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Duurzaamheid is vanaf de start van de verkenningsfase een belangrijk onderdeel van de versterking van de IJsselmeerdijk. De duurzaamheidsdoelen zijn concreet uitgewerkt en voortdurend is tijdens het ontwerpproces gemeten en gezocht naar mogelijkheden om de duurzaamheid te vergroten. Daardoor is een Voorkeursalternatief ontworpen dat in belangrijke mate invulling geeft aan de duurzaamheidsambities.

De IJsselmeerdijk beschermt de diepe Flevopolder tegen het water van het IJsselmeer. In 2018 heeft Waterschap Zuiderzeeland (hierna afgekort als: Zuiderzeeland) beoordeeld of de IJsselmeerdijk zo sterk is als de waterveiligheidsnormen voorschrijven. Dat blijkt niet zo te zijn. Zuiderzeeland is daarom in 2019 gestart met het meerjarige project Versterking IJsselmeerdijk. Het deel van de IJsselmeerdijk dat versterkt moet worden, is 17,6 km lang en ligt aan de noordwestzijde van Oostelijk Flevoland. De waterkering loopt van de Ketelbrug in het noorden tot aan de Houtribdijk in Lelystad. Het projectdoel is het realiseren van een veilige én toekomstbestendige dijk. De nieuwe dijk wordt goed ingepast in de omgeving met behoud van de huidige ruimtelijke kwaliteit en er wordt nadrukkelijk gezocht naar de mogelijkheden voor het inpassen van innovatieve en duurzame oplossingen. Momenteel bevindt het project zich in de Verkenningsfase, volgens de fasering uit het landelijke Hoogwaterbeschermingsprogramma (HWBP). De planning is nu dat de verkenning halverwege 2022 wordt afgerond en resulteert in een Voorkeursbeslissing (VKB). De periode 2022- 2024 staat gepland voor de planuitwerkingsfase, in de periode hierna volgt de realisatiefase.

De IJsselmeerdijk beschermt de diepe Flevopolder tegen het water van het IJsselmeer. In 2018 heeft Waterschap Zuiderzeeland (hierna afgekort als: Zuiderzeeland) beoordeeld of de IJsselmeerdijk zo sterk is als de waterveiligheidsnormen voorschrijven. Dat blijkt niet zo te zijn. Sinds 2017 gelden voor de waterkeringen in Nederland nieuwe wettelijke waterveiligheidsnormen. Deze norm is voor Flevoland strenger dan daarvoor om in te spelen op de gevolgen van klimaatverandering en om de grotere hoeveelheid inwoners en de hogere economische waarde in Flevoland beter te beschermen. De waterkering voldoet ruim niet aan de nieuwe strengere norm die eraan gesteld is. Dat wil niet zeggen dat er op dit moment acuut een onveilige situatie is. Het betekent wel dat een dijkversterking nodig is. Het is de wettelijke taak van het waterschap om de keringen aan de normen te laten voldoen. Zuiderzeeland is daarom in 2019 gestart met dit meerjarige project Versterking IJsselmeerdijk. Het projectdoel is het realiseren van een veilige én toekomstbestendige dijk. De nieuwe dijk wordt goed ingepast in de omgeving met behoud van de huidige ruimtelijke kwaliteit en er wordt nadrukkelijk gezocht naar de mogelijkheden voor het inpassen van innovatieve en duurzame oplossingen. De dijk dient te worden gerealiseerd op basis van een bestuurlijk en maatschappelijk gedragen plan. Momenteel bevindt het project zich in de verkenningsfase, volgens de fasering uit het landelijke Hoogwaterbeschermingsprogramma (HWBP). De planning is nu dat de verkenning halverwege 2022 wordt afgerond en resulteert in een Voorkeursbeslissing (VKB). De periode 2022- 2024 staat gepland voor de planuitwerkingsfase, in de periode hierna volgt de realisatiefase.

