Search

AIM Successful delivery of care to individuals with early psychosis depends on the ability of community providers to identify and refer appropriate candidates for services. Although specialty centres commonly rely upon education and outreach campaigns to building bridges with community providers, few studies have examined the effectiveness of these campaigns or the mechanisms by which they may achieve their intended effects. METHODS We surveyed community clinicians (N = 39) about their screening behaviours, referral practices, and confidence in managing early psychosis just before and 3-6 months after attending an educational event designed to promote recognition and quality treatment of early psychosis. RESULTS Three to six months following attendance, providers reported screening a greater proportion of clients for early psychosis, referring a greater number of clients to specialty services, and feeling more confident in their ability to respond to clients with early psychosis. Increases in confidence following attendance were associated with corresponding increases in screening behaviour. CONCLUSIONS The results suggest that outreach campaigns designed to enhance community providers' knowledge about early psychosis assessment and resources may be effective in promoting screening, referrals, and confidence in managing psychosis. Gains in provider confidence may contribute to increases in screening. Given the lack of control group and relatively short follow-up period, more research is needed to determine the effects of early psychosis educational events and the mechanisms by which they may promote successful treatment delivery for young people in need.

Schizophrenia is a complex and heterogeneous syndrome. Whether quantitative imaging biomarkers can identify discrete subgroups of patients as might be used to foster personalized medicine approaches for patient care remains unclear. Cross-sectional structural MR images of 163 never-treated first-episode schizophrenia patients (FES) and 133 chronically ill patients with midcourse schizophrenia from the Bipolar and Schizophrenia Network for Intermediate Phenotypes (B-SNIP) consortium and a total of 403 healthy controls were recruited. Morphometric measures (cortical thickness, surface area, and subcortical structures) were extracted for each subject and then the optimized subtyping results were obtained with nonsupervised cluster analysis. Three subgroups of patients defined by distinct patterns of regional cortical and subcortical morphometric features were identified in FES. A similar three subgroup pattern was identified in the independent dataset of patients from the multi-site B-SNIP consortium. Similarities of classification patterns across these two patient cohorts suggest that the 3-group typology is relatively stable over the course of illness. Cognitive functions were worse in subgroup 1 with midcourse schizophrenia than those in subgroup 3. These findings provide novel insight into distinct subgroups of patients with schizophrenia based on structural brain features. Findings of different cognitive functions among the subgroups support clinical differences in the MRI-defined illness subtypes. Regardless of clinical presentation and stage of illness, anatomic MR subgrouping biomarkers can separate neurobiologically distinct subgroups of schizophrenia patients, which represent an important and meaningful step forward in differentiating subtypes of patients for studies of illness neurobiology and potentially for clinical trials.

Aim Increasing evidence points to the value of coordinated specialty care (CSC) for early intervention in psychotic disorders. This report characterizes clinical and socio-demographic features of patients at CSC programs in Massachusetts (MA), assessed by a standardized battery incorporated into "real-world" clinical care. Methods The MA psychosis network for early treatment developed a pilot battery to coordinate assessments across six CSC clinics. Programs reported baseline, 6-month, and 12-month data from a sample of 287 patients with intake dates ranging from April 2015 to December 2020. Results Patients showed improvements in functioning, emergency service use and several symptom domains at 6 and 12 months. Missing data proved to be a limitation. Conclusions Patients improved on several meaningful domains within the first year of CSC treatment. Future implementation efforts in cross-program data collection should consider strategies to circumvent limitations related to heterogeneity between clinics, patient discharge and clinics' capacity for data collection.

Current clinical phenomenological diagnosis in psychiatry neither captures biologically homologous disease entities nor allows for individualized treatment prescriptions based on neurobiology. In this report, we studied two large samples of cases with schizophrenia, schizoaffective, and bipolar I disorder with psychosis, presentations with clinical features of hallucinations, delusions, thought disorder, affective, or negative symptoms. A biomarker approach to subtyping psychosis cases (called psychosis Biotypes) captured neurobiological homology that was missed by conventional clinical diagnoses. Two samples (called “B-SNIP1” with 711 psychosis and 274 healthy persons, and the “replication sample” with 717 psychosis and 198 healthy persons) showed that 44 individual biomarkers, drawn from general cognition (BACS), motor inhibitory (stop signal), saccadic system (pro- and anti-saccades), and auditory EEG/ERP (paired-stimuli and oddball) tasks of psychosis-relevant brain functions were replicable (r’s from .96–.99) and temporally stable (r’s from .76–.95). Using numerical taxonomy (k-means clustering) with nine groups of integrated biomarker characteristics (called bio-factors) yielded three Biotypes that were virtually identical between the two samples and showed highly similar case assignments to subgroups based on cross-validations (88.5%–89%). Biotypes-1 and -2 shared poor cognition. Biotype-1 was further characterized by low neural response magnitudes, while Biotype-2 was further characterized by overactive neural responses and poor sensory motor inhibition. Biotype-3 was nearly normal on all bio-factors. Construct validation of Biotype EEG/ERP neurophysiology using measures of intrinsic neural activity and auditory steady state stimulation highlighted the robustness of these outcomes. Psychosis Biotypes may yield meaningful neurobiological targets for treatments and etiological investigations.

Tuberculosis (TB) may affect the nervous system in many ways. We describe an immunocompetent teenage girl with lymph node TB who had first presented with bilateral optic neuritis. Detailed history identified features inconsistent with immune-mediated optic neuritis. Several unusual features prompted further investigation, including transient visual obscurations without raised intracranial pressure, prominent disc swelling and absence of laboratory findings to support an immune-mediated cause. Whole body PET/MR imaging identified widespread mediastinal and supraclavicular lymphadenopathy. Despite no known TB contacts, a negative interferon gamma release assay and a normal chest X-ray, a targeted lymph node biopsy confirmed TB.

Alzheimer’s disease (AD) is increasingly prevalent worldwide, and disease‐modifying treatments may soon be at hand; hence, now, more than ever, there is a need to develop techniques that allow earlier and more secure diagnosis. Current biomarker‐based guidelines for AD diagnosis, which have replaced the historical symptom‐based guidelines, rely heavily on neuroimaging and cerebrospinal fluid (CSF) sampling. While these have greatly improved the diagnostic accuracy of AD pathophysiology, they are less practical for application in primary care, population‐based and epidemiological settings, or where resources are limited. In contrast, blood is a more accessible and cost‐effective source of biomarkers in AD. In this review paper, using the recently proposed amyloid, tau and neurodegeneration [AT(N)] criteria as a framework towards a biological definition of AD, we discuss recent advances in biofluid‐based biomarkers, with a particular emphasis on those with potential to be translated into blood‐based biomarkers. We provide an overview of the research conducted both in CSF and in blood to draw conclusions on biomarkers that show promise. Given the evidence collated in this review, plasma neurofilament light chain (N) and phosphorylated tau (p‐tau; T) show particular potential for translation into clinical practice. However, p‐tau requires more comparisons to be conducted between its various epitopes before conclusions can be made as to which one most robustly differentiates AD from non‐AD dementias. Plasma amyloid beta (A) would prove invaluable as an early screening modality, but it requires very precise tests and robust pre‐analytical protocols.

Diffusion-weighted magnetic resonance imaging (dMRI) is the primary method for noninvasively studying the organization of white matter in the human brain. Here we introduce QSIPrep, an integrative software platform for the processing of diffusion images that is compatible with nearly all dMRI sampling schemes. Drawing on a diverse set of software suites to capitalize on their complementary strengths, QSIPrep facilitates the implementation of best practices for processing of diffusion images. QSIPrep is a software platform for processing of most diffusion MRI datasets and ensures that adequate workflows are used.

