Development of a research agenda for general practice based on knowledge gaps identified in Dutch guidelines and input from 48 stakeholders.

BACKGROUND: Several funding organizations using different agendas support research in general practice. Topic selection and prioritization are often not coordinated, which may lead to duplication and research waste. OBJECTIVES: To develop systematically a national research agenda for general practice involving general practitioners, researchers, patients and other relevant stakeholders in healthcare. METHODS: We reviewed knowledge gaps from 90 Dutch general practice guidelines and formulated research questions based on these gaps. In addition, we asked 96 healthcare stakeholders to add research questions relevant for general practice. All research questions were prioritized by practising general practitioners in an online survey (n = 232) and by participants of an invitational conference including general practitioners (n = 48) and representatives of other stakeholders in healthcare (n = 16), e.g. patient organizations and medical specialists. RESULTS: We identified 787 research questions. These were categorized in two ways: according to the chapters of the International Classification for Primary Care (ICPC) and in 12 themes such as common conditions, person-centred care and patient education, collaboration and organization of care. The prioritizing procedure resulted in top 10 lists of research questions for each ICPC chapter and each theme. CONCLUSION: The process resulted in a widely supported National Research Agenda for General Practice. We encourage both researchers and funding organizations to use this agenda to focus their research on the most relevant issues in general practice and to generate new evidence for the next generation of guidelines and the future of general practice.

Maraviroc Intensification of cART in Patients with Suboptimal Immunological Recovery: A 48-Week, Placebo-Controlled Randomized Trial.

OBJECTIVE: The immunomodulatory effects of the CCR5-antagonist maraviroc might be beneficial in patients with a suboptimal immunological response, but results of different cART (combination antiretroviral therapy) intensification studies are conflicting. Therefore, we performed a 48-week placebo-controlled trial to determine the effect of maraviroc intensification on CD4+ T-cell counts and immune activation in these patients. DESIGN: Double-blind, placebo-controlled, randomized trial. METHODS: Major inclusion criteria were 1. CD4+ T-cell count <350 cells/µL while at least two years on cART or CD4+ T-cell count <200 cells/µL while at least one year on cART, and 2. viral suppression for at least the previous 6 months. HIV-infected patients were randomized to add maraviroc (41 patients) or placebo (44 patients) to their cART regimen for 48 weeks. Changes in CD4+ T-cell counts (primary endpoint) and other immunological parameters were modeled using linear mixed effects models. RESULTS: No significant differences for the modelled increase in CD4+ T-cell count (placebo 15.3 CD4+ T cells/µL (95% confidence interval (CI) [1.0, 29.5] versus maraviroc arm 22.9 CD4+ T cells/µL (95% CI [7.4, 38.5] p = 0.51) or alterations in the expression of markers for T-cell activation, proliferation and microbial translocation were found between the arms. However, maraviroc intensification did increase the percentage of CCR5 expressing CD4+ and CD8+ T-cells, and the plasma levels of the CCR5 ligand MIP-1ß. In contrast, the percentage of ex-vivo apoptotic CD8+ and CD4+ T-cells decreased in the maraviroc arm. CONCLUSIONS: Maraviroc intensification of cART did not increase CD4+ T-cell restoration or decrease immune activation as compared to placebo. However, ex-vivo T-cell apoptosis was decreased in the maraviroc arm. TRIAL REGISTRATION: ClinicalTrials.gov NCT00875368.

POSSUM predicts hospital mortality and long-term survival in patients with hip fractures.

