bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fusion versus fixation in complex comminuted C3-type tibial pilon fractures: a systematic review
Authors: Chaudhry Yash P. , Papadelis Efstratios , Hayes Hunter , Stahel Philip F. , Hasenboehler Erik A. 
Published: October 2021

Abstract
Background
Comminuted intra-articular tibial pilon fractures can be challenging to manage, with high revision rates and poor functional outcomes. This study reviewed [1] treatment, complications, and clinical outcomes in studies of complex comminuted tibial pilon fractures (type AO43-C3); and [2] primary ankle arthrodesis as a management option for these types of complex injuries.

Methods
A systematic literature search was performed on PubMed from 1990 to 2020 to determine complications and outcomes after staged fracture fixation and primary ankle joint arthrodesis for comminuted C3-type tibial pilon fractures.
The search was conducted in compliance with the PRISMA guidelines, using the following MeSH terms: “tibial pilon”/“pilon fracture”/“plafond fracture”/“distal tibial”/“43-C3”/“ankle fracture”/“ankle fusion”/“primary ankle arthrodesis”/“pilon fracture staged”/“pilon external fixation” and “pilon open reduction internal fixation.” Inclusion criteria were restricted to original articles in English language on adult patients ≥18 years of age. Eligibility criteria for retrieved publications were determined using a “PICO” approach (population, intervention/exposure, comparison, outcomes). Weighted analysis was used to compare treatment groups on time to definitive treatment, follow-up time, range of motion, fracture classification, and complications.

Results
The systematic literature review using the defined MeSH terms yielded 72 original articles. Of these, 13 articles met the eligibility criteria based on the PICO statements, of which 8 publications investigated the outcomes of a staged fixation approach in 308 cumulative patients, and 5 articles focused on primary ankle arthrodesis in 69 cumulative patients. For staged treatment, the mean wound complication rate was 14.6%, and the malunion/nonunion rate was 9.9%. For primary arthrodesis, the mean wound complication rate was 2.9%, and the malunion/nonunion rate was 2.9%. After risk stratification for fracture type and severity, the small cumulative cohort of patients included in the primary arthrodesis publications did not provide sufficient power to determine a clinically relevant difference in complications and long-term patient outcomes compared to the staged surgical fixation group.

Conclusions
At present, there is insufficient evidence in the published literature to provide guidance towards consideration of ankle arthrodesis for complex comminuted C3-type tibial pilon fractures, compared to the standard treatment by staged surgical fracture fixation.
Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies
Authors: Zhou Jing , Ji Qing , Li Qi 
Published: October 2021

AbstractCetuximab and panitumumab are monoclonal antibodies (mAbs) against epidermal growth factor receptor (EGFR) that are effective agents for metastatic colorectal cancer (mCRC). Cetuximab can prolong survival by 8.2 months inRASwild-type (WT) mCRC patients. Unfortunately, resistance to targeted therapy impairs clinical use and efficiency. The mechanisms of resistance refer to intrinsic and extrinsic alterations of tumours. Multiple therapeutic strategies have been investigated extensively to overcome resistance to anti-EGFR mAbs. The intrinsic mechanisms include EGFR ligand overexpression, EGFR alteration,RAS/RAF/PI3Kgene mutations, ERBB2/MET/IGF-1R activation, metabolic remodelling, microsatellite instability and autophagy. For intrinsic mechanisms, therapies mainly cover the following: new EGFR-targeted inhibitors, a combination of multitargeted inhibitors, and metabolic regulators. In addition, new cytotoxic drugs and small molecule compounds increase the efficiency of cetuximab. Extrinsic alterations mainly disrupt the tumour microenvironment, specifically immune cells, cancer-associated fibroblasts (CAFs) and angiogenesis. The directions include the modification or activation of immune cells and suppression of CAFs and anti-VEGFR agents. In this review, we focus on the mechanisms of resistance to anti-EGFR monoclonal antibodies (anti-EGFR mAbs) and discuss diverse approaches to reverse resistance to this therapy in hopes of identifying more mCRC treatment possibilities.
The lockdown effects on a pediatric obese population in the COVID-19 era
Authors: Valenzise M. , D’Amico F. , Cucinotta U. , Lugarà C. , Zirilli G. , Zema A. , Wasniewska M. , Pajno G. B. 
Published: October 2021

