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BACKGROUND: Bladder dysfunction (BD) is common in people with multiple sclerosis (MS) and can reduce participation in daily life. Detecting BD early allows for effective prevention-focused treatments such as pelvic floor physical therapy. Pairing neurotechnology with patient-reported outcomes to remotely measure BD could significantly improve monitoring and treatment of BD. Therefore, we describe the process and findings of stakeholder engagement from a human-centered design process to assemble a wearables for the bladder (WeB) kit. METHODS: Four people with MS with varying BD severity, and 5 MS clinical/research experts had 4 virtual meetings. Commercially available bladder tools were graded for ability to evaluate, monitor, or treat BD. The Health Information Technology Usability Evaluation Scale (utility, usability, feasibility) was used for evaluation. Scoring was performed individually and as a group. RESULTS: Of the 11 devices, 5 obtained mean scores of greater than 6 of 10 for likability, usability, and device utility. The 2 highest scoring (9/10) devices were selected for the pilot. One device measures bladder urine levels, reporting the number/frequency of voids/leaks; the other guides pelvic floor exercises by pairing games on an app with biofeedback from intravaginal sensors. We uncovered critical differences in experts and patients appreciation of the tools, and the collaborative engagement led to substantial revisions of initial tool scores. CONCLUSIONS: This process underscores the critical role of stakeholder engagement in the selection of digital tools, especially in sensitive domains like pelvic function. Ongoing clinical validation of the selected tools will yield a validated, user-friendly WeB kit that is able to fill gaps in our ability to evaluate BD treatments in people with MS, ultimately reducing the impact of BD on quality of life.

It has recently become well-established that there is a connection between Alzheimers disease pathology and gut microbiome dysbiosis. We have previously demonstrated that antibiotic-mediated gut microbiota perturbations lead to attenuation of Aβ deposition, phosphorylated tau accumulation, and disease-associated glial cell phenotypes in a sex-dependent manner. In this regard, we were intrigued by the finding that a marine-derived oligosaccharide, GV-971, was reported to alter gut microbiota and reduce Aβ amyloidosis in the 5XFAD mouse model that were treated at a point when Aβ burden was near plateau levels. Utilizing comparable methodologies, but with distinct technical and temporal features, we now report on the impact of GV-971 on gut microbiota, Aβ amyloidosis and microglial phenotypes in the APPPS1-21 model, studies performed at the University of Chicago, and independently in the 5X FAD model, studies performed at Washington University, St. Louis.Methods To comprehensively characterize the effects of GV-971 on the microbiota-microglia-amyloid axis, we conducted two separate investigations at independent institutions. There was no coordination of the experimental design or execution between the two laboratories. Indeed, the two laboratories were not aware of each others experiments until the studies were completed. Male and female APPPS1-21 mice were treated daily with 40, 80, or 160 mg/kg of GV-971 from 8, when Aβ burden was detectable upto 12 weeks of age when Aβ burden was near maximal levels. In parallel, and to corroborate existing published studies and further investigate sex-related differences, male and female 5XFAD mice were treated daily with 100 mg/kg of GV-971 from 7 to 9 months of age when Aβ burden was near peak levels. Subsequently, the two laboratories independently assessed amyloid-β deposition, metagenomic, and neuroinflammatory profiles. Finally, studies were initiated at the University of Chicago to evaluate the metabolites in cecal tissue from vehicle and GV-971-treated 5XFAD mice.Results These studies showed that independent of the procedural differences (dosage, timing and duration of treatment) between the two laboratories, cerebral amyloidosis was reduced primarily in male mice, independent of strain. We also observed sex-specific microbiota differences following GV-971 treatment. Interestingly, GV-971 significantly altered multiple overlapping bacterial species at both institutions. Moreover, we discovered that GV-971 significantly impacted microbiome metabolism, particularly by elevating amino acid production and influencing the tryptophan pathway. The metagenomics and metabolomics changes correspond with notable reductions in peripheral pro-inflammatory cytokine and chemokine profiles. Furthermore, GV-971 treatment dampened astrocyte and microglia activation, significantly decreasing plaque-associated reactive microglia while concurrently increasing homeostatic microglia only in male mice. Bulk RNAseq analysis unveiled sex-specific changes in cerebral cortex transcriptome profiles, but most importantly, the transcriptome changes in the GV-971-treated male group revealed the involvement of microglia and inflammatory responses.Conclusions In conclusion, these studies demonstrate the connection between the gut microbiome, neuroinflammation, and Alzheimers disease pathology while highlighting the potential therapeutic effect of GV-971. GV-971 targets the microbiota-microglia-amyloid axis, leading to the lowering of plaque pathology and neuroinflammatory signatures in a sex-dependent manner when given at the onset of Aβ deposition or when given after Aβ deposition is already at higher levels.

