Paravertebral catheter versus EPidural analgesia in Minimally invasive Esophageal resectioN: a randomized controlled multicenter trial (PEPMEN trial).

BACKGROUND: Thoracic epidural analgesia is the standard postoperative pain management strategy in esophageal cancer surgery. However, paravertebral block analgesia may achieve comparable pain control while inducing less side effects, which may be beneficial for postoperative recovery. This study primarily aims to compare the postoperative quality of recovery between paravertebral catheter versus thoracic epidural analgesia in patients undergoing minimally invasive esophagectomy. METHODS: This study represents a randomized controlled superiority trial. A total of 192 patients will be randomized in 4 Dutch high-volume centers for esophageal cancer surgery. Patients are eligible for inclusion if they are at least 18 years old, able to provide written informed consent and complete questionnaires in Dutch, scheduled to undergo minimally invasive esophagectomy with two-field lymphadenectomy and an intrathoracic anastomosis, and have no contra-indications to either epidural or paravertebral analgesia. The primary outcome is the quality of postoperative recovery, as measured by the Quality of Recovery-40 (QoR-40) questionnaire on the morning of postoperative day 3. Secondary outcomes include the QoR-40 questionnaire score Area Under the Curve on postoperative days 1-3, the integrated pain and systemic opioid score and patient satisfaction and pain experience according to the International Pain Outcomes (IPO) questionnaire, and cost-effectiveness. Furthermore, the groups will be compared regarding the need for additional rescue medication on postoperative days 0-3, technical failure of the pain treatment, duration of anesthesia, duration of surgery, total postoperative fluid administration day 0-3, postoperative vasopressor and inotrope use, length of urinary catheter use, length of hospital stay, postoperative complications, chronic pain at six months after surgery, and other adverse effects. DISCUSSION: In this study, it is hypothesized that paravertebral analgesia achieves comparable pain control while causing less side-effects such as hypotension when compared to epidural analgesia, leading to shorter postoperative length of stay on a monitored ward and superior quality of recovery. If this hypothesis is confirmed, the results of this study can be used to update the relevant guidelines on postoperative pain management for patients undergoing minimally invasive esophagectomy. TRIAL REGISTRATION: Netherlands Trial Registry, NL8037. Registered 19 September 2019.

Perioperative replacement therapy in haemophilia B: An appeal to "B" more precise.

INTRODUCTION: Haemophilia B is caused by a deficiency of coagulation factor IX (FIX) and characterized by bleeding in muscles and joints. In the perioperative setting, patients are treated with FIX replacement therapy to secure haemostasis. Targeting of specified FIX levels is challenging and requires frequent monitoring and adjustment of therapy. AIM: To evaluate perioperative management in haemophilia B, including monitoring of FIX infusions and observed FIX levels, whereby predictors of low and high FIX levels were assessed. METHODS: In this international multicentre study, haemophilia B patients with FIX < 0.05 IU mL-1 undergoing elective, minor or major surgical procedures between 2000 and 2015 were included. Data were collected on patient, surgical and treatment characteristics. Observed FIX levels were compared to target levels as recommended by guidelines. RESULTS: A total of 255 surgical procedures were performed in 118 patients (median age 40 years, median body weight 79 kg). Sixty percent of FIX levels within 24 hours of surgery were below target with a median difference of 0.22 IU mL-1 [IQR 0.12-0.36]; while >6 days after surgery, 59% of FIX levels were above target with a median difference of 0.19 IU mL-1 [IQR 0.10-0.39]. Clinically relevant bleeding complications (necessity of a second surgical intervention or red blood cell transfusion) occurred in 7 procedures (2.7%). CONCLUSION: This study demonstrates that targeting of FIX levels in the perioperative setting is complex and suboptimal, but although this bleeding is minimal. Alternative dosing strategies taking patient and surgical characteristics as well as pharmacokinetic principles into account may help to optimize and individualize treatment.

Facilitating the implementation of pharmacokinetic-guided dosing of prophylaxis in haemophilia care by discrete choice experiment.

