bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of increasing dialysate magnesium on calciprotein particles, inflammation and bone markers: post hoc analysis from a randomized controlled clinical trial
Authors: Bressendorff Iain , Hansen Ditte , Pasch Andreas , Holt Stephen G , Schou Morten , Brandi Lisbet , Smith Edward R 
Published: October 2019

Abstract

Background
The formation of calciprotein particles (CPPs) may be an important component of the humoral defences against ectopic calcification. Although magnesium (Mg) has been shown to delay the transition of amorphous calcium-/phosphate-containing primary CPP (CPP-1) to crystalline apatite-containing secondary CPP (CPP-2) ex vivo, effects on the endogenous CPP pool are unknown.

Methods
We used post hoc analyses from a randomized double-blind parallel-group controlled clinical trial of 28 days treatment with high dialysate Mg of 2.0 mEq/L versus standard dialysate Mg of 1.0 mEq/L in 57 subjects undergoing maintenance hemodialysis for end-stage kidney disease. CPP load, markers of systemic inflammation and bone turnover were measured at baseline and follow-up.

Results
After 28 days of treatment with high dialysate Mg, serum total CPP (−52%), CPP-1 (−42%) and CPP-2 (−68%) were lower in the high Mg group (all P &lt; 0.001) but were unchanged in the standard dialysate Mg group. Tumour necrosis factor-α (−20%) and interleukin-6 (−22%) were also reduced with high dialysate Mg treatment (both P &lt; 0.01). High dialysate Mg resulted in higher levels of bone-specific alkaline phosphatase (a marker of bone formation) (+17%) but lower levels of tartrate-resistant acid phosphatase 5 b (a marker of bone resorption; −33%) (both P &lt; 0.01). Inflammatory cytokines and bone turnover markers were unchanged in the standard dialysate Mg group over the same period.

Conclusions
In this exploratory analysis, increasing dialysate Mg was associated with reduced CPP load and systemic inflammation and divergent changes in markers of bone formation and resorption.
GRP94 promotes brain metastasis by engaging pro-survival autophagy
Authors: Santana-Codina Naiara , Muixí Laia , Foj Ruben , Sanz-Pamplona Rebeca , Badia-Villanueva Miriam , Abramowicz Agata , Marcé-Grau Anna , Cosialls Ana María , Gil Joan , Archilla Ivan , Pedrosa Leire , Gonzalez Josep , Aldecoa Iban , Sierra Angels 
Published: October 2019

Abstract

Background
GRP94 is a glucose-regulated protein critical for survival in endoplasmic reticulum stress. Expression of GRP94 is associated with cellular transformation and increased tumorigenicity in breast cancer. Specifically, overexpression of GRP94 predicts brain metastasis (BM) in breast carcinoma patients with either triple negative or ErbB2 positive tumors. The aim of this study was to understand if microenvironmental regulation of GRP94 expression might be a hinge orchestrating BM progression.

Methods
GRP94 ablation was performed in a BM model BR-eGFP-CMV/Luc-V5CA1 (BRV5CA1) of breast cancer. In vitro results were validated in a dataset of 29 metastases in diverse organs from human breast carcinomas and in BM tissue from tumors of different primary origin. BM patient-derived xenografts (PDXs) were used to test sensitivity to the therapeutic approach.

Results
BMs that overexpress GRP94 as well as tumor necrosis factor receptor-associated factor 2 are more resistant to glucose deprivation by induction of anti-apoptotic proteins (B-cell lymphoma 2 and inhibitors of apoptosis proteins) and engagement of pro-survival autophagy. GRP94 ablation downregulated autophagy in tumor cells, resulting in increased BM survival in vivo. These results were validated in a metastasis dataset from human patients, suggesting that targeting autophagy might be strategic for BM prevention. Indeed, hydroxychloroquine treatment of preclinical models of BM from PDX exerts preventive inhibition of tumor growth (P &lt; 0.001).

Conclusions
We show that GRP94 is directly implicated in BM establishment by activating pro-survival autophagy. Disruption of this compensatory fueling route might prevent metastatic growth.
High-Frequency Spinal Cord Stimulation at 10 kHz for the Treatment of Combined Neck and Arm Pain: Results From a Prospective Multicenter Study
Authors: Amirdelfan Kasra , Vallejo Ricardo , Benyamin Ramsin , Yu Cong , Yang Thomas , Bundschu Richard , Yearwood Thomas L , Sitzman B Todd , Gliner Bradford , Subbaroyan Jeyakumar , Rotte Anand , Caraway David 
Published: October 2019

Abstract

BACKGROUND
Intractable neck and upper limb pain has historically been challenging to treat with conventional spinal cord stimulation (SCS) being limited by obtaining effective paresthesia coverage.

