Publications by authors named "Antti Sajantila"

135 Publications

The Human Bone Marrow Is Host to the DNAs of Several Viruses.

Front Cell Infect Microbiol 2021 22;11:657245. Epub 2021 Apr 22.

Department of Virology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

The long-term impact of viruses residing in the human bone marrow (BM) remains unexplored. However, chronic inflammatory processes driven by single or multiple viruses could significantly alter hematopoiesis and immune function. We performed a systematic analysis of the DNAs of 38 viruses in the BM. We detected, by quantitative PCRs and next-generation sequencing, viral DNA in 88.9% of the samples, up to five viruses in one individual. Included were, among others, several herpesviruses, hepatitis B virus, Merkel cell polyomavirus and, unprecedentedly, human papillomavirus 31. Given the reactivation and/or oncogenic potential of these viruses, their repercussion on hematopoietic and malignant disorders calls for careful examination. Furthermore, the implications of persistent infections on the engraftment, regenerative capacity, and outcomes of bone marrow transplantation deserve in-depth evaluation.
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http://dx.doi.org/10.3389/fcimb.2021.657245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100435PMC
July 2021

Autosomal STR and SNP characterization of populations from the Northeastern Peruvian Andes with the ForenSeq™ DNA Signature Prep Kit.

Forensic Sci Int Genet 2021 05 23;52:102487. Epub 2021 Feb 23.

Department of Forensic Medicine, University of Helsinki, PO Box 40, FI-00014 Helsinki, Finland; Forensic Medicine Unit, Finnish Institute for Health and Welfare, PO Box 30, FI-00271 Helsinki, Finland. Electronic address:

Autosomal DNA data from Peru for human identity testing purposes are scarce in the scientific literature, which hinders obtaining an appropriate portrait of the genetic variation of the resident populations. In this study we genetically characterize five populations from the Northeastern Peruvian Andes (Chachapoyas, Awajún, Wampís, Huancas and Cajamarca). Autosomal short tandem repeat (aSTR) and identity informative single nucleotide polymorphism (iiSNP) data from a total of 233 unrelated individuals are provided, and forensic genetic parameters are calculated for each population and for the combined set Northeastern Peruvian Andes. After correction for multiple testing in the whole dataset of the Northeastern Peruvian Andes, the only departure from Hardy-Weinberg equilibrium was observed in locus rs2111980. Twenty one out of 27 aSTR loci exhibited an increased number of alleles due to sequence variation in the repeat motif and flanking regions. For iiSNPs 33% of the loci displayed flanking region variation. The combined random match probability (RMP), assuming independence of all loci (aSTRs and iiSNPs), in the Chachapoyas, the population with the largest samples size (N = 172), was 8.14 × 10 for length-based data while for sequence-based was 4.15 × 10. In the merged dataset (Northeastern Peruvian Andes; N = 233), the combined RMP when including all markers were 2.96 × 10 (length-based) and 3.21 × 10 (sequence-based). These new data help to fill up some of the gaps in the genetic canvas of South America and provide essential length- and sequence-based background information for other forensic genetic studies in Peru.
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http://dx.doi.org/10.1016/j.fsigen.2021.102487DOI Listing
May 2021

Effects of Environmental Factors on Severity and Mortality of COVID-19.

Front Med (Lausanne) 2020 20;7:607786. Epub 2021 Jan 20.

Central Clinical Hospital of Ministry of the Interior and Administration, Warsaw, Poland.

Most respiratory viruses show pronounced seasonality, but for SARS-CoV-2, this still needs to be documented. We examined the disease progression of COVID-19 in 6,914 patients admitted to hospitals in Europe and China. In addition, we evaluated progress of disease symptoms in 37,187 individuals reporting symptoms into the COVID Symptom Study application. Meta-analysis of the mortality risk in seven European hospitals estimated odds ratios per 1-day increase in the admission date to be 0.981 (0.973-0.988, < 0.001) and per increase in ambient temperature of 1°C to be 0.854 (0.773-0.944, = 0.007). Statistically significant decreases of comparable magnitude in median hospital stay, probability of transfer to the intensive care unit, and need for mechanical ventilation were also observed in most, but not all hospitals. The analysis of individually reported symptoms of 37,187 individuals in the UK also showed the decrease in symptom duration and disease severity with time. Severity of COVID-19 in Europe decreased significantly between March and May and the seasonality of COVID-19 is the most likely explanation.
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http://dx.doi.org/10.3389/fmed.2020.607786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855590PMC
January 2021

Genetic assessment reveals no population substructure and divergent regional and sex-specific histories in the Chachapoyas from northeast Peru.

PLoS One 2020 31;15(12):e0244497. Epub 2020 Dec 31.

Department of Forensic Medicine, University of Helsinki, Helsinki, Finland.

