bluuebunny/crossref_metadata_2025_split huggingface dataset:
Can we identify individuals with an ALPL variant in adults with persistent hypophosphatasaemia?
Authors: Tornero C. , Navarro-Compán V. , Tenorio J. A. , García-Carazo S. , Buño A. , Monjo I. , Plasencia-Rodriguez C. , Iturzaeta J. M. , Lapunzina P. , Heath K. E. , Balsa A. , Aguado P. 
Published: February 2020

Abstract
Background
Hypophosphatasia (HPP) is an inborn error of metabolism characterized by low levels of serum alkaline phosphatase (ALP). Scarce evidence exists about features that should signal the potential association between hypophosphatasaemia and HPP in adults. The aim of this study is to estimate the prevalence of ALPL variants in subjects with persistent hypophosphatasaemia and determine the associated clinical and laboratory features. For this cross-sectional study, laboratory records of 386,353 subjects were screened by measurement of ALP activity. A total of 85 (0.18%) subjects with persistent hypophosphatasaemia (≥2 serum alkaline phosphatase–ALP–measurements ≤35 IU/L and none > 45 IU/L) were included (secondary causes previously discarded). ALPL genetic testing and a systematized questionnaire to retrieve demographic, clinical and laboratory data were performed. Descriptive analysis and logistic regression models were employed to identify the clinical and laboratory characteristics associated with ALPL variants.

Results
Forty subjects (47%) had a variant(s) in ALPL. With regard to clinical characteristics, the presence of an ALPL variant was significantly associated only with musculoskeletal pain (OR: 7.6; 95% IC: 1.9–30.9). Nevertheless, a trend to present more dental abnormalities (OR: 3.6; 95% IC: 0.9–13.4) was observed. Metatarsal stress fractures were also more frequent (4 vs 0; p < 0.05) in this group. Regarding laboratory features, median ALP levels were lower in subjects with ALPL variants (26 vs 29 IU/L; p < 0.005). Interestingly, the threshold of ALP levels < 25 IU/L showed a specificity, positive predictive value and positive likelihood ratio of 97.8, 94.4% and 19.8 to detect a positive ALPL test, respectively.

Conclusions
In subjects with persistent hypophosphatasaemia –secondary causes excluded– one out of two presented ALPL variants. Musculoskeletal pain and ALP levels < 25 IU/L are associated with this variant(s). In this scenario, ALP levels < 25 IU/L seem to be very useful to identify individuals with the presence of an ALPL variant.
Clinical applications of polygenic breast cancer risk: a critical review and perspectives of an emerging field
Authors: Yanes Tatiane , Young Mary-Anne , Meiser Bettina , James Paul A. 
Published: February 2020

AbstractPolygenic factors are estimated to account for an additional 18% of the familial relative risk of breast cancer, with those at the highest level of polygenic risk distribution having a least a twofold increased risk of the disease. Polygenic testing promises to revolutionize health services by providing personalized risk assessments to women at high-risk of breast cancer and within population breast screening programs. However, implementation of polygenic testing needs to be considered in light of its current limitations, such as limited risk prediction for women of non-European ancestry. This article aims to provide a comprehensive review of the evidence for polygenic breast cancer risk, including the discovery of variants associated with breast cancer at the genome-wide level of significance and the use of polygenic risk scores to estimate breast cancer risk. We also review the different applications of this technology including testing of women from high-risk breast cancer families with uninformative genetic testing results, as a moderator of monogenic risk, and for population screening programs. Finally, a potential framework for introducing testing for polygenic risk in familial cancer clinics and the potential challenges with implementing this technology in clinical practice are discussed.
Effectiveness of Gyejibongnyeong-Hwan for shoulder pain: study protocol for a randomised, wait-list controlled pilot trial
Authors: Jang Soobin , Sung Hyun Kyung , Ko Mi Mi , Shin Seon Mi , Go Ho-Yeon , Jung Jeeyoun 
Published: February 2020

Abstract
Background
Shoulder pain is an uncomfortable feeling in the muscle around the shoulder. The cause of myalgia is the accumulation of lactic acid in muscles and impaired blood circulation, which is called blood stasis in traditional East Asian medicine. This study aimed to explore the therapeutic effect of Gyejibongnyeong-Hwan (GBH) for shoulder discomfort related to blood stasis before and after treatment.