OBJECTIVE
To assess the safety and effectiveness of the 10-kHz SCS system, a paresthesia-independent therapy, in the treatment of neck and upper limb pain.

METHODS
Subjects with chronic, intractable neck and/or upper limb pain of ≥5 cm (on a 0-10 cm visual analog scale [VAS]) were enrolled in 6 US centers following an investigational device exemption from the Food and Drug Administration (FDA) and institutional review board approval. Each subject was implanted with 2 epidural leads spanning C2-C6 vertebral bodies. Subjects with successful trial stimulation were implanted with a Senza® system (Nevro Corp) and included in the evaluation of the primary safety and effectiveness endpoints.

RESULTS
In the per protocol population, the primary endpoint (≥50% pain relief at 3 mo) was achieved in 86.7% (n = 39/45) subjects. Compared to baseline, subjects reported a significant reduction (P < .001) in their mean (± standard error of the mean) VAS scores at 12-mo assessment for neck pain (7.6 ± 0.2 cm, n = 42 vs 1.5 ± 0.3 cm, n = 37) and upper limb pain (7.1 ± 0.3 cm, n = 24 vs 1.0 ± 0.2 cm, n = 20). At 12-mo assessment, 89.2% of subjects with neck pain and 95.0% with upper limb pain had ≥50% pain relief from baseline, 95.0% reported to be “satisfied/very satisfied” and 30.0% either eliminated or reduced their opioid intake.

CONCLUSION
In conclusion, 10-kHz SCS can treat intractable neck and upper limb pain with stable long-term outcomes.
OVERVIEW OF AIRCREW EXPOSURE TO COSMIC RADIATION IN THE CZECH REPUBLIC
Authors: Kubančák Ján , Kyselová Dagmar , Kovář Ivan , Hlaváčová Magdaléna , Langer Ronald , Strhársky Igor , Kudela Karel , Davídková Marie , Ploc Ondřej 
Published: October 2019

Abstract
Monitoring of exposures of aircrew members of airline operators registered in the Czech Republic has been performed since 1998. The individual effective doses are calculated using the computer code CARI annually. The calculations are based on information about participation of aircrew members on the specific flights and on the parameters describing the typical flight profiles of the flights; the latter is regularly verified with control measurements performed onboard aircraft. The results show that (1) the average annual effective doses in the period from 1998 to 2017 range from 1.3 to 2.1 mSv, (2) the maximum effective dose of a crew member is 5.7 mSv and (3) the annual collective effective doses range from 1.3 to 4.1 manSv. Combined relative uncertainty of the results is ~25%.
CAR-BORNE SURVEY OF NATURAL BACKGROUND GAMMA RADIATION IN WESTERN, EASTERN AND SOUTHERN THAILAND
Authors: Kranrod Chutima , Chanyotha Supitcha , Pengvanich Phongphaegh , Kritsananuwat Rawiwan , Ploykrathok Thamaborn , Sriploy Phongyut , Hosoda Masahiro , Tokonami Shinji 
Published: October 2019

Abstract
Natural background gamma radiation was measured along the main roads in the eastern, western and southern regions of Thailand using a car-borne survey system with a 3-in × 3-in NaI (Tl) scintillation spectrometer. The system was able to quickly survey a large area and obtain outdoor absorbed dose rate in air from a gamma ray pulse height distribution. A total of 19 219 data of the outdoor absorbed dose rate in air were collected. The average outdoor absorbed dose rate in air in the eastern, western and southern regions were found to be 8–127, 16–119 and 16–141 nGy h -1 , respectively. The highest outdoor absorbed dose rate in air was detected in the southern region of Thailand. The corresponding average outdoor annual effective dose to the public ranged from 11.7 to 80.8 μSv.
Evaluation of the abuse potential of pitolisant, a selective H3-receptor antagonist/inverse agonist, for the treatment of adult patients with narcolepsy with or without cataplexy
Authors: Setnik Beatrice , McDonnell Michael , Mills Catherine , Scart-Grès Catherine , Robert Philippe , Dayno Jeffrey M , Schwartz Jean-Charles 
Published: October 2019

Abstract

Objectives
To evaluate the human abuse potential of pitolisant, a selective histamine 3 (H3)-receptor antagonist/inverse agonist recently approved by the US Food and Drug Administration for the treatment of excessive daytime sleepiness in adult patients with narcolepsy.

