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OBJECTIVE: The objective of this study was to measure humoral responses after SARS-CoV-2 vaccination in MS patients treated with ocrelizumab (OCR) compared to MS patients without disease modifying therapies (DMTs) in relation to timing of vaccination and B-cell count.METHODS: OCR treated patients were divided into an early and a late group (cut-off time 12 weeks between infusion and first vaccination). Patients were vaccinated with mRNA-1273 (Moderna). B-cells were measured at baseline (time of first vaccination) and SARS-CoV-2 antibodies were measured at baseline, day 28, 42, 52 and 70.RESULTS: 87 patients were included (62 OCR patients, 29 patients without DMTs). At day 70, seroconversion occurred in 39.3% of OCR patients compared to 100% of MS patients without DMTs. In OCR patients, seroconversion varied between 26% (early group) to 50% (late group) and between 27% (low B-cells) to 56% (at least 1 detectable B-cell/µL).CONCLUSIONS: Low B-cell counts prior to vaccination and shorter time between OCR infusion and vaccination may negatively influence humoral response but does not preclude seroconversion. We advise OCR treated patients to get their first vaccination as soon as possible. In case of an additional booster vaccination, timing of vaccination based on B-cell count and time after last infusion may be considered.

Introduction: The Dutch Gynecological Oncology Audit (DGOA) was initiated in 2014 to serve as a nationwide audit, which registers the four most prevalent gynecological malignancies. This study presents the first results of clinical auditing for ovarian cancer in the Netherlands.Methods: The Dutch Gynecological Oncology Audit is facilitated by the Dutch Institute of Clinical Auditing (DICA) and run by a scientific committee. Items are collected through a web-based registration based on a set of predefined quality indicators. Results of quality indicators are shown, and benchmarked information is given back to the user. Data verification was done in 2016. Results: Between January 01, 2014 and December 31, 2018, 6535 patients with ovarian cancer were registered. The case ascertainment was 98.3% in 2016. The number of patients with ovarian cancer who start therapy within 28 days decreased over time from 68.7% in 2014 to 62.7% in 2018 (p < 0.001). The percentage of patients with primary cytoreductive surgery decreased over time (57.8%-39.7%, P < 0.001). However, patients with complete primary cytoreductive surgery improved over time (53.5%-69.1%, P < 0.001). Other quality indicators did not significantly change over time.Conclusion: The Dutch Gynecological Oncology Audit provides valuable data on the quality of care on patients with ovarian cancer in the Netherlands. Data show variation between hospitals with regard to pre-determined quality indicators. Results of 'best practices' will be shared with all participants of the clinical audit with the aim of improving quality of care nationwide.(c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license(http://creativecommons.org/licenses/by/4.0/).

Objectives. The challenge when performing cytoreductive surgery (CRS) is to balance the benefits and risks. The aim of this study was to report short term postoperative morbidity and mortality in relation to surgical outcome in patients undergoing primary debulking surgery (PDS) or interval debulking (IDS) surgery in the Netherlands. Methods. The Dutch Gynecological Oncology Audit (DGOA) was used for retrospective analysis. Patients undergoing PDS or IDS between January 1st, 2015 -December 31st, 2018 were included. Outcome was frequency of postoperative complications. Median time to adjuvant chemotherapy and severity of complications were related to outcome of CRS. Complications with Clavien-Dindo >= 3 were analyzed per region and case mix corrected. Statistical analysis was performed with R.Studio. Results. 1027 patients with PDS and 1355 patients with IDS were included. Complications with re-invention were significantly higher in PDS compared to IDS (5.7% vs. 3.6%, p = 0.048). Complete cytoreduction was 69.7% in PDS and 62.1% IDS, p < 0.001. Time to adjuvant chemotherapy was 49 days in patients with complete CRS and a complication with re-intervention. Regional variation for severe complications showed one region outside confidence intervals. Conclusions. Higher complete cytoreduction rate in the PDS group indicates that the correct patients have been selected, but is associated with a higher percentage of complication with re-intervention. As result, time to start adjuvant chemotherapy is longer in this group. Maintaining a balance in aggressiveness of surgery and outcome of the surgical procedure with respect to severe complications is underlined. Bench marked data should be discussed nationally to improve this balance. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

HIV-1 cell entry is mediated by binding to the CD4-receptor and chemokine co-receptors CCR5 (R5) or CXCR4 (X4). R5-tropic viruses are predominantly detected during early infection. A switch to X4-tropism often occurs during the course of infection. X4-tropism switching is strongly associated with accelerated disease progression and jeopardizes CCR5-based HIV-1 cure strategies. It is unclear whether host immunological factors play a causative role in tropism switching. We investigated the relationship between immunological factors and X4-tropism in a cross-sectional study in HIV-1 subtype C (HIV-1C)-infected patients and in a longitudinal HIV-1 subtype B (HIV-1B) seroconverter cohort. Principal component analysis identified a cluster of immunological markers (%HLA-DR+ CD4+ T-cells, %CD38+HLA-DR+ CD4+ T-cells, %CD38+HLA-DR+ CD8+ T-cells, %CD70+ CD4+ T-cells, %CD169+ monocytes, and absolute CD4+ T-cell count) in HIV-1C patients that was independently associated with X4-tropism (aOR 1.044, 95% CI 1.003–1.087, p = 0.0392). Analysis of individual cluster contributors revealed strong correlations of two markers of T-cell activation (%HLA-DR+ CD4+ T-cells, %HLA-DR+CD38+ CD4+ T-cells) with X4-tropism, both in HIV-1C patients (p = 0.01;p = 0.03) and HIV-1B patients (p = 0.0003;p = 0.0001). Follow-up data from HIV-1B patients subsequently revealed that T-cell activation precedes and independently predicts X4-tropism switching (aHR 1.186, 95% CI 1.065–1.321, p = 0.002), providing novel insights into HIV-1 pathogenesis and CCR5-based curative strategies.

