bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pregnancy‐associated immune‐mediated polyarthritis in a dog
Authors: Willemse Tijmen W.J. , Lamb Valerie , Kelly Darren 
Published: October 2019

A two‐year and seven‐month‐old female entire golden retriever was referred for investigation of sudden‐onset, suspected immune‐mediated polyarthritis (IMPA). The dog was five weeks into gestation. On presentation, the dog was unable to stand or walk without assistance. The initial clinical suspicion of IMPA was confirmed on cytology of the synovial fluid from eight joints which showed marked neutrophilic inflammation. Pregnancy was confirmed by abdominal ultrasound examination, with no other abnormalities seen on thoracic radiographs or abdominal ultrasound. Based on the known association between pregnancy and immune‐mediated diseases in human beings and the potential risks associated with administration of immunosuppressive medications to the fetuses and pregnant bitch, ovariohysterectomy was performed. Following surgery, the dog was treated with meloxicam and paracetamol. Within 48 hours of surgery and starting analgesic medications, the clinical signs had completely resolved, and follow‐up examinations one, two and six months postdiagnosis showed no evidence of relapsing disease.
A holographic study of the a-theorem and RG flow in general quadratic curvature gravity
Authors: Siahvoshan Malihe , Ghodsi Ahmad 
Published: October 2019

AbstractWe use the holographic language to show the existence of thea-theorem for even dimensional CFTs, dual to the AdS space in general quadratic curvature gravity. We find the Wess-Zumino action which is originated from the spontaneous breaking of the conformal symmetry in$$d\le 8$$d≤8, by using a radial cut-off near the AdS boundary. We also study the RG flow and (average) null energy condition in the space of the couplings of theory. In a simple toy model, we find the regions where this holographic RG flow has a monotonic decreasing behavior.
A 4D flow MRI evaluation of the impact of shear-dependent fluid viscosity on in vitro Fontan circulation flow
Authors: Cheng Andrew L. , Wee Choo Phei , Pahlevan Niema M. , Wood John C. 
Published: October 2019

The Fontan procedure for univentricular heart defects creates a nonphysiologic circulation where systemic venous blood drains directly into the pulmonary arteries, leading to multiorgan dysfunction secondary to chronic low-shear nonpulsatile pulmonary blood flow and central venous hypertension. Although blood viscosity increases exponentially in this low-shear environment, the role of shear-dependent (“non-Newtonian”) blood viscosity in this pathophysiology is unclear. We studied three-dimensional (3D)-printed Fontan models in an in vitro flow loop with a Philips 3-T magnetic resonance imaging (MRI) scanner. A 4D flow phase-contrast sequence was used to acquire a time-varying 3D velocity field for each experimental condition. On the basis of blood viscosity of a cohort of patients who had undergone the Fontan procedure, it was decided to use 0.04% xanthan gum as a non-Newtonian blood analog; 45% glycerol was used as a Newtonian control fluid. MRI data were analyzed using GTFlow and MATLAB software. The primary outcome, power loss, was significantly higher with the Newtonian fluid [14.8 (13.3, 16.4) vs. 8.1 (6.4, 9.8)%, medians with 95% confidence interval, P < 0.0001]. The Newtonian fluid also demonstrated marginally higher right pulmonary artery flow, marginally lower shear stress, and a trend toward higher caval flow mixing. Outcomes were modulated by Fontan model complexity, cardiac output, and caval flow ratio. Vortexes, helical flow, and stagnant flow were more prevalent with the non-Newtonian fluid. Our data demonstrate that shear-dependent viscosity significantly alters qualitative flow patterns, power loss, pulmonary flow distribution, shear stress, and caval flow mixing in synthetic models of the Fontan circulation. Potential clinical implications include effects on exercise capacity, ventilation-perfusion matching, risk of pulmonary arteriovenous malformations, and risk of thromboembolism. NEW & NOTEWORTHY Although blood viscosity increases exponentially in low-shear environments, the role of shear-dependent (“non-Newtonian”) blood viscosity in the pathophysiology of the low-shear Fontan circulation is unclear. We demonstrate that shear-dependent viscosity significantly alters qualitative flow patterns, power loss, pulmonary flow distribution, shear stress, and caval flow mixing in synthetic models of the Fontan circulation. Potential clinical implications include effects on exercise capacity, ventilation-perfusion matching, risk of pulmonary arteriovenous malformations, and risk of thromboembolism.
A Comprehensive PDX Gastric Cancer Collection Captures Cancer Cell–Intrinsic Transcriptional MSI Traits
Authors: Corso Simona , Isella Claudio , Bellomo Sara E. , Apicella Maria , Durando Stefania , Migliore Cristina , Ughetto Stefano , D’Errico Laura , Menegon Silvia , Moya-Rull Daniel , Cargnelutti Marilisa , Capelôa Tânia , Conticelli Daniela , Giordano Jessica , Venesio Tiziana , Balsamo Antonella , Marchiò Caterina , Degiuli Maurizio , Reddavid Rossella , Fumagalli Uberto , De Pascale Stefano , Sgroi Giovanni , Rausa Emanuele , Baiocchi Gian Luca , Molfino Sarah , Pietrantonio Filippo , Morano Federica , Siena Salvatore , Sartore-Bianchi Andrea , Bencivenga Maria , Mengardo Valentina , Rosati Riccardo , Marrelli Daniele , Morgagni Paolo , Rausei Stefano , Pallabazzer Giovanni , De Simone Michele , Ribero Dario , Marsoni Silvia , Sottile Antonino , Medico Enzo , Cassoni Paola , Sapino Anna , Pectasides Eirini , Thorner Aaron R. , Nag Anwesha , Drinan Samantha D. , Wollison Bruce M. , Bass Adam J. , Giordano Silvia 
Published: October 2019