Methods
Nondependent, recreational stimulant users able to distinguish phentermine HCl 60 mg from placebo in a drug discrimination test were randomized in a four-period, double-blind, crossover design to receive single doses of pitolisant 35.6 mg (therapeutic dose), pitolisant 213.6 mg (supratherapeutic dose), phentermine HCl 60 mg, and placebo. The primary endpoint was maximum effect (Emax) on the 100-point Drug Liking (“at this moment”) visual analog scale.

Results
In 38 study completers (73.7% male; 65.8% white; mean age, 33.3 years), mean Drug Liking Emax was significantly greater for phentermine versus pitolisant 35.6 mg (mean difference, 21.4; p &lt; 0.0001) and pitolisant 213.6 mg (mean difference, 19.7; p &lt; 0.0001). Drug Liking Emax was similar for pitolisant (both doses) and placebo. Similarly, for key secondary measures of Overall Drug Liking and willingness to Take Drug Again, mean Emax scores were significantly greater for phentermine versus pitolisant (both doses) and similar for pitolisant (both doses) versus placebo. The incidence of adverse events was 82.1% after phentermine HCl 60 mg, 72.5% after pitolisant 213.6 mg, 47.5% after pitolisant 35.6 mg, and 48.8% after placebo administration.

Conclusions
In this study, pitolisant demonstrated significantly lower potential for abuse compared with phentermine and an overall profile similar to placebo; this suggests a low risk of abuse for pitolisant.

Clinical Trial Registration
ClinicalTrials.gov NCT03152123. Determination of the abuse potential of pitolisant in healthy, nondependent recreational stimulant users. https://clinicaltrials.gov/ct2/show/NCT03152123.
A Bolus Dose of Ketamine Reduces the Amplitude of the Transcranial Electrical Motor-evoked Potential: A Randomized, Double-blinded, Placebo-controlled Study
Authors: Furutani Kenta , Deguchi Hiroyuki , Matsuhashi Mari , Mitsuma Yusuke , Kamiya Yoshinori , Baba Hiroshi 
Published: October 2019

Background:
A low-dose bolus or infusion of ketamine does not affect transcranial electrical motor-evoked potential (MEP) amplitude, but a dose ≥1 mg/kg may reduce MEP amplitude. We conducted a randomized, double-blinded, placebo-controlled study to evaluate the effect of ketamine (1 mg/kg) on transcranial electrical MEP.

Methods:
Twenty female patients (aged 12 to 18 y) with adolescent idiopathic scoliosis scheduled to undergo posterior spinal fusion were randomly allocated to receive ketamine or saline. General anesthesia was induced and maintained with continuous infusions of propofol and remifentanil. MEP was elicited by supramaximal transcranial electrical stimulation. MEP recordings were obtained at baseline and then at 2, 4, 6, 8, and 10 minutes after administration of ketamine (1 mg/kg) or saline (0.1 ml/kg). The primary endpoint was the minimum relative MEP amplitude (peak-to-peak amplitude, % of baseline value) recorded from the left tibialis anterior muscle. The baseline amplitude recorded before test drug administration was defined as 100%.

Results:
Medians (interquartile range) minimum MEP amplitudes in the left tibialis anterior muscle in the ketamine and saline groups were 26% (9% to 34%) and 87% (55% to 103%) of the baseline value, respectively (P<0.001). MEP amplitudes in other muscles were significantly reduced by ketamine. The suppressive effect of ketamine lasted for at least 10 minutes in each muscle.

Conclusion:
A 1-mg/kg bolus dose of ketamine can reduce MEP amplitude. Anesthesiologists should consider the dosage and timing of intravenous ketamine administration during MEP monitoring.
A Novel Low-Cost Surgical Simulation Tool for Pinning Supracondylar Humerus Fractures
Authors: Urwin John W. , Trionfo Arianna , Storey Eileen P. , Brusalis Christopher M. , Gajewski Christopher , Lawrence John Todd R. 
Published: October 2019

Background:
Simulation-based training is one way to improve basic competence for surgical trainees and thus improve patient safety. Closed reduction and percutaneous pinning of a supracondylar humerus fracture is a common procedure that encompasses many basic orthopaedic skills and has been identified as a residency milestone. Despite this, no quantitative tools exist to help learners attain this basic skill. This study seeks to validate a quantitative, low-cost simulation-based training tool for teaching orthopaedic surgery trainees the fundamentals of fracture stabilization with pins.

