Focal clusters of peri-synaptic matrix contribute to activity-dependent plasticity and memory in mice.

Recent findings show that effective integration of novel information in the brain requires coordinated processes of homo- and heterosynaptic plasticity. In this work, we hypothesize that activity-dependent remodeling of the peri-synaptic extracellular matrix (ECM) contributes to these processes. We show that clusters of the peri-synaptic ECM, recognized by CS56 antibody, emerge in response to sensory stimuli, showing temporal and spatial coincidence with dendritic spine plasticity. Using CS56 co-immunoprecipitation of synaptosomal proteins, we identify several molecules involved in Ca2+ signaling, vesicle cycling, and AMPA-receptor exocytosis, thus suggesting a role in long-term potentiation (LTP). Finally, we show that, in the CA1 hippocampal region, the attenuation of CS56 glycoepitopes, through the depletion of versican as one of its main carriers, impairs LTP and object location memory in mice. These findings show that activity-dependent remodeling of the peri-synaptic ECM regulates the induction and consolidation of LTP, contributing to hippocampal-dependent memory.

Dimensional clinical phenotyping using post-mortem brain donor medical records: post-mortem RDoC profiling is associated with Alzheimer's disease neuropathology.

Introduction: Transdiagnostic dimensional phenotypes are essential to investigate the relationship between continuous symptom dimensions and pathological changes. This is a fundamental challenge to post-mortem work, as assessments of phenotypic concepts need to rely on existing records. Methods: We adapted well-validated methodologies to compute National Institute of Mental Health Research Domain Criteria (RDoC) scores using natural language processing (NLP) from electronic health records (EHRs) obtained from post-mortem brain donors and tested whether cognitive domain scores were associated with Alzheimer's disease neuropathological measures. Results: Our results confirm an association of EHR-derived cognitive scores with neuropathological findings. Notably, higher neuropathological load, particularly neuritic plaques, was associated with higher cognitive burden scores in the frontal (ß = 0.38, P = 0.0004), parietal (ß = 0.35, P = 0.0008), temporal (ß = 0.37, P = 0.0004) and occipital (ß = 0.37, P = 0.0003) lobes. Discussion: This proof-of-concept study supports the validity of NLP-based methodologies to obtain quantitative measures of RDoC clinical domains from post-mortem EHR. The associations may accelerate post-mortem brain research beyond classical case-control designs.

Dimensional clinical phenotyping using post-mortem brain donor medical records: Association with neuropathology.

INTRODUCTION: Transdiagnostic dimensional phenotypes are essential to investigate the relationship between continuous symptom dimensions and pathological changes. This is a fundamental challenge to postmortem work, as assessment of newly developed phenotypic concepts needs to rely on existing records. METHODS: We adapted well-validated methodologies to compute NIMH research domain criteria (RDoC) scores using natural language processing (NLP) from electronic health records (EHRs) obtained from post-mortem brain donors and tested whether RDoC cognitive domain scores were associated with hallmark Alzheimer's disease (AD) neuropathological measures. RESULTS: Our results confirm an association of EHR-derived cognitive scores with hallmark neuropathological findings. Notably, higher neuropathological load, particularly neuritic plaques, was associated with higher cognitive burden scores in the frontal (ß=0.38, p=0.0004), parietal (ß=0.35, p=0.0008), temporal (ß=0.37, p=0. 0004) and occipital (ß=0.37, p=0.0003) lobes. DISCUSSION: This proof of concept study supports the validity of NLP-based methodologies to obtain quantitative measures of RDoC clinical domains from postmortem EHR.

Chondroitin Sulphate Proteoglycan Axonal Coats in the Human Mediodorsal Thalamic Nucleus.

Mounting evidence supports a key involvement of the chondroitin sulfate proteoglycans (CSPGs) NG2 and brevican (BCAN) in the regulation of axonal functions, including axon guidance, fasciculation, conductance, and myelination. Prior work suggested the possibility that these functions may, at least in part, be carried out by specialized CSPG structures surrounding axons, termed axonal coats. However, their existence remains controversial. We tested the hypothesis that NG2 and BCAN, known to be associated with oligodendrocyte precursor cells, form axonal coats enveloping myelinated axons in the human brain. In tissue blocks containing the mediodorsal thalamic nucleus (MD) from healthy donors (n = 5), we used dual immunofluorescence, confocal microscopy, and unbiased stereology to characterize BCAN and NG2 immunoreactive (IR) axonal coats and measure the percentage of myelinated axons associated with them. In a subset of donors (n = 3), we used electron microscopy to analyze the spatial relationship between axons and NG2- and BCAN-IR axonal coats within the human MD. Our results show that a substantial percentage (∼64%) of large and medium myelinated axons in the human MD are surrounded by NG2- and BCAN-IR axonal coats. Electron microscopy studies show NG2- and BCAN-IR axonal coats are interleaved with myelin sheets, with larger axons displaying greater association with axonal coats. These findings represent the first characterization of NG2 and BCAN axonal coats in the human brain. The large percentage of axons surrounded by CSPG coats, and the role of CSPGs in axonal guidance, fasciculation, conductance, and myelination suggest that these structures may contribute to several key axonal properties.

