bluuebunny/crossref_metadata_2025_split huggingface dataset:
Generalisability of vaccine effectiveness estimates: an analysis of cases included in a postlicensure evaluation of 13-valent pneumococcal conjugate vaccine in the USA
Authors: Link-Gelles Ruth , Westreich Daniel , Aiello Allison E , Shang Nong , Weber David J , Rosen Jennifer B , Motala Tasneem , Mascola Laurene , Eason Jeffery , Scherzinger Karen , Holtzman Corinne , Reingold Arthur L , Barnes Meghan , Petit Susan , Farley Monica M , Harrison Lee H , Zansky Shelley , Thomas Ann , Schaffner William , McGee Lesley , Whitney Cynthia G , Moore Matthew R 
Published: August 2017

ObjectivesExternal validity, or generalisability, is the measure of how well results from a study pertain to individuals in the target population. We assessed generalisability, with respect to socioeconomic status, of estimates from a matched case–control study of 13-valent pneumococcal conjugate vaccine effectiveness for the prevention of invasive pneumococcal disease in children in the USA.DesignMatched case–control study.SettingThirteen active surveillance sites for invasive pneumococcal disease in the USA.ParticipantsCases were identified from active surveillance and controls were age and zip code matched.Outcome measuresSocioeconomic status was assessed at the individual level via parent interview (for enrolled individuals only) and birth certificate data (for both enrolled and unenrolled individuals) and at the neighbourhood level by geocoding to the census tract (for both enrolled and unenrolled individuals). Prediction models were used to determine if socioeconomic status was associated with enrolment.ResultsWe enrolled 54.6% of 1211 eligible cases and found a trend toward enrolled cases being more affluent than unenrolled cases. Enrolled cases were slightly more likely to have private insurance at birth (p=0.08) and have mothers with at least some college education (p<0.01). Enrolled cases also tended to come from more affluent census tracts. Despite these differences, our best predictive model for enrolment yielded a concordance statistic of only 0.703, indicating mediocre predictive value. Variables retained in the final model were assessed for effect measure modification, and none were found to be significant modifiers of vaccine effectiveness.ConclusionsWe conclude that although enrolled cases are somewhat more affluent than unenrolled cases, our estimates are externally valid with respect to socioeconomic status. Our analysis provides evidence that this study design can yield valid estimates and the assessing generalisability of observational data is feasible, even when unenrolled individuals cannot be contacted.
Healthcare seeking patterns of families of infants with circumcision-related morbidities from two population-based cohort studies in Ghana
Authors: Gyan Thomas , McAuley Kimberley , O'Leary Maureen , Strobel Natalie A. , Edmond Karen M. 
Published: August 2017

ObjectiveThis study assessed healthcare seeking patterns of families of infants with circumcision-related morbidities and families of infants with acute illnesses in rural Ghana.DesignTwo population-based cohort studies.SettingBrong Ahafo Region of central rural Ghana.ParticipantsA total of 22 955 infants enrolled in a large population-based trial (Neovita trial) from 16 August 2010 to 7 November 2011 and 3141 infants in a circumcision study from 21 May 2012 to 31 December 2012.Primary outcomeCare seeking for circumcision-related morbidities and acute illnesses unrelated to circumcision.ResultsTwo hundred and thirty (8.1%) infants from the circumcision study had circumcision-related morbidities and 6265 (27.3%) infants from the Neovita study had acute illnesses unrelated to circumcision. A much lower proportion (35, 15.2%) of families of infants with circumcision-related morbidities sought healthcare compared with families of infants with acute illnesses in the Neovita study (5520, 88.1%). More families sought care from formal providers (24, 69%) compared with informal providers (11, 31%) for circumcision-related morbidities. There were no obvious determinants of care seeking for acute illnesses or circumcision-related morbidities in the population.ConclusionsGovernment and non-government organisations need to improve awareness about the complications and care seeking needed for circumcision-related morbidities.
Mediating effects of self-stigma on the relationship between perceived stigma and psychosocial outcomes among psychiatric outpatients: findings from a cross-sectional survey in Singapore
Authors: Picco Louisa , Lau Ying Wen , Pang Shirlene , Abdin Edimansyah , Vaingankar Janhavi Ajit , Chong Siow Ann , Subramaniam Mythily 
Published: August 2017