Abstract
Background
The social consequences of COVID-19 pandemic are universally known. In particular, the pediatric population is dealing with a radical lifestyle change. For some risk categories, such as overweight or obese children, the impact of home confinement has been greater than for others. The increased sedentary life, the wrong diet and social distancing have stopped the chance of losing weight.
The aims of this study were to analyse the impact of COVID-19 lockdown on the behavior changes in a obese pediatric population and to explore the correlation between the new lifestyle and the level of parental instruction.

Methods
Data show features of 40 obese and overweight pediatric patients of our Clinic in Messina (Italy). We evaluated weight, height, BMI and other biochemical parameters: total cholesterol, HDL, LDL, triglyceride, transaminases, glycemia and insulinemia. After the lockdown, we contacted all patients in order to get some information about diet, physical activity and sedentary lifestyle changes in correlation to the level of their parents’ instruction. Additionally, we also evaluated 20 children twice from a clinical and laboratory perspective.

Results
The study showed an increase of daily meals during COVID-19 lockdown (3.2 ± 0.4 vs 5 ± 1, P < 0.001). In particular, children whose parents have primary school diploma ate a greater significant number of meals during the lockdown, compared to those who have parents with secondary school diploma (P = 0.0019). In addition, the 95% of patients did low physical activity during the lockdown and the 97.5% spent more time in sedentary activity. Even if BMI’s values don’t show significant differences, they have increased after the lockdown. We didn’t find any correlation between biochemical parameters before and after the lockdown.

Conclusion
The lockdown has had bad consequences on good style of life’s maintenance in overweight and obese children. The absence of a significant correlation between the worsening of biochemical parameters and the lockdown doesn’t allow to exclude any long-term consequences. It’s safe to assume that, if the hours spent in sedentary activity and the number of meals don’t diminish, there will probably repercussion on the biochemical parameters.
Evaluation of zinc sulfate as an adjunctive therapy in COVID-19 critically ill patients: a two center propensity-score matched study
Authors: Al Sulaiman Khalid , Aljuhani Ohoud , Al Shaya Abdulrahman I. , Kharbosh Abdullah , Kensara Raed , Al Guwairy Alhomaidi , Alharbi Aisha , Algarni Rahmah , Al Harbi Shmeylan , Vishwakarma Ramesh , Korayem Ghazwa B. 
Published: October 2021

Abstract
Background
Zinc is a trace element that plays a role in stimulating innate and acquired immunity. The role of zinc in critically ill patients with COVID-19 remains unclear. This study aims to evaluate the efficacy and safety of zinc sulfate as adjunctive therapy in critically ill patients with COVID-19.

Methods
Patients aged ≥ 18 years with COVID-19 who were admitted to the intensive care unit (ICU) in two tertiary hospitals in Saudi Arabia were retrospectively assessed for zinc use from March 1, 2020 until March 31, 2021. After propensity score matching (1:1 ratio) based on the selected criteria, we assessed the association of zinc used as adjunctive therapy with the 30-day mortality. Secondary outcomes included the in-hospital mortality, ventilator free days, ICU length of stay (LOS), hospital LOS, and complication (s) during ICU stay.

Results
A total of 164 patients were included, 82 patients received zinc. Patients who received zinc sulfate as adjunctive therapy have a lower 30-day mortality (HR 0.52, CI 0.29, 0.92; p = 0.03). On the other hand, the in-hospital mortality was not statistically significant between the two groups (HR 0.64, CI 0.37–1.10; p = 0.11). Zinc sulfate use was associated with a lower odds of acute kidney injury development during ICU stay (OR 0.46 CI 0.19–1.06; p = 0.07); however, it did not reach statistical significance.

