bluuebunny/crossref_metadata_2025_split huggingface dataset:
Somatic Mutations Enriched in Cis-Regulatory Elements Affect Genes Involved in Embryonic Development and Immune System Response in Neuroblastoma
Authors: Lasorsa Vito Alessandro , Montella Annalaura , Cantalupo Sueva , Tirelli Matilde , de Torres Carmen , Aveic Sanja , Tonini Gian Paolo , Iolascon Achille , Capasso Mario 
Published: January 2022

Abstract

Noncoding cis-regulatory variants have gained interest as cancer drivers, yet progress in understanding their significance is hindered by the numerous challenges and limitations of variant prioritization. To overcome these limitations, we focused on active cis-regulatory elements (aCRE) to design a customized panel for the deep sequencing of 56 neuroblastoma tumor and normal DNA sample pairs. To search for driver mutations, aCREs were defined by reanalysis of H3K27ac chromatin immunoprecipitation sequencing peaks in 25 neuroblastoma cell lines. These regulatory genomic regions were tested for an excess of somatic mutations and assessed for statistical significance using a global approach that accounted for chromatin accessibility and replication timing. Additional validation was provided by whole genome sequence analysis of 151 neuroblastomas. Analysis of HiC data determined the presence of candidate target genes interacting with mutated regions. An excess of somatic mutations in aCREs of diverse genes were identified, including IPO7, HAND2, and ARID3A. CRISPR-Cas9 editing was utilized to assess the functional consequences of mutations in the IPO7-aCRE. Patients with noncoding mutations in aCREs showed inferior overall and event-free survival independent of age at diagnosis, stage, risk stratification, and MYCN status. Expression of aCRE-interacting genes correlated strongly with negative prognostic markers and low survival rates. Moreover, a convergence between the biological functions of aCRE target genes and transcription factors with mutated binding motifs was associated with embryonic development and immune system response. Overall, this strategy enabled the identification of somatic mutations in regulatory elements that collectively promote neuroblastoma tumorigenesis.

Significance:
Assessment of noncoding cis-regulatory variants and long-range interaction data highlight the combined effect of somatic mutations in regulatory elements in driving neuroblastoma.
NRF2: KEAPing Tumors Protected
Authors: Pillai Ray , Hayashi Makiko , Zavitsanou Anastasia-Maria , Papagiannakopoulos Thales 
Published: January 2022

AbstractThe Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2–related factor 2 (NRF2) pathway plays a physiologic protective role against xenobiotics and reactive oxygen species. However, activation of NRF2 provides a powerful selective advantage for tumors by rewiring metabolism to enhance proliferation, suppress various forms of stress, and promote immune evasion. Genetic, epigenetic, and posttranslational alterations that activate the KEAP1/NRF2 pathway are found in multiple solid tumors. Emerging clinical data highlight that alterations in this pathway result in resistance to multiple therapies. Here, we provide an overview of how dysregulation of the KEAP1/NRF2 pathway in cancer contributes to several hallmarks of cancer that promote tumorigenesis and lead to treatment resistance.Significance:Alterations in the KEAP1/NRF2 pathway are found in multiple cancer types. Activation of NRF2 leads to metabolic rewiring of tumors that promote tumor initiation and progression. Here we present the known alterations that lead to NRF2 activation in cancer, the mechanisms in which NRF2 activation promotes tumors, and the therapeutic implications of NRF2 activation.
Impact of Pretransplant Malignancy on Heart Transplantation Outcomes: Contemporary United Network for Organ Sharing Analysis Amidst Evolving Cancer Therapies
Authors: Batra Jaya , DeFilippis Ersilia M. , Golob Stephanie , Clerkin Kevin , Topkara Veli K. , Habal Marlena V. , Restaino Susan , Griffin Jan , Hi Lee Sun , Latif Farhana , Farr Maryjane A. , Sayer Gabriel , Raikelkar Jayant , Uriel Nir 
Published: January 2022

Background:
An aging population and improved cancer survivorship have increased the number of individuals with treated malignancy who develop advanced heart failure. The benefits of heart transplantation (HT) in patients with a pretransplant malignancy (PTM) must be balanced against risks of posttransplant malignancy in the setting of immunosuppression.

