bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomised controlled trial to investigate the effectiveness of thoracic epidural and paravertebral blockade in reducing chronic post-thoracotomy pain (TOPIC): a pilot study to assess feasibility of a large multicentre trial
Authors: Yeung Joyce , Middleton Lee , Tryposkiadis Kostas , Kerr Amy , Daniels Jane , Naidu Babu , Melody Teresa , Goebel Andreas , Wilson Matthew , Kumar Sajith , Szentgyorgyi Lajos , Flanagan Sarah , Shah Rajesh , Worrall Antony , Gao Fang 
Published: July 2019

ObjectivesThoracotomy is considered one of the most painful surgical procedures. The incidence of chronic post-thoracotomy pain (CPTP) is up to 50%. Paravertebral blockade (PVB) may be superior to thoracic epidural blockade (TEB) in preventing CPTP. The specific objective of this pilot study was to assess the feasibility of conducting a larger trial to determine whether PVB at thoracotomy is more effective in reducing CPTP compared with TEB.DesignA randomised, parallel, external pilot study was conducted to assess whether a large randomised trial of TEB and PVB with CPTP as the primary outcome is feasible.SettingTwo adult thoracic centres in the UK.ParticipantsAll adult patients admitted for elective open thoracotomy. Participants were excluded if they were American Society of Anesthesiologists physical status IV or V; or if there is contraindication to local anaesthetics; infection near the proposed puncture site; coagulation/thoracic spine disorders; required chest wall resection or emergency thoracic surgery or had a previous thoracotomy.ResultsAll patients presenting for thoracotomy were screened over a 12-month period with 194 found to be eligible. Of these, 69 (36%) were randomised (95% CI 29% to 42%). Discounting five participants who died, 54 of 64 participants (84%) returned questionnaire booklets at 6 months. The number of participants indicating at least a moderate level of chest pain at 6 months was lower with PVB but with high levels of uncertainty (RR: 0.7; 95% CI 0.3 to 1.7 for worst pain; RR: 0.3; 95% CI 0.0 to 2.8 for average pain). There were no safety concerns.ConclusionsA large, multicentre randomised controlled trial of PVB versus TEB is feasible as it is possible to randomise and follow up participants with high fidelity. Pain scores were lower on average with PVB compared with TEB but a much larger trial is required to confirm this reliably.Trial registration numberISRCTN45041624
Predicting asthma attacks in primary care: protocol for developing a machine learning-based prediction model
Authors: Tibble Holly , Tsanas Athanasios , Horne Elsie , Horne Robert , Mizani Mehrdad , Simpson Colin R , Sheikh Aziz 
Published: July 2019

IntroductionAsthma is a long-term condition with rapid onset worsening of symptoms (‘attacks’) which can be unpredictable and may prove fatal. Models predicting asthma attacks require high sensitivity to minimise mortality risk, and high specificity to avoid unnecessary prescribing of preventative medications that carry an associated risk of adverse events. We aim to create a risk score to predict asthma attacks in primary care using a statistical learning approach trained on routinely collected electronic health record data.Methods and analysisWe will employ machine-learning classifiers (naïve Bayes, support vector machines, and random forests) to create an asthma attack risk prediction model, using the Asthma Learning Health System (ALHS) study patient registry comprising 500 000 individuals across 75 Scottish general practices, with linked longitudinal primary care prescribing records, primary care Read codes, accident and emergency records, hospital admissions and deaths. Models will be compared on a partition of the dataset reserved for validation, and the final model will be tested in both an unseen partition of the derivation dataset and an external dataset from the Seasonal Influenza Vaccination Effectiveness II (SIVE II) study.Ethics and disseminationPermissions for the ALHS project were obtained from the South East Scotland Research Ethics Committee 02 [16/SS/0130] and the Public Benefit and Privacy Panel for Health and Social Care (1516–0489). Permissions for the SIVE II project were obtained from the Privacy Advisory Committee (National Services NHS Scotland) [68/14] and the National Research Ethics Committee West Midlands–Edgbaston [15/WM/0035]. The subsequent research paper will be submitted for publication to a peer-reviewed journal and code scripts used for all components of the data cleaning, compiling, and analysis will be made available in the open source GitHub website (https://github.com/hollytibble).
The (un)availability of prognostic information in the last days of life: a prospective observational study
Authors: White Nicola , Reid Fiona , Harries Priscilla , Harris Adam J L , Minton Ollie , McGowan Catherine , Lodge Philip , Tookman Adrian , Stone Patrick 
Published: July 2019

