bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulatory Network of PD1 Signaling Is Associated with Prognosis in Glioblastoma Multiforme
Authors: Lopes-Ramos Camila M. , Belova Tatiana , Brunner Tess H. , Ben Guebila Marouen , Osorio Daniel , Quackenbush John , Kuijjer Marieke L. 
Published: September 2021

AbstractGlioblastoma is an aggressive cancer of the brain and spine. While analysis of glioblastoma ‘omics data has somewhat improved our understanding of the disease, it has not led to direct improvement in patient survival. Cancer survival is often characterized by differences in gene expression, but the mechanisms that drive these differences are generally unknown. We therefore set out to model the regulatory mechanisms associated with glioblastoma survival. We inferred individual patient gene regulatory networks using data from two different expression platforms from The Cancer Genome Atlas. We performed comparative network analysis between patients with long- and short-term survival. Seven pathways were identified as associated with survival, all of them involved in immune signaling; differential regulation of PD1 signaling was validated to correspond with outcome in an independent dataset from the German Glioma Network. In this pathway, transcriptional repression of genes for which treatment options are available was lost in short-term survivors; this was independent of mutational burden and only weakly associated with T-cell infiltration. Collectively, these results provide a new way to stratify patients with glioblastoma that uses network features as biomarkers to predict survival. They also identify new potential therapeutic interventions, underscoring the value of analyzing gene regulatory networks in individual patients with cancer.Significance:Genome-wide network modeling of individual glioblastomas identifies dysregulation of PD1 signaling in patients with poor prognosis, indicating this approach can be used to understand how gene regulation influences cancer progression.
The Risk of Cutaneous Squamous Cell Carcinoma Among Patients with Type 2 Diabetes Receiving Hydrochlorothiazide: A Cohort Study
Authors: de Haan-Du Jing , Landman Gijs W.D. , Groenier Klaas H. , Vissers Pauline A.J. , Louwman Marieke W.J. , Kleefstra Nanne , de Bock Geertruida H. 
Published: September 2021

Abstract

Background:
Because of continuous hyperglycemia and hyperinsulinemia and the use of photosensitizing drug, hydrochlorothiazide (HCTZ), the risk of cutaneous squamous cell carcinoma (cSCC) might be increased among patients with diabetes. This study aimed to estimate the risk of cSCC among HCTZ users with type 2 diabetes, and to determine whether thiazide-like diuretics, another drug in the same class with HCTZ, would be safer.

Methods:
We linked the benchmarking database in Dutch primary care, the Netherlands Cancer Registry, and the Dutch Personal Records Database (1998–2019). All 71,648 patients were included, except for those who had a history of skin cancer prior to cohort entry. We used Cox modeling to estimate the HRs and 95% confidence intervals for cSCC. The model was adjusted by cumulative exposure to each antihypertensive, age, sex, smoking, body mass index, blood pressure, serum creatinine, other confounding drug use at cohort entry, and cohort entry year.

Results:
There were 1,409 cSCC events (23 among thiazide-like diuretics users), during a follow-up of 679,789 person-years. Compared with no HCTZ use, the adjusted HRs for HCTZ use were 1.18 (1.00–1.40) for ≤2 years, 1.57 (1.32–1.88) for 2 to 4 years, and 2.09 (1.73–2.52) for &gt;4 years. The HR was 0.90 (0.79–1.03) for an additional year of thiazide-like diuretic use.

Conclusions:
In patients with diabetes, exposure to HCTZ for &gt;2 years is associated with an increased risk of cSCC, whereas no increased risk associated with thiazide-like diuretics was observed.

Impact:
The potential increased risk of cSCC should be a consideration when prescribing HCTZ, with thiazide-like diuretics offering a safer alternative.
Hallmarks of RET and Co-occuring Genomic Alterations inRET-aberrant Cancers
Authors: Adashek Jacob J. , Desai Aakash P. , Andreev-Drakhlin Alexander Y. , Roszik Jason , Cote Gilbert J. , Subbiah Vivek 
Published: September 2021

