Open Source Drug Discovery in Practice: A Case Study

Background: Open source drug discovery offers potential for developing new and inexpensive drugs to combat diseases that disproportionally affect the poor. The concept borrows two principle aspects from open source computing (i.e., collaboration and open access) and applies them to pharmaceutical innovation. By opening a project to external contributors, its research capacity may increase significantly. To date there are only a handful of open source R&D projects focusing on neglected diseases. We wanted to learn from these first movers, their successes and failures, in order to generate a better understanding of how a much-discussed theoretical concept works in practice and may be implemented. Methodology/Principal Findings: A descriptive case study was performed, evaluating two specific R&D projects focused on neglected diseases. CSIR Team India Consortium's Open Source Drug Discovery project (CSIR OSDD) and The Synaptic Leap's Schistosomiasis project (TSLS). Data were gathered from four sources: interviews of participating members (n = 14), a survey of potential members (n = 61), an analysis of the websites and a literature review. Both cases have made significant achievements; however, they have done so in very different ways. CSIR OSDD encourages international collaboration, but its process facilitates contributions from mostly Indian researchers and students. Its processes are formal with each task being reviewed by a mentor (almost always offline) before a result is made public. TSLS, on the other hand, has attracted contributors internationally, albeit significantly fewer than CSIR OSDD. Both have obtained funding used to pay for access to facilities, physical resources and, at times, labor costs. TSLS releases its results into the public domain, whereas CSIR OSDD asserts ownership over its results. Conclusions/Significance: Technically TSLS is an open source project, whereas CSIR OSDD is a crowdsourced project. However, both have enabled high quality research at low cost. The critical success factors appear to be clearly defined entry points, transparency and funding to cover core material costs

Cognitive Functioning in Major Depression – A Summary

The aim of the present paper is to summarize the research during the past decade regarding cognitive functioning in Major Depressive Disorder (MDD). Cognitive impairment in the acute phase of illness has been frequently reported. The findings are shown in different cognitive domains, such as executive functions, attention, memory and psychomotor speed. Fewer reports have investigated cognitive functioning in MDD in longitudinal studies. Some longitudinal reports show that the impairment observed in the acute phase of illness may be long lasting despite symptom reduction and recovery. However, findings regarding cognitive functioning in depression are divergent. Factors that might contribute to the divergent findings, such as depression subtype, severity and comorbidity are discussed. Clinical implications and focus of future research directions is highlighted.In conclusion, depression is associated with cognitive impairment in the acute phase of illness, and some reports indicate that this impairment might be long lasting despite symptom reduction and recovery

Cognitive Impairment and Neurocognitive Profiles in Major Depression—A Clinical Perspective

Increasingly, studies have investigated cognitive functioning from the perspective of acute state- to remitted phases of Major Depressive Disorder (MDD). Some cognitive deficits observed in the symptomatic phase persist in remission as traits or scars. The etiological origin and clinical consequences of the neurocognitive profiles reported in the literature are still unclear and may vary across populations. Deficits are suspected to influence the association between MDD and neurodegenerative disorders and could thus be of particular clinical consequence. The aim of this review is to describe the clinical neuropsychological profile in MDD and how it is related to research during the past decade on cognitive deficits in MDD from a state, trait, and scar perspective. This review, with a clinical perspective, investigates research from the past decade regarding cognitive functioning in MDD in a long-term perspective. We focus on the clinical manifestation of deficits, and the potential neurodegenerative consequences of the neurocognitive profile in MDD. Searches in Medline, PsycINFO and Embase were conducted targeting articles published between 2010 and 2020. Examination of the evidence for long-lasting neurocognitive deficits in major depression within the cognitive domains of Memory, Executive Functions, Attention, and Processing Speed was conducted and was interpreted in the context of the State, Scar and Trait hypotheses. Defining the neurocognitive profiles in MDD will have consequences for personalized evaluation and treatment of residual cognitive symptoms, and etiological understanding of mood disorders, and treatments could potentially reduce or delay the development of neurodegenerative disorders.publishedVersio

A case study on Staphylococcus aureus bacteraemia: available treatment options, antibiotic R&D and responsible antibiotic-use strategies

Abstract Objectives This case study addresses: (i) antibiotic treatment options for Staphylococcus aureus bacteraemia (SAB), for both empirical and targeted therapy; (ii) the current status of and priorities for the antibiotic pipeline to ensure access of effective antibiotics for SAB; and (iii) strategies for responsible antibiotic use relevant to the clinical management of SAB. Methods Evidence to address the aims was extracted from the following information sources: (i) EUCAST and CLSI recommendations, summaries of product characteristics (SPCs), antibiotic treatment guidelines and the textbook Kucers' The Use of Antibiotics; (ii) the www.clinicaltrial.gov database; and (iii) quality indicators for responsible antibiotic use. Results Current monotherapy treatment options for SAB include only three drug classes (β-lactams, glycopeptides and lipopeptides), of which two also cover MRSA bacteraemia (glycopeptides and lipopeptides). The analysis of the antibiotic pipeline and ongoing clinical trials revealed that several new antibiotics with S. aureus (including MRSA) coverage were developed in the past decade (2009–19). However, none belonged to a new antibiotic class or had superior effectiveness and their added clinical value for SAB remains to be proven. Responsible antibiotic use for the treatment of SAB was illustrated using 11 quality indicators. Conclusions Awareness of the problem of a limited antibiotic arsenal, together with incentives (e.g. push incentives), is needed to steer the R&D landscape towards the development of novel and effective antibiotics for treating SAB. In the meantime, responsible antibiotic use guided by quality indicators should preserve the effectiveness of currently available antibiotics for treating SAB

