bluuebunny/crossref_metadata_2025 huggingface dataset:
Whole-genome sequencing of European autochthonous and commercial pig breeds allows the detection of signatures of selection for adaptation of genetic resources to different breeding and production systems
Authors: Bovo Samuele , Ribani Anisa , Muñoz Maria , Alves Estefania , Araujo Jose P. , Bozzi Riccardo , Čandek-Potokar Marjeta , Charneca Rui , Di Palma Federica , Etherington Graham , Fernandez Ana I. , García Fabián , García-Casco Juan , Karolyi Danijel , Gallo Maurizio , Margeta Vladimir , Martins José Manuel , Mercat Marie J. , Moscatelli Giulia , Núñez Yolanda , Quintanilla Raquel , Radović Čedomir , Razmaite Violeta , Riquet Juliette , Savić Radomir , Schiavo Giuseppina , Usai Graziano , Utzeri Valerio J. , Zimmer Christoph , Ovilo Cristina , Fontanesi Luca
Published: June 2020

Background

Natural and artificial directional selection in cosmopolitan and autochthonous pig breeds and wild boars have shaped their genomes and resulted in a reservoir of animal genetic diversity. Signatures of selection are the result of these selection events that have contributed to the adaptation of breeds to different environments and production systems. In this study, we analysed the genome variability of 19 European autochthonous pig breeds (Alentejana, Bísara, Majorcan Black, Basque, Gascon, Apulo-Calabrese, Casertana, Cinta Senese, Mora Romagnola, Nero Siciliano, Sarda, Krškopolje pig, Black Slavonian, Turopolje, Moravka, Swallow-Bellied Mangalitsa, Schwäbisch-Hällisches Schwein, Lithuanian indigenous wattle and Lithuanian White old type) from nine countries, three European commercial breeds (Italian Large White, Italian Landrace and Italian Duroc), and European wild boars, by mining whole-genome sequencing data obtained by using a DNA-pool sequencing approach. Signatures of selection were identified by using a single-breed approach with two statistics [within-breed pooled heterozygosity (HP) and fixation index (FST)] and group-based FST approaches, which compare groups of breeds defined according to external traits and use/specialization/type.

Results

We detected more than 22 million single nucleotide polymorphisms (SNPs) across the 23 compared populations and identified 359 chromosome regions showing signatures of selection. These regions harbour genes that are already known or new genes that are under selection and relevant for the domestication process in this species, and that affect several morphological and physiological traits (e.g. coat colours and patterns, body size, number of vertebrae and teats, ear size and conformation, reproductive traits, growth and fat deposition traits). Wild boar related signatures of selection were detected across all the genome of several autochthonous breeds, which suggests that crossbreeding (accidental or deliberate) occurred with wild boars.

Conclusions

Our findings provide a catalogue of genetic variants of many European pig populations and identify genome regions that can explain, at least in part, the phenotypic diversity of these genetic resources.
Museomics of tree squirrels: a dense taxon sampling of mitogenomes reveals hidden diversity, phenotypic convergence, and the need of a taxonomic overhaul
Authors: de Abreu-Jr Edson Fiedler , Pavan Silvia E. , Tsuchiya Mirian T. N. , Wilson Don E. , Percequillo Alexandre R. , Maldonado Jesús E.
Published: June 2020

Background

Tree squirrels (Sciuridae, Sciurini), in particular the highly diverse Neotropical lineages, are amongst the most rapidly diversifying branches of the mammal tree of life but also some of the least known. Negligence of this group by systematists is likely a product of the difficulties in assessing morphological informative traits and of the scarcity or unavailability of fresh tissue samples for DNA sequencing. The highly discrepant taxonomic arrangements are a consequence of the lack of phylogenies and the exclusive phenotypic-based classifications, which can be misleading in a group with conservative morphology. Here we used high-throughput sequencing and an unprecedented sampling of museum specimens to provide the first comprehensive phylogeny of tree squirrels, with a special emphasis on Neotropical taxa.

Results

We obtained complete or partial mitochondrial genomes from 232 historical and modern samples, representing 40 of the 43 currently recognized species of Sciurini. Our phylogenetic analyses—performed with datasets differing on levels of missing data and taxa under distinct analytical methods—strongly support the monophyly of Sciurini and consistently recovered 12 major clades within the tribe. We found evidence that the diversity of Neotropical tree squirrels is underestimated, with at least six lineages that represent taxa to be named or revalidated. Ancestral state reconstructions of number of upper premolars and number of mammae indicated that alternative conditions of both characters must have evolved multiple times throughout the evolutionary history of tree squirrels.