Methods/design
This study will be a double-centre, randomised, wait-list controlled pilot trial. Participants with shoulder pain and with a visual analogue scale score of 4 or higher out of 10, blood stasis score of 9 or higher, and triglyceride level of ≥150 mg/dl or total cholesterol level of ≥200 mg/dl will be recruited from two university hospitals. A total of 40 participants will be assigned to the immediate and waiting treatment groups. The immediate treatment group will receive GBH for 8 weeks on enrolment while the waiting treatment group will receive GBH for 8–16 weeks after 8 weeks of controlled waiting. The primary outcome is shoulder pain, and the secondary outcomes are the blood stasis score, blood pressure, ankle–brachial pressure index, brachial–ankle pulse wave velocity, body mass index, waist circumference, indexes of oximetry, and levels of blood lipid, blood sugar, resistin, C-reactive protein, serum amyloid P, and D-dimer.

Discussion
The results of this pilot trial will be the bases for a full-scale clinical trial of GBH.

Trial registration
Clinical Research Information Service, KCT0003837. Registered on 23 April 2019. https://cris.nih.go.kr/cris/en/search/search_result_st01.jsp?seq=14258
Insights into the pathogenesis of multiple system atrophy: focus on glial cytoplasmic inclusions
Authors: Kaji Seiji , Maki Takakuni , Ishimoto Tomoyuki , Yamakado Hodaka , Takahashi Ryosuke 
Published: February 2020

AbstractMultiple system atrophy (MSA) is a debilitating and fatal neurodegenerative disorder. The disease severity warrants urgent development of disease-modifying therapy, but the disease pathogenesis is still enigmatic. Neurodegeneration in MSA brains is preceded by the emergence of glial cytoplasmic inclusions (GCIs), which are insoluble α-synuclein accumulations within oligodendrocytes (OLGs). Thus, preventive strategies against GCI formation may suppress disease progression. However, although numerous studies have tried to elucidate the molecular pathogenesis of GCI formation, difficulty remains in understanding the pathological interaction between the two pivotal aspects of GCIs; α-synuclein and OLGs. The difficulty originates from several enigmas: 1) what triggers the initial generation and possible propagation of pathogenic α-synuclein species? 2) what contributes to OLG-specific accumulation of α-synuclein, which is abundantly expressed in neurons but not in OLGs? and 3) how are OLGs and other glial cells affected and contribute to neurodegeneration? The primary pathogenesis of GCIs may involve myelin dysfunction and dyshomeostasis of the oligodendroglial cellular environment such as autophagy and iron metabolism. We have previously reported that oligodendrocyte precursor cells are more prone to develop intracellular inclusions in the presence of extracellular fibrillary α-synuclein. This finding implies a possibility that the propagation of GCI pathology in MSA brains is mediated through the internalization of pathological α-synuclein into oligodendrocyte precursor cells. In this review, in order to discuss the pathogenesis of GCIs, we will focus on the composition of neuronal and oligodendroglial inclusions in synucleinopathies. Furthermore, we will introduce some hypotheses on how α-synuclein pathology spreads among OLGs in MSA brains, in the light of our data from the experiments with primary oligodendrocyte lineage cell culture. While various reports have focused on the mysterious source of α-synuclein in GCIs, insights into the mechanism which regulates the uptake of pathological α-synuclein into oligodendroglial cells may yield the development of the disease-modifying therapy for MSA. The interaction between glial cells and α-synuclein is also highlighted with previous studies of post-mortem human brains, cultured cells, and animal models, which provide comprehensive insight into GCIs and the MSA pathomechanisms.
Effects of a blend of Saccharomyces cerevisiae-based direct-fed microbial and fermentation products on plasma carbonyl-metabolome and fecal bacterial community of beef steers
Authors: Adeyemi James A. , Peters Sunday O. , De Donato Marcos , Cervantes Andres Pech , Ogunade Ibukun M. 
Published: February 2020