ObjectiveTo investigate subjective cognitive decline (SCD) in relation to β-amyloid pathology and to test for associations with anxiety, depression, objective cognition and family history of dementia in the Insight 46 study.MethodsCognitively unimpaired ~70-year-old participants, all born in the same week in 1946 (n=460, 49% female, 18% amyloid-positive), underwent assessments including the SCD-Questionnaire (MyCog). MyCog scores were evaluated with respect to18F-Florbetapir-PET amyloid status (positive/negative). Associations with anxiety, depression, objective cognition (measured by the Preclinical Alzheimer Cognitive Composite, PACC) and family history of dementia were also investigated. The informant’s perspective on SCD was evaluated in relation to MyCog score.ResultsAnxiety (mean (SD) trait anxiety score: 4.4 (3.9)) was associated with higher MyCog scores, especially in women. MyCog scores were higher in amyloid-positive compared with amyloid-negative individuals (adjusted means (95% CIs): 5.3 (4.4 to 6.1) vs 4.3 (3.9 to 4.7), p=0.044), after accounting for differences in anxiety. PACC (mean (SD) −0.05 (0.68)) and family history of dementia (prevalence: 23.9%) were not independently associated with MyCog scores. The informant’s perception of SCD was generally in accordance with that of the participant.ConclusionsThis cross-sectional study demonstrates that symptoms of SCD are associated with both β-amyloid pathology, and more consistently, trait anxiety in a population-based cohort of older adults, at an age when those who are destined to develop dementia are still likely to be some years away from symptoms. This highlights the necessity of considering anxiety symptoms when assessing Alzheimer’s disease pathology and SCD.

Accumulated studies have investigated pharmacological interventions for first-episode schizophrenia (FES) patients. However, studies on subsequent treatment steps, which are essential to guide clinicians, are largely missing. This Sequential Multiple-Assignment Randomized Trials comparing Antipsychotic Treatments (SMART-CAT) program intends to evaluate the effectiveness of commonly used antipsychotic drugs in FES patients. The major goals of this study are to examine: 1) what would be the optimal subsequent sequential treatment if the first antipsychotic drug failed; 2) whether clozapine could be used in those first-trial failed and have superior efficacy compared to other atypical antipsychotics. In this article we will report the detail protocol of SMART-CAT. The SMART-CAT is a randomized controlled clinical multicenter trial in which 9 institutions in China will participate. A total of 720 FES patients will be enrolled and followed up for 12 months in this study. The trial includes three treatment phases (each phase lasting for 8 weeks) and a naturalistic follow-up phase; participants who do well on an assigned treatment will remain on that treatment for the duration of the 12-month treatment period, while non-responders will move to the next phase of the study to receive a new treatment. Phase 1 is a randomized controlled trial; patients will be randomly assigned to one of the treatments with oral olanzapine, risperidone, amisulpride, aripiprazole or perphenazine. Subjects who fail to respond after 8 weeks will enter the phase 2 randomization. Phase 2 is an equipoise-stratified randomization trial, and patients will be randomly assigned to oral olanzapine, amisulpride or clozapine for 8 weeks. Subjects who fail to respond after phase 2 will enter an open label trial (phase 3); patients who receive clozapine in phase 2 and fail to respond will be assigned to an extended clozapine treatment or modified electroconvulsive therapy add-on therapy (Phase 3A). Patients who were not assigned to clozapine in phase 2 will be assigned to treatment with clozapine or another SGAs not previously used in phase 1 and 2 (Phase 3B). The primary outcome for the treatment phase is the treatment efficacy rate, which is defined as at least 40% reduction in Positive and Negative Syndrome Scale (PANSS) total score. We hypothesize that clozapine is more therapeutically effective than any other SGAs to patients who failed to meet efficacy criteria in Phase 1, and earlier treatment with clozapine can improve the functional outcomes of schizophrenia patients. As for the naturalistic follow-up phase, time to all-cause treatment failure, marked by its discontinuation is selected as the primary outcome, since it reflects both efficacy and side effects. The all-cause discontinuation is defined as discontinuing for any reasons, including poor efficacy, intolerance of adverse reactions, poor compliance and other reasons. The results of the SMART-CAT trial will provide evidence for the selection of antipsychotics in FES patients who fail to respond to the first trial of an antipsychotic drug. It will also provide evidence for the efficacy and safety of using clozapine in the early phase of schizophrenia treatment by comparing with other SGAs. The study is based on the combination of sequential therapy and dynamic therapy, which can be more suitable to assess the effectiveness of treatment options in the real-world clinical setting. As a result, we hope that this study can provide guidance for an optimal treatment algorithm in first-episode schizophrenia patients. Trial registration: ID NCT03510325 in ClinicalTrials.gov

Objective To assess associations between head injury (HI) with loss of consciousness (LOC), ageing and markers of later‐life cerebral pathology; and to explore whether those effects may help explain subtle cognitive deficits in dementia‐free individuals. Methods Participants (n = 502, age = 69–71) from the 1946 British Birth Cohort underwent cognitive testing (subtests of Preclinical Alzheimer Cognitive Composite), 18F‐florbetapir Aβ‐PET and MR imaging. Measures include Aβ‐PET status, brain, hippocampal and white matter hyperintensity (WMH) volumes, normal appearing white matter (NAWM) microstructure, Alzheimer’s disease (AD)‐related cortical thickness, and serum neurofilament light chain (NFL). LOC HI metrics include HI occurring: (i) >15 years prior to the scan (ii) anytime up to age 71. Results Compared to those with no evidence of an LOC HI, only those reporting an LOC HI>15 years prior (16%, n = 80) performed worse on cognitive tests at age 69–71, taking into account premorbid cognition, particularly on the digit‐symbol substitution test (DSST). Smaller brain volume (BV) and adverse NAWM microstructural integrity explained 30% and 16% of the relationship between HI and DSST, respectively. We found no evidence that LOC HI was associated with Aβ load, hippocampal volume, WMH volume, AD‐related cortical thickness or NFL (all p > 0.01). Interpretation Having a LOC HI aged 50’s and younger was linked with lower later‐life cognitive function at age ~70 than expected. This may reflect a damaging but small impact of HI; explained in part by smaller BV and different microstructure pathways but not via pathology related to AD (amyloid, hippocampal volume, AD cortical thickness) or ongoing neurodegeneration (serum NFL).

Background While an established clinical outcome of high importance, social functioning has been emerging as possibly having a broader significance to the evolution of psychosis and long term disability. In the current study we explored the association between social decline, conversion to psychosis, and functional outcome in individuals at clinical high risk (CHR) for psychosis. Methods 585 subjects collected in the North American Prodrome Longitudinal Study (NAPLS2) were divided into 236 Healthy Controls (HCs), and CHR subjects that developed psychosis (CHR + C, N = 79), or those that did not (Non-Converters, CHR-NC, N = 270). CHR + C subjects were further divided into those that experienced an atypical decline in social functioning prior to baseline (beyond typical impairment levels) when in min-to-late adolescence (CHR + C-SD, N = 39) or those that did not undergoing a decline (CHR + C-NSD, N = 40). Results Patterns of poor functional outcomes varied across the CHR subgroups: CHR-NC (Poor Social 36.3%, Role 42.2%) through CHR + C-NSD (Poor Social 50%, Poor Role 67.5%) to CHR + C-SD (Poor Social 76.9%, Poor Role 89.7%) functioning. The two Converter subgroups had comparable positive symptoms at baseline. At 12 months, the CHR + C-SD group stabilized, but social functioning levels remained significantly lower than the other two subgroups. Conclusions The current study demonstrates that pre-baseline social decline in mid-to-late adolescence predicts psychosis. In addition, we found that this social decline in converters is strongly associated with especially poor functional outcome and overall poorer prognosis. Role functioning, in contrast, has not shown similar predictor potential, and rather appears to be an illness indicator that worsens over time.

The integration of technology in clinical care is growing rapidly and has become especially relevant during the global COVID-19 pandemic. Smartphone-based digital phenotyping, or the use of integrated sensors to identify patterns in behavior and symptomatology, has shown potential in detecting subtle moment-to-moment changes. These changes, often referred to as anomalies, represent significant deviations from an individual’s baseline, may be useful in informing the risk of relapse in serious mental illness. Our investigation of smartphone-based anomaly detection resulted in 89% sensitivity and 75% specificity for predicting relapse in schizophrenia. These results demonstrate the potential of longitudinal collection of real-time behavior and symptomatology via smartphones and the clinical utility of individualized analysis. Future studies are necessary to explore how specificity can be improved, just-in-time adaptive interventions utilized, and clinical integration achieved.

