bluuebunny/crossref_metadata_2025_split huggingface dataset:
Visean high-K mafic–intermediate plutonic rocks of the Ossa–Morena Zone (SW Iberia): implications for regional extensional tectonics
Authors: Pereira M. Francisco , Dias da Silva Ícaro , Rodríguez Cármen , Corfu Fernando , Castro António 
Published: October 2022

Abstract

Field relationships and new U–Pb geochronology data indicate a temporal link between the diverse high-K mafic–intermediate magmas of the Ossa–Morena Zone (OMZ). Ages of
c.
338–335 Ma for the Vale de Maceiras gabbro and the Campo Maior microdiorite and quartz-diorite indicate that plutonism took place during a Variscan extensional D
2
deformation event in the OMZ. The syntectonic nature of the Vale de Maceiras pluton is attested to by the orientation of intrusive contacts, magmatic foliation and the growth of contact metamorphic minerals in relation to the Variscan extensional D
2
foliation. The Campo Maior microdiorite, quartz-diorite and orthomigmatites are temporally linked to high-temperature mylonitic gneisses formed simultaneously with the Variscan extensional D
2
deformation event. The geochemical features of the Vale de Maceiras and Campo Maior mafic–intermediate rocks show an affinity with the sanukitoid series. This finding suggests that the observed geochemical variability, from tholeiitic to calc-alkaline and sanukitoid, in the Visean OMZ plutonic rocks (
c.
349–335 Ma) may have been inherited from partially melted mantle domains that were previously contaminated by crustal melts during subduction.
Palinspastic restoration of Variscan oroclines – implications for dextral transpression and terrane affinities
Authors: Hynes Andrew , Johnston Stephen 
Published: October 2022

Abstract
The Paleozoic Variscan orogen in Europe has a markedly circuitous trace for which several different origins have been postulated, including deformation around promontories on the colliding continental margins, extrusion within the collision zone, folding of a ribbon continent and collision with a substantial dextral component. Adopting the latter assumption, unfolding of the large, steeply plunging folds (‘oroclines’) of Iberia and the Moroccan Meseta requires more than 4000 km of dextral lateral translation of Laurussia with respect to Gondwana. Constraints on the age of the folding require that this lateral translation occurred in mid-late Carboniferous time. Significant dextral translation of Laurussia with respect to Gondwana late in the Variscan collision is supported by palaeomagnetic data for the two supercontinents, although the exact timing of this relative motion is not well constrained due to large uncertainties in the palaeomagnetic pole positions. Our palinspastic reconstruction of the major Variscan folds of Iberia places the rocks of the South Portuguese Zone of western Iberia adjacent to the Rhenish Massif; for instance, as part of Avalonia. By the same token, the Sehoul Block in the Moroccan Meseta probably originated at the western end of Cadomia, although nothing in our analysis precludes it also being derived from Avalonia.
The 5-Hydroxymethylcytosine Landscape of Prostate Cancer
Authors: Sjöström Martin , Zhao Shuang G. , Levy Samuel , Zhang Meng , Ning Yuhong , Shrestha Raunak , Lundberg Arian , Herberts Cameron , Foye Adam , Aggarwal Rahul , Hua Junjie T. , Li Haolong , Bergamaschi Anna , Maurice-Dror Corinne , Maheshwari Ashutosh , Chen Sujun , Ng Sarah W.S. , Ye Wenbin , Petricca Jessica , Fraser Michael , Chesner Lisa , Perry Marc D. , Moreno-Rodriguez Thaidy , Chen William S. , Alumkal Joshi J. , Chou Jonathan , Morgans Alicia K. , Beer Tomasz M. , Thomas George V. , Gleave Martin , Lloyd Paul , Phillips Tierney , McCarthy Erin , Haffner Michael C. , Zoubeidi Amina , Annala Matti , Reiter Robert E. , Rettig Matthew B. , Witte Owen N. , Fong Lawrence , Bose Rohit , Huang Franklin W. , Luo Jianhua , Bjartell Anders , Lang Joshua M. , Mahajan Nupam P. , Lara Primo N. , Evans Christopher P. , Tran Phuoc T. , Posadas Edwin M. , He Chuan , Cui Xiao-Long , Huang Jiaoti , Zwart Wilbert , Gilbert Luke A. , Maher Christopher A. , Boutros Paul C. , Chi Kim N. , Ashworth Alan , Small Eric J. , He Housheng H. , Wyatt Alexander W. , Quigley David A. , Feng Felix Y. 
Published: October 2022