Abstract
Background
Previous studies have evaluated the metabolic status of animals fed direct-fed microbial (DFM) using enzyme-based assays which are time-consuming and limited to a few metabolites. In addition, little emphasis has been placed on investigating the effects of DFM on hindgut microbiota. We examined the effects of dietary supplementation of a blend of Saccharomyces cerevisiae-based DFM and fermentation products on the plasma concentrations of carbonyl-containing metabolites via a metabolomics approach, and fecal bacterial community, via 16S rRNA gene sequencing, of beef steers during a 42-day receiving period. Forty newly weaned steers were randomly assigned to receive a basal diet with no additive (CON; n = 20) or a basal diet supplemented with 19 g of Commence™ (PROB; n = 20) for a 42-day period. Commence™ (PMI, Arden Hills, MN) is a blend of 6.2 × 1011 cfu/g of S. cerevisiae, 3.5 × 1010 cfu/g of a mixture of Enterococcus lactis, Bacillus subtilis, Enterococcus faecium, and Lactobacillus casei, and the fermentation products of these aforementioned microorganisms and those of Aspergillus oryzae and Aspergillus niger. On d 0 and 40, rectal fecal samples were collected randomly from 10 steers from each treatment group. On d 42, blood was collected for plasma preparation.

Results
A total number of 812 plasma metabolites were detected. Up to 305 metabolites [fold change (FC) ≥ 1.5, FDR ≤ 0.01] including glucose, hippuric acid, and 5-hydroxykynurenamine were increased by PROB supplementation, whereas 199 metabolites (FC ≤ 0.63, FDR ≤ 0.01) including acetoacetate were reduced. Supplementation of PROB increased (P ≤ 0.05) the relative abundance of Prevotellaceae UCG-003, Megasphaera, Dorea, Acetitomaculum, and Blautia. In contrast, the relative abundance of Elusimicrobium, Moheibacter, Stenotrophomonas, Comamonas, and uncultured bacterium belonging to family p-2534-18B5 gut group (phylum Bacteroidetes) were reduced (P ≤ 0.05).

Conclusions
The results of this study demonstrated that supplementation of PROB altered both the plasma carbonyl metabolome towards increased glucose concentration suggesting an improved energy status, and fecal bacterial community, suggesting an increased hindgut fermentation of the beef steers.
Branched chain amino acids alter fatty acid profile in colostrum of sows fed a high fat diet
Authors: Ma Chang , Liu Yajng , Liu Shaoshuai , Lévesque Crystal L. , Zhao Fengqi , Yin Jindong , Dong Bing 
Published: February 2020

Abstract
Background
Branched chain amino acids (BCAAs) are important substrates for milk protein synthesis in the mammary gland, and are tightly related to lipid metabolism. No study has been performed examining the role of BCAAs with high fat diets on milk fat synthesis. This study was designed to investigate the effect of dietary BCAAs on growth performance of piglets, progeny body weight, and milk fat composition in sows fed a high fat diet. Four diets (CON = control diet; HF = high fat diet with 8% soybean oil; HF-MB=HF plus 0.39% BCAAs; HF-HB=HF plus 0.78% BCAAs) were fed to sows from late gestation to weaning.

Results
Compared to HF, BCAAs (HF-MB and HF-HB) increased the litter weight (P < 0.05) and overall litter weight gain (P < 0.05) at weaning and increased colostrum fat content by 27.3–35.8% (P < 0.01). Fatty acid profiles between the two doses of BCAAs were similar. Compared with HF, HF-MB tended to decrease the percentage of C18:3n3 (P = 0.063) and increased the percentage of C18:1n9c (P = 0.03). In addition, BCAAs in HF-MB increased the concentration of total fatty acid by 22.1% in colostrum (P = 0.03) but decreased that in serum at parturition by 53.2% (P = 0.027). The fatty acids in colostrum that increased with BCAAs were C15:0, C17:0, C20:3n6, C20:4n6, C20:5n3 and C22:6n3 (P = 0.00~0.04). Colostrum fatty acids of C20:0, C21:0, C22:0, C16:1, C20:1, C18:1n9c also tended to be increased (0.05 < P < 0.1) with BCAAs. The change in sow serum fatty acid profile due to BCAAs was different from that in colostrum.

Conclusions
BCAAs in high fat diet of sows altered the fatty acid composition in colostrum and enhanced litter growth. Our study indicated that BCAAs supplementation can enhance mammary fatty acid uptake and mammary fat synthesis and that supplemental BCAAs and fat in late gestation and lactation diets for sows can improve reproductive performance.
Computational determination of human PPARG gene: SNPs and prediction of their effect on protein functions of diabetic patients
Authors: Mustafa Howeida Abdullah , Albkrye Afraa Mohamed Suliman , AbdAlla Buthiena Mohamed , Khair Mona AbdelRahman Mohammed , Abdelwahid Nidal , Elnasri Hind Abdelaziz 
Published: February 2020