Conclusion
The use of zinc sulfate as an additional treatment in critically ill COVID-19 patients may improve survival. Furthermore, zinc supplementation may have a protective effect on the kidneys.
Lean mass as a risk factor for intensive care unit admission: an observational study
Authors: Thackeray Matthew , Mohebbi Mohammadreza , Orford Neil , Kotowicz Mark A. , Pasco Julie A. 
Published: October 2021

Abstract
Purpose
Intensive care unit (ICU) survivors have reduced physical function likely due to skeletal muscle wasting and weakness acquired during critical illness. However, the contribution of pre-morbid muscle mass has not been elucidated. We aimed to examine the association between pre-ICU muscle mass and ICU admission risk. Secondary outcomes include the relationship between muscle mass and ICU outcomes.

Methods
ICU admissions between June 1, 1998, and February 1, 2019, were identified among participants of Geelong Osteoporosis Study (GOS), a population-based cohort study. Cox proportional hazard regression models estimated hazard ratios (HR) for ICU admission across T-score strata and continuous values of DXA-derived lean mass measures of skeletal mass index (SMI, lean mass/body mass %) and appendicular lean mass corrected for height (ALM/h2, kg/m2). Multivariable regression was used to determine the relationship between lean mass and ICU outcomes.

Results
One hundred and eighty-six of 3126 participants enrolled in GOS were admitted to the ICU during the follow-up period. In adjusted models, lean mass was not predictive of ICU admission (SMI: HR 0.99 95%CI 0.97–1.01, p = 0.32; ALM/h2: HR 1.11 95%CI 0.94–1.31, p = 0.23), while greater appendicular lean mass was related to reduced 28-day mortality (ALM/h2 adjOR: 0.25, 95%CI 0.10–0.63, p = 0.003, SMI adjOR: 0.91, 95%CI 0.82–1.02, p = 0.09).

Conclusion
Lean mass was not associated with ICU admission in this population-based cohort study; however, greater appendicular lean mass was associated with reduced mortality. This suggests pre-ICU muscle status may not predict development of critical illness but is associated with better survival after critical illness occurs.
The chromatin remodeler Ino80 mediates RNAPII pausing site determination
Authors: Cheon Youngseo , Han Sungwook , Kim Taemook , Hwang Daehee , Lee Daeyoup 
Published: October 2021

Abstract
Background
Promoter-proximal pausing of RNA polymerase II (RNAPII) is a critical step for the precise regulation of gene expression. Despite the apparent close relationship between promoter-proximal pausing and nucleosome, the role of chromatin remodeler governing this step has mainly remained elusive.

Results
Here, we report highly confined RNAPII enrichments downstream of the transcriptional start site in Saccharomyces cerevisiae using PRO-seq experiments. This non-uniform distribution of RNAPII exhibits both similar and different characteristics with promoter-proximal pausing in Schizosaccharomyces pombe and metazoans. Interestingly, we find that Ino80p knockdown causes a significant upstream transition of promoter-proximal RNAPII for a subset of genes, relocating RNAPII from the main pausing site to the alternative pausing site. The proper positioning of RNAPII is largely dependent on nucleosome context. We reveal that the alternative pausing site is closely associated with the + 1 nucleosome, and nucleosome architecture around the main pausing site of these genes is highly phased. In addition, Ino80p knockdown results in an increase in fuzziness and a decrease in stability of the + 1 nucleosome. Furthermore, the loss of INO80 also leads to the shift of promoter-proximal RNAPII toward the alternative pausing site in mouse embryonic stem cells.

Conclusions
Based on our collective results, we hypothesize that the highly conserved chromatin remodeler Ino80p is essential in establishing intact RNAPII pausing during early transcription elongation in various organisms, from budding yeast to mouse.
Effects of sequence motifs in the yeast 3′ untranslated region determined from massively parallel assays of random sequences
Authors: Savinov Andrew , Brandsen Benjamin M. , Angell Brooke E. , Cuperus Josh T. , Fields Stanley 
Published: October 2021

Abstract
Background
The 3′ untranslated region (UTR) plays critical roles in determining the level of gene expression through effects on activities such as mRNA stability and translation. Functional elements within this region have largely been identified through analyses of native genes, which contain multiple co-evolved sequence features.

