Vasodilator reactive oxygen species ameliorate perturbed myocardial oxygen delivery in exercising swine with multiple comorbidities.

Multiple common cardiovascular comorbidities produce coronary microvascular dysfunction. We previously observed in swine that a combination of diabetes mellitus (DM), high fat diet (HFD) and chronic kidney disease (CKD) induced systemic inflammation, increased oxidative stress and produced coronary endothelial dysfunction, altering control of coronary microvascular tone via loss of NO bioavailability, which was associated with an increase in circulating endothelin (ET). In the present study, we tested the hypotheses that (1) ROS scavenging and (2) ETA+B-receptor blockade improve myocardial oxygen delivery in the same female swine model. Healthy female swine on normal pig chow served as controls (Normal). Five months after induction of DM (streptozotocin, 3 × 50 mg kg-1 i.v.), hypercholesterolemia (HFD) and CKD (renal embolization), swine were chronically instrumented and studied at rest and during exercise. Sustained hyperglycemia, hypercholesterolemia and renal dysfunction were accompanied by systemic inflammation and oxidative stress. In vivo ROS scavenging (TEMPOL + MPG) reduced myocardial oxygen delivery in DM + HFD + CKD swine, suggestive of a vasodilator influence of endogenous ROS, while it had no effect in Normal swine. In vitro wire myography revealed a vasodilator role for hydrogen peroxide (H2O2) in isolated small coronary artery segments from DM + HFD + CKD, but not Normal swine. Increased catalase activity and ceramide production in left ventricular myocardial tissue of DM + HFD + CKD swine further suggest that increased H2O2 acts as vasodilator ROS in the coronary microvasculature. Despite elevated ET-1 plasma levels in DM + HFD + CKD swine, ETA+B blockade did not affect myocardial oxygen delivery in Normal or DM + HFD + CKD swine. In conclusion, loss of NO bioavailability due to 5 months exposure to multiple comorbidities is partially compensated by increased H2O2-mediated coronary vasodilation.

Computational physiological models for individualised mechanical ventilation: a systematic literature review focussing on quality, availability, and clinical readiness.

BACKGROUND: Individualised optimisation of mechanical ventilation (MV) remains cumbersome in modern intensive care medicine. Computerised, model-based support systems could help in tailoring MV settings to the complex interactions between MV and the individual patient's pathophysiology. Therefore, we critically appraised the current literature on computational physiological models (CPMs) for individualised MV in the ICU with a focus on quality, availability, and clinical readiness. METHODS: A systematic literature search was conducted on 13 February 2023 in MEDLINE ALL, Embase, Scopus and Web of Science to identify original research articles describing CPMs for individualised MV in the ICU. The modelled physiological phenomena, clinical applications, and level of readiness were extracted. The quality of model design reporting and validation was assessed based on American Society of Mechanical Engineers (ASME) standards. RESULTS: Out of 6,333 unique publications, 149 publications were included. CPMs emerged since the 1970s with increasing levels of readiness. A total of 131 articles (88%) modelled lung mechanics, mainly for lung-protective ventilation. Gas exchange (n = 38, 26%) and gas homeostasis (n = 36, 24%) models had mainly applications in controlling oxygenation and ventilation. Respiratory muscle function models for diaphragm-protective ventilation emerged recently (n = 3, 2%). Three randomised controlled trials were initiated, applying the Beacon and CURE Soft models for gas exchange and PEEP optimisation. Overall, model design and quality were reported unsatisfactory in 93% and 21% of the articles, respectively. CONCLUSION: CPMs are advancing towards clinical application as an explainable tool to optimise individualised MV. To promote clinical application, dedicated standards for quality assessment and model reporting are essential. Trial registration number PROSPERO- CRD42022301715 . Registered 05 February, 2022.

The effect of antimicrobial drug use on the composition of the genitourinary microbiota in an elderly population.

