrated in both analyses. Differences by sex in latent item intercepts were found for items assessing feelings of energy and depression. Differences by MIZ in latent item intercepts were found for an item concerning how current health limits activities.

Implications
The fitting model was one where the mental and physical health subscales were correlated, which is not provided in the scoring program offered by the publishers. Participants’ sex and MIZ should be accounted for when comparing their factor scores on the SF-12. Additionally, consideration of geographic residence and associated cultural influences is recommended in future development and use of psychological measures with such populations.
Identification of a selective inhibitor of IDH2/R140Q enzyme that induces cellular differentiation in leukemia cells
Authors: Chen Jiao , Yang Jie , Wei Qingyun , Weng Ling , Wu Fei , Shi Yun , Cheng Xiaolan , Cai Xueting , Hu Chunping , Cao Peng 
Published: April 2020

Abstract
Background
IDH2/R140Q mutation is frequently detected in acute myeloid leukemia (AML). It contributes to leukemia via accumulation of oncometabolite D-2-HG. Therefore, mutant IDH2 is a promising target for AML. Discovery of IDH2 mutant inhibitors is in urgent need for AML therapy.

Methods
Structure-based in silico screening and enzymatic assays were used to identify IDH2/R140Q inhibitors. Molecular docking, mutant structure building and molecular dynamics simulations were applied to investigate the inhibitory mechanism and selectivity of CP-17 on IDH2/R140Q. TF-1 cells overexpressed IDH2/R140Q mutant were used to study the effects of CP-17 on cellular proliferation and differentiation, the wild-type TF-1 cells were used as control. The intracellular D-2-HG production was measured by LC-MS. The histone methylation was evaluated with specific antibodies by western blot.

Results
CP-17, a heterocyclic urea amide compound, was identified as a potent inhibitor of IDH2/R140Q mutant by in silico screening and enzymatic assay. It exhibits excellent inhibitory activity with IC50 of 40.75 nM against IDH2/R140Q. More importantly, it shows poor activity against the wild-type IDH1/2, resulting in a high selectivity of over 55 folds, a dramatic improvement over previously developed inhibitors such as AGI-6780 and Enasidenib. Molecular simulations suggested that CP-17 binds to IDH2/R140Q at the allosteric site within the dimer interface through extensive polar and hydrophobic interactions, locking the enzyme active sites in open conformations with abolished activity to produce D-2-HG. Cellular assay results demonstrated that CP-17 inhibits intracellular D-2-HG production and suppresses the proliferation of TF-1 erythroleukemia cells carrying IDH2/R140Q mutant. Further, CP-17 also restores the EPO-induced differentiation that is blocked by the mutation and decreases hypermethylation of histone in the TF-1(IDH2/R140Q) cells.

Conclusions
These results indicate that CP-17 can serve as a lead compound for the development of inhibitory drugs against AML with IDH2/R140Q mutant.
Towards individualized cortical thickness assessment for clinical routine
Authors: Tahedl Marlene 
Published: April 2020

Abstract
Background
Cortical thickness measures the width of gray matter of the human cortex. It can be calculated from T1-weighted magnetic resonance images (MRI). In group studies, this measure has been shown to correlate with the diagnosis/prognosis of a number of neurologic and psychiatric conditions, but has not been widely adapted for clinical routine. One of the reasons for this might be that there is no reference system which allows to rate individual cortical thickness data with respect to a control population.

Methods
To address this problem, this study compared different methods to assess statistical significance of cortical thinning, i.e. atrophy. All compared methods were nonparametric and encompassed rating an individual subject’s data set with respect to a control data population. Null distributions were calculated using data from the Human Connectome Project (HCP, n = 1000), and an additional HCP data set (n = 113) was used to calculate sensitivity and specificity to compare the different methods, whereas atrophy was simulated for sensitivity assessment. Validation measures were calculated for the entire cortex (“cumulative”) and distinct brain regions (“regional”) where possible.

Results
The approach yielding the highest combination of specificity and sensitivity implemented generating null distributions for anatomically distinct brain regions, based on the most extreme values observed in the population. With that method, while regional variations were observed, cumulative specificity of 98.9% and cumulative sensitivity at 80% was achieved for simulated atrophy of 23%.