Objective The cerebellum serves a wide range of functions and is suggested to be composed of discrete regions dedicated to unique functions. We recently developed a new parcellation of the dentate nuclei (DN), the major output nuclei of the cerebellum, which optimally divides the structure into 3 functional territories that contribute uniquely to default-mode, motor-salience, and visual processing networks as indexed by resting-state functional connectivity (RsFc). Here we test for the first time whether RsFc differences in the DN, precede the onset of psychosis in individuals at risk of developing schizophrenia. Methods We used the magnetic resonance imaging (MRI) dataset from the Shanghai At Risk for Psychosis study that included subjects at high risk to develop schizophrenia (N = 144), with longitudinal follow-up to determine which subjects developed a psychotic episode within 1 year of their functional magnetic resonance imaging (fMRI) scan (converters N = 23). Analysis used the 3 functional parcels (default-mode, salience-motor, and visual territory) from the DN as seed regions of interest for whole-brain RsFc analysis. Results RsFc analysis revealed abnormalities at baseline in high-risk individuals who developed psychosis, compared to high-risk individuals who did not develop psychosis. The nature of the observed abnormalities was found to be anatomically specific such that abnormal RsFc was localized predominantly in cerebral cortical networks that matched the 3 functional territories of the DN that were evaluated. Conclusions We show for the first time that abnormal RsFc of the DN may precede the onset of psychosis. This new evidence highlights the role of the cerebellum as a potential target for psychosis prediction and prevention.

Prevailing models of psychosis risk incorporate positive subthreshold symptoms as defining features of risk or transition to psychotic disorders. Despite this, relatively few studies have focused on characterizing longitudinal symptom features, such as prevalence, concordance and structure, which may aid in refining methods and enhancing classification and prediction efforts. The present study aimed to fill these gaps using longitudinal 24-month follow-up data from the well-characterized NAPLS-2 multi-site investigation of youth at clinical high risk (CHR) who had (n = 86) and had not (n = 268) transitioned to a threshold psychotic disorder since baseline. At baseline, among sub-delusional ideas, unusual thought content and suspicious/persecutory thinking were very common in CHR youth, and were highly concordant. Perceptual abnormalities (P4) were also common across youth regardless of symptom course and eventual transition to psychosis. Grandiose ideas were rare. Exploratory factor analysis extracted two constituent factors at multiple follow-up intervals, but there was marked instability in the structure over 24 months, and clear indicators for a single positive symptom factor. Together these findings support suggestions to combine sub-delusional symptoms into a single symptom category for classification purposes, in efforts to reduce clinical heterogeneity and ease measurement burden.

An opportunity has opened for research into primary prevention of psychotic disorders, based on progress in endophenotypes, genetics, and genomics. Primary prevention requires reliable prediction of susceptibility before any symptoms are present. We studied a battery of measures where published data supports abnormalities of these measurements prior to appearance of initial psychosis symptoms. These neurobiological and behavioral measurements included cognition, eye movement tracking, Event Related Potentials, and polygenic risk scores. They generated an acceptably precise separation of healthy controls from outpatients with a psychotic disorder. Methods: The Bipolar and Schizophrenia Network on Intermediate Phenotypes (B-SNIP) measured this battery in an ancestry-diverse series of consecutively recruited adult outpatients with a psychotic disorder and healthy controls. Participants include all genders, 16 to 50 years of age, 261 with psychotic disorders (Schizophrenia (SZ) 109, Bipolar with psychosis (BPP) 92, Schizoaffective disorder (SAD) 60), 110 healthy controls. Logistic Regression, and an extension of the Linear Mixed Model to include analysis of pairwise interactions between measures (Environmental kernel Relationship Matrices (ERM)) with multiple iterations, were performed to predict case-control status. Each regression analysis was validated with four-fold cross-validation. Results and conclusions: Sensitivity, specificity, and Area Under the Curve of Receiver Operating Characteristic of 85%, 62%, and 86%, respectively, were obtained for both analytic methods. These prediction metrics demonstrate a promising diagnostic distinction based on premorbid risk variables. There were also statistically significant pairwise interactions between measures in the ERM model. The strong prediction metrics of both types of analytic model provide proof-of-principle for biologically-based laboratory tests as a first step toward primary prevention studies. Prospective studies of adolescents at elevated risk, vs. healthy adolescent controls, would be a next step toward development of primary prevention strategies. Refereed/Peer-reviewed

An increase in invasive meningococcal disease (IMD) incidence was observed in Tuscany in 2015/2016, mainly due to hypervirulent clonal complex (cc) 11 strains. In a post-hoc analysis, we assessed b...

Objective To determine the knowledge base of common laboratory practices related to preanalytical phase of laboratory testing among medical interns and first-year postgraduate residents in a tertiary care hospital medical college. Materials and methods Questionnaire-based survey on preanalytical phase of laboratory testing was conducted among 208 participants, who volunteered and were MBBS interns and first-year postgraduate residents in a medical college, over the period from June 2018 to December 2019. A total of 15-item, multiple-choice questions (MCQs) were included, of which four were opinion-based and not considered for analysis. Responses were further categorized based on percentages with correct response, so we could identify specific knowledge points which need training. Statistical analysis Results were analyzed using Microsoft Excel functions and a simple calculator. Results A total of 208 participants were included in the study, which consisted of an equal number of interns (104) and first-year postgraduate residents (104). The term “preanalytical error” was known to 62.5% of participants. Only 9.62% participants took formal training in phlebotomy. Topics related to questions like coagulation testing, ideal fasting duration, mixing of blood, and order of draw received less than 40% correct response which meant that it requires more training. Conclusions In this era of evidence-based medicine, central laboratory plays a pivotal role in patient management, and quality of laboratory results are of paramount importance. Over a period of time, automation technology has reduced analytical phase errors to the minimum. Most errors reported are part of the preanalytical phase, and it has been found that a majority of them are committed due to a lack of knowledge and skills. In order to improve the preanalytical phase and make it as error-free as possible, the staff (technicians, nurses, and trainee doctors) should be constantly motivated and trained.

Elevations in peripheral inflammatory markers have been reported in patients with psychosis. Whether this represents an inflammatory process defined by individual or subgroups of markers is unclear. Further, relationships between peripheral inflammatory marker elevations and brain structure, cognition, and clinical features of psychosis remain unclear. We hypothesized that a pattern of plasma inflammatory markers, and an inflammatory subtype established from this pattern, would be elevated across the psychosis spectrum and associated with cognition and brain structural alterations. Clinically stable psychosis probands (Schizophrenia spectrum, n = 79; Psychotic Bipolar disorder, n = 61) and matched healthy controls (HC, n = 60) were assessed for 15 peripheral inflammatory markers, cortical thickness, subcortical volume, cognition, and symptoms. A combination of unsupervised exploratory factor analysis and hierarchical clustering was used to identify inflammation subtypes. Levels of IL6, TNFα, VEGF, and CRP were significantly higher in psychosis probands compared to HCs, and there were marker-specific differences when comparing diagnostic groups. Individual and/or inflammatory marker patterns were associated with neuroimaging, cognition, and symptom measures. A higher inflammation subgroup was defined by elevations in a group of 7 markers in 36% of Probands and 20% of HCs. Probands in the elevated inflammatory marker group performed significantly worse on cognitive measures of visuo-spatial working memory and response inhibition, displayed elevated hippocampal, amygdala, putamen and thalamus volumes, and evidence of gray matter thickening compared to the proband group with low inflammatory marker levels. These findings specify the nature of peripheral inflammatory marker alterations in psychotic disorders and establish clinical, neurocognitive and neuroanatomic associations with increased inflammatory activation in psychosis. The identification of a specific subgroup of patients with inflammatory alteration provides a potential means for targeting treatment with anti-inflammatory medications.