ObjectivesTo examine whether self-stigma mediates the relationship between perceived stigma and quality of life, self-esteem and general functioning among outpatients with depression, schizophrenia, anxiety and obsessive-compulsive disorder (OCD).DesignCross-sectional survey.SettingOutpatient clinics at a tertiary psychiatric hospital in Singapore.Participants280 outpatients with a primary clinical diagnosis of either schizophrenia, depression, anxiety or OCD.MethodsData were collected in relation to self-stigma, perceived stigma, self-esteem, functioning and quality of life. In order to examine the mediating role of self-stigma on the relationship between perceived stigma and psychosocial outcomes, bootstrapping mediation analyses were used.ResultsMediation analyses revealed that the relationship between perceived stigma and psychosocial outcomes was subject to the effects of self-stigma among the overall sample. Separate mediation analyses were conducted by diagnoses and showed differences in the mediating effects of self-stigma. Among the whole sample and the subsample with OCD, self-stigma mediated the relationship between perceived stigma and all psychosocial outcomes. For those with anxiety, depression and schizophrenia, the mediating effects of self-stigma were present in all relationships except (1) perceived stigma with physical health in the anxiety sample, (2) perceived stigma with social relationships in the depression sample and (3) perceived stigma with physical health in the schizophrenia sample.ConclusionsThe mediating effects of self-stigma on the relationship between perceived stigma and various psychosocial outcomes are evident and differ across diagnoses. Interventions to address and reduce the effects of self-stigma along with targeted treatments and psychoeducation to assist people with mental illness overcome or better manage self-stigma while providing them the skills to counteract public stigma are needed.
Improving access to the KIS in secondary care
Authors: Hall Charlie Christopher , Lunan Carey , Finucane Anne , Spiller Juliet Anne 
Published: August 2017

BackgroundEffective communication of anticipatory care planning (ACP) discussions between patients and general practitioners across different healthcare settings is vital. In Scotland, the Key Information Summary (KIS) is a new piece of software that allows clinical data for selected patients to be shared electronically across the wider National Health Service from the primary care record. This can include details of ACP discussions and decisions. The KIS is now routinely accessible in secondary care and is available through the hospital electronic record in two formats (abbreviated and full versions).AimThe primary aim of this project was to significantly improve clinician access to the full KIS record within secondary care.MethodsFour Plan Do Study Act (PDSA) cycles were undertaken in total to improve access to the full KIS between October 2014 and March 2016 in the Medical Admissions Unit of a Scottish hospital.ResultsBaseline data showed poor awareness and use of available KIS information by clinicians for patients admitted to hospital. Most were unaware the KIS was available and only 19% had seen the KIS for their patient. Where a KIS existed for a patient, clinicians felt the information contained within it was useful in 75% of cases, and one in every five KIS could alter clinical management. Data collection following the first 3 PDSA cycles revealed a significant increase in access to the full KIS after 5 months (from 4% to 45%). However 1 year on after after a fourth PDSA cycle to implement sustainable interventions this level of access was not maintained.ConclusionsReasons for these results are discussed, as well as limitations to certain interventions. Access to the full KIS at the point of hospital admission can be significantly improved using a quality improvement approach. Improved access to this information may influence the clinical management of selected patients. However sustainable, system-wide strategies are needed to maintain these changes in the longer term.
Intended arm use influences interhemispheric correlation of β-oscillations in primate medial motor areas
Authors: Nakajima Toshi , Arisawa Haruka , Hosaka Ryosuke , Mushiake Hajime 
Published: August 2017

