bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of tumor mutation burden, PD-L1 and DNA repair genes to assess relationship to immune checkpoint inhibitors response in metastatic renal cell carcinoma
Authors: Labriola Matthew Kyle , Zhu Jason , Gupta Rajan , McCall Shannon , Jackson Jennifer , Kong Eric F , White James R , Cerqueira Gustavo , Gerding Kelly , Simmons John K , George Daniel , Zhang Tian 
Published: March 2020

BackgroundImmune checkpoint inhibitors (ICIs) have expanded treatment options for metastatic renal cell carcinoma (mRCC); however, there are limited predictive biomarkers for response to ICIs in this indication, with programmed death-ligand 1 (PD-L1) status demonstrating little predictive utility in mRCC. While predictive of ICI response in other tumor types, the utility of tumor mutation burden (TMB) in mRCC is unclear. Here, we assess TMB, loss of antigen presentation genes and PD-L1 status correlated with outcomes to ICI treatment in mRCC.MethodsTumor samples from 34 patients with mRCC treated with ICI therapy at Duke Cancer Institute were retrospectively evaluated using Personal Genome Diagnostics elio tissue complete (RUO version), a tumor genomic profiling assay for somatic variants, TMB, microsatellite status and genomic status of antigen presentation genes. Tumor samples were also analyzed with the Dako 28-8 PD-L1 immunohistochemistry assay. Deidentified clinical information was extracted from the medical record, and tumor response was evaluated based on the Response Evaluation Criteria In Solid Tumors (RECIST) V.1.1 criteria.ResultsPatients were stratified by overall response following ICI therapy and designated as progressive disease (PD; n=18) or disease control groups (DC; n=16). TMB scores ranged from 0.36 to 12.24 mutations/Mb (mean 2.83 mutations/Mb) with no significant difference between the PD and DC groups (3.01 vs 2.63 mutations/Mb, respectively; p=0.7682). Interestingly, 33% of PD patients displayed loss of heterozygosity of major histocompatibility complex class I genes (LOH-MHC) vs 6% of DC patients. Nine of 34 samples were PD-L1-positive (4 in the PD group; 5 in the DC group), suggesting no correlation between PD-L1 expression and response to ICI therapy. Notably, the DC group displayed an enrichment of mutations in DNA repair genes (p=0.04), with 68.8% exhibiting at least one mutated homologous recombination repair (HRR)-related gene compared with only 38.9% of the PD group (p=0.03).ConclusionsOverall, neither TMB nor PD-L1 correlated with ICI response and TMB was not significantly associated with PD-L1 expression. The higher incidence of LOH-MHC in PD group suggests that loss of antigen presentation may restrict response to ICIs. Separately, enrichment of HRR gene mutations in the DC group suggests potential utility in predicting ICI response and a potential therapeutic target, warranting future studies.
Unlocking medical leadership’s potential: a multilevel virtuous circle?
Authors: Keijser Wouter , Martin Graeme 
Published: March 2020

Background and aimMedical leadership (ML) has been introduced in many countries, promising to support healthcare services improvement and help further system reform through effective leadership behaviours. Despite some evidence of its success, such lofty promises remain unfulfilled.MethodCouched in extant international literature, this paper provides a conceptual framework to analyse ML’s potential in the context of healthcare’s complex, multifaceted setting.ResultsWe identify four interrelated levels of analysis, or domains, that influence ML’s potential to transform healthcare delivery. These are the healthcare ecosystem domain, the professional domain, the organisational domain and the individual doctor domain. We discuss the tensions between the various actors working in and across these domains and argue that greater multilevel and multistakeholder collaborative working in healthcare is necessary to reprofessionalise and transform healthcare ecosystems.
Step-downs reduce workers’ compensation payments to encourage return to work: are they effective?
Authors: Lane Tyler J , Sheehan Luke , Gray Shannon E , Beck Dianne , Collie Alex 
Published: March 2020