Abstract

Gastric cancer is the world's third leading cause of cancer mortality. In spite of significant therapeutic improvements, the clinical outcome for patients with advanced gastric cancer is poor; thus, the identification and validation of novel targets is extremely important from a clinical point of view. We generated a wide, multilevel platform of gastric cancer models, comprising 100 patient-derived xenografts (PDX), primary cell lines, and organoids. Samples were classified according to their histology, microsatellite stability, Epstein–Barr virus status, and molecular profile. This PDX platform is the widest in an academic institution, and it includes all the gastric cancer histologic and molecular types identified by The Cancer Genome Atlas. PDX histopathologic features were consistent with those of patients' primary tumors and were maintained throughout passages in mice. Factors modulating grafting rate were histology, TNM stage, copy number gain of tyrosine kinases/KRAS genes, and microsatellite stability status. PDX and PDX-derived cells/organoids demonstrated potential usefulness to study targeted therapy response. Finally, PDX transcriptomic analysis identified a cancer cell–intrinsic microsatellite instability (MSI) signature, which was efficiently exported to gastric cancer, allowing the identification, among microsatellite stable (MSS) patients, of a subset of MSI-like tumors with common molecular aspects and significant better prognosis. In conclusion, we generated a wide gastric cancer PDX platform, whose exploitation will help identify and validate novel “druggable” targets and optimize therapeutic strategies. Moreover, transcriptomic analysis of gastric cancer PDXs allowed the identification of a cancer cell–intrinsic MSI signature, recognizing a subset of MSS patients with MSI transcriptional traits, endowed with better prognosis.

Significance:
This study reports a multilevel platform of gastric cancer PDXs and identifies a MSI gastric signature that could contribute to the advancement of precision medicine in gastric cancer.
Diverse Resistance Mechanisms to the Third-Generation ALK Inhibitor Lorlatinib in ALK-Rearranged Lung Cancer
Authors: Recondo Gonzalo , Mezquita Laura , Facchinetti Francesco , Planchard David , Gazzah Anas , Bigot Ludovic , Rizvi Ahsan Z. , Frias Rosa L. , Thiery Jean Paul , Scoazec Jean-Yves , Sourisseau Tony , Howarth Karen , Deas Olivier , Samofalova Dariia , Galissant Justine , Tesson Pauline , Braye Floriane , Naltet Charles , Lavaud Pernelle , Mahjoubi Linda , Abou Lovergne Aurélie , Vassal Gilles , Bahleda Rastilav , Hollebecque Antoine , Nicotra Claudio , Ngo-Camus Maud , Michiels Stefan , Lacroix Ludovic , Richon Catherine , Auger Nathalie , De Baere Thierry , Tselikas Lambros , Solary Eric , Angevin Eric , Eggermont Alexander M. , Andre Fabrice , Massard Christophe , Olaussen Ken A. , Soria Jean-Charles , Besse Benjamin , Friboulet Luc 
Published: October 2019