Conclusions

Complete mitogenomes were obtained from museum specimens as old as 120 years, reinforcing the potential of historical samples for phylogenetic inferences of elusive lineages of the tree of life. None of the taxonomic arrangements ever proposed for tree squirrels fully corresponded to our phylogenetic reconstruction, with only a few of the currently recognized genera recovered as monophyletic. By investigating the evolution of two morphological traits widely employed in the taxonomy of the group, we revealed that their homoplastic nature can help explain the incongruence between phylogenetic results and the classification schemes presented so far. Based on our phylogenetic results we suggest a tentative supraspecific taxonomic arrangement for Sciurini, employing 13 generic names used in previous taxonomic classifications.
Alternative splicing is highly variable among Daphnia pulex lineages in response to acute copper exposure
Authors: Suresh Sneha , Crease Teresa J. , Cristescu Melania E. , Chain Frédéric J. J.
Published: June 2020

Background

Despite being one of the primary mechanisms of gene expression regulation in eukaryotes, alternative splicing is often overlooked in ecotoxicogenomic studies. The process of alternative splicing facilitates the production of multiple mRNA isoforms from a single gene thereby greatly increasing the diversity of the transcriptome and proteome. This process can be important in enabling the organism to cope with stressful conditions. Accurate identification of splice sites using RNA sequencing requires alignment to independent exonic positions within the genome, presenting bioinformatic challenges, particularly when using short read data. Although technological advances allow for the detection of splicing patterns on a genome-wide scale, very little is known about the extent of intraspecies variation in splicing patterns, particularly in response to environmental stressors. In this study, we used RNA-sequencing to study the molecular responses to acute copper exposure in three lineages of Daphnia pulex by focusing on the contribution of alternative splicing in addition to gene expression responses.

Results

By comparing the overall gene expression and splicing patterns among all 15 copper-exposed samples and 6 controls, we identified 588 differentially expressed (DE) genes and 16 differentially spliced (DS) genes. Most of the DS genes (13) were not found to be DE, suggesting unique transcriptional regulation in response to copper that went unnoticed with conventional DE analysis. To understand the influence of genetic background on gene expression and alternative splicing responses to Cu, each of the three lineages was analyzed separately. In contrast to the overall analysis, each lineage had a higher proportion of unique DS genes than DE genes suggesting that genetic background has a larger influence on DS than on DE. Gene Ontology analysis revealed that some pathways involved in stress response were jointly regulated by DS and DE genes while others were regulated by only transcription or only splicing.

Conclusions

Our findings suggest an important role for alternative splicing in shaping transcriptome diversity in response to metal exposure in Daphnia, highlighting the importance of integrating splicing analyses with gene expression surveys to characterize molecular pathways in evolutionary and environmental studies.
Molecular genetic analysis of spring wheat core collection using genetic diversity, population structure, and linkage disequilibrium
Authors: Mourad Amira M. I. , Belamkar Vikas , Baenziger P. Stephen
Published: June 2020

Background

Wheat (Triticum aestiviumL.) is an important crop globally which has a complex genome. To identify the parents with useful agronomic characteristics that could be used in the various breeding programs, it is very important to understand the genetic diversity among global wheat genotypes. Also, understanding the genetic diversity is useful in breeding studies such as marker-assisted selection (MAS), genome-wide association studies (GWAS), and genomic selection.

Results

To understand the genetic diversity in wheat, a set of 103 spring wheat genotypes which represented five different continents were used. These genotypes were genotyped using 36,720 genotyping-by-sequencing derived SNPs (GBS-SNPs) which were well distributed across wheat chromosomes. The tested 103-wheat genotypes contained three different subpopulations based on population structure, principle coordinate, and kinship analyses. A significant variation was found within and among the subpopulations based on the AMOVA. Subpopulation 1 was found to be the more diverse subpopulation based on the different allelic patterns (Na,Ne,I,h, anduh). No high linkage disequilibrium was found between the 36,720 SNPs. However, based on the genomic level, D genome was found to have the highest LD compared with the two other genomes A and B. The ratio between the number of significant LD/number of non-significant LD suggested that chromosomes 2D, 5A, and 7B are the highest LD chromosomes in their genomes with a value of 0.08, 0.07, and 0.05, respectively. Based on the LD decay, the D genome was found to be the lowest genome with the highest number of haplotype blocks on chromosome 2D.

Conclusion

The recent study concluded that the 103-spring wheat genotypes and their GBS-SNP markers are very appropriate for GWAS studies and QTL-mapping. The core collection comprises three different subpopulations. Genotypes in subpopulation 1 are the most diverse genotypes and could be used in future breeding programs if they have desired traits. The distribution of LD hotspots across the genome was investigated which provides useful information on the genomic regions that includes interesting genes.
Transcriptomic analysis reveals hub genes and subnetworks related to ROS metabolism in Hylocereus undatus through novel superoxide scavenger trypsin treatment during storage
Authors: Li Xin , Liu Xueru , Pang Xinyue , Yin Yong , Yu Huichun , Yuan Yunxia , Li Bairu
Published: June 2020

Background

It was demonstrated in our previous research that trypsin scavenges superoxide anions. In this study, the mechanisms of storage quality improvement by trypsin were evaluated in H. undatus.

Results

Trypsin significantly delayed the weight loss and decreased the levels of ROS and membrane lipid peroxidation. Transcriptome profiles of H. undatus treated with trypsin revealed the pathways and regulatory mechanisms of ROS genes that were up- or downregulated following trypsin treatment by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses. The current results showed that through the regulation of the expression of hub redox enzymes, especially thioredoxin-related proteins, trypsin can maintain low levels of endogenous active oxygen species, reduce malondialdehyde content and delay fruit aging. In addition, the results of protein-protein interaction networks suggested that the downregulated NAD(P) H and lignin pathways might be the key regulatory mechanisms governed by trypsin.

Conclusions

Trypsin significantly prolonged the storage life of H. undatus through regulatory on the endogenous ROS metabolism. As a new biopreservative, trypsin is highly efficient, safe and economical. Therefore, trypsin possesses technical feasibility for the quality control of fruit storage.