Methods:
Two low-cost models were developed with simulated cancellous bone blocks and cortical bone sheets: a pinning agility tool to teach pin placement and redirection, and a low-cost construct stability tool to replicate pinning. A high-cost construct stability tool was cut using a pediatric supracondylar humerus model to simulate pinning a real fracture. Construct stability was assessed by adding weight until ∼1.6 mm of displacement was observed. Participants were tested naively on all 3 models and then completed a training session using only the low-cost models. Performance following training was then assessed and compared with fellowship-trained pediatric orthopaedic surgeons. Participants also rated their preintervention and postintervention confidence, skill, and knowledgeability.

Results:
A total of 18 novice trainees participated (10 PGY1 and PGY2 orthopaedic surgery residents and 8 medical student members of the orthopaedic surgery interest club), whereas the reference group consisted of 7 orthopaedic surgery attendings. The subjects significantly improved their scores on both the low-cost (P=0.002) and high-cost (P<0.001) construct stability tools after the training with only the low-cost tools. Compared with the attending benchmark, trainee scores improved on the high-fidelity model from 31% preintervention to 86% postintervention and their pinning times decreased by 38%. Trainees reported increased knowledge, skill, and confidence after the intervention (P<0.001).

Conclusions:
A novel, low-cost simulation model and training session for supracondylar humerus fracture pinning resulted in improved performance in stabilizing a supracondylar humerus model and increased trainee knowledgeability, confidence, and skill.

Level of Evidence:
Level II—economic.
Phase I Study of IGF-Methotrexate Conjugate in the Treatment of Advanced Tumors Expressing IGF-1R
Authors: Venepalli Neeta K. , Emmadi Rajyasree , Danciu Oana C. , Chowdhery Rozina , Cabay Robert J. , Gaitonde Sujata , Aardsma Nathan , Kothari Rajul , Liu Li C. , Fischer James H. , Zaidi Ayesha , Russell Meredith J. , Dudek Arkadiusz Z. 
Published: October 2019

Objectives:
Insulin-like growth factor-methotrexate (IGF-MTX) is a conjugate of methotrexate and 765IGF, a variant of IGF-1 with high affinity for insulin-like growth factor type 1 receptor. The study aim was to determine the maximum tolerated dose of IGF-MTX in refractory solid organ and hematologic malignancies expressing insulin-like growth factor type 1 receptor.

Materials and Methods:
This phase I trial used a modified toxicity probability interval design with 5 cohort dose levels, and expansion cohort at maximum tolerated dose. IGF-MTX was given intravenously over 90 minutes on days 1, 8, and 15 of a 28-day cycle.

Results:
A total of 17 patients were enrolled. The highest tolerated dose tested was 0.80 µEq/kg with dose-limiting toxicity of grade 3 hypoglycemia. Drug-related grade 3 and 4 toxicities included abdominal pain (26%), hypoglycemia (10%), and hypotension (10%). Of the 15 evaluable for response, 3 patients (20%) had stable disease, including the patient with Hodgkin lymphoma with stable disease for 12 cycles of therapy. IGF-MTX concentrations declined rapidly, with half-lives of 5.2 to 14 minutes for the initial distribution phase and 6.5 to 7.5 hours for the terminal elimination phase. Higher IGF-R1 expression did not correlate with better outcome.

Conclusions:
IGF-MTX is well tolerated. IGF-MTX pharmacokinetics suggest rapid cellular uptake. The activity of IGF-MTX in Hodgkin lymphoma should be explored.
Associations between fine particulate matter, extreme heat events, and congenital heart defects
Authors: Stingone Jeanette A. , Luben Thomas J. , Sheridan Scott C. , Langlois Peter H. , Shaw Gary M. , Reefhuis Jennita , Romitti Paul A. , Feldkamp Marcia L. , Nembhard Wendy N. , Browne Marilyn L. , Lin Shao 
Published: October 2019

Background:
Previous research reports associations between air pollution measured during pregnancy and the occurrence of congenital heart defects (CHDs) in offspring. The objective of this research was to assess if exposure to extreme heat events (EHEs) during pregnancy may modify this association.

Methods:
The study population consisted of 4,033 controls and 2,632 cases with dates of delivery between 1999 and 2007 who participated in the National Birth Defects Prevention Study, a multi-site case–control study in the United States. Daily data from the closest stationary fine particulate matter (PM2.5) monitor within 50 km from the maternal residence were averaged across weeks 3–8 post-conception. EHEs were defined as maximum ambient temperature in the upper 95th percentile for at least 2 consecutive days or the upper 90th percentile for 3 consecutive days. Logistic regression models were adjusted for maternal age, ethnicity, education, and average humidity. Relative excess risks due to interaction (RERI) were calculated.