Objective: This prospective, double-blind, randomized study aimed to compare the effects of dexmedetomidine and fentanyl on the latency and amplitude of transcranial motor evoked potentials (TcMEPs) under propofol-based total intravenous anaesthesia (TIVA) in spine surgery. Secondarily, intraoperative hemodynamics, total propofol consumption, recovery profile, and surgical field quality were compared. Methods: TcMEP amplitude and latency recordings of bilateral abductor pollicis brevis and abductor hallucis muscles posted for elective lumbar spine surgery under TcMEP monitoring randomly divided into two study groups. Throughout the surgery, TIVA was administered using intravenous propofol (100-150 µg kg-1 min-1) and dexmedetomidine (0.5-0.7 µg kg-1 h-1) in group D and intravenous propofol (100-150 µg kg-1 min-1) and fentanyl (1 µg kg-1 h-1) in group F. TcMEPs were recorded at various time points during the surgery. Immediately after extubation recovery from anaesthesia was noted. Additionally, hemodynamic parameters, total propofol consumption, and surgical field quality were assessed. Results: Latency and amplitude were comparable between the groups. Time to extubation was significantly longer in group D, but the mean (standard deviation) duration of stay in recovery was shorter in group D [47.55 (7.51) 95% confidence interval (CI) (44.863-50.237)] (P=0.046). Total propofol consumption was reduced in group D [220 (38) 95% CI (206.402-233.598)] (P=0.025) and surgical field condition was better in group D. Conclusions: Dexmedetomidine and fentanyl do not have any effect on TcMEP amplitude and latency. However, dexmedetomidine provides the additional advantage of reduced total propofol consumption, shorter stay in recovery, and better surgical field quality.

Abstract Due to the excessive growth of PM 2.5 in aerosol, the cases of lung cancer are increasing rapidly and are most severe among other types as the highest mortality rate. In most of the cases, lung cancer is detected with least symptoms at its later stage. Hence, clinical records may play a vital role to diagnose this disease at the correct stage for suitable medication to cure it. To detect lung cancer an accurate prediction method is needed which is significantly reliable. In the digital clinical record era with advancement in computing algorithms including machine learning techniques opens an opportunity to ease the process. Various machine learning algorithms may be applied over realistic clinical data but the predictive power is yet to be comprehended for accurate results. This paper envisages to compare twelve potential machine learning algorithms over clinical data with eleven symptoms of lung cancer along with two major habits of patients to predict a positive case accurately. The result has been found based on classification and heat map correlation. K-Nearest Neighbor Model and Bernoulli Naive Bayes Model are found most significant methods for early lung cancer prediction.

The paper outlines the challenges faced by street-connected children in India, particularly the lack of accurate data and the failure of governance systems to address their needs. It introduces the Rag Dreams Weaver Association case study in Aligarh, Uttar Pradesh, focusing on their mentorship programs to empower street-connected children in urban planning and policy-making processes. The paper argues for the inclusion of youth voices in participatory design, challenging traditional skepticism within city agencies. It suggests that involving young people in decision-making can rectify historical planning errors and create more equitable urban environments.

The HEALthy Brain and Child Development (HBCD) Study, a multi-site prospective longitudinal cohort study, will examine human brain, cognitive, behavioral, social and emotional development beginning prenatally and planned through early childhood. Many prenatal and early childhood exposures impact both later physical health and development. Moreover, early deficits in physical health, such as growth and vision, are associated with differences in brain development, language and cognitive functioning. For these reasons, the HBCD Study includes measures of early childhood physical health, many of which have clinical relevance, and are applicable for use as both predictors and outcomes. Study measures assess a broad range of physical health domains and include both objective measurement of child growth and health and subjective caregiver report of behaviors and attitudes about constructs known to influence growth and physical development. Lastly, we obtain caregiver report of the child’s routine medical care as well as acute and chronic medical issues. We anticipate that these data will contextualize the impact of child physical growth and health on child brain development and function. In this report we present the rationale for each domain and an overview of the physical health measures included in the current HBCD Study protocol.

