bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spatial rank-based multifactor dimensionality reduction to detect gene–gene interactions for multivariate phenotypes
Authors: Park Mira , Jeong Hoe-Bin , Lee Jong-Hyun , Park Taesung 
Published: October 2021

AbstractBackgroundIdentifying interaction effects between genes is one of the main tasks of genome-wide association studies aiming to shed light on the biological mechanisms underlying complex diseases. Multifactor dimensionality reduction (MDR) is a popular approach for detecting gene–gene interactions that has been extended in various forms to handle binary and continuous phenotypes. However, only few multivariate MDR methods are available for multiple related phenotypes. Current approaches use Hotelling’s T2statistic to evaluate interaction models, but it is well known that Hotelling’s T2statistic is highly sensitive to heavily skewed distributions and outliers.ResultsWe propose a robust approach based on nonparametric statistics such as spatial signs and ranks. The new multivariate rank-based MDR (MR-MDR) is mainly suitable for analyzing multiple continuous phenotypes and is less sensitive to skewed distributions and outliers. MR-MDR utilizes fuzzy k-means clustering and classifies multi-locus genotypes into two groups. Then, MR-MDR calculates a spatial rank-sum statistic as an evaluation measure and selects the best interaction model with the largest statistic. Our novel idea lies in adopting nonparametric statistics as an evaluation measure for robust inference. We adopt tenfold cross-validation to avoid overfitting. Intensive simulation studies were conducted to compare the performance of MR-MDR with current methods. Application of MR-MDR to a real dataset from a Korean genome-wide association study demonstrated that it successfully identified genetic interactions associated with four phenotypes related to kidney function. The R code for conducting MR-MDR is available athttps://github.com/statpark/MR-MDR.ConclusionsIntensive simulation studies comparing MR-MDR with several current methods showed that the performance of MR-MDR was outstanding for skewed distributions. Additionally, for symmetric distributions, MR-MDR showed comparable power. Therefore, we conclude that MR-MDR is a useful multivariate non-parametric approach that can be used regardless of the phenotype distribution, the correlations between phenotypes, and sample size.
Identification, visualization, statistical analysis and mathematical modeling of high-feedback loops in gene regulatory networks
Authors: Nordick Benjamin , Hong Tian 
Published: October 2021

AbstractBackgroundFeedback loops in gene regulatory networks play pivotal roles in governing functional dynamics of cells. Systems approaches demonstrated characteristic dynamical features, including multistability and oscillation, of positive and negative feedback loops. Recent experiments and theories have implicated highly interconnected feedback loops (high-feedback loops) in additional nonintuitive functions, such as controlling cell differentiation rate and multistep cell lineage progression. However, it remains challenging to identify and visualize high-feedback loops in complex gene regulatory networks due to the myriad of ways in which the loops can be combined. Furthermore, it is unclear whether the high-feedback loop structures with these potential functions are widespread in biological systems. Finally, it remains challenging to understand diverse dynamical features, such as high-order multistability and oscillation, generated by individual networks containing high-feedback loops. To address these problems, we developed HiLoop, a toolkit that enables discovery, visualization, and analysis of several types of high-feedback loops in large biological networks.ResultsHiLoop not only extracts high-feedback structures and visualize them in intuitive ways, but also quantifies the enrichment of overrepresented structures. Through random parameterization of mathematical models derived from target networks, HiLoop presents characteristic features of the underlying systems, including complex multistability and oscillations, in a unifying framework. Using HiLoop, we were able to analyze realistic gene regulatory networks containing dozens to hundreds of genes, and to identify many small high-feedback systems. We found more than a 100 human transcription factors involved in high-feedback loops that were not studied previously. In addition, HiLoop enabled the discovery of an enrichment of high feedback in pathways related to epithelial-mesenchymal transition.ConclusionsHiLoop makes the study of complex networks accessible without significant computational demands. It can serve as a hypothesis generator through identification and modeling of high-feedback subnetworks, or as a quantification method for motif enrichment analysis. As an example of discovery, we found that multistep cell lineage progression may be driven by either specific instances of high-feedback loops with sparse appearances, or generally enriched topologies in gene regulatory networks. We expect HiLoop’s usefulness to increase as experimental data of regulatory networks accumulate. Code is freely available for use or extension athttps://github.com/BenNordick/HiLoop.
Privacy-preserving storage of sequenced genomic data
Authors: Hekel Rastislav , Budis Jaroslav , Kucharik Marcel , Radvanszky Jan , Pös Zuzana , Szemes Tomas 
Published: October 2021