Abstract

Analysis of DNA methylation is a valuable tool to understand disease progression and is increasingly being used to create diagnostic and prognostic clinical biomarkers. While conversion of cytosine to 5-methylcytosine (5mC) commonly results in transcriptional repression, further conversion to 5-hydroxymethylcytosine (5hmC) is associated with transcriptional activation. Here we perform the first study integrating whole-genome 5hmC with DNA, 5mC, and transcriptome sequencing in clinical samples of benign, localized, and advanced prostate cancer. 5hmC is shown to mark activation of cancer drivers and downstream targets. Furthermore, 5hmC sequencing revealed profoundly altered cell states throughout the disease course, characterized by increased proliferation, oncogenic signaling, dedifferentiation, and lineage plasticity to neuroendocrine and gastrointestinal lineages. Finally, 5hmC sequencing of cell-free DNA from patients with metastatic disease proved useful as a prognostic biomarker able to identify an aggressive subtype of prostate cancer using the genes TOP2A and EZH2, previously only detectable by transcriptomic analysis of solid tumor biopsies. Overall, these findings reveal that 5hmC marks epigenomic activation in prostate cancer and identify hallmarks of prostate cancer progression with potential as biomarkers of aggressive disease.

Significance:
In prostate cancer, 5-hydroxymethylcytosine delineates oncogene activation and stage-specific cell states and can be analyzed in liquid biopsies to detect cancer phenotypes.
See related article by Wu and Attard, p. 3880
A Unique FOXA1-Associated Chromatin State Dictates Therapeutic Resistance in Lobular Breast Cancer
Authors: Blawski Ryan , Toska Eneda 
Published: October 2022

AbstractInvasive lobular carcinomas (ILC) are the second most common histologic subtype of breast cancer, accounting for up to 15% of cases. ILC is estrogen receptor (ER) positive, yet its biology is distinct from invasive ductal carcinomas (IDC), and retrospective analyses have indicated a poorer outcome with endocrine therapy. In this issue of Cancer Research, Nardone and colleagues investigated the mechanisms of this differential therapy response in ILC, which cannot be solely explained by the genetic profile of these tumors. The authors conducted a thorough examination of the epigenome of ILC compared with IDC in clinical and preclinical models and revealed an alternative chromatin accessibility state in ILC driven by the pioneer factor FOXA1. FOXA1 regulates its own expression in a feed-forward mechanism by binding to an ILC-unique FOXA1 enhancer site. This results in a FOXA1-ER axis that promotes the transcription of genes associated with tumor progression and tamoxifen resistance. Targeting the FOXA1 enhancer region blocks this transcriptional program and inhibits ILC proliferation. These results shed light on a new epigenetic mechanism driving ILC tumor progression and treatment resistance, which may have profound therapeutic implications.See related article by Nardone et al., p. 3673
A Detouring Experience Not Recommended: Lessons Learned from PF00299804
Authors: Li Molly , Mok Kevin , Mok Tony 
Published: October 2022