In recent years, there's been a strong focus on enhancing high-strength structural steels (HSSSs), making them tougher, stronger, lighter, and more weldable. However, these steels face challenges like cold cracking sensitivity (CCS) and reduced toughness with higher heat input. Therefore, exploring HSSSs with advanced welding techniques like electron beam welding (EBW) is crucial. EBW known for its innovation and precision, is gaining popularity in HSSSs applications for vehicles, construction industries etc. offering advantages like narrow welds, reduced heat-affected zone (HAZ) and low distortion. It is essential to understand the influence of residual stresses (RS) in HSSSs which ultimately affect structural integrity and fatigue life. Using EBW on HSSSs, coupled with synchrotron XRD for residual stress studies, has great potential to advance this research significantly. In this work, a 15-mm-thick EB-welded joint of S960QL and S960 M steels was used to study the RS. At an energy level of 20 keV, RS data from the synchrotron XRD method and its result on the top of welded joints for both types of steel were compared. S960 M steel showed a longitudinal tensile stress of 250 MPa at the weld toe, approximately 1.8 times higher than the 138 MPa observed in S960QL steel under similar conditions. In transverse stress, S960QL exhibits a higher stress of 279 MPa compared to S960 M 46 MPa at the weld toe, approximately 83% lower. The synchrotron method measured 76% lower LRS for S960QL compared to conventional XRD, while S960 M exhibited 55% lower LRS using the same approach.

Abstract Background Reducing and breaking up sitting is recommended for optimal management of Type 2 diabetes mellitus (T2DM). Yet, there is limited evidence of interventions targeting these outcomes in individuals with this condition. The primary aim of this study was to assess the feasibility and acceptability of delivering and evaluating a tailored online intervention to reduce and break up sitting in adults with T2DM. Methods A mixed-methods two-arm randomised controlled feasibility trial was conducted in ambulatory adults with T2DM who were randomised 1:1 to the REgulate your SItting Time (RESIT) intervention or usual care control group. The intervention included online education, self-monitoring and prompt tools (wearable devices, smartphone apps, computer apps) and health coaching. Feasibility outcomes were recruitment, attrition, data completion rates and intervention acceptability. Measurements of device-assessed sitting (intended primary outcome for definitive trial), standing and stepping, and physical function, psychosocial health and wellbeing were taken at baseline, 3 months and 6 months. Individual semi-structured interviews were conducted at six-months (post intervention) to explore acceptability, feasibility and experiences of the trial and intervention using the Framework Method. Results Seventy participants aged 55 ± 11 years were recruited. Recruitment rate (proportion of eligible participants enrolled into the study) was 67% and participant retention rate at 6 months was 93% (n = 5 withdrawals). Data completion rates for daily sitting were 100% at baseline and ranged from 83 to 91% at 3 months and 6 months. Descriptive analysis demonstrated potential for the intervention to reduce device-measured sitting, which was 30.9 ± 87.2 and 22.2 ± 82.5 min/day lower in the intervention group at 3 and 6 months, respectively, compared with baseline. In the control group, sitting was 4.4 ± 99.5 and 23.7 ± 85.2 min/day lower at 3 and 6 months, respectively. Qualitative analysis identified three themes: reasons for participating in the trial, acceptability of study procedures, and the delivery and experience of taking part in the RESIT intervention. Overall, the measurement visits and intervention were acceptable to participants. Conclusions This study demonstrated the feasibility and acceptability of the RESIT intervention and evaluation methods, supporting a future definitive trial. If RESIT is found to be clinically effective, this could lead to changes in diabetes healthcare with a focus on reducing sitting. Trial registration The trial was registered with ISRCTN (number ISRCTN14832389).

