bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Role of Gallstones in Gallbladder Cancer in India: A Mendelian Randomization Study
Authors: Mhatre Sharayu , Richmond Rebecca C. , Chatterjee Nilanjan , Rajaraman Preetha , Wang Zhaoming , Zhang Haoyu , Badwe Rajendra , Goel Mahesh , Patkar Shraddha , Shrikhande Shailesh V. , Patil Prachi S. , Davey Smith George , Relton Caroline L. , Dikshit Rajesh P. 
Published: November 2020

Abstract

Background:
Past history of gallstones is associated with increased risk of gallbladder cancer in observational studies. We conducted complementary observational and Mendelian randomization (MR) analyses to determine whether history of gallstones is causally related to development of gallbladder cancer in an Indian population.

Methods:
To investigate associations between history of gallstones and gallbladder cancer, we used questionnaire and imaging data from a gallbladder cancer case–control study conducted at Tata Memorial Hospital, Mumbai, Maharashtra, India (cases = 1,170; controls = 2,525). We then used 26 genetic variants identified in a genome-wide association study of 27,174 gallstone cases and 736,838 controls of European ancestry in an MR approach to assess causality. The association of these genetic variants with both gallstones and gallbladder cancer was examined in the gallbladder cancer case–control study. Various complementary MR approaches were used to evaluate the robustness of our results in the presence of pleiotropy and heterogeneity, and to consider the suitability of the selected SNPs as genetic instruments for gallstones in an Indian population.

Results:
We found a strong observational association between gallstones and gallbladder cancer using self-reported history of gallstones [OR = 4.5; 95% confidence interval (CI) = 3.5–5.8] and with objective measures of gallstone presence using imaging techniques (OR = 2.0; 95% CI = 1.5–2.7). We found consistent causal estimates across all MR techniques, with ORs for gallbladder cancer in the range of 1.3–1.6.

Conclusions:
Our findings indicate a causal relationship between history of gallstones and increased risk of gallbladder cancer, albeit of a smaller magnitude than those found in observational analysis.

Impact:
Our findings emphasize the importance of gallstone treatment for preventing gallbladder cancer in high-risk individuals.
Cervical Cancer Screening: Comparison of Conventional Pap Smear Test, Liquid-Based Cytology, and Human Papillomavirus Testing as Stand-alone or Cotesting Strategies
Authors: Liang Linda A. , Einzmann Thomas , Franzen Arno , Schwarzer Katja , Schauberger Gunther , Schriefer Dirk , Radde Kathrin , Zeissig Sylke R. , Ikenberg Hans , Meijer Chris J.L.M. , Kirkpatrick Charles J. , Kölbl Heinz , Blettner Maria , Klug Stefanie J. 
Published: November 2020

Abstract

Background:
Some countries have implemented stand-alone human papillomavirus (HPV) testing while others consider cotesting for cervical cancer screening. We compared both strategies within a population-based study.

Methods:
The MARZY cohort study was conducted in Germany. Randomly selected women from population registries aged ≥30 years (n = 5,275) were invited to screening with Pap smear, liquid-based cytology (LBC, ThinPrep), and HPV testing (Hybrid Capture2, HC2). Screen-positive participants [ASC-US+ or high-risk HC2 (hrHC2)] and a random 5% sample of screen-negatives were referred to colposcopy. Post hoc HPV genotyping was conducted by GP5+/6+ PCR-EIA with reverse line blotting. Sensitivity, specificity (adjusted for verification bias), and potential harms, including number of colposcopies needed to detect 1 precancerous lesion (NNC), were calculated.

Results:
In 2,627 screened women, cytological sensitivities (Pap, LBC: 47%) were lower than HC2 (95%) and PCR (79%) for CIN2+. Cotesting demonstrated higher sensitivities (HC2 cotesting: 99%; PCR cotesting: 84%), but at the cost of lower specificities (92%–95%) compared with HPV stand-alone (HC2: 95%; PCR: 94%) and cytology (97% or 99%). Cotesting versus HPV stand-alone showed equivalent relative sensitivity [HC2: 1.06, 95% confidence interval (CI), 1.00–1.21; PCR: 1.07, 95% CI, 1.00–1.27]. Relative specificity of Pap cotesting with either HPV test was inferior to stand-alone HPV. LBC cotesting demonstrated equivalent specificity (both tests: 0.99, 95% CI, 0.99–1.00). NNC was highest for Pap cotesting.

