bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phenome-Wide Mendelian Randomization Study of Pancreatic Cancer Using Summary Genetic Data
Authors: Langdon Ryan J. , Richmond Rebecca C. , Hemani Gibran , Zheng Jie , Wade Kaitlin H. , Carreras-Torres Robert , Johansson Mattias , Brennan Paul , Wootton Robyn E. , Munafo Marcus R. , Smith George Davey , Relton Caroline L. , Vincent Emma E. , Martin Richard M. , Haycock Philip 
Published: July 2019

Abstract

Background:
The 5-year mortality rate for pancreatic cancer is among the highest of all cancers. Greater understanding of underlying causes could inform population-wide intervention strategies for prevention. Summary genetic data from genome-wide association studies (GWAS) have become available for thousands of phenotypes. These data can be exploited in Mendelian randomization (MR) phenome-wide association studies (PheWAS) to efficiently screen the phenome for potential determinants of disease risk.

Methods:
We conducted an MR-PheWAS of pancreatic cancer using 486 phenotypes, proxied by 9,124 genetic variants, and summary genetic data from a GWAS of pancreatic cancer (7,110 cancer cases, 7,264 controls). ORs and 95% confidence intervals per 1 SD increase in each phenotype were generated.

Results:
We found evidence that previously reported risk factors of body mass index (BMI; 1.46; 1.20–1.78) and hip circumference (1.42; 1.21–1.67) were associated with pancreatic cancer. We also found evidence of novel associations with metabolites that have not previously been implicated in pancreatic cancer: ADpSGEGDFXAEGGGVR*, a fibrinogen-cleavage peptide (1.60; 1.31–1.95), and O-sulfo-l-tyrosine (0.58; 0.46–0.74). An inverse association was also observed with lung adenocarcinoma (0.63; 0.54–0.74).

Conclusions:
Markers of adiposity (BMI and hip circumference) are potential intervention targets for pancreatic cancer prevention. Further clarification of the causal relevance of the fibrinogen-cleavage peptides and O-sulfo-l-tyrosine in pancreatic cancer etiology is required, as is the basis of our observed association with lung adenocarcinoma.

Impact:
For pancreatic cancer, MR-PheWAS can augment existing risk factor knowledge and generate novel hypotheses to investigate.
SLAMF6 as a Regulator of Exhausted CD8+ T Cells in Cancer
Authors: Yigit Burcu , Wang Ninghai , ten Hacken Elisa , Chen Shih-Shih , Bhan Atul K. , Suarez-Fueyo Abel , Katsuyama Eri , Tsokos George C. , Chiorazzi Nicholas , Wu Catherine J. , Burger Jan A. , Herzog Roland W. , Engel Pablo , Terhorst Cox 
Published: July 2019

Abstract
The tumor microenvironment in leukemia and solid tumors induces a shift of activated CD8+ cytotoxic T cells to an exhausted state, characterized by loss of proliferative capacity and impaired immunologic synapse formation. Efficient strategies and targets need to be identified to overcome T-cell exhaustion and further improve overall responses in the clinic. Here, we took advantage of the Eμ-TCL1 chronic lymphocytic leukemia (CLL) and B16 melanoma mouse models to assess the role of the homophilic cell-surface receptor SLAMF6 as an immune-checkpoint regulator. The transfer of SLAMF6+ Eμ-TCL1 cells into SLAMF6−/− recipients, in contrast to wild-type (WT) recipients, significantly induced expansion of a PD-1+ subpopulation among CD3+CD44+CD8+ T cells, which had impaired cytotoxic functions. Conversely, administering anti-SLAMF6 significantly reduced the leukemic burden in Eμ-TCL1 recipient WT mice concomitantly with a loss of PD-1+CD3+CD44+CD8+ T cells with significantly increased effector functions. Anti-SLAMF6 significantly reduced leukemic burden in the peritoneal cavity, a niche where antibody-dependent cellular cytotoxicity (ADCC) is impaired, possibly through activation of CD8+ T cells. Targeting of SLAMF6 affected tumor growth not only in B cell–related leukemia and lymphomas but also in nonhematopoietic tumors such as B16 melanoma, where SLAMF6 is not expressed. In vitro exhausted CD8+ T cells showed increased degranulation when anti-human SLAMF6 was added in culture. Taken together, anti-SLAMF6 both effectively corrected CD8+ T-cell dysfunction and had a direct effect on tumor progression. The outcomes of our studies suggest that targeting SLAMF6 is a potential therapeutic strategy.
Insights Into the Pathogenesis of Catecholaminergic Polymorphic Ventricular Tachycardia From Engineered Human Heart Tissue
Authors: Park Sung-Jin , Zhang Donghui , Qi Yan , Li Yifei , Lee Keel Yong , Bezzerides Vassilios J. , Yang Pengcheng , Xia Shutao , Kim Sean L. , Liu Xujie , Lu Fujian , Pasqualini Francesco S. , Campbell Patrick H. , Geva Judith , Roberts Amy E. , Kleber Andre G. , Abrams Dominic J. , Pu William T. , Parker Kevin Kit 
Published: July 2019