Dit document rapporteert over de wijze waarop duurzaamheid is geborgd in het dijkversterkingsproject en over de mate waarin het project recht doet aan de gestelde duurzaamheidsambities. Het geeft een overzicht van de uitgevoerde werkzaamheden en geeft aan wat de resultaten zijn van de verschillende duurzaamheidsonderdelen. Na iedere fase in de planstudie wordt een duurzaamheidsrapportage opgesteld.De rapportage heeft het karakter van een ‘groeidocument’: in elke fase wordt deze rapportage aangevuld en waar nodig aangepast. Op deze manier fungeert het document als een naslagwerk om afwegingen of keuzes te herleiden, maar ook als een toetsingsdocument om na te gaan in welke mate invulling wordt gegeven aan de ambities en wat nog moet gebeuren. Het doel van dit document is: 1. Aangeven in welke mate de duurzaamheidsambities zijn gerealiseerd of nog kunnen worden gerealiseerd; 2. Vastleggen van uitgevoerde werkzaamheden, afwegingen, keuzes en resultaten in de verschillende fases rondom duurzaamheid; 3. Aanbevelingen geven voor de volgende fase om het bereik van de ambities te vergroten.

De IJsselmeerdijk beschermt de diepe Flevopolder tegen het water van het IJsselmeer. In 2018 heeft Waterschap Zuiderzeeland (hierna afgekort als: Zuiderzeeland) beoordeeld of de IJsselmeerdijk zo sterk is als de waterveiligheidsnormen voorschrijven. Dat blijkt niet zo te zijn. Sinds 2017 gelden voor de waterkeringen in Nederland nieuwe wettelijke waterveiligheidsnormen. Deze norm is voor Flevoland strenger dan daarvoor om in te spelen op de gevolgen van klimaatverandering en om de grotere hoeveelheid inwoners en de hogere economische waarde in Flevoland beter te beschermen. De waterkering voldoet ruim niet aan de nieuwe strengere norm die eraan gesteld is. Dat wil niet zeggen dat er op dit moment acuut een onveilige situatie is. Het betekent wel dat een dijkversterking nodig is. Het is de wettelijke taak van het waterschap om de keringen aan de normen te laten voldoen. Zuiderzeeland is daarom in 2019 gestart met dit meerjarige project Versterking IJsselmeerdijk.

01 juni 2019, Contains fulltext : 208811.pdf (publisher's version ) (Open Access), OBJECTIVES: We assessed the impact of MALDITOF-MS on the timeliness of optimal antimicrobial therapy through a parallel-arm randomised controlled trial in two hospitals in Vietnam. METHODS: We recruited patients with a pathogen (bacterial or fungal) cultured from a normally sterile sample. Samples were randomly assigned (1:1) to identification by MALDITOF-MS or conventional diagnostics. The primary outcome was the proportion on optimal antimicrobial therapy within 24h of positive culture, determined by a blinded independent review committee. Trial registered at ClinicalTrials.gov (NCT02306330). RESULTS: Among 1005 randomised patients, pathogens were isolated from 628 (326 intervention, 302 control), with 377 excluded as likely contaminants or discharged/died before positive culture. Most isolates were cultured from blood (421/628, 67.0%). The proportion receiving optimal antimicrobial therapy within 24h (the primary outcome) or 48h of growth was not significantly different between MALDITOF-MS and control arms (135/326, 41.4%vs 120/302, 39.7%; Adjusted Odds ration (AOR) 1.17, p=0.40 and 151/326, 46.3%vs 141/302, 46.7%; AOR 1.05 p=0.79, respectively). CONCLUSIONS: MALDITOF-MS, in the absence of an antimicrobial stewardship programme, did not improve the proportion on optimal antimicrobial therapy at 24 or 48h after first growth in a lower-middle income setting with high rates of antibiotic resistance.

Contains fulltext : 200563.pdf (publisher's version ) (Open Access), Background: Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Co-infection with HIV increases the risk of developing TBM, complicates treatment, and substantially worsens outcome. Whether corticosteroids confer a survival benefit in HIV-infected patients with TBM remains uncertain. Hepatitis is the most common drug-induced serious adverse event associated with anti-tuberculosis treatment, occurring in 20% of HIV-infected patients. The suggested concentration thresholds for stopping anti-tuberculosis drugs are not evidence-based. This study aims to determine whether dexamethasone is a safe and effective addition to the first 6-8 weeks of anti-tuberculosis treatment of TBM in patients with HIV, and investigate alternative management strategies in a subset of patients who develop drug induced liver injury (DILI) that will enable the safe continuation of rifampicin and isoniazid therapy. Methods: We will perform a parallel group, randomised (1:1), double blind, placebo-controlled multi-centre Phase III trial, comparing the effect of dexamethasone versus placebo on overall survival in HIV-infected patients with TBM, in addition to standard anti-tuberculosis and antiretroviral treatment. The trial will be set in two hospitals in Ho Chi Minh City, Vietnam, and two hospitals in Jakarta, Indonesia. The trial will enrol 520 HIV-infected adults. An ancillary study will perform a randomised comparison of three DILI management strategies with the aim of demonstrating which strategy results in the least interruption in rifampicin and isoniazid treatment. An identical ancillary study will also be performed in the linked randomised controlled trial of dexamethasone in HIV-uninfected adults with TBM stratified by LTA4H genotype (LAST ACT). Discussion: Whether corticosteroids confer a survival benefit in HIV-infected patients remains uncertain, and the current evidence base for using corticosteroids in this context is limited. Interruptions in anti-tuberculosis ch

