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Background Global health clinical research is commonly led by high-income countries (HICs) as low- and middle-income countries (LMICs) face barriers to participate, including lack of financial and human capacity and lack of research environment. Respiratory syncytial virus (RSV) vaccine development is also led by HICs, while LMICs carry the burden of life-threatening disease. Representative trials and research capacity strengthening in LMICs are needed to ensure global vaccine access and equity. This study aims to transfer an RSV neutralisation assay, which uses live cells and virus with inherent high variation, to a country eligible to receive support from the Gavi, the Vaccine Alliance.Methods Using a train-the-trainer approach, a Ghanaian researcher was trained in the Netherlands on the dried blood-based RSV neutralisation assay. Subsequently, a Dutch researcher visited Ghana to support the process of adapting the technique to the Ghanaian setting. In a previously validated RSV neutralisation assay on dried blood, Hep-2 cells were infected with a serial dilution of sample-virus mixture to determine the half-maximal inhibitory concentration. Fifty-one dried blood and serum samples were tested in parallel in both countries to assess concordance.Results Training and technology transfer was deemed successful, which was defined as neutralisation measurements by the Ghana team and high concordance (Lin’s concordance correlation coefficient (CCC)>0.8). Neutralising capacity measured in identical samples in Ghana and the Netherlands correlated highly (Lin’s CCC=0.87; Spearman rho=0.89) but was systematically lower in Ghana than the Netherlands.Conclusion We show successful transfer of an RSV neutralisation assay, thereby strengthening the laboratory research capacity in a Gavi-eligible country. Reliable measurement of RSV neutralising antibodies in a Gavi-eligible country and the use of dried blood can contribute to inclusion of LMICs in RSV vaccine development and access.

Introduction Tracheomalacia (TM) often occurs in children with oesophageal atresia (OA), leading to recurrent respiratory symptoms and in severe cases to blue spells or ultimately respiratory arrest. In some patients, a secondary posterior tracheopexy may then be indicated. This secondary surgery, as well as respiratory morbidity, may be prevented by performing a primary posterior tracheopexy (PPT) concurrent with primary OA correction. The aim of this trial is to determine if a PPT can decrease—or prevent—tracheal collapse in newborns with OA and TM. Additionally, the trial aims to determine whether the potential observed effect of PPT on tracheal stability is sustained over time.Methods and analysis This is an international multicentre double-blind randomised controlled trial. Seventy-eight children with OA type C will be randomised 1:1 into the no-PPT group or PPT group. Randomisation will be stratified by centre. The degree and location of TM are assessed during preoperative, intraoperative and two postoperative tracheobronchoscopies. The occurrence of TM will be evaluated during three routine follow-up consultations until the age of 6 months. The primary outcome is the degree of collapse of the tracheal wall during the intraoperative tracheobronchoscopy (after performing the PPT/no-PPT), measured in percentages. The difference in the mean degree of collapse will be compared between the no-PPT and the PPT groups using linear regression, adjusting for centre and the preoperative degree of tracheal collapse at baseline. The adjusted mean difference will be reported as effect size together with its 95% CI.Ethics and dissemination Patients will be included after written parental informed consent. The risks and burden associated with the trial are minimal. The institutional review board of the University Medical Center Utrecht has approved this protocol (METC-number 23-256/A). Results will be shared in a peer-reviewed scientific journal and presented at international conferences.Trial registration number NCT06335862.