Methods:
Adult patients in the United Network for Organ Sharing registry who received HT between January 1, 2010, and December 31, 2020 were included. Trends, patient characteristics, and posttransplant outcomes in HT recipients with PTM were evaluated.

Results:

From 2000 to 2020, the proportion of HT recipients with PTM increased from 3.2% to 8.2%. From 2010 to 2020, 2113 (7.7%) of 27 344 HT recipients had PTM. PTM was associated with higher rates of 1-year mortality after HT (11.9% versus 9.2%; adjusted hazard ratio, 1.25 [95% CI, 1.09–1.44],
P
=0.001), driven by increased mortality in patients with hematologic PTM (adjusted hazard ratio, 2.00 [95% CI, 1.61–2.48];
P
<0.001). For recipients who survived the first year, 5-year survival was similar between patients with and without PTM. Rates of malignancy at 5-years posttransplant were higher in the PTM group (20.4% versus 13.1%; adjusted hazard ratio, 1.57 [95% CI, 1.38–1.79],
P
<0.001).

Conclusions:
Prevalence of PTM in HT recipients nearly tripled over the past 2 decades. Patients with hematologic PTM were at increased risk of early mortality after HT. Patients with PTM were also at higher risk for posttransplant malignancy. Guidelines that reflect contemporary oncological care are needed to inform care of this heterogenous and expanding group of individuals.
Recent Hadley Circulation Strengthening: A Trend or Multidecadal Variability?
Authors: Zaplotnik Žiga , Pikovnik Matic , Boljka Lina 
Published: January 2022

Abstract
This study explores the possible drivers of the recent Hadley circulation strengthening in the modern reanalyses. Predominantly, two recent generations of reanalyses provided by the European Centre for Medium-Range Weather Forecasts are used: the fifth-generation atmospheric reanalysis (ERA5) and the interim reanalysis (ERA-Interim). Some results are also evaluated against other long-term reanalyses. To assess the origins of the Hadley cell (HC) strength variability, we employ the Kuo–Eliassen (KE) equation. ERA5 shows that both HCs were strengthening prior to the 2000s, but they have been weakening or remained steady afterward. Most of the long-term variability in the strength of the HCs is explained by the meridional gradient of diabatic (latent) heating, which is related to precipitation gradients. However, the strengthening of both HCs in ERA5 is larger than the strengthening expected from the observed zonal-mean precipitation gradient [estimated from the Global Precipitation Climatology Project (GPCP)]. This suggests that the HC strength trends in the recent decades in ERA5 can be explained partly as an artifact of the misrepresentation of latent heating and partly through (physical) long-term variability. To show that the latter is true, we analyze ERA5 preliminary data for the 1950–78 period, other long-term (e.g., twentieth century) reanalyses, and sea surface temperature observational data. This reveals that the changes in the HC strength can be a consequence of the Atlantic multidecadal oscillation (AMO) and related diabatic and frictional processes, which in turn drive the global HC variability. This work has implications for further understanding of the long-term variability of the Hadley circulation.
East Asian Rainbands and Associated Circulation over the Tibetan Plateau Region
Authors: Liu Jiabin , Fung Inez Y. , Chiang John C. H. 
Published: January 2022

Abstract
Rainbands that migrate northward from spring to summer are persistent features of the East Asian summer monsoon. This study employs a machine learning algorithm to identify individual East Asian rainbands from May to August in the 6-hourly ERA-Interim reanalysis product and captures rainband events during these months for the period 1979–2018. The median duration of rainband events at any location in East Asia is 12 h, and the centroids of these rainbands move northward continuously from approximately 28°N in late May to approximately 33°N in July, instead of making jumps between quasi-stationary periods. Whereas the length and overall area of the rainbands grow monotonically from May to June, the intensity of the rainfall within the rainband dips slightly in early June before it peaks in late June. We find that extratropical northerly winds on all pressure levels over East China are the most important anomalous flow accompanying the rainband events. The anomalous northerlies augment climatological background northerlies in bringing low moist static energy air and thus generate the front associated with the rainband. Persistent lower-tropospheric southerly winds bring in moisture that feeds the rainband and are enhanced a few days prior to rainband events, but they are not directly tied to the actual rainband formation. The background northerlies could originate as part of the Rossby waves resulting from the jet stream interaction with the Tibetan Plateau. The ageostrophic circulation in the jet entrance region peaks in May and weakens in June and July and does not prove to be critical to the formation of the rainbands.
Use of a Reflectivity Operator Based on Double-Moment Thompson Microphysics for Direct Assimilation of Radar Reflectivity in GSI-Based Hybrid En3DVar
Authors: Liu Chengsi , Li Huiqi , Xue Ming , Jung Youngsun , Park Jun , Chen Lianglyu , Kong Rong , Tong Chong-Chi 
Published: January 2022