The wMel strain of Wolbachia can reduce the permissiveness of Aedes aegypti mosquitoes to disseminated arboviral infections. Here, we report that wMel-infected Ae. aegypti (Ho Chi Minh City background), when directly blood-fed on 141 viremic dengue patients, have lower dengue virus (DENV) transmission potential and have a longer extrinsic incubation period than their wild-type counterparts. The wMel-infected mosquitoes that are field-reared have even greater relative resistance to DENV infection when fed on patient-derived viremic blood meals. This is explained by an increased susceptibility of field-reared wild-type mosquitoes to infection than laboratory-reared counterparts. Collectively, these field- and clinically relevant findings support the continued careful field-testing of wMel introgression for the biocontrol of Ae. aegypti-born arboviruses.

BACKGROUND: Dengue virus infection results in a broad spectrum of clinical outcomes, ranging from asymptomatic infection through to severe dengue. Although prior infection with another viral serotype, i.e. secondary dengue, is known to be an important factor influencing disease severity, current methods to determine primary versus secondary immune status during the acute illness do not consider the rapidly evolving immune response, and their accuracy has rarely been evaluated against an independent gold standard. METHODS: Two hundred and ninety-three confirmed dengue patients were classified as experiencing primary, secondary or indeterminate infections using plaque reduction neutralisation tests performed 6 months after resolution of the acute illness. We developed and validated regression models to differentiate primary from secondary dengue on multiple acute illness days, using Panbio Indirect IgG and in-house capture IgG and IgM ELISA measurements performed on over 1000 serial samples obtained during acute illness. RESULTS: Cut-offs derived for the various parameters demonstrated progressive change (positively or negatively) by day of illness. Using these time varying cut-offs it was possible to determine whether an infection was primary or secondary on single specimens, with acceptable performance. The model using Panbio Indirect IgG responses and including an interaction with illness day showed the best performance throughout, although with some decline in performance later in infection. Models based on in-house capture IgG levels, and the IgM/IgG ratio, also performed well, though conversely performance improved later in infection. CONCLUSIONS: For all assays, the best fitting models estimated a different cut-off value for different days of illness, confirming how rapidly the immune response changes during acute dengue. The optimal choice of assay will vary depending on circumstance. Although the Panbio Indirect IgG model performs best early on, the IgM/IgG c

Op 19 december 2006 is met het unaniem instemmen van de Planologische Kernbeslissing - Ruimte voor de Rivier (deel 4), door zowel de Eerste als de Tweede Kamer, van start gegaan met het programma Ruimte voor de Rivier. Momenteel nadert het programma zijn afronding. De Tweede Kamer heeft daarom om de eindevaluatie Ruimte voor de Rivier verzocht. Op basis van deze eindevaluatie beslist de Tweede Kamer over het al dan niet opheffen van de grootprojectstatus van het programma Ruimte voor de Rivier.