Conclusions
This study shows that validated rating of individual cortical thickness measures is possible, which can help clinicians in their daily routine to discover signs of atrophy before they become visually apparent on an unprocessed MRI. Furthermore, given different pathologies present with distinct atrophy patterns, the regional validation proposed here allows to detect distinct patterns of atrophy, which can further enhance differential diagnosis/prognosis.
Relationship between postoperative lordosis distribution index and adjacent segment disease following L4-S1 posterior lumbar interbody fusion
Authors: Zheng Guoquan , Wang Chunguo , Wang Tianhao , Hu Wenhao , Ji Quanbo , Hu Fanqi , Li Jianrui , Chaudhary Surendra K. , Song Kai , Song Diyu , Zhang Zhifa , Hao Yongyu , Wang Yao , Li Jing , Zheng Qingyuan , Zhang Xuesong , Wang Yan 
Published: April 2020

Abstract
Background
Adjacent segment disease (ASD) is an acknowledged problem of posterior lumbar interbody fusion (PLIF). Many studies have been reported concerning the role of lordosis distribution index (LDI) in spinal biomechanics. However, few reports have been published about the impact of LDI on ASD following L4-S1 PLIF.

Methods
The study enrolled 200 subjects who underwent L4-S1 PLIF for degenerative spine disease from 2009 to 2014. The average follow-up term was 84 months. Several lower lumbar parameters were measured, including lower lumbar lordosis (LLL), lumbar lordosis (LL), pelvic incidence (PI), and LDI on the pre and postoperative radiograph. Perioperative information, comorbidities, and operative data were documented. Kaplan-Meier curves were plotted for the comparisons of ASD-free survival of 3 different types of postoperative LDI subgroups.

Results
The incidence of ASD was found to be 8.5%. LL and LLL increased by 3.96° (38.71° vs 42.67°; P < 0.001) and 3.60° (26.22° vs 28.82°; P < 0.001) after lower lumbar fusion surgery, respectively. Lordosis distribution index (LDI) increased by 0.03 (0.66 vs 0.69, P = 0.004) postoperatively. A significant difference (P = 0.001) was observed when comparing the incidence of ASD among postoperative LDI subgroups. The Kaplan-Meier curves showed a marked difference in ASD-free survival between low and moderate LDI subgroup (log-rank test, P = 0.0012) and high and moderate LDI subgroup (log-rank test, P = 0.0005).

Conclusion
Patients with abnormal postoperative LDI were statistically more likely to develop ASD than those who had normal postoperative LDI. Moreover, patients with low postoperative LDI were at greater risk for developing ASD than those with high postoperative LDI over time.
Next-generation immuno-oncology agents: current momentum shifts in cancer immunotherapy
Authors: Pan Chongxian , Liu Hongtao , Robins Elizabeth , Song Wenru , Liu Delong , Li Zihai , Zheng Lei 
Published: April 2020

AbstractCancer immunotherapy has reached a critical point, now that immune checkpoint inhibitors and two CAR-T products have received market approval in treating 16 types of cancers and 1 tissue-agnostic cancer indication. Accompanying these advances, the 2018 Nobel Prize was awarded for the discovery of immune checkpoint pathways, which has led to the revolution of anti-cancer treatments. However, expanding the indications of immuno-oncology agents and overcoming treatment resistance face mounting challenges. Although combination immunotherapy is an obvious strategy to pursue, the fact that there have been more failures than successes in this effort has served as a wake-up call, placing emphasis on the importance of building a solid scientific foundation for the development of next-generation immuno-oncology (IO) agents. The 2019 China Cancer Immunotherapy Workshop was held to discuss the current challenges and opportunities in IO. At this conference, emerging concepts and strategies for IO development were proposed, focusing squarely on correcting the immunological defects in the tumor microenvironment. New targets such as Siglec-15 and new directions including neoantigens, cancer vaccines, oncolytic viruses, and cytokines were reviewed. Emerging immunotherapies were discussed in the areas of overcoming primary and secondary resistance to existing immune checkpoint inhibitors, activating effector cells, and targeting immunosuppressive mechanisms in the tumor microenvironment. In this article, we highlight old and new waves of IO therapy development, and provide perspectives on the latest momentum shifts in cancer immunotherapy.
Template for documenting and reporting data in physician-staffed pre-hospital services: a consensus-based update
Authors:   the P-EMS Template Collaborating Group, Tønsager Kristin , Krüger Andreas Jørstad , Ringdal Kjetil Gorseth , Rehn Marius 
Published: April 2020

AbstractBackgroundPhysician-staffed emergency medical services (p-EMS) are resource demanding, and research is needed to evaluate any potential effects of p-EMS. Templates, designed through expert agreement, are valuable and feasible, but they need to be updated on a regular basis due to developments in available equipment and treatment options. In 2011, a consensus-based template documenting and reporting data in p-EMS was published. We aimed to revise and update the template for documenting and reporting in p-EMS.MethodsA Delphi method was applied to achieve a consensus from a panel of selected European experts. The experts were blinded to each other until a consensus was reached, and all responses were anonymized. The experts were asked to propose variables within five predefined sections. There was also an optional sixth section for variables that did not fit into the pre-defined sections. Experts were asked to review and rate all variables from 1 (totally disagree) to 5 (totally agree) based on relevance, and consensus was defined as variables rated ≥4 by more than 70% of the experts.ResultsEleven experts participated. The experts generated 194 unique variables in the first round. After five rounds, a consensus was reached. The updated dataset was an expanded version of the original dataset and the template was expanded from 45 to 73 main variables. The experts approved the final version of the template.ConclusionsUsing a Delphi method, we have updated the template for documenting and reporting in p-EMS. We recommend implementing the dataset for standard reporting in p-EMS.
Robotic radical antegrade modular pancreatosplenectomy (RAMPS) versus standard retrograde pancreatosplenectomy (SRPS): study protocol for a randomized controlled trial
Authors: Zhang Gong , Kang Yuhao , Zhang Haifeng , Wang Fei , Liu Rong 
Published: April 2020