Abstract
Patients with mutant EGFR positive non–small cell lung cancer (NSCLC) benefit from tyrosine kinase inhibitor (TKI) treatment. However, all patients ultimately develop acquired resistance, half of which are attributed to the EGFR exon 20 T790M mutation. A landmark publication in Cancer Research in 2007 demonstrated improved drug potency and pan-human EGFR (HER) inhibition with PF00299804, a second-generation EGFR TKI. Compared with first-generation EGFR TKI, PF00299804 showed the ability to overcome T790M mutation in vitro and had the potential to improve treatment outcomes of patients with mutant EGFR-positive NSCLC. Here we review the preclinical and clinical development of PF00299804 and reflect on the lessons learned from this detouring experience.
See related article by Engelman and colleagues, Cancer Res 2007;67:11924–32.
Impact of Genetic Variants in the Nicotine Metabolism Pathway on Nicotine Metabolite Levels in Smokers
Authors: Perez-Paramo Yadira X. , Watson Christy J.W. , Chen Gang , Thomas Claire E. , Adams-Haduch Jennifer , Wang Renwei , Khor Chiea Chuen , Koh Woon-Puay , Nelson Heather H. , Yuan Jian-Min , Lazarus Philip 
Published: October 2022

Abstract

Background:
Nicotine metabolism is a major factor in nicotine dependence, with approximately 70% to 80% of nicotine metabolized to cotinine in Caucasians. Cotinine formation is catalyzed primarily by CYP2A6, which also converts cotinine to trans-3′-hydroxycotinine (3HC). The goal of the present study was to examine the effects of CYP2A6 deficiency on nicotine metabolism profiles in vivo and the importance of genetic variants in nicotine-metabolizing enzyme genes on urinary nicotine metabolites levels.

Methods:
Urine samples from 722 smokers who participated in the Singapore Chinese Health Study were analyzed using UPLC-MS/MS to detect nicotine and eight of its urinary metabolites, and a total of 58 variants in 12 genes involved in nicotine metabolism were investigated in 475 of these subjects with informative genotyping data.

Results:
Urine samples stratified by the ratio of 3HC/cotinine exhibited a 7-fold increase in nicotine-N’-oxide, a 6-fold increase in nicotine-Glucuronide (Gluc), and a 5-fold decrease in 3HC-Gluc when comparing the lower versus upper 3HC/cotinine ventiles. Significant (P &lt; 0.0001) associations were observed between functional metabolizing enzyme genotypes and levels of various urinary nicotine metabolites, including CYP2A6 genotype and levels of nicotine, nicotine-Gluc, nicotine-N’-oxide and 3HC, UGT2B10 genotype and levels of cotinine, nicotine-Gluc and cotinine-Gluc, UGT2B17 genotype and levels of 3HC-Gluc, FMO3 genotype and levels of nicotine-N’-oxide, and CYP2B6 genotype and levels of nicotine-N’-oxide and 4-hydroxy-4-(3-pyridyl)-butanoic acid.

Conclusions:
These data suggest that several pathways are important in nicotine metabolism.

Impact:
Genotype differences in several nicotine-metabolizing enzyme pathways may potentially lead to differences in nicotine dependence and smoking behavior and cessation.
Tachyarrhythmias During Hospitalization for COVID‐19 or Multisystem Inflammatory Syndrome in Children and Adolescents
Authors: Dionne Audrey , Friedman Kevin G. , Young Cameron C. , Newhams Margaret M. , Kucukak Suden , Jackson Ashley M. , Fitzgerald Julie C. , Smallcomb Laura S. , Heidemann Sabrina , McLaughlin Gwenn E. , Irby Katherine , Bradford Tamara T. , Horwitz Steven M. , Loftis Laura L. , Soma Vijaya L. , Rowan Courtney M. , Kong Michele , Halasa Natasha B. , Tarquinio Keiko M. , Schwarz Adam J. , Hume Janet R. , Gertz Shira J. , Clouser Katharine N. , Carroll Christopher L. , Wellnitz Kari , Cullimore Melissa L. , Doymaz Sule , Levy Emily R. , Typpo Katri V. , Lansell Amanda N. , Butler Andrew D. , Kuebler Joseph D. , Zambrano Laura D. , Campbell Angela P. , Patel Manish M. , Randolph Adrienne G. , Newburger Jane W. ,   for the Overcoming COVID‐19 Investigators
Published: October 2022