BACKGROUND: Each year, some 18,000 Dutch residents, most of them elderly, suffer a hip fracture. These patients constitute a major, and increasing, healthcare problem with high mortality. In an ageing population, not only the incidence of hip fractures will increase but also comorbidity. Comorbidity is a major cause of high mortality. The physiologic and operative severity score for the enumeration of mortality and morbidity (POSSUM) system predicts mortality and morbidity in surgical patients using physiologic and operative factors. METHODS: For 272 consecutive patients who were treated in our hospital for hip fractures, all complications were registered, and orthopedic POSSUM was performed. Total survival was registered with a mean follow-up of 58 months. Discriminating performance of POSSUM was estimated using receiver-operating curves. After validation, patients were divided into three equal large groups, termed low-risk group, intermediate-risk group, and high-risk group. Kaplan-Meier survival curves were made of each group. RESULTS: Orthopedic POSSUM performed well in predicting mortality with an area under the curve of 0.83 (95% confidence interval 0.76-0.89) and morbidity with an area under the curve of 0.83 (95% confidence interval 0.76-0.90). Three groups that composed of 92 (low risk), 93 (intermediate risk), and 87 (high risk) patients differed significantly in inhospital mortality, all complications, severe complications, and total survival. CONCLUSION: This study has shown that the orthopedic POSSUM is an excellent predictor of inhospital mortality and long-term survival in patients suffering from hip fractures. It is a reasonable predictor of severe postoperative complications. The orthopedic POSSUM is a useful risk stratification and audit tool.

Functional treatment versus plaster for simple elbow dislocations (FuncSiE): a randomized trial.

BACKGROUND: Elbow dislocations can be classified as simple or complex. Simple dislocations are characterized by the absence of fractures, while complex dislocations are associated with fractures. After reduction of a simple dislocation, treatment options include immobilization in a static plaster for different periods of time or so-called functional treatment. Functional treatment is characterized by early active motion within the limits of pain with or without the use of a sling or hinged brace. Theoretically, functional treatment should prevent stiffness without introducing increased joint instability. The primary aim of this randomized controlled trial is to compare early functional treatment versus plaster immobilization following simple dislocations of the elbow. METHODS/DESIGN: The design of the study will be a multicenter randomized controlled trial of 100 patients who have sustained a simple elbow dislocation. After reduction of the dislocation, patients are randomized between a pressure bandage for 5-7 days and early functional treatment or a plaster in 90 degrees flexion, neutral position for pro-supination for a period of three weeks. In the functional group, treatment is started with early active motion within the limits of pain. Function, pain, and radiographic recovery will be evaluated at regular intervals over the subsequent 12 months. The primary outcome measure is the Quick Disabilities of the Arm, Shoulder, and Hand score. The secondary outcome measures are the Mayo Elbow Performance Index, Oxford elbow score, pain level at both sides, range of motion of the elbow joint at both sides, rate of secondary interventions and complication rates in both groups (secondary dislocation, instability, relaxation), health-related quality of life (Short-Form 36 and EuroQol-5D), radiographic appearance of the elbow joint (degenerative changes and heterotopic ossifications), costs, and cost-effectiveness. DISCUSSION: The successful completion of this trial will provide evidence on the effectiveness of a functional treatment for the management of simple elbow dislocations. TRIAL REGISTRATION: The trial is registered at the Netherlands Trial Register (NTR2025).

Comparison of two HIV postexposure prophylaxis regimens among men who have sex with men in Amsterdam: adverse effects do not influence compliance.

OBJECTIVES: To compare 2 regimens for HIV postexposure prophylaxis (PEP) as to safety, adherence, outcome, and follow-up in men who have sex with men (MSM) in Amsterdam. METHODS: Since 2000, all MSM starting HIV PEP in Amsterdam have been followed in 1 location. The regimen was comprised of zidovudine or lamivudine and nelfinavir (regimen 1) until 2005, when nelfinavir was replaced by atazanavir (regimen 2). All patient data, including data on PEP side effects and testing for alanine aminotransferase (ALT), were systematically recorded and compared between the 2 regimens from 2000 to 2007. RESULTS: HIV PEP was prescribed 309 times to MSM. Of the 261 who were followed up, 237 (91%) completed their 28-day course. Although fewer patients had diarrhea on regimen 2 than on regimen 1 (P = 0.00), the proportion completing either course was the same: 98 of 110 (89%) and 139 of 151 (92%), respectively (P = 0.42). Only 1 patient with severely elevated ALT was advised to stop PEP, he also had serious illness. MSM at least 30 years of age and MSM who had sex with a partner known to be HIV-positive completed their course significantly more often than those under 30 and those who had sex with a partner of unknown HIV status (P < 0.005). Of MSM who completed PEP, 5 seroconverted for HIV despite good adherence to PEP. None of their viruses were resistant to the PEP regimen used. CONCLUSIONS: No difference in adherence was found between the 2 regimens, even though fewer adverse effects were reported on regimen 2. ALT need not be routinely tested to monitor adverse effects. The 5 seroconversions were not likely caused by PEP failure, but rather by ongoing HIV exposures.

