A panel of genes methylated with high frequency in colorectal cancer

Background: The development of colorectal cancer (CRC) is accompanied by extensive epigenetic changes, including frequent regional hypermethylation particularly of gene promoter regions. Specific genes, including SEPT9, VIM1 and TMEFF2 become methylated in a high fraction of cancers and diagnostic assays for detection of cancer-derived methylated DNA sequences in blood and/or fecal samples are being developed. There is considerable potential for the development of new DNA methylation biomarkers or panels to improve the sensitivity and specificity of current cancer detection tests. Methods: Combined epigenomic methods - activation of gene expression in CRC cell lines following DNA demethylating treatment, and two novel methods of genome-wide methylation assessment - were used to identify candidate genes methylated in a high fraction of CRCs. Multiplexed amplicon sequencing of PCR products from bisulfite-treated DNA of matched CRC and non-neoplastic tissue as well as healthy donor peripheral blood was performed using Roche 454 sequencing. Levels of DNA methylation in colorectal tissues and blood were determined by quantitative methylation specific PCR (qMSP). Results: Combined analyses identified 42 candidate genes for evaluation as DNA methylation biomarkers. DNA methylation profiles of 24 of these genes were characterised by multiplexed bisulfite-sequencing in ten matched tumor/normal tissue samples; differential methylation in CRC was confirmed for 23 of these genes. qMSP assays were developed for 32 genes, including 15 of the sequenced genes, and used to quantify methylation in tumor, adenoma and non-neoplastic colorectal tissue and from healthy donor peripheral blood. 24 of the 32 genes were methylated in \u3e50% of neoplastic samples, including 11 genes that were methylated in 80% or more CRCs and a similar fraction of adenomas. Conclusions: This study has characterised a panel of 23 genes that show elevated DNA methylation in \u3e50% of CRC tissue relative to non-neoplastic tissue. Six of these genes (SOX21, SLC6A15, NPY, GRASP, ST8SIA1 and ZSCAN18) show very low methylation in non-neoplastic colorectal tissue and are candidate biomarkers for stool-based assays, while 11 genes (BCAT1, COL4A2, DLX5, FGF5, FOXF1, FOXI2, GRASP, IKZF1, IRF4, SDC2 and SOX21) have very low methylation in peripheral blood DNA and are suitable for further evaluation as blood-based diagnostic markers

Risk Management and Built Heritage: Towards a Systematic Approach

This paper discusses the classification of risks as a tool for the identification, the assessment and the management of risks for the built heritage. Existing typologies of risk vary according to the selected criteria on which they are based and their utility within the risk management process. Indicative examples of risk classifications proposed and used in the field of cultural heritage management, as well as in other fields, are examined. The comparison of the selected criteria for analysing risks and the reflection upon their relevant aspects to the built heritage conservation provide a frame for a systematic approach to the built heritage management

Syväoppimiseen perustuva suomenkielinen neuroverkkopohjainen puhesynteesi ja sen suoriutuminen sulautetussa järjestelmässä

