Code Generation for Higher Inductive Types

Higher inductive types are inductive types that include nontrivial higher-dimensional structure, represented as identifications that are not reflexivity. While work proceeds on type theories with a computational interpretation of univalence and higher inductive types, it is convenient to encode these structures in more traditional type theories with mature implementations. However, these encodings involve a great deal of error-prone additional syntax. We present a library that uses Agda's metaprogramming facilities to automate this process, allowing higher inductive types to be specified with minimal additional syntax.Comment: 16 pages, Accepted for presentation in WFLP 201

Molecular Characterization of Circulating Tumor DNA in Pediatric Rhabdomyosarcoma: A Feasibility Study

PURPOSE Rhabdomyosarcomas (RMS) are rare neoplasms affecting children and young adults. Efforts to improve patient survival have been undermined by a lack of suitable disease markers. Plasma circulating tumor DNA (ctDNA) has shown promise as a potential minimally invasive biomarker and monitoring tool in other cancers; however, it remains underexplored in RMS. We aimed to determine the feasibility of identifying and quantifying ctDNA in plasma as a marker of disease burden and/or treatment response using blood samples from RMS mouse models and patients. METHODS We established mouse models of RMS and applied quantitative polymerase chain reaction (PCR) and droplet digital PCR (ddPCR) to detect ctDNA within the mouse plasma. Potential driver mutations, copy-number alterations, and DNA breakpoints associated with PAX3/7-FOXO1 gene fusions were identified in the RMS samples collected at diagnosis. Patient-matched plasma samples collected from 28 patients with RMS before, during, and after treatment were analyzed for the presence of ctDNA via ddPCR, panel sequencing, and/or whole-exome sequencing. RESULTS Human tumor-derived DNA was detectable in plasma samples from mouse models of RMS and correlated with tumor burden. In patients, ctDNA was detected in 14/18 pretreatment plasma samples with ddPCR and 7/7 cases assessed by sequencing. Levels of ctDNA at diagnosis were significantly higher in patients with unfavorable tumor sites, positive nodal status, and metastasis. In patients with serial plasma samples (n = 18), fluctuations in ctDNA levels corresponded to treatment response. CONCLUSION Comprehensive ctDNA analysis combining high sensitivity and throughput can identify key molecular drivers in RMS models and patients, suggesting potential as a minimally invasive biomarker. Preclinical assessment of treatments using mouse models and further patient testing through prospective clinical trials are now warranted

Identity management strategies among HIV-positive Colombian gay men in London

This study set out to explore the social-psychological aspects of living with HIV among a group of HIV-positive Colombian gay men in London, and the strategies that they deployed to manage ensuing threats to their identities. Focus group and individual interview data were collected from 14 Colombian gay men living with HIV, and were analysed using qualitative thematic analysis and identity process theory. The following themes are discussed: (1) identity struggles and conflicts in Colombia, (2), managing multiple layers of social stigma in England, and (3) changing interpersonal and intergroup dynamics, which highlight the inter-connections between sexual prejudice, sexual risk-taking and HIV stigma. Identity may be chronically threatened due to the multiple layers of stigma, which can limit the coping strategies available to individuals. Findings strongly support the need for action and programmes to highlight and tackle both racism and HIV stigma on the gay scene and to fund more specific resources for sub-communities of gay, bisexual and other men who have sex with men, which employ appropriately trained and culturally competent staff

The role of statistical learning in the acquisition of motion event construal in a second language

Learning to talk about motion in a second language is very difficult because it involves restructuring deeply entrenched patterns from the first language (Slobin 1996). In this paper we argue that statistical learning (Saffran et al. 1997) can explain why L2 learners are only partially successful in restructuring their second language grammars. We explore to what extent L2 learners make use of two mechanisms of statistical learning, entrenchment and pre-emption (Boyd and Goldberg 2011) to acquire target-like expressions of motion and retreat from overgeneralisation in this domain. Paying attention to the frequency of existing patterns in the input can help learners to adjust the frequency with which they use path and manner verbs in French but is insufficient to acquire the boundary crossing constraint (Slobin and Hoiting 1994) and learn what not to say. We also look at the role of language proficiency and exposure to French in explaining the findings

Cell-Free RNA from Plasma in Patients with Neuroblastoma: Exploring the Technical and Clinical Potential

Neuroblastoma affects mostly young children, bearing a high morbidity and mortality. Liquid biopsies, e.g., molecular analysis of circulating tumor-derived nucleic acids in blood, offer a minimally invasive diagnostic modality. Cell-free RNA (cfRNA) is released by all cells, especially cancer. It circulates in blood packed in extracellular vesicles (EV) or attached to proteins. We studied the feasibility of analyzing cfRNA and EV, isolated by size exclusion chromatography (SEC), from platelet-poor plasma from healthy controls ( n = 40) and neuroblastoma patients with localized ( n = 10) and metastatic disease ( n = 30). The mRNA content was determined using several multiplex droplet digital PCR (ddPCR) assays for a neuroblastoma-specific gene panel ( PHOX2B, TH, CHRNA3) and a cell cycle regulation panel ( E2F1, CDC6, ATAD2, H2AFZ, MCM2, DHFR). We applied corrections for the presence of platelets. We demonstrated that neuroblastoma-specific markers were present in plasma from 14/30 patients with metastatic disease and not in healthy controls and patients with localized disease. Most cell cycle markers had a higher expression in patients. The mRNA markers were mostly present in the EV-enriched SEC fractions. In conclusion, cfRNA can be isolated from plasma and EV and analyzed using multiplex ddPCR. cfRNA is an interesting novel liquid biopsy-based target to explore further

HIV-positive status disclosure in patients in care in rural South Africa: implications for scaling up treatment and prevention interventions.