Intracellular and plasma steady-state pharmacokinetics of raltegravir, darunavir, etravirine and ritonavir in heavily pre-treated HIV-infected patients.

AIM: To study the steady-state plasma and intracellular pharmacokinetics of raltegravir, etravirine, darunavir and ritonavir in heavily pre-treated patients. METHODS: Patients on a salvage regimen containing raltegravir, etravirine, darunavir and ritonavir were eligible for inclusion. During a 12 h dosing interval plasma and peripheral blood mononuclear cells were collected. Drug concentrations were measured using a validated LC-MS/MS assay and pharmacokinetic analysis was performed using non-linear mixed effect modelling. RESULTS: Irregular absorption was observed with raltegravir and darunavir, which may be caused by enterohepatic cycling. Relative bioavailability of ritonavir was low, when compared with other ritonavir regimens. Raltegravir plasma pharmacokinetics showed wide interpatient variability, while intracellular raltegravir concentrations could not be detected (<0.001 mg l(-1) in cell lysate). The intracellular to plasma ratios for etravirine, darunavir and ritonavir were 12.9, 1.32 and 7.72, respectively, and the relative standard error of these estimates were 16.3%, 12.3% and 13.0%. CONCLUSIONS: The observed distinct intracellular accumulation indicated that these drugs have different affinity for the cellular compartment. The relatively high intracellular accumulation of etravirine may explain its efficacy and its previously described absence of PK-PD relationships in the therapeutic concentration range, when compared with other non-nucleoside reverse transcriptase inhibitors. Lastly, the intracellular concentrations of ritonavir seem sufficient for inhibition of viral replication in the cellular compartment in PI-naive patients, but not in patients with HIV harbouring PI resistance.

Treatment of HIV infection with the CCR5 antagonist maraviroc.

IMPORTANCE OF THE FIELD: The emergence of resistance in treatment-experienced HIV patients often limits therapeutic success of the currently available antiretroviral drugs. New drug classes are thus required. Maraviroc is the first chemokine receptor 5 antagonist approved for use in treatment experienced HIV patients with a R5-tropic virus. AREAS COVERED IN THIS REVIEW: For this review, data from pharmacokinetic, Phase II and III clinical trials were reviewed. WHAT THE READER WILL GAIN: The objectives of this review were to discuss the pharmacokinetics and clinical efficacy and safety of maraviroc in treatment-experienced and -naive HIV patients with R5-tropic virus. Additionally, tropism testing was discussed. TAKE HOME MESSAGE: Maraviroc is effective in previously treated patients with R5-tropic virus only. Also, maraviroc will be an attractive option for HIV-1-infected treatment-naive patients with R5-tropic viruses only, once genotypic assays have been validated.

Cardiac output derived from arterial pressure waveform analysis without calibration vs. thermodilution in septic shock: evolving accuracy of software versions.

BACKGROUND AND OBJECTIVE: We studied the evolution of software in the accuracy of the FloTrac/Vigileo system to measure cardiac output less invasively from arterial pressure waveform analysis without calibration, in comparison with pulmonary artery catheter-derived thermodilution measurements, in patients with septic shock and presumed alterations in vascular tone. METHODS: Nine patients who received a pulmonary artery catheter and were on mechanical ventilation and in sinus rhythm were monitored by the FloTrac/Vigileo. Paired cardiac output measurements by both techniques were analysed for 86 measurements in four patients using the 1.07 software version and 73 measurements in five subsequent patients using the later 1.10 version. RESULTS: For the 1.07 version, bias was -1.6 L min, precision 1.6 L min, limits of agreement -4.8-1.5 L min and error 48%. Measurements correlated at partial r equal to 0.32 (P = 0.003). For the 1.10 version, bias was -1.2 L min, precision 1.1 L min, limits of agreement -3.5-1.0 L min and error 32%. Measurements correlated at partial r equal to 0.90 (P < 0.001 vs. version 1.07). Differences were inversely related to mean cardiac output (P < 0.001, generalized estimating equations), particularly for software version 1.07 vs. 1.10 (P = 0.017, generalized estimating equation). Changes in thermodilution cardiac output over the course of time were also better tracked by the FloTrac/Vigileo when applying the latest software (P < 0.001, generalized estimating equation). CONCLUSIONS: Evolving software versions are thus better able to account for the effect of vascular tone on cardiac output measurements by less invasive waveform analyses without calibration (FloTrac/Vigileo), so that the latter may become useful in the haemodynamic monitoring of septic shock.