Summary: Background: Despite the adoption of minimally invasive techniques, recovery after abdominal surgery takes a long time. Electronic health (eHealth) modalities can provide guidance to patients, facilitating early return to normal activities. We aimed to assess the impact of a personalised eHealth programme on patients' return to normal activities after major abdominal surgery. Methods: This single-blind, randomised, placebo-controlled trial was done at 11 teaching hospitals in the Netherlands. Eligible participants were aged 18–75 years who underwent a laparoscopic or open colectomy or hysterectomy. An independent researcher randomly allocated participants (in a 1:1 ratio) to either the intervention or control group by use of computer-based randomisation lists, with stratification by sex, type of surgery, and hospital. Participants in the intervention group had access to a perioperative, personalised eHealth programme consisting of both standard face-to-face care and eHealth, that comprised interactive tools offering goal attainment and a personalised outcome measurement, which managed recovery expectations and provided postoperative guidance tailored to each patient. Patients were provided with an activity tracker and had access to a website and mobile app with an electronic consultation (eConsult) functionality. The control group received standard care and access to a placebo website containing recovery advice provided by the hospital. The primary outcome was the number of days between surgery and personalised return to normal activities, assessed with Kaplan-Meier curves. Intention-to-treat and per-protocol analyses were done with a Cox regression model. This trial is registered with the Netherlands National Trial Register (NTR5686). Findings: Between Feb 11, 2016, and Aug 9, 2017, 355 participants were randomly assigned to the intervention (n=178) or control (n=177) groups. 342 participants were included in the intention-to-treat analysis. The median time until return to normal activities was 52 days (IQR 33–111) in the intervention group, and 65 days (39–152) in the control group (adjusted hazard ratio 1·30 [95% CI 1·03–1·64]; p=0·027). The frequency of postoperative complications did not differ between groups. Interpretation: This eHealth programme, delivering personalised care based on goal attainment scaling, enabled patients to return to their normal activities 13 days earlier than those who received standard care. Funding: ZonMw.

BACKGROUND:Fatigue is a disabling problem in patients with visual impairment, but its etiology is still poorly understood. Our objective was to identify the determinants of fatigue in adults with visual impairment compared to adults with normal sight. METHODS:Cross-sectional data on fatigue and sociodemographic, psychological and health-related factors was obtained with validated questionnaires. Structural equational modeling using hypothesized relationships and explorative analyses were used to identify (in)direct pathways contributing to fatigue in 247 adults with visual impairment. The model was then tested in a reference group of 151 adults with normal sight. RESULTS:The final model explained 64% of fatigue variance in participants with visual impairment and revealed the following factors to be directly associated with fatigue: depressive symptoms (β = 0.723, p

Introduction Quality of life of people with advanced dementia living in nursing homes is often suboptimal. Family caregivers can feel frustrated with limited contact with their relatives, which results in visits that are perceived as stressful and not very meaningful. Few psychosocial interventions are specifically developed for people with advanced dementia, and actively involve family caregivers or volunteers. Also, interventions usually stop when it becomes difficult for people to participate. The Namaste Care Family programme aims to increase the quality of life of people with advanced dementia, and improve family caregiving experiences through connecting to people and making them comfortable.Methods and analysis Our study will evaluate the effects of the Namaste Care Family programme on quality of life of people with advanced dementia living in nursing homes and family caregiving experiences using a cluster-randomised controlled trial. Longitudinal analyses will be performed taking into account clustering at the nursing home level. Both a cost-effectiveness and a cost-utility analysis from a societal perspective will be performed. We will modify the Namaste Care Family programme to increase family and volunteer involvement in ongoing and end-of-life care. Data collection involves assessments by family caregivers, nursing staff and elderly care physicians using questionnaires, and observations by the researchers at baseline and multiple times over 12 months. The last questionnaire will be sent up to month 24 after the death of the person with dementia. During semistructured interviews, the feasibility, accessibility and sustainability of the Namaste Care Family programme will be assessed.Ethics and dissemination The study protocol is approved by the Medical Ethics Review Committee of the VU University Medical Center in Amsterdam (protocol no. 2016.399) and registered with the Nederlands Trial Register (NTR5692). The findings will be disseminated via publications in peer-reviewed journals, conference presentations and presentations for healthcare professionals where appropriate.Trial registration number NTR5692.