BACKGROUND: The urinary tract is inhabited by a diversity of microorganisms, known as the genitourinary microbiota. Here, we investigated the association between the use of antimicrobial drugs and the composition of the genitourinary microbiota. RESULTS: Clean-catch urinary samples were collected from 27 participants of the Rotterdam Study. Bacterial DNA was extracted and the 16S ribosomal RNA gene variable regions V3 and V4 were analyzed using Illumina sequencing. 23 of the 27 participants were included in the analysis. The population consisted of 10 men and 13 women with a mean age of 75 ± 3 years. The time between the last prescription of an antimicrobial drug and sampling was determined and categorized. The use of antimicrobial drugs prior to urine sampling was associated with statistically significant differences in the beta-diversity of the genitourinary microbiota. No association was found between antimicrobial drug use and the alpha-diversity of the genitourinary microbiota. Operational Taxonomic Units (OTUs) that were lowest in participants who used antimicrobial drug belonged to Lactobacillus and Finegoldia. In contrast, an OTU belonging to the genus Parabacteroides had higher abundances. Also, an OTU belonging to the species E.coli was higher in the participants who used antimicrobial drugs. CONCLUSION: Prior use of antimicrobial drugs is associated with a different composition of the genitourinary microbiota. Our results might indicate a persisting effect of antimicrobial drugs on the composition of the microbiota, but reverse causality cannot be ruled out. Future studies are needed to differentiate between two possibilities. Genitourinary dysbiosis could be the result of antimicrobial drug use or genitourinary dysbiosis could be a risk factor for urinary tract infections resulting in increased use of antimicrobial drugs. This may have important implications for treatment and prevention of (recurrent) UTIs.

Use of other antimicrobial drugs is associated with trimethoprim resistance in patients with urinary tract infections caused by E. coli.

In recent years, high frequencies of trimethoprim resistance in urinary tract infections (UTIs) caused by E. coli are have been reported. Co-resistance to other antimicrobial drugs may play a role in this increase. Therefore, we investigated whether previous use of other antimicrobial drugs was associated with trimethoprim resistance. We conducted a nested case-control study with urinary cultures with E. coli from participants of the Rotterdam Study sent in by general practitioners to the regional laboratory between 1 January 2000 and 1 April 2016. Multivariable logistic regression analysis was performed to study the association between prior prescriptions of several antimicrobial drug groups and trimethoprim resistance using individual participant data. Urinary cultures of 1264 individuals with a UTI caused by E. coli were included. When adjusted for previous other antimicrobial drug use, a history of > 3 prescriptions of extended-spectrum penicillins (OR 1.68; 95% CI 1.10-2.55) was significantly associated with trimethoprim resistance of E. coli as was the use of > 3 prescriptions of sulfonamides and trimethoprim (OR 2.22; 95% CI 1.51-3.26). The use of > 3 prescriptions of nitrofuran derivatives was associated with a lower frequency of trimethoprim resistance (OR 0.60; 95% CI 0.39-0.92), after adjustment for other antimicrobial drug prescriptions. We found that previous use of extended-spectrum penicillins is associated with trimethoprim resistance. On the contrary, previous nitrofurantoin use was associated with a lower frequency of trimethoprim resistance. Especially in individuals with recurrent UTI, co-resistance should be taken into account and susceptibility testing before starting trimethoprim should be considered.

Antibiotic resistance of Escherichia coli isolated from uncomplicated UTI in general practice patients over a 10-year period.

Recommendations of first choice antibiotic therapy need to be based on actual antibiotic susceptibility data. We determined the antibiotic susceptibility of E. coli in uncomplicated UTI among women and compared the results with 2004 and 2009. In 30 sentinel general practitioner practices of Nivel Primary Care database, urine samples were collected from women with symptoms of uncomplicated UTI. Patient characteristics, E. coli susceptibility, and ESBL production were analyzed. Six hundred eighty-nine urine samples were collected; E. coli was the most isolated uropathogen (83%). Antibiotic susceptibility was stable over time except for ciprofloxacin (96% in 2004, 97% in 2009, and 94% in 2014; P < 0.05). The susceptibility to co-amoxiclav was 88%, 87%, and 92% in 2004, 2009, and 2014, respectively. The prevalence of ESBL-producing E. coli increased from 0.1% in 2004 to 2.2% in 2014 (P < 0.05). Regional differences in antibiotic susceptibility for co-trimoxazole were found being the highest in the west (88%) and the lowest in the north (72%, P = 0.021). Ciprofloxacin susceptibility was related to antibiotic use in the past 3 months (97% no use versus 90% use, P = 0.002) and age > 70 years (P = 0.005). In 2014, prescription of fosfomycin increased compared to 2009 (14.3% versus 5.6%) at the expense of co-amoxiclav, co-trimoxazole, and fluoroquinolones (P < 0.05). The susceptibility percentages to most antimicrobial agents tested were stable over 10 years' period although the prevalence of E. coli and ESBLs significantly increased. Performance of a survey with regular intervals is warranted.