Item does not contain fulltext, BACKGROUND: Talaromyces marneffei infection is a major cause of human immunodeficiency virus (HIV)-related death in South and Southeast Asia. Guidelines recommend initial treatment with amphotericin B deoxycholate, but this drug has substantial side effects, a high cost, and limited availability. Itraconazole is available in oral form, is associated with fewer unacceptable side effects than amphotericin, and is widely used in place of amphotericin; however, clinical trials comparing these two treatments are lacking. METHODS: In this open-label, noninferiority trial, we randomly assigned 440 HIV-infected adults who had talaromycosis, confirmed by either microscopy or culture, to receive either intravenous amphotericin B deoxycholate (amphotericin) (219 patients), at a dose of 0.7 to 1.0 mg per kilogram of body weight per day, or itraconazole capsules (221 patients), at a dose of 600 mg per day for 3 days, followed by 400 mg per day, for 11 days; thereafter, all the patients received maintenance therapy with itraconazole. The primary outcome was all-cause mortality at week 2. Secondary outcomes included all-cause mortality at week 24, the time to clinical resolution of talaromycosis, early fungicidal activity, relapse of talaromycosis, development of the immune reconstitution inflammatory syndrome (IRIS), and the side-effect profile. RESULTS: The risk of death at week 2 was 6.5% in the amphotericin group and 7.4% in the itraconazole group (absolute risk difference, 0.9 percentage points; 95% confidence interval [CI], -3.9 to 5.6; P<0.001 for noninferiority); however, the risk of death at week 24 was 11.3% in the amphotericin group and 21.0% in the itraconazole group (absolute risk difference, 9.7 percentage points; 95% CI, 2.8 to 16.6; P=0.006). Treatment with amphotericin was associated with significantly faster clinical resolution and fungal clearance and significantly lower rates of relapse and IRIS than itraconazole. The patients who received amphotericin had sign

BACKGROUND: Early prediction of severe dengue could significantly assist patient triage and case management. METHODS: We prospectively investigated 7563 children with ≤3 days of fever recruited in the outpatient departments of 6 hospitals in southern Vietnam between 2010 and 2013. The primary endpoint of interest was severe dengue (2009 World Health Organization Guidelines), and predefined risk variables were collected at the time of enrollment to enable prognostic model development. RESULTS: The analysis population comprised 7544 patients, of whom 2060 (27.3%) had laboratory-confirmed dengue; nested among these were 117 (1.5%) severe cases. In the multivariate logistic model, a history of vomiting, lower platelet count, elevated aspartate aminotransferase (AST) level, positivity in the nonstructural protein 1 (NS1) rapid test, and viremia magnitude were all independently associated with severe dengue. The final prognostic model (Early Severe Dengue Identifier [ESDI]) included history of vomiting, platelet count, AST level. and NS1 rapid test status. CONCLUSIONS: The ESDI had acceptable performance features (area under the curve = 0.95, sensitivity 87% (95% confidence interval [CI], 80%-92%), specificity 88% (95% CI, 87%-89%), positive predictive value 10% (95% CI, 9%-12%), and negative predictive value of 99% (95% CI, 98%-100%) in the population of all 7563 enrolled children. A score chart, for routine clinical use, was derived from the prognostic model and could improve triage and management of children presenting with fever in dengue-endemic areas.

BACKGROUND: Tuberculous meningitis (TBM) is the most devastating form of tuberculosis, yet very little is known about the pathophysiology. We hypothesized that the genotype of leukotriene A4 hydrolase (encoded by LTA4H), which determines inflammatory eicosanoid expression, influences intracerebral inflammation, and predicts survival from TBM. METHODS: We characterized the pretreatment clinical and intracerebral inflammatory phenotype and 9-month survival of 764 adults with TBM. All were genotyped for single-nucleotide polymorphism rs17525495, and inflammatory phenotype was defined by cerebrospinal fluid (CSF) leukocyte and cytokine concentrations. RESULTS: LTA4H genotype predicted survival of human immunodeficiency virus (HIV)-uninfected patients, with TT-genotype patients significantly more likely to survive TBM than CC-genotype patients, according to Cox regression analysis (univariate P = .040 and multivariable P = .037). HIV-uninfected, TT-genotype patients had high CSF proinflammatory cytokine concentrations, with intermediate and lower concentrations in those with CT and CC genotypes. Increased CSF cytokine concentrations correlated with more-severe disease, but patients with low CSF leukocytes and cytokine concentrations were more likely to die from TBM. HIV infection independently predicted death due to TBM (hazard ratio, 3.94; 95% confidence interval, 2.79-5.56) and was associated with globally increased CSF cytokine concentrations, independent of LTA4H genotype. CONCLUSIONS: LTA4H genotype and HIV infection influence pretreatment inflammatory phenotype and survival from TBM. LTA4H genotype may predict adjunctive corticosteroid responsiveness in HIV-uninfected individuals.