Background
Cardiac complications related to COVID‐19 in children and adolescents include ventricular dysfunction, myocarditis, coronary artery aneurysm, and bradyarrhythmias, but tachyarrhythmias are less understood. The goal of this study was to evaluate the frequency, characteristics, and outcomes of children and adolescents experiencing tachyarrhythmias while hospitalized for acute severe COVID‐19 or multisystem inflammatory syndrome in children.

Methods and Results
This study involved a case series of 63 patients with tachyarrhythmias reported in a public health surveillance registry of patients aged <21 years hospitalized from March 15, 2020, to December 31, 2021, at 63 US hospitals. Patients with tachyarrhythmias were compared with patients with severe COVID‐19–related complications without tachyarrhythmias. Tachyarrhythmias were reported in 22 of 1257 patients (1.8%) with acute COVID‐19 and 41 of 2343 (1.7%) patients with multisystem inflammatory syndrome in children. They included supraventricular tachycardia in 28 (44%), accelerated junctional rhythm in 9 (14%), and ventricular tachycardia in 38 (60%); >1 type was reported in 12 (19%). Registry patients with versus without tachyarrhythmia were older (median age, 15.4 [range, 10.4–17.4] versus 10.0 [range, 5.4–14.8] years) and had higher illness severity on hospital admission. Intervention for treatment of tachyarrhythmia was required in 37 (59%) patients and included antiarrhythmic medication (n=31, 49%), electrical cardioversion (n=11, 17%), cardiopulmonary resuscitation (n=8, 13%), and extracorporeal membrane oxygenation (n=9, 14%). Patients with tachyarrhythmias had longer hospital length of stay than those who did not, and 9 (14%) versus 77 (2%) died.

Conclusions
Tachyarrhythmias were a rare complication of acute severe COVID‐19 and multisystem inflammatory syndrome in children and adolescents and were associated with worse clinical outcomes, highlighting the importance of close monitoring, aggressive treatment, and postdischarge care.
Mitral Valve Surgery for Persistent or Recurrent Mitral Regurgitation After Transcatheter Edge‐to‐Edge Repair Is Associated With Improved Survival
Authors: El Shaer Ahmed , Chavez Ponce Alejandra , Mazur Piotr , Greason Kevin , Arghami Arman , Eleid Mackram F. , Guerrero Mayra , Rihal Charanjit S. , Crestanello Juan A. , Alkhouli Mohamad 
Published: October 2022

Background
The management of severe mitral regurgitation (MR) after transcatheter edge‐to‐edge repair (TEER) remains a clinical conundrum. Considering the growing volume of TEER, more outcomes data for mitral surgery in this cohort are needed.

Methods and Results

Symptomatic patients with persistent or recurrent severe MR after TEER evaluated between May 2014 and June 2021 were included. The primary outcome was all‐cause mortality in patients who were treated with surgery versus medical therapy. The Kaplan–Meier and Cox regression methods were used to report risk‐adjusted survival analyses. Among the 142 included patients, 44 (31.0%) underwent mitral surgery. Patients who underwent surgery were younger than those treated medically (74.1±8.9 versus 78.6±10.5 years,
P
=0.01). Major comorbidities were similar except obesity, sleep apnea, left ventricular dimensions, and ejection fraction. Society of Thoracic Surgeons Predicted Risk of Operative Mortality was 9.0±4.7 versus 7.9±4.9 in the surgical versus medical therapy groups, respectively,
P
=0.22. Time from TEER to detection of severe MR was similar in both groups (median [interquartile range] 97.5 [39.5–384] versus 93.5 [40–389] days in the surgical versus medical groups, respectively [
P
>0.05]). In the surgical group, valve replacement was performed in all patients. Operative mortality was 4.5% (observed/expected ratio 0.55), and major complications were uncommon. After risk‐adjustment, surgery was associated with significantly lower all‐cause mortality (adjusted hazard ratio, 0.33 [95% CI, 0.12–0.92],
P
=0.001) compared with medial therapy.