ObjectiveTo determine whether step-downs, which cut the rate of compensation paid to injured workers after they have been on benefits for several months, are effective as a return to work incentive.MethodsWe aggregated administrative claims data from seven Australian workers’ compensation systems to calculate weekly scheme exit rates, a proxy for return to work. Jurisdictions were further subdivided into four injury subgroups: fractures, musculoskeletal, mental health and other trauma. The effect of step-downs on scheme exit was tested using a regression discontinuity design. Results were pooled into meta-analyses to calculate combined effects and the proportion of variance attributable to heterogeneity.ResultsThe combined effect of step-downs was a 0.86 percentage point (95% CI −1.45 to −0.27) reduction in the exit rate, with significant heterogeneity between jurisdictions (I2=68%, p=0.003). Neither timing nor magnitude of step-downs was a significant moderator of effects. Within injury subgroups, only fractures had a significant combined effect (−0.84, 95% CI −1.61 to −0.07). Sensitivity analysis indicated potential effects within mental health and musculoskeletal conditions as well.ConclusionsThe results suggest some workers’ compensation recipients anticipate step-downs and exit the system early to avoid the reduction in income. However, the effects were small and suggest step-downs have marginal practical significance. We conclude that step-downs are generally ineffective as a return to work policy initiative.Postprint link:https://www.medrxiv.org/content/10.1101/19012286
Relationship between body mass index and ischaemic stroke in Chinese elderly hypertensive patients
Authors: Huang Jiayi , Liu Lin , Yu Yu-Ling , Chen Chao-Lei , Lo Kenneth , Huang Yu-Qing , Tang Song-tao , Feng Ying Qing 
Published: March 2020

ABSTRACTBackgroundDespite obesity being a major risk factor for ischaemic stroke (IS), the association between body mass index (BMI) and IS in patients with hypertension remains uncertain.ObjectiveTo assess the association between BMI and IS among elderly hypertensive patients in China.Methods and resultsWe recruited 3500 hypertensive patients aged ≥60 between 1 January 2010 and 31 December 2011 in China and ascertained their stroke status until December 2016. Multivariate Cox regression was used to evaluate the association between BMI and IS with interaction tests for exposure and covariates. A total of 3315 subjects (mean age 71.41±7.20 years, 44.5% were men) were included for data analysis. During an average follow-up period of 5.5 years, there were 206 onset cases (6.21%) of IS. When BMI was treated as a continuous variable, it was positively associated with the incidence of new onset IS (HR=1.14; 95% CI: 1.05 to 1.34; p=0.005) after adjusting for potential confounders. Meanwhile, when BMI was treated as a categorical variable, the highest category (≥28 kg/m2) was strongly associated with an increased risk for IS compared with normal BMI category (18.5 to 24 kg/m2) (HR=1.36, 95% CI: 1.09 to 1.80; p&lt;0.001) in the fully adjusted model. Subgroup and interaction analysis also demonstrated that BMI independently associated with IS among males, smokers, alcohol drinkers, diabetic patients, people with uncontrolled blood pressure, decreased estimated glomerular filtration rate and those aged ≥70 years.ConclusionBMI was significantly associated with IS and was an independent risk of IS in Chinese elderly hypertensive patients.
Understanding the role of Foundation doctors through a self-reported time-mapping pilot study
Authors: Schuster-Bruce James , Lingam Gita , Love Ryan Laurence , Kerstein Ryan 
Published: March 2020

AbstractIntroductionThere is a reduction in Foundation trainee applications to speciality training and this is attributed to an administrative job role, with subsequent fears of burnout. This pilot study presents the findings of a real-time self-reporting tool to map a group of Foundation doctors’ elective activities. Self-reporting is efficient, low cost to run and allows for repeated measures and scalability. It aimed to example how a time-map could be used by departments to address any work imbalances and improve both well-being and future workforce planning.MethodFoundation doctors’, at a busy District General Hospital, were asked to contemporaneously report their work activities over an ‘elective’ day. Outcomes measures included the mean duration per task and the time of day these were performed.ResultsNine Foundation doctors’ returned 26 timesheet days. Foundation doctors’ time was split between direct patient tasks (18.2%, 106.8 min per day), indirect patient tasks (72.9%, 428.6 min per day) and personal or non-patient activities. Indirect tasks were the most frequent reason for Foundation doctors leaving late. No clinical experience was recorded at all and only an average of 4% (23.4 min per day) of a Foundation doctors’ time was spent in theatre.ConclusionsThis particular cohort performed a high proportion of indirect tasks. These have been associated with burnout. Time-mapping is a low-cost, acceptable and seemingly scalable way to elucidate a clearer understanding of the type of activities Foundation doctors may perform. This methodology could be used to modernise the traditional Foundation doctor job description.
Tobacco price increases in Korea and their impact on socioeconomic inequalities in smoking and subsequent socioeconomic inequalities in mortality: a modelling study
Authors: Lim Hwa-Kyung , Khang Young-Ho 
Published: March 2020