Abstract
Background
The current and future applications of genomic data may raise ethical and privacy concerns. Processing and storing of this data introduce a risk of abuse by potential offenders since the human genome contains sensitive personal information. For this reason, we have developed a privacy-preserving method, named Varlock providing secure storage of sequenced genomic data. We used a public set of population allele frequencies to mask the personal alleles detected in genomic reads. Each personal allele described by the public set is masked by a randomly selected population allele with respect to its frequency. Masked alleles are preserved in an encrypted confidential file that can be shared in whole or in part using public-key cryptography.

Results
Our method masked the personal variants and introduced new variants detected in a personal masked genome. Alternative alleles with lower population frequency were masked and introduced more often. We performed a joint PCA analysis of personal and masked VCFs, showing that the VCFs between the two groups cannot be trivially mapped. Moreover, the method is reversible and personal alleles in specific genomic regions can be unmasked on demand.

Conclusion
Our method masks personal alleles within genomic reads while preserving valuable non-sensitive properties of sequenced DNA fragments for further research. Personal alleles in the desired genomic regions may be restored and shared with patients, clinics, and researchers. We suggest that the method can provide an additional security layer for storing and sharing of the raw aligned reads.
Severe drug-associated colitis with Crohn’s features in setting of ixekizumab therapy for chronic plaque psoriasis
Authors: Mu Xin , Fardy John , Reid Stephanie , Trahey Julia 
Published: October 2021

Abstract
Background
Ixekizumab is monoclonal antibody targeted against interleukin-17 (IL-17) and has been approved for use in chronic plaque psoriasis. Despite its efficacy in treating psoriasis, concerns have been raised regarding Ixekizumab’s potential to induce and exacerbate inflammatory bowel disease (IBD).

Case presentation
Here we report the new onset of severe drug-associated colitis with surgical complications in a 45-year-old male patient who was receiving Ixekizumab therapy for chronic plaque psoriasis. Review of the patient’s colonic pathology demonstrated acute inflammatory changes with features of Crohn’s disease. The patient remained disease-free 9-months following his hospitalization and cessation of Ixekizumab.

Conclusions
This case raises suspicion for an association between Ixekizumab and IBD and calls on clinicians to have heightened awareness of potential risks before prescribing anti-IL-17 agents.
The geriatric nutritional risk index mediated the relationship between serum uric acid and hypertension: a mediation analysis
Authors: Cao Zhongnan , Dai Sui , Liu Xun 
Published: October 2021

Abstract
Background
The elevated serum uric acid (SUA) is associated with an increased risk of hypertension and nutritional status. Malnutrition might modify the association of SUA with hypertension. Therefore, the aims of this study were to examine the mediation effect of malnutrition on the association of SUA with the risk of hypertension in Chinese population.

Methods
The study was based on the China Health and Nutrition Survey in 2009. Participants aged ≥ 60 years with complete analyzed data were eligible. The Geriatric Nutritional Risk Index (GNRI) was calculated by serum albumin (ALB) and BMI. Participants were identified as hypertension if systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg or receiving antihypertensive drug.

Results
There were 2371 participants included in the final analysis. In total, there was a significant mediation effect of the GNRI on the relationship between SUA level with hypertension (P < 0.001; OR: 1.096; and 95 % CI: 1.048–1.146). And the proportion mediated was 17.77 %. The results stratified by sex were consistent with those of total population. The significant mediation effects of the GNRI were found in the 60–69 years and 70–79 years groups (P = 0.002 and 0.032; OR: 1.099 and 1.075; and 95 % CI: 1.036–1.165 and 1.006–1.148, respectively) but not in the 80–99 years group (P = 0.303). The proportions mediated were16.22 % and 18.36 %, respectively.