Tiivistelmä. Puhesynteesi on oleellinen osa nykyaikaisia ja yhä enemmän käytettäviä TTS-järjestelmiä. Nykyaikaiset TTS-järjestelmät kykenevät tuottamaan luonnollista ja monipuolista puhetta moneen eri käyttötarkoitukseen, kuten esimerkiksi helppokäyttöisyystyökaluihin. Kun toteutetaan suomenkielinen syväoppivaan neuroverkkoon perustuva järjestelmä osaksi sosiaalisen robotin kokonaisuutta, tulisi synteesin tapahtua tarpeeksi nopeasti ja syntetisoidun puheen tulisi olla laadukasta ja luonnollista, jotta mahdollinen vuorovaikutus robotin kanssa olisi mahdollisimman hyvälaatuista. Puhesynteesijärjestelmän tulisi siis toimia osana sosiaalista robottia yhdessä mahdollisen keskustelumoduulin ja puheentunnistusmoduulin kanssa. Toteutettu puhesynteesimoduuli vastaanottaa syötteenä tekstin, joka syntetisoidaan raaka-aaltomuotoiseksi ääneksi eli puheeksi tiedostoon, joka lopulta toistetaan kaiuttimesta. Perinteisesti puhesynteesin menetelmiä ovat olleet formanttisynteesi, HMM-pohjainen puhesynteesi ja konkatenaatiosynteesi, joista myöhemmin on edetty neuroverkkopohjaisiin menetelmiin. Jotta saavutetaan laadukasta puhesynteesiä, tulisi neuroverkkomallia kouluttaa mahdollisimman laajalla aineistolla, joka kattaisi suomen kielen äänteet ja sananpainotukset. End-to-end -syväoppimiseen perustuva neuroverkkopohjainen puhesynteesimalli VITS valittiin työhön toteutettavaksi malliksi. Mallin kouluttaminen toteutettiin Google Colab -ympäristössä, joka tarjoaa tarvittavia resursseja mallin kouluttamista varten. Neuroverkko koostuu tyypillisesti monista yksinkertaisista toisiinsa kytketyistä prosessoivista yksiköistä, joita kutsutaan myös neuroneiksi. Neuroverkon oppimisessa on kyse siitä, että löydetään haluttuja painotuksia näille neuroneiden yhteyksille, jotta neuroverkko saadaan käyttäytymään halutulla tavalla. Tässä työssä koulutettu neuroverkko oppi tuottamaan aaltomuotoista puhetta sille annetusta tekstisyötteestä. Kehitetty ja koulutettu puhesynteesimalli arvioitiin subjektiivisella MOS- asteikolla. Puhesynteesimalli kykeni suoriutumaan Raspberry Pi 4 Model B -minitietokoneella, mutta ei vaadittavalla nopeudella, jotta reaaliaikainen keskustelu olisi mahdollista ja luonnollista. Raspberry Pi 4 Model B -minitietokoneen suorituskyky ei siis riittänyt reaaliaikaiseen keskusteluun vaan TTS-järjestelmä toteutettiin robotin omaan ROS2-ympäristöön, jota suoritetaan tehokkaammalla tietokoneella ja jossa sitä voidaan käyttää mahdollisen keskusteluälyn ja puheentunnistuksen kanssa.Deep learning based speech synthesis system for the Finnish language and its performance in an embedded system. Abstract. Speech synthesis is an integral part of modern TTS systems, which are more prevalent today than in the past. Modern TTS systems are more capable to produce speech, which is more natural and varied, and which has increasingly more applications like on accessibility features. When deep learning based neural network for Finnish speech synthesis is applied as a part of social robot, the synthesized speech should be of high quality and natural. This ensures the best possible quality for an interaction between the user and the social robot. The speech synthesis system should be able to function as a part of a social robot alongside speech logic and speech recognition modules. The developed speech synthesis module takes text as an input, which is synthesized to a raw audio wave, and the resulting audio will be outputted from a speaker. Traditional methods of speech synthesis, which include formant synthesis, HMM-based synthesis and concatenative synthesis, are supplanted by modern neural network based speech synthesis systems. In order to get the best possible speech synthesis result, the neural network should be trained with an extensive dataset that encompasses all vocal phonemes and stresses in Finnish language. For this paper a neural network based end-to-end speech synthesis model VITS was chosen. Google Colab was used to train the model, because it had sufficient resources. A neural network is typically a collection of simple evaluation nodes which are called neurons. Learning occurs by manipulating the connections between neurons to produce a desired output. In this research, the neural network was trained to transform text into an audio wave output that resembles human speech. The speech synthesis model developed and trained in this paper was evaluated on a subjective MOS scale. It was capable of functioning on a Raspberry Pi 4 Model B computer, but real-time conversation was not feasible due to performance constraints. Since the Raspberry Pi 4 Model B couldn’t facilitate real-time speech synthesis for conversation, the TTS system was implemented in its own ROS2 environment on more robust hardware. This setup integrates with potential conversational AI and speech recognition models

Scalable processing of cementitious composites reinforced with carbon nanotubes (CNTs) and carbon nanofibers (CNFs)

Utilizing the unique properties of CNTs and CNFs to enhance the mechanical and fracture properties of cement based materials and develop smart cementitious nanocomposites can be a challenge in terms of developing scalable manufacturing methods. Scaling up the manufacturing size of CNT and CNF reinforced cement based materials and produce multifunctional concrete that exhibits exceptional strength, stiffness and toughness and multifunctionality requires optimization of dispersion procedure. The effectiveness of successfully using CNTs and CNFs in concrete depends on the fiber count, the volume fraction of sand and coarse aggregates. In this work, we present the flexural strength and stiffness, fracture toughness and brittleness of nanomodified pastes and mortars reinforced at amount of 0.08 and 0.1 wt% and an investigation on the optimization of the fiber count proportioning of concrete. The addition of a very low amount, 0.1 wt%, of both CNTs and CNFs, increases approximately 1.5 times the flexural strength and the Young`s modulus of concrete nanocomposites. The nanomodified concrete also exhibits 60% higher energy absorption capability

Sex-specific associations of basal steroid hormones and neuropeptides with Conduct Disorder and neuroendocrine mediation of environmental risk

