bluuebunny/crossref_metadata_2025_split huggingface dataset:
Do antidepressants increase the risk of mania and bipolar disorder in people with depression? A retrospective electronic case register cohort study
Authors: Patel Rashmi , Reiss Peter , Shetty Hitesh , Broadbent Matthew , Stewart Robert , McGuire Philip , Taylor Matthew 
Published: December 2015

ObjectivesTo investigate the association between antidepressant therapy and the later onset of mania/bipolar disorder.DesignRetrospective cohort study using an anonymised electronic health record case register.SettingSouth London and Maudsley National Health Service (NHS) Trust (SLaM), a large provider of inpatient and community mental healthcare in the UK.Participants21 012 adults presenting to SLaM between 1 April 2006 and 31 March 2013 with unipolar depression.ExposurePrior antidepressant therapy recorded in electronic health records.Main outcome measureTime to subsequent diagnosis of mania or bipolar disorder from date of diagnosis of unipolar depression, censored at 31 March 2014.MethodsMultivariable Cox regression analysis with age and gender as covariates.ResultsThe overall incidence rate of mania/bipolar disorder was 10.9 per 1000 person-years. The peak incidence of mania/bipolar disorder incidence was seen in patients aged between 26 and 35 years (12.3 per 1000 person-years). Prior antidepressant treatment was associated with an increased incidence of mania/bipolar disorder ranging from 13.1 to 19.1 per 1000 person-years. Multivariable analysis indicated a significant association with selective serotonin reuptake inhibitors (HR 1.34, 95% CI 1.18 to 1.52) and venlafaxine (1.35, 1.07 to 1.70).ConclusionsIn people with unipolar depression, antidepressant treatment is associated with an increased risk of subsequent mania/bipolar disorder. These findings highlight the importance of considering risk factors for mania when treating people with depression.
Associations between stress disorders and cardiovascular disease events in the Danish population
Authors: Gradus Jaimie L , Farkas Dóra Körmendiné , Svensson Elisabeth , Ehrenstein Vera , Lash Timothy L , Milstein Arnold , Adler Nancy , Sørensen Henrik Toft 
Published: December 2015

ObjectivesPost-traumatic stress disorder (PTSD) is a well-documented risk factor for cardiovascular disease (CVD). However, it is unknown whether another common stress disorder—adjustment disorder—is also associated with an increased risk of CVD and whether gender modifies these associations. The aim of this study was to examine the overall and gender-stratified associations between PTSD and adjustment disorder and 4 CVD events.DesignProspective cohort study utilising Danish national registry data.SettingThe general population of Denmark.ParticipantsPTSD (n=4724) and adjustment disorder (n=64 855) cohorts compared with the general population of Denmark from 1995 to 2011.Primary outcome measuresCVD events including myocardial infarction (MI), stroke, ischaemic stroke and venous thromboembolism (VTE). Standardised incidence rates and 95% CIs were calculated.ResultsAssociations were found between PTSD and all 4 CVD events ranging from 1.5 (95% CI 1.1 to 1.9) for MI to 2.1 (95% CI 1.7 to 2.7) for VTE. Associations that were similar in magnitude were also found for adjustment disorder and all 4 CVD events: 1.5 (95% CI 1.4 to 1.6) for MI to 1.9 (95% CI 1.8 to 2.0) for VTE. No gender differences were noted.ConclusionsBy expanding beyond PTSD and examining a second stress disorder—adjustment disorder—this study provides evidence that stress-related psychopathology is associated with CVD events. Further, limited evidence of gender differences in associations for either of the stress disorders and CVD was found.
Cancer treatment decision-making processes for older patients with complex needs: a qualitative study
Authors: Bridges Jackie , Hughes Jane , Farrington Naomi , Richardson Alison 
Published: December 2015