Background:
Modeling of human arrhythmias with induced pluripotent stem cell–derived cardiomyocytes has focused on single-cell phenotypes. However, arrhythmias are the emergent properties of cells assembled into tissues, and the impact of inherited arrhythmia mutations on tissue-level properties of human heart tissue has not been reported.

Methods:
Here, we report an optogenetically based, human engineered tissue model of catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited arrhythmia caused by mutation of the cardiac ryanodine channel and triggered by exercise. We developed a human induced pluripotent stem cell–derived cardiomyocyte–based platform to study the tissue-level properties of engineered human myocardium. We investigated pathogenic mechanisms in CPVT by combining this novel platform with genome editing.

Results:

In our model, CPVT tissues were vulnerable to developing reentrant rhythms when stimulated by rapid pacing and catecholamine, recapitulating hallmark features of the disease. These conditions elevated diastolic Ca
2+
levels and increased temporal and spatial dispersion of Ca
2+
wave speed, creating a vulnerable arrhythmia substrate. Using Cas9 genome editing, we pinpointed a single catecholamine-driven phosphorylation event, ryanodine receptor–serine 2814 phosphorylation by Ca
2
+
/calmodulin-dependent protein kinase II, that is required to unmask the arrhythmic potential of CPVT tissues.

Conclusions:
Our study illuminates the molecular and cellular pathogenesis of CPVT and reveals a critical role of calmodulin-dependent protein kinase II–dependent reentry in the tissue-scale mechanism of this disease. We anticipate that this approach will be useful for modeling other inherited and acquired cardiac arrhythmias.
Enhanced Radiation of Near-Inertial Energy by Frontal Vertical Circulations
Authors: Thomas Leif N. 
Published: July 2019

AbstractNear-inertial waves (NIWs) radiate energy out of the mixed layer when they develop small lateral scales. Refraction of these waves by gradients in planetary and vertical vorticity has traditionally been invoked to explain this phenomenon. Here, a new mechanism for the enhancement of NIW radiation is described involving the interaction of NIWs with vertical circulations at fronts undergoing frontogenesis. Frontal vertical circulations drive a Doppler shift that is proportional to the wave’s vertical wavenumber m and that changes sign across a front, inducing large lateral differences in wave phase within a few inertial periods. Theory predicts that the process should generate a vertical energy flux that varies inversely with m in contrast to the m−3 dependence expected from refraction. As a consequence, high-mode NIWs are much more effective at radiating energy when fronts and their vertical circulation are present. Numerical simulations initialized with fronts, an array of eddies that drive frontogenesis, and NIWs of various modes are used to test the theory. In the simulations, the interaction of the NIWs with the frontal vertical circulations generates wave beams that radiate down from the fronts. The resultant downward energy flux varies with m following the theoretical scaling laws. In the beams, the Eulerian frequency is inertial within a few percent, yet the waves’ potential and kinetic energies are comparable, thus indicating a superinertial intrinsic frequency. The downshift in Eulerian frequency from the intrinsic frequency is due to horizontal advection of the waves by the eddies.
The Emergence of the North Icelandic Jet and Its Evolution from Northeast Iceland to Denmark Strait
Authors: Semper Stefanie , Våge Kjetil , Pickart Robert S. , Valdimarsson Héðinn , Torres Daniel J. , Jónsson Steingrímur 
Published: July 2019