Low-back pain (LBP) has been correlated to the presence of intervertebral disc (IVD) degeneration on T2-weighted (T2w) MRI. It remains challenging, however, to accurately stage degenerative disc disease (DDD) based on T2w MRI and measurements of IVD height, particularly for early DDD. Several quantitative MRI techniques have been introduced to detect changes in matrix composition signifying early DDD. In this study, we correlated quantitative T2, T1rho and Apparent Diffusion Coefficient (ADC) values to disc mechanical behavior and gold standard early DDD markers in a graded degenerated lumbar IVD caprine model, to assess their potential for early DDD detection.Lumbar caprine IVDs were injected with either 0.25 U/ml or 0.5 U/ml Chondroïtinase ABC (Cabc) to trigger early DDD-like degeneration. Injection with phosphate-buffered saline (PBS) served as control. IVDs were cultured in a bioreactor for 20 days under axial physiological loading. High-resolution 9.4 T MR images were obtained prior to intervention and after culture. Quantitative MR results were correlated to recovery behavior, histological degeneration grading, and the content of glycosaminoglycans (GAGs) and water.Cabc-injected IVDs showed aberrancies in biomechanics and loss of GAGs without changes in water-content. All MR sequences detected changes in matrix composition, with T1rho showing largest changes pre-to-post in the nucleus, and significantly more than T2 and ADC. Histologically, degeneration due to Cabc injection was mild. T1rho nucleus values correlated strongest with altered biomechanics, histological degeneration score, and loss of GAGs.T2- and T1rho quantitative MR-mapping detected early DDD changes. T1rho nucleus values correlated better than T2 and ADC with biomechanical, histological, and GAG changes. Clinical implementation of quantitative MRI, T1rho particularly, could aid in distinguishing DDD more reliably at an earlier stage in the degenerative process.

Lumbar hernias occur mostly in the posterolateral region of IVDs and mechanical loading is an important risk factor. Studies show that dynamic and static overloading affect the nucleus and annulus of the IVD differently. We hypothesize there is also variance in the effect of overloading on the IVD's anterior, lateral and posterior annulus, which could explain the predilection of herniations in the posterolateral region. We assessed the regional mechanical and cellular responses of lumbar caprine discs to dynamic and static overloading.IVDs (n = 125) were cultured in a bioreactor and subjected to simulated-physiological loading (SPL), high dynamic (HD), or high static (HS) overloading. The effect of loading was determined in five disc regions: nucleus, inner-annulus and anterior, lateral and posterior outer-annulus. IVD height loss and external pressure transfer during loading were measured, cell viability was mapped and quantified, and matrix integrity was assessed.During culture, overloaded IVDs lost a significant amount of height, yet the distribution of axial pressure remained unchanged. HD loading caused cell death and disruption of matrix in all IVD regions, whereas HS loading particularly affected cell viability and matrix integrity in the posterior region of the outer annulus.Axial overloading is detrimental to the lumbar IVD. Static overloading affects the posterior annulus more strongly, while the nucleus is relatively spared. Hence, static overloading predisposes the disc for posterior herniation. These findings could have implications for working conditions, in particular of sedentary occupations, and the design of interventions aimed at prevention and treatment of early intervertebral disc degeneration.

ObjectivesTo characterize the temporal alterations in native T1 and extracellular volume (ECV) of remote myocardium after acute myocardial infarction (AMI), and to explore their relation to left ventricular (LV) remodeling.MethodsForty-two patients with AMI successfully treated with primary PCI underwent cardiovascular magnetic resonance after 4-6 days and 3 months. Cine imaging, late gadolinium enhancement, and T1-mapping (MOLLI) was performed at 1.5T. T1 values were measured in the myocardial tissue opposite of the infarct area. Myocardial ECV was calculated from native- and post-contrast T1 values in 35 patients, using a correction for synthetic hematocrit.ResultsNative T1 of remote myocardium significantly decreased between baseline and follow-up (1002 ± 39 to 985 ± 30ms, pConclusionsIn reperfused first-time AMI patients, native T1 of remote myocardium decreased from baseline to follow-up. ECV of remote myocardium decreased over time in patients with no LV dilatation, but remained elevated at follow-up in those who developed LV dilatation. Findings from this study may add to an increased understanding of the pathophysiological mechanisms of cardiac remodeling after AMI.