The hemostatic balance in HIV-infected patients with and without antiretroviral therapy: partial restoration with antiretroviral therapy.

The incidence of arterial and venous thrombosis in HIV-infected patients is increased compared to healthy controls. In this cross-sectional analysis we measured markers of endothelial cell activation, thrombin generation, fibrinolysis and anticoagulation combined with endogenous thrombin potential (ETP) and activated protein C sensitivity ratio (APCsr) as more global markers. We included 160 consecutive HIV-infected patients with a median age of 46 years (range, 27-77), of whom 92% were male, 74% Caucasian, 11% African American, 9% Hispanic, and 6% Asian. Homosexual contact was the main transmission mode. Seventy percent of patients were using combined antiretroviral therapy (cART). In 83% of patients laboratory markers outside the normal range for a non-HIV-infected population were observed. Significant lower levels of von Willebrand factor (vWF; p = 0.03), factor VIII (p < 0.0001), D-dimer (p = 0.01), and ETP (p = 0.01) were observed in HIV-infected patients on cART compared to patients not on cART. Significant lower levels of protein C (p = 0.05) and free protein S (p < 0.0001), and increased APCsr (p < 0.0001) were found in the HIV-infected patients not on cART. A single association was observed between raised levels of fibrinogen and use of a protease inhibitor (p = 0.002). No significant difference was observed in the percentage of patients with laboratory markers outside the normal range between patients using cART-regimens containing abacavir, stavudine, or didanosine and those with other nucleoside reverse transcriptase inhibitors. Although the prevalence of coagulation abnormalities was lower in HIV-infected patients using cART, a considerable proportion of HIV-infected patients on cART show endothelial cell activation and increased APCsr, suggestive of a persistent procoagulant state.

The prevalence of human papillomavirus (HPV) infection in paired urine and cervical smear samples of HIV-infected women.

BACKGROUND: HIV-infected women are at increased risk for cervical dysplasia. Cervical dysplasia is caused by persistent infections with certain types of human papillomavirus (HPV). Conventional testing for genital HPV infections requires cervical cytology. A non-invasive screening method by detection of HPV DNA in urine samples is preferable but is not a routine practice. OBJECTIVES: To investigate the prevalence and concordance of HPV in paired urine and cervical smear samples and cytological results of Pap smears in HIV-infected women. STUDY DESIGN: Paired urine and cervical smear samples were collected from 27 HIV-infected women. RESULTS: The HPV prevalence in urine and cervical smear samples was 81.5% and 51.9%, respectively (p = 0.01). The concordance for HPV positivity and negativity between urine and cervical smear samples is 71%. Seven women (25.9%) had an abnormal cervical smear of Pap II or higher. In all urine samples from these cases HPV DNA was detected. CONCLUSION: In the present study we show that the HPV prevalence in urine and cervical smear samples of HIV-infected women is high and HPV test results are highly concordant. Therefore, urine samples can be used as medium for HPV testing. HPV testing in urine samples is a simple, reliable, non-invasive screening method.

Dynamics of nitric oxide and nitrous oxide emission during full-scale reject water treatment.