Background Deficits in inhibitory control on a Stop Signal Task (SST) were previously observed to be of similar magnitude across schizophrenia, schizoaffective, and bipolar disorder with psychosis, despite variation in general cognitive ability. Understanding different patterns of performance on the SST may elucidate different pathways to the impaired inhibitory control each group displayed. Comparing nonpsychotic bipolar disorder to the psychosis groups on SST may also expand our understanding of the shared neurobiology of this illness spectrum. Methods We tested schizophrenia (n = 220), schizoaffective (n = 216), bipolar disorder with (n = 192) and without psychosis (n = 67), and 280 healthy comparison participants with a SST and the Brief Assessment of Cognition in Schizophrenia (BACS), a measure of general cognitive ability. Results All patient groups had a similar degree of impaired inhibitory control over prepotent responses. However, bipolar groups differed from schizophrenia and schizoaffective groups in showing speeded responses and inhibition errors that were not accounted for by general cognitive ability. Schizophrenia and schizoaffective groups had a broader set of deficits on inhibition and greater general cognitive deficit, which fully accounted for the inhibition deficits. No differences were found between the clinically well-matched bipolar with and without psychosis groups, including for inhibitory control or general cognitive ability. Conclusions We conclude that 1) while impaired inhibitory control on a SST is of similar magnitude across the schizo-bipolar spectrum, including nonpsychotic bipolar, different mechanisms may underlie the impairments, and 2) history of psychosis in bipolar disorder does not differentially impact inhibitory behavioral control or general cognitive abilities.

Primary mitochondrial diseases represent some of the most common and severe inherited metabolic disorders, affecting ~1 in 4,300 live births. The clinical and molecular diversity typified by mitochondrial diseases has contributed to the lack of licensed disease‐modifying therapies available. Management for the majority of patients is primarily supportive. The failure of clinical trials in mitochondrial diseases partly relates to the inefficacy of the compounds studied. However, it is also likely to be a consequence of the significant challenges faced by clinicians and researchers when designing trials for these disorders, which have historically been hampered by a lack of natural history data, biomarkers and outcome measures to detect a treatment effect. Encouragingly, over the past decade there have been significant advances in therapy development for mitochondrial diseases, with many small molecules now transitioning from preclinical to early phase human interventional studies. In this review, we present the treatments and management strategies currently available to people with mitochondrial disease. We evaluate the challenges and potential solutions to trial design and highlight the emerging pharmacological and genetic strategies that are moving from the laboratory to clinical trials for this group of disorders.

BACKGROUND Neurovascular abnormalities are relevant to the pathophysiology of bipolar disorder (BD), which can be assessed using cerebral blood flow (CBF) imaging. CBF alterations have been identified in BD, but studies to date have been small and inconclusive. We aimed to determine cortical gray matter CBF (GM-CBF) differences between BD and healthy controls (HC) and to identify relationships between CBF and clinical or cognitive measures. METHODS Cortical GM-CBF maps were generated using Pseudo-Continuous Arterial Spin Labeling (pCASL) for 109 participants (BD, n = 61; HC, n = 48). We used SnPM13 to perform non-parametric voxel-wise two-sample t-tests comparing CBF between groups. We performed multiple linear regression to relate GM-CBF with clinical and cognitive measures. Analysis was adjusted for multiple comparisons with 10,000 permutations. Significance was set at a voxel level threshold of P

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) has rapidly spread across the world including India. Management of patients complicated with neurological illness requiring neurocritical care is challenging during this time. Patients with neurological disease may develop COVID-19 infection or there could be independent neurological manifestations of COVID-19. Critically ill neurological patients are more vulnerable to contracting SARS-CoV-2 infection. Also, neurological patients with comorbidities and multisystem involvement are at increased risk of adverse outcomes. Though SARS-CoV-2 predominantly affects the pulmonary system, it can complicate the assessment and management of neurological patients. With increasing COVID-19 numbers, the hospitalizations of both non-COVID and COVID-19 neurological patients will bring significant strain on the hospital and neurocritical care facilities. Streamlining work pattern, understanding the pathophysiology of COVID-19 and its impact on neurological function, establishing general and specific neurocritical care management strategies, ensuring protection and well-being of health care providers, and implementing effective infection control policies are key elements of efficient neurocritical care management during this pandemic. This joint position statement and advisory on the practice of neurocritical care during the COVID-19 pandemic by the Neurocritical Care Society of India and the Indian Society of Neuroanaesthesiology and Critical Care has been developed to guide clinicians providing care to the critically ill neurological patients in the neurocritical care unit during the current pandemic. As the situation from this novel disease is rapidly evolving, readers must constantly update themselves with newly emerging evidence to provide the best possible care to the critically ill neurological patients.

BACKGROUND: Comparing the course of antipsychotic-naïve psychosis in low- and middle-income countries (LMIC) may help to illuminate core pathophysiologies associated with this condition. Previous reviews-primarily from high-income countries (HIC)-identified cognitive deficits in antipsychotic-naïve, first-episode psychosis, but did not examine whether individuals with psychosis with longer duration of untreated psychosis (DUP > 5 years) were included, nor whether LMIC were broadly represented. METHOD: A comprehensive search of PUBMED from January 2002-August 2018 identified 36 studies that compared cognitive functioning in antipsychotic-naïve individuals with psychosis (IWP) and healthy controls, 20 from HIC and 16 from LMIC. RESULTS: A key gap was identified in that LMIC study samples were primarily shorter DUP (

Objectives To describe neurological manifestations in children with Influenza A (H1N1). Methods This retrospective study was conducted in the Pediatric intensive care unit (PICU) and Pediatric Neurology unit of a tertiary care teaching hospital in North India involving children with PCR confirmed Influenza A (H1N1) with neurological manifestations during 2019 outbreak. Results Six children (5 females, 1 male) were enrolled. All presented with neurological symptoms (seizures and altered sensorium) accompanied with fever and respiratory symptoms with duration of illness of 2–7 d. The admission Glasgow Coma Scale ranged from 4 to 12. Only 2 cases showed cerebrospinal fluid pleocytosis. Neuroimaging was suggestive of diffuse cerebral edema, acute necrotizing encephalopathy of childhood, and acute disseminated encephalomyelitis. All were treated with Oseltamivir. Four cases had clinical features of raised intracranial pressure (ICP) and were managed in PICU, 3 of them needed mechanical ventilation, 3 needed vasoactive drugs, 3 received 3% saline infusion, 1 underwent invasive ICP monitoring, and 3 (cases 4, 5 and 6) received intravenous methylprednisolone (30 mg/kg) for 5 d. Total duration of hospital stay was 10–30 d. Case 2 expired due to refractory raised ICP. Among survivors, 3 children had residual neurological deficits and the remaining 2 had achieved premorbid condition. Conclusions Influenza A (H1N1) can present with isolated or predominant neurological manifestations which can contribute to poor outcome. The authors suggest to rule out H1N1 in any child who presents with unexplained neurological manifestations during seasonal outbreaks of H1N1.

Digital phenotyping has potential to quantify the lived experience of mental illness and generate real-time, actionable results related to recovery, such as the case of social rhythms in individuals with bipolar disorder. However, passive data features for social rhythm clinical targets in individuals with schizophrenia have yet to be studied. In this paper, we explore the relationship between active and passive data by focusing on temporal stability and variance at an individual level as well as large-scale associations on a population level to gain clinically actionable information regarding social rhythms. From individual data clustering, we found a 19% cluster overlap between specific active and passive data features for participants with schizophrenia. In the same clinical population, two passive data features in particular associated with social rhythms, “Circadian Routine” and “Weekend Day Routine,” and were negatively associated with symptoms of anxiety, depression, psychosis, and poor sleep (Spearman ρ ranged from −0.23 to −0.30, p p

BACKGROUND: There is limited data on cerebrospinal fluid (CSF) biomarkers in sporadic amyloid-β (Aβ) cerebral amyloid angiopathy (CAA). OBJECTIVE: To determine the profile of biomarkers relevant to neurodegenerative disease in the CSF of patients with CAA. METHODS: We performed a detailed comparison of CSF markers, comparing patients with CAA, Alzheimer’s disease (AD), and control (CS) participants, recruited from the Biomarkers and Outcomes in CAA (BOCAA) study, and a Specialist Cognitive Disorders Service. RESULTS: We included 10 CAA, 20 AD, and 10 CS participants (mean age 68.6, 62.5, and 62.2 years, respectively). In unadjusted analyses, CAA patients had a distinctive CSF biomarker profile, with significantly lower (p