Funding: This study was funded by the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013) / ERC Grant Agreement n. 615159 (ERC Consolidator Grant DEPRIVEDHOODS, Socio-spatial inequality, deprived neighbourhoods, and neighbourhood effects). Contextual poverty refers to high proportions of people with a low income in a certain (residential) space, and it can affect individual socioeconomic outcomes as well as decisions to move into or out of the neighbourhood. Contextual poverty is a multiscale phenomenon: Poverty levels at the regional scale reflect regional economic development, while meso-scale concentrations of poverty within cities are related to city-specific social, economic and housing characteristics. Within cities, poverty can also concentrate at micro spatial scales, which are often neglected, largely due to a lack of data. Exposure to poverty at lower spatial scales, such as housing blocks and streets, is important because it can influence individuals through social mechanisms such as role models or social networks. This paper is based on the premise that sociospatial context is necessarily multiscalar,and therefore contextual poverty is a multiscale problem which can be better understood through the inequality within and between places at different spatial scales. The question is how to compare different spatial contexts if we know that they include various spatial scales. Our measure of contextual poverty embraces 101spatial scales and compares different locations within and between municipalities in the Netherlands. We found that the national inequality primarily came from the concentrations of poverty in areas of a few kilometres, located in cities, which have different spatial patterns of contextual poverty, such as multicentre, core-periphery and east-west. In addition to the inequality between municipalities, there are considerable within-municipality inequalities, particularly among micro-areas of a few hundred metres. Publisher PDF

BackgroundMany countries are promoting booster SARS-CoV-2 vaccination campaigns as the COVID-19 pandemic continues. Incremental short-term adverse events after two SARS-CoV-2 vaccinations have been reported in healthy individuals.1,2 However, data on incremental short-term adverse events in patients with various immune-mediated inflammatory diseases (IMIDs) after repeated SARS-CoV-2 vaccination is scarce.ObjectivesWe report risk factors for short-term adverse events in IMID patients after SARS-CoV-2 vaccination.MethodsSelf-reported daily questionnaires on adverse events in the first seven days after SARS-CoV-2 vaccination were obtained from individuals participating in an ongoing prospective multi-arm multicenter cohort study on SARS-CoV-2 vaccination in patients with various IMIDs in the Netherlands (T2B! immunity after SARS-CoV-2). Clinically relevant adverse events were defined as systemic adverse advents lasting longer than two days or hindering daily activities. Adjusted relative risks for developing clinically relevant adverse events were calculated using a logistic mixed-effects model.ResultsData of 2081 patients and 178 healthy controls were obtained. Inflammatory bowel disease (N:480), Multiple sclerosis (N:343) and Rheumatoid arthritis (N:266) were the largest disease groups. Adjusted relative risks for relevant adverse events are presented in Figure 1. Third vaccination was not associated with increased risk on adverse events when compared to a second vaccination (aRR: 0.93 95% CI: 0.84-1.02). Patients with IMIDs were at increased risk for developing adverse events after vaccination when compared to controls (aRR: 1.16 95% CI: 1.01-1.34). Female sex (aRR 1.43 95% CI: 1.32-1.56), age below 50 (aRR 1.14 95% CI: 1.06-1.23) and a preceding SARS-CoV-2 infection (aRR: 1.14 95% CI: 1.01-1.29) were also associated with increased risk of adverse events following vaccination. Allergic reactions and hospital admission were uncommon (0.67% and 0.19% respectively); 7.4% and 6.8% of patients reported adverse events impacting daily life on day seven after second and third vaccination, respectively. Data on increase in disease activity of the IMID following vaccination are currently being investigated.Figure 1.Risk factors for adverse events after SARS-CoV-2 vaccination in patients with immune-mediated inflammatory diseaseConclusionA third SARS-CoV-2 vaccination was not associated with an increased risk on short-term clinically relevant adverse events when compared to a second vaccination. Although patients with IMIDs may be slightly more at risk to develop adverse events after SARS-CoV-2 vaccination, most adverse events were transient and disappeared within seven days. This message should reassure IMID patients who are hesitant on booster vaccination. Data on potential IMID flare-ups after vaccination will follow.References[1]Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med. 2020;383(27):2603-2615. doi:10.1056/NEJMoa2034577[2]Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 2021;384(5):403-416. doi:10.1056/NEJMoa2035389AcknowledgementsWe would like to thank ZonMw (The Netherlands Organization for Health Research and Development, grant 10430072010007) for the funding of the study and the T2B partners, including the patient groups and Health Holland for the support in this study. Also, we would like to thank E.P. Moll van Charante, J.A Bogaards and R.A. Scholten for their guidance in the data safety monitoring board.Disclosure of InterestsLaura Kummer: None declared, Luuk Wieske: None declared, Eileen Stalman: None declared, Koos van Dam: None declared, Laura Boekel: None declared, Gertjan Wolbink Grant/research support from: GW reported a grant from ZonMW (Netherlands Organization for Healthcare research and Innovation) for COVID research in patients with auto-immune diseases., Adriaan Volkers: None declared, Maurice Steenhuis: None declared, Niels Verstegen: None declared, Theo Rispens: None declared, Anja ten Brinke: None declared, Zoé van Kempen: None declared, Sander Tas: None declared, Marieke van Ham: None declared, Taco Kuijpers Grant/research support from: TW reported a grant from ZonMW (Netherlands Organization for Healthcare research and Innovation) for COVID research in patients with auto-immune diseases., Filip Eftimov Grant/research support from: FE reported a grant from ZonMW (Netherlands Organization for Healthcare research and Innovation) for COVID research in patients with auto-immune diseases.

BackgroundConcerns have been raised regarding risks of COVID-19 breakthrough infections in vaccinated patients with immune-mediated inflammatory diseases (IMIDs) treated with immunosuppressants, but data on COVID-19 breakthrough infections in these patients are still scarce.ObjectivesThe primary objective was to compare the incidence and severity of COVID-19 breakthrough infections with the SARS-CoV-2 delta variant between fully vaccinated IMID patients with immunosuppressants, and controls (IMID patients without immunosuppressants and healthy controls). The secondary objective was to explore determinants of breakthrough infections.MethodsIn this study we pooled data collected from two large ongoing prospective multi-center cohort studies (Target to-B! [T2B!] study and ARC study). Clinical data were collected between February and December 2021, using digital questionnaires, standardized electronic case record forms and medical files. Post-vaccination serum samples were analyzed for anti-RBD antibodies (T2B! study only) and anti-nucleocapsid antibodies to identify asymptomatic breakthrough infections (ARC study only). Logistic regression analyses were used to assess associations with the incidence of breakthrough infections. Multivariable models were adjusted for age, sex, cardiovascular disease, chronic pulmonary disease, obesity and vaccine type.ResultsWe included 3207 IMID patients with immunosuppressants and 1810 controls (985 IMID patients without immunosuppressants and 825 healthy controls). The incidence of COVID-19 breakthrough infections was comparable between patients with immunosuppressants (5%) and controls (5%). The absence of SARS-CoV-2 IgG antibodies after COVID-19 vaccination was independently associated with an increased incidence of breakthrough infections (P 0.044). The proportion of asymptomatic COVID-19 breakthrough cases that were additionally identified serologically in the ARC cohort was comparable between IMID patients with immunosuppressants and controls; 66 (10%) of 695 patients vs. 64 (10%) of 647 controls. Hospitalization was required in 8 (5%) of 149 IMID patients with immunosuppressants and 5 (6%) of 86 controls with a COVID-19 breakthrough infection. Hospitalized cases were generally older, and had more comorbidities compared with non-hospitalized cases (Table 1). Hospitalization rates were significantly higher among IMID patients treated with anti-CD20 therapy compared to IMID patients using any other immunosuppressant (3 [23%] of 13 patients vs. 5 [4%] of 128 patients, P 0.041; Table 1).Table 1.Determinants of the severity of COVID-19 breakthrough infections.Ambulatory care (n = 222)Hospitalized (n = 13)Group - no. (%)IMID patients with immunosuppressants141(64)8(62)IMID patients without immunosuppressants49(22)3(23)Healthy controls32(14)2(15)Patient characteristicsAge, years – mean (SD)51(14)60(11)Female sex – no. (%)143(64)4(31)Comorbidities – no. (%)Cardiovascular disease17(8)5(39)Chronic pulmonary disease17(8)4(31)Diabetes15(7)3(23)Obesity34(15)5(39)Immunosuppressants– no. (%)Methotrexate36(16)2(15)TNF inhibitor48(22)2(15)Anti-CD20 therapy13(6)3(23)Mycophenolate mofetil3(1)0(0)S1P modulator5(2)0(0)Other immunosuppressants70(32)3(23)ConclusionThe incidence of COVID-19 breakthrough infections in IMID patients with immunosuppressants was comparable to controls, and infections were mostly mild. Anti-CD20 therapy might increase patients’ susceptibility to severe COVID-19 breakthrough infections, but traditional risk factors also continue to have a critical contribution to the disease course of COVID-19. Therefore, we argue that most patients with IMIDs should not necessarily be seen as a risk group for severe COVID-19, and that integrating other risk factors should become standard practice when discussing treatment options, COVID-19 vaccination, and adherence to infection prevention measures with patients.Disclosure of InterestsNone declared