This paper aims to identify the constrains faced by female entrepreneurs in Egypt. This study also intends to examine the influence of formal and informal institutional factors on women’s entry into entrepreneurship in Egypt. In addition, to explore the factors enable women entrepreneurs to overcome the barriers they may face. The qualitative research approach was adopted in the study to explore the challenges experienced by Egyptian female entrepreneurs. Purposeful sampling was employed and twenty-five (25) women entrepreneurs were selected from five Egyptian governorates to conduct semi-structured interviews to collect primary data. The findings indicated that the main constraints faced Egyptian women entrepreneurs arise from difficulty in raising capital, socio-culture commitments, sexual harassment, work-family conflict and lack of managerial skills. The study found factors such family-husband support, religious values, personal traits and technological skills are crucial for overcome constraints faced by women entrepreneurs. The study recommends creating a funding program targeting female entrepreneurs and raise the awareness about the importance of women entrepreneurship as well as take necessary actions to prevent sexual harassment phenomenon. Minimal research has examined female entrepreneurship in Egypt. Therefore, this study offers valuable insights of constraints faced by women entrepreneurs in Egypt. The study contributes to the women’s entrepreneurship literature from the perspective of an Arab Islamic developing country.

Abstract It has recently become well-established that there is a connection between Alzheimer’s disease pathology and gut microbiome dysbiosis. We have previously demonstrated that antibiotic-mediated gut microbiota perturbations lead to attenuation of Aβ deposition, phosphorylated tau accumulation, and disease-associated glial cell phenotypes in a sex-dependent manner. In this regard, we were intrigued by the finding that a marine-derived oligosaccharide, GV-971, was reported to alter gut microbiota and reduce Aβ amyloidosis in the 5XFAD mouse model that were treated at a point when Aβ burden was near plateau levels. Utilizing comparable methodologies, but with distinct technical and temporal features, we now report on the impact of GV-971 on gut microbiota, Aβ amyloidosis and microglial phenotypes in the APPPS1-21 model, studies performed at the University of Chicago, and independently in the 5X FAD model, studies performed at Washington University, St. Louis. Methods To comprehensively characterize the effects of GV-971 on the microbiota-microglia-amyloid axis, we conducted two separate investigations at independent institutions. There was no coordination of the experimental design or execution between the two laboratories. Indeed, the two laboratories were not aware of each other’s experiments until the studies were completed. Male and female APPPS1-21 mice were treated daily with 40, 80, or 160 mg/kg of GV-971 from 8, when Aβ burden was detectable upto 12 weeks of age when Aβ burden was near maximal levels. In parallel, and to corroborate existing published studies and further investigate sex-related differences, male and female 5XFAD mice were treated daily with 100 mg/kg of GV-971 from 7 to 9 months of age when Aβ burden was near peak levels. Subsequently, the two laboratories independently assessed amyloid-β deposition, metagenomic, and neuroinflammatory profiles. Finally, studies were initiated at the University of Chicago to evaluate the metabolites in cecal tissue from vehicle and GV-971-treated 5XFAD mice. Results These studies showed that independent of the procedural differences (dosage, timing and duration of treatment) between the two laboratories, cerebral amyloidosis was reduced primarily in male mice, independent of strain. We also observed sex-specific microbiota differences following GV-971 treatment. Interestingly, GV-971 significantly altered multiple overlapping bacterial species at both institutions. Moreover, we discovered that GV-971 significantly impacted microbiome metabolism, particularly by elevating amino acid production and influencing the tryptophan pathway. The metagenomics and metabolomics changes correspond with notable reductions in peripheral pro-inflammatory cytokine and chemokine profiles. Furthermore, GV-971 treatment dampened astrocyte and microglia activation, significantly decreasing plaque-associated reactive microglia while concurrently increasing homeostatic microglia only in male mice. Bulk RNAseq analysis unveiled sex-specific changes in cerebral cortex transcriptome profiles, but most importantly, the transcriptome changes in the GV-971-treated male group revealed the involvement of microglia and inflammatory responses. Conclusions In conclusion, these studies demonstrate the connection between the gut microbiome, neuroinflammation, and Alzheimer’s disease pathology while highlighting the potential therapeutic effect of GV-971. GV-971 targets the microbiota-microglia-amyloid axis, leading to the lowering of plaque pathology and neuroinflammatory signatures in a sex-dependent manner when given at the onset of Aβ deposition or when given after Aβ deposition is already at higher levels.

