Influenza Resistance to Antiviral Drugs: Virus characterization, mechanism and clinical impact

__Abstract__ Each year, approximately 5-10% of the world population is infected with the influenza viruses resulting in significant morbidity and an estimated 250.000 to 500.000 deaths every year. Among individuals at increased risk of developing severe influenza disease are those with a compromised immune system. For them being able to effectively suppress viral replication antiviral therapy can be crucial. However, in immunocompromised patients the currently available antiviral drugs show limited effectiveness. The emergence and spread of antiviral resistant viruses limit current therapeutic intervention even more. The aim of this thesis is to improve our understanding of influenza antiviral resistance. We developed new molecular tools to aid in influenza patient management, characterised a novel I222R antiviral resistance mutation and developed an immunocompromised ferret model. Finally, a key role for the influenza hemagglutinin in neuraminidase inhibitor resistance is proposed in the general discussion of this thesis. The contribution of the hemagglutinin in neuraminidase inhibitor resistance may explain the emergence of the H274Y oseltamivir-resistant influenza A/H1N1 virus in the winter season of 2007/2008

Spatial and temporal patterns of carabid activity-density in cereals do not explain levels of predation on weed seeds

Seed predation is an important component of seed mortality of weeds in agro-ecosystems, but the agronomic use and management of this natural weed suppression is hampered by a lack of insight in the underlying ecological processes. In this paper, we investigate whether and how spatial and temporal variation in activity-density of granivorous ground beetles (Coleoptera: Carabidae) results in a corresponding pattern of seed predation. Activity-density of carabids was measured by using pitfall traps in two organic winter wheat fields from March to July 2004. Predation of seeds (Capsella bursa-pastoris, Lamium amplexicaule, Poa annua and Stellaria media) was assessed using seed cards at the same sites and times. As measured by pitfall traps, carabids were the dominant group of insects that had access to the seed cards. In the field, predation of the four different species of seed was in the order: C. bursa-pastoris>P. annua>S. media>L. amplexicaule; and this order of preference was confirmed in the laboratory using the dominant species of carabid. On average, seed predation was higher in the field interior compared to the edge, whereas catches of carabids were highest near the edge. Weeks with elevated seed predation did not concur with high activity-density of carabids. Thus, patterns of spatial and temporal variation in seed predation were not matched by similar patterns in the abundance of granivorous carabid beetles. The lack of correspondence is ascribed to effects of confounding factors, such as weather, the background density of seeds, the composition of the carabid community, and the phenology and physiological state of the beetles. Our results show that differences in seed loss among weed species may be predicted from laboratory trials on preference. However, predator activity-density, as measured in pitfall traps, is an insufficient predictor of seed predation over time and space within a fiel

Investeren in competenties; een onderzoek in de Greenports

Inventarisatie van de huidige en toekomstige vraag/behoeftes aan competenties bij ondernemers, managers en werknemers in het tuinbouwcluste

Alter ego, state of the art on user profiling: an overview of the most relevant organisational and behavioural aspects regarding User Profiling.

This report gives an overview of the most relevant organisational and\ud behavioural aspects regarding user profiling. It discusses not only the\ud most important aims of user profiling from both an organisation’s as\ud well as a user’s perspective, it will also discuss organisational motives\ud and barriers for user profiling and the most important conditions for\ud the success of user profiling. Finally recommendations are made and\ud suggestions for further research are given

Public interests in the implementation of the EU ETS in the Netherlands: stakeholder perspectives - 61

Political Science; IC

The BAPRAS screening tool for reimbursement in a postbariatric population

Introduction: Reimbursement of body-contouring surgery (BCS) is a worldwide problem: there is no objective instrument to decide which postbariatric patients should qualify for reimbursement. The British Association of Plastic, Reconstructive and Aesthetic Surgeons (BAPRAS) has developed a screening tool for this purpose. In this study, we used a modified version of this screening tool in a postbariatric population and describe which patients would qualify for reimbursement using this tool. Methods: In this cross-sectional study postbariatric patients were asked to fill in an online questionnaire based on the BAPRAS screening tool with questions regarding complaints of overhanging skin and medical history. Weight loss data were extracted from a prospective database. The BODY-Q was added to assess patient-reported outcomes. Results: Patients who wanted to undergo BCS (n = 90) had higher screening tool scores and lower BODY-Q scores compared to patients who did not want BCS (n = 24). In total, 25 patients (26%) qualified for reimbursement, these patients had higher weight loss (33.5% versus 29.2%, p = 0.008), lower BMI (27.3 kg/m2 versus 30.4 kg/m2, p = 0.014) and more medical (4.0 versus 2.0, p = 0.004) and psychological complaints (88% versus 61%, p = 0.009). There was a significant, negative correlation between the screening tool scores and almost all BODY-Q scales. Conclusions: Patients with a desire for BCS have more complaints of excess skin, which negatively impacts their well-being. With the modified BAPRAS screening tool, patients with the best weight (loss) and most medical and psychological complaints of excess skin qualified for referral and reimbursement of BCS

Susceptibility of influenza B viruses to neuraminidase inhibitors: findings from the first 4 years (2008–2012) of the global Influenza Resistance Information Study (IRIS)