Many native populations in South America have been severely impacted by two relatively recent historical events, the Inca and the Spanish conquest. However decisive these disruptive events may have been, the populations and their gene pools have been shaped markedly also by the history prior to the conquests. This study focuses mainly on the Chachapoya peoples that inhabit the montane forests on the eastern slopes of the northern Peruvian Andes, but also includes three distinct neighboring populations (the Jívaro, the Huancas and the Cajamarca). By assessing mitochondrial, Y-chromosomal and autosomal diversity in the region, we explore questions that have emerged from archaeological and historical studies of the regional culture (s). These studies have shown, among others, that Chachapoyas was a crossroads for Coast-Andes-Amazon interactions since very early times. In this study, we examine the following questions: 1) was there pre-Hispanic genetic population substructure in the Chachapoyas sample? 2) did the Spanish conquest cause a more severe population decline on Chachapoyan males than on females? 3) can we detect different patterns of European gene flow in the Chachapoyas region? and, 4) did the demographic history in the Chachapoyas resemble the one from the Andean area? Despite cultural differences within the Chachapoyas region as shown by archaeological and ethnohistorical research, genetic markers show no significant evidence for past or current population substructure, although an Amazonian gene flow dynamic in the northern part of this territory is suggested. The data also indicates a bottleneck c. 25 generations ago that was more severe among males than females, as well as divergent population histories for populations in the Andean and Amazonian regions. In line with previous studies, we observe high genetic diversity in the Chachapoyas, despite the documented dramatic population declines. The diverse topography and great biodiversity of the northeastern Peruvian montane forests are potential contributing agents in shaping and maintaining the high genetic diversity in the Chachapoyas region.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244497PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774974PMC
March 2021

A roadmap to the safe practice of forensic medicine in the COVID-19 pandemic.

J Forensic Leg Med 2020 Nov 15;76:102036. Epub 2020 Oct 15.

University of Helsinki, Department of Forensic Medicine, Helsinki, Finland; National Institute for Health and Welfare, Forensic Medicine Unit, Finland.

The COVID-19 pandemic has forced forensic practitioners to consider how we perform our normal duties, especially when those duties involve humans. The potential for contracting the virus from working in close contact with living sufferers is high, and we have yet to fully determine the risk of infection from the deceased. In an attempt to support the community, the Journal of Forensic & Legal Medicine has drawn together three articles which underline the importance of continued forensic medical practice during the pandemic and highlight some factors to consider in a Roadmap towards safe practice. Our Roadmap has intentionally taken an international perspective and supports other work we have published in the Journal on our collective response to the COVID-19 crisis.
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http://dx.doi.org/10.1016/j.jflm.2020.102036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560269PMC
November 2020

A hybrid pipeline for reconstruction and analysis of viral genomes at multi-organ level.

Gigascience 2020 08;9(8)

Department of Virology, University of Helsinki, Haartmaninkatu 3, Helsinki, 00290, Finland.

Background: Advances in sequencing technologies have enabled the characterization of multiple microbial and host genomes, opening new frontiers of knowledge while kindling novel applications and research perspectives. Among these is the investigation of the viral communities residing in the human body and their impact on health and disease. To this end, the study of samples from multiple tissues is critical, yet, the complexity of such analysis calls for a dedicated pipeline. We provide an automatic and efficient pipeline for identification, assembly, and analysis of viral genomes that combines the DNA sequence data from multiple organs. TRACESPipe relies on cooperation among 3 modalities: compression-based prediction, sequence alignment, and de novo assembly. The pipeline is ultra-fast and provides, additionally, secure transmission and storage of sensitive data.

Findings: TRACESPipe performed outstandingly when tested on synthetic and ex vivo datasets, identifying and reconstructing all the viral genomes, including those with high levels of single-nucleotide polymorphisms. It also detected minimal levels of genomic variation between different organs.

Conclusions: TRACESPipe's unique ability to simultaneously process and analyze samples from different sources enables the evaluation of within-host variability. This opens up the possibility to investigate viral tissue tropism, evolution, fitness, and disease associations. Moreover, additional features such as DNA damage estimation and mitochondrial DNA reconstruction and analysis, as well as exogenous-source controls, expand the utility of this pipeline to other fields such as forensics and ancient DNA studies. TRACESPipe is released under GPLv3 and is available for free download at https://github.com/viromelab/tracespipe.
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http://dx.doi.org/10.1093/gigascience/giaa086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439602PMC
August 2020

The landscape of persistent human DNA viruses in femoral bone.

Forensic Sci Int Genet 2020 09 8;48:102353. Epub 2020 Jul 8.

Department of Forensic Medicine, University of Helsinki, Finland; Forensic Medicine Unit, Finnish Institute of Health and Welfare, Finland. Electronic address:

The imprints left by persistent DNA viruses in the tissues can testify to the changes driving virus evolution as well as provide clues on the provenance of modern and ancient humans. However, the history hidden in skeletal remains is practically unknown, as only parvovirus B19 and hepatitis B virus DNA have been detected in hard tissues so far. Here, we investigated the DNA prevalences of 38 viruses in femoral bone of recently deceased individuals. To this end, we used quantitative PCRs and a custom viral targeted enrichment followed by next-generation sequencing. The data was analyzed with a tailor-made bioinformatics pipeline. Our findings revealed bone to be a much richer source of persistent DNA viruses than earlier perceived, discovering ten additional ones, including several members of the herpes- and polyomavirus families, as well as human papillomavirus 31 and torque teno virus. Remarkably, many of the viruses found have oncogenic potential and/or may reactivate in the elderly and immunosuppressed individuals. Thus, their persistence warrants careful evaluation of their clinical significance and impact on bone biology. Our findings open new frontiers for the study of virus evolution from ancient relics as well as provide new tools for the investigation of human skeletal remains in forensic and archaeological contexts.
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http://dx.doi.org/10.1016/j.fsigen.2020.102353DOI Listing
September 2020

Buried in water, burdened by nature-Resilience carried the Iron Age people through Fimbulvinter.