Graphical abstract
Maternal dietary resistant starch does not improve piglet’s gut and liver metabolism when challenged with a high fat diet
Authors: Schroyen Martine , Leblois Julie , Uerlings Julie , Li Bing , Sureda Ester Arévalo , Massart Sébastien , Wavreille José , Bindelle Jérôme , Everaert Nadia
Published: June 2020

Background

In the past several years, the use of resistant starch (RS) as prebiotic has extensively been studied in pigs, and this mostly in the critical period around weaning. RS is believed to exert beneficial effects on the gastrointestinal tract mainly due to higher levels of short chain fatty acids (SCFAs) and an improved microbiota profile. In this study, sows were fed digestible starch (DS) or RS during late gestation and lactation and the possible maternal effect of RS on the overall health of the progeny was assessed. Since RS is also described to have a positive effect on metabolism, and to investigate a metabolic programming of the progeny, half of the piglets per maternal diet were assigned to a high fat diet from weaning on to 10 weeks after.

Results

No bodyweight differences were found between the four experimental piglet groups. The high fat diet did however impact back fat thickness and meat percentage whereas maternal diet did not influence these parameters. The impact of the high fat diet was also reflected in higher levels of serum cholesterol. No major differences in microbiota could be distinguished, although higher levels of SCFA were seen in the colon of piglets born from RS fed sows, and some differences in SCFA production were observed in the caecum, mainly due to piglet diet. RNA-sequencing on liver and colon scrapings revealed minor differences between the maternal diet groups. Merely a handful of genes was differentially expressed between piglets from DS and RS sows, and network analysis showed only one significant cluster of genes in the liver due to the maternal diet that did not point to meaningful biological pathways. However, the high fat diet resulted in liver gene clusters that were significantly correlated with piglet diet, of which one is annotated for lipid metabolic processes. These clusters were not correlated with maternal diet.

Conclusions

There is only a minor impact of maternal dietary RS on the progeny, reflected in SCFA changes. A high fat diet given to the progeny directly evokes metabolic changes in the liver, without any maternal programming by a RS diet.
Prevalence and phylogeny of Chlamydiae and hemotropic mycoplasma species in captive and free-living bats
Authors: Fritschi Janine , Marti Hanna , Seth-Smith Helena M. B. , Aeby Sébastien , Greub Gilbert , Meli Marina L. , Hofmann-Lehmann Regina , Mühldorfer Kristin , Stokar-Regenscheit Nadine , Wiederkehr Danja , Pilo Paola , Van Den Broek Peggy Rüegg- , Borel Nicole
Published: June 2020

Background

Bats are hosts for a variety of microorganisms, however, little is known about the presence of Chlamydiales and hemotropic mycoplasmas. This study investigated 475 captive and free-living bats from Switzerland, Germany, and Costa Rica for Chlamydiales and hemotropic mycoplasmas by PCR to determine the prevalence and phylogeny of these organisms.

Results

Screening for Chlamydiales resulted in a total prevalence of 31.4%. Positive samples originated from captive and free-living bats from all three countries. Sequencing of 15 samples allowed the detection of two phylogenetically distinct groups. These groups share sequence identities to Chlamydiaceae, and to Chlamydia-like organisms including Rhabdochlamydiaceae and unclassified Chlamydiales from environmental samples, respectively.

PCR analysis for the presence of hemotropic mycoplasmas resulted in a total prevalence of 0.7%, comprising free-living bats from Germany and Costa Rica. Phylogenetic analysis revealed three sequences related to other unidentified mycoplasmas found in vampire bats and Chilean bats.

Conclusions

Bats can harbor Chlamydiales and hemotropic mycoplasmas and the newly described sequences in this study indicate that the diversity of these bacteria in bats is much larger than previously thought. Both, Chlamydiales and hemotropic mycoplasmas are not restricted to certain bat species or countries and captive and free-living bats can be colonized. In conclusion, bats represent another potential host or vector for novel, previously unidentified, Chlamydiales and hemotropic mycoplasmas.
Plant transcriptome analysis reveals specific molecular interactions between alfalfa and its rhizobial symbionts below the species level
Authors: Kang Wenjuan , Jiang Zhehao , Chen Yonggang , Wu Fang , Liu Chang , Wang Haifang , Shi Shangli , Zhang Xue-Xian
Published: June 2020

Background

Leguminous plants alter patterns of gene expression in response to symbiotic colonization and infection by their cognate rhizobial bacteria, but the extent of the transcriptomic response has rarely been examined below the species level. Here we describe the identification of 12 rhizobial biotypes of Ensifer meliloti, which form nitrogen-fixing nodules in the roots of alfalfa (Medicago sativa L.), followed by a comparative RNA-seq analysis of four alfalfa cultivars each inoculated with two E. meliloti strains varying in symbiotic performance and phylogenetic relatedness.

