Global uncertainty in the diagnosis of neurological complications of SARS-CoV-2 infection by both neurologists and non-neurologists: An international inter-observer variability study.

INTRODUCTION: Uniform case definitions are required to ensure harmonised reporting of neurological syndromes associated with SARS-CoV-2. Moreover, it is unclear how clinicians perceive the relative importance of SARS-CoV-2 in neurological syndromes, which risks under- or over-reporting. METHODS: We invited clinicians through global networks, including the World Federation of Neurology, to assess ten anonymised vignettes of SARS-CoV-2 neurological syndromes. Using standardised case definitions, clinicians assigned a diagnosis and ranked association with SARS-CoV-2. We compared diagnostic accuracy and assigned association ranks between different settings and specialties and calculated inter-rater agreement for case definitions as "poor" (κ ≤ 0.4), "moderate" or "good" (κ > 0.6). RESULTS: 1265 diagnoses were assigned by 146 participants from 45 countries on six continents. The highest correct proportion were cerebral venous sinus thrombosis (CVST, 95.8%), Guillain-Barré syndrome (GBS, 92.4%) and headache (91.6%) and the lowest encephalitis (72.8%), psychosis (53.8%) and encephalopathy (43.2%). Diagnostic accuracy was similar between neurologists and non-neurologists (median score 8 vs. 7/10, p = 0.1). Good inter-rater agreement was observed for five diagnoses: cranial neuropathy, headache, myelitis, CVST, and GBS and poor agreement for encephalopathy. In 13% of vignettes, clinicians incorrectly assigned lowest association ranks, regardless of setting and specialty. CONCLUSION: The case definitions can help with reporting of neurological complications of SARS-CoV-2, also in settings with few neurologists. However, encephalopathy, encephalitis, and psychosis were often misdiagnosed, and clinicians underestimated the association with SARS-CoV-2. Future work should refine the case definitions and provide training if global reporting of neurological syndromes associated with SARS-CoV-2 is to be robust.

Evaluation of digital construction, production and intraoral position accuracy of novel 3D CAD/CAM titanium retainers.

OBJECTIVES: New opportunities have arisen to manufacture three-dimensional computer-aided design/computer-aided manufacturing (3D CAD/CAM) retainers from titanium blocks by digital cutting technology. These novel technologies need to fulfill requirements regarding digital planning and position accuracy. The aim of the present study was to investigate the digital construction, the CAD/CAM production and the intraoral positioning accuracy of custom-manufactured novel 3D CAD/CAM titanium retainers. MATERIALS AND METHODS: A total of 37 prime4me® RETAIN3R (Dentaurum, Ispringen, Germany) retainers were inserted to stabilize the upper anterior front teeth. Following insertion, an intraoral scan was used to record the position. The intraoral position was compared to the virtual setup using 3D superimposition software. Measurement points were evaluated in all three dimensions (horizontal, sagittal and vertical planes). Data were analyzed using Kruskal-Wallis test followed by Dunn's multiple comparison test. RESULTS: A total of 185 measurements were performed. The horizontal plane and the sagittal plane demonstrated a high level of positioning accuracy between the planned and the intraoral position. Statistically significant deviations between the preceding virtual setup and the intraoral situation were observed in the vertical dimension. Within the retainer, the intraoral positioning accuracy decreased for the measurement points in the direction of the distal retainer segment. CONCLUSION: Based on the results, the present study shows a high level of congruence between the 3D virtually planning and the final intraoral position of the fabricated novel 3D CAD/CAM titanium retainers.

Depression, anxiety and PTSD symptoms before and during the COVID-19 pandemic in the UK.

BACKGROUND: The impact of the coronavirus disease 2019 (COVID-19) pandemic on mental health is still being unravelled. It is important to identify which individuals are at greatest risk of worsening symptoms. This study aimed to examine changes in depression, anxiety and post-traumatic stress disorder (PTSD) symptoms using prospective and retrospective symptom change assessments, and to find and examine the effect of key risk factors. METHOD: Online questionnaires were administered to 34 465 individuals (aged 16 years or above) in April/May 2020 in the UK, recruited from existing cohorts or via social media. Around one-third (n = 12 718) of included participants had prior diagnoses of depression or anxiety and had completed pre-pandemic mental health assessments (between September 2018 and February 2020), allowing prospective investigation of symptom change. RESULTS: Prospective symptom analyses showed small decreases in depression (PHQ-9: -0.43 points) and anxiety [generalised anxiety disorder scale - 7 items (GAD)-7: -0.33 points] and increases in PTSD (PCL-6: 0.22 points). Conversely, retrospective symptom analyses demonstrated significant large increases (PHQ-9: 2.40; GAD-7 = 1.97), with 55% reported worsening mental health since the beginning of the pandemic on a global change rating. Across both prospective and retrospective measures of symptom change, worsening depression, anxiety and PTSD symptoms were associated with prior mental health diagnoses, female gender, young age and unemployed/student status. CONCLUSIONS: We highlight the effect of prior mental health diagnoses on worsening mental health during the pandemic and confirm previously reported sociodemographic risk factors. Discrepancies between prospective and retrospective measures of changes in mental health may be related to recall bias-related underestimation of prior symptom severity.