AbstractPurpose:Lorlatinib is a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor with proven efficacy in patients with ALK-rearranged lung cancer previously treated with first- and second-generation ALK inhibitors. Beside compound mutations in the ALK kinase domain, other resistance mechanisms driving lorlatinib resistance remain unknown. We aimed to characterize the mechanisms of resistance to lorlatinib occurring in patients with ALK-rearranged lung cancer and design new therapeutic strategies in this setting.Experimental Design:Resistance mechanisms were investigated in 5 patients resistant to lorlatinib. Longitudinal tumor biopsies were studied using high-throughput next-generation sequencing. Patient-derived models were developed to characterize the acquired resistance mechanisms, and Ba/F3 cell mutants were generated to study the effect of novel ALK compound mutations. Drug combinatory strategies were evaluated in vitro and in vivo to overcome lorlatinib resistance.Results:Diverse biological mechanisms leading to lorlatinib resistance were identified. Epithelial–mesenchymal transition (EMT) mediated resistance in two patient-derived cell lines and was susceptible to dual SRC and ALK inhibition. We characterized three ALK kinase domain compound mutations occurring in patients, L1196M/D1203N, F1174L/G1202R, and C1156Y/G1269A, with differential susceptibility to ALK inhibition by lorlatinib. We identified a novel bypass mechanism of resistance caused by NF2 loss-of-function mutations, conferring sensitivity to treatment with mTOR inhibitors.Conclusions:This study shows that mechanisms of resistance to lorlatinib are diverse and complex, requiring new therapeutic strategies to tailor treatment upon disease progression.
Class(y) Dissection ofBRAFHeterogeneity: Beyond Non-V600
Authors: Fontana Elisa , Valeri Nicola 
Published: October 2019

AbstractDifferent classes of BRAF mutations are present in colorectal and other cancers. Non-V600 mutations are rare; however, their detection rate will increase as the use of next-generation sequencing ramps up quickly in clinical practice. Different biochemical signaling pathways are active in non-V600 BRAF–mutant cancers and may affect treatment response.See related article by Yaeger et al., p. 7089
Cardiomyocyte Homeodomain-Interacting Protein Kinase 2 Maintains Basal Cardiac Function via Extracellular Signal-Regulated Kinase Signaling
Authors: Guo Yuanjun , Sui Jennifer Y. , Kim Kyungsoo , Zhang Zhentao , Qu Xiaoyan A. , Nam Young-Jae , Willette Robert N. , Barnett Joey V. , Knollmann Bjorn C. , Force Thomas , Lal Hind 
Published: October 2019

Background:
Cardiac kinases play a critical role in the development of heart failure, and represent potential tractable therapeutic targets. However, only a very small fraction of the cardiac kinome has been investigated. To identify novel cardiac kinases involved in heart failure, we used an integrated transcriptomics and bioinformatics analysis and identified Homeodomain-Interacting Protein Kinase 2 (HIPK2) as a novel candidate kinase. The role of HIPK2 in cardiac biology is unknown.

Methods:
We used the Expression2Kinase algorithm for the screening of kinase targets. To determine the role of HIPK2 in the heart, we generated cardiomyocyte (CM)-specific HIPK2 knockout and heterozygous mice. Heart function was examined by echocardiography, and related cellular and molecular mechanisms were examined. Adeno-associated virus serotype 9 carrying cardiac-specific constitutively active MEK1 (TnT-MEK1-CA) was administrated to rescue cardiac dysfunction in CM-HIPK2 knockout mice.

Results:

To our knowledge, this is the first study to define the role of HIPK2 in cardiac biology. Using multiple HIPK2 loss-of-function mouse models, we demonstrated that reduction of HIPK2 in CMs leads to cardiac dysfunction, suggesting a causal role in heart failure. It is important to note that cardiac dysfunction in HIPK2 knockout mice developed with advancing age, but not during development. In addition, CM-HIPK2 knockout mice and CM-HIPK2 heterozygous mice exhibited a gene dose-response relationship of CM-HIPK2 on heart function. HIPK2 expression in the heart was significantly reduced in human end-stage ischemic cardiomyopathy in comparison to nonfailing myocardium, suggesting a clinical relevance of HIPK2 in cardiac biology. In vitro studies with neonatal rat ventricular CMscorroborated the in vivo findings. Specifically, adenovirus-mediated overexpression of HIPK2 suppressed the expression of heart failure markers,
NPPA
and
NPPB
, at basal condition and abolished phenylephrine-induced pathological gene expression. An array of mechanistic studies revealed impaired extracellular signal-regulated kinase 1/2 signaling in HIPK2-deficient hearts. An in vivo rescue experiment with adeno-associated virus serotype 9 TnT-MEK1-CA nearly abolished the detrimental phenotype of knockout mice, suggesting that impaired extracellular signal-regulated kinase signaling mediated apoptosis as the key factor driving the detrimental phenotype in CM-HIPK2 knockout mice hearts.