[This corrects the article DOI: 10.1371/journal.pone.0157233.].

PURPOSE:Despite a call for earlier diagnosis of dementia, the diagnostic yield of case finding and its impact on the mental health of patients and relatives are unclear. This study assessed the effect of a two-component intervention of case finding and subsequent care on these outcomes. METHODS:In a cluster RCT we assessed whether education of family physicians (FPs; trial stage 1) resulted in more mild cognitive impairment (MCI) and dementia diagnoses among older persons in whom FPs suspected cognitive decline and whether case finding by a practice nurse and the FP (trial stage 2) added to this number of diagnoses. In addition, we assessed mental health effects of case finding and subsequent care (trial stage 2). FPs of 15 primary care practices (PCPs = clusters) judged the cognitive status of all persons ≥ 65 years. The primary outcome, new MCI and dementia diagnoses by FPs after 12 months as indicated on a list, was assessed among all persons in whom FPs suspected cognitive impairment but without a formal diagnosis of dementia. The secondary outcome, mental health of patients and their relatives, was assessed among persons consenting to participate in trial stage 2. Trial stage 1 consisted of either intervention component 1: training FPs to diagnose MCI and dementia, or control: no training. Trial stage 2 consisted of either intervention component 2: case finding of MCI and dementia and care by a trained nurse and the FP, or control: care as usual. RESULTS:Seven PCPs were randomized to the intervention; eight to the control condition. MCI or dementia was diagnosed in 42.3% (138/326) of persons in the intervention, and in 30.5% (98/321) in the control group (estimated difference GEE: 10.8%, OR: 1.51, 95%-CI 0.60-3.76). Among patients and relatives who consented to stage 2 of the trial (n = 145; 25%), there were no differences in mental health between the intervention and control group. CONCLUSIONS:We found a non-significant increase in the number of new MCI diagnoses. As we cannot exclude a clinically relevant effect, a larger study is warranted to replicate ours. TRIAL REGISTRATION:Nederlands Trial Register NTR3389.

Microvascular injury (MVI) after coronary ischemia-reperfusion is associated with high morbidity and mortality. Both ischemia and reperfusion are involved in MVI, but to what degree these phases contribute is unknown. Understanding the etiology is essential for the development of new potential therapies.Rats were divided into 3 groups receiving either 30 minutes ischemia, 90 minutes ischemia or 30 minutes ischemia followed by 60 minutes reperfusion. Subsequently hearts were ex-vivo perfused in a Langendorff-model. Fluorescence and electron microscopy was used for analysis of capillary density, vascular permeability and ultrastructure. Most MVI was observed after 30 minutes ischemia followed by 60 minutes reperfusion. In comparison to the 30' and 90' ischemia group, wall thickness decreased (207.0±74 vs 407.8±75 and 407.5±71, p = 0.02). Endothelial nuclei in the 30'-60' group showed irreversible damage and decreased chromatin density variation (50.5±9.4, 35.4±7.1 and 23.7±3.8, p = 0.03). Cell junction density was lowest in the 30'-60' group (0.15±0.02 vs 2.5±0.6 and 1.8±0.7, p

Personality influences decision making and ethical considerations. Its influence on the occurrence of research misbehavior has never been studied. This study aims to determine the association between personality traits and self-reported questionable research practices and research misconduct. We hypothesized that narcissistic, Machiavellianistic and psychopathic traits as well as self-esteem are associated with research misbehavior.Included in this cross-sectional study design were 535 Dutch biomedical scientists (response rate 65%) from all hierarchical layers of 4 university medical centers in the Netherlands. We used validated personality questionnaires such as the Dark Triad (narcissism, psychopathy, and Machiavellianism), Rosenberg's Self-Esteem Scale, the Publication Pressure Questionnaire (PPQ), and also demographic and job-specific characteristics to investigate the association of personality traits with a composite research misbehavior severity score.Machiavellianism was positively associated (beta 1.28, CI 1.06-1.53) with self-reported research misbehavior, while narcissism, psychopathy and self-esteem were not. Exploratory analysis revealed that narcissism and research misconduct were more severe among persons in higher academic ranks (i.e., professors) (p