AbstractThe North Icelandic Jet (NIJ) is an important source of dense water to the overflow plume passing through Denmark Strait. The properties, structure, and transport of the NIJ are investigated for the first time along its entire pathway following the continental slope north of Iceland, using 13 hydrographic/velocity surveys of high spatial resolution conducted between 2004 and 2018. The comprehensive dataset reveals that the current originates northeast of Iceland and increases in volume transport by roughly 0.4 Sv (1 Sv ≡ 106 m3 s−1) per 100 km until 300 km upstream of Denmark Strait, at which point the highest transport is reached. The bulk of the NIJ transport is confined to a small area in Θ–S space centered near −0.29° ± 0.16°C in Conservative Temperature and 35.075 ± 0.006 g kg−1 in Absolute Salinity. While the hydrographic properties of this transport mode are not significantly modified along the NIJ’s pathway, the transport estimates vary considerably between and within the surveys. Neither a clear seasonal signal nor a consistent link to atmospheric forcing was found, but barotropic and/or baroclinic instability is likely active in the current. The NIJ displays a double-core structure in roughly 50% of the occupations, with the two cores centered at the 600- and 800-m isobaths, respectively. The transport of overflow water 300 km upstream of Denmark Strait exceeds 1.8 ± 0.3 Sv, which is substantially larger than estimates from a year-long mooring array and hydrographic/velocity surveys closer to the strait, where the NIJ merges with the separated East Greenland Current. This implies a more substantial contribution of the NIJ to the Denmark Strait overflow plume than previously envisaged.
Electroacupuncture reduces astrocyte number and oxidative stress in aged rats with surgery-induced cognitive dysfunction
Authors: Liu Pei-Rong , Cao Feng , Zhang Yu , Peng Sheng 
Published: July 2019

Objectives To investigate the effects of electroacupuncture in regulating astrocytes and oxidative stress in a rat model of postoperative cognitive dysfunction (POCD). Methods Male aged Sprague-Dawley rats were randomized to undergo left hepatic lobe resection to induce POCD, followed by either electroacupuncture or no treatment; or similar surgery without left lobe resection or electroacupuncture (sham). Postsurgical cognitive function, hippocampal astrocyte number and oxidative stress indicators were measured. Results At days 1, 3 and 7 following surgery, escape latency was significantly shorter and platform crossing frequency was increased with electroacupuncture versus other groups. At postoperative day 1, the electroacupuncture group showed significantly fewer glial fibrillary acidic protein (GFAP)-positive hippocampal astrocytes versus the POCD model group. In POCD rats, electroacupuncture significantly decreased serum S100 calcium binding protein B and neuron-specific enolase levels, and increased brain-derived neurotrophic factor and glial cell-derived neurotrophic factor levels, at days 1, 3 and 7. Electroacupuncture significantly attenuated the hippocampal POCD-induced increase in malondialdehyde and decreased superoxide dismutase levels at day 1 following surgery. Conclusion Electroacupuncture may improve cognitive function in rats with POCD by reducing hippocampal GFAP-positive astrocyte number and suppressing oxidative stress.
Diagnostic thoracic ultrasound imaging – An exploration of respiratory physiotherapists' interest and use in clinical practice: A national survey
Authors: Hayward Simon , Smith Mike , Innes Sue 
Published: July 2019

Introduction Physiotherapists are learning to perform diagnostic thoracic ultrasound but it is currently unknown how they are learning, how they are using thoracic ultrasound in their practice, or any factors affecting the implementation of thoracic ultrasound into practice. The aim of this survey was to explore the use of thoracic ultrasound by physiotherapists. This information could be used to aid training and implementation strategies to assist physiotherapists to integrate thoracic ultrasound safely into their practice. Methods A questionnaire comprising of open/closed questions was distributed to respiratory physiotherapist. Distribution was at three national study days and via a specialist newsletter containing a link to a SurveyMonkey™ questionnaire. Results A total of 133 questionnaires were returned with 31 reported that they used thoracic ultrasound imaging and 101 reporting they did not. The most common roles of thoracic ultrasound in practice were to: enhance the ability to differentially diagnose respiratory pathologies, aid respiratory assessment and support clinical reasoning. Of the 133 respondents, 58 reported that they had undertaken training in thoracic ultrasound imaging and 75 had not. The most common factors identified regarding thoracic ultrasound implementation were team support, ultrasound machine availability/cost, time pressures and mentor availability. Discussion This survey has provided an understanding of thoracic ultrasound practice amongst respiratory physiotherapists in the UK. The survey results demonstrated the barriers that inhibit current practice and highlighted the importance of mentor support. There was a good understanding by all respondents regarding the clinical application of thoracic ultrasound. These findings are being used to develop professional guidance and ensure safe practice of thoracic ultrasound.
Helpful, albeit hazardous! Esophageal stem-cell injection in systemic sclerosis
Authors: Durchschein Franziska , Moazedi-Fuerst Florentine , Kielhauser Sonja , Lackner Angelika , Wiedner Maria , Koch Horst , Justich Ivo , Eherer Andreas 
Published: July 2019

