T1w/FLAIR ratio standardization as a myelin marker in MS patients.

INTRODUCTION: Calculation of a T1w/T2w ratio was introduced as a proxy for myelin integrity in the brain of multiple sclerosis (MS) patients. Since nowadays 3D FLAIR is commonly used for lesion detection instead of T2w images, we introduce a T1w/FLAIR ratio as an alternative for the T1w/T2w ratio. OBJECTIVES: Bias and intensity variation are widely present between different scanners, between subjects and within subjects over time in T1w, T2w and FLAIR images. We present a standardized method for calculating a histogram calibrated T1w/FLAIR ratio to reduce bias and intensity variation in MR sequences from different scanners and at different time-points. MATERIAL AND METHODS: 207 Relapsing Remitting MS patients were scanned on 4 different 3 T scanners with a protocol including 3D T1w, 2D T2w and 3D FLAIR images. After bias correction, T1w/FLAIR ratio maps and T1w/T2w ratio maps were calculated in 4 different ways: without calibration, with linear histogram calibration as described by Ganzetti et al. (2014), and by using 2 methods of non-linear histogram calibration. The first nonlinear calibration uses a template of extra-cerebral tissue and cerebrospinal fluid (CSF) brought from Montreal Neurological Institute (MNI) space to subject space; for the second nonlinear method we used an extra-cerebral tissue and CSF template of our own subjects. Additionally, we segmented several brain structures such as Normal Appearing White Matter (NAWM), Normal Appearing Grey Matter (NAGM), corpus callosum, thalami and MS lesions using Freesurfer and Samseg. RESULTS: The coefficient of variation of T1w/FLAIR ratio in NAWM for the no calibrated, linear, and 2 nonlinear calibration methods were respectively 24, 19.1, 9.5, 13.8. The nonlinear methods of calibration showed the best results for calculating the T1w/FLAIR ratio with a smaller dispersion of the data and a smaller overlap of T1w/FLAIR ratio in the different segmented brain structures. T1w/T2w and T1w/FLAIR ratios showed a wider range of values compared to MTR values. CONCLUSIONS: Calibration of T1w/T2w and T1w/FLAIR ratio maps is imperative to account for the sources of variation described above. The nonlinear calibration methods showed the best reduction of between-subject and within-subject variability. The T1w/T2w and T1w/FLAIR ratio seem to be more sensitive to smaller changes in tissue integrity than MTR. Future work is needed to determine the exact substrate of T1w/FLAIR ratio and to obtain correlations with clinical outcome.

Did it hurt? COVID-19 vaccination experience in people with multiple sclerosis.

BACKGROUND: Current guidelines recommend vaccination against SARS-CoV2 for people with multiple sclerosis (pwMS). The long-term review of the safety and effectiveness of COVID-19 vaccines in pwMS is limited. METHODS: Service re-evaluation. PwMS using the MS service at Barts Health National Health Service Trust were sent questionnaires via email to report symptoms following first and second COVID-19 vaccinations (n = 570). A retrospective review of electronic health records was conducted for clinical and safety data post-vaccination(s); cut-off was end of September 2021. Separate logistic regressions were carried out for symptoms experienced at each vaccination. Two sets of regressions were fitted with covariates: (i) Disease-modifying therapy type and (ii) patient characteristics for symptoms experienced. RESULTS: 193/570 pwMS responded. 184 pwMS had both vaccinations. 144 received the AZD1222 and 49 the BNT162b2 vaccine. 87% and 75% of pwMS experienced any symptoms at first and second vaccinations, respectively. The majority of symptoms resolved within a short timeframe. No severe adverse effects were reported. Two pwMS subsequently died; one due to COVID-19 and one due to aspiration pneumonia. Males were at a reduced risk of reporting symptoms at first vaccination. There was evidence that pwMS in certain treatment groups were at reduced risk of reporting symptoms at second vaccination only. CONCLUSIONS: Findings are consistent with our preliminary data. Symptoms post-vaccination were similar to the non-MS population and were mostly temporary. It is important to inform the MS community of vaccine safety data.

Antibody Therapies in Autoimmune Encephalitis.

