Publications

@article{Sammeth2023,

title = {OpenDSU: digital sovereignty in PharmaLedger},

author = {Michael Sammeth and Nicu-Cosmin Ursache and Sînică Alboaie},

doi = {10.3389/fbloc.2023.1126978},

issn = {2624-7852},

year  = {2023},

date = {2023-06-15},

urldate = {2023-06-15},

journal = {Front. Blockchain},

volume = {6},

publisher = {Frontiers Media SA},

abstract = {Introduction: Distributed ledger networks, chiefly those based on blockchain technologies, currently are heralding a next-generation of computer systems that aims to suit modern users’ demands. Over the recent years, several technologies for blockchains, off-chaining strategies, as well as decentralised and respectively self-sovereign identity systems have shot up so fast that standardisation of the protocols is lagging behind, severely hampering the interoperability of different approaches. Moreover, most of the currently available solutions for distributed ledgers focus on either home users or enterprise use case scenarios, failing to provide integrative solutions addressing the needs of both.Methods: Herein, we introduce the OpenDSU platform that allows to interoperate generic blockchain technologies, organised–and possibly cascaded in a hierarchical fashion–in domains. To achieve this flexibility, we seamlessly integrated a set of well conceived components that orchestrate off-chain data and provide granularly resolved and cryptographically secure access levels, intrinsically nested with sovereign identities across the different domains. The source code and extensive documentation of all OpenDSU components described herein are publicly available under the MIT open-source licence at https://opendsu.com.Results: Employing our platform to PharmaLedger, an inter-European network for the standardisation of data handling in the pharmaceutical industry and in healthcare, we demonstrate that OpenDSU can cope with generic demands of heterogeneous use cases in both, performance and handling substantially different business policies.Discussion: Importantly, whereas available solutions commonly require a pre-defined and fixed set of components, no such vendor lock-in restrictions on the blockchain technology or identity system exist in OpenDSU, making systems built on it flexibly adaptable to new standards evolving in the future.},

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@article{pmid36583938,

title = {Accuracy and Systematic Biases of Heart Rate Measurements by Consumer-Grade Fitness Trackers in Postoperative Patients: Prospective Clinical Trial},

author = {Philipp Helmer and Sebastian Hottenrott and Philipp Rodemers and Robert Leppich and Maja Helwich and Rüdiger Pryss and Peter Kranke and Patrick Meybohm and Bernd E Winkler and Michael Sammeth},

doi = {10.2196/42359},

issn = {1438-8871},

year  = {2022},

date = {2022-12-01},

urldate = {2022-12-01},

journal = {J Med Internet Res},

volume = {24},

number = {12},

pages = {e42359},

abstract = {BACKGROUND: Over the recent years, technological advances of wrist-worn fitness trackers heralded a new era in the continuous monitoring of vital signs. So far, these devices have primarily been used for sports.nnOBJECTIVE: However, for using these technologies in health care, further validations of the measurement accuracy in hospitalized patients are essential but lacking to date.nnMETHODS: We conducted a prospective validation study with 201 patients after moderate to major surgery in a controlled setting to benchmark the accuracy of heart rate measurements in 4 consumer-grade fitness trackers (Apple Watch 7, Garmin Fenix 6 Pro, Withings ScanWatch, and Fitbit Sense) against the clinical gold standard (electrocardiography).nnRESULTS: All devices exhibited high correlation (r≥0.95; P<.001) and concordance (r≥0.94) coefficients, with a relative error as low as mean absolute percentage error <5% based on 1630 valid measurements. We identified confounders significantly biasing the measurement accuracy, although not at clinically relevant levels (mean absolute error<5 beats per minute).nnCONCLUSIONS: Consumer-grade fitness trackers appear promising in hospitalized patients for monitoring heart rate.nnTRIAL REGISTRATION: ClinicalTrials.gov NCT05418881; https://www.clinicaltrials.gov/ct2/show/NCT05418881.},

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@article{pmid35956113,

title = {The Use of Non-Invasive Continuous Blood Pressure Measuring (ClearSight) during Central Neuraxial Anaesthesia for Caesarean Section-A Retrospective Validation Study},

author = {Philipp Helmer and Daniel Helf and Michael Sammeth and Bernd Winkler and Sebastian Hottenrott and Patrick Meybohm and Peter Kranke},