ObjectivesAlthough older people can experience complex health and social care needs alongside a primary cancer diagnosis, little is understood about how cancer treatment decisions are made for this population. This study aimed to investigate how cancer treatment decisions are formulated for older people with complex health and social care needs and the factors that shape these processes.DesignQualitative study involving semistructured interviews and non-participant observations. Framework approach used for data analysis.SettingBreast and colorectal cancer services in five English NHS hospital trusts.ParticipantsInterviews: purposive sample of 22 clinicians directly involved in a face-to-face clinical role with patients regarding cancer treatment and care, maximising variation across clinical roles, tumour types and trusts. Observations: purposive sample of five cancer multidisciplinary meetings, maximising variation across location, team size and tumour type.ResultsThe initial stages of cancer treatment decision-making are team-based, medically dominated and focused on the cancer. For patients with complex health and social care needs that extend beyond cancer pathology, later and less visible stages in the decision-making process are more haphazard and may result in less effective and workable treatment plans, as individual clinicians struggle to devise and deliver these plans without breaching time-based targets.ConclusionsService targets that focus resources solely on the presenting disease can disadvantage older patients with complex health and social care needs that extend beyond this primary diagnosis. Care should be taken to ensure time-based targets do not disincentivise thorough and timely assessment that can lead to the formulation of treatment plans tailored to individual needs and circumstances.
Klotho expression in cervical cancer: differential expression in adenocarcinoma and squamous cell carcinoma
Authors: Aviel-Ronen Sarit , Rubinek Tami , Zadok Oranit , Vituri Aya , Avivi Camila , Wolf Ido , Barshack Iris 
Published: December 2015

AimsKlotho is a trans-membrane protein that serves as a tumour suppressor in a wide array of malignancies. Recent data suggest it as an epigenetically silenced tumour suppressor in cervical cancer. Yet, the expression pattern of klotho in cervical cancer has not been determined. We aimed to study the expression of klotho in squamous cell carcinomas (SQCC) and adenocarcinoma (ADC) of the cervix.MethodsKlotho expression was analysed by immunohistochemistry in 44 SQCC samples, 38 ADC samples and the adjacent normal tissue. For each sample, percentage of positive stained cells, staining intensity and a combined staining score were recorded. Staining was validated by measuring klotho mRNA levels, using quantitative RT-PCR, in 18 of the samples.ResultsKlotho expression was high in all endocervical and exocervical normal tissues adjacent to tumour. No expression of klotho was noted in 7 out of 38 (18.4%) ADC samples and in 2 out of 44 (4.5%) SQCC samples. Staining intensity, number of positively stained cells and combined intensity score were all lower in tumours compared with normal adjacent tissues in ADC and SQCC. Klotho mRNA levels highly correlated with immunohistochemical (IHC) staining (p=0.008).ConclusionsWe found reduced klotho expression in cervical carcinoma, especially in ADC, compared with normal adjacent tissue. Our results support the role of klotho as a potential tumour suppressor in cervical cancer. Further studies are required in order to establish the therapeutic role of klotho in cervical carcinoma and identify patients who may benefit from it.
CCR 20th Anniversary Commentary: MAPK/ERK Pathway Inhibition in Melanoma—Kinase Inhibition Redux
Authors: Davar Diwakar , Kirkwood John M. 
Published: December 2015

Abstract
In the January 15, 2012, issue of Clinical Cancer Research, Kirkwood and colleagues published a study comparing the MEK inhibitor selumetinib with temozolomide in unselected metastatic melanoma. Although selumetinib did not improve survival or response, most responders had BRAF-activating mutations, and selumetinib has since demonstrated efficacy in BRAF-mutant melanoma. This study laid the groundwork for the evaluation of BRAF/MEK inhibitors in BRAF-mutant melanoma. Clin Cancer Res; 21(24); 5412–4. ©2015 AACR.
See related article by Kirkwood et al., Clin Cancer Res 2011;18(2) January 15, 2012;555–67
Nicotine Reduces Survival via Augmentation of Paracrine HGF–MET Signaling in the Pancreatic Cancer Microenvironment
Authors: Delitto Daniel , Zhang Dongyu , Han Song , Black Brian S. , Knowlton Andrea E. , Vlada Adrian C. , Sarosi George A. , Behrns Kevin E. , Thomas Ryan M. , Lu Xiaomin , Liu Chen , George Thomas J. , Hughes Steven J. , Wallet Shannon M. , Trevino Jose G. 
Published: December 2015