Abstract Background Severe fatigue is a common symptom for people with visual impairment, with a detrimental effect on emotional functioning, cognition, work capacity and activities of daily living. A previous study found that depression was one of the most important determinants of fatigue, but less is known about disease-specific factors in this patient population. This study aimed to explore the association between visual impairment severity and fatigue in adults with low vision, both directly and indirectly, with vision-specific factors and depression as potential mediators. Methods Cross-sectional data were collected from 220 Dutch low vision service patients by telephone interviews. Fatigue was defined as a latent variable by severity and impact on daily life. Potential mediators included vision-related symptoms, adaptation to vision loss and depression. Hypothesized structural equation models were constructed in Mplus to test (in)direct effects of visual impairment severity (mild/moderate, severe, blindness) on fatigue through above mentioned variables. Results The final model explained 60% of fatigue variance and revealed a significant total effect of visual impairment severity on fatigue. Patients with severe visual impairment (reference group) had significantly higher fatigue symptoms compared to those with mild/moderate visual impairment (β = -0.50, 95% bias-corrected confidence interval [BC CI] [-0.86, -0.16]) and those with blindness (β = -0.44, 95% BC CI [-0.80, -0.07]). Eye strain & light disturbance, depression and vision-related mobility mediated the fatigue difference between the severe and mild/moderate visual impairment categories. The fatigue difference between the severe visual impairment and blindness categories was solely explained by eye strain & light disturbance. Moreover, depressive symptoms (β = 0.65, p

Mechanical overloading of the spine is associated with low back pain and intervertebral disc (IVD) degeneration. How excessive loading elicits degenerative changes in the IVD is poorly understood. Comprehensive knowledge of the interaction between mechanical loading, cell responses and changes in the extracellular matrix of the disc is needed in order to successfully intervene in this process. The purpose of the current study was to investigate whether dynamic and static overloading affect caprine lumbar discs differently and what mechanisms lead to mechanically induced IVD degeneration. Lumbar caprine IVDs (n = 175) were cultured 7, 14 and 21 days under simulated-physiological loading (control), high dynamic or high static loading. Axial deformation and stiffness were continuously measured. Cell viability, cell density, and gene expression were assessed in the nucleus, inner- and outer annulus. The extracellular matrix (ECM) was analyzed for water, glycosaminoglycan and collagen content. IVD height loss and changes in axial deformation were gradual with dynamic and acute with static overloading. Dynamic overloading caused cell death in all IVD regions, whereas static overloading mostly affected the outer annulus. IVDs expression of catabolic and inflammation-related genes was up-regulated directly, whereas loss of water and glycosaminoglycan were significant only after 21 days. Static and dynamic overloading both induced pathological changes to caprine lumbar IVDs within 21 days. The mechanism by which they inflict biomechanical, cellular, and extracellular changes to the nucleus and annulus differed. The described cascades provide leads for the development of new pharmacological and rehabilitative therapies to halt the progression of DDD.

BackgroundInterventions relieving the burden of caregiving may postpone or prevent patient institutionalization. The objective of this study was to determine whether a family meetings intervention was superior to usual care in postponing nursing home placement of patients with dementia.MethodsA randomized multicenter trial was conducted among 192 patients with a clinical diagnosis of dementia living at home at enrolment and their primary family caregiver. Dyads of caregivers and patients were randomized to the family meetings intervention (n = 96) or usual care (n = 96) condition. The intervention consisted of two individual sessions with the primary caregiver and four family counseling sessions that included family members and friends. The primary outcome measure was the time until institutionalization of the patient. Intention-to-treat as well as per protocol analyses were performed. Survival analyses were carried out to evaluate the effectiveness of the intervention.ResultsDuring 18 months follow-up 23 of 96 relatives with dementia of caregivers in the intervention group and 18 of 96 relatives with dementia of caregivers in the usual care group were institutionalized. No significant difference between the intervention and the usual care group was found in time until institutionalization (adjusted hazard ratio (HR) 1.46, 95% confidence interval (CI) 0.78 to 2.74). The per-protocol analysis revealed no significant effect either (adjusted HR 0.57, 95% CI 0.21 to 1.57), although the number of placements among the adherers was relatively low (9.4%). A subgroup effect was found for patients' age, with a significantly higher risk of institutionalization for 'younger' patients in the intervention group compared with the usual care group (adjusted HR = 4.94, 95% CI 1.10 to 22.13).ConclusionThis family meetings intervention for primary caregivers of patients with dementia did not postpone patient institutionalization more than usual care.Trial registrationCONTROLLED-TRIALS.COM ISRCTN90163486.