IgE responses against allergens have acquired much attention due to their pathogenic nature as mediators of allergic reactions. In contrast, IgE responses against vaccines like Diphtheria-Tetanus-Pertussis (DTP) and the potential persistence of IgE production have received relatively little attention, presumably because of the low prevalence of allergic symptoms. In general, common early sensitivity reactions against vaccines, including tetanus toxoid, consist of mild local reactions and are not contraindicative of future vaccinations (1, 2). This article is protected by copyright. All rights reserved

Background The aim of this study was to investigate the effect of various immunosuppressants on the humoral immune responses after vaccination against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs). Methods The Target to B! SARS-CoV-2 study is a multicentre study, taking place in 7 Dutch academic hospitals. Patients with the following IMIDs were recruited: Crohn’s disease (CD), ulcerative colitis (UC), auto-immune hepatitis, rheumatic (e.g. rheumatoid arthritis), neurological (e.g. multiple sclerosis) and dermatological IMIDs (e.g. atopic dermatitis). Patients were recruited based on immunosuppressants (table 1) and previous SARS-CoV-2 infection. The control group consisted of healthy subjects and IMID patients without immunosuppressants. SARS-CoV-2 receptor binding domain (RBD) antibodies were measured 28 days after completed SARS-CoV-2 vaccination. Seroconversion was defined as anti-RBD IgG >4 AU/mL. In this abstract, we focus on therapies relevant for inflammatory bowel diseases (IBD) and present results for these treatments from patients with IBD, but also other IMIDs. Results Numbers of recruited patients with each immunosuppressant are shown in table 1. Amongst these patients, 312 patients had CD and 176 UC, the rest was diagnosed with another IMID. Seroconversion was reduced in patients receiving sphingosine 1-phosphate (S1P) modulators (all multiple sclerosis patients) while seroconversion was similar to controls in the other treatment groups. However, use of Anti-tumour necrosis factor (TNF), methotrexate, janus kinase (JAK) inhibitor monotherapy and all combination therapies (except for corticosteroids combined with other immunosuppressants) were associated with reduced Sars-CoV-2 antibody titres. Patients with a previous SARS-CoV-2 infection had higher median antibody titres after second vaccination than those without a previous SARS-CoV-2 infection. The type of IMID did not affect seroconversion rates. Conclusion No immunosuppressant, registered for IBD, reduced the rates of seroconversion after vaccination against SARS-CoV-2. Some immunosuppressants were associated with lower antibody titres. However, the clinical relevance of lower antibody titres remains unknown. S1P modulators, had a clear negative impact on the humoral response against SARS-CoV-2 after vaccination. This might be relevant in the future as this therapy is currently being approved for UC. Disease aetiology did not impair immunity against SARS-CoV-2 immunity after vaccination. Disclaimer: Absolute numbers of antibody titres and rates of seroconversion will be reported at the conference and are not reported in this abstract as this might negatively impact the current submission process.

Local governments make use of ‘enterprise language’ to encourage citizens to adopt entrepreneurial behaviour in managing their daily lives and solving problems that emerge in their neighbourhood. In this paper, we examine the use of enterprise language and the promotion of enterprise in Dutch urban policy focusing specifically on how Dutch cities use enterprise language to influence and encourage their inhabitants to undertake entrepreneurial action. Our analysis shows how the language of enterprise helps cities to reinforce a local identity, to legitimize institutional change in local government functioning and to formulate expectations of how citizens (and professionals) should behave. Publisher PDF

Contains fulltext : 229280.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Decrease in skeletal muscle index (SMI) during neoadjuvant chemotherapy (NACT) has been associated with worse outcome in patients with advanced ovarian cancer. To validate these findings, we tested if a decrease in SMI was a prognostic factor for a homogenous cohort of patients who received NACT in the randomized phase 3 OVHIPEC-trial. METHODS: CT-scans were performed at baseline and after two cycles of neoadjuvant chemotherapy in stage III ovarian cancer patients. The SMI (skeletal muscle area in cm(2) divided by body surface area in m(2)) was calculated using SliceOMatic software. The difference in SMI between both CT-scans (ΔSMI) was calculated. Cox-regression analyses were performed to analyze the independent effect of a difference in SMI (ΔSMI) on outcome. Log-rank tests were performed to plot recurrence-free (RFS) and overall survival (OS). The mean number of adverse events per patient were compared between groups using t-tests. RESULTS: Paired CT-scans were available for 212 out of 245 patients (87%). Thirty-four of 74 patients (58%) in the group with a decrease in ΔSMI and 73 of 138 of the patients (53%) in the group with stable/increase in ΔSMI had died. Median RFS and OS did not differ significantly (p = 0.297 and p = 0.764) between groups. Patients with a decrease in SMI experienced more pre-operative adverse events, and more grade 3-4 adverse events. CONCLUSION: Decreased SMI during neoadjuvant chemotherapy was not associated with worse outcome in patients with stage III ovarian cancer included in the OVHIPEC-trial. However, a strong association between decreasing SMI and adverse events was found.