Conclusions:
Cotesting offers no benefit in detection over stand-alone HPV testing, resulting in more false positive results and colposcopy referrals.

Impact:
HPV stand-alone screening offers a better balance of benefits and harms than cotesting.
See related commentary by Wentzensen and Clarke, p. 432
Defining the Comprehensive Genomic Landscapes of Pancreatic Ductal Adenocarcinoma Using Real-World Endoscopic Aspiration Samples
Authors: Semaan Alexander , Bernard Vincent , Lee Jaewon J. , Wong Justin W. , Huang Jonathan , Swartzlander Daniel B. , Stephens Bret M. , Monberg Maria E. , Weston Brian R. , Bhutani Manoop S. , Chang Kyle , Scheet Paul A. , Maitra Anirban , Jakubek Yasminka A. , Guerrero Paola A. 
Published: November 2020

AbstractPurpose:Most patients with pancreatic ductal adenocarcinoma (PDAC) present with surgically unresectable cancer. As a result, endoscopic ultrasound–guided fine-needle aspiration (EUS-FNA) is the most common biospecimen source available for diagnosis in treatment-naïve patients. Unfortunately, these limited samples are often not considered adequate for genomic analysis, precluding the opportunity for enrollment on precision medicine trials.Experimental Design:Applying an epithelial cell adhesion molecule (EpCAM)-enrichment strategy, we show the feasibility of using real-world EUS-FNA for in-depth, molecular-barcoded, whole-exome sequencing (WES) and somatic copy-number alteration (SCNA) analysis in 23 patients with PDAC.Results:Potentially actionable mutations were identified in &gt;20% of patients. Further, an increased mutational burden and higher aneuploidy in WES data were associated with an adverse prognosis. To identify predictive biomarkers for first-line chemotherapy, we developed an SCNA-based complexity score that was associated with response to platinum-based regimens in this cohort.Conclusions:Collectively, these results emphasize the feasibility of real-world cytology samples for in-depth genomic characterization of PDAC and show the prognostic potential of SCNA for PDAC diagnosis.
Senescent T Cells as a Resistance Mechanism to Lung Cancer Immunotherapy
Authors: Salas-Benito Diego , Eguren-Santamaria Iñaki , Sanmamed Miguel F. 
Published: November 2020

Abstract
It has been reported that a group of patients with advanced non–small cell lung cancer showed circulating T cells with a senescent phenotype, and an abundance of such cells is associated with worse clinical response to immune checkpoint inhibitors. This study encourages further analysis of the role of senescent T cells in resistance to lung cancer immunotherapy.
See related article by Ferrara et al., p. 492
FBW7 Inhibits Myeloid Differentiation in Acute Myeloid Leukemia via GSK3-Dependent Ubiquitination of PU.1
Authors: Mishra Mukul , Thacker Gatha , Sharma Akshay , Singh Anil Kumar , Upadhyay Vishal , Sanyal Sabyasachi , Verma Shailendra Prasad , Tripathi Anil Kumar , Bhatt Madan Lal Brahma , Trivedi Arun Kumar 
Published: November 2020

AbstractGlycogen synthase kinase 3β (GSK3β), an ubiquitously expressed serine/threonine kinase is reported to be overexpressed and hyperactivated in cancers including acute myeloid leukemia (AML) where it promotes self-renewal, growth, and survival of AML cells. Therefore, GSK3β inhibition results in AML cell growth inhibition and myeloid differentiation. Here we identified master transcription factor PU.1 of monocyte–macrophage differentiation pathway as potential GSK3β target. We demonstrate that GSK3β phosphorylates PU.1 at Ser41 and Ser140 leading to its recognition and subsequent ubiquitin-mediated degradation by E3 ubiquitin ligase FBW7. This GSK3-dependent degradation of PU.1 by FBW7 inhibited monocyte–macrophage differentiation. We further showed that a phospho-deficient PU.1 mutant (PU.1-S41, S140A) neither bound to FBW7 nor was degraded by it. Consequently, PU.1-S41, S140A retained its transactivation, DNA-binding ability and promoted monocyte–macrophage differentiation of U937 cells even without phorbol 12-myristate 13-acetate (PMA) treatment. We further showed that FBW7 overexpression inhibited both PMA as well as M-CSF–induced macrophage differentiation of myeloid cell lines and peripheral blood mononuclear cells (PBMC) from healthy volunteers, respectively. Contrarily, FBW7 depletion promoted differentiation of these cells even without any inducer suggesting for a robust role of GSK3β–FBW7 axis in negatively regulating myeloid differentiation. Furthermore, we also recapitulated these findings in PBMCs isolated from patients with leukemia where FBW7 overexpression markedly inhibited endogenous PU.1 protein levels. In addition, PBMCs also showed enhanced differentiation when treated with M-CSF and GSK3 inhibitor (SB216763) together compared with M-CSF treatment alone.Implications:Our data demonstrate a plausible mechanism behind PU.1 restoration and induction of myeloid differentiation upon GSK3β inhibition and further substantiates potential of GSK3β as a therapeutic target in AML.
Noninvasive Echocardiographic Left Ventricular Stroke Work Index Predicts Mortality in Cardiac Intensive Care Unit Patients
Authors: Jentzer Jacob C. , Anavekar Nandan S. , Burstein Barry J. , Borlaug Barry A. , Oh Jae K. 
Published: November 2020