Emission of NO and N2O from a full-scale two-reactor nitritation-anammox process was determined during a measurement campaign at the Dokhaven-Sluisjesdijk municipal WWTP (Rotterdam, NL). The NO and N2O levels in the off-gas responded to the aeration cycles and the aeration rate of the nitritation reactor, and to the nitrite and dissolved oxygen concentration. Due to the strong fluctuations in the NO and N2O levels in both the nitritation and the anammox reactor, only time-dependent measurements could yield a reliable estimate of the overall NO and N2O emissions. The NO emission from the nitritation reactor was 0.2% of the nitrogen load and the N2O emission was 1.7%. The NO emission from the anammox reactor was determined to be 0.003% of the nitrogen load and the N2O emission was 0.6%. Emission of NO2 could not be detected from the nitritation-anammox system. Denitrification by ammonia-oxidizing bacteria was considered to be the most probable cause of NO and N2O emission from the nitritation reactor. Since anammox bacteria have not been shown to produce N2O under physiological conditions, it is also suspected that ammonia-oxidizing bacteria contribute most to N2O production in the anammox reactor. The source of NO production in the anammox reactor can be either anammox bacteria or denitrification by heterotrophs or ammonia-oxidizing bacteria. Based on the results and previous work, it seems that a low dissolved oxygen or a high nitrite concentration are the most likely cause of elevated NO and N2O emission by ammonia-oxidizing bacteria. The emission was compared with measurements at other reject water technologies and with the main line of the Dokhaven-Sluisjesdijk WWTP. The N2O emission levels in the reject water treatment seem to be in the same range as for the main stream of activated sludge processes. Preliminary measurements of the N2O emission from a one-reactor nitritation-anammox system indicate that the emission is lower than in two-reactor systems.

Increase in HCV incidence among men who have sex with men in Amsterdam most likely caused by sexual transmission.

We retrospectively screened 1836 men who have sex with men (MSM) participating in the Amsterdam Cohort Studies (1984-2003) for hepatitis C virus (HCV) antibodies. HCV incidence was 0.18/100 person-years (PY) in human immunodeficiency virus (HIV)-positive MSM (8/4408 PY [95% confidence interval {CI}, 0.08-0.36]) but was 0/100 PY in MSM without HIV (0/7807 PY [95% CI, 0.00-0.05]). After 2000, HCV incidence among HIV-positive men increased 10-fold to 0.87/100 PY (5/572 PY [95% CI, 0.28-2.03]). Additional hospital cases (n=34) showed that MSM in Amsterdam who acquired HCV infection after 2000 reported high rates of ulcerative sexually transmitted infections (59%) and rough sexual techniques (56%), denied injection drug use, and were infected mainly with the difficult-to-treat HCV genotypes 1 (56%) and 4 (36%). Phylogenetic analysis showed 3 monophyletic clusters of MSM-specific HCV strains. The emergence of an MSM-specific transmission network suggests that HIV-positive MSM with high-risk sexual behaviors are at risk for sexually acquired HCV. Targeted prevention and routine HCV screening among HIV-positive MSM is needed to deter the spread of HCV.

Startup of reactors for anoxic ammonium oxidation: experiences from the first full-scale anammox reactor in Rotterdam.

The first full-scale anammox reactor in the world was started in Rotterdam (NL). The reactor was scaled-up directly from laboratory-scale to full-scale and treats up to 750 kg-N/d. In the initial phase of the startup, anammox conversions could not be identified by traditional methods, but quantitative PCR proved to be a reliable indicator for growth of the anammox population, indicating an anammox doubling time of 10-12 days. The experience gained during this first startup in combination with the availability of seed sludge from this reactor, will lead to a faster startup of anammox reactors in the future. The anammox reactor type employed in Rotterdam was compared to other reactor types for the anammox process. Reactors with a high specific surface area like the granular sludge reactor employed in Rotterdam provide the highest volumetric loading rates. Mass transfer of nitrite into the biofilm is limiting the conversion of those reactor types that have a lower specific surface area. Now the first full-scale commercial anammox reactor is in operation, a consistent and descriptive nomenclature is suggested for reactors in which the anammox process is employed.

Trends in HIV postexposure prophylaxis prescription and compliance after sexual exposure in Amsterdam, 2000-2004.

OBJECTIVE: The objective of this study was to evaluate trends in HIV postexposure prophylaxis (PEP) requests after sexual exposure, compliance, and outcome of follow-up HIV tests. STUDY DESIGN: The authors conducted a retrospective analysis of all HIV PEP requests after sexual exposure between January 1, 2000, and December 31, 2004, in Amsterdam. RESULTS: In 5 years, there was a very modest increase in PEP requests, of which most (75%) came from men who have sex with men (MSM). Although 70% reported side effects, 85% completed their PEP course. Sexual assault victims less often completed their course (odds ratio [OR] = 0.1; 95% confidence interval [CI] = 0.05-0.4, P = 0.001). People who used HIV PEP more often complied with follow-up tests than people who did not use PEP (OR = 3.5; 95% CI = 1.6-7.9, P = 0.002). One HIV seroconversion was found caused by a later exposure than that for which PEP was given. CONCLUSIONS: Despite a widely available PEP program in Amsterdam, the number of PEP requests remained low. Most people completed their PEP course; compliance with follow-up HIV testing was high.