The etiological evaluation of sensorineural hearing loss in children.

This study aims to evaluate the etiology of pediatric sensorineural hearing loss (SNHL). A total of 423 children with SNHL were evaluated, with the focus on the determination of causative genetic and acquired etiologies of uni- and bilateral SNHL in relation to age at diagnosis and severity of the hearing loss. We found that a stepwise diagnostic approach comprising of imaging, genetic, and/or pediatric evaluation identified a cause for SNHL in 67% of the children. The most common causative finding in children with bilateral SNHL was causative gene variants (26%), and in children with unilateral SNHL, a structural anomaly of the temporal bone (27%). The probability of finding an etiologic diagnosis is significantly higher in children under the age of 1 year and children with profound SNHL.Conclusions: With our stepwise diagnostic approach, we found a diagnostic yield of 67%. Bilateral SNHL often has a genetic cause, whereas in unilateral SNHL structural abnormalities of the labyrinth are the dominant etiologic factor. The diagnostic yield is associated with the age at detection and severity of hearing loss: the highest proportion of causative abnormalities is found in children with a young age at detection or a profound hearing loss. What is Known: • Congenital sensorineural hearing loss is one of the most common congenital disorders • Determination of the cause is important for adequate management and prognosis and may include radiology, serology, and DNA analysis What is New: • Using a stepwise diagnostic approach, causative abnormalities are found in 67% both in uni- and bilateral SNHL, with the highest diagnostic yield in very young children and those suffering from profound hearing loss • Bilateral SNHL often has a genetic cause, whereas in unilateral SNHL structural abnormalities of the labyrinth are the dominant etiologic factor.

Metabolic dysregulation and late-life depression: a prospective study.

BACKGROUND: Depression is associated with the metabolic syndrome (MS). We examined whether metabolic dysregulation predicted the 2-year course of clinical depression. METHOD: A total of 285 older persons (⩾60 years) suffering from depressive disorder according to DSM-IV-TR criteria was followed up for 2 years. Severity of depression was assessed with the Inventory of Depressive Symptomatology (IDS) at 6-month intervals. Metabolic syndrome was defined according the National Cholesterol Education Programme (NCEP-ATP III). We applied logistic regression and linear mixed models adjusted for age, sex, years of education, smoking, alcohol use, physical activity, somatic co-morbidity, cognitive functioning and drug use (antidepressants, anti-inflammatory drugs) and severity of depression at baseline. RESULTS: MS predicted non-remission at 2 years (odds ratioper component = 1.26, 95% confidence interval 1.00-1.58), p = 0.047), which was driven by the waist circumference and HDL cholesterol. MS was not associated with IDS sum score. Subsequent analyses on its subscales, however, identified an association with the somatic symptom subscale score over time (interaction time × somatic subscale, p = 0.005), driven by higher waist circumference and elevated fasting glucose level. CONCLUSIONS: Metabolic dysregulation predicts a poor course of late-life depression. This finding supports the concept of 'metabolic depression', recently proposed on population-based findings of a protracted course of depressive symptoms in the presence of metabolic dysregulation. Our findings seem to be driven by abdominal obesity (as indicated by the waist circumference) and HDL cholesterol dysregulation.

Lipoprotein(a) levels are associated with aortic valve calcification in asymptomatic patients with familial hypercholesterolaemia.