Background:
Reduced left ventricular stroke work index (LVSWI) has been associated with adverse outcomes in several populations of patients with chronic heart disease, but no prior studies have examined this metric in cardiac intensive care unit (CICU) patients. We sought to determine whether a low LVSWI, as measured noninvasively using transthoracic echocardiography, is associated with higher mortality in CICU patients.

Methods:
Using a database of unique Mayo Clinic CICU admissions from 2007 to 2018, we identified patients with LVSWI measured by transthoracic echocardiography within 1 day of CICU admission. Hospital mortality was analyzed using multivariable logistic regression, and 1-year mortality was analyzed using multivariable Cox proportional-hazards analysis, adjusted for left ventricular ejection fraction and known predictors of hospital mortality.

Results:

We included 4536 patients with a mean age of 68±14 years (36% women). Admission diagnoses (not mutually exclusive) included acute coronary syndrome in 62%, heart failure in 46%, and cardiogenic shock in 11%. The mean LVSWI was 38±14 g×min/m
2
, and in-hospital mortality occurred in 6% of patients. LVSWI had better discrimination for hospital mortality than left ventricular ejection fraction (
P
<0.001 by De Long test). Higher LVSWI was associated with lower in-hospital mortality (adjusted odds ratio, 0.72 per 10 g×min/m
2
higher [95% CI, 0.61–0.84];
P
<0.001) and lower 1-year mortality (adjusted hazard ratio, 0.812 per 1 g×min/m
2
higher [95% CI, 0.759–0.868];
P
<0.001). Stepwise decreases in hospital and 1-year mortality were observed with higher LVSWI.

Conclusions:
Low LVSWI, reflecting poor left ventricular systolic and diastolic performance, is associated with increased short-term and long-term mortality among CICU patients. This emphasizes the importance of Doppler transthoracic echocardiography as a predictor of outcomes among critically ill patients. Further study is required to determine whether early interventions to optimize LVSWI can improve outcomes in the CICU setting.
Sulle varianti d’autore
Authors: Fera Vincenzo 
Published: November 2020

Abstract
The aim of this paper is to explore the nature of author variants in the humanistic age, starting from a survey of the variants added by Petrarch to his unfinished work Africa during the revision of the text around the mid-fourteenth century. In particular, two new definitions of variant, which were presented in a previous paper, are here outlined and discussed, that is, ‘active variants’ and ‘working variants’. Furthermore, the so-called Scevola Mariotti’s norm in relation to the author variants’ authenticity is reviewed.
Surface and Interfacial Waves in a Strongly Stratified Upper Ocean
Authors: Gemmrich Johannes , Monahan Adam 
Published: November 2020