Cognitive impact of neuronal antibodies: encephalitis and beyond.

Cognitive dysfunction is a common feature of autoimmune encephalitis. Pathogenic neuronal surface antibodies are thought to mediate distinct profiles of cognitive impairment in both the acute and chronic phases of encephalitis. In this review, we describe the cognitive impairment associated with each antibody-mediated syndrome and, using evidence from imaging and animal studies, examine how the nature of the impairment relates to the underlying neuroimmunological and receptor-based mechanisms. Neuronal surface antibodies, particularly serum NMDA receptor antibodies, are also found outside of encephalitis although the clinical significance of this has yet to be fully determined. We discuss evidence highlighting their prevalence, and association with cognitive outcomes, in a number of common disorders including cancer and schizophrenia. We consider mechanisms, including blood-brain barrier dysfunction, which could determine the impact of these antibodies outside encephalitis and account for much of the clinical heterogeneity observed.

Autoantibodies to central nervous system neuronal surface antigens: psychiatric symptoms and psychopharmacological implications.

RATIONALE: Autoantibodies to central nervous system (CNS) neuronal surface antigens have been described in association with autoimmune encephalopathies which prominently feature psychiatric symptoms in addition to neurological symptoms. The potential role of these autoantibodies in primary psychiatric diseases such as schizophrenia or bipolar affective disorder is of increasing interest. OBJECTIVES: We aimed to review the nature of psychiatric symptoms associated with neuronal surface autoantibodies, in the context of autoimmune encephalopathies as well as primary psychiatric disorders, and to review the mechanisms of action of these autoantibodies from a psychopharmacological perspective. RESULTS: The functional effects of the autoantibodies on their target antigens are described; their clinical expression is at least in part mediated by their effects on neuronal receptor function, primarily at the synapse, usually resulting in receptor hypofunction. The psychiatric effects of the antibodies are related to known functions of the receptor target or its complexed proteins, with reference to supportive genetic and pharmacological evidence where relevant. Evidence for a causal role of these autoantibodies in primary psychiatric disease is increasing but remains controversial; relevant methodological controversies are outlined. Non-receptor-based mechanisms of autoantibody action, including neuroinflammatory mechanisms, and therapeutic implications are discussed. CONCLUSIONS: An analysis of the autoantibodies from a psychopharmacological perspective, as endogenous, bioactive, highly specific, receptor-targeting molecules, provides a valuable opportunity to understand the neurobiological basis of associated psychiatric symptoms. Potentially, new treatment strategies will emerge from the improving understanding of antibody-antigen interaction within the CNS.

Phenomenologically distinct psychotomimetic effects of ketamine are associated with cerebral blood flow changes in functionally relevant cerebral foci: a continuous arterial spin labelling study.

RATIONALE: The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine provides a pragmatic approach to address the link between glutamate-mediated changes in brain function and psychosis-like experiences. Most studies using PET or BOLD fMRI have assessed these symptoms broadly, which may limit inference about specific mechanisms. OBJECTIVES: The objective of this study is to identify the cerebral blood flow (CBF) correlates of ketamine-induced psychopathology, focusing on individual psychotomimetic symptom dimensions, which may have separable neurobiological substrates. METHODS: We measured validated psychotomimetic symptom factors following intravenous ketamine administration in 23 healthy male volunteers (10 given a lower dose and 13 a higher dose) and correlated ketamine-induced changes in symptoms with regional changes in CBF, measured non-invasively using arterial spin labelling (ASL). RESULTS: The main effect of ketamine paralleled previous studies, with increases in CBF in anterior and subgenual cingulate cortex and decreases in superior and medial temporal cortex. Subjective effects were greater in the high-dose group. For this group, ketamine-induced anhedonia inversely related to orbitofrontal cortex CBF changes and cognitive disorganisation was positively correlated with CBF changes in posterior thalamus and the left inferior and middle temporal gyrus. Perceptual distortion was correlated with different regional CBF changes in the low- and high-dose groups. CONCLUSIONS: Here, we provide evidence for the sensitivity of ASL to the effects of ketamine and the strength of subjective experience, suggesting plausible neural mechanisms for ketamine-induced anhedonia and cognitive disorganisation.