The brain mechanisms underlying the association of hyperglycemia with depressive symptoms are unknown. We hypothesized that disrupted glutamate metabolism in pregenual anterior cingulate cortex (ACC) in type 1 diabetes (T1D) without depression affects emotional processing. Using proton MRS, we measured glutamate concentrations in ACC and occipital lobe cortex (OCC) in 13 subjects with T1D without major depression (HbA1c 7.1 ± 0.7% [54 ± 7 mmol/mol]) and 11 healthy control subjects without diabetes (HbA1c 5.5 ± 0.2% [37 ± 3 mmol/mol]) during fasting euglycemia followed by a 60-min +5.5 mmol/L hyperglycemic clamp (HG). Intrinsic neuronal activity was assessed using resting-state blood oxygen level–dependent functional MRI to measure the fractional amplitude of low-frequency fluctuations in slow-4 band (fALFF4). Emotional processing and depressive symptoms were assessed using emotional tasks (emotional Stroop task, self-referent encoding task [SRET]) and clinical ratings (Hamilton Depression Rating Scale [HAM-D], Symptom Checklist-90 Revised [SCL-90-R]), respectively. During HG, ACC glutamate increased (1.2 mmol/kg, 10% P = 0.014) while ACC fALFF4 was unchanged (−0.007, −2%, P = 0.449) in the T1D group; in contrast, glutamate was unchanged (−0.2 mmol/kg, −2%, P = 0.578) while fALFF4 decreased (−0.05, −13%, P = 0.002) in the control group. OCC glutamate and fALFF4 were unchanged in both groups. T1D had longer SRET negative word response times (P = 0.017) and higher depression rating scores (HAM-D P = 0.020, SCL-90-R depression P = 0.008). Higher glutamate change tended to associate with longer emotional Stroop response times in T1D only. Brain glutamate must be tightly controlled during hyperglycemia because of the risk for neurotoxicity with excessive levels. Results suggest that ACC glutamate control mechanisms are disrupted in T1D, which affects glutamatergic neurotransmission related to emotional or cognitive processing. Increased prefrontal glutamate during acute hyperglycemic episodes could explain our previous findings of associations among chronic hyperglycemia, cortical thinning, and depressive symptoms in T1D.

The treatment of negative symptoms (NS) in psychosis represents an urgent unmet medical need given the significant functional impairment it contributes to psychosis syndromes. The lack of progress in treating NS is impacted by the lack of known pathophysiology or associated quantitative biomarkers, which could provide tools for research. This current analysis investigated potential associations between NS and an extensive battery of behavioral and brain-based biomarkers in 932 psychosis probands from the B-SNIP database. The current analyses examined associations between PANSS-defined NS and (1) cognition, (2) pro-/anti-saccades, (3) evoked and resting-state electroencephalography (EEG), (4) resting-state fMRI, and (5) tractography. Canonical correlation analyses yielded symptom-biomarker constructs separately for each biomarker modality. Biomarker modalities were integrated using canonical discriminant analysis to summarize the symptom-biomarker relationships into a “biomarker signature” for NS. Finally, distinct biomarker profiles for 2 NS domains (“diminished expression” vs “avolition/apathy”) were computed using step-wise linear regression. NS were associated with cognitive impairment, diminished EEG response amplitudes, deviant resting-state activity, and oculomotor abnormalities. While a connection between NS and poor cognition has been established, association to neurophysiology is novel, suggesting directions for future mechanistic studies. Each biomarker modality was related to NS in distinct and complex ways, giving NS a rich, interconnected fingerprint and suggesting that any one biomarker modality may not adequately capture the full spectrum of symptomology.

BACKGROUND: Latency of the acoustic startle reflex is the time from presentation of the startling stimulus until the response and provides an index of neural processing speed. Latency is prolonged in schizophrenia, is 90% heritable, and predicts conversion to schizophrenia in a high-risk population. The Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) consortium investigates neurobiological features found in psychotic disorders spanning diagnostic criteria for schizophrenia (SCZ), schizoaffective disorder (SAD), and psychotic bipolar disorder (BP). We investigated whether differences in startle latency and prepulse inhibition (PPI) occur in probands, their first-degree relatives, and neurobiologically defined subgroups of the probands (Biotypes). METHODS: 1143 subjects were included from the B-SNIP cohort: 143 with SCZ, 178 SCZ relatives (SCZ-Fam), 123 with SAD, 152 SAD relatives (SAD-Fam), 138 BP, 183 BP relatives (BP-Fam), and 226 controls (CON). A Biopac system recorded the eyeblink component of the startle reflex during startle testing. RESULTS: Latency differed by diagnosis (F(3,620)=5.10, p=0.002): SCZ, SAD, and BP probands had slower latency than CON, with relatives intermediate. Biotypes 1 and 2 had slower latency than CON (p

Background Recently, a biologically-driven psychosis classification (B-SNIP Biotypes) was derived using brain-based cognitive and electrophysiological markers. Here, we characterized a local functional-connectivity measure, regional homogeneity (ReHo), as a biomarker across Biotypes and conventional DSM diagnoses. Methods Whole-brain ReHo measures of resting-state functional MRI were examined in psychosis patients and healthy controls organized by Biotype and by DSM-IV-TR diagnosis (n = 737). Group-level ANOVA and individual-level prediction models using support vector machines (SVM) were employed to evaluate the discriminative characteristics in comparisons of 1) DSM diagnostic groups, 2) Biotypes, to controls, and 3) within-proband subgroups with each other. Results Probands grouped by Biotype versus controls showed a unique abnormality pattern: Biotype-1 displayed bidirectional ReHo differences in more widespread areas, with higher ReHo in para-hippocampus, fusiform, inferior temporal, cerebellum, thalamus and caudate, plus lower ReHo in the postcentral gyrus, middle temporal, cuneus, and middle occipital cortex; Biotype-2 and Biotype-3 showed lesser and unidirectional ReHo changes. Among diagnostic groups, only schizophrenia showed higher ReHo versus control values in the inferior/middle temporal area and fusiform gyrus. For within-patient comparisons, Biotype-1 showed characteristic ReHo when compared to Biotype-2 and Biotype-3. SVM results more accurately identified Biotypes than DSM diagnoses. Conclusion We characterized patterns of ReHo abnormalities across both Biotypes and DSM sub-groups. Both group-level statistical and machine-learning methods were more sensitive in capturing ReHo deficits in Biotypes than DSM. Overall ReHo is a robust psychosis biomarker.

BackgroundOnly 30% or fewer of individuals at clinical high risk (CHR) convert to full psychosis within 2 years. Efforts are thus underway to refine risk identification strategies to increase their predictive power. Our objective was to develop and validate the predictive accuracy and individualized risk components of a mobile app-based psychosis risk calculator (RC) in a CHR sample from the SHARP (ShangHai At Risk for Psychosis) program.MethodIn total, 400 CHR individuals were identified by the Chinese version of the Structured Interview for Prodromal Syndromes. In the first phase of 300 CHR individuals, 196 subjects (65.3%) who completed neurocognitive assessments and had at least a 2-year follow-up assessment were included in the construction of an RC for psychosis. In the second phase of the SHARP sample of 100 subjects, 93 with data integrity were included to validate the performance of the SHARP-RC.ResultsThe SHARP-RC showed good discrimination of subsequent transition to psychosis with an AUC of 0.78 (p < 0.001). The individualized risk generated by the SHARP-RC provided a solid estimation of conversion in the independent validation sample, with an AUC of 0.80 (p = 0.003). A risk estimate of 20% or higher had excellent sensitivity (84%) and moderate specificity (63%) for the prediction of psychosis. The relative contribution of individual risk components can be simultaneously generated. The mobile app-based SHARP-RC was developed as a convenient tool for individualized psychosis risk appraisal.ConclusionsThe SHARP-RC provides a practical tool not only for assessing the probability that an individual at CHR will develop full psychosis, but also personal risk components that might be targeted in early intervention.