The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013) / ERC Grant Agreement n. 615159 (ERC Consolidator Grant DEPRIVEDHOODS, Socio-spatial inequality, deprived neighbourhoods, and neighbourhood effects). Growing up in a disadvantaged parental neighbourhood is related to long-term exposure to similar neighbourhoods as adults. However, there are multiple socio-spatial contexts besides the residential neighbourhood to which individuals are exposed over the life course, such as households, schools, and places of work and leisure, which also influence their outcomes. For children and adolescents, the school environment is especially important. We argue that leaving these contexts out of consideration in models of neighbourhood effects could lead to a misspecification of the relevance of the residential environment in determining individual outcomes. This study examines the joint influence of the parental background, the parental neighbourhood, and a compositional measure of the childhood school environment, on individual neighbourhood trajectories later in life. We use Dutch longitudinal register data to study a complete cohort of adolescents from 1999 to 2012. We fit cross-classified multilevel models in order to partition the variance of schools and parental neighbourhoods over time. We find that parental neighbourhood quality strongly determines children’s residential outcomes later in life. The variation in individual neighbourhood outcomes at the school-level is explained by the ethnicity, parental income and personal income of the research population, suggesting grouping of children from particular backgrounds into specific school environments. Publisher PDF

This chapter develops a multi-level conceptual model of segregation, by using three conceptual levels – individuals and households, generations, and urban regions. Different socio-economic groups sort into different types of neighbourhoods and other domains, leading to patterns of segregation at the urban regional level. At the same time exposure to different socio-economic contexts also affects individual outcomes, and this subsequently leads to sorting processes into neighbourhoods and other domains. This vicious circle of sorting and contextual effects continuously crosses the three levels, and leads to higher levels of segregation. The chapter concludes with a discussion of several intervention strategies that focus on breaking the vicious circles to improve cities as places of opportunities by investing in people, in places and in transport.

Introduction The latent reservoir is the main barrier on the road to HIV cure, and clinical approaches towards eradication are often evaluated by their effect on proviral DNA. To ensure inclusiveness and representativeness in HIV cure studies, proviral DNA quantification assays that are able to detect all common circulating HIV clades are urgently needed. Here, three HIV DNA assays targeting three different genomic regions were evaluated for their sensitivity and subtype‐tolerance using digital PCR. Methods A subtype‐B‐specific assay targeting gag (GAG) and two assays targeting conserved sequences in ltr and pol (LTR and JO) were assessed for their sensitivity and subtype‐tolerance in digital PCR (Bio‐Rad QX200), using a panel of serially diluted subtype reference plasmids as well as a panel of clinical isolates. Both panels represent subtypes A, B, C, D, F, G and circulating recombinant forms (CRFs) AE and AG, which together are responsible for 94% of HIV infections worldwide. Results HIV subtype was observed to greatly affect HIV DNA quantification results. Robust regression analysis of the serially diluted plasmid panel showed that the GAG assay was only able to linearly quantify subtype B, D and G isolates (4/13 reference plasmids, average R 2 = 0.99), whereas LTR and JO were able to quantify all tested isolates (13/13 reference plasmids, respective average R 2 = 0.99 and 0.98). In the clinical isolates panel, isolates were considered detectable if all replicates produced a positive result. The GAG assay could detect HIV DNA in four out of five subtype B and one out of two subtype D isolates, whereas the LTR and JO assays detected HIV DNA in all twenty‐nine tested isolates. LTR and JO results were found to be equally precise but more precise than GAG. Conclusions The results demonstrate the need for a careful validation of proviral reservoir quantification assays prior to investigations into non‐B subtype reservoirs. The LTR and JO assays can sensitively and reliably quantify HIV DNA in a panel that represents the worldwide most prevalent subtypes and CRFs (A, B, C, D, AE, F, G and AG), justifying their application in future trials aimed at global HIV cure.

Objectives: The objective of this study was to define the natural genotypic variation of the HIV-1 integrase gene across Europe for epidemiological surveillance of integrase strand-transfer inhibitor (InSTI) resistance. Methods: This was a multicentre, cross-sectional study within the European SPREAD HIV resistance surveillance programme. A representative set of 300 samples was selected from 1950 naive HIV-positive subjects newly diagnosed in 2006-07. The prevalence of InSTI resistance was evaluated using quality-controlled baseline population sequencing of integrase. Signature raltegravir, elvitegravir and dolutegravir resistance mutations were defined according to the IAS-USA 2014 list. In addition, all integrase substitutions relative to HXB2 were identified, including those with a Stanford HIVdb score >= 10 to at least one InSTI. To rule out circulation of minority InSTI-resistant HIV, 65 samples were selected for 454 integrase sequencing. Results: For the population sequencing analysis, 278 samples were retrieved and successfully analysed. No signature resistance mutations to any of the InSTIs were detected. Eleven (4%) subjects had mutations at resistance-associated positions with an HIVdb score >= 10. Of the 56 samples successfully analysed with 454 sequencing, no InSTI signature mutations were detected, whereas integrase substitutions with an HIVdb score >= 10 were found in 8 (14.3%) individuals. Conclusions: No signature InSTI-resistant variants were circulating in Europe before the introduction of InSTIs. However, polymorphisms contributing to InSTI resistance were not rare. As InSTI use becomes more widespread, continuous surveillance of primary InSTI resistance is warranted. These data will be key to modelling the kinetics of InSTI resistance transmission in Europe in the coming years.

Part of the research leading to these results (Prof Dr Maarten van Ham) has received funding from the Marie Curie programme under the European Union's Seventh Framework Programme (FP/2007-2013) / Career Integration Grant n. PCIG10-GA-2011-303728 (CIG Grant NBHCHOICE, Neighbourhood choice, neighbourhood sorting, and neighbourhood effects). We use electoral data to analyze the ethno-political consequences that may arise from the fact that the region surrounding the city of Vilnius is dominated by residents with a Polish identity, while those who move to the suburbs are mainly ethnic Lithuanians. In the suburban ring we found increasing voting turnout, a decreasing share of votes for the Polish party, and an increase of the absolute number of votes for this party. The changing electoral behavior might be an indicator of growing ethno-political tensions and the zones of the most intense changes identify areas of potential social tensions between ethnic groups. Postprint

HIV presents one of the highest evolutionary rates ever detected and combination antiretroviral therapy is needed to overcome the plasticity of the virus population and control viral replication. Conventional treatments lack the ability to clear the latent reservoir, which remains the major obstacle towards a cure. Novel strategies, such as CRISPR/Cas9 gRNA-based genome-editing, can permanently disrupt the HIV genome. However, HIV genome-editing may accelerate viral escape, questioning the feasibility of the approach. Here, we demonstrate that CRISPR/Cas9 targeting of single HIV loci, only partially inhibits HIV replication and facilitates rapid viral escape at the target site. A combinatorial approach of two strong gRNAs targeting different regions of the HIV genome can completely abrogate viral replication and prevent viral escape. Our data shows that the accelerating effect of gene-editing on viral escape can be overcome and as such gene-editing may provide a future alternative for control of HIV-infection.