Abstract
The assimilation of reflectivity (Z) within 3DVar or hybrid ensemble-3DVar (En3DVar) requires the adjoint of the Z observation operator. With the 3DVar or En3DVar method, previous studies often use Z operators consistent with a single-moment microphysics scheme even when the forecast model uses a double-moment scheme. As such, only the mixing ratios of hydrometeors are directly updated by the data assimilation (DA) system, leading to inconsistency between the analyzed microphysics state variables and the microphysics scheme in the prediction model. In this study, we formulated a Z operator consistent with the double-moment Thompson microphysics used in the numerical integrations; in the operator the snow and graupel reflectivity components are simplified using functions fitted to T-matrix simulation results. This operator and its adjoint are implemented within the GSI hybrid En3DVar DA system to enable direct assimilation of Z with a consistent operator. The impacts of this new operator on convective storm analysis through DA cycles, and on the ensuing 3-h forecasts are first examined in detail for a tornado outbreak case of 16 May 2017 in Texas and Oklahoma, and then for five additional thunderstorm cases. Forecast reflectivity, hourly precipitation, and updraft helicity tracks are subjectively evaluated, while neighborhood ETSs and performance diagrams are examined for reflectivity and/or precipitation. Compared to experiments using a Z operator consistent with a single-moment microphysics scheme, the Z operator consistent with double-moment Thompson microphysics used in the forecast model produces better forecasts of reflectivity, hourly precipitation, and updraft helicity tracks with smaller biases, and the improvement is somewhat larger for a higher Z threshold.
The impact of the parental division of paid labour on depressive symptoms: The moderating role of social policies
Authors: Baranowska-Rataj Anna 
Published: January 2022

This study examines the association between the parental division of paid labour and depressive symptoms in a comparative perspective. It investigates how this relationship varies across couples in countries with different social policies using data from European Social Survey, and multilevel models with cross-level interactions between the parental division of paid labour and macro-level indicators of social policies. The results indicate that dual-earner couples report fewer depressive symptoms than parents in other types of families. This relative advantage of dual-earner couples varies across policy contexts. The benefits of a dual-earner model over a male breadwinner model are larger in countries where childcare services are easily available and do not disappear in countries with generous financial support from the state. Additional analyses reveal how these relationships differ across gender.
Fewer Levels of Dedicated Trauma Care Leads to Better Outcomes
Authors: Thacker Christopher , Nealon Kathleen , Torres Denise , Leonard Dianne , Young Katelyn , Rapp Megan 
Published: January 2022