Results:
Compared with women with low PM2.5 exposure and no exposure to an EHE, the odds of a ventricular septal defect in offspring associated with high PM2.5 exposure was elevated only among women who experienced an EHE (odds ratio [OR] 2.14 95% confidence interval [CI] 1.19, 3.38 vs. OR 0.97 95% CI 0.49, 1.95; RERI 0.82 95% CI −0.39, 2.17). The majority of observed associations and interactions for other heart defects were null and/or inconclusive due to lack of precision.

Conclusions:
This study provides limited evidence that EHEs may modify the association between prenatal exposure to PM2.5 and CHD occurrence.
Population Pharmacokinetics of Levobupivacaine During Transversus Abdominis Plane Block in Children
Authors: Vincent Marc , Mathieu Olivier , Nolain Patrick , Menacé Cecilia , Khier Sonia 
Published: October 2019

Background:
Levobupivacaine is commonly used during transversus abdominis plane (TAP) block in pediatric patients. However, the dosing regimen is still empirical, and the pharmacokinetic properties of levobupivacaine are not considered. Here, the pharmacokinetics of levobupivacaine during an ultrasound-guided TAP block were evaluated to optimize dosing regimen, regarding the between-subject variability (BSV) and the volume of levobupivacaine injected.

Method:
The clinical trial (prospective, randomized, double-blind study protocol) was conducted in 40 children aged 1–5 years, who were scheduled for inguinal surgery. Each patient received 0.4 mg/kg of levobupivacaine with a volume of local anesthesia solution adjusted to 0.2 mL/kg of 0.2% or 0.4 mL/kg of 0.1% levobupivacaine. Blood samples were collected at 5, 15, 20, 25, 30, 45, 60, and 75 minutes after the block injection. The population pharmacokinetic analysis was performed using the NONMEM software.

Results:
From the pharmacokinetic parameters obtained, median Cmax, tmax,, and area under the concentration versus time curve were 0.315 mg/L, 17 minutes, and 41 mg/L·min−1, respectively. BSV of clearance was explained by weight. At the dose regimen of 0.4 mg/kg, none of the infants showed signs of toxicity, but in 13 patients, TAP block failed. After analysis, BSV for absorption rate constant, distribution volume, and clearance were 81%, 47%, and 41%, respectively. Residual unexplained variability was estimated to be 14%.

Conclusions:
For improved efficiency in the pediatric population, the dose of levobupivacaine should be greater than 0.4 mg/kg. Children's weight should be considered to anticipate any risk of toxicity.
Localized Retinal Nerve Fiber Layer Defect Location Among Red-free Fundus Photographs, En Face Structural Images, and Cirrus HD-OCT Maps
Authors: Park Ji-Hye , Yoo Chungkwon , Kim Yong Yeon 
Published: October 2019

Precis:
Although the localized retinal nerve fiber layer (RNFL) defects in the en face structural images showed excellent topographic correlation with those in red-free photographs, the RNFL defect was frequently misidentified by the optical coherence tomography (OCT) deviation map.

Purpose:
The purpose of this study was to compare the location of localized RNFL defects using red-free fundus photographs, OCT en face structural images, and OCT RNFL deviation and thickness maps.

Methods:
We investigated the agreement of angular locations of localized RNFL defects. Seventy localized RNFL defects were selected in red-free photographs (red-free defect). En face images and OCT deviation and thickness maps were overlaid on the corresponding red-free photographs. The proximal/distal angular locations and angular width of the red-free defects were compared with those of en face structural images (en face defect) and OCT RNFL deviation (deviation map defect) and thickness maps (thickness map defect).

Results:
Among 70 eyes with red-free defects, 13 (18.6%), 1 (1.4%), and 0 (0%) defects were misidentified by the OCT deviation map, thickness map, and en face image, respectively. There were no significant differences among red-free defects, en face defects, and OCT thickness map defects in the angular width and proximal/distal angular locations. The angular widths were significantly greater in OCT RNFL deviation maps compared with those of other imaging modalities. The correlation coefficients of angular width and locations between the red-free defect and en face defect were significantly higher than those between the red-free defect and OCT map defects (all, P<0.001).

Conclusions:
Localized RNFL defects detected in red-free photographs showed the highest topographic correlation with defects detected in OCT en face images. En face structural images may aid in identifying the localized RNFL defects in glaucomatous eyes.