Setting and Reaching Targets with Computer-Assisted Cochlear Implant Fitting

Objective. The paper aims to demonstrate the feasibility of defining a substantial set of psychoacoustic outcome measures with preset targets and to adopt a systematic methodology for reaching these targets in a large group of subjects, by more than one clinical centre. Design. Retrospective data analysis. Setting. Multicentre with 14 participating centres. Patients. 255 adults and children using the Advanced Bionics HiRes90k cochlear implant. Intervention. Target driven fitting with the fitting to outcomes expert (FOX) system. Main Outcome Measures. For each patient, 66 measurable psychoacoustical outcomes were recorded several times after cochlear implantation: free field audiometry (6 measures) and speech audiometry (4), spectral discrimination (20), and loudness growth (36), defined from the A§E test battery. These outcomes were reduced to 22 summary variables. The initial results were compared with the latest results. Results. The state of the fitting process could be well monitored by means of the measured variables. The use of the FOX computer assisted CI-programming significantly improved the proportion of the 22 variables on target. When recipients used the automated MAPs provided at switch-on, more than half (57%) of the 22 targets were already achieved before any further optimisation took place. Once the FOX system was applied there was a significant 24% (P<0.001) increase in the number of targets achieved. Conclusions. This study demonstrates that it is feasible to set targets and to report on the effectiveness of a fitting strategy in terms of these targets. FOX provides an effective tool for achieving a systematic approach to programming, allowing for better optimisation of recipients' MAPs. The setting of well-defined outcome targets allowed a range of different centres to successfully apply a systematic methodology to monitoring the quality of the programming provided

Single DermaVir Immunization: Dose-Dependent Expansion of Precursor/Memory T Cells against All HIV Antigens in HIV-1 Infected Individuals

BACKGROUND: The GIHU004 study was designed to evaluate the safety and immunogenicity of three doses of DermaVir immunization in HIV-infected subjects on fully suppressive combination antiretroviral therapy (cART). METHODOLOGY/PRINCIPAL FINDINGS: This first-in-human dose escalation study was conducted with three topical DermaVir doses targeted to epidermal Langerhans cells to express fifteen HIV antigens in draining lymph nodes: 0.1 mg DNA targeted to two, 0.4 mg and 0.8 mg DNA targeted to four lymph nodes. Particularly, in the medium dose cohort 0.1 mg DNA was targeted per draining lymph node via ∼8 million Langerhans cells located in 80 cm(2) epidermis area. The 28-days study with 48-week safety follow-up evaluated HIV-specific T cell responses against Gag p17, Gag p24 and Gag p15, Tat and Rev antigens. DermaVir-associated side effects were mild, transient and not dose-dependent. Boosting of HIV-specific effector CD4(+) and CD8(+) T cells expressing IFN-gamma and IL-2 was detected against several antigens in every subject of the medium dose cohort. The striking result was the dose-dependent expansion of HIV-specific precursor/memory T cells with high proliferation capacity. In low, medium and high dose cohorts this HIV-specific T cell population increased by 325-, 136,202 and 50,759 counts after 4 weeks, and by 3,899, 9,878 and 18,382 counts after one year, respectively, compared to baseline. CONCLUSIONS/SIGNIFICANCE: Single immunization with the DermaVir candidate therapeutic vaccine was safe and immunogenic in HIV-infected individuals. Based on the potent induction of Gag, Tat and Rev-specific memory T cells, especially in the medium dose cohort, we speculate that DermaVir boost T cell responses specific to all the 15 HIV antigens expressed from the single DNA. For durable immune reactivity repeated DermaVir immunization might be required since the frequency of DermaVir-boosted HIV-specific memory T cells decreased during the 48-week follow up. TRIAL REGISTRATION: ClinicalTrial.gov NCT00712530

Total synthesis of the Amaryllidaceae alkaloid clivonine

Two syntheses of the Amaryllidaceae alkaloid clivonine (1) are described. Both employ previously reported 7-arylhydrindane 6 as an intermediate but differ in the method employed for subsequent introduction of what becomes the ring-B lactone carbonyl carbon (C7). The synthesis featuring a Bischler–Napieralski reaction for this transformation constitutes the first asymmetric synthesis of natural (+)-clivonine. Crystal structures for compounds (±)-13, (±)-16, (−)-20 and (±)-28 are also reported

Gender differences in the use of cardiovascular interventions in HIV-positive persons; the D:A:D Study

