The realization of materials with new optoelectronic properties draws much scientific attention toward the field of nanocrystal superstructures. Low-dimensional superstructures created by interfacial ...assembly and oriented attachment of PbSe nanocrystals are a striking example because theory showed that PbSe sheets with a honeycomb geometry possess non-trivial flat bands and Dirac cones in the valence and conduction bands. Here, we report on the formation of one-dimensional linear and zigzag structures and two-dimensional (2D) square and honeycomb structures for the entire lead chalcogenide family: PbX (X = S, Se, Te). We observe that PbTe, with a lower bulk melting temperature and enthalpy of formation than those of PbSe, shows a higher nanocrystal surface reactivity, such that the surface must be passivated and the reaction conditions moderated to obtain reasonably ordered superstructures. The present findings constitute a step forward in the realization of a larger family of atomically coherent 2D superstructures with variable IV–VI and II–VI compositions and with electronic properties dictated by the nanogeometry.
Dynamic regulation of chemical reactivity is important in many complex chemical reaction networks, such as cascade reactions and signal transduction processes. Signal responsive catalysts could play ...a crucial role in regulating these reaction pathways. Recently, supramolecular encapsulation was reported to regulate the activities of artificial catalysts. We present a host‐guest chemistry strategy to modulate the activity of commercially available synthetic organocatalysts. The molecular container cucurbit7uril was successfully applied to change the activity of four different organocatalysts and one initiator, enabling up‐ or down‐regulation of the reaction rates of four different classes of chemical reactions. In most cases CB7 encapsulation results in catalyst inhibition, however in one case catalyst activation by binding to CB7 was observed. The mechanism behind this unexpected behavior was explored by NMR binding studies and pKa measurements. The catalytic activity can be instantaneously switched during operation, by addition of either supramolecular host or competitive binding molecules, and the reaction rate can be predicted with a kinetic model. Overall, this signal responsive system proves a promising tool to control catalytic activity.
Binding an organocatalyst inside a cucurbituril molecular host can reversibly up‐ or downregulate catalytic activity, which is demonstrated in temporal control over the rate of a range of organocatalyzed transformations.
Oriented attachment of synthetic semiconductor nanocrystals is emerging as a route for obtaining new semiconductors that can have Dirac-type electronic bands such as graphene, but also strong ...spin-orbit coupling. The two-dimensional (2D) assembly geometry will require both atomic coherence and long-range periodicity of the superlattices. We show how the interfacial self-assembly and oriented attachment of nanocrystals results in 2D metal chalcogenide semiconductors with a honeycomb superlattice. We present an extensive atomic and nanoscale characterization of these systems using direct imaging and wave scattering methods. The honeycomb superlattices are atomically coherent and have an octahedral symmetry that is buckled; the nanocrystals occupy two parallel planes. Considerable necking and large-scale atomic motion occurred during the attachment process.
To compare the predictive accuracy of β-amyloid (Aβ)1-42 and total tau in CSF, hippocampal volume (HCV), and APOE genotype for Alzheimer disease (AD)-type dementia in subjects with amnestic mild ...cognitive impairment (aMCI) and nonamnestic mild cognitive impairment (naMCI).
We selected 399 subjects with aMCI and 226 subjects with naMCI from a multicenter memory clinic-based cohort. We measured CSF Aβ1-42 and tau by ELISA (n = 231), HCV on MRI (n = 388), and APOE ε4 (n = 523). Follow-up was performed annually up to 5 years. Outcome measures were progression to AD-type dementia and cognitive decline.
At least 1 follow-up was available for 538 subjects (86%). One hundred thirty-two subjects with aMCI (38%) and 39 subjects with naMCI (20%) progressed to AD-type dementia after an average follow-up of 2.5 years. CSF Aβ1-42, tau, Aβ1-42/tau ratio, HCV, and APOE ε4 predicted AD-type dementia in each MCI subgroup with the same overall diagnostic accuracy. However, CSF Aβ1-42 concentration was higher and hippocampal atrophy less severe in subjects with naMCI compared with aMCI. This reduced the sensitivity but increased the specificity of these markers for AD-type dementia in subjects with naMCI.