OBJECTIVES: Lipoprotein(a) [Lp(a)] is an independent risk factor for aortic valve stenosis and aortic valve calcification (AVC) in the general population. In this study, we determined the association between AVC and both plasma Lp(a) levels and apolipoprotein(a) [apo(a)] kringle IV repeat polymorphisms in asymptomatic statin-treated patients with heterozygous familial hypercholesterolaemia (FH). METHODS: A total of 129 asymptomatic heterozygous FH patients (age 40-69 years) were included in this study. AVC was detected using computed tomography scanning. Lp(a) concentration and apo(a) kringle IV repeat number were measured using immunoturbidimetry and immunoblotting, respectively. Univariate and multivariate logistic regression were used to assess the association between Lp(a) concentration and the presence of AVC. RESULTS: Aortic valve calcification was present in 38.2% of patients, including three with extensive AVC (>400 Agatston units). Lp(a) concentration was significantly correlated with gender, number of apo(a) kringle IV repeats and the presence and severity of AVC, but not with coronary artery calcification (CAC). AVC was significantly associated with plasma Lp(a) level, age, body mass index, blood pressure, duration of statin use, cholesterol-year score and CAC score. After adjustment for all significant covariables, plasma Lp(a) concentration remained a significant predictor of AVC, with an odds ratio per 10-mg dL(-1) increase in Lp(a) concentration of 1.11 (95% confidence interval 1.01-1.20, P = 0.03). CONCLUSION: In asymptomatic statin-treated FH patients, plasma Lp(a) concentration is an independent risk indicator for AVC.

HIV-1 drug resistance prevalence, drug susceptibility and variant characterization in the Jacobi Medical Center paediatric cohort, Bronx, NY, USA.

OBJECTIVES: With the advent of combined antiretroviral therapy (cART), perinatally HIV-infected children are surviving into adolescence and beyond. However, drug resistance mutations (DRMs) compromise viral control, affecting the long-term effectiveness of ART. The aims of this study were to detect and identify DRMs in a HIV-1 infected paediatric cohort. METHODS: Paired plasma and dried blood spots (DBSs) specimens were obtained from HIV-1 perinatally infected patients attending the Jacobi Medical Center, New York, USA. Clinical, virological and immunological data for these patients were analysed. HIV-1 pol sequences were generated from samples to identify DRMs according to the International AIDS Society (IAS) 2011 list. RESULTS: Forty-seven perinatally infected patients were selected, with a median age of 17.7 years, of whom 97.4% were carrying subtype B. They had a mean viral load of 3143 HIV-1 RNA copies/mL and a mean CD4 count of 486 cells/µL at the time of sampling. Nineteen patients (40.4%) had achieved undetectable viraemia (< 50 copies/mL) and 40.5% had a CD4 count of > 500 cells/µL. Most of the patients (97.9%) had received cART, including protease inhibitor (PI)-based regimens in 59.6% of cases. The DRM prevalence was 54.1, 27.6 and 27.0% for nucleoside reverse transcriptase inhibitors (NRTIs), PIs and nonnucleoside reverse transcriptase inhibitors (NNRTIs), respectively. Almost two-thirds (64.9%) of the patients harboured DRMs to at least one drug class and 5.4% were triple resistant. The mean nucleotide similarity between plasma and DBS sequences was 97.9%. Identical DRM profiles were present in 60% of plasma-DBS paired sequences. A total of 30 DRMs were detected in plasma and 26 in DBSs, with 23 present in both. CONCLUSIONS: Although more perinatally HIV-1-infected children are reaching adulthood as a result of advances in cART, our study cohort presented a high prevalence of resistant viruses, especially viruses resistant to NRTIs. DBS specimens can be used for DRM detection.

The plastic fly: the effect of sustained fluctuations in adult food supply on life-history traits.

Many adult traits in Drosophila melanogaster show phenotypic plasticity, and the effects of diet on traits such as lifespan and reproduction are well explored. Although plasticity in response to food is still present in older flies, it is unknown how sustained environmental variation affects life-history traits. Here, we explore how such life-long fluctuations of food supply affect weight and survival in groups of flies and affect weight, survival and reproduction in individual flies. In both experiments, we kept adults on constant high or low food and compared these to flies that experienced fluctuations of food either once or twice a week. For these 'yoyo' groups, the initial food level and the duration of the dietary variation differed during adulthood, creating four 'yoyo' fly groups. In groups of flies, survival and weight were affected by adult food. However, for individuals, survival and reproduction, but not weight, were affected by adult food, indicating that single and group housing of female flies affects life-history trajectories. Remarkably, both the manner and extent to which life-history traits varied in relation to food depended on whether flies initially experienced high or low food after eclosion. We therefore conclude that the expression of life-history traits in adult life is affected not only by adult plasticity, but also by early adult life experiences. This is an important but often overlooked factor in studies of life-history evolution and may explain variation in life-history experiments.