Abstract
Purpose: The relationship between smoking and pancreatic cancer biology, particularly in the context of the heterogeneous microenvironment, remains incompletely defined. We hypothesized that nicotine exposure would lead to the augmentation of paracrine growth factor signaling between tumor-associated stroma (TAS) and pancreatic cancer cells, ultimately resulting in accelerated tumor growth and metastasis.
Experimental Design: The effect of tobacco use on overall survival was analyzed using a prospectively maintained database of surgically resected patients with pancreatic cancer. Nicotine exposure was evaluated in vitro using primary patient–derived TAS and pancreatic cancer cells independently and in coculture. Nicotine administration was then assessed in vivo using a patient-derived pancreatic cancer xenograft model.
Results: Continued smoking was associated with reduced overall survival after surgical resection. In culture, nicotine-stimulated hepatocyte growth factor (HGF) secretion in primary patient-derived TAS and nicotine stimulation was required for persistent pancreatic cancer cell c-Met activation in a coculture model. c-Met activation in this manner led to the induction of inhibitor of differentiation-1 (Id1) in pancreatic cancer cells, previously established as a mediator of growth, invasion and chemoresistance. HGF-induced Id1 expression was abrogated by both epigenetic and pharmacologic c-Met inhibition. In patient-derived pancreatic cancer xenografts, nicotine treatment augmented tumor growth and metastasis; tumor lysates from nicotine-treated mice demonstrated elevated HGF expression by qRT-PCR and phospho-Met levels by ELISA. Similarly, elevated levels of phospho-Met in surgically resected pancreatic cancer specimens correlated with reduced overall survival.
Conclusions: Taken together, these data demonstrate a novel, microenvironment-dependent paracrine signaling mechanism by which nicotine exposure promotes the growth and metastasis of pancreatic cancer. Clin Cancer Res; 22(7); 1787–99. ©2015 AACR.
Mechanisms for the Termination of Atrial Fibrillation by Localized Ablation
Authors: Rappel Wouter-Jan , Zaman Junaid A.B. , Narayan Sanjiv M. 
Published: December 2015

Background—
Human atrial fibrillation (AF) can terminate after ablating localized regions, which supports the existence of localized rotors (spiral waves) or focal drivers. However, it is unclear why ablation near a spiral wave tip would terminate AF and not anchor reentry. We addressed this question by analyzing competing mechanisms for AF termination in numeric simulations, referenced to clinical observations.

Methods and Results—
Spiral wave reentry was simulated in monodomain 2-dimensional myocyte sheets using clinically realistic rate-dependent values for repolarization and conduction. Heterogeneous models were created by introduction of parameterized variations in tissue excitability. Ablation lesions were applied as nonconducting circular regions. Models confirmed that localized ablation may anchor spiral wave reentry, producing organized tachycardias. Several mechanisms referenced to clinical observations explained termination of AF to sinus rhythm. First, lesions may create an excitable gap vulnerable to invasion by fibrillatory waves. Second, ablation of rotors in regions of low-excitability (from remodeling) produced re-entry in more excitable tissue allowing collision of wavefront and back. Conversely, ablation of rotors in high-excitability regions migrated spiral waves to less excitable tissue, where they detached to collide with nonconducting boundaries. Third, ablation may connect rotors to nonconducting anatomic orifices. Fourth, reentry through slow-conducting channels may terminate if ablation closes these channels.

Conclusions—
Limited ablation can terminate AF by several mechanisms. These data shed light on how clinical AF may be sustained in patients’ atria, emphasizing heterogeneities in tissue excitability, slow-conducting channels, and obstacles that are increasingly detectable in patients and should be the focus of future translational studies.
Neuropsychological Status and Structural Brain Imaging in Adolescents With Single Ventricle Who Underwent the Fontan Procedure
Authors: Bellinger David C. , Watson Christopher G. , Rivkin Michael J. , Robertson Richard L. , Roberts Amy E. , Stopp Christian , Dunbar‐Masterson Carolyn , Bernson Dana , DeMaso David R. , Wypij David , Newburger Jane W. 
Published: December 2015

Background
Few studies have described the neuropsychological outcomes and frequency of structural brain or genetic abnormalities in adolescents with single ventricle who underwent the Fontan procedure.