INTRODUCTION: Patients', parents' and providers' preferences with regard to medical innovations may have a major impact on their implementation. AIM: To evaluate barriers and facilitators for individualized pharmacokinetic (PK)-guided dosing of prophylaxis in haemophilia patients, parents of young patients, and treating professionals by discrete choice experiment (DCE) questionnaire. PATIENTS/METHODS: The study population consisted of patients with haemophilia currently or previously on prophylactic treatment with factor concentrate (n = 114), parents of patients aged 12-18 years (n = 19) and haemophilia professionals (n = 91). DCE data analysis was performed, taking preference heterogeneity into account. RESULTS: Overall, patients and parents, and especially professionals were inclined to opt for PK-guided dosing of prophylaxis. In addition, if bleeding was consequently reduced, more frequent infusions were acceptable. However, daily dosing remained an important barrier for all involved. 'Reduction of costs for society' was a facilitator for implementation in all groups. CONCLUSIONS: To achieve implementation of individualized PK-guided dosing of prophylaxis in haemophilia, reduction of bleeding risk and reduction of costs for society should be actively discussed as they are motivating for implementation; daily dosing is still reported to be a barrier for all groups. The knowledge of these preferences will enlarge support for this innovation, and aid in the drafting of implementable guidelines and information brochures for patients, parents and professionals.

Statin use decreases coagulation in users of vitamin K antagonists.

PURPOSE: The purpose of the study is to determine the immediate and long-term effect of statins on coagulation in patients treated with vitamin K antagonists (VKAs). METHODS: We selected patients on VKAs of two Dutch anticoagulation clinics who initiated treatment with a statin between 2009 and 2013. Patients who initiated or stopped concomitant drugs that interact with VKAs or were hospitalised during follow-up were excluded. The VKA dosage (mg/day) after statin initiation was compared with the last VKA dosage before the statin was started. Immediate and long-term differences in VKA dosage (at 6 and 12 weeks) were calculated with a paired student t test. RESULTS: Four hundred thirty-five phenprocoumon users (mean age 70 years, 60 % men) and 303 acenocoumarol users (mean age 69 years, 58 % men) were included. After start of statin use, the immediate phenprocoumon dosage was 0.02 mg/day (95 % CI, 0.00 to 0.03) lower. At 6 and 12 weeks, these phenprocoumon dosages were 0.03 (95 % CI, 0.01 to 0.05) and 0.07 mg/day (95 % CI, 0.04 to 0.09) lower as compared with the dosage before first statin use. In acenocoumarol users, VKA dosage was 0.04 mg/day (95%CI, 0.01 to 0.07) (immediate effect), 0.10 (95 % CI, 0.03 to 0.16) (at 6 weeks), and 0.11 mg/day (95 % CI, 0.04 to 0.18) (after 12 weeks) lower. CONCLUSIONS: Initiation of statin treatment was associated with an immediate and long-term minor although statistically significant decrease in VKA dosage in both phenprocoumon and acenocoumarol users, which suggests that statins may have anticoagulant properties.

Hepatitis B virus (HBV) variants fluctuate in paired plasma and peripheral blood mononuclear cells among patient cohorts during different chronic hepatitis B (CHB) disease phases.

Hepatitis B virus is classically considered a hepatotropic virus but also infects peripheral blood mononuclear cells. Chronic hepatitis B has different disease phases modulated by host immunity. We compared HBV variability, drug resistance and immune escape mutations in the overlapping HBV polymerase/surface gene in plasma and peripheral blood mononuclear cells in different disease phases. Plasma and peripheral blood mononuclear cells were isolated from 22 treatment naïve patient cohorts (five inactive, six immune-active, nine HBeAg negative and two immune-tolerant). HBV was genotyped via line probe assay, hepatitis B surface antigen titres were determined by an in-house immunoassay, and HBV DNA was quantified by kinetic PCR. The HBV polymerase/surface region, including full genome in some, was PCR-amplified and cloned, and ~20 clones/sample were sequenced. The sequences were subjected to various mutational and phylogenetic analyses. Clonal sequencing showed that only three of 22 patients had identical HBV genotype profiles in both sites. In immune-active chronic hepatitis B, viral diversity in plasma was higher compared with peripheral blood mononuclear cells. Mutations at residues, in a minority of clones, associated with drug resistance, and/or immune escape were found in both compartments but were more common in plasma. Immune escape mutations were more often observed in the peripheral blood mononuclear cells of immune-active CHB carriers, compared with other disease phases. During all CHB disease phases, differences exist between HBV variants found in peripheral blood mononuclear cells and plasma. Moreover, these data indicate that HBV evolution occurs in a compartment and disease phase-specific fashion.