Epilepsy-related psychosis: a role for autoimmunity?

Postictal psychosis (PIP) is a serious psychiatric complication of epilepsy that occurs in approximately 6% of patients following multiple complex partial or generalized seizures. The psychosis is classically described as having a pleomorphic phenomenology, including paranoid, grandiose, and religious delusions as well as multimodal hallucinations with prominent affective changes and agitation. Little is understood about the pathophysiology of the condition. There has been a recent increase in interest in the relevance of autoimmunity to the pathogenesis of both epilepsy and psychosis. Studies have demonstrated the presence of antibodies directed against synaptic autoantigens (such as the N-methyl-d-aspartate receptor or the voltage-gated potassium channel complex) in approximately 10% of cases of sporadic epilepsy. These same autoantibodies are known to cause encephalopathy syndromes which feature psychiatric symptoms, usually psychosis, as a prominent part of the phenotype as well as other neurological features such as seizures, movement disorders, and autonomic dysfunction. It is beginning to be asked if these antibodies can be associated with a purely psychiatric phenotype. Here, we hypothesize that PIP may be an autoimmune phenomenon mediated by autoantibodies against synaptic antigens. More specifically, we outline a potential mechanism whereby long or repeated seizures cause short-lived blood-brain barrier (BBB) dysfunction during which the brain becomes exposed to pathogenic autoantibodies. In essence, we propose that PIP is a time-limited, seizure-dependent, autoantibody-mediated encephalopathy syndrome. We highlight a number of features of PIP that may be explained by this mechanism, such as the lucid interval between seizures and onset of psychosis and the progression in some cases to a chronic, interictal psychosis.

Prevalence of anti-N-methyl-D-aspartate (NMDA) receptor [corrected] antibodies in patients with schizophrenia and related psychoses: a systematic review and meta-analysis.

BACKGROUND: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an autoimmune condition caused by immunoglobulin (Ig)G antibodies directed against the NR1 subunit of the NMDA glutamate receptor. Approximately 65% of cases present with psychiatric symptoms, particularly psychosis. It remains to be established whether anti-NMDA receptor antibodies can cause a 'purely' psychotic illness without overt neurological symptoms. METHOD: We conducted a systematic literature search to establish what proportion of patients with schizophrenia and related psychoses have antibodies directed against the NMDA receptor. Studies were included if (a) subjects had a diagnosis of schizophrenia, schizophrenia spectrum disorder or first-episode psychosis (FEP) using standard criteria, (b) serum was analysed for the presence of anti-NMDA receptor antibodies; and (c) the purpose of the study was to look for the presence of anti-NMDA receptor antibodies in patients with a primary psychiatric diagnosis without clinical signs of encephalitis. RESULTS: Seven studies were included, comprising 1441 patients, of whom 115 [7.98%, 95% confidence interval (CI) 6.69-9.50] were anti-NMDA receptor antibody positive. Of these, 21 (1.46%, 95% CI 0.94-2.23) patients were positive for antibodies of the IgG subclass. Prevalence rates were greater in cases than controls only for IgG antibodies; other subclasses are of less certain aetiological relevance. There was significant heterogeneity in terms of patient characteristics and the antibody assay used. CONCLUSIONS: A minority of patients with psychosis are anti-NMDA receptor antibody positive. It remains to be established whether this subset of patients differs from antibody-negative patients in terms of underlying pathology and response to antipsychotic treatment, and whether immunomodulatory treatments are effective in alleviating psychotic symptoms in this group.

Adult hydrocoele complicating a lumboperitoneal shunt.

We report an adult patient who developed a right-sided hydrocoele following a lumboperitoneal shunt. While hydrocoeles have been described as a rare complication following ventriculo- and lumboperitoneal shunts in children, we are unaware of any previously reported cases of hydrocoeles resulting from such shunts in adults.

Critical assessment of diffusion coefficients in semidilute to concentrated solutions of polystyrene in toluene.

We have measured collective diffusion coefficients of dilute, semidilute, and concentrated solutions of polystyrene in toluene up to a polymer concentration of 0.832 mass fractions at T=25 degrees C. The three employed experimental techniques of photon correlation spectroscopy, thermal diffusion forced Rayleigh scattering, and optical beam deflection cover four orders of magnitude with respect to their characteristic diffusion lengths (200 nm-2.9 mm), corresponding to more than 8 decades of the diffusion time constants. Contrary to existing literature data, which suggest a length scale dependent anomalous diffusion at high concentrations, all our techniques yield identical diffusion coefficients and purely Fickian diffusion, irrespective of their characteristic length scale.

Transient-state method for coupled evaluation of Soret and Fick coefficients, and related tortuosity factors, using free and porous packed thermodiffusion cells: application to CuSO4 aqueous solution ( 0.25M).