ObjectivesThe aims of this study were (1) to document the clinical condition of patients considered to be in the last 2 weeks of life and (2) to compare patients who did or did not survive for 72 hours.DesignA prospective observational study.SettingTwo sites in London, UK (a hospice and a hospital palliative care team).ParticipantsAny inpatient, over 18 years old, English speaking, who was identified by the palliative care team as at risk of dying within the next 2 weeks was eligible.Outcome measuresPrognostic signs and symptoms were documented at a one off assessment and patients were followed up 7 days later to determine whether or not they had died.ResultsFifty participants were recruited and 24/50 (48%) died within 72 hours of assessment. The most prevalent prognostic features observed were a decrease in oral food intake (60%) and a rapid decline of the participant’s global health status (56%). Participants who died within 72 hours had a lower level of consciousness and had more care needs than those who lived longer. A large portion of data was unavailable, particularly that relating to the psychological and spiritual well-being of the patient, due to the decreased consciousness of the patient.ConclusionsThe prevalence of prognostic signs and symptoms in the final days of life has been documented between those predicted to die and those who did not. How doctors make decisions with missing information is an area for future research, in addition to understanding the best way to use the available information to make more accurate predictions.
Climatic and community sociodemographic factors associated with remote Indigenous Australian smoking rates: an ecological study of health audit data
Authors: Carroll Suzanne Jane , Dale Michael J , Bailie Ross , Daniel Mark 
Published: July 2019

Australian Indigenous smoking rates are highest in remote communities but likely vary between communities; few studies have assessed community features in relation to Indigenous smoking rates.Design and objectiveThis ecological study evaluated the associations between smoking rates, and community sociodemographic and climatic characteristics for a large sample of remote Indigenous communities.Setting and sampleRecords (n=2689) from an audit of community health centres in the Northern Territory and Queensland were used to estimate smoking rates dichotomised at the median for 70 predominantly Indigenous remote communities. Community characteristics were similarly dichotomised.MethodsCross-tabulations were used to calculate the odds of a community classified as high for a sociodemographic or climatic factor also being high for smoking rate. Additional cross-tabulations, stratified by sociodemographic, region (coastal or central) and geographic connectivity levels, were performed to assess potential confounding.ResultsCommunity smoking rates ranged from 25% to 96% (median 60.2%). Moderately strong relationships were observed between community smoking rate and population size (OR 6.25,(95% CI 2.18 to 17.95)), education level (OR 3.67 (1.35–10.01)), income (2.86 (11.07–7.67)) and heat (2.86 (1.07–7.67)).ConclusionsSmoking rates in Australian remote Indigenous communities are universally high. Smoking rates are associated with greater community-level socioeconomic status and size, most likely reflecting greater means of accessing tobacco with mass of smokers sufficient to sustain a normative influence. Severe heat was also associated with high smoking rates suggesting such a stressor might support smoking as a coping mechanism. Community sociodemographic and climatic factors bear consideration as context-level correlates of community smoking rates.
Accuracy of an automated three‐dimensional technique for the computation of femoral angles in dogs
Authors: Longo Federico , Savio Gianpaolo , Contiero Barbara , Meneghello Roberto , Concheri Gianmaria , Franchini Federico , Isola Maurizio 
Published: July 2019

