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Background: Multidrug-resistant organisms (MDRO) pose a significant threat to public health worldwide. The ability to identify antimicrobial resistance determinants, to assess changes in molecular types, and to detect transmission are essential for surveillance and infection prevention of MDRO. Molecular characterization based on long-read sequencing has emerged as a promising alternative to short-read sequencing. The aim of this study was to characterize MDRO for surveillance and transmission studies based on long-read sequencing only. Methods: Genomic DNA of 356 MDRO was automatically extracted using the Maxwell-RSC48. The MDRO included 106 Klebsiella pneumoniae isolates, 85 Escherichia coli, 15 Enterobacter cloacae complex, 10 Citrobacter freundii, 34 Pseudomonas aeruginosa, 16 Acinetobacter baumannii, and 69 methicillin-resistant Staphylococcus aureus (MRSA), of which 24 were from an outbreak. MDRO were sequenced using both short-read (Illumina NextSeq 550) and long-read (Nanopore Rapid Barcoding Kit-24-V14, R10.4.1) whole-genome sequencing (WGS). Basecalling was performed for two distinct models using Dorado-0.3.2 duplex mode. Long-read data was assembled using Flye, Canu, Miniasm, Unicycler, Necat, Raven, and Redbean assemblers. Long-read WGS data with > 40 × coverage was used for multi-locus sequence typing (MLST), whole-genome MLST (wgMLST), whole-genome single-nucleotide polymorphisms (wgSNP), in silico multiple locus variable-number of tandem repeat analysis (iMLVA) for MRSA, and identification of resistance genes (ABRicate). Results: Comparison of wgMLST profiles based on long-read and short-read WGS data revealed > 95% of wgMLST profiles within the species-specific cluster cut-off, except for P. aeruginosa. The wgMLST profiles obtained by long-read and short-read WGS differed only one to nine wgMLST alleles or SNPs for K. pneumoniae, E. coli, E. cloacae complex, C. freundii, A. baumannii complex, and MRSA. For P. aeruginosa, differences were up to 27 wgMLST alleles between long-read and short-read wgMLST and 0–10 SNPs. MLST sequence types and iMLVA types were concordant between long-read and short-read WGS data and conventional MLVA typing. Antimicrobial resistance genes were detected in long-read sequencing data with high sensitivity/specificity (92–100%/99–100%). Long-read sequencing enabled analysis of an MRSA outbreak. Conclusions: We demonstrate that molecular characterization of automatically extracted DNA followed by long-read sequencing is as accurate compared to short-read sequencing and suitable for typing and outbreak analysis as part of genomic surveillance of MDRO. However, the analysis of P. aeruginosa requires further improvement which may be obtained by other basecalling algorithms. The low implementation costs and rapid library preparation for long-read sequencing of MDRO extends its applicability to resource-constrained settings and low-income countries worldwide. [ABSTRACT FROM AUTHOR]

Mucormycosis is a severe complication in critically ill COVID-19 patients. Throughout the pandemic, a notable prevalence of mucormycosis has been observed in the Indian population, whereas lower occurrences have been reported in Europe. However, limited data exist regarding its prevalence in Europe, which is potentially underestimated due to the low sensitivity of bronchoalveolar lavage (BAL) cultures. We aimed to evaluate the prevalence of mucormycosis in a high-risk critically ill COVID-19 population in the Netherlands, and to evaluate the potential benefit of adding Mucor PCR to BAL as part of routine follow-up. In this study, we included 1035 critically ill COVID-19 patients admitted to either one of the two ICUs at AmsterdamUMC between March 2020 and May 2022; of these, 374 had undergone at least one bronchoscopy. Following the AmsterdamUMC protocols, bronchoscopies were conducted weekly until clinical improvement was achieved. We cultured BAL fluid for fungi and used PCR and galactomannan testing to detect Aspergillus spp. Additionally, we retrospectively performed qPCR targeting Mucorales DNA in the BAL of 89 deceased patients. All cultures were negative for Mucorales, whereas 42 (11%) cultures were positive for Aspergillus. Furthermore, qPCR targeting Mucorales was negative in all 89 deceased patients. This study showed that pulmonary mucormycosis was not present in critically ill COVID-19 patients in two tertiary care ICUs. These results indicate routine Mucorales qPCR screening is not clinically necessary in a high-standard-of-care tertiary ICU in a low-endemic area. [ABSTRACT FROM AUTHOR]