AbstractActivating receptor-tyrosine kinase rearranged during transfection (RET) mutations and fusions are potent drivers of oncogenesis. The recent FDA approvals of highly potent and selective RET inhibitors, selpercatinib and pralsetinib, has altered the therapeutic management of RET aberrant tumors. There is ample evidence of the role of RET signaling in certain cancers. RET aberrations as fusions or mutations occur in multiple cancers, however, there is considerable phenotypic diversity. There is emerging data on the lack of responsiveness of immunotherapy in RET-altered cancers. Herein, we review the registrational data from the selective RET-inhibitor trials, and comprehensively explore RET alterations in pan-cancer adult malignancies and their co-alterations. These co-occuring alterations may define the future of RET inhibition from specific selective targeting to customized combination therapies as data are rapidly emerging on both on-target and off-target acquired resistance mechanisms. Fascinatingly, oncogenic RET fusions have been reported to mediate resistance to EGFR inhibition and KRASG12C inhibition.
Atrial Fibrillation in Aging and Frail Mice
Authors: Jansen Hailey J. , Moghtadaei Motahareh , Rafferty Sara A. , Rose Robert A. 
Published: September 2021

Background:
Atrial fibrillation is prevalent in aging populations; however, not all individuals age at the same rate. Rather, health status during aging can vary from fit to frail. Frailty can be quantified using a frailty index (FI). Natriuretic peptides modulate atrial function in part by activating NP (natriuretic peptide) receptor C (NPR-C). The impacts of NPR-C on atrial structure and arrhythmogenesis in aging and as a function of frailty are unknown.

Methods:

Frailty was measured in aging wildtype and NPR-C knockout (NPR-C
−
/−
) mice. Atrial structure and function were studied using intracardiac electrophysiology in anesthetized mice, high-resolution optical mapping in intact atrial preparations, histology, and molecular biology.

Results:

NPR-C
−/−
mice had a shortened lifespan and more rapidly became frail compared with wildtype mice. Atrial fibrillation burden and P wave duration were increased in older versus younger wildtype mice and further increased in older NPR-C
−/−
mice; however, there was substantial variability among age groups and genotypes. P wave duration was strongly correlated with FI score regardless of age or genotype. Optical mapping of the atria demonstrated reduced conduction velocity and changes in action potential duration that were also graded by FI score. Atrial fibrosis was increased in aged and NPR-C
−/−
mice and was strongly correlated with FI score. Atrial fibrosis was associated with changes in expression of profibrotic genes, including MMPs (matrix metalloproteinases), TIMPs (tissue inhibitors of metalloproteinases), and TGFβ (transforming growth factor β). Gene expression changes were also correlated with FI scores.

Conclusions:
NPR-C plays an essential role in the aging-dependent decline in health status as well as alterations in atrial function and arrhythmogenesis. Frailty assessment is a highly effective approach for identifying age-dependent heterogeneity in atrial structure and function, including in the setting of shortened lifespan because of loss of NPR-C.
Exploring Scientific Inquiry via Agent-Based Modelling
Authors: Šešelja Dunja 
Published: September 2021

Abstract
In this paper I examine the epistemic function of agent-based models (ABMs) of scientific inquiry, proposed in the recent philosophical literature. In view of Boero and Squazzoni’s (2005) classification of ABMs into case-based models, typifications and theoretical abstractions, I argue that proposed ABMs of scientific inquiry largely belong to the last category. While this means that their function is primarily exploratory, I suggest that they are epistemically valuable not only as a temporary stage in the development of ABMs of science, but by providing insights into theoretical aspects of scientific rationality. I illustrate my point with two examples of highly idealized ABMs of science, which perform two exploratory functions: Zollman’s (2010) ABM which provides a proof-of-possibility in the realm of theoretical discussions on scientific rationality, and an argumentation-based ABM (Borg et al. 2019, 2017b, 2018), which provides insights into potential mechanisms underlying the efficiency of scientific inquiry.
Lost Years Recovered John Peters and Phillis Wheatley Peters in Middleton
Authors: Dayton Cornelia H. 
Published: September 2021

Abstract
A cache of Essex County legal papers reveals that when Phillis Wheatley Peters and her husband left Boston in 1780, they moved to Middleton where John became a landowner on a farm where he had been enslaved. I analyze the racial, class, and gender conflicts that led to their eviction.
Aggression towards neonates and possible infanticide in the boto, or Amazon river dolphin (Inia geoffrensis)
Authors: da Silva V.M.F. , Silva P.M. , Schlichta F. , do Carmo N.A.S. , Olson G.L. , Hintermayer B.G. , Araujo M.C. , Martin A.R. 
Published: September 2021