Conduct Disorder (CD) is characterized by severe aggressive and antisocial behavior. The stress hormone system has frequently been investigated as a neurobiological correlate of CD, while other interacting neuroendocrine biomarkers of sex hormone or neuropeptide systems have rarely been studied, especially in females. We examined multiple basal neuroendocrine biomarkers in female and male adolescents with CD compared to healthy controls (HCs), and explored whether they mediate effects of environmental risk factors on CD. Within the FemNAT-CD study, salivary cortisol, alpha-amylase, testosterone, dehydroepiandrosterone-sulfate (DHEA-S), estradiol, progesterone, oxytocin, and arginine-vasopressin were measured under basal conditions in 166 pubertal adolescents with CD, and 194 sex-, age-, and puberty-matched HCs (60% females, 9-18 years). Further, environmental risk factors were assessed. Single hormone analyses showed higher DHEA-S, and lower estradiol and progesterone levels in both females and males with CD relative to HCs. When accounting for interactions between neuroendocrine systems, a male-specific sex hormone factor (testosterone/DHEA-S) predicted male CD, while estradiol and a stress-system factor (cortisol/alpha-amylase) interacting with oxytocin predicted female CD. Estradiol, progesterone, and oxytocin partly explained associations between early environmental risk and CD. Findings provide evidence for sex-specific associations between basal neuroendocrine measures and CD. Especially altered sex hormones (androgen increases in males, estrogen reductions in females) robustly related to CD, while basal stress-system measures did not. Early environmental risk factors for CD may act partly through their effects on the neuroendocrine system, especially in females. Limitations (e.g., basal neuroendocrine assessment, different sample sizes per sex, pubertal participants, exploratory mediation analyses) are discussed

Blood Pressure Lowering With Nilvadipine in Patients With Mild-to-Moderate Alzheimer Disease Does Not Increase the Prevalence of Orthostatic Hypotension

BACKGROUND: Hypertension is common among patients with Alzheimer disease. Because this group has been excluded from hypertension trials, evidence regarding safety of treatment is lacking. This secondary analysis of a randomized controlled trial assessed whether antihypertensive treatment increases the prevalence of orthostatic hypotension (OH) in patients with Alzheimer disease. METHODS AND RESULTS: Four hundred seventy‐seven patients with mild‐to‐moderate Alzheimer disease were randomized to the calcium‐channel blocker nilvadipine 8 mg/day or placebo for 78 weeks. Presence of OH (blood pressure drop ≥20/≥10 mm Hg after 1 minute of standing) and OH‐related adverse events (dizziness, syncope, falls, and fractures) was determined at 7 follow‐up visits. Mean age of the study population was 72.2±8.2 years and mean Mini‐Mental State Examination score was 20.4±3.8. Baseline blood pressure was 137.8±14.0/77.0±8.6 mm Hg. Grade I hypertension was present in 53.4% (n=255). After 13 weeks, blood pressure had fallen by −7.8/−3.9 mm Hg for nilvadipine and by −0.4/−0.8 mm Hg for placebo (P<0.001). Across the 78‐week intervention period, there was no difference between groups in the proportion of patients with OH at a study visit (odds ratio [95% CI]=1.1 [0.8–1.5], P=0.62), nor in the proportion of visits where a patient met criteria for OH, corrected for number of visits (7.7±13.8% versus 7.3±11.6%). OH‐related adverse events were not more often reported in the intervention group compared with placebo. Results were similar for those with baseline hypertension. CONCLUSIONS: This study suggests that initiation of a low dose of antihypertensive treatment does not significantly increase the risk of OH in patients with mild‐to‐moderate Alzheimer disease. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02017340

Visualization of Fast Ion Phase-Space Flow Driven by Alfvén Instabilities

Fast ion phase-space flow, driven by Alfvén eigenmodes (AEs), is measured by an imaging neutral particle analyzer in the DIII-D tokamak. The flow firstly appears near the minimum safety factor at the injection energy of neutral beams, and then moves radially inward and outward by gaining and losing energy, respectively. The flow trajectories in phase space align well with the intersection lines of the constant magnetic moment surfaces and constant E−(ω/n)Pζ surfaces, where E, Pζ are the energy and canonical toroidal momentum of ions; ω and n are angular frequencies and toroidal mode numbers of AEs. It is found that the flow is so destructive that the thermalization of fast ions is no longer observed in regions of strong interaction. The measured phase-space flow is consistent with nonlinear hybrid kinetic-magnetohydrodynamics simulation. Calculations of the relatively narrow phase-space islands reveal that fast ions must transition between different flow trajectories to experience large-scale phase-space transport

Staging of schizophrenia with the use of PANSS: an international multi-center study