Course of cannabis use and clinical outcome in patients with non-affective psychosis: a 3-year follow-up study.

BACKGROUND: Prospective studies on the relationship between course of cannabis use and clinical outcome in patients with non-affective psychotic disorders are inconclusive. The current study examined whether (1) persistent, recently started, discontinued and non-cannabis-using patients with a psychotic disorder differed with regard to illness outcome at 3-year follow-up, and (2) whether timing of cannabis discontinuation was associated with course of clinical outcome. METHOD: This 3-year follow-up study was part of a multi-center study in the Netherlands and Belgium (Genetic Risk and Outcome of Psychosis; GROUP). We used mixed-model analyses to investigate the association between pattern of cannabis use and symptoms, global functioning and psychotic relapse. RESULTS: In our sample of 678 patients, we found persistent users to have more positive and general symptoms, worse global functioning and more psychotic relapses compared with non-users and discontinued users [Positive and Negative Syndrome Scale (PANSS) positive, p < 0.001; PANSS general, p < 0.001; Global Assessment of Functioning (GAF) symptoms, p = 0.017; GAF disability, p < 0.001; relapses, p = 0.038]. Patients who started using cannabis after study onset were characterized by worse functioning at baseline and showed an increase in general symptoms (including depression and anxiety) at the 3-year follow-up (p = 0.005). Timing of cannabis discontinuation was not associated with clinical outcome. CONCLUSIONS: These findings suggest that cannabis use in patients with a psychotic disorder has a long-lasting negative effect on illness outcome, particularly when persistent. Treatment should focus on discouraging cannabis use.

Brain volume in male patients with recent onset schizophrenia with and without cannabis use disorders.

BACKGROUND: Schizophrenia is highly comorbid with cannabis use disorders (CUDs), and this comorbidity is associated with an unfavourable course. Early onset or frequent cannabis use may influence brain structure. A key question is whether comorbid CUDs modulate brain morphology alterations associated with schizophrenia. METHODS: We used surface-based analysis to measure the brain volume, cortical thickness and cortical surface area of a priori-defined brain regions (hippocampus, amygdala, thalamus, caudate, putamen, orbitofrontal cortex, anterior cingulate cortex, insula, parahippocampus and fusiform gyrus) in male patients with schizophrenia or related disorders with and without comorbid CUDs and matched healthy controls. Associations between age at onset and frequency of cannabis use with regional grey matter volume were explored. RESULTS: We included 113 patients with (CUD, n = 80) and without (NCUD, n = 33) CUDs and 84 controls in our study. As expected, patients with schizophrenia (with or without a CUD) had smaller volumes of most brain regions (amygdala, putamen, insula, parahippocampus and fusiform gyrus) than healthy controls, and differences in cortical volume were mainly driven by cortical thinning. Compared with the NCUD group, the CUD group had a larger volume of the putamen, possibly driven by polysubstance use. No associations between age at onset and frequency of use with regional grey matter volumes were found. LIMITATIONS: We were unable to correct for possible confounding effects of smoking or antipsychotic medication. CONCLUSION: Patients with psychotic disorders and comorbid CUDs have larger putamen volumes than those without CUDs. Future studies should elaborate whether a large putamen represents a risk factor for the development of CUDs or whether (poly)substance use causes changes in putamen volume.

Cognitive functioning associated with stimulant use in patients with non-affective psychosis, their unaffected siblings and healthy controls.