Aims: The purpose of the study was to evaluate the accuracy of a three‐dimensional (3D) automated technique (computer‐aided design (aCAD)) for the measurement of three canine femoral angles: anatomical lateral distal femoral angle (aLDFA), femoral neck angle (FNA) and femoral torsion angle.Methods:Twenty‐eight femurs equally divided intotwo groups (normal and abnormal) were obtained from 14 dogs of different conformations (dolicomorphic and chondrodystrophicCT scans and 3D scanner acquisitions were used to create stereolithographic (STL) files, which were run in a CAD platform. Two blinded observers separately performed the measurements using the STL obtained from CT scans (CT aCAD) and 3D scanner (3D aCAD), which was considered the gold standard method. C orrelation coefficients were used to investigate the strength of the relationship between the two measurements.Results: A ccuracy of the aCAD computation was good, being always above the threshold of R2 of greater than 80 per cent for all three angles assessed in both groups. a LDFA and FNA were the most accurate angles (accuracy >90 per cent).Conclusions: The proposed 3D aCAD protocol can be considered a reliable technique to assess femoral angle measurements in canine femur. The developed algorithm automatically calculates the femoral angles in 3D, thus considering the subjective intrinsic femur morphology. The main benefit relies on a fast user‐independent computation, which avoids user‐related measurement variability. The accuracy of 3D details may be helpful for patellar luxation and femoral bone deformity correction, as well as for the design of patient‐ specific, custom‐made hip prosthesis implants.
Mixed-polarity random-dot stereograms alter GABA and Glx concentration in the early visual cortex
Authors: Rideaux Reuben , Goncalves Nuno R. , Welchman Andrew E. 
Published: July 2019

The offset between images projected onto the left and right retina (binocular disparity) provides a powerful cue to the three-dimensional structure of the environment. It was previously shown that depth judgements are better when images comprise both light and dark features, rather than only light or only dark elements. Since Harris and Parker ( Nature 374: 808–811, 1995) discovered the “mixed-polarity benefit,” there has been limited evidence supporting their hypothesis that the benefit is due to separate bright and dark channels. Goncalves and Welchman ( Curr Biol 27: 1403–1412, 2017) observed that single- and mixed-polarity stereograms evoke different levels of positive and negative activity in a deep neural network trained on natural images to make depth judgements, which also showed the mixed-polarity benefit. Motivated by this discovery, we seek to test the potential for changes in the balance of excitation and inhibition that are produced by viewing these stimuli. In particular, we use magnetic resonance spectroscopy to measure Glx and GABA concentrations in the early visual cortex of adult humans during viewing of single- and mixed-polarity random-dot stereograms (RDS). We find that participants’ Glx concentration is significantly higher, whereas GABA concentration is significantly lower, when mixed-polarity RDS are viewed than when single-polarity RDS are viewed. These results indicate that excitation and inhibition facilitate processing of single- and mixed-polarity stereograms in the early visual cortex to different extents, consistent with recent theoretical work (Goncalves NR, Welchman AE. Curr Biol 27: 1403–1412, 2017). NEW & NOTEWORTHY Depth judgements are better when images comprise both light and dark features, rather than only light or only dark elements. Using magnetic resonance spectroscopy, we show that adult human participants’ Glx concentration is significantly higher whereas GABA concentration is significantly lower in the early visual cortex when participants view mixed-polarity random-dot stereograms (RDS) compared with single-polarity RDS. These results indicate that excitation and inhibition facilitate processing of single- and mixed-polarity stereograms in the early visual cortex to different extents.
The 24-h savings of adaptation to novel movement dynamics initially reflects the recall of previous performance
Authors: Nguyen Katrina P. , Zhou Weiwei , McKenna Erin , Colucci-Chang Katrina , Bray Laurence C. Jayet , Hosseini Eghbal A. , Alhussein Laith , Rezazad Meena , Joiner Wilsaan M. 
Published: July 2019