Methods and Results

In a cross‐sectional, single‐center study, we enrolled 156 subjects with single ventricle, mean age 14.5±2.9 years, who had undergone the Fontan procedure. Scores in the entire cohort on a standard battery of neuropsychological tests were compared with those of normative populations or to those of a group of 111 locally recruited healthy adolescents. They also underwent brain magnetic resonance imaging and were evaluated by a clinical geneticist. Genetic abnormalities were definite in 16 subjects (10%) and possible in 49 subjects (31%). Mean Full‐Scale
IQ
was 91.6±16.8, mean Reading Composite score was 91.9±17.2, and mean Mathematics Composite score was 92.0±22.9, each significantly lower than the population means of 100±15. Mean scores on other neuropsychological tests were similarly lower than population norms. In multivariable models, risk factors for worse neuropsychological outcomes were longer total support and circulatory arrest duration at first operation, presence of a genetic abnormality, more operations and operative complications, more catheterization complications, and seizure history. The frequency of any abnormality on magnetic resonance imaging was 11 times higher among Fontan adolescents than referents (66% versus 6%); 19 (13%) patients had evidence of a stroke, previously undiagnosed in 7 patients (40%).

Conclusions
The neuropsychological deficits and high frequencies of structural brain abnormalities in adolescents who underwent the Fontan procedure highlight the need for research on interventions to improve the long‐term outcomes in this high‐risk group.
A Retrieval of Tropical Latent Heating Using the 3D Structure of Precipitation Features
Authors: Ahmed Fiaz , Schumacher Courtney , Feng Zhe , Hagos Samson 
Published: December 2015

AbstractRadar-based latent heating retrievals typically apply a lookup table (LUT) derived from model output to surface rain amounts and rain type to determine the vertical structure of heating. In this study, a method has been developed that uses the size characteristics of precipitating systems (i.e., area and mean echo-top height) instead of rain amount to estimate latent heating profiles from radar observations. This technique [named the convective–stratiform area (CSA) algorithm] leverages the relationship between the organization of convective systems and the structure of latent heating profiles and avoids pitfalls associated with retrieving accurate rainfall information from radars and models. The CSA LUTs are based on a high-resolution regional model simulation over the equatorial Indian Ocean. The CSA LUTs show that convective latent heating increases in magnitude and height as area and echo-top heights grow, with a congestus signature of midlevel cooling for less vertically extensive convective systems. Stratiform latent heating varies weakly in vertical structure, but its magnitude is strongly linked to area and mean echo-top heights. The CSA LUT was applied to radar observations collected during the DYNAMO/Cooperative Indian Ocean Experiment on Intraseasonal Variability in the Year 2011 (CINDY2011)/ARM MJO Investigation Experiment (AMIE) field campaign, and the CSA heating retrieval was generally consistent with other measures of heating profiles. The impact of resolution and spatial mismatch between the model and radar grids is addressed, and unrealistic latent heating profiles in the stratiform LUT, namely, a low-level heating peak, an elevated melting layer, and net column cooling, were identified. These issues highlight the need for accurate convective–stratiform separations and improvement in PBL and microphysical parameterizations.
Dynamics of Cloud-Top Generating Cells in Winter Cyclones. Part I: Idealized Simulations in the Context of Field Observations
Authors: Keeler Jason M. , Jewett Brian F. , Rauber Robert M. , McFarquhar Greg M. , Rasmussen Roy M. , Xue Lulin , Liu Changhai , Thompson Gregory 
Published: December 2015

