A digital waveguide-based approach for Clavinet modeling and synthesis

The Clavinet is an electromechanical musical instrument produced in the mid-twentieth century. As is the case for other vintage instruments, it is subject to aging and requires great effort to be maintained or restored. This paper reports analyses conducted on a Hohner Clavinet D6 and proposes a computational model to faithfully reproduce the Clavinet sound in real time, from tone generation to the emulation of the electronic components. The string excitation signal model is physically inspired and represents a cheap solution in terms of both computational resources and especially memory requirements (compared, e.g., to sample playback systems). Pickups and amplifier models have been implemented which enhance the natural character of the sound with respect to previous work. A model has been implemented on a real-time software platform, Pure Data, capable of a 10-voice polyphony with low latency on an embedded device. Finally, subjective listening tests conducted using the current model are compared to previous tests showing slightly improved results

Comprehensive evaluation of coding region point mutations in microsatellite-unstable colorectal cancer

Microsatellite instability (MSI) leads to accumulation of an excessive number of mutations in the genome, mostly small insertions and deletions. MSI colorectal cancers (CRCs), however, also contain more point mutations than microsatellite-stable (MSS) tumors, yet they have not been as comprehensively studied. To identify candidate driver genes affected by point mutations in MSI CRC, we ranked genes based on mutation significance while correcting for replication timing and gene expression utilizing an algorithm, MutSigCV. Somatic point mutation data from the exome kit-targeted area from 24 exome-sequenced sporadic MSI CRCs and respective normals, and 12 whole-genome-sequenced sporadic MSI CRCs and respective normals were utilized. The top 73 genes were validated in 93 additional MSI CRCs. The MutSigCV ranking identified several well-established MSI CRC driver genes and provided additional evidence for previously proposed CRC candidate genes as well as shortlisted genes that have to our knowledge not been linked to CRC before. Two genes, SMARCB1 and STK38L, were also functionally scrutinized, providing evidence of a tumorigenic role, for SMARCB1 mutations in particular. © 2018 The Authors. Published under the terms of the CC BY 4.0 licensePeer reviewe

Tailoring r-index for Document Listing Towards Metagenomics Applications

A basic problem in metagenomics is to assign a sequenced read to the correct species in the reference collection. In typical applications in genomic epidemiology and viral metagenomics the reference collection consists of a set of species with each species represented by its highly similar strains. It has been recently shown that accurate read assignment can be achieved with k-mer hashing-based pseudoalignment: a read is assigned to species A if each of its k-mer hits to a reference collection is located only on strains of A. We study the underlying primitives required in pseudoalignment and related tasks. We propose three space-efficient solutions building upon the document listing with frequencies problem. All the solutions use an r-index (Gagie et al., SODA 2018) as an underlying index structure for the text obtained as concatenation of the set of species, as well as for each species. Given t species whose concatenation length is n, and whose Burrows-Wheeler transform contains r runs, our first solution, based on a grammar-compressed document array with precomputed queries at non terminal symbols, reports the frequencies for the distinct documents in which the pattern of length m occurs in time. Our second solution is also based on a grammar-compressed document array, but enhanced with bitvectors and reports the frequencies in time, over a machine with wordsize w. Our third solution, based on the interleaved LCP array, answers the same query in time. We implemented our solutions and tested them on real-world and synthetic datasets. The results show that all the solutions are fast on highly-repetitive data, and the size overhead introduced by the indexes are comparable with the size of the r-index.Peer reviewe

Arthroscopic partial meniscectomy versus placebo surgery for a degenerative meniscus tear : a 2-year follow-up of the randomised controlled trial

Objective To assess if arthroscopic partial meniscectomy (APM) is superior to placebo surgery in the treatment of patients with degenerative tear of the medial meniscus. Methods In this multicentre, randomised, participant-blinded and outcome assessor-blinded, placebo-surgery controlled trial, 146 adults, aged 35-65 years, with knee symptoms consistent with degenerative medial meniscus tear and no knee osteoarthritis were randomised to APM or placebo surgery. The primary outcome was the between-group difference in the change from baseline in the Western Ontario Meniscal Evaluation Tool (WOMET) and Lysholm knee scores and knee pain after exercise at 24 months after surgery. Secondary outcomes included the frequency of unblinding of the treatment-group allocation, participants' satisfaction, impression of change, return to normal activities, the incidence of serious adverse events and the presence of meniscal symptoms in clinical examination. Two subgroup analyses, assessing the outcome on those with mechanical symptoms and those with unstable meniscus tears, were also carried out. Results In the intention-to-treat analysis, there were no significant between-group differences in the mean changes from baseline to 24 months in WOMET score: 27.3 in the APM group as compared with 31.6 in the placebo-surgery group (between-group difference, -4.3; 95% CI, -11.3 to 2.6); Lysholm knee score: 23.1 and 26.3, respectively (-3.2; -8.9 to 2.4) or knee pain after exercise, 3.5 and 3.9, respectively (-0.4; -1.3 to 0.5). There were no statistically significant differences between the two groups in any of the secondary outcomes or within the analysed subgroups. Conclusions In this 2-year follow-up of patients without knee osteoarthritis but with symptoms of a degenerative medial meniscus tear, the outcomes after APM were no better than those after placebo surgery. No evidence could be found to support the prevailing ideas that patients with presence of mechanical symptoms or certain meniscus tear characteristics or those who have failed initial conservative treatment are more likely to benefit from APM.Peer reviewe