High prevalence of human papillomavirus infections in urine samples from human immunodeficiency virus-infected men.

Infection with human immunodeficiency virus (HIV) and the resulting immunosuppression are associated with an increased risk for human papillomavirus (HPV) persistence and related malignancies. In the present study we investigated the prevalence of HPV in urine samples from 104 HIV-infected men with low CD4+ cell counts (<100 per mm(3)) and 115 urine samples from HIV-negative men. A high prevalence of HPV DNA (39.4%) was found in the HIV patients. Most of the HPV types were high risk (81.4%), with HPV 52 as the most prevalent type (12.5%), followed by HPV 18 (6.7%), HPV 35 (5.8%), and HPV 70 (4.8%). Multiple HPV genotypes were observed in 17 (41%) of the 41 HPV- and HIV-positive men. In contrast, only 11 (9.6%) HPV DNA-positive cases were observed among the 115 HIV-uninfected men, and 3 (27.3%) contained multiple genotypes. Quantitative analyses indicated that the HPV viral load, as measured in urine samples, is significantly higher in HIV-positive men compared to HIV-negative men. In the present study we show that urine samples are useful for detecting HPV DNA, there is a high prevalence of HPV in HIV-positive men, and the HPV viral load is substantially higher in HIV-positive than in HIV-negative men. More studies are needed to evaluate the risk and natural development of HPV-related malignancies in HIV-positive men.

Prophylaxis and follow-up after possible exposure to HIV, hepatitis B virus, and hepatitis C virus outside hospital: evaluation of policy 2000-3.

PROBLEM: Prophylactic treatment and follow-up after exposure to HIV, hepatitis B, and hepatitis C outside hospital needs to be improved. BACKGROUND AND SETTING: Until January 2000, people in Amsterdam could report exposure outside hospital to either a hospital or the municipal health service. If they reported to the municipal health service, they were then referred to hospitals for HIV prophylaxis, whereas the municipal health service handled treatment and follow-up related to hepatitis B and hepatitis C and traced sources. For cases reported to a hospital, hospital staff often did not trace HIV sources or follow up patients for hepatitis B and hepatitis C. KEY MEASURES FOR IMPROVEMENT: Providing adequate treatment for HIV, hepatitis B and hepatitis C after exposure for all reported exposures outside hospital. STRATEGIES FOR CHANGE: On 1 January 2000, a new protocol was introduced in which three Amsterdam hospitals and the municipal health service collaborated in the treatment and follow-up of exposures outside hospital. Both municipal health service and hospitals can decide whether HIV prophylaxis is necessary and prescribe accordingly. All people exposed in the community who report to hospitals are subsequently referred to the municipal health service for further treatment and follow-up. EFFECTS OF CHANGE: The protocol is effective in that most people comply with treatment and follow-up. When indicated, HIV prophylaxis is started soon after exposure. In nearly two thirds of cases the municipal health service traced and tested the source. LESSONS LEARNT: Provision of treatment and follow-up in one place enables treatment, tracing and testing sources, and follow-up, including counselling and registration of all reported exposures in Amsterdam, which allows for swift identification of emerging epidemiological trends. Since May 2004 all Amsterdam hospitals have participated in the protocol.

Safety of long-term interruption of successful antiretroviral therapy: the ATHENA cohort study.

We studied the dynamics of CD4 cell counts after the interruption of virologically successful highly active antiretroviral therapy (HAART) in 139 patients. Changes in CD4 cell counts during HAART interruption followed a biphasic pattern: an initial rapid decline during the first month followed by a slow decrease. During 48 weeks of follow-up mean CD4 cell counts remained just above the mean pre-HAART level. This limits the feasibility of structured treatment interruptions for patients with low nadir CD4 cell counts.