Load-dependent speed optimization in maritime inventory routing

Maritime inventory routing problems involve determining optimal routes for seagoing vessels between ports while managing the inventory of each port. Normally, such problems are considered with the vessels operating at fixed sailing speeds. However, the speed of vessels can typically be adjusted within an interval, and the actual fuel consumption depends on both the load and the speed of the vessel. The fuel consumption function combines speed and load in a non-linear manner, but can be approximated through linearization. In this work, to evaluate the importance of taking into account that both speeds and load levels influence the fuel costs, the resulting solutions are contrasted with solutions from the case where speeds and travel costs are taken as constants, as well as the case where speed is a decision, but the cost considered to be independent of the load. For either of these cases, load-dependent speed optimization can be added as a post-processing step. Computational experiments show that combining speed and load do have an impact on the selection of routes in maritime inventory routing problems, and that proper modelling of the fuel consumption can reduce sailing costs significantly. On the test instances considered, taking into account speed while ignoring the load leads to cost savings of around 38%. Considering the fuel consumption as a function of speed and load when planning leads to additional cost savings of 28%. Keywords: mixed integer programming, non-linear, fuel consumption, transportpublishedVersio

Evaluering av behandling av recurrensparese

The voice is part of human identity and also an important tool for communication. Voice disorders can therefore cause physical, social and emotional limitations. The purpose of this study was to evaluate the treatment procedures for patients with unilateral vocal fold paresis at Haukeland University Hospital (HUH). The study was based on the following research questions: 1) Does the treatment given at HUH result in improved quality of voice and improved voice related quality of life for patients with vocal fold paresis? 2) Does additional disease affect patients’ voice related starting point before treatment, and patients’ treatment effect? Initially there will be presented knowledge about the anatomy of voice production, different voice disorders, and how to examine these. Further knowledge about vocal fold paresis will be presented, as well as evidence of treatment. In order to evaluate the treatment procedures at HUH, a patient group of 33 people was included. The evaluation was based on the patients’ self-assessed voice quality and voice related quality of life, as well as their maximum phonation time, before and after treatment. Voice quality and voice related quality of life were measured through the self-assessment tools Voice Related Quality of Life (VRQOL), Voice Handicap Index-30(N) (VHI-30(N)) and Visual Analogue Scale (VAS). Based on our own findings and previous research, the study may be passed on to clinical work in active patient care.Stemmen er en del av menneskets identitet og er et viktig redskap for kommunikasjon. En stemmevanske kan dermed medføre fysiske, sosiale og emosjonelle begrensninger. Formålet med denne studien var å evaluere behandlingstilbudet for pasienter med stemmevansken unilateral recurrensparese ved Haukeland Universitetssykehus (HUS). Følgende problemstillinger ble anvendt: 1) Resulterer behandlingen ved HUS i forbedret stemmekvalitet og stemmerelatert livskvalitet hos pasienter med recurrensparese? 2) Påvirker tilleggssykdom pasientenes stemmerelaterte utgangspunkt før behandling, og pasientenes effekt av behandling? På bakgrunn av dette tar studien først for seg anatomiske forutsetninger for stemmeproduksjon, ulike stemmevansker og utredning av stemmevansker. Studien fokuserer videre på kunnskap om stemmevansken recurrensparese, samt evidens om behandling for diagnosen. For å evaluere behandlingstilbudet ved HUS, ble en pasientgruppe på 33 personer inkludert. Evalueringen ble basert på pasientenes selvevaluerte stemmekvalitet og stemmerelaterte livskvalitet, samt på deres maksimale fonasjonstid, før og etter behandling. Stemmekvalitet og stemmerelatert livskvalitet ble målt gjennom selvevalueringsverktøyene Voice Related Quality of Life (V-RQOL), Voice Handicap Index30(N) (VHI-30(N)) og Visual Analogue Scale (VAS). Basert på egne funn og tidligere forskning vil studien kunne videreformidles til klinisk arbeid i aktiv pasientbehandling.Masteroppgave i logopediLOGO345MAPS-LOG0

Intestinal barrier integrity in anorexia nervosa (a pilot study)

Objective There is no conclusive evidence for involvement of intestinal barrier alteration in the etiology of anorexia nervosa (AN). The aims of this pilot study were to identify serum markers of intestinal barrier integrity in patients with AN and to determine the relationships between those markers and body mass index (BMI), eating disorder symptoms, gastrointestinal complaints, and liver synthesis function (international normalized ratio [INR]). Method Twenty-five outpatients with AN prior to starting treatment and 28 healthy controls (HC) were assessed. BMI and serum markers of intestinal barrier integrity were measured, including zonulin family peptides (ZFP), lipopolysaccharide-binding protein (LBP), and intestinal fatty-acid-binding protein (i-FABP). Eating disorder symptoms and gastrointestinal complaints were evaluated via questionnaires. Results The serum ZFP concentration was significantly lower in patients with AN than in HC (44.2 [7.4] vs. 49.2 [5.6] ng/ml, mean [standard deviation], p = .008). LBP and i-FABP did not differ between the two groups. In patients with AN, serum ZFP was significantly predicted by BMI (β = 0.479, p = .009), age (β = 0.411, p = .020), and INR (β = −0.388, p = .028). No such associations were found for either gastrointestinal complaints or eating disorder symptoms. Discussion Abnormal levels of serum ZFP were observed in patients with AN. Further studies with other assessment methods are warranted to examine intestinal barrier function in AN.publishedVersio