Background Dedicated trauma intensive care units (ICUs) staffed by surgical intensivists lead to better patient outcomes. Increased length of stay (LOS) leads to worse outcomes. Little research has focused on the effect of dedicated trauma medical-surgical units or ICU/medicalsurgical systems. In 2018, our Level 1 trauma center transitioned from 3 non-dedicated levels of care (ICU/stepdown unit/medical-surgical) to 2 dedicated levels of care (ICU/medical-surgical). Our objective was to look at patient outcomes pre- and post-intervention. Methods Retrospective analysis of trauma registry data was performed on patients (age ≥18) admitted to the trauma service at a Level 1 rural trauma center over 46-months. In the pre-intervention group, step down and medical-surgical patients were combined as “Non-ICU” for analysis. Standard statistical analysis was performed. Results Analysis included 6103 patients. The group demographics were similar, except pre-intervention patients had higher ISS and fewer comorbidities. Emergency department LOS decreased from 30 versus 13.9% ( P < .0001) and 15.9 versus 5.8% ( P < .0001) for greater than 3 and 6 hours, respectively. Median LOS decreased for all patients ( P < .0001). Mortality dropped from 9.0 versus 5.5% ( P = .0009) for ICU and 1.7 versus 0.26% ( P = .0013) for non-ICU patients. Overall patient mortality was level at 3.7%. Inpatient complications dropped from 9.9 versus 8.5% ( P = .07). Unplanned ICU readmissions were unchanged ( P = .4169). For patients with 3+ comorbidities, overall LOS dropped by 2 days ( P < .0001) and home discharge increased from 42.8 versus 51% ( P < .0001). Conclusion Implementation of 2 levels of dedicated care has decreased ED and hospital LOS for all trauma patients without increasing mortality or complications. Patients with extensive comorbidities saw the most improvements.
Sharing is Caring: A Realist Evaluation of a Social Support Group for Individuals Who Have Been Bereaved by Suicide
Authors: Adshead Claire , Runacres Jessica 
Published: January 2022

Aim To understand the experiences and perceived impact on the wellbeing of individuals attending a suicide bereavement social support group. Design A qualitative study guided by a realist evaluation framework. Methods Data were collected from May–July 2020 using online semistructured individual interviews with participants ( N = 6), from the North West of England recruited from a suicide bereavement support group's social media. Data were analysed using thematic analysis informed by the realist framework. Results Effective social support includes the prioritisation of building meaningful connections with like-minded individuals, providing a safe space for authentic self-expression aiding personal relationship maintenance. Contextual factors included: Societal and cultural stigma of suicide, self-stigma and gender norms. Mechanisms influencing support seeking include: Not wanting to burden loved ones due to judgement, and a lack of understanding. Impact Policymakers can reduce demand on healthcare systems by developing tailored support groups to suit individual needs.
A genome-wide association study for varicose veins
Authors: Lee Meng-Lin , Liang Chao , Chuang Cheng-Hsun , Lee Pei-Shyuan , Chen Thay-Hsiung , Sun Shen , Liao Kuang-Wen , Huang Hsien-Da 
Published: January 2022

Background The aim was to compare the genetic information of varicose vein patients with that of a healthy population attempting to identify certain significant genetic associations. Method Patients’ clinical characteristics and demographics were collected, and their genetic samples were examined. The results were compared to the genetic information of one thousand sex-matched healthy controls from Taiwan Biobank database. The Clinical-Etiology-Anatomy-Pathophysiology classification was applied for further subgroup analysis. Results After comparison of genetic information of ninety-six patients to that of healthy controls, two significant single nucleotide polymorphisms (SNPs) were identified. One was in DPYSL2 gene, and the other was in VSTM2L gene. A further comparison between C2-3 patient subgroup and C4-6 subgroup identified another four significant SNPs, which were located in ZNF664-FAM101A, PHF2, ACOT11, and TOM1L1 genes. Conclusion Our preliminary result identified six significant SNPs located in six different genes. All of them and their genetic products may warrant further investigations.
Evaluation of the Efficacy of Vancomycin-Soaked Autograft to Eliminate Staphylococcus aureus Contamination After Anterior Cruciate Ligament Reconstruction: Based on an Infected Rat Model
Authors: Tong Kai , Wei Jian , Li Zhenyu , Wang Hui , Wen Yinxian , Chen Liaobin 
Published: January 2022