doi = {10.3390/jcm11154498},

issn = {2077-0383},

year  = {2022},

date = {2022-08-01},

urldate = {2022-08-01},

journal = {J Clin Med},

volume = {11},

number = {15},

abstract = {The close monitoring of blood pressure during a caesarean section performed under central neuraxial anaesthesia should be the standard of safe anaesthesia. As classical oscillometric and invasive blood pressure measuring have intrinsic disadvantages, we investigated a novel, non-invasive technique for continuous blood pressure measuring.  In this monocentric, retrospective data analysis, the reliability of continuous non-invasive blood pressure measuring using ClearSight (Edwards Lifesciences Corporation) is validated in 31 women undergoing central neuraxial anaesthesia for caesarean section. In addition, patients and professionals evaluated ClearSight through questioning.  139 measurements from 11 patients were included in the final analysis. Employing Bland-Altman analyses, we identified a bias of -10.8 mmHg for systolic, of -0.45 mmHg for diastolic and of +0.68 mmHg for mean arterial blood pressure measurements. Pooling all paired measurements resulted in a Pearson correlation coefficient of 0.7 for systolic, of 0.67 for diastolic and of 0.75 for mean arterial blood pressure. Compensating the interindividual differences in linear regressions of the paired measurements provided improved correlation coefficients of 0.73 for systolic, of 0.9 for diastolic and of 0.89 for mean arterial blood pressure measurements.  Diastolic and mean arterial blood pressure are within an acceptable range of deviation from the reference method, according to the Association for the Advancement of Medical Instrumentation (AAMI) in the patient collective under study. Both patients and professionals prefer ClearSight to oscillometric blood pressure measurement in regard of comfort and handling.},

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}

@article{pmid33479356,

title = {Analysis of ovarian transcriptomes reveals thousands of novel genes in the insect vector Rhodnius prolixus},

author = {Vitor Lima Coelho and Tarcísio Fontenele de Brito and Ingrid Alexandre de Abreu Brito and Maira Arruda Cardoso and Mateus Antonio Berni and Helena Maria Marcolla Araujo and Michael Sammeth and Attilio Pane},

doi = {10.1038/s41598-021-81387-1},

issn = {2045-2322},

year  = {2021},

date = {2021-01-01},

urldate = {2021-01-01},

journal = {Sci Rep},

volume = {11},

number = {1},

pages = {1918},

abstract = {Rhodnius prolixus is a Triatominae insect species and a primary vector of Chagas disease. The genome of R. prolixus has been recently sequenced and partially assembled, but few transcriptome analyses have been performed to date. In this study, we describe the stage-specific transcriptomes obtained from previtellogenic stages of oogenesis and from mature eggs. By analyzing ~ 228 million paired-end RNA-Seq reads, we significantly improved the current genome annotations for 9206 genes. We provide extended 5' and 3' UTRs, complete Open Reading Frames, and alternative transcript variants. Strikingly, using a combination of genome-guided and de novo transcriptome assembly we found more than two thousand novel genes, thus increasing the number of genes in R. prolixus from 15,738 to 17,864. We used the improved transcriptome to investigate stage-specific gene expression profiles during R. prolixus oogenesis. Our data reveal that 11,127 genes are expressed in the early previtellogenic stage of oogenesis and their transcripts are deposited in the developing egg including key factors regulating germline development, genome integrity, and the maternal-zygotic transition. In addition, GO term analyses show that transcripts encoding components of the steroid hormone receptor pathway, cytoskeleton, and intracellular signaling are abundant in the mature eggs, where they likely control early embryonic development upon fertilization. Our results significantly improve the R. prolixus genome and transcriptome and provide novel insight into oogenesis and early embryogenesis in this medically relevant insect.},

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@article{pmid30552977,

title = {Characterization of HPV integration, viral gene expression and E6E7 alternative transcripts by RNA-Seq: A descriptive study in invasive cervical cancer},

author = {Ayslan C Brant and Albert N Menezes and Shayany P Felix and Liz M de Almeida and Michael Sammeth and Miguel A M Moreira},

doi = {10.1016/j.ygeno.2018.12.008},

issn = {1089-8646},

year  = {2019},

date = {2019-12-01},

journal = {Genomics},

volume = {111},

number = {6},

pages = {1853--1861},

abstract = {Scarce data are available on the expression of papillomavirus genome and the frequency of alternatively spliced E6E7 mRNAs in invasive cervical cancer. We carried out a comprehensive characterization of HPV expression by RNA-Seq analysis in 22 invasive cervical cancer with HPV16 or HPV18, characterizing the presence of integrated/episomal viral DNA, the integration sites in human genome and the proportion of alternative splicing products of E6 and E7 genes. The expression patterns suggested the presence of episomal and/or integrated viral DNA, with integration detected in most tumors, frequently occurring within human genes in HPV18+ and in intergenic regions in HPV16+ tumors. Alternative splicing of E6E7 transcripts showed E6*I as the most frequent isoform for both viral types, followed by E6*II and E6/E7 (unspliced) transcripts in HPV16+, and by E6/E7 in HPV18+ tumors. Previously described E6*VI and E6*V transcript isoforms for HPV16, and E6*X for HPV18, were rare or not detected.},