Results

Rhizobial biotypes were identified on the basis of their symbiotic performance, particularly shoot dry weight. Differentially expressed genes (DEGs) and metabolic pathways were determined by comparing the RNA-seq data with that of the uninoculated control plant. Significant differences were found between DEGs generated in each cultivar with the inoculation of two rhizobial strains in comparison (P < 0.01). A total of 8111 genes was differentially expressed, representing ~ 17.1% of the M. sativa genome. The proportion of DEGs ranges from 0.5 to 12.2% for each alfalfa cultivar. Interestingly, genes with predicted roles in flavonoid biosynthesis and plant-pathogen interaction (NBS-LRR) were identified as the most significant DEGs. Other DEGs include Medsa002106 and genes encoding nodulins and NCR peptides whose expression is specifically induced during the development of nitrogen-fixing nodules. More importantly, strong significant positive correlations were observed between plant transcriptomes (DEGs and KEGG pathways) and phylogenetic distances between the two rhizobial inoculants.

Conclusions

Alfalfa expresses significantly distinct sets of genes in response to infection by different rhizobial strains at the below-species levels (i.e. biotype or strain). Candidate genes underlying the specific interactions include Medsa002106 and those encoding nodulins and NCR peptides and proteins in the NBS-LRR family.
Comparison of methods for handling covariate missingness in propensity score estimation with a binary exposure
Authors: Coffman Donna L. , Zhou Jiangxiu , Cai Xizhen
Published: June 2020

Background

Causal effect estimation with observational data is subject to bias due to confounding, which is often controlled for using propensity scores. One unresolved issue in propensity score estimation is how to handle missing values in covariates.

Method

Several approaches have been proposed for handling covariate missingness, including multiple imputation (MI), multiple imputation with missingness pattern (MIMP), and treatment mean imputation. However, there are other potentially useful approaches that have not been evaluated, including single imputation (SI) + prediction error (PE), SI + PE + parameter uncertainty (PU), and Generalized Boosted Modeling (GBM), which is a nonparametric approach for estimating propensity scores in which missing values are automatically handled in the estimation using a surrogate split method. To evaluate the performance of these approaches, a simulation study was conducted.

Results

Results suggested that SI + PE, SI + PE + PU, MI, and MIMP perform almost equally well and better than treatment mean imputation and GBM in terms of bias; however, MI and MIMP account for the additional uncertainty of imputing the missingness.

Conclusions

Applying GBM to the incomplete data and relying on the surrogate split approach resulted in substantial bias. Imputation prior to implementing GBM is recommended.
Applying an intersectionality lens to the theoretical domains framework: a tool for thinking about how intersecting social identities and structures of power influence behaviour
Authors: Etherington Cole , Rodrigues Isabel Braganca , Giangregorio Lora , Graham Ian D. , Hoens Alison M. , Kasperavicius Danielle , Kelly Christine , Moore Julia E. , Ponzano Matteo , Presseau Justin , Sibley Kathryn M. , Straus Sharon
Published: June 2020

Background

A key component of the implementation process is identifying potential barriers and facilitators that need to be addressed. The Theoretical Domains Framework (TDF) is one of the most commonly used frameworks for this purpose. When applying the TDF, it is critical to understand the context in which behaviours occur. Intersectionality, which accounts for the interface between social identity factors (e.g. age, gender) and structures of power (e.g. ageism, sexism), offers a novel approach to understanding how context shapes individual decision-making and behaviour. We aimed to develop a tool to be used alongside applications of the TDF to incorporate an intersectionality lens when identifying implementation barriers and enablers.

Methods

An interdisciplinary Framework Committee (n = 17) prioritized the TDF as one of three models, theories, and frameworks (MTFs) to enhance with an intersectional lens through a modified Delphi approach. In collaboration with the wider Framework Committee, a subgroup considered all 14 TDF domains and iteratively developed recommendations for incorporating intersectionality considerations within the TDF and its domains. An iterative approach aimed at building consensus was used to finalize recommendations.

Results

Consensus on how to apply an intersectionality lens to the TDF was achieved after 12 rounds of revision. Two overarching considerations for using the intersectionality alongside the TDF were developed by the group as well as two to four prompts for each TDF domain to guide interview topic guides. Considerations and prompts were designed to assist users to reflect on how individual identities and structures of power may play a role in barriers and facilitators to behaviour change and subsequent intervention implementation.

Conclusions

Through an expert-consensus approach, we developed a tool for applying an intersectionality lens alongside the TDF. Considering the role of intersecting social factors when identifying barriers and facilitators to implementing research evidence may result in more targeted and effective interventions that better reflect the realities of those involved.
The outcomes of modified endoscopic mucosal resection and endoscopic submucosal dissection for the treatment of rectal neuroendocrine tumors and the value of endoscopic morphology classification in endoscopic resection
Authors: Wang Xiang-Yao , Chai Ning-Li , Linghu En-Qiang , Qiu Shao-Tian , Li Long-Song , Zou Jia-Le , Xiang Jing-Yuan , Li Xing-Xing
Published: June 2020

Background

To compare the outcomes of modified endoscopic mucosal resection (m-EMR) and endoscopic submucosal dissection (ESD) for rectal neuroendocrine tumors (NETs) and evaluate the value of endoscopic morphology classification in endoscopic resection (ER).

Methods

Patients with rectal NET diameters less than 2 cm who were treated between April 2007 and January 2019 were enrolled. The endoscopic morphology of rectal NETs was classified based on the endoscopic views. Patients who underwent ESD and m-EMR were compared. Baseline characteristics as well as en bloc resection, complete resection, the procedure time, adverse events and the risk factors associated with incomplete resection were analyzed.