BACKGROUND: Little is known about the effect of stimulant use (amphetamines, cocaine, ecstasy) on cognitive functioning in schizophrenia patients. The current study examined (1) whether recency and frequency of stimulant use is associated with cognitive functioning and (2) whether these associations differ between psychotic patients, their unaffected siblings and controls. METHOD: Participants completed a comprehensive cognitive test battery. Stimulant use was assessed by urinalysis and by the Composite International Diagnostic Interview (CIDI). Using random effects regression models, the main effects of Stimulant Use and the interaction with Diagnostic Status on cognitive functioning were assessed. RESULTS: The interaction term between Stimulant Use and Diagnostic Status was not significant for any of the cognitive outcome variables, indicating similar effects of stimulant use in all three groups. Recent stimulant users showed more errors deficit in verbal learning in comparison to never users (Cohen's d = -0.60, p < 0.005). Lifetime frequent stimulant use was significantly associated with worse immediate and delayed verbal recall, working memory and acquired knowledge (Cohen's d = -0.22 to -0.29, p < 0.005). Lifetime infrequent stimulant use was not associated with significant cognitive alterations in comparison to never use. CONCLUSIONS: The presence of cognitive deficits associated with lifetime stimulant use is dependent on the frequency of use, with no observed deficits in infrequent users and modest negative effects in frequent users.

Cannabis use and age at onset of symptoms in subjects at clinical high risk for psychosis.

OBJECTIVE: Numerous studies have found a robust association between cannabis use and the onset of psychosis. Nevertheless, the relationship between cannabis use and the onset of early (or, in retrospect, prodromal) symptoms of psychosis remains unclear. The study focused on investigating the relationship between cannabis use and early and high-risk symptoms in subjects at clinical high risk for psychosis. METHOD: Prospective multicenter, naturalistic field study with an 18-month follow-up period in 245 help-seeking individuals clinically at high risk. The Composite International Diagnostic Interview was used to assess their cannabis use. Age at onset of high risk or certain early symptoms was assessed retrospectively with the Interview for the Retrospective Assessment of the Onset of Schizophrenia. RESULTS: Younger age at onset of cannabis use or a cannabis use disorder was significantly related to younger age at onset of six symptoms (0.33 < r(s) < 0.83, 0.004 < P < 0.001). Onset of cannabis use preceded symptoms in most participants. CONCLUSION: Our results provide support that cannabis use plays an important role in the development of psychosis in vulnerable individuals. Cannabis use in early adolescence should be discouraged.

An ultrapure plasma-derived monoclonal antibody-purified factor IX concentrate (Nonafact®), results of phase III and IV clinical studies.

Nonafact(®), an ultrapure, monoclonal antibody-purified factor IX concentrate (FIX) was developed to minimize risk of thrombotic complications and viral transmission. To investigate the pharmacokinetics, efficacy and safety, phase III/IV studies were performed in the Netherlands and Poland from 1996 to 2007. The mean half-life, in vivo response and recovery of Nonafact(®) were 18.7 (SD 2.0) h, 1.1 (SD 0.2) IU dL(-1) per IU kg(-1) b.w. of FIX infused and 49% (SD 10%), respectively. Eleven surgical procedures were performed in eight patients. During two surgeries, both high-risk, blood loss was observed. No postoperative bleeding occurred. The in vivo recovery of FIX was higher than expected. In the phase III follow-up study, 26 previously treated patients (PTP) were included with a median follow-up of 1130 days. From the 1617 minor bleedings, 80.5% was stopped after a single infusion. In the phase IV study thirteen patients were treated for a median study period of 737 days. In the two follow-up studies the investigators rated the effect of Nonafact(®) as excellent/good in 95% of major bleedings. Surgeries for which Nonafact(®) was given prophylactically were without bleeding problems. In total more than 10 million units of Nonafact(®) were used during almost 120 person-years. Only one minor adverse event was reported. No inhibitors, viral transmissions and thrombogenic events occurred. In conclusion, Nonafact(®) is safe and provides excellent haemostasis in haemophilia B patients treated for spontaneous bleeding or undergoing surgical procedures. Due to the excellent in vivo recovery characteristic, treatment with Nonafact(®) is cost saving compared to other FIX products.