Family caregivers of dementia patients are at increased risk of developing depression or anxiety. A multi-component program designed to mobilize support of family networks demonstrated effectiveness in decreasing depressive symptoms in caregivers. However, the impact of an intervention consisting solely of family meetings on depression and anxiety has not yet been evaluated. This study examines the preventive effects of family meetings for primary caregivers of community-dwelling dementia patients.A randomized multicenter trial was conducted among 192 primary caregivers of community dwelling dementia patients. Caregivers did not meet the diagnostic criteria for depressive or anxiety disorder at baseline. Participants were randomized to the family meetings intervention (n = 96) or usual care (n = 96) condition. The intervention consisted of two individual sessions and four family meetings which occurred once every 2 to 3 months for a year. Outcome measures after 12 months were the incidence of a clinical depressive or anxiety disorder and change in depressive and anxiety symptoms (primary outcomes), caregiver burden and quality of life (secondary outcomes). Intention-to-treat as well as per protocol analyses were performed.A substantial number of caregivers (72/192) developed a depressive or anxiety disorder within 12 months. The intervention was not superior to usual care either in reducing the risk of disorder onset (adjusted IRR 0.98; 95% CI 0.69 to 1.38) or in reducing depressive (randomization-by-time interaction coefficient = -1.40; 95% CI -3.91 to 1.10) or anxiety symptoms (randomization-by-time interaction coefficient = -0.55; 95% CI -1.59 to 0.49). The intervention did not reduce caregiver burden or their health related quality of life.This study did not demonstrate preventive effects of family meetings on the mental health of family caregivers. Further research should determine whether this intervention might be more beneficial if provided in a more concentrated dose, when applied for therapeutic purposes or targeted towards subgroups of caregivers.Controlled-Trials.com ISRCTN90163486.

Low-back pain (LBP) is a common medical complaint and associated with high societal costs. Degeneration of the intervertebral disc (IVD) is assumed to be an important causal factor of LBP. IVDs are continuously mechanically loaded and both positive and negative effects have been attributed to different loading conditions.In order to study mechanical loading effects, degeneration-associated processes and/or potential regenerative therapies in IVDs, it is imperative to maintain the IVDs' structural integrity. While in vivo models provide comprehensive insight in IVD biology, an accompanying organ culture model can focus on a single factor, such as loading and may serve as a prescreening model to reduce life animal testing. In the current study we examined the feasibility of organ culture of caprine lumbar discs, with the hypothesis that a simulated-physiological load will optimally preserve IVD properties.Lumbar caprine IVDs (n = 175) were cultured in a bioreactor up to 21 days either without load, low dynamic load (LDL), or with simulated-physiological load (SPL). IVD stiffness was calculated from measurements of IVD loading and displacement. IVD nucleus, inner- and outer annulus were assessed for cell viability, cell density and gene expression. The extracellular matrix (ECM) was analyzed for water, glycosaminoglycan and total collagen content.IVD biomechanical properties did not change significantly with loading conditions. With SPL, cell viability, cell density and gene expression were preserved up to 21 days. Both unloaded and LDL resulted in decreased cell viability, cell density and significant changes in gene expression, yet no differences in ECM content were observed in any group.In conclusion, simulated-physiological loading preserved the native properties of caprine IVDs during a 21-day culture period. The characterization of caprine IVD response to culture in the LDCS under SPL conditions paves the way for controlled analysis of degeneration- and regeneration-associated processes in the future.