Abnormal neuroanatomic brain networks have been reported in schizophrenia, but their characterization across patients with psychotic disorders, and their potential alterations in nonpsychotic relatives, remain to be clarified. Participants recruited by the Bipolar and Schizophrenia Network for Intermediate Phenotypes consortium included 326 probands with psychotic disorders (107 with schizophrenia (SZ), 87 with schizoaffective disorder (SAD), 132 with psychotic bipolar disorder (BD)), 315 of their nonpsychotic first-degree relatives and 202 healthy controls. Single-subject gray matter graphs were extracted from structural MRI scans, and whole-brain neuroanatomic organization was compared across the participant groups. Compared with healthy controls, psychotic probands showed decreased nodal efficiency mainly in bilateral superior temporal regions. These regions had altered morphological relationships primarily with frontal lobe regions, and their network-level alterations were associated with positive symptoms of psychosis. Nonpsychotic relatives showed lower nodal centrality metrics in the prefrontal cortex and subcortical regions, and higher nodal centrality metrics in the left cingulate cortex and left thalamus. Diagnosis-specific analysis indicated that individuals with SZ had lower nodal efficiency in bilateral superior temporal regions than controls, probands with SAD only exhibited lower nodal efficiency in the left superior and middle temporal gyrus, and individuals with psychotic BD did not show significant differences from healthy controls. Our findings provide novel evidence of clinically relevant disruptions in the anatomic association of the superior temporal lobe with other regions of whole-brain networks in patients with psychotic disorders, but not in their unaffected relatives, suggesting that it is a disease-related trait. Network disorganization primarily involving frontal lobe and subcortical regions in nonpsychotic relatives may be related to familial illness risk.

ObjectiveTo investigate predictors of performance on a range of cognitive measures including the Preclinical Alzheimer Cognitive Composite (PACC) and test for associations between cognition and dementia biomarkers in Insight 46, a substudy of the Medical Research Council National Survey of Health and Development.MethodsA total of 502 individuals born in the same week in 1946 underwent cognitive assessment at age 69–71 years, including an adapted version of the PACC and a test of nonverbal reasoning. Performance was characterized with respect to sex, childhood cognitive ability, education, and socioeconomic position (SEP). In a subsample of 406 cognitively normal participants, associations were investigated between cognition and β-amyloid (Aβ) positivity (determined from Aβ-PET imaging), whole brain volumes, white matter hyperintensity volumes (WMHV), and APOE ε4.ResultsChildhood cognitive ability was strongly associated with cognitive scores including the PACC more than 60 years later, and there were independent effects of education and SEP. Sex differences were observed on every PACC subtest. In cognitively normal participants, Aβ positivity and WMHV were independently associated with lower PACC scores, and Aβ positivity was associated with poorer nonverbal reasoning. Aβ positivity and WMHV were not associated with sex, childhood cognitive ability, education, or SEP. Normative data for 339 cognitively normal Aβ-negative participants are provided.ConclusionsThis study adds to emerging evidence that subtle cognitive differences associated with Aβ deposition are detectable in older adults, at an age when dementia prevalence is very low. The independent associations of childhood cognitive ability, education, and SEP with cognitive performance at age 70 have implications for interpretation of cognitive data in later life.

Objectives We sought to evaluate whether dynamic Arterial Spin Labeling (dASL), a novel quantitative technique robust to artifacts and noise that especially arise in inferior brain regions, could characterize neural substrates of BD pathology and symptoms. Methods Forty-five subjects (19 BD patients, 26 controls) were imaged using a dASL sequence. Maps of average perfusion, perfusion fluctuation, and perfusion connectivity with anterior cingulate cortex (ACC) were derived. Patient symptoms were quantified along four symptom dimensions determined using factor analysis of the subjects from the Bipolar and Schizophrenia Network on Intermediate Phenotypes (BSNIP) study. Maps of the perfusion measures were compared between BD patients and controls and correlated with the symptom dimensions in the BD patients only by voxel-level and region-level analyses. Results BD patients exhibited (i) significantly increased perfusion fluctuations in the left fusiform and inferior temporal regions (P = .020, voxel-level corrected) and marginally increased perfusion fluctuations in the right temporal pole and inferior temporal regions (P = .063, cluster-level corrected), (ii) significantly increased perfusion connectivity between ACC and the occipitoparietal cortex (P = .050, cluster-level corrected). In BD patients, positive symptoms were negatively associated with ACC perfusion connectivity to the right orbitofrontal and superior frontal regions (P = .002, cluster-level corrected) and right orbitofrontal and inferior frontal regions (P = .023, cluster-level corrected). Conclusion The abnormal perfusion fluctuations and connectivity alterations may underlie the mood fluctuations and cognitive and emotional dysregulation that characterize BD.

A pre- post-chart audits of 50 asthmatics assessed provider documentation for asthma classification and treatment according to national guidelines. Once baseline electronic medical records (EMR) audit was conducted the healthcare providers and clinic staff received training on the use of asthma diagnosis and treatment national guidelines. A post-training EMR chart audit (3-months after the training) was conducted for a pre-post-training comparison.

BACKGROUND: Cognitive impairment is a core deficit across psychotic disorders, the causes and therapeutics of which remain unclear. Epidemiological observations have suggested associations between cognitive dysfunction in psychotic disorders and cardiovascular risk factors, but an underlying etiology has not been established. METHODS: Neuropsychological performance using the Brief Assessment of Cognition in Schizophrenia (BACS) was assessed in 616 individuals of European ancestry (403 psychosis, 213 controls). Polygenic risk scores for coronary artery disease (PRS(CAD)) were quantified for each participant across 13 p-value thresholds (P(T) 0.5-5e(−8)). Cardiovascular and psychotropic medications were categorized for association analyses. Each PRS(CAD) was examined in relation to the BACS and the optimized P(T) was confirmed with five-fold cross-validation and independent validation. Functional enrichment analyses were used to identify biological mechanisms linked to PRS(CAD)-cognition associations. Multiple regression analyses examined PRS(CAD) under the optimal P(T) and medication burden in relation to the BACS composite and subtest scores. RESULTS: Higher PRS(CAD) was associated with lower BACS composite scores (p=0.001) in the psychosis group, primarily driven by the Verbal Memory subtest (p

Although APOE e4 carriers are at substantially higher risk of developing Alzheimer’s disease than noncarriers1, controversial evidence suggests that APOE e4 might confer some advantages, explaining the survival of this gene (antagonistic pleiotropy)2,3. In a population-based cohort born in one week in 1946 (assessed aged 69–71 years), we assessed differential effects of APOE e4 and β-amyloid pathology (quantified using 18F-Florbetapir-PET) on visual working memory (object–location binding). In 398 cognitively normal participants, APOE e4 and β-amyloid had opposing effects on object identification, predicting better and poorer recall, respectively. e4 carriers also recalled locations more precisely, with a greater advantage at higher β-amyloid burden. These results provide evidence of superior visual working memory in e4 carriers, showing that some benefits of this genotype are demonstrable in older age, even in the preclinical stages of Alzheimer’s disease. In a sample of about 400 cognitively normal older adults, APOE e4 genotype and β-amyloid pathology predicted better and poorer visual working memory, respectively, suggesting some benefits of e4 in older age, even in the preclinical stages of Alzheimer’s disease.

The clinical high-risk period before a first episode of psychosis (CHR-P) has been widely studied with the goal of understanding the development of psychosis; however, less attention has been paid to the 75%–80% of CHR-P individuals who do not transition to psychosis. It is an open question whether multivariable models could be developed to predict remission outcomes at the same level of performance and generalizability as those that predict conversion to psychosis. Participants were drawn from the North American Prodrome Longitudinal Study (NAPLS3). An empirically derived set of clinical and demographic predictor variables were selected with elastic net regularization and were included in a gradient boosting machine algorithm to predict prodromal symptom remission. The predictive model was tested in a comparably sized independent sample (NAPLS2). The classification algorithm developed in NAPLS3 achieved an area under the curve of 0.66 (0.60–0.72) with a sensitivity of 0.68 and specificity of 0.53 when tested in an independent external sample (NAPLS2). Overall, future remitters had lower baseline prodromal symptoms than nonremitters. This study is the first to use a data-driven machine-learning approach to assess clinical and demographic predictors of symptomatic remission in individuals who do not convert to psychosis. The predictive power of the models in this study suggest that remission represents a unique clinical phenomenon. Further study is warranted to best understand factors contributing to resilience and recovery from the CHR-P state.