Objectives: Among patients with haematological malignancy, bacteraemia is a common complication during chemotherapy-induced neutropenia. Resistance of gram-negative bacteria (GNB) to third-generation cephalosporins (3GC) is increasing. In order to explore the value of using surveillance cultures to guide empirical treatment e.g. choosing between carbapenem versus ceftazidime- we aimed to assess the distribution of pathogens causing bacteraemia in patients with haematological malignancy, and the proportion of 3GC-resistant GNB (3GC-R GNB) bacteraemia that was preceded by 3GC-R GNB colonization. Methods: Using 11 years of data (2008–2018) from the Dutch national antimicrobial resistance surveillance system, we assessed the prevalence of 3GC-R GNB in episodes of bacteraemia, and the proportion of 3GC-R GNB bacteraemia that was preceded by 3GC-R GNB colonization. Colonization was defined as availability of any GNB surveillance isolate in the year before, independent of the causative micro-organism (time-paired isolates). Results: We included 3887 patients, representing 4142 episodes of bacteraemia. GNB were identified in 715/4142 (17.3%), of which 221 (30.9%) were 3GC-R GNB. In 139 of these 221 patients a time-paired surveillance culture was available. In 76.2% (106/139) of patients these surveillance cultures already showed 3GC-R GNB isolates in the year prior to the culture date of the 3GC-R GNB positive blood isolate. Conclusions: This multi-centre study shows that in patients with haematological malignancy, the majority of 3GC-R GNB bacteraemia is preceded by 3GC-R GNB colonization. Prospective clinical studies are needed to assess the safety and benefits of the use of surveillance-cultures to guide empirical therapy to restrict the empirical use of carbapenems in this population. [ABSTRACT FROM AUTHOR]

Background: The Netherlands is currently considered a low endemic country for carbapenem-resistant Enterobacterales (CRE) and carbapenemase-producing Enterobacterales (CPE), experiencing only sporadic hospital outbreaks. This study aims to describe susceptibility to carbapenems and the epidemiology of carbapenemase production in Enterobacterales in the Netherlands in 2017–2019. Methods: Three complementary nationwide surveillance systems are in place to monitor carbapenem susceptibility in the Netherlands. Routine antimicrobial susceptibility test results from medical microbiology laboratories were used to study phenotypic susceptibility of Escherichia coli and Klebsiella pneumoniae. Pathogen surveillance (of all Enterobacterales species) and mandatory notifications were used to describe the characteristics of CPE positive isolates and affected persons. Results: The prevalence of isolates with gradient strip test-confirmed elevated meropenem (> 0.25 mg/L) or imipenem (> 1 mg/L) minimum inhibitory concentration (MIC) in the Netherlands was very low in 2017–2019, with percentages of 0.06% in E. coli and 0.49% in K. pneumoniae, and carbapenem resistances of 0.02% and 0.18%, respectively. A total of 895 unique species/carbapenemase-encoding allele combinations of CPE from 764 persons were submitted between 2017 and 2019, with the annual number of submissions increasing slightly each year. Epidemiological data was available for 660 persons. Screening because of presumed colonisation risk was the reason for sampling in 70.0% (462/660) of persons. Hospitalization abroad was the most common risk factor, being identified in 45.9% of persons. Conclusions: Carbapenem resistance of E. coli and K. pneumoniae remains low in the Netherlands. The annual number of CPE isolates slightly increased during the period 2017–2019. Recent hospitalization abroad is the main risk factor for acquisition of CPE. [ABSTRACT FROM AUTHOR]

Objective: Recent studies have reported suboptimal up-titration of heart failure (HF) therapies in patients with heart failure and a reduced ejection fraction (HFrEF). Here, we report on the achieved doses after nurse-led up-titration, reasons for not achieving the target dose, subsequent changes in left ventricular ejection fraction (LVEF), and mortality. Methods: From 2012 to 2018, 378 HFrEF patients with a recent (< 3 months) diagnosis of HF were referred to a specialised HF-nurse led clinic for protocolised up-titration of guideline-directed medical therapy (GDMT). The achieved doses of GDMT at 9 months were recorded, as well as reasons for not achieving the optimal dose in all patients. Echocardiography was performed at baseline and after up-titration in 278 patients. Results: Of 345 HFrEF patients with a follow-up visit after 9 months, 69% reached ≥ 50% of the recommended dose of renin-angiotensin-system (RAS) inhibitors, 73% reached ≥ 50% of the recommended dose of beta-blockers and 77% reached ≥ 50% of the recommended dose of mineralocorticoid receptor antagonists. The main reasons for not reaching the target dose were hypotension (RAS inhibitors and beta-blockers), bradycardia (beta-blockers) and renal dysfunction (RAS inhibitors). During a median follow-up of 9 months, mean LVEF increased from 27.6% at baseline to 38.8% at follow-up. Each 5% increase in LVEF was associated with an adjusted hazard ratio of 0.84 (0.75–0.94, p = 0.002) for mortality and 0.85 (0.78–0.94, p = 0.001) for the combined endpoint of mortality and/or HF hospitalisation after a mean follow-up of 3.3 years. Conclusions: This study shows that protocolised up-titration in a nurse-led HF clinic leads to high doses of GDMT and improvement of LVEF in patients with new-onset HFrEF. [ABSTRACT FROM AUTHOR]