AbstractBackgroundThe Peroxisome proliferator‐activated receptor gamma gene (PPARG), encodes a member of the peroxisome‐activated receptor subfamily of nuclear receptors. PPARs form heterodimers with retinoid X receptors (RXRs) which regulate transcription of various genes. Three subtypes of PPARs are known: PPAR‐alpha, PPAR‐delta and PPAR‐gamma. The protein encoded by this gene is PPAR‐gamma which is a regulator of adipocyte differentiation. PPARG‐gamma has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis and cancer.AimThis study aimed to perform insilico analysis to predict the effects that can be imposed by SNPs reported in PPARG gene.MethodologyThis gene was investigated in NCBI database (http://www.ncbi.nlm.nih.gov/) during the year 2016 and the SNPs in coding region (exonal SNPs) that are non‐synonymous (ns SNPs) were analyzed by computational softwares. SIFT, Polyphen, I‐Mutant and PHD‐SNP softwares). SIFT was used to filter the deleterious SNPs, Polyphen was used to determine the degree of pathogenicity, I‐Mutant was used to determine the effect of mutation on protein stability while PHD‐SNP software was used to investigate the effect of mutation on protein function. Furthermore, Structural and functional analysis of ns SNPs was also studied using Project HOPE software and modeling was conducted by Chimera.ResultsA total of 34,035 SNPs from NCBI, were found, 21,235 of them were found in Homo sapiens, 134 in coding non synonymous (missense) and 89 were synonymous. Only SNPs present in coding regions were selected for analysis. Out of 12 deleterious SNPs sorted by SIFT, 10 were predicted by Polyphen to be probably damaging with PISC score = 1 and only two were benign. All these 10 double positive SNPs were disease related as predicted by PHD‐SNPs and revealed decreased stability indicated by I‐Mutant.ConclusionBased on the findings of this study, it can be concluded that the deleterious ns SNPs (rs72551364 and rs121909244SNPs) of PPARG are important candidates for the cause of different types of human diseases including diabetes mellitus.
The association between internal migration and pulmonary tuberculosis in China, 2005–2015: a spatial analysis
Authors: Liao Wei-Bin , Ju Ke , Gao Ya-Min , Pan Jay 
Published: February 2020

Abstract
Background
Internal migration places individuals at high risk of contracting tuberculosis (TB). However, there is a scarcity of national-level spatial analyses regarding the association between TB and internal migration in China. In our research, we aimed to explore the spatial variation in cases of sputum smear-positive pulmonary TB (SS + PTB) in China; and the associations between SS + PTB, internal migration, socioeconomic factors, and demographic factors in the country between 2005 and 2015.

Methods
Reported cases of SS + PTB were obtained from the national PTB surveillance system database; cases were obtained at the provincial level. Internal migration data were extracted from the national population sampling survey and the census. Spatial autocorrelations were explored using the global Moran’s statistic and local indicators of spatial association. The spatial temporal analysis was performed using Kulldorff’s scan statistic. Fixed effects regression was used to explore the association between SS + PTB and internal migration.

Results
A total of 4 708 563 SS + PTB cases were reported in China between 2005 and 2015, of which 3 376 011 (71.7%) were male and 1 332 552 (28.3%) were female. There was a trend towards decreasing rates of SS + PTB notifications between 2005 and 2015. The result of global spatial autocorrelation indicated that there were significant spatial correlations between SS + PTB rate and internal migration each year (2005–2015). Spatial clustering of SS + PTB cases was mainly located in central and southern China and overlapped with the clusters of emigration. The proportions of emigrants and immigrants were significantly associated with SS + PTB. Per capita GDP and education level were negatively associated with SS + PTB. The internal migration flow maps indicated that migrants preferred neighboring provinces, with most migrating for work or business.