To investigate the role of interhemispheric β-synchronization in the selection of motor effectors, we trained two monkeys to memorize and perform multiple two-movement sequences that included unimanual repetition and bimanual switching. We recorded local field potentials simultaneously in the bilateral supplementary motor area (SMA) and pre-SMA to examine how the β-power in both hemispheres and the interhemispheric relationship of β-oscillations depend on the prepared sequence of arm use. We found a significant ipsilateral enhancement of β-power for bimanual switching trials in the left hemisphere and an enhancement of β-power in the right SMA while preparing for unimanual repetition. Furthermore, interhemispheric synchrony in the SMA was significantly more enhanced while preparing unimanual repetition than while preparing bimanual switching. This enhancement of synchrony was detected in terms of β-phase but not in terms of modulation of β-power. Furthermore, the assessment of the interhemispheric phase difference revealed that the β-oscillation in the hemisphere contralateral to the instructed arm use significantly advanced its phase relative to that in the ipsilateral hemisphere. There was no arm use-dependent shift in phase difference in the pairwise recordings within each hemisphere. Both neurons with and without arm use-selective activity were phase-locked to the β-oscillation. These results imply that the degree of interhemispheric phase synchronization as well as phase differences and oscillatory power in the β-band may contribute to the selection of arm use depending on the behavioral conditions of sequential arm use. NEW & NOTEWORTHY We addressed interhemispheric relationships of β-oscillations during bimanual coordination. While monkeys prepared to initiate movement of the instructed arm, β-oscillations in the contralateral hemisphere showed a phase advance relative to the other hemisphere. Furthermore, the sequence of arm use influenced β-power and the degree of interhemispheric phase synchronization. Thus the dynamics of interhemispheric phases and power in β-oscillations may contribute to the specification of motor effectors in a given behavioral context.
A Panel of Novel Detection and Prognostic Methylated DNA Markers in Primary Non–Small Cell Lung Cancer and Serum DNA
Authors: Ooki Akira , Maleki Zahra , Tsay Jun-Chieh J. , Goparaju Chandra , Brait Mariana , Turaga Nitesh , Nam Hae-Seong , Rom William N. , Pass Harvey I. , Sidransky David , Guerrero-Preston Rafael , Hoque Mohammad Obaidul 
Published: August 2017

Abstract
Purpose: To establish a novel panel of cancer-specific methylated genes for cancer detection and prognostic stratification of early-stage non–small cell lung cancer (NSCLC).
Experimental Design: Identification of differentially methylated regions (DMR) was performed with bumphunter on “The Cancer Genome Atlas (TCGA)” dataset, and clinical utility was assessed using quantitative methylation-specific PCR assay in multiple sets of primary NSCLC and body fluids that included serum, pleural effusion, and ascites samples.
Results: A methylation panel of 6 genes (CDO1, HOXA9, AJAP1, PTGDR, UNCX, and MARCH11) was selected from TCGA dataset. Promoter methylation of the gene panel was detected in 92.2% (83/90) of the training cohort with a specificity of 72.0% (18/25) and in 93.0% (40/43) of an independent cohort of stage IA primary NSCLC. In serum samples from the later 43 stage IA subjects and population-matched 42 control subjects, the gene panel yielded a sensitivity of 72.1% (31/41) and specificity of 71.4% (30/42). Similar diagnostic accuracy was observed in pleural effusion and ascites samples. A prognostic risk category based on the methylation status of CDO1, HOXA9, PTGDR, and AJAP1 refined the risk stratification for outcomes as an independent prognostic factor for an early-stage disease. Moreover, the paralog group for HOXA9, predominantly overexpressed in subjects with HOXA9 methylation, showed poor outcomes.
Conclusions: Promoter methylation of a panel of 6 genes has potential for use as a biomarker for early cancer detection and to predict prognosis at the time of diagnosis. Clin Cancer Res; 23(22); 7141–52. ©2017 AACR.
EPAC–RAP1 Axis-Mediated Switch in the Response of Primary and Metastatic Melanoma to Cyclic AMP
Authors: Rodríguez Carlos I. , Castro-Pérez Edgardo , Prabhakar Kirthana , Block Laura , Longley B. Jack , Wisinski Jaclyn A. , Kimple Michelle E. , Setaluri Vijayasaradhi 
Published: August 2017