BACKGROUND: Dengue is the most important mosquito-borne viral infection to affect humans. Although it usually manifests as a self-limited febrile illness, complications may occur as the fever subsides. A systemic vascular leak syndrome that sometimes progresses to life-threatening hypovolaemic shock is the most serious complication seen in children, typically accompanied by haemoconcentration and thrombocytopenia. Robust evidence on risk factors, especially features present early in the illness course, for progression to dengue shock syndrome (DSS) is lacking. Moreover, the potential value of incorporating serial haematocrit and platelet measurements in prediction models has never been assessed. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed data from a prospective observational study of Vietnamese children aged 5-15 years admitted with clinically suspected dengue to the Hospital for Tropical Diseases in Ho Chi Minh City between 2001 and 2009. The analysis population comprised all children with laboratory-confirmed dengue enrolled between days 1-4 of illness. Logistic regression was the main statistical model for all univariate and multivariable analyses. The prognostic value of daily haematocrit levels and platelet counts were assessed using graphs and separate regression models fitted on each day of illness. Among the 2301 children included in the analysis, 143 (6%) progressed to DSS. Significant baseline risk factors for DSS included a history of vomiting, higher temperature, a palpable liver, and a lower platelet count. Prediction models that included serial daily platelet counts demonstrated better ability to discriminate patients who developed DSS from others, than models based on enrolment information only. However inclusion of daily haematocrit values did not improve prediction of DSS. CONCLUSIONS/SIGNIFICANCE: Daily monitoring of platelet counts is important to help identify patients at high risk of DSS. Development of dynamic prediction models that incorporat

Objective. Vision loss and ischaemic stroke are feared complications in GCA. We investigated how platelet count and size and platelet inhibition with ASA relate to ischaemic complications in patients with GCA. Methods. Charts of patients with GCA were retrospectively analysed. Jaw claudication, amaurosis fugax, blurred vision, ischaemic stroke and permanent visual loss were classified as ‘ischaemic events'; ischaemic stroke and permanent visual loss were sub-grouped as ‘severe ischaemic events'. The incidence of ischaemia and the association to the pre-defined covariates age, fever, ESR, platelet count and size and ASA treatment were assessed. Results. Eighty-five patients (mean age 73 yrs, 60% women, 78% biopsy-proven) were included in the analysis. Of the 85 patients, 62 (73%) presented with ischaemic events, 29/85 patients (34%) with severe ischaemic events. At the time of diagnosis 22/85 patients (26%) were treated with ASA. Of these 22 patients, 15 (68%) presented with ischaemic events, 7/22 patients (32%) with severe ischaemic events. In multivariate analysis, neither platelet count nor size or ASA treatment were significantly associated with ischaemic or severe ischaemic events. Conclusions. The incidence of severe ischaemic events in patients with GCA was high, irrespective of platelet count and size and established ASA treatment

Deze evaluatie naar de programmabeheersing Ruimte voor de Rivier maakt deel uit van vier evaluaties naar het programma Ruimte voor de Rivier, die alle als input dienen voor de Eindevaluatie Ruimte voor de Rivier.

Contains fulltext : 165739.pdf (publisher's version ) (Open Access), BACKGROUND: Inappropriate antibiotic use for acute respiratory tract infections is common in primary health care, but distinguishing serious from self-limiting infections is difficult, particularly in low-resource settings. We assessed whether C-reactive protein point-of-care testing can safely reduce antibiotic use in patients with non-severe acute respiratory tract infections in Vietnam. METHOD: We did a multicentre open-label randomised controlled trial in ten primary health-care centres in northern Vietnam. Patients aged 1-65 years with at least one focal and one systemic symptom of acute respiratory tract infection were assigned 1:1 to receive either C-reactive protein point-of-care testing or routine care, following which antibiotic prescribing decisions were made. Patients with severe acute respiratory tract infection were excluded. Enrolled patients were reassessed on day 3, 4, or 5, and on day 14 a structured telephone interview was done blind to the intervention. Randomised assignments were concealed from prescribers and patients but not masked as the test result was used to assist treatment decisions. The primary outcome was antibiotic use within 14 days of follow-up. All analyses were prespecified in the protocol and the statistical analysis plan. All analyses were done on the intention-to-treat population and the analysis of the primary endpoint was repeated in the per-protocol population. This trial is registered under number NCT01918579. FINDINGS: Between March 17, 2014, and July 3, 2015, 2037 patients (1028 children and 1009 adults) were enrolled and randomised. One adult patient withdrew immediately after randomisation. 1017 patients were assigned to receive C-reactive protein point-of-care testing, and 1019 patients were assigned to receive routine care. 115 patients in the C-reactive protein point-of-care group and 72 patients in the routine care group were excluded in the intention-to-treat analysis due to missing primary endpoint. The number of