Conclusions:
Taken together, these findings suggest that CM-HIPK2 is required to maintain normal cardiac function via extracellular signal-regulated kinase signaling.
Should Excess Topical Decongestant Use Raise a Red Flag? Rhinitis Medicamentosa and Opioid Use Disorder
Authors: Patel Aneesh , Levi Jessica R. , Brook Christopher D. 
Published: October 2019

Objective: The objective of this study was to determine whether patients with rhinitis medicamentosa (RM) have an increased odds of having an opioid use disorder (OUD) and which characteristics may predict this association. Methods: The authors conducted a retrospective case control study of patients 18 years and older who presented to the otolaryngology clinic at an academic medical center from January 2013 through December 2017. Cases, defined as patients who presented with excessive decongestant nasal spray usage based on history, were matched to control patients who presented with chronic rhinitis and did not report regular nasal decongestant usage. The charts were reviewed for patients that carried a problem of opioid abuse, identified using ICD-9 codes 304.XX or ICD-10 codes F11.XX. The primary outcome of this study was the odds of having an OUD. Secondary outcomes were assessed by summary statistics. Results: One hundred and thirty-one cases of RM were matched to 1871 controls of chronic rhinitis. Seven cases (5.3%) and 24 (1.3%) controls had a diagnosis of OUD, consistent with an odds ratio of 3.98 for opioid abuse in patients with RM (95% CI: 1.47-9.71). Oxymetazoline was used by 85.5% (n = 112) of patients with RM. Thirty-six patients (27.1%) with RM underwent nasal surgery following a diagnosis of RM, of which twenty patients (55.6%) were prescribed opioids following the procedure. Conclusions: RM is associated with increased odds of having an OUD.
Randomized Pilot Study: A Mobile Technology-based Self-management Intervention for Sickle Cell Pain
Authors: Ezenwa Miriam O. , Yao Yingwei , Nguyen Minh-Nguyet T. , Mandernach Molly W. , Hunter Clayton T. , Yoon Saunjoo L. , Fedele David , Lucero Robert J. , Lyon Debra , Wilkie Diana J. 
Published: October 2019

Little is known about the effects of self-managed relaxation interventions on pain, stress, and autonomic responses in patients with sickle cell disease (SCD). This pre-post randomized controlled pilot study was conducted to determine the feasibility of using computer tablets for relaxation intervention delivery; acceptability of study procedures; and intervention effects on pain, stress, and indicators of relaxation. The 30 research participants ranged in age from 22 years to 59 years. All were African American; 53% were male. They were randomized to an experimental group that watched a relaxation video or a control group that discussed their disease. All participants completed the study, indicating feasibility. Acceptability rates were also high. Data were obtained for the intervention’s immediate effect on pain, stress, respiration, pulse, finger skin temperature, and self-reported relaxation. These preliminary findings will guide future, higher-powered studies to determine the intervention’s efficacy and mechanism in SCD. The ClinicalTrials.gov Identifier: NCT02729363
Humeral Retroversion and Injury Risk After Proximal Humeral Epiphysiolysis (Little Leaguer’s Shoulder)
Authors: Ito Atsushi , Mihata Teruhisa , Hosokawa Yuji , Hasegawa Akihiko , Neo Masashi , Doi Munekazu 
Published: October 2019