Background: Over 90% of patients with systemic sclerosis suffer from gastroesophageal reflux. Esophageal motility disturbances are associated with a reduced life quality and may force interstitial lung disease progression. We wanted to determine whether we can improve gastroesophageal reflux in these patients by esophageal stem-cell injection. Methods: We performed a pilot study including eights patients with systemic sclerosis and symptomatic gastroesophageal reflux. Sampling of adipose tissue was performed by an experienced plastic surgeon under local anesthesia. The collected fat was injected into the submucosa of the distal esophagus, each time 1 ml in all four quadrants starting 2, 4 and 6 cm proximal to the Z line (ending up to a total volume of 12 ml). Before the intervention, 3, 6 and finally 12 months after the procedure, patients answered the Gastroesophageal Reflux Disease Health-Related Quality of Life Questionnaire (GERD HRQL) and a high-resolution manometry was performed to quantify changes in motility function. Results: All patients showed an improvement in the GERD HRQL score after the stem-cell injection and a lower dosage of proton-pump inhibitors. The manometric findings showed no change throughout the time. A serious adverse event occurred, as one patient developed multiple cerebellar embolic infarcts. Conclusion: Because of the favorable effect in all patients, a safe route for esophageal fat injection needs to be developed.
Clinical Evaluation of a New, Lower Pain, One Touch Lancing Device for People With Diabetes: Virtually Pain-Free Testing and Improved Comfort Compared to Current Lancing Systems
Authors: Grady Mike , Lamps Greg , Shemain Ashley , Cameron Hilary , Murray Linda 
Published: July 2019

Background: Patients worldwide use lancing devices to perform self-monitoring of blood glucose (SMBG). Continued innovation remains important to minimize pain associated with finger sticking to facilitate patient adherence to SMBG regimens. The original One Touch Delica lancer (OTD) reduced the pain of testing. This study investigated a completely re-engineered lancing system, called One Touch Delica Plus (OTDP), intended to further minimize pain while improving the patient experience. Methods: One hundred and three subjects (type 1 or 2 diabetes) experienced finger sticks with both lancing systems. Device depth and blood volume (BV) generation were determined during visit 1. These parameters were used during pain assessments in visit 2. Patient feedback was also recorded using surveys. Results: Finger-stick testing was less painful using OTDP compared to original OTD irrespective of whether 30 (−48.2 mm, −30.4 mm, P < 0.0001) or 33 gauge (−42.6 mm, 30.5 mm, P = 0.0004) lancets were used. All 103 subjects generated the required BV (≥0.4 µL) per protocol. At equivalent depth penetration, OTDP generated higher average BVs than OTD using 30 (1.58 µL, 1.10 µL) or 33 gauge lancets (1.39 µL, 0.98 µL). Subjects responded that testing with OTDP was virtually pain free (78%) and that testing with OTDP was less painful than using their current lancing systems (79%) or original OTD (67%). Conclusion: OTDP demonstrated lower pain than the original OTD lancing system and participants agreed that testing with OTDP was virtually pain free and less painful than using their current lancing systems.
The Western Australia Modeling project — Part 2: Seismic validation
Authors: Shragge Jeffrey , Lumley David , Bourget Julien , Potter Toby , Miyoshi Taka , Witten Ben , Giraud Jeremie , Wilson Thomas , Iqbal Afzal , Emami Niri Mohammad , Whitney Beau 
Published: July 2019

Large-scale 3D modeling of realistic earth models is being increasingly undertaken in industry and academia. These models have proven useful for various activities such as geologic scenario testing through seismic finite-difference (FD) modeling, investigating new acquisition geometries, and validating novel seismic imaging, inversion, and interpretation methods. We have evaluated the results of the Western Australia (WA) Modeling (WAMo) project, involving the development of a large-scale 3D geomodel representative of geology of the Carnarvon Basin, located offshore of WA’s North West Shelf (NWS). Constrained by a variety of geologic, petrophysical, and field seismic data sets, the viscoelastic WAMo 3D geomodel was used in seismic FD modeling and imaging tests to “validate” model realizations. Calibrating the near-surface model proved to be challenging due to the limited amount of well data available for the top 500 m below the mudline. We addressed this issue by incorporating additional information (e.g., geotechnical data, analog studies) as well as by using soft constraints to match the overall character of nearby NWS seismic data with the modeled shot gathers. This process required undertaking several “linear” iterations to apply near-surface model conditioning, as well as “nonlinear” iterations to update the underlying petrophysical relationships. Overall, the resulting final WAMo 3D geomodel and accompanying modeled shot gathers and imaging results are able to reproduce the complex full-wavefield character of NWS marine seismic data. Thus, the WAMo model is well-calibrated for use in geologic and geophysical scenario testing to address common NWS seismic imaging, inversion, and interpretation challenges.
Automating the Capture of Structured Pathology Data for Prostate Cancer Clinical Care and Research
Authors: Odisho Anobel Y. , Bridge Mark , Webb Mitchell , Ameli Niloufar , Eapen Renu S. , Stauf Frank , Cowan Janet E. , Washington Samuel L. , Herlemann Annika , Carroll Peter R. , Cooperberg Matthew R. 
Published: July 2019