Growth in patients with mucopolysaccharidosis type III (Sanfilippo disease).

BACKGROUND: Mucopolysaccharidosis III (MPS III), known as Sanfilippo disease, is a lysosomal storage disorder mainly characterized by progressive neurodegeneration with cognitive decline and relatively attenuated somatic signs and symptoms. Although short stature is invariably present in patients with the other mucopolysaccharidoses, it has not been sufficiently addressed in MPS III. The aim of this study was to investigate growth data of a large Dutch MPS III cohort in order to construct growth charts for MPS III patients. METHODS: Height, weight, head circumference (HC), and body mass index (BMI) data from 118 MPS III patients were used to construct reference curves, using the lambda, mu, sigma (LMS) method. Genotype-group comparisons for height standard deviation scores (SDS) were performed by Kruskal-Wallis analysis for different age groups. RESULTS: Birth weight and length were within normal ranges for gestational age and showed a significantly stunted growth from age 6 years onward. Mean final heights were 169.7 cm (-2.0 SDS) and 165.4 cm (-0.84 SDS) for adult male and female, patients, respectively. Phenotypic severity, as assessed by genotyping, correlated with growth pattern and final height. In addition, mean BMI and HC SDS were significantly higher when compared with Dutch standards for both boys and girls. CONCLUSIONS: Growth in MPS III is stunted mainly in patients with the severe phenotype. We provide disease-specific growth references that can be used for clinical management of MPS III patients and may be of value for future treatment studies.

Perceptual scaling of visual and inertial cues: effects of field of view, image size, depth cues, and degree of freedom.

In the field of motion-based simulation, it was found that a visual amplitude equal to the inertial amplitude does not always provide the best perceived match between visual and inertial motion. This result is thought to be caused by the "quality" of the motion cues delivered by the simulator motion and visual systems. This paper studies how different visual characteristics, like field of view (FoV) and size and depth cues, influence the scaling between visual and inertial motion in a simulation environment. Subjects were exposed to simulator visuals with different fields of view and different visual scenes and were asked to vary the visual amplitude until it matched the perceived inertial amplitude. This was done for motion profiles in surge, sway, and yaw. Results showed that the subjective visual amplitude was significantly affected by the FoV, visual scene, and degree-of-freedom. When the FoV and visual scene were closer to what one expects in the real world, the scaling between the visual and inertial cues was closer to one. For yaw motion, the subjective visual amplitudes were approximately the same as the real inertial amplitudes, whereas for sway and especially surge, the subjective visual amplitudes were higher than the inertial amplitudes. This study demonstrated that visual characteristics affect the scaling between visual and inertial motion which leads to the hypothesis that this scaling may be a good metric to quantify the effect of different visual properties in motion-based simulation.

Ten-year follow-up on Dutch orthopaedic blood management (DATA III survey).

INTRODUCTION: Hip and knee arthroplasties are frequently complicated by the need for allogeneic blood transfusions. This survey was conducted to assess the current use of perioperative blood-saving measures and to compare it with prior results. MATERIALS AND METHODS: All departments of orthopaedic surgery at Dutch hospitals were sent a follow-up survey on perioperative blood-saving measures, and data were compared to the results of two surveys conducted 5 and 10 years earlier. RESULTS: The response rate was 94 out of 108 departments (87%). Most departments used erythropoietin prior to hip and knee replacements at the expense of preoperative autologous blood donation. The use of intraoperative autologous retransfusion in revision hip (56 vs. 54%) as well as revision knee arthroplasty (26 vs. 24%), was virtually unchanged. Postoperative autologous retransfusion is still used by the majority of departments after both primary arthroplasty and revision of hip (58/53%) and knee (65/61%). CONCLUSIONS: Currently, just as in 2007, the majority of Dutch orthopaedic departments uses erythropoietin, normothermia and postoperative autologous retransfusion with hip and knee arthroplasty. Intraoperative retransfusion is used mainly with hip revision arthroplasty. Other effective blood management modalities such as tranexamic acid have not been widely implemented.