The measurement of Soret coefficients in liquids is not easy and usually not very precise because the resulting concentration gradient is small and moreover can be perturbed by undesired convection currents. In order to suppress, or to drastically reduce these convection currents, the use of a porous medium is sometimes suggested. The question arises as to whether the Soret coefficient is the same in free fluid and in porous medium. This is the aim of this paper. To this end, for a given liquid mixture, the time evolution of the vertical concentration gradient is experimentally measured in the same thermodiffusion cell filled first with the free liquid and next with a porous medium followed by saturation by the liquid mixture. Both the isothermal diffusion (Fick) coefficient and the Soret coefficient can be deduced, providing that a correct working equation is used. The proposed equation results from integration of the general mass conservation equation with realistic boundary conditions (zero mass flux at the boundaries) and some simplifying assumptions rendering this equation more tractable than the one proposed some decades ago by Bierlein (J.A. Bierlein, J. Chem. Phys. 23, 10 (1955)). The method is applied here to an electrolytic solution (CuSO4, 0.25 M) at a mean temperature of 37 degrees C. The Soret coefficients in free and porous medium (zircon microspheres in the range of 250-315 x 10(-6) m) may be considered to be equal ( S(T) = 13.2+/-0.5 x 10(-3) K(-1)) and the tortuosity factors for the packed medium are the same relative to thermodiffusion and Fick coefficients (tau = 1.51+/-0.02).

Chlamydomonas U2, U4 and U6 snRNAs. An evolutionary conserved putative third interaction between U4 and U6 snRNAs which has a counterpart in the U4atac-U6atac snRNA duplex.

The spliceosomal UsnRNAs U2, U4 and U6 from the green alga Chlamydomonas reinhardtii (Cre) were sequenced using a combination of RNA and cDNA sequencing methods and were compared to other sequenced UsnRNAs. The lengths of Cre U6 and Cre U2 RNAs are similar to those of their higher plant equivalents. Cre U4 RNA is shorter (139 nt) than its counterpart from higher plants (150-154 nt), and contains stem IV and loop D which are absent, with the exception of the Tetrahymena U4 RNA, from the U4 RNAs of other unicellular organisms studied to date. Base-pairing interactions between U6 and U4 RNAs and between U6 and U2 RNAs, identical to those described for mammalian and yeast systems, are structurally feasible in the Cre system. In addition, based on comparative analyses of the predicted U4/U6 RNA duplex from various species, an evolutionary conserved third putative U6-U4 interaction was found. Interestingly, it can also be formed with the recently discovered U6atac and U4atac RNAs. This is a strong support in favor of the possible biological significance of this third putative interaction. Based on comparative analysis, an extension of the earlier described U6-U2 interaction patterns is also proposed.

Development of a two-site solid-phase immunochemiluminescent assay for measurement of dimeric inhibin-A in human serum and other biological fluids.

Inhibin is a heterodimeric glycoprotein that inhibits the secretion of follitropin from the pituitary and has been isolated in two distinct forms composed of a common alpha subunit and either a beta A or beta B subunit. Utilizing paired monoclonal antibodies specific to the alpha and beta A subunit, we have developed an immunochemiluminescent assay for dimeric inhibin-A. The assay is capable of quantifying free and bound inhibin-A in human serum and follicular fluid. The limit of detection is 10 ng/L. Related proteins exhibit little cross-reactivity or interference. Recovery is excellent. Whereas samples from men and postmenopausal women are near the detection limit of the assay, inhibin-A is higher in the luteal than the follicular phase of normally cycling women, 20-fold higher during in vitro fertilization treatment, and approximately 200-fold greater in pregnancy. The assay measures inhibin-A in follicular fluid from a variety of other species.

Growth and the microstructural and ferroelectric characterization of oriented BaMgF(4) thin films.

The growth of ferroelectric BaMgF(4) thin films on Si(100), sapphire, and other substrates under ultrahigh vacuum (UHV) conditions is reported. Microstructural characterization of the films using transmission electron microscopy (TEM) revealed that they were oriented crystalline films, although not epitaxial. Ferroelectric hysteresis measurements yielded spontaneous polarization and coercivity values of almost 1.0 muC/cm(2) and 160 kV/cm, respectively. The discrepancy with the bulk ferroelectric values were attributed to the electrical contacts, impurities in the film, and lack of polar axis orientation. Preliminary capacitance-voltage (C-V) hysteresis measurements on a 480-nm-thick BaMgF(4) film yielded a 10.8-V threshold shift (memory window) in response to a +/-10-V programming voltage for a MIS gate structure similar to that of the ferroelectric memory field-effect transistor (FEMFET).