Humans rapidly adapt reaching movements in response to perturbations (e.g., manipulations of movement dynamics or visual feedback). Following a break, when reexposed to the same perturbation, subjects demonstrate savings, a faster learning rate compared with the time course of initial training. Although this has been well studied, there are open questions on the extent early savings reflects the rapid recall of previous performance. To address this question, we examined how the properties of initial training (duration and final adaptive state) influence initial single-trial adaptation to force-field perturbations when training sessions were separated by 24 h. There were two main groups that were distinct based on the presence or absence of a washout period at the end of day 1 (with washout vs. without washout). We also varied the training duration on day 1 (15, 30, 90, or 160 training trials), resulting in 8 subgroups of subjects. We show that single-trial adaptation on day 2 scaled with training duration, even for similar asymptotic levels of learning on day 1 of training. Interestingly, the temporal force profile following the first perturbation on day 2 matched that at the end of day 1 for the longest training duration group that did not complete the washout. This correspondence persisted but was significantly lower for shorter training durations and the washout subject groups. Collectively, the results suggest that the adaptation observed very early in reexposure results from the rapid recall of the previously learned motor recalibration but is highly dependent on the initial training duration and final adaptive state. NEW & NOTEWORTHY The extent initial readaptation reflects the recall of previous motor performance is largely unknown. We examined early single-trial force-field adaptation on the second day of training and distinguished initial retention from recall. We found that the single-trial adaptation following the 24-h break matched that at the end of the first day, but this recall was modified by the training duration and final level of learning on the first day of training.
ID1 Is Critical for Tumorigenesis and Regulates Chemoresistance in Glioblastoma
Authors: Sachdeva Rohit , Wu Megan , Smiljanic Sandra , Kaskun Oleksandra , Ghannad-Zadeh Kimia , Celebre Angela , Isaev Keren , Morrissy A. Sorana , Guan Jennifer , Tong Jiefei , Chan Jeffrey , Wilson Taylor M. , Al-Omaishi Sayf , Munoz David G. , Dirks Peter B. , Moran Michael F. , Taylor Michael D. , Reimand Jüri , Das Sunit 
Published: July 2019

Abstract

Glioblastoma is the most common primary brain tumor in adults. While the introduction of temozolomide chemotherapy has increased long-term survivorship, treatment failure and rapid tumor recurrence remains universal. The transcriptional regulatory protein, inhibitor of DNA-binding-1 (ID1), is a key regulator of cell phenotype in cancer. We show that CRISPR-mediated knockout of ID1 in glioblastoma cells, breast adenocarcinoma cells, and melanoma cells dramatically reduced tumor progression in all three cancer systems through transcriptional downregulation of EGF, which resulted in decreased EGFR phosphorylation. Moreover, ID1-positive cells were enriched by chemotherapy and drove tumor recurrence in glioblastoma. Addition of the neuroleptic drug pimozide to inhibit ID1 expression enhanced the cytotoxic effects of temozolomide therapy on glioma cells and significantly prolonged time to tumor recurrence. Conclusively, these data suggest ID1 could be a promising therapeutic target in patients with glioblastoma.

Significance:
These findings show that the transcriptional regulator ID1 is critical for glioblastoma initiation and chemoresistance and that inhibition of ID1 enhances the effect of temozolomide, delays tumor recurrence, and prolongs survival.
Metformin Inhibits Progression of Head and Neck Squamous Cell Carcinoma by Acting Directly on Carcinoma-Initiating Cells
Authors: Wu Xingyu , Yeerna Huwate , Goto Yusuke , Ando Toshinori , Wu Victoria H. , Zhang Xuefeng , Wang Zhiyong , Amornphimoltham Panomwat , Murphy Anne N. , Tamayo Pablo , Chen Qianming , Lippman Scott M. , Gutkind J. Silvio 
Published: July 2019