Conclusions
The GNRI can mediate and account for approximately 17.77 % of the relationship between SUA level and the risk of hypertension. And this mediation effect was fully observed in both males and females, especially in the 60–79 years population.
Efficacy and safety of polymyxin B in carbapenem-resistant gram-negative organisms infections
Authors: Xia G. L. , Jiang R. L. 
Published: October 2021

Abstract
Objective
To investigate how to use polymyxin B rationally in order to produce the best efficacy and safety in patients with carbapenem-resistant gram-negative organisms (CRO) infection.

Methods
The clinical characteristics and microbiological results of 181 patients caused by CRO infection treated with polymyxin B in the First Affiliated Hospital from July 2018 to May 2020 were retrospectively analyzed. The bacterial clearance rate, clinical efficacy, adverse drug reactions and 28 days mortality were evaluated.

Results
The overall effective rate of 181 patients was 49.72%, the total bacterial clearance rate was 42.0%, and the 28 day all-cause mortality rate was 59.1%. The effective rate and bacterial clearance rate in the group of less than 24 h from the isolation of CRO to the use of polymyxin B were significantly higher than those in the group of more than 24 h. Logistics multivariate regression analysis showed that the predictive factors for effective treatment of CRO with polymyxin B were APACHEII score, duration of polymyxin B treatment, combination of polymyxin B and other antibiotics, and bacterial clearance. 17 cases (9.36%) of acute kidney injury were considered as polymyxin B nephrotoxicity and 4 cases (23.5%) recovered after polymyxin B withdrawal. After 14 days of polymyxin B use, 3 cases of polymyxin B resistance appeared, and there were 2 cases of polymyxin B resistance in the daily dose 1.5 mg/kg/day group.

Conclusion
For CRO infection, the treatment of polymyxin B should be early, combined, optimal dose and duration of treatment, which can achieve better clinical efficacy and microbial reactions, and reduce the adverse reactions and drug resistance.
Reliability of the freehand region-of-interest method in quantitative cerebral diffusion tensor imaging
Authors: Hakulinen Ullamari , Brander Antti , Ilvesmäki Tero , Helminen Mika , Öhman Juha , Luoto Teemu M. , Eskola Hannu 
Published: October 2021

Abstract
Background
Diffusion tensor imaging (DTI) is a magnetic resonance imaging (MRI) technique used for evaluating changes in the white matter in brain parenchyma. The reliability of quantitative DTI analysis is influenced by several factors, such as the imaging protocol, pre-processing and post-processing methods, and selected diffusion parameters. The region-of-interest (ROI) method is most widely used of the post-processing methods because it is found in commercial software. The focus of our research was to study the reliability of the freehand ROI method using various intra- and inter-observer analyses.

Methods
This study included 40 neurologically healthy participants who underwent diffusion MRI of the brain with a 3 T scanner. The measurements were performed at nine different anatomical locations using a freehand ROI method. The data extracted from the ROIs included the regional mean values, intra- and inter-observer variability and reliability. The used DTI parameters were fractional anisotropy (FA), the apparent diffusion coefficient (ADC), and axial (AD) and radial (RD) diffusivity.

Results
The average intra-class correlation coefficient (ICC) of the intra-observer was found to be 0.9 (excellent). The single ICC results were excellent (> 0.8) or adequate (> 0.69) in eight out of the nine regions in terms of FA and ADC. The most reliable results were found in the frontobasal regions. Significant differences between age groups were also found in the frontobasal regions. Specifically, the FA and AD values were significantly higher and the RD values lower in the youngest age group (18–30 years) compared to the other age groups.