Abstract It is well-established that women are disproportionately affected by Alzheimer’s disease. The mechanisms underlying this sex-specific disparity are not fully understood, but several factors that are often associated-including interactions of sex hormones, genetic factors, and the gut microbiome-likely contribute to the disease's etiology. Here, we have examined the role of sex hormones and the gut microbiome in mediating Aβ amyloidosis and neuroinflammation in APPPS1-21 mice. We report that postnatal gut microbiome perturbation in female APPPS1-21 mice leads to an elevation in levels of circulating estradiol. Early stage ovariectomy (OVX) leads to a reduction of plasma estradiol that is correlated with a significant alteration of gut microbiome composition and reduction in Aβ pathology. On the other hand, supplementation of OVX-treated animals with estradiol restores Aβ burden and influences gut microbiome composition. The reduction of Aβ pathology with OVX is paralleled by diminished levels of plaque-associated microglia that acquire a neurodegenerative phenotype (MGnD-type) while estradiol supplementation of OVX-treated animals leads to a restoration of activated microglia around plaques. In summary, our investigation elucidates the complex interplay between sex-specific hormonal modulations, gut microbiome dynamics, metabolic perturbations, and microglial functionality in the pathogenesis of Alzheimer's disease.

The objective of this research is to assess the influence of in-situ localised electron beam post-weld heat treatment (LEB-PWHT) on the microstructure and mechanical properties of high-strength S690QL steel welded joints utilising highly sophisticated electron beam welding (EBW) technology. Although EBW is well-known for creating high-quality welds, the addition of the novel LEB-PWHT technique may significantly improve the characteristics of the welded joints. To systematically analyse the impacts of PWHT on the welded joints, the study employs microstructural analysis like optical microscopy and mechanical properties like microhardness testing, bending, tensile, and impact tests. Furthermore, tensile fractography analysed by scanning electron microscopy (SEM) to provide detailed insights into the fracture behaviour of the welded joints. The results show that the in-situ PWHT approach improves the microstructure and mechanical characteristics of the welded joints, such as a lower hardness peak in the heat affected zone (HAZ), increased tensile strength (5%), and improved toughness by 7 times. LEB-PWHT fractured surface revealed smaller, more sharply defined dimples and micro-voids. These results suggest that in-situ PWHT is an attractive option for improving the quality and performance of welds in a wide range of applications incorporating S690QL steel.

Background The aim of this manuscript is to review the evidence and compare the efficacy and safety of catechol-O-methyltransferase inhibitors (COMT-Is), dopamine receptor agonists (DRAs) and monoamine-oxidase B inhibitors (MAOB-Is) as adjunctive treatment to levodopa in patients with Parkinson’s disease (PD) experiencing motor complications.Methods In this systematic review and network meta-analysis, literature searches were performed in MEDLINE and Embase to identify eligible randomised controlled trials (RCTs) with a minimal follow-up of at least 4 weeks published in English between 1980 and 2021. RCTs were included if either a COMT-I, DRA or MAOB-I was evaluated as an adjunctive therapy to levodopa in patients with PD experiencing motor complications and dyskinesia. The main outcomes included daily off-medication time, motor and non-motor examination scales, and adverse events including dyskinesia.Results 74 RCTs reporting on 18 693 patients were included. All three studied drug classes decreased daily off-medication time compared with placebo (COMT-Is mean −0.8 hours (95% CI −1.0 to −0.6), DRAs −1.1 hours (95% CI −1.4 to −0.8), MAOB-Is −0.9 hours (95% CI −1.2 to −0.6)). Safety analysis showed an increased risk of dyskinesia for all three drug classes (COMT-Is OR 3.3 (95% CI 2.7 to 4.0), DRAs 3.0 (95% CI 2.5 to 3.5), MAOB-Is 1.6 (95% CI 1.2 to 2.2)). According to surface under the cumulative ranking curve scores, pramipexole IR was associated with the most favourable benefit–risk profile.Conclusions COMT-Is, DRAs and MAOB-Is effectively reduce motor complications and increase incidence of dyskinesia. In the network meta-analysis, adjunctive use of DRAs appeared most effective.