PLoS One 2020 21;15(4):e0231787. Epub 2020 Apr 21.

Department of Cultures, Archaeology, University of Helsinki, Helsinki, Finland.

Levänluhta is a unique archaeological site with the remains of nearly a hundred Iron Age individuals found from a water burial in Ostrobothnia, Finland. The strongest climatic downturn of the Common Era, resembling the great Fimbulvinter in Norse mythology, hit these people during the 6th century AD. This study establishes chronological, dietary, and livelihood synthesis on this population based on stable carbon and nitrogen isotopic and radiocarbon analyses on human remains, supported by multidisciplinary evidence. Extraordinarily broad stable isotopic distribution is observed, indicating three subgroups with distinct dietary habits spanning four centuries. This emphasizes the versatile livelihoods practiced at this boundary of marine, freshwater, and terrestrial ecosystems. While the impact of the prolonged cold darkness of the 6th century was devastating for European communities relying on cultivation, the broad range of livelihoods provided resilience for the Levänluhta people to overcome the abrupt climatic decline.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231787PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7173937PMC
July 2020

Human mitochondrial DNA lineages in Iron-Age Fennoscandia suggest incipient admixture and eastern introduction of farming-related maternal ancestry.

Sci Rep 2019 11 15;9(1):16883. Epub 2019 Nov 15.

Department of Biosciences, University of Helsinki, Helsinki, Finland.

Human ancient DNA studies have revealed high mobility in Europe's past, and have helped to decode the human history on the Eurasian continent. Northeastern Europe, especially north of the Baltic Sea, however, remains less well understood largely due to the lack of preserved human remains. Finland, with a divergent population history from most of Europe, offers a unique perspective to hunter-gatherer way of life, but thus far genetic information on prehistoric human groups in Finland is nearly absent. Here we report 103 complete ancient mitochondrial genomes from human remains dated to AD 300-1800, and explore mtDNA diversity associated with hunter-gatherers and Neolithic farmers. The results indicate largely unadmixed mtDNA pools of differing ancestries from Iron-Age on, suggesting a rather late genetic shift from hunter-gatherers towards farmers in North-East Europe. Furthermore, the data suggest eastern introduction of farmer-related haplogroups into Finland, contradicting contemporary genetic patterns in Finns.
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http://dx.doi.org/10.1038/s41598-019-51045-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858343PMC
November 2019

European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death.

Eur J Hum Genet 2019 12 24;27(12):1763-1773. Epub 2019 Jun 24.

Section Community Genetics, Department of Clinical Genetics and Amsterdam Public Health research institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Sudden cardiac death (SCD) accounts for 10-20% of total mortality, i.e., one in five individuals will eventually die suddenly. Given the substantial genetic component of SCD in younger cases, postmortem genetic testing may be particularly useful in elucidating etiological factors in the cause of death in this subset. The identification of genes responsible for inherited cardiac diseases have led to the organization of cardiogenetic consultations in many countries worldwide. Expert recommendations are available, emphasizing the importance of genetic testing and appropriate information provision of affected individuals, as well as their relatives. However, the context of postmortem genetic testing raises some particular ethical, legal, and practical (including economic or financial) challenges. The Public and Professional Policy Committee of the European Society of Human Genetics (ESHG), together with international experts, developed recommendations on management of SCD after a workshop sponsored by the Brocher Foundation and ESHG in November 2016. These recommendations have been endorsed by the ESHG Board, the European Council of Legal Medicine, the European Society of Cardiology working group on myocardial and pericardial diseases, the ERN GUARD-HEART, and the Association for European Cardiovascular Pathology. They emphasize the importance of increasing the proportion of both medical and medicolegal autopsies and educating the professionals. Multidisciplinary collaboration is of utmost importance. Public funding should be allocated to reach these goals and allow public health evaluation.
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http://dx.doi.org/10.1038/s41431-019-0445-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6870982PMC
December 2019

The population history of northeastern Siberia since the Pleistocene.

Nature 2019 06 5;570(7760):182-188. Epub 2019 Jun 5.

Institute of Archaeology and Ethnography of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia.