Summary: Background: Mucosal administration of monoclonal antibodies (mAbs) against respiratory pathogens is a promising alternative for systemic administration because lower doses are required for protection. Clinical development of mucosal mAbs is a highly active field yet clinical proof-of-concept is lacking. Methods: In this investigator-initiated, double-blind, randomized placebo-controlled trial, we evaluated intranasal palivizumab for the prevention of RSV infection in preterm infants (Dutch Trial Register NTR7378 and NTR7403). We randomized infants 1:1 to receive intranasal palivizumab (1 mg/mL) or placebo once daily during the RSV season. Any RSV infection was the primary outcome and RSV hospitalization was the key secondary outcome. The primary outcome was analyzed with a mixed effect logistic regression on the modified intention-to-treat population. Findings: We recruited 268 infants between Jan 14, 2019 and Jan 28, 2021, after which the trial was stopped for futility following the planned interim analysis. Adverse events were similar in both groups (22/134 (16.4%) palivizumab arm versus 26/134 (19.4%) placebo arm). There were 6 dropouts and 168 infants were excluded from the efficacy analyses due to absent RSV circulation during the SARS-CoV-2 pandemic. Any RSV infection was similar in infants in both groups (18/47 (38.3%) palivizumab arm versus 11/47 (23.4%) placebo arm; aOR 2.2, 95% CI 0.7–6.5). Interpretation: Daily intranasal palivizumab did not prevent RSV infection in late preterm infants. Our findings have important implications for the clinical development of mucosal mAbs, namely the necessity of timely interim analyses and further research to understand mucosal antibody half-life. Funding: Funded by the Department of Pediatrics, University Medical Centre Utrecht, the Netherlands.

Rationale: Loss-of-function (LoF) mutations in GRIN2B result in neurologic abnormalities due to N-methyl-D-aspartate receptor (NMDAR) dysfunction. Affected persons present with various symptoms, including intellectual developmental disability (IDD), hypotonia, communication deficits, motor impairment, complex behavior, seizures, sleep disorders and gastrointestinal disturbance. Recently, in vitro experiments showed that D-serine mitigates function to GluN2B (mutation)-containing NMDARs. 11 previous case reports are published on (experimental) L-serine treatment of patients between 1.5 and 12 years old with GRIN2B missense or null mutations, some of whom showed notable improvement in motor and cognitive performance, communication, behavior and abnormalities on electro encephalography (EEG). Our objective is to further evaluate the effectiveness of L-serine for GRIN2B-related neurodevelopmental disorder (GRIN2B-NDD), using an n-of-1 trial design, increasing the level of evidence. Methods/design: These n-of-1 trials, consisting of 2 cycles of 6 months, will be performed to evaluate the effect of L-serine compared to placebo in 4 patients with a GRIN2B LoF mutation. The aggregation of multiple n-of-1 trials will provide an estimate of the average treatment effects.The primary outcome is the Perceive-Recall-Plan-Perform of Task Analysis, assessing developmental skills. Secondary outcomes include Goal Attainment Scaling, seizure log books, EEGs, sleep log books, the irritability subscale of the Aberrant Behavior Checklist, the Bristol Stool Scale and the Pediatric Quality of Life Inventory. Conclusion: This study employs an innovative methodological approach to evaluate the effectiveness of L-serine for patients with a GRIN2B LoF mutation. The results will establish a foundation for implementing L-serine as a disease-modifying treatment in GRIN2B-NDD.

Objectives. Quantitative flow ratio (QFR) computes fractional flow reserve (FFR) based on invasive coronary angiography (ICA). Residual QFR estimates post‐percutaneous coronary intervention (PCI) FFR. This study sought to assess the relationship of residual QFR with post-PCI FFR. Methods. Residual QFR analysis, using pre-PCI ICA, was attempted in 159 vessels with post-PCI FFR. QFR lesion location was matched with the PCI location to simulate the performed intervention and allow computation of residual QFR. A post-PCI FFR