No selection for change in polyandry under experimental evolution

What drives mating system variation is a major question in evolutionary biology. Female multiple mating (polyandry) has diverse evolutionary consequences, and there are many potential benefits and costs of polyandry. However, our understanding of its evolution is biased towards studies enforcing monandry in polyandrous species. What drives and maintains variation in polyandry between individuals, genotypes, populations and species remains poorly understood. Genetic variation in polyandry may be actively maintained by selection, or arise by chance if polyandry is selectively neutral. In Drosophila pseudoobscura, there is genetic variation in polyandry between and within populations. We used isofemale lines to found replicate populations with high or low initial levels of polyandry and tracked polyandry under experimental evolution over seven generations. Polyandry remained relatively stable, reflecting the starting frequencies of the experimental populations. There were no clear fitness differences between high versus low polyandry genotypes, and there was no signature of balancing selection. We confirmed these patterns in direct comparisons between evolved and ancestral females and found no consequences of polyandry for female fecundity. The absence of differential selection even when initiating populations with major differences in polyandry casts some doubt on the importance of polyandry for female fitness

The implications of autonomy: Viewed in the light of efforts to uphold patients dignity and integrity

This article focuses on Danish patients’ experience of autonomy and its interplay with dignity and integrity in their meeting with health professionals. The aim is to chart the meanings and implications of autonomy for persons whose illness places them in a vulnerable life situation. The interplay between autonomy and personal dignity in the meeting with health care staff are central concepts in the framework. Data collection and findings are based on eight qualitative semi-structured interviews with patients. Patients with acute, chronic, and life threatening diseases were represented including surgical as well as medical patients. The values associated with autonomy are in many ways vitalising, but may become so dominant, autonomy seeking, and pervasive that the patient's dignity is affected. Three types of patient behaviour were identified. (1) The proactive patient: Patients feel that they assume responsibility for their own situation, but it may be a responsibility that they find hard to bear. (2) The rejected patient: proactive patients take responsibility on many occasions but very active patients are at risk of being rejected with consequences for their dignity. (3) The knowledgeable patient: when patients are health care professionals, the patient's right of self-determination was managed in a variety of ways, sometimes the patient's right of autonomy was treated in a dignified way but the opposite was also evident. In one way, patients are active and willing to take responsibility for themselves, and at the same time they are “forced” to do so by health care staff. Patients would like health professionals to be more attentive and proactive

Exome-wide somatic mutation characterization of small bowel adenocarcinoma

Small bowel adenocarcinoma (SBA) is an aggressive disease with limited treatment options. Despite previous studies, its molecular genetic background has remained somewhat elusive. To comprehensively characterize the mutational landscape of this tumor type, and to identify possible targets of treatment, we conducted the first large exome sequencing study on a population-based set of SBA samples from all three small bowel segments. Archival tissue from 106 primary tumors with appropriate clinical information were available for exome sequencing from a patient series consisting of a majority of confirmed SBA cases diagnosed in Finland between the years 2003-2011. Paired-end exome sequencing was performed using Illumina HiSeq 4000, and OncodriveFML was used to identify driver genes from the exome data. We also defined frequently affected cancer signalling pathways and performed the first extensive allelic imbalance (Al) analysis in SBA. Exome data analysis revealed significantly mutated genes previously linked to SBA (TP53, KRAS, APC, SMAD4, and BRAF), recently reported potential driver genes (SOX9, ATM, and ARID2), as well as novel candidate driver genes, such as ACVR2A, ACVR1B, BRCA2, and SMARCA4. We also identified clear mutation hotspot patterns in ERBB2 and BRAF. No BRAF V600E mutations were observed. Additionally, we present a comprehensive mutation signature analysis of SBA, highlighting established signatures 1A, 6, and 17, as well as U2 which is a previously unvalidated signature. Finally, comparison of the three small bowel segments revealed differences in tumor characteristics. This comprehensive work unveils the mutational landscape and most frequently affected genes and pathways in SBA, providing potential therapeutic targets, and novel and more thorough insights into the genetic background of this tumor type.Peer reviewe