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Contains fulltext : 171871.pdf (Publisher’s version ) (Open Access)

BACKGROUND: Primary health care facilities frequently manage dengue cases on an ambulatory basis for the duration of the patient's illness. There is a great opportunity for specific messaging, aimed to reduce dengue virus (DENV) transmission in and around the home, to be directly targeted toward this high-risk ambulatory patient group, as part of an integrated approach to dengue management. The extent however, to which physicians understand, and can themselves effectively communicate strategies to stop focal DENV transmission around an ambulatory dengue case is unknown; the matter of patient comprehension and recollection then ensues. In addition, the effectiveness of N,N-diethyl-3-methylbenzamide (DEET)-based insect repellent in protecting dengue patients from Aedes aegypti mosquitoes' bites has not been investigated. METHODOLOGY: A knowledge, attitude and practice (KAP) survey, focusing on the mechanisms of DENV transmission and prevention, was performed using semi-structured questionnaires. This survey was targeted towards the patients and family members providing supportive care, and physicians routinely involved in dengue patient management in Southern Vietnam. An additional clinical observational study was conducted to measure the efficacy of a widely-used 13% DEET-based insect repellent to repel Ae. aegypti mosquitoes from the forearms of dengue cases and matched healthy controls. PRINCIPAL FINDINGS: Among both the physician (n = 50) and patient (n = 49) groups there were several respondents lacking a coherent understanding of DENV transmission, leading to some inappropriate attitudes and inadequate acute preventive practices in the household. The application of insect repellent to protect patients and their relatives from mosquito bites was frequently recommended by majority of physicians (78%) participating in the survey. Nevertheless, our tested topical application of 13% DEET conferred only ~1hr median protection time from Ae. aegypti landing. This is not

The interplay between bacterial antimicrobial susceptibility, phylogenetics and patient outcome is poorly understood. During a typhoid clinical treatment trial in Nepal, we observed several treatment failures and isolated highly fluoroquinolone-resistant Salmonella Typhi (S. Typhi). Seventy-eight S. Typhi isolates were genome sequenced and clinical observations, treatment failures and fever clearance times (FCTs) were stratified by lineage. Most fluoroquinolone-resistant S. Typhi belonged to a specific H58 subclade. Treatment failure with S. Typhi-H58 was significantly less frequent with ceftriaxone (3/31; 9.7%) than gatifloxacin (15/34; 44.1%)(Hazard Ratio 0.19, p=0.002). Further, for gatifloxacin-treated patients, those infected with fluoroquinolone-resistant organisms had significantly higher median FCTs (8.2 days) than those infected with susceptible (2.96) or intermediately resistant organisms (4.01)(pS. Typhi clade internationally, but there are no data regarding disease outcome with this organism. We report an emergent new subclade of S. Typhi-H58 that is associated with fluoroquinolone treatment failure.

BACKGROUND: The hallmark of severe dengue is increased microvascular permeability, but alterations in the microcirculation and their evolution over the course of dengue are unknown. METHODS: We conducted a prospective observational study to evaluate the sublingual microcirculation using side-stream dark-field imaging in patients presenting early (<72 hours after fever onset) and patients hospitalized with warning signs or severe dengue in Vietnam. Clinical findings, microvascular function, global hemodynamics assessed with echocardiography, and serological markers of endothelial activation were determined at 4 time points. RESULTS: A total of 165 patients were enrolled. No difference was found between the microcirculatory parameters comparing dengue with other febrile illnesses. The proportion of perfused vessels (PPV) and the mean flow index (MFI) were lower in patients with dengue with plasma than those without leakage (PPV, 88.1% vs 90.6% [P = .01]; MFI, 2.1 vs 2.4 [P = .007]), most markedly during the critical phase. PPV and MFI were correlated with the endothelial activation markers vascular cell adhesion molecule 1 (P < .001 for both) and angiopoietin 2 (P < .001 for both), negatively correlated. CONCLUSIONS: Modest microcirculatory alterations occur in dengue, are associated with plasma leakage, and are correlate with molecules of endothelial activation, angiopoietin 2 and vascular cell adhesion molecule 1.