Northeastern Siberia has been inhabited by humans for more than 40,000 years but its deep population history remains poorly understood. Here we investigate the late Pleistocene population history of northeastern Siberia through analyses of 34 newly recovered ancient genomes that date to between 31,000 and 600 years ago. We document complex population dynamics during this period, including at least three major migration events: an initial peopling by a previously unknown Palaeolithic population of 'Ancient North Siberians' who are distantly related to early West Eurasian hunter-gatherers; the arrival of East Asian-related peoples, which gave rise to 'Ancient Palaeo-Siberians' who are closely related to contemporary communities from far-northeastern Siberia (such as the Koryaks), as well as Native Americans; and a Holocene migration of other East Asian-related peoples, who we name 'Neo-Siberians', and from whom many contemporary Siberians are descended. Each of these population expansions largely replaced the earlier inhabitants, and ultimately generated the mosaic genetic make-up of contemporary peoples who inhabit a vast area across northern Eurasia and the Americas.
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http://dx.doi.org/10.1038/s41586-019-1279-zDOI Listing
June 2019

A genome-wide association study of tramadol metabolism from post-mortem samples.

Pharmacogenomics J 2020 02 11;20(1):94-103. Epub 2019 Apr 11.

Center for Human Identification, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX, 76107, USA.

Phase I tramadol metabolism requires cytochrome p450 family 2, subfamily D, polypeptide 6 (CYP2D6) to form O-desmethyltramadol (M1). CYP2D6 genetic variants may infer metabolizer phenotype; however, drug ADME (absorption, distribution, metabolism, and excretion) and response depend on protein pathway(s), not CYP2D6 alone. There is a paucity of data regarding the contribution of trans-acting proteins to idiosyncratic phenotypes following drug exposure. A genome-wide association study identified five markers (rs79983226/kgp11274252, rs9384825, rs62435418/kgp10370907, rs72732317/kgp3743668, and rs184199168/exm1592932) associated with the conversion of tramadol to M1 (M1:T). These SNPs reside within five genes previously implicated with adverse reactions. Analysis of accompanying toxicological meta-data revealed a significant positive linear relationship between M1:T and degree of sample polypharmacy. Taken together, these data identify candidate loci for potential clinical inferences of phenotype following exposure to tramadol and highlight sample polypharmacy as a possible diagnostic covariate in post-mortem genetic studies.
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http://dx.doi.org/10.1038/s41397-019-0088-yDOI Listing
February 2020

A pathway-driven predictive model of tramadol pharmacogenetics.

Eur J Hum Genet 2019 07 1;27(7):1143-1156. Epub 2019 Mar 1.

Graduate School of Biomedical Sciences, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX, 76107, USA.

Predicting metabolizer phenotype (MP) is typically performed using data from a single gene. Cytochrome p450 family 2 subfamily D polypeptide 6 (CYP2D6) is considered the primary gene for predicting MP in reference to approximately 30% of marketed drugs and endogenous toxins. CYP2D6 predictions have proven clinically effective but also have well-documented inaccuracies due to relatively high genotype-phenotype discordance in certain populations. Herein, a pathway-driven predictive model employs genetic data from uridine diphosphate glucuronosyltransferase, family 1, polypeptide B7 (UGT2B7), adenosine triphosphate (ATP)-binding cassette, subfamily B, number 1 (ABCB1), opioid receptor mu 1 (OPRM1), and catechol-O-methyltransferase (COMT) to predict the tramadol to primary metabolite ratio (T:M1) and the resulting toxicologically inferred MP (t-MP). These data were then combined with CYP2D6 data to evaluate performance of a fully combinatorial model relative to CYP2D6 alone. These data identify UGT2B7 as a potentially significant explanatory marker for T:M1 variability in a population of tramadol-exposed individuals of Finnish ancestry. Supervised machine learning and feature selection were used to demonstrate that a set of 16 loci from 5 genes can predict t-MP with over 90% accuracy, depending on t-MP category and algorithm, which was significantly greater than predictions made by CYP2D6 alone.
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http://dx.doi.org/10.1038/s41431-019-0369-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777452PMC
July 2019

Supervised Classification of CYP2D6 Genotype and Metabolizer Phenotype With Postmortem Tramadol-Exposed Finns.

Am J Forensic Med Pathol 2019 Mar;40(1):8-18

Department of Forensic Medicine, University of Helsinki, Helsinki, Finland.

Cytochrome p450 family 2, subfamily D, polypeptide 6 (CYP2D6) may be used to infer the metabolizer phenotype (MP) of an individual as poor, intermediate, extensive/normal, or ultrarapid. Metabolizer phenotypes may suggest idiosyncratic drug responses as contributing factors to cause and/or manner of death in postmortem investigations. Application of CYP2D6 has used long-range amplification of the locus and restriction enzyme digestion to detect single-nucleotide variants (SNVs) associated with MPs. This process can be cumbersome and requires knowledge of genotype phase. Phase may be achieved using long-read DNA sequencing and/or computational methods; however, both can be error prone, which may make it difficult or impractical for implementation into medicolegal practice. CYP2D6 was interrogated in postmortem autopsied Finns using supervised machine learning and feature selection to identify SNVs indicative of MP and/or rate of tramadol O-demethylation (T:M1). A subset of 18 CYP2D6 SNVs could predict MP/T:M1 with up to 96.3% accuracy given phased data. These data indicate that phase contributes to classification accuracy when using CYP2D6 data. Of these 18 SNVs, 3 are novel loci putatively associated with T:M1. These findings may enable design of small multiplexes for easy forensic application of MP prediction when cause and/or manner of death is unknown.
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http://dx.doi.org/10.1097/PAF.0000000000000447DOI Listing
March 2019

Ancient Fennoscandian genomes reveal origin and spread of Siberian ancestry in Europe.