Impact of the COVID-19 Pandemic on the Employment and Educational Outcomes of Individuals in a First-Episode Psychosis Clinic.

OBJECTIVE: A central objective of early psychosis therapy is to restore social functioning (e.g., through employment and education). Employment and educational outcomes during the COVID-19 pandemic were examined in a well-defined cohort of patients receiving care in an early psychosis clinic. METHODS: Data were extracted from the electronic health records of 128 patients receiving care at McLean Hospital's first-episode psychosis (FEP) clinic between January 1 and September 21 in 2019 and 2020. Using a generalized linear model with a Gaussian distribution and robust standard errors, the authors compared the average changes in the weekly employment and education proportions before and after COVID-19 lockdowns with the same changes in 2019. RESULTS: Employment losses among patients with FEP were greater than among the general population and persisted through the end of follow-up. In 2020, average employment after a stay-at-home order was instituted was 33% lower than before the order compared with the change in employment during the same period in 2019. The effect was stronger among men and those who identified as non-White, were age <21 years, or did not have a college education. Although educational engagement recovered in the fall of 2020, it still remained below the 2019 levels. CONCLUSIONS: Employment disruptions were major and persistent among the FEP population, which might affect short- and long-term outcomes. Innovative approaches are needed to help patients transition to remote employment, file unemployment claims, and use online hiring platforms to ameliorate the indirect effects of the COVID-19 pandemic.

The tetrapartite synapse: a key concept in the pathophysiology of schizophrenia.

Growing evidence points to synaptic pathology as a core component of the pathophysiology of schizophrenia (SZ). Significant reductions of dendritic spine density and altered expression of their structural and molecular components have been reported in several brain regions, suggesting a deficit of synaptic plasticity. Regulation of synaptic plasticity is a complex process, one that requires not only interactions between pre- and post-synaptic terminals, but also glial cells and the extracellular matrix (ECM). Together, these elements are referred to as the 'tetrapartite synapse', an emerging concept supported by accumulating evidence for a role of glial cells and the extracellular matrix in regulating structural and functional aspects of synaptic plasticity. In particular, chondroitin sulfate proteoglycans (CSPGs), one of the main components of the ECM, have been shown to be synthesized predominantly by glial cells, to form organized perisynaptic aggregates known as perineuronal nets (PNNs), and to modulate synaptic signaling and plasticity during postnatal development and adulthood. Notably, recent findings from our group and others have shown marked CSPG abnormalities in several brain regions of people with SZ. These abnormalities were found to affect specialized ECM structures, including PNNs, as well as glial cells expressing the corresponding CSPGs. The purpose of this review is to bring forth the hypothesis that synaptic pathology in SZ arises from a disruption of the interactions between elements of the tetrapartite synapse.

The orthodontic and surgical management of Zimmerman-Laband syndrome.

Zimmermann-Laband syndrome (ZLS) is a rare autosomal disorder characterized by gingival fibromatosis, abnormalities of the nose and/or ears, hypoplasia of the nails or terminal phalanges of the hands and feet, hyperextensibility of joints, hepatosplenomegaly, hirsutism, and intellectual disability. The characteristics of the syndrome are highly variable and complicated. This paper reports a case of ZLS and the clinical manifestations encountered in relation to the current available literature. The comprehensive management of the patient's dentition is described, focusing on the orthodontic and surgical considerations clinicians should be aware of when treating patients with the syndrome.

Incidental findings arising with cone beam computed tomography imaging of the orthodontic patient.

Cone beam computed tomography (CBCT) of orthodontic patients is a diagnostic tool used increasingly in hospital and primary care settings. It offers a high-diagnostic yield, short scanning times, and a lower radiation dose than conventional computed tomography. This article reports on four incidental findings-that appear unrelated to the scan's original purpose-arising in patients for whom CBCT was carried out for orthodontic purposes. It underlines the need for complete reporting of the data set.

Cone beam computed tomography: a useful tool in orthodontic diagnosis and treatment planning.

The aim of this article is to make clinicians aware of the use of cone beam computed tomography (CBCT) within the field of orthodontics. The paper describes five cases each one illustrating the improved diagnostic yield using CBCT over conventional radiography thus facilitating the appropriate treatment planning of patients.