Acid sphingomyelinase (Asm) deficiency patients in The Netherlands and Belgium: disease spectrum and natural course in attenuated patients.

Niemann-Pick disease (NPD) is a neurovisceral lysosomal storage disorder caused by acid sphingomyelinase (ASM) deficiency, which can be categorized as either Niemann-Pick disease type A [NPD-A], with progressive neurological disease and death in early childhood, or as Niemann-Pick disease type B [NPD-B], with a more variable spectrum of manifestations. Enzyme replacement therapy (ERT) with recombinant sphingomyelinase is currently studied as potential treatment for NPD-B patients. The objective of this study is to characterize the clinical features of patients with ASM deficiency in the Netherlands and Belgium with focus on the natural disease course of NPD-B patients. Prospective and retrospective data on ASM deficient patients were collected in The Netherlands and part of Belgium. Patients with NPD-B that could be followed prospectively were evaluated every 6-12 months for pulmonary function tests, 6 minute walk test (6 MWT), imaging (bone marrow infiltration measured by QCSI, organ volumes by MRI and CT scan of the lungs) and biochemical markers. Twenty-five patients with ASM deficiency were identified (13 males, 12 females, median age 13years, range 1-59 years). Nine patients had died at the time of the study, including four NPD-A patients at the age of 1,1, 2, 3 and five NPDB patents at the age of 5, 6, 43, 56 and 60 years. There was a high prevalence of homozygosity and compound heterozygosity for the common p.Arg608del mutation in 43% and 19% of NPD-B patients, respectively. In NPD-B patients, thrombocytopenia was present in most, while anemia and leucopenia were less common (33% and 6 % respectively). HDL cholesterol was reduced in most patients. Pulmonary disease was severe in several patients. Follow-up up to 11 years revealed a gradual decrease in platelet count. Detailed investigations in 6 NPD-B patients with follow-up in 4 patients revealed remarkable stable disease parameters up to 6 years, with some decline in pulmonary function and 6 MWT. Bone marrow fat fractions were decreased, indicating the presence of storage macrophages. Lung involvement was not related to the extent of visceromegaly, cytopenia or bone marrow involvement. In conclusion, in NPD-B patients pulmonary disease is the most debilitating feature. Disease manifestations are mostly stable in attenuated patients. Bone marrow infiltration is a less prominent feature of the disease.

Adherence to and usefulness of the national treatment guideline for urinary tract infections (UTI) in a risk area.

BACKGROUND: To optimize antibiotic treatment and decrease antibiotic resistance, national treatment guidelines are available for urinary tract infections (UTIs) in general practice. The usefulness of these guidelines in risk areas for antimicrobial resistance such as cross border regions or areas with dense agriculture, is unknown. METHODS: Midstream urine samples from women with symptoms of acute UTI visiting general practitioners (GPs) in the Westland area, a dense agriculture area, were microbiologically analysed, and patient characteristics, symptoms, previous and present antibiotic treatment were collected. The National Nivel data were used as reference for antibiotic resistance. RESULTS: Of 310 women with symptoms of uncomplicated UTI, 247 (80%) had a culture proven E. coli UTI. Empirical antibiotic therapy was prescribed to 148 patients (48%) in total; in 7% of women with a negative and 52% with a positive urine culture. Having more than one symptom was associated with the prescription of antibiotics; travel history or previous antibiotic use for UTI were not. The isolated uropathogens were susceptible to the empiric antibiotic therapy in 98% of patients. Resistance to co-amoxiclav was higher (22%) than reported in the national data of 2004 (12%), 2009 (13%) and 2014 (9%), as was the prevalence of extended spectrum ß-lactamase (ESBL): 3.4% in our study versus 0.1%, 1% and 2.2% in the national data respectively. CONCLUSION: The presence of environmental and socio-demographic risk factors for antibiotic resistance did not influence the empiric choice nor susceptibility for antibiotics advised by the national guidelines in women with uncomplicated UTI.