A nine-year-old female Rottweiler presented with a 6-week history of progressive impairment of hindlimb adduction. Clinical examination showed abduction of both hind legs when walking on a smooth surface, pain at the medial surface of the left thigh, and an intrarectal palpable mass at the pelvic floor. Electromyography demonstrated fibrillation potentials in the adductor muscles on both sides. Pelvic radiographs showed severe osteolysis of the ischium. Gross post-mortem examination following euthanasia disclosed a large retroperitoneal mass, invading the obturator foramina and compressing both obturator nerves. Histopathological examination revealed a high-grade anaplastic sarcoma. Immunohistochemically, the tumour cells labelled positively for vimentin and alpha-smooth muscle actin, hence the tumour was considered a "myofibroblastic fibrosarcoma". This unique case report describes a novel cause of obturator neuropathy in veterinary medicine. To date, clinical descriptions of obturator nerve lesions have been limited to pelvic fractures in small animals and following difficult labour in large animals.

Guidelines state that the CCR5-inhibitor Maraviroc should be prescribed to patients infected with R5-tropic HIV-1 only. Therefore, viral tropism needs to be assessed phenotypically or genotypically. Preliminary clinical trial data suggest that genotypic analysis in triplicate is associated with improved prediction of virological response by increasing the detection of X4-tropic variants. Our objective was to evaluate the impact of triplicate genotypic analysis on prediction of co-receptor usage in routine clinical practice. Samples from therapy-naive and therapy-experienced patients were collected for routine tropism testing at three European clinical centres. Viral RNA was isolated from plasma and proviral DNA from peripheral blood mononuclear cells. Gp120-V3 was amplified in a triplicate nested RT-PCR procedure and sequenced. Co-receptor usage was predicted using the Geno2Pheno[coreceptor] algorithm and analysed with a false-positive rate (FPR) of 5.75%, 10%, or an FPR of 20% and according to the current European guidelines on the clinical management of HIV-1 tropism testing. A total of 266 sequences were obtained from 101 patient samples. Discordance in tropism prediction for the triplicates was observed in ten samples using an FPR of 10%. Triplicate testing resulted in a 16.7% increase in X4-predicted samples and to reclassification from R5 to X4 tropism for four cases rendering these patients ineligible for Maraviroc treatment. In conclusion, triplicate genotypic tropism testing increases X4 tropism detection in individual cases, which may prove to be pivotal when CCR5-inhibitor therapy is applied.

A number of adducts of general formula Cu(PZ)x2+(anion)2− is reported. In this formula PZ stands for: pyrazole. N-methyl pyrazole. 3(5)-methylpyrazole. 3,5-dimethylpyrazole. 4-chloropyrazole, 4-bromopyrazole and 4-nitropyrazole; the anions are ClO4−, BF4−, NO3−. Br− and Cl−. The value of x varies from 2–4 for the several ligands and anions. The compounds are synthesized from the hydrated Cu(II) salts and the stoichiometric amounts of pyrazoles in ethanol or acetone solutions, with the addition of triethyl orthoformate for dehydration. The adducts were characterized and identified by chemical analyses, infrared spectra, ligand-field spectra and paramagnetic measurements. In all compounds the Cu2+ ions were found to be in a six-coordinate, distorted octahedral environment. In contrast with other divalent metal ions, solvates containing the unit Cu(PZ)62+ could not be prepared.

In autoimmune diseases or transplant graft rejection, a therapy that will prevent or reduce the present immune activation is highly desired. Ex vivo generated tolerogenic dendritic cells (DC) are considered to have a strong potential as cellular therapy for these diseases. One of the mechanisms of immune suppression mediated by tolerogenic DC is the induction of regulatory T-cells (Treg). Consequently, the efficacy of such DC to induce Treg will reflect their tolerogenic capacity. Because no specific markers have been described for human induced (i)Treg yet, the Treg can only be appreciated by functionality. Therefore, we have optimized an in vitro suppression assay to screen for human DC-induced-Treg activity. IL-10-generated tolerogenic DC were used to induce Treg that were previously shown to effectively suppress the proliferation of responder T-cells stimulated with allogeneic mature DC (mDC). Our results show that the suppressive capacity of IL-10 DC-induced Treg measured in the suppression assay increases with the iTreg dose and decreases with higher numbers of antigen-presenting cells (APC) as T-cell stimulation. Lowering the ratio between responder T-cells and stimulator mDC present in the coculture clearly improved the read-out of the suppression assay. Furthermore, mDC-primed T-cells in the suppression assay were shown to be an essential control condition. In conclusion, we recommend titrations of both APC and iTreg in the suppression assay and to include a negative control condition with T-cells primed by mDC, to distinguish specific and functional suppression by iTreg from possible generalized suppressive activity.

Eur J Clin Invest 2010; 40 (1): 4–10 Abstract Background Recent studies indicate a role for complement in the pathogenesis of aortic valve disease. However, the role of naturally occurring anti-complement mediators in this context is unknown. In this study, we have analysed this in three different pathological conditions of the aortic valve: degeneration, atherosclerosis and bacterial endocarditis. Materials and methods Human aortic valves were obtained at autopsy (n = 30): 5 control valves, 10 aortic valves with atherosclerotic changes, 10 aortic valves with degenerative changes and 5 degenerative changed aortic valves with bacterial infection. These valves were analysed immunohistochemically for the presence of activated complement (C3d and C5b9) and the complement inhibitors C1-inh and clusterin. Areas of positivity were then quantified. Results C3d, C5b9 and the complement inhibitors C1-inh and clusterin depositions were mainly found in the endothelium and extracellular matrix in aortic valves. All these mediators were already present in control valves, but the area of positivity increased significantly in response to the different diseases, with the highest increase in response to bacterial endocarditis. Interestingly, in all three aortic diseases, the depositions of complement were significantly more widespread than that of their inhibitors. Conclusions Our study indicates that anti-complement mediators (C1-inh and clusterin) are deposited in diseased aortic valves together with activated complement, indicating an existing counter response against complement locally in the valve. However, deposition of activated complement is significantly more widespread than that of its inhibitors, which could explain ongoing inflammation in those diseased aortic valves.