Autoimmune encephalitis (AE) comprises a heterogeneous group of disorders in which the host immune system targets self-antigens expressed in the central nervous system. The most conspicuous example is an anti-N-methyl-D-aspartate receptor encephalitis linked to a complex neuropsychiatric syndrome. Current treatment of AE is based on immunotherapy and has been established according to clinical experience and along the concept of a B cell-mediated pathology induced by highly specific antibodies to neuronal surface antigens. In general, immunotherapy for AE follows an escalating approach. When first-line therapy with steroids, immunoglobulins, and/or plasma exchange fails, one converts to second-line immunotherapy. Alkylating agents could be the first choice in this stage. However, due to their side effect profile, most clinicians give preference to monoclonal antibodies (mAbs) directed at B cells such as rituximab. Newer mAbs might be added as a third-line therapy in the future, or be given even earlier if shown effective. In this chapter, we will discuss mAbs targeting B cells (rituximab, ocrelizumab, inebulizumab, daratumumab), IL-6 (tocilizumab, satralizumab), the neonatal Fc receptor (FCRn) (efgartigimod, rozanolixizumab), and the complement cascade (eculizumab).

Experience with the COVID-19 AstraZeneca vaccination in people with multiple sclerosis.

BACKGROUND: Some people with multiple sclerosis (pwMS) are at increased risk of severe Coronavirus disease 19 (COVID-19) and should be rapidly vaccinated. However, vaccine supplies are limited, and there are concerns about side-effects, particularly with the ChAdOx1nCoV-19 (AstraZeneca) vaccine. OBJECTIVES: To report our first experience of pwMS receiving the AstraZeneca vaccine. METHODS: Service evaluation. pwMS using the MS service at Barts Health NHS Trust were sent questionnaires to report symptoms following vaccination. RESULTS: Thirty-three responses were returned, 29/33 pwMS received a first dose of AstraZeneca vaccine, the remaining four received a first dose of BioNTech/Pfizer vaccine. All but two patients (94%) reported any symptoms including a sore arm (70%), flu-like symptoms (64%), fever (21%), fatigue (27%), and headache (21%). In more than 2/3 patients, symptoms lasted up to 48 hours, and with the exception of two pwMS reporting symptom duration of 10 and 12 days, respectively, symptoms in the remainder resolved within seven days. No severe adverse effects occurred. CONCLUSIONS: pwMS report transient symptoms following AstraZeneca vaccination, characteristics of which were similar to those reported in the non-MS population. Symptoms may be more pronounced in pwMS due to the temperature-dependent delay in impulse propagation (Uhthoff's phenomenon) due to demyelination.

Cultivation of aerobic granular sludge for the treatment of food-processing wastewater and the impact on membrane filtration properties.

A laboratory-scale sequencing batch reactor was operated for approximately 300 days, divided into four periods based on the feeding strategy, to develop stable aerobic granular sludge (AGS) while treating chocolate processing wastewater. Application of a prolonged mixed anaerobic feeding was not sufficient to develop AGS and reach stable reactor performance. Through the application of a partially non-mixed and a partially mixed feeding strategy, the reactor performance was increased and stable AGS formation was established characterized by low diluted sludge volume index (D)SVI DSVI10,30) values of 78 ± 27 mL·g-1 and 52 ± 17 mL·g-1, respectively, and a capillary suction time/mixed liquor suspended solids value of 0.9 sec·(g·L-1)-1. The membrane bioreactor (MBR) filtration tests showed a reduction of the fouling rate (FR) and an increase of the sustainable flux (SF0.5) for AGS compared to flocs treating the same industrial wastewater. The SF0.5 (FR > 0.5 mbar·min-1) for the flocs was 10 L·(m2·h)-1 while for AGS the SF0.5 is higher than 45 L·(m2·h)-1 because the FR did not exceed 0.1 mbar·min-1. Additionally, the AGS showed reduced irreversible fouling tendencies due to pore blocking. Our results underline the need for an increased substrate gradient during anaerobic feeding for the development and long-term maintenance of AGS under minimum wash-out conditions. The AGS-MBR filtration performance also shows strong advantages compared to a floccular MBR system due to a high increase of the SF0.5 and reduced reversible and irreversible fouling.

Community-acquired bacterial meningitis in adults: emergency department management protocol.