Abstract Background Microglia, the brain-resident macrophages perform immune surveillance and engage with pathological processes resulting in phenotype changes necessary for maintaining homeostasis. In preceding studies, we showed that antibiotic-induced perturbations of the gut microbiome of APPPS1-21 mice resulted in significant attenuation in Aβ amyloidosis and altered microglial phenotypes that are specific to male mice. The molecular events underlying microglial phenotypic transitions remain unclear. Here, by generating ‘APPPS1-21-CD11br’ reporter mice, we investigated the translational state of microglial/macrophage ribosomes during their phenotypic transition and in a sex-specific manner. Methods Six groups of mice that included WT-CD11br, antibiotic (ABX) or vehicle-treated APPPS1-21-CD11br males and females were sacrificed at 7-weeks of age (n = 15/group) and used for immunoprecipitation of microglial/macrophage polysomes from cortical homogenates using anti-FLAG antibody. Liquid chromatography coupled to tandem mass spectrometry and label-free quantification was used to identify newly synthesized peptides isolated from polysomes. Results We show that ABX-treatment leads to decreased Aβ levels in male APPPS1-21-CD11br mice with no significant changes in females. We identified microglial/macrophage polypeptides involved in mitochondrial dysfunction and altered calcium signaling that are associated with Aβ-induced oxidative stress. Notably, female mice also showed downregulation of newly-synthesized ribosomal proteins. Furthermore, male mice showed an increase in newly-synthesized polypeptides involved in FcγR-mediated phagocytosis, while females showed an increase in newly-synthesized polypeptides responsible for actin organization associated with microglial activation. Next, we show that ABX-treatment resulted in substantial remodeling of the epigenetic landscape, leading to a metabolic shift that accommodates the increased bioenergetic and biosynthetic demands associated with microglial polarization in a sex-specific manner. While microglia in ABX-treated male mice exhibited a metabolic shift towards a neuroprotective phenotype that promotes Aβ clearance, microglia in ABX-treated female mice exhibited loss of energy homeostasis due to persistent mitochondrial dysfunction and impaired lysosomal clearance that was associated with inflammatory phenotypes. Conclusions Our studies provide the first snapshot of the translational state of microglial/macrophage cells in a mouse model of Aβ amyloidosis that was subject to ABX treatment. ABX-mediated changes resulted in metabolic reprogramming of microglial phenotypes to modulate immune responses and amyloid clearance in a sex-specific manner. This microglial plasticity to support neuro-energetic homeostasis for its function based on sex paves the path for therapeutic modulation of immunometabolism for neurodegeneration.

Abstract Background The effectiveness of Deep Brain Stimulation (DBS) therapy for Parkinson’s disease can be limited by side-effects caused by electrical current spillover into structures adjacent to the target area. The objective of the STEEred versus RING-mode DBS for Parkinson’s disease (STEERING) study is to investigate if directional DBS for Parkinson’s disease results in a better clinical outcome when compared to ring-mode DBS. Methods The STEERING study is a prospective multi-centre double-blind randomised crossover trial. Inclusion criteria are Parkinson’s disease, subthalamic nucleus DBS in a ‘classic’ ring-mode setting for a minimum of six months, and optimal ring-mode settings have been established. Participants are categorised into one of two subgroups according to their clinical response to the ring-mode settings as ‘responders’ (i.e., patient with a satisfactory effect of ring-mode DBS) or ‘non-responder’ (i.e., patient with a non-satisfactory effect of ring-mode DBS). A total of 64 responders and 38 non-responders will be included (total 102 patients). After an optimisation period in which an optimal directional setting is found, participants are randomised to first receive ring-mode DBS for 56 days (range 28–66) followed by directional DBS for 56 days (28–66) or vice-versa. The primary outcome is the difference between ring-mode DBS and directional DBS settings on the Movement Disorders Society Unified Parkinson’s Disease Rating Scale – Motor Evaluation (MDS-UPDRS-ME) in the off-medication state. Secondary outcome measures consist of MDS-UPDRS-ME in the on-medication state, MDS-UPDRS Activities of Daily Living, MDS-UPDRS Motor Complications–Dyskinesia, disease related quality of life measured with the Parkinson’s Disease Questionnaire 39, stimulation-induced side-effects, antiparkinsonian medication use, and DBS-parameters. Participants’ therapy preference is measured at the end of the study. Outcomes will be analysed for both responder and non-responder groups, as well as for both groups pooled together. Discussion The STEERING trial will provide insights into whether or not directional DBS should be standardly used in all Parkinson’s disease DBS patients or if directional DBS should only be used in a case-based approach. Trial registration This trial was registered on the Netherlands Trial Register, as trial NL6508 ( NTR6696 ) on June 23, 2017.