Objectives: The objective of this study was to define the natural genotypic variation of the HIV-1 integrase gene across Europe for epidemiological surveillance of integrase strand-transfer inhibitor (InSTI) resistance. Methods: This was a multicentre, cross-sectional study within the European SPREAD HIV resistance surveillance programme. A representative set of 300 samples was selected from 1950 naive HIV-positive subjects newly diagnosed in 2006-07. The prevalence of InSTI resistance was evaluated using quality-controlled baseline population sequencing of integrase. Signature raltegravir, elvitegravir and dolutegravir resistance mutations were defined according to the IAS-USA 2014 list. In addition, all integrase substitutions relative to HXB2 were identified, including those with a Stanford HIVdb score=10 to at least one InSTI. To rule out circulation of minority InSTIresistant HIV, 65 samples were selected for 454 integrase sequencing. Results: For the population sequencing analysis, 278 samples were retrieved and successfully analysed. No signature resistance mutations to any of the InSTIswere detected. Eleven (4%) subjects hadmutations at resistance-associated positions with an HIVdb score =10. Of the 56 samples successfully analysed with 454 sequencing, no InSTI signature mutationsweredetected, whereas integrase substitutionswithanHIVdbscore=10were found in8(14.3%) individuals. Conclusions:No signature InSTI-resistant variantswere circulating in Europe before the introduction of InSTIs. However, polymorphisms contributing to InSTI resistancewere not rare. As InSTI use becomes more widespread, continuous surveillance of primary InSTI resistance is warranted. These data will be key to modelling the kinetics of InSTI resistance transmission in Europe in the coming years. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

HIV persists in latently infected cells of patients on antiretroviral therapy (ART). This persistent proviral DNA reservoir is an important predictor of viral rebound upon therapy failure or interruption and forms a major obstacle towards cure. Accurate quantification of the low levels of persisting HIV DNA may aid patient monitoring and cure research. Digital PCR is a promising tool that enables direct absolute quantification with high sensitivity. With recent technological advances, several platforms are available to implement digital PCR in a clinical setting. Here, we compared two digital PCR platforms, the Quantstudio 3D (Life Technologies) and the QX100 (Bio-Rad) with a semi-nested qPCR on serial HIV DNA dilutions and DNA isolated from PBMCs of ART-suppressed patients. All three methods were able to detect target to the lowest levels of 2.5 HIV DNA copies. The QX100 excelled in having the least bias and highest precision, efficiency and quantitative linearity. Patient sample quantifications by the QX100 and semi-nested qPCR were highly agreeable by Bland-Altman analysis (0.01 ± 0.32 log10). Due to the observation of false-positive signals with current digital PCR platforms however, semi-nested qPCR may still be preferred in a setup of low quantity detection to discriminate between presence or absence of HIV DNA.

In two epidemics of bovine ephemeral fever (BEF) in Israel, one in 1990 and one in 1999, the virus was probably carried by vectors transported by air currents across the Rift Valley and through the Red Sea trough. The disease broke out under optimal ecological conditions among vulnerable cattle populations and spread rapidly; it developed in the spring and summer and ended soon after the daily average ambient temperature fell below 16 degrees C in late autumn. The proportion of herds affected reached 78.4 and 97.7 per cent in 1990 and 1999, respectively. The highest rates of incidence, morbidity and mortality were recorded in dairy cattle herds in the Jordan Valley, the initial focus of the outbreaks, with a morbidity of 20 and 38.6 per cent in 1990 and 1999, respectively, and mortality among the affected animals of 2 and 8.6 per cent in 1990 and 1999, respectively. In 1991, the disease recurred sporadically in the central and southern regions of Israel in only three herds, but in 2000 the disease returned on an epidemic scale, and 85 per cent of herds were affected, with morbidity and mortality rates of 4-3 and 0-3 per cent, respectively. In the 1999 epidemic, the morbidity rate decreased from 38-6 per cent on average in the Jordan Valley to 12.8 per cent in the inner valleys and 5.3 per cent on the Mediterranean coastal plain, but the mortality rate increased from 8-6 per cent in the Jordan Valley to 14-3 per cent in the inner valleys, and to 28 per cent on the Mediterranean coastal plain, where the outbreak declined. An average of 2-7 per cent of the animals experienced a second attack of the disease two to six weeks later. The epidemic in 2000 was milder and shorter than that in 1999. All the cattle affected in both outbreaks were more than three months old. The vector(s) is not known for certain but the available evidence indicates that mosquitoes, and not Culicoides species, are the natural vectors of BEF virus in Israel.

Background: Different patterns of drug resistance are observed in treated and therapy naive HIV-1 infected populations. Especially the NRTI-related M184I/V variants, which are among the most frequently encountered mutations in treated patients, are underrepresented in the antiretroviral naive population. M184I/V mutations are known to have a profound effect on viral replication and tend to revert over time in the new host. However it is debated whether a diminished transmission efficacy of HIV variants with a reduced replication capacity can also contribute to the observed discrepancy in genotypic patterns. As dendritic cells (DCs) play a pivotal role in HIV-1 transmission, we used a model containing primary human Langerhans cells (LCs) and DCs to compare the transmission efficacy M184 variants (HIV-M184V/I/T) to HIV wild type (HIV-WT). As control, we used HIV harboring the NNRTI mutation K103N (HIV-K103N) which has a minor effect on replication and is found at a similar prevalence in treated and untreated individuals. Results: In comparison to HIV-WT, the HIV-M184 variants were less efficiently transmitted to CCR5(+) Jurkat T cells by both LCs and DCs. The transmission rate of HIV-K103N was slightly reduced to HIV-WT in LCs and even higher than HIV-WT in DCs. Replication experiments in CCR5(+) Jurkat T cells revealed no apparent differences in replication capacity between the mutant viruses and HIV-WT. However, viral replication in LCs and DCs was in concordance with the transmission results; replication by the HIV-M184 variants was lower than replication by HIV-WT, and the level of replication of HIV-K103N was intermediate for LCs and higher than HIV-WT for DCs. Conclusions: Our data demonstrate that drug resistant M184-variants display a reduced replication capacity in LCs and DCs which directly impairs their transmission efficacy. As such, diminished transmission efficacy may contribute to the lower prevalence of drug resistant variants in therapy naive individuals.

By means of repeated, well-supported measurements of clinical dynamic indicators from the Historical, Clinical and Future - 30 (HKT-30) it is possible to monitor behavioural changes on the basis of risks and needs. The addition of extra score parameters allows us to distinguish client-specific risks and needs. In treatment evaluation it is important to visualise changes in these indicators of treatment evaluation because they are the key to the clinical decision-making process that determines further treatment and rehabilitation.To investigate whether HKT-30 indicators can be used to measure and visualise behavioral changes for the purpose of treatment evaluation.A case study is used to illustrate how clinicians at the Forensic Psychiatric Clinic (FPK), De Woenselse Poort, ascertain risks, needs and changes and clarify these factors for the purpose of treatment evaluation and clinical decision-making.Routine treatment evaluation aided by visualised clinical HKT-30 indicators give the treatment team and the client a clearer picture of the behavioral changes for which the forensic treatment was prescribed. This evaluation provides significant starting-points for clinical decision making.Routine treatment evaluation along with a suitably adjusted HKT-30 make behavioural changes visible, render clinical decisions more transparent and provide valuable starting-points for a dialogue with the client about his treatment.