Acute bacterial meningitis (ABM) is a rare but disabling infectious condition that requires a performant multidisciplinary management approach. Between 70 and 90 adult patients are diagnosed with community-acquired ABM in Belgium annually, and reported case fatality rates range from 17 to 40%. The currently available guidelines provide evidence-based guidance on how to manage this disease. However, these guidelines do not translate the evidence to the daily practice at the emergency department in a Belgian healthcare context. We created a taskforce in University Hospitals Leuven consisting of experts with complementary expertise in managing this disease: neurology, neurosurgery, intensive care medicine, microbiology and infectious diseases. The taskforce agreed upon a flowchart containing seven management steps encompassing all relevant phases in emergency ABM management. In addition to the focus on timely and adequate initiation of antimicrobial treatment, the flowchart and protocol also provide guidance on practical hurdles such as how to assess the safety of performing a lumbar puncture and when to refer patients to the intensive care department. This protocol was implemented in University Hospitals Leuven and fosters inter-disciplinary coordination of ABM care.

Position paper - progress towards standards in integrated (aerobic) MBR modelling.

Membrane bioreactor (MBR) models are useful tools for both design and management. The system complexity is high due to the involved number of processes which can be clustered in biological and physical ones. Literature studies are present and need to be harmonized in order to gain insights from the different studies and allow system optimization by applying a control. This position paper aims at defining the current state of the art of the main integrated MBR models reported in the literature. On the basis of a modelling review, a standardized terminology is proposed to facilitate the further development and comparison of integrated membrane fouling models for aerobic MBRs.

Application of online instrumentation in industrial wastewater treatment plants - a survey in Flanders, Belgium.

A survey regarding online instrumentation and control was conducted among 90 companies managing their own biological wastewater treatment plant in Flanders, Belgium. In this study, all types of online instrumentation have been found suitable for automatic process control. However, its integration in general process control as well as in nitrogen removal and chemical dosing control appeared to be rather limited. Only dissolved oxygen and pH sensors were widely applied, being present in 96% and 69% of the plants, respectively. Widespread process integration is mainly obstructed by the fact that companies, especially small and medium-sized, still do not regard wastewater treatment as a full-fledged part of the production process. Operators often lack technical expertise in this domain and tend to be skeptical towards automated control mechanisms. In addition, the price of online instrumentation is still perceived as too high, in particular at smaller companies. Lastly, the design of the existing wastewater treatment plant does not always allow for real-time control. Certain measures such as operator training, monitoring of energy and chemical consumption and reduction of instrumentation costs are essential for widespread application of online process control in future years. Additionally, water reuse can create an important incentive.

Cofactor F430 as a biomarker for methanogenic activity: application to an anaerobic bioreactor system.

Over the last decades, anaerobic bioreactor technology proved to be a competitive technology for purifying wastewater while producing biogas. Methanogens perform the crucial final step in methane production, and monitoring their activity is of paramount importance for system understanding and management. Cofactor F430 is an essential prosthetic group of the methyl-coenzyme M reductase (MCR) enzyme catalysing this final step. This research investigates whether the quantification of cofactor F430 in bioreactor systems is a viable intermediate-complexity monitoring tool in comparison to the conventional biogas and volatile fatty acid (VFA) concentration follow-up and molecular genetic techniques targeting the mcrA gene encoding the MCR protein or its transcripts. Cofactor F430 was quantified in a lab-scale anaerobic membrane bioreactor (AnMBR) using liquid chromatography. The system was subjected to two organic loading rate shocks, and the F430 content of the sludge was followed up alongside mcrA gene copy and transcript numbers and classical performance monitoring tools. The research showed for the first time the combined mcrA gene transcript and F430 content dynamics in an anaerobic bioreactor system and reveals their significant positive correlation with in situ methane production rate. The main difference between the two monitoring methods relates to the cofactor's slower degradation kinetics. The work introduces the use of cofactor F430 as a biomarker for methanogenic activity and, hence, as a monitoring tool that can be quantified within half a working day, yielding information directly related to in situ methanogenic activity in methanogenic reactors.

Corticosteroids in the management of acute multiple sclerosis exacerbations.