Nat Commun 2018 11 27;9(1):5018. Epub 2018 Nov 27.

Department of Archaeogenetics, Max Planck Institute for the Science of Human History, 07745, Jena, Germany.

European population history has been shaped by migrations of people, and their subsequent admixture. Recently, ancient DNA has brought new insights into European migration events linked to the advent of agriculture, and possibly to the spread of Indo-European languages. However, little is known about the ancient population history of north-eastern Europe, in particular about populations speaking Uralic languages, such as Finns and Saami. Here we analyse ancient genomic data from 11 individuals from Finland and north-western Russia. We show that the genetic makeup of northern Europe was shaped by migrations from Siberia that began at least 3500 years ago. This Siberian ancestry was subsequently admixed into many modern populations in the region, particularly into populations speaking Uralic languages today. Additionally, we show that ancestors of modern Saami inhabited a larger territory during the Iron Age, which adds to the historical and linguistic information about the population history of Finland.
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http://dx.doi.org/10.1038/s41467-018-07483-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258758PMC
November 2018

Ancient Fennoscandian genomes reveal origin and spread of Siberian ancestry in Europe.

Nat Commun 2018 11 27;9(1):5018. Epub 2018 Nov 27.

Department of Archaeogenetics, Max Planck Institute for the Science of Human History, 07745, Jena, Germany.

European population history has been shaped by migrations of people, and their subsequent admixture. Recently, ancient DNA has brought new insights into European migration events linked to the advent of agriculture, and possibly to the spread of Indo-European languages. However, little is known about the ancient population history of north-eastern Europe, in particular about populations speaking Uralic languages, such as Finns and Saami. Here we analyse ancient genomic data from 11 individuals from Finland and north-western Russia. We show that the genetic makeup of northern Europe was shaped by migrations from Siberia that began at least 3500 years ago. This Siberian ancestry was subsequently admixed into many modern populations in the region, particularly into populations speaking Uralic languages today. Additionally, we show that ancestors of modern Saami inhabited a larger territory during the Iron Age, which adds to the historical and linguistic information about the population history of Finland.
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http://dx.doi.org/10.1038/s41467-018-07483-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258758PMC
November 2018

Monocytes accumulate in the airways of children with fatal asthma.

Clin Exp Allergy 2018 12 16;48(12):1631-1639. Epub 2018 Oct 16.

Department of Pathology and Centre for Immune Regulation, Oslo University Hospital-Rikshospitalet and University of Oslo, Oslo, Norway.

Background: Activated T helper type 2 (Th2) cells are believed to play a pivotal role in allergic airway inflammation, but which cells attract and activate Th2 cells locally have not been fully determined. Recently, it was shown in an experimental human model of allergic rhinitis (AR) that activated monocytes rapidly accumulate in the nasal mucosa after local allergen challenge, where they promote recruitment of Th2 cells and eosinophils.

Objective: To investigate whether monocytes are recruited to the lungs in paediatric asthma.

Methods: Tissue samples obtained from children and adolescents with fatal asthma attack (n = 12), age-matched non-atopic controls (n = 9) and allergen-challenged AR patients (n = 8) were subjected to in situ immunostaining.

Results: Monocytes, identified as CD68+S100A8/A9+ cells, were significantly increased in the lower airway mucosa and in the alveoli of fatal asthma patients compared with control individuals. Interestingly, cellular aggregates containing CD68+S100A8/A9+ monocytes obstructing the lumen of bronchioles were found in asthmatics (8 out of 12) but not in controls. Analysing tissue specimens from challenged AR patients, we confirmed that co-staining with CD68 and S100A8/A9 was a valid method to identify recently recruited monocytes. We also showed that the vast majority of accumulating monocytes both in the lungs and in the nasal mucosa expressed matrix metalloproteinase 10, suggesting that this protein may be involved in their migration within the tissue.

Conclusions And Clinical Relevance: Monocytes accumulated in the lungs of children and adolescents with fatal asthma attack. This finding strongly suggests that monocytes are directly involved in the immunopathology of asthma and that these pro-inflammatory cells are potential targets for therapy.
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http://dx.doi.org/10.1111/cea.13265DOI Listing
December 2018

Monocytes accumulate in the airways of children with fatal asthma.

Clin Exp Allergy 2018 12 16;48(12):1631-1639. Epub 2018 Oct 16.

Department of Pathology and Centre for Immune Regulation, Oslo University Hospital-Rikshospitalet and University of Oslo, Oslo, Norway.

Background: Activated T helper type 2 (Th2) cells are believed to play a pivotal role in allergic airway inflammation, but which cells attract and activate Th2 cells locally have not been fully determined. Recently, it was shown in an experimental human model of allergic rhinitis (AR) that activated monocytes rapidly accumulate in the nasal mucosa after local allergen challenge, where they promote recruitment of Th2 cells and eosinophils.