Objectives: It is not clear whether dopaminergic medication influences bruxism behaviour in patients with Parkinson's disease (PD). Therefore, the aims are to investigate (i) the prevalence of possible (i.e., self-reported) bruxism (sleep and awake) in PD patients, and (ii) whether the use of dopaminergic medication and other factors (viz., demographic characteristics, PD-related factors, and possible consequences of bruxism) are associated with possible bruxism (sleep or awake). Materials and methods: This study concerns a secondary analysis of an earlier published study. Three hundred ninety-five PD patients (67.9 ± 8.6 years of age; 58.7% males) were included. The levodopa equivalent daily dosage (LEDD) was used as a measure of the dopaminergic medication level. Subsequently, a logistic regression analysis was performed for the dependent variables 'awake bruxism' and 'sleep bruxism', with the following predictors: gender, age, LEDD, time since PD diagnosis, temporomandibular disorder (TMD) pain, jaw locks, and tooth wear. Results: The prevalence of possible awake and sleep bruxism was 46.0% and 24.3%, respectively. Awake bruxism was associated with sleep bruxism (OR = 8.52; 95% CI 3.56–20.40), TMD pain (OR = 4.51; 95% CI 2.31–8.79), and tooth wear (OR = 1.87; 95% CI 1.02–3.43). Sleep bruxism was associated with tooth wear (OR = 12.49; 95% CI 4.97–31.38) and awake bruxism (OR = 9.48; 95% CI 4.24–21.19). Dopaminergic medication dose was not associated with awake bruxism (OR = 1.0; 95% CI 0.99–1.00) or sleep bruxism (OR = 1.0; 95% CI 0.99–1.00). Conclusion: Bruxism is a common condition in PD patients, but is not associated with the dopaminergic medication dose. Clinical relevance: (Oral) health care providers should be alerted about the possibility of sleep and awake bruxism activity in PD patients, along with this activity's possible negative health outcomes (viz., TMD pain, tooth wear). [ABSTRACT FROM AUTHOR]

Introduction: Acquired demyelinating syndromes (ADS) are immune-mediated demyelinating disorders of the central nervous system in children. A nationwide, multicentre and prospective cohort study was initiated in the Netherlands in 2006, with a reported ADS incidence of 0.66/100,000 per year and MS incidence of 0.15/100,000 per year in the period between 2007 and 2010. In this study, we provide an update on the incidence and the long-term follow-up of ADS in the Netherlands.Methods: Children < 18 years with a first attack of demyelination were included consecutively from January 2006 to December 2016. Diagnoses were based on the International Paediatric MS study group consensus criteria. Outcome data were collected by neurological and neuropsychological assessments, and telephone call assessments.Results: Between 2011 and 2016, 55/165 of the ADS patients were diagnosed with MS (33%). This resulted in an increased ADS and MS incidence of 0.80/100,000 per year and 0.26/100,000 per year, respectively. Since 2006 a total of 243 ADS patients have been included. During follow-up (median 55 months, IQR 28-84), 137 patients were diagnosed with monophasic disease (56%), 89 with MS (37%) and 17 with multiphasic disease other than MS (7%). At least one form of residual deficit including cognitive impairment was observed in 69% of all ADS patients, even in monophasic ADS. An Expanded Disability Status Scale score of ≥ 5.5 was reached in 3/89 MS patients (3%).Conclusion: The reported incidence of ADS in Dutch children has increased since 2010. Residual deficits are common in this group, even in monophasic patients. Therefore, long-term follow-up in ADS patients is warranted. [ABSTRACT FROM AUTHOR]

Telomere length can be considered as a biological marker for cell proliferation and aging. Obesity is associated with adipocyte hypertrophy and proliferation as well as with shorter telomeres in adipose tissue. As adipose tissue is a mixture of different cell types and the cellular composition of adipose tissue changes with obesity, it is unclear what determines telomere length of whole adipose tissue. We aimed to investigate telomere length in whole adipose tissue and isolated adipocytes in relation to adiposity, adipocyte hypertrophy and adipose tissue inflammation and fibrosis. Telomere length was measured by real-time PCR in visceral adipose tissue, and isolated adipocytes of 21 obese women with a waist ranging from 110 to 147 cm and age from 31 to 61 years. Telomere length in adipocytes was shorter than in whole adipose tissue. Telomere length of adipocytes but not whole adipose tissue correlated negatively with waist and adipocyte size, which was still significant after correction for age. Telomere length of whole adipose tissue associated negatively with fibrosis as determined by collagen content. Thus, in extremely obese individuals, adipocyte telomere length is a marker of adiposity, whereas whole adipose tissue telomere length reflects the extent of fibrosis and may indicate adipose tissue dysfunction. [ABSTRACT FROM AUTHOR]