Multiple sclerosis (MS) is an autoimmune, inflammatory demyelinating disease of the central nervous system characterized in the majority of the patients by a relapsing-remitting disease course. For decades high-dosage corticosteroids (CS) are considered the cornerstone in the management of acute MS relapses. However, many unanswered questions remain when it comes to the exact modalities of CS administration. In this review on behalf of the Belgian Study Group for MS we define the efficacy of CS in reducing MS-related morbidity and examine whether the effect is different according to type of CS, route of administration, cumulative dosage, timing of initiation and disease course. We also review the use of CS in combination with other MS treatments and during pregnancy and lactation. Furthermore, we delineate the relevant adverse events due to a pulse CS regimen and present a decision tree that can be used when treating MS relapses in clinical practice.

Integrating activated sludge floc size information in MBR fouling modeling.

Although studied extensively, modeling fouling phenomena in membrane bioreactors (MBRs) remains challenging. It has been well established that cake layer formation and pore blocking have a strong impact on the filtration performance but how to capture that in comprehensive models is not fully defined yet. Since it has been shown that bioflocculation characteristics of activated sludge have a clear link with (the extent of) membrane fouling, this study integrates activated sludge floc size (i.e., particle size distribution) information in the model for pore blocking and cake layer formation with a focus on constant flux operated MBRs. Based on these floc size distributions, a three-dimensional modeling and visualization of the cake layer is envisaged which can then provide the required input information (e.g., the porosity of the cake layer) for the fouling model. The model is calibrated and validated on the basis of experimental data from Hwang et al. (2012) in 'Membrane bioreactor: TMP rise and characterization of biocake structure using CLSM-image analysis' (see J. Membr. Sci. 419-420, 33-41).

The effect of alternating influent carbon source composition on activated sludge bioflocculation.

The impact of alternating influent carbon sources, i.e., glucose and starch, on activated sludge bioflocculation was investigated. To this end, four lab-scale reactors were operated during a long-term experiment. During this period the influent carbon source ratio (glucose/starch) was alternated every 7 or 35 days (i.e., a fast and slow switching frequency). Bioflocculation was monitored throughout the entire experiment using an extensive set of parameters, including macroscopic and microscopic activated sludge characteristics. Sludge hydrophobicity remained high (>80%) throughout the experiment indicating good bioflocculation. However, sludge settleability decreased for all four reactors after a 60 day adaptation period to the applied alternation in influent carbon source. During this adaptation period, floc size decreased due to the release of microcolonies. The subsequent period was characterized by a decrease in settleability, coinciding with a release of primary particles and an increase in floc size. The observed phenomena could be linked with the protein concentration near the floc surface. This fraction mainly consists of hydrolytic enzymes necessary for the degradation of starch and is responsible for a progressive deterioration of the EPS matrix. The results of this specific study indicate to be independent of the influent carbon source ratio or switching frequency.

Definition of realistic disturbances as a crucial step during the assessment of resilience of natural wastewater treatment systems.

Natural wastewater treatment systems (WWTSs) for urban areas in developing countries are subjected to large fluctuations in their inflow. This situation can result in a decreased treatment performance. The main aims of this paper are to introduce resilience as a performance indicator for natural WWTSs and to propose a methodology for the identification and generation of realistic disturbances of WWTSs. Firstly, a definition of resilience is formulated for natural WWTSs together with a short discussion of its most relevant properties. An important aspect during the evaluation process of resilience is the selection of appropriate disturbances. Disturbances of the WWTS are caused by fluctuations in water quantity and quality characteristics of the inflow. An approach to defining appropriate disturbances is presented by means of water quantity and quality data collected for the urban wastewater system of Coronel Oviedo (Paraguay). The main problem under consideration is the potential negative impact of stormwater inflow and infiltration in the sanitary sewer system on the treatment performance of anaerobic waste stabilisation ponds.

Prediction and interpretation of the antioxidant capacity of green tea from dissimilar chromatographic fingerprints.