Conclusions
Compared with medical therapy, mitral surgery in patients with severe persistent or recurrent MR after TEER is associated with lower mortality despite the high‐risk profile of these patients. Patients with severe MR after TEER should be considered for surgery at a referral mitral surgical center.
Cost‐of‐Illness Analysis of Long‐Term Health Care Resource Use and Disease Burden in Patients With Pulmonary Embolism: Insights From the PREFER in VTE Registry
Authors: Farmakis Ioannis T. , Barco Stefano , Mavromanoli Anna C. , Agnelli Giancarlo , Cohen Alexander T. , Giannakoulas George , Mahan Charles E. , Konstantinides Stavros V. , Valerio Luca 
Published: October 2022

Background
As mortality from pulmonary embolism (PE) decreases, the personal and societal costs among survivors are receiving increasing attention. Detailing this burden would support an efficient public health resource allocation. We aimed to provide estimates for the economic and disease burden of PE also accounting for long‐term health care use and both direct and indirect costs beyond the acute phase.

Methods and Results
This is a cost‐of‐illness analysis with a bottom‐up approach based on data from the PREFER in VTE registry (Prevention of Thromboembolic Events—European Registry in Venous Thromboembolism). We calculated direct (clinical events and anticoagulation) and indirect costs (loss of productivity) of an acute PE event and its 12‐month follow‐up in 2020 Euros. We estimated a disability weight for the 12‐month post‐PE status and corresponding disability adjusted life years presumably owing to PE. Disease‐specific costs in the first year of follow‐up after an incident PE case ranged between 9135 Euros and 10 620 Euros. The proportion of indirect costs was 42% to 49% of total costs. Costs were lowest in patients with ongoing cancer, mainly because productivity loss was less evident in this already burdened population. The calculated disability weight for survivors who were cancer free 12 months post‐PE was 0.017, and the estimated disability adjusted life years per incident case were 1.17.

Conclusions
The economic burden imposed by PE to society and affected patients is considerable, and productivity loss is its main driver. The disease burden from PE is remarkable and translates to the loss of roughly 1.2 years of healthy life per incident PE case.
Half a century of the inverse care law: A comparison of general practitioner job satisfaction and patient satisfaction in deprived and affluent areas of Scotland
Authors: Mercer Stewart W , Lunan Carey J , MacRae Clare , Henderson David AG , Fitzpatrick Bridie , Gillies John , Guthrie Bruce , Reilly Johanna 
Published: October 2022

Background and Aims The ‘inverse care law’, first described in 1971, results from a mismatch of healthcare need and healthcare supply in deprived areas. GPs in such areas struggle to cope with the high levels of demand resulting in shorter consultations and poorer patient outcomes. We compare recent national GP and patient satisfaction data to investigate the ongoing existence of this disparity in Scotland. Methods and Results Secondary analysis of cross-sectional national surveys (2017/2018) on upper and lower deprivation quintiles. GP measures; job satisfaction, job stressors, positive and negative job attributes. Patient measures; percentage positive responses per practice on survey questions on access and consultation quality. GPs in high deprivation areas reported lower job satisfaction and positive job attributes, and higher job stressors and negative job attributes compared with GPs in low deprivation areas. Patients living in high deprivation areas reported lower satisfaction with access and consultation quality than patients in low deprivation areas. These differences in GP and patient satisfaction persisted after adjusting for confounding variables. Conclusions Lower GP work satisfaction in deprived areas was mirrored by lower patient satisfaction. These findings add to the evidence that the inverse care law persists in Scotland, over 50 years after it was first described.
Modular personalized climatization testing infrastructure with smartphone-based user feedback
Authors: Metzmacher Henning , Syndicus Marc , Warthmann Alexander , Frisch Jérôme , van Treeck Christoph 
Published: October 2022