The "Berlin patient" is the first patient cured of HIV-1 infection after allogeneic transplantation with nonfunctional CCR5 coreceptor stem cells. We demonstrate that CXCR4-predicted minority viruses present prior to transplantation were unable to rebound after transplantation due to their dependence on CCR5 for replication and high genetic barrier toward CXCR4 usage.

A nine-year-old male Maltese dog was presented with an eight-month history of inspiratory stridor leading to exertional dyspnoea and cyanosis. Myokymic contractions in the palatolingual muscles were noticed and confirmed by electromyography. Brain computer tomography-scan showed ventricular dilatation. Cerebrospinal fluid analysis revealed a slightly elevated protein level. Treatment with slow-release phenytoin was unsuccessful and symptoms gradually worsened over the next nine months. At post-mortem examination a small pituitary adenoma was found. Apart from a single canine report of facial myokymia, this is the only other description of spontaneous focal myokymia in animals. Palatolingual myokymia has only been reported in one human being. Although the co-occurrence with a pituitary adenoma might be incidental, a paraneoplastic pathogenetic mechanism is proposed. Its unique clinical presentation adds a new, albeit uncommon, syndrome to the differential diagnosis of upper airway complaints in dogs.

Antigenic peptide binding to MHC class II molecules in the endocytic pathway occurs via a multifactorial process that requires the support of a specialized lysosomal chaperone called HLA-DM. DM shows both in primary amino acid sequence and quaternary structure a high homology to both MHC class I and class II molecules. Like the peptide presenting class II molecules, DM is expressed in all professional antigen presenting cells. DM catalyzes the dissociation of peptides that do not bind stably to the class II peptide-binding groove, thereby leading to the preferential presentation of stably binding antigenic peptides. The recently discovered HLA-DO molecule is mainly expressed in B cells and associates with DM, thereby markedly affecting DM function. Like DM, the genes encoding the HLA-DO heterodimer lie within the MHC class II region and exhibit strong homology to classical class II molecules. This review evaluates the unique effects of DO on DM-mediated antigen presentation by MHC class II molecules and discusses the possible physiological relevance for the B cell-specific expression of DO and its function.

BOVINE necrotic vulvovaginitis (BNVV) is a severe condition, with significant economic consequences. Possible causes include Porphyromonas levii, a Gram-negative obligate anaerobe that forms pigmented colonies on suitable media, and bovine herpesvirus type 4 (BHV-4), a member of the gamma herpesviruses (Bublot and others 1992). P levii has been recovered from bovine rumens and from cases of mastitis and foot rot. Moreover, P levii-like microorganism has been isolated from human beings with vaginosis (Hillier and others 1993). Investigation of P levii virulence factors have indicated that the microorganism is able to produce an anti-immunoglobulin G2 protease or possibly several proteases (Lobb and others 1999); it can also reduce chemotaxis, phagocytosis, and the oxidative burst of macrophages (Walter and Morck 2002), thus increasing its potential to cause and to maintain an infection. BHV-4 has a worldwide distribution. It has a tropism for lymphoid cells (Egyed and others 1996), and can remain latent and result in persistent infection (Osorio and Reed 1983). Although BHV-4 has been isolated from cattle with a variety of illnesses, including abortion, metritis, endometritis, vaginitis, enteritis and respiratory infection, it has also been isolated from healthy cattle (Frazier and others 2001). The pathogenic role of BHV-4 remains unclear; the direct correlation between particular strains of BHV-4 and different clinical conditions is still unsolved, despite studies involving experimental infection (Donofrio and others 2000). While a possible association between BHV-4 and necrotic vaginitis was reported by Marchot and others (1991), no such correlation was found by Elad and others (2004). This short communication describes the clinical, epizootiological and economic aspects of outbreaks of BNVV in dairy cattle herds in Israel, and is a continuation of the investigation by Elad and others (2004). Field observations were carried out between 2001 and 2004 in 16 family herds and 25 kibbutz herds that had been merged, that is, each herd consisted of local animals and others transferred from one or more dairy farms. Milk production, somatic cell counts, fertility and herd diseases were recorded by computerised dairy management systems. The kibbutz herds each contained 500 to 800 lactating cows and the family herds 80 to 120 lactating cows, all of the IsraeliHolstein breed. Dry cows and heifers were kept in separate sheds, grouped according to age and moved to a common calving pen three to four weeks before calving. The surface area in the calving pens was 6 to 8 m2 per animal. All the cattle were kept under a zero-grazing, loose-housing management system, in completely covered open sheds that were ventilated by means of electric fans. During the spring and summer months, the cattle were crowded in the collecting yard three to five times daily, and showered for 15 to 20 minutes each time to cool them and to reduce their heat stress. All the cows and heifers were observed at least twice daily by the herd personnel and at least twice weekly by the attending veterinarian. BNVV was diagnosed clinically by the typical lesions, as described by Elad and others (2004). Vaginal biopsies were taken from three affected first calvers, fixed in 10 per cent neutral buffered formalin and processed by standard techniques; 5 μm sections were stained with haematoxylin and eosin. Outbreaks of BNVV were diagnosed in eight of the 25 kibbutz dairy cattle herds that were merged (P=0·0603, OR=5·440); two of the affected herds included replacement heifers. Outbreaks were not observed in the 16 combined family herds; however, sporadic cases were diagnosed in two kibbutz herds and in one family herd. The disease occurred in most regions of Israel; it was diagnosed mostly in first calvers, and was prevalent all year round but most prominently during the calving season. The first clinical signs of BNVV were observed three days after calving: erythema progressed to haemorrhagic and inflammatory stages, and finally to necrosis of the vaginal mucous membranes (Fig 1), together with a foul odour and muddy vaginal discharge. An increase in body temperature, tenesmus and perivaginitis were observed in severely affected animals. Treatment consisted of daily vaginal rinses with potassium permanganate or povidone iodine from the onset of

International audience; Advanced concurrency abstractions overcome the drawbacks of low-level techniques such as locks and monitors, freeing programmers that implement concurrent applications from the burden of concentrating on low-level details. However, with current approaches the coordination logic involved in complex coordination schemas is fragmented into several pieces including join patterns, data emissions triggered in different places of the application, and the application logic that implicitly creates dependencies among channels, hence indirectly among join patterns. We present JEScala, a language that captures coordination schemas in a more expressive and modular way by leveraging a seamless integration of an advanced event system with join abstractions. We validate our approach with case studies and provide a first performance assessment.