AD biomarkers are useful to predict AD-type dementia in subjects with aMCI and naMCI. However, biomarkers might not be as sensitive for early diagnosis of AD in naMCI compared with aMCI. This may have implications for clinical implementation of the National Institute on Aging and Alzheimer's Association criteria.
Specifically we aim to demonstrate that the results of our earlier safety data hold true in this much larger multi-national and multi-ethnical population.
We sought to re-evaluate the frequency, ...manifestations, and severity of acute adverse reactions associated with administration of several gadolinium- based contrast agents during routine CMR on a European level.
Multi-centre, multi-national, and multi-ethnical registry with consecutive enrolment of patients in 57 European centres.
During the current observation 37,788 doses of Gadolinium based contrast agent were administered to 37,788 patients. The mean dose was 24.7 ml (range 5-80 ml), which is equivalent to 0.123 mmol/kg (range 0.01 - 0.3 mmol/kg). Forty-five acute adverse reactions due to contrast administration occurred (0.12%). Most reactions were classified as mild (43 of 45) according to the American College of Radiology definition. The most frequent complaints following contrast administration were rashes and hives (15 of 45), followed by nausea (10 of 45) and flushes (10 of 45). The event rate ranged from 0.05% (linear non-ionic agent gadodiamide) to 0.42% (linear ionic agent gadobenate dimeglumine). Interestingly, we also found different event rates between the three main indications for CMR ranging from 0.05% (risk stratification in suspected CAD) to 0.22% (viability in known CAD).
The current data indicate that the results of the earlier safety data hold true in this much larger multi-national and multi-ethnical population. Thus, the "off-label" use of Gadolinium based contrast in cardiovascular MR should be regarded as safe concerning the frequency, manifestation and severity of acute events.
Hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are debilitating conditions. Diagnosis is currently clinical in the absence of biomarkers, and criteria developed ...for adults are difficult to use in children and biologically immature adolescents. Generalized joint hypermobility (GJH) is a prerequisite for hEDS and generalized HSD. Current literature identifies a large proportion of children as hypermobile using a Beighton score ≥ 4 or 5/9, the cut off for GJH in adults. Other phenotypic features from the 2017 hEDS criteria can arise over time. Finally, many comorbidities described in hEDS/HSD are also seen in the general pediatric and adolescent population. Therefore, pediatric specific criteria are needed. The Paediatric Working Group of the International Consortium on EDS and HSD has developed a pediatric diagnostic framework presented here. The work was informed by a review of the published evidence.
The framework has 4 components, GJH, skin and tissue abnormalities, musculoskeletal complications, and core comorbidities. A Beighton score of ≥ 6/9 best identifies children with GJH at 2 standard deviations above average, based on published general population data. Skin and soft tissue changes include soft skin, stretchy skin, atrophic scars, stretch marks, piezogenic papules, and recurrent hernias. Two symptomatic groups were agreed: musculoskeletal and systemic. Emerging comorbid relationships are discussed. The framework generates 8 subgroups, 4 pediatric GJH, and 4 pediatric generalized hypermobility spectrum disorders. hEDS is reserved for biologically mature adolescents who meet the 2017 criteria, which also covers even rarer types of Ehlers-Danlos syndrome at any age.
This framework allows hypermobile children to be categorized into a group describing their phenotypic and symptomatic presentation. It clarifies the recommendation that comorbidities should be defined using their current internationally accepted frameworks. This provides a foundation for improving clinical care and research quality in this population.
Objective
To assess the psychometric properties of 8 pediatric Patient‐Reported Outcomes Measurement Information System (PROMIS) item banks in a clinical sample of children with juvenile idiopathic ...arthritis (JIA).