Major differences in clinical presentation, diagnosis and management of men and women with autosomal inherited bleeding disorders.

BACKGROUND: In recent years, more awareness is raised about sex-specific dilemmas in inherited bleeding disorders. However, no large studies have been performed to assess differences in diagnosis, bleeding phenotype and management of men and women with bleeding disorders. Therefore, we investigated sex differences in a large cohort of well-defined patients with autosomal inherited bleeding disorders (von Willebrand disease (VWD), rare bleeding disorders (RBDs) and congenital platelet defects (CPDs)). METHODS: We included patients from three nationwide cross-sectional studies on VWD, RBDs and CPDs in the Netherlands, respectively the WiN, RBiN and TiN study. In all studies a bleeding score (BS) was obtained, and patients filled in an extensive questionnaire on the management and burden of their disorder. FINDINGS: We included 1092 patients (834 VWD; 196 RBD; 62 CPD), of whom 665 (60.9%) were women. Women were more often referred because of a bleeding diathesis than men (47.9% vs 36.6%, p = 0.002). Age of first bleeding was similar between men and women, respectively 8.9 ± 13.6 (mean ±sd) years and 10.6 ± 11.3 years (p = 0.075). However, the diagnostic delay, which was defined as time from first bleeding to diagnosis, was longer in women (11.6 ± 16.4 years) than men (7.7 ± 16.6 years, p = 0.002). Similar results were found when patients referred for bleeding were analyzed separately. Of women aging 12 years or older, 469 (77.1%) had received treatment because of sex-specific bleeding. INTERPRETATION: Women with autosomal inherited bleeding disorders are more often referred for bleeding, have a longer diagnostic delay, and often require treatment because of sex-specific bleeding. FUNDING: The WiN study was supported (in part) by research funding from the Dutch Hemophilia Foundation (Stichting Haemophilia), Shire (Takeda), and CSL Behring (unrestricted grant).

Seroprevalence of antibodies against pestiviruses in small ruminants in The Netherlands.

In this study, a serological survey was performed to determine the prevalence of pestivirus (bovine viral diarrhea virus (BVDV) and border disease virus (BDV)) infected small ruminants herds in the Netherlands. After random selection of sheep farms, a sample size was determined to detect a 5% herd prevalence. 13 out of 29 farms were tested seropositive using an ELISA which detects antibodies directed against the non structural protein 3 (NS3) of pestiviruses. This resulted in a seroprevalence for the Netherlands of 45% [0.36; 0.54]. The within farm prevalence ranged from 4 till 65%. Using a virus neutralization assay, specific anti-BDV antibodies could be detected on two farms, while on one other farm anti-BVDV antibodies were present. On four farms antibodies to both viruses could be detected, on three of these farms antibodies against both viruses were equally present. At five farms that tested positive in the NS3-ELISA we were unable to detect pestivirus neutralizing antibodies in all sera using the VN test. This resulted in an estimated prevalence using the VN for the Netherlands of 28% [0.20; 0.60]. An additional survey in sera from dairy goats revealed that 34 out of 126 farms were serological positive resulting in a seroprevalence of 27% [0.23; 0.31], with a herd prevalence of 32% ranging from 1-100%.

Multicentre evaluation of significant bacteriuria among pregnant women in the cascade of referral healthcare system in North-western Tanzania: Bacterial pathogens, antimicrobial resistance profiles and predictors.