Abstract
Cyclic AMP (cAMP) is an important second messenger that regulates a wide range of physiologic processes. In mammalian cutaneous melanocytes, cAMP-mediated signaling pathways activated by G-protein–coupled receptors (GPCR), like melanocortin 1 receptor (MC1R), play critical roles in melanocyte homeostasis including cell survival, proliferation, and pigment synthesis. Impaired cAMP signaling is associated with increased risk of cutaneous melanoma. Although mutations in MAPK pathway components are the most frequent oncogenic drivers of melanoma, the role of cAMP in melanoma is not well understood. Here, using the Braf(V600E)/Pten-null mouse model of melanoma, topical application of an adenylate cyclase agonist, forskolin (a cAMP inducer), accelerated melanoma tumor development in vivo and stimulated the proliferation of mouse and human primary melanoma cells, but not human metastatic melanoma cells in vitro. The differential response of primary and metastatic melanoma cells was also evident upon pharmacologic inhibition of the cAMP effector protein kinase A. Pharmacologic inhibition and siRNA-mediated knockdown of other cAMP signaling pathway components showed that EPAC–RAP1 axis, an alternative cAMP signaling pathway, mediates the switch in response of primary and metastatic melanoma cells to cAMP. Evaluation of pERK levels revealed that this phenotypic switch was not correlated with changes in MAPK pathway activity. Although cAMP elevation did not alter the sensitivity of metastatic melanoma cells to BRAF(V600E) and MEK inhibitors, the EPAC–RAP1 axis appears to contribute to resistance to MAPK pathway inhibition. These data reveal a MAPK pathway–independent switch in response to cAMP signaling during melanoma progression.
Implications: The prosurvival mechanism involving the cAMP–EPAC–RAP1 signaling pathway suggest the potential for new targeted therapies in melanoma. Mol Cancer Res; 15(12); 1792–802. ©2017 AACR.
A First-in-Class TWIST1 Inhibitor with Activity in Oncogene-Driven Lung Cancer
Authors: Yochum Zachary A. , Cades Jessica , Mazzacurati Lucia , Neumann Neil M. , Khetarpal Susheel K. , Chatterjee Suman , Wang Hailun , Attar Myriam A. , Huang Eric H.-B. , Chatley Sarah N. , Nugent Katriana , Somasundaram Ashwin , Engh Johnathan A. , Ewald Andrew J. , Cho Yoon-Jae , Rudin Charles M. , Tran Phuoc T. , Burns Timothy F. 
Published: August 2017

Abstract
TWIST1, an epithelial–mesenchymal transition (EMT) transcription factor, is critical for oncogene-driven non–small cell lung cancer (NSCLC) tumorigenesis. Given the potential of TWIST1 as a therapeutic target, a chemical–bioinformatic approach using connectivity mapping (CMAP) analysis was used to identify TWIST1 inhibitors. Characterization of the top ranked candidates from the unbiased screen revealed that harmine, a harmala alkaloid, inhibited multiple TWIST1 functions, including single-cell dissemination, suppression of normal branching in 3D epithelial culture, and proliferation of oncogene driver-defined NSCLC cells. Harmine treatment phenocopied genetic loss of TWIST1 by inducing oncogene-induced senescence or apoptosis. Mechanistic investigation revealed that harmine targeted the TWIST1 pathway through its promotion of TWIST1 protein degradation. As dimerization is critical for TWIST1 function and stability, the effect of harmine on specific TWIST1 dimers was examined. TWIST1 and its dimer partners, the E2A proteins, which were found to be required for TWIST1-mediated functions, regulated the stability of the other heterodimeric partner posttranslationally. Harmine preferentially promoted degradation of the TWIST1-E2A heterodimer compared with the TWIST-TWIST1 homodimer, and targeting the TWIST1-E2A heterodimer was required for harmine cytotoxicity. Finally, harmine had activity in both transgenic and patient-derived xenograft mouse models of KRAS-mutant NSCLC. These studies identified harmine as a first-in-class TWIST1 inhibitor with marked anti-tumor activity in oncogene-driven NSCLC including EGFR mutant, KRAS mutant and MET altered NSCLC.
Implications: TWIST1 is required for oncogene-driven NSCLC tumorigenesis and EMT; thus, harmine and its analogues/derivatives represent a novel therapeutic strategy to treat oncogene-driven NSCLC as well as other solid tumor malignancies. Mol Cancer Res; 15(12); 1764–76. ©2017 AACR.
The Influential Role of BCL2 Family Members in Synovial Sarcomagenesis
Authors: Barrott Jared J. , Zhu Ju-Fen , Smith-Fry Kyllie , Susko Asia M. , Nollner Dakota , Burrell Lance D. , Pozner Amir , Capecchi Mario R. , Yap Jeffrey T. , Cannon-Albright Lisa A. , Deng Xingming , Jones Kevin B. 
Published: August 2017