Methods
A total of 154 Dutch children (mean ± SD age 14.4 ± 3.0 years; range 8–18 years) with JIA completed 8 pediatric version 1.0 PROMIS item banks (anger, anxiety, depressive symptoms, fatigue, pain interference, peer relationships, physical function mobility, physical function upper extremity) twice and the Pediatric Quality of Life Inventory (PedsQL) and the Childhood Health Assessment Questionnaire (C‐HAQ) once. Structural validity of the item banks was assessed by fitting a graded response model (GRM) and inspecting GRM fit (comparative fit index CFI, Tucker‐Lewis index TLI, and root mean square error of approximation RMSEA) and item fit (S‐X2 statistic). Convergent validity (with PedsQL/C‐HAQ subdomains) and discriminative validity (active/inactive disease) were assessed. Reliability of the item banks, short forms, and computerized adaptive testing (CAT) was expressed as the SE of theta (SEθ). Test–retest reliability was assessed using intraclass correlation coefficients (ICCs) and smallest detectable change.
Results
All item banks had sufficient overall GRM fit (CFI >0.95, TLI >0.95, RMSEA <0.08) and no item misfit (all S‐X2 P > 0.001). High correlations (>0.70) were found between most PROMIS T scores and hypothesized PedsQL/C‐HAQ (sub)domains. Mobility, pain interference, and upper extremity item banks were able to discriminate between patients with active and inactive disease. Regarding reliability, PROMIS item banks outperformed legacy instruments. Post hoc CAT simulations outperformed short forms. Test–retest reliability was strong (ICC >0.70) for all full‐length item banks and short forms, except for the peer relationships item bank.
Conclusion
The pediatric PROMIS item banks displayed sufficient psychometric properties for Dutch children with JIA. PROMIS item banks are ready for use in clinical research and practice for children with JIA.
Since the introduction of biologic therapies, the pharmacological treatment approach for juvenile idiopathic arthritis (JIA) has changed substantially, with achievement of inactive disease as a ...realistic goal.
To determine the response to therapy after initiation of etanercept therapy among patients with JIA and to examine the association between baseline factors and response to etanercept treatment.
The Arthritis and Biologicals in Children Register, an ongoing prospective observational study since 1999, includes all Dutch JIA patients who used biologic agents. All biologically naive patients who started etanercept before October 2009 were included, with follow-up data to January 2011. Among the 262 patients, 185 (71%) were female, 46 (18%) had systemic-onset, and the median age at initiation of etanercept treatment was 12.4 years.
Excellent response (inactive disease or discontinuation earlier due to disease remission), intermediate response (more than 50% improvement from baseline, but no inactive disease), and poor response (less than 50% improvement from baseline or discontinuation earlier due to ineffectiveness or intolerance) evaluated 15 months after initiation of etanercept.
At 15 months after treatment initiation, 85 patients (32%) were considered excellent responders; 92 (36%), intermediate responders; and 85 (32%), poor responders. Compared with an intermediate or poor response, an excellent response was associated with lower baseline disability score (range, 0-3 points, with 0 being the best score; adjusted odds ratio OR per point increase, 0.49; 95% CI, 0.33-0.74); fewer disease-modifying antirheumatic drugs (DMARD) (including methotrexate) used before initiating etanercept (adjusted OR per DMARD used, 0.64; 95% CI, 0.43-0.95), and younger age at onset (adjusted OR per year increase, 0.92; 95% CI, 0.84-0.99). Compared with an intermediate or excellent response, a poor response was associated with systemic JIA (adjusted OR systemic vs nonsystemic categories, 2.92; 95% CI, 1.26-6.80), and female sex (adjusted OR female vs male, 2.16; 95% CI, 1.12-4.18). Within the first 15 months of etanercept treatment, 119 patients experienced 1 or more infectious, noninfectious, or serious adverse events, including 37 among those with an excellent response, 36 with an intermediate response, and 46 with a poor response. Within the first 15 months of treatment, 61 patients discontinued etanercept treatment, including 4 with an excellent response, 0 with an intermediate response, and 57 with a poor response. In a secondary analysis of 262 patients with a median follow-up of 35.6 months after initiation of etanercept, a range of 37% to 49% of patients reached inactive disease. The mean adherence to etanercept was 49.2 months (95% CI, 46.4-52.0) for patients with an excellent response after 15 months, 47.5 months (95% CI, 44.9-50.1) for patients with an intermediate response, and 17.4 months (95% CI, 13.6-21.2) for patients with a poor response.