Antibodies against SARS-CoV-2 after natural infection in healthcare workers and clinical characteristics as putative antibody production prediction.

Introduction: There is a need for detailed data on early antibody responses against SARS-CoV-2 as this may contribute to the prediction of the clinical course of COVID-19 and the optimization of convalescent plasma treatment. This study aims to gain insight into developing antibodies to SARS-CoV-2 in health care workers (HCWs) infected in the first wave of the SARS-CoV-2 pandemic in the Netherlands. Materials and methods: In this retrospective analysis, sera from PCR-confirmed COVID-19 positive HCWs are included at the time of the initial PCR (T = 0, n = 95) and at least 21 days after the initial serum (T ≥ 21, n = 133). This study assesses correlations between qualitative total Ig, IgM, IgA, IgG, and quantitative anti-S-RBD antibody responses and participant characteristics. Results: Higher Ct values were associated with higher antibody positivity rates for total Ig (OR 1.261 (95% CI 1.095-1.452)), IgM (OR 1.373 (95% CI 1.125-1.675)), and IgA (OR 1.222 (95% CI 1.013-1.475)). Gender was predictive of IgM and IgA antibody positivity rates at T = 0 (OR 0.018 (95% CI 0.001-0.268)) and (OR 0.070 (95% CI 0.008-0.646)). At T ≥ 21, a substantial proportion of HCWs developed IgM (103/133; 77.4%) and total Ig (128/133; 96.2%) antibodies. IgA and IgG seroconversions were observed in only 51.1% (67/131) and 55.7% (73/131) of HCWs. Anti-S-RBD responses were higher when the interval between onset of symptoms and sampling was longer. Conclusion: The findings of this study give insight into early antibody responses and may have implications for the selection of convalescent plasma donors and the further development of monoclonal antibody treatment.

4-Hydroxybutyric aciduria associated with catheter usage: a diagnostic pitfall in the identification of SSADH deficiency.

Succinic semialdehyde dehydrogenase deficiency is a slowly progressive to static neurological disorder featuring elevated concentrations of 4-hydroxybutyric acid in body fluids. We present two patients with elevated 4-hydroxybutyric acid in urine which was later shown to be linked to catheter usage.

Intensive management of hyperglycaemia in acute coronary syndromes. Study design and rationale of the BIOMArCS 2 glucose trial.

BACKGROUND: Elevated admission plasma glucose is associated with increased mortality in patients who are admitted with an acute coronary syndrome. This may be mediated by increased inflammation, apoptosis and coagulation, and by a disturbed endothelial function that can be found in hyperglycaemic patients. Insulin has several characteristics that may potentially counteract these mechanisms. METHODS: The BIOMArCS programme is a multi-centre initiative and currently consists of three different studies. The effects of acute coronary syndrome on acute biomarkers washout are studied in the BIOMArCS pilot and the value of biomarkers in predicting upcoming acute coronary syndrome events is studied in BIOMArCS 1. The third study (BIOMArCS 2 glucose), which will be presented here, investigates the effectiveness and safety of intensive glucose level control compared with conventional glucose management in patients with acute coronary syndrome and an admission plasma glucose of 7.8-16 mmol/l. In BIOMArCS 2 glucose, a total of 300 patients without insulin-treated diabetes mellitus will be randomized in a 1:1 ratio to either intensive or conventional glucose management on top of standard medical care. The primary endpoint is infarct size as expressed by the cardiac troponin T level 72 h after admission. To study the metabolic effects of insulin administration, we will investigate biomarker washout patterns of various metabolic mechanisms up to 7 days after admission. These markers will address inflammation, oxidative stress, hypercoagulability, endothelial activation and vasodilatation. IMPLICATIONS: Current acute coronary syndrome guidelines lack a clear strategy for hyperglycaemia treatment. This study will extend our knowledge on this matter as it may clarify mechanisms and generate hypotheses of if and how myocardial infarct size may be limited by glucose management at admission.