Introduction: A specific clinically relevant staging model for schizophrenia has not yet been developed. The aim of the current study was to evaluate the factor structure of the PANSS and develop such a staging method. Methods: Twenty-nine centers from 25 countries contributed 2358 patients aged 37.21 ± 11.87 years with schizophrenia. Analysis of covariance, Exploratory Factor Analysis, Discriminant Function Analysis, and inspection of resultant plots were performed. Results: Exploratory Factor Analysis returned 5 factors explaining 59% of the variance (positive, negative, excitement/hostility, depression/anxiety, and neurocognition). The staging model included 4 main stages with substages that were predominantly characterized by a single domain of symptoms (stage 1: positive; stages 2a and 2b: excitement/hostility; stage 3a and 3b: depression/anxiety; stage 4a and 4b: neurocognition). There were no differences between sexes. The Discriminant Function Analysis developed an algorithm that correctly classified &gt;85% of patients. Discussion: This study elaborates a 5-factor solution and a clinical staging method for patients with schizophrenia. It is the largest study to address these issues among patients who are more likely to remain affiliated with mental health services for prolonged periods of time

COVID-19-related mortality in kidney transplant and haemodialysis patients: A comparative, prospective registry-based study

Background: Coronavirus disease 2019 (COVID-19) has exposed haemodialysis (HD) patients and kidney transplant (KT) recipients to an unprecedented life-threatening infectious disease, raising concerns about kidney replacement therapy (KRT) strategy during the pandemic. This study investigated the association of the type of KRT with COVID-19 severity, adjusting for differences in individual characteristics. Methods: Data on KT recipients and HD patients diagnosed with COVID-19 between 1 February 2020 and 1 December 2020 were retrieved from the European Renal Association COVID-19 Database. Cox regression models adjusted for age, sex, frailty and comorbidities were used to estimate hazard ratios (HRs) for 28-day mortality risk in all patients and in the subsets that were tested because of symptoms. Results: A total of 1670 patients (496 functional KT and 1174 HD) were included; 16.9% of KT and 23.9% of HD patients died within 28 days of presentation. The unadjusted 28-day mortality risk was 33% lower in KT recipients compared with HD patients {HR 0.67 [95% confidence interval (CI) 0.52-0.85]}. In a fully adjusted model, the risk was 78% higher in KT recipients [HR 1.78 (95% CI 1.22-2.61)] compared with HD patients. This association was similar in patients tested because of symptoms [fully adjusted model HR 2.00 (95% CI 1.31-3.06)]. This risk was dramatically increased during the first post-transplant year. Results were similar for other endpoints (e.g. hospitalization, intensive care unit admission and mortality &gt;28 days) and across subgroups. Conclusions: KT recipients had a greater risk of a more severe course of COVID-19 compared with HD patients, therefore they require specific infection mitigation strategies

Potentially inappropriate medication use in older adults with mild-moderate Alzheimer's disease:Prevalence and associations with adverse events

Aim: Potentially inappropriate medication (PIM) use is prevalent in older adults and is associated with adverse events, hospitalisation and mortality. We assessed the patterns and associations of PIM use in older adults with mild-to-moderate Alzheimer's Disease (AD), who may represent a particularly vulnerable group. Design: Analysis of data from NILVad, an 18-month Randomised Control Trial of Nilvadapine in mild-to-moderate AD. The v2 STOPP criteria were applied in duplicate to identify PIM use. Associations between PIM use and adverse events/unscheduled healthcare visits in addition to the associations between PIM use and AD progression were evaluated. Setting and Participants: 448 older adults with mild-to-moderate AD from 23 centres in nine European countries. Results: Of 448 participants (mean age: 72.56 ± 8.19 years), over half (55.8%) were prescribed a PIM with 30.1% being prescribed 2+ PIMs. The most frequent PIMs were (i) long-term benzodiazepines (11.6% N = 52/448), (ii) selective serotonin reuptake inhibitors without appropriate indication (11.1% N = 50/448), and (iii) Proton-Pump Inhibitors (PPIs) without appropriate indication (10.7% N = 48/448). Increasing number of PIMs was associated with a greater risk of adverse events (IRR 1.17, 1.13-1.19, P &lt; 0.001), serious adverse events (IRR 1.27; 1.17-1.37, P &lt; 0.001), unscheduled hospitalisations (IRR 1.16, 1.03-1.30, P = 0.016) and GP visits (IRR 1.22, 1.15-1.28, P &lt; 0.001). PIM use was not associated with dementia progression. Conclusions and Implications: PIM use is highly prevalent in mild-to-moderate AD and is associated with adverse events and unscheduled healthcare utilisation. Further attention to de-prescribing in this vulnerable group is warranted