Purpose Cancer pathology findings are critical for many aspects of care but are often locked away as unstructured free text. Our objective was to develop a natural language processing (NLP) system to extract prostate pathology details from postoperative pathology reports and a parallel structured data entry process for use by urologists during routine documentation care and compare accuracy when compared with manual abstraction and concordance between NLP and clinician-entered approaches. Materials and Methods From February 2016, clinicians used note templates with custom structured data elements (SDEs) during routine clinical care for men with prostate cancer. We also developed an NLP algorithm to parse radical prostatectomy pathology reports and extract structured data. We compared accuracy of clinician-entered SDEs and NLP-parsed data to manual abstraction as a gold standard and compared concordance (Cohen’s κ) between approaches assuming no gold standard. Results There were 523 patients with NLP-extracted data, 319 with SDE data, and 555 with manually abstracted data. For Gleason scores, NLP and clinician SDE accuracy was 95.6% and 95.8%, respectively, compared with manual abstraction, with concordance of 0.93 (95% CI, 0.89 to 0.98). For margin status, extracapsular extension, and seminal vesicle invasion, stage, and lymph node status, NLP accuracy was 94.8% to 100%, SDE accuracy was 87.7% to 100%, and concordance between NLP and SDE ranged from 0.92 to 1.0. Conclusion We show that a real-world deployment of an NLP algorithm to extract pathology data and structured data entry by clinicians during routine clinical care in a busy clinical practice can generate accurate data when compared with manual abstraction for some, but not all, components of a prostate pathology report.
Comorbidities and Survival in Patients With Lipodystrophy: An International Chart Review Study
Authors: Akinci Baris , Oral Elif A , Neidert Adam , Rus Diana , Cheng Wendy Y , Thompson-Leduc Philippe , Cheung Hoi Ching , Bradt Pamela , Foss de Freitas Maria Cristina , Montenegro Renan Magalhães , Fernandes Virgínia Oliveira , Cochran Elaine , Brown Rebecca J 
Published: July 2019

Abstract

Context
Limited natural history data are available in patients with non-HIV–related lipodystrophy syndromes who never received disease-specific therapies, making interpretation of benefits of therapies in lipodystrophy syndromes challenging.

Objective
We assessed the natural history of non-HIV–related generalized lipodystrophy (GL) and partial lipodystrophy (PL) in patients who have never received leptin or other lipodystrophy-specific therapies.

Design/Setting/Patients
We conducted an international chart review of 230 patients with confirmed GL or PL at five treatment centers who never received leptin or other lipodystrophy-specific therapies. Patients were observed from birth to loss to follow-up, death, or date of chart abstraction.

Outcome Measures
Lifetime prevalence of diabetes/insulin resistance and select organ abnormalities, time to diabetes/insulin resistance, first organ abnormality, disease progression, and mortality were described.

Results
Diabetes/insulin resistance was identified in 58.3% of patients. Liver abnormalities were the most common organ abnormality (71.7%), followed by kidney (40.4%), heart (30.4%), and pancreatitis (13.0%). Kaplan-Meier estimates of mean (SE) time to first organ abnormality were 7.7 years (0.9) in GL and 16.1 years (1.5) in PL (P < 0.001). Mean time to diabetes/insulin resistance was 12.7 years (1.2) in GL and 19.1 years (1.7) in PL (P = 0.131). Mean time to disease progression was 7.6 years (0.8) and comparable between GL and PL subgroups (P = 0.393). Mean time to death was 51.2 years (3.5) in GL and 66.6 years (1.0) in PL (P < 0.001).

Conclusions
This large-scale study provides comprehensive, long-term data across multiple countries on the natural history of non-HIV–related lipodystrophy.