Abstract
Recent observed attacks by male Amazon river dolphins on conspecific calves, together with post-mortem examinations, indicate that infanticide occurs in this species but that not all attacked calves are killed. If mortality occurs, it might therefore be an inadvertent consequence of the behaviour rather than the motive for it. Our observations suggest that males who commit infanticide are unlikely to gain direct fitness benefits. Evidence does not fit the sexual selection hypothesis. Aggression towards calves usually ‘drew a crowd’ and may represent socio-sexual display or simply be a form of social pathology, as found in other infanticidal mammals.
A 30-Year Climatology (1990–2020) of Aerosol Optical Depth and Total Column Water Vapor and Ozone over Texas
Authors: Mims Forrest M. 
Published: September 2021

Abstract
A 30-yr time series (4 February 1990–4 February 2020) of aerosol optical depth (AOD) of the atmosphere, total precipitable water (TPW), and total column ozone has been conducted in central Texas using simple, highly stable instruments. All three parameters in this ongoing measurement series exhibited robust annual cycles. They also responded to many atmospheric events, including the historic volcanic eruption of Mount Pinatubo (1991), a record El Niño (1998), an unprecedented biomass smoke event (1998), and La Niña that caused the driest drought in recorded Texas history (2011). Reduced air pollution caused mean AOD to decline from 0.175 to 0.14. The AOD trend measured for 30 years by a light-emitting diode (LED) sun photometer, the first of its kind, parallels the trend from 20 years of measurements by a modified Microtops II. While TPW responded to El Niño–Southern Oscillation conditions, TPW exhibited no trend over the 30 years. The TPW data compare favorably with 4.5 years of simultaneous measurements by a nearby NOAA GPS (r2 = 0.78). The 30 years of ozone measurements compare favorably with those from a series of NASA ozone satellites (r2 = 0.78). In 2016, 194 comparisons of Microtops II and world standard ozone instrument Dobson 83 at the Mauna Loa Observatory agreed within 1.9% (r2 = 0.81). The paper concludes by observing that students and citizen scientists can collect scientifically useful atmospheric data with simple sun photometers that use one or more LEDs as spectrally selective photodiodes.
Using Radio Occultation to Detect Clouds in the Middle and Upper Troposphere
Authors: Mascio Jeana , Leroy Stephen S. , d’Entremont Robert P. , Connor Thomas , Kursinski E. Robert 
Published: September 2021

AbstractRadio occultation (RO) measurements have little direct sensitivity to clouds, but recent studies have shown that they may have an indirect sensitivity to thin, high clouds that are difficult to detect using conventional passive space-based cloud sensors. We implement two RO-based cloud detection (ROCD) algorithms for atmospheric layers in the middle and upper troposphere. The first algorithm is based on the methodology of a previous study, which explored signatures caused by upper tropospheric clouds in RO profiles according to retrieved relative humidity, temperature lapse rate, and gradients in log-refractivity (ROCD-P), and the second is based on inferred relative humidity alone (ROCD-M). In both, atmospheric layers are independently predicted as cloudy or clear based on observational data, including high performance RO retrievals. In a demonstration, we use data from 10 days spanning seven months in 2020 of FORMOSAT-7/COSMIC-2. We use the forecasts of NOAA GFS to aid in the retrieval of relative humidity. The prediction is validated with a cloud truth dataset created from the imagery of the GOES-16 Advanced Baseline Imager (ABI) satellite and the GFS three-dimensional analysis of cloud state conditions. Given these two algorithms for the presence or absence of clouds, confusion matrices and receiver operating characteristic (ROC) curves are used to analyze how well these algorithms perform. The ROCD-M algorithm has a balanced accuracy, which defines the quality of the classification test that considers both the sensitivity and specificity, greater than 70% for all altitudes between 6 and 10.25 km.
Digital analysis of tooth sizes among individuals with different malocclusions: A study using three-dimensional digital dental models
Authors: Karadede Ünal Beyza , Dellaloğlu Deniz 
Published: September 2021