Background: The increased humeral retroversion on the dominant side of throwing athletes is thought to result from repetitive throwing motion. Little Leaguer’s shoulder—a rotational stress fracture of the proximal humeral epiphyseal plate—may influence the risk of humeral retroversion and injury of the shoulder or elbow joint. Purpose: To investigate the effect of Little Leaguer’s shoulder on humeral retroversion and the rates of shoulder and elbow injuries. Study Design: Cohort study; Level of evidence, 3. Methods: 10 high school baseball players (average age, 16.6 years; range, 16-18 years) who had experienced Little Leaguer’s shoulder during elementary or junior high school (average age, 12.6 years; range, 11-15 years) were enrolled in the study. As a control group, 22 high school baseball players (average age, 16.9 years; range, 16-18 years) who had never had any shoulder or elbow injury during elementary and junior high school were included. Humeral retroversion on ultrasonographic measurement, shoulder range of motion, and rates of shoulder and elbow injuries were evaluated. Results: Humeral retroversion was significantly greater on the dominant side than on the nondominant side in both players with Little Leaguer’s shoulder (dominant, 104°± 8°; nondominant, 84°± 12°; P < .001) and controls (dominant, 91°± 13°; nondominant, 81°± 10°; P < .001). In the dominant shoulder, humeral retroversion was greater in the Little Leaguer’s shoulder group than in the control group ( P = .008). When the effects of humeral retroversion were excluded, maximal external rotation was significantly less in the dominant shoulder than in the nondominant shoulder in the Little Leaguer’s shoulder group (by 11°± 12°, P = .02), whereas no significant difference was found between dominant (110°± 11°) and nondominant (111°± 13°) shoulders in the control group ( P = .64). The rates of shoulder and elbow pain were significantly higher in the Little Leaguer’s shoulder group (shoulder pain 80%, elbow pain 70%) than in the control group (shoulder pain 9%, P < .001; elbow pain 32%, P = .04). Conclusion: Humeral retroversion was increased in baseball players without any history of shoulder or elbow injury during elementary and junior high school and was further increased in players who had had Little Leaguer’s shoulder. Increased humeral retroversion after Little Leaguer’s shoulder may be a risk factor for future shoulder or elbow injury.
Associations of Tobacco Advertising Appeal With Intentions to Use Alternative Tobacco Products Among Young Tobacco Users Experiencing Homelessness
Authors: Shadel William G. , Tucker Joan S. , Seelam Rachana , Golinelli Daniela , Siconolfi Daniel 
Published: October 2019

Purpose: Virtually nothing is known about the potential effects of tobacco advertising on tobacco use among youth experiencing homelessness, a vulnerable population with high tobacco use rates. This study examines associations between the appeal of advertising for 5 classes of tobacco product (electronic cigarettes, hookah, cigars, cigarillos, and smokeless tobacco) and future intentions to use those products again among homeless youth who had indicated any level of lifetime use. Design: A cross-sectional design was used. Setting: Settings were 25 service and street sites in Los Angeles County. Participants: A probability sample of 469 young tobacco users experiencing homelessness (mean age = 22; 71% male; 29% non-Hispanic White) was recruited. Measures: Assessments included product-specific tobacco advertising appeal and future intentions to use the product again, as well as a range of covariate controls (eg, demographics, homelessness severity, current tobacco use, general advertising exposure). Analysis: Linear regression tested for associations between the appeal of advertising for a specific tobacco product and intentions to use that product again in the future, controlling for myriad covariates. Results: Advertising appeal was positively associated with future intentions to use again for electronic cigarettes ( P = .006) and hookah ( P = .001), but not cigars ( P = .486), cigarillos ( P = .126), or smokeless tobacco ( P = .109). Conclusion: Results suggest that advertising appeal may increase use of certain tobacco products among youth experiencing homelessness. However, differences in themes emphasized by advertising for specific tobacco products could differentially influence use in this population.
Development and Implementation of a Pharmacy Technician Medication History Program
Authors: Davidson Tamara R. , Hobbins Melissa A. , Blubaugh Charlene M. 
Published: October 2019

Purpose: The development and implementation of a pharmacy technician medication history program, current experience with the program, and control elements are described. Summary: A pharmacy technician medication history program was developed and implemented at a large community teaching hospital at the recommendation of a system-wide interdisciplinary medication reconciliation core team to improve the current process. Important initial steps included creation of a high-level plan for program rollout, determination of program scope and design, evaluation of staffing and workspace needs, and identification of training requirements. Development of a data collection plan for the analysis of process and outcomes measures was established to support program continuation and expansion. At the pharmacy level, regularly scheduled meetings were held to gather feedback and implement changes as the program expanded in services and scope. Educational materials were revised and additional resources created to maintain consistency with technician education. Incorporation of control elements such as monthly review of process measure data, biannual accuracy validation, and annual competency assessment helped affirm program sustainability. Throughout program implementation, the importance of using an interdisciplinary approach and establishing strong interprofessional relationships were identified as key elements for continued success. Conclusion: A successful medication history program utilizing pharmacy technicians to gather medication information can be implemented and maintained through the use of standardized training documents, regularly scheduled meetings for feedback and education, and continued interdisciplinary collaboration.