Heating and ventilation in buildings and vehicles are responsible for over a third of global final energy usage and the resulting emissions. Local climatization can help to save energy while at the same time enable more individualized and adapted micro-climates around people. For the domain of local comfort, integrative test environments for sensors, actuators, and control software are scarce, and oftentimes tailored to a specific set of components. Here, a server-based modular testing infrastructure which allows integration and evaluation of sensors, actuators, and control strategies is presented. Currently, the system is able to integrate, monitor, and log data of thermal imaging, motion sensing, environmental sensor such as temperature or air velocity and to forward signals to actuators such as fans, infrared- or contact-heaters. The generation of control signals is model-based and relies on user feedback provided via the system’s smartphone app. Lastly, learning algorithms can be trained and compared during user studies. Practical Application: Although developed in a laboratory based research context, the proposed system is based on open standards and protocols. It therefore can be applied by practitioners, developers, and manufacturers in order to test stand-alone components as well as ensembles of sensors and actuators for personalized climatization in an integrative and replicable manner.
Gender, Social Protection, and Crises of Social Reproduction: Contextualizing NREGA
Authors: Rao Smriti , Ramnarain Smita 
Published: October 2022

The COVID-19 pandemic has underscored the importance of social protection programs such as India’s Mahatma Gandhi National Rural Employment Guarantee Act (NREGA). And yet, acute crises such as pandemics are layered upon existing inequalities of gender and caste in India. We show that a distinctive feature of twenty-first-century Indian capitalism is a restructuring of the caste-gender division of labor in rural India, such that women’s unpaid labor of social reproduction has increased, particularly for women from marginalized castes. Thus, patterns of participation in NREGA cannot be understood without understanding the specifics of the underlying crisis of social reproduction for labor. Social protection programs that do not consider the labor of social reproduction and are unaccompanied by broader socialization of such labor then likely fall short of mitigating deep-rooted inequalities. JEL Classification: B54, J21, J88
Viewpoints of Residency Program Directors Regarding Depressive Symptoms in Pharmacy Residents
Authors: Putney Kaylee , Gupta Vasudha , Williams Evan , Unni Elizabeth 
Published: October 2022

Objective: Several publications have highlighted residency-specific factors being associated with depressive symptoms in pharmacy residents, but no studies have investigated the viewpoint of residency program directors (RPDs) regarding this issue. This study’s primary objectives were to identify potential contributing factors, determine current resources, and outline possible solutions to decrease depressive symptoms among pharmacy residents from the point of view of RPDs. Methods: RPDs were asked to participate in a 45-60-minute semi-structured interview conducted via phone by the primary investigator, recorded, and transcribed using NVivo. Interviews were manually analyzed by study investigators to identify emerging themes. The investigators discussed findings and discrepancies to agree upon thematic interpretations of the transcripts. Results: Ten interviews were conducted between May 2019 and February 2020. RPD experience ranged from 2-15 years. Pharmacy practice PGY1 programs comprised 60% of interviews, 20% for community practice, and 10% each for managed care and ambulatory care. All RPDs indicated increased workload as a contributing factor to depressive symptoms in residents. The inability to accept and utilize constructive feedback and difficulties transitioning from student to resident were identified as contributing factors by 50% of the RPDs. Nine RPDs reported having employee assistance programs, stating the resource was underutilized, and identified the need for additional education regarding identification and triage, not necessarily management, to help residents. Conclusion: This study highlights consistency among RPDs regarding potential contributors to depressive symptoms in pharmacy residents and emphasizes the need for additional RPD and preceptor training to identify and help residents more effectively with these issues.