ObjectiveThrough a modelling study, we assessed the impact of tobacco price increases on smoking and smoking inequalities by income, and then quantified the subsequent effects on mortality and inequalities in mortality in Korea.MethodsEleven-year pooled data from the Korea National Health and Nutrition Examination Survey (KNHANES) (n=65 197) were used to estimate the income group-specific price elasticity. The price elasticity was then used to calculate changes in current smoking prevalence and per capita cigarette consumption resulting from a spectrum of hypothetical tobacco price increases. The mortality risk function from the 10-year mortality follow-up data of the National Health Insurance Service-National Sample Cohort (n=293 858, numbers of deaths=14 953) and the current distributions of smoking-related variables from the KNHANES 2015–2017 were employed to estimate the effect of tobacco price increases on inequality in mortality.ResultsLow-income Korean smokers were more responsive to changes in tobacco price. Increasing the tobacco price by 100% would achieve the overall reduction of 2.0% for 10-year mortality. For mortality inequalities by income, the relative index of inequality (slope index of inequality) would be reduced by 3.8% (4.8%) for 10-year mortality.ConclusionsThis modelling study showed that tobacco price increases in Korea can reduce current smoking prevalence and per capita cigarette consumption in the whole population, and especially among the poor, which in turn would reduce the gap in mortality between income groups.
Possible interpretation of the newly observed $$\Omega _b$$ states
Authors: Xiao Li-Ye , Wang Kai-Lei , Liu Ming-Sheng , Zhong Xian-Hui 
Published: March 2020

AbstractInspired by the newly observed $$\Omega _b$$Ωb states by the LHCb Collaboration, we investigate the two-body strong decays of the low-lying $$\lambda $$λ-mode $$\Omega _b$$Ωb baryons up to $$N=2$$N=2 shell using the chiral quark model within the j-j coupling scheme. Our results indicate that: (i) the newly observed states $$\Omega _b(6316)^-$$Ωb(6316)- and $$\Omega _b(6330)^-$$Ωb(6330)- are good candidates of the light spin $$j=1$$j=1 states, while the spin-parity $$J^P=1/2^-$$JP=1/2- and $$J^P=3/2^-$$JP=3/2- cannot be distinguished. The other two states, $$\Omega _b(6340)$$Ωb(6340) and $$\Omega _b(6350)$$Ωb(6350) mostly correspond to the light spin $$j=2$$j=2 states, while the spin-parity $$J^P=3/2^-$$JP=3/2- and $$J^P=5/2^-$$JP=5/2- cannot be distinguished as well. (ii) The 2S states with spin-parity $$J^P=1/2^+$$JP=1/2+ and $$J^P=3/2^+$$JP=3/2+, respectively, might be narrow states with a width of $$\Gamma <2$$Γ<2 MeV. (iii) The 1D states are not broad and the total decay widths vary from several to dozens of MeV, which have a good potential to be observed in future experiments.
The Pharmacokinetic–Pharmacodynamic (PKPD) Relationships of AZD3229, a Novel and Selective Inhibitor of KIT, in a Range of Mouse Xenograft Models of GIST
Authors: Pilla Reddy Venkatesh , Anjum Rana , Grondine Michael , Smith Aaron , Bhavsar Deepa , Barry Evan , Guichard Sylvie M. , Shao Wenlin , Kettle Jason G. , Brown Crystal , Banks Erica , Jones Rhys D.O. 
Published: March 2020