Introduction Disturbed sleep is a common feature of psychotic disorders that is also present in the clinical high risk (CHR) state. Evidence suggests a potential role of sleep disturbance in symptom progression, yet the interrelationship between sleep and CHR symptoms remains to be determined. To address this knowledge gap, we examined the association between disturbed sleep and CHR symptoms over time. Methods Data were obtained from the North American Prodrome Longitudinal Study (NAPLS)-3 consortium, including 688 CHR individuals and 94 controls (mean age 18.25, 46% female) for whom sleep was tracked prospectively for 8 months. We used Cox regression analyses to investigate whether sleep disturbances predicted conversion to psychosis up to >2 years later. With regressions and cross-lagged panel models, we analyzed longitudinal and bidirectional associations between sleep (the Pittsburgh Sleep Quality Index in conjunction with additional sleep items) and CHR symptoms. We also investigated the independent contribution of individual sleep characteristics on CHR symptom domains separately and explored whether cognitive impairments, stress, depression, and psychotropic medication affected the associations. Results Disturbed sleep at baseline did not predict conversion to psychosis. However, sleep disturbance was strongly correlated with heightened CHR symptoms over time. Depression accounted for half of the association between sleep and symptoms. Importantly, sleep was a significant predictor of CHR symptoms but not vice versa, although bidirectional effect sizes were similar. Discussion The critical role of sleep disturbance in CHR symptom changes suggests that sleep may be a promising intervention target to moderate outcome in the CHR state.

As the COVID-19 pandemic has largely increased the utilization of telehealth, mobile mental health technologies – such as smartphone apps, vir­tual reality, chatbots, and social media – have also gained attention. These digital health technologies offer the potential of accessible and scalable interventions that can augment traditional care. In this paper, we provide a comprehensive update on the overall field of digital psychiatry, covering three areas. First, we outline the relevance of recent technological advances to mental health research and care, by detailing how smartphones, social media, artificial intelligence and virtual reality present new opportunities for “digital phenotyping” and remote intervention. Second, we review the current evidence for the use of these new technological approaches across different mental health contexts, covering their emerging efficacy in self-management of psychological well-being and early intervention, along with more nascent research supporting their use in clinical management of long-term psychiatric conditions – including major depression; anxiety, bipolar and psychotic disorders; and eating and substance use disorders – as well as in child and adolescent mental health care. Third, we discuss the most pressing challenges and opportunities towards real-world implementation, using the Integrated Promoting Action on Research Implementation in Health Services (i-PARIHS) framework to explain how the innovations themselves, the recipients of these innovations, and the context surrounding innovations all must be considered to facilitate their adoption and use in mental health care systems. We conclude that the new technological capabilities of smartphones, artificial intelligence, social media and virtual reality are already changing mental health care in unforeseen and exciting ways, each accompanied by an early but promising evidence base. We point out that further efforts towards strengthening implementation are needed, and detail the key issues at the patient, provider and policy levels which must now be addressed for digital health technologies to truly improve mental health research and treatment in the future.

Acknowledgements : This work was supported by the Portuguese Foundation for Science and Technology (FCT) through Strategic Project UID/MAR/04292/2019 granted to MARE – Marine and Environmental Sciences Centre and grant 2020.09455.BD awarded to Joao ˜ Reboleira. Work was also supported by VALORMAR (Mobilizing R&TD Programs, Portugal 2020) co-funded by COMPETE (POCI-01-0247-FEDER-024517), projects MACAU (MAR04.03.01-FEAMP-0128) and COSMOS (MAR2020-P04M03-1445P) funded by PO MAR2020, Portugal2020, and the European Union through the European Fund for Maritime Affairs and Fisheries (FEAMP), the Integrated Programme of SR&TD “Smart Valorisation of Endogenous Marine Biological Resources Under a Changing Climate” (reference Centro-01-0145-FEDER-000018), co-funded by Centro 2020 program, Portugal 2020, the European Union through the European Regional Development Fund (FEDER), and project ORCHESTRA (POCI-01-0247-FEDER-070155), funded by FEDER, FCT and Portugal 2020 through COMPETE 2020. Background: Seaweeds are promising substrates for biotransformation via fermentation, something that has been primarily utilized by the field of biofuels but focused less attention from other fields of research. Considering that the fermentation of abundant land resources has become an important means by which new added-value compounds can be obtained, exploring the same process for seaweeds can contribute to an effective and sustainable exploitation of marine resources. Scope and approach: In this review, recent advances demonstrating the potential behind the fermentation of seaweeds are evaluated. A breakdown of the most relevant seaweed compounds and their effect on potential bioprocesses is presented, along with pre-processing techniques that have become popular in biofuel fermentations. The applications of seaweed fermentation products in the fields of natural product research, functional foods and nutraceuticals, as well as the limitations and opportunities of seaweed fermentation are also highlighted. Key findings and conclusions: Research revealing that seaweed fermentation can be used to create novel food and nutraceutical products that demonstrate high bioactivity and sensory quality was presented. The studies included demonstrate the use of this process in algal tissues and extracts as an enhancer of antioxidant, antimicrobial, antiinflammatory and antidiabetic activities, among others. Many of the difficulties related to fermenting seaweed have been addressed by research within the field of biofuels, providing insight on the conditions and pretreatments necessary to improve seaweed fermentability. Food applications for seaweed fermentation products are still underdeveloped, but the nutritional, sensory and bioactive profiles collected so far highly encourage further developments. info:eu-repo/semantics/publishedVersion

Objective Brain-based Biotypes for psychotic disorders have been developed as part of the B-SNIP consortium to create neurobiologically distinct subgroups within idiopathic psychosis, independent from traditional phenomenological diagnostic methods. In the current study, we aimed to validate the Biotype model by assessing differences in volume and shape of the amygdala and hippocampus contrasting traditional clinical diagnoses with Biotype classification. Methods A total of 811 participants from 6 sites were included: probands with schizophrenia (n = 199), schizoaffective disorder (n = 122), psychotic bipolar disorder with psychosis (n = 160), and healthy controls (n = 330). Biotype classification, previously developed using cognitive and electrophysiological data and K-means clustering, was used to categorize psychosis probands into 3 Biotypes, with Biotype-1 (B-1) showing reduced neural salience and severe cognitive impairment. MAGeT-Brain segmentation was used to determine amygdala and hippocampal volumetric data and shape deformations. Results When using Biotype classification, B-1 showed the strongest reductions in amygdala-hippocampal volume and the most widespread shape abnormalities. Using clinical diagnosis, probands with schizophrenia and schizoaffective disorder showed the most significant reductions of amygdala and hippocampal volumes and the most abnormal hippocampal shape compared with healthy controls. Biotype classification provided the strongest neuroanatomical differences compared with conventional DSM diagnoses, with the best discrimination seen using bilateral amygdala and right hippocampal volumes in B-1. Conclusion These findings characterize amygdala and hippocampal volumetric and shape abnormalities across the psychosis spectrum. Grouping individuals by Biotype showed greater between-group discrimination, suggesting a promising approach and a favorable target for characterizing biological heterogeneity across the psychosis spectrum.

We aimed to systematically synthesize and quantify the utility of pre-treatment resting-state functional magnetic resonance imaging (rs-fMRI) in predicting antipsychotic response in schizophrenia. We searched the PubMed/MEDLINE database for studies that examined the magnitude of association between baseline rs-fMRI assessment and subsequent response to antipsychotic treatment in persons with schizophrenia. We also performed meta-analyses for quantifying the magnitude and accuracy of predicting response defined continuously and categorically. Data from 22 datasets examining 1280 individuals identified striatal and default mode network functional segregation and integration metrics as consistent determinants of treatment response. The pooled correlation coefficient for predicting improvement in total symptoms measured continuously was ~0.47 (12 datasets; 95% CI: 0.35 to 0.59). The pooled odds ratio of predicting categorically defined treatment response was 12.66 (nine datasets; 95% CI: 7.91-20.29), with 81% sensitivity and 76% specificity. rs-fMRI holds promise as a predictive biomarker of antipsychotic treatment response in schizophrenia. Future efforts need to focus on refining feature characterization to improve prediction accuracy, validate prediction models, and evaluate their implementation in clinical practice.