Results
To explore the effects of 3′ UTR sequence elements outside of native sequence contexts, we analyze hundreds of thousands of random 50-mers inserted into the 3′ UTR of a reporter gene in the yeast Saccharomyces cerevisiae. We determine relative protein expression levels from the fitness of transformants in a growth selection. We find that the consensus 3′ UTR efficiency element significantly boosts expression, independent of sequence context; on the other hand, the consensus positioning element has only a small effect on expression. Some sequence motifs that are binding sites for Puf proteins substantially increase expression in the library, despite these proteins generally being associated with post-transcriptional downregulation of native mRNAs. Our measurements also allow a systematic examination of the effects of point mutations within efficiency element motifs across diverse sequence backgrounds. These mutational scans reveal the relative in vivo importance of individual bases in the efficiency element, which likely reflects their roles in binding the Hrp1 protein involved in cleavage and polyadenylation.

Conclusions
The regulatory effects of some 3′ UTR sequence features, like the efficiency element, are consistent regardless of sequence context. In contrast, the consequences of other 3′ UTR features appear to be strongly dependent on their evolved context within native genes.
Orientia tsutsugamushi dynamics in vectors and hosts: ecology and risk factors for foci of scrub typhus transmission in northern Thailand
Authors: Elliott Ivo , Thangnimitchok Neeranuch , Chaisiri Kittipong , Wangrangsimakul Tri , Jaiboon Piangnet , Day Nicholas P. J. , Paris Daniel H. , Newton Paul N. , Morand Serge 
Published: October 2021

Abstract
Background
Scrub typhus is an important neglected vector-borne zoonotic disease across the Asia–Pacific region, with an expanding known distribution. The disease ecology is poorly understood, despite the large global burden of disease. The key determinants of high-risk areas of transmission to humans are unknown.

Methods
Small mammals and chiggers were collected over an 18-month period at three sites of differing ecological profiles with high scrub typhus transmission in Chiang Rai Province, northern Thailand. Field samples were identified and tested for Orientia tsutsugamushi by real-time PCR. The rates and dynamics of infection were recorded, and positive and negative individuals were mapped over time at the scale of single villages. Ecological analyses were performed to describe the species richness, community structure and interactions between infected and uninfected species and habitats. Generalised linear modelling (GLM) was applied to examine these interactions.

Results
The site with the highest rates of human infection was associated with the highest number of infected chigger pools (41%), individual chiggers (16%), proportion of the known vector species Leptotrombidium deliense (71%) and chigger index (151). Chigger species diversity was lowest (Shannon diversity index H′: 1.77) and rodent density appeared to be high. There were no consistent discrete foci of infection identified at any of the study sites. The small mammals Rattus tanezumi and Bandicota indica and the chiggers L. deliense and Walchia kritochaeta emerged as central nodes in the network analysis. In the GLM, the end of the dry season, and to a lesser extent the end of the wet season, was associated with O. tsutsugamushi-infected small mammals and chiggers. A clear positive association was seen between O. tsutsugamushi-positive chigger pools and the combination of O. tsutsugamushi-positive chigger pools and O. tsutsugamushi-positive small mammals with lowland habitats.

Conclusions
These findings begin to reveal some of the factors that may determine high-risk foci of scrub typhus at a fine local scale. Understanding these factors may allow practical public health interventions to reduce disease risk. Further studies are needed in areas with diverse ecology.