Poster Session: Antiviral Drugs and ResistanceBackground: Type B influenza virus infections continue to account for a substantial proportion of clinical illness. Little is known about comparative disease profiles by virus lineage. A global observational trial (the Influenza Resistance Information Study or IRIS; NCT00884117) was initiated to study neuraminidase inhibitor (NAI) susceptibility and the clinical and virological course of influenza in treated and untreated patients. Materials and Methods: Patients in the northern and southern hemispheres (USA, France, Germany, Poland, Norway, Hong Kong, Australia) with influenza-like illness and/or a positive rapid influenza test result were enrolled. Throat/nasal swabs were performed on Days 1, 3 (self-swab), 6 and 10 and tested for influenza A and B viruses by RT-PCR. Influenzapositive samples collected on Days 1, 6 or 10 were cultured and subsequently sequenced (HA and NA) and phenotypically tested for NAI susceptibility. The lineage of B viruses was determined from sequencing. Clinical information, including the scoring of seven influenza symptoms (scale: 0 [absent], 1 [mild], 2 [moderate], 3 [severe]), was recorded on diary cards by the patient or the patient’s legal guardian (Days 1–12). Symptoms were also assessed by the investigator at each visit. The decision to prescribe an NAI was left to the physician’s discretion. Results: In the first 4 years of IRIS (December 2008 to March 2012), 2262 influenza-positive (RT-PCR) patients were enrolled, of whom 697 presented with a type B influenza virus infection (564 Victoria, 98 Yamagata, 35 undetermined lineage). Most type B patients (402; 58%) were children aged < 13 years. A total of 330 (47%) type B patients were treated with oseltamivir (as monotherapy) within 2 days of symptom onset; a further 26 started oseltamivir 2 days after symptom onset. Eleven patients received zanamivir, one received amantadine and another received rimantidine. A total of 328 (47%) did not receive any influenza antiviral. Symptoms were mild to moderate on Day 1 (mean total score: 12.8, treated; 12.9, untreated), and the mean temperature on Day 1 was 38.2°C. All viruses obtained at baseline or postbaseline were susceptible to NAIs: mean (SD) IC50 values for oseltamivir were 4.8 nM (2.5 nM) and 5.5 nM (2.3 nM) for the Victoria and Yamagata viruses, respectively; the corresponding values for zanamivir were 2.0 nM (1.4 nM) and 2.9 nM (1.6 nM), respectively. No known NAI resistance mutations were detected by NA or HA population sequencing. The proportion of RT-PCR–positive patients on Day 6 was 130/309 (42.1%) for patients treated with oseltamivir and 152/312 (48.7%) for untreated patients. In Kaplan–Meier analyses, no significant differences in median time to influenza RNA clearance were found between oseltamivir-treated and -untreated patients, either in adults or children. The time to symptom resolution (all symptom scores ≤ 1) was 5 days (95% CI, 4–5 days) in oseltamivir-treated children and 6 days (95% CI, 5–6 days) in untreated children (P = .026), but no significant difference in symptom resolution time was found in adults (Kaplan–Meier analysis). Conclusions: Analysis of type B influenza viruses obtained globally between 2008 and 2012 showed that all pre-treatment B/Victoria and B/Yamagata viruses were susceptible to oseltamivir and zanamivir. Moreover, no resistant viruses were detected during treatment. Given the non-randomised design of this study, no definitive conclusions can be drawn with regard to the clinical benefit of oseltamivir in patients infected with type B influenza viruses.published_or_final_versio

The burden of depression and anxiety among medical students in South Africa: A cross-sectional survey at the University of Cape Town

Background. Depressive and anxiety disorders occur at very high rates among medical students. For instance, an international review and meta-analysis estimated the overall pooled crude prevalence of depression or depressive symptoms at 27.2%. However, South African (SA) data are very limited.Objectives. To determine rates of depression and anxiety among medical students and to examine the associations with various sociodemographic variables (biological sex, gender identity, household income, ethnicity, and clinical v. pre-clinical students). We also examined whether the ‘mini-semester’ of 2017 resulting from the 2016 ‘Fees Must Fall’ student protests was associated with increased depression/anxiety.Methods. The study was a cross-sectional electronic survey conducted in the Faculty of Health Sciences, University of Cape Town, using an anonymous, self-administered online questionnaire. The questionnaire included basic sociodemographic questions, the Patient Health Questionnaire-9 and the Hospital Anxiety and Depression Scale.Results. The sample consisted of 473 medical students, 333 (70.4%) female and 140 (29.6%) male. Based on ethnic self-identification, 165 (35.6%) were black, 144 (31.1%) white, 88 (19%) coloured, 52 (11.2%) Indian and 8 (1.7%) Asian. There were 239 pre-clinical students (50.5%) and 234 clinical students (49.5%). Of the sample, 36.4% were above the cut-off for major depressive disorder and 45.9% for anxiety disorder. Reported rates of disorders diagnosed by a health professional were 25.0% for depressive disorder and 20.5% for anxiety disorder, and 28.1% of all students were receiving psychotropic medication. Female sex was associated with both depression (prevalence ratio (PR) 3.7; p&lt;0.001) and anxiety diagnoses (PR 4.7; p&lt;0.001). None of the other sociodemographic characteristics showed significant associations. Interestingly, students who undertook the 2017 mini-semester showed an increased rate of depression (PR 2.1; p&lt;0.05) and anxiety diagnoses (PR 2.1; p&lt;0.05).Conclusions. Nearly one in four students reported depression/anxiety diagnoses and were on psychotropic medication, significantly more than age-based expectations. Even more screened positive for risk of depression/anxiety. Our findings indicate that medical students, particularly females, are at a significantly increased risk of depression and anxiety disorders. Results suggest that the 2016 student protests may have had a direct impact on the mental state of students. Multidisciplinary efforts should be targeted at initiatives to strengthen mental wellbeing and institutional culture around mental health. These efforts may help build resilience in the next generation of health professionals in SA ahead of work in an overburdened health and health education system.