Results

A total of 429 patients with 449 rectal NETs were enrolled for the classification of endoscopic morphology and were classified into four types (Ia, IIb, II, and III). There were 79 patients in the m-EMR group and 259 patients in the ESD group before matching. Propensity score matching created 77 pairs between the two groups that were well balanced. The mean procedure time was significantly shorter for m-EMR than for ESD (9.1 ± 4.4 min vs 16.0 ± 7.9 min, P = 0.000). The rates of en bloc resection (98.7% vs 100%; P = 1.000), complete resection (90.9% vs 93.5%, P = 0.548) and adverse events (2.6% vs 2.6%, P = 1.000) were similar between the two groups. Univariate and multivariate analyses showed that histopathological grade and endoscopic morphology were associated with incomplete resection.

Conclusion

Both ESD and m-EMR are effective and safe for the treatment of rectal NETs. Endoscopic morphology should be considered along with histopathological grade for ER.
Association between chronic diseases and falls among a sample of older people in Finland
Authors: Immonen Milla , Haapea Marianne , Similä Heidi , Enwald Heidi , Keränen Niina , Kangas Maarit , Jämsä Timo , Korpelainen Raija
Published: June 2020

Background

Falls are a major problem for older people and recurrent fallers are especially prone to severe consequences due to falls. This study investigated the association between chronic conditions and falls.

Methods

Responses from 872 older persons (age 65–98) to a health questionnaire were used in the analyses. Characteristics and disease prevalence between recurrent fallers, one-time fallers and non-fallers were compared. A hierarchical clustering method was applied to find combinations of chronic conditions that were associated with recent recurrent falling.

Results

The results showed that recurrent fallers had a higher number of diseases (median 4, interquartile range, IQR = 2.0–5.0) compared to non-fallers (median 2, IQR = 1.0–3.0). Eight clusters were formed based on the data. The participants in the low chronic disease cluster were younger, more physically active, not frail, and had fewer geriatric conditions. Multiple chronic disease cluster participants were older, less physically active, overweight (body mass index, BMI > 30), at risk of malnutrition, and had more geriatric conditions. Significantly increased risk of recurrent falls relative to the low chronic cluster was found for respondents in the osteoporosis cluster and multiple chronic disease cluster (OR = 5.65, 95% confidence interval CI: 1.23–25.85, p = 0.026, and OR = 13.42, 95% CI: 2.47–72.96, p = 0.002, respectively). None of the clusters were associated with increased risk of one-time falling.

Conclusions

The results implicate that the number of chronic diseases is related with risk of recurrent falling. Furthermore, the results implicate the potential of identifying certain combinations of chronic diseases that increase fall risk by analyzing health record data, although further studies are needed with a larger population sample.
Tick-borne encephalitis (TBE) cases are not random: explaining trend, low- and high-frequency oscillations based on the Austrian TBE time series
Authors: Rubel Franz , Walter Melanie , Vogelgesang Janna R. , Brugger Katharina
Published: June 2020

Background

Why human tick-borne encephalitis (TBE) cases differ from year to year, in some years more 100%, has not been clarified, yet. The cause of the increasing or decreasing trends is also controversial. Austria is the only country in Europe where a 40-year TBE time series and an official vaccine coverage time series are available to investigate these open questions.

Methods

A series of generalized linear models (GLMs) has been developed to identify demographic and environmental factors associated with the trend and the oscillations of the TBE time series. Both the observed and the predicted TBE time series were subjected to spectral analysis. The resulting power spectra indicate which predictors are responsible for the trend, the high-frequency and the low-frequency oscillations, and with which explained variance they contribute to the TBE oscillations.

Results

The increasing trend can be associated with the demography of the increasing human population. The responsible GLM explains 12% of the variance of the TBE time series. The low-frequency oscillations (10 years) are associated with the decadal changes of the large-scale climate in Central Europe. These are well described by the so-called Scandinavian index. This 10-year oscillation cycle is reinforced by the socio-economic predictor net migration. Considering the net migration and the Scandinavian index increases the explained variance of the GLM to 44%. The high-frequency oscillations (2–3 years) are associated with fluctuations of the natural TBE transmission cycle between small mammals and ticks, which are driven by beech fructification. Considering also fructification 2 years prior explains 64% of the variance of the TBE time series. Additionally, annual sunshine duration as predictor for the human outdoor activity increases the explained variance to 70%.

Conclusions

The GLMs presented here provide the basis for annual TBE forecasts, which were mainly determined by beech fructification. A total of 3 of the 5 years with full fructification, resulting in high TBE case numbers 2 years later, occurred after 2010. The effects of climate change are therefore not visible through a direct correlation of the TBE cases with rising temperatures, but indirectly via the increased frequency of mast seeding.
Pharmacokinetic study of two different rifabutin doses co-administered with lopinavir/ritonavir in African HIV and tuberculosis co-infected adult patients
Authors: Kouanda Seni , Ouedraogo Henri Gautier , Cisse Kadari , Compaoré Tegwinde Rebeca , Sulis Giorgia , Diagbouga Serge , Roggi Alberto , Tarnagda Grissoum , Villani Paola , Sangare Lassana , Simporé Jacques , Regazzi Mario , Matteelli Alberto
Published: June 2020

Background

This study aimed to assess the pharmacokinetic profile of 150 mg rifabutin (RBT) taken every other day (every 48 h) versus 300 mg RBT taken every other day (E.O.D), both in combination with lopinavir/ritonavir (LPV/r), in adult patients with human immunodeficiency virus (HIV) and tuberculosis (TB) co-infection.