Previously, multivariate calibration techniques have been successfully applied to model and predict the antioxidant activity of green tea from its chromatographic fingerprint. Since the selectivity differences between dissimilar chromatographic systems have already been valuably used in several applications, in this paper it is studied whether combining the complementary information contained in two dissimilar fingerprints can improve the predictive capacity of the multivariate calibration model. The simplest way of combining the data is concatenating both fingerprints for each sample. The resulting matrix can then be subjected to Orthogonal Projections to Latent Structures (O-PLS). Unfortunately, this approach resulted in a more complex model with a prediction error of about the average of the errors obtained with the individual fingerprints. Secondly, only the peaks with high loading and low orthogonal loading from both chromatograms were included in the O-PLS model. This resulted in a reduced complexity, but not in better predictions, probably due to a lack of complementarity of the information concerning the antioxidant capacity. Finally, the concatenated fingerprints were subjected to stepwise multiple linear regression (MLR) in order to build a model based on the variables most correlated with the antioxidant capacity. The obtained prediction error was lower than those of both previous approaches, but still higher than the error of the model based on a single analysis. This is probably again caused by a lack of complementarity in the variables. Nevertheless, it was advantageous to develop fingerprints on dissimilar system, because it enables to choose the most suited chromatographic profile to build a multivariate calibration model for the considered purpose. In contrast to what was expected, the study showed that the most simple (so the worst separated) fingerprints resulted in the best predictions. On the other hand, a more complex fingerprint in which more compounds are separated is still important to improve the interpretability of the model.

Towards a low complexity carbon removal model for the optimal design of compact decentralised wastewater treatment systems.

On-site decentralised wastewater treatment systems can provide a financially attractive alternative to a sewer connection in locations far from existing sewer networks. Operational problems and shortcomings in the design of these systems still occur frequently. The aim of this paper is to provide a low complexity (i.e. easy to calibrate) but still accurate mathematical model that can be used to optimise the operational design of compact individual wastewater treatment systems. An integrated hydraulic and biological carbon removal model of a biofilm-based compact decentralised treatment system is developed. The procedure for drafting the model is generic and can be used for similar types of wastewater treatment systems since (i) the hydraulic model is based on an N-tanks-in-series model inferred from tracer test experiments and (ii) (biofilm) respirometry experiments are exploited to determine the biodegradation kinetics of the biomass. Based on the preliminary validation results of the integrated model, the carbon removal in the system can be predicted quite accurately. While some adjustments could further improve the modelling strategy, the here presented results can already assist the manufacturers of compact treatment systems in efficiently (re)designing their systems.

Field performance assessment of onsite individual wastewater treatment systems.

On-site individual wastewater treatment systems can provide a financially attractive alternative to a sewer connection in locations far from the existing sewer network. These systems are, however, relatively new, and therefore, shortcomings in the design or operation problems still occur frequently. A previously performed survey revealed that most system owners neither carry out routine operation and maintenance tasks nor have a maintenance agreement with the manufacturer. This suggests that in reality, systems are often improperly managed and do not provide the level of treatment necessary to adequately protect surface and ground waters. To substantiate this statement, the field performance of 23 currently installed individual wastewater treatment systems in Belgium has been assessed.The results of this study confirm that many installed individual systems do not perform well: 52% of them do not meet all the legal effluent standards (BOD, COD, SS). Activated sludge systems prove to be less efficient than biofilm-based systems and extensive systems perform better than compact systems. Maintenance problems and to a lesser extent improperly designed systems are indeed the main cause of unsatisfactory results through, e.g., wash out.

Measurement of cytosolic and mitochondrial pH in living cells during reversible metabolic inhibition.

Renal ischemia and subsequent reperfusion lead to changes in the regulation of hydrogen ions across the mitochondrial membrane. This study was designed to monitor pH changes in the cytosol and mitochondria of Madin-Darby Canine Kidney cells exposed to metabolic inhibition and subsequent recovery. A classical one-photon confocal imaging approach using the pH-sensitive fluorophore carboxy SNARF-1 was used to define specific loading, calibration, and correction procedures to obtain reliable cytosolic and mitochondrial pH values in living cells. Metabolic inhibition resulted in both cytosolic and mitochondrial acidification, with a more pronounced decrease of mitochondrial pH as compared to the cytosolic pH. Shortly after removing the metabolic inhibition, cytosolic pH did not recover, whereas mitochondrial pH slowly increased. Our method is applicable to other cell types provided that the mitochondria can be loaded with SNARF-1 and that the cells possess a mitochondria-free region to measure SNARF-1 in the cytosol.