Telomere length can be considered as a biological marker for cell proliferation and aging. Obesity is associated with adipocyte hypertrophy and proliferation as well as with shorter telomeres in adipose tissue. As adipose tissue is a mixture of different cell types and the cellular composition of adipose tissue changes with obesity, it is unclear what determines telomere length of whole adipose tissue. We aimed to investigate telomere length in whole adipose tissue and isolated adipocytes in relation to adiposity, adipocyte hypertrophy and adipose tissue inflammation and fibrosis. Telomere length was measured by real-time PCR in visceral adipose tissue, and isolated adipocytes of 21 obese women with a waist ranging from 110 to 147 cm and age from 31 to 61 years. Telomere length in adipocytes was shorter than in whole adipose tissue. Telomere length of adipocytes but not whole adipose tissue correlated negatively with waist and adipocyte size, which was still significant after correction for age. Telomere length of whole adipose tissue associated negatively with fibrosis as determined by collagen content. Thus, in extremely obese individuals, adipocyte telomere length is a marker of adiposity, whereas whole adipose tissue telomere length reflects the extent of fibrosis and may indicate adipose tissue dysfunction. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE The aetiology of inflammation in the liver and vessel wall, leading to non-alcoholic steatohepatitis (NASH) and atherosclerosis, respectively, shares common mechanisms including macrophage infiltration. To treat both disorders simultaneously, it is highly important to tackle the inflammatory status. Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, reduces hepatic steatosis and has been suggested to reduce atherosclerosis; however, its effects on liver inflammation are underexplored. Here, we tested the hypothesis that exendin-4 reduces inflammation in both the liver and vessel wall, and investigated the common underlying mechanism. EXPERIMENTAL APPROACH Female APOE*3-Leiden.CETP mice, a model with human-like lipoprotein metabolism, were fed a cholesterol-containing Western-type diet for 5 weeks to induce atherosclerosis and subsequently treated for 4 weeks with exendin-4. KEY RESULTS Exendin-4 modestly improved dyslipidaemia, but markedly decreased atherosclerotic lesion severity and area (-33%), accompanied by a reduction in monocyte adhesion to the vessel wall (-42%) and macrophage content in the plaque (-44%). Furthermore, exendin-4 reduced hepatic lipid content and inflammation as well as hepatic CD68+ (-18%) and F4/80+ (-25%) macrophage content. This was accompanied by less monocyte recruitment from the circulation as the Mac-1+ macrophage content was decreased (-36%). Finally, exendin-4 reduced hepatic chemokine expression in vivo and suppressed oxidized low-density lipoprotein accumulation in peritoneal macrophages in vitro, effects dependent on the GLP-1 receptor. CONCLUSIONS AND IMPLICATIONS Exendin-4 reduces inflammation in both the liver and vessel wall by reducing macrophage recruitment and activation. These data suggest that exendin-4 could be a valuable strategy to treat NASH and atherosclerosis simultaneously. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE The aetiology of inflammation in the liver and vessel wall, leading to non-alcoholic steatohepatitis (NASH) and atherosclerosis, respectively, shares common mechanisms including macrophage infiltration. To treat both disorders simultaneously, it is highly important to tackle the inflammatory status. Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, reduces hepatic steatosis and has been suggested to reduce atherosclerosis; however, its effects on liver inflammation are underexplored. Here, we tested the hypothesis that exendin-4 reduces inflammation in both the liver and vessel wall, and investigated the common underlying mechanism. EXPERIMENTAL APPROACH Female APOE*3-Leiden.CETP mice, a model with human-like lipoprotein metabolism, were fed a cholesterol-containing Western-type diet for 5 weeks to induce atherosclerosis and subsequently treated for 4 weeks with exendin-4. KEY RESULTS Exendin-4 modestly improved dyslipidaemia, but markedly decreased atherosclerotic lesion severity and area (-33%), accompanied by a reduction in monocyte adhesion to the vessel wall (-42%) and macrophage content in the plaque (-44%). Furthermore, exendin-4 reduced hepatic lipid content and inflammation as well as hepatic CD68+ (-18%) and F4/80+ (-25%) macrophage content. This was accompanied by less monocyte recruitment from the circulation as the Mac-1+ macrophage content was decreased (-36%). Finally, exendin-4 reduced hepatic chemokine expression in vivo and suppressed oxidized low-density lipoprotein accumulation in peritoneal macrophages in vitro, effects dependent on the GLP-1 receptor. CONCLUSIONS AND IMPLICATIONS Exendin-4 reduces inflammation in both the liver and vessel wall by reducing macrophage recruitment and activation. These data suggest that exendin-4 could be a valuable strategy to treat NASH and atherosclerosis simultaneously. [ABSTRACT FROM AUTHOR]