Conclusions
The quantitative freehand ROI method can be considered highly reliable for the average ICC and mostly adequate for the single ICC. The freehand method is suitable for research work with a well-experienced observer. Measurements should be performed at least twice in the same region to ensure that the results are sufficiently reliable. In our study, reliability was slightly undermined by artifacts in some regions such as the cerebral peduncle and centrum semiovale. From a clinical point of view, the results are most reliable in adults under the age of 30, when age-related changes in brain white matter have not yet occurred.
Circulating endothelin-1 levels are positively associated with chronic kidney disease in women but not in men: a longitudinal study in the Vara-Skövde cohort
Authors: Hellgren Margareta I. , Jansson Per-Anders , Alayar Hormoz , Lindblad Ulf , Daka Bledar 
Published: October 2021

Abstract
Background
The vasoconstricting peptide endothelin-1 (ET-1) is associated with endothelial dysfunction. The aim of this paper was to investigate whether circulating ET-1 levels predicts chronic kidney disease (CKD) in a prospective population study.

Methods
In 2002–2005, 2816 participants (30–74 years) were randomly selected from two municipalities in South-Western Sweden and followed up in a representative sample of 1327 individuals after 10 years. Endothelin-1 levels were assessed at baseline. Outcome was defined as CKD stage 3 or above based on eGFR < 60 mL/min/1.73m2. Those 1314 participants with successful analysis of ET-1 were further analyzed using binary logistic regression.

Results
At follow-up, 51 (8%) men and 47 (7,8%) women had CKD stage 3 and above. Based on levels of ET-1 the population was divided into quintiles showing that women in the highest quintile (n = 132) had a significantly increased risk of developing CKD during the follow up period (OR = 2.54, 95% CI:1.19–5.45, p = 0.02) compared with the other quintiles (1–4). The association was borderline significant after adjusted for age, current smoking, alcohol consumption, hypertension, diabetes, BMI, high- sensitive CRP and LDL-cholesterol (OR = 2.25, 95% CI:0.97–5.24, p = 0.06). No significant differences were observed between quintiles of ET-1 and development of CKD in men (NS).

Conclusions
High levels of ET-1 are associated with development of CKD in women.
Expression of and correlational patterns among neuroinflammatory, neuropeptide, and neuroendocrine molecules from cerebrospinal fluid in cerebral palsy
Authors: Goracke-Postle Cory J. , Burkitt Chantel C. , Panoskaltsis-Mortari Angela , Ehrhardt Michael , Wilcox George L. , Graupman Patrick , Partington Michael , Symons Frank J. 
Published: October 2021

AbstractBackgroundThe underlying pathogenesis of cerebral palsy (CP) remains poorly understood. The possibility of an early inflammatory response after acute insult is of increasing interest. Patterns of inflammatory and related biomarkers are emerging as potential early diagnostic markers for understanding the etiologic diversity of CP. Their presence has been investigated in plasma and umbilical cord blood but not in cerebrospinal fluid (CSF).MethodsA clinical CP sample was recruited using a single-time point cross-sectional design to collect CSF at point-of-care during a standard-of-care surgical procedure (intrathecal pump implant). Patient demographic and clinical characteristics were sourced from medical chart audit.ResultsSignificant (p ≤ 0.001) associations were found among neuroinflammatory, neuroendocrine, and nociceptive analytes with association patterns varying by birth status (term, preterm, extremely preterm). When between birth-group correlations were compared directly, there was a significant difference between preterm and extremely preterm birth subgroups for the correlation between tumour necrosis factor alpha (TNFα) and substance P.ConclusionThis investigation shows that CSF can be used to study proteins in CP patients. Differences in inter-correlational patterns among analytes varying by birth status underscores the importance of considering birth status in relation to possible mechanistic differences as indicated by biomarker signatures. Future work should be oriented toward prognostic and predictive validity to continue to parse the heterogeneity of CP’s presentation, pathophysiology, and response to treatment.
Prevalence and correlates of carotid artery stenosis in a cohort of Sri Lankan ischaemic stroke patients
Authors: Mettananda K. C. D. , Eshani M. D. P. , Wettasinghe L. M. , Somaratne S. , Nanayakkkara Y. P. , Sathkorala W. , Upasena A. , Sirigampola C. , Tilakaratna P. M. Y. , Pathmeswaran A. , Ranawaka U. K. 
Published: October 2021