AbstractPurpose:The emergence of secondary mutations is a cause of resistance to current KIT inhibitors used in the treatment of patients with gastrointestinal stromal tumors (GIST). AZD3229 is a selective inhibitor of wild-type KIT and a wide spectrum of primary and secondary mutations seen in patients with GIST. The objective of this analysis is to establish the pharmacokinetic–pharmacodynamic (PKPD) relationship of AZD3229 in a range of mouse GIST tumor models harboring primary and secondary KIT mutations, and to benchmark AZD3229 against other KIT inhibitors.Experimental Design:A PKPD model was developed for AZD3229 linking plasma concentrations to inhibition of phosphorylated KIT using data generated from several in vivo preclinical tumor models, and in vitro data generated in a panel of Ba/F3 cell lines.Results:AZD3229 drives inhibition of phosphorylated KIT in an exposure-dependent manner, and optimal efficacy is observed when &gt;90% inhibition of KIT phosphorylation is sustained over the dosing interval. Integrating the predicted human pharmacokinetics into the mouse PKPD model predicts that an oral twice daily human dose greater than 34 mg is required to ensure adequate coverage across the mutations investigated. Benchmarking shows that compared with standard-of-care KIT inhibitors, AZD3229 has the potential to deliver the required target coverage across a wider spectrum of primary or secondary mutations.Conclusions:We demonstrate that AZD3229 warrants clinical investigation as a new treatment for patients with GIST based on its ability to inhibit both ATP-binding and A-loop mutations of KIT at clinically relevant exposures.
miR-128-3p Is a Novel Regulator of Vascular Smooth Muscle Cell Phenotypic Switch and Vascular Diseases
Authors: Farina Floriana Maria , Hall Ignacio Fernando , Serio Simone , Zani Stefania , Climent Montserrat , Salvarani Nicolò , Carullo Pierluigi , Civilini Efrem , Condorelli Gianluigi , Elia Leonardo , Quintavalle Manuela 
Published: March 2020

Rationale:
MicroRNAs (miRNAs, miRs) are small noncoding RNAs that modulate gene expression by negatively regulating translation of target genes. Although the role of several miRNAs in vascular smooth muscle cells (VSMCs) has been extensively characterized, the function of miRNA-128-3p (miR-128) is still unknown.

Objective:
To determine if miR-128 modulates VSMC phenotype and to define the underlying mechanisms.

Methods and Results:

We screened for miRNAs whose expression is modulated by an altered DNA methylation status in VSMCs, and among the hits, we selected miR-128. We found that miR-128 was expressed in various tissues, primary murine cells, and pathological murine and human vascular specimens. Through gain- and loss-of-function approaches, we determined that miR-128 affects VSMC proliferation, migration, differentiation, and contractility. The alterations of those properties were dependent upon epigenetic regulation of key VSMC differentiation genes; notably, Kruppel-like factor 4 was found to be a direct target of miR-128 and able to modulate the methylation status of the pivotal VSMC gene myosin heavy chain 11 (
Myh11
). Finally, in vivo lentiviral delivery of miR-128 prevented intimal hyperplasia in a mouse model of carotid restenosis without modifying vital cardiovascular parameters.

Conclusion:
miR-128 is a critical modulator of VSMCs and is regulated by epigenetic modifications upon stress. Its modulation in the context of disease could be exploited for therapeutic purposes.
Application of Clustering Algorithms to TRMM Precipitation over the Tropical and South Pacific Ocean
Authors: Pike Maxwell , Lintner Benjamin R. 
Published: March 2020