Background:Childhood obesity is a major health problem. An association between children's body mass index (BMI) and overeating has been established, but mechanisms leading to overeating are poorly understood. The personality characteristics impulsivity and reward responsiveness may be involved in the tendency to overeat. Impulsivity might relate to overeating through poor inhibition of food intake; reward responsiveness through the rewarding value of food.Objective:This study aimed to reveal the relationships between impulsivity, reward responsiveness, overeating and BMI in a sample of 346 Dutch children aged 6-13 years. The BMI distribution in the sample was representative of the BMI distribution in the Dutch pediatric population.Methods:Impulsivity and reward responsiveness were measured with the Dutch version of the parent-report Sensitivity to Punishment and Sensitivity to Reward Questionnaire for children. Overeating was assessed with the Dutch translation of the parent-report Children's Eating Behaviour Questionnaire.Results:Overeating, impulsivity and reward responsiveness were significantly associated with childhood BMI. Mediation analysis revealed that impulsivity and reward responsiveness equally and significantly predicted BMI indirectly through overeating.Conclusions:The personality characteristics impulsivity and reward responsiveness predict childhood BMI indirectly through overeating. This suggests that these personality characteristics are risk factors for obesity. [ABSTRACT FROM AUTHOR]

High fat feeding induces a variety of obese and lean phenotypes in inbred rodents. Compared to Diet Resistant (DR) rodents, Diet Induced Obese (DIO) rodents are insulin resistant and have a reduced dopamine receptor D2 (DRD2) mediated tone. We hypothesized that this differing dopaminergic tone contributes to the distinct metabolic profiles of these animals. C57B16 mice were classified as DIO or DR based on their weight gain during 10 weeks of high fat feeding. Subsequently DIO mice were treated with the DRD2 agonist bromocriptine and DR mice with the DRD2 antagonist haloperidol for 2 weeks. Compared to DR mice, the bodyweight of DIO mice was higher and their insulin sensitivity decreased. Haloperidol treatment reduced the voluntary activity and energy expenditure of DR mice and induced insulin resistance in these mice. Conversely, bromocriptine treatment tended to reduce bodyweight and voluntary activity, and reinforce insulin action in DIO mice. These results show that DRD2 activation partly redirects high fat diet induced metabolic anomalies in obesity-prone mice. Conversely, blocking DRD2 induces an adverse metabolic profile in mice that are inherently resistant to the deleterious effects of high fat food. This suggests that dopaminergic neurotransmission is involved in the control of metabolic phenotype. [ABSTRACT FROM AUTHOR]

Different regimens are used to achieve immune tolerance in patients with severe haemophilia A and inhibitory allo-antibodies against factor VIII (FVIII). In this study, results of 26 years of low dose immune tolerance induction are evaluated. We evaluated 21 patients, who were treated with regular infusions of low dose FVIII (25–50 IU kg−1 every other day or three times a week) to obtain immune tolerance. Several risk factors for success rate and time to success were analysed. In 18 of 21 patients (86%) immune tolerance induction (ITI) was successful. The median of the maximum inhibitor titre before start of ITI was 4.5 BU mL−1. Success rate was associated with both a pre-ITI titre and a maximum titre during ITI below 40 BU mL−1 ( P = 0.003). The time to success was significantly shorter if the maximum inhibitor level during ITI was below 40 BU mL−1 ( P = 0.040). In low titre inhibitors (<5 BU mL−1) this effect was even stronger ( P = 0.033). Low dose immune tolerance induction therapy was successful in severe haemophilia A patients with a pre-ITI titre below 40 BU mL−1. The time to success is predicted by a maximum ITI titre below 40 BU mL−1, and is even shorter in low titre inhibitors (<5 BU mL−1). We suggest that all patients with severe haemophilia A and a pre-ITI inhibitor titre below 5 BU mL−1, should be treated with low dose immune tolerance induction therapy. Patients with a maximum titre below 40 BU mL−1 may also strongly benefit from the beneficial effects of low dose immune tolerance induction therapy. [ABSTRACT FROM AUTHOR]