OBJECTIVES: The aim of this multicentre study was to evaluate the magnitude of significant bacteriuria (SB) as well as the implicated bacterial pathogens, antimicrobial resistance (AMR) profiles and risk factors for SB among pregnant women attending different levels of healthcare facilities (HCFs) in Tanzania in order to guide antimicrobial therapy and preventive measures. METHODS: Information on sociodemographic and clinical characteristics, midstream urine culture and antimicrobial susceptibility testing was collected from 1828 pregnant women between March 2016 and May 2017. Data were analysed using STATA v.13.0 software. RESULTS: The prevalence of SB among pregnant women was 17.7% (323/1828; 95% CI 16.0-19.5%), with a predominance of Escherichia coli (164/323; 50.8%), Klebsiella spp. (55/323; 17.0%) and Staphylococcus aureus (28/323; 8.7%). Moreover, 37.5% (121/323) of bacteria were multidrug-resistant [84.3% (102/121) Gram-negative bacteria and 15.7% (19/121) in Gram-positive bacteria; P<0.001]. Third-generation cephalosporin resistance in E. coli, Klebsiella spp. and other Enterobacteriaceae was 13.4%, 21.8% and 27.5%, respectively, and was higher in strains from a tertiary hospital (OR=3.27, 95% CI 1.02-10.49; P=0.046) compared with lower HCFs. Predictors of SB among pregnant women were lack of formal occupation, current hospital admission and presence of co-morbidities. CONCLUSIONS: The prevalence of SB among pregnant women in this study was high (17.7%) and was within the same range reported 10 years ago in a single-centre baseline study. However, there is an increase in AMR in the cascade of referral healthcare system, underscoring the need for health facility level-specific antimicrobial stewardship.

[The interaction between anticoagulant therapy with vitamin K-antagonists and treatment with antibiotics: a practical recommendation]. / De interactie tussen antistollingstherapie met vitamine K-antagonisten en behandeling met antibiotica: een praktische aanbeveling.

--In users of vitamin K-antagonists (VKA), antibiotics can lead to excessive anticoagulation. --It is unclear what the optimal policy is for prevention of an excessive anticoagulant effect during use of antibiotics. --This article describes the increased sensitivity to VKA during use of antibiotics, and also provides a practical recommendation for the correct method for use of antibiotics in combination with VKA treatment. --During use of antibiotics for more than one day, the prothrombin time-'international normalized ratio' (PTT-INR) must be checked both after 3 and after 7 days, and the dose of VKA must be adapted if necessary. --Use of co-trimoxazole for more than one day should, if possible, be avoided.

Bovine viral diarrhea virus genomic variation within persistently infected cattle.

Bovine viral diarrhea virus (BVDV) is a single stranded RNA virus in the family Flaviviridae that causes a form of persistent infection. If a fetus is infected in utero during the first 120days of gestation the resulting calf will be immunotolerant to the infecting strain and maintain the virus for life. These animals are epidemiologically important in maintaining BVDV on farms, but also present a unique opportunity to study quasispecies in vivo in the absence of significant selection by the host adaptive immune response. We used deep sequencing and novel analytical methods to characterize the viral populations within the mesenteric lymph nodes of 10 persistently infected animals. Our results indicate that the pattern of variability across the viral genome from animal to animal is very consistent within BVDV subgenotypes. However, the individual mutations that constitute this variation are not necessarily the same in each animal. Even in the absence of significant immune selection the structural genes of BVDV vary more extensively than the non-structural genes. These findings could be useful for future vaccine design against BVDV as well as for measuring and understanding patterns of variation in other ssRNA viruses, especially those that belong to the family Flaviviridae.

Preliminary insights into the occurrence of similar clones of extended-spectrum beta-lactamase-producing bacteria in humans, animals and the environment in Tanzania: A systematic review and meta-analysis between 2005 and 2016.

The emergence and spread of extended-spectrum beta-lactamase producing Enterobacteriaceae (ESBL-PE) are complex and of the public health concern across the globe. This review aimed at assessing the ESBL-PE clones circulating in humans, animals and the environment to provide evidence-based insights for combating ESBL-PE using One Health approach. Systematic search from Medline/PubMed, Google Scholar and African Journals Online was carried out and retrieved nine eligible articles (of 131) based on phenotypic and genotypic detection of ESBL-PE between 2005 and 2016 in Tanzania. Analysis was performed using STATA 11.0 software to delineate the prevalence of ESBL-PE, phenotypic resistance profiles and clones circulating in the three interfaces. The overall prevalence of ESBL-PE in the three interfaces was 22.6% (95% CI: 21.1-24.2) with the predominance of Escherichia coli (E. coli) strains (51.6%). The majority of ESBL-PE were resistant to the commonly used antimicrobials such as trimethoprim-sulfamethoxazole and tetracycline/doxycycline, 38%-55% were resistant to ciprofloxacin and all were sensitive to meropenem/imipenem. ESBL-PE infections were more associated with deaths compared to non-ESBL-PE infections. Strikingly, E. coli ST38, ST131 and ST2852 were found to intersect variably across the three interfaces. The predominant allele, blaCTX-M-15, was found mostly in the conjugative IncF plasmids connoting transmission potential. The high prevalence of ESBL-PE and shared clones across the three interfaces, including the global E. coli ST131 clone, indicates wide and inter-compartmental spread that calls for One Health genomic-driven studies to track the resistome flow.