This research was funded by the ESRC under the Understanding Population Trends and Processes (UPTAP) programme (Award Ref: RES-163-25-0045). Most studies investigating residential segregation of ethnic minorities ignore the fact that the majority of adults live in couples. In recent years there has been a growth in the number of mixed-ethnic unions that involve a minority member and a white member. To our knowledge, hardly any research has been undertaken to explicitly examine whether the ethnic mix within households has an impact on the residential mobility of households in terms of the ethnic mix of destination neighbourhoods. Our study addresses this research gap and examines the tendencies of mobility among mixed-ethnic unions in comparison with their co-ethnic peers. We used data from the Longitudinal Study for England and Wales. Our statistical analysis supports the spatial assimilation theory; ethnic minorities move towards less deprived areas and to a lesser extent also towards less ethnically concentrated areas. However, the types of destination neighbourhood of minority people living in mixed-ethnic unions varied greatly with the ethnicity of the ethnic minority partner. Postprint

OBJECTIVES Using deep sequencing methods, we intensively investigated the selective pressure of maraviroc on the viral population in four patients with dual/mixed HIV-1 experiencing treatment failure. METHODS Patients received maraviroc add-on therapy (n = 4). Tropism was determined by Monogram's Trofile assay and/or 'deep' sequencing. Longitudinal 'deep' sequence analysis used triplicate HIV V3 RT-PCR on plasma samples. Sequences were interpreted using the geno2phenocoreceptor algorithm with a 3.5% false-positive rate (FPR) cut-off. RESULTS Patients had a median viral load of 4.7 log10 HIV RNA copies/mL with a median of 24% chemokine (C-X-C motif) receptor 4 (CXCR4)-using virus at baseline. Following maraviroc exposure, the chemokine (C-C motif) receptor 5 (CCR5)-using virus (R5) plasma viral load decreased by at least 1 log10, and only non-R5 variants with extremely low FPR values predominated after 21 days. Virus with an FPR ≤1.8% accounted for more than 90% of the circulating virus, having expanded to occupy the 'space' left by the suppression of R5 variants. Population genetic estimates of viral fitness in the presence of maraviroc showed a steep rise around an FPR value of 2%. CONCLUSIONS Longitudinal analysis of independent R5 and non-R5 HIV populations shows that maraviroc selects viruses with an extremely low FPR, implying that the antiviral activity of maraviroc may extend to a broader range of HIV variants than previously suspected.

Transmitted resistant HIV may revert to wild-type in the absence of drug pressure due to reduced replication capacity (RC). We observed eight therapy-naive patients infected with HIV harbouring four mutations at nucleoside reverse transcriptase inhibitor (NRTI) resistance-related positions: M41L, T69S, L210E and T215S. If partial reverted resistance patterns like these are detected at baseline, concerns for more extensive resistance in the quasispecies often directs selection of first-line combination antiretroviral therapy (cART) towards more complex regimens.Genotypic resistance testing and phylogenetic analysis was performed using pol sequences of 400 therapy-naive patients and 1322 patients with at least one NRTI-related mutation. Reverse transcriptase (RT) genes were cloned into a reference strain and RC was investigated.Phylogenetic analysis showed that all eight patients are part of a transmission cluster (bootstrap value 92). The patients resided in three distinct geographical regions and were either homosexually or heterosexually infected. Prior negative serology and analysis of base ambiguity demonstrated circulation for at least 7 years. In vivo evolution showed a mixture with wild-type (T215S/T) in only one untreated patient more than 6 years after diagnosis. The reverted resistance pattern did not confer a substantial reduction in RC compared with wild-type, explaining its persistence in vivo and long-term circulation in the population. Four patients started cART; three of them received quadruple cART. All patients showed good virological and immunological response.Long-term circulation transcending distinct regions and transmission groups suggests reversion occurred in previous hosts in the transmission chain. Identification of clusters using epidemiological data and active-partner tracing may broaden therapeutic options in cases of transmitted resistance.

The reverse transcriptase-polymerase chain reaction (RT-PCR) and direct sequencing were employed in the diagnosis and typing of foot-and-mouth disease virus (FMDV) in samples taken during the 1994 disease outbreak in Israel. Using PCR, virus isolation and serological methods it was shown that the 1994 disease outbreak in Israel and other Middle-Eastern countries was caused by O1 type virus. Direct PCR sequencing of VP1 genes and homology analysis of the virus isolates revealed that there were two distinct outbreaks in Israel. The first originated in Jordan, moved to the West Bank territory and then to the Lower Galilee. The second outbreak, caused by another virus, was responsible for disease outbreaks in South Lebanon, Upper Galilee and the Golan Heights. When viral sequences of isolates from the 1993 outbreaks in Egypt and Lebanon were included in the analysis, they showed a high degree of VP1 sequence homology between themselves, suggesting a common origin.

A nine-year-old female Rottweiler presented with a 6-week history of progressive impairment of hindlimb adduction. Clinical examination showed abduction of both hind legs when walking on a smooth surface, pain at the medial surface of the left thigh, and an intrarectal palpable mass at the pelvic floor. Electromyography demonstrated fibrillation potentials in the adductor muscles on both sides. Pelvic radiographs showed severe osteolysis of the ischium. Gross post-mortem examination following euthanasia disclosed a large retroperitoneal mass, invading the obturator foramina and compressing both obturator nerves. Histopathological examination revealed a high-grade anaplastic sarcoma. Immunohistochemically, the tumour cells labelled positively for vimentin and alpha-smooth muscle actin, hence the tumour was considered a "myofibroblastic fibrosarcoma". This unique case report describes a novel cause of obturator neuropathy in veterinary medicine. To date, clinical descriptions of obturator nerve lesions have been limited to pelvic fractures in small animals and following difficult labour in large animals.

International audience; On the one hand, languages like EventJava combine Event- Based Programming with concurrency. On the other hand, extending Aspect-Oriented Programming with concurrency has been studied as well. Seamlessly combining both styles with concurrency in a single language is possible with the right building blocks. We claim that the join is such a build- ing block.

Demand of social housing normally exceeds supply and various allocation mechanisms are used to ensure that social housing is allocated to those most in need. There is large variation in the function and meaning of social housing, the size and quality of the social housing stock, and the allocation mechanisms used between and even within countries. In the last decade there has been a shift across Europe from needs-based to choice-based allocation mechanisms. In the choice-based quasi-market setting, applicants show typical consumer behaviour. Policy-makers try to influence this behaviour and the outcomes of lettings in order to obtain their policy goals. Examples of allocation systems from several countries and their outcomes are discussed.

There is a strong belief among academics and policy-makers that the social and physical environment of neighbourhoods can have an effect on residents’ life chances over and above the effect of their individual characteristics: the so-called neighbourhood effects. There are a range of theoretical explanations for neighbourhood effects from role model effects and peer group influences to stigma and discrimination. Both quantitative and qualitative studies have identified neighbourhood effects on outcomes such as educational achievement, health, employment, social exclusion, and social mobility. There is a lively debate on the theoretical foundations of neighbourhood effects, whether neighbourhood effects really exist, and how to measure them. The main challenge in the empirical investigation of neighbourhood effects is the identification of causal relationships.