CAPRISA, 2015Abstract available in pdf

Targeted locus amplification to develop robust patient-specific assays for liquid biopsies in pediatric solid tumors

BackgroundLiquid biopsies combine minimally invasive sample collection with sensitive detection of residual disease. Pediatric malignancies harbor tumor-driving copy number alterations or fusion genes, rather than recurrent point mutations. These regions contain tumor-specific DNA breakpoint sequences. We investigated the feasibility to use these breakpoints to design patient-specific markers to detect tumor-derived cell-free DNA (cfDNA) in plasma from patients with pediatric solid tumors.Materials and methodsRegions of interest (ROI) were identified through standard clinical diagnostic pipelines, using SNP array for CNAs, and FISH or RT-qPCR for fusion genes. Using targeted locus amplification (TLA) on tumor organoids grown from tumor material or targeted locus capture (TLC) on FFPE material, ROI-specific primers and probes were designed, which were used to design droplet digital PCR (ddPCR) assays. cfDNA from patient plasma at diagnosis and during therapy was analyzed.ResultsTLA was performed on material from 2 rhabdomyosarcoma, 1 Ewing sarcoma and 3 neuroblastoma. FFPE-TLC was performed on 8 neuroblastoma tumors. For all patients, at least one patient-specific ddPCR was successfully designed and in all diagnostic plasma samples the patient-specific markers were detected. In the rhabdomyosarcoma and Ewing sarcoma patients, all samples after start of therapy were negative. In neuroblastoma patients, presence of patient-specific markers in cfDNA tracked tumor burden, decreasing during induction therapy, disappearing at complete remission and re-appearing at relapse.ConclusionWe demonstrate the feasibility to determine tumor-specific breakpoints using TLA/TLC in different pediatric solid tumors and use these for analysis of cfDNA from plasma. Considering the high prevalence of CNAs and fusion genes in pediatric solid tumors, this approach holds great promise and deserves further study in a larger cohort with standardized plasma sampling protocols

Van Noord tot Noordwest: Een studie naar de berging van baggerspecie op loswallen

Tot juni 1996 werd baggerspecie uit het Rijnmondgebied op Loswal Noord gestort. Deze baggerspecie heeft het al bodemleven op de loswal bedolven dat daardoor grotendeels verdwenen is. In de vier jaar na juni 1996 is het bodemleven grotendeels teruggekeerd, vooral wat betreft de kleinere organismen. Het bodemleven is echter nog niet op hetzelfde niveau als in de referentiegebieden. Van de hogere gebieden van Loswal Noord is het slib< 63 ?m grotendeels verdwenen. Zoals verwacht mag worden voldoet de resterende baggerspecie op de loswal aan de norm, die gesteld is aan baggerspecie die op zee gestort mag worden, de zg. Uniforme Gehalte Toets (UGT). De resterende baggerspecie heeft geen toxische effecten op bodemorganismen. Het retourpercentage van baggerspecie vanaf Loswal Noord is volgens modelonderzoek uit 1999 44 ± 22 %. In 1995 is een nieuwe locatie aangewezen als toekomstige stortlocatie, nl. Loswal Noordwest, omdat het retourpercentage hier lager zou zijn dan vanaf Loswal Noord. Voordat op Loswal Noordwest werd gestort, was dit deel van de zeebodem niet te onderscheiden van de omringende zeebodem. Nadat in juni 1996 begonnen werd met het storten van baggerspecie, verdween het leven op de zeebodem van de stortlocatie grotendeels. Tot op 4 km afstand van de stortplaats was invloed op het zeebodemleven merkbaar. Op een stortvak waar niet meer gestort werd, keerden sommige organismen weer terug. Ook hier voldoet, uiteraard, de resterende baggerspecie op de loswal aan de norm. Voor de kosten van het baggeren is de omvang van het wegstroompercentage en retourpercentage van belang. Deze stromen zijn gekwantificeerd. Het wegstroom- en retourpercentage van baggerspecie vanaf Loswal Noordwest bedraagt 50,4 respectievelijk 17,4 %. Voor slib< 63 ?m zijn deze percentages 77,9 en 27,0 %. Deze waarden liggen hoger dan in het milieu-effectrapport uit 1995 verondersteld was. Er werd destijds voorspeld dat er geen retourtransport naar vaargeul en haven zou plaatsvinden. De gemeten waarden in dit rapport worden grotendeels ondersteund door latere modelberekeningen. Na het verplaatsen van de loswal 'van Noord tot Noordwest' is een afname van de baggerinspanning in vaargeul en haven geconstateerd van ongeveer 40 % van de opgezogen hoeveelheid baggerspecie, hoewel ook andere ingrepen invloed hebben gehad op de baggerinspanning