Abstract
Synovial sarcomas are deadly soft tissue malignancies associated with t(X;18) balanced chromosomal translocations. Expression of the apoptotic regulator BCL2 is prominent in synovial sarcomas and has prompted the hypothesis that synovial sarcomagenesis may depend on it. Herein, it is demonstrated that Bcl2 overexpression enhances synovial sarcomagenesis in an animal model. Furthermore, we determined increased familial clustering of human synovial sarcoma patients with victims of other BCL2-associated malignancies in the Utah Population Database. Conditional genetic disruption of Bcl2 in mice also led to reduced sarcomagenesis. Pharmacologic inhibition specific to BCL2 had no demonstrable efficacy against human synovial sarcoma cell lines or mouse tumors. However, targeting BCLxL in human and mouse synovial sarcoma with the small molecule BH3 domain inhibitor, BXI-72, achieved significant cytoreduction and increased apoptotic signaling. Thus, the contributory role of BCL2 in synovial sarcomagenesis does not appear to render it as a therapeutic target, but mitochondrial antiapoptotic BCL2 family members may be.
Implications: The association of BCL2 expression with synovial sarcoma is found to fit with a subtle, but significant, impact of its enhanced presence or absence during early tumorigenesis. However, specific pharmacologic inhibition of BCL2 does not demonstrate a persistent dependence in fully developed tumors. Conversely, inhibition of the BCL2 family member BCLxL resulted in nanomolar potency against human synovial sarcoma cell lines and 50% tumor reduction in a genetically engineered mouse model. Mol Cancer Res; 15(12); 1733–40. ©2017 AACR.
Assessment of Remote Heart Rhythm Sampling Using the AliveCor Heart Monitor to Screen for Atrial Fibrillation
Authors: Halcox Julian P.J. , Wareham Kathie , Cardew Antonia , Gilmore Mark , Barry James P. , Phillips Ceri , Gravenor Michael B. 
Published: August 2017

Background:
Asymptomatic atrial fibrillation (AF) is increasingly common in the aging population and implicated in many ischemic strokes. Earlier identification of AF with appropriate anticoagulation may decrease stroke morbidity and mortality.

Methods:
We conducted a randomized controlled trial of AF screening using an AliveCor Kardia monitor attached to a WiFi-enabled iPod to obtain ECGs (iECGs) in ambulatory patients. Patients ≥65 years of age with a CHADS-VASc score ≥2 free from AF were randomized to the iECG arm or routine care (RC). iECG participants acquired iECGs twice weekly over 12 months (plus additional iECGs if symptomatic) onto a secure study server with overread by an automated AF detection algorithm and by a cardiac physiologist and/or consultant cardiologist. Time to diagnosis of AF was the primary outcome measure. The overall cost of the devices, ECG interpretation, and patient management were captured and used to generate the cost per AF diagnosis in iECG patients. Clinical events and patient attitudes/experience were also evaluated.

Results:

We studied 1001 patients (500 iECG, 501 RC) who were 72.6±5.4 years of age; 534 were female. Mean CHADS-VASc score was 3.0 (heart failure, 1.4%; hypertension, 54%; diabetes mellitus, 30%; prior stroke/transient ischemic attack, 6.5%; arterial disease, 15.9%; all CHADS-VASc risk factors were evenly distributed between groups). Nineteen patients in the iECG group were diagnosed with AF over the 12-month study period versus 5 in the RC arm (hazard ratio, 3.9; 95% confidence interval=1.4–10.4;
P
=0.007) at a cost per AF diagnosis of $10 780 (£8255). There was a similar number of stroke/transient ischemic attack/systemic embolic events (6 versus 10, iECG versus RC; hazard ratio=0.61; 95% confidence interval=0.22–1.69;
P
=0.34). The majority of iECG patients were satisfied with the device, finding it easy to use without restricting activities or causing anxiety.

Conclusions:
Screening with twice-weekly single-lead iECG with remote interpretation in ambulatory patients ≥65 years of age at increased risk of stroke is significantly more likely to identify incident AF than RC over a 12-month period. This approach is also highly acceptable to this group of patients, supporting further evaluation in an appropriately powered, event-driven clinical trial.

Clinical Trial Registration:

URL:
https://www.isrctn.com
. Unique identifier: ISRCTN10709813.