AbstractMetformin may reduce the progression of head and neck squamous cell carcinoma (HNSCC); however, whether metformin acts by altering the host metabolism or targets cancer-initiating cells remains poorly understood. This gap in knowledge has prevented the stratification of patient populations who are most likely to benefit from metformin treatment. Here, we explored whether metformin acts directly on HNSCC cells to inhibit aberrant cell growth. To investigate the tumor cell autonomous effects of metformin, we engineered representative HPV− and HPV+ HNSCC cells harboring typical genetic alternations to express the yeast mitochondrial NADH dehydrogenase (NDI1) protein, which is insensitive to metformin. NDI1 expression rescued the inhibitory effects of metformin on mitochondrial complex I, abolished the ability of metformin to activate AMP-activated protein kinase, and inhibited mTOR signaling both in vitro and in vivo, and was sufficient to render metformin ineffective to prevent HNSCC tumor growth. This experimental system provided an opportunity to identify metformin-regulated transcriptional programs linked to cancer cell growth inhibition in the tumor microenvironment. Remarkably, computational analysis of the metformin-induced transcriptome revealed that metformin downregulated gene expression signatures associated with cancer stemness and epithelial–mesenchymal transition, concomitant with increased expression of squamous differentiation genes. These findings support that metformin may act directly on cancer-initiating cells to prevent their progression to HNSCC, which may inform the selection of patients at risk of developing HNSCC in future early-stage clinical trials.Significance:Metformin's ability to directly target HNSCC-initiating cells instead of exerting cancer preventive activity based solely on its systemic effects may inform the selection of patients in future precision prevention trials.
Recent Advances Targeting CCR5 for Cancer and Its Role in Immuno-Oncology
Authors: Jiao Xuanmao , Nawab Omar , Patel Tejal , Kossenkov Andrew V. , Halama Niels , Jaeger Dirk , Pestell Richard G. 
Published: July 2019

Abstract
Experiments of nature have revealed the peculiar importance of the G-protein–coupled receptor, C-C chemokine receptor type 5 (CCR5), in human disease since ancient times. The resurgence of interest in heterotypic signals in the onset and progression of tumorigenesis has led to the current focus on CCR5 as an exciting new therapeutic target for metastatic cancer with clinical trials now targeting breast and colon cancer. The eutopic expression of CCR5 activates calcium signaling and thereby augments regulatory T cell (Treg) differentiation and migration to sites of inflammation. The misexpression of CCR5 in epithelial cells, induced upon oncogenic transformation, hijacks this migratory phenotype. CCR5 reexpression augments resistance to DNA-damaging agents and is sufficient to induce cancer metastasis and “stemness”. Recent studies suggest important cross-talk between CCR5 signaling and immune checkpoint function. Because CCR5 on Tregs serves as the coreceptor for human immunodeficiency virus (HIV) entry, CCR5-targeted therapeutics used in HIV, [small molecules (maraviroc and vicriviroc) and a humanized mAb (leronlimab)], are now being repositioned in clinical trials as cancer therapeutics. As CCR5 is expressed on a broad array of tumors, the opportunity for therapeutic repositioning and the rationale for combination therapy approaches are reviewed herein.
Risk Prediction Models for Colorectal Cancer Incorporating Common Genetic Variants: A Systematic Review
Authors: McGeoch Luke , Saunders Catherine L. , Griffin Simon J. , Emery Jon D. , Walter Fiona M. , Thompson Deborah J. , Antoniou Antonis C. , Usher-Smith Juliet A. 
Published: July 2019

Abstract
Colorectal cancer screening reduces colorectal cancer incidence and mortality. Risk models based on phenotypic variables have relatively good discrimination in external validation and may improve efficiency of screening. Models incorporating genetic variables may perform better. In this review, we updated our previous review by searching Medline and EMBASE from the end date of that review (January 2014) to February 2019 to identify models incorporating at least one SNP and applicable to asymptomatic individuals in the general population. We identified 23 new models, giving a total of 29. Of those in which the SNP selection was on the basis of published genome-wide association studies, in external or split-sample validation the AUROC was 0.56 to 0.57 for models that included SNPs alone, 0.61 to 0.63 for SNPs in combination with other risk factors, and 0.56 to 0.70 when age was included. Calibration was only reported for four. The addition of SNPs to other risk factors increases discrimination by 0.01 to 0.06. Public health modeling studies suggest that, if determined by risk models, the range of starting ages for screening would be several years greater than using family history alone. Further validation and calibration studies are needed alongside modeling studies to assess the population-level impact of introducing genetic risk–based screening programs.