Methods

This is a two-arm, open-label, pharmacokinetic, randomised study conducted in Burkina Faso between May 2013 and December 2015. Enrolled patients were randomised to receive either 150 mg RBT EOD (arm A, 9 subjects) or 300 mg RBT EOD (arm B, 7 subjects), both associated with LPV/r taken twice daily. RBT plasma concentrations were evaluated after 2 weeks of combined HIV and TB treatment. Samples were collected just before drug ingestion and at 1, 2, 3, 4, 6, 8, and 12 h after drug ingestion to measure plasma drug concentration using an HPLC-MS/MS assay.

Results

The Cmax and AUC0–12hmedians in arm A (Cmax = 296 ng/mL, IQR: 205–45; AUC0–12h = 2528 ng.h/mL, IQR: 1684–2735) were lower than those in arm B (Cmax = 600 ng/mL, IQR: 403–717; AUC0–12h = 4042.5 ng.h/mL, IQR: 3469–5761), with a statistically significant difference in AUC0–12h(p = 0.044) but not in Cmax (p = 0.313). No significant differences were observed in Tmax (3 h versus 4 h). Five patients had a Cmax below the plasma therapeutic limit (< 300 ng/mL) in the 150 mg RBT arm, while the Cmax was above this threshold for all patients in the 300 mg RBT arm. Additionally, at 48 h after drug ingestion, all patients had a mycobacterial minimum inhibitory concentration (MIC) above the limit (> 64 ng/mL) in the 300 mg RBT arm, while 4/9 patients had such values in the 150 mg RBT arm.

Conclusion

This study confirmed that the 150 mg dose of rifabutin ingested EOD in combination with LPV/r is inadequate and could lead to selection of rifamycin-resistant mycobacteria.

Trial registration

PACTR201310000629390, 28th October 2013.
Monitoring progress towards the first UNAIDS 90-90-90 target in key populations living with HIV in Norway
Authors: Whittaker Robert , Case Kelsey K. , Nilsen Øivind , Blystad Hans , Cowan Susan , Kløvstad Hilde , van Sighem Ard
Published: June 2020

Background

In line with the Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 target, Norway aims for at least 90% of people living with HIV (PLHIV) to know their HIV-status. We produced current estimates of the number of PLHIV and undiagnosed population in Norway, overall and for six key subpopulations: Norwegian-born men who have sex with men (MSM), migrant MSM, Norwegian-born heterosexuals, migrant Sub-Saharan Africa (SSA)-born heterosexuals, migrant non-SSA-born heterosexuals and people who inject drugs.

Methods

We used the European Centre for Disease Prevention and Control (ECDC) HIV Modelling Tool on Norwegian HIV surveillance data through 2018 to estimate incidence, time from infection to diagnosis, PLHIV, and the number and proportion undiagnosed. As surveillance data on CD4 count at diagnosis were not collected in Norway, we ran two models; using default model CD4 assumptions, or a proxy for CD4 distribution based on Danish national surveillance data. We also generated alternative overall PLHIV estimates using the Spectrum AIDS Impact Model, to compare with those obtained from the ECDC tool.

Results

Estimates of the overall number of PLHIV in 2018 using different modelling approaches aligned at approximately 5000. In both ECDC models, the overall number undiagnosed decreased continuously from 2008. The proportion undiagnosed in 2018 was lower using default model CD4 assumptions (7.1% [95%CI: 5.3–8.9%]), than the Danish CD4 proxy (10.2% [8.3–12.1%]). This difference was driven by results for heterosexual migrants. Estimates for Norwegian-born MSM, migrant MSM and Norwegian-born heterosexuals were similar in both models. In these three subpopulations, incidence in 2018 was < 30 new infections, and the number undiagnosed had decreased in recent years. Norwegian-born MSM had the lowest estimated number of undiagnosed infections (45 [30–75], using default CD4 assumptions) and undiagnosed fraction (3.6% [2.4–5.7%], using default CD4 assumptions) in 2018.

Conclusions

Results allow cautious confidence in concluding that Norway has achieved the first UNAIDS 90–90-90 target, and clearly highlight the success of prevention strategies among MSM. Estimates for subpopulations strongly influenced by migration remain less clear, and future modelling should appropriately account for all-cause mortality and out-migration, and adjust for time of in-migration.
First phenotypic description of a female patient with c.610 T > C variant of GLA: a renal-predominant presentation of Fabry disease
Authors: Greillier Sophie , Daniel Laurent , Caillaud Catherine , Dussol Bertrand , Touchard Guy , Goujon Jean-Michel , Jourde-Chiche Noémie , Bobot Mickaël
Published: June 2020

Background

Fabry disease (FD) is an X-linked lysosomal storage disorder due to deficient alpha-galactosidase activity leading to intracellular glycosphingolipid accumulation. Multiple variants have been reported in the GLA gene coding for alpha-galactosidase, and the question of the pathogenicity of rare variants needs to be addressed, especially in patients with mild phenotypes.