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pubstate = {published},

tppubtype = {article}

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@article{pmid31616643,

title = {Echocardiographic Measurements in a Preclinical Model of Chronic Chagasic Cardiomyopathy in Dogs: Validation and Reproducibility},

author = {Eduardo B Carvalho and Isalira P R Ramos and Alvaro F S Nascimento and Guilherme V Brasil and Debora B Mello and Martin Oti and Michael Sammeth and Maria T Bahia and Antonio C Campos de Carvalho and Adriana B Carvalho},

doi = {10.3389/fcimb.2019.00332},

issn = {2235-2988},

year  = {2019},

date = {2019-01-01},

journal = {Front Cell Infect Microbiol},

volume = {9},

pages = {332},

abstract = { The failure to translate preclinical results to the clinical setting is the rule, not the exception. One reason that is frequently overlooked is whether the animal model reproduces distinctive features of human disease. Another is the reproducibility of the method used to measure treatment effects in preclinical studies. Left ventricular (LV) function improvement is the most common endpoint in preclinical cardiovascular disease studies, while echocardiography is the most frequently used method to evaluate LV function. In this work, we conducted a robust echocardiographic evaluation of LV size and function in dogs chronically infected by .  Echocardiography was performed blindly by two distinct observers in mongrel dogs before and between 6 and 9 months post infection. Parameters analyzed included end-systolic volume (ESV), end-diastolic volume (EDV), ejection fraction (EF), and fractional shortening (FS). We observed a significant LVEF and FS reduction in infected animals compared to controls, with no significant variation in volumes. However, the effect of chronic infection in systolic function was quite variable, with EF ranging from 17 to 66%. Using the cut-off value of EF ≤ 40%, established for dilated cardiomyopathy (DCM) in dogs, only 28% of the infected dogs were affected by the chronic infection.  The canine model of CCC mimics human disease, reproducing the percentage of individuals that develop heart failure during the chronic infection. It is thus mandatory to establish inclusion criteria in the experimental design of canine preclinical studies to account for the variable effect that chronic infection has on systolic function.},

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pubstate = {published},

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@article{pmid29868795,

title = {An automated method for detecting alternatively spliced protein domains},

author = {Vitor Coelho and Michael Sammeth},

doi = {10.1093/bioinformatics/bty425},

issn = {1367-4811},

year  = {2018},

date = {2018-11-01},

journal = {Bioinformatics},

volume = {34},

number = {22},

pages = {3809--3816},

abstract = {MOTIVATION: Alternative splicing (AS) has been demonstrated to play a role in shaping eukaryotic gene diversity at the transcriptional level. However, the impact of AS on the proteome is still controversial. Studies that seek to explore the effect of AS at the proteomic level are hampered by technical difficulties in the cumbersome process of casting forth and back between genome, transcriptome and proteome space coordinates, and the naïve prediction of protein domains in the presence of AS suffers many redundant sequence scans that emerge from constitutively spliced regions that are shared between alternative products of a gene.nnRESULTS: We developed the AstaFunk pipeline that computes for every generic transcriptome all domains that are altered by AS events in a systematic and efficient manner. In a nutshell, our method employs Viterbi dynamic programming, which guarantees to find all score-optimal hits of the domains under consideration, while complementary optimizations at different levels avoid redundant and other irrelevant computations. We evaluate AstaFunk qualitatively and quantitatively using RNAseq in well-studied genes with AS, and on large-scale employing entire transcriptomes. Our study confirms complementary reports that the effect of most AS events on the proteome seems to be rather limited, but our results also pinpoint several cases where AS could have a major impact on the function of a protein domain.nnAVAILABILITY AND IMPLEMENTATION: The JAVA implementation of AstaFunk is available as an open source project on http://astafunk.sammeth.net.nnSUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},

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@article{pmid30303955,

title = {Transcriptomic and functional analyses of the piRNA pathway in the Chagas disease vector Rhodnius prolixus},

author = {Tarcisio Brito and Alison Julio and Mateus Berni and Lisiane de Castro Poncio and Emerson Soares Bernardes and Helena Araujo and Michael Sammeth and Attilio Pane},