Among patients with JIA who initiated treatment with etanercept, one-third achieved an excellent response, one-third an intermediate response, and one-third a poor response to therapy. Achievement of an excellent response was associated with low baseline disability scores, DMARDs used before initiating etanercept, and younger age at onset of JIA. Achievement of a poor treatment response was associated with systemic JIA and female sex.
Approximately 30% of juvenile idiopathic arthritis (JIA) patients fail to respond to anti-TNF treatment. When clinical remission is induced, some patients relapse after treatment has been stopped. We ...tested the predictive value of MRP8/14 serum levels to identify responders to treatment and relapse after discontinuation of therapy.
Samples from 88 non-systemic JIA patients who started and 26 patients who discontinued TNF-blockers were analyzed. MRP8/14 serum levels were measured by in-house MRP8/14 ELISA and by Bühlmann Calprotectin ELISA at start of anti-TNF treatment, within 6 months after start and at discontinuation of etanercept in clinical remission. Patients were categorized into responders (ACRpedi ≥ 50 and/or inactive disease) and non-responders (ACRpedi < 50) within six months after start, response was evaluated by change in JADAS-10. Disease activity was assessed within six months after discontinuation.
Baseline MRP8/14 levels were higher in responders (median MRP8/14 of 1466 ng/ml (IQR 1045-3170)) compared to non-responders (median MRP8/14 of 812 (IQR 570-1178), p < 0.001). Levels decreased after start of treatment only in responders (p < 0.001). Change in JADAS-10 was correlated with baseline MRP8/14 levels (Spearman's rho 0.361, p = 0.001). Patients who flared within 6 months after treatment discontinuation had higher MRP8/14 levels (p = 0.031, median 1025 ng/ml (IQR 588-1288)) compared to patients with stable remission (505 ng/ml (IQR 346-778)). Results were confirmed by Bühlmann ELISA with high reproducibility but different overall levels.
High levels of baseline MRP8/14 are associated with good response to anti-TNF treatment, whereas elevated MRP8/14 levels at discontinuation of etanercept are associated with higher chance to flare.
Background and purpose
John Cunningham virus (JCV) seropositivity is a risk factor for the development of natalizumab‐associated progressive multifocal leukoencephalopathy (PML) in multiple sclerosis ...(MS) patients. When JCV seronegative patients seroconvert, their risk of developing PML increases. Limited longitudinal data exist about the seroconversion rate amongst natalizumab‐treated relapsing−remitting MS (RRMS) patients. Our objective was to evaluate the seroconversion rate in a large Dutch cohort of natalizumab‐treated RRMS patients. Seroconversion was defined as at least two consecutive seropositive serum samples (or cessation of therapy after a single seropositive sample because of seropositivity) after initial seronegative testing.
Methods and results
In our study of 179 patients for whom longitudinal blood samples were available over a long period (median 4.2 years), anti‐JCV antibody indices were measured in 933 available samples. Eighty‐six patients (48.0%) tested seronegative initially. Of these 86 seronegative patients, 23 patients (26.7%) seroconverted during follow‐up. The annualized seroconversion rate was 7.1%. Seroconversion occurred between 9 and 90 months (median 43 months) of treatment. The rate of seroconversion was independent of follow‐up duration. No significant increase was seen in the anti‐JCV antibody index in the non‐converting patients during the follow‐up.
Conclusion
The annualized seroconversion rate of 7.1% in patients using natalizumab, cumulatively leading to more than 25% of seronegative patients becoming seropositive in 4 years, is of clinical relevance and should be taken into account in the risk assessment when considering the start of natalizumab therapy.
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