BACKGROUND: Dengue endangers billions of people in the tropical world, yet no therapeutic is currently available. In part, the severe manifestations of dengue reflect inflammatory processes affecting the vascular endothelium. In addition to lipid lowering, statins have pleiotropic effects that improve endothelial function, and epidemiological studies suggest that outcomes from a range of acute inflammatory syndromes are improved in patients already on statin therapy. METHODS: Following satisfactory review of a short pilot phase (40 mg lovastatin vs placebo in 30 cases), we performed a randomized, double-blind, placebo-controlled trial of 5 days of 80 mg lovastatin vs placebo in 300 Vietnamese adults with a positive dengue NS1 rapid test presenting within 72 hours of fever onset. The primary outcome was safety. Secondary outcomes included comparisons of disease progression rates, fever clearance times, and measures of plasma viremia and quality of life between the treatment arms. RESULTS: Adverse events occurred with similar frequency in both groups (97/151 [64%] placebo vs 82/149 [55%] lovastatin; P = .13), and were in keeping with the characteristic clinical and laboratory features of acute dengue. We also observed no difference in serious adverse events or any of the secondary outcome measures. CONCLUSIONS: We found lovastatin to be safe and well tolerated in adults with dengue. However, although the study was not powered to address efficacy, we found no evidence of a beneficial effect on any of the clinical manifestations or on dengue viremia. Continuing established statin therapy in patients who develop dengue is safe.Chinese Clinical Trials Registration. ISRCTN03147572.

BACKGROUND: The burden of dengue continues to increase globally, with an estimated 100 million clinically apparent infections occurring each year. Although most dengue infections are asymptomatic, patients can present with a wide spectrum of clinical symptoms ranging from mild febrile illness through to severe manifestations of bleeding, organ impairment, and hypovolaemic shock due to a systemic vascular leak syndrome. Clinical diagnosis of dengue and identification of which patients are likely to develop severe disease remain challenging. This study aims to improve diagnosis and clinical management through approaches designed a) to differentiate between dengue and other common febrile illness within 72 h of fever onset, and b) among patients with dengue to identify markers that are predictive of the likelihood of evolving to a more severe disease course. METHOD/DESIGN: This is a prospective multi-centre observational study aiming to enrol 7-8000 participants aged ≥ 5 years presenting with a febrile illness consistent with dengue to outpatient health facilities in 8 countries across Asia and Latin America. Patients presenting within 72 h of fever onset who do not exhibit signs of severe disease are eligible for the study. A broad range of clinical and laboratory parameters are assessed daily for up to 6 days during the acute illness, and also at a follow up visit 1 week later. DISCUSSION: Data from this large cohort of patients, enrolled early with undifferentiated fever, will be used to develop a practical diagnostic algorithm and a robust clinical case definition for dengue. Additionally, among patients with confirmed dengue we aim to identify simple clinical and laboratory parameters associated with progression to a more severe disease course. We will also investigate early virological and serological correlates of severe disease, and examine genetic associations in this large heterogeneous cohort. In addition the results will be used to assess the new World Heal

Meer en meer vindt er samenwerking plaats tussen partijen om opgaven te kunnen realiseren. Samenwerking tussen overheden onderling, maar ook met kennisinstellingen, maatschappij en bedrijfsleven. Het Deltaprogramma is een voorbeeld van een programma waar bij uitstek samengewerkt wordt over de grenzen van organisaties heen. Om samenwerking te laten slagen, is er vertrouwen tussen partijen nodig. In dit artikel beschrijven Theo Camps, Martine Olde Wolbers en Atze Kamma de resultaten van een pilot in het IJsselmeergebied, waarbij het vertrouwen tussen de samenwerkende partners in het Deltaprogramma IJsselmeergebied is gemeten. Doel van deze pilot was om potentiële risico’s in beeld te brengen die een succesvolle samenwerking in de weg kunnen gaan staan.