Objective: To investigate whether monocytes are recruited to the lungs in paediatric asthma.

Methods: Tissue samples obtained from children and adolescents with fatal asthma attack (n = 12), age-matched non-atopic controls (n = 9) and allergen-challenged AR patients (n = 8) were subjected to in situ immunostaining.

Results: Monocytes, identified as CD68+S100A8/A9+ cells, were significantly increased in the lower airway mucosa and in the alveoli of fatal asthma patients compared with control individuals. Interestingly, cellular aggregates containing CD68+S100A8/A9+ monocytes obstructing the lumen of bronchioles were found in asthmatics (8 out of 12) but not in controls. Analysing tissue specimens from challenged AR patients, we confirmed that co-staining with CD68 and S100A8/A9 was a valid method to identify recently recruited monocytes. We also showed that the vast majority of accumulating monocytes both in the lungs and in the nasal mucosa expressed matrix metalloproteinase 10, suggesting that this protein may be involved in their migration within the tissue.

Conclusions And Clinical Relevance: Monocytes accumulated in the lungs of children and adolescents with fatal asthma attack. This finding strongly suggests that monocytes are directly involved in the immunopathology of asthma and that these pro-inflammatory cells are potential targets for therapy.
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http://dx.doi.org/10.1111/cea.13265DOI Listing
December 2018

Challenges in investigation of diabetes-related aviation fatalities-an analysis of 1491 subsequent aviation fatalities in USA during 2011-2016.

Int J Legal Med 2018 Nov 4;132(6):1713-1718. Epub 2018 Jul 4.

Department of Forensic Medicine, University of Helsinki, Helsinki, Finland.

Diabetes mellitus (DM) could cause pilot incapacitation and result in aviation fatalities. The mechanisms could be directly as a consequence of acute hypoglycemia/subacute diabetic ketoacidosis (DKA) or indirectly as an acute cardiovascular event by contributing to the development of atherosclerosis in coronary or carotid and cerebral arteries. In this study, DM-related fatal flight accidents in the US National Transport Bureau's database between years 2011-2016 were analyzed with special emphasis on postmortem (PM) glucose levels and correlation of toxicological reports with anamnestic information on DM. Additionally, autopsy results on coronary arteries were reviewed. In 43 out of 1491 (~ 3%) fatal accidents pilots had DM. Postmortem glucose or glycated hemoglobin percentage (Hb1Ac) was measured in 12 of the 43 cases; while antidiabetic medication was found in 14 of the cases (only two of the cases had both glucose measurements and medication). With the increasing prevalence of DM, a possibility of pilot incapacitation due to DM or complications of DM should be actively studied, even if no anamnestic information of DM was available. While PM hypoglycemia is difficult to assess, we propose a systematic investigation based on measurement of glucose, Hb1Ac%, and ketone bodies, and documentation of atherosclerotic lesions in major arteries to identify or rule out DM as a cause of pilot incapacitation.
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http://dx.doi.org/10.1007/s00414-018-1879-4DOI Listing
November 2018

Duty of Notification and Aviation Safety-A Study of Fatal Aviation Accidents in the United States in 2015.

Int J Environ Res Public Health 2018 06 13;15(6). Epub 2018 Jun 13.

Occupational and Aviation Medicine, University of Otago, 6242 Wellington, New Zealand.

After the Germanwings accident, the French Safety Investigation Authority (BEA) recommended that the World Health Organization (WHO) and European Community (EC) develop clear rules for the duty of notification process. Aeromedical practitioners (AMEs) face a dilemma when considering the duty of notification and conflicts between pilot privacy and public and third-party safety. When balancing accountability, knowledge of the duty of notification process, legislation and the clarification of a doctor’s own set of values should be assessed a priori. Relatively little is known of the magnitude of this problem in aviation safety. To address this, the National Transportation Safety Board (NTSB) database was searched to identify fatal accidents during 2015 in the United States in which a deceased pilot used a prescribed medication or had a disease that potentially reduced pilot performance and was not reported to the AME. Altogether, 202 finalized accident reports with toxicology were available from (the year) 2015. In 5% (10/202) of these reports, the pilot had either a medication or a disease not reported to an AME which according to the accident investigation was causal to the fatal accident. In addition, the various approaches to duty of notification in aviation in New Zealand, Finland and Norway are discussed. The process of notification of authorities without a pilot’s express permission needs to be carried out by using a guidance protocol that works within legislation and professional responsibilities to address the pilot and the public, as well as the healthcare provider. Professional guidance defining this duty of notification is urgently needed.
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http://dx.doi.org/10.3390/ijerph15061258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025115PMC
June 2018

Exploring the 1000 Genomes Project haplotype reporting for the CYP2D6 pharmacogene.

Int J Legal Med 2019 05 2;133(3):807-810. Epub 2018 Jun 2.

Center for Human Identification, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX, 76107, USA.