Background: Vancomycin-soaked autograft application in anterior cruciate ligament reconstruction (ACLR) significantly reduces postoperative infection rates. However, the optimal vancomycin concentrations and time of vancomycin presoaking of autografts for preventing infection are still unknown. Purpose: To evaluate the efficacy of vancomycin-soaked autografts in preventing infection in rats with ACLR. Study Design: Controlled laboratory study. Methods: A total of 102 tendons of Wistar rats were harvested under sterile conditions from fresh cadaveric legs. Contamination with 2.0 × 104 colony forming units per milliliter of Staphylococcus aureus and soaking in different vancomycin concentrations for different soaking times was performed in vitro. In vivo, after being contaminated with S. aureus and soaked with optimal vancomycin solution treatment and sterile saline, the grafts were implanted in rat knees to finish ACLR surgery. At 2, 4, and 12 weeks after surgery, samples were harvested to observe signs of infection and tendon-bone incorporation via general postoperative conditions, serum inflammatory markers, microbiological counting, knee radiographs, micro–computed tomography, histologic staining, scanning electron microscopy, and biomechanical testing. Results: Bacterial contamination was eliminated when at least 5 or 10 mg/mL of vancomycin was applied for 30 minutes in vitro. Rats in the vancomycin-soaked graft group (5 mg/mL of vancomycin for 30 minutes) showed no significant signs of infection and fewer positive cultures than did those without presoaking. The vancomycin-soaked graft group had reduced serum inflammatory markers, tissue scores, inflammatory reactions in the joint tissue, and radiographic evidence of periarticular osseous destruction compared with the control group. At postoperative week 12, the vancomycin-soaked graft group showed good outcomes in tendon-bone incorporation via micro–computed tomography, histologic staining, and biomechanical testing. Conclusion: In a rat model of infection after ACLR, presoaking grafts in a 5-mg/mL vancomycin solution for 30 minutes could effectively prevent S. aureus contamination without affecting tendon-bone incorporation and knee function. Clinical Relevance: The present study could provide a specific solution for the use of vancomycin in the prevention of infection after ACLR clinically.
Biomechanical Assessment of Knee Laxity After a Novel Posterolateral Corner Reconstruction Technique
Authors: Vivacqua Thiago , Vakili Samira , Willing Ryan , Moatshe Gilbert , Degen Ryan , Getgood Alan M. 
Published: January 2022

Background: Different techniques to restore knee stability after posterolateral corner (PLC) injury have been described. The original anatomic PLC reconstruction uses 2 separate allografts to reconstruct the PLC. Access to allograft tissue continues to be a significant limitation of this technique, which led to the development of a modified anatomic approach utilizing a single autologous semitendinosus graft fixed on the tibia with an adjustable suspensory loop to enable differential tensioning of the PLC components. Purpose/Hypothesis: The purpose of this study was to compare the modified anatomic technique with the original anatomic reconstruction in terms of varus and external rotatory laxity in a cadaveric biomechanical model. The hypothesis was that both techniques would restore varus and external rotatory laxity after a simulated complete PLC injury. Study Design: Controlled laboratory study. Methods: Eight pairs of fresh-frozen cadaveric knee specimens were tested to compare the 2 techniques. Varus and external tibial rotation laxity of the knee were measured while applying 10-N·m varus and 5-N·m external rotatory torques at 0°, 30°, 60°, and 90° of flexion. These measurements were tested under 3 conditions: (1) intact fibular collateral ligament, popliteal tendon, and popliteofibular ligament; (2) complete transection of the fibular collateral ligament, popliteal tendon, and popliteofibular ligament; (3) after PLC reconstruction with either the modified (n = 8) or the original (n = 8) technique. Results: After PLC reconstruction, varus laxity was restored with no statistically significant differences from the intact condition after both reconstruction techniques. Similar outcomes were observed for external rotation in extension; however, in terms of the external rotation limit with respect to the intact joint, significant reductions of mean ± SD 4.1°± 6.3° ( P = .036) and 5.1°± 6.6° ( P = .016) were recorded with the modified technique at 60° and 90° of flexion, respectively. No significant effect was observed on the neutral flexion kinematics from 0° to 90° of flexion, and no significant differences were observed between reconstructions ( P = .222). Conclusion: Both PLC reconstruction techniques restored the normal native varus as compared with the intact knee. Although the modified technique constrained end-range external rotation at 60° and 90° of flexion, no differences were noted with neutral flexion kinematics. Care should be taken when tensioning in the modified technique so that the tibia is in a neutral position to avoid overconstraining the knee. Clinical Relevance: The modified technique may prove useful in situations where there are limited graft options, particularly where allografts are not available or are restricted.