Orthodontic extrusion: an interdisciplinary approach to patient management.

UNLABELLED: Root fractures that occur at the cervical margin do not always heal predictably, even following a period of splinting. This often leaves margins either sub-gingival or sub-crestal. This provides an unsatisfactory situation for restoring the remaining root as restorations will impinge on the biological width. Provided a root is long enough to support a post crown, then orthodontic extrusion to provide sufficient supra-gingival tooth tissue is a useful treatment option to consider. A review of the literature on orthodontic extrusion is considered in conjunction with a case report of the management of a young male who fractured a canine and lateral incisor whilst playing cricket. CLINICAL RELEVANCE: Trauma to upper anterior teeth is frequently seen in practice. One treatment option in the management of sub-crestal cervical root fractures is orthodontic extrusion, rather than removal of the tooth.

An exploratory study of the cost-effectiveness of orthodontic care in seven European countries.

This study investigated the orthodontic treatment of 429 consecutive patients [172 male (40.1 per cent) and 257 female (59.9 per cent)] carried out by 10 orthodontic specialist practitioners in seven European countries [two in the Czech Republic (A and B), two in Germany (A and B), Italy, Latvia, Lithuania, and Netherlands, and two in Slovenia (A and B)]. The median age of the patients at the start of treatment was 13.0 years (minimum 7.3 years maximum 50.3 years). The patients had a range of malocclusions and the majority (97 per cent) were treated with upper and lower fixed appliances. Real exchange rates were calculated using purchasing power parity (PPP) indicators to allow cross-border comparisons of costs. The Index of Complexity, Outcome and Need (ICON) was used to measure the effectiveness of treatment and cost per ICON point reduction to compare cost-effectiveness of orthodontic treatment between practitioners in different European countries. The median cost per ICON point reduction for all the cases treated was 57.69 euro. The median cost per ICON point reduction varied greatly between practitioners from 21.70 euro (Lithuania) to 116.62 euro (Slovenia A). Analysis of variance and Tukey post hoc tests showed the differences in cost-effectiveness between the practitioners to be statistically significant (P<0.001). The cost per ICON point reduction is a simple and effective method of comparing cost-effectiveness between orthodontic practitioners in different countries.

League tables for orthodontists.

The aim of this study was to explore the complexities in constructing league tables purporting to measure orthodontic clinical outcomes. Eighteen orthodontists were invited to participate in a cost-effectiveness study. Each orthodontist was asked to provide information on 100 consecutively treated patients. The Index of Complexity, Outcome, and Need (ICON) was used to assess treatment need, complexity, and outcome prior to, and on completion of, orthodontic treatment. The 18 orthodontists were ranked based on achieving a successful orthodontic outcome (ICON score less than or equal to 30) and the uncertainty in both the success rates and rankings was also quantified using confidence intervals. Successful outcomes were achieved in 62 per cent of the sample (range 19-94 per cent); four of the 18 orthodontists failed to achieve more than a 50 per cent success rate. In developing league tables, it is imperative that factors such as case mix are identified and accounted for in producing rankings. Bayesian hierarchical modelling was used to achieve this and to quantify uncertainty in the rankings produced. When case mix was taken into account, the four with low success rates were clearly not as good as the top four performing orthodontists. League tables can be valuable for the individual orthodontist, groups of orthodontists, payment/insurance agencies, and the public to enable informed choice for orthodontic provision but must be correctly constructed so that users can have confidence in them.

Measuring the cost, effectiveness, and cost-effectiveness of orthodontic care.

AIM: To determine the relative effectiveness and cost-effectiveness of orthodontic treatment per case in one "fee for item" and two different types of salaried orthodontic clinics. SUBJECTS AND METHODS: This prospective study recruited a random sample of six self-employed orthodontists (fee-for-item) and six orthodontists from both hospital and community clinics (salaried services). One hundred patients were followed to completion of orthodontic care. Questionnaires were employed to determine cost of treatment from the clinicians' and patients' points of views. Four cost-effectiveness models were developed. RESULTS: Complete records of outcome were available for 1,087 patients, but only 789 had complete data on costing. Three of the four cost-effectiveness models indicated similar rankings for the 18 clinicians. The most cost-effective service was provided by clinicians working in community clinics, followed by clinicians working in hospitals, then self-employed clinicians. The preferred cost-effective model takes into consideration the initial need and successful outcome of orthodontic treatment. CONCLUSION: Cost-effectiveness models have been developed to quantify the performance of individual clinicians working in self-employed and salaried clinics. Costs and effectiveness of the clinicians in each clinical setting show considerable variation.