Nationwide screening of surface water toxicity to algae.

According to the European Water Framework Directive (WFD), chemical water quality is assessed by monitoring 45 priority substances. However, observed toxic effects can often not be attributed to these priority substances, and therefore there is an urgent need for an effect-based monitoring strategy that employs bioassays to identify environmental risk. Algal photosynthesis is a sensitive process that can be applied to identify the presence of hazardous herbicides in surface water. Therefore, the aim of this study was to employ an algal photosynthesis bioassay to assess surface water toxicity to algae and to identify the compounds causing the observed effects. To this purpose, Raphidocelis subcapitata was exposed to surface water samples and after 4.5 h photosynthetic efficiency was determined using PAM fluorometry. In this rapid high throughput bioassay, algal photosynthesis was affected by surface water from only one of 39 locations. Single compounds toxicity confirmation elucidated that the observed effect could be solely attributed to the herbicide linuron, which occurred at 110 times the EQS concentration and which is not included in the WFD priority substances list. In conclusion, applying the algal photosynthesis bioassay enables more efficient and effective assessment of toxicity to primary producers because it: (i) identifies the presence of herbicides that would be overlooked by routine chemical WFD monitoring, and (ii) avoids redundant chemical analyses by focusing only on (non-)target screening in samples with demonstrated effects.

Characteristics and quality of oral anticoagulation treatment in pediatric patients in the Netherlands based on the CAPS cohort.

Essentials The knowledge of quality and safety of acenocoumarol and phenprocoumon use in children is limited. We used data from a multicenter retrospective follow-up study in children in the Netherlands. The quality of anticoagulation control in the first month of use was low, but improved thereafter. No thromboembolic events occurred, however bleeding events occurred in 1-3 out of 10 patients. SUMMARY: Background The use of vitamin-K antagonists in pediatric patients is rare and information on the quality and safety of treatment with acenocoumarol and phenprocoumon is limited. Objectives To assess the quality, safety and effectiveness during the first year of acenocoumarol and phenprocoumon treatment in pediatric patients in the Netherlands. Methods The Children Anticoagulation and Pharmacogenetics Study (CAPS) was designed as a multicenter retrospective follow-up study. Patients who used acenocoumarol or phenprocoumon at an age of ≤ 18 years, were selected from four pediatric hospitals and one anticoagulation clinic in the Netherlands. The quality of treatment was assessed by calculating the percentage of time in therapeutic INR range (TTR) for the first month and for every 3 months of use during the first year of treatment. Effectiveness and safety were assessed by the number of thromboembolic and bleeding events. Results In total, 213 patients participated, of whom 187 (155 acenocoumarol; 32 phenprocoumon) were included in this analysis. The mean TTR was 47.0% and 51.4% in the first month of use for acenocoumarol and phenprocoumon, respectively. After the first 3 months the mean TTR for both VKAs was above 64%. In 14.6% (acenocoumarol) and 31.3% (phenprocoumon) of the patients a bleeding event occurred during the first year of treatment; no thromboembolic events were reported. Conclusions The quality of anticoagulation treatment was low during the first month of use and leaves room for improvement. After the first month it increased to an acceptable level. However, bleeding events occurred frequently during the first year.

The pediatric acenocoumarol dosing algorithm: the Children Anticoagulation and Pharmacogenetics Study.