Abstract
Background
Large artery atherosclerotic disease is an important cause of stroke, accounting for 15–46% of ischaemic strokes in population-based studies. Therefore, current guidelines from west recommend urgent carotid imaging in all ischaemic strokes or transient ischaemic attacks and referral for carotid endarterectomy. However, the clinical features and epidemiology of stroke in Asians are different from those in Caucasians and therefore the applicability of these recommendations to Asians is controversial. Data on the prevalence of carotid artery stenosis (CAS) among South Asian stroke patients is limited. Therefore, we sought to determine the prevalence and associated factors of significant CAS in a cohort of Sri Lankan patients with ischaemic stroke.

Methods
We prospectively studied all ischaemic stroke patients who underwent carotid doppler ultrasonography admitted to the stroke unit of a Sri Lankan tertiary care hospital over 5 years. We defined carotid stenosis as low (< 50%), moderate (50–69%) or severe (70–99%) or total-occlusion (100%) by North American Symptomatic Trial Collaborators (NASCET) criteria. We identified the factors associated with CAS ≥ 50% and ≥ 70% by stepwise multiple logistic regression analysis.

Results
A total of 550 ischaemic stroke patients (326 (59.3%) male, mean age was 58.9 ± 10.2 years) had carotid doppler ultrasonography. Of them, 528 (96.0%) had low-grade, 12 (2.2%) moderate and 7 (1.3%) severe stenosis and 3 (0.5%) had total occlusion. On multivariate logistic regression, age was associated with CAS ≥ 50% (OR 1.12, p = 0.001) and CAS ≥ 70% (OR 1.14, p = 0.016), but none of the other vascular risk factors studied (sex, hypertension, diabetes mellitus, smoking, past history of TIA, stroke or ischemic heart disease) showed significant associations.

Conclusions
Carotid stenosis is a minor cause of ischemic stroke in Sri Lankans compared to western populations with only 4.0% having CAS ≥ 50 and 3.5% eligible for carotid endarterectomy. Our findings have implications for the management of acute strokes in Sri Lanka.
Intrauterine fetal death followed by shoulder dystocia and birth by modified posterior axillary sling method: a case report
Authors: Kwan Angel Hoi Wan , Hui Annie Shuk Yi , Lee Jacqueline Ho Sze , Leung Tak Yeung 
Published: October 2021

Abstract
Background
Various manoeuvres such as McRoberts position, suprapubic pressure, rotational methods, posterior arm extraction and all-four position (HELPERR) have been proposed for relieving shoulder dystocia with variable success. Posterior axillary sling method using a rubber catheter was proposed in 2009 but has not been widely used. We modified this method using ribbon gauzes and a long right-angle forceps and report a successful case.

Case presentation
A 44 years old parity one Chinese woman with a history of a caesarean delivery and poorly controlled type 2 diabetes mellitus was admitted to the Accident and Emergency Department for advanced stage of labour at term. Upon arrival, intrauterine fetal demise was diagnosed with severe asynclitism causing obstruction at the perineum. Episiotomy resulted in birth of the fetal head. The fetal posterior right shoulder, however, remained very high up in the pelvis and HELPERR methods failed to extract the shoulders. We then tied two long ribbon gauzes together, and guided its knot to the anterior aspect of the posterior axilla. By using a long right-angle forceps (24 cm long) to grasp the knot on the posterior side of the axilla and pulling it through, a sling was formed. Traction was then applied through the sling to simultaneously pull and rotate the posterior shoulder. A stillbirth of 3488 g was finally extracted.

Conclusions
We modified the sling method by using two ribbon gauzes, tied together and a right-angle forceps with several advantages. Compared to a rubber catheter, ribbon gauze with a knot can be easily held between the fingers for easy guidance past the fetal axilla. It is also thin, non-elastic and stiff enough to ensure a good grip for traction. The long and slim design of the right-angle forceps makes it easy to pass through a narrow space and reach the axilla high up in the pelvis. We emphasize simultaneous traction and rotation, so that the shoulders are delivered through the wider oblique pelvic outlet dimension.