Abstract
This paper assesses the influence of radiative forcing and latent heating on the development and maintenance of cloud-top generating cells (GCs) in high-resolution idealized Weather Research and Forecasting Model simulations with initial conditions representative of the vertical structure of a cyclone observed during the Profiling of Winter Storms campaign. Simulated GC kinematics, structure, and ice mass are shown to compare well quantitatively with Wyoming Cloud Radar, cloud probe, and other observations. Sensitivity to radiative forcing was assessed in simulations with longwave-only (nighttime), longwave-and-shortwave (daytime), and no-radiation parameterizations. The domain-averaged longwave cooling rate exceeded 0.50 K h−1 near cloud top, with maxima greater than 2.00 K h−1 atop GCs. Shortwave warming was weaker by comparison, with domain-averaged values of 0.10–0.20 K h−1 and maxima of 0.50 K h−1 atop GCs. The stabilizing influence of cloud-top shortwave warming was evident in the daytime simulation’s vertical velocity spectrum, with 1% of the updrafts in the 6.0–8.0-km layer exceeding 1.20 m s−1, compared to 1.80 m s−1 for the nighttime simulation. GCs regenerate in simulations with radiative forcing after the initial instability is released but do not persist when radiation is not parameterized, demonstrating that radiative forcing is critical to GC maintenance under the thermodynamic and vertical wind shear conditions in this cyclone. GCs are characterized by high ice supersaturation (RHice &gt; 150%) and latent heating rates frequently in excess of 2.00 K h−1 collocated with vertical velocity maxima. Ice precipitation mixing ratio maxima of greater than 0.15 g kg−1 were common within GCs in the daytime and nighttime simulations.
Dynamics of Cloud-Top Generating Cells in Winter Cyclones. Part II: Radiative and Instability Forcing
Authors: Keeler Jason M. , Jewett Brian F. , Rauber Robert M. , McFarquhar Greg M. , Rasmussen Roy M. , Xue Lulin , Liu Changhai , Thompson Gregory 
Published: December 2015

Abstract
Recent field observations suggest that cloud-top precipitation generating cells (GCs) are ubiquitous in the warm-frontal and comma-head regions of midlatitude winter cyclones. The presence of fallstreaks emanating from the GCs and their persistence either to the surface or until merging into precipitation bands suggests that GCs are a critical component of the precipitation process in these cyclones. This paper is the second part of a three-part series that investigates the dynamics of GCs through very-high-resolution idealized Weather Research and Forecasting (WRF) Model simulations. This paper assesses the role of cloud-top instability paired with nighttime, daytime, or no radiative forcing on the development and maintenance (or lack) of GCs. Under initially unstable conditions at cloud top, GCs develop regardless of radiative forcing but only persist clearly with radiative forcing. Cloud-top destabilization due to longwave cooling leads to development of GCs even under initially neutral and stable conditions, providing a physical explanation for the observed ubiquity of GCs atop winter cyclones. GCs do not develop in initially stable simulations with no radiation. Decreased range in vertical velocity spectra under daytime radiative forcing is consistent with offset of the destabilizing influence of longwave cooling by shortwave heating.
The immunogenicity of platelet-derived FVIII in hemophilia A mice with or without preexisting anti-FVIII immunity
Authors: Chen Yingyu , Schroeder Jocelyn A. , Chen Juan , Luo Xiaofeng , Baumgartner Christina K. , Montgomery Robert R. , Hu Jianda , Shi Qizhen 
Published: December 2015

Key PointsInfusion of platelets containing FVIII triggers neither a primary nor memory anti-FVIII immune response in hemophilia A mice. Total body irradiation plus platelet-FVIII infusion suppresses anti-FVIII immune response.
In vivo experience with natural scaffolds for myocardial infarction: the times they are a-changin’
Authors: Perea-Gil Isaac , Prat-Vidal Cristina , Bayes-Genis Antoni 
Published: December 2015

AbstractTreating a myocardial infarction (MI), the most frequent cause of death worldwide, remains one of the most exciting medical challenges in the 21st century. Cardiac tissue engineering, a novel emerging treatment, involves the use of therapeutic cells supported by a scaffold for regenerating the infarcted area. It is essential to select the appropriate scaffold material; the ideal one should provide a suitable cellular microenvironment, mimic the native myocardium, and allow mechanical and electrical coupling with host tissues. Among available scaffold materials, natural scaffolds are preferable for achieving these purposes because they possess myocardial extracellular matrix properties and structures. Here, we review several natural scaffolds for applications in MI management, with a focus on pre-clinical studies and clinical trials performed to date. We also evaluate scaffolds combined with different cell types and proteins for their ability to promote improved heart function, contractility and neovascularization, and attenuate adverse ventricular remodeling. Although further refinement is necessary in the coming years, promising results indicate that natural scaffolds may be a valuable translational therapeutic option with clinical impact in MI repair.