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http://dx.doi.org/10.1007/s00414-018-1874-9DOI Listing
May 2019

Exploring the 1000 Genomes Project haplotype reporting for the CYP2D6 pharmacogene.

Int J Legal Med 2019 05 2;133(3):807-810. Epub 2018 Jun 2.

Center for Human Identification, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX, 76107, USA.

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http://dx.doi.org/10.1007/s00414-018-1874-9DOI Listing
May 2019

Exploring the 1000 Genomes Project haplotype reporting for the CYP2D6 pharmacogene.

Int J Legal Med 2019 05 2;133(3):807-810. Epub 2018 Jun 2.

Center for Human Identification, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX, 76107, USA.

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http://dx.doi.org/10.1007/s00414-018-1874-9DOI Listing
May 2019

Improved Y-STR typing for disaster victim identification, missing persons investigations, and historical human skeletal remains.

Int J Legal Med 2018 Nov 23;132(6):1545-1553. Epub 2018 Feb 23.

Center for Human Identification, University of North Texas Health Science Center, Fort Worth, TX, USA.

Bones are a valuable source of DNA in forensic, anthropological, and archaeological investigations. There are a number of scenarios in which the only samples available for testing are highly degraded and/or skeletonized. Often it is necessary to perform more than one type of marker analysis on such samples in order to compile sufficient data for identification. Lineage markers, such as Y-STRs and mitochondrial DNA (mtDNA), represent important systems to complement autosomal DNA markers and anthropological metadata in making associations between unidentified remains and living relatives or for characterization of the remains for historical and archaeological studies. In this comparative study, Y-STR typing with both Yfiler™ and Yfiler™ Plus (Thermo Fisher Scientific, Waltham, MA, USA) was performed on a variety of human skeletal remains, including samples from the American Civil War (1861-1865), the late nineteenth century gold rush era in Deadwood, SD, USA (1874-1877), the Seven Years' War (1756-1763), a seventeenth-century archaeological site in Raspenava, Bohemia (Czech Republic), and World War II (1939-1945). The skeletal remains used for this study were recovered from a wide range of environmental conditions and were extracted using several common methods. Regardless of the DNA extraction method used and the age/condition of the remains, 22 out of 24 bone samples yielded a greater number of alleles using the Yfiler™ Plus kit compared to the Yfiler™ kit using the same quantity of input DNA. There was no discernable correlation with the degradation index values for these samples. Overall, the efficacy of the Yfiler™ Plus assay was demonstrated on degraded DNA from skeletal remains. Yfiler™ Plus increases the discriminatory power over the previous generation multiplex due to the larger set of Y-STR markers available for analysis and buffer modifications with the newer version kit. Increased haplotype resolution is provided to infer or refute putative genetic relationships.
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http://dx.doi.org/10.1007/s00414-018-1794-8DOI Listing
November 2018

Predicted activity of UGT2B7, ABCB1, OPRM1, and COMT using full-gene haplotypes and their association with the CYP2D6-inferred metabolizer phenotype.

Forensic Sci Int Genet 2018 03 26;33:48-58. Epub 2017 Nov 26.

Center for Human Identification, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, USA; Graduate School of Biomedical Sciences, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, USA; Center of Excellence in Genomic Medicine (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia.

The pharmacogene, CYP2D6, is commonly used to infer metabolizer phenotype of many marketed drugs and endogenous toxins in ante- and post-mortem patients but only represents the efficiency of phase 1 metabolism. Downstream metabolic enzymes encoded by UGT2B7, ABCB1, OPRM1, and COMT also have been implicated in variable individual response to drugs due to their activity at different stages of the tramadol ADME (absorption, distribution, metabolism, and excretion) process. While commonly studied as single genes using targeted genotyping approaches, a more comprehensive tramadol metabolism profile has not been evaluated. 1000 Genomes Project data for UGT2B7, ABCB1, OPRM1, and COMT were used to characterize full-gene haplotypes and their effect on protein function using in-house excel-based workbooks, PopART, and TreeView. Population genetic summary statistics and intergenic analyses associated these haplotypes with full-gene CYP2D6-inferred metabolizer phenotype. The findings suggest that UGT2B7, ABCB1, OPRM1, and COMT may contribute to predicted metabolizer phenotype as opposed to relying solely on CYP2D6.
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http://dx.doi.org/10.1016/j.fsigen.2017.11.012DOI Listing
March 2018

Full-gene haplotypes refine CYP2D6 metabolizer phenotype inferences.

Int J Legal Med 2018 Jul 26;132(4):1007-1024. Epub 2017 Oct 26.

Center for Human Identification, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., CBH-250, Fort Worth, TX, 76107, USA.