Graphical abstract
Comprehensive multi-omics integration identifies differentially active enhancers during human brain development with clinical relevance
Authors: Yousefi Soheil , Deng Ruizhi , Lanko Kristina , Salsench Eva Medico , Nikoncuk Anita , van der Linde Herma C. , Perenthaler Elena , van Ham Tjakko J. , Mulugeta Eskeatnaf , Barakat Tahsin Stefan 
Published: October 2021

Abstract
Background
Non-coding regulatory elements (NCREs), such as enhancers, play a crucial role in gene regulation, and genetic aberrations in NCREs can lead to human disease, including brain disorders. The human brain is a complex organ that is susceptible to numerous disorders; many of these are caused by genetic changes, but a multitude remain currently unexplained. Understanding NCREs acting during brain development has the potential to shed light on previously unrecognized genetic causes of human brain disease. Despite immense community-wide efforts to understand the role of the non-coding genome and NCREs, annotating functional NCREs remains challenging.

Methods
Here we performed an integrative computational analysis of virtually all currently available epigenome data sets related to human fetal brain.

Results
Our in-depth analysis unravels 39,709 differentially active enhancers (DAEs) that show dynamic epigenomic rearrangement during early stages of human brain development, indicating likely biological function. Many of these DAEs are linked to clinically relevant genes, and functional validation of selected DAEs in cell models and zebrafish confirms their role in gene regulation. Compared to enhancers without dynamic epigenomic rearrangement, DAEs are subjected to higher sequence constraints in humans, have distinct sequence characteristics and are bound by a distinct transcription factor landscape. DAEs are enriched for GWAS loci for brain-related traits and for genetic variation found in individuals with neurodevelopmental disorders, including autism.

Conclusion
This compendium of high-confidence enhancers will assist in deciphering the mechanism behind developmental genetics of human brain and will be relevant to uncover missing heritability in human genetic brain disorders.
A global cancer data integrator reveals principles of synthetic lethality, sex disparity and immunotherapy
Authors: Yogodzinski Christopher , Arab Abolfazl , Pritchard Justin R. , Goodarzi Hani , Gilbert Luke A. 
Published: October 2021

AbstractBackgroundAdvances in cancer biology are increasingly dependent on integration of heterogeneous datasets. Large-scale efforts have systematically mapped many aspects of cancer cell biology; however, it remains challenging for individual scientists to effectively integrate and understand this data.ResultsWe have developed a new data retrieval and indexing framework that allows us to integrate publicly available data from different sources and to combine publicly available data with new or bespoke datasets. Our approach, which we have named the cancer data integrator (CanDI), is straightforward to implement, is well documented, and is continuously updated which should enable individual users to take full advantage of efforts to map cancer cell biology. We show that CanDI empowered testable hypotheses of new synthetic lethal gene pairs, genes associated with sex disparity, and immunotherapy targets in cancer.ConclusionsCanDI provides a flexible approach for large-scale data integration in cancer research enabling rapid generation of hypotheses. The CanDI data integrator is available athttps://github.com/GilbertLabUCSF/CanDI.
Genomic approaches to trace the history of human brain evolution with an emerging opportunity for transposon profiling of ancient humans
Authors: Wang Yilan , Zhao Boxun , Choi Jaejoon , Lee Eunjung Alice 
Published: October 2021

AbstractTransposable elements (TEs) significantly contribute to shaping the diversity of the human genome, and lines of evidence suggest TEs as one of driving forces of human brain evolution. Existing computational approaches, including cross-species comparative genomics and population genetic modeling, can be adapted for the study of the role of TEs in evolution. In particular, diverse ancient and archaic human genome sequences are increasingly available, allowing reconstruction of past human migration events and holding the promise of identifying and tracking TEs among other evolutionarily important genetic variants at an unprecedented spatiotemporal resolution. However, highly degraded short DNA templates and other unique challenges presented by ancient human DNA call for major changes in current experimental and computational procedures to enable the identification of evolutionarily important TEs. Ancient human genomes are valuable resources for investigating TEs in the evolutionary context, and efforts to explore ancient human genomes will potentially provide a novel perspective on the genetic mechanism of human brain evolution and inspire a variety of technological and methodological advances. In this review, we summarize computational and experimental approaches that can be adapted to identify and validate evolutionarily important TEs, especially for human brain evolution. We also highlight strategies that leverage ancient genomic data and discuss unique challenges in ancient transposon genomics.