AbstractIn an idealized two-layer fluid, surface waves can generate waves at the internal interface through class-3 resonant triads in which all waves are propagating in the same direction. The triads are restricted to wavenumbers above a critical value kcrit that depends on the density ratio R between the two layers and their depths. We perform numerical simulations to analyze the evolution of a surface wave field, initially specified by a Pierson–Moskowitz-type spectrum, for R = 0.97 (representing a realistic lower a bound for oceanic stratification). At high initial steepness and peak wavenumber kp ≪ kcrit, the energy increases in the spectral tail; as a parameterization of resulting wave breaking, at each time step individual waves with a steepness greater than the limiting Stokes steepness are removed. The energy change of the surface wave field is a combination of energy transfer to the interfacial waves, spectral downshift, and wave breaking dissipation. At wavenumbers there is a net loss of energy, with the greatest dissipation at ≈1.3kp. The maximum gain occurs at ≈0.5kp. The onset of the spectral change shows a strong threshold behavior with respect to the initial wave steepness. For steep initial waves the integrated energy dissipation can reach >30% of the initial energy, and only ≈1% of the initial surface wave energy is transferred to the interfacial wave field. The spectral change could be expressed as an additional dissipation source term, and coupled ocean–wave models should include additional mixing associated with the interfacial waves and enhanced wave breaking turbulence.
Demonstration of a Remotely Piloted Atmospheric Measurement and Charge Release Platform for Geoengineering
Authors: Harrison R. Giles , Nicoll Keri A. , Tilley Douglas J. , Marlton Graeme J. , Chindea Stefan , Dingley Gavin P. , Iravani Pejman , Cleaver David J. , du Bois Jonathan L. , Brus David 
Published: November 2020

AbstractElectric charge is always present in the lower atmosphere. If droplets or aerosols become charged, their behavior changes, influencing collision, evaporation, and deposition. Artificial charge release is an unexplored potential geoengineering technique for modifying fogs, clouds, and rainfall. Central to evaluating these processes experimentally in the atmosphere is establishing an effective method for charge delivery. A small charge-delivering remotely piloted aircraft has been specially developed for this, which is electrically propelled. It carries controllable bipolar charge emitters (nominal emission current ±5 μA) beneath each wing, with optical cloud and meteorological sensors integrated into the airframe. Meteorological and droplet measurements are demonstrated to 2 km altitude by comparison with a radiosonde, including within cloud, and successful charge emission aloft verified by using programmed flight paths above an upward-facing surface electric field mill. This technological approach is readily scalable to provide nonpolluting fleets of charge-releasing aircraft, identifying and targeting droplet regions with their own sensors. Beyond geoengineering, agricultural, and biological aerosol applications, safe ionic propulsion of future electric aircraft also requires detailed investigation of charge effects on natural atmospheric droplet systems.
Age differences in the relationships between risk factors and loss of kidney function: a general population cohort study
Authors: Toyama Tadashi , Kitagawa Kiyoki , Oshima Megumi , Kitajima Shinji , Hara Akinori , Iwata Yasunori , Sakai Norihiko , Shimizu Miho , Hashiba Atsushi , Furuichi Kengo , Wada Takashi 
Published: November 2020

Abstract
Background
Annual decline in kidney function is a widely applied surrogate outcome of renal failure. It is important to understand the relationships between known risk factors and the annual decline in estimated glomerular filtration rate (eGFR) according to baseline age; however, these remain unclear.

Methods
A community-based retrospective cohort study of adults who underwent annual medical examinations between 1999 and 2013 was conducted. The participants were stratified into different age groups (40–49, 50–59, 60–69, 70–79, and ≥ 80 years) to assess the risk for loss of kidney function. A mixed-effects model was used to estimate the association between risk factors and annual changes in eGFR.

Results
In total, 51,938 participants were included in the analysis. The age group of ≥80 years included 8127 individuals. The mean annual change in eGFR was − 0.39 (95% confidence interval: − 0.41 to − 0.37) mL/min/1.73 m2 per year. Older age was related to faster loss of kidney function. In the older age group, higher systolic blood pressure, proteinuria, and current smoking were related to faster loss of kidney function (p trend < 0.01, 0.03, and < 0.01, respectively). Conversely, each age group showed similar annual loss of kidney function related to lower hemoglobin levels and diabetes mellitus (p trend 0.47 and 0.17, respectively).

Conclusions
Higher systolic blood pressure, proteinuria, and smoking were related to faster loss of kidney function, and a greater effect size was observed in the older participants. More risk assessments for older people are required for personalized care.
Hepatitis C core antigen testing to diagnose active hepatitis C infection among haemodialysis patients
Authors: Wong Xue Zheng , Gan Chye Chung , Mohamed Rosmawati , Yahya Rosnawati , Ganapathy Shubash , Tan Soek Siam , Lim Soo Kun 
Published: November 2020

Abstract
Background
Hepatitis C virus (HCV) infects more than 71 million people worldwide and chronic HCV infection increases the risk of liver cirrhosis and failure. Haemodialysis (HD) is one of the renal replacement therapies with risk of HCV transmission. Anti-HCV antibodies are the serological screening test for HCV infection that does not detect active phase of infection. Majority HCV infected HD patients in Malaysia do not have further HCV RNA performed due to high cost and thus HCV treatment is less frequently offered. HCV Core Antigen (HCV Ag) can potentially be used to diagnose active HCV infection in HD population in comparison to HCV RNA, at lower cost.