Background In view of reported associations between high adiposity, particularly in midlife and late-life dementia risk, we aimed to determine associations between body mass index (BMI), and BMI changes across adulthood and brain structure and pathology at age 69–71 years. Methods Four hundred sixty-five dementia-free participants from Insight 46, a sub-study of the British 1946 birth cohort, who had cross-sectional T1/FLAIR volumetric MRI, and florbetapir amyloid-PET imaging at age 69–71 years, were included in analyses. We quantified white matter hyperintensity volume (WMHV) using T1 and FLAIR 3D-MRI; β-amyloid (Aβ) positivity/negativity using a SUVR approach; and whole brain (WBV) and hippocampal volumes (HV) using 3D T1-MRI. We investigated the influence of BMI, and BMI changes at and between 36, 43, 53, 60–64, 69 and 71 years, on late-life WMHV, Aβ-status, WBV and mean HV. Analyses were repeated using overweight and obese status. Results At no time-point was BMI, change in BMI or overweight/obese status associated with WMHV or WBV at age 69–71 years. Decreasing BMI in the 1–2 years before imaging was associated with an increased odds of being β-amyloid positive (OR 1.45, 95% confidence interval 1.09, 1.92). There were associations between being overweight and larger mean HV at ages 60–64 (β = 0.073 ml, 95% CI 0.009, 0.137), 69 (β = 0.076 ml, 95% CI 0.012, 0.140) and 71 years (β = 0.101 ml, 95% CI 0.037, 0.165). A similar, albeit weaker, trend was seen with obese status. Conclusions Using WMHV, β-amyloid status and brain volumes as indicators of brain health, we do not find evidence to explain reported associations between midlife obesity and late-life dementia risk. Declining BMI in later life may reflect preclinical Alzheimer’s disease.

Key Points Question Are clinical and demographic factors associated with brain glutamate or glutamate plus glutamine (Glx) levels in schizophrenia? Findings In this mega-analysis of 1251 patients with schizophrenia and 1197 healthy volunteers, medial frontal cortex glutamatergic metabolite levels were lower in patients and negatively associated with the dose of antipsychotic medication, although a reduction in glutamate levels with age was not accelerated in patients with schizophrenia compared with healthy individuals. Higher medial frontal cortex and medial temporal lobe glutamate levels were associated with more severe symptoms in patients with schizophrenia. Meaning Lower brain glutamate levels may be associated with antipsychotic exposure rather than with greater age-related decline, whereas higher glutamate levels may serve as a biomarker of illness severity in patients with schizophrenia., Importance Proton magnetic resonance spectroscopy (1H-MRS) studies indicate that altered brain glutamatergic function may be associated with the pathophysiology of schizophrenia and the response to antipsychotic treatment. However, the association of altered glutamatergic function with clinical and demographic factors is unclear. Objective To assess the associations of age, symptom severity, level of functioning, and antipsychotic treatment with brain glutamatergic metabolites. Data Sources The MEDLINE database was searched to identify journal articles published between January 1, 1980, and June 3, 2020, using the following search terms: MRS or magnetic resonance spectroscopy and (1) schizophrenia or (2) psychosis or (3) UHR or (4) ARMS or (5) ultra-high risk or (6) clinical high risk or (7) genetic high risk or (8) prodrome* or (9) schizoaffective. Authors of 114 1H-MRS studies measuring glutamate (Glu) levels in patients with schizophrenia were contacted between January 2014 and June 2020 and asked to provide individual participant data. Study Selection In total, 45 1H-MRS studies contributed data. Data Extraction and Synthesis Associations of Glu, Glu plus glutamine (Glx), or total creatine plus phosphocreatine levels with age, antipsychotic medication dose, symptom severity, and functioning were assessed using linear mixed models, with study as a random factor. Main Outcomes and Measures Glu, Glx, and Cr values in the medial frontal cortex (MFC) and medial temporal lobe (MTL). Results In total, 42 studies were included, with data for 1251 patients with schizophrenia (mean [SD] age, 30.3 [10.4] years) and 1197 healthy volunteers (mean [SD] age, 27.5 [8.8] years). The MFC Glu (F1,1211.9 = 4.311, P = .04) and Glx (F1,1079.2 = 5.287, P = .02) levels were lower in patients than in healthy volunteers, and although creatine levels appeared lower in patients, the difference was not significant (F1,1395.9 = 3.622, P = .06). In both patients and volunteers, the MFC Glu level was negatively associated with age (Glu to Cr ratio, F1,1522.4 = 47.533, P, This mega-analysis assesses whether age, symptom severity, level of functioning, and antipsychotic treatment are associated with glutamate or glutamatergic metabolite levels measured with proton magnetic resonance spectroscopy in the medial frontal cortex or medial temporal lobe of patients with schizophrenia.

Background Vaccination strategies against bacterial meningitis vary across countries. In the United States, a single dose of quadrivalent meningococcal conjugate vaccine (MenACWY) is recommended at 11–12 years of age, with a booster dose approximately 5 years later. We assessed immune responses to a booster dose of MenACWY-CRM vaccine after priming with MenACWY-CRM or MenACWY-D vaccines in adolescents and adults. Methods In this phase IIIb, multicenter, open-label study, healthy 15–55-year-olds, who received MenACWY-CRM (N = 301) or MenACWY-D (N = 300) 4–6 years earlier or were meningococcal vaccine-naive (N = 100), received one MenACWY-CRM vaccine dose. Immunogenicity was evaluated pre-vaccination, 3 or 5 days post-vaccination (sampling subgroups), and 28 days post-vaccination by serum bactericidal activity assay using human complement (hSBA). After vaccination, participants were monitored for 7 days for reactogenicity, 29 days for unsolicited adverse events (AEs), and 181 days for serious AEs and medically-attended AEs. Results Sufficiency of the immune response to a MenACWY-CRM booster dose was demonstrated; the lower limit of the 1-sided 97.5% confidence interval for percentages of participants with hSBA seroresponse at 28 days post-vaccination was >75% for each serogroup in those primed with either the MenACWY-CRM or MenACWY-D vaccine. Seroresponse was observed in ≥93.24% of primed participants and ≥35.87% of naive participants 28 days post-vaccination. At 5 days post-booster, among primed participants, hSBA titers ≥1:8 were achieved in ≥47.14% of participants for MenA and in ≥85.52% of participants for MenC, MenW and MenY, and 3.25- to 8.59-fold increases in hSBA geometric mean titers against each vaccine serogroup were observed. No safety concerns were raised throughout the 6-month follow-up period. Conclusions A booster dose of the MenACWY-CRM vaccine induced a robust and rapid anamnestic response in adolescents and adults, irrespectively of either MenACWY-CRM or MenACWY-D vaccine administered 4–6 years earlier, with an acceptable clinical safety profile. ClinicalTrials.gov registration: NCT02986854 .

BackgroundNeurological Examination Abnormalities (NES) are quantified by measuring subtle, partially localizable (cerebello-thalamo-prefrontal cortical circuit) and heritable neurological signs comprising sensory integration, motor coordination and complex motor sequencing that are associated with first-episode psychosis (FEP). A few studies have evaluated NES longitudinally and as a predictor for diagnostic and response classification, but these studies have been confounded, underpowered and divergent. We examined (1) baseline and longitudinal NES differences between diagnostic and year 1 response groups; (2) if NES predicts diagnostic and response groups and (3) relationships between clinical variables and NES measures in antipsychotic-naïve FEP.MethodsNES and clinical measures were obtained for FEP-schizophrenia (FEP-SZ,n= 232), FEP non-schizophrenia (FEP-NSZ,n= 117) and healthy controls (HC,n= 204). Response groups with >25% improvement in average year 1 positive and negative symptomatology scores were classified as responsive (n= 97) and n= 95). Analysis of covariance, NES trajectory analysis and logistic regression models assessed diagnostic and response group differences. Baseline and longitudinal NES relationships with clinical variables were performed with Spearman correlations. Data were adjusted for age, sex, race, socioeconomic status and handedness.ResultsCognitive perceptual (COGPER) score was better than repetitive motor (REPMOT) at differentiating FEP-SZ from FEP-NSZ and distinguishing responders from non-responders. We identified significant group-specific associations between COGPER and worse GAF, positive and negative symptomatology and some of these findings persisted at 1-year assessment.ConclusionNES are an easy to administer, bedside-elicited, endophenotypic measure and could be a cost-effective clinical tool in antipsychotic-naïve FEP.

Objective:The choroid plexus is an important physiological barrier and produces CSF and neurotrophic, angiogenic, and inflammatory factors involved in brain development. Choroid plexus abnormalitie...