Peer reviewe

Complement lectin pathway activation is associated with COVID-19 disease severity, independent of MBL2 genotype subgroups

IntroductionWhile complement is a contributor to disease severity in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, all three complement pathways might be activated by the virus. Lectin pathway activation occurs through different pattern recognition molecules, including mannan binding lectin (MBL), a protein shown to interact with SARS-CoV-2 proteins. However, the exact role of lectin pathway activation and its key pattern recognition molecule MBL in COVID-19 is still not fully understood.MethodsWe therefore investigated activation of the lectin pathway in two independent cohorts of SARS-CoV-2 infected patients, while also analysing MBL protein levels and potential effects of the six major single nucleotide polymorphisms (SNPs) found in the MBL2 gene on COVID-19 severity and outcome.ResultsWe show that the lectin pathway is activated in acute COVID-19, indicated by the correlation between complement activation product levels of the MASP-1/C1-INH complex (p=0.0011) and C4d (p&lt;0.0001) and COVID-19 severity. Despite this, genetic variations in MBL2 are not associated with susceptibility to SARS-CoV-2 infection or disease outcomes such as mortality and the development of Long COVID.ConclusionIn conclusion, activation of the MBL-LP only plays a minor role in COVID-19 pathogenesis, since no clinically meaningful, consistent associations with disease outcomes were noted

Automatic Identification of Harmful, Aggressive, Abusive, and Offensive Language on the Web: A Survey of Technical Biases Informed by Psychology Literature

The automatic detection of conflictual languages (harmful, aggressive, abusive, and offensive languages) is essential to provide a healthy conversation environment on the Web. To design and develop detection systems that are capable of achieving satisfactory performance, a thorough understanding of the nature and properties of the targeted type of conflictual language is of great importance. The scientific communities investigating human psychology and social behavior have studied these languages in details, but their insights have only partially reached the computer science community.In this survey, we aim both at systematically characterizing the conceptual properties of online conflictual languages, and at investigating the extent to which they are reflected in state-of-the-art automatic detection systems. Through an analysis of psychology literature, we provide a reconciled taxonomy that denotes the ensemble of conflictual languages typically studied in computer science. We then characterize the conceptual mismatches that can be observed in the main semantic and contextual properties of these languages and their treatment in computer science works; and systematically uncover resulting technical biases in the design of machine learning classification models and the dataset created for their training. Finally, we discuss diverse research opportunities for the computer science community and reflect on broader technical and structural issues.Web Information SystemsHuman-Centred Artificial Intelligenc

Human submandibular gland (HSG) cell line as a model for studying salivary gland Ca2+ signalling mechanisms

The human submandibular gland cell line (HSG) has been used as a model for studying the molecular mechanisms of salivary cells. The aim of this study was to investigate some aspects of salivary Ca2+ signalling. We focused on the presence and function of specific molecular markers of salivary cells to see whether this cell line retained normal salivary characteristics, despite the neoplastic changes. We detected the M3 acetylcholine receptor and intracellular salivary amylase mRNA with RT-PCR. Carbachol treatment caused a rapid, transient elevation of [Ca2+]i , showing that the cholinergic receptors are functional in HSG cells. Protein kinase C activation by phorbol-esther PMA, prior to carbachol treatment, inhibited the normal Ca2+ signalling pathway in HSG cells. Using selective antagonists, we also identified the dominant muscarinic receptor subtype M3 on HSG cells. We also observed that functional extracellular purinergic receptors were present on HSG cells and coupled to intracellular Ca2+ signalling. Our results suggested that the coupling mechanisms of these receptors remained relatively intact despite the neoplastic transformation. This enables us to use this cell line to model the role of muscarinic and purinergic control of salivary gland function, cell proliferation and differentiation

Excavation and support design of the Dicle-Kralkizi water tunnel: an overview

Tunneling projects have their uniqueness in terms of engineering problems. The expertise gained from analyzing these projects establishes a sound basis for future application. This paper conveys experiences gained during the construction and support of the design of the Dicle-Kralkizi water tunnel, Turkey. Tunnel stability problems including overbreaks and surface subsidence are evaluated. An analysis of the breakdowns, factors controlling advance rate and the overall performance of tunnel are covered. The accumulated information presented here is believed to be useful and reliable for a successful tunnel excavation in similar formations. (C) 2004 Elsevier Ltd. All rights reserved