Conclusions
This study found a significant spatial autocorrelation between SS + PTB and internal migration. Both emigration and immigration were statistically associated with SS + PTB, and the association with emigration was stronger than that for immigration. Further, we found that SS + PTB clusters overlapped with emigration clusters, and the internal migration flow maps suggested that migrants from SS + PTB clusters may influence the TB epidemic characteristics of neighboring provinces. These findings can help stakeholders to implement effective PTB control strategies for areas at high risk of PTB and those with high rates of internal migrants.
Antiviral treatment perspective against Borna disease virus 1 infection in major depression: a double-blind placebo-controlled randomized clinical trial
Authors: Dietrich Detlef E. , Bode Liv , Spannhuth Carsten W. , Hecker Hartmut , Ludwig Hanns , Emrich Hinderk M. 
Published: February 2020

Abstract
Background
Whether Borna disease virus (BDV-1) is a human pathogen remained controversial until recent encephalitis cases showed BDV-1 infection could even be deadly. This called to mind previous evidence for an infectious contribution of BDV-1 to mental disorders. Pilot open trials suggested that BDV-1 infected depressed patients benefitted from antiviral therapy with a licensed drug (amantadine) which also tested sensitive in vitro. Here, we designed a double-blind placebo-controlled randomized clinical trial (RCT) which cross-linked depression and BDV-1 infection, addressing both the antidepressant and antiviral efficacy of amantadine.

Methods
The interventional phase II RCT (two 7-weeks-treatment periods and a 12-months follow-up) at the Hannover Medical School (MHH), Germany, assigned currently depressed BDV-1 infected patients with either major depression (MD; N = 23) or bipolar disorder (BD; N = 13) to amantadine sulphate (PK-Merz®; twice 100 mg orally daily) or placebo treatment, and contrariwise, respectively. Clinical changes were assessed every 2–3 weeks by the 21-item Hamilton rating scale for depression (HAMD) (total, single, and combined scores). BDV-1 activity was determined accordingly in blood plasma by enzyme immune assays for antigens (PAG), antibodies (AB) and circulating immune complexes (CIC).

Results
Primary outcomes (≥25% HAMD reduction, week 7) were 81.3% amantadine vs. 35.3% placebo responder (p = 0.003), a large clinical effect size (ES; Cohen’s d) of 1.046, and excellent drug tolerance. Amantadine was safe reducing suicidal behaviour in the first 2 weeks. Pre-treatment maximum infection levels were predictive of clinical improvement (AB, p = 0.001; PAG, p = 0.026; HAMD week 7). Respective PAG and CIC levels correlated with AB reduction (p = 0,001 and p = 0.034, respectively). Follow-up benefits (12 months) correlated with dropped cumulative infection measures over time (p < 0.001). In vitro, amantadine concentrations as low as 2.4–10 ng/mL (50% infection-inhibitory dose) prevented infection with human BDV Hu-H1, while closely related memantine failed up to 100,000-fold higher concentration (200 μg/mL).

Conclusions
Our findings indicate profound antidepressant efficacy of safe oral amantadine treatment, paralleling antiviral effects at various infection levels. This not only supports the paradigm of a link of BDV-1 infection and depression. It provides a novel possibly practice-changing low cost mental health care perspective for depressed BDV-1-infected patients addressing global needs.

Trial registration
The trial was retrospectively registered in the German Clinical Trials Registry on 04th of March 2015. The trial ID is DRKS00007649; https://www.drks.de/drks_web/setLocale_EN.do
Causes and consequences of individual variation in animal movement
Authors: Shaw Allison K. 
Published: February 2020

AbstractAnimal movement comes in a variety of ‘types’ including small foraging movements, larger one-way dispersive movements, seasonally-predictable round-trip migratory movements, and erratic nomadic movements. Although most individuals move at some point throughout their lives, movement patterns can vary widely across individuals within the same species: differing within an individual over time (intra-individual), among individuals in the same population (inter-individual), or among populations (inter-population). Yet, studies of movement (theoretical and empirical alike) more often focus on understanding ‘typical’ movement patterns than understanding variation in movement. Here, I synthesize current knowledge of movement variation (drawing parallels across species and movement types), describing the causes (what factors contribute to individual variation), patterns (what movement variation looks like), consequences (why variation matters), maintenance (why variation persists), implications (for management and conservation), and finally gaps (what pieces we are currently missing). By synthesizing across scales of variation, I span across work on plasticity, personality, and geographic variation. Individual movement can be driven by factors that act at the individual, population, community and ecosystem level and have ramifications at each of these levels. Generally the consequences of movement are less well understood than the causes, in part because the effects of movement variation are often nested, with variation manifesting at the population level, which in turn affects communities and ecosystems. Understanding both cause and consequence is particularly important for predicting when variation begets variation in a positive feedback loop, versus when a negative feedback causes variation to be dampened successively. Finally, maintaining standing variation in movement may be important for facilitating species’ ability to respond to future environmental change.