Case presentation

The patient, a 37-year-old female, presented with a persistent proteinuria after an otherwise uncomplicated first pregnancy. Renal biopsy showed both mild mesangial IgA deposits, and a striking vacuolization of podocytes and tubular cells consistent with Fabry disease. On electron microscopy, discrete but characteristic pseudo-myelinic lamellar inclusions were observed in the podocytes’ lysosomes. A more detailed physical examination revealed an angiokeratoma, and medical history ancient acroparesthesia. There was no cardiac or cerebral involvement of Fabry disease on magnetic resonance imaging. While blood enzymatic activity of alpha-ga lactosidase was normal in this patient, lysoGb3 was elevated (3 N), and a rare heterozygous variant called c.610 T > C was documented in GLA gene. The patient was treated with an ACE inhibitor, with a rapid decrease in proteinuria. After a 5-year follow-up, her renal function has remained normal, with mild proteinuria, and normal cardiac echography.

Conclusions

We report and phenotypically describe the first case of a Fabry disease female patient carrying the GLA c.610 T > C variant associated with a renal-predominant clinical presentation.
The Rajarata Pregnancy Cohort (RaPCo): study protocol
Authors: Agampodi Thilini Chanchala , Wickramasinghe Nuwan Darshana , Prasanna Rampathige Indika Ruwan , Irangani Malawara Kankanamalage Lasandha , Banda Jayasundara Mudiyanselage Samarakoo , Jayathilake Pradana Mudiyanselage Bandula , Hettiarachchi Ayesh , Amarasinghe Gayani , Jayasinghe Imasha , Koralagedara Iresha , Gunarathne Sajaan Praveena , Wickramage Sujanthi , Warnasekara Janith , Lokunarangoda Niroshan , Mendis Vasana , Dissanayaka Ajith Kumara , Premadasa Jagath , Hettigama Nandana , Koralagedara Dayaratne , Weerasinghe Manjula , Malawanage Krishanthi , Jayakodi Hemali , Wickramasinghe Anuprabha , Agampodi Suneth Buddhika
Published: June 2020

Background

Ending preventable maternal deaths remains a global priority and in the later stages of obstetric transition, identifying the social determinants of maternal health outcomes is essential to address stagnating maternal mortality rates. Countries would hardly achieve the Sustainable Development Goal (SGD) targets on maternal health, unless the complex and context-specific socio-economic aetiologies associated with maternal mental health and suicide are identified. The Rajarata Pregnancy Cohort (RaPCo) is a prospective cohort study, designed to explore the interactions between social determinants and maternal mental health in determining pregnancy and new-born outcomes.

Methods

The study will recruit all eligible pregnant women in the maternal care programme of Anuradhapura district, Sri Lanka from July to September 2019. The estimated sample size is 2400. We will assess the socio-demographic and economic status, social capital, gender-based violence and mental health, including a clinical examination and biochemical investigations during the first trimester. Participants will undergo four follow-ups at 2nd and 3rd trimesters, at delivery and in early postpartum. The new-borns will be followed up at birth, neonatal period, at 6 six months and at 1 year. Pregnancy and child outcome data will be collected using direct contact. Qualitative studies will be carried out to understand the complex social factors and behavioural dimensions related to abortion, antenatal depression, maternal deaths and near misses.

Discussion

This is the first reported maternal cohort in Sri Lanka focusing on social determinants and mental health. As a country in stage four of obstetric transition, these findings will provide generalizable evidence on achieving SGD targets in low- and middle-income countries. The study will be conducted in a district with multi-cultural, multi-ethnic and diverse community characteristics; thus, will enable the evidence generated to be applied in many different contexts. The study also possesses the strength of using direct participant contact, data collection, measurement, examination and biochemical testing to minimise errors in routinely collected data. The RaPCo study will be able to generate evidence to strengthen policies to further reduce maternal deaths in the local, regional and global contexts particularly focusing on social factors and mental health, which are not optimally addressed in the global agenda.
MiR-34c downregulation leads to SOX4 overexpression and cisplatin resistance in nasopharyngeal carcinoma
Authors: Bissey Pierre-Antoine , Teng Mona , Law Jacqueline H. , Shi Wei , Bruce Jeff P. , Petit Valentin , Tsao Sai W. , Yip Kenneth W. , Liu Fei-Fei
Published: June 2020

Background

A major cause of disease-related death in nasopharyngeal carcinoma (NPC) is the development of distant metastasis (DM) despite combination chemoradiotherapy treatment. We previously identified and validated a four microRNA (miRNA) signature that is prognostic for DM. In this study, characterization of a key component of this signature, miR-34c, revealed its role in chemotherapy resistance.

Methods

Two hundred forty-six NPC patient biopsy samples were subject to comprehensive miRNA profiling and immunohistochemistry (IHC). Two human normal nasopharyngeal cell lines (immortalized; NP69 and NP460), as well as the NPC cell line C666–1, were used for miR-34c gain-of-function and loss-of-function experiments. Signaling pathways were assessed using quantitative real-time PCR (qRT-PCR) and Western blot. Cell viability was measured using the ATPlite assay.

Results

MiR-34c was downregulated in NPC patient samples, and confirmed in vitro to directly target SOX4, a master regulator of epithelial-to-mesenchymal transition (EMT). MiR-34c downregulation triggered EMT-representative changes in NP69 and NP460 whereby Snail, ZEB1, CDH2, and SOX2 were upregulated, while Claudin-1 and CDH1 were downregulated. Phenotypically, inhibition of miR-34c led to cisplatin resistance, whereas miR-34c over-expression sensitized NPC cells to cisplatin. TGFβ1 decreased miR-34c and increased SOX4 expression in vitro. The TGFβ receptor 1 inhibitor SB431542 reduced SOX4 expression and increased cisplatin sensitivity. Finally, IHC revealed that lower SOX4 expression was associated with improved overall survival in chemotherapy-treated NPC patients.