Objective: It is aimed to examine the tooth sizes of digital models of patients with different malocclusions with the help of three-dimensional measurement software. Methods: Digital models of 252 patients aged between 13 and 25 years of age were included. According to the Angle classification, three different malocclusion groups were allocated such that there were 84 patients in each group, plaster models of patients scanned with the three-dimensional model browser 3Shape R700 3D Scanner (3Shape A/S Copenhagen, Denmark) and transferred to the digital format. 3Shape Ortho Analyzer (3Shape A/S Copenhagen, Denmark) software was used for making the necessary tooth size measurements. Results: When the measurements were evaluated, it was determined that significant changes occurred between tooth sizes of individuals with different malocclusions. Generally, higher values were observed in mesiodistal and buccolingual tooth dimensions of class II individuals compared to other groups. There was no difference between the groups in the anterior ratio values, but when the overall ratio values were evaluated among the groups, a statistically significant difference was determined. Class II malocclusion group was found to have a significantly lower overall ratio of occurrence. Conclusion: Individuals with different malocclusions differ in tooth size.
Predictors of Success After Furlow Palatoplasty for Repair of Cleft Palate: Does Syndrome Matter?
Authors: Evans Sean S. , Bly Randall A. , Paulsgrove Kaylee , Perkins Jonathan A. , Sie Kathleen 
Published: September 2021

ObjectiveTo determine predictors of success following Veau 1 and 2 cleft palate repair in patients with and without syndromes.Study DesignRetrospective review of prospectively collected data.SettingTertiary care children’s hospital.MethodsAll children <18 months of age undergoing Furlow palatoplasty for Veau 1 and 2 cleft repair between 2000 and 2014 with postoperative perceptual speech assessment (PSA).ResultsIn total, 368 consecutive patients were identified; 95 were excluded, resulting in 273 patients. Median age at surgery was 13.0 months (interquartile range [IQR], 11‐15 months) with postoperative PSA at a median of 32.3 months (IQR, 26.3‐44.5 months). Fifty patients (18.3%) had syndrome diagnosis; 59 patients (21.6%) had nonsyndromic Robin sequence. Velopharyngeal insufficiency (VPI) occurred in 27 patients (10.5%); 13 underwent secondary speech surgery. Cleft‐related speech errors occurred in 46 patients (17.6%). Non‐cleft‐related speech errors occurred in 155 patients (59.6%) and reduced intelligibility in 127 patients (47.9%). Oronasal fistula occurred in 23 patients (8.8%) and was exclusive to Veau 2 clefts. In multivariate analysis, age >13 months at palatoplasty demonstrated a 6‐fold higher rate of VPI (hazard ratio [HR], 6.64; P <. 01), worse speech outcomes (HR, 6.04; P <. 01; HR, 1.60; P <. 01; HR, 1.57; P =. 02), and greater speech therapy utilization (HR, 2.18; P <. 01).ConclusionVPI occurred in 10% of patients undergoing Furlow palatoplasty repair of Veau 1 or 2 clefts. Age <13 months at palatoplasty was associated with improved speech outcomes and lower VPI incidence (2.8% vs 16.2%). Syndromic diagnosis was associated with noncleft speech errors and reduced intelligibility on univariate analysis but not velopharyngeal function after palatoplasty.
Asian patients’ perspectives on advance care planning: A mixed-method systematic review and conceptual framework
Authors: Martina Diah , Geerse Olaf P , Lin Cheng-Pei , Kristanti Martina S , Bramer Wichor M , Mori Masanori , Korfage Ida J , van der Heide Agnes , Rietjens Judith AC , van der Rijt Carin CD 
Published: September 2021

Background: Asian healthcare professionals hold that patients’ families play an essential role in advance care planning. Aim: To systematically synthesize evidence regarding Asian patients’ perspectives on advance care planning and their underlying motives. Design: Mixed-method systematic review and the development of a conceptual framework (PROSPERO: CRD42018099980). Data sources: EMBASE, MEDLINE, Web of Science, and Google Scholar were searched for studies published until July 27, 2020. We included studies concerning seriously-ill Asian patients’ perspectives on advance care planning or their underlying motives for engaging or not engaging in it. Results: Thirty-six articles were included; 22 were quantitative and 27 were from high-income countries. Thirty-nine to ninety percent of Asian patients were willing to engage in advance care planning. Our framework highlighted that this willingness was influenced not only by their knowledge of their disease and of advance care planning, but also by their beliefs regarding: (1) its consequences; (2) whether its concept was in accordance with their faith and their families’ or physicians’ wishes; and (3) the presence of its barriers. Essential considerations of patients’ engagement were their preferences: (1) for being actively engaged or, alternatively, for delegating autonomy to others; (2) the timing, and (3) whether or not the conversations would be documented. Conclusion: The essential first step to engaging patients in advance care planning is to educate them on it and on their diseases. Asian patients’ various beliefs about advance care planning should be accommodated, especially their preferences regarding their role in it, its timing, and its documentation.
Familial Risk and Its Interaction With Body Mass Index and Physical Activity in Anterior Cruciate Ligament Injury Among First-Degree Relatives: A Population-Based Cohort Study
Authors: Ahn Hyeong Sik , Lee Dae-Hee , Kazmi Sayada Zartasha , Kang Taeuk , Lee Young Sung , Sung Ryunsu , Cha Jaewoo , Choi Yoon Jung , Hong Gahwi , Hann Hoo Jae , Kim Hyun Jung 
Published: September 2021