Henneman P, Janssens ACJW, Carola Zillikens M, Frolich M, Frants RR, Oostra BA, van Duijn CM, van Dijk KW (Leiden University Medical Center, Leiden; Erasmus Medical Center, Rotterdam, The Netherlands). Menopause impacts the relation of plasma adiponectin levels with the metabolic syndrome. J Intern Med 2010; 267: 402–409. Objective. Plasma adiponectin is negatively correlated with metabolic syndrome (MetS) components obesity and insulin sensitivity. Here, we set out to evaluate the effect of menopause on the association of plasma adiponectin with MetS. Design. Data on plasma adiponectin and MetS were available from 2256 individuals participating in the Erasmus Rucphen Family study. Odds ratios for MetS were calculated by logistic regression analysis using plasma adiponectin quartiles. The discriminative accuracy of plasma adiponectin for MetS was determined by calculating the area under the curve (AUC) of receiver operator. Analyses were performed in women and men, pre- and postmenopausal women and younger and older men. Results. Virtually all determinants of MetS differed significantly between groups. Low plasma adiponectin showed the highest risk for MetS in postmenopausal women (odds ratio = 18.6, 95% CI = 7.9–44.0). We observed a high discriminative accuracy of age and plasma adiponectin for MetS not only in postmenopausal women (AUC = 0.76) but also in other subgroups (AUC from 0.67 to 0.87). However, in all groups, the discriminative accuracy of age and body mass index (BMI) for MetS was similar to the discriminative accuracy of age and plasma adiponectin. Conclusions. Low plasma levels of adiponectin are associated with increased prevalence of MetS, especially in postmenopausal women. Age and BMI have similar discriminatory accuracies for presence of MetS when compared with age and plasma adiponectin. Thus, we conclude that the association of plasma adiponectin with MetS is significantly affected by menopause but challenge the additional value of adiponectin for the discriminatory accuracy for presence of MetS. [ABSTRACT FROM AUTHOR]

We here report a 13-year-old Marfan patient who suffered from severe, medication-resistant, intermittent headache, which was provoked when getting into an upright position and immediately relieved by lying down or after intravenous rehydration. The postural benefit and the sudden relief after intravenous hydration suggested (intermittent) intracranial hypotension, although a normal opening pressure on lumbar punction was observed and no cerebrospinal fluid (CSF) leakage was identified. Imaging studies revealed severe dural ectasia at lumbosacral level, and two intradural cysts and two extradural presacral cysts were detected. Most likely, altered hydrodynamics in intraand extracranial spinal meningeal cysts caused intermittent CSF hypotension above these cysts, resulting in intermittent intracranial hypotension. Surgical marsupialisation of the intradural cysts proved to be effective. This resulted in a significant reduction of the headache during the clinical follow-up of eight years. [ABSTRACT FROM AUTHOR]

Background: Metabolic syndrome (MetS) is defined by a combination of abnormalities that are all individual risk factors for the development of type 2 diabetes and/or cardiovascular disease. The aetiology of MetS includes both an environmental and genetic component. We studied the prevalence and heritability of MetS and its individual components Dutch genetic isolate. Methods: The Erasmus Rucphen Family study (ERF) consists of some 3000 genealogically documented individuals from a Dutch genetic isolate. Data on waist circumference (WC), blood pressure (BP), high density lipoprotein cholesterol (HDL-C), triglycerides (TG) and fasting plasma glucose values (FPG) are available. MetS was defined according to the International Diabetes Federation (IDF) (2003) and National Cholesterol Education program Adult Panel III (NCEP ATPIII) criteria. Variance component analysis was applied to extended family data to test for evidence of heritability. Results: The prevalence of MetS in the EAF cohort ranged from 23-37% depending on MetS definition and gender considered. Low HDL-C and high WC are the main contributors to MetS. The heritability of MetS corrected for sibship effect was 10.6% (p = 0.01) according to IDF and 13.2% (p = 0.07) according to NCEP ATPIII criteria. In addition, the heritability of individual components of MetS were analysed and found to range from 21.9-42.9%. The highest heritability was found for HDL-C (42.9%, p<0.0001) and WC (37.8%, p<0.0001(. In addition, WC, systolic BP, HDL-C and TO showed low to moderate genetic correlation (RhoG) between genders, whereas FPG and diastolic BP showed absolute genetic correlation between genders. Conclusion: Although the prevalence of MetS was high, the heritability of MetS in the ERF population was found to be moderate. The high heritability of the individual components of MetS indicates that the genetic dissection of MetS should be approached from its individual components. [ABSTRACT FROM AUTHOR]