CYP2D6 is a critical pharmacogenetic target, and polymorphisms in the gene region are commonly used to infer enzyme activity score and predict resulting metabolizer phenotype: poor, intermediate, extensive/normal, or ultrarapid which can be useful in determining cause and/or manner of death in some autopsies. Current genotyping approaches are incapable of identifying novel and/or rare variants, so CYP2D6 star allele definitions are limited to polymorphisms known a priori. While useful for most predictions, recent studies using massively parallel sequencing data have identified additional polymorphisms in CYP2D6 that are predicted to alter enzyme function but are not considered in current star allele nomenclature. The 1000 Genomes Project data were used to produce full-gene haplotypes, describe their distribution in super-populations, and predict enzyme activity scores. Full-gene haplotypes generated lower activity scores than current approaches due to inclusion of additional damaging polymorphisms in the star allele. These findings are critical for clinical implementation of metabolizer phenotype prediction because a fraction of the population may be incorrectly considered normal metabolizers but actually may be poor or intermediate metabolizers.
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http://dx.doi.org/10.1007/s00414-017-1709-0DOI Listing
July 2018

Population resequencing of European mitochondrial genomes highlights sex-bias in Bronze Age demographic expansions.

Sci Rep 2017 09 21;7(1):12086. Epub 2017 Sep 21.

Department of Genetics & Genome Biology, University of Leicester, Leicester, UK.

Interpretations of genetic data concerning the prehistory of Europe have long been a subject of great debate, but increasing amounts of ancient and modern DNA data are now providing new and more informative evidence. Y-chromosome resequencing studies in Europe have highlighted the prevalence of recent expansions of male lineages, and focused interest on the Bronze Age as a period of cultural and demographic change. These findings contrast with phylogeographic studies based on mitochondrial DNA (mtDNA), which have been interpreted as supporting expansions from glacial refugia. Here we have undertaken a population-based resequencing of complete mitochondrial genomes in Europe and the Middle East, in 340 samples from 17 populations for which Y-chromosome sequence data are also available. Demographic reconstructions show no signal of Bronze Age expansion, but evidence of Paleolithic expansions in all populations except the Saami, and with an absence of detectable geographical pattern. In agreement with previous inference from modern and ancient DNA data, the unbiased comparison between the mtDNA and Y-chromosome population datasets emphasizes the sex-biased nature of recent demographic transitions in Europe.
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http://dx.doi.org/10.1038/s41598-017-11307-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608872PMC
September 2017

FANTOM5 CAGE profiles of human and mouse samples.

Sci Data 2017 08 29;4:170112. Epub 2017 Aug 29.

Scottish Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK.

In the FANTOM5 project, transcription initiation events across the human and mouse genomes were mapped at a single base-pair resolution and their frequencies were monitored by CAGE (Cap Analysis of Gene Expression) coupled with single-molecule sequencing. Approximately three thousands of samples, consisting of a variety of primary cells, tissues, cell lines, and time series samples during cell activation and development, were subjected to a uniform pipeline of CAGE data production. The analysis pipeline started by measuring RNA extracts to assess their quality, and continued to CAGE library production by using a robotic or a manual workflow, single molecule sequencing, and computational processing to generate frequencies of transcription initiation. Resulting data represents the consequence of transcriptional regulation in each analyzed state of mammalian cells. Non-overlapping peaks over the CAGE profiles, approximately 200,000 and 150,000 peaks for the human and mouse genomes, were identified and annotated to provide precise location of known promoters as well as novel ones, and to quantify their activities.
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http://dx.doi.org/10.1038/sdata.2017.112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5574368PMC
August 2017

Attention-Deficit/Hyperactivity Disorder and Fatal Accidents in Aviation Medicine.

Aerosp Med Hum Perform 2017 Sep;88(9):871-875

Background: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with symptoms of inattention and/or hyperactivity-impulsivity that interfere with functioning and/or development. ADHD occurs in about 2.5% of adults. ADHD can be an excluding medical condition among pilots due to the risk of attentional degradation and therefore impact on flight safety. Diagnosis of ADHD is complex, which complicates aeromedical assessment. This study highlights fatal accident cases among pilots with ADHD and discusses protocols to detect its presence to help to assess its importance to flight safety.

Methods: To identify fatal accidents in aviation (including airplanes, helicopters, balloons, and gliders) in the United States between the years 2000 to 2015, the National Transportation Safety Board (NTSB) database was searched with the terms ADHD, attention deficit hyperactivity disorder, and attention deficit disorder (ADD).

Results: The NTSB database search for fatal aviation accidents possibly associated with ADHD yielded four accident cases of interest in the United States [4/4894 (0.08%)]. Two of the pilots had ADHD diagnosed by a doctor, one was reported by a family member, and one by a flight instructor. An additional five cases were identified searching for ADD [5/4894 (0.1%)]. Altogether, combined ADHD and ADD cases yielded nine accident cases of interest (0.18%).

Discussion: It is generally accepted by aviation regulatory authorities that ADHD is a disqualifying neurological condition. Yet FAA and CASA provide specific protocols for tailor-made pilot assessment. Accurate evaluation of ADHD is essential because of its potential negative impact on aviation safety.Laukkala T, Bor R, Budowle B, Sajantila A, Navathe P, Sainio M, Vuorio A. Attention-deficit/hyperactivity disorder and fatal accidents in aviation medicine. Aerosp Med Hum Perform. 2017; 88(9):871-875.
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http://dx.doi.org/10.3357/AMHP.4919.2017DOI Listing
September 2017
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