Conclusion

miR-34c is downregulated in NPC. Repression of miR-34c was shown to increase SOX4 expression, which leads to cisplatin resistance, while TGFβ1 was found to repress miR-34c expression. Taken together, our study demonstrates that inhibition of the TGFβ1 pathway could be a strategy to restore cisplatin sensitivity in NPC.
Rationale and design of “Hearts & Parks”: study protocol for a pragmatic randomized clinical trial of an integrated clinic-community intervention to treat pediatric obesity
Authors: Armstrong Sarah C. , Windom McAllister , Bihlmeyer Nathan A. , Li Jennifer S. , Shah Svati H. , Story Mary , Zucker Nancy , Kraus William E. , Pagidipati Neha , Peterson Eric , Wong Charlene , Wiedemeier Manuela , Sibley Lauren , Berchuck Samuel I. , Merrill Peter , Zizzi Alexandra , Sarria Charles , Dressman Holly K. , Rawls John F. , Skinner Asheley C.
Published: June 2020

Background

The prevalence of child and adolescent obesity and severe obesity continues to increase despite decades of policy and research aimed at prevention. Obesity strongly predicts cardiovascular and metabolic disease risk; both begin in childhood. Children who receive intensive behavioral interventions can reduce body mass index (BMI) and reverse disease risk. However, delivering these interventions with fidelity at scale remains a challenge. Clinic-community partnerships offer a promising strategy to provide high-quality clinical care and deliver behavioral treatment in local park and recreation settings. The Hearts & Parks study has three broad objectives: (1) evaluate the effectiveness of the clinic-community model for the treatment of child obesity, (2) define microbiome and metabolomic signatures of obesity and response to lifestyle change, and (3) inform the implementation of similar models in clinical systems.

Methods

Methods are designed for a pragmatic randomized, controlled clinical trial (n = 270) to test the effectiveness of an integrated clinic-community child obesity intervention as compared with usual care. We are powered to detect a difference in body mass index (BMI) between groups at 6 months, with follow up to 12 months. Secondary outcomes include changes in biomarkers for cardiovascular disease, psychosocial risk, and quality of life. Through collection of biospecimens (serum and stool), additional exploratory outcomes include microbiome and metabolomics biomarkers of response to lifestyle modification.

Discussion

We present the study design, enrollment strategy, and intervention details for a randomized clinical trial to measure the effectiveness of a clinic-community child obesity treatment intervention. This study will inform a critical area in child obesity and cardiovascular risk research—defining outcomes, implementation feasibility, and identifying potential molecular mechanisms of treatment response.

Clinical trial registration

NCT03339440.
The application research of xTAG GPP multiplex PCR in the diagnosis of persistent and chronic diarrhea in children
Authors: Wang Chunli , Zhou Xiaoying , Zhu Mengshu , Yin Hanjun , Tang Jiamei , Huang Yan , Zheng Bixia , Jin Yu , Liu Zhifeng
Published: June 2020

Background

Persistent and chronic diarrhea is difficult to treat, and infection is still the main cause. In this study, we investigate the application value of xTAG gastrointestinal pathogen panel (xTAG GPP) multiplex PCR in the early diagnosis of persistent and chronic diarrhea in children and to understand the epidemiology of intestinal diarrhea pathogens.

Methods

One hundred ninety-nine specimens were collected from Nanjing Children’s Hospital Affiliated to Nanjing Medical University (Nanjing, China). We compared the xTAG GPP multiplex PCR assay with traditional methods (culture, rapid enzyme immunoassay chromatography, and microscopic examination) and performed a statistical analysis.

Results

The positive rate of the xTAG GPP multiplex PCR assay of diarrhea specimens from 199 patients was 72.86% (145/199). The virus detection rate was 48.7%, and rotavirus A was the most common organism detected (34.67%), concentrated in winter, and was common in children. The second most common organism detected was norovirus GI/GII (20.6%). The positive rate of this bacteria was 40.2%, and Campylobacter (22.11%, 44/199) was most frequently detected. C. difficile toxins A/B and Salmonella was detected in 44 and 17 samples, respectively. Infections with Shigella occurred 4 times, and E. coli O157 was only detected once. Three samples were parasitic (1.51%), two samples were positive for Entamoeba histolytica, and one was positive for Cryptosporidium. Adenovirus 40/41, STEC, ETEC, Giardia, Yersinia enterocolitica and Vibrio cholerae were not detected. In total, 86 (43.2%) infected specimens with a single pathogen were detected. There were 59 coinfections (29.65% of the samples) of viruses and/or bacteria and/or parasites. Coinfections involved 49 double infections (24.62%), 9 triple infections (4.52%) and 1 quadruple infections (0.5%). Norovirus GI/GII was found to have the highest involvement, with 32 coinfections (16.08%).

Conclusion

The xTAG GPP multiplex PCR assay is simple, sensitive, and specific and can be used as a quick way to diagnose persistent and chronic diarrhea in children.