Background The application of serotype 5 adenoviruses (Ad5) in macrophages is hampered by the absence of the endogenous coxsackie adenovirus receptor (CAR). Methods To overcome this limitation, we first generated a linker protein consisting of the virus-binding domain of CAR and the C-terminus of avidin. Second, to target macrophages, this linker protein was equipped with the biotinylated (bio) oligonucleotide dA6G10, which was previously shown to display a high affinity for the scavenger receptor A (SR-A). Results As compared to nontargeted virus, the linker protein equipped with bio-dA6G10 showed a 500-fold increased reporter gene expression in mouse macrophage RAW264.7 cells. A linker protein equipped with a bio-dA16 control oligonucleotide was inactive. Moreover, the bio-dA6G10-equipped linker showed a 390-fold increased luciferase expression in the macrophage cell line J774 and 276- and 150-fold increased reporter gene expression in primary peritoneal and bone marrow (BM)-derived macrophages, respectively. Using BM-derived macrophages from SR-A knockout mice, it was shown that the dA6G10-mediated uptake is predominantly SR-A-mediated. Conclusions Thus, we have developed a novel tool to link biotinylated ligands to a virus-binding fragment of CAR and have exploited this linker protein to extend the applicability of Ad5 to infect transformed and primary macrophages. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Prophylaxis is the treatment of choice for children with severe haemophilia. As prophylaxis is especially important during the period of growth, the need for continued prophylaxis in adulthood should be considered. The aim of this study was to describe the incidence and outcome of stopping prophylaxis in patients with severe haemophilia who were offered prophylaxis during childhood. All patients with severe haemophilia (factor VIII/IX <0·01 IU/ml), born 1970–80, treated in two Danish and one Dutch treatment centre were studied. Data on discontinuation of prophylaxis, treatment, joint bleed frequency, clinical scores and radiological scores were collected. Eighty patients were studied. Median follow-up was 19 years (range 7–29). A total of 35% of patients discontinued prophylaxis at a median age of 21·5 years [interquartile range (IQR) 18·4–24·4], experiencing only three joint bleeds per year (IQR 1·4–8·7). Median clinical scores were similar in patients who discontinued prophylaxis [4 points (IQR 0–6)] and those who continued [3 points (IQR 1–6)], as were median Pettersson scores at 13 (IQR 1–24) vs. 13 points (IQR 5–23) respectively. In conclusion one-third of young adults with severe haemophilia on a prophylactic regimen discontinued prophylaxis in early adulthood, while maintaining a low joint bleed frequency and similar arthropathy after 4 years. [ABSTRACT FROM AUTHOR]

Unlabelled: Posthaemorrhagic ventricular dilatation (PHVD) in very preterm infants carries a poor prognosis. As earlier studies have failed to show a benefit of early intervention, it is recommended that PHVD be first treated when head circumference is rapidly increasing and/or when symptoms of raised intracranial pressure develop. Infants with PHVD, admitted to 5 of the 10 Dutch neonatal intensive care units were studied retrospectively, to investigate whether there was a difference in the time of onset of treatment of PHVD and, if so, whether this was associated with a difference in the requirement of a ventriculo-peritoneal (VP) shunt and/or neurodevelopmental outcome. The surviving infants with a gestational age <34 wk, born between 1992 and 1996, diagnosed as having a grade III haemorrhage according to Papile on cranial ultrasound and who developed PHVD were included in the study. PHVD was defined as a ventricular index (VI) exceeding the 97th percentile according to Levene (1981), and severe PHVD as a VI crossing the p 97 + 4 mm line. Ninety-five infants met the entry criteria. Intervention was not deemed necessary in 22 infants, because of lack of progression. In 31 infants lumbar punctures (LP) were done before the p 97 + 4 mm line was crossed (early intervention). In 20/31 infants, stabilization occurred. In 9 a subcutaneous reservoir was placed, with subsequent stabilization in 6. In 5/31 infants a VP shunt was eventually inserted. In 42 infants treatment was started once the p 97 + 4 mm line was crossed (late intervention). In 30 infants LPs were performed and in 17 of these a VP shunt was eventually inserted. In 11 infants a subcutaneous reservoir was immediately inserted and in 8 of these infants a VP shunt was needed. In one infant a VP shunt was immediately inserted, without any other form of treatment. Infants with late intervention crossed the p 97 + 4 mm earlier (p 0.03) and needed a shunt (26/42; 62%) more often than those with early intervention (5/31; 16%). Early LP was associated with a strongly reduced risk of VP-shunting (odds ratio = 0.22, 95% confidence interval: 0.08-0.62). The number of infants who developed a moderate or severe handicap was also higher (11/42; 26%) in the late intervention group, compared with those not requiring any intervention (3/22; 14%) or treated early (5/31; 16%).Conclusion: In this retrospective study, infants receiving late intervention required shunt insertion significantly more often than those treated early. A randomized prospective intervention study, comparing early and late drainage, is required to further assess the role of earlier intervention. [ABSTRACT FROM AUTHOR]

Objective: To quantify and evaluate drug utilisation in a sample of Dutch nursing homes. Methods: A retrospective analysis of computerised medication data of 2355 residents aged 65 years and over from six nursing homes in the Netherlands was performed. For each therapeutic drug group, the number of users was determined. The ten therapeutic groups used most frequently were investigated further. For these, patient characteristics, use of therapeutic subgroups, the average daily dosages and the chronicity of drug use were determined. Chronicity was expressed as the percentage of treatment days divided by the number of residents' days in the nursing home. Results: During the study period, 89%, 77% and 56% of the study population used a drug from the anatomical therapeutic chemical (ATC) main group N (nervous system), A (alimentary tract and metabolism) and C (cardiovascular system), respectively. Eight of the ten therapeutic drug groups prescribed most frequently were used for more than 50% of the time. In particular, psycholeptic drugs, diuretics and laxatives were used chronically (83%, 81%, and 80% of the nursing home stay, respectively). Except for a few drug groups, such as laxatives and diuretics, the prescribed daily dosages were relatively low. Twenty-eight percent of the residents received loop diuretics; these were prescribed in relatively high dosages. Conclusion: Drug utilisation in the nursing homes was high and many drugs were used chronically. In view of the risk of possible adverse effects and drug–drug interactions, the prescribing and dosage of psycholeptic drugs, laxatives, loop diuretics and ulcer-healing drugs should be re-evaluated, carefully. [ABSTRACT FROM AUTHOR]