Background: Genetic and behavioral risk factors have been suggested to play a role in anterior cruciate ligament (ACL) injury. However, population-based familial risk estimates are unavailable. Purpose: To quantify familial risk of ACL injury among first-degree relatives (FDRs) after controlling for certain behavioral risk factors. To estimate the combined effect of family history and body mass index (BMI) or physical activity on the risk of ACL injury. Study Design: Cohort study; Level of evidence, 3. Methods: Using nationwide data from the Korean National Health Insurance and National Health Screening Program databases on kinship, lifestyle habits, and anthropometrics, 5,184,603 individuals with blood-related FDRs were identified from 2002 to 2018. Familial risk of ACL injury, as represented as incidence risk ratios (IRRs) with 95% CIs, was analyzed using Cox proportional hazards models among individuals with versus without affected FDRs. Analyses were adjusted for age, sex, and behavioral risk factors. Interaction testing between familial history and BMI or physical activity was performed on an additive scale. Results: The risk of ACL injury was 1.79-fold higher (IRR, 1.79; 95% CI, 1.73-1.85) among individuals with versus without affected FDRs, and the incidence was 12.61 per 10,000 person-years. The IRR (95% CI) was highest with affected twins at 4.49 (3.01-6.69), followed by siblings at 2.31 (2.19-2.44), the father at 1.58 (1.49-1.68), and the mother at 1.52 (1.44-1.61). High BMI and high level of physical activity were significantly associated with the risk of ACL injury. Individuals with positive family history and either high BMI or physical activity had a 2.59- and 2.45-fold increased risk of injury as compared with the general population, respectively, and the combined risks exceeded the sum of their independent risks. Conclusion: Familial factors are risk factors for ACL injury with an additional contribution of 2 behavioral factors: BMI and physical activity level. A significant interaction was observed between family history of ACL injury and high BMI/level of physical activity.
Ethical challenges during the COVID-19 pandemic: Perspectives of nursing students
Authors: Palacios-Ceña Domingo , Velarde-García Juan Francisco , Espejo Marta Mas , González-Hervías Raquel , Álvarez-Embarba Beatriz , Rodríguez-García Marta , Oliva-Fernández Oscar , González-Sanz Pilar , Moro-López-Menchero Paloma , Fernández-de-las-Peñas César , Cachón-Pérez Jose Miguel 
Published: September 2021

Background: The first wave of the COVID-19 pandemic caused a shortage of qualified nurses in Spain. As a result, the government authorized the hiring of senior students. Objectives: To explore the ethical dilemmas and ethical conflicts experienced by final-year nursing students who worked during the first outbreak of the COVID-19 pandemic in Spain. Research design: A qualitative exploratory study was conducted using purposive sampling. Semi-structured interviews were carried out using a question guide. Interviews took place via a private video chat room platform. A thematic, inductive analysis was performed of the information gathered. Participants and research context: Eighteen nursing students were recruited from two universities of Madrid, aged between 18 and 65 years old, enrolled in the fourth year of nursing studies and who were hired under a relief contract for health professionals during the pandemic. Ethical considerations: The present study was carried out in accordance with the Declaration of Helsinki, and the study was approved by the Local Ethics Committee of Universidad Rey Juan Carlos. Results: Three specific themes emerged: (a) coping with patient triage, (b) difficulties in providing end-of-life care, and (c) coping with patient death. Nursing students participated in the process of patient selection for resource allocation and ICU bed occupancy. They were shown how to care for patients who were not admitted to the ICU, in their last moments and were faced with the difficulties of applying end-of-life care. Finally, the nursing students were confronted with the death of their patients, in overwhelming numbers and under adverse conditions. Conclusions: These findings can help shed light on the ethical dilemmas and ethical conflicts faced by novice nursing students, incorporated into the workforce during the COVID-19 pandemic. Moreover, it was described that students may normalize the death due to the exhaustion and overwhelmed routine.