Abstract
Background
Data from meta-analysis suggest that robotic radical antegrade modular pancreatosplenectomy (RAMPS) is a safe and effective procedure for treating adenocarcinoma in the body or tail of the pancreas, and is oncologically superior to standard retrograde pancreatosplenectomy (SRPS). RAMPS is an operation that actively expands the scope of resection, and achieves a higher R0 resection rate and lymph nodes acquisition through expanded resection. However, previous studies on RAMPS were conducted under open and laparoscopic surgery. Robotic surgery, on the other hand, plays a role in ergonomics and offers several advantages, including less fatigue, tremor filtering, 7° of wrist-like motion, motion scaling, and three-dimensional vision. At present, there is still a world-wide lack of clinical studies to observe the safety and clinical efficacy of robotic RAMPS. Hence, prospective randomized controlled trials (RCTs) comparing robotic RAMPS and SRPS are required. We begin an RCT to compare short-term surgical and oncological outcomes of robotic RAMPS and SRPS in patients undergoing distal pancreatectomy.

Methods
This is a randomized, single-center clinical trial. All participants are adult patients with primary pancreatic cancer, who are undergoing RAMPS or SRPS. The primary endpoints are R0 rate (resection margins are classified by a margin to tumor distance ≥ 1 mm). The secondary endpoints are the number of harvested lymph nodes, perioperative complications and perioperative indicators (duration of surgery, blood loss, blood transfusion volume, costs).

Discussion
We are undertaking a prospective RCT to evaluate the surgical and oncological outcomes of robotic RAMPS. This procedure may become a standard approach to robotic pancreatosplenectomy.

Trial registration
Chinese Clinical Trial Registry: ChiCTR1900020833, Registered on 20 January 2019.
The relation between physical joint examination and MRI-depicted inflammation of metatarsophalangeal joints in early arthritis
Authors: Dakkak Yousra J. , Boer Aleid C. , Boeters Debbie M. , Niemantsverdriet Ellis , Reijnierse Monique , van der Helm-van Mil Annette H. M. 
Published: April 2020

AbstractBackgroundThe relationship between physical joint examination (PE) and MRI-detected inflammation in early inflammatory arthritis has mostly been studied in the hands. Physical examination of MTP joints is considered difficult, and for these joints, this relationship is unknown. Therefore, we studied the concordance of PE with MRI inflammation in MTP joints. Metacarpophalangeal (MCP) joints were included for comparison.MethodsOne thousand seven hundred fifty-nine MTP(2–5) and 1750 MCP(2–5) joints of 441 consecutive patients with early arthritis underwent PE (for joint swelling) and MRI, all evaluated by two assessors. MRI was scored for synovitis, tenosynovitis, and osteitis (summed MRI inflammation). Synovial intermetatarsal bursae may enlarge upon inflammation and become palpable and were therefore also assessed. Analyses (frequencies, GEE) were performed on joint level.ResultsPE and MRI were concordant in 79% of MTP joints. Of 1606 non-swollen MTP joints, 83% showed no MRI inflammation and 17% showed subclinical MRI inflammation. Of 153 swollen MTP joints, 48% had MRI inflammation and 52% (79 MTP joints) did not. Of these 79 swollen MTP joints without MRI inflammation, 31 showed intermetatarsal bursitis and 48 joints had none of these MRI abnormalities (this concerned 31% of swollen MTP joints). MTP swelling was statistically independently associated with tenosynovitis (OR 2.21, 95% CI 1.1–4.3) and intermetatarsal bursitis (OR 2.91, 95% CI 1.8–4.8).MTP joints showed subclinical inflammation less often than MCP joints (17% vs. 34%,P < 0.001). Swollen MTP joints showed MRI inflammation less often than swollen MCP joints (48% vs. 88%,P < 0.001).ConclusionsThe absence of swelling of MTP joints in early arthritis is mostly accompanied by the absence of MRI-detected inflammation. Swollen MTP joints are, in addition to synovitis, also explained by tenosynovitis and intermetatarsal bursitis and partly unexplained by MRI. Their clinical relevance must be determined in longitudinal studies.