doi = {10.1371/journal.pntd.0006760},

issn = {1935-2735},

year  = {2018},

date = {2018-10-01},

journal = {PLoS Negl Trop Dis},

volume = {12},

number = {10},

pages = {e0006760},

abstract = {The piRNA pathway is a surveillance system that guarantees oogenesis and adult fertility in a range of animal species. The pathway is centered on PIWI clade Argonaute proteins and the associated small non-coding RNAs termed piRNAs. In this study, we set to investigate the evolutionary conservation of the piRNA pathway in the hemimetabolous insect Rhodnius prolixus. Our transcriptome profiling reveals that core components of the pathway are expressed during previtellogenic stages of oogenesis. Rhodnius' genome harbors four putative piwi orthologs. We show that Rp-piwi2, Rp-piwi3 and Rp-ago3, but not Rp-piwi1 transcripts are produced in the germline tissues and maternally deposited in the mature eggs. Consistent with a role in Rhodnius oogenesis, parental RNAi against the Rp-piwi2, Rp-piwi3 and Rp-ago3 results in severe egg laying and female adult fertility defects. Furthermore, we show that the reduction of the Rp-piwi2 levels by parental RNAi disrupts oogenesis by causing a dramatic loss of trophocytes, egg chamber degeneration and oogenesis arrest. Intriguingly, the putative Rp-Piwi2 protein features a polyglutamine tract at its N-terminal region, which is conserved in PIWI proteins encoded in the genome of other Triatomine species. Together with R. prolixus, these hematophagous insects are primary vectors of the Chagas disease. Thus, our data shed more light on the evolution of the piRNA pathway and provide a framework for the development of new control strategies for Chagas disease insect vectors.},

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pubstate = {published},

tppubtype = {article}

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@article{pmid29497070,

title = {Landscape of the spliced leader trans-splicing mechanism in Schistosoma mansoni},

author = {Mariana Boroni and Michael Sammeth and Sandra Grossi Gava and Natasha Andressa Nogueira Jorge and Andréa Mara Macedo and Carlos Renato Machado and Marina Moraes Mourão and Glória Regina Franco},

doi = {10.1038/s41598-018-22093-3},

issn = {2045-2322},

year  = {2018},

date = {2018-03-01},

journal = {Sci Rep},

volume = {8},

number = {1},

pages = {3877},

abstract = {Spliced leader dependent trans-splicing (SLTS) has been described as an important RNA regulatory process that occurs in different organisms, including the trematode Schistosoma mansoni. We identified more than seven thousand putative SLTS sites in the parasite, comprising genes with a wide spectrum of functional classes, which underlines the SLTS as a ubiquitous mechanism in the parasite. Also, SLTS gene expression levels span several orders of magnitude, showing that SLTS frequency is not determined by the expression level of the target gene, but by the presence of particular gene features facilitating or hindering the trans-splicing mechanism. Our in-depth investigation of SLTS events demonstrates widespread alternative trans-splicing (ATS) acceptor sites occurring in different regions along the entire gene body, highlighting another important role of SLTS generating alternative RNA isoforms in the parasite, besides the polycistron resolution. Particularly for introns where SLTS directly competes for the same acceptor substrate with cis-splicing, we identified for the first time additional and important features that might determine the type of splicing. Our study substantially extends the current knowledge of RNA processing by SLTS in S. mansoni, and provide basis for future studies on the trans-splicing mechanism in other eukaryotes.},

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@article{pmid29440659,

title = {The effects of death and post-mortem cold ischemia on human tissue transcriptomes},

author = {Pedro G Ferreira and Manuel Muñoz-Aguirre and Ferran Reverter and Caio P Sá Godinho and Abel Sousa and Alicia Amadoz and Reza Sodaei and Marta R Hidalgo and Dmitri Pervouchine and Jose Carbonell-Caballero and Ramil Nurtdinov and Alessandra Breschi and Raziel Amador and Patrícia Oliveira and Cankut Çubuk and João Curado and François Aguet and Carla Oliveira and Joaquin Dopazo and Michael Sammeth and Kristin G Ardlie and Roderic Guigó},

doi = {10.1038/s41467-017-02772-x},

issn = {2041-1723},

year  = {2018},

date = {2018-02-01},

journal = {Nat Commun},

volume = {9},

number = {1},

pages = {490},

abstract = {Post-mortem tissues samples are a key resource for investigating patterns of gene expression. However, the processes triggered by death and the post-mortem interval (PMI) can significantly alter physiologically normal RNA levels. We investigate the impact of PMI on gene expression using data from multiple tissues of post-mortem donors obtained from the GTEx project. We find that many genes change expression over relatively short PMIs in a tissue-specific manner, but this potentially confounding effect in a biological analysis can be minimized by taking into account appropriate covariates. By comparing ante- and post-mortem blood samples, we identify the cascade of transcriptional events triggered by death of the organism. These events do not appear to simply reflect stochastic variation resulting from mRNA degradation, but active and ongoing regulation of transcription. Finally, we develop a model to predict the time since death from the analysis of the transcriptome of a few readily accessible tissues.},

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