Essentials A pediatric pharmacogenetic dosing algorithm for acenocoumarol has not yet been developed. We conducted a multicenter retrospective follow-up study in children in the Netherlands. Body surface area and indication explained 45.0% of the variability in dose requirement. Adding the genotypes of VKORC1, CYP2C9 and CYP2C18 to the algorithm increased this to 61.8%. SUMMARY: Background The large variability in dose requirement of vitamin K antagonists is well known. For warfarin, pediatric dosing algorithms have been developed to predict the correct dose for a patient; however, this is not the case for acenocoumarol. Objectives To develop dosing algorithms for pediatric patients receiving acenocoumarol with and without genetic information. Methods The Children Anticoagulation and Pharmacogenetics Study was designed as a multicenter retrospective follow-up study in Dutch anticoagulation clinics and children's hospitals. Pediatric patients who used acenocoumarol between 1995 and 2014 were selected for inclusion. Clinical information and saliva samples for genotyping of the genes encoding cytochrome P450 (CYP) 2C9, vitamin K epoxide reductase complex subunit 1 (VKORC1), CYP4F2, CYP2C18 and CYP3A4 were collected. Linear regression was used to analyze their association with the log mean stable dose. A stable period was defined as three or more consecutive International Normalized Ratio measurements within the therapeutic range over a period of ≥ 3 weeks. Results In total, 175 patients were included in the study, of whom 86 had a stable period and no missing clinical information (clinical cohort; median age 8.9 years, and 49% female). For 80 of these 86 patients, genetic information was also available (genetic cohort). The clinical algorithm, containing body surface area and indication, explained 45.0% of the variability in dose requirement of acenocoumarol. After addition of the VKORC1, CYP2C9, and CYP2C18 genotypes to the algorithm, this increased to 61.8%. Conclusions These findings show that clinical factors had the largest impact on the required dose of acenocoumarol in pediatric patients. Nevertheless, genetic factors, and especially VKORC1, also explained a significant part of the variability.

Population pharmacokinetics of factor IX in hemophilia B patients undergoing surgery.

Essentials Factor IX (FIX) dosing using body weight frequently results in under and overdosing during surgery. We aimed to establish a population pharmacokinetic (PK) model describing the perioperative FIX levels. Population PK parameter values for clearance and V1 were 284 mL h-170 kg-1 and 5450 mL70 kg-1. Perioperative PK parameters differ from those during non-surgical prophylactic treatment. SUMMARY: Background Hemophilia B is a bleeding disorder characterized by a deficiency of coagulation factor IX (FIX). In the perioperative setting, patients receive FIX concentrates to ensure hemostasis. Although FIX is usually dosed according to bodyweight, under- and overdosing occurs frequently during surgery. Aim The objective was to quantify and explain the interpatient variability of perioperatively administered plasma-derived (pd) and recombinant (r) FIX concentrates. Methods Data were collected from 118 patients (median age, 40 years [range, 0.2-90]; weight, 79 kg [range, 5.3-132]) with moderate (28%) or severe hemophilia B (72%), undergoing 255 surgical procedures. Population pharmacokinetic (PK) parameters were estimated using nonlinear mixed-effect modeling in NONMEM. Results Measured perioperative FIX level vs. time profiles were adequately described using a three-compartment PK model. For a typical 34-year-old patient receiving rFIX, clearance (CL), intercompartmental clearance (Q2, Q3), distribution volume of the central compartment (V1) and peripheral compartments (V2, V3) plus interpatient variability (%CV) were: CL, 284 mL h-170 kg-1 (18%); V1, 5450 mL70 kg-1 (19%); Q2, 110 mL h-170 kg-1; V2, 4800 mL70 kg-1; Q3, 1610 mL h-170 kg-1; V3, 2040 mL70 kg-1. From 0.2 years, CL and V1 decreased 0.89% and 1.15% per year, respectively, until the age of 34 years. Patients receiving pdFIX exhibited a lower CL (11%) and V1 (17%) than patients receiving rFIX. Interpatient variability was successfully quantified and explained. Conclusions The estimated perioperative PK parameters of both pdFIX and rFIX are different from those reported for prophylactic treatment. The developed model may be used to apply PK-guided dosing of FIX concentrates during surgery.