AbstractUnderstanding multiscale rainfall variability in the South Pacific convergence zone (SPCZ), a southeastward-oriented band of precipitating deep convection in the South Pacific, is critical for both the human and natural systems dependent on its rainfall, and for interpreting similar off-equatorial diagonal convection zones around the globe. A k-means clustering method is applied to daily austral summer (December–February) Tropical Rainfall Measuring Mission (TRMM) satellite rainfall to extract representative spatial patterns of rainfall over the SPCZ region for the period 1998–2013. For a k = 4 clustering, pairs of clusters differ predominantly via spatial translation of the SPCZ diagonal, reflecting either warm or cool phases of El Niño–Southern Oscillation (ENSO). Within each of these ENSO phase pairs, one cluster exhibits intense precipitation along the SPCZ while the other features weakened rainfall. Cluster temporal behavior is analyzed to investigate higher-frequency forcings (e.g., the Madden–Julian oscillation and synoptic-scale disturbances) that trigger deep convection where SSTs are sufficiently warm. Pressure-level winds and specific humidity from the Climate Forecast System Reanalysis are composited with respect to daily cluster assignment to investigate differences between active and quiescent SPCZ conditions to reveal the conditions supporting enhanced or suppressed SPCZ precipitation, such as low-level poleward moisture transport from the equator. Empirical orthogonal functions (EOFs) of TRMM precipitation are computed to relate the “modal view” of SPCZ variability associated with the EOFs to the “state view” associated with the clusters. Finally, the cluster number is increased to illustrate the change in TRMM rainfall patterns as additional degrees of freedom are permitted.
Decadal Change of Combination Mode Spatiotemporal Characteristics due to an ENSO Regime Shift
Authors: Jiang Feng , Zhang Wenjun , Stuecker Malte F. , Jin Fei-Fei 
Published: March 2020

AbstractPrevious studies have shown that nonlinear atmospheric interactions between ENSO and the warm pool annual cycle generates a combination mode (C-mode), which is responsible for the termination of strong El Niño events and the development of the anomalous anticyclone over the western North Pacific (WNP). However, the C-mode has experienced a remarkable decadal change in its characteristics around the early 2000s. The C-mode in both pre- and post-2000 exhibits its characteristic anomalous atmospheric circulation meridional asymmetry but with somewhat different spatial structures and time scales. During 1979–99, the C-mode pattern featured prominent westerly surface wind anomalies in the southeastern tropical Pacific and anticyclonic anomalies over the WNP. In contrast, the C-mode-associated westerly anomalies were shifted farther westward to the central Pacific and the WNP anticyclone was farther westward extended and weaker after 2000. These different C-mode patterns were accompanied by distinct climate impacts over the Indo-Pacific region. The decadal differences of the C-mode are tightly connected with the ENSO regime shift around 2000; that is, the occurrence of central Pacific (CP) El Niño events with quasi-biennial and decadal periodicities increased while the occurrence of eastern Pacific (EP) El Niño events with quasi-quadrennial periodicity decreased. The associated near-annual combination tone periodicities of the C-mode also changed in accordance with these changes in the dominant ENSO frequency between the two time periods. Numerical model experiments further confirm the impacts of the ENSO regime shift on the C-mode characteristics. These results have important implications for understanding the C-mode dynamics and improving predictions of its climate impacts.
Assessing the Skill and Reliability of Seasonal Climate Forecasts in Sahelian West Africa
Authors: Pirret Jennifer S. R. , Daron Joseph D. , Bett Philip E. , Fournier Nicolas , Foamouhoue Andre Kamga 
Published: March 2020

Abstract
Seasonal climate forecasts have the potential to support planning decisions and provide advanced warning to government, industry, and communities to help reduce the impacts of adverse climatic conditions. Assessing the reliability of seasonal forecasts, generated using different models and methods, is essential to ensure their appropriate interpretation and use. Here we assess the reliability of forecasts for seasonal total precipitation in Sahelian West Africa, a region of high year-to-year climate variability. Through digitizing forecasts issued from the regional climate outlook forum in West Africa known as Prévisions Climatiques Saisonnières en Afrique Soudano-Sahélienne (PRESASS), we assess their reliability by comparing them to the Climate Hazards Group Infrared Precipitation with Stations (CHIRPS) project observational data over the past 20 years. The PRESASS forecasts show positive skill and reliability, but a bias toward lower forecast probabilities in the below-normal precipitation category. In addition, we assess the reliability of seasonal precipitation forecasts for the same region using available global dynamical forecast models. We find all models have positive skill and reliability, but this varies geographically. On average, NCEP’s CFS and ECMWF’s SEAS5 systems show greater skill and reliability than the Met Office’s GloSea5, and in turn than Météo-France’s Sys5, but one key caveat is that model performance might depend on the meteorological situation. We discuss the potential for improving use of dynamical model forecasts in the regional climate outlook forums, to improve the reliability of seasonal forecasts in the region and the objectivity of the seasonal forecasting process used in the PRESASS regional climate outlook forum.