Methods
We conducted a cross-sectional study to assess the correlation between HCV Ag and HCV RNA and to identify the prevalence of active HCV infection among HCV seropositive HD patients from dialysis centres across West Malaysia from July 2019 to May 2020. Pre-dialysis blood was taken and tested for both HCV Ag and HCV RNA tests. HCV Ag was tested with Abbott ARCHITECT HCV Ag test.

Results
We recruited 112 seropositive HD patients from 17 centres with mean age of 54.04 ± 11.62 years, HD vintage of 14.1 ± 9.7 years, and male constitute 59.8% (67) of the study population. HCV Ag correlates well with HCV RNA (Spearman test coefficient 0.833, p < 0.001). The sensitivity was 90.7%, specificity 100%, positive predictive value (PPV) 100%, negative predictive value (NPV) 76.5%, and accuracy 92.9%. For HCV RNA level > 3000 IU/mL, HCV Ag had a higher sensitivity of 95.1% and greater correlation (Spearman test coefficient 0.897, p < 0.001). The prevalence of active HCV infection was 76.8% among HCV seropositive HD patients.

Conclusions
Although HCV Ag is less sensitive, it shows an excellent correlation with HCV RNA and has 100% PPV. HCV Ag can be considered as an alternative diagnostic tool for chronic active HCV infection among HD cohort, who can then be considered for HCV treatment. For seropositive HD patient with negative HCV Ag, we recommend to follow-up with HCV RNA test.
Implementation and evaluation of a quality improvement initiative to reduce late gestation stillbirths in Australia: Safer Baby Bundle study protocol
Authors:   on behalf of the Safer Baby Bundle collaborators, Andrews C. J. , Ellwood D. , Middleton P. F. , Gordon A. , Nicholl M. , Homer C. S. E. , Morris J. , Gardener G. , Coory M. , Davies-Tuck M. , Boyle F. M. , Callander E. , Bauman A. , Flenady V. J. 
Published: November 2020

Abstract
Background
In 2015, the stillbirth rate after 28 weeks (late gestation) in Australia was 35% higher than countries with the lowest rates globally. Reductions in late gestation stillbirth rates have steadily improved in Australia. However, to amplify and sustain reductions, more needs to be done to reduce practice variation and address sub-optimal care. Implementing bundles for maternity care improvement in the UK have been associated with a 20% reduction in stillbirth rates. A similar approach is underway in Australia; the Safer Baby Bundle (SBB) with five elements: 1) supporting women to stop smoking in pregnancy, 2) improving detection and management of fetal growth restriction, 3) raising awareness and improving care for women with decreased fetal movements, 4) improving awareness of maternal safe going-to-sleep position in late pregnancy, 5) improving decision making about the timing of birth for women with risk factors for stillbirth.

Methods
This is a mixed-methods study of maternity services across three Australian states; Queensland, Victoria and New South Wales. The study includes evaluation of ‘targeted’ implementer sites (combined total approximately 113,000 births annually, 50% of births in these states) and monitoring of key outcomes state-wide across all maternity services. Progressive implementation over 2.5 years, managed by state Departments of Health, commenced from mid-2019. This study will determine the impact of implementing the SBB on maternity services and perinatal outcomes, specifically for reducing late gestation stillbirth. Comprehensive process, impact, and outcome evaluations will be conducted using routinely collected perinatal data, pre- and post- implementation surveys, clinical audits, focus group discussions and interviews. Evaluations explore the views and experiences of clinicians embedding the SBB into routine practice as well as women’s experience with care and the acceptability of the initiative.

Discussion
This protocol describes the evaluation of the SBB initiative and will provide evidence for the value of a systematic, but pragmatic, approach to strategies to reduce the evidence-practice gaps across maternity services. We hypothesise successful implementation and uptake across three Australian states (amplified nationally) will be effective in reducing late gestation stillbirths to that of the best performing countries globally, equating to at least 150 lives saved annually.

Trial registration
The Safer Baby Bundle Study was retrospectively registered on the ACTRN12619001777189 database, date assigned 16/12/2019