Carbapenemase-producing Klebsiella pneumoniae emerged as a nosocomial pathogen causing morbidity and mortality in patients. For infection prevention it is important to track the spread of K. pneumoniae and its plasmids between patients. Therefore, the major aim was to recapitulate the contents and diversity of the plasmids of genetically related K. pneumoniae strains harboring the beta-lactamase gene blaKPC-2 or blaKPC-3 to determine their dissemination in the Netherlands and the former Dutch Caribbean islands from 2014 to 2019. Next-generation sequencing was combined with long-read third-generation sequencing to reconstruct 22 plasmids. wgMLST revealed five genetic clusters comprised of K. pneumoniae blaKPC-2 isolates and four clusters consisted of blaKPC-3 isolates. KpnCluster-019 blaKPC-2 isolates were found both in the Netherlands and the Caribbean islands, while blaKPC-3 cluster isolates only in the Netherlands. Each K. pneumoniae blaKPC-2 or blaKPC-3 cluster was characterized by a distinct resistome and plasmidome. However, the large and medium plasmids contained a variety of antibiotic resistance genes, conjugation machinery, cation transport systems, transposons, toxin/antitoxins, insertion sequences and prophage-related elements. The small plasmids carried genes implicated in virulence. Thus, implementing long-read plasmid sequencing analysis for K. pneumoniae surveillance provided important insights in the transmission of a KpnCluster-019 blaKPC-2 strain between the Netherlands and the Caribbean. [ABSTRACT FROM AUTHOR]

Background: Metabolomics techniques are increasingly applied in epidemiologic research. Many available assays are still relatively expensive and therefore measurements are often performed in small patient population studies such as case series or case-control designs with strong participant selection criteria. Subsequently, metabolomics data are frequently used to assess secondary associations for which the original study was not explicitly designed. Especially in these secondary analyses, there is a risk that the original selection criteria and the conditioning that takes place due to this selection are not properly accounted for which can lead to selection bias.Aim of review: In this tutorial, we start with a brief theoretical introduction on the issue of selection bias. Subsequently, we demonstrate how selection bias can occur in metabolomics studies by means of an investigation into associations of metabolites with total body fat in a nested case-control study that was originally designed to study effects of elevated fasting glucose.Key scientific concepts of review: We demonstrate that standard analytical methods, such as stratification or adjustment in regression analyses, are not suited to deal with selection bias and may even induce the bias when analysing metabolite-phenotype relationships in selected groups. Finally, we show that inverse probability weighting, also known as survey weighting, can be used in some situations to make unbiased estimates of the outcomes. [ABSTRACT FROM AUTHOR]

Purpose: Toll-like receptor-4 (TLR4), a receptor of the innate immune system, is suggested to have detrimental effects on cardiac function after myocardial infarction (MI). RP105 (CD180) is a TLR4 homolog lacking the intracellular signalling domain that competitively inhibits TLR4-signalling. Thus, we hypothesized that RP105 deficiency, by amplifying TLR4 signalling, would lead to aggravated cardiac dysfunction after MI.Methods and Results: First, whole blood from RP105-/- and wild-type (WT) male C57Bl/6N mice was stimulated with LPS, which induced a strong inflammatory TNFα response in RP105-/- mice. Then, baseline heart function was assessed by left ventricular pressure-volume relationships which were not different between RP105-/- and WT mice. Permanent ligation of the left anterior descending coronary artery was performed to induce MI. Infarct sizes were analysed by (immuno)histology and did not differ. Fifteen days post MI heart function was assessed and RP105-/- mice had significantly higher heart rate (+21%,P<0.01), end systolic volume index (+57%,P<0.05), end systolic pressure (+22%,P<0.05) and lower relaxation time constant tau (-12%,P<0.05), and a tendency for increased end diastolic volume index (+42%,P<0.06), compared to WT mice. In the area adjacent to the infarct zone, compared to the healthy myocardium, levels of RP105, TLR4 and the endogenous TLR4 ligand fibronectin-EDA were increased as well as the number of macrophages, however this was not different between both groups.Conclusion: Deficiency of the endogenous TLR4 inhibitor RP105 leads to an enhanced inflammatory status and more pronounced cardiac dilatation after induction of MI, underscoring the role of the TLR4 pathway in post-infarction remodelling. [ABSTRACT FROM PUBLISHER]